Synthesis of α,α-disubstituted aryl amines by rhodium-catalyzed amination of tertiary allylic trichloroacetimidates

Article abstract of DOI:10.1021/ol202313y

The rhodium-catalyzed regioselective amination of tertiary allylic trichloroacetimidates with unactivated aromatic amines is a direct and efficient approach to the preparation of α,α-disubstituted allylic aryl amines in good yield and with excellent regio

Full text of DOI:10.1021/ol202313y

ORGANIC
LETTERS
2011
Vol. 13, No. 20
5576–5579
Synthesis of r,r-Disubstituted Aryl
Amines by Rhodium-Catalyzed Amination
of Tertiary Allylic Trichloroacetimidates
Jeffrey S. Arnold, Gregory T. Cizio, and Hien M. Nguyen*
Department of Chemistry, University of Iowa, Iowa City, Iowa 52242, United States
hien-nguyen@uiowa.edu
Received August 25, 2011
ABSTRACT
The rhodium-catalyzed regioselective amination of tertiary allylic trichloroacetimidates with unactivated aromatic amines is a direct and efficient
approach to the preparation of R,R-disubstituted allylic aryl amines in good yield and with excellent regioselectivity. This method is applicable to a
variety of unactivated primary and secondary amines and allows for the preparation of reverse prenylated indoles in two steps.
Amines are present in a wide range of natural products,
pharmaceutically bioactive drug candidates, materials, and
catalysts.1 Consequently, manypracticalandelegant routes
to the synthesis of amine-containing compounds have been
developed.2 In contrast, approaches for preparation of R,R-
disubstituted amines, although important synthetic targets,
are limited.3À5 Transition-metal-catalyzed amination of
allylic carbonates or acetates has been utilized to prepare
R,R-disubstituted allylic amines.6,7,9 Palladium catalysts in
combination with 1,1-dimethyl-1-propenyl acetate and al-
kyl amines selectively favor the thermodynamically formed
linear products.6 The branched products, R,R-disubstituted
amines, can be formed as the major isomer when DBU
(1 equiv) is used to suppress product isomerization. Iridium
catalysis of allylic acetates with alkyl amines also provides
R,R-disubstituted amines in high yield and regioselectivity.7
In both palladium6 and iridium7 methods, only aniline has
been reported as the aryl amine nucleophile.8 Recently, the
iron-catalyzed allylic amination reaction of 1,1-dimethyl-2-
propenyl carbonate was reported to work with para- and
meta-substituted anilines, providing the R,R-disubstituted
allylic aryl amines in good yield and with excellent levels of
regioselectivity.9 Substituents at the ortho position of ani-
line, however, did not result in the desired allylic amine
products.
(1) For review, see: Chiral Amine Synthesis; Nugent, T. C, Ed.; Wiley-
VCH: New York, 2008.
(2) Several representative examples: (a) Brown, S. P.; Goodwin,
N. C.; MacMillan, D. W. C. K. J. Am. Chem. Soc. 2003, 125, 1192.
(b) Ooi, T.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 2003, 125,
5139. (c) Saaby, S.; Bella, M.; Jørgensen, K. A. J. Am. Chem. Soc. 2004,
126, 8120. (d) Kano, T.; Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc.
2006, 128, 2174. (e) Balskus, E. P.; Jacobsen, E. N. J. Am. Chem. Soc.
2006, 128, 6810. (f) Terada, M.; Nakano, M.; Ube, H. J. Am. Chem. Soc.
2006, 128, 16044. (g) Mashiko, T.; Hara, K.; Tanaka, D.; Fujiwara, Y.;
Kumagai, N.; Shbasaki, M. J. Am. Chem. Soc. 2007, 129, 11342.
(h) Clayden, J.; Donnard, M.; Lefrance, J.; Minassi, A.; Tetlow, D. J.
J. Am. Chem. Soc. 2010, 132, 6624. (i) Shibasaki, M.; Kanai, M. Chem.
Rev. 2008, 108, 2853.
(3) For diastereoselective and enantioselective nucleophilic addition
of organometallic reagents to ketimines, see: (a) Spero, D. M.; Kapadia,
S. R. J. Org. Chem. 1997, 62, 5537. (b) Cogan, D. A.; Ellman, J. A. J. Am.
Chem. Soc. 1999, 121, 268. (c) Robak, M. T.; Herbage, M. A.; Ellman,
J. A. Chem. Rev. 2010, 110, 3600. (d) Bloch, R. Chem. Rev. 1998, 98,
1407. (e) Enders, D.; Reinhold, U. Tetrahedron: Asymmetry 1997, 8,
1895. (f) Shintani, R.; Takeda, M.; Tsuji, T.; Hayashi, T. J. Am. Chem.
Soc. 2010, 132, 13168.
(4) (a) Shea, R. G.; Fitzner, J. N.; Fankhauser, J. E.; Spaltenstein, A.;
Carpino, P. A.; Peevey, R. M.; Pratt, D. V.; Tenge, B. J.; Hopkins, P. B.
J. Org. Chem. 1986, 51, 5243.
(5) There is only one example of palladium-catalyzed enantioselec-
tive rearrangement of 3,3-disubstituted allylic trifluoroacetimidates to
form 1,1-disubstituted allylic amines, see: (a) Fischer, D. F.; Xin, Z.-Q.;
Peters, R. Angew. Chem., Int. Ed. 2007, 46, 7704. (b) Fischer, D. F.;
Barakat, A.; Xin, Z.-Q.; Weiss, M. E.; Peters, R. Chem.;Eur. J. 2009,
15, 8722.
We recently reported a rhodium-catalyzed regioselective
amination of secondary allylic trichloroacetimidates with
(6) (a) Watson, I. D. G.; Yudin, A. K. J. Am. Chem. Soc. 2005, 127,
17156. (b) Dubovyk, I.; Watson, I. D. G.; Yudin, A. K. J. Am. Chem.
Soc. 2007, 129, 14172.
(7) Takeuchi, R.; Ue, N.; Tanabe, K.; Yamashita, K.; Shiga, N.
J. Am. Chem. Soc. 2001, 123, 9525.
(8) For recent iridium-catalyzed regio- and enantioselective reaction
of primary allylic carbonates with aryl amines to form R-substituted
allylic aryl amines, see: Shu, C.; Leitner, A.; Hartwig, J. F. Angew.
Chem., Int. Ed. 2004, 43, 4797.
(9) Plietker, B. Angew. Chem., Int. Ed. 2006, 45, 6053.
r
10.1021/ol202313y
Published on Web 09/29/2011
2011 American Chemical Society

Table 1. Optimization Studiesa
loading temp time yieldb 7/8c
Figure 1. Rh-catalyzed regioselective amination of tertiary
allylic trichloroacetimidates.
entry
Rh catalyst
(mol %) (°C)
(h)
(%) Ratio
1
2
3
4
5
6
7
8
9
RhCl(P(OPh)3)3
RhCl(P(OPh)3)3
RhCl(P(OPh)3)3
RhCl(P(OPh-F-4)3)3
[RhCl(COD)]2
2
4
40
40
40
40
40
40
25
25
25
6
45
60
69
86
84
89
87
90
87
14:1
13:1
18:1
31:1
54:1
50:1
62:1
62:1
56:1
unactivated anilines.10,11 Our method is applicable to a
wide range of allylic trichloroacetimidates and aromatic
amines to provide the branched N-arylamines in excellent
yields and regioselectivity. With the success of this method,
we sought to further investigate our rhodium conditions
with tertiary trichloroacetimidates 1 (Figure 1) for the
synthesis of R,R-disubstituted aryl amines 2. An advantage
of using branched allylic imidates such as 1 is that they are
readily prepared from a variety of ketones and a vinyl
Grignard reagent. In addition, the branched substrates
react at a faster rate than their corresponding linear
isomers because they are less hindered at the olefin
unit.10,12 The potential pitfalls to this approach are that
tertiary allylic imidates are prone to undergo Overman
rearrangement13 forming allylic trichloroacetamide 3
(Figure 1) and elimination-forming diene 4 when compared
to their secondary allylic counterparts.
We commenced by investigating the amination reaction
of tertiary allylic trichloroacetimidate 5 with aniline 6a
(Table 1). Under previous conditions,10 R,R-disubstituted
aryl amine 7a was isolated in moderate yield and with 14:1
regioselectivity (entry 1). Increasing the catalyst loading
improved both yield and regioselectivity (entries 2 and 3).
Switching to a more electron-withdrawing phosphite li-
gand (entry 4), P(O-Ph-F-4)3, improved both yield (69%f
86%) and regioselectivity (18:1 f 31:1). Although diene
ligands were inefficient in the rhodium-catalyzed regiose-
lective amination reactions with the secondary allylic
imidates,10 cyclooctadiene (COD) and norbornadiene
(NBD) rhodium dimers efficiently catalyze the allylic
amination of tertiary trichloroacetimidate 5 (entries 5À9)
within 30 min to provide R,R-disubstituted aryl amine 7a in
high yield (84%À90%) and regioselectivity (50:1À62:1).
4
10
10
5
2
2
0.5
0.5
0.5
0.5
0.5
d
[RhCl(NBD)]2
5
d
[RhCl(NBD)]2
5
d
[RhCl(NBD)]2
2.5
d
[RhCl(NBD)]2
1
a All reactions were conducted at 0.2 M in THF with 1 equiv of 5 and
3 equiv of 6a. b Isolated yields. c The ratio of 7 and 8 was determined by
GC in the crude reaction mixture. d NBD = Norbornadiene.
Under these conditions, both rearrangement and elimina-
tion products (e.g., 3 and 4, Figure 1) were not observed.14
Comparedtoother methods, ourapproach provides allylic
aryl amine 7a with higher regioselectivity. For instance,
reaction of allylic acetate with aniline in the presence of
the [(allyl)PdCl]2-P(OEt)3 complex provided 7a with
4:1 regioselectivity.6 In another case, reactions of both
branched and linear allylic alcohols with aniline in the
Pd(acac)2-PPh3 complex provided linear aryl amine 8a
(Table 1) as the major product.15
Withoptimized reaction conditions in place, the scopeof
thisamination wasexaminedwitha widerangeofaromatic
amines 6bÀn (Table 2). Good to excellent yields and
regioselectivities were obtained with both electron-donat-
ing and -withdrawing 4-substituted anilines (entries 1À4).
Allylic aryl amines 6fÀg containing meta-carbonyl func-
tionality also provided R,R-disubstituted allylic amines
7fÀg (entries 5 and 6) in good yield (87% and 84%) and
regioselectivity (b/l = 98:1 and >99:1). The amination
reaction catalyzed by [RhCl(NBD)]2 is very tolerant of
ortho-substitution on the aniline nucleophiles (entries 7
and 8), which did not result in allylic aryl amines under
iron-catalyzed conditions.9 This method is also feasible
with challenging secondary aniline 6j (entry 9), and the
corresponding allylic amine 7j was isolated in 85% yield
and with 15:1 regioselectivity.
(10) Arnold, J. S.; Stone, R. F.; Nguyen, H. M. Org. Lett. 2010, 12,
4580.
(11) For other rhodium conditions with secondary allylic carbonates,
see: (a) Evans, P. A.; Nelson, J. A. Tetrahedron Lett. 1998, 39, 1725.
(b) Evans, P. A.; Robinson, J. E.; Nelson, J. D. J. Am. Chem. Soc. 1999,
121, 6761. (c) Evans, P. A.; Robinson, J. E.; Moffett, K. K. Org. Lett.
2001, 3, 3269.
Next, we broadened the scope and showed that tertiary
allylic imidates 9À12 (Table 3) are suitable substrates
under rhodium reaction conditions, generating R,R-disub-
stituted allylic aryl amines 13À16 in good yields and with
excellent levels of regioselectivity. It is notable that allylic
amination reactions of tertiary imidates 9 and 10 bearing
an oxygen substituent at the β-position generally result in
(12) (a) Bartels, B.; Garcıa-Yebra, C.; Rominger, F.; Helmchen, G.
Eur. J. Org. Chem. 2002, 2569. (b) Fischer, C.; Defieber, C.; Suzuki, T.;
Carreira, E. M. J. Am. Chem. Soc. 2004, 126, 1628.
(13) (a) Overman, L. E. J. Am. Chem. Soc. 1974, 96, 597. (b) For a
comprehensive review, see: Overman, L. E.; Carpenter, N. E. In Organic
Reactions; Overman, L. E., Ed.; WILEY-VCH: Weiheim, 2005; Vol. 66,
pp 1À107.
(14) Tertiary allylic trichloroacetimidate 5 did slowly undergo the
Overman rearrangement to form the undesired trichloroacetamide
product (e.g., 3, Figure 1) upon standing at 25 °C over a period of a
few days.
(15) Yang, S. C.; Hsu, Y. C.; Gan, K. H. Tetrahedron Lett. 2006, 62,
3439–3958.
Org. Lett., Vol. 13, No. 20, 2011
5577

Table 2. Survey of Various Aniline Nucleophilesa
Table 3. Survey of Tertiary Allylic Trichloroacetimidatesa
a All reactions were conducted with 1À5 mol % [RhCl(NBD)]2 at
0.2 M in THF. b Isolated yields. c The b/l ratio was determined by GC.
a All reactions were conducted at 25 °C at 0.2 M in THF with 1 equiv
of allylic imidate and 3 equiv of aniline. b Yields are isolated values. c The
b/l ratio was determined by GC.
higher regioselectivity compared to tertiary imidates 11
and 12, suggesting additional chelation control on the
metal center. This phenomenon is also observed when
comparing the amination reaction of tertiary allylic imi-
date 9 (Table 3, entry 9) with sterically hindered aniline 6j
to that of 1,1-dimethyl-2-propenyl imidate 5 (Table 2,
entry 9), where regioselectivity is 62:1 versus 15:1.
The N-1,1-dimethyl-2-propenyl indoles and derivatives
are structural motifs found in biologically active natural
products.16 These compounds are commonly prepared via
a multistep sequence involving N-propargylation of indo-
line, oxidation to indole, and partial hydrogenation
of alkyne to the alkene.16 Recently, a direct reverse
(16) (a) Li, S.-M. Nat. Prod. Rep. 2010, 27, 57. (b) Baran, P. S.;
Guerrero, C. A.; Corey, E. J. J. Am. Chem. Soc. 2003, 125, 5628.
(c) Sugiyama, H.; Yokokawa, F.; Aoyama, T.; Shioiri, T. Tetrahedron
Lett. 2001, 42, 7277. (d) Sala, G. D.; Capozzo, D.; Izzo, I.; Giordano, A.;
Iommazzo, A.; Spinella, A. Tetrahedron Lett. 2002, 43, 8839.
(e) Sugiyama, H.; Shioiri, T.; Yokokawa, F. Tetrahedron Lett. 2002,
3489. (f) Roe, J. M.; Webster, R. A.; Ganesan, A. Org. Lett. 2003, 2825.
5578
Org. Lett., Vol. 13, No. 20, 2011

Scheme 1. Synthesis of N-Isoprenyl Indoles
Scheme 2. Control Experiments
isoprenylation of indole has been described.17 Transition-
metal-catalyzed ring closure of 2-alkynyl anilines could
potentially provide access to 1,1-disubstituted indoles;18
thus we reasoned that allylic amination of tertiary trichlor-
oacetimidates (Scheme 1) in the presence of 2-
((trimethylsilyl)ethynyl) aniline and subsequent ring
closure would result in an efficient two-step synthesis of
varied reverse prenylated indoles. Accordingly, tertiary
trichloroacetimidates 5, 9, and 10 (Scheme 1) were sub-
jected to optimized amination conditions with aniline 6k
resulting in the allylic aryl amine products 7k, 13k, and
14k, respectively, in good yield (69%À85%) and with
excellent levels of regioselectivity (54:1À90:1). The
branched aryl amine products subsequently cyclized to
the corresponding reverse prenylated indoles 17, 18, and 19
(Scheme 1) in high yield after treatment with CuI at 80 °C
for 15 h.
It has been proposed that palladium coordinates to
both the imidate nitrogen and the double bond of primary
allylic trichloroacetimidates to form the corresponding
palladiumÀolefin complex, which is activated toward the
nucleophilic attack.19 It is envisioned that a complemen-
tary approach would arise from coordination of a rhodium
catalyst to both the nitrogen and the double bond of
tertiary allylic imidate to form the activated rhodiumÀ
olefin complex. Thus, we decided to verify the unique
features of the trichloroacetimidate to potentially act as
both the directing group and the leaving group in allylic
amination reaction by subjecting both allylic carbonate
and acetate 20 and 21 (Scheme 2a) to our reaction condi-
tions. Although the starting materials were completely
consumed, less than 2% yield of amination product 7a
was isolated after 18 h. In another control experiment,
N-phenyl trifluoroacetimidate 22 (Scheme 2b) was sub-
jected to our rhodium conditions which resulted in a 22%
yield of branched allylic amine 7a and 32% of the rear-
rangement product 23. These results demonstrate that the
strongly coordinating nitrogen atom of the trichloroaceti-
midate group to the rhodium catalyst is crucial for efficient
allylic amination. We also performed a control study with
allylic trichloroacetamide 24 (Scheme 2c), which results
from Overman rearrangement,13 to determine if it is an
intermediate in the amination reaction. No allylic amine
products were observed after 18 h.
In summary, we have developed a rhodium-catalyzed
reaction that efficiently facilitates regioselective amination
of tertiary allylic trichloroacetimidates with a variety of
aromatic amines to provide the desired R,R-disubstituted
allylic amines in good yields and with excellent levels
of regioselectivity. Application of the procedure to a
variety of tertiary allylic imidates and amines, exploration
of the possibility of rendering the amination enantioselec-
tive, and mechanistic studies of this rhodium-catalyzed
amination are underway and will be reported in due
course.
(17) Luzung, M. R.; Lewis, C. A.; Baran, P. S. Angew. Chem., Int. Ed.
2009, 121, 7159.
(18) (a) Castro, C. E.; Gaughan, E. J.; Owsley, D. C. J. Org. Chem.
1966, 31, 4071. (b) Sakamoto, T.; Kondo, Y.; Iwashita, S.; Nagano, T.;
Yamanaka, H. Chem. Pharm. Bull. 1988, 36, 4071. (c) Kamijo, S.; Jin, T.;
Yamamoto, Y. Angew. Chem., Int. Ed. 2002, 41, 1780. (d) Kamijo, S.;
Yamamoto, Y. J. Am. Chem. Soc. 2002, 124, 11940. (e) Nair, R. N.; Lee,
P. J.; Rheinhold, A. L.; Grotjahn, D. B. Chem.;Eur. J. 2010, 16, 7992.
(19) (a) Kirsch, S. F.; Overman, L. E. J. Am. Chem. Soc. 2005, 127,
2866. (b) Kirsch, S. F.; Overman, L. E.; White, N. S. Org. Lett. 2007, 9,
911. (c) Olson, A. C.; Overman, L. E.; Sneddon, H. F.; Ziller, J. W. Adv.
Synth. Catal. 2009, 351, 3186. (d) Cannon, J. S.; Kirsch, S. F.; Overman,
L. E. J. Am. Chem. Soc. 2010, 132, 15185. (e) Cannon, J. S.; Kirsch, S. F.;
Overman, L. E.; Sneddon, H. F. J. Am. Chem. Soc. 2010, 132, 15192.
Acknowledgment. We thank the University of Iowa for
financial support and Robert F. Stone (2010 REU student)
for initial studies with tertiary imidates 9 and 10.
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.
Org. Lett., Vol. 13, No. 20, 2011
5579