Facile synthesis of 4-alkyl (and aryl)-2-aryl-6-diazo-4H-thieno[3,2-b] pyridine-5,7-diones

Article abstract of DOI:10.1021/jo049769a

Treatment of 3-{3-alkyl (and aryl)amino-5-arylthieno-2-yl}-2-diazo-3- oxopropanoates 8 with TMSOTf (3 equiv) in the presence of Et3N (6 equiv) in CH₂Cl₂ for 1 h at room temperature afforded 4-alkyl (and aryl)-2-aryl-6-diazo-4H-thieno

Full text of DOI:10.1021/jo049769a

SCHEME 1
F a cile Syn th esis of 4-Alk yl (a n d
Ar yl)-2-a r yl-6-d ia zo-4H-
th ien o[3,2-b]p yr id in e-5,7-d ion es
Dong J oon Lee and Kyongtae Kim*
School of Chemistry and Molecular Engineering,
Seoul National University, Seoul 151-742, Korea
SCHEME 2
kkim@plaza.snu.ac.kr
Received February 10, 2004
Ab st r a ct : Treatment of 3-{3-alkyl (and aryl)amino-5-
arylthieno-2-yl}-2-diazo-3-oxopropanoates 8 with TMSOTf
(3 equiv) in the presence of Et3N (6 equiv) in CH2Cl2 for 1 h
at room temperature afforded 4-alkyl (and aryl)-2-aryl-6-
diazo-4H-thieno[3,2-b]pyridine-5,7-diones 14 in excellent
yields. On heating of 14 in the presence of a catalytic amount
of Rh2(CF3CF2CF2CO2)4 in PhH for 4-10 h at reflux,
corresponding ring contraction products, 4-alkyl (and aryl)-
5,6-dihydro-4H-thieno[3,2-b]pyrrol-5-ones 16, were produced
in good to excellent yields.
SCHEME 3
2-Diazocyclohexane-1,3-dione and diazoquinolinedione
derivatives are an important class of organic compounds.
The former are utilized as intermediates for the synthesis
of â-substituted R-chloroenones that are used as valuable
intermediates in the synthesis of R-carbon-substituted
enones1 and biologically active natural products.2 For
example, treatment of 2-diazocyclohexane-1,3-dione 1
with acetyl chloride at room temperature for 3 h gave
Taber’s method.7 Quinolinediones, precursors of 3, are
either commercially available or can be prepared by
cyclizing the corresponding anthranilic acids with acetic
anhydride in acetic acid.8 Surprisingly, 6-diazo-4H-thieno-
[3,2-b]pyridine-5,7-diones or 6-diazo-4H-furo[3,2-b]pyri-
dine-5,7-diones, analogous to compounds 3, have not been
reported.
A search of the literature revealed that there is one
report9 describing the synthesis of 7-hydroxy-4H-thieno-
[3,2-b]pyridine-5-one 7 by hydrolysis, followed by decar-
boxylation of 6-ethoxycarbonyl-7-hydroxy-4H- thieno[3,2-
b]pyridin-5-one 6, prepared starting from ethyl 3-amino-
thiophene-2-carboxylate and diethyl malonate in two
steps (Scheme 3). However, the method is of limited
usefulness due to difficulty with accessing the introduc-
tion of aryl groups at the nitrogen atom of the pyridine
moiety as well as the inaccessibility of the starting
materials, i.e., 3-aminothiophene-2-carboxylate with di-
verse substituents at the 5-position.
3-acetoxy-2-chlorocyclohex-2-enone
(Scheme 1).
2
in 81% yield3
The latter are useful for the synthesis of biologically
active compounds. For example, N-alkyldiazoquinolinedi-
one 3 undergoes cyclization with vinyl acetate in the
presence of Rh2(piv)4 catalyst in acidic EtOH to give
2-acetoxy-9-alkyl-2,3-dihydrofuro[2,3-b]quinoline-4-one 44
(Scheme 2), which can be further converted to naturally
occurring alkaloids.
In addition, rhodium(II)-catalyzed reactions of 3 in
refluxing CH3CN gave oxindoles 55,6 (Scheme 2), which
are valuable synthetic intermediates of natural and
pharmaceutical reagents. Compounds 1 and 3 were
readily prepared by the diazo transfer reactions of the
corresponding 1,3-diones with mesyl azide according to
Accordingly, it may be worthwhile to explore the
synthetic method of the foregoing unexplored fused
pyridine-5,7-diones, whose diazo compounds would be
expected to comprise a promising starting material for
the synthesis of novel bioactive compounds.
* Phone: 82 2880 6636. Fax: 82 2874 8858.
(1) Lee, Y. R.; J ung, Y. S. J . Chem. Soc., Chem. Commun. 1998,
2621-2622 and references cited therein.
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11014-11015. (b) J ohnson, C. R.; Harikrishnan; Golebiowski, A.
Tetrahedron Lett. 1994, 35, 7735-7738.
Recently, we reported a synthesis of a mixture of 5,6-
dihydro-4H-thieno[3,2-b]pyrrol-5-one and the correspond-
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Chem. Res., Synop. 1980, 6-7.
10.1021/jo049769a CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/17/2004
J . Org. Chem. 2004, 69, 4867-4869
4867

SCHEME 4
SCHEME 6
SCHEME 5
Alternatively, compounds 14 could be prepared utiliz-
ing di-tert-butoxycarbonate (BOC2O) and N,N-(dimethyl-
amino)pyridine (DMAP)15 (method B). Their yields are
listed in Table 2.
TABLE 1. Yield s of Com p ou n d s 11 a n d 8
Ar
R2
compd % yielda compd % yielda
Ph
Ph
Ph
Me
Et
i-Pr
Me
4-MeOC6H4
2-MeC6H4
4-ClC6H4
11a
11b
11c
11d
11e
11f
11g
11h
11i
87
80
72
66
78
74
71
64
69
53
72
68
69
8a
8b
8c
8d
8e
8f
8g
8h
8i
91
71
52
77
80
83
87
38
88
53
57
77
88
Table 2 shows that very high yields of 14 were obtained
in 1 h reactions regardless of whether R2 is alkyl or aryl
group when TMSOTf and Et3N were used, whereas low
yields of 14a -d were obtained in the cases of R2 ) alkyl
groups when BOC2O and DMAP were used. In contrast,
yields of 14 were comparable or inferior to those obtained
under conditions involving TMSOTf in the cases where
R2 ) aryl groups. One crucial drawback of the reactions
involving BOC2O and DMAP was the recovery of a
considerable amount of 8 in most of the reactions. In
addition, the reaction times were variable depending on
the properties of R2. It appeared that the cyclization
reactions proceeded slowly when R2 was an aryl group
having an electron-donating group such as methoxy (14e
and 14i) and alkyl groups (14a -d ). In particular, it took
10 and 24 h, respectively, when Ar ) Ph, R2 ) Me (14a )
4-MeC6H4
Ph
Ph
Ph
Ph
2-NCC6H4
4-MeOC6H4 4-MeOC6H4
4-MeOC6H4 4-BrC6H4
4-MeOC6H4 4-NCC6H4
4-BrC6H4
4-BrC6H4
11j
11k
11l
8j
8k
8l
Ph
4-MeOC6H4
11m
8m
a
Isolated yields.
ing enols 9 from the reactions of 3-(3-alkylamino-5-
arylthieno-2-yl)-2-diazo-3-oxopropanoates 8 (R1 ) R2 )
alkyl) with a catalytic amount of Rh2(OAc)4‚2H2O in
benzene at reflux10 (Scheme 4).
and Ar ) 4-MeC6H4, R2 ) Me (14d ). When R2
)
2-MeC6H4 (14f), it took 15 h presumably due to the steric
hindrance arising from the o-methyl group. It may be
worthwhile to mention that the reactions of 8h and 8k
occurred smoothly at room temperature for a shorter time
(0.5 h) to give the corresponding cyclized product 14h and
14k , along with t-BOC-protected starting materials 15h
(27%) and 15k (17%), respectively, in addition to the
starting material. The role of BOC2O and DMAP in the
cyclization of 8 to give 14 is uncertain. Treatment of 15h ,
presumably formed via 1-tert-butoxycarbonyl-4-dimethy-
laminopyridinium tert-butyl carbonate,16 with a mixture
of BOC2O and DMAP for 24 h at reflux under the same
foregoing conditions, did not give 14h . Only 15h was
quantitatively recovered. The result suggests that N-
BOC-protected 8 may not be a reactive intermediate
leading to 14. In contrast, treatment of 8a , 8c, 8e, and
8g with tert-BuOK (0.2 equiv) in THF at room temper-
ature gave 14a (93%), 14c (78%), 14e (95%), and 14g
Synthesis of compounds 8e-m was achieved by treat-
ment of thioaroylketene S,N-acetals 11e-m , prepared by
the reactions of aroylketene S,S-acetals 10 with aryl-
amines in the presence of BF3‚OEt,11 followed by treat-
ment of Lawesson’s reagent,12 with 2-diazo-3-trimethyl-
silyloxy-3-butenoate 12 in the presence of Hg(OAc)2
(Scheme 5). Yields of compounds 8 and 11 are sum-
marized in Table 1.
We found that compounds 8 were excellent starting
materials for the synthesis of title compounds 14, which
were prepared by the reactions of compounds 8 with
trimethylsilyl trifluoromethanesulfonate (TMSOTf) (3
equiv) in the presence of Et3N (6 equiv) in CH2Cl2 for 1
h at room temperature in excellent yields (Scheme 6,
method A). Yields of 14 are summarized in Table 2.
It is interesting to note that dihydro- and tetrahy-
drothieno[3,2-b]pyridines are seldom reported13 despite
ample examples of thieno[3,2-b]pyridine-5-one deriva-
tives that are biologically important.14 However, no
diazothieno[3,2-b]pyridinediones whatsoever have been
reported.
(14) (a) Suzuki, F.; Miwa, Y.; Hayashi, H.; Ishii, A.; Ichikawa, S.;
Miki, I. Eur. Pat. Appl. CODEN; EPXXDW EP 503822 A1 19920916,
1992. (b) Luo, J . K.; Castle, R. N. J . Heterocycl. Chem. 1991, 28, 205-
208. (c) Malicorne, G.; Bompart, J .; Giral, L.; Despaux, E. Eur. J . Org.
Chem. 1991, 26, 3-11. (d) Davies, R. V. Eur. Pat. Appl. CODEN;
EPXXDW EP 269295 A1 199880601, 1998.
(15) Koskinen, A. M. P.; Pihko, P. M. Tetrahedron Lett. 1994, 35,
7417-7420.
(16) (a) Kno¨lker, H.-J .; Braxmeier, T.; Schlechtingen, G. Angew.
Chem., Int. Ed. Engl. 1995, 34, 7-2500. (b) Ragnarsson, U.; Grehn,
L. Acc. Chem. Res. 1998, 31, 494-501.
(10) Lee, D. J .; Kim, K.; Park, Y. J . Org. Lett. 2002, 4, 873-876.
(11) Kohra, S.; Turuya, S.; Kimura, M.; Ogata, K. Chem. Pharm.
Bull. 1993, 41, 1293-1296.
(12) Huang, Z.-t.; Liu, Z.-r. Synth. Commun. 1989, 19, 943-958.
(13) Brugier, D.; Oututquin, F.; Paulmier, C. J . Chem. Soc., Perkin
Trans. 1. 2001, 37-43.
4868 J . Org. Chem., Vol. 69, No. 14, 2004

TABLE 2. Yield s of Com p ou n d s 14 a n d 16
method A
method B
method C
method D
reactant
product
% yielda
% yielda
time, h
product
% yielda
time, h
% yielda
time, h
8a
8b
8c
8d
8e
8f
8g
8h
8i
14a
14b
14c
14d
14e
14f
14g
14h
14i
91
63
57
96
90
95
b
91
87
94
b
54 (40)c
0 (94)c
0 (95)c
49 (44)c
93
10
24
24
24
1
16a
16b
16c
16d
16e
16f
16g
16h
16i
77
79
70
88
87
92
96
95
99
62
71
87
92
6
7
7
4
5
8
4
6
5
72
73
44
47
79
28
34
33
35
45
65
74
59
3
5
5
4
6
4
5
3
4
3
3
2
2
64 (30)c
93
15
1
64 (27)d
80 (19)c
95
0.5e
2
8j
8k
8l
14j
14k
14l
0.5
0.5e
0.5
0.5
16j
16k
16l
5
10
8
81 (17)d
95
89
95
8m
14m
96
16m
7
a
b
d
Isolated yields. Reactions were not carried out. c Yields of recovered 8. Yields of compounds 15h and 15k . e Reactions were carried
out at room temperature.
SCHEME 7
(86%), respectively. The result suggests the importance
of an amide ion, which facilitates intramolecular nucleo-
philic displacement of an alkoxide to yield 14. However,
it is necessary to delineate the role of BOC2O and DMAP
in view of the basicity of DMAP. In the meantime, the
high yields of 14 resulting from the TMSOTf-derived
reactions in the presence of Et3N may be rationalized on
the basis of the intramolecular nucleophilic attack of the
amino group of 8 onto the ester carbonyl carbon activated
by the interaction of the carbonyl oxygen with TMSOTf.
Et3N would be expected to trap the CF3SO3H generated.
Nucleophilic attack of cyanophenylamino groups of 8h
mediates proposed in the reactions of 11 with carbonyl
and 8k onto BOC2O would give compounds 15h and 15k ,
compounds having active methylene hydrogen atoms in
respectively.
the presence of Hg(OAc)2.17 Intramolecular nucleophilic
Heating compounds 14 in the presence of a catalytic
attack of the imino nitrogen to the carbonyl group of the
amount of Rh2(OAc)4‚2H2O in PhH afforded 4-alkyl (and
succinic anhydride moiety, followed by decarboxylation,
aryl)-2-aryl-5,6-dihydro-4H-thieno[3,2-b]pyrrol-5-ones 16.
concomitant with aromatization of dihydrothiophene
Much better yields of 16 were obtained utilizing a
moiety, would result in the formation of 16.
catalytic amount of Rh2(CF3CF2CF2CO2)4 in place of
In summary, stirring 3-{3-alkyl (and aryl)amino-5-
Rh2(OAc)4‚2H2O (Scheme 6). Yields of 16 and reaction
arylthieno-2-yl}-3-oxo-2-diazopropanoates with TMSOTf
times are summarized in Table 2. Although compounds
and Et3N in CH2Cl2 at room temperature produced
16 are all new, an analogous type of ring contraction of
diazothieno[3,2-b]pyridine-5,7-diones in excellent yields.
diazoquinolines has been reported.5,15
The compounds underwent ring contraction reactions by
Alternatively, compound 16a was directly obtained
heating in the presence of Rh2(CF3CF2CF2CO2)4 catalyst
from the reaction of 11a with maleic anhydride 13 in
in PhH at reflux to give 5,6-dihydro-4H-thieno[3,2-b]-
various solvents such as PhH (2 h, 56%), CH3CN (45 min,
pyrrol-5-ones. Both classes of compounds are all newly
49%; 3 h, 52%), toluene (1.5 h, 34%), and CH2Cl2 (10 h,
discovered despite the existence of analogous compounds
92%) at reflux (Scheme 6). Similar treatment of 11b in
such as 2-diazocyclohexane-1,3-diones and diazoquino-
CH2Cl2 for 40 h gave 16b in 41% yield. In addition,
linediones.
compounds 16n -p were obtained in 76, 41, and 42%
yields, respectively, using the corresponding starting
materials 11n -p . Yields were variable depending on the
structures of 11, and the reaction times were relatively
Ack n ow led gm en t. This work was supported by
Korea Research Foundation Grant (KRF-2000-DP-
0261).
longer compared with those in listed in Table 2.
The formation of 16 from 11 could be rationalized on
the basis of Michael-type addition of the thione sulfur to
maleic anhydride, leading to succinic anhydride deriva-
tive 17, which equilibrates with its enol 18 (Scheme 7).
Intramolecular nucleophilic attack of the enolic carbon
of 18 to the imino carbon would give intermediate 19.
Loss of a methanethiolate ion from 19 gives 2,3-dihy-
drothiophene intermediate 20, analogous to the inter-
Su p p or tin g In for m a tion Ava ila ble: General procedure
1
for the synthesis of 8, 10, 11, and 14-16, H NMR, 13C NMR,
IR, and elemental analysis of 8a -m , 11a -p , 14a -m , 15h ,
15k , and 16a -p . This material is available free of charge via
the Internet at http://pubs.acs.org.
J O049769A
(17) Kim, B. S.; Kim, K. J . Org. Chem. 2000, 65, 3690-3699.
J . Org. Chem, Vol. 69, No. 14, 2004 4869