Synthesis of N-tosyl-3,3,4-trisubstituted pyrrolidine derivatives starting from the Baylis-Hillman adducts via radical cyclization

Article abstract of DOI:10.1016/j.tet.2008.01.001

N-Tosyl-3,3-disubstituted-4-vinylpyrrolidine derivatives 3a-c were synthesized via radical cyclization from the modified Baylis-Hillman adducts 2. The required starting materials 2a-c were prepared in moderate yields from the Baylis-Hillman adducts in thr

Full text of DOI:10.1016/j.tet.2008.01.001

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Tetrahedron 64 (2008) 2397e2404
www.elsevier.com/locate/tet
Synthesis of N-tosyl-3,3,4-trisubstituted pyrrolidine derivatives starting
from the BayliseHillman adducts via radical cyclization
*
Hyun Seung Lee, Hoo Sook Kim, Jeong Mi Kim, Jae Nyoung Kim
Department of Chemistry and Institute of Basic Science, Chonnam National University, Gwangju 500-757, Republic of Korea
Received 10 December 2007; received in revised form 28 December 2007; accepted 2 January 2008
Available online 5 January 2008
Abstract
N-Tosyl-3,3-disubstituted-4-vinylpyrrolidine derivatives 3aec were synthesized via radical cyclization from the modified BayliseHillman
adducts 2. The required starting materials 2aec were prepared in moderate yields from the BayliseHillman adducts in three steps: (i) acetylation
of the BayliseHillman adducts, (ii) SN20 reaction with tosylamide to prepare 1, and (iii) alkylation with 1,4-dibromo-2-butene.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Pyrrolidines; BayliseHillman adducts; Radical cyclization
1. Introduction
allyl radical cyclization protocol6,7 as in Scheme 1 (vide infra).
Although the synthesis of piperidine skeleton via the allyl
radical cyclization strategy was reported,7 to the best of
our knowledge, synthesis of pyrrolidine derivatives from the
BayliseHillman adducts has not been examined.
The importance of nitrogen heterocycles, especially pyrro-
lidine and piperidine types as subunits of bioactive molecules,
stimulates the development of new synthetic methods. Suit-
ably substituted pyrrolidines constitute key skeleton in many
biologically important compounds1e3 and were used as key
intermediates in the synthesis of natural products.1e3 Conse-
quently, the efficient preparation method of pyrrolidines has
received significant attention.1e3 Metal-catalyzed cyclization
of a suitable acyclic precursor,2a,c,3a,b,eeg [3þ2] cycloaddition
of azomethine ylide,1a,c and ring-closing metathesis (RCM)
reaction1d,3c are the most frequently used methods for the
synthesis of pyrrolidines.
Recently we were interested in radical cyclizations of
modified BayliseHillman adducts.4,5a We and other research
groups also reported the synthesis of various heterocyclic
compounds4,5 including exo-methylene dihydrofuran and di-
hydropyrroles via the radical cyclization reaction as the key
step from suitably modified BayliseHillman adducts. During
the studies we imagined that we could synthesize 3,3-disubsti-
tuted-4-vinylpyrrolidine derivatives via the in situ generated
2. Results and discussion
The starting material 2a was synthesized from the Baylise
Hillman adduct via the following sequential reactions: (i) acet-
ylation of BayliseHillman adduct of methyl acrylate and
benzaldehyde, (ii) SN20 reaction with tosylamide (TsNH2,
K2CO3, aq THF, 70e80 ꢀC) to produce 1a,8 (iii) alkylation
with 1,4-dibromo-2-butene (K2CO3, DMF, rt). The next radi-
cal cyclization of 2a was examined under the influence of
n-Bu3SnH (1.5 equiv)/AIBN (cat) in benzene, and we obtained
desired compound 3a in moderate yield as a diastereomeric
mixture (67%). We separated the two isomers in pure form
and found that syn-3a was the major component (57%) by
spectroscopic analysis including NOE experiments (vide infra,
Fig. 2). The formation of 3a can be explained as shown in
Scheme 1 involving the rearrangement of initially formed al-
lylic radical (I) to (II), which undergoes 5-exo-trig type cycli-
zation. In addition, the reason for the predominant formation
of syn-3a could be explained by the transition state model
* Corresponding author. Tel.: þ82 62 530 3381; fax: þ82 62 530 3389.
E-mail address: kimjn@chonnam.ac.kr (J.N. Kim).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.001

2398
H.S. Lee et al. / Tetrahedron 64 (2008) 2397e2404
n-Bu3SnH
MeOOC
Ph
AIBN
COOMe
Br
COOMe
NHTs
PhH, reflux
Ph
Br
Ph
Br
K2CO3
DMF, rt
N
N
Ts
Ts
1a
3a (syn/anti)
2a
COOMe
COOMe
Ph
Ph
N
N
Ts
(II)
Ts
(I)
Scheme 1.
(Fig. 1). The compound syn-3a might be formed via the TS 1
and anti-3a from TS 2. As shown in Figure 1, appreciable ste-
ric crowdedness arose in the transition state TS 2 between the
p-toluenesulfonyl group and the phenyl moiety, thus made
anti-3a as the minor product.
2,5-dihydrofuran. Thus, we decided to prepare trans-2f and
examine the radical cyclization. The synthesis of trans-2f
was carried out in two steps: (i) synthesis of compound 6
from 1f and allyl alcohol (52%) and (ii) cross metathesis reac-
tion between 6 and allyl bromide using second-generation
Grubbs catalyst in moderate yield (45%).13 As expected, the
reaction of trans-2f under the same radical cyclization condi-
tions produced 3f in higher yield (78%) in a syn/anti¼67:11
ratio and compound 4 was not formed in this case.
In summary, we disclosed the synthesis of some 3,3,4-tri-
substituted pyrrolidines and tertahydrofuran starting from rear-
ranged aza-BayliseHillman adducts or BayliseHillman
adduct. Synthetic applications of prepared compounds are
actively underway and the results will be published in due
course.
Encouraged by the successful results we synthesized pyrro-
lidines 3b and 3c as summarized in Table 1. For the ethyl ester
3b (entry 2), the results were almost same with those of the
case of methyl ester 3a. The nitrile derivative 1c was prepared
as an E/Z mixture and the separation was very difficult. Thus
we used 1c without further purification. After alkylation with
1,4-dibromo-2-butene, fortunately, we could separate each iso-
mer in pure state albeit in low yields.9 Either from E-2c or Z-
2c we obtained similar results as in entries 3 and 4. As a next
trial, we examined the synthesis of cyclopentane derivative 3d
by the radical cyclization of 2d and observed the formation of
almost equal amounts of syn-3d (36%) and anti-3d (45%).
When we used 2e as substrate (entry 6) we obtained piperidine
derivative 3e (64%) as the sole isolable product.7 The stereo-
chemistry of products was determined by NOE experiments.
Important NOE results of compounds syn-3a, anti-3a, anti-
3c, and 3e are summarized in Figure 2.
As a next trial we examined the synthesis of 2f, the precur-
sor for the synthesis of tetrahydrofuran derivative 3f.10
Initially we made cis-2f as follows: (i) montmorillonite K10-
catalyzed reaction5c,11 of BayliseHillman adduct 1f and cis-
1,4-butenediol according to the reported method in a similar
case5c,11 to obtain compound 5 (30%) and (ii) bromination
with PBr3 (50%). However, radical cyclization of cis-2f
gave the desired tetrahydrofuran 3f in low yield (37%,
Scheme 2). From the reaction we isolated compound 412 in
44% yield and the formation of compound 4 could be ex-
plained as depicted in Scheme 2 involving the liberation of
3. Experimental
3.1. General procedure
1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were
recorded in CDCl3. The signal positions are reported in parts
per million relative to TMS (d scale) used as an internal stan-
dard. IR spectra are reported in cmꢁ1. Mass spectra were ob-
tained from the Korea Basic Science Institute (Gwangju
branch). Melting points are uncorrected. The elemental analy-
ses were carried out at Korea Research Institute of Chemical
Technology, Taejeon, Korea. All reagents were purchased
from commercial sources and used without further treatment.
The separations were carried out by flash column chromatog-
raphy over silica gel (230e400 mesh ASTM). Organic extracts
were dried over anhydrous MgSO4 and the solvents were evap-
orated on a rotary evaporator under water aspirator pressure.
Ph
N
N
COOMe
Ts
Ts
(E)
(E)
VS
3a-syn
3a-anti
COOMe
Ph
TS 2
TS 1
Figure 1. Plausible transition states for the formation of 3a.

H.S. Lee et al. / Tetrahedron 64 (2008) 2397e2404
2399
Table 1
Radical cyclization of modified BayliseHillman adducts 2aee
Entry
Substrate 1
Substrate 2a
Product 3c
MeOOC
MeOOC
Ph
COOMe
COOMe
Ph
Ph
Ph
Br
Br
Br
1
N
Ts
N
Ts
N
NHTs
Ts
1a
2a (70)
Ph
3a-syn (57)
3a-anti (10)
EtOOC
EtOOC
Ph
COOEt
COOEt
NHTs
Ph
Ph
2
3
N
Ts
N
Ts
N
Ts
1b
2b (64)
Ph
3b-anti (10)
3b-syn (55)
CN
CN
Ph
NC
NC
N
NHTs
1c (E/Z mixture)
Ph
Ph
Ts
N
Ts
N
Ts
2c-E (15)
Ph
3c-anti (28)
3c-syn (55)
Br
N
4
5
CN Ts
2c-Z (40)
3c-anti (30)
3c-syn (59)
MeOOC
MeOOC
COOMe
COOMe
Ph
Ph
Ph
Br
Ph
COOMe
COOMe
MeOOC COOMe
MeOOC COOMe
MeOOC COOMe
3d-syn (36)
1d
2d (63)b
3d-anti (45)
Ts
N
Ts
N
Br
NHTs
COOMe
COOMe
6
Ph
Ph
1e
Ph
COOMe
3e (64)
2e (76)
a
Conditions for 2aec and 2e: 1,4-dibromo-2-butene (1.5 equiv), K2CO3 (2.0 equiv), DMF, rt, 2e3 h.
Conditions for 2d: 1,4-dibromo-2-butene (1.5 equiv), NaH (2.0 equiv), dry THF, 0 ꢀC, 2 h.
Conditions: n-Bu3SnH (1.5 equiv), AIBN (cat), benzene, reflux, 4e5 h.
b
c
H
H
Ph
MeOOC
H
H
H
H
H
Ph
H
H
H
H
MeOOC
H
N
H
H
N
H
Ts
H
Ts
3a-syn
H
H
H
H
N
H
H
Ts
H
H
H
Ph
NC
Ph
H
H
H
H
H
MeOOC
H
H
MeOOC
Ph
H
H
N
H
N
Ts
H
Ts
3a-anti
3c-anti
3e
Figure 2. NOE results of syn-3a, anti-3a, anti-3c, 3e (CDCl3, 500 MHz).

2400
H.S. Lee et al. / Tetrahedron 64 (2008) 2397e2404
OH
COOMe
COOMe
O
Ph
Ph
Montmorillonite K10
COOMe
Ph
100 °C, 3 h (5, 30%)
O
X
1f
PBr3, CH2Cl2
0 °C, 2 h (2f: 50%)
+
5: X = OH
2f-cis: X = Br
HO
OH
COOMe
O
Ph
n-Bu3SnH
AIBN, PhH
reflux, 4 h
MeOOC
Ph
MeOOC
COOMe
Ph
Ph
O
O
3f-syn (32%)
3f-anti (5%)
4 (44%)
3f-anti (11%)
+
3f-syn (67%)
n-Bu3SnH
AIBN, PhH
reflux, 4 h
COOMe
O
Ph
Br
2f-trans
Grubbs cat II
CH2Cl2
reflux, 4 h (45%)
1f
Montmorillonite K10
100 °C, 3 h (52%)
COOMe
Ph
+
O
Br
OH
6
Scheme 2.
3.2. Typical procedure for the synthesis of compound 2a
C22H24BrNO4S: C, 55.23; H, 5.06; N, 2.93. Found: C, 55.14;
H, 5.22; N, 2.78.
Starting materials 1 were synthesized according to the re-
ported methods8 and the synthesis of compound 2a was car-
ried out as follows: a solution of 1a (518 mg, 1.5 mmol),
1,4-dibromo-2-butene (481 mg, 2.25 mmol), and K2CO3
(415 mg, 3.0 mmol) in DMF (3 mL) was stirred at room tem-
perature for 2 h. After the usual aqueous workup and column
chromatographic purification process (hexanes/ether, 3:1) we
obtained 2a (502 mg, 70%) as colorless oil. Other compounds
2bee were synthesized analogously and the spectroscopic data
are as follows.
3.2.2. Compound 2b
Yield 64%; colorless oil; IR (CH2Cl2) 1708, 1342, 1242,
1159 cmꢁ1
; d 1.31 (t,
1H NMR (CDCl3, 300 MHz)
J¼7.2 Hz, 3H), 2.41 (s, 3H), 3.66 (d, J¼6.3 Hz, 2H), 3.72
(d, J¼5.4 Hz, 2H), 4.20 (q, J¼7.2 Hz, 2H), 4.26 (s, 2H),
5.38e5.53 (m, 2H), 7.24 (d, J¼8.7 Hz, 2H), 7.37e7.44 (m,
5H), 7.56 (d, J¼8.7 Hz, 2H), 7.82 (s, 1H); 13C NMR
(CDCl3, 75 MHz) d 14.18, 21.48, 31.43, 43.36, 49.13, 61.23,
127.48, 127.88, 128.62, 129.15, 129.55, 129.56, 129.74,
130.21, 134.38, 136.00, 143.32, 143.53, 167.37; ESIMS m/z
492 (Mþþ1). Anal. Calcd for C23H26BrNO4S: C, 56.10; H,
5.32; N, 2.84. Found: C, 55.24; H, 5.19; N, 2.71.
3.2.1. Compound 2a
Yield 70%; colorless oil; IR (CH2Cl2) 1715, 1343, 1266,
;
1160 cmꢁ1 1H NMR (CDCl3, 300 MHz) d 2.42 (s, 3H),
3.66 (d, J¼6.3 Hz, 2H), 3.71e3.72 (m, 2H), 3.72 (s, 3H),
4.25 (s, 2H), 5.44e5.49 (m, 2H), 7.25 (d, J¼8.1 Hz,
2H), 7.39e7.44 (m, 5H), 7.56 (d, J¼8.1 Hz, 2H), 7.83
(s, 1H); 13C NMR (CDCl3, 75 MHz) d 21.51, 31.43,
43.30, 49.13, 52.19, 127.54, 127.65, 128.68, 129.26,
129.58, 129.68, 129.79, 130.23, 134.33, 136.04, 143.38,
143.88, 167.86; ESIMS m/z 478 (Mþþ1). Anal. Calcd for
3.2.3. Compound E-2c
Yield 15%; white solid, mp 100e102 ꢀC; IR (CH2Cl2)
1
2217, 1347, 1160, 1092 cmꢁ1; H NMR (CDCl3, 300 MHz)
d 2.43 (s, 3H), 3.67 (d, J¼6.3 Hz, 2H), 3.78 (d, J¼6.0 Hz,
2H), 4.18 (d, J¼1.2 Hz, 2H), 5.47e5.65 (m, 2H), 7.24e7.30
(m, 4H), 7.38 (s, 1H), 7.43e7.45 (m, 3H), 7.68 (d,
J¼8.4 Hz, 2H); 13C NMR (CDCl3, 75 MHz) d 21.54, 30.76,

H.S. Lee et al. / Tetrahedron 64 (2008) 2397e2404
2401
43.70, 49.05, 112.32, 118.73, 127.70, 128.65, 128.89, 129.34,
129.78, 130.01, 131.64, 132.88, 135.70, 144.05, 147.28;
ESIMS m/z 445 (Mþþ1).
2.70 (d, J¼13.8 Hz, 1H), 2.78 (dd, J¼14.7 and 6.9 Hz, 1H),
3.16 (dd, J¼9.9 and 6.9 Hz, 1H), 3.23 (d, J¼13.8 Hz,
1H), 3.45 (s, 2H), 3.45 (s, 3H), 3.71 (dd, J¼9.9 and 6.9 Hz,
1H), 5.00e5.06 (m, 2H), 5.35e5.47 (m, 1H), 6.97e7.06 (m,
2H), 7.19e7.28 (m, 3H), 7.32 (d, J¼8.4 Hz, 2H), 7.71 (d,
J¼8.4 Hz, 2H); 13C NMR (CDCl3, 75 MHz) d 21.46, 40.72,
50.85, 50.91, 51.22, 51.56, 58.06, 118.38, 126.99, 127.47,
128.43, 129.60, 129.76, 133.91, 134.11, 136.17, 143.39,
171.95; ESIMS m/z 400 (Mþþ1). Anal. Calcd for
C22H25NO4S: C, 66.14; H, 6.31; N, 3.51. Found: C, 66.34;
H, 6.29; N, 3.35.
3.2.4. Compound Z-2c
Yield 40%; white solid, mp 96e98 ꢀC; IR (CH2Cl2) 2214,
1
1342, 1159, 1093 cmꢁ1; H NMR (CDCl3, 300 MHz) d 2.42
(s, 3H), 3.89 (d, J¼7.5 Hz, 2H), 3.94 (d, J¼6.3 Hz, 2H),
4.12 (s, 2H), 5.61e5.70 (m, 1H), 5.82e5.92 (m, 1H), 7.13
(s, 1H), 7.30 (d, J¼8.1 Hz, 2H), 7.42e7.44 (m, 3H), 7.70e
7.56 (m, 4H); 13C NMR (CDCl3, 75 MHz) d 21.53, 30.98,
48.98, 50.38, 105.92, 117.64, 127.44, 128.92, 128.96,
129.06, 129.90, 130.94, 131.85, 132.62, 136.53, 144.02,
146.60; ESIMS m/z 445 (Mþþ1). Anal. Calcd for
C21H21BrN2O2S: C, 56.63; H, 4.75; N, 6.29. Found: C,
56.46; H, 4.91; N, 6.03.
3.3.2. Compound anti-3a
Yield 10%; colorless oil; IR (CH2Cl2) 2924, 1731, 1346,
;
1166, 1090 cmꢁ1 1H NMR (CDCl3, 300 MHz) d 2.44 (s,
3H), 2.62 (d, J¼13.5 Hz, 1H), 3.01 (dd, J¼14.4 and 7.2 Hz,
1H), 3.05 (d, J¼13.5 Hz, 1H), 3.35e3.47 (m, 3H), 3.46 (s,
3H), 3.57 (d, J¼10.5 Hz, 1H), 5.12e5.30 (m, 2H), 5.76e
5.89 (m, 1H), 6.97e7.00 (m, 2H), 7.20e7.23 (m, 3H), 7.32
(d, J¼8.1 Hz, 2H), 7.71 (d, J¼8.1 Hz, 2H); 13C NMR
(CDCl3, 125 MHz) d 29.69, 37.36, 49.21, 50.69, 51.94,
52.12, 57.32, 118.95, 126.94, 127.57, 128.44, 129.47,
129.66, 133.67, 134.06, 136.61, 143.48, 173.33; ESIMS m/z
400 (Mþþ1). Anal. Calcd for C22H25NO4S: C, 66.14; H,
6.31; N, 3.51. Found: C, 66.25; H, 6.52; N, 3.43.
3.2.5. Compound 2d
Yield 63%; colorless oil; IR (CH2Cl2) 1734, 1718, 1437,
1
1264, 1241, 1205 cmꢁ1; H NMR (CDCl3, 300 MHz) d 2.41
(d, J¼7.5 Hz, 2H), 3.38 (s, 2H), 3.56e3.59 (m, 2H), 3.59 (s,
6H), 3.77 (s, 3H), 4.94e5.04 (m, 1H), 5.42e5.52 (m, 1H),
7.27e7.44 (m, 5H), 7.82 (s, 1H); 13C NMR (CDCl3, 75 MHz)
d 28.33, 32.27, 35.03, 52.09, 52.32 (2C), 57.59, 128.41,
128.66, 128.72, 128.95, 129.54, 130.21, 135.30, 142.55,
168.33, 170.82 (2C); ESIMS m/z 439 (Mþþ1). Anal. Calcd
for C20H23BrO6: C, 54.68; H, 5.28. Found: C, 54.87; H, 5.21.
3.3.3. Compound syn-3b
Yield 55%; colorless oil; IR (CH2Cl2) 1728, 1345, 1163,
; d 1.02 (t,
1090 cmꢁ1 1H NMR (CDCl3, 300 MHz)
3.2.6. Compound 2e
Yield 76%; colorless oil; IR (CH2Cl2) 1719, 1437, 1340,
;
1158 cmꢁ1 1H NMR (CDCl3, 300 MHz) d 2.44 (s, 3H),
J¼7.2 Hz, 3H), 2.36 (s, 3H), 2.63 (d, J¼13.8 Hz, 1H), 2.69
(dd, J¼14.4 and 6.6 Hz, 1H), 3.11 (dd, J¼10.2 and 6.9 Hz,
1H), 3.16 (d, J¼13.8 Hz, 1H), 3.38 (s, 2H), 3.64 (dd,
J¼10.2 and 6.9 Hz, 1H), 3.83e3.94 (m, 2H), 4.92e4.99 (m,
2H), 5.29e5.42 (m, 1H), 6.94e6.97 (m, 2H), 7.14e7.20 (m,
3H), 7.24 (d, J¼8.1 Hz, 2H), 7.64 (d, J¼8.1 Hz, 2H); 13C
NMR (CDCl3, 75 MHz) d 14.02, 21.46, 40.79, 50.91, 50.96,
51.23, 57.78, 60.81, 118.29, 126.94, 127.44, 128.38, 129.60,
129.81, 133.97, 134.20, 136.25, 143.40, 171.49; ESIMS m/z
414 (Mþþ1). Anal. Calcd for C23H27NO4S: C, 66.80; H,
6.58; N, 3.39. Found: C, 66.63; H, 6.39; N, 3.46.
3.61 (s, 3H), 3.64 (d, J¼7.5 Hz, 2H), 3.79 (dd, J¼16.5 and
7.2 Hz, 1H), 3.81 (dd, J¼16.5 and 7.2 Hz, 1H), 5.12e5.19
(m, 1H), 5.34e5.44 (m, 1H), 5.67 (d, J¼1.2 Hz, 1H), 6.12
(s, 1H), 6.43 (d, J¼0.9 Hz, 1H), 7.00e7.04 (m, 2H), 7.22e
7.26 (m, 3H), 7.28 (d, J¼8.1 Hz, 2H), 7.71 (d, J¼8.1 Hz,
2H); 13C NMR (CDCl3, 75 MHz) d 21.54, 31.49, 46.86,
52.02, 61.71, 127.54, 127.75, 128.20, 128.53, 128.67,
129.06, 129.54, 131.13, 136.88, 137.61, 139.05, 143.41,
166.21; ESIMS m/z 478 (Mþþ1). Anal. Calcd for
C22H24BrNO4S: C, 55.23; H, 5.06; N, 2.93. Found: C,
55.21; H, 4.97; N, 2.61.
3.3.4. Compound anti-3b
Yield 10%; colorless oil; 1H NMR (CDCl3, 300 MHz)
d 1.06 (t, J¼7.2 Hz, 3H), 2.44 (s, 3H), 2.61 (d, J¼13.8 Hz,
1H), 3.01 (dd, J¼14.7 and 6.6 Hz, 1H), 3.05 (d, J¼13.8 Hz,
1H), 3.40e3.46 (m, 3H), 3.59 (d, J¼10.2 Hz, 1H), 3.83e
4.04 (m, 2H), 5.11e5.25 (m, 2H), 5.79e5.89 (m, 1H),
6.96e7.05 (m, 2H), 7.19e7.26 (m, 3H), 7.32 (d, J¼8.1 Hz,
2H), 7.72 (d, J¼8.1 Hz, 2H); ESIMS m/z 414 (Mþþ1).
Anal. Calcd for C23H27NO4S: C, 66.80; H, 6.58; N, 3.39.
Found: C, 66.95; H, 6.26; N, 3.31.
3.3. Typical procedure for the synthesis of 3a
To a refluxed solution of 2a (478 mg, 1.0 mmol) and AIBN
(16 mg) in benzene (5 mL) was added n-Bu3SnH (437 mg,
1.5 mmol) slowly and the reaction mixture was heated to re-
flux for 5 h. After removal of solvent and column chromato-
graphic purification process (hexanes/ether, 4:1) we obtained
syn-3a (228 mg, 57%) and anti-3a (40 mg, 10%). Other com-
pounds 3bee were synthesized analogously and the spectro-
scopic data are as follows.
3.3.5. Compound syn-3c
Colorless oil; IR (CH2Cl2) 2238, 1348, 1166, 1091 cmꢁ1
;
3.3.1. Compound syn-3a
Yield 57%; colorless oil; IR (CH2Cl2) 1732, 1346, 1165,
;
1091 cmꢁ1 1H NMR (CDCl3, 300 MHz) d 2.43 (s, 3H),
1H NMR (CDCl3, 300 MHz) d 2.42 (s, 3H), 2.70 (d,
J¼13.8 Hz, 1H), 2.70 (dd, J¼18.0 and 8.1 Hz, 1H), 3.02
(d, J¼13.8 Hz, 1H), 3.20 (dd, J¼10.2 and 7.8 Hz, 1H), 3.45

2402
H.S. Lee et al. / Tetrahedron 64 (2008) 2397e2404
(d, J¼11.1 Hz, 1H), 3.51 (d, J¼11.1 Hz, 1H), 3.70 (dd,
J¼10.2 and 7.8 Hz, 1H), 5.24e5.36 (m, 2H), 5.68e5.81 (m,
1H), 7.18e7.21 (m, 2H), 7.30e7.34 (m, 5H), 7.68 (d,
J¼8.4 Hz, 2H); 13C NMR (CDCl3, 75 MHz) d 21.53, 40.36,
48.41, 50.83, 51.09, 55.71, 119.24, 121.74, 127.36, 127.87,
128.84, 129.64, 129.91, 131.62, 133.47, 134.12, 144.10;
ESIMS m/z 367 (Mþþ1). Anal. Calcd for C21H22N2O2S: C,
68.82; H, 6.05; N, 7.64. Found: C, 68.97; H, 6.32; N, 7.59.
J¼13.8 and 4.2 Hz, 1H), 5.02e5.09 (m, 2H), 5.55e5.65 (m,
1H), 5.67 (d, J¼5.4 Hz, 1H), 7.20e7.22 (m, 7H), 7.61 (d,
J¼8.4 Hz, 2H); 13C NMR (CDCl3, 75 MHz) d 21.43, 26.63,
38.67, 43.61, 45.37, 51.87, 55.77, 115.75, 126.94, 127.54,
128.16, 128.37, 129.63, 136.75, 137.41, 138.18, 143.22,
172.21; ESIMS m/z 400 (Mþþ1). Anal. Calcd for
C22H25NO4S: C, 66.14; H, 6.31; N, 3.51. Found: C, 66.23;
H, 6.56; N, 3.43.
3.3.6. Compound anti-3c
3.4. Synthesis of compound cis-2f
Colorless oil; IR (CH2Cl2) 2239, 1350, 1167, 1092 cmꢁ1
;
1H NMR (CDCl3, 300 MHz) d 2.45 (s, 3H), 2.65 (d,
J¼13.5 Hz, 1H), 2.88 (d, J¼13.5 Hz, 1H), 3.07 (dd, J¼15.6
and 7.8 Hz, 1H), 3.17 (d, J¼10.2 Hz, 1H), 3.53 (dd, J¼10.2
and 8.1 Hz, 1H), 3.56 (dd, J¼10.2 and 8.1 Hz, 1H), 3.59 (d,
J¼10.2 Hz, 1H), 5.30e5.40 (m, 2H), 5.71e5.83 (m, 1H),
7.20e7.23 (m, 2H), 7.30e7.40 (m, 5H), 7.71 (d, J¼8.1 Hz,
2H); 13C NMR (CDCl3, 75 MHz) d 21.56, 36.02, 46.67,
49.80, 50.86, 53.20, 120.43, 121.35, 127.42, 127.77, 128.80,
129.99 (2C), 130.80, 133.53, 134.46, 144.21; ESIMS m/z
367 (Mþþ1). Anal. Calcd for C21H22N2O2S: C, 68.82; H,
6.05; N, 7.64. Found: C, 68.74; H, 6.22; N, 7.33.
A mixture of BayliseHillman adduct 1f (384 mg, 2.0 mmol),
cis-1,4-butenediol (1.0 mL), and montmorillonite K10 (1.15 g)
was heated to 100 ꢀC for 3 h.11 After cooling to room tempera-
ture, dilution with CH2Cl2, passing through a pad of Celite, and
column chromatographic purification process (hexanes/ether,
1:1) we obtained alcohol 5 (157 mg, 30%). To a stirred solutio-
n of alcohol 5 (131 mg, 0.5 mmol) in CH2Cl2 (1.0 mL)
was added a solution of PBr3 (203 mg, 1.5 mmol) in CH2Cl2
(0.5 mL) at 0 ꢀC, and stirred further for 2 h. After the usual
aqueous workup and column chromatographic purification pro-
cess (hexanes/ether, 6:1) we obtained cis-2f (82 mg, 50%) as
colorless oil.
3.3.7. Compound syn-3d
Yield 36%; colorless oil; IR (CH2Cl2) 1738, 1731, 1454,
3.4.1. Compound 5
Yield 30%; colorless oil; IR (CH2Cl2) 3436, 1715, 1436,
1
1434, 1260, 1198 cmꢁ1; H NMR (CDCl3, 300 MHz) d 2.29
1
(dd, J¼13.8 and 6.6 Hz, 1H), 2.42 (d, J¼12.0 Hz, 1H), 2.51
(d, J¼14.7 Hz, 1H), 2.62e2.69 (m, 1H), 2.66 (d, J¼13.5 Hz,
1H), 2.77 (d, J¼14.7 Hz, 1H), 3.38 (d, J¼13.5 Hz, 1H), 3.60
(s, 3H), 3.70 (s, 3H), 3.72 (s, 3H), 5.11e5.18 (m, 2H),
5.67e5.79 (m, 1H), 7.15e7.28 (m, 5H); 13C NMR (CDCl3,
75 MHz) d 38.18, 41.14, 41.93, 51.38, 52.72, 53.00, 53.49,
57.99, 58.44, 117.12, 126.50, 128.16, 129.92, 135.85,
137.73, 172.08, 173.52, 174.16; ESIMS m/z 361 (Mþþ1).
Anal. Calcd for C20H24O6: C, 66.65; H, 6.71. Found: C,
66.54; H, 6.97.
1238, 1204, 1117 cmꢁ1; H NMR (CDCl3, 300 MHz) d 3.84
(s, 3H), 4.17 (d, J¼6.0 Hz, 2H), 4.21 (d, J¼6.0 Hz, 2H),
4.31 (s, 2H), 5.66e5.91 (m, 2H), 7.38e7.45 (m, 3H), 7.49e
7.54 (m, 2H), 7.93 (s, 1H); 13C NMR (CDCl3, 75 MHz)
d 52.23, 58.58, 64.30, 65.97, 128.09, 128.46, 128.52, 129.43,
129.77, 132.71, 134.56, 144.87, 168.11; ESIMS m/z 263
(Mþþ1).
3.4.2. Compound cis-2f
Yield 50%; colorless oil; IR (CH2Cl2) 1717, 1436, 1237,
;
1204, 1116 cmꢁ1 1H NMR (CDCl3, 300 MHz) d 3.85 (s,
3.3.8. Compound anti-3d
Yield 45%; colorless oil; IR (CH2Cl2) 1737, 1731, 1454,
3H), 4.02 (d, J¼8.4 Hz, 2H), 4.23 (dd, J¼6.3 and 1.2 Hz,
2H), 4.32 (s, 2H), 5.75e5.83 (m, 1H), 5.86e5.96 (m, 1H),
7.38e7.45 (m, 3H), 7.51e7.54 (m, 2H), 7.94 (s, 1H); 13C
NMR (CDCl3, 75 MHz) d 26.35, 52.18, 64.61, 65.46,
128.45, 128.50, 128.52, 129.40, 129.76, 131.03, 134.59,
144.80, 167.94; ESIMS m/z 325 (Mþþ1). Anal. Calcd for
C15H17BrO3: C, 55.40; H, 5.27. Found: C, 55.54; H, 5.12.
1
1434, 1259, 1199 cmꢁ1; H NMR (CDCl3, 300 MHz) d 2.23
(dd, J¼13.8 and 8.7 Hz, 1H), 2.53 (d, J¼13.8 Hz, 1H), 2.60
(d, J¼15.0 Hz, 1H), 2.66 (dd, J¼13.8 and 8.7 Hz, 1H), 2.83
(d, J¼15.0 Hz, 1H), 3.03 (dd, J¼15.9 and 7.8 Hz, 1H), 3.13
(d, J¼13.8 Hz, 1H), 3.61 (s, 3H), 3.70 (s, 3H), 3.75 (s, 3H),
5.11e5.21 (m, 2H), 5.93e6.06 (m, 1H), 7.08e7.11 (m, 2H),
7.15e7.26 (m, 3H); 13C NMR (CDCl3, 75 MHz) d 37.96,
39.07, 39.23, 51.14, 51.79, 52.85, 52.92, 57.82, 57.83,
117.27, 126.51, 128.17, 129.65, 136.20, 137.66, 172.37,
172.77, 175.42; ESIMS m/z 361 (Mþþ1). Anal. Calcd for
C20H24O6: C, 66.65; H, 6.71. Found: C, 66.51; H, 6.89.
3.5. Synthesis of compound trans-2f
A
mixture of BayliseHillman adduct 1f (384 mg,
2.0 mmol), allyl alcohol (0.5 mL), and montmorillonite K10
(1.15 g) was heated to 100 ꢀC for 3 h.11 After cooling to
room temperature, dilution with CH2Cl2, passing through
a pad of Celite, and column chromatographic purification pro-
cess (hexanes/ether, 25:1) we obtained alcohol 6 (241 mg,
52%). A mixture of compound 6 (232 mg, 1.0 mmol), allyl
bromide (302 mg, 2.5 mmol), and second-generation Grubbs
catalyst (42 mg, 5 mol %) in CH2Cl2 (50 mL) was heated
to reflux for 4 h. After removal of solvent and column
3.3.9. Compound 3e
Yield 64%; colorless oil; IR (CH2Cl2) 1734, 1341,
1
1162 cmꢁ1; H NMR (CDCl3, 300 MHz) d 1.84 (dd, J¼26.4
and 12.9 Hz, 1H), 2.07 (d, J¼14.7 Hz, 1H), 2.14e2.24 (m,
1H), 2.39 (s, 3H), 2.62 (dd, J¼13.8 and 12.0 Hz, 1H), 2.88
(ddd, J¼12.6, 5.4 and 3.6 Hz, 1H), 3.58 (s, 3H), 3.82 (dd,

H.S. Lee et al. / Tetrahedron 64 (2008) 2397e2404
2403
chromatographic purification process (hexanes/ether, 10:1) we
obtained trans-2f (146 mg, 45%) as colorless oil.
References and notes
1. For some review articles on the synthesis of pyrrolidines, see: (a) Pandey,
G.; Banerjee, P.; Gadre, S. R. Chem. Rev. 2006, 106, 4484e4517; (b)
Bellina, F.; Rossi, R. Tetrahedron 2006, 62, 7213e7256; (c) Husinec,
S.; Savic, V. Tetrahedron: Asymmetry 2005, 16, 2047e2061; (d) Felpin,
F.-X.; Lebreton, J. Eur. J. Org. Chem. 2003, 3693e3712.
3.5.1. Compound trans-2f
Yield 45%; colorless oil; IR (CH2Cl2) 1714, 1435, 1237,
;
1204, 1115 cmꢁ1 1H NMR (CDCl3, 300 MHz) d 3.85 (s,
2. For the synthesis of vinyl pyrrolidines and related compounds, see: (a)
Takimoto, M.; Nakamura, Y.; Kimura, K.; Mori, M. J. Am. Chem. Soc.
2004, 126, 5956e5957; (b) Pedrosa, R.; Andres, C.; Martin, L.; Nieto,
J.; Roson, C. J. Org. Chem. 2005, 70, 4332e4337; (c) Montgomery, J.;
Song, M. Org. Lett. 2002, 4, 4009e4011.
3. For the synthesis of vinyl pyrrolidines and their synthetic applications,
see: (a) Zhu, G.; Zhang, Z. Org. Lett. 2004, 6, 4041e4044; (b) Zhang,
Q.; Xu, W.; Lu, X. J. Org. Chem. 2005, 70, 1505e1507; (c) Yang, Q.;
Alper, H.; Xiao, W.-J. Org. Lett. 2007, 9, 769e771; (d) Aoyagi, K.;
Nakamura, H.; Yamamoto, Y. J. Org. Chem. 2002, 67, 5977e5980; (e)
Yu, C. M.; Lee, S.; Hong, Y. T.; Yoon, S. K. Tetrahedron Lett. 2004,
45, 6557e6561; (f) Goeta, A.; Salter, M. M.; Shah, H. Tetrahedron
2006, 62, 3582e3599; (g) Michelet, V.; Galland, J.; Charruault, L.;
Savignac, M.; Genet, J. Org. Lett. 2001, 3, 2065e2067.
3H), 3.95 (d, J¼5.7 Hz, 2H), 4.11 (d, J¼4.2 Hz, 2H), 4.31
(s, 2H), 5.86e6.01 (m, 2H), 7.36e7.45 (m, 3H), 7.50e7.54
(m, 2H), 7.94 (s, 1H); 13C NMR (CDCl3, 75 MHz) d 31.92,
52.20, 64.38, 69.94, 128.54, 128.56, 128.90, 129.41, 129.80,
131.58, 134.67, 144.80, 168.01; ESIMS m/z 325 (Mþþ1).
Anal. Calcd for C15H17BrO3: C, 55.40; H, 5.27. Found: C,
55.61; H, 5.23.
3.6. Radical cyclization of compound 2f
Radical cyclizations of compounds cis-2f and trans-2f were
carried out similarly to that of compound 3a and the spectro-
scopic data of products are as follows.
4. For the radical cyclizations involving BayliseHillman adducts, see: (a)
Gowrisankar, S.; Kim, S. J.; Lee, J.-E.; Kim, J. N. Tetrahedron Lett.
2007, 48, 4419e4422; (b) Gowrisankar, S.; Lee, H. S.; Kim, J. N. Tetra-
hedron Lett. 2007, 48, 3105e3108; (c) Gowrisankar, S.; Lee, K. Y.; Kim,
T. H.; Kim, J. N. Tetrahedron Lett. 2006, 47, 5785e5788; (d) Gowrisan-
kar, S.; Lee, H. S.; Kim, J. N. Bull. Korean Chem. Soc. 2006, 27, 2097e
2100; (e) Gowrisankar, S.; Lee, K. Y.; Kim, J. N. Bull. Korean Chem. Soc.
2006, 27, 929e932; (f) Park, D. Y.; Gowrisankar, S.; Kim, J. N. Bull.
Korean Chem. Soc. 2005, 26, 1440e1442. For the radical cyclizations
of other groups, see: (g) Majhi, T. P.; Neogi, A.; Ghosh, S.; Mukherjee,
A. K.; Chattopadhyay, P. Tetrahedron 2006, 62, 12003e12010; (h)
Alcaide, B.; Almendros, P.; Aragoncillo, C. Chem. Commun. 1999,
1913e1914; (i) Singh, V.; Batra, S. Tetrahedron Lett. 2006, 47, 7043e
7045; (j) Alcaide, B.; Almendros, P.; Aragoncillo, C. J. Org. Chem.
2001, 66, 1612e1620.
3.6.1. Compound syn-3f
Colorless oil; IR (CH2Cl2) 1731, 1204 cmꢁ1 1H NMR
;
(CDCl3, 300 MHz) d 2.80 (s, J¼13.5 Hz, 1H), 2.86 (dd,
J¼15.9 and 6.9 Hz, 1H), 3.34 (d, J¼13.5 Hz, 1H), 3.66 (s,
3H), 3.73 (dd, J¼9.0 and 6.6 Hz, 1H), 3.85 (d, J¼9.3 Hz,
1H), 4.07e4.15 (m, 2H), 5.11e5.18 (m, 2H), 5.64e5.76 (m,
1H), 7.06e7.29 (m, 5H); 13C NMR (CDCl3, 75 MHz)
d 40.95, 51.53, 53.37, 59.19, 71.85, 71.95, 117.92, 126.76,
128.32, 129.72, 134.89, 137.11, 172.77; ESIMS m/z 247
(Mþþ1). Anal. Calcd for C15H18O3: C, 73.15; H, 7.37. Found:
C, 73.02; H, 7.44.
We could not separate syn-3f and anti-3f in pure states at
this stage, unfortunately. Thus, the ratio of syn-3f/anti-3f (ca.
85:15, Scheme 2) and the NMR data were determined from
the spectra of mixture.
5. (a) Gowrisankar, S.; Lee, K. Y.; Kim, J. N. Tetrahedron Lett. 2005, 46,
4859e4863; (b) Shanmugam, P.; Rajasingh, P. Synlett 2005, 939e942;
(c) Shanmugam, P.; Rajasingh, P. Tetrahedron 2004, 60, 9283e9295;
(d) Shanmugam, P.; Rajasingh, P. Tetrahedron Lett. 2005, 46, 3369e3372.
6. For the radical cyclization involving allyl radicals, see: (a) Lin, H.; Schall,
A.; Reiser, O. Synlett 2005, 2603e2606; (b) Stork, G.; Reynolds, M. E.
J. Am. Chem. Soc. 1988, 110, 6911e6913; (c) Hirashita, T.; Tanaka, J.;
Hayashi, A.; Araki, S. Tetrahedron Lett. 2005, 46, 289e292. For an excel-
lent review on the synthesis of heterocycles under radical conditions, see:
(d) Majumdar, K. C.; Basu, P. K.; Chattopadhyay, S. K. Tetrahedron 2007,
63, 793e826.
3.6.2. Compound anti-3f
1H NMR (CDCl3, 300 MHz) d 2.70 (d, J¼13.5 Hz, 1H),
3.16 (d, J¼13.5 Hz, 1H), 3.20 (dd, J¼15.3 and 7.8 Hz, 1H),
3.63 (s. 3H), 3.78e3.82 (m, 2H), 4.03e4.18 (m, 2H), 5.23e
5.28 (m, 2H), 5.89e6.01 (m, 1H), 7.06e7.29 (m, 5H); 13C
NMR (CDCl3, 75 MHz) d 37.06, 51.00, 51.88, 58.05, 71.65,
72.78, 118.58, 126.67, 128.30, 129.40, 134.22, 137.44, 174.37.
7. For the synthesis of vinyl piperidines via an allylic radical cyclization
protocol, see: Yoo, S.-e.; Yi, K. Y.; Lee, S.-H.; Jeong, N. Synlett 1990,
575e576.
8. For the synthesis of starting materials 1aee, see: (a) Kim, J. N.; Lee, H. J.;
Lee, K. Y.; Kim, H. S. Tetrahedron Lett. 2001, 42, 3737e3740; (b) Kim,
J. N.; Lee, H. J.; Lee, K. Y.; Gong, J. H. Synlett 2002, 173e175; (c) Im,
Y. J.; Kim, J. M.; Kim, J. N. Bull. Korean Chem. Soc. 2002, 23,
1361e1362.
3.6.3. Compound 412
Yield 44%; colorless oil; 1H NMR (CDCl3, 300 MHz)
d 2.12 (d, J¼1.5 Hz, 3H), 3.82 (s, 3H), 7.29e7.40 (m, 5H),
7.69 (d, J¼1.5 Hz, 1H).
9. The separation of E-2c and Z-2c was also somewhat difficult and we
isolated 15% of E-2c, 40% of Z-2c, and appreciable amounts of 2c as
a E/Z mixture (ca. 8%).
10. For the synthesis of vinyl tetrahydrofurans and their synthetic applica-
tions, see: (a) Sekido, M.; Aoyagi, K.; Nakamura, H.; Kabuto, C.; Yama-
moto, Y. J. Org. Chem. 2001, 66, 7142e7147; (b) Shim, J.-G.; Yamamoto,
Y. J. Org. Chem. 1998, 63, 3067e3071; (c) Komatsu, Y.; Sakamoto, T.;
Kitazume, T. J. Org. Chem. 1999, 64, 8369e8374; (d) Bertrand, M. P.;
Surzur, J.-M.; Oumar-Mahamat, H.; Moustrou, C. J. Org. Chem. 1991,
56, 3089e3097.
Acknowledgements
This work was supported by the Korea Research Founda-
tion Grant funded by the Korean Government (MOEHRD,
KRF-2006-311-C00384). Spectroscopic data was obtained
from the Korea Basic Science Institute, Gwangju branch.
11. For the recent applications of montmorillonite K10 in organic synthesis,
see: (a) Shanmugam, P.; Rajasingh, P. Chem. Lett. 2005, 34, 1494e1495;

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H.S. Lee et al. / Tetrahedron 64 (2008) 2397e2404
(b) Shanmugam, P.; Rajasingh, P. Synlett 2001, 1314e1316; (c) Das, B.;
Majhi, A.; Banerjee, J.; Chowdhury, N.; Venkateswarlu, K. Chem. Lett.
2005, 34, 1492e1493.
13. For the cross metathesis reaction involving allyl bromide, see: (a) Bandini,
M.; Cozzi, P. G.; Licciulli, S.; Umani-Ronchi, A. Synthesis 2004, 409e414;
(b) Blanco, O. M.; Castedo, L. Synlett 1999, 557e558; (c) Merino, P.;
Tejero, T.; Mannucci, V.; Prestat, G.; Madec, D.; Poli, G. Synlett 2007,
944e948; (d) Liu, B.; Das, S. K.; Roy, R. Org. Lett. 2002, 4, 2723e2726.
12. Das, B.; Banerjee, J.; Majhi, A.; Mahender, G. Tetrahedron Lett. 2004, 45,
9225e9227.