Cu-Catalyzed Enantioselective Boron Addition to N-Heteroaryl-Substituted Alkenes

Article abstract of DOI:10.1021/acs.orglett.7b03327

Catalytic enantioselective Cu-B(pin) (pin = pinacolato) addition to N-heteroaryl-substituted alkenes followed by protonation promoted by phosphine-Cu complexes is presented. The resulting alkylboron products that contain a N-heteroaryl moiety are afforded in up to 97% yield and 99:1 enantiomeric ratio. The highly versatile C-B(pin) bond can be converted to a range of useful functional groups, delivering a variety of enantiomerically enriched building blocks that are otherwise difficult to access. The utility of this method is further demonstrated by application to a fragment synthesis of biologically active molecule U-75302. Preliminary mechanistic studies revealed that the adjacent N atom of the heterocycles plays a unique role in high reactivity and enantioselectivity.

Full text of DOI:10.1021/acs.orglett.7b03327

Letter
pubs.acs.org/OrgLett
Cu-Catalyzed Enantioselective Boron Addition to N‑Heteroaryl-
Substituted Alkenes
Lu Wen,† Zhenting Yue,† Haiyan Zhang, Qinglei Chong, and Fanke Meng*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Lingling Road, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: Catalytic enantioselective Cu−B(pin) (pin =
pinacolato) addition to N-heteroaryl-substituted alkenes
followed by protonation promoted by phosphine−Cu
complexes is presented. The resulting alkylboron products
that contain a N-heteroaryl moiety are afforded in up to 97%
yield and 99:1 enantiomeric ratio. The highly versatile C−
B(pin) bond can be converted to a range of useful functional
groups, delivering a variety of enantiomerically enriched building blocks that are otherwise difficult to access. The utility of this
method is further demonstrated by application to a fragment synthesis of biologically active molecule U-75302. Preliminary
mechanistic studies revealed that the adjacent N atom of the heterocycles plays a unique role in high reactivity and
enantioselectivity.
unctionalized N-containing aromatic heterocycles are
Scheme 1. Catalytic Enantioselective Nucleophilic Addition
F
prevalent motifs in biologically active pharmaceutical
to N-Heteroaryl Alkenes
molecules (88%).1 Furthermore, approximately half of the
pharmaceutical ingredients bear stereogenic centers.1 It is
crucial to produce any chiral pharmaceutical molecule as a
single enantiomer, since the two enantiomers of a chiral drug
can exhibit different biological activity. Catalytic enantioselec-
tive formation of a versatile C−B bond represents one of the
most important strategies for construction of chiral molecules,
as the C−B bond can be easily transformed into C−C, C−O,
C−N, and C−halogen bonds.2 Catalytic enantioselective boron
addition to alkenes represents a powerful method for creating
new stereogenic C−B bonds from easily accessible alkenes.3 In
this context, the catalytic enantioselective addition of a boron
nucleophile to conjugated heteroaryl alkenes constitutes an
attractive strategy to generate valuable chiral heterocyclic
aromatic compounds. Although there are few reports on
transition-metal-catalyzed enantioselective addition of carbon
nucleophiles to β-substituted alkenyl N-heteroarenes,4 enantio-
selective addition of a boron nucleophile remains unprece-
dented.5
decided to explore the addition of a boron group to alkenyl
heteroaromatic compounds. We reasoned that a proper choice
of ligand might solve challenges to the reactivity and
enantioselectivity. Herein, we described an unprecedented
protocol of phosphine−Cu-catalyzed enantioselective boron
addition to N-heteroaryl alkenes, affording versatile alkylboron
products that can be further converted to a variety of useful
heterocycle-containing chiral building blocks in high efficiency
and enantioselectivity (Scheme 1, eq 3).
In 1998, a pioneering work of Ni-catalyzed addition of
Grignard reagents to alkenylpyridines was reported, although
the reaction provided low enantioselectivity.4a It was not until
2010 that a highly enantioselective Rh-catalyzed addition of
arylboronic acids to β-substituted alkenyl N-heteroarenes was
disclosed (Scheme 1, eq 1).4b In 2016, the first Cu-catalyzed
enantioselective addition of alkyl Grignard reagents was
revealed (Scheme 1, eq 2).4e The paucity of methodologies
for catalytic enantioselective nucleophilic addition to N-
heteroaryl alkenes was attributed to the relatively weak
activation from the N-heteroaromatic moiety. Furthermore,
coordination of the heteroatoms to the metal center might
negatively impact the reactivity and enantioselectivity. We
We began our studies by investigating ligand optimization.
Reaction of alkenylpyridine 1a with B2(pin)2 and MeOH in the
Received: October 25, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03327
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Letter
presence of a BINAP−Cu complex followed by oxidative
workup with NaBO3·4H2O afforded alcohol 2a in 71% yield
and 78:22 er (3a) (Scheme 2). The initial alkylboron product
angles promoted the reaction in 77−80% yield and 90:10−91:9
er (3c−d). Modification of the substituents on phosphorus to
3,5-dimethylphenyl did not lead to any improvement in
enantioselectivity (3b). Transformation of 1a promoted by a
Cu complex generated from 3e delivered 2a in 71% yield and
90:10 er. Reactions with bisphosphines that have stereogenic
centers on phosphorus provided a 36−39% yield with a
78.5:21.5−93:7 er (3f−g). Finally, a Cu complex derived from
(R,R)-Ph-BPE 3h provided the desired product in 86% yield
and 98:2 er.
a
Scheme 2. Ligand Screen
With the optimal conditions in hand, we investigated the
substrate scope (Scheme 3). Alkenes substituted with pyridines
containing electron-donating and -withdrawing groups are
suitable substrates (2b−m), although reactions of pyridyl
alkenes with electron-donating groups resulted in lower
efficiency (2d−f). It is worth mentioning that ketone,
carboxylic acid ester, and cyano groups are well tolerated
(2k−m). Alkenes with a wide range of N-heteroaryl groups can
be used in the reaction. Reactions of alkenes substituted with
quinoline and isoquinoline delivered desired products in 92−
97% yield and 96:4 er (2n−o). Transformations of pyrimidine-
and triazine-substituted alkenes provided alcohols in 87−96%
yield and 90:10−97:3 er (2p−r). Products bearing thiazole 2s,
benzothiazole 2t−u, oxazole 2v, and 1,3,4-oxadiazole 2w were
generated in 89−97% yield and 94:6−97:3 er. Alkenylpyridines
substituted with functionalized alkyl groups at the β-position
afforded desired products in 43−90% yield and 92:8−98:2 er
(2t−w, 4a−4e). A terminal alkene remained untouched under
a
The reactions were performed under a N2 atmosphere. Yields
correspond to isolated and purified products; er was determined by
HPLC analysis. See the Supporting Information (SI) for details.
was not stable during silica gel column chromatography
purification due to chelation of the Lewis basic pyridine to
boron. Cu complexes of bisphosphines with smaller dihedral
a
Scheme 3. Substrate Scope
a
b
Same conditions and analytical methods as in Scheme 2; see the SI for details. 7.5 mol % 3g was used.
B
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reaction conditions (2u). Reactions of styrylpyridines in the
presence of the (R,R)-Ph-BPE−Cu complex provide lower
efficiency and enantioselectivity (4f). Reinvestigation of other
ligands revealed that a Cu complex formed from 3g led to
higher efficiency in spite of slightly lower enantioselectivity
(4f−i). No regioisomers were observed in these cases,
indicating the N-heteroaryl can stabilize the C−Cu bond better
in the Cu−B(pin) addition process.
Scheme 5. Investigations on the Function of N-Heterocycles
The utility of this method is demonstrated by a fragment
synthesis of an LTB4 inhibitor U-75302.6 Reaction of
alkenylpyridine 1b bearing an unprotected hydroxyl group
promoted by the (R,R)-Ph-BPE−Cu complex followed by
oxidative workup afforded alcohol 5 in 92% yield and 96:4 er
(Scheme 4a). Compound 5 may serve as a precursor for
Scheme 4. Functionalization and Applications
hydroboration product 12 in lower yield (55% vs 86%) and
lower enantioselectivity (87:13 er vs 98:2 er). Furthermore, 4-
alkenylpyridine 13 was transformed in 41% yield and 60:40 er
and 3-alkenylpyridine 15 did not undergo any reaction. All
these results indicate that the heterocycles have significant
impacts on both reactivity and enantioselectivity. It is plausible
that the N atom might coordinate to the Lewis acidic metal
center, enhancing the electrophilicity of the β-carbon of
heteroaryl alkenes (II, Scheme 6) and leading to a better-
organized transition state for higher enantioselectivity.
To further explore the nature of the organocopper
intermediate and protonation process, we conducted the
reaction with d4-methanol. As indicated in Scheme 6, a single
diastereomer 2a-D was generated, illustrating that the possible
isomerization of the C−Cu bond that has been proposed
Scheme 6. Proposed Catalytic Cycle
synthesis of LTB4 inhibitor U-75302. In addition, the boron
addition products can be transformed into a wide range of
enantioenriched building blocks that contain N-heterocycles.
The C−B(pin) bond was converted to a C−Br bond according
to the conditions developed by Aggarwal and co-workers, albeit
with lower stereospecificity.7 Zweifel olefination of heterocycle-
containing alkylboron 6 led to 8 in 91% yield and 99:1 er, a
formal enantioselective alkenyl addition product that was
otherwise difficult to access.8 Arylation of alkylboron 6 in the
presence of 2-furyllithium followed by treatment of NBS
provided 9 in 78% yield and 99:1 er.9 Homologation of the C−
B(pin) bond in 6 resulted in alkylboron 10 in 98:2 er albeit in
40% yield.10
To investigate the influence of the heterocycles on the
reactivity and enantioselectivity, we performed the reactions in
Scheme 5. Transformation of phenyl-substituted alkene 11
under the optimal conditions for the pyridyl-substituted analog
resulted in incomplete conversion of substrate and afforded
C
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previously is slower than the protonation process.4g−i The
proposed catalytic cycle is shown in Scheme 6. Cu−B(pin)
species generated from reaction of Cu−alkoxide with B2(pin)2
underwent syn-addition to the N-heteroaryl alkene 1a to
provide an organocopper intermediate III through transition
state II, which reacted with methanol to deliver 2a and
regenerated the Cu−alkoxide. The organocopper intermediate
III was afforded in high diastereoselectivity.
In summary, we have developed an operationally simple and
chemoselective Cu-catalyzed boron enantioselective addition to
a wide range of N-heteroaryl alkenes, affording alkylboron
compounds that can be functionalized to a variety of useful N-
heterocycle-containing chiral building blocks with high
efficiency and enantioselectivity. The utility of the method is
further demonstrated by a fragment synthesis of LTB4 inhibitor
U-75302. Further mechanistic studies and development of new
reactions with N-heteroaryl alkenes are underway.
Chem. Rev. 2011, 111, 1417−1492. (d) Collins, B. S. L.; Wilson, C. M.
W.; Myers, E. L.; Aggarwal, V. K. Angew. Chem., Int. Ed. 2017, 56,
11700−11733.
(3) For recent reviews on Cu-catalyzed C−B bond forming reactions
of alkenes, see: (a) Shimizu, Y.; Kanai, M. Tetrahedron Lett. 2014, 55,
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Huaxue 2016, 36, 2249−2271. (d) Sawamura, M.; Ito, H. Carbon−
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Weinheim, 2014; pp 157−178.
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see: (a) Houpis, I. N.; Lee, J.; Dorziotis, I.; Molina, A.; Reamer, B.;
Volante, R. P.; Reider, P. J. Tetrahedron 1998, 54, 1185−1195 For Rh-
catalyzed enantioselective additions of aryl boronic acids, see:.
(b) Pattison, G.; Piraux, G.; Lam, H. W. J. Am. Chem. Soc. 2010,
132, 14373−14375. (c) Saxena, A.; Lam, H. W. Chem. Sci. 2011, 2,
2326−2331. (d) Roy, I. D.; Burns, A. R.; Pattison, G.; Michel, B.;
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(e) Jumde, R. P.; Lanza, F.; Veenstra, M. J.; Harutyunyan, S. R. Science
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addition, see: (f) Rupnicki, L.; Saxena, A.; Lam, H. W. J. Am. Chem.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03327.
Experimental procedures, spectroscopic data, and NMR
spectra of all products (PDF)
(5) For Cu-catalyzed enantioselective Cu−B(pin) addition to
unactivated alkenes followed by protonation, see: (a) Lee, Y.;
Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 3160−3161. (b) Lee,
Y.; Jang, H.; Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 18234−
Accession Codes
CCDC 1574301 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
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18235. (c) Corberan, R.; Mszar, N. W.; Hoveyda, A. H. Angew. Chem.,
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Chem. - Eur. J. 2013, 19, 3204−3214. (e) Wang, Z.; He, X.; Zhang, R.;
Zhang, G.; Xu, G.; Zhang, Q.; Xiong, T.; Zhang, Q. Org. Lett. 2017, 19,
3067−3070. (f) Kong, D.; Han, S.; Wang, R.; Li, M.; Zi, G.; Hou, G.
Chem. Sci. 2017, 8, 4558−4564. (g) Kubota, K.; Watanabe, Y.;
Hayama, K.; Ito, H. J. Am. Chem. Soc. 2016, 138, 4338−4341.
AUTHOR INFORMATION
■
́
(h) Guisan-Ceinos, M.; Parra, A.; Martín-Heras, V.; Tortosa, M.
Corresponding Author
*E-mail: mengf@sioc.ac.cn.
ORCID
Angew. Chem., Int. Ed. 2016, 55, 6969−6972. (i) Kubota, K.; Hayama,
K.; Iwamoto, H.; Ito, H. Angew. Chem., Int. Ed. 2015, 54, 8809−8813.
(j) Kubota, K.; Watanabe, Y.; Ito, H. Adv. Synth. Catal. 2016, 358,
2379−2384. (k) Tian, B.; Liu, Q.; Tong, X.; Tian, P.; Lin, G.-Q. Org.
Chem. Front. 2014, 1, 1116−1122. (l) Kubota, K.; Yamamoto, E.; Ito,
H. Adv. Synth. Catal. 2013, 355, 3527−3531. (m) Sasaki, Y.; Zhong,
C.; Sawamura, M.; Ito, H. J. Am. Chem. Soc. 2010, 132, 1226.
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1989, 30, 5081−5084.
Fanke Meng: 0000-0003-1009-631X
Author Contributions
†L.W. and Z.Y. contributed equally.
Notes
The authors declare no competing financial interest.
(7) Larouche-Gauthier, R.; Elford, T. G.; Aggarwal, V. K. J. Am.
Chem. Soc. 2011, 133, 16794−16797.
(8) Aggarwal, V. K.; Binanzer, M.; de Ceglie, M.; Gallanti, M.;
ACKNOWLEDGMENTS
■
This work was financially supported by the “Thousand Youth
Talents Plan”, Shanghai Sailing Program (Grant No.
17YF1424100), The Science and Technology Commission of
Shanghai Municipality (No. 17JC1401200) and Strategic
Priority Research Program of the Chinese Academy of Sciences
(Grant No. XDB20000000).
Glasspoole, B. W.; Kendrick, S. J. F.; Sonawane, R. P.; Vaz
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Romero, A.; Webster, M. P. Org. Lett. 2011, 13, 1490−1493.
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Harvey, J. N.; Leonori, D.; Aggarwal, V. K. J. Am. Chem. Soc. 2016,
138, 9521−9532.
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