Iron-catalysed enantioselective Suzuki-Miyaura coupling of racemic alkyl bromides

Article abstract of DOI:10.1039/c8cc09523j

The first iron-catalysed enantioselective Suzuki-Miyaura coupling reaction has been developed. In the presence of catalytic amounts of FeCl₂ and (R,R)-QuinoxP?, lithium arylborates are cross-coupled with tert-butyl α-bromopropionate in an enantioconvergent manner, enabling facile access to various optically active α-arylpropionic acids including several nonsteroidal anti-inflammatory drugs (NSAIDs) of commercial importance. (R,R)-QuinoxP? is specifically able to induce chirality when compared to analogous P-chiral ligands that give racemic products, highlighting the critical importance of transmetalation in the present asymmetric cross-coupling system.

Full text of DOI:10.1039/c8cc09523j

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Iron-catalysed enantioselective Suzuki–Miyaura
coupling of racemic alkyl bromides†
Cite this:DOI: 10.1039/c8cc09523j
ab
Takahiro Iwamoto,
Chiemi Okuzono,ab Laksmikanta Adak,a Masayoshi Jinc and
Masaharu Nakamura*ab
Received 3rd December 2018,
Accepted 27th December 2018
DOI: 10.1039/c8cc09523j
rsc.li/chemcomm
The first iron-catalysed enantioselective Suzuki–Miyaura coupling
reaction has been developed. In the presence of catalytic amounts
of FeCl2 and (R,R)-QuinoxP*, lithium arylborates are cross-coupled
with tert-butyl a-bromopropionate in an enantioconvergent manner,
enabling facile access to various optically active a-arylpropionic acids
including several nonsteroidal anti-inflammatory drugs (NSAIDs)
of commercial importance. (R,R)-QuinoxP* is specifically able to
induce chirality when compared to analogous P-chiral ligands
that give racemic products, highlighting the critical importance of
transmetalation in the present asymmetric cross-coupling system.
Fig. 1 Enantioconvergent couplings of alkyl halides with organoboron
reagents.
Transition-metal-catalysed coupling reactions with organoboron
reagents, namely Suzuki–Miyaura coupling reactions, are among combinations of alkyl halides and nucleophiles,3a,e,5 and to
the most powerful methods for the construction of carbon–carbon other transition-metal catalysts;6 however, the use of organo-
bonds in both academic and industrial chemical syntheses.1 boron reagents is still severely limited to nickel catalysis.
Intensive studies involving catalysts and ligands have firmly
Iron has gained considerable attention due to its cost-
established this synthetic method; however enantioselective effectiveness and safe properties, which advantages this metal
versions remain challenging, particularly for the construction of catalyst in pharmaceutical and agrochemical syntheses.7 Over
sp3 carbon centres. Owing to the appreciable significance of such the past decade, our group and others have developed iron-
stereogenic centres in current pharmaceutical design,2 consider- catalysed coupling reactions involving organoboron reagents,8
able effort has been devoted to developing enantioselective cross including those with alkyl halides.9 However, the application of
couplings involving alkyl reagents.3
an organoboron reagent to an enantioselective iron-catalysed
Enantioconvergent coupling reactions of alkyl halides with coupling reaction has not been achieved so far. Here we report
boron nucleophiles represent the most sophisticated approaches the first examples of iron-catalysed enantioselective couplings
because they directly synthesise optically active molecules from of organoboron reagents to produce optically active a-aryl esters
readily available racemic halides. Fu and co-workers have made from racemic a-haloesters and arylboron reagents (Fig. 1b).
significant progress in such transformations through the use of
Our studies began by screening ligands in the coupling of
nickel catalysts (Fig. 1a).4 At present, the scope of this type tert-butyl a-bromopropionate (1) with the lithium phenylborate
of enantioconvergent reaction has been expanded to various 2a, which was easily prepared from the boronic ester and BuLi
(Table 1).9b In the previously reported enantioselective iron-
catalysed coupling of aryl Grignard reagents, P-chiral bisphos-
phine ligand of (R,R)-BenzP* was the most effective among a
variety of ligands.6c Based on these results, we initially examined
several P-chiral bisphosphines10 and found that the ligand back-
bone has a remarkable effect on enantioselectivity. As shown in
Table 1, to our surprise, the present reaction with (R,R)-BenzP*
L1 did not exhibit chiral induction at all. In addition, the
reaction needed an unexpectedly long reaction time (198 h) for
a Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan.
E-mail: masaharu@scl.kyoto-u.ac.jp
b Department of Energy and Hydrocarbon Chemistry, Graduate School of
Engineering, Kyoto University, Kyoto 615-8510, Japan
c Process Technology Research Laboratories, Pharmaceutical Technology Division,
Daiichi Sankyo Co., Ltd., 1-12-1 Shinomiya, Hiratsuka, Kanagawa 254-0014,
Japan
† Electronic supplementary information (ESI) available: Experimental procedures,
theoretical calculation, and spectroscopic data. See DOI: 10.1039/c8cc09523j
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Table 1 Chiral-ligand screeninga
Table 2 Arylboron reagent scope
Time Yield [%]
(h)
(er)a
Product
Entry
1
4b: R = Me
4c: R = OMe
4d: R = NMe2
4e: R = CF3
4f: R = Cl
6
35
3
23
12
90 (81 : 19)
85 (82 : 18)
89 (82 : 18)
81 (76 : 24)
83 (84 : 16)
2b
3
4
5
6
7
4g
20
19
65 (88 : 12)
91 (77 : 23)
4h
8c
9
3i
15
5
80 (81 : 19)
95 (82 : 18)
a
Yields and er values were determined by GC and HPLC, respectively.
full conversion of the alkyl halide. The use of P-chiral ligands
L2–L4, which have aliphatic backbones, were also totally ineffec-
tive, providing the racemic coupling product. In sharp contrast,
chiral ligands bearing a quinoxaline backbone were specifically
able to induce chirality; (R,R)-QuinoxP* L5 was found to be optimal
and gave product 3a in 99% yield with 84 : 16 er. C1-Symmetric
(R)-3H-QuinoxP* L6 also provided 3a with comparable enantio-
selectivity, although the reaction proceeded slowly probably due to
the steric hindrance of three t-Bu groups. Other types of chiral
ligand, including nitrogen-based ones, were less effective in this
reaction (see ESI†). It is noteworthy that the yield is affected by the
synthetic procedure; the arylborate, a-haloester, and MgBr2 need to
be added in this order to the mixture of FeCl2 and the chiral ligand
as depicted in Table 1 (see ESI† for experimental details).
Optically active a-aryl esters are useful intermediates for the
synthesis of several bioactive molecules, such as a-arylpropionic
acids, which are well known to be nonsteroidal anti-inflammatory
drugs (NSAIDs).11 Indeed, the coupling product was smoothly
transformed into a-phenylpropionic acid without any loss of
optical purity upon hydrolysis with TFA (Scheme 1). Notably,
this sequential method involving coupling and hydrolysis did
not require any chromatographic purification, and simple
liquid–liquid extraction provided pure a-phenylpropionic acid
in high yield.
(S)-Ibuprofen 4j
10
(S)-Flurbiprofen 4k 16
51 (84 : 16)
11
12
(S)-Fenoprofen 4l 22
(S)-Cicloprofen 4m 13
52 (82 : 18)
49 (81 : 19)
13b
(S)-Naproxen 4n
22
80 (80 : 20)
a
b
Isolated yields; er values determined by HPLC. FeCl2 (1 mol%) and
c
(R,R)-QuinoxP* (2 mol%) were used. Hydrolysis failed due to the
decomposition of the indolyl group, and yield was determined by
1H NMR.
and deficient (entry 4) arylborates provided the coupling products
in high yields and with reasonable enantioselectivities. The chloro
substituent, which is potentially useful for further synthetic
elaborations including cross-couplings, was untouched under
the present reaction conditions; the product was obtained in
83% yield with 84 : 16 er (entry 5). ortho-Substituted phenyl- and
2-naphthylborates were also amenable to the reaction (entries 6
and 7). Coupling with the indolylborate also proceeded smoothly
and enantioselectively (entry 8); however, hydrolysis of the
coupling product failed due to the decomposition of the indolyl
unit under acidic condition. Furthermore, the developed syn-
thetic method was applied to the synthesis of a variety of bio-
active a-phenylpropionic acids with enantioselectivities in excess
of 80: 20 (entries 9–13).
With the optimal procedure in hand, we examined the scope
of the arylboron reagent (Table 2). Both electron-rich (entries 1–3)
Scheme 1 Synthesis of chiral a-phenylpropionic acid by iron-catalysed
enantioconvergent coupling and hydrolysis.
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We next turned to the specific chiral-inducing ability of
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(R,R)-QuinoxP* compared to other P-chiral bisphosphine ligands.
We previously reported that both (R,R)-QuinoxP* and (R,R)-BenzP*
induced comparable enantioselectivities in iron-catalysed couplings
involving aryl Grignard reagents, which is in stark contrast to the
present system.6c,12 On the basis of these results, we have tentatively
concluded that the observed difference between (R,R)-QuinoxP*
and (R,R)-BenzP* in the present system cannot be attributed to
their chiral induction abilities. To examine the difference
between the two ligands, we performed stoichiometric reac-
tions of pre-formed complexes, namely FeCl2/(R,R)-QuinoxP* A1
and FeCl2/(R,R)-BenzP* A2, with phenyl borate 2a in the pre-
sence of MgBr2 (Fig. 2). The reaction of A2 proceeded quite slowly,
and more than 60% of the starting iron complex remained even
after 62 h. On the other hand, iron complex A1 was completely
consumed within 2 h under the same conditions. These results
indicate that (R,R)-QuinoxP* is crucial to facilitate transmetalation,
which is most likely the key step for the generation of the active
iron species in the enantioselective catalytic cycle (vide infra).
The electron-withdrawing nature of the quinoxaline backbone
renders the iron centre more electrophilic, thereby accelerating
transmetalation.13
Based on our experimental and theoretical studies on the
iron-catalysed couplings of alkyl halides, we present a plausible
mechanism in Fig. 3a.6c,9b,13a,14 Transmetalation of FeCl2/
bisphosphine A with the boron reagent15 and subsequent
reductive elimination provides FeIX/bisphosphine B, which is
the active species during the first C–Br bond-activation step.
Complex B then abstracts the bromine atom from the alkyl bromide
to generate the corresponding alkyl radical; this radical recombines
with complex C, which is generated by the transmetalation of A with
the boron reagent,16 to produce FeIIIBrArAlkyl/bisphosphine D.
Reductive elimination of complex D provides the coupling product.
In the case of (R,R)-BenzP*, transmetalation with the arylborate is
quite slow. As a consequence, the racemic background reaction
triggered by ligand dissociation from complex A dominates
(Fig. 3a, left).17 Due to tiny amount of ligand-dissociated iron
species in the reaction solution, the coupling with (R,R)-BenzP*
proceeded quite slowly.
Fig. 3 (a) Plausible mechanism for the enantioselective coupling reaction
of aryl boron reagents and (b) energy profile of recombination and reduc-
tive elimination calculated at the B3LYP/6-311G* with GD3BJ empirical
dispersion. Energy values (kcal molÀ1) relative to sum of C and alkyl radical
are shown in parentheses. For the detail of complex structures and discus-
sion, see ESI.†
22.6 kcal molÀ1, respectively (Fig. 3b). In addition, the energy
barrier for reductive elimination is predicted to be 11.8 kcal molÀ1
.
Although the transition state for the recombination step was
unable to be optimized due to the flatness of the potential
energy surface, the calculated energy profile suggests that each
step proceeds irreversibly under the reaction conditions; hence,
we conclude that recombination is most likely to be the enantio-
determining step.
In summary, we developed the first iron-catalysed enantio-
selective coupling reactions involving organoboranes, in which
the use of a P-chiral ligand containing an electron-deficient
quinoxaline backbone is the key to attaining high enantios-
electivities. This reaction enables facile access to a variety of
optically active a-arylpropionic esters from racemic a-bromoesters,
which are readily deprotected to the corresponding a-arylpropionic
acids, including several pharmaceutical compounds. Although the
enantioselectivity can still be improved, the combination of an
iron catalyst with a boron reagent clearly endows this method with
practical advantages over other coupling reactions. Efforts to
further develop more-selective iron catalysts and expand the
scope are underway in our laboratory.18
This work was supported in part by the Core Research for
Evolutional Science and Technology (CREST 1102545) Program
and Advanced Low Carbon Technology Research and Develop-
ment Program (ALCA JPMJAL1504) from the Japan Science and
Technology Agency (JST), and the MEXT program ‘‘Elements
Strategy Initiative to Form Core Research Center’’. This
work was also supported by JSPA KAKENHI Grant Numbers
15K13695, 26620085, 15K17854, 26888009. We are grateful to
the Nissan Chemical Industries Corporation for their financial
support. Elemental analyses and mass spectrometry were
supported by the JURC at ICR, Kyoto University. The authors
thank Dr Tsuneo Imamoto (Prof. Emeritus, Chiba University
and Nippon Chemical Industries) for kindly gifting the P-chiral
ligands.
DFT calculations reveal that the recombination and the final
reductive elimination are exergonic, with DG values of 14.1 and
Fig. 2 Stoichiometric reactions of FeCl2/bisphosphine with borate 2a in
the presence of MgBr2. Conversions of FeCl2/(R,R)-QuinoxP* A1 (circles)
and FeCl2/(R,R)-BenzP* A2 (squares) were determined by 1H NMR spectro- Conflicts of interest
scopy. The produced iron complex was unable to be characterised by
NMR techniques.
There are no conflicts to declare.
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Adv. Synth. Catal., 2014, 356, 705; (e) R. Shang, L. Ilies, S. Asako
and E. Nakamura, J. Am. Chem. Soc., 2014, 136, 14349; ( f ) L. Ilies,
Y. Itabashi, R. Shang and E. Nakamura, ACS Catal., 2017, 7, 89.
9 (a) R. B. Bedford, M. A. Hall, G. R. Hodges, M. Huwe and
M. C. Wilkinson, Chem. Commun., 2009, 6430; (b) T. Hatakeyama,
T. Hashimoto, Y. Kondo, Y. Fujiwara, H. Seike, H. Takaya,
Y. Tamada, T. Ono and M. Nakamura, J. Am. Chem. Soc., 2010,
132, 10674; (c) T. Hashimoto, T. Hatakeyama and M. Nakamura,
J. Org. Chem., 2012, 77, 1168; (d) T. Hatakeyama, T. Hashimoto,
K. K. A. D. S. Kathriarachchi, T. Zenmyo, H. Seike and M. Nakamura,
Angew. Chem., Int. Ed., 2012, 51, 8834; (e) R. B. Bedford, P. B.
Brenner, E. Carter, J. Clifton, P. M. Cogswell, N. J. Gower, M. F.
Haddow, J. N. Harvey, J. A. Kehl, D. M. Murphy, E. C. Neeve, M. L.
Neidig, J. Nunn, B. E. R. Snyder and J. Taylor, Organometallics, 2014,
33, 5767; ( f ) R. B. Bedford, P. B. Brenner, E. Carter, T. W. Carvell,
P. M. Cogswell, T. Gallagher, J. N. Harvey, D. M. Murphy, E. C.
Neeve, J. Nunn and D. R. Pye, Chem. – Eur. J., 2014, 20, 7935;
(g) N. Nakagawa, T. Hatakeyama and M. Nakamura, Chem. Lett.,
2015, 44, 486; (h) R. B. Bedford, T. Gallagher, D. R. Pye and
W. Savage, Synthesis, 2015, 1761; (i) S. Nakajima, H. Takaya and
M. Nakamura, Chem. Lett., 2017, 46, 711.
Notes and references
1 For selected reviews, see: (a) N. Miyaura and A. Suzuki, Chem. Rev.,
1995, 95, 2457; (b) S. Kotha, K. Lahiri and D. Kashinath, Tetrahedron,
2002, 58, 9633; (c) J. S. Carey, D. Laffan, C. Thomson and M. T.
Williams, Org. Biomol. Chem., 2006, 4, 2337; (d) J. Magano and
J. R. Dunetz, Chem. Rev., 2011, 111, 2177; (e) A. Suzuki, Angew. Chem.,
Int. Ed., 2011, 50, 6723; ( f ) D. G. Brown and J. Bostrom, J. Med. Chem.,
2016, 59, 4443.
2 F. Lovering, J. Bikker and C. Humblet, J. Med. Chem., 2009, 52, 6752.
3 For a review, see: (a) A. H. Cherney, N. T. Kadunce and S. E.
Reisman, Chem. Rev., 2015, 115, 9587; For reviews related to stereo-
specific Suzuki–Miyaura-type couplings using chiral substrates, see:
(b) D. Leonori and V. K. Aggarwal, Angew. Chem., Int. Ed., 2015,
54, 1082; (c) X.-P. Zeng, Z.-Y. Cao, Y.-H. Wang, F. Zhou and J. Zhou,
Chem. Rev., 2016, 116, 7330; (d) J. P. G. Rygus and C. M. Crudden,
J. Am. Chem. Soc., 2017, 139, 18124; For a review relating to enantio-
convergent couplings, see: (e) V. Bhat, E. R. Welin, X. Guo and
B. M. Stoltz, Chem. Rev., 2017, 117, 4528.
4 (a) B. Saito and G. C. Fu, J. Am. Chem. Soc., 2008, 130, 6694;
(b) P. M. Lundin and G. C. Fu, J. Am. Chem. Soc., 2010, 132, 11027;
(c) N. A. Owston and G. C. Fu, J. Am. Chem. Soc., 2010, 132, 11908;
(d) Z. Lu, A. Wilsily and G. C. Fu, J. Am. Chem. Soc., 2011, 133, 8154;
(e) S. L. Zultanski and G. C. Fu, J. Am. Chem. Soc., 2011, 133, 15362;
( f ) A. Wilsily, F. Tramutola, N. A. Owston and G. C. Fu, J. Am. Chem.
Soc., 2012, 134, 5794.
¨
10 T. Imamoto, Chem. Rec., 2016, 16, 2659.
11 (a) P. J. Harrington and E. Lodewijk, Org. Process Res. Dev., 1997,
1, 72; (b) M. F. Landoni and A. Soraci, Curr. Drug Metab., 2001, 2, 37.
12 On the basis of our DFT calculations, coupling reactions with either
boron- or Grignard reagents proceed through similar mechanisms,
in which the nucleophile is not directly involved in the enantio-
determining step; see ref. 13a.
13 (a) A. K. Sharma, W. M. C. Sameera, M. Jin, L. Adak, O. Chiemi,
T. Iwamoto, M. Kato, M. Nakamura and K. Morokuma, J. Am. Chem.
Soc., 2017, 139, 16117; (b) T. Imamoto, K. Sugita and K. Yoshida,
J. Am. Chem. Soc., 2005, 127, 11934.
5 G. C. Fu, ACS Cent. Sci., 2017, 3, 692.
6 (a) J. Mao, F. Liu, M. Wang, B. Zheng, S. Liu, J. Zhong, Q. Bian and
P. J. Walsh, J. Am. Chem. Soc., 2014, 136, 17662; (b) F. Liu, Q. Bian,
J. Mao, Z. Gao, D. Liu, S. Liu, X. Wang, Y. Wang, M. Wang and
J. Zhong, Tetrahedron: Asymmetry, 2016, 27, 663; (c) M. Jin, L. Adak
and M. Nakamura, J. Am. Chem. Soc., 2015, 137, 7128.
7 For selected reviews, see: (a) C. Bolm, J. Legros, J. L. Paih and
L. Zani, Chem. Rev., 2004, 104, 6217; (b) W. M. Czaplik, M. Mayer,
14 (a) T. Hatakeyama, Y. Fujiwara, Y. Okada, T. Itoh, S. Hashimoto,
K. Kawamura, K. Ogata, H. Takaya and M. Nakamura, Chem. Lett.,
2011, 40, 1030; (b) H. Takaya, S. Nakajima, N. Nakagawa, K. Isozaki,
T. Iwamoto, R. Imayoshi, N. Gower, L. Adak, T. Hatakeyama,
T. Honma, M. Takagaki, Y. Sunada, H. Nagashima, D. Hashizume,
O. Takahashi and M. Nakamura, Bull. Chem. Soc. Jpn., 2015, 88, 410.
15 When the coupling reaction was performed using FeCl2/(R,R)-
QuinoxP* (5 mol%) instead of a mixture of FeCl2 (5 mol%) and
(R,R)-QuinoxP* (10 mol%), the reaction proceeded quantitatively to
provide the product with 79 : 21 er, which is almost identical to that
obtained under optimal conditions. Therefore, we concluded that
(R,R)-QuinoxP* is coordinated to iron in 1 : 1 ratio.
ˇ
J. Cvengros and A. J. von Wangelin, ChemSusChem, 2009, 2, 396;
¨
(c) I. Bauer and H.-J. Knolker, Chem. Rev., 2015, 115, 3170;
`
(d) J. Legros and B. Figadere, Nat. Prod. Rep., 2015, 32, 1541;
(e) O. M. Kuzmina, A. K. Steib, A. Moyeux, G. Cahiez and
P. Knochel, Synthesis, 2015, 1696; ( f ) R. B. Bedford and P.
B. Brenner, Top. Organomet. Chem., 2015, 50, 19; (g) A. Fu¨rstner,
ACS Cent. Sci., 2016, 2, 778; (h) K. S. Egorova and V. P. Ananikov,
´
Angew. Chem., Int. Ed., 2016, 55, 12150; (i) A. Guerinot and J. Cossy,
Top. Curr. Chem., 2016, 374, 49; ( j) A. Piontek, E. Bisz and
M. Szostak, Angew. Chem., Int. Ed., 2018, 57, 11116. For the pioneering
works, see: (k) M. Tamura and J. Kochi, J. Am. Chem. Soc., 1971, 93, 16 Based on our previous mechanistic study, complex C is the pre-
1487; (l) M. Tamura and J. Kochi, Synthesis, 1971, 303; (m) M. Tamura
and J. Kochi, J. Organomet. Chem., 1971, 31, 289.
8 For examples of iron-catalysed couplings of organoboron reagents:
(a) Y. Guo, D. J. Young and T. S. A. Hor, Tetrahedron Lett., 2008,
dominant iron species in the reaction mixture.
17 In the absence of chiral ligands, the background coupling reaction
proceeded rapidly, with the racemic product obtained in 98% yield
after 1 h.
49, 5620; (b) A. Deb, S. Manna, A. Maji, U. Dutta and D. Maiti, Eur. 18 Since we have already reported that alkenyl borates can participate
J. Org. Chem., 2013, 5251; (c) Y. Zhong and W. Han, Chem. Commun.,
2014, 50, 3874; (d) A. Deb, S. Agasti, T. Saboo and D. Maitia,
in iron-catalyzed coupling of alkyl halides,9c the present method
could be applied to the enantioselective installation of alkenyl units.
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