Copper-Catalyzed Three-Component Carboazidation of Alkenes with Acetonitrile and Sodium Azide

Article abstract of DOI:10.1002/anie.201705353

A copper-catalyzed three-component reaction of alkenes, acetonitrile, and sodium azide afforded γ-azido alkyl nitriles by formation of one C(sp³)?C(sp³) bond and one C(sp³)?N bond. The transformation allows concomitant introduction of two highly versatile groups (CN and N₃) across the double bond. A sequence involving the copper-mediated generation of a cyanomethyl radical and its subsequent addition to an alkene, and a C(sp³)?N bond formation accounted for the reaction outcome. The resulting γ-azido alkyl nitrile can be easily converted into 1,4-diamines, γ-amino nitriles, γ-azido esters, and γ-lactams of significant synthetic value.

Full text of DOI:10.1002/anie.201705353

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Accepted Article
Title: Copper-Catalyzed Three-Component Carboazidation of Alkenes
with Acetonitrile and Sodium Azide
Authors: Ala Bunescu, Tu M Ha, Qian Wang, and Jieping Zhu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201705353
Angew. Chem. 10.1002/ange.201705353
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Angewandte Chemie International Edition
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COMMUNICATION
Copper-Catalyzed Three-Component Carboazidation of Alkenes
with Acetonitrile and Sodium Azide
+
+
Ala Bunescu, Tu M. Ha, Qian Wang, and Jieping Zhu*
Abstract: A copper-catalyzed three-component reaction of alkenes,
the olefin leading to different azidation products. As a matter of
acetonitrile and sodium azide afforded γ-azido alkyl nitriles via
fact, a majority of the reported examples of azidocyanation,
oxyazidation and haloazidation were initiated by the addition of
3
3
3
formation of one C(sp )-C(sp ) bond and one C(sp )-N bond. The
transformation allows the concomitant introduction of two highly
[
3]
azide radical to the double bonds. Therefore, to realize our
planned transformation, we would have to inverse the
established reactivity order and to generate selectively the
cyanomethyl radical from acetonitrile in the presence of azide.
3
versatile groups (-CN and -N ) across the double bond. A sequence
involving a copper mediated generation of cyanomethyl radical
3
followed by its addition to alkene and a C(sp )-N bond formation
accounted for the reaction outcome. The resulting γ-azido alkyl nitrile
can be easily converted to 1,4-diamine, γ-amino nitrile, γ-azido ester
and γ-lactam of significant synthetic value.
We report herein a novel and efficient copper-catalyzed
azidocyanomethylation of alkenes using acetonitrile and sodium
azide as reaction partners (Scheme 1b). The protocol provides
an easy access to γ-azido alkylnitriles, which are precursors of
1
,4-diamine, γ-amino nitrile, γ-azido ester, γ-lactam and many
Recent years have witnessed important progress in the field
of difunctionalization of alkenes. However, the development of
three-component carboamination reactions using simple starting
other important motifs of high synthetic value.
3
3
a) Renaud's work on carboazidation of alkenes with C(sp )-C(sp ) bond formation
[
1-2]
R2
materials remains a standing challenge.
nitrogen sources, the azide is of particular interest as the
Among various
3 2 2
(Bu Sn) , (tBuON)
O
O
S
I
2
CO Et
R1
N
3
1
1
N3 Ph
O
Benzene, 70 °C
[
3]
resulting organoazides are valuable intermediates in synthesis.
R2
O
S
R1
2
CO Et
[
4]
[5]
[6]
(tBuON) , tBuOH
2
R2
Indeed, diazidation, azidocyanation, azidophosphonation,
2
CO Et
[
7]
[8]
R
1
N3
oxyazidation,
and haloazidation of alkenes
have been
sun lamp, 300 W, reflux
reported recently. However, three-component carboazidation
b) This work: azidocyanomethylation of alkenes
3
3
N
3
R2
reaction with the formation of C(sp )-C(sp ) bond is restricted
[Cu], [O]
[
9-10]
NaN
3
R1
H
CN
CN
only to few examples.
In this regard, Renaud and co-workers
R1
R2
1
2
developed a carboazidation of alkenes 1 employing ethyl α-
iodoacetate and phenylsulfonyl azide as the alkyl and the azide
Scheme 1. Carboazidation of Alkenes.
[
9a-9b]
sources, respectively (Scheme 1a).
Subsequently, the same
group developed an elegant, tin-free desulfonylative
carboazidation reaction employing alkanesulfonyl azides as
Me
Me
N
[
9c]
Ph
Ph
CN
CN
3
OMe
donors of both alkyl and azide groups. These methodologies
have been applied to the syntheses of a series of alkaloids,
N
3
Ph
Ph
CN
Me
Me
[
9d]
demonstrating the utility of these azido carbonyl compounds.
Alternatively, three-component azidotrifluoromethylation of
3
a
4a
5a
[
10a]
alkenes has also been developed by the groups of Liu
and
Figure 1. Side Products Isolated During Our Initial Studies.
[
10b]
Masson,
respectively.
We have recently initiated a research program aimed at
developing copper-catalyzed alkylative difunctionalization of
The feasibility of the proposed transformation was assessed
1
2
[
11-12]
using α-methylstyrene (1a, R = Ph, R = Me, Scheme 1b) as a
test substrate. Initial survey of the azide sources, the copper
salts and the oxidants prompted us to focus on the following
alkenes using alkylnitrile as a key reactant.
The salient
3
feature of this approach is that the C(sp )-H bond of alkyl nitriles
[
13-15]
was directly functionalized.
As a continuation of this project,
three-component
basic reaction parameters: NaN
equiv) and di-tert-butyl peroxide (DTBP, 2.0 equiv), acetonitrile
c 0.1 M), 140 °C (see Supporting Information for details). Under
these conditions, the desired 4-azido-4-phenylpentanenitrile (2a,
3 2
(2.0 equiv), Cu(OAc) (0.5
we became interested in developing
a
azidocyanomethylation of alkenes 1 for the synthesis of γ-azido
alkylnitriles 2 (Scheme 1b). While conceptually simple, several
challenges could impede the practical execution of the planned
transformation. Indeed, azide anion is easily oxidized to azide
radical which could subsequently initiate the radical process with
(
1
2
R = Ph, R = Me) was formed in 26% yield together with 4,5-
dimethyl-4,5-diphenyloctanedinitrile (3a, 21%) and vicinal
diazide 4a (9%, Figure 1).
The formation of diazide 4a was indicative of the presence
[
a]
Dr. A. Bunescu, Dr. T. M. Ha, Dr. Q. Wang, Prof. Dr. J. Zhu
Laboratory of Synthesis and Natural Products
Institute of Chemical Sciences and Engineering
Ecole Polytechnique Federale de Lausanne
EPFL-SB-ISIC-LSPN, BCH 5304, 1015 Lausanne, Switzerland
E-mail: jieping.zhu@epfl.ch
of the azide radical and we assumed that it was generated by
[
16]
oxidation of azide ion by Cu(II) salt.
Since ligands are known
to modulate the redox potential of Cu(II)/Cu(I), a series of
bidentate and tridentate ligands including bisoxazoline,
bipyridine, terpyridine and phenanthroline derivatives were
tested (see Supporting Information). Gratefully, addition of 1,10-
phenanthroline (1,10-phen, 0.5 equiv) to the reaction mixture
suppressed completely the formation of 1,2-diazide 4a. Further
Homepage: http://lspn.epfl.ch
+
[
]
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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Angewandte Chemie International Edition
10.1002/anie.201705353
COMMUNICATION
screening of reaction parameters showed that the yield of 2a
was increased significantly (63%) when methanol was used as
co-solvent. Importantly, only a trace amount of γ-methoxy
alkylnitrile 5a (Figure 1) was detected under these conditions.
Performing the reaction at 110 °C under otherwise identical
conditions produced 2a in 66% yield together with 5a (4% yield).
When the reaction was conducted with stoichiometric amount of
CF
3
, p-OMe, o-Me, m-Me, p-Me). Styrene derivatives such as 1-
methoxy-4-vinylbenzene
or
p-phenylvinylbenzene
were
transformed into 4-azido-4-arylbutanenitriles 2y and 2z without
event. Different alkyl groups including primary (Et, nPr,
2 2
CH CH Ph), secondary (cyclohexyl) and those bearing
functional groups (ester, OH) at the a-position of styrene were
compatible (2aa-2af). Exocyclic double bond and endocyclic
trisubstituted alkene were also successfully difunctionalized,
albeit with moderate yields (2ag-2ai). Unfortunately, propionitrile
failed to react under our optimized conditions.
2
Cu(OAc) , 2a was formed in 88% yield as the only product. This
result indicated that the active copper species might not be
regenerated effectively under sub-stoichiometric conditions.
Therefore, various co-oxidants were surveyed (see Supporting
CN
CN
3
Information) and MnF under air atmosphere turned out to be the
NaN3
conditions[a]
most effective. Overall, the optimum conditions consisted of
+
heating a solution of 1a in MeCN/MeOH (v/v = 1/1, c 0.1 M) in
H
CN
N3
the presence of Cu(OAc)
2
(0.2 equiv), MnF
3
(0.3 equiv), 1,10-
6
7 36%
8 20%
phen (0.65 equiv) and DTBP (2.0 equiv) at 110 °C. Under these
Me
NaN3
Me
Me
conditions, 2a was isolated in 72% yield.
Me
conditions[a]
N3
H
CN
NC
conditions[a]
N3
9 (-)-β-Pinene
10 42%
R2
NaN3
H
CN
R1
CN
R1
R2
Scheme 3. Radical Clock Experiments. [a] Cu(OAc)
0.65 equiv), NaN (2.0 equiv), MnF (0.3 equiv), DTBP (2.5 equiv),
MeCN/MeOH (1:1), 110 °C, air.
2
(0.2 equiv), 1,10-Phen
1
2
(
3
3
N3
N3
N3
CN
CN
CN
R
Me
Me
Ph
R
N
2
j, 52%
2l, R = H, 76%
2
a, R = H, 72%
Control experiments were performed to gain insights on the
reaction mechanism. The azidocyanomethylation of 1a took
place in the absence of DTBP albeit with low conversion. On the
other hand, compound 2a was not formed in the absence of
2
2
2
2
2
2
2
2
b, R = 3-Me, 62%
c, R = 4-Me, 72%
d, R = 4-OMe, 73%
e, R = 4-Ph, 74%
f, R = 3-NO2, 54%
g, R = 3-Cl, 57%
h, R = 4-Cl, 50%
i, R = 3-CF3, 51%
2m, R = 2-Me, 61%
2n, R = 3-Me, 73%
2o, R = 4-Me, 73%
2p, R = 4-OMe, 67%
2q, R = 4-Br, 69%
2r, R = 4-F, 73%
N3
S
CN
CN
Me
2
Cu(OAc) , suggesting the essential role of copper to this
2k, 48%
2s, R = 3-Cl, 59%
2t, R = 3-CF3, 71%
reaction. Submitting 1-(1-cyclopropylvinyl)benzene (6) to our
standard conditions afforded rearranged products 7 and 8 in
yields of 36% and 20%, respectively (Scheme 3). Similarly,
treatment of β-pinene (9) under our standard conditions afforded
the ring-opened product 10 in 42% yield. The results of these
two radical clock experiments are indicative of the radical
N3
N3
N3
CN
Ph
CN
R1
R1
R2
R
aa, R1 = Et, 65%
2
2
1
ab, R = nPr, 63%
2
2
2
2
2
u, R1 = R = 4-Me, 75%
v, R1 = R = 4-Cl, 69%
w, R1 = R2 = 4-F, 72%
1
2y, R = 4-OMe, 46%[b]
2z, R = 4-Ph, 58%[b]
2ac, R = CH CH Ph, 61%
2
2
2
2ad, R1 = cC H , 58% (72%)[c]
11
ae, R1 = CH2CH2CO2Me, 61%[b]
6
intermediate in these reactions. By monitoring the reaction
2
x, R1 = 4-MeO, R2 =3-CF3, 67%
2af, R1 = CH2CH2OH, 50% (57%)
[c]
1
CN
progress by H NMR spectroscopy [Cu(OAc)
2
(0.5 equiv), 1,10-
N3
CN
N3
N3
CN
phen (0.5 equiv), DTBP (2.0 equiv), MeOH/MeCN = 1:1, 140 °C],
we noticed that the yield of 2a reached maximum (63%) after
only 20 min and that only a trace amount of dimer 3a was
produced at this stage. Prolonging the reaction time (2 h)
produced dimer 3a in 7% yield without increasing the amount of
Ph
2
ag, 48%
2ah, 46% (54%)[b,c]
2ai, 46%[d]
Scheme 2. Scope of Carboazidation Reaction. [a] Cu(OAc)
Phen (0.65 equiv), MnF
M), 110 °C, air. [b] Cu(OAc)
2
(0.2 equiv), 1,10-
(0.3 equiv), DTBP (2.0 equiv), MeCN/MeOH (1:1, 0.1
(0.5 equiv), MnF (0.15 equiv) were used. [c]
2
a. This observation indicated that active copper species, most
3
probably Cu(II) salt, was required for the C-N bond formation. In
3
2
3
yield in parenthesis was calculated based on conversion. [d] only one
diastereoisomer was isolated.
its absence, dimerization of benzyl radical would become
competitive leading to dimer 3a.
On the basis of the above experimental results, a possible
reaction pathway for the azidocyanomethylation of alkenes is
With the optimized conditions in hand, the generality of the
carboazidation process was investigated (Scheme 2). Electron
[
17]
depicted in Scheme 4.
followed by deprotonation would afford cuprate A,
upon homolytic cleavage, would afford cyanomethyl radical B.
Addition of B to alkenes 1 led to benzyl radical C, which upon
reaction with Cu(II)LN (ligand transfer or Cu(III) intermediate),
would deliver γ-azido alkylnitrile 2 with the concurrent release of
Coordination of acetonitrile to Cu(II)
[
14d-g]
which,
2 3
donating (Me, OMe) and withdrawing groups (NO , Cl, CF ) on
[
18]
the phenyl ring of the α-methyl styrene derivatives were well
tolerated leading to γ-azido alkylnitriles (2b-2i) in good yields.
Heteroaromatics such as pyridine and thiofuran were compatible
with the reaction conditions (2j, 2k). The 1,1-diaryl ethylenes
were similarly difunctionalized to afford the desired products (2l-
3
I
[19]
3
Cu(I) salt. Finally, oxidation of Cu by DTBP or by MnF would
regenerate the catalytic Cu(II) species. The presence of
2
x) in good yields regardless of the electronic nature and the
intermediate C was clearly evidenced by our radical clock
position of substituent on the aromatic ring (p-Cl, p-Br, o-F, p-
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Angewandte Chemie International Edition
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COMMUNICATION
experiments (cf Scheme 3). The dimerization of C leading to
dinitrile 3 (path c) was suppressed when the Cu(II) salt was
3
hydrogenation using Lindlar catalyst (Pd/CaCO ) allowed the
chemoselective reduction of azido function to provide γ-amino
alkylnitrile 12. Treatment of 2a under acidic conditions (HCl in
dioxane, MeOH) afforded γ-azido ester 13 which, upon
hydrogenation of azide, was converted to pyrrolidinone 14.
efficiently regenerated or a stoichiometric amount of Cu(OAc)
2
was employed. The important role played by ligand could be
explained by the fact that the coordination of 1,10-phen to
copper acetate reduced effectively the redox potential of
[
16]
In conclusion, we reported the first examples of copper-
catalyzed azidocyanomethylation of alkenes using acetonitrile
and sodium azide as reaction partners. The reaction produced γ-
Cu(II)/Cu(I), inhibiting thereby the generation of azide radical
which would be responsible for the formation of 1,2-diazide 4. It
is worth noting that only a trace amount of 4 was generated
despite the presence of Mn(III) salt that was known to oxidize
3
3
azido alkylnitriles via formation of one C(sp )–C(sp ) bond and
3
[
4d, 4e, 7b]
one C(sp )–N bond. The γ-azido alkylnitrile was readily
azide ion to azide radical.
converted to 1,4-diamine, γ-amino nitrile, γ-azido ester and γ-
lactam, useful building blocks in organic synthesis and in
medicinal chemistry.
CuIIL
tBuO-
3
CH CN, Base
1/2 DTBP
MnII
CuIIL
MnIII
NC
Acknowledgements
R1
A
CuIL
CN
CN
R2
R1
We thank EPFL (Switzerland), Swiss National Science
Foundation (SNSF) and Swiss National Centers of Competence
in Research NCCR-Chemical Biology for financial supports.
N3
R2
3
R1
path a
CH -CN
2
CN
path c
R2
R1
B
2
II
Cu LN3
R2
R1
CN
C
Keywords: Homogeneous catalysis • multicomponent reaction •
CuII
R2
path b
1
CuI
azide • alkenes • difunctionalization
N3
R1
OMe
R1
+
CN
R2
R1
R2
R2
CN
CN
2
D
5
[
1]
For two-component carboamination other than carboazidation reactions,
see: a) D. Wang, L. Wu, F. Wang, X. Wan, P. Chen, Z. Lin, G. Liu, J.
Am. Chem. Soc. 2017, 139, 6811; b) Z. Hu, X. Tong, G. Liu, Org. Lett.
Scheme 4. Proposed Reaction Pathway for Carboazidation Reaction.
2
016, 18, 1702; c) A. Faulkner, J. S. Scott, J. F. Bower, J. Am. Chem.
Soc. 2015, 137, 7224; d) D. R. White, J. T. Hutt, J. P. Wolfe, J. Am.
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15, 5420; g) C. F. Rosewall, P. A. Sibbald, D. V. Liskin, F. E. Michael, J.
Am. Chem. Soc. 2009, 131, 9488.
Alternatively, oxidation of radical C by Cu(II) followed by
trapping of the resulting tertiary carbocation D by azide could
[
20]
also afford the carboazidation product 2 (path b). Should this
be the case, carbocation D would also be trapped by methanol
[
2]
For two-component carboazidation reactions, see: a) Z. Wu, R. Ren, C.
Zhu, Angew. Chem. Int. Ed. 2016, 55, 10821; Angew. Chem. 2016, 128,
in a MeOH/CH
3
CN solvent mixture leading to a competitive
[
11c]
formation of γ-methoxy alkylnitrile 5.
However, this was not
1
0979; b) X.-H. Ouyang, R.-J. Song, Y. Liu, M. Hu, J.-H. Li, Org. Lett.
015, 17, 6038; c) W. Kong, E. Merino, C. Nevado, Angew. Chem. Int.
observed under our optimized conditions. Furthermore, the fact
that azidocyanomethylation of methyl 4-phenylpent-4-enoate
2
Ed. 2014, 53, 5078; Angew. Chem. 2014, 126, 5178-5182; d) X.-H. Wei,
Y.-M. Li, A.-X. Zhou, T.-T. Yang, S.-D. Yang, Org. Lett. 2013, 15, 4158;
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account on the chemistry of 1,3-dicarbonyl derived radical, see B. B.
Snider, Tetrahedron 2009, 65, 10738.
(
1ae) produced 2ae without competitive formation of γ-lactone
[
11b]
was also against the carbenium intermediate.
Consequently,
we assumed that a copper-mediated azide transfer to radical C
was more likely to occur (path a).
[
[
3]
4]
K. Wu, Y. Liang, N. Jiao, Molecules 2016, 21, 352.
a) Y. A. Yuan, D. F. Lu, Y. R. Chen, H. Xu, Angew. Chem. Int. Ed. 2016,
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H
2
(1 atm)
H2 (1 atm)
10% Pd/C
NH
2
N
3
NH
Pd/CaCO
3
2
NH
2
Ph
CN
Ph
N
CN
Ph
EtOH, rt
MeOH, rt
Me
Me
Me
11 56%
1
2 72%
2a
HCl/dioxane
MeOH, rt
O
2
H (1 atm)
Pd/CaCO
3
HN
3
[
5]
a) D. Wang, F. Wang, P. Chen, Z. Lin, G. Liu, Angew. Chem. Int. Ed.
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Chem. Commun. 2015, 51, 11240.
Me
Ph
14 88%
Ph
COOMe
Me
EtOH, rt
1
3 45% (92% brsm)
[
[
6]
7]
Scheme 5. Post Transformation of γ-Azido Alkylnitrile 2a.
a) G. Fumagalli, P. T. G. Rabet, S. Boyd, M. F. Greaney, Angew. Chem.
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X. Sun, X. Li, S. Song, Y. Zhu, Y.-F. Liang, N. Jiao, J. Am. Chem. Soc.
Conversion of γ-azido alkylnitrile 2a to other useful structural
motifs is depicted in Scheme 5. Hydrogenation of 2a in the
presence of Pd/C afforded diamine 11. On the other hand,
2
015, 137, 6059; d) X.-F. Xia, Z. Gu, W. Liu, H. Wang, Y. Xia, H. Gao,
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Angewandte Chemie International Edition
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COMMUNICATION
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Angewandte Chemie International Edition
10.1002/anie.201705353
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 1:
Cu(OAc)2 (0.2 equiv)
,10-phen (0.65 equiv)
MnF3 (0.3 equiv)
Synthetic Method
1
N3
R2
NaN3
Ala Bunescu, Tu Minh Ha, Qian Wang and
H
CN
R1
CN
R1
DTBP (2.0 equiv)
CH3CN/MeOH (1/1) (0.1 M)
1
R2
Jieping Zhu*__________ Page – Page
10 °C, air
Formation of one C(sp )-C(sp ) bond and one C-N bond
* Introduction of two versatile functional groups (N3, CN)
Creation of a quaternary carbon
High chemo- and regioselectivities
Copper-Catalyzed Three-Component
3
3
*
Carboazidation of Alkenes with
Acetonitrile and Sodium Azide
*
*
Be disciplined Regioselective azidocyanomethylation of alkenes took place smoothly in the presence of
2 3
di-tert-butyl peroxide, a catalytic amount of Cu(OAc) and MnF to afford g-azido alkylnitriles, highly
valued synthetic building blocks.
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