Sihem Ben

Establishing relationships with distant suppliers to explore discontinuous innovation

Keywords: Discontinuous innovation, early supplier involvement, distant search, open innovation, exploration, ambidextrous organization. Establishing relationships with distant suppliers to explore discontinuous innovation

A controversy exists in the literature regarding the type of suppliers to consider when leveraging external knowledge in order to explore discontinuous innovation (DI): familiar suppliers or distant ones. We argue that in pursuing DI, firms need to establish relationships with distant suppliers on cognitive and relational dimensions and that it requires a specific process.

Based on a longitudinal study of a firm that developed such relationships and succeeded in exploring DI, we underline how firms can develop such relationships through an approach having three main characteristics: (i) building a documented mapping, coupling the concepts and their underlying technologies with the potential suppliers providing and mastering such technologies, (ii) having a structured and transparent process, supporting a mutual and progressive commitment and (iii) dedicating a specific entity separate from the rest of the and in the same time, connected to the experts that master the internal knowledge that will be combined with the external knowledge leveraged and to the top managers that will take the decisions regarding the further development of the opportunities of DI explored. By cooperating with distant suppliers simultaneously with the familiar ones, firms can achieve ambidextrous sourcing enabling an ambidextrous organization that pursues incremental and DI.

Introduction

In innovation driven competition, leveraging external knowledge and innovation capabilities is crucial [START_REF] Quinn | Outsourcing innovation: the new engine of growth[END_REF][START_REF] Chesbrough | Open innovation: The new imperative for creating and profiting from technology[END_REF][START_REF] Enkel | Open RD and open innovation: exploring the phenomenon[END_REF][START_REF] Gassmann | The future of open innovation[END_REF][START_REF] West | Open Innovation: the next decade[END_REF][START_REF] Weiblen | Engaging with Startups to Enhance Corporate Innovation[END_REF]. Several authors such as [START_REF] Laursen | Open for innovation: the role of openness in explaining innovation performance among UK manufacturing firms[END_REF] show that suppliers are one of the most important external sources of innovation. However there is a controversy about the type of supplier to partner with when pursuing innovation that requires a shift in the market and/or the technology: discontinuous innovation (DI) [START_REF] Bessant | Managing innovation beyond the steady state[END_REF]. This type of innovation is highly risky and is associated with strong uncertainty. Some authors [START_REF] Petersen | A model of supplier integration into new product development[END_REF]Ryu et al., 2007;[START_REF] Zirpoli | The limits of design and engineering outsourcing: performance integration and the unfulfilled promises of modularity[END_REF] suggest that DI require leveraging knowledge from a selection of close, trustful and familiar suppliers, whereas others [START_REF] Mukherji | Mutual adaptation in buyer-supplier relationships[END_REF][START_REF] Gassmann | Opening up the innovation process: Towards an agenda[END_REF][START_REF] Phillips | Discontinuous innovation and supply relationships: Strategic dalliances[END_REF][START_REF] Schiele | Early supplier integration: the dual role of purchasing in new product development[END_REF] claim that DI require leveraging new knowledge from new suppliers distant both on the cognitive (technological) and the relational dimensions. We intend to focus on the second option and the specificity of processes leading to such relationships. Thus we aim at bringing a novel analytical perspective to this controversy.

Establishing relationships with distant suppliers, new to the network of the firm and mastering knowledge distant from the firm's one, while stimulating, raises critical challenges. The identification of such suppliers, their attraction and selection, the building of trust required when dealing with uncertainty are complex issues. Indeed, the firm does not know the suppliers and does not have the required knowledge for this selection. In order to shed light on such a process, we undertook a longitudinal study in a firm that developed this kind of relationships and succeeded in exploring discontinuous innovation. Based on this study, we underline three characteristics that we argue are crucial in the successful development of these relationships which resulted in DI: (i) building a documented mapping, coupling the concepts and their underlying technologies with the potential suppliers providing and mastering such technologies, (ii) having a structured and transparent process, supporting a mutual and progressive commitment and (iii) dedicating a specific entity separate from the rest of the and in the same time, connected to the experts that master the internal knowledge that will be combined with the external knowledge leveraged and to the top managers that will take the decisions regarding the further development of the opportunities of DI explored.

The article proceeds as follows. We first present the literature on organizational learning and open innovation that deals with leveraging suppliers knowledge. Then we specify the gap in this literature that we intend to address. We then detail the methodology adopted to collect and analyze data and present the case, and more specifically the process adopted by the firm studied to build such relationships. Last, we characterize this process and discuss these characteristics in the light of the existing literature, stressing our contributions on building relationships with new and distant suppliers to explore DI and therefore achieving ambidextrous sourcing and organization.

Literature Review

In this section, we will highlight the rationale for leveraging distant suppliers' knowledge when pursuing discontinuous innovation and the challenges associated based on the literature on organizational learning and knowledge. This section ends by highlighting the open questions related to these challenges that remain unstudied in this literature.

Literature on open innovation [START_REF] Quinn | Outsourcing innovation: the new engine of growth[END_REF][START_REF] Chesbrough | Open innovation: The new imperative for creating and profiting from technology[END_REF][START_REF] Almirall | Open versus closed innovation: A model of discovery and divergence[END_REF][START_REF] Enkel | Open RD and open innovation: exploring the phenomenon[END_REF][START_REF] Gassmann | The future of open innovation[END_REF][START_REF] West | Open Innovation: the next decade[END_REF]) highlights the benefits of having access to a diverse set of knowledge and its positive influence on the innovation performance. [START_REF] Laursen | Open for innovation: the role of openness in explaining innovation performance among UK manufacturing firms[END_REF] point out that leveraging suppliers' knowledge is a source of competitive advantage. [START_REF] Johnsen | Supplier involvement in product development and innovationtaking stock and looking to the future[END_REF] suggests that the supplier selection and the supplier relationship development are success factors to leverage the supplier innovation capacities. [START_REF] Schiele | Early supplier integration: the dual role of purchasing in new product development[END_REF] stresses the different implications of various kinds of relationships with suppliers. Long term relationships with a set of selected suppliers sharing a long history of collaboration and trust have been extensively analyzed [START_REF] Takeishi | Bridging inter-and intra-firm boundaries: Management of supplier involvement in automobile product development[END_REF][START_REF] Petersen | A model of supplier integration into new product development[END_REF][START_REF] Van Echtelt | Managing supplier involvement in NPD: a multiple-case study[END_REF] especially in the automotive industry [START_REF] Lenfle | Innovation-based competition and the dynamics of design in upstream suppliers[END_REF][START_REF] Wynstra | In Chains? An Empirical Study of Antecedents of Supplier Product Development Activity in the Automotive Industry[END_REF][START_REF] Zirpoli | The limits of design and engineering outsourcing: performance integration and the unfulfilled promises of modularity[END_REF]. [START_REF] Schiele | Early supplier integration: the dual role of purchasing in new product development[END_REF] considers that this type of relationships should favor incremental innovation rather than discontinuous ones. Indeed, DI require a shift in the market and/or the technology [START_REF] Bessant | Managing innovation beyond the steady state[END_REF][START_REF] Tidd | Open Innovation Research Management and Practice[END_REF]Phillips et al., 2006a) and therefore the exploration of new knowledge (Danneels, 2002). Adopting a network perspective, other authors [START_REF] Hughes | Re-shaping social capital in buyer-supplier relationships[END_REF][START_REF] Mukherji | Mutual adaptation in buyer-supplier relationships[END_REF] show that strong ties can create a kind of convergence through which firms might miss future opportunities that emerge outside the bundle of their relationships with their suppliers whereas weak ties give access to novel information by bridging disconnected groups, enabling the development of DI (Dhanaraj and Parkhle, 2006). Thus, [START_REF] Phillips | Discontinuous innovation and supply relationships: Strategic dalliances[END_REF] suggest that short term involvements with suppliers from outside the usual realm of the firm's network, maximize its chances of discovering ideas outside of its own core discipline. This type of relationships designated as "strategic dalliances" by [START_REF] Phillips | Discontinuous innovation and supply relationships: Strategic dalliances[END_REF] are rooted in a firm's ability to "develop a broad range of noncommittal supply relationships that it can dip in and out of or dally with, in concurrence with its longer-term strategic partnerships". Before going forward, let's specify the notion of distance between the firm and the suppliers, as it is addressed in the literature.

To better characterize how close or distant a supplier is from a company, we propose to introduce the notion of knowledge distance as articulated by Li et al. (2008). They propose to apprehend the knowledge distance through the cognitive attribute, or the substantial content of knowledge. It refers to differences in (i) scientific disciplines (biology, chemistry, physics, electronics), (ii) technology fields (the knowledge of a firm in the electronic technology is distant on the cognitive dimension from the knowledge of a firm in the pharmaceutical technology), and (iii) the product market level (knowledge on market segments). Therefore, the supplier knowledge can be close to the firm's one on the substantial content (science, technology, or product market level) or distant to it.

Besides this cognitive dimension, another way to think about the distance relates to the relational dimension. [START_REF] Ahuja | Entrepreneurship in the large corporation: A longitudinal study of how established firms create breakthrough inventions[END_REF] highlight that a firm can search for new knowledge outside its network or inside it. Either the supplier is new to the network and hence the relation did not exist previously or it belongs to the firm's network and hence the relation is already established or can benefit from an indirect link and a reputation effect.

In the following, we will consider suppliers distant on the cognitive level (a different knowledge base) and on the relational level (new to the network). [START_REF] Gassmann | Opening up the innovation process: Towards an agenda[END_REF] observes that cross-industry innovations are rarely studied in the literature despite their importance. We intend to address this gap.

Several authors stress issues faced when establishing such relationships. [START_REF] Afuah | Crowdsourcing as a solution to distant search[END_REF] highlight the hurdles associated with the distant search being the exploration of "alternatives on new and different technological trajectories or markets» (p.357). They show that the decision makers tend to conduct local searches: alternatives that are in the neighborhood of its existing position [START_REF] Katila | New product search over time: Past ideas in their prime?[END_REF][START_REF] Katila | Something old, something new: A longitudinal study of search behavior and new product introduction[END_REF]. Building on the search literature and on the behavioral theories of the firm, (e.g., [START_REF] Cyert | A behavioral theory of the firm[END_REF][START_REF] Dosi | On the evolutionary and behavioral theories of organizations: A tentative roadmap[END_REF] Tucci is to outsource the problem solving to a supplier belonging to another neighborhood and for which therefore the search will be local. This moves/displaces the hurdle ahead: how does the firm will identify, select and build such relationships with these suppliers is not addressed by these authors.

A second issue relates to the actor who will be in charge of the establishment of these relationships. The literature on supply chain management highlights that the purchasing and sourcing function masters such capabilities and provides crucial information about suppliers (cost, performance, market availability, quality, and reliability) [START_REF] Burt | Purchasing's role in new product development[END_REF]. However, [START_REF] Johnsen | Purchasing and Supplier Involvement in Discontinuous Innovation: a Literature Review[END_REF] distinguish two types of sourcing teams: the one involved in innovation (advanced sourcing) the other involved in operations. [START_REF] Schiele | Early supplier integration: the dual role of purchasing in new product development[END_REF] highlights that in order to interact fruitfully with suppliers during the innovation process, buyers should establish an advanced sourcing department as a distinct organizational unit, and endow this unit with support tools, such as technology roadmaps. This unit should be involved in innovation meetings so as to link the procurement strategy with the innovation strategy of the firm. [START_REF] Johnsen | Purchasing and Supplier Involvement in Discontinuous Innovation: a Literature Review[END_REF] propose the notion of early purchasing involvement (mirroring the early supplier involvement) to highlight the benefits of enhancing the dialogue between engineering and purchasing in the innovation process [START_REF] Atuahene-Gina | Involving organizational buyers in new product development[END_REF][START_REF] Handfield | Involving suppliers in new product development[END_REF][START_REF] Nijssen | Involving purchasing in new product development[END_REF]. Thus a specific and independent unit thanks to its independence from the rest of the organization can identify new potential suppliers and progressively involve them in the innovation process.

Hence, the organization adopted by the firm to identify and establish relations with the suppliers has been emphasized as a critical factor. However the appropriate processes have not been delineated.

Research question

The literature mentioned above, that value establishing relationships with suppliers from outside the usual realm of the firms and that master distant knowledge in order to benefit from their innovation capacities and explore discontinuous innovations, did not address the process the buyer should set up to build such relationships neither who will be in charge of such a process.

We will address this twofold gap (how and who) because we the establishment of these relationships raises critical challenges.

We argue that establishing relationships with distant suppliers in order to explore discontinuous innovation requires a specific process because it raises several critical challenges especially during the early phases: opportunity identification and concept generation and selection. We intend to investigate such a process and outline its characteristics.

Methodology

We analyze the approach undertaken by a firm that developed DI by collaborating with new and distant suppliers. We conducted a detailed longitudinal analysis of this approach. Such a qualitative and longitudinal method is appropriate, as little research has been hitherto undertaken on this how question. Such a method is widely adopted to generate theoretical insights [START_REF] Galunic | The evolution of intracorporate domains: divisional charter losses in high-technology, multidivisional corporations[END_REF][START_REF] Adler | Flexibility versus efficiency? A case study of model changeovers in the Toyota production systems[END_REF][START_REF] Carlile | A pragmatic view of knowledge and boundaries: boundary objects in new product development[END_REF][START_REF] Jacobides | Designing the boundaries of the firm: from make, buy or ally, to the dynamic benefits or vertical architecture[END_REF][START_REF] Kellogg | Life in the trading zone: structuring coordination across boundaries in postbureaucratic organizations[END_REF][START_REF] Loch | Diagnosing unforeseeable uncertainty in a new venture[END_REF].

Research Setting

Domauto 1 (a pseudonym) is one of the ten largest suppliers in the automotive industry. The multidivisional firm decided to enhance its capacity to develop discontinuous innovation on the powertrain scope and especially in fuel efficiency and emission reduction. The objective was to address these challenges in a radically distinct manner from the current technologies and components already commercialized. For that purpose, the firm created an independent and dedicated entity: the innovation platform (IPL). IPL is composed of a core team (a leader, a marketing, and a technical managers) and an extended team of eight people (marketing and technical representatives from the four divisions involved in the powertrain scope: transmission 1 In 2014, the sales are about 12,7 billions of euros, the R&D budget is about 6% of the sales, it has 6000 RD staff distributed in 60 research and development centers in the world. systems, electrical systems, thermal cooling systems and engine control). Six years after the creation of IPL, several DI aimed at reducing fuel consumption were identified and prototyped.

The majority was developed jointly with distant suppliers. None of the concepts formulated existed before in the firm's technical road maps. The solutions developed to embody these concepts were radically different from the offers of the competitors as well as from the typical components requirements of car manufacturers To achieve such a renewal of the innovation portfolio, this entity developed a specific approach towards new and distant suppliers in order to involve them in the design of novel solutions. We undertook a detailed analysis of the process structured by this entity to develop such relationships with distant suppliers.

Data collection

Our data collection focused on the process adopted by the entity to identify and develop a collaboration with these suppliers. Data was collected over 6 years and was gathered from multiple sources: observations, interviews, presentations, internal reports and public information. It started with the launch of IPL. The authors attended IPL's meetings on a regular basis (lasting three hours on average). In addition, informal interviews took place with the meetings attendees and lasted one hour on average. Other interviews were conducted with senior managers (R&D, marketing, etc.) at the corporate and division levels and also with the suppliers. Furthermore, during these 6 years, the researchers met (2 hour on average) on a quarterly basis with the IPL leader (who did not change) to share feedback with him on the operation of the unit. This research design secured the access to fine-grained data over several years. We could access to the documents issued and associated to these projects, and also gathered data thanks to 42 interviews of 90 minutes on average and 50 meetings of 3 hours on average.

Data analysis

The case studied corresponds to a theoretical sampling [START_REF] Eisenhardt | Building theory from case study research[END_REF]: it was not chosen for statistical reasons but rather because it was particularly relevant to the research question. In line with the paradigm of inductive research [START_REF] Miles | Qualitative Data Analysis[END_REF][START_REF] Eisenhardt | Building theory from case study research[END_REF][START_REF] Corbin | Grounded theory research: procedures, canons and evaluative criteria[END_REF][START_REF] Suddaby | From the editors: what grounded theory is not[END_REF] our aim was to generate insights on the process developed by a buyer to establish relationships with distant suppliers.

As [START_REF] Langley | Strategies for theorizing from process data[END_REF] states, the researcher who have chosen to "plunge itself directly into the processes themselves, collecting fine grained qualitative data-often but not always in real timeand attempting to extract theory from the ground up" often come up with messy data and face a constant challenge in making sense of them. One of the generic modes of analysis of process data she suggests is the "temporal bracketing strategy" in which the time scale is decomposed into successive periods. There is continuity in the activities within each period and discontinuities at its frontiers. Developing process theory requires understanding pattern in events and the most common pattern found in the literature is the linear sequence of phases that occur over time to product a result. We adopted this temporal bracketing strategy and inductively derived phases from our data. Because qualitative analysis is an inherently dynamic process, multiple readings of interviews, field notes, and documentation were conducted in order to characterize the process set up. Regular presentations to the IPL leader enabled the verification of the researchers' understanding accuracy.

Case study and analysis

We present the data in a longitudinal way. We differentiate stages and focus on what was accomplished at each stage in order to develop the relationships with new and distant suppliers and explore discontinuous innovation. Then we characterize this process by highlighting three elements that differentiate this process from the one leading to the establishment of relationships with familiar suppliers in order to co-develop innovations.

The case study

At its launch, and during the first year, IPL organized workshops involving, beyond its team, internal resources and external experts (no suppliers at this stage) to identify innovation tracks or domains that could enable fuel consumption and emission reduction. For some technological domains, the company could leverage strong internal competencies whereas, for others, the search for external knowledge appeared as a priority. We focused on the latter and more specifically on the three following domains that were considered: supercharging system, injection system, and energy recovery system. Innovation in these domains has significant implications on fuel consumption and emissions. Named this way, these domains seem to correspond to already existing solutions rather than discontinuous innovations. However in order to radically change the performances, the innovation targeted should not mobilize the current technologies used for these solutions.

In the case study presented below, we focus on one specific domain: supercharging systems. . The objective of Domauto was to enter this market, which the company was not in, with a technology that differed from those mastered by the established players. Since it is a new domain for the company, there is no existing technology roadmap. Thus, it corresponds to what is designated in the literature as discontinuous innovation.

Jointly with distant and new suppliers, IPL identified through an exploration process, a concept then a detailed design and a prototype that was favorably welcomed by potential customers (automotive assemblers OEMs). Therefore, it appears relevant to analyze this case to understand how a firm can establish relationships with new and distant suppliers to target discontinuous innovation.

In the followings, we will present the approach deployed to identify suppliers, initiate the collaboration with them, generate concepts, test the feasibility of the various solutions generated and assess them.

Even though we focus on the supercharging domain, the same process was adopted by the firm for the two others (injection system and energy recovery system). (see Figure N°1 to have an overview of the overall process that will be detailed below).

- -----------------------------------------Insert Figure 1 about here. -------------------------------------------Stage 1: From a domain to explore to a documented mapping of concepts and potential suppliers

The first stage was dedicated to gathering knowledge about supercharging systems by IPL team through documentary research. It enabled the team to come up with a better understanding of: (i) the existing solutions and the heir advantages and limits, (ii) the future solutions under development in the industry and the technological strategy of the main players, (iii) the current market and forecasts and the issues to be faced in the coming years. It resulted in a first list of functional specifications for a supercharging system targeting fuel efficiency and emission reduction. In addition, a detailed list of constraints was specified regarding the integration of this potential innovation in the car. Then, a search formulation comprising the key functional specifications and the key constraints was delineated and kept along the process as a common starting reference.

The team didn't send a request for quotation to the company's current suppliers. There were at least two reasons for that. The first one is that the search formulation is too wide and could not been sent as such: it would have either attracted too many answers between which it would have been difficult to select one or none. The second was that, the objective being an innovative answer to the "search formulation", the decision was made to target new and distant suppliers.

But how to reach and attract these players who are not used to work with the automotive industry? How to decide which to further interact with? The team needed to document further the possible concepts For that purpose, creativity sessions were then undertaken and involved internal and external resources such as experts, future clients and drivers. They resulted in a set of 10 concepts related to various different technologies (turbocompressor, e-charger, etc). Then a mapping of these concepts was proposed. They were positioned along two axes: the type of technology (the type of energy used to compress the air, for example), and the level of maturity of the concept (do we observe products corresponding to this concept on the market or is it at a research stage?).

Then suppliers mastering these technologies were identified using semantic analyzes on patent databases and scientific articles in journals, etc. The objective was not to identify suppliers having a product to sell but the search targeted rather to types of company:

-technology providers that had accumulated a certain level of knowledge on the technology or had already developed a functional prototype ; -suppliers with a solution using an interesting technology but in another industry than the automotive sector and which would already have relevant production capabilities for this kind of solution. An investigation of the necessary adaptation for the automotive industry was therefore required.

By screening through these criteria, 20 relevant suppliers were identified mastering 4 technologies required, able to develop solution in line with 6 concepts among the 10 generated.

Table N°1 below summarizes the analysis conducted resulting in a coupled mapping of concepts and suppliers. This mapping highlights various technical strategies and positions the suppliers that have developed solutions corresponding to the concepts generated during the creativity sessions.

-

---------------------------------------- Insert Table 1 about here. -------------------------------------------
Based on this mapping, 3 concepts that were neither already commercialized in the automotive industry nor in a too early research stage were selected along with 6 suppliers or technology providers associated. These suppliers were new and outside the usual realm of the firm's network and mastered distant knowledge. Indeed, so far, the company had partnerships with suppliers from the automotive industry sector and with academic teams specialized in knowledge familiar to the one mastered by the R&D departments of the company. These new suppliers were SMEs, start-ups or academic teams that were not used to work in automotive industry and mastered distant knowledge. At this stage, the selection did not involve the suppliers: the selection was based on an analysis based on public documents about their activities and skills.

Stage 2: Detailing/improving/deepening the search and selecting a concept and a supplier

The second stage required to go further and to acquire more knowledge on the implementation of these concepts into solutions and about the suppliers.

Organizing direct interactions with these suppliers offered the opportunity to challenge their willingness and capacity to develop a solution for the auto industry (that is beyond their familiar markets) and adapting their solution. Furthermore, the process followed until this stage has been shared with the suppliers during these interactions: the first search formulation, the 10 concepts generated, the set of concepts and suppliers mapping, etc. Therefore, it was not only an audition of the supplier and a presentation of the proposed solution in order to assess its capacities but a conversation on the opportunities the development of such a novel solution would bring to the firm.

Regarding the solutions, additional information was needed on the following dimensions: (i) the performance of the solution itself, (ii) the constraints related to its integration within a powertrain and then within a vehicle, (iii) the complexity of the solution's industrialization, (iv) the estimated costs, (v) the time required to have access to the solution and the time to market and finally (vii) the accessibility of the firm to complementary assets required to support the deployment of the solution. The objective at this stage was to gather information about the various issues that would be faced in developing the novel solution with the considered novel supplier.

Based on the knowledge gathered, the next stage was an assessment of the 3 preselected concepts associated with the 6 potential suppliers by the IPL team. The intent is to obtain a shared and documented assessment of the solution to focus on.

Furthermore, the outcome of this phase is to identify the business unit within the firm in which the development of the solution could be pursued since IPL does not have all the required resources. The objective was to involve progressively these development players in the exploration process to prepare the transfer of the solution to be developed.

Based on this assessment, one medium-sized supplier mastering an interesting technology and ready to get involved in further developments of a solution in order to fulfill the requirements of the automotive industry was selected.

These stages (domain identification, concepts generation and selection, assessment of the preselected concepts and suppliers) form the "paper analysis" phase that ends with the selection of a set of concepts and suppliers. This process is quite different from traditional practices of contracting with suppliers: it is rather open given the multitude of options considered and the knowledge distance that impedes an easy assessment of their potential.

During the "paper analysis" phase, the investment is limited (below 10K€) and is based mainly on documentation and meetings. No contract is signed, only a non-disclosure agreement (NDA) for discussion.

Stage 3: Realization of mock ups

The subsequent stage is dedicated to designing and building a functional prototype of the selected solution. For a mock-up tested on a subsystem bench, the investment is below 50K€.

At this point, an agreement was signed with the supplier. Even-though, the big part of the work is undertaken by the suppliers at this stage, it is extremely rich in terms of knowledge generated and exchanged between both players. The supplier belonging to another sector, he ignores the adaptation required for the automotive industry. On the other hand, the firm, through IPL team, needs to understand further the technology embedded in the solution to help in the identification of the adaptations. Many interactions took place in order that both players could acquire the necessary knowledge. This joint exploration can eventually lead to a shift to a second concept of solution because the performance cannot be achieved with the first one besides other difficulties encountered.

However, the systematic study conducted in the previous stage with the identification of alternative concepts facilitates the shift to another set of concept and supplier without reanalysing the problem from the start.

For the second concept considered, the completion of the mock-up of the subsystem was conclusive. The next step was to develop a more complex mock-up to be integrated in a democar. Because the investment was higher (between 200 and 500K€), a contract was signed with the supplier. This stage can be considered as the last step before a NPD project is launched and goes along with an intensification of the relationships. Potential customers (meaning original equipment manufacturer, car assemblers) are also involved in order to take part in the exploration as well.

After the validation of the demo-car including the mock-up of the solution, and considering the promising performance of the solution and the positive reaction of car assemblers, a development project was launched and the solution was transferred to a division.

The case study analysis

Therefore the process set up by the firm to establish relationships with new and distant suppliers includes: (i) a broad exploration of technologies, market requirements and trends and creativity sessions that help build an exploration map on a domain on which the firm was not previously positioned and consider to enter with innovation based on a shift in technology; (ii) a first selection among these concepts and a search for suppliers knowledgeable on the technologies underlying the pre-selected concepts; (iii) an identification of relevant suppliers and solutions and a selection of sets of concepts and suppliers with whom further development will be undertaken; and (iv) the realization of mock-ups at two different levels (the solution per se and its integration in a demo-car) to test the feasibility and the performance of the solution.

Below, we underline three characteristics of the process presented above: (i) building a documented mapping, coupling the concepts and their underlying technologies with the potential suppliers providing and mastering such technologies, (ii) having a structured and transparent process, supporting a mutual and progressive commitment and (iii) dedicating a specific entity separate from the rest of the and in the same time, connected to the experts that master the internal knowledge that will be combined with the external knowledge leveraged and to the top managers that will take the decisions regarding the further development of the opportunities of DI explored.

1 st Characteristic: A documented mapping of the concepts and the suppliers When targeting DI associated with a shift in the technology, firms cannot articulate specifications at the beginning of the process. Indeed, the specifications result from an interactive coupling between the requirements of the firm on one hand and the potential of the technologies mastered by the suppliers on the other. In its search, the firm articulates the main functional requirements and the constraints, regarding interaction with the other subsystems for example, without narrowing the search funnel. This formulation is not as precise as what is posted on a traditional open innovation platform. It does not neither compare to traditional specifications that can be advertised to current suppliers through traditional channels.

Consequently, the firm undertook creativity sessions based on this search formulation in order to generate concepts to which potential suppliers once identified could contribute.

Progressively, along the exploration process, new knowledge is developed and structured around various concepts that are documented and mapped. This mapping of the concepts (their pros and cons), the technologies and the suppliers is built and shared with potential suppliers who thus extend their knowledge and get benefits to their involvement in such a relation despite an uncertain context. This mapping plays a crucial role at two stages: for the identification of the new suppliers and during the interaction with them helping bridge the knowledge distance.

2 nd Characteristic: A structured and progressive process Considering the discontinuous nature of the innovation targeted, the firm cannot be very specific on the content to be delivered. However, the firm deployed a structured process that was very helpful in coping with the double uncertainty characterizing the exploration of DI with new and distant suppliers. Indeed, it was explicit on the stages and the set of solutions competing at each stage as well as on the decision mode. It is a progressive process involving increasing interactions and commitment. With this transparent and shared reference, players have some visibility to reduce the uncertainty they are encountering. In addition, the relation can stop at each stage and each party could decide to go its separate way. As a matter of fact, in the firm analyzed, several relationships with new and distant suppliers were stopped at the initiative of either party after having cooperated during one or two phases. Because of this eventuality, the nature and degree of information shared are focused on the project at stake. The interactions are restricted to the scope of the technology the supplier was selected for and which is specified in advance. NDA is signed before meetings and confidentiality agreements are clearly defined before the beginning of the development of a mock-up. The suppliers commit resources until the next stage. Hence, the investment for each stage is clear for both parties. Exclusivity is not required. The relationships established are thus characterized by a limited and a progressive commitment.

These relationships with suppliers are also different from traditional ones because of their premises and objectives. First, the expected result is unusual. It is not a commercial product developed jointly but rather the validation of a solution concept that would fulfill a functional need and the realization of a mock-up of this concept enabling to assess its technical feasibility, its performances and potential on the market. Second, the selection of the solutions requires a knowledge that the firm does not have. The documented mapping and the structured process help address these specificities.

3 rd Characteristic: A separate, dedicated and connected entity In the firm analyzed, a specific entity was in charge of: (i) generating new concepts, (ii) identifying new suppliers, (iii) establishing relationships with these suppliers, (iv) organizing the joint study of a set of selected concepts, and (v) coupling between technical solutions, needs, potential partners and the competitive positions of the firm. This entity was separated from the rest of the firm. This independence made the search for new suppliers outside the usual realm of the firm possible. They experimented new and specific search tools for that purpose. Despite separate, the entity could rely on a network of experts within the firm to ensure the combination of existing internal knowledge with externally acquired one. Access to these experts is of tremendous value due to their knowledge of system specifications, technical, industrial and costs constraints. Even though the entity is the prime contact of the new supplier, it favors direct relationships between the supplier and the relevant experts within the company. Though in charge of developing relationships with new suppliers to enhance DI, the entity tended to leverage external knowledge but also combine it with internal knowledge distributed in different business lines, so as to come up with novel systems and architectures.

Its role is to introduce the supplier to the project team that will further develop the innovation.

Thus, the dedicated entity helps reduce the complexity of the firm to the new supplier.

The entity reports to top managers of the company who can approve the strategy on these novel domains. The technical and the strategic issues are worked on simultaneously enabling the company to move forward and commit if the technology is promising. When a joint exploration with a new supplier succeeds and the prototype reaches the expected performance, the top management who is aware of this partnership can rapidly get involved in supporting the transfer of the project to the appropriate business line and pushing the detailed development and then the launch of this novel product or system.

Though dedicated to early phases of concepts generation and proof of concepts, the entity was in charge of transferring the novel solution, once ready for industrial development to the business line that will produce and commercialize it. It organized regular meetings with clients to show the various concepts considered and includes their feedbacks in making the decisions about which to further develop.

Discussion

Based on the case study of a firm that succeeded in establishing relationships with new and distant suppliers in order to explore jointly discontinuous innovation, we highlight the process and the organization deployed and we underline three characteristics that, we argue, help answering the question: how do firms establish such relationships? We will in the following, discuss these characteristics presented above, with the literature on organizational knowledge and open innovation, stressing thus our contribution.

By specifying these characteristics, we complement the work of [START_REF] Afuah | Crowdsourcing as a solution to distant search[END_REF] about the conditions under which transforming distant search into local search is possible. They pointed out the problem framing and the ease with which the final solution can be evaluated. We specify these elements by highlighting the way the problem can be framed, through the coupled mapping of the concepts, the technologies and the suppliers (first characteristic), and the organization (structured and progressive process on one hand, and dedicated and connected entity on the other) through which the firm can evaluate the solution sourced (second and third characteristic).

A documented mapping of the concepts and the suppliers

Technological discontinuities trigger the start of a fluid phase where alternative technologies compete for dominance (Abernathy and Utterback, 1978;[START_REF] Utterback | Mastering the Dynamics of Innovation[END_REF] and where there isn't a stabilized definition for a product or a technology. Therefore, it is difficult and possibly not appropriate to articulate specifications to be addressed to suppliers. Hence, we highlighted the critical role played by the search formulation that supported the creativity session as well as the coupled mapping of the concepts, technologies and suppliers in the establishment of the relationships with new and distant suppliers targeting discontinuous innovation. Focusing on functional rather than on technical specifications is not specifically new in the literature on innovation. The benefits of maintaining a fuzzy front end during the early phases of the innovation process were also previously highlighted [START_REF] Khurana | Integrating the Fuzzy Front End of New Product Development[END_REF][START_REF] Reid | The Fuzzy Front End of New Product Development for Discontinuous Innovations: A Theoretical Model[END_REF]. A similar approach was highlighted by researchers in design theory [START_REF] Krippendorf | The semantic turn. A new foundation for design[END_REF] as well when they emphasized that design is about monitoring and coupling two processes: one divergent, that enables the exploration of novel ideas in a wide space of possibilities and the other convergent, that specifies the boundaries (constraints) that form the scope of the issue to be addressed. We emphasize that it is specifically critical in the case of new and distant suppliers and that the mapping enables it. This combination of a rather broad exploration process with a convergence process is also highlighted in the innovation management literature. [START_REF] Liker | Involving suppliers in product development in the United States and Japan: Evidence for set-based concurrent engineering[END_REF] show the benefits of involving suppliers in the simultaneous development of several solutions in parallel that they have designated as set-based design as opposed as to the development of one solution or pointbased design. This is efficient when time constraints and uncertainty are high. However they have studied suppliers belonging to the suppliers' base of the firm for co-development initiative whereas we focus on an upstream phase and co-exploration with new and distant suppliers.

Therefore, we complement this work by emphasizing that the mapping tool help to conduct the development of several concepts in parallel and to quickly switch from one potential solution to another one when an issue cannot be overcome. Indeed, suppliers are new and belong to other networks in which the firm is not embedded. They are therefore difficult to identify. The mapping supports and structures this search: it is a reference all along this process. Furthermore, the suppliers master a knowledge/technology that the firm does not. It is therefore difficult to assess and evaluate the opportunities that it represents. On the other hand, the suppliers do not master the constraints of the automotive industry. Therefore, the mapping supports the development of knowledge that both players need to do in common. It is a shared element all along the process that bridges the knowledge distance.

A structured process supporting a progressive commitment

We highlighted the process especially the fact that it is structured and progressive.

Considering that the objective was to co-explore DI, it was not possible to rely on a traditional project development process. However, a structure was put in place in order to organize such an endeavor. It was critical in reducing the uncertainty associated for both players. This result is coherent with the characteristics of DI processes that are highly iterative involving probing and learning (Lynn, Paulson and Moronne, 1996). It is as well in line with the work of Maniak and Midler (2008) and [START_REF] Seidel | Concept Shifting and the Radical Product Development Process[END_REF] when they underline that exploring DI requires periodic revisions of the perimeters and the involvements. It is as well coherent with the findings of [START_REF] Fixson | Shifting grounds: how industry emergence changes the effectiveness of knowledge creation strategiesthe case of the US automotive airbag industry[END_REF] in their empirical study of the emerging US automotive airbag industry: they showed that the best knowledge search strategy is one that during the fluid phase looks inward into the organization but outside of the mastered technology area, and later during the take-off phase shifts to looking outward from the organization. Since DI are generally developed during the fluid phase, we showed a process combining the leveraging of internal knowledge and the search for new technologies from potential suppliers outside the firm. Therefore, we complement this work.

We highlighted as well the progressive dimension of the process. Indeed, the combination of a broad mapping, a focused prototyping with selected partners and iterations to test several concepts identified, leads to dedicate limited and progressive resources to the trials. This result complements the research of [START_REF] Phillips | Discontinuous innovation and supply relationships: Strategic dalliances[END_REF] on "strategic dalliances" that emphasizes the low commitment of the partners without however addressing how some of these nascent relationships evolve towards stronger ones. Indeed, the relationships characterized by [START_REF] Phillips | Beyond the steady state: managing discontinuous product and process innovation[END_REF] allow the firms to assess the potential of several technologies and competencies through a wide variety of partnerships. While agreeing on the benefits of this approach when targeting DI, we argue that transforming some of these temporary relationships into sustainable ones is crucial for succeeding in developing DI. We show that, in contrast to the large number of partners considered, only a few mock-ups were developed with a selected set of suppliers. A structured process enables the progressive transformation of these relationships from nascent to sustainable if functional, economic, industrial and strategic conditions are fulfilled. This is critical because the suppliers are new: how to attract them to build relationships with a firm in an unknown sector? In the other hand, the firm does not know these players and needs as well a progressive process to reduce the uncertainty. The structured process we highlighted framed a progressive commitment from both sides and contributed to reducing the double uncertainty generally associated with this type of innovation and nascent relations.

A dedicated entity combining several roles -

We highlighted the independence of the firm from the sourcing and purchasing function and in the same time its connectedness to the rest of the firm especially to the experts in order to leverage external knowledge as well as internal one and combine them. Therefore, the entity plays the role of a tertius iungens or a broker between the supplier and the firm [START_REF] Obstfeld | Social Networks, the Tertius Iungens Orientation and Involvement in Innovation[END_REF][START_REF] Crespin-Mazet | Open innovation processes within clustersthe role of tertius iugens[END_REF]. It plays the role of boundary spanner [START_REF] Tushman | Boundary Spanning Individuals -Their Role in Information-Transfer and Their Antecedents[END_REF].

or gatekeeper [START_REF] Tushman | External communication and project performance: An investigation into the role of gatekeepers[END_REF] because it targets the external search activities while preparing their integration and combination with internal resources. By involving progressively members from the rest of the firm (R&D, sourcing, etc.), it prepares the transfer of the innovation to the division where it will be developed further. By highlighting the boundaryspanning role of this entity, our work is in the same line of thought as [START_REF] Monteiro | The external knowledge sourcing process in multinational corporations[END_REF] who studied the role of a dedicated scouting unit of a multinational corporation in the search and the use of external knowledge by the home organization. They highlight the role of this entity in the external knowledge translation, its transformation and combination with internal knowledge to ensure the matchmaking with internal needs. However, while [START_REF] Monteiro | Connecting the dots: Uncovering the technology scouting process[END_REF] mention that the role of transferring the innovation development to the most appropriate division is critical the question has not been studied.

The dedicated entity studied also present similarities with an advanced sourcing entity [START_REF] Schiele | Early supplier integration: the dual role of purchasing in new product development[END_REF][START_REF] Johnsen | Purchasing and Supplier Involvement in Discontinuous Innovation: a Literature Review[END_REF]) in identifying, selecting and involving suppliers during the concept phase. [START_REF] Schiele | Early supplier integration: the dual role of purchasing in new product development[END_REF] underlines two roles for such an entity: the strategic coupling and the organization of the interactions with suppliers. He also emphasizes that this distinct organizational unit should be endowed with tools, such as technology roadmaps, and be involved in the innovation strategy of the firm. As in the case of DI these roadmaps do not exist, we show that this dedicated entity was indeed involved in the creation of such roadmaps by interacting with the suppliers and the customers,. The involvement of the entity in the definition of a technical strategy of the firm on these new domains was not considered previously in the literature addressing opportunistic behavior leading to a set of relationships with novel suppliers.

On the contrary we note that a strategic rationale was articulated and refined along the process.

The entity was in charge of identifying opportunities and building a strategy: it thus identified and explored a portfolio of exploratory projects rather than a single project. It did not focus on one solution to be developed. This portfolio approach is critical considering the uncertainty associated to DI. In that perspective, the entity differs from a tiger team or an autonomous project (Clark & Wheelwright, 1991) as documented in the literature on new product development in being responsible for a portfolio of early stage exploration projects. It is thus a specific organization.

We stress various roles fulfilled by such an entity and how these roles while complementing each other achieve the establishment of relationships with new and distant suppliers and the joint exploration of DI that can be developed further by the firm. We underline similarities and differences with various dedicated units studied in the literature on innovation. In doing so, we contribute to the debate in the literature about whether the development of relationships with new supplier targeting DI should be managed by a separate unit or by the current organization.

Targeting new and distant suppliers: an enabler for organizational ambidexterity

The innovation targeted by the firm studied involved radically new technologies for the firm and thus presented characteristics of DI according to Bessant el al. definition. Indeed, in order to develop offers that reduce fuel consumption and emissions, the firm explored solutions based on technologies that did not belong to its knowledge base. This led the firm to work during the innovation process with suppliers who mastered this knowledge and that did not belong to its current network. The firm established new relationships with these suppliers who dedicated resources and innovation capacities to these joint and risky explorations. This situation is different from the one generally addressed by NPD literature focusing on early supplier involvement [START_REF] Petersen | A model of supplier integration into new product development[END_REF][START_REF] Obstfeld | Social Networks, the Tertius Iungens Orientation and Involvement in Innovation[END_REF][START_REF] Van Echtelt | Managing supplier involvement in NPD: a multiple-case study[END_REF] and which emphasizes generally the long-term commitment to the buyers. On the contrary, the relationships studied are similar to what [START_REF] Phillips | Discontinuous innovation and supply relationships: Strategic dalliances[END_REF] designate as "strategic dalliance" with regard to their characteristics and the suppliers involved: new suppliers, low commitment, easy to break off, short term orientation, temporary relations, etc. We complement the work of [START_REF] Phillips | Discontinuous innovation and supply relationships: Strategic dalliances[END_REF] by addressing a specific outcome resulting in a specific kind of cooperation. It is not about developing jointly a product ready for commercialization, but a prototype embodying a new concept and a new technology on the basis of which the technical feasibility and functional performances will be assessed.

These new relationships were developed in addition to long-term relationships involving suppliers belonging to the traditional network of the firm. Our analysis reinforces the work of [START_REF] Hughes | Re-shaping social capital in buyer-supplier relationships[END_REF] and [START_REF] Noke | Strategic dalliances as an enabler for discontinuous innovation in slow clockspeed industries: evidence from the oil and gas industry[END_REF] by stressing the coexistence of two types of relationships: temporary with new and distant suppliers and long term with a set of preferred suppliers. This simultaneous development of two different types of relations with two categories of suppliers leading simultaneously to incremental and DI can be considered as a peculiar implementation of the ambidextrous organization (Tushman and O'Reilly, 1996;[START_REF] O'reilly | Organizational ambidexterity : past, present and future[END_REF]. The exploration of new concepts and technologies is undertaken jointly with new suppliers mastering knowledge critical for the development of these novel solutions. This way of managing exploration compares to network ambidexterity as characterized by Rothaermel and Deeds (2004): a form in which exploration is externalized through the relationships with external players. This form of organizational ambidexterity is different from the structural (Tushman and O'Reilly, 1996) and the contextual (Gibson and Birkinshaw, 2004) forms.

Propositions

Our research was based on a single qualitative and longitudinal case study which is relevant considering that few research have been done on the process of establishing relationships with new and distant supplier to explore DI the type of research question dealing with "how to establish relationships with suppliers from outside their usual realm that master distant knowledge in order to explore DI?" In the following, we articulate propositions based on our results and that could be tested on a larger and more diversified sample.

Conclusion

Previous research has extensively analyzed close and long-term relationships with a selected set of suppliers. However, relationships with suppliers new to the firm's network and with distant knowledge have been less studied, despite the benefits underlined by the literature particularly for discontinuous innovation. Furthermore, cooperation between buyers and suppliers during the early phases (exploration, concept generation, preliminary prototypes) of NPD or co-innovation as coined by Maniak and Midler (2008) has been less studied than the codevelopment.

In this research, we focus on the establishment of relationships with distant suppliers targeting the exploration of discontinuous innovation. Based on a fine-grained longitudinal study of a buyer that succeeded in developing DI as a result of cooperation with such suppliers, we suggest inductively three characteristics of the process set up: (i) building a documented mapping, coupling the concepts and their underlying technologies with the potential suppliers providing and mastering such technologies, (ii) having a structured and transparent process, supporting a mutual and progressive commitment and (iii) dedicating a specific entity separate from the rest of the and in the same time, connected to the experts that master the internal knowledge that will be combined with the external knowledge leveraged and to the top managers that will take the decisions regarding the further development of the opportunities of DI explored.

Our research has limitations associated to the methodology adopted and based on a single case study in one sector and specific context. The context of the automotive industry that was studied may present specificities with regard to the complexity of the product, the length of the development cycle, the manufacturing requirements and the relationships to customers, as first tier suppliers are in a B to B context. Furthermore, our research studied how a large firm established relationships with new and distant small and medium size firms in order to coexplore new knowledge by leveraging theirs. We do not address the negative effects that can be encountered while dealing with suppliers especially in the case where the latters have high bargaining power that could result in expropriating the buying firm from the benefits of the cooperation. However, the research question we addressed can be examined in different contexts involving firms with different sizes or evolving in different sectors. The work opens new avenues for research on this understudied and more and more emphasized kind of relationships.

  they explain this dominant behavior by the managers limitations-cognitive, resource, information, and time-as well as his history In addition, distant search may lead to causal ambiguity because the large number of alternatives and the little understanding of their consequences make it more difficult to tell which alternatives result in what level of problem-solving effectiveness. Furthermore, distant search often involves experimentation, trial, error and failure. The solution suggested by Afuah &

Proposition 1a :

 1a In a double uncertain and risky context of exploring DI with new and distant suppliers, buyers that build a documented mapping of the concepts and the suppliers increase their ability to establish relationships with new and distant suppliers. It helps selecting the one to go further with.Proposition 1b:In a double uncertain and risky context of exploring DI with new and distant suppliers, buyers that share a documented mapping of the concepts and the suppliers helps bridging the knowledge gap, visualize the several strategic options considered and decide whether a common development is valuable.Proposition 2a: In a double uncertain and risky context of exploring DI with new and distantsuppliers, buyers that have a structured and transparent process, with short decision cycles at each stage, increase their ability to establish relationships with new and distant suppliers.Proposition 2b: In a double uncertain and risky context of exploring DI with new and distant suppliers, buyers, buyers that propose a limited and progressive commitment increase their ability to establish relationships with new and distant suppliers.Proposition 3: In a double uncertain and risky context of exploring DI with new and distant suppliers, buyers that dedicate an organizational entity separate from the rest of the firm while connected to it with access to the relevant technical specialists as well as to the top management, increase their ability to establish relationships with new and distant suppliers and to leverage their knowledge.

We argue that these characteristics were success factors for establishing such relationships and led to the explorations of DI.

These results are a contribution to the literature on open innovation and NPD by specifying the process and the organizational setting to build relationships with distant suppliers on technical and relational knowledge while targeting DI. It has to be stressed that these new relationships coexist beside the long-term relationships with a set of suppliers involved in the development of current products that continued. Thus, it is an implementation of ambidexterity within established firms.

Hence, the contribution of this research is twofold. First it is a fine-grained longitudinal case analysis of a company establishing relationships with a new kind of supplier in order to generate discontinuous innovation. It discusses similarities and differences between the new relationships analyzed and the notion of strategic dalliances introduced by [START_REF] Phillips | Discontinuous innovation and supply relationships: Strategic dalliances[END_REF]. Second, based on this case study, it articulates three success factors characterizing the process and the organization that were set up and that, we argue, contribute to the establishment of these new relationships.

Further research can focus on testing the success factors in a larger sample through a quantitative approach in order to expand these findings. This research has also managerial implications documenting the process and the tools developed to establish relationships with distant suppliers. The organizational setting that we characterize for an entity in charge of managing this process can be helpful for firms trying to design organizations to develop relationships with new suppliers (either SME or suppliers not belonging to the usual supply chain) and target discontinuous innovation.


Clément Ghiazza

Thierry Billard

Callum Dickson

Anis Tlili

Christian M Gampe

Chalcogen OCF 3 Isosteres Modulate Drug Properties without Introducing Inherent Liabilities

The selenylated analog of Riluzole was first prepared (Scheme 3, top). In a visible-light metal-free procedure, using Eosin Y as organic photocatalyst, aryldiazonium salt 1 was combined with the trifluoromethylselenolating agent TsSeCF3 under white LED irradiation. This procedure allows the formation of the desired product 2 in 75 % yield. [6b] Afterwards, the reduction of the nitro moiety was performed with iron powder in aqueous HCl media leading to the corresponding aniline 3 with 81 % yield within 1 hour. [9] Finally, Se-Riluzole analog 4 was obtained after a cyclization with bromine and potassium thiocyanate in acetic acid with an overall yield of 40 %. [10] The Se-Pretomanid derivative was prepared in a three steps sequence (Scheme 3, bottom). First, commercially available boronic acid 5 was converted to the trifluoromethylselenylated arene 6 under copper catalysis with a moderate yield. [6a] Next, the benzyl alcohol was mesylated. Afterwards, removal of both NEt3 as well as the excess of MsCl was undertaken. Finally, Se-Pretomanid 8 was obtained by mixing 7 with commercially available and enantiopure alcohol 9 in the presence of sodium hydride furnishing the desired compounds in overall yield of 30 %.

Scheme 3. Se-Riluzole and Se-Pretomanid syntheses. a) TsSeCF3 (3 equiv.), eosin Y (5 mol%), DMSO, rt, 16 h, white LED, 75 %. b) Fe (3.5 equiv.), HCl 37 % (10 equiv.) 90 °C, 1 h, 81 %. c) KSCN (4 equiv.), Br2 (1 equiv.), AcOH, rt, 16 h, 66 %. d) TsSeCF3 (1 equiv.), Cu(OAc)2 (10 mol%), bpy (10 mol%), Cs2CO3 (1 equiv.), THF, rt, 16 h, 45 %. e) NEt3 (4 equiv.), MsCl (2 equiv.), CH2Cl2, 0 °C, 30 min. f) 9 (1 equiv.), NaH (2 equiv.), DMF, rt, 16 66%. Scheme 4. S-Riluzole and S-Pretomanid syntheses. a) TsSCF3 (3 equiv.), [Ru(phen)3Cl2] (5 mol%), DMSO, rt, 16 h, white LED, 50 %. b) Fe (3.5 equiv.), HCl 37 % (10 equiv.) 90 °C, 1 h, 73 %. c) KSCN (4 equiv.), Br2 (1 equiv.), AcOH, rt, 16 h, 54 %. d) NEt3 (4 equiv.), MsCl (2 equiv.), CH2Cl2, 0 °C, 30 min. f) 9 (1 equiv.), NaH (2 equiv.), DMF, rt, 16 h, 66%. Sulfur analogs were synthesized using similar procedures. Trifluoromethylthiolated arene 10 was prepared from the corresponding diazonium salt 1 with a Ru-based photocatalyst with a moderate yield of 50 % (Scheme 4, top). [11] Nitro reduction was then performed with good efficiency, and aniline 11 was obtained in 73 % yield. The desired compound 12 was isolated after the third step with an overall yield of 20 %. The synthesis of Se-Pretomanid started with commercially available trifluoromethylthiolated arene 13 (Scheme 4, bottom). A sequential mesylation/substitution with 9 allowed us to prepare the desired product 15 in 66 % yield.

Isosteric replacement of functional groups is a powerful strategy in medicinal chemistry to modulate physicochemical and ADME properties while retaining on-target potency. [12] Since molecular structure determines properties, bioisosteres need to strike a balance: Structural and electronic differences between the isostere and the parent functional group must be small enough to enable recognition by the biological target but large enough to significantly change other properties. Thus, we set out to assess the influence of chalcogen replacement in aryl-OCF3-containing compounds on structure and electronic properties. First, we performed a search for bond lengths and angle distributions in x-ray crystal structures of Ar-X-CF3 containing compounds in the Cambridge Crystallographic Data Centre database using the Mogul Software (Scheme 5, top). We found that both sigma-bonds, the F3C-X and X-Ar bonds, significantly increase in length going from X=O (ca. 1.4 Å) to X=S (ca. 1.8 Å). The corresponding bonds in the selenium-containing structures are only marginally longer (ca. 1.9 Å). The mean bond angle at the chalcogen decreases from 118° in F3C-O-Ar to 99.2° in F3C-S-Ar compounds (no entries for the Se-homolog were found). When the dihedral angle of F3C-X-C-C was assessed, we saw a clear preference of the CF3-group to adopt a conformation perpendicular to the aromatic plane for both OCF3 and SCF3 groups; although significantly less CCDC entries exist for the sulfur derivatives than for the OCF3-compounds. Only two values for the dihedral angle in ArSeCF3 structures are listed in the CCDC database, both close to 90°. We obtained an x-ray crystal structure of compound 12 and found the geometry around the SCF3 group to be comparable to the mean values obtained from the CCDC (Scheme 5, bottom). Next, we assessed the influence of chalcogen replacement on electronics via quantum mechanical calculations. We did not find significant differences in the dipole moments, electron densities, or the HOMO-LUMO gaps for the Pretomanid and Riluzole chalcogen matched pairs (see SI for details). Taken together with the structural information, we concluded that chalcogen replacement does not overly perturb conformation and electronics of the molecules, suggesting that desired biological activity may be conserved. However, if structural differences manifest in property differences we would expect the sulfur and selenium derivatives to be more similar to one another than to the Ar-OCF3-compounds. With S-and Se-matched molecular pairs of Riluzole and Pretomanid in hand, we studied their fundamental physicochemical properties (Table 1). We noted that replacement of O by S and Se increases lipophilicity by about 0.5 logP-units in both cases. Notably, no further increase in lipophilicity was observed in either case going from S to Se. These differences in lipophilicity follow the same trend seen for the structural differences between the chalcogen homologs (vide infra). Increased lipophilicity results in a decrease in solubility. This difference is marginal in case of Pretomanid, which has low solubility itself, but is more pronounced in case of the Riluzole homologs. In that case, decreased solubility of the S-and Se-homologs is likely owed to a combination of increased lipophilicity and increased lattice energy, which manifests in higher melting points compared to their OCF3 parent (ca. 30 °C higher). Again, no further decrease in solubility was observed going from SCF3 to SeCF3. Passive permeability was not significantly affected by replacement of O with the higher chalcogens, as measured in Martin-Darby Canine Kidney cells. Next, we studied the impact of the chalcogen replacement on in vitro ADME properties and off-target activity. Perhaps counter-intuitively to medicinal chemists, we found stability in human liver microsomes not to be impacted by S-and Sereplacement in either case (Table 2). We conclude that the SCF3 and SeCF3 groups introduce "nonmetabolizable lipophilcity", which may improve in vivo half-life, an important pharmacological feature that enables low clinical doses. [13] Furthermore, we found no flags for inhibition of CYP3A4 for any of the matched molecular pairs of the two drugs. Timedependent inhibition of CYP3A4 did slightly increase in case of the Riluzole chalcogen isosteres. However, we found the opposite to be true in case of Pretomanid, indicating no general, intrinsic liabilities of the SCF3 and SeCF3 groups for CYP3A4 inhibition. Likewise, human plasma protein binding was affected differently in the two test cases: While PPB increased for the Pretomanid analogs, a slight decrease was noted for the Riluzole homologs. Most importantly, we profiled the matched molecular pairs in a principal in vitro safety panel to test if replacement of OCF3 by SCF3 and SeCF3 was associated with a change in off-target potency. We found no significant changes in off-target activity in either case, indicating that, in the present case, the SCF3 and SeCF3 groups do not carry any intrinsic safety liabilities (see SI for details). Melting point [°C] [b] MDCK-LE Papp A-B [c] Pretomanid In summary, we utilized novel photocatalytic and copper-catalyzed methods to rapidly access the S-and Se-homologs of two OCF3 containing pharmaceuticals. We showed that these isosteric replacements increase lipophilicity of the compound without impacting microsomal stability, qualifying the SCF3 and SeCF3 groups as potential handles to increase in vivo half-life. Additionally, we demonstrated that chalcogen isosteres of OCF3 can be used to tweak physicochemical and ADME properties, and that the SCF3 and SeCF3 groups do not carry any intrinsic liabilities. This data should put the SCF3 and SeCF3 groups on every medicinal chemist's radar.

Scheme 5 .

 5 Scheme 5. While structural and conformational trends are generally conserved between chalcogen homologs, differences between OCF3-and SCF3-compounds are larger than between SCF3-and SeCF3-compounds. Cambridge Crystallographic Data Centre (CCDC) queries were performed using Mogul software. "Entries" refers to number of entries in the CCDC. X-ray crystal structure of 12 was obtained and analysed using PyMol.

Table 1 .

 1 Basic physico-chemical properties of the chalcogen matched molecular pairs.

	Compound	Measured	Aq. Sol. pH
		logP	6.8 [mM] [a]

Table 2 .

 2 Advanced in vitro ADME data for the chalcogen matched molecular pairs.

	2.2	0.008	149.9	21.1

[a] Clint: intrinsic clearance; HLM: human liver microsomes;

[b]

rate of time dependent enzyme inhibition (TDI).

Acknowledgements

C.G. held a doctoral fellowship from la region Rhône Alpes. The authors are grateful to the CNRS, ICBMS (UMR 5246), ICL (Institut de Chimie de Lyon) and Pulsalys for financial support. The French Fluorine Network is also acknowledged for its support. We thank Dr. Guillaume Pilet (Université Lyon 1) for collecting the crystallographic data. We are grateful to Dr. S. Skolnik and the PKS group at Novartis for support with generation of the physicochemical and in vitro ADME data. Dr. M. Shultz, Dr. A. Nadipuram, and the referees are acknowledged for valuable suggestions during data analysis and preparation of the manuscript.


Clément Ghiazza

Cyrille Monnereau

Lhoussain Khrouz

Thierry Billard

Anis Tlili
email: anis.tlili@univ-lyon1.fr

Visible-Light Mediated Synthesis of Trifluoromethythiolated Arenes

The visible light-mediated synthesis of trifluoromethylthiolated arenes in the presence of ruthenium based photocatayst under mild reaction conditions is reported herein. The trifluoromethylthiolated arenes are obtained using the shelf-stable reagent trifluoromethyl toluenethiosulfonate, at room temperature. The reaction proceeds selectively and does not require the presence of any additive. According to mechanistic investigations, a mechanism was proposed based on the obtained results of EPR as well as luminescence

Direct formation of C-SCF3 chemical bond has recently been the object of many research endeavours. 1 . Indeed, the Hansch parameter of SCF3 (R = 1.44) 2 confers to trifluoromethylthiolated molecules a high lipophilicity, thus contributing to a better transmembrane permeation of CF3S-substituted molecules allowing improved bioavailability, thus making it a much soughtafter feature. 3 Among the most studied reactions, we can find the direct trifluoromethylthiolation of arenes or heteroarenes.

 We questioned whether such a procedure could be extrapolated to the formation of C(sp2)-SCF3 . Consequently, a similar trifluoromethylthiolating reagent (TsSCF3, 2) has been synthesized in almost quantitative yield starting from our 2 nd generation of trifluoromethanesulfenamide reagent . 8

With our continuous interest to discover and develop new synthetic methodologies, we turned our attention to study the formation of C(sp2)-SCF3 bonds from arenes diazonium salts using this shelf stable reagent. During this work, similar results have been described.

Initial attempt was devoted to study the influence of the solvents on the reaction outcome. Indeed, our previous studies on related selenide reagents had evidenced a crucial influence of this parameter. 7 Indeed, while reaction using Eosin Y (5 mol%) as photocatalyst allowed reaching 59 % of product formation using DMSO as solvent at room temperature (entry 1), the use of other solvents showed the formation of desired products in lower yields (entries 2-5). Next, we tested the influence of the photocatalyst on the reaction outcome. Only marginal amount of the product was formed when Rhodamine 6G was used as photocatalyst. The use of transition metal based photocatalyst showed good reactivity when Ir(ppy)3 was used (entry 7) but the best yield was obtained with Ru(II) as photocatalyst as the targeted product was formed in 67% yield (entry 8). We also verified that the presence of the photocatalyst is primordial for the formation of the product since only traces were observed in the blank experiment (entry 9). [a] Reactions were performed with TsSCF3 (0.3 mmol, 3 equiv.), arene diazonium (0.1 mmol, 1 equiv.), Photocatalyst (5 mol%), and solvent (1 mL). The reaction mixture was stirred at rt for 16 hours under inert conditions. [b] Determined by 19 F NMR spectroscopy with PhOCF3 as an internal standard.

With the best conditions in hand we turned our focus to study the reaction scope. Initial attempts demonstrated that electron donating groups could be transformed to the desired product in moderate to very good yields (up to 69%) and no significant change was observed when the starting aryl diazonium salts 1c and 1d were substituted in the ortho position. Interestingly, taking in advantage the base free conditions, free hydroxyl aryl diazonium salt was also tolerated, furnishing the desired product 3e in 55% yield. Similarly, aryl diazonium salts substituted with electron withdrawing groups were also successfully evaluated under our reaction conditions. Obviously, very strong electron withdrawing substituted arenes (including NO2, CN and EtO2C) could be converted to their trifluoromethylthiolated analogues in acceptable to very good yields (up to 77%). Halogenated products were also tolerated since 3i and 3j could be formed in moderate to good yields. Finally, we could demonstrate through the example of product 3k that a heterocyclic starting material could be also converted to its desired product although in low reaction outcome.

Mechanistic details were further investigated using luminescence spectroscopy. We first aimed at establishing the occurrence of an energy transfer process between the ruthenium catalyst and the tolyldiazonium reagent 1a by following extinction of the former luminescence upon incremental additions of the latter (see SI for further experimental details). Quite surprisingly, unlike previously observed in earlier works dealing with Ru complexes, plot of the resulting data using a Stern Volmer model did not lead to a straight line. Instead, we noticed a distinct upward curvature of the plotted data. Such behavior suggests that, while a photoinduced reaction is clearly seen between the Ru catalyst and the diazonium quencher, it cannot be fully rationalized based on a diffusion-controlled charge transfer mechanism as postulated in the Stern Volmer Theory. Indeed, such positive curvature deviations from Stern Volmer model have been largely documented in the past, on a variety of donor/acceptor (D/A) pairs. Among the most currently admitted causes for this phenomenon, the occurrence of increased static quenching at high quencher concentration ([Q]) is often mentioned. 10 The latter adds to the dynamic, diffusion controlled process encountered at low [Q], thus increasing the extent of quenching at high [Q]. Accordingly, those effects can find two distinct origins either 1/ the occurrence of a non-emissive ground state luminophore-quencher complex which is highly favoured at high [Q] 11 or 2/ the so-called "sphere of action" model, 12 in which concentration-dependent spatial proximity of the excited luminophore and the quencher molecule ensures that diffusion is not a limiting factor of the quenching process. The latter is also obviously favoured at high [Q] and is more prone to occur when slow charge transfer processes are involved within the D/A pair. Indeed, the latter model seems to account for the observed trend in our case, as plotting ln(I0/If) vs [Q] affords a quasi linear evolution as predicted by the aforementioned model (See SI for details).

Scheme 2.

[a] Reactions were performed with TsSCF3 (0.6 mmol, 3 equiv.), arene salt 1 (0.2 mmol, 1 equiv.), [Ru] (5 mol%), and DMSO (2 mL). The reaction mixture was stirred at room temperature for 16 hours under inert conditions. Yields shown are those of isolated products; yields determined by 19 F NMR spectroscopy with PhOCF3 as internal standard are shown in parentheses.

Next, we determined the reaction quantum yield (QY), in order to establish whether a step or chain mechanism was more likely involved in the reaction. Using the Xenon lamp of the fluorimeter as an irradiation source, we performed controlled irradiation of a degassed 3 mL sample of the reaction medium set in a 1 cm quartz cuvette, and followed reactant-to-product conversion using 19 F NMR on aliquots of the reaction mixture taken up at various reaction time. As for our previously reported example using eosin as a catalyst, catalytic conversion was seen to proceed in two stages: first a buildup of a dimeric CF3S-SCF3 species, which was then consumed upon addition to the diazonium reagent. Linearization of the data collected in the initial stage of the reaction (first 30 minutes) allowed establishing a quantum yield ca 1.5, following the general methodology detailed in SI. This value, which clearly exceeds unity, is in line with a chain propagation mechanism, consistent with what had been previously shown with the selenium counterpart of the current sulfur reagent in the presence of eosin (with a QY slightly exceeding 1 in the latter case).

By analogy with our previous works on related trifluoromethylselenosulfonate reagents, radicals formed upon irradiation of the ruthenium catalyst-free sample are attributed to the outcome of a light induced homolytic cleavage of the trifluoromethyl toluenethiosulfonate reagent 2. In this case, a hallmark of the reaction is the production of a CF3S • radical species that forms the most prominent adduct (65%) with PBN radical trap, which features (aN=14.4G, aH=1.9G) are in good agreement with what we reported for its CF3Se • counterpart. Formation of two other readily attributable species can be observed in the EPR spectrum: the first one (7% aN=14.4G, aH=1.2G) corresponds to the second member of homolytic cleavage, the Ts • radical; the other by-product (8%, aN=14.4G, aH=2.7G) most likely corresponds to an adduct of an Ar • radical (tolyl) that evolves from this first Ts • radical intermediate, by elimination of SO2. Two other species of significant intensity are observed, but their chemical nature is less straightforward. The 5% species (aN= 8.1 G) and 15% species (aN= 12.4 G) can both be attributed to oxidation products of the aforementioned BPN-radical adduct as no hyperfine interaction with the adjacent proton (Hß) is observed (Figure 1).

When ruthenium catalyst is added to the mixture, EPR signal obtained upon photoirradiation is enhanced by almost one order of magnitude. Moreover, species distribution pattern is largely different from that obtained in the absence of catalyst. As a consequence of the electron transfer taking place between Ru(II) catalyst and the diazonium reactant 1a, decomposition of the latter by elimination of nitrogen provides a Ar • tolyl radical (40% aN=14.6G, aH=2.8G) that is within error margin identical to the abovementioned evolution product of the Ts • radical, thereby retrospectively confirming the attribution of the latter. Surprisingly, the two others adducts (40%, aN=12.3G, 20%, aN=8.2G) does not seem to correspond to the CF3S • radical as observed in the absence of ruthenium, but to similar PBN oxidation products as monitored in the absence of the ruthenium catalyst. With these results in hand, we are able to propose a plausible mechanism. The diazonium salt is reduced through a single electron transfer (SET) by the triplet state ruthenium photocatalyst. The resulting aryl radical could then react with the transient dimer CF3SSCF3, obtained from the reagent 2 under light irradiation. The obtained trivalent sulfur radical A is then oxidized by the diazonium salt furnishing the cationic species B and a new aryl radical. Finally, the cationic intermediate could react with a nucleophile from the reaction media (DMSO can also play this role), yielding the desired product 1.

Scheme 3. Proposed mechanism

To conclude, the direct synthesis of trifluoromethylthiolated arenes could occur under visible light catalysis starting with arene diazonium salts and a shelf-stable reagent under mild reaction conditions. Furthremore, mechanistic investigations were also performed to shed some light on the reaction pathway. It turns out that trifluoromethylsulfur radical is a key intermediate in the reaction mechanism. Further developments are under way in our laboratory.

Procedures

Synthesis of 1a-1d and 1f-1k: In a 25 mL round bottom-flask are added aniline (10 mmol) and aqueous HBF4 48% (20 mmol, 2.6 mL) in absolute EtOH (3 mL). The mixture is stirred until total homogeneity and at 0°C. t-BuONO 90% (20 mmol, 2.7 mL) is added dropwise to the solution. The reaction is stirred at room temperature for 30 minutes. Et2O (10 mL) is then added to precipitate the salt. The solid is then filtered and washed 3 times with Et2O and dried under reduced pressure to afford the desired product.

Synthesis of 1e:

In a 25 mL round bottom-flask are added aniline (10 mmol) and aqueous HBF4 48% (20 mmol, 2.6 mL). The mixture is stirred until total homogeneity and cooled at 0°C. NaONO (20 mmol, 1.38 mg) dissolved in water (2 mL) is added dropwise to the solution. The reaction is stirred at room temperature for 30 minutes. Et2O (10 mL) is then added to precipitate the salt. The solid is then filtered and washed 3 times with Et2O and dried under reduced pressure to afford desired product.

Synthesis of 2:

To a flame-dried flask under nitrogen atmosphere equipped with a magnetic stir bar are added 4-Methyl-N-[(trifluoromethyl)sulfanyl]-benzene-1-sulfonamide (37.2 mmol, 1 equiv.), sodium sulfonate (44.6 mmol, 1.2 equiv.) and acetic acid (70 mL).

The reaction is stirred at 25°C for 16 hours. The reaction mixture is partitioned between EtOAc and brine. The aqueous layer is extracted with EtOAc and the combined organic layers are dried over MgSO4, filtered and concentrated to dryness. The crude residue is purified by chromatography to afford the desired product 2 obtained as colorless liquid (9.2 g, 35.9 mmol, 97 %).

Eluent for the flash chromatography: Cyclohexane/EtOAc : 100/0 to 95/5 data matched that reported in the literature. 13 General procedure: To a flame-dried flask under nitrogen atmosphere equipped with a magnetic stir bar are added 2 (0.6 mmol, 3 equiv.), aryldiazonium salt 1 (0.2 mmol, 1.0 equiv.), dichlorotris(1,10-phenanthroline) ruthenium (II) hydrate [Ru(phen)3Cl2] (0.01 mmol, 5mol%) and anhydrous dimethyl sulfoxide (2 mL). The reaction is stirred at 25°C under white led irradiation for 16 hours. Conversion is checked by 19 F NMR with PhOCF3 as internal standard. The reaction mixture is partitioned between Et2O and water. The aqueous layer is extracted with Et2O and the combined organic layers are dried over MgSO4, filtered and concentrated to dryness. The crude residue is purified by chromatography to afford the desired product 3.

Synthesis of 1-methyl-4-[(trifluoromethyl)sulfanyl]benzene (3a)

Slightly yellow liquid (20 mg, 0.104 mmol, 52 %)

Eluent for the flash chromatography: n-Pentane 100%

Figure 1 :

 1 Figure 1: EPR spin-traping spectra on visible irradiation in the presence of PBN in DMSO at room temperature. Blue: experimental, red simulated after 4 minutes with Ru (top) and 7 minutes without Ru (bottom) of irradiation

Table 1 . Reaction optimisation a

 1

	3	EtOH instead of DMSO	47
	4	THF instead of DMSO	27
	5	ACN instead of DMSO	45
	6	Rhodamine 6G instead of Eosin Y	19
	7	Ir(ppy)3 instead of Eosin Y	59
	8	[Ru(phen)3Cl2].xH2O instead of Eosin Y	67
	9	No photocatalyst	< 5

  H NMR (300 MHz, CDCl3)  = 7.88 (d, J = 8.3 Hz, 2H), 7.40 (d, J = 8.3 Hz, 2H), 2.49 (s, 3H).

1 19 F NMR (282 MHz, CDCl3)  = -38.48 (s, 3F).

Acknowledgment

We thank Dr. Maurice Médebielle (ICBMS) for cyclic voltametry measurement.

Funding Information

C.G. held a doctoral fellowship from la region Auvergne Rhône Alpes. The authors are grateful to the CNRS, ICBMS (UMR 5246), ICL (Institut de Chimie de Lyon) for financial support. The French Fluorine Network as well as the federation RENARD are also acknowledged for their support.

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