Eduard Badarau

Frédéric Robert

Stéphane Massip

Florian Jakob

Simon Lucas

Sven Frormann

Léon Ghosez

Design and synthesis of spirocyclic ligands of glucorticoid receptors

Keywords: Spirocycles, Benzopyrazole, Glucocorticoids, Burgess reagent

Spirocyclic indazoles were designed as potential ligands for the glucocorticoid receptors (GRs). A short and efficient synthetic sequence was developed allowing the preparation of pure diastereomeric spirocyclic analogs of fluorocortivazol. Our studies also revealed a new application of Burgess reagent leading to a ring expansion. The structures and conformations of several key intermediates and products were confirmed by single crystal X-ray diffraction analysis. Conformational assignments were also supported by DFT calculations. As a proof of concept we tested the affinity of diastereomeric compounds 13b and 14b for the GRs. Rewardingly, it was found that 14b showed a promising IC50 of 27 nM.

Introduction

Glucocorticoids (GCs) belong to the most efficient agents currently used for the treatment of allergic and inflammatory diseases. Prednisolone, dexamethasone and fluorocortivazol are notable examples of this class of drugs. Unfortunately their immunosuppressive effects are often accompanied by side effects such as muscle atrophy, 1 steroid-induced osteoporosis, 2 diabetes mellitus 3 and hypertension. 4 We have recently initiated a research program aiming at developing new potential ligands for the glucocorticoid receptors (GRs). We started from the simplified analogues of fluorocortivazol (MK, Scheme 1) uncovered by Ali and coll. 5 which were developed as promising selective glucocorticoid receptor modulators (SEGRMs). 6 As originally demonstrated, the steroidal rings C and D of fluorocortivazol could be successfully replaced by lipophilic substituents at C11. The introduction of various side-chains R carrying aryl substituents led to the discovery of fluorocortivazol analogs with an IC50 in the low nM range for hGRs.

Starting from the MK ligand, we decided to explore a spirocyclic pattern resulting from disconnecting C7 from C7a and reconnecting C7 with the methyl group at C4a (Scheme 1, target structures). The replacement of steroidal fused-rings by a spiranic structure should increase the conformational freedom of the B-D rings with less entropy loss than with a simple alkyl tether. Several low-energy conformations could be available in solution thus offering more possibilities for a better interaction with the receptor.

--- Corresponding author. Tel.: +33 (5) 40 00 30 38; e-mail: l.ghosez@iecb.u-bordeaux.fr Scheme 1. Design of new potential spiro-corticoids

Synthesis

This initial study was intended to validate the synthetic access to this type of compounds and not to fully explore the structure-activity relationships generated by variation of substituents (R), or the size (n) of the spirocyclic ring (Scheme 1). From this perspective, it did not require an access to enantiopure compounds. The stereochemical challenge was thus limited to the generation of pure diastereomers. Since the conformational flexibility should increase with the size of the spirocyclic ring, we decided to prepare representative alcohols of the homologous 5-and 6-membered B-rings. These should be easily obtained by addition of an organometallic reagent to the corresponding 5-and 6-membered ring ketone (Scheme 2). Scheme 2. Retrosynthetic analysis

Synthesis of the spirodiketone intermediates

The preparation of the known spirodiketones 5a-b was inspired by literature precedents (Scheme 3). As already pointed out by Eaton and Jobe 7 the formylation of cyclopentanone was best effected with ethylformate in the presence of potassium hydride. For the higher homologs (n = 2) we found that the reaction proceeded smoothly in the presence of the cheaper but weaker base, sodium hydride. Compounds 1a-b were used without purification in the Michael addition to methyl vinyl ketone in the presence of catalytic amounts of DBU and triethylamine. 8 This classical sequence of reactions allowed the preparation of multigram quantities of 2a-b in good overall yields.

Surprisingly the spiroannulation step turned out to be more difficult than anticipated (Scheme 3). The methanesulfonic acid-catalyzed spiroannulation described by Eaton and Job 7 for the preparation of 5a-b did not work well in our hands giving low yields of the desired spirodiketones. Variations of some reaction parameters (concentration, temperature, use of PTSA or triflic acid) were not successful: these reactions gave complex mixtures or starting material was recovered. Eventually, an annulation product 3 was isolated in 60% yield from the treatment of 2b (n = 2) with 0.5 eq. of MsOH in benzene followed by azeotropic distillation of water. An X-ray diffraction analysis of a crystal of the corresponding 2,4dinitrophenylhydrazone 4 confirmed the structure of 3. Compound 3 was the result of an acid-catalyzed deformylation of the non-enolizable ketone 2b (n = 2) followed by an intramolecular aldol reaction. Both acidic and basic conditions have indeed been used for the decarbonylation of non-enolizable αformylated ketones. 9 This competitive reaction could be avoided by applying a variation of the conditions described earlier by de Groot et al. for related spiroannulation reactions. [START_REF] De Groot | [END_REF] The spiroannulation of 2a-b was thus performed in the presence of a 1:1 mixture of morpholine and acetic acid in DMSO at room temperature, and conducted to the

Construction of the pyrazole ring

The construction of the pyrazole ring first required the protection of the saturated ketone. Inspection of molecular models had revealed that the saturated ketone was fairly congested which raised the problem of chemoselectivity of the ketalization reaction. The desired selective ketalization of the saturated ketone was observed upon treatment of 5b (n = 2) with 1 eq. PTSA in the presence of molecular sieves at room temperature. The lower homolog 5a (n = 1) behaved differently: treatment of 5a with 1 equivalent PTSA at room temperature yielded compound 7. The structure of 7 was confirmed by X-ray diffraction analysis of monocrystals of diphenylhydrazone 8. The formation of 7 could be explained by an acid-catalyzed cleavage of the tetrahedral intermediate generated by addition of ethylene glycol to the carbonyl group of 5a (Scheme 4). A DFT study of the fragmentation reactions in the 5-and 6-membered spirocycles showed that, despite similar energy barriers for the fragmentation in both series, the reaction was exothermic only in the case of the 5-membered ring (Scheme 5). Eventually we were able to obtain the desired ketal 6a in 69% yields after treatment of 5a with 0.1 eq. of CSA for 40 min. The structure and conformation of the six-membered ketone 10b (n=2) was established by X-ray diffraction analysis. A DFT conformational analysis (M06-2X/6-311+G(2d,p) level in chloroform) was also performed on this derivative (Scheme 7). They revealed that the conformer observed in the crystal was also preferred in chloroform (A, Scheme 7) although another chair conformation, quite similar in energy, of the cyclohexanone ring exists (B, Scheme 7). The full details of the conformational analyses can be found in the supplementary material.

Synthesis of the target alcohols

The final step of the synthesis was the generation of the target alcohols from ketones 10a-b. Our studies were first conducted on the 6-membered ring ketone 10b. The stereochemical course of addition of metal hydrides, organolithium or Grignard reagents to cyclohexanones is known to be a complex process depending on many experimental parameters. In addition, the conformational analysis of each ketone had revealed the presence of several conformers of similar energy. However, as different diastereomeric alcohols could provide more informative biological data, mixtures of diastereoisomers were therefore acceptable as long as these could be separated and purified.

Reduction of the ketone 10b with DIBAL-H yielded a 1:3 mixture of secondary alcohols 11 and 12 in 90% yield (Scheme 8). The evidence for the presence of the two isomers was provided by the splitting of 1 H-NMR signals (especially those of the vinylic protons) in the crude reaction mixture. Axial and equatorial alcohols 11 and 12 were separated by preparative HPLC. Their structures, relative configurations and their conformations were confirmed by X-ray diffraction analyses (Figure 1). As expected, addition of organolithium or Grignard reagent to ketone 10b generated a mixture of tertiary alcohols (Table 1). The structure of the major diastereoisomer 13 was revealed in the case of 13a, by X-rays diffraction analysis of crystals obtained in acetonitrile (Figure 2,13a). Molecular modeling showed that the minor distereoisomer 14 would have another orientation of the spirocyclic ring, carrying the bulky substituent on the alcohol in the equatorial position (Figure 2,13b). As the orientation of the alcohol moiety is different from one diasteroisomer to another, this should strongly influence the interaction the glucocorticoid receptors.

An unprecedented behaviour of Burgess reagent

We were also interested in the dehydrated derivatives starting from a mixture of 11 and 12. Unfortunately classical dehydration conditions (Tf2O/toluene or pyridine, or Ac2O/pyridine) yielded a complex mixture of products containing only traces of elimination product 15. As an alternative, we tested the Burgess reagent which has been successfully used for the syn-dehydration of alcohols. [START_REF] Holsworth | Burgess dehydrating reagent, Name Reactions for Functional Group Transformations[END_REF] However, refluxing a mixture of alcohols 11 and 12 with 1.1 equiv. of methyl-N-(triethylammoniumsulfonyl)-carbamate (Burgess reagent) in dry THF did not yield the expected elimination product 15 (Scheme 9, pathway A), but partially converted the starting material into a new product 16. A complete transformation of the starting material into 16 was observed in the presence of 2.2 equiv. of Burgess reagent (Scheme 9). The structure of this unexpected product 16 was unequivocally confirmed by X-rays diffraction analysis. Compound 16 thus resulted from a ring expansion of the cyclohexadiene B-ring. We first envisaged (Pathway B) involving an intramolecular abstraction of a hydrogen atom of the B-ring concerted with a nucleophilic attack of the activated alkene on the carbon carrying the leaving group (noted a). This would give a strained norcaradiene that would isomerize readily to the more stable cycloheptatriene 16. [START_REF] Mcnamara | [END_REF] An alternative mechanism preferred by the referees would be a direct attack of the fairly nucleophilic and properly oriented double bond (pathway C) to give a stabilized tetracyclic cation that would undergo a base-catalyzed rearrangement to 16. Scheme 9. (a). Burgess reagent / THF, reflux, 1 h (87%).

We applied the same experimental conditions to the saturated analogue 17 (Scheme 10). The reaction did not yield a ring expansion product nor an elimination product: the sulfonylated was recovered unchanged after 3 h at 80°C.

As far as we can tell this ring expansion reaction represents an unprecedented application of Burgess reagent.

Eventually we managed to obtain the elimination product 15 using the Shapiro reaction. The hydrazone 19 was obtained in good yield (77%) by treatment of the ketone 10b with tosylhydrazine in ethanol. Subsequent addition of n-BuLi (2 eq.) at temperature delivered a rather low yield of the olefin 15 along with unidentified degradation products (Scheme 11).

Conclusions

Spirocyclic indazoles were designed as potential ligands for the glucocorticoid receptors. Although the synthetic route to these compounds originally appeared as straightforward, in practice the construction of the homologous in 5-and 6-membered spiranic ring systems required specific sequences for each member of the homologous series as a consequence of very different reactivity patterns. Eventually, we were able to establish practical synthetic routes for each member of the homologous series. The last step leading to the alcohols yielded two diastereomers. As examples, we separated both diastereoisomers 11 and 12 and also 13b and 14b. The conformations of representative final products and key intermediates were also studied by DFT calculations and confirmed by X-rays diffraction analyses. These synthetic studies offer chemists an easy access to a wide variety of structural analogs of this new class of spirocycles. They can be easily modulated to conduct to new glucocorticoids. In order to test the validity of our design we tested both diastereoisomers 13b and 14b. If the isomer 13b is devoid of affinity for the GRs, having an IC50 of 5.7 µM, the corresponding diastereoisomer 14b has a promising IC50 of 27 nM. The completely different binding pattern of these isomers could result from the different position of the hydroxyl moiety, expected to mimic the initial C11 alcohol of fluorocortivazol. More examples in this series are necessary in order to define the SAR for this class of derivatives. This will be discussed in a forthcoming publication in a medicinal chemistry journal.

In the course of synthetic studies, we also discovered an unprecedented application of Burgess reagent. Instead of generating an olefin by an intramolecular syn-elimination, the product resulting from the treatment of spirocyclic alcohols 11 and 12 with Burgess reagent led to the expansion of the cyclohexadiene ring. Our future plan is to examine whether this observation could be generalized to other systems containing an allylic hydrogen atom.

We believe that these preliminary synthetic studies open a new window for the discovery of new potent and selective glucocorticoid ligands.

Experimental

General experimental

The infrared (IR) spectra were recorded on a Bruker IRFT IFS 55 spectrometer on zinc selenide plates, unless stated otherwise.

1 H-NMR and 13 C-NMR were recorded with Bruker Avance II 300 (at 300.18 MHz and 75.48 MHz, respectively) in CDCl3-d1 and DMSO-d6, using tetramethylsilane (TMS) as an internal standard. Chemical shifts are reported in parts per million (ppm) and the coupling constants are reported in units of Hertz [Hz]. Multiplicities were abbreviated as follows: singlet (s), doublet (d), triplet (t), quartet (q). Low resolution mass spectra (MS) / High resolution mass spectra (HRMS) were recorded with a ThermoElectron LCQ Advantage and a ThermoElectron Exactive spectrometer, respectively.

Melting points were recorded using a Buchi B-540 apparatus and are uncorrected. Flash chromatography was performed on Merck 40-70 nM (230-400 mesh) silica gel under air pressure. Thinlayer chromatography (TLC) was carried out on Merck silica gel 60 F254 precoated plates. Visualization was made with ultraviolet light (λ = 254/365 nm) or using an aqueous potassium permanganate staining solution.

Experimental details and characterization data 4.1.1. 2-Oxo-1-(3-oxobutyl )cyclopentanecarb -aldehyde (2a).

To a stirred suspension of KH (2.58 g, 30% w/w in oil, 19.39 mmol) in anhydrous Et2O (10 ml) was added dropwise a solution of cyclopentanone (1 g, 11.89 mmol) and ethyl formate (1.07 ml, 13.32 mmol) in anhydrous Et2O (5 ml) at -5°C for 15 min under argon atmosphere. The reaction mixture was stirred for additional 30 min and poured in ice/water (25 ml). The aqueous layer was separated and washed with Et2O (10 ml × 2). The organic phase was discarded and aqueous phase was acidified with NaH2PO4 (1 g) and concentrated HCl (3 ml, pH = 1-2). The aqueous phase was extracted with Et2O (50 ml × 8). The combined organic phase was washed with saturated aqueous NH4Cl solution (25 ml), dried over Na2SO4 and evaporated under vacuum to give a pale brown residue. The resulting residue was triturated with n-pentane (25 ml × 6) to give (E/Z)-2-(hydroxymethylene)cyclopentanone 1a as a white solid. The crude product 1a (8 g, 71.30 mmol) was dissolved in methyl vinyl ketone (14.5 ml) and powdered KOH (181 mg, 3.23 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. After the reaction was complete methyl vinyl ketone was evaporated under vacuum. The residue was dissolved in DCM (100 ml) and washed with 1 M aqueous solution of NaH2PO4 (30 ml × 2) followed by brine wash (20 ml). The organic phase was dried over Na2SO4 and evaporated under vacuum to give the adduct 2a (12.2 g, 55% over 2 steps, brown oil). This compound was used as such without purification for the next step. C10H14O3; brown oil; yield: 55%; M = 182.22 g / mol; IR (KBr, cm -1 ): 2959, 1713. 1 H NMR (400 MHz; CDCl3): 1.64-1.66 (m, 1H), 1.74-1.89 (m, 3H), 1.99-2.10 (m, 5H), 2.14-2.19 (m, 2H), 2.26-2.37 (m, 2H), 9.25 (s, 1H).

2-oxo-1-(3-oxobutyl)cyclohexanecarb -aldehyde (2b)

Sodium hydride (60% dispersion in mineral oil, 11.4 g) was added under nitrogen to dry diethyl ether (250 ml). Subsequently, ethyl formate (12.7 g, 13.8 ml, 1.2 eq.) and then cyclohexanone (12 g, 12.6 ml, 1 eq.) were added and the mixture was stirred for 48 h at room temperature. The orange mixture was slowly poured on ice-cold water (200 ml), the aqueous layer separated and washed with diethyl ether (2 x 200 ml) before being acidified with hydrogen chloride (aq. soln., 6 N). The organic materials were extracted with diethyl ether (3 x 150 ml), the combined organic layers were dried over magnesium sulfate and the solvent was evaporated to conduct to the desired α-formylated cyclohexanone 1b as a light-yellow liquid subsequently used without further purification. The crude compound 1b (6.42 g, 1 eq.) was dissolved in THF (50 ml), then DBU (0.06 ml, 0.05 eq.), TEA (0.06 ml, 0.05 eq.) and methyl acrylate (1 ml, 1.5 eq.) were consecutively added to the mixture and stirred for 24 h at room temperature under atmosphere. After the complete consumption of the starting material, the solvent was evaporated, the residue diluted with DCM (200 ml) and washed with ammonium chloride (sat. soln., 2 x 100 ml) and sodium chloride (sat. soln., 1 x 100 ml). The organic solvent was dried over magnesium sulfate and evaporated under vacuum. The crude product was purified by flash-chromatography (eluent: PE / EtOAc 7/3) to give the desired addition derivative 2b as a colorless oil (10 g). C11H16O3; colorless oil; yield: 49%; M = 196.24 g / mol; IR (ZnSe) ν = 2940, 1715, 1450, 1367, 1169 cm -1 ; 1 H NMR (300 MHz, CDCl3) δ 1.55-2.46 (m, 15 H); 13 C NMR (75 MHz, CDCl3) δ 21.4 (CH2), 25.1 (CH2), 26.7 (CH2), 30.0 (CH3), 32.9 (CH2), 38.2 (CH2), 40.7 (CH2), 64.0 (Cq), 201.2 (CHO), 207.6 (Cq), 210.2 (Cq).

4. 1.3. 4,4a,5,6,7,8-

hexahydro-3H-naphthalen-2-one (3)

A solution of the previously obtained Michael adduct 2b (1.3 g, 6.62 mmol, 1 eq.) in benzene (60 ml) was refluxed overnight with water removal (using a Dean-Stark trap) in the presence of methane sulfonic acid (0.22 ml, 3.31 mmol, 0.5 eq.). After the solvent evaporation, the residue was diluted with water (50 ml) and neutralized by sodium bicarbonate (NaHCO3 satd. soln.). The organic materials were subsequently extracted with DCM (3 x 50 ml), the combined organic layers were dried over magnesium sulfate and the solvent evaporated under reduced pressure. The crude product was purified by flash-chromatography (PE / EtOAc 8/2) to give the pure annulation product 3. C10H14O; light brown oil; yield: 60%; M = 150.22 g / mol; IR (ZnSe) ν = 2933, 1714, 1671, 1452 cm - 1 ; 1 H NMR (300 MHz, CDCl3) δ 1.12-1.66 (m, 4H),

Spiro[4.5] dec-6-ene-1,8-dion (5a)

To a solution of compound 2a (8 g, 43.90 mmol) in DMSO (100 ml) was added morpholine (3.90 g, 45.27 mmol) and AcOH (2.7 ml, 45.27 mmol) at room temperature under Ar atmosphere. The reaction mixture was stirred at room temperature for 20 h. TLC analysis showed the complete consumption of starting material. The reaction was quenched with saturated aqueous Na2CO3 solution and extracted with EtOAc (50 ml × 4). The combined organic phase was washed with saturated aqueous NH4Cl solution (50 ml). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The resulting residue was purified by column chromatography (neutral alumina; eluent: EtOAc/PE 1/9) to afford the derivative 5a (2.5 g). C10H12O2; M = 164.08 g/mol; yield: 34%; IR (KBr, cm -1 ): 2958, 1736, 1680; 1

Spiro[5.5] undec -10-ene-5,9-dione (5b)

Under inert atmosphere, morpholine (6.66 ml, 1 eq.) and acetic acid (4.4 ml, 1 eq.) were added to a solution of the previously obtained Michel adduct 2b (15 g, 1 eq.) in DMSO (130 ml). The mixture was vigorously stirred for 48 h at room temperature, then, after the complete consumption of the starting material, slowly added to sodium carbonate (satd. soln., 100 ml). The organics were extracted with ethyl acetate (4 x 50 ml), then washed with ammonium chloride (100 ml) before drying over magnesium sulfate. The solvent was evaporated under reduced pressure and the crude product was purified by flash chromatography (PE / EtOAc 7/3) to give the desired annulated compound 5b as a colourless oil (10 g). C11H14O2; colourless oil; yield: 73%; M = 178.23 g / mol; IR (ZnSe) ν = 2939, 1703, 1680, 1125 cm -1 ; 1 H NMR (300 MHz, CDCl3) δ 1.88-2.05 (m, 5H), 2.30-2.61 (m, 5H), 6.02 (dd, J = 10.2 Hz, J = 7.8 Hz, 1H), 6.95 (dd, J = 10.2 Hz, J = 4.5 Hz, 1H); 13 C NMR (75 MHz, CDCl3) δ 20.9 (CH2), 27.6 (CH2), 30.5 (CH2), 34.0 (CH2), 38.3 (CH2), 39.2 (CH2), 51.2 (Cq), 129.7 (CH), 150.8 (CH), 198.7 (Cq), 210.9 (Cq); HRMS: calcd. for C11H14O2Na 201.0886, found 201.0887 (0.3737 ppm).

1,4-Dioxadispiro[4.0.5.3] tetradec -7-en-9-one (6a)

To a suspension of compound 5a (4 g, 24.38 mmol) in ethylene glycol (40 ml) was added (+)-camphor sulfonic acid (1.69 g, 7.3 mmol) and 4Å molecular sieves (12 g) at 0°C under Ar atmosphere. The reaction mixture was allowed to stir for 40 min at room temperature. The reaction mixture was filtered and the filtrates was poured into saturated aqueous NaHCO3 solution (50 ml) and extracted with EtOAc (100 ml × 3). The combined organic phase was washed with brine solution, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (neutral alumina; eluent: EtOAc/PE 1/4)) to give the ketal 6a (

4-5] pentadec-7-en-9-one (6b)

Under nitrogen atmosphere, to solution of the spiro-derivative 5b (5 g, 1 eq.) in ethylene glycol (50 ml), were successively added PTSA (5.35 g, 1 eq.) and activated molecular sieves (5 g). After 1 h of reaction, the mixture was poured in a water / sodium bicarbonate (satd. soln.) mixture (2/1, 100 ml), then extracted with ethyl acetate (3 x 150 ml). The combined organic layers were washed with brine (100 ml), dried over magnesium sulfate and the solvent evaporated under vacuum. The desired ketal was purified by flash-chromatography (PE/EtOAc 9/1) and isolated as a light-yellow oil. C13H18O3; light-yellow visc. oil; yield: 72%; M = 222.28 g / mol; IR (ZnSe) ν = 2936, 1679, 1448, 1088 cm -1 ; 1 [4.5] dec -8-en-8-yl)butanoate (7) Under nitrogen atmosphere, to a solution of the spiro derivative 5b (5 g, 30.47 mmol, 1 eq.) in ethylene glycol (50 ml), were successively added PTSA (5.8 g, 30.47 mmol, 1 eq.) and activated molecular sieves (8 g). After 1 h of reaction, the mixture was poured in a water / sodium bicarbonate (satd. soln.) mixture (2/1, 100 ml), then extracted with ethyl acetate (3 x 150 ml). The combined organic layers were washed with brine (100 ml), dried over magnesium sulfate and the solvent evaporated under vacuum. The ketal was isolated by flashchromatography (PE/EtOAc 8/2) as a colorless oil (5.14 g). C14H22O5; colorless oil; yield: 63%; M = 270.32 g / mol; IR (ZnSe) ν = 3492, 2952, 1733, 1452, 1382, 1254, 1116 cm -1 ; 1 H NMR (300 MHz, CDCl3) δ 1.66-1.76 (m, 3H), 1.97 (t, J = 7.6 Hz, 2H), 2.09-2.13 (m, 2H), 2.19 (as, 2H), 2.28 (t, J = 7.5 Hz, 2H), 2.53 (t, J = 5.8 Hz, 1H), 3.73-3.78 (m, 2H), 3.92 (s, 4H), 4.13-4.16 (m, 2H), 5.27 (as, 1H); 13

2-hydroxyethyl 4-(1,4-dioxaspiro

Ethyl 4-(1,4-dioxaspiro[4.5] dec -8-en-8-yl)butanoate

Sodium hydride (60% dispersion in mineral oil, 6.4 g) was added under nitrogen to a dry solution of compound 7 (8.3 g, 39.9 mmol) in toluene (80 ml). The mixture was cooled to -40°C, stirred for 10 min at low temperature before addition of 0.1 ml of dry methanol. The mixture was left to come back to room temperature, an, after complete consumption of starting material, the mixture was slowly poured onto ice-cold water. The organics were extracted with ethyl acetate (100 ml x 3). The combined organic layers were dried over magnesium sulfate, then the solvent was evaporated under vacuum. The crude product was further purified by flash chromatography (eluent PE / EtOAc 7/3) to conduct to the ring-opening product. C14H22O4; colorless oil; yield: 77%; M = 254.32 g / mol; IR (ZnSe) ν = 2952, 1736, 1375, 1116 cm -1 ; 1 H NMR (300 MHz, CDCl3) δ 1.19 (t, J = 7.1 Hz, 3H), 1.65-1.75 (m, 4H), 1.96 (t, J= 7.4 Hz, 2H), 2.09-2.13 (m, 2H), 2.20-2.25 (m, 4H), 3.92 (s, 4H), 4.06 (q, J = 7.1 Hz, 2H), 5.27 (as, 1H); 13 C NMR (75 MHz, CDCl3) δ 14.2 (CH3), 22.9 (CH2), 27.

1-(4-fluorophenyl)spiro[4H -indazole-5-2'-cyclopentane] -1'-one-ethylelene-acetal (9a)

To a cooled solution (-40°C) of ketal 6a (1 g, 4.80 mmol) in anhydrous toluene (30 ml) was added ethyl formate (1.55 ml, 19.22 mmol) and NaH (768 mg, 60% on mineral oil, 19.22 mmol) under Ar atmosphere. The reaction mixture was stirred for 10 min at -40°C, then MeOH (97 µl, 2.4 mmol) was added. Reaction mixture was left to come back to room temperature and stirred for 10 additional minutes. TLC analysis showed the complete consumption of starting material. The reaction mixture was poured into ice-cold water (20 ml) and extracted with EtOAc (50 ml × 4). The combined organic phase was washed with brine solution (25 ml), dried over Na2SO4 and evaporated under vacuum to give the crude α-formylation product (1.09 g, 96%, pale yellow liquid). IR (KBr, cm - 1 ): 2925, 1644. 1 To a solution of the previously obtained crude product (1.05 g, 4.44 mmol) in acetic acid (20 ml) was added NaOAc (730 mg, 8.89 mmol) and 4-fluorophenyl hydrazine chlorhydrate (795 mg, 4.89 mmol) at room temperature. The reaction mixture was stirred at room temperature for 30 min. TLC analysis showed the complete consumption of starting material. Then, the reaction mixture was poured into ice-cold saturated aqueous Na2CO3 solution (20ml) and extracted with EtOAc (50ml × 4). The combined organic phase was washed with brine (25 dried over Na2SO4 and purified over neutral alumina (PE/EtOAc 9/1). The collected fraction was evaporated under vacuum to give the title compound 9a (930 mg). C19H19FN2O2; pale yellow oil; yield: 64%; M = 326.14 g/ mol; IR (KBr): 2922, 2322, 1514 cm -1 ; 1 H NMR (400 MHz; CDCl3): 1.72-1.85 (m, 4H), 1.93-1.98 (m, 2H), 2.62 (d, J = 17.6 Hz, 3.00 (d, J = 16 Hz, 1H), 3.90-3.94 (m, 4H), 6.04 (d, J = 10.4 Hz, 1H), 6.44 (d, J = 10.0 Hz, 1H), 7.12-7.17 (m, 2H), 7.43-7.47 (m, 3H). 13

1-(4-fluorophenyl)spiro[4H -indazole-5,2'-cyclohexane] -1'-one-ethylene-acetal (9b)

Under inert atmosphere, the previously obtained ketal 6b (4.90 g, 1 eq.) was dissolved in dry toluene (150 ml) and the mixture cooled to -40°C. Ethyl formate (7.1 ml, 4 eq.) and then sodium hydride (60% dispersion in oil, 3.5 g, 4 eq.) were subsequently added before slowly add methanol (0.44 ml, 0.5 eq.) at low temperature over 15 minutes. The mixture was stirred for 30 min at low temperature, then left to slowly come back to room and stirred for two additional hours. After the complete consumption of the starting material, the mixture was slowly poured onto ice-cold water (100 ml), the organic was separated and washed two additional times with water (2 x 75 ml). The combined aqueous layers were subsequently acidified to with hydrogen chloride (aq. soln., 6 N) before extracting the organic materials with diethyl ether (3 x 100 ml). The combined organic layers were dried over magnesium sulfate and the solvent evaporated to give a light yellow oil turning brown on standing (4.47 g) which was subsequently used without further purification.C14H18O4; lightyellow oil; yield: 84%; M = 250.29 g / mol; IR (SeO2) ν = 2937, 1645, 1186, 1086 cm -1 ; 1 H NMR (300 MHz, CDCl3) δ 1.41-1.47 (m, 2H), 1.51-1.75 (m, 6H), 2.33 (dd, J = 14.7 Hz, J = 1.2 Hz, 1H), 2.76 (dd, J = 14.6 Hz, J = At room temperature, sodium acetate (0.31 g, 1.1 eq.) and 4-F-phenylhydrazine (0.61 g, 1.1 eq.) were added to a solution of the previously-obtained α-formylation product (0.85 g, 1 eq.) in acetic acid (15 ml). The mixture was stirred until the complete consumption of the starting material (approx. 1.5 h), then the reaction was quenched by addition of sodium carbonate (sat. soln. 100 ml). The aqueous mixture was washed with ethyl acetate (3 x 100 ml), the combined organic layers were dried over magnesium sulfate and the solvent evaporated under reduced pressure. The crude product was subsequently purified by flash-chromatography (eluent: PE / EtOAc 8/2) to conduct to the desired indazole derivative 9b, isolated as a light yellow visc. oil. C20H21FN2O2; light-yellow visc. oil; yield: 87%; M = 340.39 g / mol; IR (ZnSe) ν = 2936, 1515, 1222, 840 cm -1 ; 1

1-(4-fluorophenyl)spiro[4H -indazole-5-2'-cyclopentane] -1'-one (10a)

To a solution of ketal 9a (930 mg, 2.85 mmol) in THF (27 ml) was added 6M aqueous HCl (14 ml) and the reaction mixture was stirred at room temperature for 10 min. TLC analysis showed the complete consumption of starting material. Then, the reaction mixture was poured into saturated aqueous NaHCO3 solution (30ml) and extracted with EtOAc (50 ml × 4). The combined organic phase was washed with brine solution (25 ml), dried over Na2SO4 and evaporated under vacuum to give residual thick oil. The residue was purified by column chromatography (neutral alumina, eluent: PE/EtOAc 9/1) to afford the desired ketone 10a (530 mg). C17H15FN2O; pale yellow liquid; yield: 66%; M = 282.32 g/mol; IR (KBr): 1737, 1514 cm -1 ; 1 H NMR (400 MHz; CDCl3): 1.90-2.11 (m, 4H), 2.37-2.41 (m, 2H), 2.70 (d, J = 16.0 Hz, 1H), 2.95 (d, J = 16.0 Hz, 1H), 5.69 (d, J = 9.6 Hz, 1H), 6.54 (d, J = 10.0 Hz, 1H), 7.12-7.16 (m, 2H), 7.41-7.46 (m, 3H); 13 C NMR (400 MHz; CDCl3): 18.57, 27.16, 35.93, 36.83, 52.08, 116.00, 116.23, 116.97, 125.18, 125.26, 131.71, 137.94, 160.33, 162.80, 220.09; MS: m/z = 282.9 [M+1] + ;

1-(4-fluorophenyl)spiro[4H -indazole-5,2'-cyclohexane] -1'-one (10b)

The ketal moiety of compound 9b was deprotected by adding hydrogen chloride (aq. soln. 6N, 15 ml) to a solution of indazole 9b (1 g, 1 eq.) in THF (30 ml). The reaction was conducted at 65°C for 1.5 h, and then quenched by pouring onto a solution of sodium bicarbonate (10% aq. soln. 100 ml). The aqueous solution was washed with ethyl acetate (3 x 100 ml), then the combined organic layers were dried over magnesium sulfate and the solvent evaporated under vacuum. The desired ketone 10b was isolated as a white solid after purification on flash chromatography (eluent PE/EtOAc 8/2). C18H17FN2O; white solid; Mp = 91-93°C; yield: 71%; M = 296.34 g / mol; IR (ZnSe) ν = 2936, 1706, 1515, 1222, 840 -1 ; 1 H NMR (300 MHz, CDCl3) δ 1.74-1.93 (m, 6H), 2.40-2.49 (m, 1H), 2.52-2.61 (m, 1H), 2.77 (d, J = 16.0 Hz, 1H), 3.13 (d, J = 16.0 Hz, 1H), 6.10 (d, J = 10.1 Hz, 1H), 6.48 (dd, J = 10.1 Hz, J = 0.5 Hz, 1H), 7.10-7.16 (m, 2H), 7.40-7.45 (m, 3H); 13 C NMR (75 MHz, CDCl3) δ 20.9 (CH2), 27.3 (CH2), 27.8 (CH2), 37.

Reduction of the ketone moieties

Under inert atmosphere and at -78°C, DIBAL-H (1M soln. in THF, 1.02 ml, 1.02 mmol, 3 eq.) was slowly added to a solution of the ketone 10b (0.1 g, 0.34 mmol, 1 eq.) in dry THF (10 ml). The reaction mixture was stirred at low temperature for 1 h. reaction was quenched by addition of water (20 ml) at low temperature the organics extracted with ethyl acetate (3 x 30 ml). The combined organic layers were dried over magnesium sulfate and concentrated under vacuum. The crude product was purified by flash-chromatography (P.E. / EtOAc 7/3) to conduct to the desired product as a 3/1 mixture of diastereoisomers. (11) (12). (5S, 8S)-diastereoisomer: C18H19FN2O; White solid; Mp = 144-146°C; Yield: 68%; M = 298.35 g/mol; IR (ZnSe) ν = 3320, 2926, 1517, 842 cm -1 ; 1 H NMR (300 MHz, CDCl3) δ 1.18-1.60 (m, 5H), 1.72-1.81 (m, 3H), 2.71 (d, J = 16.2 Hz, 1H), 3.00 (d, J = 16.2 1H), 3.63 (dd, J1 = 9.7 Hz, J2 = 3.4 Hz, 1H), 5.75 (d, J = 10.0 Hz, 1H), 6.48 (d, J = 10.0 Hz, 1H), 7.12-7.18 (m, 2H), 7.43-7.47 (m, 3H); 13 C NMR (75 MHz, CDCl3) δ 20.1 (CH2), 22.1 (CH2), 23.5 (CH2), 29.5 (CH2), 32.7 (CH2), 42.8 (Cq), 75.4 (CH), 115.4 (Cq), 116.1 (CH), 116.1 (CH), 116.4 (CH), 125.3 (CH), 125.4 (CH), 136.6 (Cq), 138.4 (CH), 139.2 (CH), 160.1 (Cq), 163.3 (Cq); HRMS: calcd. for C18H20FN2O 299.15542, found 299.15534 (-0.26 ppm).

1-(4-fluorophenyl)-1'-phenyl-spiro[4H-indazole-5,2'-cyclohexane]-1'-ol

1-(4-fluorophenyl)-1'-phenyl-spiro[4H-indazole-5,2'-cyclohexane]-1'-ol

1-(4-fluorophenyl)-1'-prop-1-ynyl-spiro[4H-indazole-5,2'-cyclohexane] -1'-ol (13a)

Under inert atmosphere and at 0°C, the previously obtained ketone 10b (0.3 g, 1 eq.) was dissolved in dry THF (10 ml). A solution of 1-propynylmagnesium bromide bromide (0.5 M soln. in THF, 2.04 ml, 3 eq.) was slowly added at low temperature and the mixture was stirred 2 additional hours at 0°C until the complete conversion of the starting material. The reaction was quenched by addition of ammonium chloride (satd. soln. 30 ml) and the organic-soluble materials extracted with ethyl acetate (3 x 50 ml). The organic phase was dried over magnesium sulfate and concentrated under vacuum to give to a crude product. The crude alcohol was subsequently purified by flash chromatography (PE/EtOAc 9/1) to conduct to a white solid which was subsequently crystallized in acetonitrile to give colorless needles. Under inert atmosphere and at 0°C, the previously obtained ketone 10b (0.3 g, 1 eq.) was dissolved in dry THF (10 ml). Benzylmagnesium bromide (1M soln. in THF, 1.02 ml, 3 eq.) was slowly added at low temperature and the mixture was stirred 2 additional hours at 0°C until the complete conversion of the starting material. The reaction was quenched by addition of ammonium chloride (satd. soln. 30 ml) and the organic-soluble materials extracted with ethyl acetate (3 x 50 ml). The organic phase was dried over magnesium sulfate and concentrated under vacuum to give to a crude product. This was further purified by flash-chromatography (eluent: PE / EtOAc 9/1) to conduct to the desired diastereoisomers in a 5/1 ratio.

1'-(4-fluorophenyl)-2-(naphthalen-2-yl)-1',4' -dihydrospiro[ cyclohexane-1,5'indazol] -2-ol

2-bromo-naphtyl (0.69 g, 1 eq.) was dissolved in a dry THF/toluene mixture (1.7 ml / 5 ml) before cooling to -78°C. n-butyl lithium (soln. 1.6 M in hexane, 2.5 ml, 2.4 eq.) was added at low temperature and the mixture was stirred for 1 h. Subsequently, a solution of the ketone 10b (0.5 g, 1.69 mmol, 1 eq.) in dry THF (9 ml) was added low temperature, and the mixture was allowed to come back to -30°C over 1 h, under vigorously stirring. After complete consumption of the starting material, the reaction was quenched by addition of ammonium chloride (satd. soln., 50 ml), then the organics extracted with ethyl acetate (3 x 50 ml). By analogy with the previously conducted organometallic additions on the ketone precursor 10b, the main diastereoisomer isolated by flashchromatography (PE/EtOAc 8/2) was assigned the (5S, 8S) stereochemistry.

1-(4-fluorophenyl)-1'-(4-methoxyphenyl ) spi ro[4H-indazole-5,2'-cyclohexane] -1'-ol

Under inert atmosphere, iPrMgCl (2M in THF, 0.84 ml, 3.55 mmol, 2.1 eq.) was added at -20°C to a solution of 4-iodo-anisole (0.4 g, 1.69 mmol, 1 eq.) in dry THF (10 ml). After 1 h of stirring at -20°C, a solution of ketone precursor 10b (0.5 g, 1.69 mmol) in dry THF (3 ml) was slowly added. The temperature was allowed to come back to room temperature and the mixture stirred overnight. The reaction was quenched by addition of sodium bicarbonate (20% aq. soln., 50 ml), then extracted with ethyl acetate (3 x 50 ml). The combined organic layers were dried over magnesium sulfate, the solvent evaporated under reduced pressure and the crude purified by flash chromatography (cyclohexane / EtOAc 8/2) to deliver the addition product 13d. A mixture of alcohols 11 and 12 (0.1 g, 0.335 mmol, 1 eq.) obtained by addition of DIBAL-H to the ketone 10b (vide supra) was treated with the Burgess reagent (0.176 g, 0.74 mmol, 2.2 eq.) in dry THF (20 ml). The mixture was refluxed under nitrogen atmosphere for 1 h, then, after complete consumption of the starting material, the solvent was evaporated. The crude product was purified by flash chromatography (PE / EtOAc 95/5) to conduct to the rearrangement product 16.

1'-(4-fluorophenyl)-1',4',6',7' -tetrahydrospiro[cy clohexane-1,5'-indazol] -2-ol (17)

A crude mixture of alcohols 11 and 12 (0.15 g, 0.5 mmol, 1 eq.) was dissolved in ethanol (5 ml). Pd/C (0.015 g) was added and hydrogen gas was bubbled for 10 min in the reaction mixture. Aqueous hydrogen chloride (1 M soln, 0.5 ml, 0.5 mmol, 1 eq.) was added to the solution, and the reaction was stirred under hydrogen atmosphere overnight. The mixture was filtered on a celite pad and the solvent was evaporated. Subsequently the residue was dissolved in DCM (20 ml) and washed with sodium bicarbonate (20 ml). The organic materials were further extracted from the aqueous layer with DCM (2 x 20 ml), and the combined organic layers were dried over magnesium sulfate and evaporated to conduct to a crude product which was subsequently used without further purification. C18H21FN2O; White solid; m.p. 179-180°C; Yield: 60%; M = 300.16 g / mol; IR (ZnSe) ν = 3324, 2933, 1514, 1222, 1057, 838 cm -1 ; 1

methyl{[(1'-(4-fluorophenyl)-1',4',6',7' -tetrahydrospiro[cyclohexane -1,5'-indazol] -2yl)oxy] sulfonyl} -carbamate (18)

Burgess reagent (0.04 g, 0.159 mmol, 2.2 eq.) was added to a solution of alcohol 17 (0.04 g, 0.133 mmol, 1 eq.) in dry THF (8 ml). The mixture was refluxed under nitrogen atmosphere for 1 h, then, after complete consumption of the starting material, the solvent was evaporated. The crude product was purified by flash chromatography (DCM / MeOH 9/1) to conduct to the sulfonamide 18. C20H24FN3O5S; White solid; m.p. 105°C; Yield: 26%; M = 437.5 g / mol; IR (ZnSe) ν = 2937, 1758, 1517, 1236, 1174, 900 cm -1 ; 1 H NMR (300 MHz, CDCl3) δ 1.47-1.99 (m, 10H), 2.39-2.86 (m, 5H), 3.73-3.75 (m, 3H), 4.70 (ls, 1H); 7.12 (t, J = 8.6 Hz, 1H), 7.42-7.47 (m, 3H); 13

N-[(E)-[1-(4-fluorophenyl)spiro[4H -indazol e-5,2'-cyclohexane] -1'-ylidene] amino] -4methyl-benzenesulfonamide (19)

A solution of the ketone 10b (0.5 g, 1.69 mmol, 1 eq.) in ethanol (3 ml) was added to a solution of ptosylhydrazide (0.38 g, 0.02 mmol, 1.2 mmol) in ethanol (10 ml). Subsequently, a few drops of concentrated hydrochloric acid were added, and the mixture was vigorously stirred overnight at room temperature. The white precipitate was filtered and further washed with n-pentane to conduct to a white powder subsequently used without further purification. C25H25FN4O2S; White solid; Mp = 183-185°C; Yield: 77%; M = 464.56 g / mol; IR (ZnSe) ν = 3214, 2941, 1514, 1335, 1167 cm -1 ; 1

1-(4-fluorophenyl)spiro[4H -indazole-5,3'-cyclohexene] (15)

Under inert atmosphere, n-BuLi (0.55 ml, 0.81 mmol, 2.5 eq.) was slowly added over 15 min to a solution of the tosylhydrazone 25 (0.15 g, 0.32 mmol, 1 eq.) in dry THF (3 ml). The mixture was allowed to come back to room temperature over 3 h, and then quenched with water (20 ml) before extracting the organic materials with EtOAc (3 x 20 ml). Flash chromatography (PE/EtOAc 95/5) of the obtained crude material conducted to the desired elimination product 15. C18H17FN2; Light yellow solid; Mp = Yield: 34%; M = 280.34 g / mol; IR (ZnSe) ν = 2930, 1667, 1609, 1514 cm -1 ; 1 H NMR (300 MHz, CDCl3) δ 1.63-1.70 (m, 4H), 2.02 (ls, 2H), 2.70 (d, J = 2.0 Hz, 2H), 5.63-5.69 (m, 2H), 5.81 (d, J = 9.9 Hz, 1H), 6.36 (d, J = 9.9 Hz, 1H), 7.15 (t, J = 8.6 Hz, 2H), 7.41-7.48 (m, 3H); 13 C NMR (75 MHz, CDCl3) δ 18.7 (CH2), 25.2 (CH2), 32.5 (CH2), 33.9 (CH2), 37.

Scheme 3 .

 3 Scheme 3. Synthesis of the spirodiketones 5. (a) for n = 1: KH, HCOOEt in Et2O, 1 h, 0°C to rt; for n = 2: NaH, HCOOEt in Et2O, 48 h, rt ; (b) for n = 1: methyl vinyl ketone, KOH / 2 h, rt, 55%; for n = 2: methyl vinyl ketone, DBU, TEA / THF, 12 h, rt, 49%; (c) MsOH (0.5 eq.) / PhCH3, 12 h, reflux, 60%; (d) dinitrophenylhydrazine, H2SO4 / EtOH, 30 min, rt; (e) morpholine : AcOH (1:1) / DMSO, 24 h, rt, (n = 1: 34%, n = 2: 73%).

Scheme 4 .

 4 Scheme 4. Selective ketalization of spiranediones 5. (a) ethylene glycol, CSA (0.1 eq.), m.s. 4 Å / 40 min, rt, 69%; (b) ethylene glycol, PTSA (1 eq.), m.s. 4 Å / 1 h, rt, 72%; (c) ethylene glycol, PTSA (1 eq.), m.s. 4 Å / 40 min, rt, 63%; (d) NaH, HCOOEt, PhCH3 / 1 h, 0°C to rt; (e) 2,4-dinitrophenyl-hydrazine, H2SO4 in EtOH / H2O.

Scheme 5 .

 5 Scheme 5. DFT calculations at the M06-2X/6-31+G(d,p) level.

Scheme 6 :

 6 Scheme 6: Construction of the pyrazole ring. (a) : NaH, HCOOEt, MeOH / toluene / 48 h, rt; (b) 4-F-Ph-NHNH2, AcONa / AcOH / 24 h, rt, (over two steps, 9a: 61%, 9b: 73%); (c) HCl / THF / 1.5 h, 65°C, (10a: 66%, 10b: 71%).

Scheme 7 :

 7 Scheme 7 : DFT conformational analysis of the 6-membered ketone 10b

Scheme 8 .

 8 Scheme 8. (a) DIBAL-H, Toluene, -78°C, 1h, 11 (22%) and 12 (68%).

Figure 1 .

 1 Figure 1. Crystal structures of secondary alcohols 11 and 12

Figure 2 .

 2 Figure 2. Structures of tertiary alcohols 13a and 14a (R = 1-propynyl)

Scheme 10 .

 10 Scheme 10. (a) H2, Pd/C, HCl (1N) / EtOH; (b) Burgess reagent (2.2 eq.) / THF, reflux, 3 h (16% over two steps).

Scheme 11 .

 11 Scheme 11. (a) p-Toluenesulfonyl hydrazide, HCl / EtOH, 12 h, r.t. (77%); (b) n-BuLi / THF, 3 h, 0°C to r.t. (34%).

  H NMR (300 MHz, CDCl3) δ 1.41-1.55 (m, 2H), 1.58-1.64 (m, 5H), 1.75-1.95 (m, 2H), 2.21-2.44 (m, 2H), 2.50-2.59 (m, 1H), (m, 4H), 5.96 (dd, J = 10.4 Hz, J = 1.3 Hz, 1H), 6.95 (d, J = 10.5 Hz); 13 C NMR (75 MHz, CDCl3) δ 20.8 (CH2), 23.4 (CH2), 27.6 (CH2), 30.8 (CH2), 33.9 33.9 (CH2), 44.1 (Cq), 65.1 (CH2), 65.2 (CH2), 111.7 (Cq), 129.4 (CH), 154.6 200.0 (Cq); HRMS: calcd. for C13H18O3Na 245.1154, found 245.1147 (-0.5494 ppm).

  C NMR (75 MHz, CDCl3) δ 22.8 (CH2), 27.3 (CH2), 31.1 (CH2), 33.6 (CH2), 35.6 (CH2), 36.3 (CH2), 61.0 (CH2), 64.4 (2CH2), 65.9 (CH2), 108.1 (Cq), 118.9 (CH), 136.4 (Cq), 174.0 (Cq); MS m/z = 271.1 [M+H] + ; HRMS: calcd. for C14H23O5 271.15540, found 271.15509 (4.019 ppm).

  3 (CH2), 31.1 (CH2), 33.8 (CH2), 35.6 (CH2), 36.3 (CH2), 60.1 (CH2), 64.2 (2CH2), 108.0 (Cq), 118.8 (CH), 136.5 (Cq), 173.6 (Cq); MS m/z = 255.1 [M+H] + ; HRMS: calcd. for C14H23O4 255.16048, found 255.15995 (3.387 ppm).

12 2 .

 2 73 (d, J = 14.8 Hz, 1H), 3.90-3.95 (m, 4H), 6.06 (d, J = 10.0 Hz, 1H), 6.83 (d, J = 10.0 Hz, 1H), 7.47 (bs, 1H), 13.65 (bs, 1H).

1 . 3

 13 Hz, 1H), 3.90-4.01 (m, 4H), 6.06 (d, J = 10.3 Hz, 1H), 6.91 (dd, J = 10.3 Hz, J = 1.5 Hz, 1H), 7.43 (s, 1H), 13.66 (s, 1H); 13 C NMR (75 MHz, CDCl3) δ 21.0 (CH2), 23.4 (CH2), 28.8 (CH2), 30.7 (CH2), 33.8 (CH2), 45.3 (Cq), 65.1 (CH2), 65.3 (CH2), 106.6 (Cq), 111.2 (Cq), 128.2 (CH), 152.5 (CH), 166.4 (CH), 189.2 (Cq); MS: m/z = 249.2 [M-H] + ; HRMS: calcd. for C14H17O4 249.1121, found 249.1126 (1.8817 ppm).

  H NMR (300 MHz, CDCl3) δ 1.78-1.36 (m, 8H), 2.74 (d, J = 16.0 Hz, 1H), 2.97 (d, J = 16.0 Hz, 1H), 3.97-3.98 (m, 4H), 6.09 (d, J = 10.3 Hz, 1H), 6.43 (d, J = 10.3 Hz, 1H), 7.10-7.15 (m, 2H), 7.41-7.46 (m, 3H); 13 C NMR (75 MHz, CDCl3) δ 20.5 (CH2), 23.4 (CH2), 25.1 (CH2), 30.8 (CH2), 33.6 (CH2), 45.7 (Cq), 65.3 (CH2), 65.3 (CH2), 111.8 (Cq), 115.1 (CH), 115.4 (Cq), 116.0 (CH), 116.3 (CH), 125.1 (CH), 125.2 (CH), 135.7 (CH), 136.5 (Cq), 138.4 (CH), 159.9 (Cq), 163.1 (Cq); MS: m/z = 341.2 [M+H] + ; HRMS: calcd. for C20H21FN2O2 341.1660, found 341.1654 (-1.7188 ppm).

  7 (CH2), 38.8 (CH2), 52.0 (Cq), 114.7 (Cq), 116.0 (CH), 116.2 (CH), 116.3 (CH), 125.1 (CH), 125.3 (CH), 132.6 (CH), 136.1 (Cq), 138.2 (CH), 160.0 (Cq), 163.3 (Cq), 211.5 (Cq); MS: m/z = 297.2 [M + H] + ; HRMS: calcd. for C18H18FN2O 297.1398, found 297.1394 (-1.2857 ppm).

  (5S, 8R)-diastereoisomer: C18H19FN2O; White solid; Mp = 164-166°C; Yield: 22% (based on the 1 H-NMR); M = 298.35 g/mol; IR (ZnSe) ν = 3302, 2941, 1514, 1222, 988, 842; 1 H NMR (300 MHz, CDCl3) δ 1.34-1.98 (m, 8H), 2.49 (d, J = 15.9 Hz, 1H), 3.11 (d, J = 15.9 Hz, 1H), 3.54 (dd, J1 = 9.7 Hz, J2 = 4.1 Hz, 1H), 6.13 (d, J = 10.3 Hz, 1H), 6.54 (d, J = 10.2 Hz, 1H), 7.15-7.18 (m, 2H), 7.43-7.48 (3H); 13 C NMR (75 MHz, CDCl3) δ 21.6 (CH2), 23.8 (CH2), 30.5 (CH2), 30.8 (CH2), 36.0 (CH2), 42.4 (Cq), 75.8 (CH), 115.8 (Cq), 116.1 (CH), 116.4 (CH), 116.6 (CH), 125.2 (CH), 125.3 (CH),134.4 (CH), 136.9 (Cq), 138.2 (CH); 160.0 (Cq), 163.3 (Cq).

  C21H21FN2O; colorless crystals; Mp = 188-190°C; Yield: 61%; M = 336.40 g / mol; IR (ZnSe) ν = 2936, 1516, 1223, 839 cm -1 ; 1 H NMR (300 MHz, DMSO) δ 1.24-1.63 (m, 6H), 1.79-1.90 (m, 5H), 2.67 (d, J = 16.2 Hz, 1H), 3.00 (d, J = 16.2 Hz, 1H), 5.21 (s, 1H), 6.20 (d, J = 10.2 Hz, 1H), 6.48 (d, J = 10.2 Hz, 1H), 7.32-7.38 (m, 2H), 7.47-7.54 (m, 3H); 13 C NMR (75 MHz, CDCl3) δ 3.8 (CH3), 20.4 (CH2), 22.5 (CH2), 32.1 (CH2), 35.6 (CH2), 45.5 (CH2), 92.1 (Cq), 83.5 (Cq), 115.7 (CH), 115.8 (Cq), 116.1 (CH), 116.7 (CH), 125.1 (CH), 125.2 (CH), 136.5 (Cq), 137.2 (CH), 138.5 (CH), 160.0 (Cq), 163.2 (Cq); HRMS: calcd. for C21H22FN2O 337.1711, found 337.1710 (-0.2661 ppm).

4. 1 .

 1 16. 1'-benzyl-1-(4-fluorophenyl)spiro[4H -indazole-5,2'-cyclohexane] -1'-ol

(

  5S,8R)-1'-benzyl-1-(4-fluorophenyl)spiro[4H-indazole-5,2'-cyclohexane]-1'-ol (13b): C25H25FN2O; White solid; Mp = 56-58°C; Yield: 81%; M = 388.48 g / mol; IR (ZnSe) = 2931, 1515, 1224, 840 cm -1 ; 1 H NMR (300 MHz, CDCl3) δ 1.41-1.86 (m, 8H), 2.57 (d, J = 13.5 Hz, 1H), 2.67 (d, J = 16.6 Hz, 1H), 3.07 (d, J = 13.5 Hz, 1H), 3.36 (d, J = 16.6 Hz, 1H), 6.13 (d, J = 10.4 Hz, 1H), 6.51 (d, J = 10.3 Hz, 1H), 7.14-7.34 (m, 7H), 7.46-7.51 (m, 3H); 13 C NMR (75 MHz, CDCl3) δ 21.3 (CH2), 21.5 (CH2), 27.2 (CH2), 32.7 (CH2), 34.9 (CH2), 44.1 (CH2), 44.3 (Cq), 74.7 (Cq), 115.2 (CH), 116.0 (CH), 116.3 (CH), 125.2 (CH), 125.2 (CH), 126.6 (CH), 128.3 (2CH), 131.1 (2CH), 135.5 (CH), 136.2 (Cq), 137.1 (Cq), 138.5 (CH), 159.9 (Cq), 163.2 (Cq); HRMS: calcd. for C25H26FN2O 389.2014, found 389.2022 (-0.4729 ppm).(5S,8S)-1'-benzyl-1-(4-fluorophenyl)spiro[4H-indazole-5,2'-cyclohexane]-1'-ol (14b):C25H25FN2O; White solid; Mp = 73-75°C; Yield: 13%; M = 388.48 g / mol; IR (ZnSe) ν = 3415, 2935, 1515, 1223, 839 cm -1 ; 1 H NMR (300 MHz, CDCl3) δ 1.46-1.93 (m, 9H), 2.85 (dd, J = 35.4 Hz, J = 13.2 Hz, 2H), 3.00 (q, J = 16.0 Hz, 2H), 6.35 (d, J = 10.3 Hz, 1H), 6.54 (dd, J = 10.3 Hz, J = 0.6 Hz, 1H), 7.17-7.37 (m, 7H), 7.49-7.53 (m, 3H);13 C NMR (75 MHz, CDCl3) δ 20.3 (CH2), 21.3 (CH2), 25.2 (CH2), 31.3 (CH2), 31.7 (CH2), 43.7 (CH2), 45.0 (Cq), 74.6 (Cq), 114.8 (CH), 115.2 (Cq), 116.0 (CH), 116.3 (CH), 125.2 (CH), 125.3 (CH), 126.7 (CH), 128.4 (2CH), 131.2 (2CH), 136.8 (Cq), 136.9 (Cq), 137.9 (CH), 138.3 (CH), 160.0 (Cq), 163.2 (Cq); MS: m/z = 389.2 [M + H] + ; HRMS: calcd. for C25H26FN2O 389.20237, found 389.20155 (-2.102 ppm).

(

  5S, 8S)-1'-4-fluorophenyl)-2-(naphthalen-2-yl)-1',4'-dihydrospiro[cyclohexane-1,5'-indazol]-2-ol (13c): C28H25FN2O; White solid; Mp = 159-161°C; Yield: 49%; M = 424.51 g / mol; IR (ZnSe) ν = 3325, 2936, 1516, 1225, 839 cm -1 ; 1 H NMR (300 MHz, CDCl3) δ 1.65-1.99 (m, 8H), 2.55 (d, J = 16.4 Hz, 1H), 2.66 (td, J = 13.5 Hz, J = 4.2 Hz, 1H), 3.21 (d, J = 16.4 Hz, 1H), 6.23 (d, J = 10.3 Hz, 1H), 6.32 (d, J = 10.3 Hz, 1H), 6.91-7.00 (m, 3H), 7.18 (s, 1H), 7.35-7.44 (m, 2H), 7.59 -7.77 (m, 4H), 7.88 (as, 1H); 13 C NMR (75 MHz, CDCl3) δ 21.4 (CH2), 21.8 (CH2), 27.8 (CH2), 35.0 (CH2), 35.8 (CH2), 45.0 (Cq), 77.0 (Cq), 115.7 (CH), 116.0 (CH), 116.0 (CH), 116.5 (Cq), 125.1 (CH), 125.3 (2CH), 125.6 (CH), 125.9 (CH), 125.9 (CH), 126.4 (CH), 127.4 (CH), 128.2 (CH), 132.3 (Cq), 132.4 (Cq), 134.5 (CH), 135.6 (Cq), 135.6 (Cq), 137.8 (CH), 143.1 (Cq), 159.8 (Cq), 163.1 (Cq); MS: m/z = 425.2 [M + H] + ;

4. 1 .

 1 19. 1-(4-fluorophenyl)-1,6-dihydrocyclohepta -5,6-cyclohexyl[c] pyrazole ( 16)

  H NMR (300 MHz, CDCl3) δ 1.39-2.10 (m, 9H), 2.29 (d, J = 15.6 Hz, 1H), 2.51-2.84 (m, 4H), 3.50-3.62 (m, 1H), 7.13 (t, J = 8.6 Hz, 2H), 7.45-7.51 (m, 3H); 13 C NMR (75 MHz, CDCl3) δ 19.6,19.7 (CH2), 21.1, 21.1 (CH2), 22.7, 23.5 (CH2), 30.2, 30.2 (CH2), 30.4, 30.5 (CH2), 31.5, 32.4 (CH2), 37.5, 37.5 (CH2), 74.1, 76.2 (CH), 116.0, 116.3 (2CH), 117.0, 117.2 (2Cq), 124.8, 124.8 (CH), 124.9, 124.9 (CH), 137.5, 137.8 (2Cq), 139.0, 139.3 (CH), 159.8, 163.1 (2Cq); MS m/z = 301.3 [M+H] + .

  C NMR (75 MHz, CDCl3) δ 19.1, 19.3 (CH2), 20.5 (CH2), 27.0, 27.4 (CH2), 29.5, 30.2 (CH2), 31.0, 31.2 (CH2), 37.4, 37.6 (CH2), 54.0 (CH3), 115.7, 115.9 (Cq), 116.1, 116.3 (2CH), 124.9, 125.0 (2CH), 136.2, 136.2 (Cq), 136.7, 137.3 (Cq), 139.1, 139.4 (CH), 159.8, 163.1 (Cq); MS m/z = 438.1 [M+H] + .

  H NMR (300 MHz, CDCl3) δ 1.70-1.73 (m, 6H), 2.28 (s, 3H), 2.23 (as, 2H), 2.75 (d, J = 16.0 Hz, 1H), 3.10 (d, J = 16.0 Hz, 1H), 6.10 (d, J = 10.1 Hz, 1H), 6.42 (d, J = 10.1 Hz, 16 1H), 7.15-7.20 (m, 4H), 7.39-7.48 (m, 3H), 7.70 (d, J = 8.3 Hz, 2H), 13 C NMR (75 MHz, CDCl3) δ 21.0 (CH2), 21.6 (CH3), 23.5 (CH2), 25.9 (CH2), 29.2 (CH2), 37.1 (CH2), 45.1 (CH2), 115.1 (CH), 115.8 (Cq), 116.1 (CH), 116.4 (CH), 125.0 (CH), 125.1 (CH), 127.9 (2CH), 129.5 (2CH), 134.7 (CH), 135.3 (Cq), 136.2 (Cq), 138.1 (CH), 143.9 (Cq), 160.0 (Cq), 163.2 (Cq), 163.2 (Cq); HRMS: calcd. for C25H26FN4O2S 465.175501, found 465.17683 (2.86 ppm).

5 (

 5 Cq), 113.8 (CH), 115.4 (Cq), 116.0 (CH), 116.3 (CH), 125.2 (CH), 125.3 (CH), 127.3 (CH), 132.2 (CH), 138.4 (CH), 139.3 (CH), 160.0 (Cq), 163.3 (Cq); MS m/z = 281.2 [M+H] + ; HRMS: calcd. for C18H18FN2 281.14485, found 281.14570 (3.011 ppm).

Table 1 . Reaction of organometallics with ketone 10b

 1

	R	Conditions a,b	Diastereoisomers c
	H	DIBAL-H	11 (22%)	12 (68%)
	1-propynyl	1-propynylMgBr	13a (61%)	14a (NI)
	benzyl	benzylMgBr	13b (81%)	14b (13%)
	2-Naphtyl	2-naphtyl-Li	13c (49%)	14c (NI)
	p-MeOPh	p-MeOPhMgBr	13d (48%) d	14d (NI)
	a reactions performed in THF; b not optimized; c yields of pure compounds after chromatography or/and
	recrystallization unless otherwise mentioned; d conversion (40% starting material was recovered); NI = Not
	isolated.

  1 g, 69%). C12H16O3; yellow liquid; yield: 69%; M = 208.11 g/mol; IR (KBr): 2953, 1680 cm -1 ; 1 H NMR (400 MHz; CDCl3): 1.76-2.00 (m, 7H), 2.19-2.26 (m, 1H), 2.35-2.43 (m, 1H), 2.56-2.62 (m, 1H), 3.85-3.94 (m, 4H), 5.97 (d, J = 10.4 Hz, 1H), 6.92 (d, J = 10.0 Hz, 1H); 13 C NMR (100 MHz; CDCl3): 18.53, 28.51, 33.86, 34.52, 34.58, 48.42, 64.83, 65.25, 119.54, 128.86, 153.80, 199.91; MS (APCI): m/z = 209.0 (M+1); 4.1.7. 1,4-dioxadispiro[4.0.5 -6.

  C NMR (400 MHz; CDCl3): 17.85, 25.64, 33.82, 35.07, 49.82, 65.19, 65.20, 115.25, 115.49, 115.94, 116.17, 119.25, 125.10, 125.19, 134.78, 138.01, 160.25, 162.71; MS: m/z = 327 [M+1] + .

  Yield: 48%; M = 404.48 g / mol; IR (ZnSe) ν = 3368, 2941, 1517, 1247, 842 cm -1 ; 1 H NMR (300 MHz, CDCl3) δ 1.60-1.91 (m, 7H), 2.45-2.54 (m, 1H), 2.53 (d, J = 16.4 Hz, 1H), 3.10 (d, J = 16.3 Hz, 1H), 3.70 (s, 3H), 6.25 (q, J = 10.1 Hz, 2H), 6.71 (d, J = 9.0 Hz, 2H), 7.07-7.13 (m, 2H), 7.24-7.30 (m, 3H), 7.38 (d, J = 9.0 Hz, 2H); 13 C NMR (75 MHz, CDCl3) δ 21.5 (CH2), 21.8 (CH2), 27.7 (CH2), 34.9 (CH2), 35.9 (CH2), 44.9 (CH2), 55.3 (CH3), 76.6 (Cq), 112.5 (2CH), 115.8 (CH), 115.9 (CH), 116.2 (CH), 116.6 (Cq), 125.1 (CH), 125.2 (CH), 127.9 (2CH), 135.1 (CH), 135.9 (Cq), 138.0 (Cq), 138.1 (CH), 158.4 (Cq), 159.9 (Cq), 163.2 (Cq); HRMS: calcd. for C25H26O2N2F405.19728, found 405.19811 (2.042 ppm).

	1-(4-fluorophenyl)-1'-(4-methoxyphenyl)spiro[4H-indazole-5,2'-cyclohexane]-1'-ol (13d): C25H25FN2O2; White
	solid; Mp = 186-188°C;


Ravi D Raninga

Robert A Jagt

Dr Solène Béchu

Prof. J Tahmida N L Huq

Dr Mark Nikolka

Yenhung Hung Lin

Mengyao Sun

Zewei Li

Muriel Wen Li

Yen-Hung Lin

Dr Muriel Bouttemy

Dr Mathieu Frégnaux

Henry J Snaith

Dr Philip Schulz

Judith L Macmanus-Driscoll

Dr Robert L Z Hoye
email: r.hoye@imperial.ac.uk

Dr R L Z Macmanus-Driscoll

Hoye

Dr Y.-H Lin

Prof. H J Snaith

Strong performance enhancement in

Keywords: lead-halide perovskite, photovoltaics, atmospheric pressure chemical vapor deposition, oxide buffer layer

Introduction

Lead-halide perovskites are attracting substantial attention for energy and optoelectronic applications, owing to rapidly rising efficiencies in devices, including photovoltaics, [1] lightemitting diodes, [2,3] X-ray detectors [4] and photodetectors. [5] These materials have the stoichiometry ABX3, in which A is a monovalent cation (e.g., methylammonium or MA + ), B a divalent cation (i.e., Pb 2+ ) and X a halide (e.g., I -). As such, lead-halide perovskites are versatile materials with band gaps that can be tuned over the entire visible light range by changing the composition. [6] These materials exhibit an exceptional tolerance to point defects, i.e., the leadhalide perovskites can achieve long charge-carrier lifetimes and high luminescence quantum yields, despite being grown from solution with high densities of vacancies and interstitials. [7,8] An important restriction, however, is the limited thermal, environmental and mechanical stability of lead-halide perovskites. MAPbI3, in particular, is thermodynamically unstable [START_REF] Nagabhushana | Proc. Natl. Acad. Sci[END_REF] and thin films have been reported to degrade in ambient air at room temperature within days. [START_REF] Hoye | [END_REF] Improved thermal stability has been achieved in 'triple-cation' perovskites, in which the MA + is replaced with a mixture of Cs + , formamidinium (FA + ) and MA + . [11] However, the photovoltaic performance of triple-cation perovskites still decreases from 20% to 18% after 250 h continuous operation at room temperature in an inert nitrogen environment. [11] Similarly, the low mechanical stability of the perovskites results in films being damaged when bombarded by energetic particles, such as during sputter-deposition. [12] Recently, the use of compact oxides grown over the perovskite and organic charge transport layer has led to significant improvements in stability. By depositing a 50 nm thick layer of Al-doped ZnO nanoparticles on p-i-n structured perovskite solar cells, Bush et al. successfully protected the perovskite from mechanical damage when growing a transparent indium tin oxide (ITO) electrode on top by sputter-deposition. The resultant semi-transparent perovskite top-cells were used in fourterminal tandems with silicon. [12] However, the nanoparticle layer needed to be thick to be pinhole-free, leading to series resistance losses. [12,13] This limitation was subsequently overcome by using atomic layer deposition (ALD) to grow a pinhole-free, thin bilayer of 4 nm SnOx and 2 nm zinc tin oxide. [13] ALD has also recently been used to grow a 18-40 nm thick layer of amorphous TiO2 over triple-cation perovskite, which protected the perovskite for 2 h in acidic electrolytes, allowing them to be used as photocathodes for water splitting. [14] Whilst ALD is now used in the industrial-scale production of silicon solar cells, deposition times are long due to the low growth rate and need to carry out the reaction under vacuum. For example, growing 7 nm ALD SnO2 at 100 °C takes 1 h. [15] Sputter-deposition grows oxides faster but usually damages the perovskite. [12,13,16] A recent work showed that perovskites with sputtered ZnO buffer layers were less efficient than similar devices with spin-coated ZnO nanoparticle buffer layers (12.5% vs. 16.1% respectively). [17] Although a wide range of deposition methods and processing conditions can be used to grow oxide charge transport layers beneath the perovskite, only a small selection of these methods and a narrow range of growth temperatures have been shown to be compatible with growing oxides over the perovskite. Apart from spin-coating colloidal nanocrystals, ALD and sputterdeposition, thermal evaporation has also been used, but mainly for high work function n-type oxides to extract holes rather than low work function oxides for extracting electrons. In order to manufacture oxide buffer layers on a large scale for device applications (e.g., top-cells or photocathodes), the growth technique should: 1) yield conductive oxides without damaging the perovskite, 2) result in pinhole-free and dense films, 3) feature rapid but uniform film growth, 4) be scalable, and 5) produce films that are conformal to textured substrates. The latter is particularly important for applications in tandem solar cells with silicon, in which the highest efficiencies have been achieved with front-textured silicon, requiring conformal perovskite, charge transport and oxide buffer layers. [18,19] However, the current techniques used for growing oxide buffer layers are not able to achieve all requirements simultaneously (Table 1). Whilst dense, conformal and uniform oxide films can be achieved by ALD and thermal evaporation, both techniques are slow, vacuum-based methods with limited throughput. By contrast, spincoating oxide nanoparticles is a fast and facile method on a lab-scale without requiring vacuum, but is not conformal and is challenging to scale-up to the module-level. A particular challenge with all growth methods is that the thermal instability of the lead-halide perovskite limits the maximum processing temperature which can be used for the deposition of oxides over perovskite films. For example, Palmstrom et al. found that cesium-formamidinium-based perovskites (more thermally-stable than MAPbI3) degraded when ALD SnO2 was deposited at 110 °C or above. [15] As shown in Table S1, SI, oxides grown by any of the current techniques have typically been processed at up to 100 °C, and in many cases at room temperature. But this limits the electronic properties of the oxides achievable, since higher mobilities and, presumably in some cases, improved band alignment of the oxide with the perovskite is achieved at higher deposition or annealing temperatures. [20][21][22] Variants of ALD have also been proposed that can grow pinhole-free and conformal oxides more rapidly. These are pulsed chemical vapor deposition (pulsed-CVD, in which the purge times in ALD are reduced) [15] and spatial atomic layer deposition (in which the metal precursor and oxidant are spatiallyseparated). [23,[START_REF] Hoye | Adv. Micro-and Nanomater. Photovoltaics[END_REF] However, Palmstrom et al. found that cesium-formamidinium-based perovskites still degrade when depositing SnO2 buffer layers at 110 °C or above by pulsed-CVD. [15] Riedl et al. found that when increasing the temperature for growing SnO2 on perovskites by spatial ALD to above 80 °C, there was still a decrease in the efficiency of MAPbI3 solar cells. [START_REF] Hoffmann | [END_REF] These methods are therefore not suited to overcome the challenges of the current techniques for growing oxide buffer layers on perovskites. a '-' signifies partial fulfilment b Processing window captures the range of deposition temperatures compatible with growing on perovskites, range of oxidants that can be used, extent to which the deposition method damages the perovskite and ultimately the efficiencies that can be achieved An unexplored alternative for oxide film growth over lead-halide perovskites is atmospheric pressure chemical vapor deposition (AP-CVD). AP-CVD uses the same precursors as ALD, but mixes them in the gas phase to obtain CVD rather than self-limiting growth (Figure 1a). Thus AP-CVD has higher growth rates per unit time and per cycle than spatial ALD. [23,26] Also, AP-CVD processes oxides under ambient conditions without a vacuum chamber and is compatible with high-throughput roll-to-roll manufacturing, unlike pulsed-CVD. [23,[START_REF] Hoye | Adv. Micro-and Nanomater. Photovoltaics[END_REF][27][28][29] We previously developed a gas manifold (Vertical Cambridge University Close Proximity reactor, or V-CUCP) that distributes the gas precursors uniformly across the manifold and guides the gases vertically down to the substrate held tens of µm below (Figure 1a). ZnO films grown by AP-CVD using the V-CUCP reactor were deposited at similar temperatures as ALD, with comparable thickness uniformity, [23,[START_REF] Hoye | Adv. Micro-and Nanomater. Photovoltaics[END_REF]30,31] conformality to high-aspect ratio nanowires, [START_REF] Hoye | Adv. Micro-and Nanomater. Photovoltaics[END_REF]32] and with growth rates of 1.1 nm s -1 , which was an order of magnitude larger than by ALD.

Although AP-CVD has the potential to fulfil the film quality, growth rate, scalability and conformality requirements for manufacturing oxide buffer layers, a key question is whether the shorter deposition times achievable can allow higher deposition temperatures to be used, and whether this can lead to increased device performance. Furthermore, we have previously only demonstrated the growth of ZnO and Zn1-xMgxO on MAPbBr3 for light-emitting diodes. [33] However, ZnO is known to degrade MAPbI3 perovskites due to the high isoelectric point, [34,35] and groups have reported that the diethylzinc precursor itself may react with the perovskite. [26] It is therefore important to understand whether AP-CVD can grow alternative oxides that are chemically inert to iodide-based perovskites and overcome the limitations of the current methods for growing oxide overlayers on lead-halide perovskites.

In this work, we aim to understand whether AP-CVD can be used to broaden the processing window of n-type oxides grown over lead-halide perovskite solar cells. For the n-type oxides, we investigate TiOx and SnOx, grown by AP-CVD over perovskites for the first time, and compare with ZnO. We investigate the properties of the oxides grown, and compare their deposition on perovskite solar cells based on thermally-sensitive MAPbI3 and the more thermally-stable triple-cation perovskites (Cs0.05(MA0.17FA0.83)0.95Pb(I0.84Br0.16)3). For all oxide films, we compare the oxide growth at 100 °C with O2 gas oxidant vs. 150 °C with H2O vapor oxidant. In this work, we refer to these as mild and strong growth conditions respectively. We then investigate the impact of the oxide films formed under these two conditions on the performance of perovskite solar cells. Both the mild and strong growth conditions are typically inaccessible when using ALD to grow oxides over perovskites, either because chemisorption is not possible (mild conditions), [36] or because the perovskite would degrade (strong conditions).

Strong growth conditions are also not accessible by solution-processing, thermal evaporation or sputter-deposition for growing oxide buffer layers on perovskites.

Results and Discussion

TiOx Overlayers

We began by focusing on TiOx. By varying the exposure time per cycle in our V-CUCP reactor from 27 ms to 800 ms, we found the growth regime to be CVD rather than ALD based on the linear dependence of the film thickness on exposure time, with no evidence of saturation being reached (Figure 1b; in ALD, the Ti precursor pulse times are typically 100-150 ms). [14,37] Under mild processing conditions, the growth rate was 0.63±0.03 nm s -1 , while under strong processing conditions, the growth rate was 1.19±0.04 nm s -1 (Figure 1c). The growth rates per AP-CVD cycle are shown in Figure S1, SI. The growth rates achieved by AP-CVD for TiOx are over two orders of magnitude larger than TiOx grown by ALD at comparable temperatures. [38] Our X-ray photoemission spectroscopy (XPS) measurements of the TiOx films (Figure S2, SI) had no distinct Cl 2p core level peak, indicating a high reaction yield of the TiCl4 precursor, with insignificant Cl incorporation in the resulting TiOx films. From XPS measurements of TiOx grown on gold, we found the x values to be 2.00±0.05 under mild and strong conditions. X-ray diffraction measurements showed the films to be amorphous (Figure S4, SI), which is consistent with ALD films grown at comparable temperatures. [39] The refractive indices of the TiOx films were 2.2 (mild conditions) and 2.3 (strong conditions) at 640 nm wavelength (Figure S5, SI), which are comparable to the refractive indices of TiO2 grown by ALD under fully-saturated conditions at similar temperatures. [39,40] This indicates that AP-CVD TiOx was dense and compact, with the films grown under strong conditions being slightly denser. In addition, atomic force microscopy measurements showed the films to be free from pinholes (Figure S6, SI).

To understand whether the growth of AP-CVD TiOx over perovskites leads to damage, we used strong processing conditions (150 °C, H2O vapor) with the most unstable perovskite (MAPbI3).

After we grew 5 AP-CVD cycles of TiOx (7 nm film thickness, as determined from Figure S1, SI) directly over MAPbI3 thin films, there was no noticeable visual change in the film appearance or morphology, as measured by atomic force microscopy (Figure 1d,e). This suggests that the rapid growth of TiOx avoided the degradation of thermally-sensitive MAPbI3.

This contrasts to previous reports for ALD TiOx, in which a 50 nm thick PC61BM layer was required over MAPbI3 to avoid degradation when growing TiOx on top by ALD, due to the much longer total deposition time of approximately 1 h. [41] We next focused on the structural and optoelectronic properties of MAPbI3 films after the growth of the AP-CVD TiOx overlayer. To keep the system investigated comparable to the structure used in photovoltaic devices, we covered the MAPbI3 film with a 5 nm layer of PC61BM (thickness measured by atomic force microscopy). In this layout, the samples mimic the layer stack in the solar cells with comparable chemical reactivity between the individual layers. At the same time, the PC61BM layer is not sufficiently thick to protect the perovskite from thermal damage, and there would thus be more degradation than in full devices. However, when we measured the diffraction pattern of the PC61BM-coated MAPbI3 samples after depositing 5 AP-CVD cycles of TiOx under mild and strong conditions, the films remained phase-pure with no PbI2 peaks appearing (Figure 2a; close-up in Figure S7, SI). This suggests that the rapid growth of TiOx by AP-CVD led to an avoidance of bulk structural damage. By contrast the growth of TiO2 with comparable thickness by ALD at only 100 °C has been reported to lead to degradation. [41] We also observed no significant quenching of the photoluminescence (PL) lifetime when TiOx was grown by AP-CVD over MAPbI3/PC61BM under strong processing conditions (Figure 2b). Similarly, TiOx grown under strong conditions directly over MAPbI3 films did not lead to faster PL decay (Figure S8, SI). These suggest that no extra non-radiative recombination pathways were introduced by AP-CVD growth. To determine whether the growth of the AP-CVD TiOx overlayer damaged the perovskite surface and to access potential chemical reactions at the interface, [42] we performed X-ray photoemission spectroscopy measurements (hn = 1486.6 eV) on a set of sister MAPbI3 samples covered with a 5 nm layer of PC61BM. The thin PC61BM layer was non-compact and we were able to capture the signal from the perovskite surface. The survey spectra are shown in Figure S3a, SI. Figure 2c shows that the samples with no oxide have an O 1s core peak centered at 532.6 eV (Figure S3b&c, SI), which is attributed to adventitious oxygen and oxygen in the carboxylic acid group of the PC61BM molecule. [43] Following the deposition of the TiOx overlayers, another O 1s core peak centered at a binding energy of 531.1 eV appeared (Figure 2c & Figure S3b&c, SI). This has been attributed to oxygen bonded to titanium. [44] These results are consistent with the Ti 2p3/2 core level spectra, which only have peaks for the samples covered with TiOx (Figure S3d-f, SI). Figure 2d shows the N 1s core levels. The peak centered at 402.5 eV is consistent with nitrogen present in methylammonium. [45] Following TiOx deposition, no N 1s core peaks associated with degradation products from MA + (which would be located at lower binding energies) [45] were found. The N 1s full width at half maximum (FWHM) also did not become broader and the N/Pb ratio did not decrease (Table 2). Both suggest that the thermally-sensitive MA + cation was not damaged and may not have been significantly removed from the lattice. The inorganic lattice of MAPbI3 also exhibited no damage, since no metallic Pb 0 core peaks (Figure 2e) or oxyiodide (Figure 2f) peaks were found.

Whilst the I/Pb ratio was lower after the deposition of TiOx (Table 2), the ratio remains within the 'defect-tolerant' region for MAPbI3. [45] Our XPS results therefore indicate that the surface of MAPbI3 was not thermally damaged after the deposition of AP-CVD TiOx on the MAPbI3/(5 nm) PC61BM stack owing to the rapid growth rates achievable. To determine the effect of the TiOx growth conditions on the performance of MAPbI3 solar cells, we fabricated devices using a p-i-n structure (Figure 3a), with solution-processed NiOx as the hole transport layer and 40 nm thick PC61BM as the electron transport layer (as detailed in the Experimental Procedures). We used bathocuproine (BCP) and Ag for the top electrode, in which the BCP acted as an interface modifier to ensure no barrier to electron extraction. Devices with a TiOx overlayer grown under mild conditions not only showed no decrease in performance compared to the control, but rather gave an improvement in efficiency (Figure 3b). Similarly, devices with TiOx grown under strong conditions gave more efficient devices than the control.

We then kept the oxidant used to H2O vapor and varied the TiOx growth temperature from 60 °C to 200 °C. Surprisingly, we found that there was no significant decrease in the power conversion efficiency compared to the control until the growth temperature was 180 °C (Figure 3b). This is significantly higher than the perovskite-compatible growth temperatures reported for solution processing, ALD or TiO2, in which the oxide layers could only be processed at up to 100 °C (Table SI, SI). [35] We found that the range of perovskite-compatible growth temperatures was larger for triple-cation perovskites. With these samples, the power conversion efficiencies did not significantly decrease until the growth temperature was above 180 °C (Figure 3c). Even for the triple-cation perovskite devices with TiOx grown at 220 °C, there were some devices that were more efficient than the control (Figure S10, SI). This suggests that despite such elevated processing temperatures, not all of the perovskite device was degraded, which contrasts with perovskite devices that have solution-processed, sputter-deposited or ALD overlayers. [15,41] Our most efficient devices were triple-cation perovskites that had TiOx grown at 150 °C using H2O vapor as the oxidant (Figure 3b&c). When we replaced the BCP/Ag top electrodes with more reflective Al electrodes to obtain a more efficient control device (15.9% power conversion efficiency), adding a TiOx layer grown under strong conditions improved the performance to 17.1% (details in Figure S11 and Table S2, SI). The improvement in performance over the control was primarily due to an increase in the shunt resistance from 3000±1000 W cm 2 (control) to 4000±3000 W cm 2 (with TiOx), which correlated with increases in the fill factor from 70±3% to 76.4±0.3%. This is likely due to the spin-coated PC61BM layer being noncompact (Figure S12, SI) and the dense AP-CVD TiOx forming a pinhole-free layer covering it, thereby reducing shunt pathways.

But growing TiOx at 150 °C also led to more efficient performance compared to other growth temperatures (Figure 3b&c). We hypothesized that the improvement in device performance when increasing the TiOx growth temperature to 150 °C was due to a reduction in the resistivity of the oxide films. To test this, we grew 300 nm thick AP-CVD TiOx on ITO and evaporated Al on top. We measured the current density against applied bias and fitted the linear regime to calculate the resistivity (refer to Figure S13, SI for representative measurements). From these measurements, we found that the resistivity decreased from (4.7±0.8) × 10 4 W cm (100 °C) to

(1.7±0.2) × 10 3 W cm (150 °C), as shown in Figure 4. This correlated with a decrease in the series resistance of the MAPbI3 solar cells from 3.9±0.6 W cm 2 (100 °C) to 2.2±0.2 W cm 2 (150 °C), and an increase in the fill factor from 56±1% (100 °C) to 74±1% (150 °C). Similar trends were observed with the triple-cation perovskite devices. This shows the importance of being able to open-up the processing window for TiOx in order to achieve higher-performing devices. We note that the TiOx films grown at temperatures above 150 °C had comparable or lower resistivity (Figure 4). However, further increases in efficiency were not observed. By contrast devices with TiOx grown at 180 °C and higher had larger series resistance and lower fill factors. This is likely due to the thermally-induced degradation of the perovskite, which manifested as an overall reduction in the power conversion efficiency compared to the control when growth temperatures were higher than 180 °C.

We also note that TiOx films grown at 100 °C using O2 gas as the oxidant have similar resistivity ((4±3) × 10 4 Ω cm) as the films grown using H2O vapor ((4.7±0.8) × 10 4 Ω cm). However, in both MAPbI3 and triple-cation perovskite devices, the series resistance of the devices with TiOx grown with O2 gas was lower than those with H2O vapor. This was likely because the TiOx films were approximately half the thickness, due to the lower growth rate (Figure 1b), since the same number of AP-CVD cycles were used. To determine whether AP-CVD can be more generally applied to enable other n-type oxides to be grown over perovskites across a wider processing window, we investigated ZnO and SnOx.

ZnO and SnOx Overlayers

We have previously shown that ZnO deposited with our V-CUCP reactor is grown under CVD mode with a growth rate of 1.1 nm s -1 . [30] We investigated the growth regime of SnOx and found it to also be CVD from the linear relationship between film thickness and exposure time (Figure S14a, SI). The growth rates were 0.41±0.04 nm s -1 (mild growth conditions) and 0.27±0.02 nm s -1 (strong growth conditions), as shown in Figure S14b, SI. These growth rates were two orders of magnitude larger than literature reports for ALD SnO2 grown at 80 °C [25] or 100 °C, [14] as well as being an order of magnitude higher than pulsed-CVD. [14] The films grown were amorphous (Figure S15, SI), and the refractive indices were 1.8 at a wavelength of 632 nm under both growth conditions (Figure S16, SI), which is similar to previous reports of dense ALD SnO2 films grown at these temperatures. [22] Atomic force microscopy measurements of the films showed them to be free from pinholes (Figure S17, SI). The AP-CVD SnOx films were uniform over the deposition area, with the thickness varying by only 1% (two standard errors compared to the average thickness), as shown in Figure S18, SI. From X-ray photoemission spectroscopy measurements, we found the x value for SnOx grown under both mild and strong conditions to be 1.98±0.07 (Figure S19&S20, SI). We previously found that AP-CVD ZnO grown in the same reactor has a thickness variation of only 3% over the entire deposition area. [41] We grew 100 AP-CVD cycles of ZnO and SnOx (2 min total deposition time) directly onto MAPbI3 and triple-cation perovskite films. The control triple-cation perovskite films without oxide overlayers have a small quantity of residual PbI2, which has been commonly observed in previous works. [42,43] The growth of the ZnO overlayers under mild conditions resulted in a higher relative intensity of the PbI2 peak for both MAPbI3 and triple-cation perovskite films (Figure 5a, Figure S21a&b, SI and Figure S22a&b, SI). This may have been due to ZnO itself degrading the perovskite due to its high isoelectric point, as discussed in previous reports. [44,45] But with the SnOx overlayers, the MAPbI3 films did not form a PbI2 diffraction peak, even under strong growth conditions (Figure 5b & Figure S21c, SI and Figure S22c, SI). For the triple-cation perovskites, the residual PbI2 peak did not increase when SnOx was grown on top under mild conditions (Figure 5b). However, under strong growth conditions, there was a small increase in the PbI2 peak and small decrease in the intensity of the (002) and (110) perovskite peaks, as well as the appearance of a small peak at 11.7° 2θ (Figure S21d, SI and Figure S22d, SI), which we attribute to the appearance of the cesium lead halide delta phase. [46] It has previously been reported that at temperatures above 110 °C, the tetrakis(dimethylamido)tin precursor can remove the FA + cation from the perovskite. [15] This would agree with our observations, in which the deposition of the SnOx overlayer at 150 °C could have removed a small quantity of FA + , resulting in a small increase in PbI2 content and the formation of a cesium lead halide delta phase due to a more Cs-rich perovskite being present. However, we note that the intensity of both the PbI2 and delta-phase peaks remain small, whereas previous reports of ALD or pulsed-CVD SnO2 grown at 150 °C on Cs-FA perovskites resulted in the PbI2 peak being larger than the perovskite (002) & (110) peaks. We attribute the limited bulk damage to the perovskite to the deposition time being significantly shorter (2 min here vs. <15 min for pulsed-CVD and ~60 min for ALD). [15] In addition, our results suggest that MA + was not as significantly affected by the tin precursor, hence the absence of PbI2 formation in MAPbI3.

Overall, our results show the growth of a SnOx overlayer to not be as damaging to the bare perovskite films as ZnO, thus showing the importance of looking beyond ZnO for AP-CVD oxide overlayers for lead-halide perovskites.

Consistent with our X-ray diffraction measurements, we found that the growth of a ZnO overlayer led to a significant decrease in device performance, especially for MAPbI3 devices with ZnO grown under strong conditions (Figure 5c&d). This is consistent with an increased PbI2 content in the perovskite films following the deposition of the oxide overlayer. By contrast, the growth of the AP-CVD SnOx overlayer under both mild and strong conditions did not lead to an as significant decrease in performance. This is consistent with the X-ray diffraction measurements showing that only a small increase in PbI2 content occurred following the growth of the SnOx overlayer on the triple-cation perovskites under strong conditions. Indeed, the growth of SnOx using mild conditions led to comparable (MAPbI3) or improved (triple-cation perovskite) performance compared to the control devices (Figure 5c&d).

After optimizing the thickness of the SnOx layer (grown under mild conditions) to 60 nm, we achieved a triple-cation perovskite device with a power conversion efficiency of 19.7% (reverse sweep)/19.3% (forward sweep), which was close to the steady-state efficiency of 19.4% (Figure 5e, inset). This was higher than the performance of the control device (16.5% reverse sweep;

16.3% forward sweep; 16.5% steady-state efficiency). The improvement in efficiency was statistically significant, with the SnOx-coated devices having an average efficiency of 18±1%, compared to 15±1 % for the control. The means were calculated from six devices for each condition, and the average forward and reverse sweep efficiencies were the same. The improvement in performance was primarily due to an increase in the fill factor from 72±2%

(control) to 82±2% (60 nm SnOx). This correlated with an increase in the shunt resistance from 1300±600 W cm 2 (control) to 3000±1000 W cm 2 (60 nm SnOx). Our dark current-density vs.

voltage measurements (Figure 5f) are consistent with a reduction in shunting with the SnOx overlayer, in which the coated triple-cation perovskite devices showed lower reverse-bias dark current density and a higher rectification ratio. This is similar to our results with the TiOx overlayer and is likely due to the dense oxide covering shunt pathways in the PC61BM layer (Figure S12, SI). We note that we only measured the dark current density curves to -0.2 V because these devices exhibited voltage breakdown at more negative biases. The fill factor of our champion device with AP-CVD SnOx was 84%. By contrast, perovskite devices with oxide buffer layers grown by solution-processing and sputter deposition have lower fill factors because of current leakage through less dense films (solution-processing), [48] or because of damage to the perovskite surface and more resistive oxides grown under sub-optimal conditions (sputter deposition). [17] To our knowledge, the champion steady-state efficiency of 19.4% is currently the highest reported for a perovskite device with an oxide buffer layer deposited by ALD, solution processing or sputter deposition (Table S1, SI).

Broad Applications of AP-CVD Oxides in Devices

To investigate whether we can apply our AP-CVD SnOx to cover textured perovskite films, we grew wrinkled Cs0.17FA0.83Pb(I0.83Br0.17)3 perovskites (Figure 6a). These thin films wrinkle during annealing due to compressive stresses, [47] which is achievable by tuning the fraction of dimethyl sulfoxide in the perovskite solvent. After depositing PC61BM by solution processing, clusters and streaks formed (Figure 6b), suggesting non-uniform coverage of the PC61BM.

Depositing 20 nm SnOx on top resulted in the same morphology as the PC61BM-coated sample, suggesting conformal coverage (Figure 6c). We imaged a cross-section of the sample with PC61BM and SnOx, and found that while the PC61BM did not cover some regions of the wrinkled perovskite, the SnOx layer was conformal over the entire surface of the sample (Figure S23, SI). The devices with only a PC61BM layer exhibited significant shunting (Figure 6c,d), with fill factors of 38±2% and shunt resistances of only 300±50 W cm 2 . However, after the growth the SnOx overlayer, the fill factor increased and reverse-bias dark current-density decreased with increasing thickness (Figure 6c,d). Through the use of AP-CVD SnOx, we were able to increase the power conversion efficiency from 6.5±0.6% (no oxide; forward sweep) to 10.9±0.5% (115 nm SnOx; forward sweep). This has potential future applications in conformally covering evaporated perovskite films grown over textured silicon cells for tandem photovoltaic devices, which are becoming increasingly popular because they have led to the most efficient perovskite-silicon tandems, and industry-standard silicon solar cells are fronttextured to reduce light scattering. [48,49] We note that the AP-CVD SnOx and TiOx films exhibit high transmittances >90% in the visible light wavelength range, rising to >98% in the nearinfrared wavelength range (Figure S24a&b, SI). This makes them suitable as buffer layers for a semi-transparent perovskite top-cell that have minimal contribution to parasitic optical losses.

Finally, we note that when we grew 60 nm SnOx over (Cs,FA)-based perovskites with a more optimized composition and device structure, with less wrinkling, we improved the median efficiency from 14.7% (no SnOx) to 15.4% (with SnOx; peak value of 16.8%), as detailed in

Conclusion

Growth of oxide buffer layers over lead-halide perovskites and their organic charge transport layers is critically important for protecting against environmental and mechanical damage, and requires finely-tuned processing parameters compatible to the thermally-unstable perovskite layer. In this work, we have shown AP-CVD to overcome the limitations of the current methods to fulfil all key requirements for growing oxide buffer layers on lead-halide perovskites. AP-CVD films are pinhole-free and uniform over large area, can be grown rapidly without vacuum, and are conformal to textured perovskites. Using TiOx as the main test material (x = 2.00±0.05), we found that the short processing times allowed us to broaden the range of deposition temperatures compatible with the perovskite stack from <110 °C (spin-coating, ALD, sputterdeposition and thermal evaporation) to ³180 °C (AP-CVD). TiOx grown at higher temperature has lower resistivity, resulting in efficiencies improving by >2% in single-junction perovskite solar cells.

More broadly, we showed that AP-CVD can also grow uniform SnOx (x = 1.98±0.07) and ZnO on perovskites, but the ZnO degraded the perovskite, emphasizing the importance of looking beyond ZnO for buffer layers. Using pinhole-free AP-CVD SnOx to cover the non-continuous PC61BM layer in triple-cation perovskite devices, we reduced current leakage, resulting in fill factors reaching 84% and steady-state efficiencies increasing from 16.5% (no SnOx) to 19.4%

(with 60 nm SnOx). To our knowledge, 19.4% is currently the highest power conversion efficiency amongst p-i-n structured perovskite solar cells with oxide buffer layers grown by any practical coating method. AP-CVD is therefore a versatile technique that is appealing for manufacturing oxide buffer layers for perovskite optoelectronic devices.

Figure 1 .

 1 Figure 1. (a) Illustration of growing oxides on lead-halide perovskite films by AP-CVD. Metalprecursor vapor (M), oxidant (Ox) and inert gas (I, in this case Ar) are introduced to the gas manifold from both sides (cross-section of manifold shown), where they are guided vertically down to the substrate. The metal precursor and oxidant mix in the gas phase, and the oxide thin film is grown by chemical vapor deposition. The oxide thickness depends on the number of times the substrate is moved through the gas channels. The oxide is grown by a soft chemicalbased method (unlike sputter-deposition), and the growth rates are high with no vacuum required (unlike ALD and thermal evaporation). Properties of AP-CVD TiOx grown onto MAPbI3. (b) Thickness of TiOx against exposure time per AP-CVD cycle, (c) thickness against total deposition time. Morphology, measured by atomic force microscopy, of (d) MAPbI3 thin film deposited on glass and (e) a sister sample with TiOx grown directly on top at 150 °C using H2O vapor as the oxidant. The root mean square roughness for both samples was 14 nm. Photographs of the samples measured are inset.

Figure 2 .

 2 Figure 2. Analysis of MAPbI3 films coated with a non-compact 5 nm layer PC61BM. (a) Diffraction patterns and (b) time-resolved photoluminescence (PL) of MAPbI3/PC61BM with TiOx grown on top. * denotes the position of where the PbI2 (001) peak would be. X-ray photoemission spectra of (c) O 1s, (d) N 1s, (e) Pb 4f and (f) I 3d core level regions for MAPbI3/PC61BM thin films compared to corresponding samples with TiOx (5 AP-CVD cycles) grown on top. The legend for parts c) -f) are the same.

Figure 3 .

 3 Figure 3. (a) Device structure used. The AP-CVD oxide here was TiOx. Power conversion efficiency of (b) MAPbI3 and (c) triple-cation perovskite solar cells as a function of the temperature of the platen the samples were mounted on when depositing an overlayer of TiOx by AP-CVD. The triple-cation perovskite was Cs0.05(MA0.17FA0.83)0.95Pb(I0.84Br0.16)3. The blue points are for cells with TiOx grown under strong conditions. The red point is for cells with TiOx grown under mild conditions. These are compared to cells with no oxide overlayer (control). In each case, the performance of six samples was averaged. The error bars each represent two standard errors.

Figure 4 .

 4 Figure 4. Resistivity of TiOx grown at different temperatures using H2O vapor as the oxidant.We note that the TiOx films grown at temperatures above 150 °C had comparable or lower resistivity (Figure4). However, further increases in efficiency were not observed. By contrast

Figure 5 .

 5 Figure 5. Growth of AP-CVD ZnO and SnOx on MAPbI3 and triple-cation (TC) perovskite. The TC perovskite was Cs0.05(MA0.17FA0.83)0.95Pb(I0.84Br0.16)3. X-ray diffraction patterns of asdeposited perovskite films compared to films that have (a) ZnO or (b) SnOx overlayers grown at 100 °C with O2 gas as the oxidant. Performance of (c) MAPbI3 or (d) TC solar cells with oxide overlayers. The device structure was

Figure

  Figure S25, SI.

Figure 6 .

 6 Figure 6. Atomic force microscopy image of wrinkled Cs0.17FA0.83Pb(I0.83Br0.17)3 thin film (a) with no overlayer, (b) coated with PC61BM and (c) coated with PC61BM and SnOx. The color scales in all atomic force microscopy images were adjusted to range from -400 nm to 400 nm. (d) Illuminated current density-voltage curves and (e) dark current density-voltage curves of

Table 1 .

 1 Summary of the key requirements for growing oxide buffer layers on lead-halide perovskite device stacks and how much each oxide growth method fulfils each requirement a

		Wide
	Deposition method/Requirement	processing	Pinhole-free	Fast growth	Scalable	Conformal
		window b
	Spin-coating oxide nanoparticles	O	-	P	O	O
	Atomic layer deposition	O	P	-	P	P
	Sputter deposition	O	P	P	P	P
	Thermal evaporation	O	P	-	-	P
	AP-CVD (this work)	P	P	P	P	P

Table 2 .

 2 Ratio of elements in MAPbI3 films measured by X-ray photoemission spectroscopy

			With TiOx
	Ratio	No Oxide
			100 °C, O2 gas	150 °C, H2O vapor
	N/Pb	1.1±0.1	1.3±0.1	1.1±0.1
	I/Pb	3.1±0.1	2.7±0.1	2.7±0.1

Acknowledgements

The authors would like to thank Prof. Richard Friend for useful discussions on this project. The authors also thank Shahab Akhavan for technical assistance in evaporating Al electrodes onto the oxides for resistivity measurements and Yu-Hsien Chiang for discussions on perovskite fabrication. R.D.R. and R.A.J. acknowledge support from DTP studentships funded by the EPSRC (No.: EP/N509620/1). R.A.J. and J.L.M.-D. thank Bill Welland for financial support. R.L.Z.H. acknowledges support from the Royal Academy of Engineering under the Research Fellowship scheme (No.: RF\201718\1701), the Isaac Newton Trust (Minute 19.07(d)), the Centre of Advanced Materials for Integrated Energy Systems (CAM-IES; EP/P007767/1), and Magdalene College Cambridge. We also acknowledge support from the EPSRC (Nos.: EP/P027032/1 and EP/M005143/1), as well as from the Winton Programme for the Physics of Sustainability under the Pump-Prime scheme. This work was partly carried out in the framework of a project of IPVF, which was supported by the French Government as part of their programme of investment in the future (Programme d'Investissement d'Avenir ANR-IEED-002-01). P.S. thanks the French Agence Nationale de la Recherche for funding under the contract number ANR-17-MPGA-0012. T.N.H. was supported by the EPSRC Centre for Doctoral Training in Graphene Technology (No.: EP/L016087/1). M.N. acknowledges financial support from the European Commission through a Marie-Curie Individual Fellowship (EC Grant Agreement Number: 747461). W.L. acknowledges the National Natural Science Foundation of China (no. 61805203).

Author Contributions R.D.R. and R.A.J. contributed equally to this work. R.L.Z.H. conceived of the project, fabricated the perovskite films and devices, performed the profilometry measurements on the oxide films, performed the X-ray diffraction and time-resolved photoluminescence measurements. R.D.R. developed the growth of the oxide films by AP-CVD. R.A.J. grew the oxide films and performed the spectroscopic ellipsometry measurements with the help of T.N.H. S.B., M.B., M.F. and P.S. performed and analyzed the photoemission spectroscopy measurements. T.N.H. performed the atomic force microscopy measurements. M.N. performed the current-voltage measurements for determining the oxide film resistivity. Y.-H.L., M.S. and W.L. contributed to fabricating the perovskite devices and analysis. Z.L. performed the UVvisible spectrophotometry measurements. All authors contributed to writing the paper and discussing the results.