Diastereo- and enantioselective Pd(II)-catalyzed additions of 2-alkylazaarenes to N -boc imines and nitroalkenes

Article abstract of DOI:10.1021/ja3083494

A chiral Pd(II)-bis(oxazoline) complex was found to be highly effective in promoting the first direct diastereo- and enantioselective addition of alkylazaarenes to N-Boc aldimines and nitroalkenes under mild conditions. Deprotection of Boc-protected products proceeded readily to provide amines in high yields.

Full text of DOI:10.1021/ja3083494

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Communication
Diastereo- and Enantioselective Pd(II)-Catalyzed Additions
of 2-Alkylazaarenes to N-Boc Imines and Nitroalkenes
Daniel Best, Szymon Kujawa, and Hon Wai Lam
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 10 Oct 2012
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Diastereo- and Enantioselective Pd(II)-Catalyzed Additions of
2-Alkylazaarenes to N-Boc Imines and Nitroalkenes
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Daniel Best, Szymon Kujawa, and Hon Wai Lam*
EaStCHEM, School of Chemistry, University of Edinburgh, Joseph Black Building, The King’s Buildings, West Mains
Road, Edinburgh, EH9 3JJ, United Kingdom
Supporting Information Placeholder
ABSTRACT: A chiral Pd(II)–bis(oxazoline) complex was
found to be highly effective in promoting the first direct
diastereo- and enantioselective addition of alkylazaarenes to
N-Boc aldimines and nitroalkenes under mild conditions.
Deprotection of Boc-protected products proceeded readily to
provide amines in high yields.
Azaarenes and α-stereogenic amines are ubiquitous structures
in biologically active pharmaceuticals, agrochemicals, and
natural products. Therefore, the development of new catalytic
enantioselective methods to construct molecules containing
both of these chemotypes should be of significant utility. In
this regard, the catalytic enantioselective Friedel–Crafts addi-
tion of electron-rich azaarenes (such as indoles and pyrroles)
to imines or enamides has been studied extensively.1 A com-
plementary but currently undeveloped strategy is the direct
catalytic enantioselective union of alkylazaarenes with imines
or their derivatives (Figure 1). In this reaction, complexation
of a chiral metal complex to the nitrogen atom of a C=N moie-
ty within the azaarene can potentially facilitate α-
Figure 1. Catalytic additions of alkylazaarenes to imines (1A and
deprotonation of a 2-alkyl substituent under basic conditions to
1C) and relevant biologically active molecules (1B).
generate a chiral azaallylmetal species2 that can then undergo
stereoselective addition to an imine (Figure 1A). This ap-
proach would allow enantioselective access to 2-(β-
aminoalkyl)azaarenes, substructures that appear in various
biologically active drug candidates such as DPP-4 inhibitors3
and GlyT-1 inhibitors4 for the treatment of type 2 diabetes and
schizophrenia, respectively (Figure 1B).
enantioselective additions of 2-alkylazaarenes to N-Boc
imines. The reactions are promoted by a chiral Pd(II)-
bis(oxazoline)complex under experimentally convenient con-
ditions, proceeding at ambient temperature or at 50–60 °C in
undried solvent under an air atmosphere. Importantly, depro-
tection of the amine in the products can be achieved simply by
treatment with mild acid. Furthermore, examples of the corre-
sponding additions to nitroalkenes are also provided.
We envisaged that incorporation of an electron-withdrawing
group into an azaarene would further acidify the α-protons of a
pendant alkyl substituent by stabilization of the conjugate base
through conjugation (Scheme 1), allowing deprotonation under
conditions that would be much milder than those previously
reported9−11 and hence more suited to enantioselective cataly-
sis.16 In addition, acidifying groups such as nitro, cyano, or
ester substituents would provide highly useful functional han-
dles for subsequent manipulation of the products.
Although this strategy has not yet, to our knowledge, been
realized,5,6,7,8 encouraging partial progress has been described
by the groups of Huang,9 Rueping,10 and Kanai and Matsuna-
ga11 who have reported racemic additions of alkylazaarenes to
N-sulfonylimines catalyzed by Pd(II),9a Sc(III),9b or Cu(II)10,11
complexes (Figure 1C).12 Also of relevance are racemic
Sc(III)-catalyzed Michael additions of alkylazaarenes to
enones and an α,β-unsaturated pyrrole,11,13 and Yb(III)-
catalyzed Michael additions of alkylazaarenes to alkylidine
malononitriles.14 While these reports demonstrate important
proof of concept, the low acidity of alkylazaarenes means that
high temperatures are often required, which may hinder the
development of enantioselective variants. Furthermore, the
substrates employed were mostly methylazaarenes; when
higher alkylazaarenes were employed, poor diastereoselectivi-
ties were often obtained.9a,b,13–15 Finally, in the additions to
imines,9–11 the substrates employed were mainly N-
tosylimines, and removal of the tosyl group from the products
would require strongly reducing conditions that are generally
incompatible with sensitive functionality.
Scheme 1. Strategy for lowering the pKa of alkylazaarenes.
Herein, we describe the first catalytic diastereo- and
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Table 1. Enantioselective Pd-catalyzed additions of various
2-alkylazaarenes to imine 2a.a
Chart 1. Enantioselective Pd-catalyzed additions of 2-
alkylazaarenes to various imines.a
1
2
3
4
5
6
7
8
9
yield
(%)a
ee
entry
product
drb
(%)c
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3a R = Me
3b R = Et
3c R = n-Pr
3d R = OMe
1
2
3
4
83d
84
92:8
>95:5
>95:5
83:17
94 (92)
96
97
86
77d
88 (47)
4ab R = CN, 87%, >95:5 dr, 87% ee
4bb R = NO2, 93%, >95:5 dr, 97% ee
4cb R = 4-Me, 86%, 93:7 dr, 84% ee
4dc R = 3-Cl, 83%,d >95:5 dr, 89% eed
4e R = 2-NO2, 70%, 77:23 dr, 94% ee
5e
6e
3e R = Me
3f R = n-Pr
93d
96
86:14
>95:5
88 (84)
95
7e
3g
3h
98
78
>95:5
91:9
95
91
4f 87%, >95:5 dr, 88% ee
4g >95%, >95:5 dr, 91% ee
4h R = 4-Br, 84%, >95:5 dr, 98% ee
4i R = 4-CN, 80%,>95:5 dr, >99% ee
4j R = 3-OMe, 94%, 93:7 dr, 93% ee
8
9e,f
3i R = H
3j R = Ph
70
95
93:7
>95:5
88
98
a
Unless stated otherwise, yields are of pure isolated major diastere-
omers. Diastereomeric ratios were determined by 1H NMR analysis of
the unpurified reaction mixtures. Enantiomeric excesses were deter-
10e
b
a
mined by chiral HPLC analysis. Reaction conducted at room tem-
Unless stated otherwise, yields are of pure isolated major diastere-
omers. Determined by H NMR analysis of the unpurified reaction
mixtures. Enantiomeric excesses of the major diastereomer as de-
termined by chiral HPLC analysis. Where indicated, values in paren-
perature. c Reaction conducted at 60 °C. d Yield of a 96:4 inseparable
mixture of diastereomers.
b
1
c
d
theses refere to enantiomeric excess of the minor diastereomer.
aldimines containing various substituents (such methyl, bro-
mo, chloro, nitro, cyano, or methoxy) at the para or meta posi-
tions of the phenyl ring successfully reacted with a number of
alkylazaarenes to provide products with high diastereo- and
enantioselectivities. An ortho-substituted phenyl group on the
imine was also tolerated (product 4e), although the diastere-
oselectivity was somewhat diminished in this case.
Further experiments were conducted to shed light upon the
importance of the position of the electron-withdrawing group
on the azaarene. First, the reactivity of 2-ethyl-5-
nitrobenzoxazole (5) was evaluated, since mesomeric stabiliza-
tion (−M effect) of the conjugate base of 5 by the 5-nitro sub-
stituent is not possible. Surprisingly, 5 underwent efficient
coupling with 2a at room temperature to give 6 as a 94:6 in-
separable mixture of diastereomers in 74% yield, with enanti-
omeric excesses of 90% ee and 78% ee for the major and mi-
nor diastereomers, respectively (eq 1). This result demon-
strates that in this case, the inductive electron-withdrawing
Yield of an inseparable mixture of diastereomers. e Reaction conduct-
ed at 50 °C. f Reaction conducted in THF.
Our investigations began with evaluation of chiral complex-
es based around metal acetate salts, where it was hoped that
the acetate counterions would exhibit sufficient basicity to
effect α-deprotonation of an alkylazaarene. Following exten-
sive investigations, we found that the complex composed of
Pd(OAc)2 (5 mol %) and a tetraphenyl bis(oxazoline) ligand
L117 (5 mol %) was highly effective in promoting the addition
of various alkylazaarenes 1a–1j18 to N-Boc imine 2a in CHCl3
with high diastereoselectivities (up to >95:5 dr) and enantiose-
lectivities (up to 98% ee) (Table 1). For example, 2-alkyl-6-
nitrobenzoxazoles reacted smoothly with 2a at room tempera-
ture to provide products 3a–3c containing methyl, ethyl, or n-
propyl groups at the α-carbon, respectively (entries 1–3).19 An
α-methoxy substituent on the alkylazaarene was also tolerated,
although the ee of the minor diastereomer was only 47% (entry
4). Interestingly, 2-methyl-6-nitrobenzoxazole was not a good
substrate as the addition product formed initially underwent a
second addition to imine 2a. The process is not limited to the
use of substrates containing nitro groups on the azaarene; sub-
strates containing ester or cyano groups underwent reaction to
give products 3e–3g, respectively, in high yields (entries 5–7).
While the lower reactivities of these substrates required an
increase in reaction temperature to 50 °C to obtain high con-
versions, high stereoselectivities were maintained. Other
azaarenes that are tolerated include 6-nitrobenzothiazole (entry
8) and 3-nitropyridine (entries 9 and 10).
Next, the scope of the process with respect to the imine was
studied (Chart 1). Pleasingly, a range of aromatic N-Boc
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nature of the nitro group (−I effect) is sufficient for good reac-
tivity, and suggests the scope of this process may be signifi-
cantly broader than presented herein.
Chart 2. Enantioselective Pd-catalyzed additions of 2-
alkylazaarenes to nitroalkenes.a
1
2
In contrast, while 2-ethyl-4-nitrobenzoxazole (7) might have
been expected to exhibit high reactivity in this process, this
substrate provided the product 8 in low yield with poor dia-
stereo- and enantioselectivity (eq 2). Presumably, coordination
of the nitro group to the palladium center of the catalyst is
responsible for the poor performance of this alkylazaarene.
Deprotection of the Boc group from the products was readi-
ly accomplished by treatment with HCl in MeOH (generated
by dissolving TMSCl in MeOH), as shown by the formation of
the amines 9 and 10 from 3c and 3j in 93% and 90% yield,
respectively (eq 3 and 4). In the case of 10, very slight erosion
in the diastereochemical purity was observed (eq 4).
3
4
5
6
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9
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12a 58%, >95:5 dr, 90% ee
12b Ar = Ph, 73%, >95:5 dr, >99% ee
12cb Ar = 2-thienyl, 78%, >95:5 dr, 95% ee
a
Yields are of isolated compounds. Diastereomeric ratios were de-
termined by 1H NMR analysis of the unpurified reaction mixtures.
b
Enantiomeric excesses were determined by chiral HPLC analysis.
Reaction conducted at 60 °C for 48 h.
56:44 dr, and 80/90% ee (major/minor). The dependence of
both the diastereo- and enantioselectivity on the counterion
suggests that the carboxylate is involved in the stereoselectivi-
ty-determining step.21 Presumably, one carboxylate remains
bound to palladium throughout the reaction.
On this basis, Figure 2 presents a tentative stereochemical
model for these reactions. Deprotonation of the alkylazaarene
by an acetate ligand of complex 13 leads to species 14, in
which the azaallyl ligand possesses E-stereochemistry to min-
imize steric interactions between the R-substituent and the
other ligands. Approach of the imine toward the azaallyl lig-
and is likely to occur via trajectories approximately perpendic-
ular to the ligand plane, to allow binding/activation of the
imine at an axial coordination site. In species 14, approach of
the imine from the top face is relatively unhindered. In species
15, however, in which the azaallyl ligand adopts an alternative
conformation, approach of the imine from the top face is hin-
dered by the acetate ligand, whereas approach from the bottom
We have found that nitroalkenes are also suitable coupling
partners for 2-alkylazaarenes using the same catalyst system.20
For example, substrates 1c and 1j underwent conjugate addi-
tion to nitroalkenes 11a or 11b to provide 12a–12c as single
diastereomers with high enantioselectivities (Chart 2).19
To investigate the role of the acetate counterions in this pro-
cess, the reaction of Table 1, entry 1 was repeated using
Pd(TFA)2 in place of Pd(OAc)2. No reaction occurred, indicat-
ing that the basicity of the counterion is crucial for reactivity.21
An analogous experiment using Pd(OBz)2 gave 3a in 90%
yield, 74:26 dr, and 87/94% ee (major/minor). Furthermore, a
similar experiment using Pd(OPiv)2 gave 3a in 38% yield,
Figure 2. Stereochemical model.
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face is hindered by the phenyl groups of the chiral ligand.
Page 4 of 5
(1) For relevant reviews, see: (a) Poulsen, T. B.; Jørgensen, K. A.
1
2
3
4
5
6
7
8
Four distinct transition state models resulting from confor-
mation 14 can be envisaged. TS 3 and TS 4, in which the
imine possesses an s-cis geometry, appear to be unfavorable
on the basis of their eclipsing interactions. Of the more favor-
able staggered conformations TS 1 and TS 2, in which an
imine s-trans geometry is adopted, TS 2 is likely to disfavored
due to the steric clash of the tert-butyl group of the imine with
one of the methyl groups of the chiral ligand. Therefore, reac-
tion through TS 1 is favored. Similar arguments can be in-
voked to explain the stereochemical outcome of the nitroal-
kene additions, through TS 5.
Chem. Rev. 2008, 108, 2903-2915. (b) Bandini, M.; Eichholzer, A.
Angew. Chem., Int. Ed. 2009, 48, 9608-9644. (c) You, S.-L.; Cai, Q.;
Zeng, M. Chem. Soc. Rev. 2009, 38, 2190-2201. (d) Bartoli, G.;
Bencivenni, G.; Dalpozzo, R. Chem. Soc. Rev. 2010, 39, 4449-4465.
(e) Terrasson, V.; de Figueiredo, R. M.; Campagne, J. M. Eur. J. Org.
Chem. 2010, 2635-2655. (f) Kobayashi, S.; Mori, Y.; Fossey, J. S.;
Salter, M. M. Chem. Rev. 2011, 111, 2626-2704.
(2) For a review of 1-azaallylic anions in heterocyclic chemistry,
see: Mangelinckx, S.; Giubellina, N.; De Kimpe, N. Chem. Rev. 2004,
104, 2353-2400.
(3) Xu, J.; Wei, L.; Mathvink, R. J.; Edmondson, S. D.; Eiermann,
G. J.; He, H.; Leone, J. F.; Leiting, B.; Lyons, K. A.; Marsilio, F.;
Patel, R. A.; Patel, S. B.; Petrov, A.; Scapin, G.; Wu, J. K.;
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(4) Kolczewski, S.; Marty, H.-P.; Narquizian, R.; Pinard, E.;
Stalder, H. U.S. Pat. Appl. Publ. 2010 US 20100210592 A1.
(5) For racemic additions of alkylazaarenes to aldehydes promoted
by stoichiometric quantities of dialkylboron triflates and trialkylamine
bases, see: (a) Hamana, H.; Sugasawa, T. Chem. Lett. 1983, 333-336.;
(b) Hamana, H.; Sugasawa, T. Chem. Lett. 1984, 1591-1594.
(6) For racemic rhodium-catalyzed hydrogenative coupling of vi-
nylazines with N-sulfonylaldimines, see: Komanduri, V.; Grant, C.
D.; Krische, M. J. J. Am. Chem. Soc. 2008, 130, 12592-12593.
(7) For enantioselective copper-catalyzed reductive coupling of
alkenylazaarenes with ketones, see: Saxena, A.; Choi, B.; Lam, H. W.
J. Am. Chem. Soc. 2012, 134, 8428-8431.
(8) For other examples of catalytic enantioselective additions of α-
deprotonated alkylazaarenes to carbon electrophiles, see: (a) Trost, B.
M.; Thaisrivongs, D. A. J. Am. Chem. Soc. 2008, 130, 14092-14093.
(b) Trost, B. M.; Thaisrivongs, D. A. J. Am. Chem. Soc. 2009, 131,
12056-12057. (c) Trost, B. M.; Thaisrivongs, D. A.; Hartwig, J. J.
Am. Chem. Soc. 2011, 133, 12439-12441. (d) Fallan, C.; Lam, H. W.
Chem. Eur. J. 2012, 18, 11214-11218.
(9) (a) Qian, B.; Guo, S.; Shao, J.; Zhu, Q.; Yang, L.; Xia, C.;
Huang, H. J. Am. Chem. Soc. 2010, 132, 3650-3651. (b) Qian, B.;
Guo, S.; Xia, C.; Huang, H. Adv. Synth. Catal. 2010, 352, 3195-3200.
(c) Qian, B.; Xie, P.; Xie, Y.; Huang, H. Org. Lett. 2011, 13, 2580-
2583.
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Finally, to demonstrate the synthetic utility of the products,
3j was converted into biaryl 18 by a sequence involving nitro
group reduction, conversion of the resulting amine 16 into
bromide 17, and Suzuki–Miyaura coupling (Scheme 2).
Scheme 2. Manipulation of product 3j.
In conclusion, we have described the first catalytic enanti-
oselective additions of alkylazaarenes to N-Boc imines and
nitroalkenes. Under the action of a chiral Pd(II)–bis(oxazoline)
complex, the reactions proceed with high levels of diastereo-
and enantioselection. By exploiting the acidifying effect of
nitro, cyano, or ester groups on the azaarene, the reactions
occur under mild, experimentally convenient reaction condi-
tions (undried solvent, air atmosphere, and often ambient tem-
perature). In the case of the imine addition products, deprotec-
tion of the Boc group is readily accomplished to reveal the
corresponding amines. This work lays the foundation for the
development of further catalytic enantioselective addition re-
actions of alkylazaarenes for the production of novel chiral
azaarene-containing building blocks. Studies in this area are
ongoing in our laboratories.
(10) Rueping, M.; Tolstoluzhsky, N. Org. Lett. 2011, 13, 1095-
1097.
(11) Komai, H.; Yoshino, T.; Matsunaga, S.; Kanai, M. Synthesis
2012, 2185-2194.
(12) A catalyst-free addition of alkylazaarenes to imines was also
recently described: Yan, Y.; Xu, K.; Fang, Y.; Wang, Z. J. Org.
Chem. 2011, 76, 6849-6855.
(13) Komai, H.; Yoshino, T.; Matsunaga, S.; Kanai, M. Org. Lett.
2011, 13, 1706-1709.
(14) Qian, B.; Shi, D.; Yang, L.; Huang, H. Adv. Synth. Catal.
2012, 2146-2150.
ASSOCIATED CONTENT
Supporting Information
(15) In one case, a good diastereomeric ratio of 9:1 was obtained
by the Rueping group. See ref. 10.
(16) For amine-catalyzed racemic addition of 3,5-diethyl-4-
nitroisoxazole to carbonyl compounds, see: Adamo, M. F. A.; Suresh,
S. Tetrahedron 2009, 65, 990-997.
Experimental procedures, full spectroscopic data for all new com-
pounds, and crystallographic data in cif format. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
(17) Desimoni, G.; Faita, G.; Mella, M. Tetrahedron 1996, 52,
13649-13654.
Corresponding Author
(18) See Supporting Information for the structures of 1a–1j.
(19) The relative and absolute configurations of the products ob-
tained herein were assigned by analogy with those of 3j, 9, and 12b
which were determined by X-ray crystallography using a copper radi-
ation source. See Supporting Information for details.
(20) For reviews of nitroalkenes as conjugate acceptors, see: (a)
Barrett, A. G. M.; Graboski, G. G. Chem. Rev. 1986, 86, 751-762. (b)
Barrett, A. G. M. Chem. Soc. Rev. 1991, 20, 95-127. (c) Berner, O.
M.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem. 2002, 1877-1894.
(21) Repeating the reaction of Table 1, entry 1 using Pd(TFA)2 in
place of Pd(OAc)2, in the presence of Et3N (10 mol %) gave 3a in
32% conversion, 95:5 dr, and 88/44% ee (major/minor).
h.lam@ed.ac.uk
ACKNOWLEDGMENT
We thank the ERC (Starting Grant No. 258580) and the EPSRC
(Leadership Fellowship to H. W. L.) for support of this work. We
are grateful to Dr. Gary S. Nichol (University of Edinburgh) for
X-ray crystallography, and the EPSRC National Mass Spectrome-
try Service Centre for high-resolution mass spectra.
REFERENCES
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