Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
One-Step Synthesis of Aliphatic Potassium Acyltrifluoroborates (KATs) from Organocuprates Sizhou M. Liu,‡ Dino Wu,‡ and Jeffrey W. Bode* Laboratorium für Organische Chemie, Department of Chemistry and Applied Biosciences, ETH Zürich, 8093 Zürich, Switzerland S Supporting Information *
ABSTRACT: A one-step synthesis of aliphatic KATs from organocuprates is reported. Organolithium and organomagnesium reagents were readily transmetalated onto Cu(I) and coupled with a KAT-forming reagent to yield the respective aliphatic KAT. The protocol is suitable for primary, secondary andfor the first timetertiary alkyl substrates. These protocols considerably expand the range of KATs that can be readily accessed in one step from commercially available starting materials.
A
Scheme 1. One-Step Synthesis of Potassium Acyltrifluoroborates
cylboronates are a fascinating and underdeveloped class of functional groups for organic synthesis. While their existence was proposed as reactive intermediates in several transformations over the last century,1 it was not until 2007 that the first fully characterized acyl boron species was disclosed by Nozaki and co-workers.2 Several approaches for the synthesis of acylboronates have since been reported. In 2010, Curran and Lacôte3 reported the synthesis of an acylborane species from an N-heterocyclic carbene-stabilized borane. In the same year, Molander and co-workers4 synthesized a single example of a potassium acyltrifluoroborate. In 2012, Yudin developed a multistep approach to N-methyliminodiacetyl (MIDA) acylboronates from a vinyl boron species5 and, just recently, Ito and Perrin independently reported the synthesis of acylboronates by oxidation of vinyl (MIDA) boronates.6,7 As part of our group’s long-standing interest in new amideforming reactions, we gained interest in KATs after finding that they undergo rapid ligation reactions with hydroxylamines in water.8,9 In order to expand synthetic access to KATs, our research group previously devised a route exploiting Katritzky’s benzotriazole chemistry10 to prepare a range of KATs, albeit in somewhat poor yields and limited substrate scope.11,12 In order to provide direct access to aromatic KATs from the corresponding halides, we also introduced KAT transfer reagent (ethylthiotrifluoroborate)methane dimethyliminium (1), (Scheme 1).13 Unfortunately, these conditions were largely unsuccessful for the synthesis of aliphatic KATs, because of the double addition of the more nucleophilic aliphatic organolithium reagents. In this report, we document the synthesis of aliphatic KATs from in-situ-generated organocuprates and KAT transfer reagent 1. This convenient protocol allows readily prepared or commercially available organolithium and Grignard reagents derived from primary, secondary, and tertiary alkyl halides to be easily converted to the corresponding KATs in high yields. This chemistry affords the first known tertiary acylboronates, and we © XXXX American Chemical Society
demonstrate that even these hindered examples undergo KAT ligation with hydroxylamines. At the onset of this work, we envisioned the direct conversion of organometallic reagents to KATs through the reaction of the desired substrate with the formerly developed KAT transfer reagent 1 in a one-pot fashion. Our initial attempts using n-butyllithium and n-butylmagnesium chloride for this transformation failed to give the desired product (see Scheme 2). Instead, double addition of the substrate to the transfer reagent and formation of the bis-alkylated product were observed. Received: March 4, 2018
A
DOI: 10.1021/acs.orglett.8b00720 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
organomagnesium toward CuCN for the transmetalation could be observed. Performing the reaction with an equimolar amount of Cu(I) to generate the neutral heteroleptic organocopper reagent (Table 1, entry 5) failed to give the desired product. Addition of the Grignard reagents to KAT transfer reagent 1 at 0 °C over an hour resulted in better yield in the case of CuCN. However, no product was formed with CuI under these conditions, because of cuprate decomposition (Table 1, entries 6 and 8). Exchanging organocuprates for organozinc reagents (Table 1, entries 10 and 11) failed to give any product. With the optimized protocol in hand, we expanded the substrate scope to include primary KATs bearing simple alkyl chains, alkene, alkyne, acetal, and hydroxyl moieties (see Scheme 3).
Scheme 2. Previous Work on Thioiminium Mono-alkylation
Scheme 3. Synthesis of Primary Aliphatic KATs with Organocupratesa
Selective mono-alkylation of thioiminium reagents has been deemed challenging, with little precedence in the literature.14 Bosch and Renaud independently reported the selective monoalkylation of thioiminium moieties with organocuprates.15,16 Inspired by these works, we attempted the addition of organocuprates to transfer reagent 1, and we were pleased to observe the formation of the desired product. Encouraged by this finding, we set out to optimize the reaction conditions for the synthesis of aliphatic KATs (see Table 1). Table 1. Optimized Conditions for Organocuprate Addition to KAT Transfer Reagent 1a
No.
M
1 2 3 4 5 6 7 8 9 10 11
Li MgCl Li Li Li MgCl MgCl MgCl MgCl Li MgCl
conditions −78 °C −78 °C 1.1 equiv 1.1 equiv 2.2 equiv 1.1 equiv 1.1 equiv 1.1 equiv 1.1 equiv 1.1 equiv 1.1 equiv
CuCN, −78 °C, 1 h CuI, −78 °C, 1 h CuCN, −78 °C, 1 h CuCN, −78 to 0 °C, 1 h CuI, −78 °C, 1 h CuI, −78 to 0 °C, 1 h CuBr·SMe2, −78 °C, 1 h ZnI2, −78 °C, 1 h ZnI2, −78 °C, 1 h
yieldb (%) 0 0 79 86 0 81 70 0 7 0 0
a
Reactions were conducted with 2.3 equiv organometallic species and 1.1 equiv Cu(I) salt. In the case of organolithium species, CuI was used and the organocuprate was preformed at −78 °C. For organomagnesium species, CuCN was used to preform the cuprate at 0 °C. bReaction carried out in gram scale (5.4 mmol).18
While the organocuprate formation with primary Grignard reagents and organolithium reagents proceeded rapidly, even at low temperatures, secondary Grignards required significantly longer reaction times in the transmetalation step. In order to accelerate the transmetalation and ensure complete cuprate formation, the reaction temperature was increased to 0 °C. However, this necessitated the use of CuCN, because of the low thermal stability of CuI-derived organocuprates. Subsequent addition of the preformed organocuprate species to KAT transfer reagent 1 at −78 °C and warming to room temperature overnight had a favorable effect on the selectivity toward monoalkylation, compared to conducting the reaction at 0 °C throughout. With these revised conditions, we were able to prepare a broad range of secondary aliphatic KATs ranging from branched to cyclic products in good yields (see Scheme 4). For the synthesis of the saturated heterocyclic KATs (16, 17), we observed fast decomposition of the organocuprate at 0 °C,
a
All reactions were conducted with 2.2 equiv organolithium or organomagnesium species on a 0.28 mmol scale, unless otherwise specified. Organocuprates were preformed at 0 °C or −78 °C. b Isolated yield.
In early efforts, we performed transmetalation of commercially available n-butylmagnesium chloride and n-butyllithium onto copper(I) salts to generate the corresponding organocuprates. As organocuprates display high functional group tolerance and are readily accessible from a broad range of commercial Grignard and alkyllithium reagents, 17 they represented the ideal candidate for our transformation. We found that the use of CuCN (Table 1, entries 3 and 6) and CuI (Table 1, entries 4 and 7) generally provided the highest yielding results for both organolithium and organomagnesium species. A slight preference of organolithium toward CuI and B
DOI: 10.1021/acs.orglett.8b00720 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 4. Synthesized Secondary and Tertiary Aliphatic KATsa
Scheme 5. Reactivity Studies of Aliphatic KATs
a
Reactions were conducted with 2.4 equiv organometallic species and 1.1 equiv Cu(I) salt. In the case of organolithium species, CuI was used and the organocuprate was preformed at −78 °C. For organomagnesium species, CuCN was used to preform the cuprate at 0 °C. bReaction carried out in gram scale (5.4 mmol).
even with CuCN. By forming the organocuprate at −78 °C under sonication, we were able to circumvent this problem and were able to obtain KATs 16 and 17 in good yields. With these promising results in hand, we investigated if this method allowed for the synthesis of previously inaccessible tertiary KATs. Upon conversion to the respective organocuprates, bulky reagents such as t-butyllithium and 1,1-dimethylpropylmagnesium chloride reacted readily with KAT transfer reagent 1 to give the first isolated examples of tertiary KATs 18 and 19 in satisfying yields. To probe the scalability of the reaction, we repeated the reaction on gram scale (5.4 mmol) for selected substrates (compounds 4, 10, 18). The scaleup proved to be successful, with yields comparable to those observed in small-scale reactions. Having primary, secondary, and tertiary alkyl KATs in hand, we probed the degree to which sterics influence the ligation rate of KATs with O-carbamoyl hydroxylamine 20 (see Scheme 5). In competition experiments, the ligation of unbranched alkyl KAT 4 and secondary KAT 10 gave a 2:1 product ratio in favor of the less-hindered substrate. This indicates that the ligation of secondary KATs is still relatively fast. In comparison, the competition between the primary KAT 4 and tertiary KAT 18 showed a clear selectivity of 99:1 toward the unbranched product. The ligation of tert-butyl KAT (18) with hydroxylamine (20) can proceed to full conversion with increased reaction time (24 h) to give the desired amide in 92% yield. These findings indicated that sterics are significant components of reaction rate in the KAT ligation. In summary, we have developed a convenient and robust protocol for the preparation of aliphatic KATs from readily available Grignards and commercially available KAT transfer reagent 1 in a one-pot fashion. We demonstrated the scalability of this new procedure and prepared 18 new KATs bearing a variety of functional groups. This route is significantly simpler
than the two-step benzotriazole route requiring demanding reaction conditions and purification steps. This method also allowed access to the first tertiary potassium acyltrifluoroborates. Furthermore, ligation experiments of aliphatic KATs with O-carbamoyl hydroxylamine were performed to determine the relative reactivity for primary, secondary, and tertiary alkyl KATs. We found that sterics influenced the reaction with the expected correlation between steric bulk and conversion.
■
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00720. Experimental procedures and characterization of aliphatic acyltrifluoroborates (PDF)
■
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Jeffrey W. Bode: 0000-0001-8394-8910 Author Contributions ‡
These authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS This work was supported by an ETH Research Grant (No. ETH-43 13-2). We thank Alberto Osuna Galvez (ETH) for compound 8. Furthermore, we thank the LOC Mass C
DOI: 10.1021/acs.orglett.8b00720 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Spectrometry Service and the LOC NMR Service for analysis and helpful discussions.
■
REFERENCES
(1) Selected papers for further reading: (a) Schmid, G.; Nöth, H. Chem. Ber. 1968, 101, 2502−2505. (b) Hillman, M. E. D. J. Am. Chem. Soc. 1962, 84, 4715−4720. (c) Hillman, M. E. D. J. Am. Chem. Soc. 1963, 85, 982−984. (d) Brown, H. C. Acc. Chem. Res. 1969, 2, 65−72. (e) Brown, H. C.; Rathke, M. W. J. Am. Chem. Soc. 1967, 89, 2738− 2740. (f) Kabalka, G. W.; Gotsick, J. T.; Pace, R. D.; Li, N.-S. Organometallics 1994, 13, 5163−5165. (2) Yamashita, M.; Suzuki, Y.; Segawa, Y.; Nozaki, K. J. Am. Chem. Soc. 2007, 129, 9570−9571. (3) Curran, D. P.; Solovyev, A.; Makhlouf Brahmi, M.; Fensterbank, L.; Malacria, M.; Lacôte, E. Angew. Chem., Int. Ed. 2011, 50, 10294− 10317. (4) Molander, G. A.; Raushel, J.; Ellis, N. M. J. Org. Chem. 2010, 75, 4304−4306. (5) He, Z.; Trinchera, P.; Adachi, S.; St. Denis, J. D.; Yudin, A. K. Angew. Chem., Int. Ed. 2012, 51, 11092−11096. (6) Taguchi, J.; Ikeda, T.; Takahashi, R.; Sasaki, I.; Ogasawara, Y.; Dairi, T.; Kato, N.; Yamamoto, Y.; Bode, J. W.; Ito, H. Angew. Chem., Int. Ed. 2017, 56, 13847−13851. (7) Lepage, M. L.; Lai, S.; Peressin, N.; Hadjerci, R.; Patrick, B. O.; Perrin, D. M. Angew. Chem., Int. Ed. 2017, 56, 15257−15261. (8) Dumas, A. M.; Molander, G. A.; Bode, J. W. Angew. Chem., Int. Ed. 2012, 51, 5683−5685. (9) Noda, H.; Erő s, G.; Bode, J. W. J. Am. Chem. Soc. 2014, 136, 5611−5614. (10) Katritzky, A. R.; Rachwal, S.; Hitchings, G. J. Tetrahedron 1991, 47, 2683−2732. (11) Dumas, A. M.; Bode, J. W. Org. Lett. 2012, 14, 2138−2141. (12) Liu, S. M.; Mazunin, D.; Pattabiraman, V. R.; Bode, J. W. Org. Lett. 2016, 18, 5336−5339. (13) Erő s, G.; Kushida, Y.; Bode, J. W. Angew. Chem., Int. Ed. 2014, 53, 7604−7607. (14) (a) Takahata, H.; Takahashi, K.; Wang, E.-C.; Yamazaki, T. J. Chem. Soc., Perkin Trans. 1 1989, 1211−1214. (b) Murai, T.; Mutoh, Y.; Ohta, Y.; Murakami, M. J. Am. Chem. Soc. 2004, 126, 5968−5969. (c) Murai, T.; Toshio, R.; Mutoh, Y. Tetrahedron 2006, 62, 6312− 6320. (15) Amat, M.; Llor, N.; Hidalgo, J.; Escolano, C.; Bosch, J. J. Org. Chem. 2003, 68, 1919−1928. (16) Mateo, P.; Cinqualbre, J. E.; Meyer Mojzes, M.; Schenk, K.; Renaud, P. J. Org. Chem. 2017, 82, 12318−12327. (17) For selected reviews on organocuprate chemistry, see: (a) Breit, B.; Schmidt, Y. Chem. Rev. 2008, 108, 2928−2951. (b) Yoshikai, N.; Nakamura, E. Chem. Rev. 2012, 112, 2339−2372. (18) Performing the reaction with benzyl magnesium chloride failed to give the desired KAT.
D
DOI: 10.1021/acs.orglett.8b00720 Org. Lett. XXXX, XXX, XXX−XXX
