A facile synthesis of chromeno[4,3-b]pyrroles derived from allyl derivatives of Baylis-Hillman adducts through intramolecular 1,3-dipolar cycloaddition using ultrasonication

Article abstract of DOI:10.1016/j.tetlet.2007.12.066

Synthesis of a series of chromene[4,3-b]pyrroles 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 same products wer

Full text of DOI:10.1016/j.tetlet.2007.12.066

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1125–1128
A facile synthesis of chromeno[4,3-b]pyrroles derived from allyl
derivatives of Baylis–Hillman adducts through intramolecular
1,3-dipolar cycloaddition using ultrasonication
Ekambaram Ramesh, Raghavachary Raghunathan *
Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai 600 025, India
Received 18 October 2007; revised 4 December 2007; accepted 12 December 2007
Abstract
Synthesis of a series of chromene[4,3-b]pyrroles 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 same products were obtained
when the reaction was carried out under ultrasonication.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Baylis–Hillman adduct; Chromene pyrrole; Cycloaddition; Azomethine ylide
Intramolecular [3+2] cycloaddition of azomethine ylides
has been used widely to construct complex cyclic systems
from relatively simple precursors. This mode of cycloaddi-
tion simultaneously constructs two carbon–carbon bonds
and forms complex ring systems with regio- and stereocon-
trol.1–5
a-Methylene-b-hydroxy esters 1a–f are easily prepared
by the Baylis–Hillman reaction6,7 and are well-utilized as
versatile building blocks for the stereoselective construc-
tion of natural products, including alkaloids,8 macrolides,9
terpenoids10–12 and pheromones.13–16
Multifunctional allylic compounds such as 1a–f and
derivatives 2a–f 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 which had not been exploited previously
as internal olefins for the intramolecular 1,3-dipolar cyclo-
addition reactions.
Activation of organic reactions with ultrasound consti-
tutes an important domain of modern chemistry. This is
largely due to the fact that sonochemistry and the recent
upsurge of interest in sustainable chemistry share similar
aims, such as the use of less hazardous chemicals and envi-
ronmentally benign solvents, while minimizing energy con-
sumption and increasing the selectivity of the product.17,18
Although 1,3-dipolar cycloaddition reactions carried out
under conventional methods have proved to be beneficial
in terms of regio- and stereoselectivity, only a few reports
are available on the use of ultrasonic irradiation in 1,3-
dipolar cycloaddition.19–21
In continuation of our research in the area of 1,3-dipolar
cycloaddition,22–31 we herein report for the first time, the
ultrasonic mediated synthesis of chromeno[4,3-b]pyrroles
using allyl bromides derived from Baylis–Hillman adducts
as dipolarophiles in an intramolecular cycloaddition
reaction.
Treatment of Baylis–Hillman adducts 1a–f with salicyl-
aldehydes 3a–c in the presence of a catalytic amount of
H2SO4 in dichloromethane gave moderate yields of adducts
4a–r (64–74%). However, synthesis of the same products
4a–r could be accomplished in good yields by treating
the allyl derivatives of Baylis–Hillman adducts 2a–f32 with
*
Corresponding author. Tel.: +91 44 22208211; fax: +91 44 22300488.
E-mail address: ragharaghunathan@yahoo.com (R. Raghunathan).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.066

1126
E. Ramesh, R. Raghunathan / Tetrahedron Letters 49 (2008) 1125–1128
OH
OH
X
R1
CHO
3a-c
R
H2SO4 (cat), CH2Cl2
rt
1a-f
R
X
O
H2SO4 (cat)
CH2Cl2
HBr
OH
R1
CHO
R1
CHO
4a-r
X
3a-c
R
Br
K2CO3 / Acetone
R1 = H, Me, Br
2a-f
4a R = H, X=COOCH3, R1= H
4j R = H, X=CN, R1= H
4k R =Cl, X=CN, R1= H
4l R = OMe, X=CN, R1= H
4m R = H, X=CN, R1= Br
4n R = Cl, X=CN,R1= Br
4o R = OMe, X=CN,R1= Br
4p R = OMe, X=CN,R1= OMe
4q R = OMe, X=CN,R1= OMe
4r R = OMe, X=CN,R1= OMe
R = H, X=COOCH3
4b R =Cl, X=COOCH3, R1= H
4c R = OMe, X =COOCH3, R1= H
4d R = H, X=COOCH3, R1= Br
4e R = Cl, X=COOCH3, R1= Br
4f R = OMe, X=COOCH3, R1= Br
R = Cl, X=COOCH3
R = OMe, X=COOCH3
R = H, X=CN
R = Cl, X=CN
4g R = H, X=COOCH3, R1= OMe
4h R = Cl, X=COOCH3, R1= OMe
4i R = OMe, X=COOCH3,R1= OMe
R = OMe, X=CN
Scheme 1.
salicylaldehydes 3a–c in the presence of K2CO3 and dry
acetone (86–94%) in 3 h (Scheme 1).
spectrometry, which showed a peak at m/z 323.15. The
assignment of cis-stereochemistry to the ring junction of
all the cycloadducts was initially made by analogy with
the stereochemistry observed in similar systems.35,36
Further, the X-ray structure of 5b confirmed the cis
stereochemistry at the ring junction (Fig. 1).37
To establish the generality of this cycloaddition reac-
tion, we extended the method to salicylaldehyde derivatives
4j–r containing a –CN moiety using similar conditions to
give a series of cycloadducts 5j–r in moderate to good
yields. The structures and regiochemistry of the cycload-
ducts were similar to those of 5a–i as confirmed by the
spectroscopic data.
To improve the yield, we examined the reaction under
two different conditions. Thus, the reactions of 4a–r with
sarcosine in methanol under reflux afforded cycloadducts
5a–r in 68–78% yields, but required long reaction times
and higher temperature.
When the same reactions were carried out under ultra-
sonic irradiation in methanol at room temperature, there
was a dramatic increase in the yields of the products along
The structural assignments of products 4a–r were based
on the analysis of NMR spectra. Thus compound 4b exhib-
ited a singlet at d 3.79 for the methyl protons of the ester, a
singlet at d 4.88 for the OCH2 protons, a singlet at d 7.19
for the alkene hydrogen and a singlet at d 10.35 for the
aldehyde proton.33 The O-allyl salicylaldehyde derivatives
4a–i were refluxed with sarcosine in anhydrous methanol
to give chromeno[4,3-b]pyrroles in moderate to good yields
(70–78%)34 (Scheme 2).
The structure and the regiochemistry of the cycload-
ducts were confirmed by spectral analysis. The IR spectrum
of 5a showed a sharp peak at 1744 cmÀ1 for the ester car-
1
bonyl. The H NMR spectrum of 5a showed doublets for
each of the OCH2 protons. The NCH2 protons of the pyr-
rolidine protons appeared as doublet of doublets at d 2.95
(J = 9.9, 5.4) and at d 3.38 (J = 9.9, 3.3). The benzylic pro-
ton occurred as a doublet of doublets at d 3.75 (J = 3.3,
5.4) and the ring junction proton appeared as a singlet at
d 3.67. Finally, the structure of 5a was confirmed by mass
R
X
O
O
Method A or B
X
CH3-NH-CH2COOH
H
R1
R1
CHO
H
N
R
5a-r
4a-r
Scheme 2.

E. Ramesh, R. Raghunathan / Tetrahedron Letters 49 (2008) 1125–1128
1127
References and notes
1. Vedejs, E.; Piotrowski, D. W.; Tucci, F. C. J. Org. Chem. 2000, 65,
5498–5505.
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.
4. Coldham, I.; Crapnell, K. M.; Moseley, J. D.; Rabot, R. J. Chem.
Soc., Perkin Trans. 1 2001, 1758–1764.
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,
p 201.
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.
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.
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. Morrocchi, S.; Ricca, A.; Velo, L. Tetrahedron Lett. 1967, 331–334.
18. Levna, I. S.; Morticova, E. I.; Kamernitzky, A. V. Synthesis 1972,
562–563.
19. Okuhawa, F.; Mizuno, N.; Misono, M. Adv. Catal. 1996, 41, 113–114.
20. Misono, M. Catal. Rev. Sci. Engl. 1987, 29, 269–272.
21. Kozhevnikov, I. V. Catal. Rev. Sci. Engl. 1995, 37, 311–352.
22. Poornachandran, M.; Raghunathan, R. Tetrahedron Lett. 2005, 46,
7197–7200.
23. Poornachandran, M.; Raghunathan, R. Tetrahedron 2006, 62, 11274–
11281.
24. Arumugam, N.; Jayashankaran, J.; Rathnadurga, R.; Raghunathan,
R. . Tetrahedron 2005, 61, 8512–8516.
Fig. 1. ORTEP diagram of 5b.
Table 1
Synthesis of chromeno[4,3-b]pyrrole derivatives using methods A and B
Entry
Chromeno [4,3-b]
Method A
Method B
pyrroles
R
X
R1
Time
(h)
Yield
(%)
Time
Yield
(%)
(h)
5a
5b
5c
5d
5e
5f
H
Cl
COOCH3
COOCH3
OMe COOCH3
COOCH3 Br
COOCH3 Br
OMe COOCH3 Br
COOCH3 OMe 7.0
COOCH3 OMe 7.5
OMe COOCH3 OMe 8.0
H
H
H
4.0
4.0
4.5
5.0
5.5
6.5
68
71
78
65
53
51
65
77
73
71
69
71
69
64
73
77
81
78
1.5
3.0
2.5
3.0
3.5
4.5
4.0
5.0
5.5
1.0
3.0
2.5
3.0
3.5
4.5
4.0
5.0
5.5
81
84
85
81
76
71
77
82
85
85
82
89
81
77
78
82
87
89
H
Cl
5g
5h
5i
H
Cl
5j
H
Cl
CN
CN
H
H
H
Br
Br
Br
3.0
4.0
4.5
5.0
5.5
6.0
5k
5l
OMe CN
H
Cl
OMe CN
OMe CN
OMe CN
OMe CN
5m
5n
5o
5p
5q
5r
CN
CN
OMe 7.0
OMe 7.5
OMe 8.0
25. Jayashankaran, J.; Rathnadurga, R.; Raghunathan, R. Tetrahedron
Lett. 2004, 45, 7303–7305.
26. Amalraj, A.; Raghunathan, R.; Sridevikumari, M. R.; Raman, N.
Bioorg. Med. Chem. 2003, 11, 407–419.
27. Subramaniyan, G.; Raghunathan, R.; Martin Castro, A. M. Synthesis
2002, 2440–2445.
28. Subramaniyan, G.; Raghunathan, R. Tetrahedron 2001, 57, 2909–
2913.
29. Amalraj, A.; Raghuanthan, R. Tetrahedron 2001, 57, 10293–10298.
30. Suresh Babu, A. R.; Raghunathan, R. Tetrahedron Lett. 2007, 48,
6809–6813.
31. Ramesh, E.; Kathiresan, K.; Raghunathan, R. Tetrahedron Lett.
2007, 48, 1835–1839.
32. Buchholz, R.; Hoffmann, H. M. R. Helv. Chim. Acta. 1991, 74, 1213–
1221.
33. Spectral data for new compounds: (Z)-methyl 2-((2-formylphenoxy)-
methyl)-3-(phenyl)acrylate 4a: IR (KBr) 1715, 1700 cmÀ1; mp 85 °C;
1H NMR (300 MHz, CDCl3): d 3.85 (s, 3H), 4.99 (s, 2H), 8.09 (s, 1H),
6.96–7.95 (m, 9H), 10.42 (s, 1H). 13C NMR (75 MHz, CDCl3): d 52.4,
63.6, 113.3, 121.2, 125.4, 126.6, 127.1, 128.2, 128.6, 128.7, 128.5,
129.8, 134.2 135.8, 146.0, 160.9, 167.3, 189.6. MS (EI) m/z: 296.10.
Anal. Calcd for C18H16O4: C, 72.97; H, 5.40. Found: C, 72.74;
H, 5.45. (Z)-methyl 2-((2-formylphenoxy)methyl)-3-(4-chlorophenyl)-
acrylate 4b: IR (KBr) 1719, 1707 cmÀ1; mp 116 °C; 1H NMR
Method A: Methanol under reflux.
Method B: Methanol at rt under ultrasonic irradiation.
with a decrease in reaction time. Under these conditions,
cycloadducts were obtained in good yields (81–89%) with
high regio- and stereoselectivity. The results are summa-
rized in Table 1.
In conclusion, we have developed a method for the syn-
thesis of a variety of chromeno[4,3-b]pyrroles by intramo-
lecular 1,3-dipolar cycloaddition using Baylis–Hillman
adducts as dipolarophiles. We found that the reaction
can be more efficiently carried out to give good yields of
products in short reaction times under ultrasonic
irradiation.
Acknowledgements
E.R. thanks CSIR, New Delhi, for fellowships. R.R.
thanks DST, DST-FIST for financial assistance.

1128
E. Ramesh, R. Raghunathan / Tetrahedron Letters 49 (2008) 1125–1128
(300 MHz, CDCl3): d 3.79 (s, 3H), 4.88 (s, 2H), 7.19 (s, 1H), 6.96–7.95
benzylic H, J = 3.3, 5.4 Hz), 4.02 (d, J = 10.8 Hz, 1H, OCH2),
6.81–7.343 (m, 9H). 13C NMR (75 MHz, CDCl3): d 29.7, 39.7, 48.52,
52.0, 52.3, 60.8, 65.8, 67.0, 76.7, 116.9, 119.7, 120.0,127.2, 128.2,
128.83, 129.0, 131.3, 138.0, 154.4, 173.8. MS (EI) m/z = 323.15 (M+)
Anal. Calcd for C20H21NO3: C, 74.30; H, 6.50; N, 4.33. Found: C,
73.83; H, 6.55; N, 4.38. Methyl 3-(4-chlorophenyl)-1,2,3,3a,4,9b-
hexahydro-1-methylchromeno[4,3-b]pyrrole-3a-carboxylate 5b: IR
(KBr): 1706 cmÀ1; mp 210 °C; 1H NMR (300 MHz, CDCl3): 2.51
(s, 3H, –NMe), 2.85 (dd, 1H, J = 9.3, 5.6 Hz), 3.38 (dd, 1H, J = 3.3,
9.3 Hz), 3.63 (d, 1H, –OCH2, J = 10.8 Hz), 3.67 (s, 1H,), 3.62 (s, 3H,
–COOCH3), 3.65 (dd, 1H, benzylic H, J = 3.3, 5.6 Hz), 4.02 (d,
J = 10.8 Hz, 1H, OCH2), 6.81–7.343 (m, 8H). 13C NMR (75 MHz,
(m, 8H), 10.35 (s, 1H). 13C NMR (75 MHz, CDCl3): d 52.3, 68.7,
114.8, 121.6, 126.4, 126.4, 127.6, 128.7, 128.7, 128.0, 130.9, 133.6,
135.2, 135.6, 137.0, 161.2, 167.2, 191.0. MS (EI) m/z = 330.07 Anal.
Calcd for C18H15ClO4: C, 65.36; H, 4.57; Cl, 10.72. Found: C, 65.13;
H, 4.59; Cl, 10.65.
34. Typical procedure: Method A: A solution of (Z)-methyl 2-((2-
formylphenoxy)methyl)-3-(phenyl)acrylate (1 mmol) and sarcosine
(1 mmol), in anhydrous methanol (10 ml), was refluxed. Completion
of the reaction was 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. Method B: A mixture of (Z)-methyl
2-((2-formylphenoxy)methyl)-3-(phenyl)acrylate (1 mmol), sarcosine
(1 mmol), and anhydrous methanol (10 ml), at room temperature was
irradiated by ultrasound until the disappearance of the starting
materials (1 h, 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. Methyl 3-(phenyl)-1,2,3,3a,4,9b-hexahydro-1-methylchromeno-
[4,3-b]pyrrole-3a-carboxylate 5a: IR (KBr): 1706 cmÀ1; mp 122 °C; 1H
NMR (300 MHz, CDCl3): 2.53 (s, 3H, –NMe), 2.95 (dd, 1H, J = 9.9,
5.4 Hz), 3.38 (dd, 1H, J = 3.3, 9.9 Hz), 3.63 (d, 1H, –OCH2,
J = 10.8 Hz), 3.67 (s, 1H,), 3.67 (s, 3H, –COOCH3), 3.75 (dd, 1H,
CDCl3):
d 29.7, 39.7, 47.7, 52.9, 52.4, 60.7, 65.6, 67.0, 76.7,
116.9, 119.4, 120.1, 128.4, 130.2, 131.3, 133.3, 133.0, 136.6, 154.6,
173.6 ppm; MS (EI) m/z: 357.83 (M+) Anal. Calcd for C20H20ClNO3:
C, 67.13; H, 5.63; N, 3.91; Cl, 9.91. Found: C, 67.30; H, 5.74; N, 3.88;
Cl, 9.85.
35. Shengjun Luo, S.; Fang, F.; Zhao, M.; Zhai, H. Tetrahedron 2004, 60,
5353–5355.
36. Confalone, P. N.; Huie, E. M. J. Am. Chem. Soc. 1984, 106, 7175–
7178.
37. The crystal structure of 5b has been deposited at the Cambridge
Crystallographic Data Centre and allocated the deposition number
CCDC 651813.