Copper-Catalyzed Ligand-Free Diazidation of Olefins with TMSN3 in CH3CN or in H2O

Article abstract of DOI:10.1021/acs.orglett.7b02982

An environmentally benign, copper-catalyzed diazidation of a broad range of olefins, including vinylarenes, unactivated alkenes, allene, and dienes, under mild conditions with TMSN₃ (trimethylazidosilane) as azido source, has been developed. This reaction can be carried out in organic solvent or in aqueous solution where water is the sole solvent. The functional group compatibility of this reaction is good, which is proved by late-stage functionalizations of complex substrates.

Full text of DOI:10.1021/acs.orglett.7b02982

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
Copper-Catalyzed Ligand-Free Diazidation of Olefins with TMSN3 in
CH3CN or in H2O
Huan Zhou,† Wujun Jian,† Bo Qian,† Changqing Ye,† Daliang Li,‡ Jing Zhou,† and Hongli Bao*,†
†Key Laboratory of Coal to Ethylene Glycol and Its Related Technology, State Key Laboratory of Structural Chemistry, Fujian
Institute of Research on the Structure of Matter, University of Chinese Academy of Sciences, 155 Yangqiao Road West, Fuzhou,
Fujian 350002, P. R. China
‡Biomedical Research Center of South China & College of Life Science, Fujian Normal University, 1 Keji Road, Minhou, Fuzhou,
Fujian Province 350117, P. R. China
S
* Supporting Information
ABSTRACT: An environmentally benign, copper-catalyzed diazidation
of a broad range of olefins, including vinylarenes, unactivated alkenes,
allene, and dienes, under mild conditions with TMSN3 (trimethylazido-
silane) as azido source, has been developed. This reaction can be carried
out in organic solvent or in aqueous solution where water is the sole
solvent. The functional group compatibility of this reaction is good,
which is proved by late-stage functionalizations of complex substrates.
ifunctionalization of olefins is a powerful approach for
reactivities of a reaction taking place in water and in organic
1
Dinstalling two functional groups on hydrocarbons. solvents. Although radical reactions are sometimes insensitive
Among such reactions, diazidation2,3 is of particular interest
to water and many organic radical reactions have been carried
out in a mixed solvent containing water, very few radical
reactions can be achieved both in organic solvent and in
water.11,12
because of the diverse applications of 1,2-diazides. Besides the
existence of azido groups in natural products and bioactive
compounds,4 1,2-diazides could serve as precursors for the
synthesis of valuable 1,2-diamines,5,6 which are prevalent in
bioactive compounds, drugs, and molecular ligands. Recently,
Greaney and co-workers,2a as well as Loh and co-workers,2b
developed the useful copper-catalyzed diazidation of styrenes
separately with hypervalent iodine compounds. More recently,
Xu and co-workers2c reported a powerful diazidation of general
alkenes including vinylarenes and unactivated alkenes in the
presence of coordinated iron catalyst, and very recently, Lin
disclosed the metal-catalyzed electrochemical diazidation of
general alkenes (Scheme 1, eqs 1−3).3 Notwithstanding these
significant breakthroughs, the need for ligand, toxic NaN3, or
azidoiodine(III) reagent attaches limitations to the state of art
in diazidation of alkenes.
In this paper, we report the copper-catalyzed, ligand-free
diazidation of styrenes, unactivated alkenes, dienes, and allene
with TMSN3 in organic solvent or in water (Scheme 1, eq 5) in
interrupted Kharasch−Sosnovsky reaction conditions.
We initiated our studies with the diazidation reaction of
styrene 1a (0.5 mmol) in water with TMSN3 in the presence of
TBPB. The 1,2-diazide 3 was obtained in 24% yield in 1 mL of
H2O in the presence of CuI (Table 1, entry 1). The yield was
improved to 50% when 2 mL of H2O was used (entry 2). An
investigation of phase-transfer catalysts revealed N(Bu)4I as
optimal, and product was obtained in up to 88% yield using 10
mol % of N(Bu)4I (entries 3−6). Examination of different
metal catalysts revealed that Cu(OTf)2 was a better catalyst
than CuI (entry 7). Other catalysts and peroxides failed to
provide better results (entries 8−18). Interestingly, this
reaction proceeded smoothly in CH3CN with CuI as catalysts,
delivering even better results (entry 19, up to 96% yield). These
versatile reaction conditions could be useful in a practical
application and bioorthogonal chemistry.
We have developed iron-catalyzed methylation of vinylarenes
using tert-butyl perbenzoate (TBPB).7 Methyl radical is
generated in this reaction from TBPB. But interestingly, in
the presence of a copper catalyst, we did not observe any
formation of methyl radicals. This observation is consistent
with the results from the classical Kharasch−Sosnovsky
reaction.8 We speculate that, in the presence of a copper
catalyst, diazidation might happen taking advantage of multiple
functionalities of TBPB and the probability of generation of an
Si−O bond (Scheme 1, eq 4), given that the bond energy of
Si−O is 452 kJ/mol.9
With the identified conditions in hand, we proceeded to
study the scope of olefins in two systems (H2O and CH3CN),
and the results are summarized in Table 2. Substrates with
various substituents (R) such as alkyl, halogen, ester, and
methyl ether on aromatic rings are compatible with this
Water is an ideal solvent for organic chemistry10 not only
because of its inexpensive and environmentally benign
characteristics, but also because of its well-known different
Received: September 22, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02982
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Diazidation of Olefins and This Work
Table 2. Generalization of Scope of the Reaction
a
Table 1. Reaction Condition Optimization
a
Results outside the parentheses were obtained in water via method A.
Results in parentheses were obtained in CH3CN via method B.
Method A for vinylarenes, dienes, and allene: olefin (0.5 mmol),
Cu(OTf)2 (5 mol %), TBAI (10 mol %), TBPB (1.5 equiv), TMSN3
(3.5 equiv), H2O (2 mL), 50 °C; for other olefins: olefin (0.5 mmol),
Cu(OTf)2 (5 mol %), TBAI (10 mol %), TBPB (1.5 equiv), TMSN3
(4.5 equiv), H2O(2 mL), 70 °C. Method B for vinylarenes, dienes and
allene: olefin (0.5 mmol), CuI (10 mol %), TBPB (1.5 equiv), TMSN3
(3.5 equiv), CH3CN (2 mL), 50 °C; for other olefins: olefin (0.5
mmol), CuBr·SMe2 (5 mol %), TBPB (2 equiv), TMSN3 (4.5 equiv),
CH3CN (2 mL), 70 °C. See additional details in the Supporting
Information.
bc
,
entry
catalyst (mol %)
CuI (10)
solvent (mL)
H2O (1)
yield (%)
d
1
24
d
2
CuI (10)
H2O (2)
50
e
3
CuI (10)
H2O (2)
trace
8
f
4
CuI (10)
H2O (2)
g
5
CuI (10)
H2O (2)
80
6
CuI (5)
H2O (2)
85
7
Cu(OTf)2 (5)
Cu(CH3CN)4PF6 (5)
CuCl (5)
H2O (2)
H2O (2)
88 (86)
86
8
9
H2O (2)
70
10
11
12
13
14
Fe(OTf)2 (5)
CoCl2 (5)
H2O (2)
26
transformation and give the desired products 4−20 in good
yields. Disubstituted thiazole is compatible, delivering the
corresponding product 21 in 61% yield. 1,1-Disubstituted
vinylarenes and 1,2-disubstituted vinylarenes are suitable
substrates for this reaction and afford the corresponding
products 22 and 23 in 51−84% yield. Interestingly, the reaction
in different solvent systems behaves differently with cyclized
olefins and products with different diastereoisomeric ratios (dr)
are obtained 24−26. Encouraged by these results, we examined
the reactivity of unactivated olefins. Simple olefins with an
isolated CC bond are compatible with this reaction and lead
to the expected products 27−33. The products 32 and 33
containing a free hydroxyl group and a carboxylic acid are not
observed in the CH3CN system but in H2O are obtained in
63−67% yield. Dienes and allene are compatible with this
reaction giving products 34−38 in moderate yield.
H2O (2)
24
NiCl2(5)
H2O (2)
21
Mn(OAc)3 (5)
Pd(OAc)2 (5)
Cu(OTf)2 (5)/LPO
Cu(OTf)2 (5)/TBHP
Cu(OTf)2 (5)/DTBP
Cu(OTf)2(5)/H2O2
CuI (10)
H2O (2)
trace
trace
trace
74
H2O (2)
h
15
H2O (2)
h
16
H2O (2)
h
17
H2O (2)
trace
20
h
18
H2O (2)
d
19
CH3CN (2)
CH3CN (1), H2O (1)
96 (92)
88
d
20
CuI (10)
a
1a (0.5 mmol), 2 (3.5 equiv), TBPB (1.5 equiv), N+(Bu)4I− (10 mol
b
c
%) and solvent. Yields were determined by 1H NMR. Yield of
d
e
f
isolated product. PTC free. 18-crown-6 (100 mol %). C11H23CO2H
g
h
(100 mol %). N+(Bu)4Br− (100 mol %). Other peroxides were used
instead of TBPB. LPO = lauroyl peroxide, TBHP = tert-butyl hydrogen
peroxide, DTBP = di-tert-butyl peroxide.
To highlight the synthetic utility of this method, late-stage
functionalization of several complex molecules was investigated
B
DOI: 10.1021/acs.orglett.7b02982
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
under the standard reaction conditions (Table 3). The natural
product nootkatone, a component of grapefruit, was trans-
Scheme 2. Preliminary Mechanistic Study
Table 3. Late-Stage Functionalization of Complex Substrates
and Different Chemoselectivity of Vinyl Pyridine in CH3CN
a
and H2O
Scheme 3. Proposed Catalytic Cycle
a
Results outside the parentheses were obtained in water via method A.
Results in parentheses were obtained in CH3CN via method B.
Method A: olefin (0.25 mmol), Cu(OTf)2 (5 mol %), TBAI (10 mol
%), TBPB (1.5 equiv), TMSN3 (3.5−4.5 equiv) H2O (2 mL), 50 or 70
°C. Method B: olefin (0.25 mmol), CuI (10 mol %) or CuBr·SMe2 (5
mol %), TBPB (1.5 or 2 equiv), TMSN3 (3.5−4.5 equiv), CH3CN (2
mL), 50 or 70 °C. See additional details in the Supporting
Information.
generating a tert-butoxyl radical and a Cu(II) species. A radical
relay process then occurs between TMSN3 and the tert-butoxyl
radical to afford an azido radical that adds to the olefin,
generating an internal radical. Ligand exchange delivers
Cu(II)N3, and finally, this Cu(II)N3 reacts with the internal
radical to deliver the desired diazidation products and
regenerate Cu(I). Considering the result of 1,6-heptadiene,
the formation of Cu(III) species is an alternative pathway.15
The formation of Cu(II)OH species which reacts with TMSN3
to generate azido radical, especially in aqueous solution, cannot
be excluded. Similarly, the hydrolysis of TMSN3 in H2O to
HN3, which participates in the following reaction, cannot be
ruled out.16
In summary, we have developed a general diazidation of
vinylarenes, unactivated olefins, dienes, and allene with TMSN3
as nitrogen functionality. The reaction conditions are mild, and
the functional group compatibility is considerable. This reaction
is operationally simple and environmentally benign, and most
importantly, it can be carried out in both an organic solvent
system and a water system. Such versatile reaction conditions
could be useful in practical applications by offering more
options.
formed to 39 in 56% yield in 1:1 diastereoisomeric ratio (dr).
The drug molecules exemestane and simvastain are also
compatible with the reaction conditions and deliver the
diazidation products 40 and 41 as single isomers in 75% and
64% yields. Two other estrone-based complex molecules were
also investigated and delivered products 42 and 43 in good
yields. Amino acid derivative was examined and gave product
44 in moderate yields. Surprisingly, reaction of 2-vinylpyridine
shows different chemoselectivities, producing the diazidation
product 46 in CH3CN and the hydroazidation product 47 in
water. The reason for this different reactivity remains unclear.
We performed preliminary experiments to probe the
mechanism of the reaction (Scheme 2). When a radical spin
trap experiment is performed with 2,6-di-tert-butyl-4-methyl-
phenol (BHT) as radical scavenger, no product is observed
while 4-azido-2,6-ditert-butyl-4-methylcyclohexa-2,5-dienone
48 is isolated in 24% yield.13 Reactions of trans-stilbene and
cis-stilbene deliver the same products in different yields but with
the same dr. These results are consistent with a stepwise radical
process. To further understand this reaction, reaction of 1,6-
heptadiene was investigated. To our surprise, a mixture of
cyclized and uncyclized products 53 and 52 was obtained in
2.9:1 ratio. 5-Exo cyclization of 5-hexanyl radical is fast, and the
rate constant for this step is known (about 105 s−1).14 This
result implies that the second azidation step is fast or that
unfree radical exists.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02982.
In view of the results of these mechanistic experiments, a
radical catalytic cycle is proposed (Scheme 3). A single-electron
transfer between Cu(I) and TBPB initiates the reaction by
Experimental details and NMR spectra (PDF)
C
DOI: 10.1021/acs.orglett.7b02982
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: hlbao@fjirsm.ac.cn.
ORCID
Hongli Bao: 0000-0003-1030-5089
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank NSFC (Grant Nos. 21402200, 21502191,
21672213), Strategic Priority Research Program of the Chinese
Academy of Sciences (Grant No. XDB20000000), The 100
Talents Program, “The 1000 Youth Talents Program”, and the
Innovative Research Teams Program II of Fujian Normal
University in China (IRTL1703) for financial support. We
thank Professor Weiping Su from our institute for the useful
suggestions.
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DOI: 10.1021/acs.orglett.7b02982
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