Metal-Free Regioselective Chloroazidation of Internal Alkynes

Article abstract of DOI:10.1002/chem.201805320

A metal-free, room temperature protocol for the regioselective chloroazidation of internal alkynes is disclosed. The reactions of internal alkynes with trimethylsilyl azide (TMSN₃) in the presence of 1,3-dichloro-5,5-dimethylhydantoin (DCDMH) afforded the corresponding chloroazidoalkenes in good yields. This reaction has good functional group tolerance and is operationally simple.

Full text of DOI:10.1002/chem.201805320

A Journal of
Accepted Article
Title: Metal Free Regioselective Chloroazidation of Internal Alkynes
Authors: Bin Huang, Raphael Liffert, Anthony Linden, and Karl
Gademann
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To be cited as: Chem. Eur. J. 10.1002/chem.201805320
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Metal Free Regioselective Chloroazidation of Internal Alkynes
Bin Huang, Raphael Liffert, Anthony Linden and Karl Gademann*
Abstract:
A
metal-free, room temperature protocol for the
using the simple alkyne 3-phenylprop-2-yn-1-yl benzoate 1a as a
substrate, TMSN3 (1.2 eq) as the azide source and 1,2-
dichloroethane as the solvent. After screening of various chloro
sources (Table 1, entries 1-4), we found the most promising
regioselective chloroazidation of internal alkynes is disclosed. The
reactions of internal alkynes with trimethylsilyl azide (TMS-N3) in the
presence of 1,3-dichloro-5,5-dimethylhydantoin (DCDMH) afforded
the corresponding chloroazidoalkenes in good yields. This reaction
has good functional group tolerance and is operationally simple.
results with 2,4-N-chlorosaccharin or
1,3-dichloro-5,5-
dimethylhydantoin (DCDMH),[12] which afforded the desired
product 2a as a single (Z)-isomer in 26% and 35% yield,
respectively. Encouraged by this result, we tested different
solvents (Table 1, entries 4-7) and identified CH2Cl2 as the best
choice. Attempts to improve the yield of 2a by increasing the
amount of chloro source were unsuccessful (entry 8), but
increasing the number of equivalents of TMSN3 gave a slight
improvement (entry 9). Finally, by increasing the amount of
DCDMH (2.2 eq) and TMSN3 (4.4 eq), full conversion of the
starting material was observed and the yield increased to 57%
(entry 10). Further optimization by varying the concentration
(entries 11-12) or temperature (entries 13-14) did not lead to any
improvement in the yield.
Vinyl azides are energetic intermediates towards bioactive
nitrogen-containing molecules, such as synthetically and
biologically valuable 2H-azirines, formed via a reactive vinyl
nitrene species.[1,2] Therefore, procedures for the simple
preparation of vinyl azides are highly desirable. Easily available
alkynes have been shown to serve as an ideal starting point and
elegant metal catalytic methods of hydroazidation and
trifluoromethylazidation of unhindered terminal alkynes have
been developed during the past decade (Scheme 1A).[3,4] Very
recently, Zhang and co-workers pioneered the hydroazidation of
more challenging internal alkynes using a ligand-accelerated
gold-catalyzed protocol (Scheme 1B).[5] Extending this concept to
the haloazidation of alkynes would give access to highly valuable
bifunctional haloazidoalkenes. To date, this transformation has
been relatively underexplored, presumably due to the high
intrinsic reactivity of the compounds involved: haloazidoalkenes,
halogen azide species or reagents that serve as a halogen source,
all of which tend to form various other products such as nitriles,[6]
,-diazidoketones,[7] ,-dihaloketones[8] and diketones.[9]
Transition-metal free reactions of unreactive substrates have
attracted considerable attention from the synthetic community, as
they are often less costly, more environmentally friendly and, most
importantly, avoid possible transition metal impurities in
pharmaceutical products.[10,11] Therefore, in order to enlarge the
library of functionalized vinyl azides, we have developed a metal-
free protocol for the convenient preparation of chloroazidoalkenes
from internal alkynes at room temperature. The formed
chloroazidoalkenes can easily be converted into the
corresponding triazoles via click chemistry or into a new type of
chloro-2H-azirines under thermal conditions. Chloro-2H-azirines
provide new possibilities for biological studies of 2H-azirines and
their transformation into more complex skeletons. It was
envisaged that treatment of an internal alkyne with an appropriate
combination of an azide donor and a chloro source would lead to
the desired chloroazidoalkene. Initially, this reaction was studied
Scheme 1. Functionalized Vinyl Azides Synthesis via Alkynes
Table 1. Optimization of the Reaction Conditions
[*]
Dr. B. Huang, Dr. R. Liffert,Prof. Dr. A. Linden and Prof. Dr. K.
Gademann
Department of Chemistry, University of Zurich, Winterthurerstrasse
190, Zurich CH 8057, Switzerland
E-mail: karl.gademann@uzh.ch
We are grateful for the support of this work by the Dr. Helmut
Legerlotz Stiftung. We thank Dr. S. Williams, Dr. F. Huber, and J.
Rösslein for carefully proofreading this manuscript, and Dr. W. Shu,
Dr. X. Wei for helpful discussions.
entry chloro source TMSN3 solvent
Yielde
(%)
0
(equiv)
(equiv)
(1.2)
(1.2)
[**]
1
2
NCS (1.2)
TCICA (1.2)
DCE
DCE
0
3
2,4
N- (1.2)
DCE
26
Supporting information for this article is given via a link at the end of
the document.
chlorosaccharin
(1.2)
4
DCDMH (1.2)
(1.2)
DCE
35
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10.1002/chem.201805320
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5
6
7
8
DCDMH (1.2)
DCDMH (1.2)
DCDMH (1.2)
DCDMH (2.2)
DCDMH (1.2)
DCDMH (2.2)
DCDMH (2.2)
DCDMH (2.2)
DCDMH (2.2)
DCDMH (2.2)
(1.2)
(1.2)
(1.2)
(1.2)
(2.2)
(4.4)
(4.4)
(4.4)
(4.4)
(4.4)
CH3CN
pentane
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
29
0
procedure starting from readily available alkynes. To the best of
our knowledge, this is the first example of a chloro-2H-azirine
bearing a neighbouring CH2OR group. As 2H-azirines are
prevalent in medicines and crop protection agents,[18] this new
type of chloro-2H-azirine may provide a new scaffold for
biologically active compounds. Meanwhile, these azirines, which
process a good leaving group at the C2 position, are of special
interest as precursors for a variety of reactions involving either
retention of the azirine system (Cl displacement by various
41
38
45
57
54
45
29
trace
9
10
11a
12b
13c
14d
-
nucleophiles such as MeOH, CH3S-, N3 and AcO-) or ring
expansion to more complex skeletons (formation of diazepines,
oxazines, quinoxalines, triazines, etc).[19]
General reaction conditions: 1a (0.1 mmol, 1.0 equiv) in CH2Cl2 (0.6 ml) at 25 °C. Solvent
volume used for a: 0.3 ml; for b: 1.2 ml. Reaction temperature for c: 0 °C; for d: 50 °C. e:
isolated yield. NCS: N-chlorosuccinimide, TCICA: trichloroisocyanuric acid.
Scheme 2. Substrate Scope of Alkynes.
With the optimized conditions in hand (Table 1, entry 10), the
substrate scope involving various alkynes was investigated. As
shown in Scheme 2, a range of R1 substituents such as halides
(1b-1e), alkyl (1f-1g, 1k) and aryl (1h) groups, as well as an ester
(1i) and a nitrile (1j), were tolerated at various positions on the
phenyl ring and furnished 2b-2k in 56-73% yield. It was noted that
the (E)-isomer was observed in small amounts for ortho (1c-1j) or
meta (1k) substituents. The structure of (E)-2c was confirmed by
conversion to the corresponding triazole (E)-3a using click
chemistry and single-crystal X-ray analysis of the formed
product.[13,14,15]
Subsequently, the effect of the R2 group was studied, as
summarized in Scheme 2. The electron-donating group OMe (1l,
1m), a chloride substituent (1n) and the electron-withdrawing
group NO2 (1o) at different positions on the phenyl ring were
tolerated and afforded the corresponding chloroazidoalkenes as
single isomers in 38-50% yield. The structure of compound 2o
was unambiguously confirmed by single-crystal X-ray analysis. [15]
Next, the effect of the R3 and R4 group was examined, as
summarized in Scheme 2. Both dialkyl (1p-1s), monoalkyl (1t)
and monophenyl were tolerated and delivered the corresponding
chloroazidoalkenes in 49-72% yield. The (E)-isomer was also
observed in small amounts for 1s-1u. Interestingly, internal
alkynes are required for reactivity, which is in line with the
iodoazidation reaction reported earlier. [8a]
To demonstrate the synthetic utility of the chloroazidoalkene
products, 2o was reacted with 1-ethynyl-4-methylbenzene in the
presence of CuI and N,N-diisopropylethylamine (DIPEA) in
CH2Cl2 at room temperature for 24 h to deliver the triazole 3b in
63% yield (scheme 3); the structure of 3b was confirmed by
single-crystal X-ray analysis.[15] Furthermore, heating 2o in
toluene at 90 C for 12 h afforded the chloro-2H-azirine 4a in 79%
yield as a single isomer. However, the structure obtained by
single-crystal X-ray analysis revealed migration of the chloride
away from the benzylic position.[15] Interestingly, the same
phenomenon was observed for chloroazidoalkenes (Z)-2a, (Z/E)-
2c and (Z/E)-2f, which, upon heating, afforded the corresponding
chloro-2H-azirines 4b (76%), 4c (88%) and 4d (73%),
respectively. For this migration process we propose the
intermediate of a two -electron azacyclopropenyl (azirinium) ion,
as illustrated in Scheme 3.[16] Neighboring group participation by
the benzoate might facilitate the reaction and the observed
regioselectivity.
There are hardly any literature reports for the preparation of
chloro-2H-azirines.[16,17] and our method is an easy two-step
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General reaction conditions: 1b-1u (0.1 mmol, 1.0 equiv),
DCDMH (0.22 mmol, 2.2 equiv), TMSN3 (0.44 mmol, 4.4 equiv),
CH2Cl2 (0.6 mL), 25 oC, 12-16 h under nitrogen, isolated yield.
replacing the benzoate group with H (1v), OH (1w), OTBS (1x) or
OAc (1y) substituents, and this, along with the unique
regioselectivity of the final product, implied neighboring group
participation of the benzoate group in the reaction pathway.
Yanada and co-workers demonstrated isomerization of the C=C
double bond during the iodoazidation process of alkynes, after the
isolated mixture of E and Z isomers was exposed to the same
reaction conditions.[8a] However, using our standard reaction
conditions, no isomerization of the double bond of isolated (E)-2c
took place after stirring for 12 h. The formation of the
corresponding chloroazidoalkenes of dialkyl (1p-1s) substrates
excludes the existence of allene intermediates.
Scheme 3. Synthetic Transformation of Chloroazidoalkenes
O
NO2
O
O
O
Me
NO2
Cl
N
CuI, DIPEA
N
N
CH2Cl2, rt, 24 h
63%
N3
Cl
2o
3b
Me
90 oC, toluene
12 h, 79%
On the basis of the results obtained, the possible reaction
pathway is outlined in Scheme 5. Firstly, DCDMH reacts with the
alkyne to form a chlorirenium ion A，followed by intramolecular
attack of the benzoate group to give the oxocarbenium ion B.
Such an intermediate would explain the participation of the
benzoate in the reaction. Finally, the azide liberated from TMSN3
attacks the oxocarbenium ion B to deliver the chloroazidoalkene
product. The Z/E selectivity may be due to the instability of the E
isomer under the reaction conditions and is still under
investigation.
NO2
N
Cl
O
O
4a
O
R
R
N
N
Cl
Ph
90 oC, toluene
12 h
O
Ph
O
Ph
O
R
Scheme 5. A Possible Reaction Pathway.
O
O
N3
Cl
2a: R = H, Z isomer
2c: R = F, Z/E = 5:1
2f: R = Me, Z/E = 3:1
4b: R = H, 76%
4c: R = F, 88%
4d: R = Me, 73%
Scheme 4. Mechanistic Studies.
In conclusion, we have developed a novel metal-free chloro-
azidation of internal alkynes promoted by TMS-N3 and DCDMH.
The presented reaction proceeds under mild reaction conditions,
with good functional group tolerance and in good yield. In addi-
tion, we successfully showed that the synthesized chloroazidoal-
kenes can easily be converted into a new type of chloro-2H-
azirines, which might find application in medicinal and synthetic
chemistry. Investigation of their biological activities and transfor-
mations into more complex skeletons is ongoing in our laboratory.
Keywords: metal-free • chloroazidation • regioselective •
internal alkynes •
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internal alkynes, several control experiments were carried out, as
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10.1002/chem.201805320
Chemistry - A European Journal
COMMUNICATION
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10.1002/chem.201805320
Chemistry - A European Journal
COMMUNICATION
Layout 2:
COMMUNICATION
Bin Huang, Raphael Liffert, Anthony
Linden and Karl Gademann*
Page No. – Page No.
Metal Free Regioselective
Chloroazidation of Internal Alkynes
A metal-free, room temperature protocol for the regioselective chloroazidation of
internal alkynes is disclosed. The reactions of internal alkynes with trimethylsilyl azide
(TMS-N3) in the presence of 1,3-dichloro-5,5-dimethylhydantoin (DCDMH) afforded
the corresponding chloroazidoalkenes in good yields. This reaction has good
functional group tolerance and is operationally simple.
This article is protected by copyright. All rights reserved.