Dihydro-3-(triphenylphosphoranylidene)-2,5-thiophendione: A convenient synthon for the preparation of substituted 1,4-thiazepin-5-ones and piperidinones via the intermediacy of thioacids

Article abstract of DOI:10.1016/j.tet.2010.04.002

Reaction of thiomaleic anhydride with triphenylphosphine gives the title compound, which undergoes reaction with a variety of aldehydes to give a range of alkylidene thiomaleic anhydrides (substituted monothioitaconic anhydrides). Subsequent treatment with tert-butoxycarbonylamino-substituted thiols, or under radical conditions with tert-butoxycarbonylamino-substituted alkyl halides results in a series of substituted monothiomaleic anhydrides, that on exposure to trifluoroacetic acid and then base lead to thiocarboxyl substituted 1,4-thiazepin-5-ones and piperidinones, respectively, that are ultimately trapped by reaction with 2,4-dinitrobenzenesulfonamides to give the corresponding amides.

Full text of DOI:10.1016/j.tet.2010.04.002

Tetrahedron 66 (2010) 6383–6390
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Dihydro-3-(triphenylphosphoranylidene)-2,5-thiophendione: a convenient
synthon for the preparation of substituted 1,4-thiazepin-5-ones and
piperidinones via the intermediacy of thioacids
,
b
,
b
David Crich a , Md. Yeajur Rahaman
*
a Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France
b Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, MI 48202, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Reaction of thiomaleic anhydride with triphenylphosphine gives the title compound, which undergoes
reaction with a variety of aldehydes to give a range of alkylidene thiomaleic anhydrides (substituted
monothioitaconic anhydrides). Subsequent treatment with tert-butoxycarbonylamino-substituted thiols,
or under radical conditions with tert-butoxycarbonylamino-substituted alkyl halides results in a series of
substituted monothiomaleic anhydrides, that on exposure to trifluoroacetic acid and then base lead to
thiocarboxyl substituted 1,4-thiazepin-5-ones and piperidinones, respectively, that are ultimately trap-
ped by reaction with 2,4-dinitrobenzenesulfonamides to give the corresponding amides.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 20 December 2009
Received in revised form 27 March 2010
Accepted 1 April 2010
Available online 8 April 2010
Keywords:
Thioacid
Amide
Coupling
Thioanhydride
Conjugate addition
Radical reactions
1. Introduction
2. Results and discussion
Monothioacids1–6 present numerous advantages over the sim-
ple carboxylic acids by virtue of their acidity and the enhanced
nucleophilicity of the thiocarboxylate function. Thus, for example,
thioacids may be alkylated selectively in the presence of acids,7 and
react with electrophiles such as electron-deficient aromatic and
heteroaromatic systems,8–11 isothiocyanates, and isocyanates,12,13
isonitriles,14–17 a variety of coupling reagents,18–21 azides,22–30
and alkenes31–34 more efficiently and under milder conditions
than the corresponding acids. In this context we35,36 and others37
have been exploring new methods for the preparation of a vari-
ety of thioacids for subsequent application in amide and peptide
bond formation. In particular we have been interested in methods
based on the nucleophilic ring opening of monothio thiosuccinic
By analogy with the chemistry of 2-(triphenylphosphanylidene-
succinic anhydride),44–51 we reasoned that treatment of mono-
thiomaleic anhydride39,40,52,53 with triphenylphosphine would result
in the formation of dihydro-3-(triphenylphosphoranylidene)-2,5-
thiophendione 1, and that this ylide would be stable, isolable, and
a suitable partner for reaction with aldehydes to give substituted
monothioitaconic anhydride derivatives. In the event, reaction of
monothiomaleic anhydride with triphenylphosphine in glacial acetic
acid at room temperature provided the crystalline 1 in 86% yield
(Scheme 1).
S
S
PPh3,
O
O
O
O
and thiomaleic anhydrides,38–42 and of monothio- -lactones43 and
b
HOAc, 86%
PPh3
1
on the application of the ensuing thioacids in multicomponent
coupling processes. Here, we report on the preparation of dihydro-
3-(triphenylphosphoranylidene)-2,5-thiophendione, its elabora-
tion to a variety of monothioitaconic anhydride derivatives, and the
use of these latter products in multicomponent coupling reactions
leading to the formation of 1,4-thiazepin5-ones.
Scheme 1. Formation of dihydro-3-(triphenylphosphoranylidene)-2,5-thiophendione.
Subsequent reaction with a selection of aromatic and aliphatic
aldehydes at room temperature gave the corresponding substituted
monothioitaconic anhydrides in excellent yields as the pure
E-isomers (Table 1), as ascertained by NOE studies, in agreement
with the comparable reactions46 of 2-(triphenylphosphanylide-
ne)succinic anhydride.
* Corresponding author. Fax: þ33 1 69 07 77 52; e-mail address: dcrich@
icsn.cnrs-gif.fr (D. Crich).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.002

6384
D. Crich, Md.Y. Rahaman / Tetrahedron 66 (2010) 6383–6390
Table 1
carbon radicals and the preparation of piperidinone-based systems.
Olefination reactions of reagent 1
Thus, radical addition of N-(tert-butoxycarbonyl) 2-iodoethylamine
22 totheethylidene succinicanhydride 3 intolueneat80 ꢀC under the
aegis of tris(trimethylsilyl)silane (TTMS)68 and azobisisobutyronitrile
(AIBN), gave the adduct 23 in 52% yields as a 3:1 anti/syn mixture of
diastereoisomers (Scheme 3), whose stereochemistry was assigned
following subsequent conversion to the cis- and trans-piperidinones,
respectively (vide infra). The stereoselectivity of this radical addition
is rationalized by a model directly analogous to that advanced for
enolate protonation in Scheme 2. Thus, hydrogen atom transfer to the
S
S
O
O
O
O
RCHO
PPh3
1
R
2 5
-
Entry
1
RCHO
Product
% Yield
78
S
O
O
a
-carbonyl radical occurs from the face opposite the more bulky alkyl
chain in a conformation that minimizes A1,3 strain, as is the case for
PhCHO
other related diastereoselective radical reactions.69–74
2
Ph
Subsequent treatment of this mixture of diastereomers with tri-
fluoroacetic acid removed the tert-butyloxycarbonyl protecting
groups resulting, after removal of the acid under vacuum and treat-
ment with base, in the cyclization of the liberated amine onto the
proximal carbonyl carbon and the formation of the piperidinone
skeleton bearing a thioacid substituent. Without isolation, this last
species was captured by reaction with electron-deficient sulfon-
amides resulting overall in the piperidinonyl acetamides 24 and 25
(Scheme 4).54,75
S
O
O
O
2
3
MeCHO
76
72
3
Me
S
O
C7H15CHO
4
C7H15
3. Conclusion
S
Dihydro-3-(triphenylphosphoranylidene)-2,5-thiophendione is
readily accessed by reaction of monothiomaleic anhydride with
triphenylphosphine. It reacts with a range of aldehydes in highly
E-selective Wittig reactions to give substituted monothioitaconic
anhydride derivatives. These latter substances undergo conjugate
addition reactions with tert-butoxycarbonylamino-derived thiols
and alkyl radicals to give a series of adducts that, on treatment with
trifluoroacetic anhydride followed by base, lead to thiocarboxyl-
substituted heterocycles. Finally, the thiocarboxylates can be trap-
ped in situ by reaction with 2,4-dinitrobenzenesulfonamides to
give the corresponding amides.
O
O
4
c-C3H5CHO
84
5
With a series of alkylidene monothiosuccinic anhydrides in hand,
we turned our attention to tandem Michael addition–nucleophilic
ring opening processes with suitably constituted mercaptoamines, of
the kind previously practiced on monothiomaleic anhydride,39,40
with subsequent trapping of the released thioacid by reaction with
2,4-dinitrobenzenesulfonamides.9–11,36 A series of reactions were
conducted in which either 2-mercaptoaniline or 2-mercaptoethyl-
amine were stirred in DMF at 0 ꢀC overnight with the alkylidene
thiosuccinic anhydride before the addition of cesium carbonate and
a 2,4-dinitrobenzenesulfonamide leading, ultimately, to the isolation
of a series of substituted 1,4-thiazepin-5-ones, or their benzo-fused
analogs, as presented in Table 2.
4. Experimental section
4.1. Dihydro-3-(triphenylphosphoranylidene)-2,5-
thiophendione (1)
Triphenylphosphine (2.62 g, 10 mmol) was added to mono-
thiomaleic anhydride (1.14 g,10 mmol) in glacial acetic acid (5 mL) at
room temperature and stirred for 3 h. Removal of the solvent under
vacuum at room temperature and trituration of the residue with
diethyl ether (3ꢁ5 mL) afforded an off-white solid in 86% yield. mp:
For each of the tandem sequences reported in Table 2 only the
thiazepinone regioisomer, arising from ring closure of the amine onto
the proximal carbonyl group following conjugate addition, was iso-
lated.54 In the case of the ethylidene succinic anhydride (Table 2,
entries 5–8), two diastereomeric products were formed in an ap-
proximate equimolar ratio and no attempt was made to separate the
two isomers. With moderately more bulky octylidene and cyclo-
propylidene systems 4 and 5 (Table 2, entries 9–12), low to moderate
selectivity was observed in favor of the trans-isomer, whereas in the
case of the somewhat more hindered benzylidene system 2 the trans-
isomer was typically favored by a factor of 4–5:1 over the cis-isomer
(Table 2, entries 1–4). This preferential formation of the trans-iso-
mers, with selectivity increasing with the size of the olefinic sub-
stituent, is best rationalized in terms the standard models for
stereoselective protonation of enolates bearing a stereogenic center
137–137.5 ꢀC (decomp.); IR (film) 1700 and 1611 cmꢂ1
;
1H NMR
(500 MHz, CDCl3)
d
7.69–7.67 (m, 9H), 7.56 (dt, J¼2.5, 7.5 Hz, 6H), 3.34
(d, J¼1 Hz, 2H); 13C NMR (125 MHz, CDCl3)
d
205.6,178.8,133.6,129.6,
12.78; ESIHRMS, m/z
124.8,124.07, 50.0; 31P NMR (400 MHz, CDCl3)
d
calcd for C22H17O2PSNa (MþNa)þ: 399.0585, found: 399.0588.
4.2. General procedure for Wittig reactions
Reagent 1 (376 mg, 1 mmol) was stirred with excess aldehyde
(1 mL) at room temperature for 10 h. Excess aldehyde was removed
under vacuum at room temperature and the residue was purified
by chromatographic purification over silica gel, that had been pre-
washed with acetone followed by hexanes, to give the alkylidene
monothiosuccinic anhydrides.
b
-to the incipient carbonyl group.55–64 Thus, following conjugate
addition of the thiolate anion, the enolate adopts a conformation that
minimizes A1,3 strain65,66 leading to protonation through either of
transitions states A or B (Scheme 2). As the size of the alkene sub-
stitutent (R) increases transition state B is increasingly favored,
resulting in overall increased trans-selectivity.67
4.2.1. E-2-(Benzylidene)thiosuccinic anhydride (2). Rapid chro-
matographic purification over silica gel eluting with 10% EtOAc in
hexanes afforded a pale yellow oil in 78% yield. IR (film) 1731 and
Having demonstrated the 1,4-additionsequencewith aminothiols,
we turned our attention to the conjugate addition of functionalized
1692 cmꢂ1
;
1H NMR (500 MHz, CDCl3)
d
7.68 (t, J¼2.5 Hz, 1H),

D. Crich, Md.Y. Rahaman / Tetrahedron 66 (2010) 6383–6390
6385
Table 2
Reaction of alkylidene monothiosuccinic anhydrides with mercaptoamines and 2,4-dinitrobenzenesulfonamides
H
N
O
H
N
Cs2CO3
,
O
O
NH2
SH
S
ArSO2NR2R3,
O
O
COSH
NR2R3
DMF,
0 o
+
S
C
DMF, 25 o
C
S
R1
R1
R1
Entry
Substrate
Aminothiol
Sulfonamide
Product
% Yield (cis/trans) ratio
(Ar¼C6H3(NO2)2
O
H
N
O
S
O
O
O
O
N
ArSO2
N
1
72 (1:5)
76 (1:5)
65 (1:4)
S
8
H2N
SH
Ph
2
6
Ph
10
O
O
H
N
S
S
O
O
NH
ArSO2 NH(CH2)2Ph
2
3
Ph
S
9
H2N
H2N
SH
Ph
2
6
Ph
Ph
Ph
11
O
O
H
N
N
ArSO2
N
SH
SH
7
S
8
Ph
2
12
O
H
N
O
S
S
O
O
O
O
NH
ArSO2 NH(CH2)2Ph
4
5
67 (1:4)
74 (1:1)
H2N
Ph
7
9
S
Ph
2
13
O
O
H
N
N
ArSO2
N
S
H2N
SH
8
3
6
Me
14
O
H
O
S
O
O
N
NH
ArSO2 NH(CH2)2Ph
6
72 (1:1)
9
Ph
H2N
H2N
SH
SH
S
3
6
Me
15
O
H
O
S
O
O
O
O
N
N
ArSO2
N
7
8
58 (1:1)
62 (1:1)
7
8
S
3
Me
16
O
H
O
S
N
NH
ArSO2 NH(CH2)2Ph
H2N
SH
7
Ph
9
S
3
Me
17
O
H
O
S
O
O
N
N
ArSO2
N
9
67 (2:5)
8
S
H2N
H2N
SH
SH
4
6
C7H15
C7H15
18
O
O
H
N
S
O
O
NH
ArSO2 NH(CH2)2Ph
10
61 (2:5)
Ph
9
S
4
C7H15
6
C7H15
19
(continued on next page)

6386
Table 2 (continued)
D. Crich, Md.Y. Rahaman / Tetrahedron 66 (2010) 6383–6390
Entry
Substrate
Aminothiol
Sulfonamide
Product
% Yield (cis/trans) ratio
(Ar¼C6H3(NO2)2
O
O
H
N
S
O
O
O
N
ArSO2
N
11
12
57 (2:3)
60 (2:3)
S
H2N
H2N
SH
8
5
6
20
O
O
H
S
O
N
NH
ArSO2 NH(CH2)2Ph
Ph
9
S
SH
5
6
21
H
S
S
S
R'SH
O
O
O
O
O
O
R
H
R
H
H
SR'
R
SR'
B
[
]
A
]
[
H
O
H
S
S
H
R
R
O
O
O
SR'
H
SR'
H
cis-1,4-thiazepin-5-ones
Scheme 2. Model for stereoselective protonation en route to the 1,4-thiazepin-5-ones.
trans-1,4-thiazepin-5-ones
1706 cmꢂ1
;
1H NMR (500 MHz, CDCl3)
d
6.99–6.94 (m, 1H), 3.66–
NHBoc
S
S
3.65 (m, 2H), 1.91 (dt J¼2.0, 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3)
O
O
S
O
O
O
O
I
d
197.6, 191.3, 135.2, 134.0, 43.2, 16.5; ESIHRMS m/z calcd for
22
C6H5O2S (Mꢂ1)ꢂ: 141.0016, found: 141.0022.
TTMS, AIBN, 90 °C, 52%
3
4.2.3. E-2-(Octylidene)thiosuccinic anhydride (4). Rapid chromato-
graphic purification over silica gel eluting with 10% EtOAc in hexanes
afforded a colorless oil in 72% yield. IR (film) 1742 and 1706 cmꢂ1; 1H
BocHN
BocHN
anti-23
syn-23
anti-:syn- = 3:1
NMR (500 MHz, CDCl3)
d
6.91–6.87 (m, 1H), 3.64 (dd, J¼1.0, 2.5 Hz,
2H), 2.19 (q, J¼7.5 Hz, 2H), 1.56–1.50 (m, 2H), 1.38–1.24 (m, 8H), 0.89
Scheme 3. Radical addition to ethylidene monothiosuccinic anhydride.
(t, J¼7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 197.7, 191.5, 140.5,
7.51–7.46 (m, 5H), 3.98 (d, J¼2.5 Hz, 2H); 13C NMR (125 MHz, CDCl3)
132.8, 43.3, 31.9, 31.0, 29.6, 29.2, 28.2, 22.8, 14.3; ESIHRMS m/z calcd
d
197.7, 192.7, 135.3, 133.8, 131.2, 131.1, 130.8, 130.1, 129.5, 128.4,
for C12H17O2S (Mꢂ1)ꢂ: 225.0955, found: 225.0941.
45.3; ESIHRMS m/z calcd for C11H7O2S (Mꢂ1)ꢂ: 203.0172, found:
203.0180.
4.2.4. E-2-(Cyclopropylmethylidene)thiosuccinic anhydride (5). Rapid
chromatographic purification over silica gel eluting with 10% EtOAc
in hexanes afforded a colorless oil in 84% yield. IR (film) 1737 and
4.2.2. E-2-(Ethylidene)thiosuccinic anhydride (3). Rapid chromato-
graphic purification over silica gel eluting with 10% EtOAc in hex-
anes afforded a colorless oil in 76% yield. IR (film) 1742 and
1699 cmꢂ1; 1H NMR (500 MHz, CDCl3)
3.77 (d, J¼2.0 Hz, 2H), 1.45–1.38 (m, 1H), 1.16–1.12 (m, 2H), 0.85–
d
6.27 (dt, J¼11.0, 2.5 Hz,1H),

D. Crich, Md.Y. Rahaman / Tetrahedron 66 (2010) 6383–6390
6387
S
O
O
O
i) CF3CO2H,
ii) sym-collidine,
NR1R2
HN
iii) Cs2CO3, ArSO2NR1R2
O
NHBoc
24: NR1R2 = NH(CH2)2Ph, 78% (cis:trans = 3:1)
23 (anti:syn = 3:1)
1
2
25:
NR R = NH(CH2)5, 75% (cis:trans = 3:1)
Ar = C6H3(NO2)2
Scheme 4. Synthesis of piperidinonyl acetamides.
0.81 (m, 2H); 13C NMR (125 MHz, CDCl3)
d
43.6, 14.4, 10.3; ESIHRMS m/z calcd for C8H7O2S (Mꢂ1)ꢂ: 167.0172,
found: 167.0166.
198.2, 190.9, 145.6, 130.0,
123.9, 57.1, 44.9, 40.8, 36.6, 35.8; ESIHRMS m/z calcd for
C25H24N2O2SNa (MþNa)þ: 439.1456, found: 439.1457.
cis-Isomer: pale yellow solid, mp 151–151.5 ꢀC; IR (film)
1671 cmꢂ1; 1H NMR (500 MHz, CDCl3)
d
7.66 (d, J¼6.5 Hz, 1H), 7.60
4.3. General procedure for the three component coupling of
alkylidene thiosuccinic anhydrides with aminothiols and 2,4-
dinitrobenzenesulfonamides
(br s,1H), 7.47–7.38 (m, 3H), 7.35–7.28 (m, 4H), 7.24–7.12 (m, 6H), 5.45
(br s,1H), 4.94 (d, J¼7.0 Hz,1H), 3.57–3.52 (m,1H), 3.47–3.34 (m, 2H),
2.72 (t, J¼7.0 Hz, 2H), 2.28 (dd, J¼9.0, 15.0 Hz, 1H), 1.89 (dd, J¼5.0,
15.0 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 173.4, 170.7, 141.5, 138.9,
The aminothiol (0.5 mmol) was added to a stirred solution of the
alkylidene thiosuccinic anhydride (0.5 mmol) in DMF (5 mL) at
0 ꢀC. The reaction mixture was stirred for overnight at 0 ꢀC before
Cs2CO3 (0.6 mmol) was added, followed immediately by the sul-
fonamide (0.5 mmol). Stirring was continued while the reaction
mixture was allowed to warm to room temperature and the sub-
sequently for a further 1 h. The solvent was then removed under
vacuum and the residue was dissolved in ethyl acetate, washed
with water followed by brine, and dried over Na2SO4. Purification
was then realized by silica gel column chromatography.
136.8, 135.4, 130.6, 129.7, 128.9, 128.8, 128.4, 127.0, 126.7, 123.4, 58.2,
42.5, 40.1, 36.2, 35.7; ESIHRMS m/z calcd for C25H24N2O2SNa
(MþNa)þ: 439.1456, found: 439.1462.
4.3.3. cis- and trans-N-[(5-Oxo-7-phenyl-1,4-thiazepin-6yl)ace-
tyl]piperidine (12). Chromatographic purification eluting with 4%
methanol in dichloromethane afforded the trans and cis isomers
with yields of 52% and 13%, respectively.
trans-Isomer: light yellow gum, IR (film) 1675 and 1614 cmꢂ1
;
1H NMR (500 MHz, CDCl3)
d 7.28–7.25 (m, 2H), 7.22–7.19 (m, 3H),
5.85 (br s, 1H), 4.15 (d, J¼9.5 Hz, 1H), 3.66–3.54 (m, 2H), 3.52–3.43
4.3.1. cis- and trans-N-[(Benzo[b]-5-oxo-7-phenyl-1,4-thiazepin-
6yl)acetyl]piperidine (10). Chromatographic purification by eluting
with 70% ethyl acetate in hexanes afforded the trans and cis isomers
with yields of 60% and 12%, respectively.
(m, 2H), 3.33–3.28 (m, 1H), 3.14–3.05 (m, 3H), 2.96–2.85 (m, 3H),
1.50–1.18 (m, 6H); 13C NMR (125 MHz, CDCl3)
d 171.7, 171.6, 139.4,
129.7, 128.5, 126.7, 47.0, 43.8, 43.4, 43.0, 42.0, 37.3, 28.5, 25.5, 24.6;
ESIHRMS m/z calcd for C18H24N2O2SNa (MþNa)þ: 355.1456, found:
355.1445.
trans-Isomer: pale yellow solid, mp 226–227 ꢀC; IR (film) 1678
and 1631 cmꢂ1; 1H NMR (500 MHz, CDCl3)
d
7.53 (d, J¼7.5 Hz, 1H),
cis-Isomer: light yellow gum, IR (film) 1638 cmꢂ1 1H NMR
;
7.44 (t, J¼7.7 Hz, 1H), 7.35 (d, J¼7.5 Hz, 1H), 7.30–7.24 (m, 3H), 7.20
(t, J¼7.2 Hz, 2H), 7.11 (d, J¼7.5 Hz, 2H), 4.32 (d, J¼12.5 Hz, 1H), 3.61
(dt, J¼2.0, 11.5 Hz, 1H), 3.46–3.39 (m, 1H), 3.36–3.24 (m, 2H), 3.18–
3.12 (m, 1H), 3.08 (dd, J¼11.0, 16.0 Hz, 1H), 1.80 (d, J¼16.0 Hz, 1H),
(500 MHz, CDCl3)
d
7.37–7.27 (m, 5H), 5.95 (t, J¼6.5 Hz, 1H), 4.10–
4.00 (m, 2H), 3.89 (d, J¼10.0 Hz, 1H), 3.68–3.61 (m, 1H), 3.52–3.46
(m, 1H), 3.44–3.36 (m, 1H), 3.28–3.22 (m, 1H), 3.16–3.10 (m, 1H),
2.97–2.89 (m, 1H), 2.87–2.81 (m, 2H), 1.88 (dd, J¼3.0, 16.0 Hz, 1H),
1.56–1.32 (m, 6H); 13C NMR (125 MHz, CDCl3)
d
174.5, 169.0, 143.4,
1.58–1.30 (m, 6H); 13C NMR (125 MHz, CDCl3)
d 177.0, 169.5, 140.5,
141.7, 136.0, 130.8, 129.2, 128.1, 126.7, 126.6, 126.3, 124.0, 56.9, 46.5,
44.6, 43.0, 33.9, 26.3, 25.6, 24.6; ESIHRMS m/z calcd for
C22H24N2O2SNa (MþNa)þ: 403.1456, found: 403.1473.
131.6, 129.3, 129.1, 128.1, 128.0, 47.3, 46.5, 46.0, 43.2, 43.0, 34.0, 32.1,
26.3, 25.6, 24.7; ESIHRMS m/z calcd for C18H24N2O2SNa (MþNa)þ:
355.1456, found: 355.1454.
cis-Isomer: yellow solid, mp163–164 ꢀC; IR (film) 1676 and
1637 cmꢂ1; 1H NMR (500 MHz, CDCl3)
d
7.66 (dd, J¼1.5, 8.0 Hz, 1H),
4.3.4. cis- and trans-N-(2-Phenylethyl) (5-oxo-7-phenyl-1,4-thiaze-
pin-6yl)acetamide (13). Chromatographic purification eluting with
4% methanol in dichloromethane afforded a pale yellow gum in 67%
yield as 1:4 cis/trans-mixture.
7.54 (br s, 1H), 7.51 (d, J¼7.0 Hz, 2H), 7.42–7.34 (m, 4H), 7.21
(t, J¼7.0 Hz, 2H), 5.02 (d, J¼7.0 Hz, 1H), 3.66–3.61 (m, 1H), 3.59–3.54
(m, 1H), 3.34–3.29 (m, 1H), 3.17–3.07 (m, 2H), 3.53(dd, J¼8.0,16.5 Hz,
1H), 2.07 (dd, J¼5.5, 16.5 Hz, 1H), 1.55–1.37 (m, 6H); 13C NMR
trans-Isomer: IR (film) 1666 and 1640 cmꢂ1; 1H NMR (500 MHz,
(125 MHz, CDCl3)
d
173.8, 168.6, 141.9, 137.2, 135.3, 130.6, 129.7, 128.8,
CDCl3)
d
7.35–7.28 (m, 7H), 7.24–7.19 (m, 2H), 7.16 (d, J¼7.0 Hz, 2H),
128.6,126.7,123.4, 57.8, 46.5, 43.0, 42.1, 32.9, 26.3, 25.7, 24.7; ESIHRMS
6.01 (br s, 1H), 5.52 (br s, 1H), 4.02–3.84 (m, 3H), 3.66–3.60 (m, 1H),
3.49–3.35 (m, 2H), 2.96–2.87 (m, 1H), 2.82–2.71 (m, 2H), 2.43 (dd,
J¼11.0, 14.7 Hz, 1H), 1.91 (dd, J¼3.2, 14.7 Hz, 1H); 13C NMR
m/z calcd for C22H24N2O2SNa (MþNa)þ: 403.1456, found: 403.1469.
4.3.2. cis- and trans-N-(2-Phenylethyl) (benzo[b]-5-oxo-7-phenyl-
1,4-thiazepin-6yl)acetamide (11). Chromatographic purification
eluting with 70% ethyl acetate in hexanes afforded the trans and cis
isomers with yields of 63% and 13%, respectively.
(125 MHz, CDCl3) d 176.8, 171.5, 139.9, 139.0, 129.1, 129.0, 128.8,
128.3, 128.1, 126.6, 46.3, 43.6, 40.9, 37.5, 35.8, 32.5; ESIHRMS m/z
calcd for C21H24N2O2SNa (MþNa)þ: 391.1456, found: 391.1449.
cis-Isomer: the minor cis-isomer was identified in the mixture
trans-Isomer: pale yellow solid, mp 214–215 ꢀC; IR (film) 1665 and
by characteristic signals at
d 6.09 (br s,1H), 5.63 (br s,1H), 3.06–3.01
1642 cmꢂ1
;
1H NMR (500 MHz, CDCl3)
d
7.56 (d, J¼8 Hz, 1H), 7.50–
(m, 1H), 2.53 (dd, J¼8.2, 14.7 Hz, 1H), 2.09 (dd, J¼4.7, 14.7 Hz, 1H) in
7.45 (m, 2H), 7.34–7.26 (m, 5H), 7.24–7.20 (m, 2H), 7.14 (d, J¼7.5 Hz,
3H), 7.09 (d, J¼6.5 Hz, 2H), 5.56 (br s, 1H), 4.27 (d, J¼12 Hz, 1H), 3.55
(dt, J¼2.5, 11.5 Hz, 1H), 3.39 (q, J¼6.5 Hz, 2H), 2.73–2.65 (m, 3H), 1.82
the 1H NMR spectrum, and by
d 175.2, 171.2, 139.3, 128.7, 128.2,
126.7, 48.0, 45.9, 40.7, 38.1, 29.8 in the 13C NMR spectrum.
(dd, J¼2.5,15 Hz,1H); 13C NMR (125 MHz, CDCl3)
d
173.9,170.7,142.9,
4.3.5. cis- and trans-N-[(Benzo[b]-5-oxo-7-methyl-1,4-thiazepin-
6yl)acetyl]piperidine (14). Chromatographic purification eluting
141.1, 139.0, 136.2, 130.8, 129.3, 129.0, 128.8, 128.2, 127.1, 126.7, 126.4,

6388
D. Crich, Md.Y. Rahaman / Tetrahedron 66 (2010) 6383–6390
with 70% ethyl acetate in hexanes afforded a pale yellow solid in
74% yield as 1:1 cis/trans-mixture.
40.9, 38.6, 37.0, 36.2, 26.9, 20.3, 16.5; ESIHRMS m/z calcd for
C
16H22N2O2SNa (MþNa)þ: 329.1300, found: 329.1302.
trans-Isomer: IR (film) 1674 and 1633 cmꢂ1; 1H NMR (500 MHz,
cis-Isomer: the cis-isomer was identified in the mixture by
CDCl3)
d
7.61 (dd, J¼1.5, 7.5 Hz, 1H), 7.42 (br s, 1H), 7.40–7.32
characteristic signals at d 6.07 (br s, 1H), 5.94–5.90 (m, 1H), 3.89
(m, 1H), 7.24 (d, J¼7.0 Hz, 1H), 7.19–7.13 (m, 1H), 3.57–3.51 (m, 1H),
3.47–3.38 (m, 2H), 3.33–3.27 (m, 1H), 3.16 (dd, J¼10.5, 16 Hz, 1H),
2.92 (dt, J¼2.5,11 Hz,1H), 2.24 (dd, J¼2.7,16.2 Hz,1H),1.65–1.42 (m,
(dd, J¼4.5, 9.5 Hz, 1H), 3.27–3.21 (m, 1H), 2.94 (dd, J¼10.7,
15.0 Hz, 1H), 2.75–2.66 (m, 2H), 2.38 (dd, J¼3.7, 14.2 Hz, 1H),1.38
(d, J¼7.0 Hz, 3H) in the 1H NMR spectrum, and by
d 176.5, 171.3,
6H), 1.39 (d, J¼6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d
175.0, 169.1,
139.1, 128.8, 126.6, 49.1, 40.8, 36.3, 35.9, 28.9 in the 13C NMR
spectrum.
141.5, 136.6, 135.0, 130.7, 128.3, 126.5, 125.8, 123.7, 48.3, 47.7, 46.7,
45.9, 43.2, 33.6, 26.5, 23.1, 16.9; ESIHRMS m/z calcd for
C17H22N2O2SNa (MþNa)þ: 341.1300, found: 341.1291.
4.3.9. cis- and trans-N-[(Benzo[b]-5-oxo-7-octanyl-1,4-thiazepin-
6yl)acetyl]piperidine (18). Chromatographic purification eluting
with 70% ethyl acetate in hexanes afforded a pale yellow oil in 67%
yield as 2:5 cis/trans-mixture.
cis-Isomer: the cis-isomer was identified in the mixture by
characteristic signals at
d
7.57 (dd, J¼12.0, 7.7 Hz, 1H), 3.95–3.87 (m,
1H), 2.17 (dd, J¼3.7, 16.2 Hz, 1H), 1.37 (d, J¼6.5 Hz, 3H) in the 1H
NMR spectrum, and by
d
173.3, 168.7, 141.8, 123.4, 126.4, 130.2, 47.7,
trans-Isomer: IR (film) 1677 and 1641 cmꢂ1; 1H NMR (500 MHz,
43.1, 41.5, 32.5, 25.7, 24.7 in the 13C NMR spectrum.
CDCl3)
d
7.57 (t, J¼8.0 Hz, 1H), 7.51 (br s, 1H), 7.34–7.31 (m, 1H), 7.23
(d, J¼8.0 Hz, 1H), 7.17–7.12 (m, 1H), 3.53–3.36 (m, 4H), 3.19–3.09
(m, 1H), 3.00 (dt, J¼2.0, 11.0 Hz, 1H), 2.26 (d, J¼15.5 Hz, 1H), 1.84–
1.70 (m, 1H), 1.50–1.56 (m, 4H), 1.56–1.40 (m, 5H), 1.40–1.14 (m, 9H),
4.3.6. cis- and trans-N-(2-Phenylethyl) (benzo[b]-5-oxo-7- methyl
-1,4-thiazepin-6yl)acetamide (15). Chromatographic purification
eluting with 70% ethyl acetate in hexanes afforded a pale yellow oil
in 72% yield as 1:1 cis/trans-mixture.
0.92–0.83 (m, 3H); 13C NMR (125 MHz, CDCl3)
d 175.3, 169.2, 141.8,
136.6, 130.6, 126.4, 126.3, 123.6, 54.2, 46.7, 44.6, 43.2, 43.1, 34.9,
33.5, 32.0, 29.8, 29.4,, 26.5, 25.7, 24.8, 22.9, 14.3; ESIHRMS m/z calcd
for C23H34N2O2SNa (MþNa)þ: 425.2239, found: 425.2249.
cis-Isomer: the cis-isomer was identified in the mixture by
trans-Isomer: IR (film) 1670 cmꢂ1 1H NMR (500 MHz, CDCl3)
;
d
7.62 (d, J¼7.5 Hz,1H), 7.57–7.30 (m, 4H), 7.25–7.14 (m, 5H), 6.15 (br
s, 1H), 3.50–3.40 (m, 2H), 3.26–3.20 (m, 1H), 2.82–2.76 (m, 3H), 2.70
(dd, J¼10.5, 14.5 Hz, 1H), 2.30 (dd, J¼2.2, 14.2 Hz, 1H), 1.39 (d,
characteristic signals at
d
7.65 (br s, 1H), 7.32 (t, J¼7.5 Hz, 3H),
J¼7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 173.1, 170.8, 141.3, 139.0,
7.05 (d, J¼7.5 Hz, 1H), 3.78–3.74 (m, 1H), 2.16 (dd, J¼3.2, 16.2 Hz,
136.7, 130.7, 129.0, 128.8, 126.8, 125.8, 123.6, 48.0, 46.6,, 41.0, 35.9,
35.6, 23.0, 16.5; ESIHRMS m/z calcd for C20H22N2O2SNa (MþNa)þ:
377.1300, found: 377.1284.
1H) in the 1H NMR spectrum, and by
d 173.6, 168.8, 135.1, 130.0,
128.1, 123.4, 53.6, 41.4, 32.7, 27.7, 26.4, 24.7 in the 13C NMR
spectrum.
cis-Isomer: the cis-isomer was identified in the mixture by
characteristic signals at
d
7.57 (d, J¼7.5 Hz, 1H), 7.08 (d, J¼7.5 Hz,
4.3.10. cis- and trans-N-(2-Phenylethyl) (benzo[b]-5-oxo-7-octanyl
-1,4-thiazepin-6yl)acetamide (19). Chromatographic purification
eluting with 70% ethyl acetate in hexanes afforded a pale yellow oil
in 61% yield as 2:5 cis/trans-mixture.
1H), 5.72 (br s, 1H), 3.87 (q, J¼6.5 Hz, 1H), 3.36–3.32 (m, 2H), 2.06
(dd, J¼3.5, 14.7 Hz, 1H), 1.31 (d, J¼6.5 Hz, 3H) in the 1H NMR
spectrum, and by d 175.1, 170.9, 141.1, 139.2, 135.1, 130.2, 128.1, 126.7,
123.4, 48.8, 42.3, 40.8, 36.5, 35.87 in the 13C NMR spectrum.
trans-Isomer: IR (film) 1672 cmꢂ1 1H NMR (500 MHz, CDCl3)
;
d
7.61–7.54 (m, 2H), 7.38 (dt, J¼1.5, 7.5 Hz, 1H), 7.35–7.30 (m, 3H),
4.3.7. cis- and trans-N-[(5-Oxo-7-methyl-1,4-thiazepin-6yl)ace-
tyl]piperidine (16). Chromatographic purification eluting with 4%
methanol in dichloromethane afforded a pale yellow oil in 58%
yield as 1:1 cis/trans-mixture.
7.25–7.14 (m, 4H), 6.18 (br s, 1H), 3.54–3.41 (m, 2H), 3.06
(t, J¼10.0 Hz, 1H), 2.88–2.70 (m, 4H), 2.32 (dd, J¼2.5, 14.0 Hz, 1H),
1.67–1.52 (m, 2H), 1.45–1.20 (m, 10H), 0.92–0.88 (m, 3H); 13C NMR
(125 MHz, CDCl3)
d 175.2, 171.1, 141.4, 139.2, 136.7, 135.3, 130.6,
trans-Isomer: IR (film) 1663 cmꢂ1
;
1H NMR (500 MHz, CDCl3)
129.0, 128.5, 126.8, 126.7, 123.6, 54.6, 45.3, 40.9, 36.6, 35.8, 34.7,
32.0, 29.7, 29.4, 26.4, 22.9, 14.3; ESIHRMS m/z calcd for
C26H34N2O2SNa (MþNa)þ: 461.2239, found: 461.2261.
d
6.00 (br s, 1H), 3.93–3.97(m, 1H), 3.60–3.49 (m, 5H), 3.40 (dt,
J¼3.5, 9.7 Hz, 1H), 3.11–3.05 (m, 1H), 2.98 (dd, J¼11.7, 14.2 Hz, 1H),
2.54 (dd, J¼11.5, 14.5 Hz, 1H), 2.37 (dd, J¼3.2, 16.2 Hz, 1H), 1.70–1.51
cis-Isomer: the cis-isomer was identified in the mixture by
(m, 6H), 1.38 (d, J¼7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d
176.2,
characteristic signals at
d
7.66 (br s, 1H), 7.07 (d, J¼8.0 Hz, 1H), 5.76
169.2, 48.5, 46.7, 45.7, 43.1, 36.0, 33.2, 26.6, 25.8, 24.8, 20.3, 16.7;
ESIHRMS m/z calcd for C13H22N2O2SNa (MþNa)þ: 293.1300, found:
293.1284.
(br s, 1H), 3.77–3.72 (m, 1H), 3.40–3.35 (m, 1H), 2.06 (dd, J¼3.7,
14.2 Hz, 1H), 1.78–1.72 (m, 1H) in the 1H NMR spectrum, and by
d
173.2, 170.8, 141.2, 139.0, 130.1, 126.4, 123.3, 53.8, 42.2, 31.7, 27.5 in
cis-Isomer: the cis-isomer was identified in the mixture by
the 13C NMR spectrum.
characteristic signals at
d
5.87 (br s, 1H), 4.03 (dd, J¼5.5, 8.0 Hz,
1H), 3.80–3.73 (m, 1H), 3.48–3.41 (m, 5H), 2.88 (dt, J¼4.5, 14.5 Hz,
4.3.11. cis- and trans-N-[(Benzo[b]-5-oxo-7-cyclopropyl-1,4-thiaze-
pin-6yl)acetyl]piperidine (20). Chromatographic purification elut-
ing with 70% ethyl acetate in hexanes afforded a pale yellow oil in
57% yield as 2:3 cis/trans-mixture.
1H), 2.83–2.74 (m, 3H), 2.24 (dd, J¼5.5, 16.0 Hz, 1H), 1.37 (d,
J¼7.0 Hz, 3H) in the 1H NMR spectrum, and by
d 176.9, 169.4, 48.3,
46.8, 43.2, 42.2, 35.9, 34.7, 27.3, 26.5, 25.7 in the 13C NMR
spectrum.
trans-Isomer: IR (film) 1677 and 1638 cmꢂ1
;
1H NMR
(500 MHz, CDCl3)
d
7.55 (dd, J¼1.0, 7.5 Hz, 1H), 7.38–7.31 (m, 2H),
4.3.8. cis- and trans-N-(2-Phenylethyl) (5-oxo-7-methyl-1,4-thiaze-
pin-6yl)acetamide (17). Chromatographic purification eluting with
4% methanol in dichloromethane afforded a pale yellow oil in 62%
yield as 1:1 cis/trans-mixture.
7.24–7.12 (m, 2H), 3.58–3.35 (m, 5H), 3.26 (dd, J¼3.0, 11.5 Hz, 1H),
3.20–3.15 (m, 1H), 3.09 (dd, J¼11.0, 16.0 Hz, 1H), 2.46 (dd, J¼5.0,
16.5 Hz, 1H), 1.52–1.40 (m, 6H), 0.76–0.60 (m, 2H), 0.35–0.25 (m,
2H); 13C NMR (125 MHz, CDCl3)
d 173.9, 169.0, 141.6, 135.1, 130.1,
trans-Isomer: IR (film) 1649 cmꢂ1
;
1H NMR (500 MHz, CDCl3)
126.6, 123.5, 59.0, 45.3, 42.4, 32.8, 25.7, 24.7, 18.4, 12.5, 7.1, 3.9,
ESIHRMS m/z calcd for C19H24N2O2SNa (MþNa)þ: 367.1456, found:
367.1450.
d
7.31 (t, J¼7.5 Hz, 2H), 7.24–7.19 (m, 3H), 6.09 (br s, 1H), 5.96 (br s,
1H), 3.83–3.77 (m, 1H), 3.66–3.59 (m, 1H), 3.57–3.44 (m, 3H), 2.87
(dt, J¼4.2, 19.7 Hz, 1H), 2.82–2.77 (m, 4H), 2.52 (dd, J¼5.5, 15.0 Hz,
1H), 2.16 (dd, J¼4.7, 14.2 Hz, 1H), 1.33 (d, J¼7.0 Hz, 3H); 13C NMR
cis-Isomer: the minor cis-isomer was identified in the mixture
by characteristic signals at
d
7.63 (dd, J¼1.0, 4.5 Hz, 1H), 2.73–2.67
(125 MHz, CDCl3)
d
176.0, 171.2, 139.2, 129.0, 126.7, 49.2, 45.8, 42.2,
(m, 1H), 0.53–0.48 (m, 2H) in the 1H NMR spectrum, and by
d
174.8,

D. Crich, Md.Y. Rahaman / Tetrahedron 66 (2010) 6383–6390
6389
169.4, 141.3, 136.1, 130.4, 128.7, 126.4, 123.4, 59.4, 46.7, 43.1, 33.5,
26.5, 9.0, 3.1 in the 13C NMR spectrum.
4.4.1. N-(2-Phenylethyl) (4-methyl-2-oxopiperidin-3-yl)acetamide
(24). Chromatographic purification eluting with 4% methanol in
dichloromethane afforded a pale yellow solid in 78% yield as a 3:1
cis/trans-mixture.
4.3.12. cis- and trans-N-(2-Phenylethyl) (benzo[b]-5-oxo-7-cy-
clopropyl-1,4-thiazepin-6yl)acetamide (21). Chromatographic
purification eluting with 70% ethyl acetate in hexanes affor-
ded a pale yellow oil in 60% yield as 2:3 cis/trans-mixture.
cis-Isomer: IR (film) 1650 cmꢂ1; 1H NMR (500 MHz, CDCl3)
d 7.30
(t, J¼7.5 Hz, 2H), 7.24–7.19 (m, 3H), 6.86 (br s, 1H), 5.78 (br s, 1H),
3.54–3.45 (m, 2H), 3.38 (dt, J¼5.5, 11.5 Hz, 1H), 3.32–3.23 (m, 1H),
2.84–2.79 (m, 2H), 2.77–2.70 (m, 1H), 2.28–2.21 (m, 1H), 2.09 (dd,
J¼4.5, 14.5 Hz, 1H), 2.01–1.94 (m, 1H), 1.88–1.78 (m, 2H), 0.93
trans-Isomer, IR (film) 1671 cmꢂ1 1H NMR (500 MHz, CDCl3)
;
d
7.65 (dd, J¼1.0, 7.5 Hz, 1H), 7.40–7.30 (m, 4H), 7.25–7.15 (m, 5H),
5.93 (br s, 1H), 3.53–3.45 (m, 2H), 3.22–3.17 (m, 1H), 2.79
(d, J¼7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 174.7, 172.6, 139.4,
(q, J¼7.0 Hz, 2H), 2.70 (d, J¼7.0 Hz, 2H),1.04–0.97 (m,1H), 0.77–0.59
129.0, 126.5, 43.4, 40.9, 39.1, 36.4, 35.9, 30.6, 28.9, 13.9; ESIHRMS m/z
calcd for C16H22N2O2Na (MþNa)þ: 297.1579, found: 297.1591.
trans-Isomer: the minor trans-isomer was identified in the
(m, 3H), 0.32–0.22 (m, 2H); 13C NMR (125 MHz, CDCl3)
d 174.6,
171.3, 140.8, 139.2, 136.2, 130.4, 129.0, 128.9, 128.8 126.4, 123.4, 59.5,
45.9, 40.9, 36.7, 35.9, 31.5, 18.2, 9.0, 3.8; ESIHRMS m/z calcd for
C22H24N2O2SNa (MþNa)þ: 403.1456, found: 403.1472.
mixture by characteristic signals at
d 6.50 (br s, 1H), 5.85 (br s,
1H),2.50 (dd, J¼6.0, 14.5 Hz, 1H), 2.18–2.14 (m, 1H), 1.72–1.66 (m,
cis-Isomer: the minor cis-isomer was identified in the mixture
1H) 1.1 (d, J¼6.5 Hz, 3H) in the 1H NMR spectrum, and by
d 174.4,
by characteristic signals at
d
7.56 (dd, J¼1.2, 7.7 Hz, 1H), 7.09
171.9, 139.3, 129.0, 128.7, 46.6, 41.3, 40.7, 36.0, 35.8, 31.9, 30.7, 20.4
(d, J¼7.5 Hz, 1H), 5.72 (br s, 1H), 3.42–3.38 (m, 1H), 3.11 (dd, J¼5.5,
10.5 Hz, 1H), 3.00 (dd, J¼9.7, 14.7 Hz, 1H), 2.64 (dd, J¼9.5, 11.5 Hz,
1H), 2.26 (dd, J¼4.5, 14.5 Hz, 1H), 1.19–1.14 (m, 1H), 0.92–0.86
in the 13C NMR spectrum.
4.4.2. N-[(4-Methyl-2-oxopiperidin-3-yl)acetyl]piperidine
(25). Chromatographic purification eluting with 4% methanol in
dichloromethane afforded the cis- and trans-isomers with yields of
56% and 19%, respectively.
(m, 1H), 0.51–0.46(m, 1H) in the 1H NMR spectrum, and by
d 173.5,
171.1, 141.2, 135.1, 130.2, 128.5, 126.8, 126.7, 123.5, 59.4, 43.1, 35.9,
25.9, 12.4, 7.2, 3.0 in the 13C NMR spectrum.
cis-Isomer: light yellow gum, IR (film) 1635 cmꢂ1
;
1H NMR
4.3.13. 2-[3-(tert-Butyloxycarbonylamino)-2-methylpropyl]succinic
thioanhydride (23). Tris(trimethylsilyl)silane (373 mg, 1.5 mmol)
and AIBN (33 mg, 0.2 mmol) in dry degassed toluene (5 mL) were
added drop-wise to a stirred mixture of 22 (407 mg, 1.5 mmol) and 3
(142 mg, 1 mmol) in dry degassed toluene (10 mL) at 90 ꢀC over 5 h
by syringe pump under a N2 atmosphere. When the addition was
complete, the reaction mixture was allowed to stir for an additional
1 h at 90 ꢀC before it was cooled to room temperature and the sol-
vent was removed under vacuum. Rapid chromatographic purifica-
tion over silica gel, pre-washed with acetone followed by hexanes,
eluting with 30% ethyl acetate in hexanes afforded a colorless oil in
52% yield as a 3:1 inseparable anti/syn diastereomeric mixture.
(500 MHz, CDCl3) d 5.63 (br s, 1H), 3.64–3.59 (m, 1H), 3.56–3.39 (m,
4H), 3.34–3.29 (m, 1H), 3.14–3.09 (m, 2H), 2.43–2.37 (m, 1H), 2.27
(dd, J¼9.7, 17.2 Hz, 1H), 2.09–2.03 (m, 1H), 1.75–1.52 (m, 7H), 0.96
(d, J¼7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 174.1, 170.0, 46.8,
43.1, 42.9, 38.9, 30.6, 29.3, 28.5, 26.7, 25.8, 24.9, 14.0; ESIHRMS m/z
calcd for C13H22N2O2Na (MþNa)þ: 261.1579, found: 261.1561.
trans-Isomer: light yellow gum, IR (film) 1646 cmꢂ1 1H NMR
;
(500 MHz, CDCl3)
d 5.72 (br s, 1H), 3.59–3.40 (m, 5H), 3.32–3.26
(m, 1H), 2.94 (dd, J¼5.5, 16.5 Hz, 1H), 2.70 (dd, J¼3.2, 16.2 Hz, 1H),
2.26–2.20 (m, 1H), 2.17–2.12 (m, 1H), 1.85 (dd, J¼3.2, 13.2 Hz, 1H),
1.68–1.50 (m, 7H), 1.02 (d, J¼7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d
174.6, 169.6, 46.7, 45.6, 43.0, 41.2, 37.9, 32.1, 31.5, 31.1, 29.9, 26.6,
anti-Isomer: IR (film) 1708 cmꢂ1
;
1H NMR (500 MHz, CDCl3)
25.8, 24.8, 20.6; ESIHRMS m/z calcd for C13H22N2O2Na (MþNa)þ:
d
4.58 (br s, 1H), 3.55–3.02 (m, 4H), 2.88 (dd, J¼4.0, 6.5 Hz, 1H),
261.1579, found: 261.1564.
2.26–2.18 (m, 1H), 1.66–1.58 (m, 1H), 1.54–1.41 (m, 10H), 1.04
(d, J¼7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 203.0, 199.9, 156.2,
Acknowledgements
79.6, 57.4, 44.4, 38.6, 35.7, 33.3, 28.6, 17.2; ESIHRMS m/z calcd for
C13H21NO4SNa (MþNa)þ: 310.1089, found: 310.1082.
We thank the NIH (GM57335 and GM62160) for support of this
work.
syn-Isomer: the minor syn-isomer was identified in the mix-
ture by characteristic signals at
d
2.84 (dd, J¼4.0, 6.5 Hz, 1H), 2.44–
2.36 (m, 1H), 0.96 (d, J¼7.0 Hz, 3H) in the 1H NMR spectrum, and
Supplementary data
by
d
199.8, 56.9, 42.3, 38.3, 32.6, 31.5, 14.7 in the 13C NMR
spectrum.
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.04.002.
4.4. General procedure for piperidinone synthesis from the
radical adduct 23
References and notes
To a stirred solution of 23 (145 mg, 0.5 mmol) in dichloro-
methane (20 mL) at 0 ꢀC, trifluoroacetic acid (5 mL) was added
drop-wise. Stirring was maintained for 1 h before the acid was
removed by azeotropic distillation with toluene (5 mLꢁ3), after
which the residue was dried under vacuum. The residue was dis-
solved in DMF (20 mL) and cooled down to 0 ꢀC before 2,4,6-col-
lidine (0.090 mg, 0.75 mmol) was added drop-wise and the
reaction mixture was stirred for 1 h at 0 ꢀC. The resulting reaction
mixture was maintained at 0 ꢀC, and Cs2CO3 (0.195 mg, 0.6 mmol)
followed by the sulfonamide (0.6 mmol) was added. The reaction
mixture was warmed to room temperature and stirred for 1.5 h
before the solvent was removed under vacuum and the residue was
dissolved in EtOAc (30 mL). The organic layer was washed succes-
sively with water and brine, dried over Na2SO4, concentrated, and
purified by silica gel column chromatography.
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