General silver-catalyzed hydroazidation of terminal alkynes by combining TMS-N3 and H2O: Synthesis of vinyl azides

Article abstract of DOI:10.1021/ol501661k

A general hydroazidation of unactivated alkynes using silver catalysis is reported. The reactions of diverse terminal alkynes with trimethylsilyl azide (TMS-N₃) in the presence of H₂O afforded the corresponding vinyl azides in good to excellent yields. This reaction has a broad substrate scope, good functional group tolerance, simple operation, and high reaction efficiency, thus providing an easy access to various functionalized vinyl azides.

Full text of DOI:10.1021/ol501661k

Letter
pubs.acs.org/OrgLett
General Silver-Catalyzed Hydroazidation of Terminal Alkynes by
Combining TMS‑N3 and H2O: Synthesis of Vinyl Azides
Zhenhua Liu,† Peiqiu Liao,† and Xihe Bi*,†,‡
†Department of Chemistry, Northeast Normal University, Changchun 130024, China
‡State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
S
* Supporting Information
ABSTRACT: A general hydroazidation of unactivated alkynes using silver
catalysis is reported. The reactions of diverse terminal alkynes with
trimethylsilyl azide (TMS-N3) in the presence of H2O afforded the
corresponding vinyl azides in good to excellent yields. This reaction has a
broad substrate scope, good functional group tolerance, simple operation, and high reaction efficiency, thus providing an easy
access to various functionalized vinyl azides.
inyl azides have been known for 100 years, since the first
the chemoselective reactions of alkynes with TMS-N3 were
reported by the Jiao6,7a and Echavarren7b research groups by
varying the catalysts. In our ongoing efforts to develop novel
organic reactions using functionalized alkynes,8 we accomplished
a chemo- and regioselective silver-catalyzed hydroazidation of
ethynyl carbinols with TMS-N3, affording diverse 2-azidoallyl
alcohols (Figure 1, b).8b The hydroxyl group of ethynyl carbinols
played a critical role as the proton source, and a trace amount of
water in DMSO was necessary for the reaction. Therefore, we
envisaged that the presence of a stoichiometric amount of H2O
would avoid the dependence of the hydroxyl group, thus
establishing a general hydroazidation reaction of unactivated alkynes
in a real sense. The experimental results confirmed this
hypothesis, and we found that diverse terminal alkynes could
react with trimethylsilyl azide (TMS-N3) by means of silver
catalysis in the presence of H2O to afford the corresponding vinyl
azides in excellent yields (Figure 1, c). Herein, we report this
powerful method for the synthesis of vinyl azides.
V
report by Forster and Newman in 1910.1 These compounds
are versatile synthetic intermediates for numerous trans-
formations,2 particularly in recently developed transition-metal-
catalyzed azaheterocyclization reactions.3 However, the synthetic
potency of vinyl azides remains largely underexplored because of
the intrinsic high reactivity and limited general and efficient
methods available for their preparation.2 Therefore, the
development of practical synthetic methods for the convenient
preparation of newly functionalized vinyl azides is still highly
appealing. Alkynes are easily available building blocks, and the
hydroelementation of alkynes is a powerful method to access
various functionalized alkenes.4 The hydroazidation of alkynes is
an ideal route to vinyl azides.5 Such reactions have been rarely
reported and almost all have been limited to the Michael addition
of azide anions to electron-deficient alkynes. Regarding
unactivated alkynes, only two examples have been known: (1)
Banert reported the reaction of butadiyne with lithium azide
(LiN3) to give 1-azidoenyne,5d and (2) Jiao and co-workers
isolated a vinyl azide intermediate during the mechanistic studies
of the nitrogenation of alkynes to nitriles (Figure 1, a).6 Recently,
First, the effect of the amount of H2O in the solvent was
investigated using the reaction of 4-bromophenylacetylene (1a)
and TMS-N3 as the model. In dry DMSO, a mixture of 2a and
1
substrate 1a was obtained at a ratio of 1:3 determined by H
NMR analysis of the reaction mixture. Once H2O (2.0 equiv) was
added to the reaction system, a single product 2a was obtained.
However, increasing the amount of H2O to 1 mL resulted in a
large amount of substrate 1a left in the reaction, and only a trace
amount of the vinyl azide 2a was detected. These results
demonstrated that an appropriate amount of H2O was essential
for the hydroazidation of terminal alkynes with TMS-N3, in
which the role of H2O might react with TMS-N3 to generate
HN3.8b,9
Further, a detailed study on the conversion of 1a into 2a in the
presence of 2.0 equiv of H2O was carried out in a time course. An
aliquot of the reaction mixture was taken out at regular intervals
(ca. 10 min) and directly analyzed by 1H NMR spectra. As shown
Received: May 19, 2014
Figure 1. Hydroazidation of unactivated alkynes.
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol501661k | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Hydroazidation of Aryl, Alkyl, and Alkenyl
ab
,
Terminal Alkynes
in Figure 2, a proportional increase of product 2a and
consummation of substrate 1a was observed. This result proved
Figure 2. Time course of the reaction of 1a with TMS-N3 in the
presence of 2.0 equiv of H2O.
the clean transformation from 1a to 2a in the reaction with TMS-
N3. However, once the reaction time ws prolonged, the 4-
bromobenzonitrile could be detected like Jiao’s report.6
Consequently, the strict control of the reaction time was
necessary in order to avoid the further conversion of vinyl azides
to nitriles.
a
Reaction conditions: 1 (0.5 mmol), H2O (1.0 mmol), Ag2CO3 (0.05
b
mmol), DMSO (2 mL), 80 °C, 20−60 min. 30 mol % Ag2CO3 was
used.
The silver-catalyzed hydroazidation of terminal alkynes with
TMS-N3 in the presence of two equivalents of H2O was first
investigated using various aryl-, alkyl-, and alkenylalkynes
(Scheme 1). In general, the substrate scope was quite broad,
and diverse aryl-, alkyl-, and alkenylalkynes could be applied to
this silver-catalyzed procedure, thus affording the corresponding
vinyl azides (2a−p) chemoselectively and in good-to-high yields
(67−86%). All the reactions proceeded smoothly and were
complete within 20−60 min. Various substitutents on the
benzene ring of phenylacetylene were well tolerated such as
electron-donating (Me, and Ph) and -withdrawing groups (Cl,
Br, CO2Me, NO2, CH3CO, and HCO). Some of these functional
groups are useful for further synthetic diversification. Similar to
aryl alkynes, aliphatic alkynes (1l, and 1m) were also applicable.
Notably, the reaction of sterically bulky alkyne 1l reacted with
TMS-N3 smoothly afforded the corresponding vinyl azide, 2l, in
85% yield, albeit requiring a slightly large amount of the silver
catalyst (30 mol %). The reactivity of several alkenyl alkynes (1n,
1o, and 1p) was investigated, and the corresponding 2-
azidobuta-1,3-dienes (2n, 2o, and 2p) were obtained in good
yields. Notably, the reaction of a terminal alkyne sterically
encumbered in a complex molecular skeleton such as α-ethynyl
ketene dithioacetal (1p) with TMS-N3 smoothly afford vinyl
azide 2p in a good yield (67%).
(4a−p) in good-to-excellent yields (66−89%). The functional
groups on the N-atom were well tolerated, including electron-
rich and -poor aryl, fused aryl, tosyl, benzyl, benzoyl, and alkenyl
groups (4a−h). The variation in the substituents at the 3-
position of allylamines had no influence on the reaction outcome
(4i−p). Notably, the reactions of substrates (3j and 3k)
containing a sterically bulky quaternary carbon center with
TMS-N3 also smoothly afforded the corresponding products (4j
and 4k) in 76% and 66% yields, respectively. Next, other
heteroatoms such as oxygen and sulfur instead of nitrogen were
investigated. To our delight, propargyl ethers (5a−i) and
thioether (5j) participated in this hydroazidation reaction,
affording diverse functionalized vinyl azides (6a−j) in good
yields. Notably, the products, 2, 4, and 6 are highly functionalized
and thus of great interest for further synthetic exploitation.
Encouraged by these results, we further investigated the
hydroazidation of other types of easily accessible terminal
alkynes. 4-Alkynones can be easily prepared by the base-
catalyzed nucleophilic substitution of β-dicarbonyl compounds
with propargyl bromides. Previously, we investigated the
synthetic potency of these functionalized alkynes in the [4C +
1N] annulation with primary amines, leading to polysubstituted
pyrroles.8j When they were subjected to the silver-catalyzed
hydroazidation reaction (Scheme 3), to our delight, the
corresponding vinyl azides (8a−d) were obtained in high yields
(80−86%) within a short reaction time (60−90 min). These
novel multifunctionalized vinyl azides have great potential for
further synthetic utilization.
Functionalized allylamines are not only useful building blocks
in organic synthesis10a,b but also possess remarkable biological
activity.10c,d Therefore, we next applied the silver-catalyzed,
H2O-participating hydroazidation of terminal alkynes to
synthesize 2-azidoallyl amines. To the best of our knowledge,
such compounds are unknown.11 As summarized in Scheme 2,
diverse N-protected allylamines participated in this silver-
catalyzed method to afford the desired 2-azidoallyl amines
The substrate scope of the hydroazidation of terminal alkynes
can be extended to dialkynes such as N,N-di(prop-2-yn-1-
yl)aniline (9a) and 1,7-octadiyne (9b). Under the slightly
B
dx.doi.org/10.1021/ol501661k | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
To demonstrate the synthetic utility of this hydroazidation
reaction, we conducted the reaction on a gram scale, which
provided 4e in 78% yield (Scheme 4). Subsequently, we also
Scheme 2. Hydroazidation of Propargyl Compounds.
Scheme 4. Synthetic Transformation of Vinyl Azides
showed that 4e can be converted to the desired 1,2,3-triazole
(11a)12 and the α-amino ketone13 (11b) in 95% and 80% yields,
respectively, using the known transformations.14 Meanwhile, a
rearrangement of vinyl azide (2d) to yield the amide (11c) in
75% yield was realized.15
In summary, we have developed a novel and practical silver-
catalyzed hydroazidation of terminal alkynes by combining
TMS-N3 and H2O. This reaction represents the general
hydroazidation of unactivated alkynes in a real sense. The
reaction has a broad substrate scope of terminal alkynes,
affording the corresponding vinyl azides in good-to-excellent
yields. Easy access to these highly functionalized vinyl azides has
paved a way in organic synthesis to explore their synthetic
potency in the future.
ASSOCIATED CONTENT
* Supporting Information
■
S
a
Reaction conditions: 3/5 (0.5 mmol), H2O (1.0 mmol), Ag2CO3
(0.05 mmol), DMSO (2 mL), 80 °C, 60−90 min.
Experimental procedures and spectra copies. This material is
available free of charge via the Internet at http://pubs.acs.org.
a
Scheme 3. Hydroazidation of 4-Alkynones
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: bixh507@nenu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by NSFC (21172029, 21202016,
21372038), the Ministry of Education of the People’s Republic of
China (NCET-13-0714), and the Jilin Provincial Research
Foundation for Basic Research (20140519008JH).
a
Reaction conditions: 7 (0.5 mmol), H2O (1.0 mmol), Ag2CO3 (0.05
mmol), DMSO (2 mL), 80 °C, 60−90 min.
REFERENCES
■
(1) (a) Forster, M. O.; Newman, S. H. J. Chem. Soc. 1910, 97, 2570−
2579. (b) Forster, M. O.; Newman, S. H. J. Chem. Soc. 1911, 99, 1277−
1282.
(2) For a general review on the synthesis and reactions of vinyl azides,
see: Banert, K. in Organic Azides: Syntheses and Applications; Brase, S.;
modified reaction conditions, i.e., using double the amount of
silver catalyst, H2O, and TMS-N3, the desired divinyl azides (10a
and 10b) could be obtained in 77% and 72% yields, respectively.
̈
Banert, K.; Eds., John Wiley & Sons Ltd.: Chichester, 2010.
(3) For recent examples, see: (a) Farney, E. P.; Yoon, T. P. Angew.
Chem., Int. Ed. 2014, 53, 793−797. (b) Zhang, G.; Ni, H.; Chen, W.;
Shao, J.; Liu, H.; Chen, B.; Yu, Y. Org. Lett. 2013, 15, 5967−5969.
(c) Chen, F.; Shen, T.; Cui, Y.; Jiao, N. Org. Lett. 2012, 14, 4926−4929.
(d) Wang, Y.-F.; Toh, K. K.; Lee, J.-Y.; Chiba, S. Angew. Chem., Int. Ed.
2011, 50, 5927−5931. (e) Wang, Y.-F.; Toh, K. K.; Ng, E. P. J.; Chiba, S.
J. Am. Chem. Soc. 2011, 133, 6411−6421. (f) Wang, Y.-F.; Chiba, S. J.
Am. Chem. Soc. 2009, 131, 12570−12572. (g) Stokes, B. J.; Dong, H.;
C
dx.doi.org/10.1021/ol501661k | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Leslie, B. E.; Pumphrey, A. L.; Driver, T. G. J. Am. Chem. Soc. 2007, 129,
7500−7501. (h) Hu, B.; Wang, Z.; Ai, N.; Zheng, J.; Liu, X.-H.; Shan, S.;
Wang, Z. Org. Lett. 2011, 13, 6362−6365. (i) Chen, W.; Hu, M.; Wu, J.;
Zou, H.; Yu, Y. Org. Lett. 2010, 12, 3863−3865. (j) Stokes, B. J.; Vogel,
C. V.; Urnezis, L. K.; Pan, M.; Driver, T. G. Org. Lett. 2010, 12, 2884−
2887. (k) Chiba, S.; Zhang, L.; Ang, G. Y. B.; Hui, W.-Q. Org. Lett. 2010,
12, 2052−2055. (l) Wang, Y.-F.; Toh, K. K.; Chiba, S.; Narasaka, K. Org.
Lett. 2008, 10, 5019−5022. (m) Chiba, S.; Wang, Y.-F.; Lapointe, G.;
Narasaka, K. Org. Lett. 2008, 10, 313−316. (n) Dong, H.; Shen, M.;
Redford, J. E.; Stokes, B. J.; Pumphrey, A. L.; Driver, T. G. Org. Lett.
2007, 9, 5191−5194.
(4) For general reviews on the hydroelementation of alkynes, see:
(a) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2004, 104, 3079−
3159. (b) Zeng, X. Chem. Rev. 2013, 113, 6864−6900.
(5) (a) Hyatt, I. F. D.; Croatt, M. P. Angew. Chem., Int. Ed. 2012, 51,
7511−7514. (b) Palacios, F.; Aparicio, D.; de los Santos, J. M.; Perez de
Heredia, I.; Rubiales, G. Org. Prep. Proced. Int. 1995, 27, 171−178.
(c) Haddach, M.; Pastor, R.; Riess, J. G. Tetrahedron 1993, 49, 4627−
4638. (d) Banert, K. Chem. Ber. 1989, 122, 1175−1178. (e) Kitamura,
T.; Stang, P. J. Tetrahedron Lett. 1988, 29, 1887−1889. (f) Ochiai, M.;
Kunishima, M.; Fuji, K.; Nagao, Y. J. Org. Chem. 1988, 53, 6144−6145.
(g) Ostroverkhov, V. G.; Shilov, E. A. Ukrain. Khim. Zhur. 1957, 23,
615−622.
(6) Shen, T.; Wang, T.; Qin, C.; Jiao, N. Angew. Chem., Int. Ed. 2013,
52, 6677−6680.
(7) (a) Qin, C.; Feng, P.; Ou, Y.; Shen, T.; Wang, T.; Jiao, N. Angew.
Chem., Int. Ed. 2013, 52, 7850−7854. (b) Gaydou, M.; Echavarren, A. M.
Angew. Chem., Int. Ed. 2013, 52, 13468−13471.
(8) (a) Fang, Z.; Liu, J.; Liu, Q.; Bi, X. Angew. Chem., Int. Ed. 2014,
DOI: 10.1002/anie.201403014. (b) Liu, Z.; Liu, J.; Zhang, L.; Liao, P.;
Song, J.; Bi, X. Angew. Chem., Int. Ed. 2014, 53, 5305−5309. (c) Liu, J.;
Liu, Z.; Wu, N.; Liao, P.; Bi, X. Chem.Eur. J. 2014, 20, 2154−2158.
(d) Fang, Z.; Liao, P.; Yang, Z.; Wang, Y.; Zhou, B.; Yang, Y.; Bi, X. Eur. J.
Org. Chem. 2014, 924−927. (e) Liu, J.; Fang, Z.; Zhang, Q.; Liu, Q.; Bi,
X. Angew. Chem., Int. Ed. 2013, 52, 6953−6957. (f) Fang, G.; Li, J.;
Wang, Y.; Gou, M.; Liu, Q.; Li, X.; Bi, X. Org. Lett. 2013, 15, 4126−4129.
(g) Liu, Y.; Barry, B.-D.; Yu, H.; Liu, J.; Liao, P.; Bi, X. Org. Lett. 2013, 15,
2608−2611. (h) Fang, Z.; Yuan, H.; Liu, Y.; Tong, Z.; Li, H.; Yang, J.;
Barry, B.-D.; Liu, J.; Liao, P.; Zhang, J.; Liu, Q.; Bi, X. Chem. Commun.
2012, 48, 8802−8804. (i) Wang, K.; Bi, X.; Xing, S.; Liao, P.; Fang, Z.;
Meng, X.; Zhang, Q.; Liu, Q.; Ji, Y. Green Chem. 2011, 13, 562−565.
(j) Wang, Y.; Bi, X.; Li, D.; Liao, P.; Wang, Y.; Yang, J.; Zhang, Q.; Liu, Q.
Chem. Commun. 2011, 47, 809−811.
(9) (a) Jin, T.; Kamijo, S.; Yamamoto, Y. Tetrahedron Lett. 2004, 45,
9435−9437. (b) Jin, T.; Kamijo, S.; Yamamoto, Y. Eur. J. Org. Chem.
2004, 3789−3791.
(10) (a) Jiang, Z.; Zhang, L.; Dong, C.; Cai, Z.; Tang, W.; Li, H.; Xu, L.;
Xiao, J. Adv. Synth. Catal. 2012, 354, 3225−3230. (b) Trost, B. M.;
Spagnol, M. D. J. Chem. Soc., Perkin Trans. 1 1995, 2083−2097.
(c) Birnbaum, J. E. J. Am. Acad. Dermatol. 1990, 23, 782−785. (d) Ryder,
N. S. Biochem. Soc. Trans. 1990, 18, 45−46.
(11) For one report regarding the preparation and reaction of 3-
azidoallyl amines, see: Alajarín, M.; Vidal, A.; Orenes, R.-A. Eur. J. Org.
Chem. 2002, 4222−4227.
(12) Raushel, J.; Fokin, V. V. Org. Lett. 2010, 12, 4952−4955.
(13) For synthetic applications of α-amino ketones, see: (a) Fujita, M.;
Hiyama, T. J. Am. Chem. Soc. 1984, 106, 4629−4630. (b) Takahashi, H.;
Sakuraba, S.; Takeda, H.; Achiwa, K. J. Am. Chem. Soc. 1990, 112, 5876−
5878.
(14) Nitta, M.; Kobayashi, T. Bull. Chem. Soc. Jpn. 1984, 57, 1035−
1039.
(15) (a) Hassner, A.; Ferdinandi, E. S.; Isbister, R. J. J. Am. Chem. Soc.
1970, 92, 1672−1675. (b) Zhang, F.-L.; Wang, Y.-F.; Lonca, G. H.; Zhu,
X.; Chiba, S. Angew. Chem., Int. Ed. 2014, 53, 390−4394.
D
dx.doi.org/10.1021/ol501661k | Org. Lett. XXXX, XXX, XXX−XXX