A Novel [3+2] Cycloaddition Approach to Nitrogen Heterocycles via Phosphine-Catalyzed Reactions of 2,3-Butadienoates or 2-Butynoates and Dimethyl Acetylenedicarboxylate with Imines: A Convenient Synthesis of Pentabromopseudilin

Article abstract of DOI:10.1021/jo9723063

The reactivity of a new three carbon synthon, generated in situ from the reaction of 2,3-butadienoates 2-butynoates with an appropriate phosphine as the catalyst, toward the electron-deficient imines is described. Triphenylphosphine-catalyzed reaction of methyl 2,3-butadienoate with N-sulfonylimines gave the single [3+2] cycloadduct in excellent yield; tributylphosphine-catalyzed reaction of methyl 2,3-butadienoate or 2-butynoate with N-tosylimines afforded the corresponding [3+2] cycloadduct as the major product along with a small amount of the three components adduct. Aliphatic N-tosylimines gave moderate yield for this reaction. In addition, a new phosphine-catalyzed cyclization reaction of dimethyl acetylenedicarboxylate with N-tosylimines is also described. A reaction mechanism is proposed. Further elaborations of the cycloaddition products and the synthesis of pentabromopseudilin using this method are exemplified.

Full text of DOI:10.1021/jo9723063

J . Org. Chem. 1998, 63, 5031-5041
5031
A Novel [3+2] Cycloa d d ition Ap p r oa ch to Nitr ogen Heter ocycles
via P h osp h in e-Ca ta lyzed Rea ction s of 2,3-Bu ta d ien oa tes or
2-Bu tyn oa tes a n d Dim eth yl Acetylen ed ica r boxyla te w ith Im in es:
A Con ven ien t Syn th esis of P en ta br om op seu d ilin †
Zhenrong Xu and Xiyan Lu*
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, China
Received December 22, 1997
The reactivity of a new three carbon synthon, generated in situ from the reaction of 2,3-butadienoates
or 2-butynoates with an appropriate phosphine as the catalyst, toward the electron-deficient imines
is described. Triphenylphosphine-catalyzed reaction of methyl 2,3-butadienoate with N-sulfo-
nylimines gave the single [3+2] cycloadduct in excellent yield; tributylphosphine-catalyzed reaction
of methyl 2,3-butadienoate or 2-butynoate with N-tosylimines afforded the corresponding [3+2]
cycloadduct as the major product along with a small amount of the three components adduct.
Aliphatic N-tosylimines gave moderate yield for this reaction. In addition, a new phosphine-
catalyzed cyclization reaction of dimethyl acetylenedicarboxylate with N-tosylimines is also
described. A reaction mechanism is proposed. Further elaborations of the cycloaddition products
and the synthesis of pentabromopseudilin using this method are exemplified.
In tr od u ction
the highly reactive carbon-nitrogen double bond have
been successfully applied in cycloaddition reactions.11,12
In preliminary studies we have tested the reaction of
methyl 2,3-butadienoate with N-tosylimines, and the
corresponding [3+2] cycloaddition product was formed in
excellent yield.13 The success of this reaction led to the
examination of other imines bearing alternative electron-
withdrawing groups on a nitrogen atom that similarly
activate the imine but are easier to remove after reaction.
Thus, N-(ethoxycarbonyl)benzaldimine, N-(diphenylphos-
phinyl)benzaldimine (diphenylphosphinyl ) DPP), N-(p-
nitrobenzenesulfonyl)benzaldimine (p-nitrobenzenesulfo-
The pyrrolidine ring is an important structural unit
existing in a large number of natural products and
pharmaceutical molecules.1,2 Efficient synthesis of the
pyrrolidine ring has thus attracted much attention in
synthetic organic chemistry.3-7 Of the numerous known
methodologies, the [3+2] cycloaddition is an efficient
strategy for the construction of the pyrrolidine ring
directly from simple building blocks and has been widely
utilized in synthesis.8 Recently, our discovery of a new
three carbon synthon, generated in situ from the reaction
of 2,3-butadienoates or 2-butynoates with an appropriate
phosphine as the catalyst,9 stimulates us to explore its
reaction to other dipolarophiles. N-Tosylimines10 with
(7) For recent examples, see: (a) Coldham, I.; Hufton, R. Tetrahe-
dron 1996, 52, 12541. (b) Steiner, A.; Wessig, P.; Polborn, K. Helv.
Chim. Acta 1996, 79, 1843. (c) Hollinshead, S. P. Tetrahedron Lett.
1996, 37, 9157. (d) Tokuda, M.; Fujita, H.; Nitta, M.; Suginome, H.
Heterocycles 1996, 42, 385. (e) Wu, S.; Lee, S.; Beak, P. J . Am. Chem.
Soc. 1996, 118, 715. (f) Kercher, T.; Livinghouse, T. J . Am. Chem. Soc.
1996, 118, 4200. (g) Harvey, D. F.; Sigano, D. M. J . Org. Chem. 1996,
61, 2268. (h) Larock, R. C.; Hightower, T. R.; Hasvold, L. A.; Peterson,
K. P. J . Org. Chem. 1996, 61, 3584. (i) Sole, D.; Cancho, Y.; Llebaria,
A.; Moreto, J . M.; Delgado, A. J . Org. Chem. 1996, 61, 5895. (j) Alvarez-
Ibarra, C.; Csaky, A. G.; Lopez de Silanes, I.; Quiroga, M. L. J . Org.
Chem. 1997, 62, 479.
(8) Pearson, W. H. In Studies in Natural Products Chemistry;
Rahman, A. U., Ed.; Elsevier: Amsterdam, 1988; Vol. 1, p 323.
(9) Zhang, C.; Lu, X. J . Org. Chem. 1995, 60, 2906.
(10) For recent synthesis of N-tosylimines, see: (a) Georg, G. I.;
Harriman, G. C. B.; Peterson, S. A. J . Org. Chem. 1995, 60, 7366. (b)
Love, B. E.; Raje, P. S.; Williams, T. C., II Synlett 1994, 493. (c) Boger,
D. L.; Corbett, W. L. J . Org. Chem. 1992, 57, 4777. (d) Trost, B. M.;
Marrs, C. J . Org. Chem. 1991, 56, 6468. (e) J ennings, W. B.; Lovely,
C. J . Tetrahedron 1991, 47, 5561.
(11) For reviews of six-membered rings, see: (a) Hetero Diels-Alder
Methodology in organic synthesis; Boger, D. L., Weinreb, S. M., Eds.;
Academic Press: San Diego, 1987. (b) Weinreb, S. M. In Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford,
1991; Vol. 5, p 401.
(12) For the formation of five-membered rings, see: (a) J iang, S.;
Chen, T.; Turos, E. Organometallics 1995, 14, 4710. (b) Chen, T.; J iang,
S.; Turos, E. Tetrahedron Lett. 1994, 35, 8325. (c) Trost, B. M.; Marrs,
C. M. J . Am. Chem. Soc. 1993, 115, 6636. (d) Trost, B. M.; Matelich,
M. C. J . Am. Chem. Soc. 1991, 113, 9007. (e) Saigo, K.; Shimada, S.;
Hasegawa, M. Chem. Lett. 1990, 905.
† Dedicated to Professor Weiyu Ding on the occasion of her 70th
birthday.
(1) Massiot, G.; Delaude, C. In The Alkaloids, Chemistry and
Pharmacology; Brossi, A., Ed.; Academic Press: Orlando, 1986; Vol.
27, Chapter 3, p 269.
(2) For recent examples, see: (a) Winn, M.; von Geldern, T. W.;
Opgenorth, T. J .; J ae, H.-S.; Tasker, A. S.; Boyd, S. A.; Kester, J . A.;
Mantei, R. A.; Bal, R.; Sorensen, B. K.; Wu-Wong, J . R.; Chion, W. J .;
Dixon, D. B.; Novosad, E. I.; Hernandez, L.; Marsh, K. C. J . Med. Chem.
1996, 39, 1039. (b) Wittenberger, S. J . J . Org. Chem. 1996, 61, 356.
(c) Mulzer, J .; Meier, A.; Buschmann, J .; Luger, P. J . Org. Chem. 1996,
61, 566. (d) Yoda, Y.; Yamazaki, H.; Takabe, K. Tetrahedron: Asym-
metry 1996, 7, 373. (e) Kang, S. H.; Choi, H. Chem. Commun. 1996,
1521. (f) Yoda, H.; Nakajima, T.; Takabe, K. Tetrahedron Lett. 1996,
37, 5531. (g) Shibano, M.; Kitagawa, S.; Kusano, G. Chem. Pharm. Bull.
1997, 45, 505. (h) Miyata, O.; Ozawa, Y.; Nimomiya, I.; Naito, T. Synlett
1997, 275. (i) Bachi, M. D.; Melman, A. J . Org. Chem. 1997, 62, 1896.
(3) For a general review, see: Bird, C. W.; Cheeseman, G. W. H. In
Katritzky and Rees Comprehensive Heterocyclic Chemistry; Bird, C.
W., Cheeseman, G. W. H., Eds.; Pergamon Press: Oxford, 1984; Vol.
4, p 89.
(4) Trost, B. M.; Marrs, C. J . Am. Chem. Soc. 1993, 115, 6636.
(5) For reviews on azomethine ylides, see: (a) Lown, J . W. In 1,3-
Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley-Interscience:
New York, 1984; Vol. 1, Chapter 6, p 653. (b) Tsuge, O.; Kanemasa, S.
In Advances in Heterocyclic Chemistry; Katritzky, A. R., Ed.; Academic
Press: San Diego, 1989; Vol. 45, p 231.
(6) For a recent review on nitrogen radicals, see: Esker, J . L.;
Newcomb, M. In Advances in Heterocyclic Chemistry; Katritzky, A. R.,
Ed.; Academic Press: San Diego, 1993; Vol. 58, p 1.
(13) Xu, Z.; Lu, X. Tetrahedron Lett. 1997, 38, 3461.
S0022-3263(97)02306-2 CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/07/1998

5032 J . Org. Chem., Vol. 63, No. 15, 1998
Xu and Lu
Ta ble 1. Tr ip h en ylp h osp h in e-Ca ta lyzed Cycloa d d ition
nyl ) Ns), and N-(â-trimethylsilylethanesulfonyl)benz-
aldimines (â-trimethylsilylethanesulfonyl ) SES) were
examined.
of Meth yl 2,3-Bu ta d ien oa te w ith N-Tosylim in esa
product
In this paper, we wish to report the result of this new
[3+2] reaction toward various electron-deficient imines.
The further elaborations of the cycloaddition products
will also be discussed.
entry
2
3
yieldb (%)
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
3a
3b
3c
3d
3e
3f
3g
3h
3i
98
96
98
98
97
Resu lts a n d Discu ssion
88c
98
Cycloa d d ition of Meth yl 2,3-Bu ta d ien oa te w ith
N-Tosylim in es. Our initial attempt explored the reac-
tion of methyl 2,3-butadienoate (1a ) with N-tosyl ben-
zaldimine (2a , R1 ) Ph) in the presence of a catalytic
amount of triphenylphosphine in dry benzene at room
temperature, and the corresponding [3+2] cycloaddition
product 3a was obtained in nearly quantitative yield (eq
1).
98
53d
83e
trace
trace
10
11
12
2j
2k
2l
3j
3k
3l
a
Reaction conditions: A mixture of 1a (1.1 mmol), 2 (1.0 mmol),
and Ph3P (0.1 mmol) in dry benzene at room temperature.
Isolated yield. c A small amount of methyl 4-(p-toluenesulfona-
b
mido)-2-butenoate (4)14 was isolated. 34% of 2i was recovered.
d
e Another adduct, methyl 4,5-dihydro-5-furyl-1-tosyl-pyrrole-2-
carboxylate (5j), was isolated in 15% yield.
amounts of 3k and 3l were detected due to the low
reactivity of 2k and 2l and to self-cycloaddition of 1a .15
The nitrogen nucleophiles such as DABCO and DMAP
could not catalyze this reaction.
Cycloa d d it ion of 2,3-Bu t a d ien oa t es w it h Ot h er
Electr on -Deficien t Im in es. To further examine the
scope of this three carbon synthon, other imines bearing
alternative electron-withdrawing groups on a nitrogen
atom that similarly activate the imine but are easier to
remove after reaction were tried. Thus, N-(diphenylphos-
phinyl)benzaldimine (diphenylphosphinyl ) DPP),16 N-(p-
nitrobenzenesulfonyl)benzaldimine (p-nitrobenzenesulfo-
nyl ) Ns),17 and N-(â-trimethylsilylethanesulfonyl)benzal-
dimines (â-trimethylsilylethanesulfonyl ) SES)18 were
reacted with 1 in the presence of a catalytic amount of
triphenylphosphine. Again, the cycloaddition reaction
occurred. In particular, the SES imines gave the cy-
cloadducts in high yields (Table 2, entries 3-6). The
success of the reaction of these imines further expands
the synthetic flexibility of the cycloaddition products. For
N-(p-nitrobenzenesulfonyl)benzaldimine, methyl 4-(p-ni-
trobenzenesulfonamido)-2-butenoate (6), a phosphine-
catalyzed γ-addition adduct of p-nitrobenzenesulfonamide
to 1a , was also isolated in 38% yield.14
Unlike the reaction of 2,3-butadienoates with electron-
deficient olefins,9 the reactions of 1a with aromatic
N-tosylimines (2b-h ) in the presence of a catalytic
amount of triphenylphosphine all afforded the single
cycloaddition products (3b-h ), respectively, in excellent
yields and high chemoselectivity (Table 1). Indeed, aryl
N-tosylimines with both electron-releasing and electron-
withdrawing groups in benzene ring all gave satisfactory
results. For N-tosyl 4-nitrobenzaldimine (2f), a small
amount of methyl 4-(p-toluenesulfonamido)-2-butenoate
(4), a phosphine-catalyzed γ-addition adduct of p-tolu-
enesulfonamide to 1a , was also isolated due to the
decomposition of 2f.14 The reaction of 1a with an R,â-
unsaturated N-tosylimine, N-tosyl cinnamaldimine (2i),
also gave the normal [3+2] cycloaddition product 3i in
53% yield. However, under the same conditions, treat-
ment of 1a with N-tosyl 2-furaldimine (2j) afforded two
cycloaddition products, 3j and 5j (R1 ) 2-furyl, 85:15),
in excellent overall yield. When aliphatic N-tosylimines
lacking R-protons 2k and 2l were used, merely trace
However, under the same conditions, N-(ethoxycarbo-
nyl)benzaldimine (7) which was employed in place of
N-sulfonylimines as the dipolarophile reacted with 1a to
afford a noncyclized adduct 8 in 45-53% yield, and no
expected [3+2] cycloaddition product was isolated imply-
ing that the ethoxycarbonylnitrogen anion is not reactive
enough for further reaction (eq 2).
Cycloa d d it ion of 2-Bu t yn oa t es w it h N-Tosyl-
im in es. The success of the cycloaddition of 2,3-
(15) If a trapping reagent is less active than 1a , the self-cycloaddi-
tion product of 1a is formed. See ref 9.
(16) J ennings, W. B.; Lovely, C. J . Tetrahedron 1991, 47, 5561.
(17) Fukuyama, T.; J ow, C.-K.; Cheung, M. Tetrahedron Lett. 1995,
36, 6373.
(18) Aggarwal, V. K.; Thompson, A.; J ones, R. V. H.; Standen, M.
C. H. J . Org. Chem. 1996, 61, 8368.
(14) Addition of carbon and oxygen nucleophiles to 2,3-butadienoates
under the catalysis of a phosphine gave γ-addition products regiose-
lectively, see: Zhang, C.; Lu, X. Synlett 1995, 645. While this
manuscript was under preparation, Trost et al. reported phosphine-
catalyzed γ-addition of nitrogen pronucleophiles to methyl 2-butynoate,
see: Trost, B. M.; Dake, G. R. J . Org. Chem. 1997, 62, 5670.

A Convenient Synthesis of Pentabromopseudilin
J . Org. Chem., Vol. 63, No. 15, 1998 5033
Ta ble 2. Cycloa d d ition of 2,3-Bu ta d ien oa tes w ith Oth er
Electr on -Deficien t Im in es Ca ta lyzed by
Tr ip h en ylp h osp h in ea
Ta ble 3. 1H a n d 13C NMR Sp ectr a l Da ta of 10a
entry
1
R1
R2
yieldb of 3 (%)
1H NMR (300 MHz)
5.43 (br s, 1H)
13C NMR (75 MHz)
1
2
3
4
5
6
7
1b
1a
1a
1b
1a
1a
1a
Ph
Ph
Ph
Ph
DPP
Ns
26c
59d
96
90
96
2
4
5
1′
2′
3′
4′
70.48
136.46
70.98
6.47 (br s, 1H)
SES
SES
SES
SES
SES
4.95 (dt, J ) 7.5, 2.1 Hz, 1H)
4.61 (dd, J ) 7.5, 3.6 Hz, 1H)
6.05 (d, J ) 3.6 Hz, 1H)
6.63 (d, J ) 7.3 Hz, 2H)
7.83 (d, J ) 8.2 Hz, 2H)
62.02
p-MeC6H4
p-ClC6H4
(E)-PhCHdCH
97
127.65
128.30
36e
a
b
Reaction conditions are similar to Table 1. Isolated yield.
c 54% of starting material was recovered. Methyl 4-(p-nitroben-
d
Ta ble 4. Tr ibu tylp h osp h in e-Ca ta lyzed Cycloa d d ition of
Meth yl 2,3-Bu ta d ien oa te or 2-Bu tyn oa tes w ith
N-Tosylim in esa
zenesulfonamido)-2-butenoate (6)14 was isolated in 38% yield.
e 10% of starting material was recovered.
products
butadienoates with N-sulfonylimines encourages us to
explore the reaction of 2-butynoates. When a mixture
of ethyl 2-butynoate (9b) and 2a in dry benzene in the
presence of 15 mol % of triphenylphosphine was heated
at 110 °C for 57 h, no reaction occurred, implying that
the nucleophilicity of triphenylphosphine was too weak
to trigger the 2-butynoate to the active allenic intermedi-
ate, which was consistent with our previous result.9
Thus, tributylphosphine was used instead of triph-
enylphosphine as the catalyst. Interestingly, treatment
of 9b with 2a in dry benzene in the presence of a catalytic
amount of tributylphosphine at room temperature ob-
tained a small amount of the three components adduct
10a ′ besides the corresponding [3+2] cycloadduct 3a ′ as
the major product in 96% overall yield (eq 3).
entry
1/9
2
yieldb (%)
3:10c
1
2
3
4
5
6
7
8
9
1a
9b
9a
9b
9b
9a
9a
9a
9a
2a
2a
2b
2c
2d
2e
2k
2l
98
96
95
86
93
87
57
14
47
87:13 (3a :10a )
85:15 (3a ′:10a ′)
81:19 (3b:10b)
90:10 (3c′:10c′)
82:18 (3d ′:10d ′)
85:15 (3e:10e)
100:0 (3k :10k )
100:0 (31:101)
100:0 (3m :10m )
2m
a
Reaction conditions: A mixture of 1 or 9 (1.1 mmol), 2 (1.0
mmol), and Bu3P (0.1 mmol) in dry benzene at room temperature.
Isolated yield. c Ratios were determined by isolation.
b
with H-2, also has a NOE signal with H-1′. Here, the
chemical shift of H-3′ is shifted to high fields possibly
due to the shielding effect of the benzene ring of 1-tosyl.
Moreover, H-4′, which has a NOE signal with H-2, also
has a NOE signal with H-5 implying that the relative
stereochemistry is 1, 2-trans and 2, 5-cis.
Similarly, the reactions of 9 with other N-tosylimines
(2b-e) using tributylphosphine as the catalyst afforded
identical results (Table 4). For the reaction of 9a with
aliphatic N-tosylimine, N-tosyl pivalaldimine (2k ), the
corresponding cycloaddition product 3k was also isolated
in 57% yield. Similarly, 3l and 3m were obtained in 14%
and 47% yields, respectively. Here, the success of the
reaction of the aliphatic imines 2k and 2m expanded the
synthetic utility of this cycloaddition reaction again. For
the aliphatic N-tosylimines, the tributylphosphine-
catalyzed reaction of 2-butynoates gave better results
than the triphenylphosphine-catalyzed reaction of 2,3-
butadienoates (compare entries 11 and 12 of Table 1 with
entries 7-9 of Table 4).
Furthermore, the reaction of 1a with 2a using tribu-
tylphosphine instead of triphenylphosphine as the cata-
lyst was carried out affording an identical result. We,
therefore, speculated that the electrophilicity of vi-
nylphosphonium salt intermediate may also play a role
in this reaction (vide infra).
The structure of 10a (R ) Me, R1 ) Ph) was deter-
1
mined by H and 13C NMR spectral analysis, involving
COSY, HMQC, NOESY, and deuterium exchange experi-
ments. 1H and 13C NMR spectral data of 10a are partly
summarized in Table 3. In the 1H-1H COSY spectra, H-2,
H-4, and H-5 have coupling signals to each other. Both
H-5 and H-2′ also have coupling signals with H-1′. In
the NOESY spectra, both H-4 and H-1′ have NOE signals
with H-5. In particular, H-3′, which has a NOE signal
Cycloa d d ition of Dim eth yl Acetylen ed ica r boxy-
la te a n d N-Tosylim in es. Recently, Nozaki et al.19
reported a triphenylphosphine-catalyzed cyclization of
R-keto esters, R-keto nitriles, or R,R,R-trifluoroacetophe-
(19) Nozaki, K.; Sato, N.; Ikeda, K.; Takaya, H. J . Org. Chem. 1996,
61, 4516.

5034 J . Org. Chem., Vol. 63, No. 15, 1998
Xu and Lu
Sch em e 1
none with dimethyl acetylenedicarboxylate to produce
highly functionalized R,â-unsaturated γ-butyrolactones
in moderate yields. In this reaction, an electron-
withdrawing substituent attached to the carbonyl group
is essential. From our previous work, we anticipated that
N-sulfonylimines could also carry out the cyclization
reaction instead of the electron-deficient carbonyl com-
pounds as trapping reagents. Treatment of dimethyl
acetylenedicarboxylate (11) with N-tosyl benzaldimine
(2a ) in the presence of 20 mol % of triphenylphosphine
in dry benzene under reflux did give 1-tosyl-5-phenyl-3-
methoxy-4-methoxycarbonyl-3-pyrrolin-2-one (12a) in 84%
isolated yield (eq 4).
Other N-tosylimines were also examined under similar
conditions, and the results are summarized in Table 5.
It is obvious that the steric factors influence yields of the
reaction of 11 with aromatic N-tosylimines. For example,
2-methoxyphenyl and 1-naphthyl N-tosylimines gave the
corresponding cyclization products in lower yields with
the recovery of the starting materials. In fact, for the
less hindered aromatic N-tosylimines (e.g., 2a ), the
reaction could be carried out at room temperature af-
fording the products in higher yields. The reaction of 11
with the R,â-unsaturated N-tosylimine, N-tosyl cinna-
maldimine (2i), also gave the cyclization product 12i in
85% yield. However, under the same conditions, treat-
ment of 11 with N-tosyl 2-methylpropenaldimine (2n )
afforded the cyclization product 12n only in 4.2% yield
probably due to the instability of 2n .
Rea ction Mech a n ism . Since both the phosphine as
the catalyst and the imines bearing different electron-
withdrawing groups on a nitrogen atom as the dipolaro-

A Convenient Synthesis of Pentabromopseudilin
J . Org. Chem., Vol. 63, No. 15, 1998 5035
Ta ble 5. F or m a tion of P yr r olin -2-on es fr om
N-Tosylim in es a n d Dim eth yl Acetylen ed ica r boxyla te
Ca ta lyzed by Tr ip h en ylp h osp h in ea
Sch em e 2
product
entry
2
reaction time (h)
12
yieldb (%)
1
2
3
4
5
6
7
8
9
2a
2a
2b
2c
2d
2e
2g
2h
2i
4
11c
52
14
14
4
3.5
28
4
12a
12a
12b
12c
12d
12e
12g
12h
12i
84
93
27 (68)d
86 (94)e
83 (92)e
96
97
56 (77)f
85 (95)g
4.2 (5)i
10
2n h
42
12n
Sch em e 3
a
Reaction conditions: A mixture of 11 (1.2 mmol), 2 (1.0 mmol),
b
and Ph3P (0.2 mmol) in dry benzene was refluxed. Isolated yield.
Yields in parentheses are based on the reacted starting materials.
d
c The reaction was carried out at room temperature. 60% of
starting material was recovered. e 9% of starting materials was
g
recovered. f 27% of starting material was recovered. 10% of
h
i
starting material was recovered. R1 ) 2-propenyl. 14% of start-
ing material was recovered.
philes likely change the products formed (eq 5); a reaction
13′ can be generated, a speculated mechanism is similar
to that of the tributylphosphine-catalyzed reaction of 1
via the intermediate 13′ (Scheme 2).
mechanism is proposed as outlined in Scheme 1.
First, allenoate 1a reacts with a phosphine to generate
the reactive dipolar intermediate 13, which is trapped
by the dipolarophilic imine to form an open chain
intermediate 14. Here, both the nucleophilicity of the
nitrogen anion and the electrophilicity of the vinylphos-
phonium salt intermediate are critical for the cycloaddi-
tion reaction. For path a, when Ts, DPP, Ns, and SES
are used as the activating groups of the imine, the normal
cyclization takes place forming the intermediate 15AA.
When the ethoxycarbonyl is used as an activating group,
the proton transfer affords the intermediate 15AB.
Finally, the intermediates 15AB and 15AA which will
first transform to 16AA by the proton transfer give the
corresponding products 3 and 8, respectively, with the
regeneration of the phosphine as the catalytic species.
Compound 5j might be formed by path b due to the lower
reactivity of 2j which could not react with 13 quickly
enough to prohibit the transformation of 13 to the
delocalized structure 13′.20 For the tributylphosphine-
catalyzed reaction of 1a , the intermediate 15BB is formed
by the proton transfer of 14B and further reacts with
another molecule of the imine affording the three com-
ponents adduct 10. For the tributylphosphine-catalyzed
reaction of 2-butynoates 9, since the same intermediate
For the phosphine-catalyzed γ-addition reaction of
sulfonamides to 1a , a possible mechanism is outlined in
Scheme 3. First, triphenylphosphine attacks the â-car-
bon of 1a to give the phosphonium salt intermediate 20,
which then abstracts a proton from the sulfonamide 21
to form the corresponding vinylphosphonium salt 22, and
subsequent Michael addition of sulfonamide anion 23 to
22 followed by a proton transfer affords the γ-addition
product with the regeneration of triphenylphosphine to
complete the catalytic cycle.
For the reaction of dimethyl acetylenedicarboxylate
with N-tosylimines catalyzed by triphenylphosphine, a
proposed mechanism of the reaction is outlined in Scheme
4. First, nucleophilic attack of triphenylphosphine on the
â-carbon of the electron-deficient alkyne 11 generates the
zwitterionic intermediate 24, which is trapped by the
electrophilic N-tosylimine 2 followed by intramolecular
nucleophilic addition of the nitrogen atom of toluene-
sulfonamide to the carbonyl group of ester and subse-
quent elimination of methoxy group to form the cyclic
phosphonium alkoxide intermediate 25. Finally, conju-
gate addition of the methoxy anion to the â-triph-
enylphosphonium R,â-unsaturated ester counterpart af-
fords the corresponding cyclization product 12 with the
regeneration of triphenylphosphine to complete the cata-
lytic cycle.
(20) The π orbitals of the two carbon-carbon double bonds in allenes
are perpendicular to each other. In the initially generated intermediate
13, the orbital of the unshared electron pair is also perpendicular to
the π orbital of the R,â-carbon-carbon double bond. After a 90° rotation
around the CR-Câ bond, the delocalized structure 13′ was formed,
which results in the formation of 5. For a similar result, see: Zhang,
C.; Lu, X. Synlett 1995, 645.
Ela bor a tion s of th e Cycloa d d ition P r od u cts. To
further confirm the stucture of the cycloaddition product
and to develop a new route to pyrrole derivatives, we
carried out the aromatization of the cycloadduct using

5036 J . Org. Chem., Vol. 63, No. 15, 1998
Xu and Lu
Sch em e 4
tion of p-toluenesulfinic acid as the by-product, the
structure of which was further confirmed by its conver-
sion to the benzyl sulfone 29 (eq 8).22
Ta ble 6. Syn th esis of 2-Ar yl P yr r ole Der iva tives
product
DDQ
(eq)
time
(days)
yielda
(%)
yielda
(%)
entry
3
26
27
1
2
3
4
5
3a
3b
3e
3g
3h
2.0
1.5
1.5
2.0
1.5
1.5
2.5
2
3
2
26a
26b
26e
26g
26h
92
81
95
38
99
27a
27b
27e
27g
27h
86
92
88
87
95
While sodium methoxide was used instead of Bu4NF
as a base, no expected product was isolated.
The aromatization reaction mediated by Bu4NF is a
convenient and efficient method for the synthesis of
pyrrole derivatives. For instance, methyl 2-furyl-1H-
pyrrole-3-carboxylate (27j) was synthesized in 66% yield
using this method, which could not be obtained using
DDQ dehydrogenation method (eq 9).
a
Isolated yield.
DDQ as the oxidant followed by treatment with sodium
methoxide in methanol to eliminate the tosyl group (eq
6).
Heating the mixture of the cycloadduct, 3a , 3b, 3e, 3g,
or 3h , and DDQ (1.5-2.0 equiv) in dry benzene at about
130 °C for about 2-3 days until the starting material
completely disappeared as monitored by TLC gave the
dehydrogenation product, 26a , 26b, 26e, 26g or 26h , in
moderate to good yield (Table 6). Subsequent detosyla-
tion of 26 using sodium methoxide produced the pyrrole
27 in excellent yield. Surprisingly, aromatization of 3i
gave the defurylated product (26, R1 ) H) in 14% yield.
The SES group has been shown to be easily removed
from amines by fluoride.21 Thus, we carried out the
deprotection of its corresponding cycloaddition products
using Bu4NF in THF at room temperature or reflux.
Unexpectedly, the desulfonylated aromatized products
(27) were directly obtained instead of the corresponding
desulfonylated products (28) in moderate yields (eq 7).
It is worth noting that this reaction can also be applied
to the aromatization of N-tosyl derivative 3a . In this
case, it was suggested that the reaction occurred via a
tandem desulfination-isomerization process by the isola-
Furthermore, 2-aryl-substituted pyrroles can also be
formed readily via the decarboxylation of 27 as shown
in eq 10.23 Thus, this provides a new and efficient route
to 2-aryl-substituted pyrrole derivatives.
The removal of the tosyl group from p-toluenesulfony-
lamide usually requires relatively harsh reaction condi-
tions.24 We applied the radical approach developed by
(22) Kamiyama, T.; Enomoto, S.; Inoue, M. Chem. Pharm. Bull.
1988, 36, 2652.
(23) Pavri, N. P.; Trudell, M. L. J . Org. Chem. 1997, 62, 2649.
(21) Weinreb, S. M.; Demko, D. M.; Lessen, T. A. Tetrahedron Lett.
1986, 27, 2099.

A Convenient Synthesis of Pentabromopseudilin
J . Org. Chem., Vol. 63, No. 15, 1998 5037
Sch em e 5
Sch em e 6
Sch em e 7
Parsons et al.25 to the N-desulfonation of the highly
functionalized substrate 12a , yielding the expected deto-
sylated product 31a in 84% yield (eq 11). This provides
a convenient synthesis of pyrrolin-2-one derivatives.
Syn t h esis of P en t a b r om op seu d ilin . Pentabro-
mopseudilin (32), a potent marine antibiotic isolated from
Pseudomonas bromoutiliz,26 Chromobacteria,27 and Al-
teromonas luteoviolaceus,28 is a stronger antibiotic than
penicillin29 and exhibits antitumor, antimicrobial, and
phytotoxic activities.30 The interesting biological proper-
ties and the high bromine content (over 70%) made it an
interesting object. To date, two different syntheses have
been reported,28,31 and the biosynthesis was also inves-
tigated.29 At the same time, numerous analogues have
been synthesized, and their biological and pharmacologi-
cal activities were tested.28,30,32 We now report a novel
synthesis of pentabromopseudilin on the basis of this new
[3+2] cycloaddition.
All syntheses reported involved the same key inter-
mediate, 2-(3,5-dibromo-2-methoxyphenyl)-1H-pyrrole (33)
(Scheme 5, path a). Initially, we also attempted to
synthesize the intermediate as shown in Scheme 6. The
easy hydrolysis of N-tosyl 2-methoxy-3,5-dibromoben-
zaldimine led to direct use of the crude product in the
cycloaddition without further purification. The cycload-
duct 35 was obtained in 60% yield based on the starting
aldehyde. Subsequent aromatization mediated by Bu4-
NF afforded 2-aryl-substitued pyrrole carboxylate 36 in
83% yield. However, hydrolysis and subsequent decar-
boxylation of 36 with ethanolamine or Cu powder/
quinoline methods was unsuccessful due to the thermoin-
stability of 33.
Then, we chose the parent compound, 2-(2-hydrox-
yphenyl)-1H-pyrrole (34), as the key intermediate as
shown in Scheme 7. The adduct 3b is available from
N-tosyl 2-methoxybenzaldimine (2b) and methyl 2,3-
butadienoate (1a ) or methyl 2-butynoate (9a ) under the
catalysis of a phosphine. Aromatization of 3b gave the
pyrrole derivative 27b readily by treatment of Bu4NF in
THF at room temperature. Hydrolysis and subsequent
decarboxylation of 27b with ethanolamine or Cu powder/
quinoline followed by demethylation with sodium sulfide
in N-methylpyrrolidone (NMP)33 afforded the key inter-
mediate 34. Subsequent bromination to introduce five
bromine atoms to 34 in a single operation is a challenging
step. Several attempts directly using elemental bromine
as a bromination reagent were unsucessful. The desired
bromination was finally achieved by employing pyri-
dinium bromide perbromide,34 and the target molecule
32 was thus obtained in 20% overall yield from N-
tosylimine 2b.
Con clu sion
In summary, we presented the reactivity of the new
three carbon synthon, generated in situ from the reaction
of 1 or 9 with an appropriate phosphine toward imines
bearing an electron-withdrawing group on nitrogen atoms
such as sulfonyl (Ts, Ns, SES), diphenylphosphinyl, and
ethoxycarbonyl. It was found that the phosphine used
can influence the electrophilic reactivity of vinylphos-
phonium salt intermediate 14. That is, vinyltriph-
enylphosphonium salt has stronger electrophilicity and
(24) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 2nd ed.; Wiley: New York, 1991.
(25) Parsons, A. F.; Pettifer, R. M. Tetrahedron Lett. 1996, 37, 1667.
(26) Burkholder, P. R.; Pfister, R. M.; Leitz, F. H. Appl. Microbiol.
1966, 14, 649.
(27) Anderson, R. J .; Wolfe, M. S.; Faulkner, D. Mar. Biol. 1974,
27, 281.
(28) Laatsch, H.; Pudleiner, H. Liebigs Ann. Chem. 1989, 863.
(29) Hanefeld, U.; Floss, H. G.; Laatsch, H. J . Org. Chem. 1994, 59,
3604.
(30) Laatsch, H.; Renneberg, B.; Hanefeld, U.; Kellner, M.; Pudlein-
er, H.; Hamprecht, G.; Kraemer, H. P.; Anke, H. Chem. Pharm. Bull.
1995, 43, 537.
(31) Hanessian, S.; Kaltenbronn, J . S. J . Am. Chem. Soc. 1966, 88,
4509.
(32) (a) Pudleiner, H.; Laatsch, H. Liebigs Ann. Chem. 1990, 423.
(b) Hanefeld, U.; Laatsch, H. Liebigs Ann. Chem. 1991, 865. (c)
Renneberg, B.; Kellner, M.; Laatsch, H. Liebigs Ann. Chem. 1993, 847.
(33) Newman, M. S.; Sankaran, V.; Olson, D. R. J . Am. Chem. Soc.
1976, 98, 3237.
(34) Reagents for Organic Synthesis; Fieser, L. F., Fieser, M., Eds;
Wiley-Interscience: New York, 1967; Vol. 1, p 967.

5038 J . Org. Chem., Vol. 63, No. 15, 1998
Xu and Lu
takes advantage of [3+2] cycloaddition.35,36 Although
nucleophilic attack of tributylphosphine is easier than
that of triphenylphosphine, the electrophility of its cor-
respounding vinylphosphonium salt intermediate is
weaker. On the other hand, the stronger the electron-
withdrawing group on the nitrogen atom of imines as the
dipolarophiles, the more favored the cycloaddition. For
the ethoxycarbonyl, no cycloaddition product was pro-
duced due to the nucleophilicity of the corresponding
nitrogen anion. For the diphenylphosphinyl, the cycload-
duct was obtained only in low yield with the recovery of
the starting material due to the low electrophilicity of
the carbon atom of the corresponding imine. For the
p-nitrobenzenesulfonyl, the cycloaddition product was
obtained in moderate yield due to the low stability of the
imine. Thus, Ts and SES are the most suitable activating
groups for this cycloaddition reaction. In addition, a new
phosphine-catalyzed cyclization reaction of dimethyl
acetylenedicarboxylate with N-tosylimines was devel-
oped. The transformation of the cycloaddition products
was also studied, and as an illustration, pentabro-
mopseudilin was synthesized efficiently from easily
available N-tosyl 2-methoxybenzaldimine. The investi-
gation of the appropriate dipolarophiles and the synthetic
utilization of the three carbon synthon is in progress.
mixture was refluxed on a Dean-Stark apparatus for 24 h.
The cooled solution was poured into saturated NaHCO3 (100
mL), the benzene layer was isolated, and the water layer was
extracted once with ethyl acetate (50 mL). The combined
organic phase was dried over Na2SO4. After solvents were
evaporated under reduced pressure, the residue was purified
by column chromatography on silica gel (eluent: petroleum
ether/ethyl acetate ) 9:1) to yield a solid which was recrystal-
lized from petroleum ether or CH2Cl2/petroleum ether.
N-(p-Nitr oben zen esu lfon yl)ben za ld im in e. Yield 81%;
mp 148.5-149.5 °C (EtOAc/petroleum ether); 1H NMR δ 9.14
(s, 1H), 8.41 (d, J ) 8.80 Hz, 2H), 8.22 (d, J ) 8.75 Hz, 2H),
7.97 (deformed d, J ) 7.13 Hz, 2H), 7.69 (deformed t, J ) 7.44
Hz, 1H), 7.54 (deformed t, J ) 7.67 Hz, 2H); IR 1528, 1351,
1164 cm-1; MS m/z 290 (M+, 15.75), 104 (PhCHdN+, 100.00);
HRMS calcd for C13H10N2O4S 290.0361, found 290.0381.
N-(â-Tr im eth ylsilyleth an esu lfon yl)ben zaldim in e. Yield
82%; mp 54-56 °C (hexane); 1H NMR δ 9.04 (s, 1H), 7.97
(deformed d, J ) 7.06 Hz, 2H), 7.66 (deformed t, J ) 7.35 Hz,
1H), 7.53 (deformed t, J ) 7.60 Hz, 2H), 3.18-3.12 (m, 2H),
1.09-1.03 (m, 2H), 0.06 (s, 9H); IR 1609, 1316, 1136 cm-1; MS
m/z 192 (M+-Ph, 56.96), 104 (M+-SES, 19.43), 73 (TMS+,
100.00); HRMS calcd for
269.0871.
C12H19NO2SSi 269.0906, found
N-(â-Tr im et h ylsilylet h a n esu lfon yl)cin n a m a ld im in e.
1
Yield 69%; mp 93-94 °C (petroleum ether); H NMR δ 8.77
(d, J ) 9.38 Hz, 1H), 7.62-7.42 (m, 6H), 7.04 (dd, J ) 15.80,
9.49 Hz, 1H), 3.13-3.06 (m, 2H), 1.07-1.01 (m, 2H), 0.07 (s,
9H); IR 1621, 1584, 1312, 1141 cm-1; MS m/z 295 (M+, 0.17),
188 (M+-SO2-C2H4-CH3, 42.46), 130 (M+-SES, 25.51), 73
(TMS+, 100.00). Anal. calcd for C14H21NO2SSi: C, 56.91; H,
7.16; N, 4.74. Found: C, 56.82; H, 7.29; N, 4.73.
Exp er im en ta l Section
Ma ter ia ls. Methyl 2,3-butadienoate (1a ),37 ethyl 2,3-buta-
dienoate (1b),38 N-tosylimines 2a -k ,39 2l,10e and 2n ,40 and
N-(diphenylphosphinyl)benzaldimine10e were prepared by the
reported methods. Tetrabutylammonium fluoride (1.0 M
solution in tetrahydrofuran) was purchased from Aldrich and
used directly. All solvents were purified by distillation from
the indicated drying agents: benzene (sodium), dichlo-
romethane (CaH2), and THF (sodium, benzophenone). 1H
NMR spectra were recorded on a 300 MHz spectrometer in
CDCl3 using tetramethylsilane as the internal standard.
Infrared spectra were measured using KBr disk unless oth-
erwise stated.
N-(p -Nit r ob en zen esu lfon yl)b en za ld im in e a n d N-(â-
Tr im eth ylsilyleth a n esu lfon yl)ben za ld im in es18 were syn-
thesized according to a procedure analogous to that described
by McKay.39 To a solution of benzaldehyde (1 mL, 10 mmol)
and â-trimethylsilylethanesulfonamide (1.81 g, 10 mmol) in
benzene (80 mL) was added BF3‚Et2O (0.08 mL). The
N-Tosyl 2-m eth yl-1,3-d ith ia n e-2-ca r boxa ld im in e (2m )
was similarly synthesized from 2-methyl-1,3-dithiane-2-car-
1
boxaldehyde.39 Yield 56%; mp 85-88 °C; H NMR δ 8.34 (s,
1H), 7.84 (d, J ) 8.2 Hz, 2H), 7.35 (d, J ) 8.2 Hz, 2H), 3.06
(ddd, J ) 14.7, 12.9, 2.6 Hz, 2H), 2.56 (ddd, J ) 14.7, 4.2, 3.3
Hz, 2H), 2.44 (s, 3H), 2.11-2.04 (m, 1H), 1.85-1.69 (m, 1H),
1.56 (s, 3H); IR 1618, 1316, 1153 cm-1; MS m/z 315 (M+, 3.32),
133 (M+-CHdNTs, 100.00); HRMS calcd for C13H17NO2S3
315.0421, found 315.0382.
N-(Eth oxyca r bon yl)ben za ld im in e (7)41 was synthsized
according to a procedure analogous to that described by
Greene.42 Benzaldehyde (3 mL, 29 mmol) in methanol (10 mL)
and 88% formic acid (5 mL) was added to a solution of urethane
(2.23 g, 25 mmol) and sodium benzenesulfinate dihydrate (5.01
g, 25 mmol) in water (25 mL). The mixture was heated at 70
°C for 2 h and then allowed to stir overnight at room
temperature. The resulting white precipitate was filtered and
washed sequentially with water, petroleum ether, and diiso-
propyl ether and dried in vacuo to give 3.69 g (46%) of
N-ethoxycarbonyl-R-(phenylsulfonyl)benzyl-
amine, suitable for use in the next step without purification.
Data for sulfone: 1H NMR (90 MHz) δ 7.90-7.77 (m, 2H),
7.67-7.18 (m, 8H), 5.98 (br s, 2H), 3.97 (q, J ) 7.5 Hz, 2H),
1.12 (t, J ) 7.5 Hz, 3H). A mixture of sulfone (0.58 g, 1.8
mmol), obtained as described above, and anhydrous K2CO3 (1.5
g, 10.8 mmol) in THF (20 mL) under nitrogen was refluxed at
95-100 °C on an oil bath for 12 h. The mixture was then
allowed to cool to room temperature and filtered through filter
paper, and the solid was washed with THF (5 mL). The
combined filtrate was concentrated under reduced pressure
and then dried in vacuo at room temperature for several hours,
furnishing 0.31 g (97%) of imine 7.41 1H NMR (90 MHz, CCl4)
δ 8.71 (s, 1H), 7.90-7.68 (m, 2H), 7.50-7.23 (m, 3H), 4.18 (q,
J ) 7.5 Hz, 2H), 1.28 (t, J ) 7.5 Hz, 3H).
(35) The extent of the electron deficientcy of the â carbon in
vinylphosphonium salts is interpreted as due to the overlap of the π
orbital of the vinyl group with an empty d orbital on phosphorus, that
is dπ-pπ bonding between phosphorus and carbon. A comparison of
the 31P chemical shifts or the 13C chemical shifts of the â vinyl carbon
in vinyltriphenylphosphonium bromide (38) and vinyltributylphospho-
nium bromide (39) shows that the phosphorus in 38 (δ 19.3 ppm) is
shifted to high fields relative to the phosphorus in 39 (δ 27.4 ppm)
and that the â vinyl carbon in 38 (δ 145.2 ppm) is shifted to low fields
relative to the â vinyl carbon in 39 (δ 141.2 ppm). Indeed, these both
indicate that the contribution of significant dπ-pπ conjugation in
vinyltriphenylphosphonium salt with resonance structure B is impor-
tant and that the â vinyl carbon of vinyltriphenylphosphonium salt
can be regarded as positive. Therefore, the cycloaddition of vinyltriph-
enylphosphonium salt is preferred.36
Tr iph en ylph osph in e-Catalyzed Cycloaddition of Meth -
yl 2,3-Bu ta d ien oa te w ith N-Tosylim in es. Gen er a l P r o-
ced u r e for th e P r ep a r a tion of Meth yl 2,5-Dih yd r o-2-
su bstitu ed-1-tosyl-pyr r ole-3-car boxylate (3). To a mixture
of triphenylphosphine (30 mg, 0.1 mmol) and N-tosylimine 2
(36) Albright, T. A.; Freeman, W. J .; Schweizer, E. E. J . Am. Chem.
Soc. 1975, 97, 2946.
(37) (a) Lang, R. W.; Hansen, H.-J . Helv. Chim. Acta 1980, 63, 438.
(b) Lang, R. W.; Hansen, H.-J . Org. Synth. 1984, 62, 202.
(38) Paik, Y. H.; Dowd, P. J . Org. Chem. 1986, 51, 2910.
(39) McKay, W. R.; Proctor, G. R. J . Chem. Soc., Perkin Trans. 1
1981, 2435.
(41) Kupfer, R.; Meier, S.; Wurthwein, E.-U. Synthesis 1984, 688.
(42) Kanazawa, A. M.; Denis, J .-N.; Greene, A. E. J . Org. Chem.
1994, 59, 1238.
(40) Burgess, K.; Ohlmeyer, M. J . J . Org. Chem. 1991, 56, 1027.

A Convenient Synthesis of Pentabromopseudilin
J . Org. Chem., Vol. 63, No. 15, 1998 5039
(1.0 mmol) in benzene (5 mL) was added a solution of methyl
2,3-butadienoate (1a ) (110 mg, 1.1 mmol) in benzene (5 mL).
The mixture was then stirred at room temperature under
nitrogen and monitored by TLC (eluent: petroleum ether/ethyl
acetate ) 4/1). After the reaction was complete, the reaction
mixture was concentrated under reduced pressure and the
residue was purified by column chromatography on silica gel
(eluent: petroleum ether/ethyl acetate ) 17:3) to give 3.
Meth yl 2,5-Dih yd r o-2-p h en yl-1-tosyl-p yr r ole-3-ca r box-
Meth yl 2,5-Dih ydr o-2-ph en yl-1-(â-tr im eth ylsilyleth an e-
su lfon yl)-pyr r ole-3-car boxylate. Mp 98.5-99.5 °C (benzene/
1
hexane); H NMR δ 7.35-7.31 (m, 5H), 6.92 (q, J ) 1.91 Hz,
1H), 5.81 (dt, J ) 6.11, 2.07 Hz, 1H), 4.75 (dt, J ) 17.03, 2.50
Hz, 1H), 4.39 (ddd, J ) 17.00, 6.20, 1.92 Hz, 1H), 3.61 (s, 3H),
2.31 (dtd, J ) 30.50, 13.54, 4.40 Hz, 2H), 0.71 (dtd, J ) 44.16,
13.7, 4.47 Hz, 2H), -0.19 (s, 9H); IR 1724, 1639, 1149, 1091
cm-1; MS m/z 352 (M+-CH3, 1.99), 202 (M+-SES, 33.47), 170
(M+-SESH-OMe, 33.01), 73 (TMS+, 100.00). Anal. calcd for
1
yla te (3a ). Mp 109-110 °C; H NMR δ 7.42 (d, J ) 8.2 Hz,
C17H25NO4SSi: C, 55.55; H, 6.86; N, 3.81. Found: C, 55.77;
H, 7.10; N, 3.99.
2H), 7.23 (s, 5H), 7.14 (d, J ) 8.2 Hz, 2H), 6.77 (q, J ) 1.9 Hz,
1H), 5.75 (dt, J ) 5.7, 1.9 Hz, 1H), 4.53 (dt, J ) 17.1, 2.4 Hz,
1H), 4.37 (ddd, J ) 17.1, 5.7, 1.9 Hz, 1H), 3.58 (s, 3H), 2.36 (s,
Met h yl 2,5-Dih yd r o-2-cin n a m yl-1-(â-t r im et h ylsilyl-
eth an esu lfon yl)-pyr r ole-3-car boxylate. Mp 82-84 °C (hex-
ane); 1H NMR δ 7.40-7.23 (m, 5H), 6.82 (q, J ) 1.85 Hz, 1H),
6.76 (d, J ) 15.75 Hz, 1H), 6.07 (dd, J ) 15.77, 8.16 Hz, 1H),
5.50-5.46 (m, 1H), 4.65 (dt, J ) 17.10, 2.30 Hz, 1H), 4.31 (ddd,
J ) 17.13, 5.74, 1.91 Hz, 1H), 3.81 (s, 3H), 2.97-2.88 (m, 2H),
1.10-0.89 (m, 2H), -0.09 (s, 9H); IR 1722, 1642, 1334, 1272,
1147 cm-1; MS m/z 393 (M+, 1.17), 228 (M+-SES, 8.80), 196
(M+-SESH-OMe, 6.89), 73 (TMS+, 100.00). Anal. calcd for
3H); IR 1726, 1648, 1341, 1159 cm-1; MS m/z 357 (M+, 3.89),
280 (M+-Ph, 42.20), 202 (M+-Ts, 68.89), 91 (CH3C6H4
,
+
100.00). Anal. calcd for C19H19NO4S: C, 63.85; H, 5.36; N,
3.92. Found: C, 63.59; H, 5.18; N, 3.65.
Meth yl 4-(p-Tolu en esu lfon a m id o)-2-bu ten oa te (4). Mp
100-101 °C; 1H NMR δ 7.75 (d, J ) 8.2 Hz, 2H), 7.33 (d, J )
7.9 Hz, 2H), 6.78 (dt, J ) 15.7, 5.20 Hz, 1H), 5.95 (dt, J )
15.7, 1.84 Hz, 1H), 4.58 (deformed t, J ) 6.07 Hz, 1H), 3.79-
3.74 (m, 2H), 3.72 (s, 3H), 2.44 (s, 3H); IR 3265, 3242, 1726,
1702, 1663, 1160 cm-1; MS m/z 238 (M+-OMe, 1.16), 114 (M+-
C
19H27NO4SSi: C, 57.98; H, 6.91; N, 3.56. Found: C, 58.17;
H, 6.98; N, 3.73.
Tr ip h en ylp h osp h in e-Ca ta lyzed Rea ction of Meth yl
2,3-Bu t a d ien oa t e w it h N-(E t h oxyca r b on yl)b en za ld i-
m in e. To a solution of triphenylphosphine (30 mg, 0.10 mmol)
in benzene (4 mL) was added a solution of allenoate 1a (0.14
g, 1.43 mmol) and imine 7 (0.215 g, 1.21 mmol) in benzene
(10 mL) at room temperature under nitrogen with a springe
pump at 0.35 mL/h rate for 22 h, and the mixture was stirred
for 24 h. The reaction mixture was then concentrated under
reduced pressure, and the residue was purified by column
chromatography on silica gel (eluent: petroleum ether/ethyl
acetate ) 17:3) to afford 0.255 g (54%) of a noncyclized adduct
8 as a syrup. 1H NMR δ 7.37-7.24 (m, 5H), 5.79 (deformed d,
J ) 9.1 Hz, 1H), 5.71 (deformed d, J ) 9.1 Hz, 1H), 5.35 (br s,
2H), 4.12 (q, J ) 7.1 Hz, 2H), 3.66 (s, 3H), 1.22 (t, J ) 7.1 Hz,
3H); 13C NMR (75 MHz) δ 213.1 (allenic C), 165.8 (C), 155.6
(C), 140.2 (C), 128.4 (CH), 127.5 (CH), 126.5 (CH), 101.8 (C),
81.3 (CH2), 61.0 (CH2), 53.8 (CH), 52.1 (CH3), 14.4 (CH3); IR
(film) 3333, 1966 (allene), 1719, 1506, 1269, 1252 cm-1; MS
m/z 275 (M+, 17.86), 187 (M+-NHCO2Et, 43.13), 178
(PhCHNHCO2Et+, 100.00); HRMS calcd for C15H17NO4
275.1157, found 275.1170.
Tr ibu tylp h osp h in e-Ca ta lyzed Cycloa d d ition of 2-Bu -
tyn oa tes w ith N-Tosylim in es. Gen er a l P r oced u r e for
th e P r ep a r a tion of 2,5-Dih yd r o-2-su bstitu ed -1-tosyl-p yr -
r ole-3-ca r boxyla tes (3) a n d 2,5-Dih yd r o-2,5-d isu bstitu ed -
1-tosyl-pyr r ole-3-car boxylates (10). 2-Butynoate (1.1 mmol)
in benzene (4 mL) and tributylphosphine (0.17 M in benzene,
0.6 mL, 0.1 mmol) were added to N-tosylimine 2 (1.0 mmol)
in benzene (5 mL). The mixture was then stirred at room
temperature under nitrogen and monitored by TLC (eluent:
petroleum ether/ethyl acetate ) 4/1). After the reaction was
complete, the reaction mixture was concentrated under re-
duced pressure and the residue was purified by column
chromatography on silica gel (eluent: petroleum ether/ethyl
acetate ) 17:3 for first fraction and then 3:1 for second fraction)
to afford 3 and 10.
Ts, 100.00), 82 (M+-TsH-OMe, 52.30). Anal. calcd for C12H15
-
NO4S: C, 53.51; H, 5.61; N, 5.20. Found: C, 53.48; H, 5.38;
N, 5.00.
Meth yl 2,5-Dih yd r o-2-cin n a m yl-1-tosyl-p yr r ole-3-ca r -
boxyla te (3i). Mp 118.5-119.5 °C (CCl4); 1H NMR (400 MHz)
δ 7.71 (d, J ) 8.3 Hz, 2H), 7.30-7.22 (m, 7H), 6.69 (d, J )
15.8 Hz, 1H), 6.66 (q, J ) 1.6 Hz, 1H), 6.01 (dd, J ) 15.8, 7.1
Hz, 1H), 5.39 (tm, J ) 5.5 Hz, 1H), 4.44 (dt, J ) 17.2, 2.3 Hz,
1H), 4.32 (ddd, J ) 17.3, 5.4, 1.9 Hz, 1H), 3.71 (s, 3H), 2.38 (s,
3H); IR 1717, 1647, 1271, 1167 cm-1; MS m/z 383 (M+, 0.72),
280 (M+-PhCHdCH, 7.23), 228 (M+-Ts, 55.77), 196 (M+-
TsH-OMe, 100.00). Anal. calcd for C21H21NO4S: C, 65.77; H,
5.52; N, 3.65. Found: C, 65.35; H, 5.38; N, 3.40.
Meth yl 2,5-Dih yd r o-2-fu r yl-1-tosyl-p yr r ole-3-ca r boxy-
1
la te (3j). Mp 136-137 °C (CCl4); H NMR (400 MHz) δ 7.47
(d, J ) 8.3 Hz, 2H), 7.19 (d, J ) 8.2 Hz, 2H), 7.15 (dd, J ) 1.7,
0.7 Hz, 1H), 6.81 (dt, J ) 2.4, 1.8 Hz, 1H), 6.36 (dd, J ) 3.2,
0.8 Hz, 1H), 6.27 (dd, J ) 3.2, 1.8 Hz, 1H), 5.86 (dt, J ) 5.6,
1.7 Hz, 1H), 4.47 (dt, J ) 16.9, 2.3 Hz, 1H), 4.30 (ddd, J )
16.8, 5.6, 1.9 Hz, 1H), 3.65 (s, 3H), 2.38 (s, 3H); IR 1726, 1647,
1343, 1163 cm-1; MS m/z 347 (M+, 0.82), 192 (M+-Ts, 84.68),
160 (M+-TsH-OMe, 89.01), 91 (CH3C6H4+, 100.00). Anal.
calcd for C17H17NO5S: C, 58.78; H, 4.93; N, 4.03. Found: C,
58.71; H, 4.86; N, 3.87.
Meth yl 4,5-Dih yd r o-5-fu r yl-1-tosyl-p yr r ole-2-ca r boxy-
la te (5j). Mp 104-106 °C; 1H NMR δ 7.86 (d, J ) 8.4 Hz,
2H), 7.67 (d, J ) 1.4 Hz, 1H), 7.31 (d, J ) 8.3 Hz, 2H), 7.32-
7.25 (m, 2H), 7.11 (d, J ) 3.6 Hz, 1H), 6.56 (dd, J ) 3.7, 1.6
Hz, 1H), 3.75 (s, 3H), 2.42 (s, 3H), 1.77 (d, J ) 7.2 Hz, 2H); IR
1726, 1648, 1261, 1157 cm-1; MS m/z 348 (M+ + 1, 4.64), 192
(M+-Ts, 40.57), 160 (M+-TsH-OMe, 43.87), 91 (CH3C6H4
,
+
100.00); HRMS calcd for C17H17NO5S 347.0828, found 347.0829.
Cycloa d d ition s of 2,3-Bu ta d ien oa tes w ith Oth er Elec-
t r on -Deficien t Im in es Ca t a lyzed b y Tr ip h en ylp h os-
p h in e. The procedure was similar to that described above.
E t h yl 2,5-Dih yd r o-2-p h en yl-1-d ip h en ylp h osp h in yl-
p yr r ole-3-ca r boxyla te. Syrup; 1H NMR δ 7.83-7.77 (m, 2H),
7.58-7.07 (m, 11H), 6.87-6.84 (m, 3H), 5.54-5.48 (m, 1H),
4.43-4.32 (m, 2H), 4.06-3.93 (m, 2H), 1.09 (t, J ) 7.14 Hz,
3H); IR 1718, 1650, 1440, 1262, 1209, 1124 cm-1; MS m/z 418
(M+ + 1, 80.25), 216 (M+-DPP, 49.92), 201 (DPP+, 100.00);
HRMS calcd for C25H24NO3P 417.1494, found 417.1462.
Meth yl 2,5-Dih yd r o-2-p h en yl-1-(p-n itr oben zen esu lfo-
n yl)-p yr r ole-3-ca r boxyla te. Mp 181.5-182.5 °C (benzene/
hexane); 1H NMR δ 8.06 (d, J ) 8.87 Hz, 2H), 7.47 (d, J )
8.74 Hz, 2H), 7.25-7.08 (m, 5H), 6.88-6.86 (m, 1H), 5.86-
5.83 (m, 1H), 4.70 (dt, J ) 16.63, 2.27 Hz, 1H), 4.38 (ddd, J )
16.62, 5.96, 1.84 Hz, 1H), 3.60 (s, 3H); IR 1728, 1648, 1531,
1350, 1165 cm-1; MS m/z 388 (M+, 6.62), 329 (M+-CO2Me,
76.79), 311 (M+-Ph, 73.06), 202 (M+-Ns, 99.73), 170 (M+-
NsH-OMe, 100.00). Anal. calcd for C18H16N2O6S: C, 55.66;
H, 4.15; N, 7.21. Found: C, 55.72; H, 3.92; N, 7.15.
Tr ibu tylp h osp h in e-Ca ta lyzed Rea ction of Meth yl 2,3-
Bu ta d ien oa te w ith N-Tosyl Ben za ld im in e. The procedure
was similar to that described above except that methyl 2,3-
butadienoate was used instead of 2-butynoates.
Met h yl 2,5-Dih yd r o-2-p h en yl-5-(1-p h en yl-p -t olu en e-
su lfon a m id om eth yl)-1-tosyl-p yr r ole-3-ca r boxyla te (10a ).
1
Mp 101-104 °C; H NMR δ 7.83 (d, J ) 8.2 Hz, 2H), 7.64 (d,
J ) 8.2 Hz, 2H), 7.35-7.29 (m, 5H), 7.19-7.03 (m, 7H), 6.63
(d, J ) 7.3 Hz, 2H), 6.47 (br s, 1H), 6.05 (d, J ) 3.5 Hz, 1H),
5.43 (br s, 1H), 4.95 (dt, J ) 7.5, 2.1 Hz, 1H), 4.61 (dd, J )
7.5, 3.6 Hz, 1H), 3.49 (s, 3H), 2.43 (s, 3H), 2.36 (s, 3H); 13C
NMR (75 MHz) δ 161.89 (C), 144.63 (C), 143.25 (C), 138.74
(C), 136.86 (C), 136.46 (CH), 136.27 (C), 135.39 (C), 132.75 (C),
130.08 (CH), 129.48 (CH), 128.97 (CH), 128.53 (CH), 128.30
(CH), 128.13 (2CH), 127.82 (CH), 127.65 (CH), 127.22 (CH),
70.98 (CH), 70.48 (CH), 62.02 (CH), 51.89 (CH3), 21.58 (CH3),
21.54 (CH3); IR 3280, 1728, 1335, 1163 cm-1; MS m/z 617 (M+

5040 J . Org. Chem., Vol. 63, No. 15, 1998
Xu and Lu
+ 1, 0.34), 260 (PhCHNHTs+, 52.61), 202 (M+ + 1-PhCH-
NHTs-Ts, 20.39), 91 (CH3C6H4+, 100.00); HRMS calcd for
C33H32N2O6S2 616.1702, found 616.1723.
the residue was purified by column chromatography on silica
gel (eluent: petroleum ether/ethyl acetate ) 9:1) to afford
0.032 g (86%) of 27a . Mp 99.5-100.5 °C (benzene/hexane),
1
Meth yl 2,5-Dih yd r o-2-ter t-bu tyl-1-tosyl-p yr r ole-3-ca r -
lit.,43 96.5-97.5 °C; H NMR δ 8.51 (br s, 1H), 7.59 (dd, J )
1
boxyla te (3k ). Mp 135-136 °C; H NMR δ 7.67 (d, J ) 8.3
7.9, 1.4 Hz, 2H), 7.45-7.37 (m, 3H), 6.76 (t, J ) 2.7 Hz, 1H),
6.74 (t, J ) 2.9 Hz, 1H), 3.74 (s, 3H); IR 3314, 3298, 1701,
1682, 1292, 1146 cm-1; MS m/z 201 (M+, 84.47), 170 (M+-
OMe, 100.00).
Hz, 2H), 7.23 (d, J ) 8.0 Hz, 2H), 6.37 (br s, 1H), 4.68 (d, J )
3.1 Hz, 1H), 4.16-4.00 (m, 2H), 3.66 (s, 3H), 2.38 (s, 3H), 0.97
(s, 9H); IR 1720, 1629, 1239, 1162 cm-1; MS m/z 338 (M+ + 1,
100.00), 280 (M+-t-Bu, 93.03). Anal. calcd for C17H23NO4S:
C, 60.51; H, 6.87; N, 4.15. Found: C, 60.29; H, 6.74; N, 3.81.
Meth yl 2,5-Dih yd r o-2-(2-m eth yl-1,3-d ith ia n e-2-yl)-1-to-
syl-p yr r ole-3-ca r boxyla te (3m ). Mp 186-188 °C (benzene/
Ar om a tiza tion of th e Cycloa d d ition P r od u cts Med i-
a ted by Bu 4NF . Gen er a l P r oced u r e for th e Syn th esis
of 2-Ar yl-1H-p yr r ole-3-ca r boxyla tes (27). To a solution of
methyl 2,5-dihydro-2-aryl-1-sulfonyl-pyrrole-3-carboxylate (1.0
mmol) in THF (3 mL) was added a solution of Bu4NF in THF
(1M, 3 mL, 3 equiv). The mixture was then stirred at room
temperature for 24-36 h. Methanol (2 mL) was added, and
the mixture was concentrated under reduced pressure. The
residue was diluted with ethyl acetate and washed with
saturated NaHCO3, and the aqueous layer was extracted twice
with ethyl acetate. The combined organic phase was washed
with brine, dried (Na2SO4), and concentrated. The residue was
purified by column chromatography on silica gel (eluent:
petroleum ether/ethyl acetate ) 37/3) to afford 27.
1
hexane); H NMR δ 7.76 (d, J ) 8.2 Hz, 2H), 7.26 (d, J ) 8.0
Hz, 2H), 6.41 (br s, 1H), 5.65 (d, J ) 3.2 Hz, 1H), 4.16 (dd, J
) 18.3, 2.9 Hz, 1H), 4.01 (ddd, J ) 18.3, 3.2, 1.5 Hz, 1H), 3.71
(s, 3H), 3.35 (ddd, J ) 14.7, 11.6, 2.9 Hz, 1H), 3.16 (ddd, J )
14.5, 11.9, 2.9 Hz, 1H), 2.76 (dt, J ) 14.7, 4.2 Hz, 1H), 2.60
(dt, J ) 14.6, 4.0 Hz, 1H), 2.40 (s, 3H), 2.15-2.08 (m, 1H),
1.92-1.82 (m, 1H), 1.39 (s, 3H); IR 1717, 1638, 1354, 1254,
1163 cm-1; MS m/z 413 (M+, 0.17), 280 (M+-C5H9S2, 2.10),
133 (C5H9S2+, 100.00). Anal. calcd for C18H23NO4S3: C, 52.27;
H, 5.60; N, 3.39. Found: C, 52.14; H, 5.61; N, 3.28.
Tr ip h en ylp h osp h in e-Ca ta lyzed Cycliza tion Rea ction
of Dim eth yl Acetylen ed ica r boxyla te a n d N-Tosylim in es.
A Typ ica l P r oced u r e for t h e P r ep a r a t ion of 1-Tosyl-
5-ph en yl-3-m eth oxy-4-m eth oxycar bon yl-3-pyr r olin -2-on e
(12a ). A mixture of dimethyl acetylenedicarboxylate (11, 0.170
g, 1.20 mmol), N-tosyl benzaldimine (2a , 0.260 g, 1.00 mmol),
and triphenylphosphine (0.052 g, 0.20 mmol) in dry benzene
(5 mL) was degassed and then refluxed for 4 h under nitrogen.
The reaction mixture was concentrated in vacuo, and the
residue was chromatographed on silica gel (petroleum ether/
ethyl acetate ) 17:3) to give 12a (0.335 g, 84% yield). Mp
Meth yl 2-F u r yl-1H-p yr r ole-3-ca r boxyla te (27j). Mp
109-109.5 °C (benzene/hexane); 1H NMR δ 8.91 (br s, 1H),
7.44 (d, J ) 3.65 Hz, 1H), 7.36 (d, J ) 1.54 Hz, 1H), 6.70 (t, J
) 2.85 Hz, 1H), 6.64 (t, J ) 2.98 Hz, 1H), 6.46 (dd, J ) 3.32,
1,70 Hz, 1H), 3.80 (s, 3H); IR 3351, 1683, 1304, 1135 cm-1
;
MS m/z 191 (M+, 100.00), 160 (M+-OMe, 75.67). Anal. calcd
for C10H9NO3: C, 62.82; H, 4.74; N, 7.33. Found: C, 63.04;
H, 4.51; N, 7.28.
Syn th esis of 2-P h en yl-1H-p yr r ole (30). A mixture of 3a
(0.177 g, 0.88 mmol) and KOH (0.635 g, 12 equiv) in methanol
(2 mL) was refluxed at 120 °C for 2.5 h. The cooled mixture
was poured into water, acidified with concentrated HCl, and
then extracted three times with ethyl acetate. After drying
(Na2SO4), the solvent was evaporated under reduced pressure,
and the residue (0.152 g) was heated in ethanolamine (2 mL)
at 220 °C for 2 h. The cooled mixture was acidified with dilute
HCl and extracted three times with ethyl acetate. The
combined organic phase was washed with brine and dried over
Na2SO4. After the solvent was evaporated under reduced
pressure, the residue was purified by column chromatography
on silica gel (eluent: petroleum ether/ethyl acetate ) 50/1) to
give 0.069 g (55%) of 30. Mp 128-129 °C (hexane), lit.,44 mp
129-130 °C; 1H NMR δ 8.45 (br s, 1H), 7.50-7.46 (m, 2H),
7.39-7.34 (m, 2H), 7.24-7.18 (m, 1H), 6.88-6.86 (m, 1H),
6.55-6.52 (m, 1H), 6.32-6.30 (m, 1H); IR 3435, 3391, 757, 718,
691 cm-1; MS m/z 143 (M+, 100.00).
1
126.5-127.5 °C (benzene/hexane); H NMR δ 7.31-7.23 (m,
5H), 7.12-7.07 (m, 4H), 5.82 (s, 1H), 4.27 (s, 3H), 3.62 (s, 3H),
2.36 (s, 3H); IR 1732, 1707, 1643, 1201, 1174 cm-1; MS m/z
401 (M+, 31.88), 342 (M+-CO2Me, 100.00), 246 (M+-Ts, 86.89).
Anal. calcd for C20H19NO6S: C, 59.84; H, 4.77; N, 3.49.
Found: C, 59.71; H, 4.66; N, 3.31.
1-Tosyl-5-cin n a m yl-3-m eth oxy-4-m eth oxyca r bon yl-3-
p yr r olin -2-on e (12i). Mp 129.5-130.5 °C (benzene/hexane);
1H NMR δ 7.86 (d, J ) 8.35 Hz, 2H), 7.35-7.27 (m, 5H), 7.21
(d, J ) 8.09 Hz, 2H), 6.83 (d, J ) 15.34 Hz, 1H), 5.56 (dd, J )
15.36, 8.44 Hz, 1H), 5.46 (d, J ) 8.62 Hz, 1H), 4.22 (s, 3H),
3.76 (s, 3H), 2.40 (s, 3H); IR 1727, 1718, 1642, 1162 cm-1; MS
m/z 427 (M+, 9.14), 272 (M+-Ts, 100.00). Anal. calcd for
C
22H21NO6S: C, 61.81; H, 4.95; N, 3.28. Found: C, 62.10; H,
4.94; N, 3.27.
Deh yd r ogen a t ion of 2,5-Dih yd r o-2-a r yl-1-t osyl-p yr -
r ole-3-ca r boxyla tes w ith DDQ. A Typ ica l P r oced u r e for
th e P r ep a r a tion of Meth yl 2-P h en yl-1-tosyl-p yr r ole-3-
ca r boxyla te (26a ). A mixture of the cycloadduct 3a (0.23 g,
0.64 mmol) and DDQ (0.30 g, 1.32 mmol, 2.0 equiv) in benzene
(5 mL) was heated at about 130 °C under nitrogen and
monitored by TLC (eluent: petroleum ether/ethyl acetate )
4/1). After the reaction was complete, the reaction mixture
was concentrated under reduced pressure and the residue was
purified twice by column chromatography on silica gel (elu-
ent: petroleum ether/ethyl acetate ) 17:3 for the first time
and then 9:1 for the second time) to afford 0.21 g (92%) of 26a .
Mp 113-114 °C (benzene/hexane); 1H NMR δ 7.48 (d, J ) 3.4
Hz, 1H), 7.40 (tt, J ) 7.5, 1.5 Hz, 1H), 7.28 (t, J ) 7.6 Hz,
2H), 7.19 (d, J ) 8.4 Hz, 2H), 7.12 (d, J ) 8.3 Hz, 2H), 7.04
(dd, J ) 7.5, 1.5 Hz, 2H), 6.73 (d, J ) 3.4 Hz, 1H), 3.58 (s,
3H), 2.38 (s, 3H); IR 1719, 1358, 1173 cm-1; MS m/z 355 (M+,
52.35), 200 (M+-Ts, 100.00). Anal. calcd for C19H17NO4S: C,
64.21; H, 4.82; N, 3.94. Found: C, 64.21; H, 4.65; N, 3.81.
Detosyla tion of 2-Ar yl-1-tosyl-p yr r ole-3-ca r boxyla tes
w ith Sod iu m Meth oxid e. A Typ ica l P r oced u r e for th e
P r ep a r a tion of Meth yl 2-P h en yl-1H-p yr r ole-3-ca r boxy-
la te (27a ). A mixture of 26a (0.065 g, 0.18 mmol) and sodium
methoxide (0.57 M in methanol, 5.5 mL) was stirred at room
temperature and monitored by TLC (eluent: petroleum ether/
ethyl acetate ) 4/1). After the reaction was complete, the
reaction mixture was concentrated under reduced pressure and
Desu lfon yla tion of 12a . The solution of 12a (0.370 g, 0.92
mmol) in dry benzene (20 mL) was heated to reflux under
nitrogen, and Bu3SnH (0.55 mL, 2.0 mmol) and AIBN (0.030
g, 0.18 mmol) in dry benzene (5 mL) were added as a solution.
After 2 h, the reaction was completed as monitored by TLC
analysis. After an additional hour, the solvent was removed
in vacuo to afford a white solid. Diethyl ether (70 mL),
saturated KF (15 mL), and water (55 mL) were added, and
the resulting mixture was stirred overnight. After filtering
off the precipitated solid, the water layer was extracted with
benzene. The combined organic layer was dried (Na2SO4), and
the solvents were removed to afford a white solid. The solid
was combined with the precipitated solid above and crystal-
lized in acetone to give 5-phenyl-3-methoxy-4-methoxycarbo-
nyl-3-pyrrolin-2-one (31a , 0.190 g, 84%) as a white crystal. Mp
1
189-190 °C (acetone); H NMR δ 7.38-7.34 (m, 3H), 7.32-
7.25 (m, 2H), 6.47 (br s, 1H), 5.26 (s, 1H), 4.32 (s, 3H), 3.64 (s,
3H); 13C NMR (75 MHz) δ 166.98, 162.49, 153.23, 136.45,
128.71, 128.59, 127.23, 118.72, 60.10, 57.81, 51.70; IR 3182,
3086, 1701, 1634, 1228 cm-1; MS m/z 247 (M+, 8.15), 188 (M+-
CO2Me, 100.00). Anal. calcd for C13H13NO4: C, 63.15; H, 5.30;
N, 5.67. Found: C, 63.05; H, 5.25; N, 5.80.
(43) Padwa, A.; Smolanoff, J .; Tremper, A. J . Am. Chem. Soc. 1975,
97, 4682.
(44) Rapoport, H.; Look, M. J . Am. Chem. Soc. 1953, 75, 4605.

A Convenient Synthesis of Pentabromopseudilin
J . Org. Chem., Vol. 63, No. 15, 1998 5041
N-Tosyl 3,5-Dibr om o-2-m eth oxyben za ld im in e was pre-
pared according to a procedure analogous to that described
above. After solvents were evaporated under reduced pres-
sure, the crude product was obtained as a gum and was
directly utilized in the next step without further purification.
Data for the imine: 1H NMR (90 MHz) δ 9.21 (s, 1H), 8.07-
7.70 (m, 3H), 7.41-7.20 (m, 3H), 3.92 (s, 3H), 2.45 (s, 3H).
2-(2-Hyd r oxyp h en yl)-1H-p yr r ole (34).46 A mixture of 37
(0.426 g, 2.46 mmol) and anhydrous Na2S (1.149 g, 6 equiv)
in N-methylpyrrolidone (NMP, 10 mL) was heated at about
160 °C for 3.5 h. The cooled mixture was poured into dilute
HCl and extracted twice with ethyl acetate. The combined
organic phase was washed with brine and dried over Na2SO4.
After the solvent was evaporated under reduced pressure, the
residue was purified by column chromatography on silica gel
(eluent: petroleum ether/ethyl acetate ) 9/1) to give 0.203 g
Meth yl 2,5-Dih yd r o-2-(3,5-d ibr om o-2-m eth oxyp h en yl)-
1-tosyl-p yr r ole-3-ca r boxyla te (35). To a solution of the
crude imine (1.126 g, 2.5 mmol), obtained as described above,
and triphenylphosphine (0.080 g, 0.3 mmol) in dry benzene
(25 mL) was added a solution of methyl 2,3-butadienoate (0.30
g, 3.0 mmol) in benzene (5 mL). The mixture was then stirred
at room temperature for 18 h. The reaction mixture was
concentrated under reduced pressure, and the residue was
purified by column chromatography on silica gel (eluent:
petroleum ether/ethyl acetate ) 17/3) to give 0.814 g (60%) of
1
(52%) of 34 as a solid. Mp 99-101 °C (benzene/hexane); H
NMR δ 9.42 (br s, 1H), 7.54 (dd, J ) 7.68, 1.51 Hz, 1H), 7.10
(deformed td, J ) 7.63, 1.51 Hz, 1H), 6.97 (deformed td, J )
7.52, 1.13 Hz, 1H), 6.90 (m, 1H), 6.86 (d, J ) 7.94 Hz, 1H),
6.58 (m, 1H), 6.34-6.31 (m, 1H), 5.48 (m, 1H); 13C NMR (75
MHz, DMSO-d6) δ 152.62, 128.65, 126.11, 125.82, 119.69,
119.34, 118.05, 116.14, 108.05, 106.85; IR 3433, 1496, 1466,
1099, 749 cm-1; MS m/z 159 (M+, 100.00). Anal. calcd for
C10H9NO: C, 75.45; H, 5.70; N, 8.80. Found: C, 75.28; H, 5.65;
N, 8.65.
1
35. Mp 120.5-121.5 °C (benzene/hexane); H NMR δ 7.535
(d, J ) 8.31 Hz, 2H), 7.534 (d, J ) 2.56 Hz, 1H), 7.22 (d, J )
8.16 Hz, 2H), 7.01 (d, J ) 2.58 Hz, 1H), 6.84 (q, J ) 1.94 Hz,
1H), 5.99-5.96 (m, 1H), 4.52-4.48 (m, 2H), 3.99 (s, 3H), 3.61
(s, 3H), 2.41 (s, 3H); IR 1725, 1645, 1353, 1165 cm-1; MS m/z
548, 546, 544 (M+ + 1, 2.06, 4.02, 2.14), 360, 358, 356 (M+-
TsH-OMe, 34.42, 68.87, 35.03), 91 (MeC6H4+, 100.00). Anal.
calcd for C20H19Br2NO5S: C, 44.06; H, 3.51; N, 2.57; Br, 29.31.
Found: C, 44.45; H, 3.51; N, 2.43; Br, 29.55.
2,3,4-Tr ib r om o-5-(3,5-d ib r om o-2-h yd r oxyp h en yl)-1H -
p yr r ole (P en ta br om op seu d ilin , 32). To a solution of 34
(0.129 g, 0.81 mmol) in absolute ethanol (20 mL) was added
pyridinium bromide perbromide (1.58 g, 6 equiv), and the
mixture was then stirred at room temperature for 65 h. The
reaction mixture was concentrated under reduced pressure,
and the residue was purified by column chromatography on
silica gel (eluent: petroleum ether/dichloromethane ) 3/2) to
afford 0.303 g (68%) of 32 as a solid. Mp 150 °C dec (benzene/
hexane), lit.,28 mp 152 °C dec; 1H NMR δ 9.50 (br s, 1H), 8.11
(d, J ) 2.17 Hz, 1H), 7.58 (d, J ) 2.10 Hz, 1H), 6.05 (s, 1H);
1H NMR (300 MHz, DMSO-d6) δ 12.61 (br s, 1H), 9.81 (br s,
1H), 7.80 (d, J ) 2.36 Hz, 1H), 7.40 (d, J ) 2.45 Hz, 1H); 13C
NMR (75 MHz, DMSO-d6) δ 151.54, 134.95, 133.11, 126.48,
122.03, 112.80, 110.44, 100.99, 100.41, 98.52; IR 3460, 3427,
3064, 1471, 1429, 1344, 1321, 1232, 1153, 1125, 994, 976, 858,
749, 688 cm-1; MS m/z 559, 557, 555, 553, 551, 549 (M+, 5.10,
24.15, 49.62, 50.77, 25.81, 5.14), 479, 477, 475, 473, 471 (M+
+ 1-Br, 15.85, 63.13, 100.00, 71.06, 21.74), 478, 476, 474, 472,
470 (M+-Br, 21.03, 65.03, 93.03, 59.91, 15.87), 451, 449, 447,
445, 443 (M+-Br-HCN, 5.90, 24.50, 38.41, 26.45, 7.80), 398,
396, 394, 392 (M+ + 1-2Br, 10.18, 33.20, 42.59, 25.56), 397,
395, 393, 391 (M+-2Br, 35.29, 80.29, 71.62, 23.35), 371, 369,
367, 365 (M+-2Br-CN, 17.21, 55.10, 59.56, 26.53), 317, 315,
313 (M+ + 1-3Br, 46.33, 89.43, 48.01), 316, 314, 312 (M+-
3Br, 38.15, 46.60, 18.04). Anal. calcd for C10H4Br5NO: C,
21.69; H, 0.73; N, 2.53; Br, 72.16. Found: C, 21.39; H, 0.80;
N, 2.44; Br, 72.40.
Meth yl 2-(3,5-Dibr om o-2-m eth oxyp h en yl)-1H-p yr r ole-
3-ca r boxyla te (36). To a solution of 35 (1.366 g, 2.50 mmol)
in THF (7.5 mL) was added a solution of Bu4NF in THF (1 M,
7.5 mL, 3 equiv). The mixture was then stirred at room
temperature for 22.5 h. After workup, the residue was purified
by column chromatography on silica gel (eluent: petroleum
ether/ethyl acetate ) 19/1) to afford 0.808 g (83%) of 36. Mp
119.5-120 °C (benzene/hexane); 1H NMR δ 9.08 (br s, 1H),
7.82 (d, J ) 2.22 Hz, 1H), 7.68 (d, J ) 2.26 Hz, 1H), 6.84
(deformed t, J ) 2.76 Hz, 1H), 6.76 (deformed t, J ) 2.86 Hz,
1H), 3.78 (s, 3H), 3.51 (s, 3H); IR 3356, 1710 cm-1; MS m/z
391, 389, 387 (M+, 38.83, 71.74, 36.80), 360, 358, 356 (M+-
OMe, 54.36, 100.00, 52.32). Anal. calcd for C13H11Br2NO3: C,
40.13; H, 2.85; N, 3.60. Found: C, 40.03; H, 2.73; N, 3.32.
Meth yl 2-(2-Meth oxyp h en yl)-1H-p yr r ole-3-ca r boxyla te
(27b). To a solution of 3b (1.854 g, 4.78 mmol) in THF (14
mL) was added a solution of Bu4NF in THF (1 M, 14 mL, 3
equiv). The mixture was then stirred at room temperature
for 24.5 h. After workup, the residue was purified by column
chromatography on silica gel (eluent: petroleum ether/ethyl
acetate ) 17/3) to give 0.880 g (80%) of 27b, idential with the
sample obtained by the DDQ dehydrogenation method.
2-(2-Meth oxyp h en yl)-1H-p yr r ole (37). A mixture of 27b
(1.247 g, 5.39 mmol) and KOH (3.79 g, 12 equiv) in methanol
(15 mL) was refluxed at 100-110 °C for 4 h. The cooled
mixture was poured into water, acidified with concentrated
HCl, and extracted three times with ethyl acetate. After
drying (Na2SO4), the solvent was evaporated under reduced
pressure and the residue (1.160 g) was heated with Cu powder
(0.336 g) in quinoline (20 mL) at 170 °C for 3 h. The reaction
mixture was cooled and acidified with dilute HCl and then
extracted three times with ethyl acetate. The combined
organic phase was washed with brine and dried over Na2SO4.
After the solvent was evaporated under reduced pressure, the
residue was purified by column chromatography on silica gel
(eluent: petroleum ether/ethyl acetate ) 97/3) to afford 0.695
g (74%) of 37 as an oil which solidified on refrigeration. Mp
69-70 °C, lit.,45 mp 66-67 °C; 1H NMR δ 9.85 (br s, 1H), 7.68
(dd, J ) 7.67, 1.69 Hz, 1H), 7.17 (deformed td, J ) 7.73, 1.65
Hz, 1H), 7.01 (deformed td, J ) 7.45, 1.24 Hz, 1H), 6.98 (d, J
) 8.15 Hz, 1H), 6.88 (m, 1H), 6.65-6.63 (m, 1H), 6.32-6.29
Ack n ow led gm en t. We thank the National Natural
Science Foundation of China and Chinese Academy of
Sciences for financial support.
Su p p or tin g In for m a tion Ava ila ble: Characterization
data for N-(â-trimethylsilylethanesulfonyl)-4-methylbenzaldi-
mine, N-(â-trimethylsilylethanesulfonyl)-4-chlorobenzaldi-
mine, 3b-h , 6, ethyl 2,5-dihydro-2-phenyl-1-(â-trimethylsi-
lylethanesulfonyl)-pyrrole-3-carboxylate, methyl 2,5-dihydro-
2-(4-methylphenyl)-1-(â-trimethylsilylethanesulfonyl)-pyrrole-
3-carboxylate, methyl 2,5-dihydro-2-(4-chlorophenyl)-1-(â-
trimethylsilylethanesulfonyl)-pyrrole-3-carboxylate, 3a ′, 10a ′,
10b, 3c′, 10c′, 3d ′, 10d ′, 10e, 3l, 12b-e, 12g, 12h , 12n , 26b,
26e, 26g, 26h , 26 (R1 ) H), 27b, 27e, 27g, 27h , and 27d (12
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
(m, 1H), 3.97 (s, 3H); IR 3443, 1492, 1235, 1112, 1023 cm-1
;
MS m/z 173 (M+, 100.00), 158 (M+-CH3, 43.69).
J O9723063
(45) Kruse, C. G.; Bouw, J . P.; van Hes, R.; van de Kuilen, A.; den
Hartog, J . A. J . Heterocycles 1987, 26, 3141.
(46) Koenig, H.; Franke, A.; Frickel, F. F.; Steglich, W.; Engel, N.
Ger. Offen. 2835439, 1980; Chem. Abstr. 1980, 93, 132363a.