Et3B-induced radical addition of N,N-dichlorosulfonamide to alkenes and pyrrolidine formation via radical annulation

Article abstract of DOI:10.1021/jo034043k

A highly regioselective radical addition of N,N-dichlorobenzenesulfonamide (dichloramine-B) to 1-alkenes is achieved at -78 °C by the use of triethylborane as a radical initiator. The reaction of 1,3-dienes with N,N-dichlorosulfonamide in the presence of

Full text of DOI:10.1021/jo034043k

Et3B-In d u ced Ra d ica l Ad d ition of N,N-Dich lor osu lfon a m id e to
Alk en es a n d P yr r olid in e F or m a tion via Ra d ica l An n u la tion
Takayuki Tsuritani, Hiroshi Shinokubo,* and Koichiro Oshima*
Department of Material Chemistry, Graduate School of Engineering, Kyoto University,
Kyoto 606-8501, J apan
shino@fm1.kuic.kyoto-u.ac.jp; oshima@fm1.kuic.kyoto-u.ac.jp
Received J anuary 15, 2003
A highly regioselective radical addition of N,N-dichlorobenzenesulfonamide (dichloramine-B) to
1-alkenes is achieved at -78 °C by the use of triethylborane as a radical initiator. The reaction of
1,3-dienes with N,N-dichlorosulfonamide in the presence of Et3B regioselectively provides N-chloro-
N-allylamide derivatives. N-Chloro-N-allylamides thus obtained react with a variety of alkenes to
furnish pyrrolidine derivatives in good yields. A radical annulation reaction among N,N-
dichlorosulfonamide, 1,3-dienes, and alkenes has been developed.
SCHEME 1
In tr od u ction
N-Chlorosulfonamides and related compounds are
inexpensive N1 sources that allow efficient introduction
of nitrogen with a variety of unsaturated molecules,
providing important compounds such as aziridines and
hydroxylamine derivatives.1 However, utility of N,N-
dichlorosulfonamides in organic synthesis is limited so
far. N,N-Dichlorosulfonamides are known to yield ad-
ducts readily in the reaction with alkenes.2 The reaction
with 1-alkenes generally affords a regioisomeric mixture
of anti-Markovnikov and Markovnikov adducts.2e,f The
failure in regiocontrol is mainly due to the mixed reaction
pathways where both radical and cationic species such
SCHEME 2
* To whom correspondence should be addressed. Phone: +81-75-
753-5523. Fax: +81-75-753-4863.
(1) (a) Ando T.; Minakata, S.; Ryu, I.; Komatsu, M. Tetrahedron Lett.
1998, 39, 309. (b) Ando, T.; Kano, D.; Minakata, S.; Ryu, I.; Komatsu,
M. Tetrahedron 1998, 54, 13485. (c) J eong, J . U.; Tao, B.; Sagasser, I.;
Henniges, H.; Sharpless, K. B. J . Am. Chem. Soc. 1998, 120, 6844. (d)
Albone, D. P.; Aujla, P. S.; Taylor, P. C.; Challenger, S.; Derrick, A.
M. J . Org. Chem. 1998, 63, 9569. (e) Ali, S. I.; Nikalje, M. D.; Sudalai,
A. Org. Lett. 1999, 1, 705. (f) Chanda, B. M.; Vyas, R.; Bedekar, A. V.
J . Org. Chem. 2001, 66, 30. (g) Nishimura, M.; Minakata, S.; Taka-
hashi, T.; Oderaotoshi, Y. Komatsu, M. J . Org. Chem. 2002, 67, 2101.
(h) Sharpless, K. B.; Chong, A. O.; Oshima, K. J . Org. Chem. 1976,
41, 177. (i) Herranz, E.; Sharpless, K. B. J . Org. Chem. 1978, 43, 2544.
(j) Li, G.; Chang, H.-T.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl.
1996, 35, 451. (k) Rubin, A. E.; Sharpless, K. B. Angew. Chem., Int.
Ed. Engl. 1997, 36, 2637. (l) Campbell, M. M.; J ohnson, G. Chem. Rev.
1976, 78, 65.
•
as Cl+, Cl•, and N(Cl)SO2R are involved (Scheme 1).3 The
thermally or photochemically induced addition increases
the selectivity for the anti-Markovnikov adduct. However,
the selectivity is not necessarily satisfactory. Further-
more, a prolonged reaction time leads to undesirable
reactions such as rearrangement or further addition
reactions of the initial 1:1 adducts. Thus, the efficient
regioselective addition of N,N-dichlorosulfonamides to
1-alkenes has not been addressed so far.
We envisaged that N,N-dichlorobenzenesulfonamide
(dichloramine-B)4 would serve as a nitrogen diradical
equivalent to allow two-directional and sequential carbon-
nitrogen bond formations (Scheme 2). Thus, we have
investigated the regiocontrol in the addition of N,N-
dichlorobenzenesulfonamide (1) to 1-alkenes. Here we
(2) (a) Ziegler, K.; Spath, A.; Schaat, E.; Schumann, W.; Winkel-
mann, E. J ustus Liebigs Ann. Chem. 1942, 551, 80. (b) Thielacker, W.;
Wessel, H. J ustus Liebigs Ann. Chem. 1967, 703, 34. (c) Seden, T. P.;
Turner, R. W. J . Chem. Soc. C 1968, 876. (d) Ueno, Y.; Takemura, S.;
Ando, Y.; Terauchi, H. Chem. Pharm. Bull. 1965, 13, 1369. (e) Ohashi,
T.; Sugie, M.; Okahara, M.; Komori, S. Tetrahedron Lett. 1968, 39,
4195. (f) Ohashi, T.; Sugie, M.; Okahara, M.; Komori, S. Tetrahedron
1969, 25, 5349. (g) Matsarev, G. V.; Ushakov, A. A.; Inshakova, V. T.;
Raskina, A. D.; Rozenberg, V. R.; Kolbasov, V. I. Zh. Vses. Khim. O-va.
im. D. I. Mendeleeva 1986, 31, 467. (h) Markov, V. I.; Danileiko, D. A.;
Doroshenko, V. A. Gella, I. M.; Polyakov, A. E. Org. Soedin. Sery, 2
1980, 176. (i) Glushkova, N. E.; Kochina, T. A.; Kharitonov, N. P. Zh.
Org. Khim. 1984, 20, 447. (j) Vorob’eva, I. S.; Stadnichuk, M. D. Zh.
Obshch.. Khim. 1984, 54, 2731. (k) Daniher, F. A.; Melchior, M. T.;
Butler, P. E. J . Chem. Soc., Chem. Commun. 1968, 931. (l) Daniher,
F. A.; Butler, P. E. J . Org. Chem. 1968, 33, 4336.
(3) For reviews on N-centered radicals, see: (a) Fallis, A. G.; Brinza,
I. M. Tetrahedron 1997, 53, 17543. (b) Neale, R. S. Synthesis, 1971, 1.
(c) Stella, L. Angew. Chem., Int. Ed. Engl. 1983, 22, 337. (d) Zard, S.
Z. Synlett 1996, 1148. (e) Esker, J . L.; Newcomb, M. Adv. Heterocycl.
Chem. 1993, 58, 1. (f) Stella, L. In Radicals in Organic Synthesis;
Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001; Vol. 2,
Chapter 5.1, p 407.
(4) N,N-Dichlorobenzenesulfonamide is commercially available from
TCI.
10.1021/jo034043k CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/19/2003
3246
J . Org. Chem. 2003, 68, 3246-3250

Radical Addition of N,N-Dichlorosulfonamide
TABLE 1. Ad d ition of N,N-Dich lor oben zen esu lfon a m id e
to 1-Hexen e
SCHEME 3
equiv equiv of
entry of 1 1-hexene
combined
yielda (%)
conditions
benzene
2/3
1b
1.5
1.5
1.0
1.0
95
96
62/38
rt
2b
benzene
71/29
Et3B (5 mol %)
rt
3b
4b
1.5
1.5
1.0
1.0
toluene
45
71
62/38
87/13
-78 °C
toluene
Et3B (5 mol %)
-78 °C
toluene
5c
1.0
3.0
98
>95/5
SCHEME 4
Et3B (5 mol %)
-78 °C
a
NMR yield with dibenzyl ether as an internal standard.
b
Reaction conditions: 1 (1.5 mmol), 1-hexene (1.0 mmol), toluene
or benzene (4 mL), 3 h. c Reaction conditions: 1 (1.0 mmol),
1-hexene (3.0 mmol), toluene (7 mL), 3 h.
wish to report a Et3B-initiated regioselective addition of
N,N-dichlorobenzenesulfonamide to various carbon-
carbon double bonds. Radical annulation5 of 1 with 1,3-
dienes and alkenes to provide pyrrolidine derivatives is
also described.
(entry 5). The use of hexane as the solvent afforded a
poor result because of the low solubility of 1 in hexane.
The reaction in THF or ether resulted in formation of
byproducts bearing a tetrahydrofuranyl or 1-ethoxyethyl
groups, respectively. In these cases, an N-centered radical
from 1 abstracts hydrogen at the R-position of the ether
linkage.
Having optimized reaction conditions of the regiose-
lective addition of 1, we then investigated exploitation
of the product 2, which has still one N-Cl bond, as a
nitrogen-centered radical precursor.7 The reaction of 2
with styrene (2.0 equiv) and 2-ethyl-1-butene (9.0 equiv)
in the presence of Et3B furnished the corresponding
adduct in good yields with high regioselectivity via a
chlorine atom transfer radical process (Scheme 3).8 Ethyl
vinyl ether (2.0 equiv) afforded R-amino aldehyde 4c in
good yield, which probably resulted from hydrolysis of
the initial adduct 5 (R-chloro ether). Although the hy-
drogen abstraction with a N-centered radical can be
problematic in the intermolecular reaction, such side
reactions are much slower than the addition reaction in
these cases.
Resu lts a n d Discu ssion
(1) Et3B-In d u ced Ad d ition of N,N-Dich lor oben -
zen esu lfon a m id e to 1-Alk en es. The regioselectivity
observed in the addition of N,N-dichlorobenzenesulfona-
mide (1) to 1-alkenes was examined with 1-hexene as the
1-alkene. The results under a variety of conditions are
listed in Table 1. The use of 1.5 equiv of 1 to 1-hexene in
benzene at room temperature provided a mixture of anti-
Markovnikov 2 and Markovnikov adduct 3 along with
other products (entries 1 and 2). The reaction in toluene
at -78 °C proceeded cleanly and yielded only a mixture
of 2 and 3 (entries 3 and 4). However, the regioselectivity
was still not sufficient. Although the addition took place
without Et3B as a radical initiator, the presence of Et3B
enhanced the reactivity and the regioselectivity.6 When
an excess of 1-hexene (3.0 equiv) was employed in the
presence of Et3B in toluene at -78 °C, anti-Markovnikov
adduct 2 was obtained in good yield as a sole product
(2) Et3B-In d u ced Ad d ition of N,N-Dich lor oben -
zen esu lfon a m id e to 1,3-Dien es. With an efficient
protocol of 1 as a nitrogen diradical equivalent in hand,
we then attempted to synthesize pyrrolidine derivatives
via three-component radical coupling reaction. Recently,
(5) For examples of radical annulation with carbon-centered radicals,
see: (a) Cekovic, Z.; Saicic, R. Tetrahedron Lett. 1986, 27, 5893. (b)
Barton, D. H. R.; Zard, S. Z.; da Silva, E. J . Chem. Soc., Chem.
Commun. 1988, 285. (c) Curran, D. P.; Chen, M.-H. J . Am. Chem. Soc.
1987, 109, 6558. (d) Curran, D. P.; Chen, M.-H.; Spletzer, E.; Seong,
C. M.; Chang, C.-T. J . Am. Chem. Soc. 1987, 111, 8872. (e) Feldman,
K. S.; Romanelli, A. L.; Ruckle, R. E., J r.; Miller, R. F. J . Am. Chem.
Soc. 1988, 110, 3300. (f) Miura, K.; Fugami, K.; Oshima, K.; Utimoto,
K. Tetrahedron Lett. 1988, 29, 5135. (g) Curran, D. P.; van Elburg, P.
A. Tetrahedron Lett. 1989, 30, 2501. (h) Kitagawa, O.; Yamada, Y.
Fujiwara, H.; Taguchi, T. J . Org. Chem. 2002, 67, 922. (i) Kitagawa,
O.; Yamada, Y. Sugawara, A.; Taguchi, T. Org. Lett. 2002, 4, 1011.
(6) For reviews on Et3B as a radical initiator, see: (a) Ollivier, C.;
Renaud, P. Chem. Rev. 2001, 101, 3415. (b) Yorimitsu, H.; Oshima, K.
In Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-
VCH: Weinheim, 2001; Vol. 1, Chapter 1.2, p 11. (c) Yorimitsu, H.;
Shinokubo, H.; Oshima, K. Synlett 2002, 674.
(7) For intermolecular addition of N-centered radicals to alkenes,
see: (a) Newcomb, M.; Kumar, M. U. Tetrahedron Lett. 1990, 31, 1675.
(b) Nagao, Y.; Katagiri, S. Chem. Lett. 1992, 2379. (c) Goosen, A.;
McCleland, C. W.; Merrifield, A. J . J . Chem. Soc., Perkin Trans. 1 1992,
627.
(8) For reviews on atom transfer radical reactions, see: (a) Byers,
J . In Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.;
Wiley-VCH: Weinheim, 2001; Vol. 1, Chapter 1.5, p 72. (b) Curran,
D. P.; Chen, M.-H.; Kim, D. J . Am. Chem. Soc. 1986, 108, 2489. (c)
Curran, D. P. Synthesis 1988, 417; 489.
J . Org. Chem, Vol. 68, No. 8, 2003 3247

Tsuritani et al.
TABLE 3. Ra d ica l An n u la tion w ith Styr en ea
TABLE 2. Ra d ica l Ad d ition of Dich lor a m in e to
1,3-Dien esa
a
N-Chlorosulfonamide (6, 0.5 mmol), styrene (1.0-1.5 mmol),
a
Et3B (0.05 mmol), benzene, rt, 3 h.
N,N-Dichlorobenzenesulfonamide (1.0 mmol), 1,3-dienes (1.5-
2.0 mmol), Et3B (0.05 mmol), toluene, -78 °C, 30 min to 1 h.
Benzene, rt, 3 h.
b
Treatment of 1,3-alkadienes with 1 exclusively pro-
vides the 1,4-adducts, 4-chloro-2-butenylamides 6, in good
yields (Table 2). None of the 1,2-addition products could
be detected in the crude reaction mixture. However, the
use of 1-phenyl-1,3-butadiene yielded the 1,2-adduct 6f
predominantly. The reaction tolerates the presence of
nonconjugated alkenes in the substrate (entry 4). Cyclic
dienes such as 1,3-cyclooctadiene also yields 1,4-adduct
6e (entry 5). The use of a vinylcyclopropane as a
substrate provided a ring opening adduct 6g in moderate
yield (entry 7).
(3) Ra d ica l An n u la tion w ith N-Ch lor osu lfon a -
m id e. The study on radical annulation was commenced
with the reaction of 6 with styrene (Table 3). Treatment
of a mixture of 6 and styrene with 10 mol % of Et3B in
benzene yielded the cyclized products 8 in modest to good
yields at room temperature. A terminal alkenyl moiety
of 6d survived under the reaction conditions, and no
addition of the N-centered radical to the alkene occurred
(entry 4). Unfortunately, cyclic N-chloroamide 6e pro-
vided none of the cyclized product, and only the reduction
product, 4-chlorocyclooct-2-en-1-ylsulfonamide 8e, was
obtained (entry 5). N-Chloroamide 6g derived via ring
opening of cyclopropane also afforded annulation adduct
8g in 87% yield. In the reaction with 6b, dechlorination
Taguchi et al. and we have independently reported
radical [3 + 2] annulation strategy that exploits an
N-allylsulfonamidyl radical as a key intermediate.9 As
depicted in Scheme 4, the reaction of 1,3-dienes with 1
in a 1,4-addition manner provides N-allyl-N-chloroben-
zenesulfonamides 6, which further react with alkenes to
furnish pyrrolidine derivatives 8 via a radical addition-
cyclization sequence. The N-centered radical from 6
undergoes the intermolecular addition toward an alkene
to form an alkyl radical 7. The subsequent 5-exo radical
cyclization proceeds to yield the cyclized product 8 via a
chlorine atom transfer process.
Daniher and Butler reported the predominant mode
of the addition of N,N-dichlorosulfonamides toward 1,3-
dienes is 1,4-fashion with a selectivity of >95%.2l How-
ever, they examined only 1,3-butadiene and chloroprene
as a substrate. Consequently, we reinvestigated the
reaction of 1 with various 1,3-dienes with Et3B as a
radical initiator.
(9) (a) Tsuritani, T.; Shinokubo, H.; Oshima, K.Org. Lett. 2001, 3,
2709. (b) Kitagawa, O.; Yamada, Y.; Fujiwara, H.; Taguchi, T. Angew.
Chem., Int. Ed. 2001, 40, 3865.
3248 J . Org. Chem., Vol. 68, No. 8, 2003

Radical Addition of N,N-Dichlorosulfonamide
TABLE 4. Ra d ica l An n u la tion w ith Va r iou s Alk en esa
TABLE 5. Con ver sion of Vicin a l Dich lor id es to
Alk en esa
a
Reactions conditions: Conditions A: TiCl4 (1.2-2.0 equiv),
LiAlH4 (1.2-2.0 equiv), THF reflux. Conditions B: Zn(Cu) (20
equiv), AcOH, reflux. trans/cis. c The stereochemistry was as-
b
d
signed on the basis of NOE difference experiments. The stereo-
selectivity could not be determined.
product 9b was also obtained in 9% yield (entry 2). The
formation of olefin 9 can be attributed to fragmentation
of the cyclized radical via elimination of chlorine radical
in the case of slow abstraction of chlorine from 6 due to
steric reasons (Scheme 5).10
We then investigated the radical annulation reaction
with a variety of alkenes (Table 4). Aromatic alkenes
other than styrene yielded the corresponding pyrrolidine
a
Reactions employed 6a (0.5 mmol) and alkene (1.0-1.5 mmol)
in benzene (4.0 mL) in the presence of Et3B (0.05 mmol) unless
otherwise noted. The reaction mixture was stirred for 3 h at room
b
temperature. An excess amount of alkenes (9.0 equiv) was
employed. c The reaction employed 25 mL of benzene under
otherwise the same reaction conditions.
J . Org. Chem, Vol. 68, No. 8, 2003 3249

Tsuritani et al.
SCHEME 5
SCHEME 6
derivatives 8 in good to excellent yields with 2.0-3.0
equiv of alkenes. On the other hand, the reaction with
aliphatic alkenes as a radical acceptor requires the use
of a large excess (9.0 equiv) of the alkene. Although
indene is a good hydrogen donor toward radical species,
the radical addition-cyclization sequence is much faster
than the hydrogen abstraction reaction with the N-
centered radical derived from 6a (entry 2). Ethyl vinyl
ether was also a good partner in this radical annulation
reaction (entry 8). Interestingly, cyclic alkenes such as
indene and benzofuran provided the corresponding tri-
cyclic compounds 8i and 8m in excellent yields (entries
2 and 6). A minor amount of alkenyl byproducts 9 was
formed in addition to vicinal dichlorides when the reac-
tion employed 1,1-disubstituted alkenes or vinyl ether
as a substrate (entries 5, 7, and 8).
As a result of the presence of many stereocenters,
analysis of the cyclized products 8 with NMR was quite
difficult, and the isomeric ratio could not be determined.
Conversion of vicinal dichloride 8 into alkenes 9 would
simplify the spectrum of the products. Moreover, intro-
duction of the alkenyl moiety is also beneficial for further
functionalization of the pyrrolidine derivatives obtained
with the present protocol. Dechlorination of 8 was suc-
cessfully achieved upon treatment with either a low
valent titanium reagent (TiCl4-LiAlH4) in THF (Method
A) or a zinc-copper couple in refluxing acetic acid
(Method B) (Table 5).11
6). To a mixture of N,N-dichlorobenzenesulfonamide and
1,3-butadiene (2.0 equiv) in toluene was added a hexane
solution of Et3B at -78 °C. After stirring for 1 h at -78
°C, the reaction mixture was warmed to room tempera-
ture, and excess 1,3-butadiene was removed under
reduced pressure. An addition of alkenes such as styrene,
allyltrimethylsilane, or indene, followed by a solution of
Et3B at room temperature eventually furnished the
desired pyrrolidine derivatives in excellent overall yields.
Con clu sion
In the reaction of N,N-dichlorobenzenesulfonamide
with 1-hexene, complete regioselection for anti-Mark-
ovnikov addition has achieved by using Et3B as a radical
initiator at -78 °C. The obtained product can be further
utilized as a nitrogen-centered radical precursor. This
protocol is applicable to construct pyrrolidine derivatives
via a radical annulation reaction by taking advantage of
regioselective 1,4-addition of N,N-dichlorosulfonamide to
1,3-dienes. This facile protocol provides an easy access
to nitrogen heterocycles from 1,3-dienes and alkenes,
demonstrating the utility of N,N-dichlorosulfonamide as
a nitrogen diradical equivalent.
Ack n ow led gm en t. This work was supported by a
Grant-in-Aid for Scientific Research on Priority Areas
(no. 412: Exploitation of Multi-Element Cyclic Mol-
ecules) from the Ministry of Education, Culture, Sports,
Science, and Technology, J apan.
Finally, we conducted this radical [2 + 2 + 1] annu-
lation reaction among N,N-dichlorosulfonamide, 1,3-
butadiene, and alkenes in a one-pot operation (Scheme
(10) â-Elimination of chlorine radical is significantly slower than
chlorine abstraction. The addition of N,N-dichlorosulfonamide to allyl
chloride was reported to provide a vicinal dichloride. See ref 2h.
(11) (a) Olah, G. A.; Prakash, G. K. S. Synthesis 1976, 607. (b)
Handa, S.; Earlam, G. J .; Geary, P. J .; Hawes, J . E.; Phillips, G. T.;
Pryce, R. J .; Ryback, G. Shears, J . H. J . Chem. Soc., Perkin Trans. 1
1994, 1885.
Su p p or tin g In for m a tion Ava ila ble: General procedures
and spectral data for compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O034043K
3250 J . Org. Chem., Vol. 68, No. 8, 2003