An efficient access to 4-alkylidene-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3] triazoles

Article abstract of DOI:10.1055/s-2006-939708

From alkylidenecyclopropanes (MCPs), 4-alkylidene-5,6-dihydro-4H-pyrrolo- [1,2-c][1,2,3]triazoles 6 were prepared in moderate yields through diiodogenation, Cu(I)-catalyzed 1,3-dipolar cycloaddition and subsequent intramolecular Heck reaction. Georg Thiem

Full text of DOI:10.1055/s-2006-939708

1446
LETTER
An Efficient Access to 4-Alkylidene-5,6-dihydro-4H-
pyrrolo[1,2-c][1,2,3]triazoles
A
ccess to 4-Alkylidene-
a
5,6-dihydr
o
n
-4
H
-pyrrolo
-
[
1,2-
c
][1
l
,2,3]tri
i
a
zoles Chen,a Chen-liang Su,a Xian Huang*a,b
a
Department of Chemistry, Zhejiang University (Campus Xixi), Hangzhou 310028, P. R. of China
Fax +86(571)88807077; E-mail: huangx@mail.hz.zj.cn
b
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, P. R. of China
Received 22 January 2006
According to the above synthetic route, herein we wish to
report an efficient synthesis of 4-alkylidene-5,6-dihydro-
4H-pyrrolo[1,2-c][1,2,3]triazoles 6 through the Cu(I)-cat-
alyzed regioselective 1,3-dipolar cycloaddition followed
by an intramolecular Heck reaction from (Z)-2,4-di-
halobutenes in moderate yields.
Abstract: From alkylidenecyclopropanes (MCPs), 4-alkylidene-
5,6-dihydro-4H-pyrrolo-[1,2-c][1,2,3]triazoles 6 were prepared in
moderate yields through diiodogenation, Cu(I)-catalyzed 1,3-di-
polar cycloaddition and subsequent intramolecular Heck reaction.
Key words: 1,2,3-trizaole, alkylidenecyclopropanes (MCPs), 1,3-
dipolar cycloaddition, Heck reaction
The various (Z)-2,4-diiodobutenes 2 could be convenient-
ly prepared by CuX2-mediated dihalogenation of MCPs
1.6 By refluxing (Z)-2,4-diiodobutenes with NaN3 and
subsequent Cu(I)-catalyzed regioselective 1,3-dipolar
cycloaddition,4 3-iodo-3-butenyl-1H-[1,2,3]triazoles 5
were obtained at moderate yields in one pot (Scheme 1).8,9
The results are summarized in Table 1.
Pyrrolotriazoles are an important class of heterocycles
due to their applications as bioactive compounds and syn-
thetic intermediates in organic synthesis.1 However, there
are only limited reports about their synthesis with sub-
stituent groups and they involve thermal intramolecular
cycloaddition.2,3 Thus, there is a need to develop new
methodology for the efficient synthesis of these com-
pounds with different substituent groups.
R1
R1
NaN3
CuI–I2
I
MeCN
I
R2
R2
95% EtOH
reflux
1
2
Recently, Cu(I)-catalyzed one-pot synthesis of 1,4-disub-
stituted 1,2,3-triazoles derived from organic azides gener-
ated in situ from halides and inorganic azides with alkynes
has enjoyed considerable use since its discovery.4 During
our study of methylenecyclopropanes (MCPs),5 we found
that CuX2-mediated dihalogenation of MCPs 1 offered a
stereoselective synthesis of (Z)-2,4-dihalobutenes.6 These
dihalobutenes, containing a homoallylic halogen and a
vinyl halogen, may react with various reagents and can be
used as building blocks for further organic transforma-
tions.6,7 Retrosynthetically, pyrrolotriazoles could be
prepared by scission of the C–C bond of the pyrrole to the
triazole containing a vinyl iodide. This triazole could be
obtained by a dipolar cycloaddition of the pendant azide,
which in turn could be synthesized from (Z)-2,4-di-
halobutenes (Figure 1).
N
R1
R2
R1
R2
(4)
ascorbate
R3
N
N
N3
I
I
H2O,
R3
CuSO
4, 70 °C
3
5
Scheme 1
Next, we carried out the Heck-type10 reactions of 1,4-di-
substituted 1,2,3-triazoles 5a–l. Initially, we tested the
reaction of 4-butyl-1-(3-iodo-4,4-diphenyl-but-3-enyl)-
1H-[1,2,3]triazole (5a) with 10 mol% of Pd(OAc)2 and 2
equivalents of Et3N at 85 °C in acetonitrile. After work-up
and isolation, the product 6a was obtained in 71% yield
(Scheme 2).
R1
N
Pd(OAc)2
N
Ph
Ph
N
N
N
N
R2
N
N
N
Ph
Ph
I
R1
R2
N
N
Et3N
MeCN
85 °C
I
N
Bu
R3
R3
Bu
5a
6a 71%
R1
R2
R1
R2
I
N3
I
Scheme 2
I
Figure 1
1
The structure was assigned on the basis of its H NMR,
13C NMR, and IR spectra, MS data and microanalyses.
Further screening demonstrated that DMF as the solvent,
NaHCO3 as the base were more suitable for this reaction
SYNLETT 2006, No. 9, pp 1446–1448
Advanced online publication: 26.04.2006
DOI: 10.1055/s-2006-939708; Art ID: W02106ST
© Georg Thieme Verlag Stuttgart · New York
0
1.
0
6.
2
0
0
6

LETTER
Access to 4-Alkylidene-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazoles
1447
Table 1 Synthesis of 3-Iodo-3-butenyl-1H-[1,2,3]triazole 5a
Table 2 Synthesis of 4-Alkylidene-5,6-dihydro-4H-pyrrolo[1,2-
c][1,2,3]triazoles 6a
Entry R1/R2 (2)
R3 (4)
Time Yield
Pd(OAc)2
NaHCO3
(h)
18
17
(%)a
R1
R2
N
N
N
R1
R2
N
N
Bu4N+Cl–
DMF 100 °C
1
2
Ph/Ph (2a)
Bu (4a)
5a (65)
5b (62)
5c (51)
5d (70)
5e (63)
5f (60)
5g (57)
5h (62)
5i (61)
5j (59)
5k (60)
5l (62)
I
N
R3
2a
2a
2a
C5H11 (4b)
R3
Entry R1/R2/R3
Time (h) Yield (%)a
3
MeOCH2 (4c) 18
4
Ph (4d)
15
20
20
19
19
17
15
16
15
1
2
3
4
5
6
7
8
Ph/Ph/Bu (5a)
20
20
19
21
22
23
22
20
6a (82)
6b (85)
6c (52)
6e (82)
6f (58)
6g (68)
6h (70)
6i (71)
5
p-ClC6H4/p-ClC6H4 (2b) 4a
Ph /Ph/C5H11 (5b)
6
2b
4b
4a
4b
4b
4a
4b
4d
Ph /Ph/MeOCH2 (5c)
7
p-FC6H4/p-FC6H4 (2c)
p-ClC6H4/p-ClC6H4/Bu (5e)
p-ClC6H4/p-ClC6H4/C5H11 (5f)
p-FC6H4/p-FC6H4/Bu (5g)
p-FC6H4/p-FC6H4/C5H11 (5h)
Me/Ph/C5H11 (5i)
8
2c
9
Me/Ph (2d)
10
11
12
H/p-ClC6H4 (2e)
2e
2e
a Overall yields based on 5.
a Overall yield based on 2.
Acknowledgment
and the yield of 6a could increase to 82% (Table 2, entry
1). With this result in hand, we then carried out the reac-
tions of various 1,4-disubstituted 1,2,3-triazoles 5 in the
presence of 10 mol% Pd(OAc)2 under the optimized con-
ditions.11 The results were summarized in Table 2. Using
this method, we obtained the new pyrrolotriazole ring sys-
tem incorporating an exocyclic double bond and the con-
figuration of the double bond was retained through the
Heck reaction. However, when substrates containing a
vinyl hydrogen were employed (5j–l), only the elimina-
tion products (7a–c) were obtained (Scheme 3). This
showed that the intramolecular elimination reaction oc-
curred more readily than the Heck reaction and could be
used to access triazoles incorporating a homopropargyl
substituent.
This work was supported by the National Natural Science Founda-
tion of China (20332060, 20472072) and Academician Fundation of
Zhejiang Province.
References and Notes
(1) (a) Pearson, W. H.; Bergmeier, S. C.; Chytra, J. A. Synthesis
1990, 156. (b) Dulcere, J. P.; Tawil, M.; Santelli, M. J. Org.
Chem. 1990, 55, 571. (c) Pearson, W. H.; Bergmeier, S. C.;
Degan, S.; Lin, K. C.; Poon, Y. F.; Schkeryantz, J. M.;
Williams, J. P. J. Org. Chem. 1990, 55, 5719. (d) Marco-
Contelles, J.; Rodríguez-Fernández, M. J. Org. Chem. 2001,
66, 3717.
(2) Marei, M. G.; El-Ghanam, M.; Salem, M. M. Bull. Chem.
Soc. Jpn. 1994, 67, 144.
(3) (a) Mukai, C.; Kobayashi, M.; Kubota, S.; Takahashi, Y.;
Kitagaki, S. J. Org. Chem. 2004, 69, 2128. (b) Guerin, D.
J.; Miller, S. J. J. Am. Chem. Soc. 2002, 124, 2134.
(4) (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless,
K. B. Angew. Chem. Int. Ed. 2002, 41, 2596. (b) Feldman,
A. K.; Colasson, B.; Fokin, V. V. Org. Lett. 2004, 6, 3897.
(c) Appukkuttan, P.; Dehaen, W.; Fokin, V. V.; Van der
Eycken, E. Org. Lett. 2004, 6, 4223. (d) Kacprzak, K.
Synlett 2005, 943. (e) Akula, R. A.; Temelkoff, D. P.; Artis,
N. D.; Norris, P. Heterocycles 2004, 63, 2719.
In summary, we have developed an efficient method for
the preparation of 4-alkylidene-5,6-dihydro-4H-pyrrolo-
[1,2-c][1,2,3]triazoles and 1H-[1,2,3]triazoles incorporat-
ing a homopropargyl group in moderate yields. It is ex-
pected that this kind of pyrrolotriazole derivatives could
be used as bioactive compounds and synthetic intermedi-
ates.1 Further application of this synthetic methodology is
being investigated in our laboratory.
(5) (a) Huang, X.; Chen, W. L.; Zhou, H. W. Synlett 2004, 329.
(b) Huang, X.; Zhou, H.; Chen, W. J. Org. Chem. 2004, 69,
839. (c) Chen, W.; Huang, X.; Zhou, H. Synthesis 2004,
1573. (d) Zhou, H.; Huang, X.; Chen, W. J. Org. Chem.
2004, 69, 5471. (e) Chen, W.; Huang, X.; Zhou, H.; Ren, L.
Synthesis 2006, 609. (f) For synthesis of MCPs, see: Brandi,
A.; Goti, A. Chem. Rev. 1998, 98, 589. For recent reviews,
see: (g) Nakamura, I.; Yamamoto, Y. Adv. Synth. Catal.
2002, 344, 111. (h) Brandi, A.; Cicchi, S.; Cordero, F. M.;
Goti, A. Chem. Rev. 2003, 103, 1213. (i) Nakamura, E.;
H
N
N
N
N
p-ClC6H4
N
I
N
p-ClC6H4
R3
R3
R
3 = Bu
(5j)
82%
7a
7b
7c
C5H11
(5k)
(5l)
80%
85%
Ph
Scheme 3
Synlett 2006, No. 9, 1446–1448 © Thieme Stuttgart · New York

1448
W.-l. Chen et al.
LETTER
Yamago, S. Acc. Chem. Res. 2002, 35, 867. See also:
(j) Nakamura, I.; Oh, B. H.; Saito, S.; Yamamoto, Y. Angew.
Chem. Int. Ed. 2001, 40, 1298. (k) Oh, B. H.; Nakamura, I.;
Saito, S.; Yamamoto, Y. Tetrahedron Lett. 2001, 42, 6203.
(l) Camacho, D. H.; Nakamura, I.; Saito, S.; Yamamoto, Y.
J. Org. Chem. 2001, 66, 270. (m) Yamago, S.; Nakamura,
E. J. Org. Chem. 1990, 55, 5553. (n) Yamago, S.;
Yanagawa, M.; Nakamura, E. Chem. Lett. 1999, 879.
(o) Lautens, M.; Han, W.; Liu, J. H.-C. J. Am. Chem. Soc.
2003, 125, 4028. (p) Shi, M.; Chen, Y.; Xu, B. Org. Lett.
2003, 5, 1225. (q) Shi, M.; Xu, B. Tetrahedron Lett. 2003,
44, 3839. (r) Chen, Y.; Shi, M. J. Org. Chem. 2004, 69, 426.
(10) (a) Heck, R. F. J. Am. Chem. Soc. 1968, 90, 5518. (b)Tsuji,
J. Palladium Reagents and Catalysts; Wiley: New York,
1995. Reviews: (c) de Meijere, A.; Meyer, F. E. Angew.
Chem., Int. Ed. Engl. 1994, 33, 2379. (d) Cabri, W.;
Candiani, I. Acc. Chem. Res. 1995, 28, 2. (e) Crisp, G. T.
Chem. Soc. Rev. 1998, 27, 427. (f)Geret, J. P.; Savignac, M.
J. J. Organomet. Chem. 1999, 576, 305. (g) Beletskaya, I.
P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009. (h) For a
recent mechanistic study on Heck-type reaction see:
Amatorc, C.; Jutand, A. J. Organomet. Chem. 1999, 576,
254.
(11) Typical Procedure for the Synthesis of 6.
Compound 5 (0.25 mmol), Pd(OAc)2 (0.025 mmol),
tetrabutylammonium chloride (TBAC, 0.25 mmol),
NaHCO3 (0.5 mmol), and N,N-dimethylformamide (DMF,
1 mL) were added into a Schlenk tube at r.t. The reaction
mixture was stirred at 100 °C until the reaction was
complete, as monitored by TLC. Then the reaction mixture
was cooled and H2O (15 mL) was added. The aqueous layer
was extracted with EtOAc (3 × 15 mL). The organic layer
was dried over anhyd MgSO4. After evaporation, the residue
was subjected to preparative TLC (eluent: PE–EtOAc, 1:6
to 1:3) to afford 4-alkylidene-5,6-dihydro-4H-pyrrolo-
[1,2-c][1,2,3]-triazoles 6.
(6) Zhou, H. W.; Huang, X.; Chen, W. L. Synlett 2003, 2080.
(7) (a) Shi, M.; Shao, L.-X. Synlett 2004, 807. (b) Shi, M.; Liu,
L. P.; Tang, J. Org. Lett. 2005, 7, 3085.
(8) Typical Procedure for the Synthesis of 5.
To a stirred 95% EtOH (2 mL) solution of NaN3 (0.6 mmol),
2 (0.5 mmol) was added and the reaction mixture was stirred
under reflux until the reaction was complete, as monitored
by TLC. Then, H2O (4 mL), ascorbic acid (0.1 g, 0.56
mmol), NaOH (0.022 g, 0.56 mmol), CuSO4 (0.01 g, 0.04
mmol), and alkyne 4 (0.6 mmol) were added and heated
together at 70 °C until the reaction was complete (monitored
by TLC). Afterwards, the mixture was cooled to r.t. and H2O
(15 mL) was added. The aqueous layer was extracted with
EtOAc (3 × 15 mL). The organic layer was dried over anhyd
MgSO4. After evaporation, the residue was subjected to
preparative TLC (eluent: PE–EtOAc, 1:6 to 1:3) to afford
1,4-disub-stituted 1,2,3-triazoles 5.
Selected Data.
Compound 6a: solid, mp 124–126 °C. IR: 2948, 2924, 1440,
764, 703 cm–1. 1H NMR (400 MHz, CDCl3): d = 0.74 (t, 3 H,
J = 7.26 Hz), 0.92–1.00 (m, 2 H), 1.20–1.28 (m, 2 H), 1.49
(t, 2 H, J = 7.45 Hz), 3.51 (t, 2 H, J = 6.89 Hz), 4.36 (t, 2 H,
J = 6.89 Hz), 7.18–7.38 (m, 10 H). 13C NMR (100 MHz,
CDCl3): d = 141.97, 141.94, 141.30, 138.43, 137.67, 129.92,
129.18, 128.72, 128.21, 127.86, 127.70, 123.51, 45.24,
37.50, 31.62, 25.35, 22.28, 13.76. MS (EI, 70 eV): m/z (%)
= 329 (19) [M+]. Anal. Calcd for C22H23N3: C, 80.21; H,
7.04; N, 12.76. Found: C, 80.00; H, 7.16; N, 12.83.
Compound 7a: solid, mp 126–128 °C. IR: 2926, 1486, 1086,
828 cm–1. 1H NMR (400 MHz, CDCl3): d = 0.91 (t, 3 H,
J = 7.33 Hz), 1.34–1.40 (m, 2 H), 1.61–1.68 (m, 2 H), 2.73
(t, 2 H, J = 7.58 Hz), 2.99 (t, 2 H, J = 6.71 Hz), 4.54 (t, 2 H,
J = 6.71 Hz), 7.27 (s, 4 H), 7.40 (s, 1 H). 13C NMR (100
MHz, CDCl3): d = 148.35, 134.24, 132.75, 128.61, 121.27,
120.96, 86.01, 82.23, 48.65, 31.55, 25.28, 22.22, 21.63,
13.78. MS (EI, 70 eV): m/z (%) = 287 (29.08) [M+]. Anal.
Calcd for C16H18ClN3: C, 66.78; H, 6.30; N, 14.60. Found:
C, 66.90; H, 6.21; N, 14.65.
Selected Spectral Data for 5a.
Solid, mp 70–72 °C. 1H NMR (400 MHz, CDCl3): d = 0.95
(t, 3 H, J = 7.33 Hz), 1.39–1.44 (m, 2 H), 1.64–1.71 (m, 2 H),
2.74 (t, 2 H, J = 7.66 Hz), 3.08 (t, 2 H, J = 6.41 Hz), 4.58 (t,
2 H, J = 6.41 Hz), 6.75 (dd, 2 H, J = 1.75, 7.79 Hz), 7.10–
7.32 (m, 9 H). 13C NMR (100 MHz, CDCl3): d = 152.17,
148.27, 146.08, 139.29, 128.50, 128.24, 127.91, 127.60,
127.56, 121.04, 102.68, 49.67, 42.45, 31.77, 25.32, 22.35,
13.85. IR: 2955, 2926, 1437, 1043, 701 cm–1.
(9) The temperature (70 °C) is required for the triazole synthesis
step in our reaction by trial and error. At higher temperature
1,5-regioisomers can be formed and at lower temperature the
reaction was not complete after several hours.
Synlett 2006, No. 9, 1446–1448 © Thieme Stuttgart · New York