Copper-catalyzed intermolecular chloroazidation of α,β-unsaturated amides

Article abstract of DOI:10.1039/c6ob01352j

A highly practical copper-catalyzed intermolecular chloroazidation of α,β-unsaturated amides has been described, giving a series of azidochlorides in good-to-excellent yields. The stable azidoiodine(iii) reagent and SOCl₂ were used as azide and chlorine sources, respectively. The synthetic applications of this protocol were also explored by a variety of synthetically useful transformations.

Full text of DOI:10.1039/c6ob01352j

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: L. Chen, H. Xing,
H. Zhang, Z. Jiang and Z. Yang, Org. Biomol. Chem., 2016, DOI: 10.1039/C6OB01352J.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/obc

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 1 of 4
View Article Online
DOI: 10.1039/C6OB01352J
Orgainc & Biomolecular Chemistry
COMMUNICATION
Copper‐catalyzed intermolecular chloroazidation of α,β‐
unsaturated amides
Received 00th January 20xx,
Accepted 00th January 20xx
Long Chen, Haotian Xing, Huaibin Zhang, Zhong‐Xing Jiang* and Zhigang Yang*
DOI: 10.1039/x0xx00000x
www.rsc.org/
a) Chloroazidation of alkenes (Finn)18b
NaOCl, NaN3
A highly practical copper‐catalyzed intermolecular chloroazidation
of α,β‐unsaturated amides has been described, giving a series of
azidochlorides in good‐to‐excellent yields. The stable azidoiodine‐
(III) reagent and SOCl2 were used as azide and chlorine sources,
respectively. The synthetic applications of this protocol were also
explored by a variety of synthetically useful transformations.
Cl
N3
R
R
AcOH
R = alkyl, aryl
b) Chloroazidation of aryl alkenes (Hamaashima)18c
N3
Cl
I
O
Organic azides are one of the most important nitrogen
containing compounds and have attracted ever‐increasing
interest of chemists due to their potential application as
versatile intermediates and building blocks in organic synthesis
as well as their remarkable bioactivities.1 For example, Many
efficient approaches have been developed for the
transformation of organoazides into nitrogen‐containing
heterocycles which have shown wide applications in material
science, chemical biology and drug discovery.2 Therefore, the
development of new methods for highly efficient and reliable
incorporation of an azide group into organic molecules with a
highly regio‐ and chemoselectivity has attracted much
attention.1‐3 A number of transition‐metal‐catalyzed methods
for the azidation of aromatic halides,4 boronic acids,5 C−H
positions,3h,6 arenes,7 carbonyl compounds8 and alkenes9 have
been well documented.
CCsF, TMSN3
CH2Cl2
Cl
Ar
R
O
O
c) This work:
N3
I
O
Cl
Cuu2O, SOCl2
N3
EWG
EWG
EtOAc
EWG= Amide, Ester
copper-catalyzed
chemoselectivity
on grram scales
electtron-deficient alkenes
Scheme 1 Previous and Present Works
reaction temperature, and complex reaction conditions.
Therefore, the development of a simple, low cost, effective,
mild and economic approache for the preparation of
azidochlorides from electron‐deficient alkenes is still highly
desirable. Furthermore, chloridized compounds also serve as
useful building blocks due to they can be readily transformed
to amine, hydroxyl, hydrocarbon, and hydrogen. Inspired by
recent advances and our continuing interest in copper
catalyzed the intermolecular difunctionalization of alkenes,19
we disclose here a novel Cu(I)‐catalyzed chloroazidation of
electron‐deficient alkenes employed the stable Zhdankin’s
reagent and thionyl chloride (SOCl2) as the azide and chlorine
sources, respectively (Scheme 1c).
In recent years, the azidation of alkenes using electrophilic
azidation reagents, such as Zhdankin’s reagents,10 has become
a research hotspot and many effective methods have been
studied intensively.9‐18 Especially, a variety of alkene
difunctionalizations involving azidation, such as oxy‐,11 amino‐
,
9a,12 hydro‐,13 azido‐,14 cyano‐,15 aryl‐,16 phosphono17 and halo‐
containing18 azidation, have also been developed. Although
similar vicinal haloazidations of alkenes have been reported
(Scheme 1a and 1b),18b‐c their applications are limited due to
certain disadvantages, including the use of hazardous azide
sources, such as NaN3 or TMSN3, addition of excess base, low
At the outset of our studies, we chose 3‐methylene‐1‐(1‐
naphthylmethyl)‐2‐pyrrolidinon 1a as the model substrate to
optimize the reaction conditions (Table 1). Initially, the
reaction was carried out with Zhdankin’s reagent 2a (1.5 equiv)
and thionyl chloride (1.5 equiv) in the presence of 5 mol %
Hubei Province Engineering and Technology Research Center for Fluorinated
Pharmaceuticals and Wuhan University School of Pharmaceutical Sciences, Wuhan
430071, P. R. China. E‐mail: zxjiang@whu.edu.cn, zgyang@whu.edu.cn;
†
Electronic Supplementary Information (ESI) available: Experimental procedures
and characterization of new compounds. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
Org. Biomol. Chem, 2016, 00, 1‐4 | 1
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 2 of 4
COMMUNICATION
Orgainc & Biomolecular Chemistry
Table 1 Optimization of reaction conditionsa
View Article Online
DOI: 10.1039/C6OB01352J
[N3] (1.5 equiv)
O
O
O
Cu2O (5 mol %)
Cl
N3
SOCl2 (x equiv)
N
R
N
R
N
R
Cl
Cl
solvent, Ar, rt, 12 h
1a
3a
4a
I
O
N3
I
O
N3
TMSN3
TMSN3/PhI(OAc)2
(1 : 1)
O
2a
R=1-naphthalenylmethyl
2b
2c
2d
Entry
[N3]
x equiv Solvent
Yieldb (%) 3a 4ab
/
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2a
2a
1.5
1.0
0.75
0.6
0.5
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
MeCN
EtOAc
MeOH
THF
40
35
37
47
42
34
52
52
40
45
46
46
73
48
N.R.
62
88
N.R.
1:1
3:2
7:2
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
1:4
1:3
1:1
>20:1
>20:1
‐
9
10
11
12
13c
14c
15c
16c
17c,d
18c,d,e
dioxane
DMF
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
3:2
>20:1
‐
a Reaction conditions: 1a (0.2 mmol), azide sources (0.3 mmol, 1.5 equiv),
Cu2O (5 mol %) and SOCl2 in solvent (1.0 mL) at rt for 12 h. b The ratio of
3a/4a and yield were based on 1H NMR spectra of the crude reaction
mixture with 1,3,5‐trimethoxybenzene as the internal standard. c 0.5 mL
solvent was used. d 0.5 equiv Et2NH was added. e Without Cu2O.
Scheme 2 Scope of chloroazidation. Reaction conditions: 1 (0.4 mmol), 2a
(0.6 mmol, 1.5 equiv), Cu2O (5 mol %) and SOCl2 (0.24mmol, 0.6 equiv),
diethylamine (0.2 mmol, 0.5 equiv), in EtOAc (1.0 mL) at rt for 12 h. a PCl3
(0.4 equiv) was used as the chlorine source without diethylamine.
Considering ethyl acetate is much cheaper than acetonitrile,
EtOAc was chosen as the best solvent for the following
investigation. To our delight, when half amount of solvent (0.5
mL) was used, the product was obtained in good yield (Table 1,
entry 13). For comparison, other azide sources were also
studied. Using Zhdankin’s reagent 2b led to much lower yield,
probably due to its lower reactivity (48% yield, Table 1, entry
14). No reaction occurred with the use of trimethyl‐silylazide
Cu2O in CHCl3 at room temperature under an argon
atmosphere for 12 h. Gratifyingly, the desired chloroazide 3a
was obtained in 40% yield with an unexpected almost equal
amount byproduct dichlorine 4a (Table 1, entry 1). It was
further found that the amount of thionyl chloride was an
important factor for the chemoselectivity of the reaction
(Table 1, entries 2‐5). Almost no dichlorine 4a was observed
and the yield was increased slightly when the amount of SOCl2
was decreased from 1.5 equiv to 0.6 equiv. Further
optimization of the solvent revealed that EtOAc and MeCN
provided the best results, giving the corresponding product 3a
in 52% yield (Table 1, entries 7‐8). It is noteworthy that
dichlorine 4a was detected as the major product when THF
and dioxane were employed. Other solvents, such as DCM,
MeOH, and DMF were investigated, but no superior result was
obtained. It should be indicated that, the reaction was very
sensitive to water, air, and the purity of chlorine sources.
(TMSN3). A mixture (3a/4a = 3/2) in 62% yield was obtained
when PhI(OAc)2 was used as an oxidant combined with TMSN3.
When 0.5 equiv Et2NH was used in the end, the reaction yield
was increased to 88% (Table 1, entry 17). Changing the catalyst
loading from 5% to 1%, 2% and 10% slightly decreased the
catalyst performance, providing the azidochloride 3a in 86%,
86% and 81% yields, respectively (see the ESI, Table S7). Finally,
the controlled experiment indicated that the copper catalyst
was essential in catalyzing the reaction (Table 1, entry 18).
2 | Org. Biomol. Chem, 2016, 00, 1‐4
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 4
Organic & Biomolecular Chemistry
Please do not adjust margins
Orgainc & Biomolecular Chemistry
COMMUNICATION
Under the optimized conditions (Table 1, entry 17), a study
on the substrate scope of this transformation was carried out,
and the results are summarized in Scheme 2. First, different
alkyl and aryl substituted groups on the nitrogen atom of 2‐
pyrrolidinon were compatible with the reaction conditions
afforded the corresponding products with excellent yields
(Scheme 2, 3a‐3e). Meanwhile, a single crystal of 3a was
obtained, and the product structure was further confirmed
(Figure 1). Six‐membered α,β‐unsaturated cyclic amides
reacted smoothly to provide the desired products (3f‐3g) in
good yields. Second, linear unsaturated amides with different
substituted groups on the nitrogen atom or bearing H, Et, nBu,
Bn on the α‐position were also suitable substrates for the
reaction and afforded the corresponding products 3l‐o with
good yields (48‐76%). It is noteworthy that phenyl substitution
on the α‐position was also tested under the reaction
conditions, an eliminated product (azide substituted alkene)
was formed. And it undergoes the second chloroazidation to
provide the diazido chloride 3p. Finally, under the similar
reaction conditions, two α,β‐unsaturated esters were tested,
affording the corresponding adducts in satisfactory yields (3q
and 3r).
View Article Online
DOI: 10.1039/C6OB01352J
Scheme 4 Mechanistic studies
To further probe the potential scalability of this approach, a
gram scale synthesis of chloroazide was carried. The reaction yield using only a 1 mol% catalyst loading (Scheme 3). The
proceeded smoothly delivering 3l in synthetically acceptable chloroazide 3l could be converted into various derivatives.
Reacting with phenyl acetylene afforded a 97% yield of the
triazole product
5. A vicinal diazide 6 was obtained with
excellent yield by the treatment of 3l with NaN3 in DMSO at 75
O
oC. The azide moiety in 3l was easily reduced by Pd/C and
N3
N
successfully afforded the valuable 2‐chloro amine
chlorine group can also be readily transformed into the
corresponding ester in 86% yield.
7. The
Cl
8
To further investigate the mechanism of this reaction,
several control experiments were conducted under the
standard conditions (Scheme 4). When 1.5 equiv of radical
scavenger TEMPO (2,2,6,6‐tetramethyl‐1‐piperidinyloxy) or
BHT (2,6‐di‐tert‐butyl‐4‐methylphenol) were respectively
added to the reaction of 1a, no desired product 3a could be
detected except a messy reaction system. These results may
suggest that a radical process was possibly involved during the
initial stage of this reaction. Moreover, the combination of
chloroiodane(III) reagent 2e, TMSN3 and Cu2O provided the
same azidochloride product 3a in 87% yield. Finally, we
measured the 1H NMR spectrum of crude reaction mixture that
Zhdankin’s reagent 2a was treated in the absence of alkene 1a
after 30 min, only chloroiodane(III) reagent 2e was obtained
(see the ESI for details). It indicated that the chlorine azide
(ClN3) may be generated in the reaction mixture.18c
Figure 1 Crystal structure of 3a.
O
Cu2O ( 1 mol %)
PCl3 (0.4 equiv)
O
NEt2
N3
2a
NEt2
EtOAc, Ar, rt, 12 h
56%
Cl
(10.0 mmol, 1.27 g)
(1.15 g)
3l
O
O
a
b
N
NEt2
N3
NEt2
N
N
97%
95%
N3
Cl
5
6
O
Ph
NEt2
N3
Cl
O
O
c
d
On the basis of the above results and related publications, a
plausible mechanism of this intermolecular transformation is
proposed (Scheme 5).9‐18 Initially, a copper catalyst activates
Zhdankin’s reagent 2a, reacting with SOCl2 to generate the
NEt2
N3
NEt2
BocHN
64%
86%
OAc
Cl
7
8
Scheme
3
Scale‐Up of Cu(l)‐Catalyed chloroazidation and synthetic
a
intermediate I. Further decomposition of I affords Cu(I) species
transformation. Reaction conditions: (a) Phenyl acetylene (1.1 equiv),
.
CuSO4 5H2O, sodium ascorbate, THF/H2O, rt, 12 h. (b) NaN3 (1.5 equiv),
II with simultaneous release of the chlorine azide (ClN3), which
reacts with the alkene 1a resulting in the radical intermediate
III. Finally, the radical intermediate III was trapped by the
o
DMSO, 75 C, 4 h. (c) Pd/C, H2 and (Boc)2O, rt, 36 h. (d) NaOAc (1.5 equiv),
DMF, 80 oC, 10 h.
This journal is © The Royal Society of Chemistry 20xx
Org. Biomol. Chem, 2016, 00, 1‐4 | 3
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 4 of 4
COMMUNICATION
Orgainc & Biomolecular Chemistry
7
8
(a) C. Tang, N. Jiao, J. Am. Chem. Soc., 2012, 134, 18924; (b) Y.
View Article Online
Fan, W. Wan, G. Ma, W. Gao, H. JiangD, OS.I:Z1h0.u10, 3J9. /HCa6oO,BC01h3e5m2J.
Commun., 2014, 50, 5733.
(a) Q. H. Deng, T. Bleith, H. Wadepohl, L. H. Gade, J. Am.
Chem. Soc., 2013, 135, 5356; (b) M. V. Vita, J. Waser, Org.
Lett., 2013, 15, 3246; (c) Y. Shinomoto, A. Yoshimura, H.
Shimizu, M. Yamazaki, V. V. Zhdankin, A. Saito, Org. Lett.,
2015, 17, 5212.
9
(a) F. C. Sequeira, B. W. Turnpenny, S. R. Chemler, Angew.
Chem., Int. Ed., 2010, 49, 6365; (b) B. Zhang, A. Studer, Org.
Lett., 2014, 16, 1790; (c) J. Li, M. Liu, Q. Li, H. Tian, Y. Shi, Org.
Biomol. Chem., 2014, 12, 9769; (d) Z. Li, C. Zhang, L. Zhu, C.
Scheme 5 Proposed reaction mechanism.
Liu, C. Li, Org. Chem. Front., 2014,
1, 100; (e) F. Wang, X. Qi,
Z. Liang, P. Chen, G. Liu, Angew. Chem., Int. Ed., 2014, 53
,
1881; (f) N. Zhu, F. Wang, P. Chen, J. Ye, G. Liu, Org. Lett.,
2015, 17, 3580.
chlorine radical from ClN3 to generate the final chloroazidation
product 3a
.
10 (a) V. V. Zhdankin, C. J. Kuehl, A. P. Krasutsky, M. S.
Formaneck, J. T. Bolz, Tetrahedron Lett., 1994, 35, 9677; (b)
A. P. Krasutsky, C. J. Kuehl, V. V. Zhdankin, Synlett, 1995,
1081; (c) V. V. Zhdankin, A. P. Krasutsky, C. J. Kuehl, A. J.
Simonsen, J. K. Woodward, B. Mismash, J. T. Bolz, J. Am.
Chem. Soc., 1996, 118, 5192.
In summary, we have developed an efficient and practical
approach to construct chloroazides via copper catalyzed three
component reaction of α,β‐unsaturated amides under mild
reaction conditions. The reaction takes advantage of the
Zhdankin’s reagent 2a and SOCl2 as azide and chlorine sources,
respectively. The synthetic utility of the current method is also
11 (a) B. Zhang, A. Studer, Org. Lett., 2013, 15, 4548; (b) L. Zhu,
H. Yu, Z. Xu, X. Jiang, L. Lin, R. Wang, Org. Lett., 2014, 16
,
demonstrated by
a
variety of synthetically useful
1562; (c) H. Yin, T. Wang, N. Jiao, Org. Lett., 2014, 16, 2302;
(d) R. Zhu, S. L. Buchwald, J. Am. Chem. Soc., 2015, 137, 8069;
(e) X.‐F. Xia, Z. Gu, W. Liu, H. Wang, Y. Xia, H. Gao, X. Liu, Y.‐
M. Liang, J. Org. Chem., 2015, 80, 290; (f) X. Sun, X. Li, S.
transformations. Further studies on the asymmetric version of
the reaction and applications of this multicomponent reaction
in organic synthesis are currently underway in our lab.
This work was supported by the National Natural Science
Foundation of China (grant no. 21402144, 21372181 and
21572168).
Song, Y. Zhu, Y.‐F. Liang, N. Jiao, J. Am. Chem. Soc., 2015, 137
6059; (g) G. Fumagalli, P. T. G. Rabet, S. Boyd, M. F. Greaney,
Angew. Chem., Int. Ed., 2015, 54, 11481.
,
12 H. Su, W. Li, Z. Xuan, W. Yu, Adv. Synth. Catal., 2015, 357, 64.
13 J. Waser, H. Nambu, E. M. Carreira, J. Am. Chem. Soc., 2005,
127, 8294.
14 (a) M.‐Z. Lu, C.‐Q. Wang, T.‐P. Loh, Org. Lett., 2015, 17, 6110;
(b) Y. A. Yuan, D. F. Lu, Y. R. Chen, H. Xu, Angew. Chem., Int.
Ed., 2016, 55, 534.
15 L. Xu, X. Q. Mou, Z. M. Chen, S. H. Wang, Chem. Commun.,
2014, 50, 10676.
16 (a) Y. Yuan, T. Shen, K. Wang, N. Jiao, Chem. Asian J., 2013, 8,
Notes and references
1
(a) D. M. Huryn, M. Okabe, Chem. Rev., 1992, 92, 1745; (b) S.
Bräse, C. Gil, K. Knepper, V. Zimmermann, Angew. Chem., Int.
Ed., 2005, 44, 5188; (c) S. Bräse, K. Banert, Organic Azides:
Syntheses and Applications, Wiley‐VCH, Weinheim, 2010; (d)
N. Jung, S. Bräse, Angew. Chem., Int. Ed., 2012, 51, 12169; (e)
E. T. Hennessy, T. A. Betley, Science, 2013, 340, 591; (f) Chiba,
S. Synlett, 2012, 21. (g) W. Song, S. I. Kozhushkov, L.
Ackermann, Angew. Chem., Int. Ed., 2013, 52, 6576.
2932; (b) X. H. Wei, Y. M. Li, A. X. Zhou, T. T. Yang, S. D. Yang,
Org. Lett., 2013, 15, 4158; (c) K. Matcha, R. Narayan, A. P.
Antonchick, Angew. Chem., Int. Ed., 2013, 52, 7985; (d) W.
Kong, E. Merino, C. Nevado, Angew. Chem., Int. Ed., 2014, 53
,
2
3
(a) E. M. Sletten, C. R. Bertozzi, Acc. Chem. Res., 2011, 44,
5078; (e) J. Qiu, R. Zhang, Org. Biomol. Chem., 2014, 12, 4329.
17 J. Xu, X. Li, Y. Gao, L. Zhang, W. Chen, H. Fang, G. Tang, Y.
Zhao, Chem. Commun., 2015, 51, 11240.
666; (b) P. M. E. Gramlich, C. T. Wirges, A. Manetto, T. Carell,
Angew. Chem., Int. Ed., 2008, 47, 8350; (c) G. Franc, A. K.
Kakkar, Chem. Soc. Rev., 2010, 39, 1536.
18 (a) S. Hajra, M. Bhowmick, D. Sinha, J. Org. Chem., 2006, 71
,
For selected reviews: (a) V. V. Zhdankin, Chem. Rev., 2008,
108, 5299; (b) F. Amblard, J. H. Cho, R. F. Schinazi, Chem.
Rev., 2009, 109, 4207; (c) M. Minozzi, D. Nanni, P. Spagnolo,
Chem.–Eur. J., 2009, 15, 7830; (d) T. G. Driver, Org. Biomol.
9237; (b) R. A. Valiulin, S. Mamidyala, M. G. Finn, J. Org.
Chem., 2015, 80, 2740; (c) H. Egami, T. Yoneda, M. Uku, T.
Ide, Y. Kawato, Y. Hamashima, J. Org. Chem., 2016, 81, 4020.
19 M. Fu, L. Chen, Y. Jiang, Z.‐X. Jiang, Z. Yang, Org. Lett., 2016,
18, 348.
Chem., 2010, 8, 3831; (e) C. I. Schilling, N. Jung, M. Biskup, U.
Schepers, S. Bräse, Chem. Soc. Rev., 2011, 40, 4840; (f) Y. Li,
D. P. Hari, M. V. Vita, J. Waser, Angew. Chem., Int. Ed. 2016,
55, 4436; (g) K. Wu, Y. Liang, Ning Jiao, Molecules, 2016, 21
352; (h) X. Huang, J. T. Groves, ACS Catal., 2016, , 751.
,
6
4
5
6
(a) P. A. S. Smith, C. D. Rowe, L. B. Bruner, J. Org. Chem.,
1969, 34, 3430; (b) W. Zhu, D. Ma, Chem. Commun., 2004,
888.
(a) C. Tao, X. Cui, J. Li, A. Liu, L. Liu, Q. Guo, Tetrahedron Lett.,
2007, 48, 3525; (b) Y. Li, L.‐X. Gao, F.‐S. Han, Chem.–Eur. J.,
2010, 16, 7969;
(a) A. Sharma, J. F. Hartwig, Nature, 2015, 517, 600; (b) T. G.
R. Pauline, F. Gabriele, B. Scott, F. G. Michael, Org. Lett.,
2016, 18, 1646; (c) Y. Wang, G.‐X. Li, G. Yang, G. He, G, Chen,
Chem. Sci., 2016, 7, 2679.
4 | Org. Biomol. Chem, 2016, 00, 1‐4
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins