Rhodium-catalyzed regioselective amination of secondary allylic trichloroacetimidates with unactivated aromatic amines

Article abstract of DOI:10.1021/ol1019025

The use of unactivated aromatic amines in the rhodium-catalyzed regioselective amination of secondary allylic trichloroacetimidates is explored. The desired N-arylamines are obtained in high yields and regioselectivity, favoring the branched amination pro

Full text of DOI:10.1021/ol1019025

ORGANIC
LETTERS
2010
Vol. 12, No. 20
4580-4583
Rhodium-Catalyzed Regioselective
Amination of Secondary Allylic
Trichloroacetimidates with Unactivated
Aromatic Amines
Jeffrey S. Arnold, Robert F. Stone, and Hien M. Nguyen*
Department of Chemistry, UniVersity of Iowa, Iowa City, Iowa 52242, United States
hien-nguyen@uiowa.edu
Received August 12, 2010
ABSTRACT
The use of unactivated aromatic amines in the rhodium-catalyzed regioselective amination of secondary allylic trichloroacetimidates is explored.
The desired N-arylamines are obtained in high yields and regioselectivity, favoring the branched amination products. The presence of the
trichloroacetimidate leaving group was found to be critical for successful regioselective amination reactions with unactivated aromatic amines.
Control studies show that rhodium is not simply acting as a Lewis acid to activate the trichloroacetimidate leaving group.
Allylic N-arylamines are important structural motifs found
in a variety of biologically important natural and unnatural
products.1 Recently, several approaches to the preparation
of N-arylamines have been investigated with allylic carbon-
ates and acetates employing transition metal catalysts.2 The
use of palladium catalysts in allylic amination of unsym-
metrical allylic acetates with anilines tends to favor the
thermodynamic linear product.2c The kinetically branched
isomer, however, can be formed as the major product when
DBU is employed to suppress product isomerization.2c The
Hartwig group has recently reported an elegant strategy for
accessing branched N-arylamines with excellent regio- and
enantioselectivity via iridium-catalyzed amination of allylic
carbonates with unactivated anilines.2b This method, how-
ever, does not work well with acyclic secondary aromatic
amines. The rhodium method reported by Evans is limited
to activating and stabilized anionic anilines.2a When neutral
aromatic amines without an activating group on the nitrogen
atom were employed as nucleophiles, the branched N-ary-
lamines were isolated in modest yields and regioselectivity.3
Given our recent interest in transition-metal-catalyzed
reaction methodologies with secondary allylic and glycosyl
trichloroacetimidate substrates in carbohydrate synthesis,4 we
investigated a new strategy for the synthesis of N-arylamines
2 employing allylic trichloroacetimidates 1 and neutral
aromatic amines (Figure 1).5 A potential problem in this
(1) (a) Glasby, J. S. Encyclopedia of the Alkaloids; Plenum: New York,
NY, 1975; Vol. 1-5. (b) Johannsen, M.; Jorgensen, K. A. Chem. ReV. 1998,
98, 1689. (c) Trost, B. M.; Crawley, M. L. Chem. ReV. 2003, 103, 2921.
(2) (a) Evans, P. A.; Robinson, J. E.; Moffett, K. K. Org. Lett. 2001, 3,
3269. (b) Shu, C.; Leitner, A.; Hartwig, J. F. Angew. Chem., Int. Ed. 2004,
43, 4797. (c) Dubovyk, I.; Watson, I. D. G.; Yudin, A. K. J. Am. Chem.
Soc. 2007, 129, 14172. (d) Takeuchi, R.; Ue, N.; Tanabe, I.; Yamashita,
K.; Shiga, N. J. Am. Chem. Soc. 2001, 123, 9525.
Figure 1. Rh-catalyzed regioselective amination of allylic trichlo-
roacetimidates.
approach is that imidates 1 could undergo the Overman
rearrangement to the corresponding products 3.6 Herein, we
10.1021/ol1019025  2010 American Chemical Society
Published on Web 09/15/2010

report a complementary rhodium-catalyzed regioselective
amination of secondary allylic trichloroacetimidates 1. In
contrast to other known methods,2a,b our reaction conditions
are feasible with acyclic secondary anilines and R-substituted
allylic substrates.
product in poor yield and with 10:1 regioselectivity.3 Under
iridium conditions, reaction of allylic carbonate with 13a
provided the products with 13:1 regioselectivity.2d
With the initial optimal conditions in hand, a variety of
aniline derivatives 13a-f were investigated with allylic
trichloroacetimidates 4-6 (Table 2). The branched N-
The Rh-catalyzed regioselective amination reaction was
optimized by changing the reaction parameters (Table 1).
Table 2. Rh-Catalyzed Amination with Anilines 13a-f
Table 1. Optimization of Rh-Catalyzed Amination of Allylic
Trichloroacetimidate 4 with Aniline 13a
Rh
P(OR)3 time
14/15
entry
Rh source
(mol %) P(OR)3 (mol %) (h) yielda ratiob
1
2
3
4
5
6
7
8
RhCl(PPh3)3
[RhCl(cyclooct)2]2
[RhCl(COD)2]2
[RhCl(ethylene)2]2
[RhCl(ethylene)2]2
[RhCl(ethylene)2]2
[RhCl(ethylene)2]2
[RhCl(ethylene)2]2
10
5
5
5
5
5
2
1
P(OMe)3
P(OMe)3
P(OMe)3
P(OMe)3
P(OiPr)3
P(OPh)3
P(OPh)3
P(OPh)3
20
20
20
20
20
20
8
24
24
24
7
13%
37%
39%
84%
23%
5:1
4:1
41:1
65:1
10:1
24
0.5 95% >99:1
0.5 95% >99:1
0.5 96% >99:1
4
a Reported based on GC purity of isolated products. b The ratio was
determined by GC in the crude reaction mixture.
Utilizing 10 mol % of Wilkinson’s catalyst modified with
trimethyl phosphite ligand (20 mol %)3 in the presence of
aniline nucleophile 13a (3 equiv) at 40 °C provided the
corresponding N-arylamines 14a and 15a in a combined 13%
yield, with 5:1 regioselectivity favoring the branched product
14a (entry 1). The branched product 14a was obtained in
higher yield and regioselectivity (65:1) in the presence of 5
mol % of [RhCl(ethylene)2]2 and 20 mol % of P(OMe)3
(entry 4). The use of a more sterically hindered ligand,
P(OiPr)3, was detrimental to the reaction (entry 5), while
use of a more electron-withdrawing ligand, P(OPh)3,7
significantly shortened the reaction time and improved both
the yield (84% f 95%) and regioselectivity (65:1 f 99:1)
(entry 6). Lowering the metal and ligand loadings further
did not diminish the yield or the regioselectivity (entries 7
and 8). Compared to other systems, this chemistry provides
the branched product such as 14a with higher regioselectivity.
For instance, reaction of allylic carbonate with 13a in the
presence of Wilkinson’s catalyst provided the branched
a Reported based on GC purity of isolated products. b The ratio was
determined by GC in the crude reaction mixture. c 5 mol % Rh and 20 mol
% P(OPh)3 at room temperature.
arylamines 14, 16, and 17 were obtained in good yield and
with excellent regioselectivity. Importantly, the Overman
rearrangement products 3 (Figure 1) were not observed in
these reactions. The observed reaction time for electron-
rich aniline 13c was longer than more electron-deficient
nucleophiles in the allylic amination reaction (entry 2).
This is likely due to the binding of rhodium metal to both
the nitrogen and oxygen groups of the product 14c,
resulting in slow turnover rates of the rhodium catalyst.
The current method is also feasible with sterically hindered
anilines 13d-f (entries 4-6). Reaction of 4 with second-
ary aniline 13f provided the N-arylamine 14f with 60:1
regioselectivity (entry 6). Under iridium conditions,2b
reaction of allylic carbonates with secondary anilines such
as 13f provided the products with poor regioselectivities
(1:1 f 4:1).
(3) Evans, P. A.; Robinson, J. E.; Nelson, J. D. J. Am. Chem. Soc. 1999,
121, 6761.
(4) (a) Mercer, G. J.; Yang, J.; McKay, M. J.; Nguyen, H. M. J. Am.
Chem. Soc. 2008, 130, 11210. (b) Yang, J.; Cooper-Vanosdell, C.; Mensah,
E. A.; Nguyen, H. M. J. Org. Chem. 2008, 73, 794. (c) Mensah, E. A.;
Nguyen, H. M. J. Am. Chem. Soc. 2009, 131, 8778.
(5) Fagnou, K.; Lautens, M. Org. Lett. 2000, 2, 2319.
(6) (a) Overman, L. E. J. Am. Chem. Soc. 1974, 96, 597. For a
comprehensive review, see: (b) Overaman, L. E.; Carpenter, N. E. In
Organic Reactions; Overman, L. E., Ed.; Wiley-VCH: Weiheim, 2005; Vol.
66, pp 1-107.
(7) Tolman, C. A. Chem. ReV. 1977, 77, 313.
Org. Lett., Vol. 12, No. 20, 2010
4581

The Rh-catalyzed regioselective allylic amination also
works well with ꢀ-substituted allylic trichloroacetimidates
7-9 (Table 3). In the presence of anilines 13a-f, the desired
trichloroacetimidates 10-12 with anilines 13a-d in the
presence of 5 mol % [RhCl(ethylene)2]2 and 20 mol %
P(OPh)3 at 25 °C provided the branched products 21-23 as
the major isomers (Table 4). The regioselectivity decreased
Table 3. Rh-Catalyzed Regioselective Amination of
ꢀ-Substituted Allylic Trichloroacetimidates 7-9
Table 4. Rh-Catalyzed Regioselective Amination of
R-Substituted Allylic Trichloroacetimidates 10-12
a Reported based on GC purity of isolated products. b The ratio was
determined by GC in the crude reaction mixture.
as the aniline became more sterically hindered (entry 4).
Under the Wilkinson catalyst modified with trimethyl phos-
phite conditions, reaction of the isopropyl allylic carbonate
derivative of 11 with TolNLi(Mbs) provided the linear
product as the major isomer.2a
a Reported based on GC purity of isolated products. b The ratio was
determined by GC in the crude reaction mixture. c 5 mol % Rh and 20 mol
% P(OPh)3 at room temperature.
Trichloroacetimidate is among the most widely used
anomeric leaving groups in carbohydrate chemistry,8 and it
is generally activated with strong and moisture-sensitive
Lewis acids such as BF3-OEt2,9 TMSOTf,10 TBSOTf,11 and
Tf2O.12 To determine if rhodium acts as a Lewis acid to
activate the trichloroacetimidate group, we investigated
reaction of secondary trichloroacetimidate 4 with aniline 13a
in the presence of 2 mol % of BF3-OEt2 at 40 °C (Scheme
1). At 15 h, GC analysis showed that the reaction reached
products 18-20 were formed with excellent regioselectivity
(entries 1-6). As expected, reaction of 7 and 8, containing
the OTBS and OBn at the ꢀ-position, provided the products
18c and 19c in much lower yields (entry 3). These results
are consistent with what had been observed with substrate 4
(Table 2). Reaction of ꢀ-phenyl allylic trichloroacetimidate
9 with sterically demanding anilines 13e,f required higher
catalyst loading (entries 5 and 6). Overall, our reaction is
more regioselective than other systems.2a For instance,
reaction of the allylic carbonate derivative of 7 with
TolNLi(Mbs) provided the amination product with 23:1
regioselectivity. Similarly, reaction of allylic carbonate
derivatives of 8 and 9 provided the amination products with
regioselectivity of 8:1 and 20:1, respectively.
(8) (a) Schmidt, R. R.; Kinzy, W. AdV. Carbohydr. Chem. Biochem.
1994, 50, 21. (b) Schmidt, R. R.; Jung, K.-H. Carbohydr. Chem. Biochem.
2000, 5. (c) Zhu, X.; Schmidt, R. R. Angew. Chem., Int. Ed. 2009, 48,
1900.
(9) (a) Schmidt, R. R.; Michel, J. J. Carbohydr. Chem. 1985, 4, 141.
(b) Zimmermann, P.; Bommer, R.; Ba¨r, T.; Schmidt, R. R. J. Carbohydr.
Chem. 1988, 7, 435.
(10) (a) Schmidt, R. R.; Behrendt, M.; Toepfer, A. Synlett 1990, 694.
(b) Paulsen, H.; Wilkens, R.; Reck, F.; Brockhausen, I. Liebigs. Ann. Chem.
1992, 1303. (c) Kulkarni, S. S.; Hung, S.-C. Lett. Org. Chem. 2005, 2,
670.
Allylic carbonates containing substituents at the R-position
with respect to the carbonate leaving group are known to be
challenging substrates, and they often provide amination
products with poor regioselectivity in favor of linear
products.2a We found that reactions of R-substituted allylic
(11) Haase, W. C.; Seeberger, P. H. Curr. Org. Chem. 2000, 4, 481.
(12) Dobarro-Rodriguez, A.; Trumtel, M.; Wessel, H. P. J. Carbohydr.
Chem. 1992, 11, 255.
4582
Org. Lett., Vol. 12, No. 20, 2010

product 26 was obtained in 90% yield (branched/linear >99:
1) with less than 7% ee. This experiment indicates that the
amination reaction proceeds with a significant amount of
racemization. Furthermore, this result implies that our
rhodium-catalyzed amination reaction with allylic trichlo-
roacetimidates is completely different from other systems
such as palladium,16 molybdenum,17 iridium,18 ruthenium,19
and rhodium with allylic carbonates and activated anilines,3
whose reactions have been established to proceed with the
conservation of stereochemistry in the products.
Scheme 1. BF3-OEt2-Promoted Allylic Amination Reaction
99% conversion with a 1:1 mixture of the branched product
14a and the linear product 15a.13 This result provides evidence
that the rhodium catalyst does not act as a Lewis acid.
To compare the reactivity and efficiency of the allylic
trichloroacetimidate with the commonly used allylic acetate
and carbonate under our conditions, reactions of allylic
methyl carbonate 24 and acetate 25 were attempted with
aniline 13a (Scheme 2). The amination products were not
In summary, a rhodium-phosphite complex is found to
be an efficient catalyst for the regioselective amination of
secondary allylic trichloroacetimidates with unactivated,
neutral primary and secondary anilines to provide N-
arylamines in high yield and with excellent regioselectivity,
favoring the branched products. Our allylic amination
reaction is also applicable with acyclic secondary aniline and
R-substituted allylic trichloroacetimidates to provide the
amination products with high regioselectivity. Distinct from
other amination methods where the reaction proceeds with
overall retention, our reaction proceeds with a significant
amount of racemization. Overall, these unique features make
our rhodium-catalyzed amination reaction of secondary
allylic trichloroacetimidates a useful method for the develop-
ment of enantioselective reactions. The mechanistic studies
of this allylic amination reaction are underway.
Scheme 2
.
Control Experiments with Allylic Carbonate 23 and
Acetate 24
Acknowledgment. We thank the University of Iowa for
finanical support and Prof. Tom Livinghouse at Montana
State for helpful discussions.
observed in these control experiments even if the reactions
had been stirring at 40 °C for 12 h, suggesting that both
allylic carbonate 24 and acetate 25 were less reactive than
secondary allylic trichloroacetimidate 4.14
To clarify the stereochemical outcome of the rhodium-
catalyzed amination with allylic trichloroacetimidate and gain
insight into the possible mechanism of the reaction, the
enantiomerically enriched allylic trichloroacetimidate 715 was
subjected to our rhodium reactions in the presence of
4-trifluoromethylaniline 13h (Scheme 3). The branched
Supporting Information Available: Experimental pro-
cedure and full compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL1019025
(13) Amination reactions of both primary (E)- and (Z)-allylic trichlo-
roacetimidates proceeded to completion within 6 h with use of 2 mol %
BF3-OEt2, and the linear product was obtained as the major isomer.
(14) We also performed the control experiments with both primary (E)-
and (Z)-allylic trichloroacetimidates. The amination products were not
observed with use of 1 mol % [Rh(ethylene)2Cl]2 and 4 mol % P(OPh)3.
(15) Davoille, R. J.; Rutherford, D. T.; Christie, S. D. R. Tetrahedron.
Lett. 2000, 41, 1225.
Scheme 3
. Rh-Catalyzed Amination of Enantiomerically
Enriched Allylic Trichloroacetimidate 7
(16) Trost, B, M.; Verhoeven, T. R. J. Am. Chem. Soc. 1980, 102, 4730.
(17) (a) Trost, B. M.; Lautens, M. J. Am. Chem. Soc. 1987, 109, 1469.
(b) Trost, B. M.; Merlic, C. A. J. Am. Chem. Soc. 1990, 112, 9590.
(18) (a) Takeuchi, R.; Kashio, M. J. Am. Chem. Soc. 1998, 120, 8647.
(b) Stanley, L. M.; Bai, C.; Ueda, M.; Hartwig, J. F. J. Am. Chem. Soc.
2010, 132, 8918.
(19) Trost, B. M.; Fraisse, P. L.; Ball, Z. T. Angew. Chem., Int. Ed.
2002, 41, 1059.
Org. Lett., Vol. 12, No. 20, 2010
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