Diastereoselective nitrocyclopropanation of 2,5-dihydrothiophene-3- carbaldehydes

Article abstract of DOI:10.1016/j.tetlet.2012.10.134

An unprecedented domino Michael/α-alkylation reaction between 2,5-dihydrothiophene-3-carbaldehydes and bromonitromethane is presented. This process, efficiently catalyzed by DL-proline in the presence of MeOH/NaOAc system, provides access to novel 6-nitro

Full text of DOI:10.1016/j.tetlet.2012.10.134

Tetrahedron Letters 54 (2013) 283–286
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Diastereoselective nitrocyclopropanation of 2,5-dihydrothiophene-3-
carbaldehydes
⇑
Carmela De Risi , Simonetta Benetti, Marco Fogagnolo, Valerio Bertolasi
Dipartimento di Scienze Chimiche e Farmaceutiche, Via Fossato di Mortara 17, 44121 Ferrara, Italy.
a r t i c l e i n f o
a b s t r a c t
Article history:
Anunprecedented domino Michael/a-alkylation reaction between 2,5-dihydrothiophene-3-carbaldehydes
Received 20 September 2012
Revised 26 October 2012
Accepted 30 October 2012
Available online 21 November 2012
and bromonitromethane is presented. This process, efficiently catalyzed by DL-proline in the presence
of MeOH/NaOAc system, provides access to novel 6-nitro-3-thiabicyclo[3.1.0]hexane-1-carbaldehyde
derivatives in good yields with good to excellent diastereoselectivities.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Domino reactions
Diastereoselectivity
Cyclopropanes
S-Heterocycles
The cyclopropane ring system represents the structure motif of
a vast array of natural products and therapeutics.1
1-bromonitroalkanes to acyclic
a,b-enals catalysed by either achi-
ral14 or chiral secondary amines.15
Representative examples include the NMDA receptor
partial agonist 1-aminocyclopropanecarboxylic acid (ACC, 1),2
(+)-deltamethrin 2,3 a pyrethroid insecticide, (+)-curacin A 3,4 and
(+)-ptaquiloside 45 displaying antimicotic and anticancer
properties, respectively, as well as the class I antiarrhythmic drug
(+)-cibenzoline 56 (Fig. 1).
On the other hand, nitrocyclopropanes have been stereoselec-
tively prepared via the addition of halomalonates to nitroolefins.16
In continuation with our studies on the synthesis of sulfur-con-
taining heterocycles,17 we were intrigued with the possibility of
studying the nitrocyclopropanation of suitable 2,5-dihydrothioph-
ene-3-carbaldehydes.
Among the many cyclopropane compounds are nitrocyclopro-
panes,7 which are found in some natural products, such as the
peptide lactone hormaomycin 6 (Fig. 2),8 or used as building blocks
for other important targets.9
These compounds were expected to act as Michael acceptors to-
ward the anion of bromonitromethane, with the derived adducts
providing 6-nitro-3-thiabicyclo[3.1.0]hexane-1-carbaldehyde deriv
In recent years, the stereoselective synthesis of nitrocyclopro-
pane compounds has been the focus of intensive efforts. In this
context, the Michael-initiated ring closure (MIRC) reaction has
emerged as one of the most common synthetic routes.
For example, the diastereoselective nitrocyclopropanation of
electrophilic alkenes has been reported by Ballini et al.,10 while
Ley and co-workers11 provided a general organocatalytic enantio-
O
CO2H
NH2
1
ACC
O
CN
Br Br
2
(+)-Deltamethrin
selective synthesis of nitrocyclopropanes from
ketones.
a,b-unsaturated
OPh
S
Similar cascade processes have been recently developed by
Wang and co-workers12 and Yan and co-workers13 using chiral pri-
mary amines as the catalysts.
Furthermore, stereoselective synthesis of nitro-substituted
cyclopropanes has been achieved by conjugate addition of
3
OMe
N
(+)-Curacin A
Me
Me
H
HO
Me
Ph
Ph
O
Me
NH
N
5
OGlu
4
(+)-Cibenzoline
(+)-Ptaquiloside
⇑
Corresponding author. Tel.: +39 0532 455287; fax: +39 0532 455953.
E-mail address: drc@unife.it (C. De Risi).
Figure 1. Structure of cyclopropane-based compounds 1–5.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.134

284
C. De Risi et al. / Tetrahedron Letters 54 (2013) 283–286
Table 2
O2N
Synthesis of nitrocyclopropanes
O
NO2
CHO
NO2
H CHO
O
DL-proline
NH
HN
HN
CHO
R
(50 mol %)
H
O
+
NH
R
R
O
Br NO2
S
S
S
O
O
NO2
Cl
MeOH, NaOAc
0 °C to rt, 16 h
18-22
18'-22'
13-17
N
O HN
HN
O
Entry
R
Products
dra
Yieldb (%)
N
O
6
1
2
3
4
5
Ph
18/180
19/190
20/200
21/210
22/220
97:3
68c
71
67
HO
Hormaomycin
2-NO2C6H4
2-MeOC6H4
2-Furanyl
Me
100:0
100:0
100:0
80:20
Figure 2. Structure of hormaomycin 6.
70
55c
a
b
c
Diastereomeric ratio as determined by 1H NMR.
Isolated yield after purification by column chromatography.
Combined yield of both diastereomers.
NO2
CHO
CHO
R
R
S
S
These results suggested that activation of the aldehyde is
required for it to act as a Michael acceptor in the carbon–carbon
bond forming reaction.
Iminium ion activation with secondary amines (e.g., pyrroli-
dine) was ineffective, providing the cyclopropane product in very
low yield after long reaction times, regardless of the experimental
conditions or the presence of co-catalysts.
NO2
CHO
Br NO2
Br
R
S
Scheme 1. General approach to the synthesis of 6-nitro-3-thiabicyclo[3.1.0]
hexane-1-carbaldehydes.
On the other hand, remarkable rate acceleration was observed
with the use of DL-proline in the presence of basic co-catalysts
such as Et3N or NaOAc.
To our delight, reaction of dihydrothiophene 13 with bromoni-
tromethane (1.1 equiv) in MeOH containing DL-proline (50 mol %)
and NaOAc (1.1 equiv)14,21 gave rise to adducts 18 and 180 as an
inseparable 97:3 mixture (from 1H NMR), in 68% isolated yield
(Table 2, entry 1).22
Remarkably, the system MeOH/NaOAc gave superior results in
terms of both yields and stereoselectivities compared with CHCl3/
Et3N one,15b as previously observed by Yan and co-workers.14,15a
The optimized reaction conditions were then used with dihy-
drothiophenes 14–17 to give the corresponding cyclopropane ad-
ducts in good yields (Table 2, entries 2–5),22 diastereoselectivities
depending strongly on the substrate.
atives, possibly through a subsequent intramolecular alkylation
cyclization (Scheme 1).
To the best of our knowledge, cyclopropanation of cyclic
a,
b-enals via domino Michael/ -alkylation reactions is unprecedented,
a
this approach being largely applied to acyclic
a,b-unsaturated
aldehydes.14,15,18
Herein, we wish to report our preliminary studies which led to
the synthesis of novel 6-nitro-3-thiabicyclo[3.1.0]hexane-1-carbal-
dehyde scaffolds in a diastereoselective manner.
At the outset, 1,4-dithiane-2,5-diol 7, the dimer of mercapto-
acetaldehyde, was reacted with
a,b-unsaturated aldehydes 8–12
in dichloromethane containing catalytic pyrrolidine and benzoic
acid (20 mol % each),19 providing dihydrothiophenes 13–17 in
moderate to good unoptimized yields (Table 1).20
The reaction worked fine with dihydrothiophenes 14–16 bearing
at C-2 an ortho-substituted phenyl ring (Table 2, entries 2–3) or a
heterocycle (Table 2, entry 4), producingcompounds 19–21 as single
stereoisomers. When methyl substituted dihydrothiophene 17 was
used (Table 2, entry 5), a lower diastereoselectivity was observed,
probably because of the weaker steric hindrance of the alkyl moiety.
The structures of the nitrocyclopropane derivatives have been
elucidated by a combination of X-ray crystallographic analysis
and NMR techniques.
To provide proper reaction conditions for the nitrocyclopropa-
nation step, we carried out a set of experiments using dihydrothi-
ophene 13 as the model compound.
We observed that either no transformation or very slow conver-
sion into the desired cyclopropane adduct occurred when 13 was
treated with bromonitromethane in the presence of stoichiometric
amounts of a base (TMG, Et3N, or NaOAc).
Thus, single-crystal X-ray analysis allowed us to unequivocally
assign the structure of bicyclic compound 19, which features a
trans cyclopropane subunit and a cis configuration between the
aldehyde group and the substituent on the carbon alpha to the sul-
fur atom (Fig. 3).23
These observations were further established by NOE experi-
ments and confirmed with the value of the coupling constant in
the cyclopropane ring (JH5,H6 = 3.6 Hz).
Table 1
Synthesis of dihydrothiophene compounds 13–17
R
CHO
CHO
R
8-12
S
S
7
OH
S
HO
NH (20 mol %)
13-17
PhCO2H (20 mol %)
CH2Cl2, 0 °C, 4 h
The structures of isomers 18, 20, 21, and 22 were attributed on
the basis of the strict similarity of their 1H NMR spectra with that
of 19.
Aldehyde
R
Product
Yielda (%)
1H NMR analysis also supported the assignment of the relative
configurations to compounds 180 and 220, with the signals for
8
9
10
11
12
Ph
13
14
15
16
17
75
85
70
50
30
2-NO2C6H4
2-MeOC6H4
2-Furanyl
Me
the C-6 hydrogens being particularly diagnostic of
a trans
cyclopropane.25 Accordingly, we have tentatively identified 180
and 220 by assuming that they were C-2 epimers of 18 and 22,
respectively.
a
Isolated yield after purification by column chromatography.

C. De Risi et al. / Tetrahedron Letters 54 (2013) 283–286
285
The authors thank Dr. Alberto Casolari for his contribution to
NMR spectral analyses.
O2C Br NO2
N
CHO
R
R
References and notes
S
S
A
O2C
N
NO2
1. For selected reviews on cyclopropane-containing natural products and drugs,
see: (a) Chen, D. Y.-K.; Pouwer, R. H.; Richard, J.-A. Chem. Soc. Rev. 2012, 41,
4631–4642; (b) Wessjohann, L. A.; Brandt, W.; Thiemann, T. Chem. Rev. 2003,
103, 1625–1648; (c) Faust, R. Angew. Chem., Int. Ed. 2001, 40, 2251–2253; (d)
Donaldson, W. A. Tetrahedron 2001, 57, 8589–8627.
2. (a) Burroughs, L. F. Nature 1957, 179, 360–361; (b) Vähätalo, M. L.; Virtanen, A.
I. Acta Chem. Scand. 1957, 11, 741–743.
3. For a review, see: Barlow, S. M.; Sullivan, F. M.; Lines, J. Food Chem. Toxicol.
2001, 39, 407–422.
H2O
Br
CO2
HO2C
HN
B
R
S
NO2
H2O NO2
H
CHO
H
N
R
S
D
R
C
S
4. Wipf, P.; Reeves, J. T.; Day, B. W. Curr. Pharm. Des. 2004, 10, 1417–1437.
5. Yamada, K.; Ojika, M.; Kigoshi, H. Nat. Prod. Rep. 2007, 24, 798–813.
6. Koyata, N.; Miura, T.; Akaiwa, Y.; Sasaki, H.; Sato, R.; Nagai, T.; Fujimori, H.;
Noguchi, T.; Kirihara, M.; Imai, N. Tetrahedron: Asymmetry 2009, 20, 2065–
2071; and the references cited therein.
Scheme 2. Proposed mechanism of nitrocyclopropanation.
7. (a) Ballini, R.; Fiorini, D.; Palmieri, A. ARKIVOC 2007, 7, 172–194; (b) Averina, E.
B.; Yashin, N. V.; Kuznetsova, T. S.; Zefirov, N. S. Russ. Chem. Rev. 2009, 78, 887–
902.
8. Zlatopolskiy, B. D.; Loscha, K.; Alvermann, P.; Kozhushkov, S. I.; Nikolaev, S. V.;
Zeeck, A.; de Meijere, A. Chem. Eur. J. 2004, 10, 4708–4717; and the references
cited therein.
9. For an application of a nitrocyclopropyl derivative as precursor of the antibiotic
Trovafloxacin, see: Brighty, K. E.; Castaldi, M. J. Synlett 1996, 1097–1099.
10. Ballini, R.; Fiorini, D.; Palmieri, A. Synlett 2003, 1704–1706.
11. Wascholowski, V.; Hansen, H. M.; Longbottom, D. A.; Ley, S. V. Synthesis 2008,
1269–1275.
12. Lv, J.; Zhang, J.; Lin, Z.; Wang, Y. Chem. Eur. J. 2009, 15, 972–979.
13. Dong, L.-T.; Du, Q.-S.; Lou, C.-L.; Zhang, J.-M.; Lu, R.-J.; Yan, M. Synlett 2010,
266–270.
14. Zhang, J.-M.; Hu, Z.-P.; Zhao, S.-Q.; Yan, M. Tetrahedron 2009, 65, 802–806.
15. (a) Zhang, J.-M.; Hu, Z.-P.; Dong, L.-T.; Xuan, Y.-N.; Lou, C.-L.; Yan, M.
Tetrahedron: Asymmetry 2009, 20, 355–361; (b) Vesely, J.; Zhao, G.-L.;
Bartoszewicz, A.; Cordova, A. Tetrahedron Lett. 2008, 49, 4209–4212.
16. (a) Lee, H. J.; Kim, S. M.; Kim, D. Y. Tetrahedron Lett. 2012, 53, 3437–3439; (b)
Russo, A.; Lattanzi, A. Tetrahedron: Asymmetry 2010, 21, 1155–1157; (c) Xuan,
Y.-N.; Nie, S.-Z.; Dong, L.-T.; Zhang, J.-M.; Yan, M. Org. Lett. 2009, 11, 1583–
1586; (d) McCooey, S. H.; McCabe, T.; Connon, S. J. J. Org. Chem. 2006, 71, 7494–
7497.
17. Baricordi, N.; Benetti, S.; Bertolasi, V.; De Risi, C.; Pollini, G. P.; Zamberlan, F.;
Zanirato, V. Tetrahedron 2012, 68, 208–213.
18. For some recent examples, see: (a) Uria, U.; Vicario, J. L.; Badía, D.; Carrillo, L.;
Reyes, E.; Pesquera, A. Synthesis 2010, 701–713; (b) Companyó, X.; Alba, A.-N.;
Cárdenas, F.; Moyano, A.; Rios, R. Eur. J. Org. Chem. 2009, 3075–3080; (c)
Ibrahem, I.; Zhao, G.-L.; Rios, R.; Vesely, J.; Sundén, H.; Dziedzic, P.; Córdova, A.
Chem. Eur. J. 2008, 14, 7867–7879; (d) Xie, H.; Zu, L.; Li, H.; Wang, J.; Wang, W. J.
Am. Chem. Soc. 2007, 129, 10886–10894.
19. Typical procedure for the preparation of dihydrothiophenes 13–17: The
a,b-
unsaturated aldehyde (1.0 mmol) was added to an ice-cooled solution of
pyrrolidine (0.2 mmol) and benzoic acid (0.2 mmol) in CH2Cl2 (5 mL). After
10 min stirring, 7 (0.5 mmol) was added and the reaction mixture was kept at
0 °C for 4 h. Evaporation of the solvent and column chromatography of the
residue (EtOAc-PE) gave the title compounds.
20. Selected analytical data for compounds 13–17: physical and spectroscopic data
for compounds 13, 15, and 16 were in agreement with those reported: Tang, J.;
Xu, D. Q.; Xia, A. B.; Wang, Y. F.; Jiang, J. R.; Luo, S. P.; Xu, Z. Y. Adv. Synth. Catal.
2010, 352, 2121–2126.
Figure 3. ORTEP24 view of 19 showing the thermal ellipsoids at 30% level of
probability.
2-(2-Nitrophenyl)-2,5-dihydrothiophene-3-carbaldehyde (14): brownish solid
A plausible mechanism for the nitrocyclopropanation is likely to
involve the formation of enamine B, which is converted into imin-
ium-ion intermediate C through intramolecular nucleophilic sub-
stitution (Scheme 2). Hydrolysis of the latter eventually produces
D with cis stereochemistry between the aldehyde and nitro substit-
uents, a result consistent with previous findings observed by Yan
group.14
In conclusion, we reported a highly diastereoselective nitrocy-
clopropanation of 2,5-dihydrothiophene-3-carbaldehydes giving a
small library of new cyclopropane-containing S-heterocycles.
These compounds could be potentially useful as pharmacological
active compounds. Further extension of this process is currently
under study.
(EtOAc-PE, 1:1). Mp 95–96 °C; IR (neat): 1520, 1575, 1605, 1634, 1682 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d = 4.05 (ddd, 1H, J = 18.4, 3.2, 2.4 Hz, H-5), 4.19
(ddd, 1H, J = 18.4, 5.4, 2.4 Hz, H-5), 6.03 (m, 1H, H-2), 7.20–7.25 (m, 1H, H-4),
7.27 (dd, 1H, J = 7.8, 1.6 Hz, ArH), 7.37 (td, 1H, J = 7.8, 1.6 Hz, ArH), 7.53 (td, 1H,
J = 8.0, 1.6 Hz, ArH), 7.93 (dd, J = 8.4, 1.2 Hz, 1H, ArH), 9.78 (s, 1H, CHO); 13C
NMR (100 MHz, CDCl3): d = 38.45 (CH2), 49.66 (CH), 124.98 (CH), 128.25 (CH),
128.63 (CH), 130.24 (C), 133.60 (CH), 137.36 (C), 147.25 (C), 151.28 (CH),
186.83 (CHO). Anal. Calcd. for C11H9NO3S: C, 56.16; H, 3.86. Found: C, 55.95; H,
4.02.
2-Methyl-2,5-dihydrothiophene-3-carbaldehyde (17): orange oil (EtOAc-PE, 1:9).
IR (neat): 1631, 1676 cmꢀ1 1H NMR (400 MHz, CDCl3): d = 1.51 (d, 3H,
;
J = 6.8 Hz, CH3), 3.87 (ddd, 1H, J = 18.2, 3.0, 2.4 Hz, H-5), 4.04 (ddd, 1H, J = 18.2,
5.4, 2.4 Hz, H-5), 4.40–4.60 (m, 1H, H-2), 6.84 (m, 1H, H-4), 9.77 (s, 1H, CHO);
13C NMR (100 MHz, CDCl3): d = 23.49 (CH3), 37.82 (CH2), 46.29 (CH), 149.23
(CH), 150.43 (C), 187.97 (CHO). Anal. Calcd. for C6H8OS: C, 56.22; H, 6.29.
Found: C, 56.30; H, 6.18.
21. Typical procedure for the nitrocyclopropanation reaction: DL-proline (0.5 mmol)
was added to an ice-cooled solution of 2,5-dihydrothiophene-3-carbaldehyde
(1.0 mmol) in MeOH (4.0 mL), and the mixture was stirred for 10 min.
Bromonitromethane (1.1 mmol) and NaOAc (1.1 mmol) were successively
added, and stirring was continued at rt overnight. The solvent was removed at
reduced pressure and the residue was purified by column chromatography
(EtOAc-PE) to afford the pure nitrocyclopropane compounds.
Acknowledgments
This work was financially supported by MIUR (PRIN 2009) with-
in the project ‘Metodologie sintetiche per la generazione di diver-
sità molecolare di rilevanza biologica’.

286
C. De Risi et al. / Tetrahedron Letters 54 (2013) 283–286
22. Selected analytical data for nitrocyclopropanes
Anal. Calcd. for C13H13NO4S: C, 55.90; H, 4.69. Found: C, 55.80; H, 4.75
6-Nitro-2-phenyl-3-thiabicyclo[3.1.0]hexane-1-carbaldehyde (18 and 180):
2-Furan-2-yl-6-nitro-3-thiabicyclo[3.1.0]hexane-1-carbaldehyde (21): orange
amorphous orange solid (93:7 ratio, EtOAc-PE, 1:3). IR (neat): 1540, 1600,
syrup (EtOAc-PE, 1:3). IR (neat): 1501, 1541, 1712 cmꢀ1 1H NMR (400 MHz,
;
1711 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d (major isomer 18) = 3.34 (d, 1H,
CDCl3): d = 3.26 (d, 1H, J = 12.0 Hz, H-4), 3.61 (ddd, 1H, J = 11.6, 3.6, 0.4 Hz, H-
4), 3.68 (td, 1H, J = 3.6, 0.8 Hz, H-5), 4.93 (s, 1H, H-2), 5.14 (d, 1H, J = 3.6 Hz, H-
6), 6.19 (dd, 1H, J = 3.2, 0.8 Hz, furan H), 6.31 (dd, 1H, J = 3.2, 1.6 Hz, furan H),
7.32 (d, 1H, J = 1.2 Hz, furan H), 9.57 (s, 1H, CHO); 13C NMR (100 MHz, CDCl3):
d = 32.33 (CH2), 36.03 (CH), 45.85 (CH), 50.44 (C), 65.74 (CH), 107.31 (CH),
110.93 (CH), 142.70 (CH), 152.41 (C), 191.79 (CHO). Anal. Calcd. for C10H9NO4S:
C, 50.20; H, 3.79. Found: C, 50.35; H, 3.60.
J = 12.4 Hz, H-4), 3.59 (dd, 1H, J = 12.4, 4.0 Hz, H-4), 3.74 (t, 1H, J = 3.6 Hz, H-5),
4.87 (s, 1H, H-2), 5.13 (d, 1H, J = 3.6 Hz, H-6), 7.10–7.40 (m, 5H, ArH), 9.51 (s,
1H, CHO); 13C NMR (100 MHz, CDCl3): d (major isomer 18) = 32.64 (CH2), 36.47
(CH), 52.82 (C), 53.52 (CH), 66.52 (CH), 126.78 (2CH), 128.31 (CH), 129.48
(2CH), 141.29 (C), 192.14 (CHO). Anal. Calcd. for C12H11NO3S (mixture of 18
and 180): C, 57.82; H, 4.45. Found: C, 58.00; H, 4.25.
6-Nitro-2-(2-nitrophenyl)-3-thiabicyclo[3.1.0]hexane-1-carbaldehyde
cream colored solid (EtOAc-PE, 4:6). Mp 130–131 °C; IR (neat): 1518, 1541,
1605, 1712 cmꢀ1 1H NMR (400 MHz, CDCl3): d = 3.36 (d, 1H, J = 12.4 Hz, H-4),
(19):
2-Methyl-6-nitro-3-thiabicyclo[3.1.0]hexane-1-carbaldehyde (22 and 220): yellow
oil (80:20 ratio, EtOAc-PE, 1:9). IR (neat): 1540, 1720 cmꢀ1 1H NMR (400 MHz,
;
;
CDCl3): d (major isomer 22) = 1.42 (d, 3H, J = 6.8 Hz, CH3), 3.16 (d, 1H,
3.53 (dd, 1H, J = 12.4, 4.0 Hz, H-4), 3.85 (t, 1H, J = 3.6 Hz, H-5), 5.25 (d, 1H,
J = 3.6 Hz, H-6), 5.51 (bs, 1H, H-2), 7.21 (dd, 1H, J = 7.8, 1.2 Hz, ArH), 7.42 (td,
1H, J = 7.8, 1.2 Hz, ArH), 7.59 (td, 1H, J = 7.8, 1.2 Hz, ArH), 7.96 (dd, 1H, J = 8.0,
1.2 Hz, ArH), 9.58 (s, 1H, CHO); 13C NMR (100 MHz, CDCl3): d = 32.20 (CH2),
36.93 (CH), 47.86 (CH), 52.24 (C), 65.94 (CH), 125.61 (CH), 127.75 (CH), 128.82
(CH), 133.90 (CH), 136.26 (C), 147.82 (C), 191.78 (CHO). Anal. Calcd. for
J = 12.0 Hz, H-4), 3.36 (dd, 1H, J = 12.0, 4.0 Hz, H-4), 3.47 (td, 1H, J = 3.6,
0.8 Hz, H-5), 3.85 (q, 1H, J = 6.8 Hz, H-2), 5.10 (d, 1H, J = 3.6 Hz, H-6), 9.71 (s,
1H, CHO); 13C NMR (100 MHz, CDCl3): d (major isomer 22) = 22.02 (CH3), 30.61
(CH2), 35.26 (CH), 44.69 (CH), 52.92 (C), 66.08 (CH), 193.16 (CHO). Anal. Calcd.
for C7H9NO3S (mixture of 22 and 220): C, 44.91; H, 4.85. Found: C, 44.85; H,
4.90.
C
12H10N2O5S: C, 48.98; H, 3.43. Found: C, 49.05; H, 3.32.
2-(2-Methoxyphenyl)-6-nitro-3-thiabicyclo[3.1.0]hexane-1-carbaldehyde
white solid (EtOAc-PE, 1:4). Mp 135–136 °C; IR (neat): 1538, 1596,
1702 cmꢀ1 1H NMR (400 MHz, CDCl3): d = 3.26 (d, 1H, J = 11.6 Hz, H-4), 3.55
23. Crystallographic data (excluding structural factors) for structure 19 have been
deposited with the Cambridge Crystallographic Data Centre as supplementary
publication number CCDC 893219. Copies of the data can be obtained, free of
charge, via www.ccdc.cam.ac.uk./conts/retrieving.html or on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK. Fax: +44(0) 1223 336033 or e-
mail: deposit@ccdc.cam.ac.uk.
(20):
;
(dd, 1H, J = 11.6, 4.0 Hz, H-4), 3.67 (t, 1H, J = 3.6 Hz, H-5), 3.86 (s, 3H, OCH3),
5.10 (d, 1H, J = 3.6 Hz, H-6), 5.22 (bs, 1H, H-2), 6.87 (dd, 1H, J = 8.0, 0.8 Hz, ArH),
6.92 (td, 1H, J = 7.6, 1.2 Hz, ArH), 7.07 (dd, 1H, J = 7.6, 1.6 Hz, ArH), 7.26 (td, 1H,
J = 8.0, 2.0 Hz, ArH), 9.51 (s, 1H, CHO); 13C NMR (100 MHz, CDCl3): d = 32.91
(CH2), 38.09 (CH), 52.19 (C), 55.55 (CH3), 67.01 (CH), 111.15 (CH), 121.25 (CH),
127.45 (C), 128.41 (C), 128.52 (CH), 129.56 (CH), 155.89 (C), 192.19 (CHO).
24. Burnett, M. N.; Johnson, C. K. ORTEPIII, Report ORNL-6895; Oak Ridge National
Laboratory: Oak Ridge TN, 1996.
25. Compound 180: dH6 = 5.48 (d, J = 3.6 Hz). Compound 220: dH6 = 5.10 (d,
J = 3.6 Hz).