Enantioselective synthesis of homoallylic amines through reactions of (pinacolato)allylborons with aryl-, heteroaryl-, alkyl-, or alkene-substituted aldimines catalyzed by chiral C 1-symmetric NHC-Cu complexes

Article abstract of DOI:10.1021/ja200311n

A catalytic method for enantioselective synthesis of homoallylamides through Cu-catalyzed reactions of stable and easily accessible (pinacolato)allylborons with aryl-, heteroaryl-, alkyl-, or alkenyl-substituted N-phosphinoylimines is disclosed. Transformations are promoted by 1-5 mol % of readily accessible NHC-Cu complexes, derived from C₁-symmetric imidazolinium salts, which can be prepared in multigram quantities in four steps from commercially available materials. Allyl additions deliver the desired products in up to quantitative yield and 98.5:1.5 enantiomeric ratio and are amenable to gram-scale operations. A mechanistic model accounting for the observed selectivity levels and trends is proposed.

Full text of DOI:10.1021/ja200311n

COMMUNICATION
pubs.acs.org/JACS
Enantioselective Synthesis of Homoallylic Amines through Reactions
of (Pinacolato)allylborons with Aryl-, Heteroaryl-, Alkyl-, or
Alkene-Substituted Aldimines Catalyzed by Chiral C1-Symmetric
NHC-Cu Complexes
Erika M. Vieira, Marc L. Snapper,* and Amir H. Hoveyda*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, United States
S Supporting Information
b
Scheme 1. Catalytic Cycle for Reaction of
(Pinacolato)allylboron with Aldimines Promoted by an
NHC-Cu Complex [B(pin) = pinacolatoboron]
ABSTRACT: A catalytic method for enantioselective
synthesis of homoallylamides through Cu-catalyzed reac-
tions of stable and easily accessible (pinacolato)allylborons
with aryl-, heteroaryl-, alkyl-, or alkenyl-substituted N-
phosphinoylimines is disclosed. Transformations are pro-
moted by 1-5 mol % of readily accessible NHC-Cu
complexes, derived from C1-symmetric imidazolinium salts,
which can be prepared in multigram quantities in four steps
from commercially available materials. Allyl additions deli-
ver the desired products in up to quantitative yield and
98.5:1.5 enantiomeric ratio and are amenable to gram-scale
operations. A mechanistic model accounting for the ob-
served selectivity levels and trends is proposed.
of enantiomerically enriched homoallylamides by reactions of stable
allylboron reagents that can be either purchased or easily prepared.
Transformations are performed with an inexpensive Cu salt and 1-
5 mol % of chiral C1-symmetric imidazolinium salts,9 multigram
quantities of which can be synthesized from commercially available
materials by a straightforward four- to five-vessel protocol (∼30%
overall yield). Complete conversion is observed in 6-18 h; the
desired products are isolated in 61% to >98% yield and in up to
98.5:1.5 enantiomer ratio (er). Conversion of the resulting N-
phosphinoylamides to the derived amines can be effected under
aqueous acidic conditions, as demonstrated previously.10
The present investigations were conceived as a result of our
interest in designing catalytic transformations promoted by N-
heterocyclic carbene (NHC) copper complexes generated in situ
by an initial reaction with a boron-based reagent.9b,c,11 We surmised
that reaction of Cu-alkoxide i with (pinacolato)allylboron 1 should
afford NHC-Cu-allyl ii (Scheme 1), a process driven by the
formation of the energetically favorable B-O bond. We have
previously adopted a similar strategy with B-B11 and B-Si9b
reagents to generate NHC-Cu-B complexes or the corresponding
silanes, which participate in enantioselective C-B or C-Si bond
forming reactions. We sought to examine whether the above
approach might be utilized such that the B-C bond reacts with
an NHC-Cu-alkoxide to yield a catalytically active NHC-Cu-C
system (vs NHC-Cu-B or NHC-Cu-Si).12 The resulting
omoallylic amines are imbedded within structures of many
H
biologically active agents and can serve as entities for the
preparation of myriad N-containing molecules.1,2 Development
of efficient and enantioselective allyl additions to aldimines, a
direct approach for accessing chiral homoallylic amines, is thus a
compelling objective in chemical synthesis. Enantiomerically
pure allyl-containing reagents, used in stoichiometric quantities,
react efficiently and diastereoselectively with aldimines; the utility of
these strategies has been demonstrated in complex molecule
synthesis.3 Substrates containing a chiral auxiliary can participate
in highly diastereoselective allyl additions.4 Such an approach,
however, requires especially reactive allylmetals (e.g., Grignard
reagents4a or allylzincs4g) that could be intolerant of a number of
key functional groups and/or preparation of which might be
complicated; alternatively, stoichiometric quantities of costly
allylindiums4b-f and/or Pd-based catalysts are needed.4b,e Several
reports have demonstrated that chiral catalysts promote additions of
allyl groups to aldimines.5-8 Nonetheless, such protocols also
demand precious indium salts (at times in stoichiometric amounts
or more)6 or require allyl reagents that are highly toxic8a or relatively
unstable (so that high reactivity is achieved);7b some reported
catalytic enantioselective approaches are operative with imines
derived from activated aldehydes (e.g., glyoxylates)5-7 or furnish
products that necessitate somewhat harsh or costly conditions for
conversion to the unprotected amine.5-8 A reasonably general, cost-
effective, and functional group tolerant catalytic enantioselective
process thus remains lacking. We outline a method for the synthesis
Received: January 12, 2011
Published: February 22, 2011
r
2011 American Chemical Society
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|

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Table 1. Screening of Chiral NHC Complexesa
Table 2. NHC-Cu-Catalyzed Enantioselective Allyl Addi-
tion to Aryl-Substituted Phosphinoyliminesa
imid.
salt
conv
(%)b
yield
(%)c
entry
substrate (aryl)
erd
1
Ph
7a
7b
7c
7d
7e
7f
6b
6d
6b
6b
6d
6d
6b
6b
6b
6b
6d
>98
>98
>98
>98
>98
>98
>98
>98
>98
97
95
89
97:3
97:3
2
2-naphthyl
o-FC6H4
3
95
98:2
4
o-BrC6H4
92
98:2
5
o-MeC6H4
o-MeOC6H4
m-BrC6H4
p-ClC6H4
p-BrC6H4
p-CF3CeH4
p-OMeC6H4
98
96:4
6
98
97:3
entry
imid. salt
conv (%)b
erc
7
7g
7h
7i
88
96:4
1
2
2
>98
70
57.5:42.5
47.5:52.5
55.5:44.5
56:44
8
92
98:2
3
9
92
98.5:1.5
98.5:1.5
98:2
3
4a
4b
5a
5b
5c
6a
6b
6c
84
10
7j
95
4
>98
>98
>98
>98
>98
>98
>98
e
11
7k
>98
>98
a Reactions performed under N2 atmosphere with 1.4 equiv of
(pinacolato)allylboron 1. b Values determined by analysis of 400 MHz
1H NMR spectra of unpurified mixtures (9-methylanthracene as internal
standard). c Yields of isolated products after purificaton ((5%). d Values
determined by HPLC analysis; see the Supporting Information for
details. e Carried out at -15 °C.
5
72.5:27.5
70:30
6
7
67.5:32.5
73.5:26.5
91:9
8
9
10
88:12
a Reactions performed under N2 atmosphere with 2.0 equiv of 1. b Values
1
Scheme 2. NHC-Cu-Catalyzed Enantioselective Allyl Ad-
determined by analysis of 400 MHz H NMR spectra of unpurified
dition to Heteroaryl-Substituted Phosphinoyliminesa
mixtures. c Values determined by HPLC analysis; see the Supporting
Information for details. Mes = 2,4,6-(Me)3C6H2.
NHC-Cu-allyl ii could undergo reaction with an N-phosphinoyl-
imine to initiate C-C bond formation, furnishing iii. Catalyst
release might occur either by σ-bond metathesis between the
Cu-O bond of iii and the C-B of another molecule of 1 to
generate the boronic ester derivative of the desired product13 or
through the agency of an alcohol additive.14
To probe the feasibility of the envisioned catalytic cycle, we
investigated the ability of various chiral NHC-Cu complexes to
catalyze the reaction of 7a and 1 (Table 1). Catalysts were
formed and utilized in situ by treatment of the corresponding
imidazolinium salts with NaOt-Bu and CuCl; MeOH filled the
role of a proton source. Bidentate Cu complexes derived from
phenol 2 or sulfonate 3 (entries 1, 2) readily promote trans-
formation but deliver 8a with minimal stereoselectivity. Simi-
larly high efficiency and inferior enantioselectivity are obtained
with C2-symmteric 4a,b (entries 3, 4). Enantiomeric purity is
improved when C1-symmetric NHC-Cu complexes derived
from 5a-5c or 6a serve as catalysts (entries 5-8).
However, it is through the use of 6b (entry 9, Table 1), bearing
an o-substituted mesitylphenyl as its dissymmetric N-aryl group,
that, without any diminution in efficiency (>98% conv), a
significantly improved er is achieved (91:9 er). Incorporation of
a m-isopropyl unit, beneficial in certain previous studies (6c, entry
10),9b does not enhance selectivity. Performing the reaction with
1.4 equivalents of 1 at -50 °C, under otherwise identical
conditions, delivers 8a in 95% yield and 97:3 er (entry 1, Table 2).
A variety of aryl-substituted substrates can be used; the
resulting homoallylamides are isolated in 88% to >98% yield
a Performed under the conditions shown in Table 2 with 6b (for 9 and
11) or 6d (for 10) as the imidazolinium salt. Conversions and
selectivities determined as indicated in Table 2; yields of isolated and
purified products ((5%).
and 96:4-98.5:1.5 er (Table 2). Electron-deficient aldimines
(entries 3, 4, 7-10) as well as those containing an electron-
donating substituent (entries 6 and 11), undergo facile transfor-
mation to afford products in g97:3 er. In the case of sterically
congested aldimines 7b,e,f (entries 2, 5, 6), and 7k, the latter of
which contains a p-methoxyphenyl unit (entry 11), higher
enantioselectivity is achieved with the NHC-Cu complex
derived from 6d [7b,e,f,k in 84:16-87.5:12.5 er (>98% conv)
with 6b]. The catalytic protocol can be performed with aldimines
bearing a heteroaromatic unit (9-11, Scheme 2).
Similar to 6b, 6d is C1-symmetric but bears two dissymmetric
N-Ar units, existing as a 5:1 mixture of stereoisomers in solution
(determined by analysis of 400 MHz 1H NMR); imidazolinium
salt 6d is used as a mixture of isomers. The X-ray structure of the
major isomer of 6d is shown in Figure 1; the same conformer is
predominant in solution, as established by nOe experiments.15
Whether both of the derived NHC-Cu complexes promote
reaction and the facility with which the two stereoisomers
undergo interconversion (after complexation) is unclear.16
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COMMUNICATION
Figure 1. Nuclear Overhauser effect (nOe) experiments and X-ray
structure, indicating the identity of the major isomer of imidazolinium
salt 6d (5:1; see the Supporting Information for details).
Figure 2. Model for origin of enantioselectivity in NHC-Cu-catalyzed
allyl additions to N-phosphinoylimines.
Scheme 3. NHC-Cu-Catalyzed Enantioselective Allyl Ad-
dition to Alkyl-Substituted Phosphinoyliminesa,b,c
Severalmechanistic issues merit a briefdiscussion. There is <5%
conversion in the absence of MeOH under catalytic conditions.
With stoichiometric amounts of the NHC-Cu complex, the
desired homoallylamine is obtained without the protic additive.
These observations indicate that the role of the additive is in
connection with the release of the NHC-Cu catalyst (i.e., iiifi in
Scheme 1 with ROH = MeOH). The facile formation of various
homoallylamines under conditions that include 1-5 mol %
catalyst loading but 1 and 2 equiv of aldimine and MeOH,
respectively, indicates that the rate of reaction of NHC-Cu-allyl
complexes (cf. ii) with aldimines is substantially faster than
adventitious protonation of the C-Cu bond of the allylmetal
intermediate. Reaction with d2-(pinacolato)allylboron (labeled at
C3) leads to complete scrambling of deuterium at C1 and C3,
suggesting the intermediacy of π-allylcopper and providing a
rationale for low diastereoselectivity with the crotylboron reagents.
Modes of reaction I-II (Figure 2) may be used to account for
the stereochemical outcome of the Cu-catalyzed processes. Coordi-
nation of the N-phosphinoylimine’s Lewis basic oxygen is likely the
key contact point that brings substrate and catalyst together. The
less Lewis basic N may be weakly associated with the transition
metal. Involvement of the Lewis basic P-O of the aldimine
substrate offers a rationale for the high er values observed with N-
phosphinoyl-derived imines versus the corresponding o-anisidyl-
imines, which react readily under the same conditions but deliver
racemic products.19 Molecular models suggest that a preference for
the reaction via I versus the competing modes of reaction, such as
that represented by II, might be due to subtle variations in catalyst-
substrate interactions. Steric repulsion between the protruding Me
unit and the aldimine substituent (G) in I appears to be less severe
than that existing between a phenyl group of the phosphinoyl
moiety in II (Figure 2); this difference might arise from tighter
binding of the phosphinoyl oxygen with the Lewis acidic Cu,
compared to the imine nitrogen. Superior enantioselectivities with
6d (vs 6b), particularly in the case of sterically congested aldimines,
may be attributed to the tilt of the NAr moiety (Figure 1), lifting the
resident o-Me group to accommodate the substrate molecule better.
Such conformational change leads to an improvement in enantios-
electivity since it may not sufficiently reduce the more severe
interaction in II. It should be noted that the identity of the
stereochemistry-determining step has not been determined and
the energetics of the catalytic cycle might vary with different
substrates. The models in Figure 2 are meant to serve primarily
for the prediction of the stereochemical preferences.
a Performed under identical conditions for R-13. Conversions and
selectivities determined as indicated in Table 2; yields are of the purified
products ((5%). b With catalyst derived from 6d. c Performed with 5.0
mol % of 6d and CuCl and 12 mol % NaOt-Bu.
A difficult class of substrates consists of alkyl-substituted
imines,5-8,17 which can be converted to the derived homoallylic
amines in high enantiomeric purity (13-16, Scheme 3). Con-
trary to aldimines that bear a linear (e.g., 13 in 97:3 er) or
β-branched (e.g., 14 in 96:4 er) group, enantioselectivity is
diminished with an R-substituted alkyl unit (cf. 15 in 81:19 er).
The highly enantioselective generation of diene 16 with the Cu
complex derived from 6d demonstrates that enal-derived aldi-
mines are suitable substrates as well (85:15 er and >98% conv
with 6b).
Another class of allyl-containing agents that has received less
attention is 2-substituted allylboronates such as methyl- and
phenyl-containing 17a,b (eq 1).5,8a,18 Cu-catalyzed reactions are
promoted, albeit with a higher catalyst loading and longer
reaction times (5.0 mol % 6d or 6b), to deliver 18a,b in 96%
and 91% yield and 95:5 and 91:9 er, respectively. Transforma-
tions with E- or Z-crotylborons proceed efficiently and with
appreciable enantioselectivity (85:15-90:10 er), but diastereo-
selectivities are low (∼60:40 dr).
As shown in eq 2, the enantioselective Cu-catalyzed transfor-
mation can be performed on a reasonable laboratory scale (1.0 g)
with only 1.0 mol % of the chiral catalyst. In the case of
homoallylamide 8a, material of high enantiomeric purity
(97.5:2.5 er) is isolated in 75% yield by simple filtration without
resorting to silica gel chromatography.
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COMMUNICATION
’ ASSOCIATED CONTENT
A.; Konishi, H.; Yamaguchi, M.; Schneider, U.; Kobayashi, S. Angew.
Chem., Int. Ed. 2010, 49, 1838.
S
Supporting Information. Experimental procedures and
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N-acyl R-amino esters, see: (a) Fujita, M.; Nagano, T.; Schneider, U.;
Hamada, T.; Ogawa, C.; Kobayashi, S. J. Am. Chem. Soc. 2008, 130, 2914.
For diol-catalyzed reactions of allylborons with N-acyl imines, see: (b)
Lou, S.; Moquist, P. N.; Schaus, S. E. J. Am. Chem. Soc. 2007, 129, 15398.
(8) For enantioselective allyl additions to N-aryl aldimines, see: (a)
From aryl-substituted aldehydes: Gastner, T.; Ishitani, H.; Akiyama, R.;
Kobayashi, S. Ang. Chem., Int. Ed. 2001, 40, 1896. (b) From Ph-substituted
aldehydes: Naodovic, M.; Wadamoto, M.; Yamamoto, H. Eur. J. Org.
Chem. 2009, 5129. For reactions of allylstannanes with N-benzyl
aldimines (aryl-substituted) and Pd-based catalysts, see: (c) Fernandes,
R. A.; Stimac, A.; Yamamoto, Y. J. Am. Chem. Soc. 2003, 125, 14133. (d)
Fernandes, R. A.; Yamamoto, Y. J. Org. Chem. 2004, 69, 735.
(9) For use of C1-symmetric NHC-Cu complexes in enantioselec-
tive synthesis of C-C, C-Si, and C-B bonds, respectively, see: (a) Lee,
K-s.; Hoveyda, A. H. J. Org. Chem. 2009, 74, 4455. (b) Lee, K-s.;
Hoveyda, A. H. J. Am. Chem. Soc. 2010, 132, 2898. (c) O’Brien, J. M.;
Lee, K-s.; Hoveyda, A. H. J. Am. Chem. Soc. 2010, 132, 10630.
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M. J. Am. Chem. Soc. 2008, 130, 16146. (b) Burgos, P. O.; Fernꢀandez, I.;
Iglesias, M. J.; García-Granda, S.; Ortiz, F. L. Org. Lett. 2008, 10, 537.
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Guzman-Martinez, A.; Hoveyda, A. H. J. Am. Chem. Soc. 2010, 132, 10634.
(12) For a previous report where an achiral NHC-Cu-allyl is
generated from an allylsilane and an NHC-Cu-F and the subsequent
additions to aldehydes, see: (a) Russo, V.; Herron, J. R.; Ball, Z. T. Org.
Lett. 2010, 12, 220. For an example of a chiral Cu-allyl complex, generated
from a CuF or CuOAc complex, respectively, in the presence of 1, see:
(b) Wada, R.; Shibuguschi, T.; Makino, S.; Oisaki, K.; Kanai, M.; Shibasaki,
M. J. Am. Chem. Soc. 2006, 128, 7687. (c) Shi, S.-L.; Xu, L.-W.; Oisaki, K.;
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b
spectral, analytical data for all products. This material is available
free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
amir.hoveyda@bc.edu
’ ACKNOWLEDGMENT
Financial support was provided by the NIH (GM-57212). E.M.
V. is an AstraZeneca graduate fellow. We thank Adil R. Zhugralin
and Dr. Simon J. Meek for helpful discussions, Shalise D.
Couvertier for valuable experimental assistance, and Dr. Bo Li
for assistance in securing X-ray structures. Mass spectrometry
facilities at Boston College are supported by the NSF (DBI-
0619576).
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(19) See the Supporting Information for details.
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