Transition metal-catalyzed regioselective and stereoselective aminochlorination of cinnamic esters

Article abstract of DOI:10.1021/ol990059e

(formula presented) A new aminohalogenation process has been developed for the synthesis of vicinal haloamine derivatives using cinnamic esters as substrates. The reaction was performed in CH₃CN using ZnCl₂ or Cu(OTf)₂ as catalyst and N,N-dichloro-p-toluenesulfonamide as chlorine/nitrogen source. Good to excellent yields and regio-and stereoselectivities have been obtained. The stereochemistry was unambiguously determined by transforming one of the products to a known sample.

Full text of DOI:10.1021/ol990059e

ORGANIC
LETTERS
1
999
Vol. 1, No. 3
95-397
Transition Metal-Catalyzed
Regioselective and Stereoselective
Aminochlorination of Cinnamic Esters
3
Guigen Li,* Han-Xun Wei, Sun Hee Kim, and Margret Neighbors
Department of Chemistry and Biochemistry, Texas Tech UniVersity,
Lubbock, Texas 79409-1061
qeggl@ttu.edu
Received April 27, 1999
ABSTRACT
A new aminohalogenation process has been developed for the synthesis of vicinal haloamine derivatives using cinnamic esters as substrates.
The reaction was performed in CH CN using ZnCl or Cu(OTf) as catalyst and N,N-dichloro-p-toluenesulfonamide as chlorine/nitrogen source.
3
2
2
Good to excellent yields and regio- and stereoselectivities have been obtained. The stereochemistry was unambiguously determined by
transforming one of the products to a known sample.
The vicinal haloamine functionality presents a very useful
structural moiety in synthetic organic chemistry. Even
Cinnamic esters are believed to be among the most
1
8
synthetically useful substrate classes for olefin oxidative
9
a,b
though some progress has been made in developing efficient
synthetic approaches to this functionality,2 very few reports
about the heterolytic additions of nitrogen and chlorine to
olefins have appeared in the past decade. Furthermore, the
application of this process in organic chemistry has not been
reactionswhichincludecatalyticasymmetricdihydroxylation,
epoxidation, aziridination,
-7
10
8,9c,11
12
aminohydroxylation, etc.
Obviously, these olefin substrates should also be subjected
to a vicinal aminochlorination process because the resulting
chlorinated amino acids can be converted to numerous useful
organic molecules by replacing chlorine atom with a series
of nucleophiles. Surprisingly, a successful cinnamic ester-
based aminochlorination has not been developed so far.
1
very successful yet. The study of highly regioselective and
stereoselective aminohalogenation of olefins still remains
important and challenging.
2
Recently, we tried to render this reaction by using the CrCl -
4
,5
(
1) Kemp, J. E. G. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 3, pp 471-513.
2) (a) Griffith, D. A.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112,
5
5
promoted addition of N-chlorocarbamates and direct ad-
dition of N,N-dichlorosulfonamides or dichlorocarbamates6
onto cinnamic esters. Unfortunately, no haloamine product
(
811. (b) Griffith, D. A.; Danishefsky, S. J. J. Am. Chem. Soc. 1991, 113,
863.
(
3) (a) Barton, D. H. R.; Britten-Kelley, M. R.; Ferreira, D. J. Chem.
Soc., Perkin Trans. 1 1978, 1090. (b) Theilacker, W.; Wessel, H. Liebigs
Ann. Chem. 1967, 34, 703. (c) Ueno, Y.; Takemura, Y.; Ando, Y.; Teruaki,
H. Chem. Pharm. Bull. 1967, 15, 1193.
(9) (a) Jacobsen, E. J.; Marko, I.; Mungall, W. S.; Schroder, G.; Sharpless,
K. B. J. Am. Chem. Soc. 1988, 110, 1968. (b) Kolb, H.; VanNieuwenhze,
M. S.; Sharpless, K. B. Chem. ReV. 1994, 94, 2483. (c) Jeong, J. U.; Tao,
B.; Henniges, H.; Sharpless, K. B. J. Am. Chem. Soc. 1998, 120, 6844 (a
haloamine intermediate was suggested in this aziridination process).
(10) Zhang, W.; Loebach, J. L.; Wilson, S. R.; Jacobsen, E. J. J. Am.
Chem. Soc. 1990, 112, 2801.
(4) Lessard, J.; Driguez, H.; Vermes, J.-P. Tetrahedron Lett. 1970, 4887.
(5) Driguez, H.; Vermes, J.-P.; Lessard, J. Can. J. Chem. 1978, 56, 119.
(6) (a) Daniher, F. A.; Butler, P. E. J. Org. Chem. 1968, 33, 4336. (b)
Daniher, F. A.; Butler, P. E. J. Org. Chem. 1968, 33, 2637. (c) Daniher, F.
A.; Melchior, M. T.; Butler, P. E. J. Chem. Soc., Chem. Commun. 1968,
31.
(11) Li, Z.; Conser, K. R.; Jacobsen, E. N. J. Am. Chem. Soc. 1993,
115, 5326.
9
(
(
7) Seden, T. P.; Turner, R. W. J. Chem. Soc. (C) 1968, 876.
8) Evans, D. A.; Faul, M. M.; Bilodeau, M. T.; Anderson, B. A.; Barnes,
(12) (a) Li, G.; Chang, H.-T.; Sharpless, K. B. Angew. Chem., Int. Ed.
Engl. 1996, 35, 451. (b) Li, G.; Sharpless, K. B. Acta Chem. Scand. 1996,
50, 649.
D. M. J. Am. Chem. Soc. 1993, 115, 5328.
1
0.1021/ol990059e CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/25/1999

2 2 3
CH Cl , CHCl , THF, benzene, toluene, MeCN, etc. were
tried for the direct aminochlorination without success.
Transition metal compounds were then screened to catalyze
Scheme 1. Transition Metal-Catalyzed Aminochlorination of
Methyl Cinnamate15
the reaction. These compounds include Hg
SnCl , RuCl , PdCl , FeCl , Cu(OTf) , etc. Among these
catalysts, we found that ZnCl and Cu(OTf) can efficiently
2 2 2 2
Cl , NiCl , ZnCl ,
2
3
2
2
2
2
2
catalyze the aminochlorination only when acetonitrile was
used as the solvent. It is interesting to note that little or no
products were obtained in all other solvent systems. More
interestingly, both regioselectivity and stereoselectivity were
controlled very well in acetonitrile. Essentially, only the
1
trans-â-chloro R-amino isomer was observed by H NMR
was obtained under these known conditions. In this report
we describe a successful transition metal-catalyzed ami-
nochlorination of cinnamic esters by using N,N-dichloro-p-
toluenesulfonamide as the nitrogen source. The reaction is
represented in Scheme 1 with the results summarized in
Scheme 2 and Table 1.
analysis of the crude products for most cases (1-4 and 6)
in Table 1. For example 5, the modest stereoselectivity
observed indicated trans:cis ) 4:1 and 5:1 for ZnCl
Cu(OTf) , respectively. For most cases in Table 1, yields
were improved by about 5-10% by addition of 4 Å
2
and
2
molecular sieves to the reaction systems.
For non-metal-catalyzed aminochlorination processes, both
ionic and radical mechanisms were proposed.3
b,c,6-7
The
Scheme 2
stereoselectivity of haloamine products depends on different
olefin substrates. For example, the reaction of N,N-dichloro-
4-toluenesulfonamide with (E)-stilbene resulted in a mixture
of anti and syn adducts. However, the same reaction using
indene as the substrate gave predominantly trans adduct. The
stereochemistry of the products in Table 1 indicates a
possible bridged chloronium ion mechanism in the present
catalytic process. Lewis acidic catalysts could coordinate to
the oxygen atom of the sulfonyl group to activate the N-Cl
bond prior to the addition reaction.
The regioselectivity and anti-selectivity were determined
by the conversion of product 1 to a known sample which
was synthesized by using the CT-based Sharpless AA
N,N-Dichloro-p-toluenesulfonamide (TsNCl
this system was prepared by the treatment of p-toluene-
sulfonamide with commercial bleach, followed by CH
COOH acidification. At first, a series of solvents such as
2
) employed in
3
-
Table 1. Results of ZnCl
Aminochlorination of Methyl Cinnamates
2
- and Cu(OTf)
2
-Catalyzed
(13) (a) Mitsunobu, O. Synthesis, 1981, 1. For an alternative AA-based
cis-aziridine formation, see: (b) Rubin, A. E.; Sharpless, K. B. Angew.
Chem., Int. Ed. Engl. 1997, 36, 2637.
16
(
14) A similar titanium-mediated epoxide opening see: Chong, J. M.;
Sharpless, K. B. J. Org. Chem. 1985, 50, 1560.
15) Typical Procedure: ZnCl2-Catalyzed Aminochlorination Reac-
(
tion of Methyl trans-Cinnamate with N,N-Dichloro-4-Toluenesulfona-
mide As Described in Scheme 1. Into a dry vial was added methyl
cinnamate (81.0 mg g, 0.50 mmol) and freshly distilled acetonitrile (1.5
mL). The reaction vial was immersed in a room temperature bath, and loaded
with freshly activated 4 Å molecular sieves (150 mg), TsNCl2 (144 mg,
0
.60 mmol, 1.20 equiv), and ZnCl2 (5.50 mg, 8 mol %). The resulting
solution in the capped vial was stirred at room temperature for 22 h without
argon protection. The reaction was finally quenched by dropwise addition
of saturated aqueous Na2SO3 solution (2 mL). The phases were separated,
and the aqueous phase was extracted with ethyl acetate (3 × 10 mL). The
combined organic layers were washed with 10% aqueous ammonia and
brine, dried over anhydrous magnesium sulfate, and concentrated to dryness.
Purification by flash chromatography (EtOAc/hexane, 1/3, v/v) provided
trans-methyl 3-chloro-2-(p-toluenesulfonamido)-3-phenylpropionate 1 (0.129
1
g, 85.0% yield) as colorless solid: mp 142-144 °C; H NMR (200 MHz,
DMSO-d6) δ 8.75 (d, J ) 9.93 Hz, 1 H), 7.24-7.52 (m, 9 H), 5.04 (d, J
1
3
)
10.3, 1 H), 4.29 (t, J ) 10.3, 1 H), 3.35 (s, 3H), 2.25 (s, 3H); C NMR
(
75 MHz, CDCl3) δ 169.3, 142.8, 137.3, 136.7, 129.4, 128.9, 128.5, 128.2,
126.3, 61.1, 60, 52.0, 21.0.
1
(
16) H NMR data of the pure products in Table 1 (200 MHz, CDCl3):
2
4
1
δ 8.91 (d, J ) 10 Hz, 1H), 7.30-7.53 (m, 8H), 5.42 (d, J ) 10, 1H),
.64 (t, J ) 10, 1H), 3.35 (s, 3H), 2.37 (s, 3H); 3 δ 8.77 (d, J ) 10 Hz,
H), 7.20-7.58 (m, 8H), 5.22 (d, J ) 10.7, 1H), 4.48 (t, J ) 10.4, 1H),
a
The yields of two isomers which were difficult to separate by column
3.31 (s, 3H), 2.36 (s, 3H); 4 δ 8.74 (d, J ) 10 Hz, 1H), 7.06-7.50 (m,
8
3
7
H), 4.99 (d, J ) 10.4, 1H), 4.25 (t, J ) 10, 1H), 3.35 (s, 3H), 2.35 (s,
H), 2.25 (s, 3H); 6 δ 8.92 (d, J ) 9.8 Hz, 1H), 8.04 (d, J ) 8.7 Hz, 2H),
.62 (d, J ) 8.7 Hz, 2H), 7.34 (d, J ) 8.2 Hz, 2H), 7.17 (d, J ) 8.2 Hz,
chromatography, trans/cis ) 4/1 and 5/1 for ZnCl2 and Cu(OTf)2
respectively. The reaction needs 2 equiv of TsNCl2 and 48 h. Otherwise,
b
the standard conditions.
2H), 5.18 (d, J ) 10.3, 1H), 4.34 (t, J ) 10, 1H), 3.39 (s, 3H), 2.29 (s,
3H).
396
Org. Lett., Vol. 1, No. 3, 1999

Scheme 3. Stereochemistry Determination by Synthetic Conversions to a Known Sample
reaction12,13 (Scheme 3). In this procedure, the Sharpless AA
2 2
using ZnCl and Cu(OTf) as catalysts and N,N-dichloro-4-
product, (2R,3S)-methyl 2-hydroxy-3-(p-toluenesulfonamido)-
toluenesulfonamide as an oxidative nitrogen source. The
reaction is easy to perform at room temperature in any vial
of appropriate size. The stereochemistry was unambiguously
assigned by synthetic conversions to a known sample and
further confirmed by MS spectroscopy. Similar transition
metal/ligand-catalyzed aminohalogenation processes will be
next explored to ascertain the possibility of its asymmetric
version.
3
-phenylpropionate, was first subjected to the Mitsunobu
13
conditions to give a cis-N-tosylaziridine. This transforma-
tion can also serve as a new efficient approach to cis-N-
4
tosylaziridines. TiCl -promoted ring opening of the resulting
cis-N-tosylaziridine with PhSNa gave (2R,3S)-methyl 3-(phen-
ylthio)-2-(p-toluenesulfonamido)-3-phenylpropionate as the
1
4
major isomer. The minor regioisomer was identical to the
product of a similar ring opening in the absence of TiCl in
4
which the nucleophilic substitution took place quantitatively
on the R-position of aziridine. Mass spectroscopy analysis
Acknowledgment. We are extremely indebted to Profes-
sor K. Barry Sharpless for his enlightening advice. We would
like to acknowledge the Robert A. Welch Foundation (grant
no. D-1361) and the South Plains Foundation for supporting
our work.
of 1 also further supported the assigned regioselectivity in
+
which two major species, [C
COOMe] , were clearly observed.
6
H
5
CHCl] and [TsNHCH-
+
In conclusion, a novel regio- and stereoselective ami-
nochlorination of alkyl cinnamates has been established by
OL990059E
Org. Lett., Vol. 1, No. 3, 1999
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