A practical route to 2,3-di-/1,2,3-trisubstituted indolizines from α-EWG ketene S,S-acetals and their application in bis(1-indolizinyl) methane synthesis

Article abstract of DOI:10.1055/s-2008-1032144

An easy synthesis of 2,3-di-/1,2,3-trisubstituted indolizines has been developed via a formal [3+2] annulation of α-EWG ketene S,S-acetals with 2-pyridine-/2-quinolinecarbaldehyde. The disubstituted products are formed via an intramolecular aza-Michael addition and subsequent elimination of acetic acid, followed by desulfenylation assisted by acetic acid, whereas the trisubstituted products are obtained via a similar conjugate addition followed by elimination of alkanethiol. This strategy has been applied to the synthesis of bis(1-indolizinyl)methanes by the condensation of a 2,3-disubstituted indolizine with aldehydes/ketones in the presence of a catalytic amount of BF₃·OEt₂. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032144

PAPER
573
A Practical Route to 2,3-Di-/1,2,3-Trisubstituted Indolizines from a-EWG
Ketene S,S-Acetals and Their Application in Bis(1-indolizinyl)methane
Synthesis
2
, 3-Di-/1,2,3-T
h
risubstituted
a
Indolizine
o
s
guang Sun, Mang Wang*, Hongxia Deng, Qun Liu*
Department of Chemistry, Northeast Normal University, Changchun 130024, P. R. of China
Fax +86(431)85099759; E-mail: wangm452@nenu.edu.cn
Received 1 October 2007; revised 5 November 2007
amides with heteroaryl bromides by a catalyzed tandem
coupling and cycloisomerization reaction,10 or Pt(II)-cat-
alyzed cycloisomerization of pyridinepropargylic alco-
hols and derivatives11 can also be used. Recently, a new
Abstract: An easy synthesis of 2,3-di-/1,2,3-trisubstituted indol-
izines has been developed via a formal [3+2] annulation of a-EWG
ketene S,S-acetals with 2-pyridine-/2-quinolinecarbaldehyde. The
disubstituted products are formed via an intramolecular aza-Michael
addition and subsequent elimination of acetic acid, followed by access to 2-substituted or 2,3-disubstituted indolizines
desulfenylation assisted by acetic acid, whereas the trisubstituted
starting from the Baylis–Hillman (BH) adducts based on
products are obtained via a similar conjugate addition followed by
2-pyridinecarbaldehyde and activated alkenes having no
elimination of alkanethiol. This strategy has been applied to the syn-
or one b-substituent has been reported.12 In this regard, al-
thesis of bis(1-indolizinyl)methanes by the condensation of a 2,3-
though many approaches have been described,1,5–12 the
disubstituted indolizine with aldehydes/ketones in the presence of a
development of new synthetic methods, especially for the
production of polysubstituted indolizines, from readily
available starting materials with high selectivity and con-
version under mild conditions is highly desired.
catalytic amount of BF3·OEt2.
Key words: indolizines, a-EWG ketene S,S-acetals, bis(1-indol-
izinyl)methanes, annulation, condensation
a-EWG ketene S,S-acetals (EWG = electron-withdrawing
group) and related compounds are versatile synthons13
and have found wide application in the synthesis of vari-
ous carbo-14 and heterocyclic compounds.15 In our re-
search on the synthetic applications of a-EWG ketene S,S-
acetals,16 we recently showed that their a-carbon atom
possess a high nucleophility17–19and could add to alde-
hydes or ketones in the presence of Lewis acid via Baylis–
Hillman-type reaction20 to afford the double BH adducts
(Scheme 1, Path A).18 In the case of the reaction with o-
nitrobenzaldehydes, substituted indole N-oxides were
formed by the TiCl4-mediated BH reaction and subse-
Indolizines are important heterocycles broadly found in
naturally occurring and biological molecules1,2 and used
in the area of therapy3 and dyestuffs.1,4 Recently, much at-
tention has been focused on the synthesis of the indolizine
structural motif.5 In general, the synthetic approaches to
indolizine derivatives have mainly employed the Scholtz
or Tschitschibabin reaction,6 1,3-dipolar cycloadditions,7
and 1,5-dipolar cyclizations.8 In addition to these proce-
dures, a variety of other methods, including cyclization of
the silicon-capped (Z)-2-pyridinevinylacetylenes with ba-
sic alcohol solutions,9 reactions of propargylamines or
S
R1 R2
CHO
NO2
O
EWG
O
EWG
RS
EWG
SR
R1
S
R1
R2
S
RS
SR
R1
path B
path A
SR
SR
double BH adducts
1
R,R = (CH2)2
N
S
O
indole N-oxides
path C
CHO
N
X
OH
EWG
SR
EWG
SR
N
N
RS
indolizine derivatives
BH adducts
Scheme 1
SYNTHESIS 2008, No. 4, pp 0573–0583
x
x
.
x
x
.2
0
0
8
Advanced online publication: 31.01.2008
DOI: 10.1055/s-2008-1032144; Art ID: F17707SS
© Georg Thieme Verlag Stuttgart · New York

574
S. Sun et al.
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quent cyclization reaction (Scheme 1, Path B).19 Combin- noteworthy that the efficiency of this methodology was
ing with our previous studies,16b,e–g,i,k,17–19 in the present demonstrated by the straightforward synthesis of bis(1-in-
work, 2-pyridinecarbaldehyde and 2-quinolinecarbalde- dolizinyl)methanes via the condensation of 2,3-disubsti-
hyde were chosen as probes to react with a-EWG ketene tuted indolizines with various aldehydes or ketones in the
S,S-acetals 1 with the consideration that a formal [3+2] presence of catalytic amount of BF3·OEt2. Here, we wish
annulation between them would be realizable for the con- to present these experimental results and the possible
struction of substituted indolizines (Scheme 1, Path mechanism of the annulation of BH adducts to indolizine
C).12,21 As expected, BH adducts were obtained, catalyzed derivatives.
by TiCl4, in high yields in acetonitrile. Then, the annula-
tion of these new BH adducts was examined in the pres-
ence of acetic anhydride, which afforded 2,3-disubstituted
and 1,2,3-trisubstituted indolizines in good yields. It is
The reaction between 3,3-bis(ethylthio)acrylonitrile (1a)
and 2-pyridinecarbaldehyde (2A) was first carried out us-
ing TiCl4 as a catalyst in different solvents. The best re-
sults were obtained when 1a was treated with 2A in
Table 1 BH Reactions between a-EWG Ketene S,S-Acetals 1 and 2-Pyridine-/2-Quinolinecarbaldehyde 2
OH
CHO
EWG
SR
EWG
SR
TiCl4
+
N
N
RS
RS
MeCN
1
2
3
Entrya Substrate 1
R
EWG
Aldehyde 2 Product 3
Time (h) Yieldb (%)
1
2
3
4
1a
1b
1c
1d
Et
CN
2A
2A
2A
2A
3Aa
3Ab
3Ac
2
4
5
5
85
83
78
–
n-Bu
Bz
CN
CN
c
Et
MeCO
–
OH
O
O
5
6
1e
1f
2A
2A
6
7
73
55
3Ae
3Af
N
S
EtS
EtS
S
EtS
OH
O
O
N
S
S
EtS
Cl
Cl
7
8
9
1a
1b
1c
Et
CN
CN
CN
2B
2B
2B
3Ba
3Bb
3Bc
4
5
7
79
67
69
n-Bu
Bz
OH
O
S
O
10
11
1e
1f
2B
2B
3Be
10
10
66
N
EtS
S
EtS
O
c
–
–
EtS
S
Cl
a 1:2:TiCl4 = 1:1:1.1, r.t.
b Isolated yields after silica column chromatography.
c Unidentified mixture.
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2,3-Di-/1,2,3-Trisubstituted Indolizines
575
acetonitrile in the presence of TiCl4 for two hours at room cleophiles to react with 2A. To our delight, the desired BH
temperature, thus providing the desired 3,3-bis(ethylthio)- adducts 3Ae and 3Af were obtained in good yields (en-
2-[hydroxyl(pyridin-2-yl)methyl]acrylonitrile (3Aa) in tries 5 and 6). Similarly, BH adducts 3Ba–Bc and 3Be
85% yield (Table 1, entry 1). Under identical conditions, were successfully synthesized in 66–79% yields from the
a-EWG ketene S,S-acetals 1b–d were selected to react reaction of 1a–c and 1e with 2-quinolinecarbaldehyde
with 2A. It is clear from Table 1 that the reactions of 1b (2B) (entries 7–10), respectively. In the case of the reac-
and 1c proceeded smoothly to afford the corresponding tion of 1f and 2B, a complex mixture was obtained (entry
adducts 3Ab and 3Ac (entries 2 and 3), while 1d gave an 11).
unidentified mixture (entry 4). The cyclic a-EWG ketene
Then, the annulation of adducts 3 were tested. Kaye and
co-workers reported that the annulation of acetylated BH
adducts derived from activated alkenes having no b-sub-
S,S-acetals 1e and 1f, which could be readily prepared ac-
cording to our previous report,16g were also tested as nu-
Table 2 Annulations of BH Adducts 3
OH
X
EWG
SR
Ac2O
EWG
N
N
∆
RS
SR
4: X = H
5: X = OAc
3
Entry Substrate 3
R
EWG
CN
Product 4 or 5
X
Time
(h)
Yield a
(%)
SEt
SEt
OAc
SEt
H (4Aa)
SEt (4Aa¢)
OAc (5Aa)
31
47
5
CN
CN
+
CN
1b
3Aa
Et
+
N
N
N
6
SEt
4Aa
4Aa'
5Aa
2c
3d
4c
3Aa
3Ab
3Ac
Et
CN
CN
CN
4Aa
H
H
H
6
6
7
88
77
79
n-Bu
Bz
4Ab
4Ac
OH
O
S
O
5c
H
H
5
5
66
55
4Ae
3Ae
3Af
N
N
S
EtS
OH
O
S
O
6c
4Af
N
N
S
EtS
Cl
Cl
7d
8d
9d
3Ba
3Bb
3Bc
Et
CN
CN
CN
5Ba
5Bb
5Bc
OAc
OAc
OAc
7
7
9
87
79
83
n-Bu
Bz
O
OH
O
10d
H
5
82
N
3Be
4Be
N
S
S
EtS
a Isolated yields after silica column chromatography.
b 3Aa (1.0 mmol), Ac2O (0.4 mL), DMF (4.0 mL), 120 °C.
c 3 (1.0 mmol), Ac2O (1.0 mL), 50 °C for 2 h, then heating to 120 °C.
d 3 (1.0 mmol), Ac2O (1.0 mL), 50 °C for 1 h, then heating to 80 °C.
Synthesis 2008, No. 4, 573–583 © Thieme Stuttgart · New York

576
S. Sun et al.
PAPER
stituent with 2-pyridinecarbaldehyde afforded the 2-sub- temperature was enough to complete the reaction for the
stituted indolizine derivatives via an intramolecular substrates 3Ba–Bc and 3Be derived from 2-quinolinecar-
Michael-type addition and elimination of acetic acid se- baldehyde. Thus, heating a mixture of 3 and acetic anhy-
quence.12a,b Interestingly, in our experiment, when the BH dride under 80 °C furnished 1,2,3-trisubstituted indolizine
adduct 3Aa bearing b,b-dialkylthio groups was treated derivatives 5Ba–Bc in 79–87% yields (entries 7–9), while
with acetic anhydride at 120 °C in DMF for six hours, 2,3-disubstituted product 4Be was formed in the case of
three indolizine derivatives, namely 3-(ethylthio)indoliz- 3Be as substrate (entry 10).
ine-2-carbonitrile (4Aa), 1,3-bis(ethylthio)indolizine-2-
On the basis of the above results, a possible mechanism
carbonitrile (4Aa¢), and 2-cyano-3-(ethylthio)indolizin-1-
for the formations of 4, 4¢, and 5 is proposed as depicted
yl acetate (5Aa), were obtained in 31%, 47%, and 5% iso-
in Scheme 2 using annulation of 3Aa as an example. This
lated yields, respectively (Table 2, entry 1). Of these prod-
pathway begins with the formation of 8 by acetylation of
3Aa in the presence of acetic anhydride. An intramolecu-
ucts, the minor product 5Aa should be reasonably
explained to have formed via an intramolecular aza-
lar aza-Michael addition of the pyridine nitrogen on the
Michael addition of the pyridine nitrogen on the ketene
ketene dithioacetal moiety gives intermediate I. Then, two
different elimination pathways (Path A and Path B) would
lead to the formation of two kinds of indolizine deriva-
tives 4Aa and 5Aa. Path A involves an elimination of
ethanethiol from I followed by deprotonation to afford
5Aa. Correspondingly, in the path B, the elimination of
dithioacetal moiety of 3Aa and subsequent elimination of
ethanethiol. However, the favorable formation of 4Aa and
4Aa¢ seemed unexpected. It was found that the products of
this reaction strongly depended on the reaction time. By
prolonging the reaction time, the yield of 4Aa¢ was in-
creased along with the decrease of 4Aa. By optimizing the
acetic acid from I first provides intermediate II. Subse-
reaction conditions, 4Aa could be obtained in 88% yield
quently, desulfenylation of II assisted by acetic acid in the
as the sole product when the reaction was performed in
aromatization step yields 4Aa along with the formation of
unstable ethanesulfenyl acetate (9) (a potent sulfenylating
agent). Thus, the formation of 4Aa¢ should be due to the
electrophilic substitution at the 1-position of 4Aa by 9. In
neat acetic anhydride first at 50 °C for two hours to allow
the complete acetylation of 3Aa and then at 120 °C for an
additional four hours (entry 2).
Subsequently, the annulation reactions of other BH ad- 1993, Hamel and co-workers reported a nonreductive
ducts 3 obtained in our work were carried out under the method for the desulfenylation of 3-indolyl sulfides using
optimized reaction conditions (entry 2). As shown in trifluoroacetic acid as catalyst.22 Compared to their work,
Table 2, all the reactions proceeded smoothly to afford the desulfenylation of II is believed to be assisted by ace-
two kinds of substituted indolizine derivatives 4 and 5 de- tic acid in our experiment.
pending on the substrates. 2,3-Disubstituted indolizines
4Ab and 4Ac were obtained in high yields from 3Ab and
3Ac (entries 3 and 4). Thiopyrano-fused indolizines 4Ae
and 4Af were also formed from the corresponding BH ad-
As presented above, we have found a novel method to rap-
idly synthesize 1,2-di- and 1,2,3-trisubstituted indolizine
derivatives 4 and 5 via formal [3+2] annulation of a-EWG
ketene dithioacetals and 2-pyridine-/2-quinolinecarbalde-
ducts 3Ae and 3Af (entries 5 and 6). In contrast, lower
hyde. With the readily available 2,3-disubstituted indoliz-
OH
CN
OAc
CN
OAc
CN
H
N
– H+
N
SEt
N
EtS
3Aa
SEt
SEt
5Aa
Ac2O
– EtSH
path A
OAc
OAc
CN
CN
CN
– AcOH
N
N
N
SEt
SEt
path B
SEt
SEt
O
EtS
EtS
AcO
8
I
II
S
O
Et
9
SEt
9
CN
CN
N
N
SEt
SEt
4Aa'
4Aa
Scheme 2 Proposed mechanism for the construction of indolizines 4 and 5 from 3
Synthesis 2008, No. 4, 573–583 © Thieme Stuttgart · New York

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2,3-Di-/1,2,3-Trisubstituted Indolizines
577
ine derivatives 4 in hand, we then explored their utility in Encouraged by the above results, we then investigated the
the synthesis of bis(1-indolizinyl)methanes.
scope of the reaction. A variety of aldehydes and ketones
were thus selected as electrophiles to react with 4Aa un-
der the identical conditions and the experimental results
are listed in Table 3. All aldehydes tested, including aryl-
aldehydes with electron-donating groups (entries 1 and 2)
and electron-withdrawing groups (entries 4 and 5), het-
eroaromatic aldehydes (entries 7 and 8), and aliphatic al-
dehydes (entry 9) could readily react with 4Aa to afford
the condensation products, bis(1-indolizinyl)aryl-
methanes 7a–e1, bis(1-indolizinyl)heteroarylmethanes 7f
and 7g, and bis(1-indolizinyl)alkanes 7h, respectively, in
excellent yields. Notably, 2-fold excess of 4Aa with re-
spect to phthalaldehyde (6e) was enough to afford the
double-condensation adduct 7e2 in 92% yield (entry 6). In
comparison to the reactions with aldehydes (entries 1–9),
the reaction with ketone (entry 10) afforded the corre-
sponding bis(1-indolizinyl)alkane 7i in slightly lower
yield. The structure of 7 was further established by X-ray
diffraction studies of 7d (Figure 1).28 All the above results
indicated the extraordinarily high reactivity of 4Aa to-
ward carbonyl electrophiles. It is noteworthy that the
alkylthio group at the 3-position of indolizines 4 can act
as either an activating group to promote the C–C coupling
reaction as mentioned or as a protecting group29 (easily
displaced30 or removed by Raney Ni desulfurization) to
make the electrophilic substitution reaction occur only at
the 1-position of the indolizine core. Thus, an efficient
and regiospecific synthesis of bis(1-indolizinyl)methanes
has been provided.
Bis- and tris(heteroaryl)methanes and analogues are often
present as natural compounds in foods and beverages,23
and are broadly used in cyanine dyes24 and in the synthesis
of various heterocyclic macromolecules.25 Despite the
fact that indolizine is one of the basic nitrogen heterocy-
clic compounds with 10p electron system, the synthesis
and utility of triheteroarylmethanes based on indolizine
are much less recognized in comparison to its isomer in-
dole, which has found extensive application in trihet-
eroarylmethane synthesis.26 In 2001, Tominaga et al.
synthesized bis(1-indolizinyl)methane derivatives by the
condensation of 3,7-di- or 2,3,7-trisubstituted indolizines
with aldehydes in the presence of excess trifluoroacetic
acid to be used as the precursors of oxidative chromogenic
reagents in clinical analysis.27 In our work, indolizines 4
bearing 2,3-disustituted groups provide a novel subject for
the regiospecific synthesis of bis(1-indolizinyl)methanes.
Initially, the condensation of indolizine 4Aa with piper-
onaldehyde (6a) was tried in the presence of BF3·OEt2 at
room temperature in dichloromethane. To our delight, the
reaction produced bis(1-indolizinyl)piperonylmethane
(7a) in quantitative isolated yield within two hours. Inter-
estingly, when a catalytic amount of BF3·OEt2 (10 mol%)
was used, the desired product 7a was also obtained in 99%
yield (Table 3, entry 1).
Table 3 Condensation Reaction between Indolizine 4Aa with Alde-
hydes/Ketone 6
R1 R2
O
BF3·OEt2
CN
+
R1
R2
N
N
N
CH2Cl2
SEt
EtS
SEt
CN NC
4Aa
6
7
Entrya
6
R1
R2
Time Product Yield
(h)
7
(%)b
1
2
6a
6b
6c
6d
6e
6e
6f
3,4-(OCH2O)C6H3
4-MeOC6H4
Ph
H
2
7a
7b
7c
7d
7e1
7e2
7f
99
H
H
H
H
H
H
H
H
Me
4
96
3
8
95
4
4-ClC6H4
4-CHOC6H4
4-CHOC6H4
2-furyl
10
12
18
4
93
5
87
6
92c
96
7
8
6g
6h
6i
2-thienyl
Et
6
7g
7h
7i
99
9
5
89
Figure 1 Molecular structure of 7d
10
Me
24
75d
In summary, we have demonstrated an easy and practical
method for the synthesis of 2,3-disubstituted indolizines 4
and 1,2,3-trisubstituted indolizines 5 via formal [3+2] an-
nulation of a-EWG ketene dithioacetals and 2-pyridine-/
a BF3·OEt2 (10 mol%), r.t.
b Isolated yield after silica gel chromatography.
c 4Aa:6e = 2:1.
d Large excess of 6i was used.
Synthesis 2008, No. 4, 573–583 © Thieme Stuttgart · New York

578
S. Sun et al.
PAPER
13C NMR (125 MHz, CDCl3): d = 12.3 (2 C), 20.4, 20.5, 30.4, 30.8,
33.3, 33.8, 69.4, 108.5, 114.7, 119.9, 122.1, 136.0, 146.9, 154.4,
155.4.
2-quinolinecarbaldehyde. The formation of indolizines 4
and 5 involve two pathways: 1) an intramolecular aza-
Michael addition of the pyridine nitrogen and elimination
of acetic acid, followed by a desulfenylation with the as-
sistance of acetate acid to afford 4; and 2) a similar aza-
Michael addition followed by the elimination of alkane-
thiol to give 5. Indolizines 4 and 5, including their thiopy-
rano-fused analogues, are expected to be useful building
blocks in organic synthesis. Thus, 4Aa has been success-
fully applied to the synthesis of bis(1-indolizinyl)meth-
anes 7 by the condensation of 4Aa with a broad range of
aldehydes and ketones in the presence of catalytic amount
of BF3·OEt2.
ES-MS: m/z = 337 [M + 1]+.
Anal. Calcd for C17H24N2OS2: C, 60.68; H, 7.19; N, 8.32. Found: C,
60.92; H, 7.44; N, 8.12.
3,3-Bis(benzylthio)-2-[hydroxy(pyridin-2-yl)methyl]acryloni-
trile (3Ac)
Colorless crystals; mp 80–82 °C.
IR (KBr): 2923, 2227, 1484, 1234 cm–1.
1H NMR (500 MHz, CDCl3): d = 4.14–4.25 (m, 4 H), 5.36 (br s, 1
H), 5.90 (s, 1 H), 6.48 (d, J = 7.5 Hz, 1 H), 7.21 (dd, J = 7.5, 5.5 Hz,
1 H), 7.24–7.35 (m, 10 H), 7.52 (t, J = 7.5 Hz, 1 H), 8.51 (d, J = 5.5
Hz, 1 H).
All reagents were purchased from commercial sources and used
without treatment, unless otherwise indicated. Petroleum ether (PE)
used refers to the fraction boiling in the range 60–90 °C. The prod-
ucts were purified by column chromatography over silica gel (300–
400 mesh). All reactions were monitored by TLC, which was per-
formed on precoated aluminum sheets of silica gel 60 (F254). Melt-
13C NMR (125 MHz, CDCl3): d = 39.5, 39.9, 70.9, 115.8, 120.9,
123.4, 123.9, 128.0, 128.1, 128.9 (2 C), 129.2 (4 C), 129.5 (2 C),
136.3, 136.8, 137.4, 148.2, 153.4, 156.3.
ES-MS: m/z = 405 [M + 1]+.
Anal. Calcd for C23H20N2OS2: C, 68.29; H, 4.98; N, 6.92. Found: C,
68.39; H, 4.90; N, 6.95.
1
ing points were uncorrected. H NMR and 13C NMR spectra were
recorded at r.t. on a Varian spectrometer operating at 500 MHz and
125 MHz, respectively, using TMS as internal standard. Chemical
shifts are in d (ppm). IR spectra (KBr) were recorded on a Magna-
560 FTIR spectrophotometer in the range of 400–4000 cm–1. Mass
spectra were measured on an Agilient 1100 LCMsD spectrometer.
Elemental analyses were obtained on a VarioEL analyzer. X-ray
diffraction was measured on a Siemens P4 diffractometer. Com-
pounds 1 were prepared according to our previous reports.16g,h
6-(Ethylthio)-5-[hydroxy(pyridin-2-yl)methyl]-2-(p-tolyl)-2,3-
dihydrothiopyran-4-one (3Ae)
Yellow crystals; 100 °C (dec.).
IR (KBr): 3346, 2924, 1659, 1471 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.32 (t, J = 7.0 Hz, 3 H), 2.35 (s,
3 H), 2.88 (dd, J = 16.5, 3.0 Hz, 1 H), 3.04–3.10 (m, 2 H), 3.16 (d,
J = 14.0 Hz, 1 H), 4.64 (dd, J = 14.0, 3.0 Hz, 1 H), 5.08 (br s, 1 H),
6.16 (s, 1 H), 7.14 (t, J = 6.5 Hz, 1 H), 7.18 (d, J = 8.0 Hz, 2 H), 7.26
(d, J = 8.0 Hz, 2 H), 7.48 (d, J = 8.0 Hz, 1 H), 7.66 (t, J = 7.0 Hz, 1
H), 8.53 (d, J = 4.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 14.1, 20.4, 26.8, 44.2, 45.3, 70.6,
119.3, 121.0, 126.7 (2 C), 129.0 (2C), 130.6, 133.2, 135.7, 135.8,
137.9, 147.3, 161.0, 191.4.
3,3-Bis(ethylthio)-2-[hydroxy(pyridin-2-yl)methyl]acryloni-
trile (3Aa); Typical Procedure
To a solution of 3,3-bis(ethylthio)acrylonitrile (1a; 692 mg, 4.0
mmol) and 2-pyridinecarbaldehyde (2A; 471 mg, 4.4 mmol) in
MeCN (10.0 mL) was added TiCl4 (0.49 mL, 4.4 mmol) at 0 °C. The
reaction was allowed to proceed at 0 °C and was complete in 4 h.
The above mixture was quenched with sat. aq NaHCO3 (10 mL).
After filtration, the filtrate was extracted with CH2Cl2 (3 × 10 mL).
The combined organic extracts were washed with H2O (20 mL),
dried (MgSO4), filtered, and concentrated. The residue was purified
by flash chromatography on silica gel to give 3Aa (952 mg, 85%)
as colorless crystals (eluent: Et2O–PE, 1:3); mp 96–98 °C.
ES-MS: m/z = 372 [M + 1]+.
Anal. Calcd for C20H21NO2S2: C, 64.66; H, 5.70; N, 3.77. Found: C,
64.96; H, 5.91; N, 3.65.
2-(4-Chlorophenyl)-6-(ethylthio)-5-[hydroxyl(pyridin-2-
yl)methyl]-2,3-dihydrothiopyran-4-one (3Af)
Yellow crystals; 130 °C (dec.).
IR (KBr): 3347, 2922, 1655, 1470 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.33 (t, J = 7.0 Hz, 3 H), 2.89 (d,
J = 13.5 Hz, 1 H), 2.97–3.15 (m, 3 H), 4.62 (d, J = 13.5 Hz, 1 H),
5.06 (br s, 1 H), 6.14 (s, 1 H), 7.08 (t, J = 6.5 Hz, 1 H), 7.31 (d,
J = 8.0 Hz, 2 H), 7.35 (d, J = 8.0 Hz, 2 H), 7.46 (d, J = 6.5 Hz, 1 H),
7.65 (t, J = 7.0 Hz, 1 H), 8.52 (d, J = 4.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 14.9, 27.9, 44.9, 45.7, 71.2,
120.2, 121.5, 122.1, 129.2 (2 C), 129.5 (2 C), 134.8, 135.8, 136.4,
148.0, 148.5, 161.7, 191.9.
IR (KBr): 3197, 2985, 2208, 1521, 1418 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.31 (t, J = 7.0 Hz, 3 H), 1.35 (t,
J = 7.0 Hz, 3 H), 2.93–3.14 (m, 4 H), 5.62 (d, J = 5.0 Hz, 1 H), 6.14
(d, J = 5.0 Hz, 1 H), 7.23 (d, J = 8.0 Hz, 1 H), 7.30 (dd, J = 5.0, 7.0
Hz, 1 H), 7.73 (dd, J = 8.0, 7.0 Hz, 1 H), 8.60 (d, J = 5.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 15.0, 15.5, 29.5, 29.9, 70.8,
116.3, 120.9, 122.0, 123.6, 137.6, 148.4, 154.9, 156.8.
ES-MS: m/z = 281 [M + 1]+.
Anal. Calcd for C13H16N2OS2: C, 55.68; H, 5.75; N, 9.99. Found: C,
55.82; H, 5.61; N, 10.01.
ES-MS: m/z = 392 [M + 1]+.
3,3-Bis(butylthio)-2-[hydroxy(pyridin-2-yl)methyl]acryloni-
trile (3Ab)
Colorless oil.
Anal. Calcd for C19H18ClNO2S2: C, 58.22; H, 4.63; N, 3.57. Found:
C, 58.51; H, 4.71; N, 3.56.
IR (KBr): 3417, 2960, 2209, 1484, 1592 cm–1.
3,3-Bis(ethylthio)-2-[hydroxy(quinolin-2-yl)methyl]acryloni-
trile (3Ba)
Yellow crystals; mp 92–94 °C.
IR (KBr): 3147, 2925, 2229 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.88 (t, J = 7.0 Hz, 3 H), 1.94 (t,
J = 7.5 Hz, 3 H), 1.39–1.46 (m, 4 H), 1.56–1.65 (m, 4 H), 2.89–3.12
(m, 4 H), 6.12 (s, 1 H), 7.22 (d, J = 8.0 Hz, 1 H), 7.27 (dd, J = 7.5,
5.0 Hz, 1 H), 7.71 (t, J = 7.5 Hz, 1 H), 8.57 (d, J = 5.0 Hz, 1 H).
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2,3-Di-/1,2,3-Trisubstituted Indolizines
579
1H NMR (500 MHz, CDCl3): d = 1.32 (t, J = 7.5 Hz, 3 H), 1.38 (t,
J = 7.5 Hz, 3 H), 1.59 (br s, 1 H), 2.95–3.14 (m, 3 H), 3.16–3.18 (m,
1 H), 6.29 (s, 1 H), 7.27 (d, J = 8.5 Hz, 1 H), 7.59 (t, J = 8.0 Hz, 1
H), 7.77 (t, J = 8.0 Hz, 1 H), 7.84 (d, J = 8.0 Hz, 1 H), 8.14 (d,
J = 8.0 Hz, 1 H), 8.19 (d, J = 8.5 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 15.0, 15.5, 29.7, 30.0, 71.2,
116.2, 118.2, 121.7, 127.3, 127.8, 128.2, 129.3, 130.5, 138.1, 146.4,
155.3, 156.5.
2-Cyano-3,3-bis(ethylthio)-1-(pyridin-2-yl)allyl Acetate (8)
A solution of 3Aa (280 mg, 1.0 mmol) in Ac2O (2 mL) was stirred
at 50 oC for 2.0 h. The resulting mixture was poured into ice-water,
basified with aq K2CO3, and extracted with CH2Cl2 (2 × 5 mL). The
combined organic extracts were washed with H2O (10 mL), dried
(Na2SO4), filtered, and concentrated to give 8 (318 mg, 99%) as col-
orless crystals; mp 80–81 °C.
IR (KBr): 2974, 2212, 1736, 1565, 1219 cm–1.
ES-MS: m/z = 331 [M + 1]+.
1H NMR (500 MHz, CDCl3): d = 1.28 (t, J = 7.5 Hz, 3 H), 1.32 (t,
J = 7.5 Hz, 3 H), 2.22 (s, 3 H), 2.88–3.00 (m, 2 H), 3.02–3.11 (m, 2
H), 7.11 (s, 1 H), 7.23–7.25 (m, 1 H), 7.51 (d, J = 8.0 Hz, 1 H),
7.71–7.75 (m, 1 H), 8.59 (d, J = 4.5 Hz, 1 H).
Anal. Calcd for C17H18N2OS2: C, 61.79; H, 5.49; N, 8.48. Found: C,
61.93; H, 5.66; N, 8.44.
3,3-Bis(butylthio)-2-[hydroxy(quinolin-2-yl)methyl]acryloni-
trile (3Bb)
13C NMR (125 MHz, CDCl3): d = 14.9, 15.5, 21.2, 29.8, 30.1, 74.1,
116.2, 116.5, 121.2, 123.6, 137.2, 149.9, 156.3, 158.5, 169.7.
Colorless oil.
IR (KBr): 3420, 2953, 2220, 1480 cm–1.
ES-MS: m/z = 323 [M + 1]+.
Anal. Calcd for C15H18N2O2S2: C, 55.87; H, 5.63; N, 8.69. Found:
C, 55.99; H, 5.76; N, 8.65.
1H NMR (500 MHz, CDCl3): d = 0.90 (t, J = 7.5 Hz, 3 H), 0.96 (t,
J = 7.5 Hz, 3 H), 1.41–1.50 (m, 4 H), 1.59–1.69 (m, 4 H), 2.91–3.15
(m, 4 H), 6.15 (br s, 1 H), 6.28 (s, 1 H), 7.25 (d, J = 8.5 Hz, 1 H),
7.57 (t, J = 6.5 Hz, 1 H), 7.73–7.76 (m, 1 H), 7.83 (d, J = 7.5 Hz, 1
H), 8.11 (d, J = 8.5 Hz, 1 H), 8.17 (d, J = 8.5 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 13.8 (2 C), 21.8, 22.0, 31.9, 32.3,
35.0, 35.3, 71.2, 116.2, 118.2, 121.0, 127.2, 127.8, 128.1, 129.1,
130.4, 138.0, 146.3, 156.3, 156.5.
Compounds 4 and 5; Typical Procedures
Conditions A; 3-(Ethylthio)indolizine-2-carbonitrile (4Aa)
A solution of 3Aa (2.8 g, 10 mmol) in Ac2O (10 mL) was stirred at
50 °C for 2 h to allow the complete acetylation of 3Aa (TLC moni-
toring). Then, the above mixture was heated to 120 °C for an addi-
tional 4 h. The mixture was poured into ice-water, basified with aq
K2CO3, and extracted with CH2Cl2 (3 × 20 mL). The combined or-
ganic extracts were washed with H2O (30 mL), dried (Na2SO4), fil-
tered, and concentrated. The residue was purified by flash
chromatography on silica gel to give 4Aa (1.78 g, 88%) as a light
yellow oil (eluent: Et2O–PE, 1:40).
ES-MS: m/z = 387 [M + 1]+.
Anal. Calcd for C21H26N2OS2: C, 65.25; H, 6.78; N, 7.25. Found: C,
65.49; H, 6.92; N, 7.35.
IR (KBr): 2957, 2231, 1463 cm–1.
3,3-Bis(benzylthio)-2-[hydroxy(quinolin-2-yl)methyl]acryloni-
trile (3Bc)
Light yellow crystals; mp 92–94 °C.
IR (KBr): 3360, 2920, 2227, 1480 cm–1.
1H NMR (500 MHz, CDCl3): d = 4.15–4.28 (m, 4 H), 6.01 (br s, 1
H), 6.42 (d, J = 8.5 Hz, 1 H), 7.24–7.36 (m, 11 H), 7.55 (t, J = 8.0,
6.0 Hz, 1 H), 7.71 (t, J = 8.0, 6.0 Hz, 1 H), 7.78 (d, J = 8.0 Hz, 1 H),
7.93 (d, J = 8.5 Hz, 1 H), 8.05 (d, J = 8.5 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 39.6. 39.9, 71.2, 115.9, 118.2,
123.3, 127.3, 127.8, 128.0, 128.1, 128.2, 129.0, 129.2, 129.5 (2 C),
129.7 (4 C), 130.4 (2 C), 136.3, 136.8, 137.9, 146.2, 154.2, 155.9.
1H NMR (500 MHz, CDCl3): d = 1.20 (t, J = 7.5 Hz, 3 H,), 2.75 (q,
J = 7.5 Hz, 2 H), 6.76 (s, 1 H), 6.77 (d, J = 7.0 Hz, 1 H), 6.90 (dd,
J = 9.0, 7.0 Hz, 1 H), 7.39 (d, J = 9.0 Hz, 1 H), 8.37 (d, J = 7.0 Hz,
1 H).
13C NMR (125 MHz, CDCl3): d = 15.4, 30.6, 103.7, 106.3, 113.7,
116.3, 118.3, 120.1, 120.8, 124.1, 135.0.
ES-MS: m/z = 203 [M + 1]+.
Anal. Calcd for C11H10N2S: C, 65.32; H, 4.98; N, 13.85. Found: C,
65.59; H, 4.89; N, 13.84.
ES-MS: m/z = 455 [M + 1]+.
1,3-Bis(ethylthio)indolizine-2-carbonitrile (4Aa¢)
Light yellow oil.
Anal. Calcd for C27H22N2OS2: C, 71.33; H, 4.88; N, 6.16. Found: C,
71.49; H, 4.85; N, 6.14.
IR (KBr): 2957, 2231, 1500 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.17–1.24 (m, 6 H), 2.75–2.82 (m,
4 H), 6.84 (t, J = 7.0 Hz, 1 H), 7.01–7.04 (m, 1 H), 7.69 (d, J = 9.0
Hz, 1 H), 8.42 (d, J = 7.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 15.4 (2 C), 30.7, 31.5, 106.2,
112.7, 114.3, 115.2, 119.0, 119.2, 122.0, 124.4, 138.2.
6-(Ethylthio)-5-[hydroxy(quinolin-2-yl)methyl]-2-(p-tolyl)-2,3-
dihydrothiopyran-4-one (3Be)
Yellow crystals; mp 115 °C (dec.).
IR (KBr): 3141, 2928, 1670, 1451 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.29 (t, J = 8.0 Hz, 3 H), 2.37 (s,
3 H), 2.94 (t, J = 17.0, 2.0 Hz, 1 H), 2.98–3.11 (m, 2 H), 3.21 (t,
J = 17.0 Hz, 1 H), 4.65 (d, J = 14.0 Hz, 1 H), 5.65 (d, J = 6.5 Hz, 1
H), 6.38 (d, J = 6.5 Hz, 1 H), 7.20 (d, J = 8.0 Hz, 2 H), 7.28 (d,
J = 8.0 Hz, 2 H), 7.38 (d, J = 8.0 Hz, 1 H), 7.52 (t, J = 6.5, 2.5 Hz,
1 H), 7.70 (t, J = 8.5, 7.0 Hz, 1 H), 7.80 (d, J = 8.5 Hz, 1 H), 8.10
(d, J = 8.5 Hz, 2 H).
ES-MS: m/z = 263 [M + 1]+.
Anal. Calcd for C13H14N2S2: C, 59.51; H, 5.38; N, 10.68. Found: C,
60.39; H, 5.06; N, 10.74.
3-(Butylthio)indolizine-2-carbonitrile (4Ab)
Light yellow oil.
13C NMR (125 MHz, CDCl3): d = 13.8, 20.2, 26.6, 43.9, 45.2, 69.6,
117.2, 125.1, 126.3, 126.5 (2 C), 128.0 (2 C), 128.4 (2 C), 128.7 (2
C), 130.0, 133.0, 135.6, 137.7, 145.4, 160.0, 190.7.
IR (KBr): 2957, 2231, 1464 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.88 (t, J = 7.5 Hz, 3 H), 1.40–
1.53 (m, 4 H), 2.73 (t, J = 7.5 Hz, 2 H), 6.76 (s, 1 H), 6.78 (d, J = 7.0
Hz, 1 H), 6.90 (dd, J = 9.0, 7.0 Hz, 1 H), 7.40 (d, J = 9.0 Hz, 1 H),
8.36 (d, J = 7.0 Hz, 1 H).
ES-MS: m/z = 422 [M + 1]+.
Anal. Calcd for C24H23NO2S2: C, 68.38; H, 5.50; N, 3.32. Found: C,
68.69; H, 5.78; N, 3.29.
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PAPER
13C NMR (125 MHz, CDCl3): d = 13.9, 21.9, 32.1, 36.1, 103.7,
IR (KBr): 2924, 2227, 1753, 1200 cm–1.
106.1, 113.6, 116.3, 118.8, 120.1, 120.8, 124.0, 135.0.
1H NMR (500 MHz, CDCl3): d = 1.28 (t, J = 7.0 Hz, 3 H), 2.43 (s,
3 H), 2.93 (q, J = 7.0 Hz, 2 H), 7.11 (d, J = 9.0 Hz, 1 H), 7.14 (d,
J = 9.0 Hz, 1 H), 7.45 (t, J = 7.0 Hz, 1 H), 7.58 (t, J = 7.0 Hz, 1 H),
7.66 (d, J = 7.0 Hz, 1 H), 9.90 (d, J = 9.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 14.5, 20.6, 32.0, 103.4, 110.0,
113.6, 114.9, 118.0, 121.1, 122.9, 125.9, 126.0 (2C), 128.7, 129.4,
135.3, 168.6.
ES-MS: m/z = 231 [M + 1]+.
Anal. Calcd for C13H14N2S: C, 67.79; H, 6.13; N, 12.16. Found: C,
67.93; H, 6.29; N, 12.10.
3-(Benzylthio)indolizine-2-carbonitrile (4Ac)
Light yellow crystals; mp 78–80 °C.
IR (KBr): 2958, 2232, 1334 cm–1.
ES-MS: m/z = 311 [M + 1]+.
1H NMR (500 MHz, CDCl3): d = 3.92 (s, 2 H), 6.55 (t, J = 7.0 Hz,
1 H), 6.72 (s, 1 H), 6.82 (t, J = 7.5 Hz, 1 H), 6.95 (d, J = 7.5 Hz, 2
H), 7.11–7.16 (m, 3 H), 7.32 (d, J = 9.0 Hz, 1 H), 7.97 (d, J = 7.0
Hz, 1 H).
Anal. Calcd for C17H14N2O2S: C, 65.79; H, 4.55; N, 9.03. Found: C,
65.93; H, 4.48; N, 9.09.
2-Cyano-3-(ethylthio)indolizin-1-yl Acetate (5Aa)
Colorless crystals; mp 116–118 °C.
IR (KBr): 2961, 2926, 2361, 1774, 1368 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.24 (t, J = 7.5 Hz, 3 H), 2.41 (s,
3 H), 2.79 (q, J = 7.5 Hz, 2 H), 6.74 (t, J = 7.0 Hz, 1 H), 6.86 (dd,
J = 9.5 Hz, 1 H), 7.25 (dd, J = 9.5, 4.5 Hz, 1 H), 8.33 (d, J = 7.0 Hz,
1 H).
13C NMR (125 MHz, CDCl3): d = 41.3, 103.6, 106.3, 109.7, 113.0,
115.6, 117.3, 119.5, 120.6, 123.6, 127.5, 128.5, 128.7, 128.9, 134.8,
137.0.
ES-MS: m/z = 265 [M + 1]+.
Anal. Calcd for C16H12N2S: C, 72.70; H, 4.58; N, 10.60. Found: C,
72.86; H, 4.50; N, 10.64.
13C NMR (125 MHz, CDCl3): d = 15.4, 20.6, 30.8, 100.2, 113.5,
113.9, 115.4, 117.1, 120.3, 123.4, 125.9, 127.7, 168.7.
2-(p-Tolyl)-2,3-dihydrothiopyrano[3,2-b]indolizin-4-one (4Ae)
Yellow crystals; mp 118–120 °C.
IR (KBr): 2926, 1670, 1451 cm–1.
ES-MS: m/z = 261 [M + 1]+.
Anal. Calcd for C13H12N2O2S: C, 59.98; H, 4.65; N, 10.76. Found:
C, 60.32; H, 4.79; N, 10.70.
1H NMR (500 MHz, CDCl3): d = 2.38 (s, 3 H), 3.09 (d, J = 16.0 Hz,
1 H), 3.36 (dd, J = 16.0, 13.0 Hz, 1 H), 4.89 (d, J = 13.0 Hz, 1 H),
6.57–6.59 (m, 1 H), 6.64–6.66 (m, 1 H), 6.93 (s, 1 H), 7.21 (d,
J = 8.0 Hz, 2 H), 7.34 (d, J = 7.0 Hz, 1 H), 7.37 (d, J = 8.0 Hz, 2 H),
7.52 (d, J = 7.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 20.1, 46.1, 48.6, 96.8, 111.5,
117.1, 119.9, 120.9, 122.2, 123.8, 126.3 (2 C), 128.6 (2 C), 132.6,
134.1, 137.6, 190.7.
1-(Butylthio)-2-cyanopyrrolo[1,2-a]quinolin-3-yl Acetate (5Bb)
Colorless crystals; mp 67–69 °C.
IR (KBr): 2957, 2924, 2856, 2231, 1774, 1194 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.88 (t, J = 7.0 Hz, 3 H), 1.42–
1.48 (m, 2 H), 1.56–1.62 (m, 2 H), 2.43 (s, 3 H), 2.89 (t, J = 7.0 Hz,
2 H), 7.10 (d, J = 10.0 Hz, 1 H), 7.13 (d, J = 9.0 Hz, 1 H), 7.46 (t,
J = 7.5 Hz, 1 H), 7.57 (dd, J = 8.5, 7.0 Hz, 1 H), 7.65 (d, J = 8.5 Hz,
1 H), 9.89 (d, J = 9.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 13.8, 20.7, 22.0, 31.2, 37.7,
103.0, 113.6, 114.9, 117.9, 121.6, 122.9, 125.8, 125.9, 126.0, 128.7,
129.4 (2 C), 135.3, 168.6.
ES-MS: m/z = 292 [M + 1]+.
Anal. Calcd for C18H15NOS: C, 73.69; H, 5.15; N, 4.77. Found: C,
74.25; H, 4.96; N, 4.86.
2-(4-Chlorophenyl)-2,3-dihydrothiopyrano[3,2-b]indolizin-4-
one (4Af)
Yellow crystals; mp 187–189 °C.
IR (KBr): 2927, 1658, 1451 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.10 (d, J = 17.0 Hz, 1 H), 3.32
(dd, J = 17.0, 13.0 Hz, 1 H), 4.88 (d, J = 12.0 Hz, 1 H), 6.59 (t,
J = 7.0 Hz, 1 H), 6.67 (t, J = 6.5 Hz, 1 H), 6.92 (s, 1 H), 7.35–7.43
(m, 5 H), 7.52 (d, J = 7.0 Hz, 1 H).
ES-MS: m/z = 339 [M + 1]+.
Anal. Calcd for C19H18N2O2S: C, 67.43; H, 5.36; N, 8.28. Found: C,
67.29; H, 5.41; N, 8.33.
1-(Benzoylthio)-2-cyanopyrrolo[1,2-a]quinolin-3-yl Acetate
(5Bc)
Light yellow crystals; mp 127–129 °C.
13C NMR (125 MHz, CDCl3): d = 45.9, 47.9, 96.9, 111.7, 117.3 (2
C), 119.9, 120.9, 122.1, 127.8 (2 C), 128.1 (2 C), 132.7, 133.5,
135.6, 190.1.
IR (KBr): 2925, 2226, 1745, 1484, 1201 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.41 (s, 3 H), 4.07 (s, 2 H), 7.03–
7.13 (m, 7 H), 7.43 (t, J = 7.5 Hz, 1 H), 7.53 (dd, J = 8.5, 7.5 Hz, 1
H), 7.63 (d, J = 7.5 Hz, 1 H), 9.83 (d, J = 8.5 Hz, 1 H).
ES-MS: m/z = 314 [M + 1]+.
Anal. Calcd for C17H12ClNOS: C, 65.07; H, 3.85; N, 4.46. Found:
C, 65.33; H, 3.72; N, 4.45.
13C NMR (125 MHz, CDCl3): d = 20.7, 42.9, 103.5, 113.2, 114.8,
118.0, 123.0, 125.7, 125.9 (2 C), 127.9, 128.7 (4 C), 129.3 (4 C),
135.0, 135.7, 168.6.
ConditionsB;2-Cyano-1-(ethylthio)pyrrolo[1,2-a]quinolin-3-yl
Acetate (5Ba)
ES-MS: m/z = 373 [M + 1]+.
Anal. Calcd for C22H16N2O2S: C, 70.95; H, 4.33; N, 7.52. Found: C,
70.63; H, 4.49; N, 7.50.
A solution of 3Ba (1.65 g, 5.0 mmol) in Ac2O (5 mL) was stirred at
50 °C for 1 h to allow the complete acetylation of 3Ba monitored by
TLC. Then, the above mixture was heated to 80 °C for an additional
6 h. The mixture was poured into ice-water, basified with aq K2CO3,
and extracted with CH2Cl2 (3 × 10 mL). The combined organic ex-
tracts were washed with H2O (20 mL), dried (Na2SO4), filtered, and
concentrated. The residue was purified by flash chromatography on
silica gel to give 5Ba (1.35 g, 87%) as colorless crystals (eluent:
Et2O–PE, 1:40); mp 88–90 °C.
2-(p-Tolyl)-4H-thiopyrano[3,2-b]benzindolizin-4-one (4Be)
Light yellow crystals; mp 168–170 °C.
IR (KBr): 2923, 2223, 1665, 1460 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.39 (s, 3 H), 3.10 (d, J = 17.0 Hz,
1 H), 3.39 (dd, J = 17.0, 14.0 Hz, 1 H), 4.90 (d, J = 14.0 Hz, 1 H),
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6.94 (d, J = 9.5 Hz, 1 H), 7.05 (s, 1 H), 7.20–7.26 (m, 3 H), 7.34 (t,
J = 7.0 Hz, 1 H), 7.41 (d, J = 8.0 Hz, 3 H), 7.58 (d, J = 7.0 Hz, 1 H),
8.45 (d, J = 9.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 21.4, 46.0, 50.5, 102.1, 117.6 (2
C), 119.8, 121.0, 125.1, 126.2, 127.4, 127.7 (3 C), 128.6, 129.9 (2
C), 133.3, 134.7, 135.1, 139.0, 191.3.
1H NMR (500 MHz, CDCl3): d = 1.20 (t, J = 7.0 Hz, 6 H), 2.76 (q,
J = 7.5 Hz, 4 H), 6.26 (s, 1 H), 6.75–6.77 (m, 4 H), 6.89 (d, J = 7.5
Hz, 2 H), 7.18 (d, J = 8.5 Hz, 2 H), 7.31 (d, J = 8.5 Hz, 2 H), 8.40
(d, J = 5.5 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 15.3 (2 C), 30.6 (2 C), 40.1, 107.1
(2 C), 113.8 (2 C), 115.1 (2 C), 117.3 (2 C), 118.8 (4 C), 120.8 (2
C), 124.3 (2 C), 129.2 (2 C), 130.3 (2 C), 133.0 (2 C), 133.4, 139.3.
ES-MS: m/z = 344 [M + 1]+.
ES-MS: m/z = 527 [M + 1]+.
Anal. Calcd for C22H17NOS: C, 76.94; H, 4.99; N, 4.08. Found: C,
76.72; H, 4.81; N, 4.12.
Anal. Calcd for C29H23ClN4S2: C, 66.08; H, 4.40; N, 10.63. Found:
C, 66.49; H, 4.58; N, 10.58.
1,1¢-[(Benzo[d][1,3]dioxol-5-yl)methylene]bis[3-(ethylthio)in-
dolizine-2-carbonitrile] (7a)
Colorless crystals; mp 110 °C (dec.).
1,1¢-[(4-Formylphenyl)methylene]bis[3-(ethylthio)indolizine-2-
carbonitrile] (7e1)
Light yellow crystals; mp 156–158 °C.
IR (KBr): 2925, 2227, 1670, 1521 cm–1.
IR (KBr): 2923, 2227, 1484, 1234 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.20 (t, J = 7.5 Hz, 6 H), 2.76 (q,
J = 7.5 Hz, 4 H), 5.98 (s, 2 H), 6.21 (s, 1 H), 6.72–6.78 (m, 7 H),
6.93 (dd, J = 7.5, 2.0 Hz, 2 H), 8.39 (d, J = 6.0 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 15.3 (2 C), 30.6 (2 C), 40.3,
101.4, 107.0, 108.6, 109.5, 113.7, 115.1 (3 C), 118.1, 118.6 (2 C),
119.0 (3 C), 120.6 (3 C), 122.1, 124.2 (3 C), 133.0, 134.7, 147.1,
148.4.
1H NMR (500 MHz, CDCl3): d = 1.21 (t, J = 7.5 Hz, 6 H), 2.77 (q,
J = 7.5 Hz, 4 H), 6.35 (s, 1 H), 6.76 (t, J = 8.0, 3.5 Hz, 4 H), 6.91 (t,
J = 6.0, 4.5 Hz, 2 H), 7.43 (d, J = 8.0 Hz, 2 H), 7.86 (d, J = 8.0 Hz,
2 H), 8.41 (t, J = 7.5, 3.0 Hz, 2 H), 10.03 (s, 1 H).
13C NMR (125 MHz, CDCl3): d = 15.4 (2 C), 30.6 (2 C), 40.7, 107.1
(2 C), 113.9 (2 C), 115.0 (2 C), 116.6 (2 C), 118.6 (2 C), 119.1 (2
C), 121.0 (2 C), 124.4 (2 C), 129.7 (2 C), 130.5 (2 C), 133.1 (2 C),
135.7, 147.7, 192.0.
ES-MS: m/z = 537 [M + 1]+.
Anal. Calcd for C30H24N4O2S2: C, 67.14; H, 4.51; N, 10.44. Found:
C, 67.29; H, 4.42; N, 10.39.
ES-MS: m/z = 521 [M + 1]+.
Anal. Calcd for C30H24N4OS2: C, 69.20; H, 4.65; N, 10.76. Found:
C, 69.46; H, 4.57; N, 10.72.
1,1¢-[(4-Methoxyphenyl)methylene]bis[3-(ethylthio)indolizine-
2-carbonitrile] (7b)
Colorless crystals; mp 130 °C (dec.).
IR (KBr): 2920, 2225, 1507 cm–1.
1,1¢,1¢¢,1¢¢¢-[1,4-Phenylenebis(methanetriyl)]tetrakis[3-(ethyl-
thio)indolizine-2-carbonitrile] (7e2)
Colorless crystals; mp 202–204 °C.
IR (KBr): 2926, 2226, 1440, 749 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.19 (t, J = 7.0 Hz, 12 H), 2.75 (q,
J = 7.0 Hz, 8 H), 6.31 (s, 2 H), 6.72–6.78 (m, 8 H), 6.99 (d, J = 9.5
Hz, 4 H), 7.22 (s, 4 H), 8.39 (d, J = 6.5 Hz, 4 H).
13C NMR (125 MHz, CDCl3): d = 15.3 (4 C), 30.6 (4 C), 40.3 (2 C),
107.1 (4 C), 113.7 (4 C), 115.2 (4 C), 117.7 (4 C), 118.6 (4 C), 119.2
(4 C), 120.7 (4 C), 124.2 (4 C), 129.4 (4 C), 133.1 (4 C), 139.9 (2 C).
1H NMR (CDCl3): d = 1.20 (t, J = 7.0 Hz, 6 H), 2.76 (q, J = 7.0 Hz,
4 H), 3.81 (s, 3 H), 6.24 (s, 1 H), 6.71–6.73 (m, 4 H), 6.87 (dd,
J = 8.0, 4.0 Hz, 4 H), 7.16 (d, J = 8.5 Hz, 2 H), 8.39 (dd, J = 5.0, 3.0
Hz, 2 H).
13C NMR (CDCl3): d = 15.3 (2 C), 30.6 (2 C), 40.0, 55.5, 107.1,
113.6 (2 C), 114.4 (2 C), 115.1 (2 C), 118.5 (4 C), 119.1 (2 C), 120.4
(2 C), 124.1 (2 C), 129.9 (2 C), 132.9 (2 C), 133.1 (2 C), 159.1.
ES-MS: m/z = 523 [M + 1]+.
ES-MS: m/z = 907 [M + 1]+.
Anal. Calcd for C30H26N4OS2: C, 68.94; H, 5.01; N, 10.72. Found:
C, 69.26; H, 5.49; N, 10.78.
Anal. Calcd for C52H42N8S4: C, 68.84; H, 4.67; N, 12.35. Found: C,
69.13; H, 4.79; N, 12.27.
1,1¢-(Phenylmethylene)bis[3-(ethylthio)indolizine-2-carboni-
trile] (7c)
Colorless crystals; 140 °C (dec.).
1,1¢-(2-Furylmethylene)bis[3-(ethylthio)indolizine-2-carboni-
trile] (7f)
Yellowish crystals; mp 130 °C (dec.).
IR (KBr): 2974, 2224, 1330 cm–1.
IR (KBr): 2923, 2227, 1484, 1234 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.20 (t, J = 7.5 Hz, 6 H), 2.76 (q,
J = 7.5 Hz, 4 H), 6.30 (s, 1 H), 6.72 (dd, J = 6.0, 9.0 Hz, 4 H), 6.84
(dd, J = 4.0, 10.0 Hz, 2 H), 7.25–7.27 (m, 2 H), 7.32–7.36 (m, 3 H),
8.39 (dd, J = 4.5, 7.5 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 15.3 (2 C), 30.6 (2 C), 40.7, 107.1
(2 C), 113.7 (2 C), 115.1 (2 C), 118.1 (2 C), 118.6, 119.0 (2 C),
120.5 (2 C), 124.2 (2 C), 127.7 (2 C), 128.9 (2 C), 129.0 (2 C), 133.1
(2 C), 140.8.
1H NMR (500 MHz, CDCl3): d = 1.18 (t, J = 7.0 Hz, 6 H), 2.74 (q,
J = 7.0 Hz, 4 H), 6.07 (s, 1 H), 6.23 (s, 1 H), 6.40 (s, 1 H), 6.75 (t,
J = 7.0 Hz, 2 H), 6.81 (dd, J = 9.0, 7.0 Hz, 2 H), 7.04 (d, J = 9.0 Hz,
2 H), 7.46 (s, 1 H), 8.38 (d, J = 7.0 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 15.6 (2 C), 30.6, 34.6 (2 C), 106.5
(2 C), 109.23 (2 C), 111.0 (2 C), 113.8 (2 C), 115.1, 116.2, 118.5,
118.9 (2 C), 120.9 (2 C), 124.1 (2 C), 132.9 (2 C), 142.5 (2 C),
153.2.
ES-MS: m/z = 493 [M + 1]+.
ES-MS: m/z = 483 [M + 1]+.
Anal. Calcd for C29H24N4S2: C, 70.70; H, 4.91; N, 11.37. Found: C,
70.99; H, 5.12; N, 11.30.
Anal. Calcd for C27H22N4OS2: C, 67.19; H, 4.59; N, 11.61. Found:
C, 67.33; H, 4.48; N, 11.66.
1,1¢-[(4-Chlorophenyl)methylene]bis[3-(ethylthio)indolizine-2-
carbonitrile] (7d)
Yellowish crystals; mp 130 °C (dec.).
1,1¢-(2-Thienylmethylene)bis[3-(ethylthio)indolizine-2-carboni-
trile] (7g)
Yellowish crystals; 120 °C (dec.).
IR (KBr): 2924, 2227, 1520, 1360 cm–1.
Synthesis 2008, No. 4, 573–583 © Thieme Stuttgart · New York

582
S. Sun et al.
PAPER
IR (KBr): 2969, 2226, 1516, 1235 cm–1.
35, 981. (b) Micheal, J. P. Alkaloids 2001, 55, 91.
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1H NMR (500 MHz, CDCl3): d = 1.19 (t, J = 7.0 Hz, 6 H), 2.76 (q,
J = 7.0 Hz, 4 H), 6.49 (s, 1 H), 6.75–6.89 (m, 5 H), 6.99 (dd, J = 5.0,
4.0 Hz, 1 H), 7.06 (d, J = 9.0 Hz, 2 H), 2.28 (t, J = 5.0 Hz, 1 H), 8.39
(d, J = 7.0 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 14.1 (2 C), 29.3 (2 C), 34.8,
105.3, 112.6 (2 C), 113.8, 116.7 (2 C), 117.4, 117.8 (2 C), 119.5 (2
C), 122.9 (2 C), 124.3 (2 C), 125.6 (2 C), 126.0 (2 C), 131.6 (2 C),
143.7.
(d) Pourashraf, M.; Delair, P.; Rasmussen, M. O.; Greene, A.
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P.; Chatelain, P. J. Med. Chem. 1993, 36, 1425. (g) Gupta,
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ES-MS: m/z = 499 [M + 1]+.
Anal. Calcd for C27H22N4S3: C, 65.03; H, 4.45; N, 11.23. Found: C,
65.39; H, 4.38; N, 11.32.
1,1¢-(Propane-1,1-diyl)bis[3-(ethylthio)indolizine-2-carboni-
trile] (7h)
Colorless crystals; 80 °C (dec.).
IR (KBr): 2924, 2226, 1507, 1361 cm–1.
(4) Weidner, C. H.; Wadsworth, D. H.; Bender, S. L.; Beltman,
D. J. J. Org. Chem. 1989, 54, 3660.
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1976, 209.
1H NMR (500 MHz, CDCl3): d = 1.02 (t, J = 7.0 Hz, 3 H), 1.17 (t,
J = 7.5 Hz, 6 H), 2.60 (q, J = 7.0 Hz, 2 H), 2.73 (q, J = 7.5 Hz, 4 H),
4.66 (t, J = 8.0 Hz, 1 H), 6.71 (t, J = 6.0, 7.5 Hz, 2 H), 6.83–6.85 (m,
2 H), 7.58 (d, J = 9.5 Hz, 2 H), 8.32 (d, J = 7.0 Hz, 2 H).
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Heterocycles 1994, 22, 701. (b) Poissonnet, G.; Theret-
Bettiol, M.-H.; Dodd, R. H. J. Org. Chem. 1996, 61, 2273.
(c) Katritzky, A. R.; Qiu, G.; Yang, B.; He, H.-Y. J. Org.
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Wang, S.-W. Tetrahedron 2004, 60, 5487. (e) Pearson, W.
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Y.; Hu, H.-Y.; Liu, Q.-J.; Hu, H.-W.; Xu, J.-H. Tetrahedron
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13C NMR (125 MHz, CDCl3): d = 13.4, 15.3 (2 C), 27.2, 30.5 (2 C),
37.4, 105.7 (2 C), 113.8 (2 C), 116.7 (2 C), 117.5 (2 C), 119.0 (2 C),
119.3 (2 C), 120.3 (2 C), 124.04 (2 C), 132.5 (2 C).
ES-MS: m/z = 445 [M + 1]+.
Anal. Calcd for C25H24N4S2: C, 67.53; H, 5.44; N, 12.60. Found: C,
67.32; H, 5.31; N, 12.55.
1,1¢-(Propane-2,2-diyl)bis[3-(ethylthio)indolizine-2-carboni-
trile] (7i)
Colorless crystals; mp 70–72 °C.
IR (KBr): 2923, 2227, 1484, 1234 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.20 (t, J = 7.5 Hz, 6 H), 2.15 (s,
6 H), 2.77 (q, J = 7.5 Hz, 4 H), 6.63 (d, J = 8.5 Hz, 2 H), 6.66 (d,
J = 6.5 Hz, 2 H), 6.97 (d, J = 7.0 Hz, 2 H), 8.38 (d, J = 6.5 Hz, 2 H).
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Tetrahedron 1972, 28, 4947. (b) Pohjala, E. Tetrahedron
Lett. 1972, 13, 2585. (c) Østbly, O. B.; Dalhus, B.;
Gundersen, L.-L.; Rise, F.; Bast, A.; Haenen, G. R. M. M.
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Hirata, K.; Zuo, P. Chem. Pharm. Bull. 2000, 48, 865.
(e) Kakehi, A.; Suga, H.; Kako, T.; Fujii, T.; Tanaka, N.;
Kobayashi, T. Chem. Pharm. Bull. 2003, 51, 1246.
(9) Kaloko, J. Jr.; Hayford, A. Org. Lett. 2005, 7, 4305.
(10) Liu, Y.; Song, Z.; Yan, B. Org. Lett. 2007, 9, 409.
(11) Smith, C. R.; Bunnelle, E. M.; Rhodes, A. J.; Sarpong, R.
Org. Lett. 2007, 9, 1169.
(12) (a) Bode, M. L.; Kaye, P. T. J. Chem. Soc., Perkin Trans. 1
1990, 2612. (b) Bode, M. L.; Kaye, P. T. J. Chem. Soc.,
Perkin Trans. 1 1993, 1809. (c) Basavaiah, D.; Rao, A. J.
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13C NMR (125 MHz, CDCl3): d = 15.2 (2 C), 30.5 (2 C), 31.7 (2 C),
38.0, 104.9 (2 C), 110.0 (2 C), 113.3 (2 C), 116.6 (2 C), 119.6 (2 C),
119.9 (2 C), 124.3 (2 C), 125.0 (2 C), 131.9 (2 C).
ES-MS: m/z = 445 [M + 1]+.
Anal. Calcd for C25H24N4S2: C, 67.53; H, 5.44; N, 12.60. Found: C,
67.81; H, 5.59; N, 12.49.
Acknowledgment
Financial support by the NNSFC (20672019), and analysis and
testing foundation of Northeast Normal University is gratefully
acknowledged.
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Synthesis 2008, No. 4, 573–583 © Thieme Stuttgart · New York

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2,3-Di-/1,2,3-Trisubstituted Indolizines
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(28) Crystal data for 7d: C29H23ClN4S2, yellowish, M = 527.08,
monoclinic, space group P2 (1)/n, a = 15.109 (3) Å,
b = 11.0197 (18) Å, c = 16.741 (3) Å, V = 2630.8 (7) Å3,
a = 90.00, b = 109.287 (2), g = 90.00, Z = 4, T = 293 K,
F000 = 1096, R1 = 0.0610, wR2 = 0.1646. The
supplementary crystallographic data for this structure
(CCDC 657119) can be obtained free of charge from the
Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/products/csd/request.
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