Diastereoselective and enantioselective Rh(I)-catalyzed additions of arylboronic acids to N-tert-butanesulfinyl and N-diphenylphosphinoyl aldimines

Article abstract of DOI:10.1021/ja044003d

Two new Rh(I)-catalyzed methods for the synthesis of chiral α-branched amines via addition of arylboronic acids to N-tert-butanesulfinyl and N-diphenylphosphinoyl imines have been developed. The syntheses are more functional group tolerant than alternativ

Full text of DOI:10.1021/ja044003d

Published on Web 01/07/2005
Diastereoselective and Enantioselective Rh(I)-Catalyzed Additions of
Arylboronic Acids to N-tert-Butanesulfinyl and N-Diphenylphosphinoyl
Aldimines
Daniel J. Weix, Yili Shi, and Jonathan A. Ellman*
Center for New Directions in Organic Synthesis, Department of Chemistry, UniVersity of California,
Berkeley, California 94720
Received October 1, 2004; E-mail: jellman@uclink.berkeley.edu
Table 1. Catalyst Optimization
Chiral, R-branched amines are prevalent, essential components
of many drugs and drug candidates, and therefore, general methods
for their asymmetric synthesis are of considerable importance. The
stereoselective addition of organometallic reagents to imines repre-
sents one of the most convergent and efficient approaches,1 and
the diastereoselective addition of Grignard and lithium reagents to
N-tert-butanesulfinyl imines has proven to be a particularly reliable
No.
[Rh]
L
conv. (%)a
dr
and popular method.2 However, despite recent advances in the
synthesis of functionalized Grignard and organolithium reagents,3
a more functional group tolerant method remains highly desirable.
Arylboronic acids are extremely useful organometallic reagents
because they are stable compounds that can easily be prepared
displaying a wide array of functionality, and large numbers are
commercially available. Although arylboronic acids are poor
nucleophiles, rhodium(I) phosphine complexes have been found
to efficiently catalyze their addition to N-arenesulfonyl imines.4,5
Recently, good to excellent enantioselectivities have been reported
with chiral ligands.4b,c However, these methods are limited to aryl
aldimines, and the p-toluenesulfonyl-protecting group could only
be cleaved using a large excess of the costly, high molecular weight
reagent, SmI2. The cleavage conditions led to significant hydro-
dehalogenation of the 4-chlorobenzhydrylamine product.
We report here the highly diastereoselective addition of arylbo-
ronic acids to both aromatic and aliphatic N-tert-butanesulfinyl
imines as well as the initial disclosure of the highly enantioselective
addition of arylboronic acids to N-diphenylphosphinoyl benzaldi-
mine. Importantly, both the N-tert-butanesulfinyl group and the
N-diphenylphosphinoyl group can be cleaved under mildly acidic
conditions that tolerate even sensitive functionality.2,6
1b
2
3
4
5
6
7
8
9
[Rh(cod)(MeCN)2]BF4
[Rh(cod)(MeCN)2]SbF6
[Rh(cod)2]SbF6
Rh(acac)(coe)2
Rh(acac)(coe)2
Rh(acac)(coe)2
Rh(acac)(coe)2
Rh(acac)(coe)2
Rh(acac)(coe)2
Rh(acac)(coe)2
Rh(acac)(coe)2
Rh(acac)(coe)2
Rh(acac)(coe)2
-
-
-
25c
5
11
11
42
18
7
91:9
93:7
92:8
92:8
96:4
98:2
96:4
96:4
96:4
97:3
96:4
96:4
97:3
dppm
dppe
dppp
dppb
dppf
2
dppbenz
dppbenz
dppbenz
dppbenz
dppbenz
65
58
45
69
65
10d
11e
12f
13g
a Conversion and dr determined by HPLC. b Reaction performed with 3
mol % rhodium. c Isolated yield after chromatography. d Reaction run at
0.5 M in imine. e Reaction run at 1.0 M in imine. f Reaction run at 0.13 M
in imine. g Reaction run with 5 equiv of phenylboronic acid.
Table 2. Substrate Scope
While various cationic rhodium complexes catalyzed the addition
of phenylboronic acid (PBA) to N-sulfinyl imine 1a with promising
levels of diastereoselectivity (Table 1, entries 1-3), the initial low
conversions could not be improved upon.7 In contrast, Rh(acac)-
(coe)2-catalyzed reactions were accelerated by the presence of bis-
phosphines with a two-carbon backbone and gave high diastereosel-
ectivities (entries 4-9). 1,2-Bis(diphenylphosphino)benzene (dpp-
benz) formed the most active catalyst by a large margin (entry 9).
The reaction concentration was varied to further improve the
yield, but higher concentrations resulted in lower conversions (Table
1, entries 10 and 11), while a lower concentration gave a modest
increase in conversion (entry 12). Moreover, increasing the number
of equivalents of PBA also did not improve the yield (entry 13).
No.a
R1
R2
yield (%)b
dr
1
2
3
4
5
6
7
8
4-methylphenyl
2-phenylethyl
2-phenylethyl
2-phenylethyl
2-phenylethyl
phenyl
phenyl (3a)
phenyl (3a)
96
86
70
73
80
76
71
93
97:3
96:4
96:4
96:4
98:2
98:2
98:2
99:1
4-methoxyphenyl (3b)
4-(CF3)phenyl (3c)
3-acetylphenyl (3d)
4-methoxyphenyl (3b)
4-(CF3)phenyl (3c)
4-chlorophenyl (3e)
phenyl
phenyl
a See Supporting Information for reaction details, dr determination, and
assignment of configuration. b Isolated yields after chromatography.
addition should only be dependent upon [PBA]. Slow addition of
PBA should maintain low concentrations of PBA and, therefore,
should favor imine addition to provide significantly higher product
yields.
We were gratified to find that when PBA in dioxane was added
over 6 h, addition product 2a was obtained in 96% yield with high
diastereoselectivity (Table 2, entry 1). Notably, the method provides
the first rhodium(I)-catalyzed addition of arylboronic acids to
aliphatic imines (entries 2-5). The successful addition of 3-acetylphe-
1
By following the reaction by H NMR, we observed that benzene
formation was competitive with imine addition, perhaps explaining
the effects of concentration and boronic acid stoichiometry. Rh-
(I)-phenyl species can be decomposed by acids via a protonation
and reductive elimination mechanism that generates benzene.8 If
this is the operative mechanism for the side reaction that produces
benzene, with PBA serving as the acid, then the rate of benzene
formation should be dependent on [PBA]2 while the desired imine
9
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J. AM. CHEM. SOC. 2005, 127, 1092-1093
10.1021/ja044003d CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. One-Pot Conversion of Aldehydes to Amines
In summary, two new, highly practical methods for the asym-
metric synthesis of R-branched amines have been developed. The
addition of arylboronic acids to both aliphatic and aromatic
N-sulfinyl imines proceeds with very high dr, and imine synthesis
and arylboronic acid addition can be accomplished in one pot. The
enantioselective addition of arylboronic acids to N-diphenylphos-
phinoyl imine 4 also proceeded with high enantioselectivity and
yield. Further determination of the scope and generality of these
methods is ongoing.
Table 3. Catalytic Enantioselective Reaction
Acknowledgment. This work was supported by the NSF
CHE0446173. The Center for New Directions in Organic Synthesis
is supported by Bristol-Myers Squibb as a sponsoring member and
Novartis as a supporting member.
No.a
chiral ligand
3
yield (%)b
ee (%)
configuration
Supporting Information Available: Experimental procedures and
characterization data. This material is available free of charge via the
Internet at http://pubs.acs.org.
1c
dppbenz
(R)-tol-BINAP
(R)-PROPHOS
3e
3e
3e
3e
3e
3e
3e
3e
3d
3c
3b
99
89
35
86
37
45
46
97
93
87
93
-
32
65
60
75
90
96
94
88
88
93
(
R
R
R
S
2c
3
4c
(R,R)-i-Pr-DUPHOS
(S,S)-NORPHOS
(R,R)-Et-BPE
(R,R)-DeguPHOS
(R,R)-DeguPHOS
(R,R)-DeguPHOS
(R,R)-DeguPHOS
(R,R)-DeguPHOS
5
6
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a See Supporting Information for reaction details, ee determination, and
assignment of configuration. b Isolated yields after chromatography. c Re-
actions were run at 70 °C. d Reaction run with 3 equiv of 3 added over 20
h.13 e Configuration assigned by analogy.
nylboronic acid demonstrates the promising functional group
tolerance of the reaction (entry 5).5 Moreover, both arylboronic acids
with electron-donating (entries 3 and 6) and -withdrawing (entries
4, 7, and 8) substituents add effectively.
To enhance the efficiency of the method, a one-pot procedure
for the asymmetric synthesis of 2 from the starting aldehyde was
developed. Condensation of hydrocinnamaldehyde with tert-bu-
tanesulfinamide in the presence of Ti(i-Pr-O)4 in dioxane, followed
by addition of catalyst and then slow addition of 3d, directly
provided 2 (R1 ) 2-phenylethyl, R2 ) 3-acetylphenyl) with high
diastereoselectivity and in 71% yield (Scheme 1).
We concurrently pursued the catalytic enantioselective addition
of arylboronic acids to achiral imines. The diphenylphosphinoyl
group is one of the most desirable of the available achiral imine
activating groups because it is easily cleaved from the addition
products.1b,6 When the optimal conditions for additions to tert-
butanesulfinyl imines were applied to diphenylphosphinoyl imine
4, only imine hydrolysis was observed. However, when the reaction
was performed in the presence of activated, powdered MS 3 Å
and 1 equiv of Et3N, a quantitative yield of racemic product 5 could
be obtained (Table 3, entry 1).9,10 A screen of a wide variety of
chiral bisphosphines revealed that acceptable conversions were only
observed for bisphosphines with a two-atom backbone or a
binaphthyl backbone, which is consistent with the additions to
N-tert-butanesulfinyl imines.11 Most importantly, the bisphosphine
(+)-(3R,4R)-bis(diphenylphosphino)-1-benzylpyrrolidine ((R,R)-
DeguPHOS)12 provided 5 in near quantitative yield and with very
high enantioselectivity (entry 8). The addition of electron-rich and
-poor as well as functionalized arylboronic acids also proceeded
with good yields and selectivities (entries 9-11). The diphe-
nylphosphinoyl group was also easily cleaved using HCl/MeOH
to afford the pure amine hydrochloride in 95% yield with little to
no loss in stereochemical purity.7
(5) Rhodium-catalyzed additions of arylboronic acids to aldehydes and R,â-
unsaturated ketones proceed with a high level of functional group
compatibility. (a) Hayashi, T.; Yamasaki, K. Chem. ReV. 2003, 103, 2829-
2844. (b) Fagnou, K.; Lautens, M. Chem. ReV. 2003, 103, 169-196.
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(7) See Supporting Information for details and complete tables of results.
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Field, L. D.; Hambley, T. W.; Partridge, M. G. Organometallics 1993,
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(9) Under these conditions, the arylboronic acid may form boroxime-Et3N
complexes, which may transmetalate more rapidly. See: McKinley, N.
F.; O’Shea, D. F. J. Org. Chem. 2004, 69, 5088-5090.
(10) In contrast, MS 3 Å/Et3N did not improve the conversion for addition of
arylboronic acid 3b to N-sulfinyl imine 1 (R1 ) 2-phenylethyl).
(11) Other ligands screened gave very low conversions; for example, PHA-
NEPHOS, DIOP, QUINAP, JOSIPHOS, WALPHOS, MANDYPHOS,
i-Pr-PHOX, Me-BPE.
(12) This ligand is available as “catASium D(R)” from Strem Chemicals, Inc.
and ACBR, GmbH. Nagel, U.; Kinzel, E.; Andrade, J.; Prescher, G. Chem.
Ber. 1986, 119, 3326-2243.
(13) Quantities of 3.6 (ref 4c) to 5.0 (ref 4b) equiv of arylboronic acid are
generally used with N-toluenesulfonyl imine substrates in similar reactions.
JA044003D
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