Copper-catalyzed aminohalogenation using the 2-NsNCl(2)/2-NsNHNa combination as the nitrogen and halogen sources for the synthesis of anti-alkyl 3-chloro-2-(o-nitrobenzenesulfonamido)-3-arylpropionates.

Article abstract of DOI:10.1021/ol000120b

New regio- and stereoselective aminohalogenation of cinnamic esters has been developed using the combination of 2-NsNCl(2)/2-NsNHNa as the nitrogen and chlorine sources and copper(I) triflate as the catalyst. The new procedure provides an efficient synthe

Full text of DOI:10.1021/ol000120b

ORGANIC
LETTERS
2000
Vol. 2, No. 15
2249-2252
Copper-Catalyzed Aminohalogenation
Using the 2-NsNCl2/2-NsNHNa
Combination as the Nitrogen and
Halogen Sources for the Synthesis of
anti-Alkyl
3-Chloro-2-(o-nitrobenzenesulfonamido)-3-arylpropionates
Guigen Li,* Han-Xun Wei, and Sun Hee Kim
Department of Chemistry and Biochemistry, Texas Tech UniVersity,
Lubbock, Texas 79409-1061
qeggl@ttu.edu
Received May 3, 2000
ABSTRACT
New regio- and stereoselective aminohalogenation of cinnamic esters has been developed using the combination of 2-NsNCl2/2-NsNHNa as
the nitrogen and chlorine sources and copper(I) triflate as the catalyst. The new procedure provides an efficient synthesis of anti-alkyl 3-chloro-
2-(o-nitrobenzenesulfonamido)-3-phenylpropionate derivatives. Nine examples are presented with good yields (62−82%) and stereoselectivity
((5:1)−(30:1)).
The vicinal haloamine derivatives are important building
blocks in modern organic and medicinal chemistry.1 The
development of highly regioselective and stereoselective
synthetic approaches to this functionality has been attempted
for several decades but still remains important and challeng-
ing.2,3 In actuality, this synthetic area has not been well-
documented in the past 15 years. Very recently, we devel-
oped the aminohalogenation of cinnamic esters by using N,N-
dichloro-p-toluenesulfonamide (TsNCl2) as the nitrogen and
chlorine sources and the transition-metal compounds ZnCl2
and Cu(OTf)2 as the catalysts (Scheme 1).4 In the continuing
Scheme 1
(1) Kemp, J. E. G., In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, U.K., 1991; Vol. 3, pp 471-513.
(2) (a) Griffith, D. A.; Danishefsky, S. J. J. Am. Chem. Soc. 1991, 113,
5863. (b) Barton, D. H. R.; Britten-Kelley, M. R.; Ferreira, D. J. Chem.
Soc., Perkin Trans. 1 1978, 1090. (c) Driguez, H.; Vermes, J.-P.; Lessard,
J. Can. J. Chem. 1978, 56, 119. (d) Lessard, J.; Driguez, H.; Vermes, J.-P.
Tetrahedron Lett. 1970, 4887.
(3) (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,
931. (d) Seden, T. P.; Turner, R. W. J. Chem. Soc. C 1968, 876.
study of this reaction, we anticipated that the replacement
of N,N-dichloro-p-toluenesulfonamide with the analogous
nitrogen/chlorine sources N,N-dichloro-p-nitro and o-nitro-
(4) Li, G.; Wei, H.-X.; Kim, S. H.; Neighbors, M. Org. Lett. 1999, 1,
385.
10.1021/ol000120b CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/27/2000

benzenesulfonamide (2-NsNCl2 and 4-NsNCl2) under similar
conditions could result in anti-alkyl 3-chloro-2-(o-nitroben-
zenesulfonamido)-3-phenylpropionate derivatives. The ad-
vantage of such a modification is that the N-nitrobenzene-
sulfonyl protecting group of the resulting products can be
readily cleaved by PhSH/K2CO3 in DMF at room tempera-
ture.5 However, our attempts to react NsNCl2 with methyl
cinnamate under the conditions we previously developed
failed to give the desired haloamine product. Instead, anti-
methyl 3-chloro-2-(o-nitrobenzenesulfonamido)-3-phenyl-
propionate was determined to be the predominant product
(Scheme 2).6
and subsequently drying overnight under high vacuum prior
to use. An excess amount of 2-NsNCl2 (1.5 equiv) and
2-NsNHNa (3.0 equiv)7 was found to be necessary for
optimal yields and complete consumption of cinnamic ester
starting materials. The surplus 2-NsNH2, after the reaction
was quenched with aqueous Na2SO3, can be readily recov-
ered because of its high polarity and low solubility in several
organic solvents such as CHCl3, CH2Cl2, etc. Copper(I)
triflate was the first catalyst found effective for this process.
In the absence of this triflate, no reaction occurred between
methyl cinnamate and 2-NsNCl2/2-NsNHNa even after more
than 3 h. Later on, copper(II) triflate and copper(I) chloride
were also proven to be efficient catalysts for this reaction,
giving similar results. Less than 10 mol % of catalyst can
be utilized, but the reaction takes longer. The concentration
of reactants should also be maintained around the amount
shown in the typical procedure.8 In actuality, when the
reaction mixture was diluted to half of the current concentra-
tion, only a trace amount of haloamine product was observed
after the reaction was performed over 20 h.
Scheme 2
Examination of the results listed in Table 1 reveals that
cinnamic esters with either electron-donating or electron-
While the study of diamination is ongoing in our labora-
tories, we concurrently have been searching for new condi-
tions to direct the reaction toward the formation of N-nosyl
haloamine derivatives. We found that N-nosyl group-based
aminohalogenation of cinnamic esters can be achieved by
using NsNCl2-NsNHNa (1:2 mole ratio) as the nitrogen and
chlorine sources in the presence of copper(I) triflate as the
catalyst. In this report, we describe the preliminary results
of this new reaction system, which is represented in Scheme
3; the results are summarized in Table 1.
(7) The mixture of NsNCl2/NsNHNa has been previously utilized as the
nitrogen source to react with selenium for the formation of diimidoselenium
compounds: Bruncko; M.; Khuong, T.-A. V.; Sharpless, K. B. Angew.
Chem., Int. Ed. Engl. 1996, 35, 454.
(8) Typical procedure: CuOTf-catalyzed aminochlorination reaction of
methyl trans-cinnamate with 2-NsNCl2/2-NsNHNa as described in Scheme
1. Into a dry vial was added methyl cinnamate (162 mg g, 1.00 mmol) and
freshly distilled acetonitrile (3 mL). The reaction vial was immersed in a
room-temperature bath, and 2-NsNCl2 (407 mg, 1.50 mmol), 2-NsNHNa
(672 mg, 3.00 mmol), and copper(I) trifluoromethanesulfonate benzene
complex (50.3 mg, 0.10 mmol, 10 mol %) were added. The resulting dark
brown solution in the capped vial was stirred at room temperature for 20 h
without argon protection. As the reaction proceeded to completion over
the course of 20 h, the color of the solution changed from dark brown to
light green and finally to yellow. The reaction was 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 water and brine, dried
over anhydrous magnesium sulfate, and concentrated to dryness. Purification
by flash chromatography (3/7 EtOAc/hexane, v/v) provided anti-methyl
3-chloro-2-(o-nitrobenzenesulfonamido)-3-phenylpropionate (1; 303 mg,
76% yield) as a colorless oil. 1H NMR data (Table 1; 200 MHz, CDCl3; J
values in Hz): 1, δ 8.04-7.87 (m, 2H), 7.92-7.87 (m, 1H), 7.74-7.69
(m, 2H), 7.35-7.29 (m, 5H), 6.12 (d, J ) 9.61, 1H), 5.28 (d, J ) 6.12,
1H), 4.74 (dd, J ) 6.12, 9.61, 1H), 3.62 (s, 3H); 3, δ 8.03-7.86 (m, 2H),
7.72-7.68 (m, 2H), 7.21-7.17 (m, 2H), 7.09-7.05 (m, 2H), 6.08 (d, J )
9.72, 1H), 5.22 (d, J ) 6.30, 1H), 4.72 (dd, J ) 6.30, 9.72, 1H), 3.58 (s,
3H); 4, δ 7.95-7.85 (m, 2H), 7.73-7.67 (m, 2H), 7.44-7.39 (m, 1H),
7.17-7.07 (m, 3H), 6.25 (d, J ) 9.9.56, 1H), 5.41 (d, J ) 7.41, 1H), 4.73
(dd, J ) 7.41, 9.56, 1H), 3.54 (s, 3H), 2.38 (s, 3H); 6, δ 7.98-7.87 (m,
2H), 7.76-7.69 (m, 2H), 7.30-7.20 (m, 4H), 6.14 (d, J ) 9.73), 1H), 5.19
(d, J ) 6.78, 1H), 4.71 (dd, J ) 6.78, 9.73, 1H), 3.62 (s, 3H); 7, δ 7.97-
7.87 (m, 2H), 7.76-7.69 (m, 2H), 7.40-7.36 (m, 2H), 7.22-7.18 (m, 2H),
6.13 (d, J ) 9.76, 1H), 5.17 (d, J ) 6.87, 1H), 4.70 (dd, J ) 6.87, 9.76,
1H), 3.61 (s, 3H); 8, δ 8.01-7.88 (m, 2H), 7.78-7.70 (m, 2H), 7.36-7.27
(m, 2H), 7.01-6.93 (m, 2H), 6.14 (d, J ) 9.77, 1H), 5.23 (d, J ) 6.55,
1H), 4.71 (dd, J ) 6.55, 9.77, 1H), 3.58 (s, 3H); 9, δ 8.22-8.16 (m, 2H),
8.07-8.03 (m, 1H), 7.93-7.89 (m, 1H), 7.82-7.72 (m, 3H), 7.61-7.53
(m, 1H)6.30 (d, J ) 9.38, 1H), 5.38 (d, J ) 6.11, 1H), 4.73 (dd, J ) 6.11,
9.38, 1H), 4.05 (m, 2H), 1.12 (t, J ) 7.19, 3H). 13C NMR data (Table 1;
50 MHz, CDCl3): 1, δ 168.3, 147.4, 135.5, 134.1, 133.7, 133.0, 130.5,
129.4, 128.8, 127.6, 125.6, 63.1, 61.3, 52.8; 3, δ 168.4, 147.3, 139.3, 134.3,
133.5, 132.9, 132.4, 130.5, 129.4, 127.4, 125.6, 63.1, 61.1, 52.8, 21.2; 4, δ
168.5, 147.2, 135.7, 133.9, 6.5, 125.6, 61.6, 57.8, 52.6, 19.2; 6, δ 168.3,
147.3, 135.3, 134.2, 134.1, 133.7, 133.0, 130.3, 129.1, 128.9, 125.6, 62.9,
60.5, 52.9; 7, δ 168.3, 147.3, 134.8, 134.1, 133.7, 133.1, 131.9, 130.3, 129.4,
125.6, 123.5, 62.8, 60.5, 52.9; 8, δ 168.3, 165.4, 160.5, 147.4, 134.1, 133.7,
133.0, 131.5, 131.5, 130.4, 129.6, 129.5, 125.6, 116.0, 115.6, 63.0, 60.5,
52.9; 9, δ 167.2, 148.1, 147.5, 138.1, 134.0, 133.9, 133.8, 133.0, 130.4,
129.8, 125.7, 124.1, 123.0, 62.8, 60.6, 13.8.
Scheme 3
The reaction can be conducted in a convenient vessel of
appropriate size without the need of inert-atmosphere protec-
tion which is similar to the case for the previous TsNCl2-
based reaction system. 2-NsNCl2 was prepared by treating
o-nitrobenzenesulfonamide with commercial bleach, followed
by CH3COOH acidification.4 Interestingly, 2-NsNCl2 showed
greater stability than p-TsNCl2. In fact, it can be stored at
room temperature for a few months without nitrogen protec-
tion. The 2-NsNHNa salt was obtained by deprotonating
2-NsNH2 with sodium hydroxide in methanol/water solution
(5) (a) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995,
36, 6373. (b) Nelson, S. G.; Spencer, K. L. Angew. Chem., Int. Ed. 2000,
39, 1323. (c) Wipf, P.; Henninger, T. C. J. Org. Chem. 1997, 62, 1586. (d)
Miller, S. C.; Scanlan, T. S. J. Am. Chem. Soc. 1997, 119, 2301.
(6) Li, G.; Kim, S. H.; Wei, H.-X. Tetrahedron Lett., submitted for
publication.
2250
Org. Lett., Vol. 2, No. 15, 2000

Table 1. Results of CuOTf-Catalyzed Aminochlorination of Cinnamic Esters
withdrawing groups on their aromatic rings can be subjected
to this reaction. So far, only cinnamic esters have been used
as the reaction substrates simply because of the convenience
of TLC monitoring. Preliminary results showed that aliphatic
R,â-unsaturated carboxylic esters can also be employed as
the starting materials. For all of the aromatic substrates we
examined, the regioselectivity has been completely con-
trolled. Excellent anti/syn stereoselectivity was realized for
most of the examples we studied. Only in two cases, 5 and
9, was modest stereoselectivity obtained (anti:syn ) 5:1 and
10:1, respectively).
identical with the product synthesized from the TsNCl2-based
aminohalogenation procedure.4
Scheme 4
Structure determination was carried out by the conversion
of product 1 in Table 1 to a known sample (Scheme 4). In
this determination, the deprotection of the NR-Ns group was
performed by using Fukuyama’s method5 followed by the
protection of the free amine product with p-toluenesulfonyl
chloride in pyridine. The resulting anti-methyl 3-chloro-2-
(p-toluenesulfonamido)-3-phenylpropionate was proven to be
Org. Lett., Vol. 2, No. 15, 2000
2251

It is reasonable to suggest that this aminohalogenation
proceeds through the formation of an unprecedented N-nosyl-
N-chloroaziridinium intermediate at the initial step rather than
the chloronium ion as previously proposed (Scheme 5).4 This
SN2 mechanism for this opening is responsible for the high
anti stereoselectivty. The regioselectivity can be explained
by the fact that the â-position of the aziridinium intermediate
has more positive charge than the R-position because of the
stabilization effect from the phenyl ring. At this early stage,
it is not clear why Cl- is the dominant nucleophile over other
species which coexist with Cl- in the reaction system.
Scheme 5
In summary, highly regio- and stereoselective amino-
halogenation of cinnamic esters has been developed using
the 2-NsNCl2/2-NsNHNa combination as the nitrogen and
chlorine sources and copper(I) triflate as the catalyst. This
new process provides a novel approach to ant-methyl
3-chloro-2-(o-nitrobenzenesulfonamido)-3-phenylpropi-
onate derivatives. The N-nosyl protecting group of the
resulting products can be readily cleaved under mild condi-
tions. The unprecedented N-nosyl-N-chloroaziridinium in-
termediate generated during this new process could find more
applications in organic synthesis by reactions with various
other nucleophiles.
hypothesis is supported by the new diamination results.6 In
this diamination process, the existence of an N-nosyl-N-
chloroaziridinium intermediate was proven by its reaction
with acetonitrile to give anti-methyl NR-nosyl-Nâ-acetyl-
diaminophenylpropionate after quenching the reaction with
aqueous Na2SO3 solution.6 The copper catalysts help to re-
move the chlorine anion from N,N-dichloro-o-nitrobenzene-
sulfonamide, which is beneficial in forming “Ns-N+-Cl”
electrophilic species for the electrophilic addition. The nearby
copper-associated “Cl-” around the aziridinium intermediate
acts as the nucleophile to open the three-membered ring. An
Acknowledgment. We acknowledge the Robert A. Welch
Foundation and the South Plains Foundation for generous
support. We thank Mr. David W. Purkiss for assistance in
NMR spectroscopic analysis.
1
Supporting Information Available: Figures giving H
and 13C NMR spectra for all pure products. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL000120B
2252
Org. Lett., Vol. 2, No. 15, 2000