Synthesis of pyrrolo[2,3-a]pyrrolizine and pyrrolizine[2,3-a]pyrrolizine derived from allyl derivatives of Baylis-Hillman adducts through intramolecular 1,3-dipolar cycloaddition

Article abstract of DOI:10.1016/j.tetlet.2009.02.222

The synthesis of a series of pyrrole-based polycyclic heterocycles has been accomplished through an intramolecular 1,3-dipolar cycloaddition reaction of an azomethine ylide with the dipolarophile derived from Baylis-Hillman adducts. Improved yields of the

Full text of DOI:10.1016/j.tetlet.2009.02.222

Tetrahedron Letters 50 (2009) 2389–2391
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of pyrrolo[2,3-a]pyrrolizine and pyrrolizine[2,3-a]pyrrolizine
derived from allyl derivatives of Baylis–Hillman adducts through
intramolecular 1,3-dipolar cycloaddition
*
Subban Kathiravan, Ekambaram Ramesh, Raghavachary Raghunathan
Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai 600 025, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of a series of pyrrole-based polycyclic heterocycles has been accomplished through an
intramolecular 1,3-dipolar cycloaddition reaction of an azomethine ylide with the dipolarophile derived
from Baylis–Hillman adducts. Improved yields of the products were obtained when the reaction was car-
ried out under microwave conditions.
Received 18 November 2008
Revised 19 February 2009
Accepted 28 February 2009
Available online 5 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Intramolecular [3+2] cycloaddition of azomethine ylide has
been used widely to construct complex cyclic systems from rela-
tively simple precursors.1 This mode of cycloaddition simulta-
neously constructs two carbon–carbon bonds and forms complex
The structure of N-allyl pyrrole derivatives was confirmed by
spectroscopic analysis.
With N-alkenyl aldehyde 4a–c in hand, the cycloaddition reac-
tions were carried out with the unstabilized azomethine ylide gen-
erated by decarboxylative condensation with various secondary
amino acids. The condensation of 4a–c with sarcosine 5 in reflux-
ing toluene under Dean–Stark reaction conditions, generated azo-
methine ylide that underwent neat intramolecular cycloaddition
to yield cis-adducts 6a–c in moderate yields in all cases.33,34
When the same reaction was extended with proline and thia-
zolidine carboxylic acid, we obtained a series of novel pyrrolizidine
and thiopyrrolizidine heterocycles in good yield. The structures of
these compounds were also established on the basis of their spec-
troscopic data (Scheme 1).
To improve the yield, we carried out the reaction under two dif-
ferent conditions. Thus, the reactions of 4a–c with sarcosine, pro-
line, and thiazolidine carboxylic acid in toluene under reflux
afforded cycloadducts 6a–c in moderate yields in all cases, but re-
quired long reaction times and higher temperature.
ring systems with regio- and stereocontrol.2–5
a-Methylene-b-hy-
droxy esters 1a–c are easily prepared by the Baylis–Hillman reac-
tion6,7 and are well utilized as versatile building blocks for the
stereoselective construction of natural products, including alka-
loids,8 macrolides,9 terpenoids,10–12 and pheromones.13–15
Multifunctional allylic compounds such as 1a–c16 and deriva-
tives 2a–c17 are useful scaffolds for the synthesis of a wide range
of complex molecular frameworks.
With the objective of expanding the scope of these allyl halides
in synthetic organic chemistry, we have used the allyl bromides
derived from Baylis–Hillman adducts as dipolarophiles for intra-
molecular 1,3-dipolar cycloaddition.
In continuation of our research in the area of 1,3-dipolar cyclo-
addition,18–29 we herein report for the first time, the synthesis of
pyrrolo[2,3-a]pyrrolizine and pyrrolizine[2,3-a]pyrrolizine using
allyl bromides derived from Baylis–Hillman derivatives in an intra-
molecular cycloaddition reaction.
The treatment of methyl 3-acetoxy-3-phenyl-2-methylenepro-
panoate 1a–c30 with pyrrole-2-carbaldehyde 3 in the presence of
K2 CO3/dry DMF at 80 °C for 6 h gave moderate yields of the prod-
ucts 4a–c. However, a synthesis of the same products can be
accomplished in good yields by treating Baylis–Hillman bromide
derivatives 2a–c31 with pyrrole 2-carbaldehyde in the presence
of K2 CO3/dry DMF in 3 h.32
When the same reactions were carried out under microwave
irradiation in a toluene solvent, there was a dramatic increase in
the yields of the products with a decrease in reaction time. Under
these conditions, cycloadducts were obtained in good yields (79–
85%) with high regio- and stereoselectivity.35 The results are sum-
marized in Table 1.
In conclusion, we have developed a simple method for the syn-
thesis of a variety of polycyclic heterocycles by 1,3-dipolar cyclo-
addition
using
Baylis–Hillman
adduct
derivatives
as
dipolarophiles. We have observed that the reaction can be carried
out more efficiently to give good yields of products in short reac-
tion times under microwave conditions.
* Corresponding author. Tel.: +91 044 22202811.
E-mail address: ragharaghunathan@yahoo.com (R. Raghunathan).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.222

2390
S. Kathiravan et al. / Tetrahedron Letters 50 (2009) 2389–2391
CHO
N
H
OAc
3
COOCH3
K2CO3 / DMF /rt
Path A - 56-64 % yield
CHO
N
R
R
COOCH3
1a-c
CHO
N
H
COOCH3
Br
R
3
4a-c
E-Isomer
K2CO3 / acetone/800C
Path B - 78-89 % yield
2a-c
R = H
4a, R = H(92%)
4b, R = Cl(90%)
4c, R = Br(91%)
R = Cl
R = Br
H
CH3
N
R
N
H3C
H3C N
N
HN CH2-COOH
CH3
H3COOC
5
R
COOCH3
N
N
COOCH3
toluene reflux
CHO
N
COOCH3
R
6a-c
X
R
COOH
N
4a-c
H
H
R
7
8
X = CH2
X = S
X
X
N
N
X
N
N
toluene reflux
H3COOC
R
N
COOCH3
COOCH3
N
9a R = H, X = CH2
9b R = Cl, X = CH2
9c R = Br, X = CH2
9d R = H, X = S
9e R = Cl, X = S
9f R = Br, X = S
R
9a-f
Scheme 1.
Table 1
Synthesis of pyrrole[2,3-a]pyrrolizine/pyrrolizine[2,3-a]pyrrolizine derivatives using Method A and Method B
Entry
Pyrrole[2,3-a]pyrrolizine/pyrrolizine[2,3-a]pyrrolizine
Method A
Method B
Time (h)
Yield (%)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
6a
6b
6c
9a
9b
9c
9d
9e
9f
2.0
3.0
3.5
2.0
2.5
3.0
3.0
3.5
4.0
65
56
59
55
61
63
51
48
48
3.5
4.0
4.0
2
2.5
2.5
2
85
75
79
87
85
78
84
81
78
2.5
2.5
Method A: toluene reflux.
Method B: toluene under microwave irradiation.
4. Coldham, I.; Crapnell, K. M.; Moseley, J. D.; Rabot, R. J. Chem. Soc., Perkin Trans. 1
2001, 1758–1764.
References and notes
5. Novikov, M. S.; Khlebnikov, A. F.; Besidina, O. V.; Kastikov, R. R. Tetrahedron Lett.
2001, 42, 533–535.
6. Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev. 2003, 103, 811–891.
7. Ciganek, E.. In Organic Reactions; Wiley: New York, 1997; Vol. 51. pp 201–350.
8. Drewes, S. E.; Emslie, N. D. J. Chem. Soc., Perkin Trans 1 1982, 2079–2083.
9. Roush, W. R.; Brown, B. B. J. Org. Chem. 1993, 58, 2151–2161.
1. (a) Coldham, I.; Hufton, R. Chem. Rev. 2005, 105, 2765–2810; (b) Pandey, G.;
Banerjee, P.; Gadre, S. R. Chem. Rev. 2006, 106, 4484–4517; (c) Broggini, G.;
Zecchi, G. Synthesis 1999, 905–917.
2. Pandey, G.; Sahoo, A. K.; Bagul, T. D. Org. Lett. 2000, 2, 2299–2301.
3. Vedejs, E.; Klapers, A.; Naidu, B. N.; Piotrowski, D. W.; Tucci, F. C. J. Am. Chem.
Soc. 2000, 122, 5401–5404.

S. Kathiravan et al. / Tetrahedron Letters 50 (2009) 2389–2391
2391
10. Jenn, T.; Heissler, D. Tetrahedron 1998, 54, 97–106.
11. Grassi, D.; Lippuner, V.; Aebi, M.; Brunner, J.; Vasella, A. J. Am. Chem. Soc. 1997,
119, 10992–10999.
refluxed at 80 °C for 4–6 h till the completion of the reaction as evidenced by
TLC. The reaction mixture was concentrated in vacuo and diluted with water
(50 mL) .The aqueous layer was extracted with ethyl acetate (4 Â 20 mL), the
combined organic layers were dried (MgSO4) and the solvent was removed in
vacuo. The crude product was subjected to column chromatography (100–
200 mesh) using a hexane–ethyl acetate mixture (8:2).(E)-Methyl 2-((2-formyl-
1H-pyrrol-1-yl)methyl)-3-phenylacrylate 4a: Viscous liquid, Yield: 92%. IR (KBr):
12. Hoffmann, H. M. R.; Rabe, J. . J. Org. Chem. 1985, 50, 3849–3859.
13. Moiseenkov, A. M.; Cheskis, B. A.; Shapiro, N. A.; Stashina, G. A.; Zhulin, V. M.
Bull. Acad. Sci. USSR, Div. Chem. Sci. (Engl. Transl.) 1990, 39, 517–521.
14. Cheskis, B. A.; Moiseenkov, A. M.; Shapiro, N. A.; Stashina, G. A.; Zhulin, V. M.
Bull. Acad. Sci. USSR, Div. Chem. Sci. (Engl. Transl.) 1990, 39, 716–720.
15. Mateus, C. R.; Feltrin, M. P.; Costa, A. M.; Coelho, F.; Almeida, W. P. Tetrahedron
2001, 57, 6901–6908.
16. Basavaiah, D.; Hyma, R. S. Tetrahedron 1996, 52, 1253–1258.
17. Deng, J.; Hu, X. P.; Huang, J. D.; Yu, S. B.; Dao-Yong Wang, D. Y.; Duan, Z. C.;
Zheng, Z. J. Org. Chem. 2008, 73, 2015–2017.
18. Fernandes, L.; Bortoluzzi, A. J.; Sá, M. M. Tetrahedron 2004, 60, 9983–9989.
19. Poornachandran, M.; Raghunathan, R. Tetrahedron 2008, 64, 6461–6474.
20. Poornachandran, M.; Raghunathan, R. Tetrahedron: Asymmetry 2008, 19, 2177–
2183.
21. Arumugam, N.; Jayashankaran, J.; Rathnadurga, R.; Raghunathan, R.
Tetrahedron 2005, 61, 8512–8516.
1675, 1715 cmÀ1 1H NMR (300 MHz, CDCl3): d 3.77(s, 3H), 6.96 (d, J = 1.5 Hz,
,
1H), 6.97 (d, J = 1.8 Hz, 1H), 8.07 (s, 1H), 6.20–6.97 (m, 3H), 7.24–7.37 (m, 5H),
9.57 (s, 1H). 13C NMR (75 MHz, CDCl3): d 45.1, 52.3, 126.6, 128.0, 128.4, 128.5,
129.0, 129.1, 129.7, 131.8, 133.9, 145.1, 167.3, 179.5.
33. Poornachandran, M.; Raghunathan, R. Tetrahedron Lett. 2005, 46, 7197–7200.
34. Ramesh, E.; Raghunathan, R. Tetrahedron Lett. 2008, 49, 1125–1128.
35. Synthesis of cycloadducts: Method A: A solution of an N-allyl derivative of
pyrrole (1 mmol) and cyclic and acyclic amino acids (1 mmol), in anhydrous
toluene (10 mL), was refluxed until the completion of the reaction as evidenced
by TLC analysis. The solvent was removed under vacuum. The crude product
was subjected to column chromatography on silica gel (100–200 mesh) using
petroleum ether–ethyl acetate (7:3) as the eluent.
22. Jayashankaran, J.; Rathnadurga, R.; Raghunathan, R. Tetrahedron Lett. 2004, 45,
7303–7305.
23. Amalraj, A.; Raghunathan, R.; Sridevikumari, M. R.; Raman, N. Bioorg. Med.
Chem. 2003, 11, 407–419.
24. Subramaniyan, G.; Raghunathan, R.; Martin Castro, A. M. Synthesis 2002, 2440–
2445.
Method B: A mixture of an N-allyl derivative of pyrrole (1 mmol), cyclic and
acyclic amino acids (1 mmol), in anhydrous toluene (10 mL), was irradiated by
microwave irradiations until the disappearance of the starting materials (1–
2 min, monitored by TLC). After standing for 1 h, the reaction mixture was
concentrated under vacuum and the crude mixture was purified by column
chromatography to afford the pure product.
25. Subramaniyan, G.; Raghunathan, R. Tetrahedron 2001, 57, 2909–2913.
26. Amalraj, A.; Raghuanthan, R. Tetrahedron 2001, 57, 10293–10298.
27. Suresh Babu, A. R.; Raghunathan, R. Tetrahedron Lett. 2007, 48, 6809–6813.
28. Ramesh, E.; Kathiresan, K.; Raghunathan, R. Tetrahedron Lett. 2007, 48, 1835–
1839.
29. Suresh Babu, A. R.; Raghunathan, R. Tetrahedron Lett. 2008, 49, 4487–4490.
30. Kim, J. N.; Lee, H. J.; Gong, J. H. Tetrahedron Lett. 2002, 43, 9141–9146.
31. Basavaiah, D.; Roy, S. Org. Lett. 2008, 10, 1819–1822.
32. Synthesis and spectral data for new compounds: Path A: To a refluxing solution of
Methyl 1,2,3,3a,4,8b-hexahydro-1-methyl-3-phenylpyrrolo[2,3-a]pyrrolizine-3a-
carboxylate 6a: Yield: 85% IR (KBr): 1712 cmÀ1
,
Mp: 80 °C, 1H NMR
(300 MHz, CDCl3): d 2.51 (s, 3H), 2.79 (t, J = 9.6 Hz, 1H), 3.09 (dd, J = 6.6,
3.0 Hz, 1H), 3.55 (d, J = 11.7 Hz, 1H), 3.76 (s, 3H), 4.02 (d, J = 11.7 Hz, 1H), 4.05
(dd, J = 6.9, 4.2 Hz, 1H), 4.67 (s, 1H), 5.88–6.39 (m, 3H), 7.00–7.23 (m, 5H). 13C
NMR (75 MHz, CDCl3): d 30.9, 38.3, 49.8, 50.4, 52.9, 58.3, 67.2, 102.0, 113.0,
114.3, 127.2, 128.5, 128.6, 138.4, 175.0. MS (EI) m/z = 296.15 (M+) Anal. Calcd
for C18H20N2O2: C, 72.96; H, 6.80; N, 9.45. Found: C, 73.08; H, 6.92; N, 9.37.
Methyl
1,2,3,3a,4,8b-hexahydro-3-phenylthiopyrrolizine[2,3-a]pyrrolizine-3a-
pyrrole 2-carbaldehyde (20 mmol), K2CO3 (25 mmol) in 25 ml of DMF,
a
carboxylate 9d:Yield: 84% Viscous liquid, IR (KBr): 1709 cmÀ1
,
1H NMR
Baylis–Hillman derivative (22 mmol) was added. The reaction mixture was
stirred for 4–6 h at room temperature, and diluted with water (50 mL). The
aqueous layer was extracted with ethyl acetate (4 Â 20 mL), the combined
organic layers were dried (MgSO4) and the solvent was removed in vacuo .The
crude product was subjected to column chromatography (100–200 mesh)
using a hexane–ethyl acetate mixture (8:2).Path B: To a refluxing solution of
pyrrole 2-carbaldehyde (20 mmol), K2 CO3 (25 mmol) in 25 ml of acetone, a
Baylis–Hillman bromide (22 mmol) was added. The reaction mixture was
(300 MHz, CDCl3): 3.77 (s, 3H), 3.9 (d, 3.3 Hz, 1H), 3.9 (m, 1H), 3.02 (dd,
J = 4.2, 5.4 Hz, 1H), 3.21 (dd, J = 4.8, 5.3 Hz, 1H), 4.34 (d, J = 9.9 Hz, 1H), 4.28 (d,
J = 10.2 Hz, 1H), 4.02 (d, J = 9.9 Hz, 1H), 3.87 (d, J = 9.9 Hz, 1H), 4.61 (s, 1H),
5.97–6.46 (m, 3H), 7.23–7.36 (m, 5H).
13C NMR (75 MHz, CDCl3): 37.1, 50.4, 53.1, 54.1, 58.3, 68.7, 69.8, 75.7, 109.8,
112.7, 114.7, 127.5, 128.8, 129.6, 135.2, 139.0, 174.4. MS (EI) m/z = 340.10 (M+).
Anal. Calcd for C19H20N2O2S: C, 67.03; H, 5.92; N, 8.23. Found: C, 67.17; H, 6.03;
N, 8.14.