Formal [6+3] cycloaddition of fulvenes with 2H-azirine: A facile approach to the [2]pyrindines system

Article abstract of DOI:10.1016/j.tetlet.2003.12.105

2H-Azirine reacts with fulvenes to give either alkylated fulvene azirines (ultrasound) or the formal [6+3] cycloaddition adducts (Lewis acid). The later constitutes an efficient and novel route to [2]pyrindines.

Full text of DOI:10.1016/j.tetlet.2003.12.105

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1663–1666
Formal [6+3] cycloaddition of fulvenes with 2H-azirine: a facile
approach to the [2]pyrindines systemq
Bor-Cherng Hong,* Arun Kumar Gupta, Ming-Fun Wu and Ju-Hsiou Liao
Department of Chemistry and Biochemistry, National Chung Cheng University, Chia-Yi 621, Taiwan, ROC
Received 20 November 2003; revised 16 December 2003; accepted 18 December 2003
Abstract—2H-Azirine reacts with fulvenes to give either alkylated fulvene azirines (ultrasound) or the formal [6+3] cycloaddition
adducts (Lewis acid). The later constitutes an efficient and novel route to [2]pyrindines.
Ó 2003 Elsevier Ltd. All rights reserved.
The theoretical, mechanistic, and synthetic importance
of fulvene and its derivatives has intrigued chemists for
more than a century.1 Cycloadditions of fulvenes (e.g.,
[4+3],2 [2+2],3 [4+2],4 [2+4],5 [6+4],6 [6+2]7) provide
versatile and powerful approaches to various polycyclic
systems and natural products. Recently, we reported a
new type of reaction: the [6+3] cycloaddition of ful-
venes8 for the facile synthesis of indane derivatives.9
More recently, Barluenga et al. demonstrated that the
[6+3] cycloaddition of chromium alkenyl carbene com-
plexes with fulvene leads to indanes.10 Additionally, we
recently reported the novel hetero [6+3] cycloaddition of
fulvenes for the synthesis of 11-oxasteroids11 and hetero
[6+3] cycloaddition of fulvenes with N-alkylidene gly-
cine esters.12 In conjunction with our continuing efforts
in fulvene chemistry,13 we have now developed a formal
[6+3] cycloaddition of fulvenes and 2H-azirine that
yields [2]pyrindines. [2]Pyrindine systems can be
found in a variety of natural products including incar-
villine,14 incarvine A,15 scaevodimerine A,16 louisianin
C,17 altemicidin18, racemigerine,19 kopsirachin,20
(Scheme 1).
O
O
H
N
O
H
MeO2C
MeO2C
HO
N
N
H
N
H
N
N
Racemigerine
Louisianin C
Incarvilline
Scaevodimerine A
H
H2N
O
OH
O
S
MeN
OH
O
NMe
O
H
HO
Me
H
O
NH
N
CO2H
OH
O
O
H
H
MeN
OH
OH
H
Incarvine A
NMe
CONH2
Altemicidin
Kopsirachin
Scheme 1.
Keywords: Cycloaddition; Fulvene; Azirine; Pyrindines.
q Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.tetlet.2003.12.105
* Corresponding author. Tel.: +886-5-2428174; fax: +886-5-2721040; e-mail: chebch@ccunix.ccu.edu.tw
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.105

1664
B.-C. Hong et al. / Tetrahedron Letters 45 (2004) 1663–1666
The cycloaddition and regioselective ring cleavage of
2H-azirines is known to give rise to reactive species such
as vinylnitrenes, iminocarbenes, and nitrile ylides.21
These versatile 2H-azirines can act as nucleophiles,
electrophiles, dienophiles, and dipolarophiles in cyc-
loadditions. Yet the cycloaddition of 2H-azirines with
polyenes has received little attention; only one example
of a [6+3] cycloaddition of cycloheptatriene and
2H-azirine has been reported.22
We suspected that the addition of 2H-azirine to fulvene
would afford the hetero [6+3] cycloadduct and provide a
novel route to the [2]pyrindine skeleton. The azirines
were prepared from the corresponding methyl-1-azido
cinnamates (heptane, heat, 2–4 h),23 and the crude
product was used without further purification. In a
model study, dimethyl fulvene (1a) and crude azirine 2
were stirred in dry THF for 3 days to afford [2]pyrindine
4a as the only isolable product (19% yield) and recov-
ered starting fulvene. The yield of 4a was improved to
83% in the presence of 20 mol % of Y(OTf)3 in THF.
1
The structure of 4a was assigned based on IR, H, 13C
Figure 1. ORTEP plots for X-ray crystal structures of 6 and 7.
NMR, COSY, DEPT, HMQC HMBC, MS, and HRMS
analysis. [2]Pyrindine 4a proved unstable and gradually
converted to 5a after a few days in the refrigerator. This
isomerization is accelerated in the presence of Et3N in
CH2Cl2 at ambient temperature. The formation of 4a
maybe rationalized via the stepwise mechanism shown
in Scheme 2. Initial addition of the fulvene to the acti-
vated 2H-azirine generates the zwitterionic intermediate,
which cyclizes to [2]pyrindine 4a. Unlike the typical
concerted 1,3-dipolar reaction of N-alkylidene glycine
ester with fulvenes,12 the addition of 2H-azirines to
fulvenes occurs most likely via a stepwise mechanism.
Such behavior is a direct result of the ambient nature of
2H-azirines, and can be attributed to the high ring
strain, reactive p-bond and the nitrogen lone pair. On
the other hand, reaction of fulvene 1a and azirine 2 in an
ultrasonic bath (neat, RT, 2 days) yielded the alkylation
product 3a. Although unexpected and unprecedented, it
is possible that the initial Diels–Alder adduct of 1a and 2
rearranges to give 3a (Scheme 3). The structure of 3a
was unambiguously assigned by the single crystal X-ray
analysis of its DIBAL-H reduction product 6 (Fig. 1).24
A series of homologous fulvenes were then reacted with
2H-azirine to afford the corresponding [2]pyrindines,
(entries 2–7, Table 1).25 Interestingly, fulvenes 1e and 1f
afforded 4 as the only product regardless of the method
used. The structure of 5f was unambiguously assigned
by the single crystal X-ray analysis of its p-bromo-
benzoate derivative 7 (Fig. 1).26 The two-step transfor-
mation of 1 to 5 can be carried out in one-pot by
addition of excess of Et3N after formation of adduct 4.
Reaction of monosubstituted fulvene 1g with 2H-azirine
gave 4g in 85% (Method C), which gave 5g in THF at
ambient temperature for 36 h (Method E). 5g was
Cl
Cl
R
R
Cl
R
Cl
R
R
R
R
R
2
H3CO2C
N
N δ+
1
NH
CO2CH3
N
4
H3CO2C
M
M
H2O
CO2CH3
HO
Scheme 2.
R
R
R
N
R
R
R
N
R
R
H3CO2C
R
H
N
MeO2C
Cl
N
Cl
Cl
+
CO2CH3
MeO2C
N
R
MeO2C
3
H
1
2
Cl
Cl
Scheme 3.

B.-C. Hong et al. / Tetrahedron Letters 45 (2004) 1663–1666
Table 1. Reaction of fulvenes with 2H-azirines
1665
Cl
Cl
R1
R2
Cl
R1
R2
R1
N
R2
NH
R1
R2
Et3N
RT or
Y(OTf)3
[6+3]
Cl
NH
+
CO2CH3
Ultrasound
N
HO CO2CH3
CO2CH3
H3CO2C
3
1
5
4
2
Entry
1
Fulvene
Product
Method
Time (h)
Yield (%)a
Me
R1 ¼ R2 ¼ Me, 4a
R1 ¼ R2 ¼ Me, 3a
R1 ¼ R2 ¼ Me, 4a
R1 ¼ R2 ¼ Me, 5a
A
B
72
48
12
0.5
19b
75c
83d
100
Me
C
D
1a
2
3
4
R1 ¼ R2 ¼ Et, 3b
R1 ¼ R2 ¼ Et, 3b
R1 ¼ R2 ¼ Et, 4b
R1 ¼ R2 ¼ Et, 5b
A
B
72
48
15b
62c
68d
100
C
D
12
0.25
1b
R1 ¼ R2 ¼ C3H7, 3c
R1 ¼ R2 ¼ C3H7, 3c
R1 ¼ R2 ¼ C3H7, 4c
R1 ¼ R2 ¼ C3H7, 5c
A
B
72
48
12
0.5
23b
71c
74d
100
C
D
1c
27b
75c
80d
100
ꢀ
R1 ¼ R2 ¼ –(CH2)5 , 3d
A
B
72
48
12
0.5
ꢀ
R1 ¼ R2 ¼ –(CH2)5 , 3d
ꢀ
R1 ¼ R2 ¼ –(CH2)5 , 4d
C
D
ꢀ
R1 ¼ R2 ¼ –(CH2)5 , 5d
1d
35b
Ph
5
6
7
Ph
R1 ¼ R2 ¼ Ph, 4e
R1 ¼ R2 ¼ Ph, 4e
R1 ¼ R2 ¼ Ph, 4e
R1 ¼ R2 ¼ Ph, 5e
A
B
72
120
12
N.R.
85d
C
D
1e
0.25
100
23b
Cl
R1 ¼ R2 ¼ p-ClC6H4, 4f
R1 ¼ R2 ¼ p-ClC6H4, 4f
R1 ¼ R2 ¼ p-ClC6H4, 4f
R1 ¼ R2 ¼ p-ClC6H4, 5f
A
B
72
Cl
120
12
N.R
85d
100
C
D
0.5
1f
30b
32b
85d
93
Ph
H
R1 ¼ H, R2 ¼ Ph, 3g:4g (4:1)
R1 ¼ H, R2 ¼ Ph, 3g:4g (4:1)
R1 ¼ H, R2 ¼ Ph, 4g
A
B
C
E
F
72
72
12
36
36
1g
R1 ¼ H, R2 ¼ Ph, 5g
R1 ¼ H, R2 ¼ Ph, 8
85
a Isolated yield based on starting azirine.
b Only isolated product, fulvene SM was recovered. The 2H-azirine decomposed and prolonged reaction time did not increase the yield.
c No 4 was observed.
d No 3 was observed. Method A: THF, 25 °C. Method B: neat, ultrasound, 25 °C. Method C: 20 mol % Y(OTf)3, THF, 25 °C. Method D: start from
4, Et3N, CH2Cl2, 25 °C. Method E: start from 4, THF, 25 °C. Method F: start from 5, Et3N, CH2Cl2, 25 °C.
converted to 8 after reaction with Et3N in CH2Cl2
(Method F).
In summary, we have developed a novel synthesis
of [2]pyrindine derivatives via a regioselective one-
pot hetero [6+3] cycloaddition of 2H-azirine to ful-
venes. We are currently pursuing the application of
this methodology to the solid-phase synthesis of
Cl
Ph
N
a large [2]pyrindine library and other natural
products.
8
CO2Me

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B.-C. Hong et al. / Tetrahedron Letters 45 (2004) 1663–1666
S. J. Chem. Soc., Perkin Trans. 1 1999, 1135–1137; (f)
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References and notes
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(a) Hong, B. C.; Shr, Y. J.; Wu, J. L.; Gupta, A. K.; Lin,
K. J. Org. Lett. 2002, 4, 2249–2252; (b) For an example of
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K. Tetrahedron Lett. 1977, 2453–2456; (c) Wu, T. C.;
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23. Knittel, D. Synthesis 1985, 2, 186–188.
24. Crystallographic data for 6: C17H20ClNO, M ¼ 289.79,
monoclinic, space group P21=c, T ¼ 298 K, a ¼ 8:925ð2Þ,
ꢁ
b ¼ 9:141ð2Þ, c ¼ 19:223ð5Þ A, b ¼ 97:949ð5Þ°, V ¼
3
1553:1ð7Þ A , Z ¼ 4, D ¼ 1:239 g/cm3,
k
(Mo-Ka) ¼
ꢁ
ꢁ
0.71073 A, 9179 reflections collected, 3618 unique reflec-
tions, 189 parameters refined on F 2, R ¼ 0:0623,
wR2½F 2ꢁ ¼ 0:1143 [3618 data with F 2 > 2rðF 2Þ].
9. For a recent review on the synthesis of indane systems, see:
Hong, B.-C.; Sarshar, S. Org. Prep. Proced. Int. 1999, 31,
1–86.
25. All new compounds were fully characterized by 1H NMR,
13C NMR, DEPT, IR, MS, and HRMS. In most cases
COSY and HMQC spectra were also obtained. Yields
refer to spectroscopically and chromatographically homo-
geneous (>95%) materials.
ꢀ
ꢀ
10. Barluenga, J.; Martinez, S.; Suarez-Sobrino, A. L.; Tomas,
M. J. Am. Chem. Soc. 2001, 123, 11113–11114.
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2647–2649.
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G.-H. Org. Lett. 2003, 5, 1689–1692.
26. Compound 7 was prepared from 5f with p-BrC6H4COCl,
Et3N, DMAP, CH2Cl2; 90% yield. Crystallographic data
for 7: C35H23BrCl3NO3, M ¼ 691.80, monoclinic, space
13. For previous papers in this series, see: (a) Hong, B.-C.;
Shr, Y.-J.; Liao, J.-H. Org. Lett. 2002, 4, 663–666; (b)
Hong, B.-C.; Shen, I.-C.; Liao, J.-H. Tetrahedron Lett.
2001, 42, 935–938; (c) Hong, B.-C.; Jiang, Y.-F.; Kumar,
E. S. Bioorg. Med. Chem. Lett. 2001, 11, 1981–1984; (d)
Hong, B.-C.; Sun, H.-I.; Chen, Z.-Y. Chem. Commun.
1999, 2125–2126; (e) Hong, B.-C.; Chen, Z.-Y.; Kumar, E.
group P21=n, T ¼ 298 K, a ¼ 10:1791ð7Þ, b ¼ 20:1109ð13Þ,
3
ꢁ
ꢁ
c ¼ 15:2109ð10Þ A, b ¼ 92:063ð2Þ°, V ¼ 3111:8ð4Þ A , Z ¼
3
ꢁ
4, D ¼ 1:477 g/cm , k (Mo-Ka) ¼ 0.71073 A, 19,116 reflec-
tions collected, 7267 unique reflections, 389 parameters
refined on F 2, R ¼ 0:0574, wR2½F 2ꢁ ¼ 0:1114 [3612 data
with F 2 > 2rðF 2Þ].