Rhodium-catalyzed synthesis of branched amines by direct addition of benzamides to imines

Article abstract of DOI:10.1021/ol300723x

Rhodium-catalyzed addition of benzamide C-H bonds to a range of aromatic N-sulfonyl aldimines has been developed and proceeds with high functional group compatibility. The synthetic utility of the resulting branched amine products has also been demonstrated by the preparation of isoindoline and isoindolinone frameworks.

Full text of DOI:10.1021/ol300723x

ORGANIC
LETTERS
2012
Vol. 14, No. 9
2304–2307
Rhodium-Catalyzed Synthesis of
Branched Amines by Direct Addition of
Benzamides to Imines
Kevin D. Hesp,† Robert G. Bergman,*,‡,§ and Jonathan A. Ellman*,†
Department of Chemistry, Yale University, New Haven, Connecticut 06520,
United States, Division of Chemical Sciences, Lawrence Berkeley National Laboratory,
Berkeley, California 94720, United States, and Department of Chemistry, University of
California, Berkeley, California 94720, United States
jonathan.ellman@yale.edu; rbergman@berkeley.edu
Received March 21, 2012
ABSTRACT
Rhodium-catalyzed addition of benzamide CÀH bonds to a range of aromatic N-sulfonyl aldimines has been developed and proceeds with high
functional group compatibility. The synthetic utility of the resulting branched amine products has also been demonstrated by the preparation of
isoindoline and isoindolinone frameworks.
Transition-metal-catalyzed methods for the direct func-
tionalization of CÀH bonds have emerged as powerful
alternatives to more traditional reactions that rely heavily
on stoichiometric substrate preactivation. While signifi-
cant progress has been documented for the addition of sp2
CÀH bonds across alkenes and alkynes,1 the identification
of analogous methods for the arylation of CÀN multiple
bonds, such as imines,2 isocyanates,3 nitriles,4 and
isocyanides,5 have seen considerably less development.
The ability to selectively install nitrogen-based functional
groups into molecules through the direct addition of CÀH
bonds to CÀN π-bonds represents a powerful method for
rapid and convergent amine synthesis.
Recently, the synthesis of R-branched amines by the
Rh(III)-catalyzed addition of 2-arylpyridine CÀH bonds
to N-Boc- and N-sulfonyl imines has been reported.2a,b
While these studies serve as excellent proof-of-principle
models for CÀH additions to CÀN multiple bonds, the
pyridyl directing group is of limited utility for the synthesis
of biologically interesting drugs and natural products.
With this limitation in mind, we have focused our efforts
on expanding the repertoire of directing groups that are
effective for the Rh(III)-catalyzed addition of CÀH bonds
to imines. In particular, we have become interested in the
use of benzamide derivatives as directing groups6;an
† Yale University.
‡ Lawrence Berkeley National Laboratory.
§ University of California, Berkeley.
(1) For recent reviews on CÀH alkenylation/alkynylation, see: (a)
€
Wencel-Delord, J.; Droge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev. 2011,
40, 4740. (b) Satoh, T.; Miura, M. Chem. ÀEur. J. 2010, 16, 11212. (c)
Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624.
(d) Karimi, B.; Behzadnia, H.; Elhamifar, D.; Akhavan, P. F.; Zamani,
A. Synthesis 2010, 1399. (e) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu,
J.-Q. Angew. Chem. Int., Ed. 2009, 48, 5094.
(2) (a) Tsai, A. S; Tauchert, M. E.; Bergman, R. G.; Ellman, J. A.
J. Am. Chem. Soc. 2011, 133, 1248. (b) Li, Y.; Li, B.-J.; Wang, W.-H.;
Huang, W.-P.; Zhang, X.-S.; Chen, K.; Shi, Z.-J. Angew. Chem., Int. Ed.
2011, 50, 2115. (c) Qian, B.; Guo, S.; Shao, J.; Zhu, Q.; Yang, L.; Xia, C.;
Huang, H. J. Am. Chem. Soc. 2010, 132, 3650. (d) Gao, K.; Yoshikai, N.
Chem. Commun. 2012, 48, 4305.
(3) (a) Hesp, K. D.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc.
2011, 133, 11430. (b) Kuninobu, Y.; Tokunaga, Y.; Kawata, A.; Takai,
K. J. Am. Chem. Soc. 2006, 128, 202. (c) Hong, P.; Yamazaki, H.;
Sonogashira, K.; Hagihara, N. Chem. Lett. 1978, 535.
(4) Zhou, C.; Larock, R. C. J. Am. Chem. Soc. 2004, 126, 2302.
(5) Zhu, C.; Xie, W.; Falck, J. R. Chem. ÀEur. J 2011, 17, 12591.
(6) Selected recent examples of the use of benzamides as directing
groups in CÀH addition chemistry: (a) Sharma, S.; Park, E.; Park, J.;
Kim, I. S. Org. Lett. 2012, 14, 906. (b) Patureau, F. W.; Besset, T.;
Glorius, F. Angew. Chem., Int. Ed. 2011, 50, 1064. (c) Du, Y.; Hyster,
T. K.; Rovis, T. Chem. Commun. 2011, 47, 12074. (d) Park, J.; Park, E.;
Kim, A.; Lee, Y.; Chi, K.-W.; Kwak, J. H.; Jung, Y. H.; Kim, I. S. Org.
Lett. 2011, 13, 4390. (e) Yoo, E. J.; Ma, S.; Mei, T.-S.; Chan, K. S. L.; Yu,
J.-Q. J. Am. Chem. Soc. 2011, 133, 7652. (f) Wasa, M.; Worrell, B. T.;
Yu, J.-Q. Angew. Chem., Int. Ed. 2010, 49, 1275. (g) Shibata, Y.; Otake,
Y.; Hirano, M.; Tanaka, K. Org. Lett. 2009, 11, 689.
r
10.1021/ol300723x
Published on Web 04/13/2012
2012 American Chemical Society

important motif that provides rapid access to organic
frameworks that are well-represented in natural products
and drugs. Herein, we report the preparation of R-
branched amines using the Rh(III)-catalyzed, amide-direc-
ted arylation of aromatic N-sulfonyl imines. In addition, we
have demonstrated the utility of these amine products for the
preparation of isoindoline and isoindolinone frameworks.7
Our initial investigations focused on the identification of
a suitable catalyst and reaction conditions for the regiose-
lective coupling of N,N-dimethyl benzamide (1a) with N-
tosyl imine 2a to afford the branched amine product 3a
(Table 1). Although the use of 2.5 mol % of [Cp*RhCl2]2
proved unsuccessful in catalyzing the reaction (entry 1),
employing a mixture of [Cp*RhCl2]2 (2.5 mol %) and
AgSbF6 (5 mol %) in CH2Cl2 at 75 °C provided the desired
adduct 3a in a 30% yield (entry 2). In comparison, the use of
the preformed cationic Rh(III) precursor [Cp*Rh(MeCN)3]-
(SbF6)2 showed negligible catalytic activity (entry 3),
DCE as the reaction solvent led to reactivity similar to that
observed with CH2Cl2 and so DCE was used for all
subsequent optimization studies due to its higher boiling
point (entries 4À6). Further optimization studies showed
that improved yields of 3a could be achieved at higher
concentration and that the stoichiometry of reactants had
no effect on the reaction outcome (entries 7 and 8). In
search of further yield improvements, a series of alternative
halide abstracting reagents were screened in combination
with [Cp*RhCl2]2 for the preparation of 3a (entries 9À12).
From this survey it was observed that the use of the more
noncoordinating tetrakis(pentafluorophenyl)borate9 anion,
in place of SbF6, provided a modest increase in 3a with a
67% 1H NMR yield (entry 12).
The influence of the electronic and steric properties of
the amide directing group on the progress of the CÀH
arylation of imine 2a was next assessed (Table 2). Replace-
ment of the N,N-dimethyl substituents in 1a with more
bulky diethyl (1b) or dibenzyl (1c) groups resulted in a
marked decrease in yield (entries 2 and 3, 40% and <5%,
respectively). In addition, the use of a secondary amide
directing group (1d), in place of the tertiary amide, pro-
vided only trace amine product (entry 4).
Table 1. Catalyst and Reaction Optimization
Table 2. Substrate Scope for Benzamide Directing Groupa
entry
catalyst
solvent concn (M) yieldb (%)
1
[Cp*RhCl2]2
[Cp*RhCl2]2, AgSbF6
CH2Cl2
CH2Cl2
0.2
<5
30
<5
17
<5
32
46
45
33
42
53
67
2
0.2
3
[Cp*Rh(MeCN)3](SbF6)2 CH2Cl2
0.2
4
[Cp*RhCl2]2, AgSbF6
[Cp*RhCl2]2, AgSbF6
[Cp*RhCl2]2, AgSbF6
[Cp*RhCl2]2, AgSbF6
[Cp*RhCl2]2, AgSbF6
[Cp*RhCl2]2, AgOTf
THF
0.2
entry
R
yieldb (%)
5
t-BuOH
DCE
DCE
DCE
DCE
DCE
DCE
0.2
1
2
3
4
5
6
7
8
NMe2 (1a)
NEt2 (1b)
NBn2 (1c)
NHMe (1d)
58
6
0.2
40c
<5c
<5c
19c
34
7
0.75
0.75
0.75
0.75
0.75
0.75
8c
9c
10c [Cp*RhCl2]2, AgBF4
11c [Cp*RhCl2]2, AgNTf2
morpholinyl (1e)
piperidinyl (1f)
12c [Cp*RhCl2]2, AgB(C6F5)4 DCE
pyrrolidinyl (1g)
80
73d
2-methylpyrrolidinyl (1h)
a Conditions: 1a/2a = 2:1, 0.15 mmol scale, 5 mol % of Rh; Rh/Ag =
1
1:2; 75 °C for 20 h. b Determined by H NMR relative to 2,6-dimethox-
a Conditions: 1/2a = 1:1.5, 0.15 mmol scale (0.75 M DCE), 5 mol %
of Rh, Rh/Ag = 1:2, 75 °C for 20 h. b Isolated yield. c Determined by 1H
NMR relative to 2,6-dimethoxytoluene as an internal standard. d Dia-
stereomeric ratio = 1:1.
ytoluene as an internal standard. c 1a/2a = 1:1.5.
which we postulate is due to competitive coordination of
the acetonitrile ligands with the N-tosyl imine to the Cp*Rh
catalyst.8 Although the use of alternative solvents, such as
THF and t-BuOH, provided inferior yields, employing
Given the observed sensitivity of product formation to
the steric profile of the directing group, a series of cyclic
tertiary amides were surveyed (entries 5À8). The use of
both morpholino (1e) and piperidinyl (1f) amides provided
inferior yields of amine product (19% and 34%,
respectively) relative to the N,N-dimethyl amide 1a. In
contrast to these results, the pyrrolidine amide afforded
significant gains in product yield, providing the R-
branched amine product in an 80% isolated yield (entry 7).
In a study by Tanaka and co-workers,6g a similar result
was observed for the amide-directed, Rh(I)-catalyzed
(7) For selected examples of isoindoline/isoindolinone sturctural
motifs in drugs and drug candidates, see: (a) Li, E.; Jiang, L.; Guo, L.;
Zhang, H.; Che, Y. Bioorg. Med. Chem. 2008, 16, 7894. (b) Stuk, T. L.;
Assink, B. K.; Bates, R. C.; Erdman, D. T.; Fedij, V.; Jennings, S. M.;
Lassig, J. A.; Smith, R. J.; Smith, T. L. Org. Process Res. Dev. 2003, 7,
851. (c) Kukkola, P. J.; Bilci, N. A.; Ikler, T.; Savage, P.; Shetty, S. S.;
DelGrande, D.; Jeng, A. Y. Bioord. Med. Chem. Lett. 2001, 11, 1737. (d)
Zhuang, Z.-P.; Kung., M.-P.; Mu, M.; Kung, H. F. J. Med. Chem. 1998,
41, 157.
(8) For a study on the mechanism of the Rh(III)-catalyzed arylation
of 2-phenylpyridine with N-carbamate or N-Ts imines, see: (a) Tauchert,
M. E.; Incarvito, C. D.; Rheingold, A. L.; Bergman, R. G.; Ellman, J. A.
J. Am. Chem. Soc. 2012, 134, 1482. (b) Li, Y.; Zhang, X.-S.; Li, H.;
Wang, W.-H.; Chen, K.; Li, B.-J.; Shi, Z.-J. Chem. Sci. 2012, 3, 1634.
(9) Kuprat, M.; Lehmann, M.; Schulz, A.; Villinger, A. Organome-
tallics 2010, 29, 1421.
Org. Lett., Vol. 14, No. 9, 2012
2305

good to excellent yields, imines with electron-donating
substituents provided only moderate yields (3oÀp). In
addition, aromatic imines with m- and o-fluoro groups
were effective coupling partners under optimized condi-
tions (3qÀr). The 2-thienyl-substituted branched amine
product 3s was isolated in 58% yield from the correspond-
ing heteroaromatic imine substrate.
Scheme 1. Substrate Scopea
Electron-rich or -poor pyrrolidine amides featuring
meta- or para-substitution gave the desired branched
amine products with good to excellent yields (3tÀ3x,
49À85%). Moreover, when meta-substituted amide sub-
strates were used, exclusive reaction at the less-hindered
CÀH site occurred (3wÀx).
The aggregate collection of benzamide and imine sub-
strates investigated also established a high level of func-
tional group compatibility. Only the nitrile group (3m)
resulted in poor yields, presumably due to competitive
coordination to the metal. Otherwise, nitro (3i), ester (3k),
keto (3v), chloro (3n), fluoro (3q), bromo (3w), thienyl (3s),
methoxy (3t), and trifluoromethyl (3u) funtional groups
were all compatible with the reaction conditions.
The product regiochemistry observed for the Rh(III)-
catalyzed addition of benzamide substrates to imines is
most consistent with a Rh-mediated CÀH cleavage step
directedbythe Lewis basic amide group ratherthana more
traditional electrophilic aromatic substitution (EAS) me-
chanism. Specifically, exclusive ortho-functionalization is
observed in all cases, as opposed to the expected meta-
substitution for EAS of a deactivated amide substrate.
To demonstrate the synthetic versatility of the CÀH
addition products, several transformations of 3g were
performed (Scheme 2). Using a previously developed pro-
tocol for the reduction of tertiary amides to the corre-
sponding aldehydes,11 treatment of 3g with Cp2Zr(H)Cl
(Schwartz’s reagent) promoted reduction of the pyrroli-
dine amide to a cyclic aminal intermediate,12 which could
a Conditions: 1/2 = 1:1.5, 0.15 mmol (0.75 M DCE) scale, 5 mol % of
Rh, Rh/Ag = 1:2, 75 °C for 20 h; yields represent isolated material.
b Determined by 1H NMR relative to 2,6-dimethoxytoluene as an
internal standard.
alkenylation of aromatic and R, β-unsaturated CÀH
bonds, where substitution of an N,N-dimethyl amide for
a pyrrolidine amide provided a dramatic reaction rate
enhancement. In entry 8, substitution of the pyrrolidine
amide with rac-2-methylpyrrolidine (1h) afforded the
desired product with activity similar to that observed with
amide 1g; however, negligible diastereoselectivity was
achieved for this transformation.
Scheme 2. Synthetic Transformations of Branched Amine 3g
Having defined a highly effective catalyst system and
reaction conditions for the addition of pyrrolidine benza-
mide 1g to N-tosylimine 2a, we sought to further explore
the reaction scope for pyrrolidine benzamides and a broad
range of aromatic N-sulfonyl imines (Scheme 1). In addi-
tion to the use of N-tosyl imines, the more electronegative
N-nosyl10 protecting group also served as an effective
imine substituent under the standard reaction conditions
providing 3i in a 85% isolated yield. While the use of
electron-deficient aromatic imines possessing nitro (3j),
carbomethoxy (3k), trifluoromethyl (3l), and chloro (3n)
para substituents delivered branched amine products in
be further reduced with NaBH4 in trifluoroacetic acid to
the isoindoline 4 in reasonable overall yield over the two
steps. The isoindolinone 5 was also obtained in excellent
(11) (a) Leighty, M. W.; Spletstoser, J. T.; Georg, G. I.; Umihara, H.;
Fukuyama, T. Org. Synth. 2011, 88, 427. (b) Spletstoser, J. T.; White,
J. M.; Tunoori, A. R.; Georg, G. I. J. Am. Chem. Soc. 2007, 129, 3408.
(12) See the Supporting Information for further details.
(10) Kan, T.; Fukuyama, T. Chem. Commun. 2004, 353.
2306
Org. Lett., Vol. 14, No. 9, 2012

yield by the p-TsOH-mediated transamidation/cyclization
of 3g. Cleavage of the N-Ts protecting group in 5 was
readily achieved by exposure to Na/naphthalene. Further-
more, reduction of insituprepared5 with LiAlH4 provided
access to the corresponding alcohol 7 in 83% yield, which
is poised for further synthetic elaboration.
In summary, mixtures of [Cp*RhCl2]2 and AgB(C6F5)4
have been shown to catalyze the addition of N,N-dialkyl
benzamide CÀH bonds to a variety of aromatic N-sulfonyl
imines to provide branched amine products. The obtained
products were also shown to be easily transformed into
isoindoline and isoindolinone frameworks. Further investi-
gations to extend the reaction scope and illustrate applica-
tions of this process in organic synthesis are underway.
Acknowledgment. This work was supported by NIH
Grant No. GM069559 (to J.A.E.). R.G.B. acknowledges
funding from The Director, Office of Energy Research,
Office of Basic Energy Sciences, Chemical Sciences Divi-
sion, U.S. Department of Energy, under Contract No. DE-
AC02-05CH11231. K.D.H. is grateful to the National
Sciences and Engineering Research Council of Canada
(NSERC) for a postdoctoral fellowship.
Supporting Information Available. Full experimental
details and characterization data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 9, 2012
2307