Catalytic enantioselective addition of arylboronic acids to N-Boc imines generated in situ

Article abstract of DOI:10.1021/ol702045w

(Chemical Equation Presented) The rhodium-catalyzed addition of arylboronic acids to N-Boc imines generated in situ from stable and easily prepared α-carbamoyl sulfones has been developed. High enantioselectivities are observed for additions of arylboroni

Full text of DOI:10.1021/ol702045w

ORGANIC
LETTERS
2007
Vol. 9, No. 25
5155-5157
Catalytic Enantioselective Addition of
Arylboronic Acids to N-Boc Imines
Generated in Situ
Hiroshi Nakagawa, Jason C. Rech, Robert W. Sindelar, and Jonathan A. Ellman*
Department of Chemistry, UniVersity of California, Berkeley, California 94720-1460
jellman@berkeley.edu
Received August 28, 2007
ABSTRACT
The rhodium-catalyzed addition of arylboronic acids to N-Boc imines generated in situ from stable and easily prepared
r-carbamoyl sulfones
has been developed. High enantioselectivities are observed for additions of arylboronic acids with a variety of steric and electronic properties.
Miyaura’s first report on the Rh-catalyzed addition of
arylboronic acids to activated imines1 captured the attention
Scheme 1. Arylboronic Acid Additions to Activated Imines
of the synthetic organic community due to the preponderance
of amines in drugs and due to the synthetic opportunities
presented by the large number and diversity of commercially
available arylboronic acid inputs. Subsequently, a number
of enantioselective variants have been developed that proceed
with good yields and very high selectivities (Scheme 1).2
MostreportsdescribeadditionstoN-toluenesulfonylimines.2a,b,f-h
the toluenesulfonyl group from the addition product, alterna-
However, due to the harsh conditions necessary to remove
tive activating groups have increasingly been investigated,
including the 2-nitrobenzenesulfonyl group cleaved by ad-
(1) Ueda, M.; Saito, A.; Miyaura, N. Synlett 2000, 1637-1639.
dition of thiolate nucleophiles,2c the diphenylphosphinoyl
(2) (a) Kuriyama, M.; Soeta, T.; Hao, X.; Chen, Q.; Tomioka, K. J. Am.
group cleaved with HCl,2d and the N,N-dimethylsulfamoyl
Chem. Soc. 2004, 126, 8128-8129. (b) Tokunaga, N.; Otomaru, Y.;
Okamoto, K.; Ueyama, K.; Shintani, R.; Hayashi, T. J. Am. Chem. Soc.
group cleaved by refluxing in 1,3-diaminopropane (bp
2004, 126, 13584-13585. (c) Otomaru, Y.; Tokunaga, N.; Shintani, R.;
140 °C) for 2 h.2e While these nitrogen protecting groups
Hayashi, T. Org. Lett. 2005, 7, 307-310. (d) Weix, D. J.; Shi, Y.; Ellman,
J. A. J. Am. Chem. Soc. 2005, 127, 1092-1093. (e) Jagt, R. B. C.; Toullec,
are more easily cleaved than the toluenesulfonyl group, they
P. Y.; Geerdink, D.; de Vries, J. G.; Feringa, B. L.; Minnaard, A. J. Angew.
either suffer from inconvenient or nonstandard cleavage
conditions or, in the case of the diphenylphosphinoyl group,
high molecular weight. An additional liability of all of these
methods is the inherent hydrolytic lability of activated imines,
Chem., Int. Ed. 2006, 45, 2789-2791. (f) Duan, H. F.; Jia, Y. X.; Wang,
L. X.; Zhou, Q. L. Org. Lett. 2006, 8, 2567-2569. (g) Wang, Z. Q.; Feng,
C. G.; Xu, M. H.; Lin, G. Q. J. Am. Chem. Soc. 2007, 129, 5336-5337.
(h) Marelli, C.; Monti, C.; Gennari, C.; Piarulli, U. Synlett, 2007, 14, 2213-
2216.
10.1021/ol702045w CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/08/2007

which makes them difficult to manipulate and purify,
complicating their use in amine synthesis.3
Table 1. Selection of Base for in Situ Generation of N-Boc
The Boc protecting group is the most extensively used of
all amine protecting groups because it is low in molecular
weight, is cleaved under convenient acidic conditions (HCl
or TFA), and upon deprotection produces volatile byproducts
that enable straightforward isolation of pure amine products.4
Enantioselective catalytic additions to N-Boc imines would
therefore provide significant practical advantages over ad-
ditions to other activated imine derivatives.
Imine and Enantioselective Arylboronic Acid Addition
N-Boc imines 2 show considerable hydrolytic lability
(Scheme 2). However, R-carbamoyl sulfones 1, which serve
Scheme 2. Preparation of N-Boc Imines 2
entry
base
Et3N
LiF
MgO
NaOMe
NaOH
K2CO3
Cs2CO3
K2CO3
additive
yield (%)a
1
2
3
4
5
6
7
8
-
-
-
-
-
-
-
Et3Nc
<5
<5
<5
<5
<50b
53
as key intermediates in the most popular route to N-Boc
imines, are prepared under mild conditions in high yields
and are stable, crystalline compounds.5 We envisioned that
in situ generation of imines 2 from the stable R-carbamoyl
sulfones 1 during the arylboronic acid addition step would
provide a particularly efficient and straightforward protocol
(Table 1).6,7
51
76
a Isolated yields after chromatography. b The addition product was
contaminated with inseparable impurities. c 1.5 equiv of base was added.
We initiated our study on the addition of arylboronic acids
to in situ generated N-Boc imines by using conditions that
we had previously developed for the enantioselective addition
of arylboronic acids to N-diphenylphosphinoyl imines.2d
Specifically, Rh(acac)(coe)2 was used as the precatalyst,
and deguPHOS8 was used as the chiral ligand. To minimize
imine hydrolysis 4 Å molecular sieves were added, and Et3N
was included because it had been found to result in higher
yields. Dioxane was also selected as the solvent because we
had previously observed that it gave superior yields and %
ee.2d Unfortunately, little if any addition product was
observed due to inefficient in situ conversion of R-carbamoyl
sulfone 1a to the corresponding N-Boc imine 2a (entry 1,
Table 1). A number of anionic bases that might more
efficiently convert 1 to 2 were next evaluated. While LiF,
MgO, and NaOMe were not effective (entries 2-4), the
relatively strong bases, NaOH (entry 5), K2CO3 (entry 6),
and Cs2CO3 (entry 7) gave promising initial results, with
K2CO3 and Cs2CO3 giving the cleanest conversion to product.
Because Et3N had previously proven to be beneficial in
arylboronic acid additions to N-diphenylphosphinoyl imines,
this additive was evaluated along with K2CO3 resulting in a
significant increase in yield (entry 8). Notably, chiral HPLC
analysis established that the product was obtained with very
high selectivity (98% ee). Increasing the reaction time did
not increase the yield of the product (data not shown).
Presumably, competitive substrate hydrolysis and/or catalyst
decomposition prevents complete reaction conversion.
The optimal conditions were next evaluated with a range
of different arylboronic acids. Electron-rich arylboronic acids
added in good yields and with excellent enantioselectivities
(entries 2 and 3, Table 2). Arylboronic acids with electron-
withdrawing substituents also added with very high selectivi-
ties although with a moderate reduction in yield (entries 4
and 7). The reaction was tolerant of steric interactions with
the ortho-methyl-substituted arylboronic acid also adding in
reasonable yield and with high selectivity (entry 8).
(3) For a comprehensive review on reactivity and properties of activated
imines see: Petrini, M.; Torregiani, E. Synthesis 2007, 159-186.
(4) Greene, T. W.; Wuts, P. G. ProtectiVe Groups in Organic Synthesis;
John Wiley & Sons: New York, 1999; pp 518-525.
(5) (a) Kanazawa, A. M.; Denis, J.-N.; Greene, A. E. J. Org. Chem. 1994,
59, 1238-1240. (b) Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem. Soc.
2002, 124, 12964-12965. (c) Song, J.; Wang, Y.; Deng, L. J. Am. Chem.
Soc. 2006, 128, 6048-6049. (d) Trost, B. M.; Jaratjaroonphong, J.;
Reutrakul, V. J. Am. Chem. Soc. 2006, 128, 2778-2779.
(6) To our knowledge, the addition of arylboronic acids to activated
imines generated in situ has not previously been reported.
(7) For in situ generation of N-Boc imines in an aza-Henry reaction see:
Fini, F.; Sgarzani, V.; Pettersen, D.; Herrera, R. P.; Bernardi, L. Ricci, A.
Angew. Chem., Int. Ed. 2005, 44, 7975-7978.
(8) DeguPHOS is available from a number of chemical suppliers,
including Strem Chemicals, Inc., ACBR GmbH KG, and Degussa AG.
Nagel, U.; Kinzel, E.; Andrade, J.; Prescher, G. Chem. Ber. 1986, 119,
3326-3343.
(9) (a) Hayashi, T.; Ishigedani, M. J. Am. Chem. Soc. 2000, 122, 976-
977. (b) Plobeck, N.; Powell, D. Tetrahedron: Asymmetry 2002, 13, 303-
310.
Additions of arylboronic acids to N-Boc imines with
diverse structural and electronic properties were next inves-
tigated. Additions of phenylboronic acid to N-Boc benzaldi-
mines with methyl substitution at the ortho-, meta-, and para-
positions each proceeded with high selectivities (entries
9-11). Addition to the ortho-substituted derivative is
particularly significant because the increased steric interaction
did not appreciably impact reaction yield (entry 11). The
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Org. Lett., Vol. 9, No. 25, 2007

with high enantioselectivity to the electron-rich imine derived
from 4-anisaldehyde (entry 14). Interestingly, while clean
addition also occurred to the electron-deficient imine derived
from 4-trifluoromethylbenzaldehyde, significantly reduced
enantioselectivity was observed (entry 15). A final notable
feature of this method is the high level of functional group
tolerance, with keto (entry 7), alkoxy (entries 3 and 14),
bromo (entry 12), and chloro (entry 1 and 5) groups all
compatible with the addition reaction.
Table 2. Selection of Base for in Situ Generation of N-Boc
Imine and Enantioselective Arylboronic Acid Addition
entry
Ar1
Ar2
yield (%)a
ee (%)b
In conclusion, the enantioselective addition of arylboronic
acids to N-Boc imines has been reported for the first time.
The method was evaluated for a range of functionalized
arylboronic acids and N-Boc imines, including electron-poor
and -rich as well as ortho-substituted derivatives, and very
high selectivities were observed for all but one of the
substrate combinations examined. The reported method
should be of considerable utility due to the well-documented
popularity and convenience of N-Boc protected amine
derivatives. Moreover, this method is considerably more
straightforward to carry out than previously reported2 aryl-
boronic acid additions to imines because the N-Boc amine
products 3 are obtained in situ from stable and easily
prepared R-carbamoyl sulfones 1.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-MeC6H4
3-MeC6H4
2-MeC6H4
4-BrC6H4
2-thienyl
4-ClC6H4
4-MeC6H4
4-MeOC6H4
4-CF3C6H4
3-ClC6H4
3-MeC6H4
3-AcC6H4
2-MeC6H4
Ph
Ph
Ph
Ph
Ph
76
70
76
51
55
66
52
62
71
70
63
59
71
76
69
98c
96
93c
95c
99
95
94
93
90
95
97
90
96
96c
79c
4-MeOC6H4
4-CF3C6H4
Ph
Ph
a Isolated yields after chromatography. b Enantiomeric purity determined
by chiral HPLC analysis. c Absolute configuration established by comparison
of the optical rotation of amine obtained upon Boc cleavage to literature
values9 (see Supporting Information).
Acknowledgment. The support of NSF (CHE-0446173),
Dainippon Sumitomo Pharma Co., Ltd., and Merck are
gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
addition to N-Boc 2-thiophenyl carboxaldimine also pro-
ceeded cleanly, demonstrating both compatibility of hetero-
cyclic imines and compounds incorporating sulfur (entry 13).
Addition of phenylboronic acid proceeded in good yield and
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5157