Novel synthesis of naphtho[2,1-b]pyrano pyrrolizidines and indolizidines through intramolecular 1,3-dipolar cycloaddition reaction

Article abstract of DOI:10.1016/j.tetlet.2010.04.017

A facile synthesis of a series of naphtho[2,1-b]pyrano pyrrolizidines and indolizidines was accomplished in good yields in a one-pot reaction through intramolecular 1,3-dipolar cycloaddition of azomethine ylides with Baylis-Hillman adducts as dipolarophiles. The protocol is applicable to a wide variety of photochromic and biologically active napthopyrano products. The regio and stereochemical outcome of the cycloaddition reaction was ascertained by X-ray crystallographic study of some of the products.

Full text of DOI:10.1016/j.tetlet.2010.04.017

Tetrahedron Letters 51 (2010) 3065–3070
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Tetrahedron Letters
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Novel synthesis of naphtho[2,1-b]pyrano pyrrolizidines and indolizidines
through intramolecular 1,3-dipolar cycloaddition reaction
*
Subban Kathiravan, Devannah Vijayarajan, 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:
A facile synthesis of a series of naphtho[2,1-b]pyrano pyrrolizidines and indolizidines was accomplished
in good yields in a one-pot reaction through intramolecular 1,3-dipolar cycloaddition of azomethine
ylides with Baylis–Hillman adducts as dipolarophiles. The protocol is applicable to a wide variety of pho-
tochromic and biologically active napthopyrano products. The regio and stereochemical outcome of the
cycloaddition reaction was ascertained by X-ray crystallographic study of some of the products.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 13 February 2010
Revised 31 March 2010
Accepted 6 April 2010
Available online 10 April 2010
Keywords:
Pyrrolizidines
Indolizidines
1,3-Dipolar cycloaddition
Azomethine ylides
Baylis–Hillman adduct
The 3H-naphtho[2,1-b]pyran and 3H-naphtho[2,1-b]pyran-
7,10-dione ring systems form the core unit in a number of natural
products.1 Conocurvone which contains the skeleton 3H-naphtho
[2,1-b]pyran-7,10-dione (Fig. 1) is a unique natural product and
possesses remarkable anti-HIVactivity.1a
3H-Naphtho[2,1-b]pyrans are also known to exhibit photochro-
mic properties and found to have wide applications in the manu-
facture of ophthalmic lenses, contact lenses, solar protection
glasses, filters, camera optics, transmission devices, agrochem
films, glazing, decorative objects, and information storage by opti-
cal inscription.2
Indolizidine and pyrrolizidine alkaloids are naturally occurring
N-heterocyclic metabolites which include a large number of com-
pounds that display pronounced biological and pharmacological
activities with therapeutic potential.3 Swainsonine exhibits metas-
tasis and tumor growth control besides immunomodulatory activ-
ity.4 Stellettamide A, a recently discovered indolizidine alkaloid,
has shown antifungal activity and cytotoxicity against K562 epi-
thelium cells.5 The increasing need of indolizidine and pyrrolizi-
dine alkaloids for biological screening makes these heterocyclic
compounds an attractive target in organic synthesis. As a conse-
quence, new and practical methodologies leading to these classes
of molecules are not only desirable but also necessary.
neously constructs two carbon–carbon bonds and forms ring
systems with regio and stereocontrol.6
Although many methods are available for the synthesis of
indolizidine and pyrrolizidines most of them require vigorous reac-
tion conditions and use of an expensive catalyst. Recent synthesis
of pyrrolizidine and indolizidine includes organolanthanide cata-
lyzed intra and intermolecular tandem C–N and C–C bond forming
process,7 conjugate addition of b and
c-chloroamines to acetylenic
sulfones,8 and ring-closing metathesis reactions of
acid.9
L-pyroglutamic
9
10
O
8
1
2
3
7
O
6
O
4
O
5
3H-naptho[2,1-b]pyran 3H-naptho[2,1-b]pyran-7,10-dione
O
OMe
OH
MeO
Intramolecular [3+2] cycloaddition of azomethine ylide has
been used widely to construct complex cyclic systems from rela-
tively simple precursors. This mode of cycloaddition simulta-
O
OH
Biologically active napthopyran natural product
* Corresponding author. Tel.: +91 044 22202811.
E-mail address: ragharaghunathan@yahoo.com (R. Raghunathan).
Figure 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.04.017

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S. Kathiravan et al. / Tetrahedron Letters 51 (2010) 3065–3070
a
-Methylene-b-hydroxy esters are easily accessible by Baylis–
The required Baylis–Hillman adducts 3a–g were prepared by
the direct alkylation of the hydroxynapthaldehyde with Baylis–
Hillman bromides in the presence of K2CO3 and dry acetone
(94%) in 3 h (Scheme 1).
The reaction of secondary amino acids with the aldehydes 3a–g
generates azomethine ylide, which underwent neat 1,3-dipolar
cycloaddition intramolecularly with N-tethered alkenes to give
pyrrolizidines and indolizidines in a one-pot reaction (Scheme 2).
The aldehydes 3a–g derived from Baylis–Hillman bromides
Hillman reaction,10 and are well utilized as versatile building
blocks for the stereoselective construction of natural products
including alkaloids,11 macrolides,12 terpenoids,13 and harmones.14
As part of our ongoing programme for the synthesis of
novel heterocycles through cycloaddition reaction,15 herein we
report an expeditious and facile protocol for the synthesis of
novel napthopyrano pyrrolizidines and indolizidines by intramo-
lecular 1,3-dipolar cycloaddition of azomethine ylides generated
from naptho-O-alkenyl aldehydes prepared from Baylis–Hillman
adducts in a one-pot reaction.
were also condensed with L-proline 4 to generate azomethine
ylides in refluxing toluene under Dean–Stark conditions, which
R2
CHO
COOMe
R1
R
K2CO3
Dry acetone
OH
R
R1
O
CHO
Br
MeOOC
R2
1
2 a-g
3 a-g
R=H, Cl, Br, Me, OMe,
R1=NO2, R2=Cl
Scheme 1. Synthesis of O-alkenyl aldehydes.
R2
R1
R
Condensation
R
O
O
CHO
MeOOC
MeOOC
N
O
R1
COOH
N
H
R2
O
3 a-g
4 or 6
Cyclization
R2
R2
R1
R
R1
O
O
Decarboxylation
MeOOC
MeOOC
R
N
CO2
O
N
O
Cycloaddition
O
H
N
COOMe
H
R2
R
R1
5a-g or 7a-g
Scheme 2. Mechanism for the generation of azomethine ylide and intramolecular 1,3-dipolar cycloaddition reaction.

S. Kathiravan et al. / Tetrahedron Letters 51 (2010) 3065–3070
3067
O
H
R
toluene, heat
O
N
COOH
N
COOMe
CHO
MeOOC
H
R1
H
R2
R2
R
R1
4
5 a-g
3 a-g
R=H, Cl, Br, Me, OMe,
R1=NO2, R2=Cl
Scheme 3. Synthesis of naptho pyrano pyrrolizidine.
Table 1
Synthesis of naptho[2,1-b]pyrano pyrrolizidine derivatives
Entry
Substrate
R
R1
R2
Producta
Time (h)
Yieldb (%)
5a
O
H
N
1
3a
H
H
H
12
90
COOMe
H
H
5b
O
H
N
2
3
4
5
3b
3c
3d
3e
Cl
H
H
H
H
H
H
H
H
12
85
COOMe
Cl
5c
O
H
N
Br
13
12
14
80
COOMe
Br
H
H
H
5d
O
H
N
Me
72
COOMe
Me
5e
O
H
N
OMe
70
COOMe
OMe
(continued on next page)

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S. Kathiravan et al. / Tetrahedron Letters 51 (2010) 3065–3070
Table 1 (continued)
Entry
Substrate
R
R1
R2
Producta
Time (h)
Yieldb (%)
5f
O
H
N
COOMe
6
3f
H
NO2
H
11
92
H
O2N
5g
O
H
N
7
3g
H
H
Cl
11
81
COOMe
H
Cl
a
Isolated products were characterized by 1H NMR, 13C NMR, and mass, spectral analysis.
Yields refer to pure isolated products after purification by silica gel column chromatography.
b
Figure 2. ORTEP diagram of compound 5e.
Figure 3. ORTEP diagram of compound 7c.
underwent intramolecular cycloaddition to give naphthopyrano
pyrrolizidines 5a–g in good yield (Scheme 3, Table 1, entries 1–8).
The formation of the cycloadducts was confirmed through spec-
tral analysis.16 Thus the IR spectrum of 5a showed a sharp peak at
1745 cmÀ1 for the ester carbonyl group. The 1H NMR spectrum of
the 5a exhibited a singlet at d 3.45 for methyl protons of the ester.
The benzylic proton exhibited a doublet at d 6.98 (J = 9.0 Hz) and
the ring junction proton appeared as a singlet at d 5.18. The
–OCH2 protons appeared as two doublets at d 4.20 and 4.79.
Finally, the structure of 5a was confirmed by mass spectrometry,
which showed a peak at m/z 398.83 [M+]. Further, the X-ray struc-
ture17 of 5e confirmed the cis stereochemistry at the ring junction
(Fig. 2).
To establish the generality of this cycloaddition reaction we
extended the method for the synthesis of naptho[2,1-b]pyranoind-
olizidine derivatives using similar reaction conditions. Thus
O
H
R
R1
toluene, heat
O
N
COOMe
CHO
N
COOH
H
H
R2
MeOOC
R2
R
R1
6
7 a-g
3 a-g
R=H, Cl, Br, Me, OMe,
R1=NO2, R2=Cl
Scheme 4. Synthesis of naptho pyrano indolizidine.

S. Kathiravan et al. / Tetrahedron Letters 51 (2010) 3065–3070
3069
Table 2
Synthesis of naptho[2,1-b]pyrano indolizidine derivatives
Entry
Substrate
R
R1
R2
Producta
Time (h)
Yieldb (%)
7a
O
H
N
1
3a
H
H
H
12
88
COOMe
H
7b
O
H
N
2
3
4
5
3b
3c
3d
3e
Cl
H
H
H
H
H
H
H
H
12
13
12
14
86
COOMe
Cl
H
7c
O
H
N
Br
83
78
72
COOMe
Br
H
H
H
H
7d
O
H
N
Me
COOMe
Me
7e
O
H
N
OMe
COOMe
OMe
7f
O
H
N
COOMe
6
3f
H
NO2
H
11
94
O2N
7g
O
H
N
7
3g
H
H
Cl
11
85
COOMe
H
Cl
a
Isolated products were characterized by 1H NMR, 13C NMR, and mass, spectral analysis.
Yields refer to pure isolated products after purification by silica gel column chromatography.
b

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S. Kathiravan et al. / Tetrahedron Letters 51 (2010) 3065–3070
9. Lesma, G.; Colombo, A.; Sacchetti, A.; Silvani, A. J. Org. Chem. 2009, 74, 590–596.
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12. Roush, W. R.; Brown, B. B. J. Org. Chem. 1993, 58, 2151–2161.
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V.; Aebi, M.; Brunnerm, J.; Vasella, A. J. Am. Chem. Soc. 1997, 119, 10992–10999.
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azomethine ylide generated by the condensation of DL-pipecolinic
acid 6 with naphtho-O-alkenyl aldehydes 3a–g underwent smooth
intramolecular cycloaddition reaction in refluxing toluene to afford
the indolizidine derivatives 7a–g in good yield (Scheme 4).
The structures and regiochemistry of the cycloadducts 7a–g
were confirmed by the spectroscopic data, and also by X-ray crys-
tallographic analysis (Fig. 3).18 The reactions were found to be
highly regioselective leading to the formation of only one product
in which ring junction protons were found to be cis. It was
observed that the azomethine ylide generated from the alkenyl
aldehyde with an electron-withdrawing group in the phenyl ring
was found to be more reactive (Table 2, entry 6) than those which
possess electron-donating group (Table 2, entries 4 and 5). How-
ever the yield of the cycloadducts was found to be moderate to
good in all cases irrespective of the nature of the substituent pres-
ent in the phenyl ring (Table 2).
16. Synthesis of naphtho[2,1-b]pyrano pyrrolizidine (5a): Typical procedure:
A
solution of 3a (1 mmol) and
L
-proline 4 (1.5 mmol) was heated under reflux
in toluene in a Dean–Stark apparatus. After completion of the reaction as
evidenced by TLC the solvent was removed under reduced pressure. The crude
product was purified by short column chromatography on silica gel (hexane/
ethyl acetate, 95:5) to provide the product in 94% yield as white solid. Mp 68–
70 °C; 1H NMR (CDCl3, 300 MHz): d 1.06–1.24 (m, 4H); 2.60–2.77 (m, 1H);
2.78–3.03 (m, 1H); 3.45 (s, 3H); 4.18 (s, 2H); 4.20 (d, J = 10.8 Hz, 1H); 4.79 (d,
J = 10.8 Hz, 1H); 5.18 (s, 1H); 6.98–8.23 (m, 12 H); 13C NMR (CDCl3, 75 MHz); d
31.13, 49.83, 51.33, 54.68, 58.94, 63.34, 67.48, 110.44, 117.22, 122.69, 122.83,
126.04, 126.13, 127.12, 127.28, 127.89, 128.12, 128.63, 132.49, 135.32, 150.94,
172.30. m/z 398.83 [M+]. Anal. Calcd for C26H25NO3: C, 78.19; H, 6.26; N, 3.50.
Found: C, 78.30; H, 6.19; N, 3.58.
In conclusion, we have developed a new method for the synthe-
sis of a variety of naphthopyranoindolizidines and pyrrolizidines
by intramolecular 1,3-dipolar cycloaddition using the Baylis–Hill-
man adducts as internal dipolarophiles.
Acknowledgments
Naphtho[2,1-b]pyrano pyrrolizidine (5c): white solid. Mp 120–122 °C; 1H NMR
(CDCl3, 300 MHz): d 1.71–1.81 (m, 2H); 2.65–2.70 (m, 1H); 2.84–2.93 (m, 1H);
3.54 (s, 3H); 3.60 (s, 1H); 4.19–4.28 (s, 3H); 4.26 (d, J = 10.8 Hz, 1H); 4.81 (d,
J = 10.8 Hz, 1H); 5.24 (s, 1H); 7.06–8.30 (m, 10 H); 13C NMR (CDCl3, 75 MHz); d
26.52, 31.96, 51.17, 54.25, 55.12, 59.86, 63.45, 68.37, 111.48, 118.26, 133.54,
123.83, 127.15, 128.23, 129.78, 131.44, 131.66, 135.46, 151.98, 173.19, m/z
477.12 [M+]. Anal. Calcd for C26H24NO3Br: C, 65.27; H, 5.02; N, 2.92. Found: C,
65.33; H, 4.99; N, 2.99.
S.K. thanks the Council of Scientific and Industrial Research
(CSIR) for the award of Senior Research Fellowship (SRF). R.R.
thanks DST-FIST New Delhi for NMR facility and DST for financial
assistance.
References and notes
Naptho[2,1-b]pyrano indolizidine (7a): Colorless solid, Mp 156–158 °C; 1H NMR
(CDCl3, 300 MHz): d 2.82–2.86 (m, 1H); 2.95–2.99 (m, 1H); 3.09–3.14 (m, 1H);
3.29–3.35 (m, 1H); 3.58 (s, 3H); 3.82 (d, J = 5.4 Hz, 1H); 4.00–4.12 (m, 3H);
4.28–4.37 (m, 1H); 4.49–4.53 (m, 1H); 4.61–4.72 (m, 2H); 5.12 (s, 1H); 7.04–
8.33 (m, 11H); 13C NMR (CDCl3, 75 MHz); d 39.85, 52.54, 53.67, 57.46, 58.22,
64.99, 71.81, 111.48, 118.77, 121.94, 123.39, 123.78, 127.01, 127.31, 127.56,
127.94, 128.52, 128.62, 128.74, 129.15, 130.18, 133.55, 133.83, 133.62, 135.70,
152.53, 172.05. m/z 412.73 [M+]. Anal. Calcd for C27H27NO3: C, 70.45; H, 6.53;
N, 3.38. Found: C, 70.55; H, 6.47; N, 3.46.
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Naptho[2,1-b]pyrano indolizidine (7c): Colorless solid, Mp 172–174 °C; 1H NMR
(CDCl3, 300 MHz): d 1.01–1.16 (m, 4H); 1.26–1.42 (m, 3H); 1.51–1.53 (m, 1H);
2.865–2.88 (m, 1H); 2.99–3.05 (m, 1H); 3.67 (d, J = 12.0 Hz, 1H); 3.75 (s, 3H);
4.02 (d, J = 11.7 Hz, 1H); 5.75 (s, 1H); 7.15 (m, 10H); 13C NMR (CDCl3, 75 MHz);
d 22.72, 25.31, 30.32, 49.05, 52.61, 57.85, 59.47, 63.52, 69.96, 116.51, 118.56,
121.31, 122.75, 123.84, 126.37, 128.88, 129.13, 129.68, 131.53, 131.81, 133.91,
135.93, 156.39, 174.43, m/z 467.14 [M+]. Anal. Calcd for C25H26NO3Br: C, 71.77;
H, 5.55; N, 2.99. Found: C, 71.89; H, 5.49; N, 3.06.
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