A room-temperature protocol for the rhodium(I)-catalyzed addition of arylboron compounds to sulfinimines

Article abstract of DOI:10.1021/ol050014f

(Chemical Equation Presented) The addition of organoboronic acids to chiral sulfinimines proceeds under mild conditions at room temperature, using Rh(I) catalysis in the absence of external phosphine ligands. Clean reaction only occurs in the presence of

Full text of DOI:10.1021/ol050014f

ORGANIC
LETTERS
2005
Vol. 7, No. 8
1481-1484
A Room-Temperature Protocol for the
Rhodium(I)-Catalyzed Addition of
Arylboron Compounds to Sulfinimines
Yuri Bolshan and Robert A. Batey*
Department of Chemistry, UniVersity of Toronto, 80 St. George St., Toronto,
Ontario, Canada, M5S 3H6
rbatey@chem.utoronto.ca
Received January 4, 2005
ABSTRACT
The addition of organoboronic acids to chiral sulfinimines proceeds under mild conditions at room temperature, using Rh(I) catalysis in the
absence of external phosphine ligands. Clean reaction only occurs in the presence of water as a cosolvent. The sulfinamide adducts are
formed with high diastereoselectivities, providing a convenient route to the synthesis of enantiomerically enriched chiral benzylic amines.
Chiral amines are synthetically important targets as a result
of their presence in natural products, pharmaceuticals, and
other bioactive molecules. For example, chiral benzylic
amines such as diarylmethylamines are found in such
biologically active compounds as the histamine H1-receptor
antagonist (S)-cetirizine dihydrochloride1 and the non-peptide
selective opioid receptor agonist SNC80.2 Although various
methods for the enantioselective synthesis of chiral amines
are known,3 a completely general approach to their formation
remains elusive. Conceptually one of the most attractive
approaches to their synthesis is the enantioselective addition
of nucleophilic organometallic species to imine derivatives.4
The most well-known examples of this strategy are the
catalytic asymmetric additions of organzinc reagents (R2-
Zn), including the additions of dialkylzinc reagents (usually
diethylzinc or dimethylzinc) to sulfonylimines,5 N-phosphi-
noylimines,6 and N-arylimines,7 and the addition of diphe-
nylzinc to in situ generated N-formylimines.8 These additions
typically occur in moderate to good ee’s, but the protocols
employed suffer from several limitations, including the
requirement for highly electron-deficient imines, very narrow
substrate scope for the organozinc reagents, the use of
unusual non-commercial chiral ligands, and the inherent air
and water sensitivity of R2Zn reagents.9
A potential solution to at least some of these problems is
afforded by the use of metal-catalyzed additions of orga-
noboron compounds.10 The use of boronic acids rather than
other organometallic reagents is highly desirable as a result
of their relative stability toward air and moisture, their
(5) Fujihara, H.; Nagai, K.; Tomioka, K. J. Am. Chem. Soc. 2000, 122,
12055-12056.
* To whom correspondence should be addressed. Fax: (+1) 416-978-
5059.
(6) Boezio, A. A.; Pytkowicz, J.; Coˆte´, A.; Charette, A. B. J. Am. Chem.
Soc. 2003, 125, 14260-14261.
(1) Opalka, C. J.; D’Ambra, T. E.; Faccone, J. J.; Bodson, G.; Cossement,
E. Synthesis 1995, 766-768.
(7) Porter, J. R.; Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L. J. Am.
Chem. Soc. 2001, 123, 10409-10410.
(2) Calderon, S. N.; Rothman, R. B.; Porreca, F.; Flippen-Anderson, J.
L.; McNutt, R. W.; Xu, H.; Smith, L. E.; Bilsky, E. J.; Davis, P.; Rice K.
C. J. Med. Chem. 1994, 37, 2125-2128.
(8) Hermanns, N.; Dahmen, S.; Bolm, C.; Bra¨se, S. Angew. Chem., Int.
Ed. 2002, 41, 3692-3694.
(3) (a) Bloch, R. Chem. ReV. 1998, 98, 1407-1438. (b) Kobayashi, S.;
Ishitani H. Chem. ReV. 1999, 99, 1069-1094.
(9) Dimethylzinc has also been used to promote the addition of
alkenylzirconocenes to N-phosphinoylimines; see: Wipf, P.; Stephenson,
C. R. J. Org. Lett. 2003, 5, 2449-2452.
(4) For a general review on catalyzed asymmetric arylation reactions,
see: Bolm, C.; Hildebrand, J. P.; Mun˜iz, K.; Hermanns, N. Angew. Chem.,
Int. Ed. 2001, 40, 3284-3308.
(10) For a review of rhodium-catalyzed asymmetric additions, see:
Hayashi, T.; Yamasaki, K. Chem. ReV. 2003, 103, 2829-2844.
10.1021/ol050014f CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/17/2005

functional group tolerance, and their commercial availability
or ease of synthesis. Boronic acids have been shown to
undergo addition to imines, as demonstrated by Miyaura’s
Rh(I)-catalyzed addition of arylboronic acids to sulfo-
nylimines11,12 and Jamison’s Ni(0)-catalyzed three-component
coupling of boronic acids, alkynes, and imines.13 Ami-
dophosphines14 and C2-symmetric bicyclo[2.2.2]octadienes15
have been used as chiral ligands for the addition of
triarylboroxines to sulfonylimines at 60-100 °C. The major
limitations associated with these protocols are the require-
ment for triarylboroxines14,15 rather than arylboronic acids,
and in the former case, substrate scope is limited, since high
enantioselectivities can be achieved only when reacting
ortho-substituted sulfonylimines.14
Scheme 1. Effect of Water on Rhodium-Catalyzed Addition of
Phenylboronic Acid to Sulfinimine 1b
Following our earlier studies on the Lewis acid catalyzed
addition of crotyl and allyltrifluoroborate salts to N-tert-
butylsulfinimines,16 our goal at the outset of this project was
to develop a convenient room-temperature protocol for the
addition of arylboronic acids. Although an auxiliary-based
strategy, the use of N-sulfinimines is growing in importance
due to the ease of introduction and removal of the auxilia-
ries.17 The condensation of arylboronic acids and N-tert-
butylsulfinamide with either glyoxylic or pyruvic acid has
been reported in a Petasis borono-Mannich reaction but
afforded the adducts as 1:1 diastereoisomeric mixtures.18
While this report appeared to offer little hope for the
stereocontrolled addition of an arylboron reagent, a variety
of other organometallic reagents (e.g., organo-Li, Mg, Al,
and Zn reagents)17 are known to undergo highly diastereo-
selective additions to N-sulfinimines, including the use of
arylmetal reagents.19 Most significantly, during the course
of our studies, Ellman and co-workers disclosed the diaste-
reoselective addition of arylboronic acids to N-sulfinimines
at 70 °C using catalytic Rh(acac)(coe)2 in the presence of
1,2-bis(diphenylphosphino)benzene.20 The optimized condi-
tions require heating at 70 °C and slow addition of the
boronic acids over 6-10 h. We now demonstrate that
diastereoselective addition to N-sulfinimines can be achieved
using an operationally simpler set of conditions that avoids
the use of phosphines, heating, or slow addition of reagents
via syringe pump.
Our investigations have focused upon the use of N-tert-
butanesulfinyl aldimines.17b,21 Initial attempts at Rh(I)-
catalyzed additions under a variety of anhydrous conditions
led to the formation of side-products 2 or poor conversions
to product 3. For example, reaction of phenylboronic acid
with enantiomerically pure (S)-sulfinimine 1b in the presence
of 10 mol % [Rh(COD)(CH3CN)2]BF4 catalyst resulted in
no reaction at room temperature but at 95 °C led to the
addition-deoxygenation product 2 in 68% yield (Scheme 1).
Interestingly, this side-product was not observed in the case
of more electron-deficient N-tert-butanesulfinyl aldimines.
Several other rhodium-based catalysts (e.g., [Rh(COD)-
Cl]2, Rh(acac)(CO)2, and Rh(acac)(C2H4)2) were submitted
to the reaction conditions in the absence of any ligand and
in the presence of both monodentate and bidentate phosphine
ligands. However, no reaction occurred at room temperature
using these catalyst systems. The key breakthrough occurred
with the recognition of the importance of triethylamine as
an additive and the use of water as a cosolvent. The desired
product 3 was obtained in 45% yield and with 82%
diastereoselectivity when the solvent system was changed
to dioxane and water in a 1:2 ratio, using PhB(OH)2 (2 equiv)
and Et3N (2 equiv)11 at room temperature. The side-product
2 was not formed under these conditions. Reaction under
the same conditions but at 95 °C led to 3 in 25% yield and
with 79% diastereoselectivity. The best yields were obtained
with a heterogeneous 1:2 mixture of dioxane and water. Any
attempts to homogenize the system by using equivalent
amounts of solvents or adding tert-butyl alcohol to the
suspension led to lower yields of the compound 3.
(11) Ueda, M.; Saito, A.; Miyaura, N. Synlett 2000, 11, 1637-1639.
(12) For the Rh(I)-catalyzed arylation of N-sulfonylimines with aryl-
stannanes using MOP-based ligands at 110 °C, see: Hayashi, T.; Ishigedani,
M. J. Am. Chem. Soc. 2000, 122, 976-977.
(13) Patel, S. J.; Jamison, T. F. Angew. Chem., Int. Ed. 2003, 42, 1364-
1367.
(14) Kuriyama, M.; Soeta, T.; Hao, X. Y.; Chen, O.; Tomioka, K. J.
Am. Chem. Soc. 2004, 126, 8128-8129.
(15) Tokunaga, N.; Otomaru, Y.; Okamoto, K.; Ueyama, K.; Shintani,
R.; Hayashi, T. J. Am. Chem. Soc. 2004, 126, 13584-13585.
(16) Li, S.-W.; Batey, R. A. Chem. Commun. 2004, 1382-1383.
(17) For recent reviews, see: (a) Zhou, P.; Chen, B.-C.; Davis F. A.
Tetrahedron 2004, 60, 8003-8030. (b) Ellman, J. A.; Owens, T. D.; Tang,
T. P. Acc. Chem. Res. 2002, 35, 984-995.
(18) Naskar, D.; Roy, A.; Seibel, W. L.; Portlock, D. E. Tetrahedron
Lett. 2003, 44, 8865-8868.
A range of substituted aryl-, heteroaryl-, and alkyl-based
N-tert-butanesulfinimines 1 were reacted with p-tolylboronic
acid (2 equiv) under a standard set of conditions (Table 1),
using 5 mol % of Rh(I) catalyst and Et3N (2 equiv) in
(19) For examples of the addition of aryl Grignard and aryllithium
reagents to N-sulfinylimines, see: (a) Liu, G.; Cogan, D. A.; Ellman, J. A.
J. Am. Chem. Soc. 1997, 119, 9913-9914. (b) Cogan, D. A.; Liu, G.;
Ellman, J. A. Tetrahedron 1999, 55, 8883-8904. (c) Davis, F. A.; McCoull,
W. J. Org. Chem. 1999, 64, 3396-3397. (d) Plobeck, N.; Powell, D.
Tetrahedron: Asymmetry 2002, 13, 303-310. (e) Plum, D. A.; Krishna-
murthy, D.; Han, Z.; Wald, S. A.; Senanayake, C. H. Tetrahedron Lett.
2002, 43, 923-926.
(21) N-tert-Butanesulfinyl aldimines are readily synthesized in enan-
tiopure form and in high yields via the condensation of N-tert-butylsulfi-
namide and the corresponding aldehydes. See: (a) Liu, G.; Cogan, D. A.;
Owens, T. D.; Tang, T. P.; Ellman, J. A. J. Org. Chem. 1999, 64, 1278-
1284. (b) Weix, D. J.; Ellman, J. A. Org. Lett. 2003, 5, 1317-1320.
(20) Weix, D. J.; Shi, Y.; Ellman, J. A. J. Am. Chem. Soc. 2005, 127,
1092-1093.
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Org. Lett., Vol. 7, No. 8, 2005

Table 1. Reaction of Sulfinimines 1 with p-tolylboronic Acid
Table 2. Reactions of 1d with Different Arylboronic Acids
a Isolated yields using a standardized set of conditions and reaction times.
believe that the use of triethylamine may serve as a buffer
to prevent protonation of the intermediate Ar1-Rh(I) species,
which occurs under acidic conditions.23 Indeed, Ellman
suggests that slow-addition of the arylboronic acids by
syringe-pump is required to prevent arylboronic acid-
catalyzed protonation.20 Finally, we believe the choice of a
cationic Rh(I) catalyst precursor, using the conditions
described herein, may lead to a more active catalyst system,
either due to enhanced transmetalation ability by the Rh(I)-
OH species or due to the greater reactivity of the Ar1-Rh(I)
species in the addition step.
The major diastereoisomers of the adducts obtained in
these additions are consistent with addition of the aryl-
rhodium species to 1 via a nonchelated transition state, as
has been proposed for the addition of organolithium re-
agents.17,19 The chiral auxiliary of the sulfinamide products
4/5 is readily removed under acidic methanolysis conditions
at room temperature. For example, sulfinamides 5a, 4f, and
4h were deprotected in 76%, 86%, and 70% yields, respec-
tively, to afford the amines as their HCl salts 6, with no
detectable loss of enantiopurity.
a Isolated yields using a standardized set of conditions and reaction times.
b The reaction was warmed from 0 °C to room temperature over 1 h. c 3
equiv of the boronic acid was used.
dioxane/water (1:2) at room temperature for 2 h. The
diastereoselectivities of the adducts were generally high (83-
98% de). The product yields were more variable, with lower
yields being obtained for the alkyl-based products 4i and 4j
and the nitrile and furan compounds 4e and 4h. The effect
of the arylboronic acid was probed using the p-trifluorom-
ethylphenyl substrate 1d under the standard set of conditions
(Table 2). Good stereoselectivities were obtained for a range
of arylboronic acids, including both electron-rich and
electron-poor examples. However, the reaction yields were
sensitive to steric and electronic effects on the boronic acid
(5d and 5e, Table 2).
The reaction conditions outlined in this paper differ
considerably from those employed by Ellman, and it is
appropriate to comment on the differences. The importance
of water under our conditions is consistent with a mechanism
in which the arylboronic acid Ar1B(OH)2 undergoes trans-
metalation with the catalyst to an Ar1-Rh(I) species. This
then undergoes insertion (addition) with 1 to produce an
(Ar1R2HC)(SOtBu)N-Rh(I) intermediate. In the presence of
water, hydrolysis of this species would give the product (e.g.,
3) and regenerate the active Rh(I)-OH species required for
transmetalation.22 In the absence of water, either â-hydride
elimination or deoxygenation/proton loss would give 2. We
In addition to boronic acids, other boronic acid equivalents
also undergo reaction (Table 3). Under the standard condi-
tions, phenylpinacol boronate ester, phenylisopropyl boronate
(22) A similar mechanism has been demonstrated for the case of Rh-
(I)-catalyzed addition of phenylboronic acids to enones; see: Hayashi, T.;
Takahashi, M.; Takaya, Y.; Ogasawara, M. J. Am. Chem. Soc. 2002, 126,
5052-5058.
(23) (a) Keim, W. J. Organomet. Chem. 1968, 14, 179-184. (b) Boyd,
S. E.; Field, L. D.; Hambley, T. W.; Partridge, M. G., Organometallics
1993, 12, 1720-1724.
Org. Lett., Vol. 7, No. 8, 2005
1483

Scheme 2. Formal Synthesis of (S)-Cetirizine
Table 3. Reactions of 1d with Different Phenylboron
Derivatives to Form 5a
a Isolated yields using a standardized set of conditions and reaction times.
ester and phenyl potassium trifluoroborate salt all reacted
with 1d to give 4d in diastereoselectivities comparable to
that of phenylboronic acid.
by Ellman and co-workers, occurring over 2 h at room
temperature, without the need for the addition of an external
phosphine ligand or syringe pump addition of the arylboronic
acids. This feature may prove advantageous, as for example
in parallel synthesis applications.
This Rh(I)-catalyzed method was applied in a formal
synthesis of 6d, which is useful as a precursor for (S)-
cetirizine (Scheme 2).19e,24 Sulfinimine 1c was reacted with
phenylboronic acid in the presence of the Rh(I) catalyst to
afford 7 in 83% yield and 90% de. The chiral auxiliary was
then cleaved under acidic conditions to give product 6d in
95% yield and 90% de.
In conclusion, rhodium-catalyzed diastereoselective addi-
tions of arylboron compounds to N-sulfinylimines have been
demonstrated. The sufinamide adducts are obtained with high
diastereoselectivities and provide ready access to enantio-
merically enriched diarylmethylamines. The reactions pro-
ceed under milder conditions than those recently outlined
Acknowledgment. This work was supported by the
Natural Science and Engineering Research Council (NSERC)
of Canada, the Ontario Research and Development Fund
(ORDCF), and Merck-Frosst. We also thank Dr. Alex Young
for mass spectral analysis.
Supporting Information Available: Experimental details
and characterization data. This material is available free of
charge via the Internet at http://pubs.acs.org.
(24) The racemic version of cetirizine is a histamine H1-receptor
antagonist, and is used to treat the symptoms of allergic rhinitis. (R)-
Cetirizine (levocetirizine) is known to bind with twice the affinity of racemic
cetirizine to the human H1-receptor; see: Gillard, M.; Van Der Perren, C.;
Moguilevsky, N.; Massingham, R.; Chatelain, P. Mol. Pharmacol. 2002,
61, 391-399.
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Org. Lett., Vol. 7, No. 8, 2005