Novel synthesis of 5,6-dihydro-4H-thieno[3,2-b]pyrrol-5-ones via the rhodium(II)-mediated Wolff rearrangement of 3-(thieno-2-yl)-3-oxo-2-diazopropanoates

Article abstract of DOI:10.1021/ol016995n

(equation presented) Treatment of thioaryolketene S,N-acetals 12 with Hg(OAc)₂ followed by addition of 2-diazo-3-trimethylsilyloxy-3-butenoic acid alkyl esters 15 in CH₂Cl₂ at room temperature gave 3-(3-alkylamino-5-arylth

Full text of DOI:10.1021/ol016995n

ORGANIC
LETTERS
2002
Vol. 4, No. 6
873-876
Novel Synthesis of
5,6-Dihydro-4H-thieno[3,2-b]pyrrol-5-ones
via the Rhodium(II)-Mediated Wolff
Rearrangement of
3-(Thieno-2-yl)-3-oxo-2-diazopropanoates
,†
Dong Joon Lee,† Kyongtae Kim,* and Yung Ja Park‡
School of Chemistry and Molecular Engineering, Seoul National UniVersity,
Seoul 151-742, Korea, and Department of Chemistry, Sook Myung Women’s
UniVersity, Seoul 140-742, Korea
kkim@plaza.snu.ac.kr
Received November 3, 2001
ABSTRACT
Treatment of thioaryolketene S,N-acetals 12 with Hg(OAc)2 followed by addition of 2-diazo-3-trimethylsilyloxy-3-butenoic acid alkyl esters 15
in CH Cl2 at room temperature gave 3-(3-alkylamino-5-arylthieno-2-yl)-3-oxo-2-diazopropanoates 16 in good yields. Subsequent reactions of 16
2
with a catalytic amount of Rh2(OAc)4‚2H O in benzene at reflux afforded a mixture of 5,6-dihydro-4H-thieno[3,2-b]pyrrol-5-ones 18 and the
2
corresponding enols 19 in excellent yields.
The exploration of synthetic methods for diverse thieno[3,2-
b]pyrroles has received growing attention since it became
known that some of them act as MCP-1 inhibitors useful as
antiinflammatory agents, immunomodulators,1 and bioiso-
steric analogues of the hallucinogen and seratonin agonist
N,N-dimethyltryptamine.2 Only a few methods are available
for the synthesis of thieno[3,2-b]pyrroles. The first method,
which has been most widely used, consists of condensation
of an amino group with a suitably positioned carbonyl
function of thiophenes, which are exemplified by either the
cyclization of ethyl 2-formyl-3-thienylaminoacetate 1 into
thieno[3,2-b]pyrroles 2 (X ) CO2Et, Y ) H)3 or reduction
of ethyl (3-nitro-2-thienyl)pyruvate 3 with tin(IV) chloride
followed by spontaneous cyclization of intermediate amino
derivative4 (Scheme 1). The second method involves the
suitable insertion of nitrene intermediates. For instance, the
action of triethyl phosphite on 3-nitro-3-styrylthiophenes 4
led to 2 (X ) Ar, Y ) H).5 Alternatively, azidoacrylate 5
cyclized thermally to give 2 (X ) CO2Et, Y ) H).6
(3) (a) Soth, S.; Farnier, M.; Paulmier, C. Can. J. Chem. 1978, 56, 1429.
(b) Mamaev, V. P.; Lyubimova, E. N. IzV. Akad. Nauk SSSR, Ser. Khim.
1966, 1607.
(4) Gale, W. W.; Scott, A. N.; Snyder, H. R. J. Org. Chem. 1964, 29,
2160.
(5) (a) Srinivasan, K.; Srinivasan, K. G.; Balasubramanian, K. K.;
Swaminathan, S. Synthesis 1973, 313. (b) Chippendale, K. E.; Iddon, B.;
Suschitzky, H. J. Chem. Soc., Chem. Commun. 1971, 203.
* Fax: 82 2874 8858. Tel: 82 2880 6636.
† Seoul National University.
‡ Sook Myung Women’s University.
(1) Baker, A. J.; Kettle, J. G.; Faull, A. W. PCT Int. Appl. WO 9940,
914, GB Appl. 1998/ 3, 228; Chem. Abstr. 1999, 131, 170342d.
(2) Blair, J. B.; Marona-Lewicka, D.; Kanthasamy, A.; Lucaites, V. L.;
Nelson, D. L.; Nichols, D. E. J. Med. Chem. 1999, 42, 1106.
10.1021/ol016995n CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/28/2002

synthesis of (E)-6-(carbethoxymethylene)-5-oxo-4-(tert-
butoxycarbonyl)-5,6-dihydrothieno[3,2-b]pyrrole 119 (Scheme
4).
Scheme 1
Scheme 4
All the methods reported have the drawback, as regards
their general use for the synthesis of thieno[3,2-b]pyrroles
bearing desired substituents, of difficult access to some of
the starting materials.
In connection with an ongoing project on the development
of the potential synthetic utility of thioaroylketene S,N-acetals
12,10 we became interested in the investigation of the reaction
of 12 with carbenes since compound 12 possesses a variety
of functional groups, i.e., CdS, CdC, RS, RNH, etc. Each
of these functional groups is known to be susceptible to an
electron-deficient carbene. However, it would be difficult
to predict the reactivity of 12 toward carbenes. Preliminary
experiments show that the reaction of 12 (Ar ) Ph, R1 )
R2 ) Me) with ethyl R-diazoacetate in the presence of Rh2-
(OAc)4‚2H2O in CH2Cl2 at room temperature gave thiophene
derivative 13 (61%) and pyrrole derivative 14 (16%) (Scheme
5). Using this methodology, we intended to prepare 5,6-
dihydro-4H-thieno[3,2-b]pyrrol-6-ones 17 by the reaction
of 3-(3-alkylamino-5-arylthieno-2-yl)-3-oxo-2-diazopro-
Photolysis of 3-azido-2-vinylthiophenes 6 (X ) H, SMe,
SOMe, Y ) H, SO2Me) gave 2 and thieno[3,2-b]pyrrole 7
via nitrene intermediates7 (Scheme 2). Yields of 2 and 7 were
variable depending on the substituents X and Y.
Scheme 2
The third method involves the reactions of 4-alkoxycar-
bonyl-5-alkyl-3-arylaminothiophenes 8 with oxalyl chloride,
yielding 5,6-dioxothieno[3,2-b]pyrroles 98 (Scheme 3).
Scheme 5a
Scheme 3
In addition, Heck cyclization of N-BOC protected N-
allylamino-o-iodothiophenes in DMF may be utilized for the
(6) (a) Soth, S.; Farnier, M.; Paulmier, C. Can. J. Chem. 1978, 56, 1710.
(b) Hemetsberger, H.; Knittel, D. Monatsh. Chem. 1972, 103, 194.
(7) Gairns, R. S.; Moody, C. J.; Rees, C. W. J. Chem. Soc., Chem.
Commun. 1985, 1818.
(8) (a) Shvedov, V. I.; Vasile´va, V. K.; Kharizomenova, I. A.; Grinev,
A. N. Khim. Geterotsikl. Soedin, 1975, 767. (b) Shevedov, V. I.; Vasile´va,
V. K.; Kharizomenova, I. A.; Otkrytiya, A. N. Grinev. Izobret., Prom.
Obraztsy, ToVarnye Znaki 1973, 50, 62.
a Reagents: (a) Rh2(OAc)4‚2H2O, CH2Cl2, rt; (b) Hg(OAc)2,
CH2Cl2, rt; (c) Rh2(OAc)4‚2H2O, PhH, reflux.
874
Org. Lett., Vol. 4, No. 6, 2002

panoates 16, which may be prepared from 12 and 2-diazo-
3-trimethylsilyloxy-3-butenoate 15, using a rhodium(II)
catalyst under the same conditions. It was envisaged that 17
would be formed upon insertion of carbene or carbenoid,
generated from 16, into the N-H bond of the alkylamino
group at C-3. This would occur in view of the formation of
various products by tandem cyclization-cycloaddition se-
quence of rhodium(II) carbenoids and application of the
resulting metallocarbenoids to a wide variety of hetero-
cycles.11
Scheme 6
Compounds 1210 and 1511 were prepared according to
documented procedures. Treatment of 12 with Hg(OAc)2 (1.2
equiv) in CH2Cl2 at room temperature, followed by addition
of 15 (1 equiv) gave diazocarbonyl compounds 16 in good
yields as expected. All of the compounds 16 were stable in
air and recrystallizable from a mixture of CH2Cl2 and
n-hexane. Subsequent treatment of 16 with a catalytic amount
of Rh2(OAc)4‚2H2O (0.5 mg) in benzene for 30 min at reflux
afforded 5,6-dihydro-4H-thieno[3,2-b]pyrrol-5-ones 18 rather
envisaged that there exists a hydrogen bond between the
carbonyl oxygen and a hydrogen on an alkylamino group as
depicted in the intermediates 20 and 21. A cis relationship
of diazo and carbonyl is highly preferred in diazo ketones
of the type RCOCHN2.13 The cis form represents a desirable
feature of the migrating group being trans to the leaving
group. As a result, the rhodium carbenoids 20 and 21 undergo
Wolff rearrangement to give a ketene 22. The ketene
functional group would be rapidly trapped by an intra-
molecular nucleophilic attack of the alkylamino group at C-3
of the thienyl ring to give 18.
1
than thieno[3,2-b]pyrrol-6-ones 17. The H NMR spectra
(300 MHz, CDCl3) of 18 showed a singlet at 4.42-4.60 ppm,
assigned to a methine proton of 18, and two sets of alkyl
protons corresponding to N-alkyl and alkoxycarbonyl groups,
which indicates that the products exist as a mixture of keto
forms 18 and enol forms 19. The ratios of 18 and 19 were
determined on the basis of the intensities of N-alkyl proton
absorptions.12 Yields of compounds 16, 18, and 19 are
summarized in Table 1.
Treatment of a mixture of 16a (70 mg, 0.213 mmol) and
n-PrSH (486 mg, 6.39 mmol) with Rh2(OAc)4‚2H2O (0.5
mg) in benzene for 3 h at reflux gave 23a (47%), a dimer of
18a together with an insertion product 24 (6 mg, 7%) and
unknown mixtures, which are inseparable by chromatography
(Scheme 7). On the other hand, the reaction of 16a (70 mg,
Table 1. Yields of Compounds 16, 18 + 19, and 23
yield,a
R1 R3 compd 16 18+19 (keto: enol) 23
%
entry
Ar
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
Me Et
Me t-Bu
Et Et
Et t-Bu
Bn Et
Bn t-Bu
a
b
c
d
e
f
g
h
i
91
87
71
79
73
82
71
68
74
71
71
72
99 (1:1.26)
94 (1:0.87)
90 (1:1.46)
91 (1:0.78)
91 (1:1.23)
89 (1:0.70)
97 (1:0.88)
95 (1:0.65)
95 (1:1.11)
93 (1:0.77)
92 (1:2.07)
90 (1:2.33)
89
89
86
91
96
91
87
90
75
87
86
88
Scheme 7a
4-MeOC6H4 Me Et
4-MeOC6H4 Me t-Bu
4-MeOC6H4 Et Et
10 4-MeOC6H4 Et t-Bu
11 3-ClC6H4
12 3-ClC6H4
j
k
l
Me Et
Et Et
a Isolated yields. Compounds 16 are yellow solids except for 16h (yellow
liquid). Mixtures of compounds 18 and 19 are pale yellowish sticky liquids.
Compounds 23 are pale yellow solids.
The exclusive formation of thieno[3,2-b]pyrrol-5-ones may
be rationalized by assuming a cis relationship of rhodium
carbenoid and the keto carbonyl group (Scheme 6). It is
0.213 mmol) with ethyl vinyl ether (460 mg, 6.39 mmol) in
the presence of the same catalyst for 30 min at reflux gave
23a in 90% yield.
It has been found that compounds 18 were labile and
underwent slow dimerization reactions to give compounds
(9) Wensbo, D.; Annby, U.; Gronowitz, S. Tetrahedron 1995, 51, 10323.
(10) Kim, B.; Kim, K. J. Org. Chem. 2000, 65, 3690.
(11) (a) Ye, T.; McKervey, M. A. Chem. ReV. 1994, 94, 1091. (b) Padwa,
A.; Hornbuckle, S. F. Chem. ReV. 1991, 91, 263. (c) Padwa, A.; Weingarten,
M. D. Chem. ReV. 1996, 96, 223. (d) Ueda, Y.; Roberge, G.; Vinet, V.
Can. J. Chem. 1984, 62, 2936.
Org. Lett., Vol. 4, No. 6, 2002
875

23, whose structures were confirmed by an X-ray crystal
structure study of 23a.
It is worth noting that hydrolysis of 23a with aqueous
NaOH (1%) in EtOH at reflux gave an oxidative decarboxy-
lation product 26 in 53% yield (Scheme 9).
To confirm the significance of oxygen dissolved in the
solution, oxygen gas was bubbled into a solution of a mixture
of 18a and 19a (49 mg, 0.163 mmol) in CH2Cl2 (30 mL)
for 5 days at room temperature. From the reaction were
isolated a hydroxyl compound 25 (7 mg, 14%), 23a (24 mg,
49%), and unknown mixtures, which were inseparable by
chromatography (Scheme 8).
Scheme 9a
Scheme 8a
a Reagents: aqueous NaOH (1%), EtOH, reflux.
The structures of 26 were determined on the basis of
spectroscopic (1H and 13C NMR, IR, MS) and analytical data.
In conclusion, we have found that treatment of 3-(3-
alkylamino-5-arylthieno-2-yl)-3-oxo-2-diazopropanones, readily
prepared starting from thioaroylketene S,N-acetals, Hg-
(OAc)2, and trimethylsilyl enol ether of alkyl R-diazoacetate,
with a catalytic amount of Rh2(OAc)4‚2H2O, underwent
Wolff rearrangement yielding 5,6-dihydro-4H-thieno[3,2-b]-
pyrrol-5-ones in excellent yields.
a Reagents: (a) CH2Cl2, rt; (b) O2, CH2Cl2, rt, 5 days; (c)
Cu(OAc)2‚H2O, EtOH, N2, rt hydroxyl compound 25 (7 mg, 14%),
23a (24 mg, 49%), and unknown mixtures, which were inseparable
by chromatography (Scheme 8).
Acknowledgment. This work was supported by the Brain
Korea 21 program.
Interestingly, treatment of a mixture of 18 and 19 with
Cu(OAc)2‚H2O (1.2 equiv), which has been well-known to
give a single good electron oxidant,14 for 30 min in EtOH
(30 mL) at room temperature under nitrogen atmosphere gave
23 in excellent yields. Yields of 23 are summarized in Table
1.
Supporting Information Available: Copies of 1H NMR,
IR, and elemental analyses of 13, 14, 16, a mixture of 18
and 19, 23, 24, 25, and 26; 13C NMR spectra of 13, 16, and
26; X-ray crystallographic data for 23a; and an ORTEP
drawing of 23a. This material is available free of charge via
the Internet at http://pubs.acs.org.
(12) For R1 ) Me (entries 1, 2, 7, 8, and 11), the absorptions of the Me
protons of 18 and 19 are 3.25-3.26 and 3.58-3.60 ppm, respectively. For
R1 ) Et (entries 3, 4, 9, 10, and 12), the absorptions of the CH2 protons of
18 and 19 are 3.74-3.77 and 4.02-4.05 ppm, respectively. For R1 ) Bn
(entries 5 and 6), the absorptions of the benzylic protons of 18 and 19 are
4.82-4.95 and 5.15 ppm, respectively.
OL016995N
(13) Harrison, J. F. In Carbene Chemistry, 2nd ed.; Kirmse, W.;
Academic Press: New York, 1971; Chapter 12, pp 457-503.
(14) Nonhebel, D. C.; Walton, J. C. Free-Radical Chemistry, Cambridge
University Press: New York, 1974; Chapter 10, pp 305-416.
876
Org. Lett., Vol. 4, No. 6, 2002