A Pummerer-based generation and trapping of furo[3,4-c]pyridines: An approach to nitrogen containing heterocyclic analogues of 1-arylnaphthalene lignans

Article abstract of DOI:10.1016/S0040-4039(01)02379-6

The Pummerer reaction of o-benzoyl substituted pyridylmethyl sulfoxides generates α-thiocarbocations, the interception of which by the neighbouring keto functionality produces thio-substituted furo[3,4-c]pyridines as transient intermediates; the latter un

Full text of DOI:10.1016/S0040-4039(01)02379-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1341–1344
A Pummerer-based generation and trapping of
furo[3,4-c]pyridines: an approach to nitrogen containing
heterocyclic analogues of 1-arylnaphthalene lignans
Tarun K. Sarkar,* Sankar Basak and Niranjan Panda
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
Received 12 September 2001; revised 5 December 2001; accepted 14 December 2001
Abstract—The Pummerer reaction of o-benzoyl substituted pyridylmethyl sulfoxides generates a-thiocarbocations, the interception
of which by the neighbouring keto functionality produces thio-substituted furo[3,4-c]pyridines as transient intermediates; the latter
undergo [4+2] cycloaddition with an added dienophile. Base-induced ring opening of the cycloadducts followed by aromatization
gives substituted isoquinolines related to heterocyclic analogues of 1-arylnaphthalene lignans. © 2002 Published by Elsevier
Science Ltd.
In contrast to the phenomenal growth of the chemistry
of o-quinoid 10-p electron isobenzofuran ring system,
heteroisobenzofurans such as furo[3,4-c]pyridines have
not been studied so well.1–3 Recently, in a series of
papers we have described the use of both stable as well
as reactive furo[3,4-c]pyridine intermediates in the syn-
thesis of polycyclic ring systems involving tandem4
Hamaguchi–Ibata and Diels–Alder reactions.5–7 In con-
tinuation of our work in this area, we now report the
first Pummerer based generation8,9 of furo[3,4-
c]pyridines and their applications in the synthesis of
substituted isoquinolines related to the nitrogen con-
taining heterocyclic analogues of 1-arylnaphthalene
lignans.10
Scheme 1.
Keywords: azaisobenzofuran; Pummerer rearrangement; Diels–Alder reaction; heterolignan.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(01)02379-6

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T. K. Sarkar et al. / Tetrahedron Letters 43 (2002) 1341–1344
Our strategy towards arylisoquinoline lignans 5–7 is
outlined in Scheme 1. This involves generation of a-
thiocarbocation 28,9 from sulfoxide 1 and its intercep-
basis of the Alder endo rule.18 Similarly, keto-sulfoxides
12 and 13 gave 16 (mp 200–202°C) and 1718 (mp
164–166°C) in only 18 and 20% yield, respectively.
Thus, this route turns out to be less efficient in all these
cases. This prompted us to develop improved condi-
tions for this type of sequential reaction. After consid-
erable efforts with a variety of Pummerer promoters,
we overcame this difficulty simply by replacing acetic
anhydride by heptafluorobutyric anhydride. In this
modified protocol (conditions B), keto-sulfoxides 11–13
smoothly gave bridged cycloadducts 15–17 with
improved yields as shown in Table 1.
tion by
a neighbouring carbonyl group to give
furo[3,4-c]pyridine 3; the latter should undergo a Diels–
Alder reaction with an added dienophile to give 4,
which is readily convertible to heterolignans 5–7.
In this context, a series of pyridine containing sulfoxide
precursors 10–13 was synthesized from the readily
available nitrile 811 by a standard synthetic protocol as
shown in Scheme 2.14
To test the viability of the proposed sequential Pum-
merer-Diels–Alder process, we first treated simple sulf-
oxide 1015 with a suitable dienophile under standard
Pummerer reaction conditions.8,9 Thus, exposure of 10
to a mixture of acetic anhydride, dimethyl maleate and
a catalytic amount of p-toluenesulfonic acid (p-TsOH)
in refluxing toluene for 30 min gave 14,16 in 44% yield,
as a white crystalline solid, mp 109–111°C (Scheme 3).
In this case, the [4+2] adduct (cf. 4) underwent sponta-
neous ring cleavage followed by dehydration.
The oxa-bridge in the initially formed cycloadducts
15–17 could be readily cleaved leading to substituted
isoquinolines 18,19 19 and 20 using DBU in refluxing
toluene (Scheme 4).20 The synthesis of these compounds
can also be conducted in one-pot by exposing keto-sul-
foxides to the Pummerer conditions (conditions B) and
then adding DBU to the reaction mixture.
In conclusion, we have demonstrated a Pummerer-
based route for the generation of transient furo[3,4-
c]pyridines. Further work utilizing the thio-substituted
azaisobenzofuran-derived cycloadducts 15–17 for the
synthesis of arylisoquinoline lignan analogues (cf. 5–7)
of potential biological interest is currently underway in
this laboratory.
However, when keto-sulfoxide 11 was used, the sequen-
tial Pummerer-Diels–Alder reaction proceeded as
expected, but here only the bridged product 1517 (mp
174–175°C) was obtained in 17% yield (Table 1). The
stereochemistry of 15 is tentatively assigned on the
Scheme 2.
Scheme 3.

T. K. Sarkar et al. / Tetrahedron Letters 43 (2002) 1341–1344
1343
Table 1.
Substrate
R
Product
Conditions Aa yield (%)
Conditions Bb yield (%)
11
12
13
H
CH3
OMe
15
16
17
17
18
20
33
37
40
a Conditions A: Ac2O, p-TsOH (cat.), dimethyl maleate, PhMe, reflux, 1 h.
b Conditions B: (C4F7CO)2O, p-TsOH (cat.), dimethyl maleate, PhMe, reflux, 1 h.
Scheme 4.
Acknowledgements
7. Sarkar, T. K.; Basak, S.; Ghosh, S. K. Tetrahedron Lett.
2000, 41, 759.
8. Kappe, C. O.; Cochran, J. E.; Padwa, A. Tetrahedron
Financial support from CSIR [No. 1 (1602)99-EMR-
II], Government of India is gratefully acknowledged.
We are also grateful to Professor H. K. Fun (Malaysia)
for help with the X-ray crystal structure determination
of 17 and to Professor T. Gallagher (Bristol, UK) for
help with microanalysis. S.B. is thankful to CSIR,
Government of India for a Senior Research Fellowship.
Lett. 1995, 36, 9285.
9. Kappe, C. O.; Padwa, A. J. Org. Chem. 1996, 61, 6166.
10. For a review on heterolignans, see: Ramos, A. C.; De
Clairac, R. P.-L.; Medarde, M. Heterocycles 1999, 51,
1443.
11. Compound 8 (mp 118–119°C) was prepared via base-
induced condensation12 of ethyl 4-(phenylthio)aceto-
acetate13 with cyanoacetamide followed by treatment
with POCl3.
References
12. Meislich, H. In The Chemistry of Heterocyclic Com-
pounds; Pyridine and its derivatives, Part III. Wiley: New
York, 1962; Chapter XII; p. 509.
13. Campaigne, E.; Homfeld, E. J. Heterocycl. Chem. 1979,
16, 1321.
1. Rodrigo, R. Tetrahedron 1988, 44, 2093.
2. Friedrichsen, W. Adv. Heterocycl. Chem. 1999, 73, 1.
3. Padwa, A. Chem. Commun. 1998, 1417.
4. Ho, T.-L. Tandem Organic Reactions; Wiley–Interscience:
New York, 1992.
5. Sarkar, T. K.; Ghosh, S. K.; Nandy, S. K.; Chow, T. J.
Tetrahedron Lett. 1999, 40, 397.
14. R=H (89%, Swern); R=Me (78%, Swern); R=OMe
(96%, PCC).
15. [10]=1H NMR (200 MHz, CDCl3:CCl4 7:3): l 10.27 (s,
1H), 7.50 (s, 5H), 7.05 (s, 1H), 4.75 (d, 1H, J=11.9 Hz),
4.08 (d, 1H, J=11.9 Hz); 13C NMR (50 MHz,
CDCl3:CCl4 7:3): l 190.1 (d), 154.0 (s), 153.6 (s), 145.0
6. Sarkar, T. K.; Ghosh, S. K.; Chow, T. J. J. Org. Chem.
2000, 65, 3111.

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T. K. Sarkar et al. / Tetrahedron Letters 43 (2002) 1341–1344
(s), 142.4 (s), 131.5 (d), 129.1 (d), 127.1 (d), 125.6 (s),
124.0 (d), 59.1 (t).
53.5 (d), 52.5 (d), 52.3 (q), 51.9 (q).
18. Support for such an assignment came from the X-ray
crystal structure determination of 17, details of which will
be published elsewhere.
16. [14]=1H NMR (200 MHz, CDCl3): l 9.10 (d, 1H, J=0.9
Hz), 8.21 (d, 1H, J=0.9 Hz), 7.30–7.07 (m, 5H); 4.01 (s,
3H), 3.98 (s, 3H); 13C NMR (50 MHz, CDCl3): 167.0 (s),
164.0 (s), 152.9 (s), 147.8 (s), 144.5 (s), 142.8 (s), 134.9 (s),
131.9 (d), 129.4 (d), 128.9 (s), 128.5 (d), 127.2 (s), 127.0
(d), 125.5 (s), 118.9 (d), 53.2 (q), 53.0 (q).
19. [18]=mp 178–179°C; 1H NMR (200 MHz, CDCl3:CCl4
7:3): l 8.37 (s, 1H), 7.48–7.35 (m, 4H), 7.32–7.15 (m, 6H),
3.88 (s, 3H), 3.43 (s, 3H); 13C NMR (50 MHz,
CDCl3:CCl4 7:3): 166.9 (s), 166.5 (s), 151.7 (s), 146.2 (s),
142.7 (s), 141.6 (s), 141.0 (s), 137.3 (s), 135.0 (s), 133.4 (s),
129.6 (d), 129.5 (d), 128.8 (d), 128.6 (d), 128.0 (s), 127.9
(d), 127.2 (d), 124. 8 (s), 119.0 (d), 53.0 (q), 52.5 (q).
20. Initial attempts for the conversion of 15“18 using a
variety of other reagents, e.g. MeOH/HCl, p-TsOH in
refluxing toluene and CF3CO2H were unsuccessful.
17. [15]=1H NMR (200 MHz, CDCl3:CCl4 7:3): l 7.70–7.25
(m, 11H), 4.16 (d, 1H, J=11.2 Hz), 3.61 (d, 1H, J=11.2
Hz), 3.57 (s, 6H); 13C NMR (50 MHz, CDCl3:CCl4 7:3):
168.9 (s), 167.6 (s), 157.2 (s), 148.7 (s), 137.7 (s), 135.3
(d), 133.9 (s), 129.5 (d), 129.4 (d), 129.1 (d), 128.4 (d),
128.0 (d), 127.9 (s), 127.7 (s), 117.9 (d), 93.7 (s), 89.8 (s),