Reaction of allenyl esters with sodium azide: An efficient synthesis of E-vinyl azides and polysubstituted pyrroles

Article abstract of DOI:10.1021/jo062376m

(Chemical Equation Presented) The nucleophilic addition of sodium azide to 1,2-allenyl esters can generate vinyl azides in excellent yields with excellent regio- and stereoselectivities. Moreover, pyrroles are synthesized using 1-allyllic 1,2-allenyl este

Full text of DOI:10.1021/jo062376m

nucleophilic functionalities at the R-carbon atom, leading to
stereodefined functionalized vinylic products efficiently.3 More-
over, with diverse and appropriate substitutes connected, allenes
can be utilized as versatile starting materials to develop
sequential reactions either employing metal catalysts or not,
affording an efficient method for preparation of many com-
pounds with synthetic and biological importance.4,5
Reaction of Allenyl Esters with Sodium Azide:
An Efficient Synthesis of E-Vinyl Azides and
Polysubstituted Pyrroles
Xian Huang,*,†,‡ Ruwei Shen,† and Tiexin Zhang†
Department of Chemistry, Zhejiang UniVersity (Xixi Campus),
Hangzhou 310028, P. R. China, and State Key Laboratory
of Organometallic Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, P. R. China
Meanwhile, vinyl azides have drawn much attention for their
growing applications in synthesis of various heterocycles,6,7 as
well as polysubstituted pyrroles, because of their wide occur-
rence in nature,8 profound pharmaceutical activities,9 and
considerable application in material science.10 Hence, continuous
interest has been directed to development of new and efficient
synthesis of vinyl azides and polysubstituted pyrroles.11 Based
upon the above considerations and in the context of our effort
on developing new strategies toward heterocycles and related
libraries,12 herein we wish to present our findings in the reaction
of allenyl esters with sodium azide affording functionalized vinyl
azides and describe a facile synthesis of polysubstituted pyrroles
from 1-allylic 1,2-allenyl esters. To the best of our knowledge,
the reaction of allenyl esters with sodium azide has not yet been
huangx@mail.hz.zj.cn
ReceiVed NoVember 17, 2006
(4) (a) Ma, S. Pd-Catalyzed two- or three-component cyclization of
functionalized allenes. In Topics in Organometallic Chemistry; Tsuji,
J., Ed.; Springer-Verlag: Heidelberg, 2005; pp 183-210. (b) Zimmer,
R.; Dinesh, C. U.; Nandanan, E.; Khan, F. A. Chem. ReV. 2000, 100,
3067.
(5) For recent examples, see: (a) Lambert, T. H.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2002, 124, 13646. (b) Ma, S.; Yu, Z. Org. Lett. 2003,
5, 1507. (c) Brummond, K. M.; Gao, D. Org. Lett. 2003, 5, 3491. (d) Mukai,
C.; Takahashi, Y. Y. Org. Lett. 2005, 7, 5793. (e) Ma, S.; Jiao, N.; Zheng,
Z.; Ma, Z.; Lu, Z.; Ye, L; Deng, Y.; Chen, G. Org. Lett. 2004, 6, 2193. (f)
Petit, M.; Aubert, C.; Malacria, M. Org. Lett. 2004, 6, 3937. (g) Zhu, G.;
Zhang, Z. Org. Lett. 2004, 6, 4041. (h) Inagaki, F.; Mukai, C. Org. Lett.
2006, 8, 1217. (i) Kuroda, N.; Takahashi, Y.; Yoshinaga, K.; Mukai, C.
Org. Lett. 2006, 8, 1843. (j) Ohno, H.; Takeoka, Y.; Miyamura, K.; Kadoh,
Y.; Tanaka, T. Org. Lett. 2003, 5, 4763. (k) Feldman, K. S.; Iyer, M. R. J.
Am. Chem. Soc. 2005, 127, 4590. (l) Ma, S.; Gu, Z. J. Am. Chem. Soc.
2005, 127, 6182. (m) Parthasarathy, K.; Jeganmohan, M.; Cheng, C.-H. J.
Am. Chem. Soc. 2006, 8, 621. (n) Ohno, H.; Miyamura, K.; Mizutani, T.;
kadoh, Y.; Takeoka, Y.; Hamaguchi, H.; Tanaka, T. Chem. Eur. J. 2005,
11, 3728. (o) Hamaguchi, H.; S., Kosaka; Ohno, H.; Tanaka, T. Angew.
Chem., Int. Ed. 2005, 44, 1513. (p) Wender, P. A.; Croatt, M. P.; Deschamps,
N. M. Angew. Chem., Int. Ed. 2006, 45, 2459.
(6) (a) Singh, P. N. D.; Carter, C. L.; Gudmundsdottir, A. D. Tetrahedron
Lett. 2003, 44, 6763. (b) Timen, A. S.; Risberg, E.; Somfai, P. Tetrahedron
Lett. 2003, 44, 5339. (c) Jonas, C. M. J. Tetrahedron 2002, 58, 2729. (d)
Alonso-Cruz, C. R.; Kennedy, A. R.; Rodriguez, M. S.; Suarez, E. Org.
Lett. 2003, 5, 3729.
(7) (a) Scriven, E. F. V.; Turnbull, K. Chem. ReV. 1988, 88, 297. (b)
Smolinsky, G.; Pryde, C. A. In The Chemistry of the Azido Group; Patai,
S., Ed.; John Wiley & Sons: London, 1971; pp 555-585. (c) Hassner, A.
In Azides and Nitrenes: ReactiVity and Utility; Scriven, E. F. V., Ed.;
Academic Press: Orlando, 1984; pp 35-94.
The nucleophilic addition of sodium azide to 1,2-allenyl
esters can generate vinyl azides in excellent yields with
excellent regio- and stereoselectivities. Moreover, pyrroles
are synthesized using 1-allyllic 1,2-allenyl esters as substrates
in t-BuOH at 65 °C. The sequential reaction for pyrroles is
developed on the basis of a novel domino process involving
nucleophilic addition, cycloaddition, denitrogenation, and
aromatization.
Allenes show unique reactivity in organic synthesis due to
the presence of the cumulated CdC double bonds.1 In past
decades, much attention has been paid to the study of their
reactivity, especially the control of the related selectivity and
their potential synthetic utilities.2-4 Recently, researchers have
found that regioselective and in some cases stereoselective
addition of allenes can be conducted by introducing various
† Zhejiang University.
‡ Shanghai Institute of Organic Chemistry.
(1) (a) Patai, S. The Chemistry of Ketenes, Allenes, and Related
Compounds; John Wiley & Sons: New York, 1980; Part 1. (b) Schuster,
H. F.; Coppola, G. M. Allenes in Organic Synthesis; John Wiley & Sons:
New York, 1984. (c) Landor, S. R. The Chemistry of Allenes; Academic
Press: New York, 1982; Vols. 1-3. (d) Krause, N.; Hashmi, A. S. K.
Modern Allene Chemistry; Wiley-VCH: Weinheim, 2004; Vols. 1-2.
(2) (a) Smadja, W. Chem. ReV. 1983, 83, 263. (b) Marshall, J. A. Chem.
ReV. 1996, 96, 31. (c) Yamamoto, Y.; Radhakrishnan, U. Chem. Soc. ReV.
1999, 28, 199. (d) Hashimi, A. S. K. Angew. Chem., Int. Ed. 2000, 39,
3590. (e) Ma, S. Acc. Chem. Res. 2003, 36, 701. (f) Ma, S. Chem. ReV.
2005, 105, 2829. (g) Reissing, H. U.; Schade, W.; Amombo, M. O.; Pulz,
R.; Hausherr, A. Pure Appl. Chem. 2002, 175.
(8) (a) Christophersen, C. In The Alkaloids; Brossei, A., Ed.; Academic
Press: Orlando, 1985; Vol. 24, Chapter 2. (b) Boger, D. L.; Boyce, C. W.;
Labroli, M. A.; Sehon, C. A.; Jin, Q. J. Am. Chem. Soc. 1999, 121, 54. (c)
Battersby, A. R. Nat. Prod. Rep. 2000, 17, 507. (d) Hoffmann, H.; Lindel,
T. Synthesis 2003, 1753. (e) Fu¨rstner, A. Angew. Chem., Int. Ed. 2003, 42,
3582.
(9) (a) Huffman, J. W. Curr. Med. Chem. 1999, 6, 705. (b) Cozzi, P.;
Mongelli, N. Curr. Pharm. Des. 1998, 4, 181. (c) Wilkerson, W. W.;
Galbraith, W.; Gans-Brangs, K.; Grubb, M.; Hewes, W. E.; Jaffee, B.;
Kenney, J. P.; Kerr, J.; Wong, N. J. Med. Chem. 1994, 37, 988. (d)
Wilkerson, W. W.; Copeland, R. A.; Covington, M.; Trzaskos, J. M. J.
Med. Chem. 1995, 38, 3895.
(3) (a) Ma, S.; Ren, H.; Wei, Q. J. Am. Chem. Soc. 2003, 125, 4817. (b)
Ma, S.; Wei, Q. Eur. J. Org. Chem. 2000, 1, 1939. (c) Ma, S.; Wei, Q.;
Wang, H. Org. Lett. 2000, 2, 3893. (d) Ma, S.; Li, L. Synlett 2001, 1, 1206
and references therein.
(10) (a) Deronzier, A.; Moutet, J.-C. Curr. Top. Electrochem. 1994, 3,
159. (b) Baumgarten, M.; Tyutyulkov, N. Chem. Eur. J. 1998, 4, 987. (c)
Curran, D.; Grimshaw, J.; Perera, S. D. Chem. Soc. ReV. 1991, 20, 391. (d)
Yamaguchi, S.; Tamao, K. J. Organomet. Chem. 2002, 653, 223.
10.1021/jo062376m CCC: $37.00 © 2007 American Chemical Society
Published on Web 01/19/2007
1534
J. Org. Chem. 2007, 72, 1534-1537

TABLE 1. Preparation of Functionalized Vinyl Azides from
1,2-Allenyl Esters
SCHEME 2
entry
R1
R2
R3
2 or 3 yielda (%)
E/Z
1
2
3
4
5
6
7
8
9
Ph
Me
Et
R-C10H7
n-Bu
n-C7H15
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
2a
2b
2c
2d
2e
2f
3a
3b
3c
3d
3e
95
89
93
88
96
93
91
90
93
91
95
mixture
91:9b
89:11b
93:7b
100:0b
94:6b
94:6b
94:6
94:6
93:7
93:7
92:8
SCHEME 3
Me
allyl
Bn
2-methylallyl
H
10
11
12
n-Bu
1
a Isolated yields. b Deduced by H NMR.
SCHEME 1. Configuration of E-2d and Z-3d
precursors to generate novel 1-vinylic substituted 1,2,3-triazoles
via Cu(I)-catalyzed cycloaddition with alkyne (Scheme 2).
Furthermore, it was interesting to observe that the reaction
of ethyl 2-vinylidenepent-4-enoate with sodium azide afforded
5a in 40% yield and 3c (E/Z ) 8:1) in 47% yield with prolonged
reaction time at room temperature (eq 1, Scheme 3). Thus, the
formation of 5a may come from a series of consecutive
transformations of E-3c. This hypothesis is further supported
by the fact that 5a was obtained in 95% yield after E-3c being
heated for 3 h at 80 °C (eq 2, Scheme 3). Because of the
instablility and potentially explosive nature of organic azides,
we then attempted a one-pot synthesis of pyrroles. After a variety
of reaction conditions (typically shown in Table 2) were
examined, we fortunately found 5a could be obtained in good
yield when the reaction was carried out in t-BuOH at 65 °C,
and no Z-3c was observed. It is important to note here that (1)
a trace amount of Z-3c was obtained using water as proton
source mainly due to the fast addition of azide anion to allenyl
esters and its instability in such conditions (entries 1-4, Table
2); (2) relative low yield of 5a was observed when DMSO and
water were used as solvents (entry 3, Table 2); (3) 3.0 equiv of
sodium azide was enough for the reaction in t-BuOH (entries
5-7, Table 2) and the yield dropped when the reaction was
performed at higher temperature (entry 8, Table 2); (4) solvents
such as MeOH, EtOH, and i-PrOH were proven to be ineffective
(entries 10-12, Table 2).
fully studied13 and the synthesis of substituted pyrroles by this
type of reactions is novel and of interest.
The reaction of allenyl esters with sodium azide was initially
carried out by mixing 2.0 equiv of sodium azide with ethyl
4-phenylbuta-2, 3-dienoate in t-BuOH/H2O (4:1) at room
temperature. After the mixture was stirred for 30 min, an
excellent yield of (E)-ethyl 3-azido-4-phenylbut-3-enoate was
obtained along with a small amount of (Z)-ethyl 3-azido-4-
phenylbut-3-enoate (entry 1, Table 1). Then a series of allenyl
esters were tested. The results in Table 1 show that the reactions
proceeded smoothly to give the corresponding vinyl azides 2
for 3-monosubstituted allenyl esters; only the CdC bond
migrated products 3 were obtained when 3-unsubstituted allenyl
esters were used as substrates; the two types of vinyl azides 2
and 3 were both obtained in high yields with good E-
selectivities; however, for disubstituted allenyl esters it gave
an inseparable mixture (entry 12, Table 1). Configurations of
the products E-2d and Z-3d were established by the NOESY
spectrum studies (Scheme 1). Our further experimental results
demonstrate that these stereodefined vinyl azides are ready
(11) For some of recent reports on the synthesis of pyrroles, see: (a)
Grigg, R.; Savic, V. Chem. Commun 2000, 873. (b) Takaya, H.; Kojima,
S.; Murahashi, S. I. Org. Lett. 2001, 3, 421. (c) Wang, Y. L.; Zhu, S. Z.
Org. Lett. 2003, 5, 745. (d) Dhawan, R.; Arndtsen, B. A. J. Am. Chem.
Soc. 2004, 126, 468. (e) Larionov, O. V.; de Meijere, A. Angew. Chem.,
Int. Ed. 2005, 44, 5664. (f) Fuchibe, K.; Ono, D.; Akiyama, T. Chem.
Commun. 2006, 2271. (g) Braun, R. U.; Zeitler, K.; Mu¨ller, T. J. J. Org.
Lett. 2001, 3, 3297. (h) Merlic, C. A.; Baur, A.; Aldrich, C. C. J. Am. Chem.
Soc. 2000, 122, 7398. (i) Quiclet-Sire, B.; Wendeborn, F.; Zard, S. Z. Chem.
Commun. 2002, 2214.
(12) (a) Huang, X.; Sheng, S.-R. J. Comb. Chem. 2003, 5, 273. (b) Huang,
X.; Zhou, H.; Chen, W. J. Org. Chem. 2004, 69, 839. (c) Xu, Q.; Huang,
X.; Yuan, J. J. Org. Chem. 2005, 70, 6948. (d) Huang, X.; Xu, W.-M.
Org. Lett. 2003, 5, 4649. (e) Huang, X.; Tang, E.; Xu, W.-M.; Cao, J. J.
Comb. Chem. 2005, 7, 802.
Main results for synthesis of tri- and tetrasubstituted pyrroles
are summarized in Table 3. The reaction generated correspond-
ing products in moderate to good yields in most cases; one more
CdC bond at the side chain in 1′ was tolerated (entries 8, 14,
and 15, Table 3); and pyrroles annulated with a 6- or
8-membered ring could also be obtained in satisfactory yields
using the present protocol (entries 7 and 8, Table 3). However,
(13) For previous study, see: Harvey, G. R.; Ratts, K. W. J. Org. Chem.
1966, 31, 3907.
J. Org. Chem, Vol. 72, No. 4, 2007 1535

TABLE 2. Optimization of Conditions for the Synthesis of Pyrrole
5aa
SCHEME 4
yieldb
(%)
NaN3
T
time
yieldb
entry (equiv)
solvent
(°C)
(h) (%) (5a) (Z-3c)
1
2
3
4
5
6
7
8
9c
2.0
3.0
3.0
3.0
2.0
3.0
5.0
3.0
3.0
3.0
3.0
3.0
t-BuOH/H2O (4:1) 65
t-BuOH/H2O (8:1) 65
DMSO/H2O (8:1) 65
acetone/H2O (8:1) 55
8
8
78
79
55
78
85
91
92
81
trace
trace
trace
trace
12
16
20
20
20
16
60
24
24
24
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
MeOH
EtOH
65
65
65
80
rt
reflux
65
11
complex
10
11d
12
A plausible mechanism for the reaction is outlined in Scheme
4. Conjugate addition of azide anion to allenyl ester occurs first
to give vinyl azide in which the double bond has “migrated”
on the given conditions, followed by a thermally intramolecular
1,3-dipolar cycloaddition to form the unstable triazoline inter-
mediate 6. Then, 6 may decompose to produce zwitterionic
species 7, which undergoes 1,2 H-shift with loss of nitrogen
and 1,3 H-shift to give the stable pyrrole 5 (path a).14 Another
possiblility is that the formed triazoline 6 may expel N2 to
produce biradical intermediate 8 which would provide the
expected pyrroles 5 after 1,2 H-radical shift and the following
1,3 H-shift (path b).15
i-PrOH
65
complex
a All of the reactions were carried out on a 1.0 mmol scale. b Isolated
yields. c 68% of starting material was recovered; 9% of E-3c was isolated.
d Ethyl 2-(1-ethoxyethylidene)pent-4-enoate was isolated as the major
product.
TABLE 3. Synthesis of Tri- and Tetrasubstituted Pyrroles from
1-Allylic 1,2-Allenyl Esters
In conclusion, we found that hydroazidation of allenyl esters
can give vinyl azides in excellent yields with high regio- and
stereoselectivities. A new method for the synthesis of pyrroles
from 1-allylic allenyl esters through a series of consecutive
transformations has been developed. Further studies of this type
of reaction are currently underway in our laboratory.
Experimental Section
General Procedure for Access to Vinyl Azides. To a solution
of NaN3 (1 mmol) in t-BuOH/H2O (v/v ) 4:1, 2 mL) was added
1,2-allenyl ester 1 (0.5 mmol) at room temperature with stirring.
After the reaction was complete (30 min), the reaction was quenched
with saturated NH4Cl and extracted with EtOAc (3 × 10 mL). The
organic phase was washed with saturated brine and dried over
MgSO4. After filtration and removal of the solvent in vacuo, the
residue was purified with flash chromatography (silica/petroleum
ether-ethyl acetate 20:1 v/v) to afford 2 or 3.
General Procedure for Access to Polysubstituted Pyrroles.
A solution of NaN3 (3 mmol) and 1-allyllic 1,2-allenyl esters 1′ (1
mmol) in t-BuOH (3 mL) was heated to 65 °C with stirring. After
the reaction was complete (monitored by TLC), the reaction was
quenched with saturated NH4Cl and extracted with EtOAc (3 ×
15 mL). The organic phase was washed with saturated brine and
dried over MgSO4. After filtration and removal of the solvent in
a Isolated yields. b t-BuOH/H2O (8:1) were used as solvents. c 17% of
starting material was recovered. d Reaction conditions: the mixture of 1,
2-allenyl ester and 5.0 equiv of NaN3 was heated with stirring in t-BuOH
at 80 °C.
(14) (a) Ogawa, H.; Kumermura, M.; Imoto, T.; Miyamoto, I.; Kato,
H.; Taniguchi, Y. J. Chem. Soc., Chem. Commun. 1984, 423. (b) Ogawa,
H.; Kumermura, M.; Imoto, T. Tetrahedron Lett. 1988, 29, 219. (c) Hassner,
A.; Amarasekara, A. S.; Andisik, D. J. Org. Chem. 1988, 53, 27. (d) Shea,
K. J.; Kim, J.-S. J. Am. Chem. Soc. 1992, 114, 4846. (e) de Kimpe, N.;
Boeyk, M. J. Org. Chem. 1994, 59, 5189.
the reaction failed to afford the expected pyrrole when R4 or
R7 was a phenyl group (entries 9 and 10, Table 3).
(15) Feldman, K. S.; Lyer, M. R. J. Am. Chem. Soc. 2005, 127, 4590.
1536 J. Org. Chem., Vol. 72, No. 4, 2007

vacuo, the residues were purified with flash chromatography (silica/
petroleum ether-ethyl acetate 6:1 v/v) to afford 5.
Supporting Information Available: General experimental
1
details and H and 13C NMR spectra for compounds 2a-f, 3a-e,
4a-c, 5a-h,k-m are given in this section. This material is
available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We are grateful to the National Natural
Science Foundation of China (Project Nos. 20472072 and
20332060) for financial support.
JO062376M
J. Org. Chem, Vol. 72, No. 4, 2007 1537