Ti-Catalyzed Multicomponent Oxidative Carboamination of Alkynes with Alkenes and Diazenes

Article abstract of DOI:10.1021/jacs.6b09939

The inter- or intramolecular oxidative carboamination of alkynes catalyzed by [py₂TiCl₂NPh]₂ is reported. These multicomponent reactions couple alkenes, alkynes and diazenes to form either α,β-unsaturated imines or α-(iminomethyl)cyclopropanes via a Ti^II/Ti^IV redox cycle. Each of these products is formed from a common azatitanacyclohexene intermediate that undergoes either β-H elimination or α,γ-coupling, wherein the selectivity is under substrate control.

Full text of DOI:10.1021/jacs.6b09939

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Communication
Ti-Catalyzed Multicomponent Oxidative
Carboamination of Alkynes with Alkenes and Diazenes
Zachary W Gilbert, Letitia J. Yao, and Ian A. Tonks
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 24 Oct 2016
Downloaded from http://pubs.acs.org on October 24, 2016
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Ti-Catalyzed Multicomponent Oxidative Carboamination of Alkynes
with Alkenes and Diazenes
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Zachary W. Gilbert, Letitia J. Yao and Ian A. Tonks*
Department of Chemistry, University of Minnesota – Twin Cities, 207 Pleasant St SE, Minneapolis MN 55455
Supporting Information Placeholder
mode of TiII/TiIV redox reactivity has the potential to
open up vast new classes of Ti-catalyzed reactions.
ABSTRACT: The inter- or intramolecular oxidative
carboamination
of
alkynes
catalyzed
by
[py2TiCl2NPh]2 is reported. These multicomponent
reactions couple alkenes, alkynes and diazenes to form
Given that the mechanisms of each alkyne coupling
step in the [2+2+1] pyrrole synthesis are different, we
postulated that it should be possible to decouple the
reacting partners and design multicomponent coupling
reactions of different unsaturated substrates.
Encouragingly, Odom,8 Livinghouse9 and Mindiola3c,d,e
have recently demonstrated that isocyanides, nitriles,
and imines can intercept analogous [2+2]
imide+alkyne azatitanacyclobutene intermediates in
hydroamination-like reactions.
either
α,β-unsaturated
imines
or
α-
(iminomethyl)cyclopropanes via a TiII/TiIV redox cycle.
Each of these products is formed from a common
azatitanacyclohexene intermediate that undergoes
either β-H elimination or α,γ-coupling, wherein the
selectivity is under substrate control.
Simple intermolecular alkyne carboamination reactions
can potentially provide convenient access points to a
range of important functional groups and reactive
intermediates such as α,β-unsaturated imines, α-
functionalized
imines,
Although
or
α-functionalized
cyclopropanes.1
analogous alkyne
hydrofunctionalization reactions2 have been heavily
studied, the current methods for alkyne carboamination
are limited to coupling of diaryl aldimines and alkynes
using early transition metals,3 through intramolecular
reactions catalyzed by late transition metals,4 or
through multistep processes catalyzed by Cu and Rh.5
Similarly,
alkene
carboamination6
has seen
considerable advances recently, but these methods are
still mainly limited to intramolecular cyclization
reactions.
Accessing
practical,
intermolecular
multicomponent carboamination catalysis remains a
significant challenge.
Figure 1. Overview of Ti-catalyzed nitrene transfer
reactions.
Recently,
we
reported
a
multicomponent,
py3TiCl2(NPh)-catalyzed formal [2+2+1] reaction of
alkynes and diazenes for the oxidative synthesis of
penta- and trisubstituted pyrroles (Figure 1).7 In our
preliminary studies of the mechanism, we found that
an alkyne initially undergoes [2+2] cycloaddition with
a Ti imido to generate an azatitanacyclobutene
intermediate, I, which then undergoes insertion of a
second alkyne to generate an azatitanacyclohexadiene,
II. This species then reductively eliminates pyrrole,
and the resulting TiII fragment is reoxidized to a TiIV
imido by azobenzene. We anticipate that this new
Our initial target of this strategy was the
multicomponent coupling of an alkyne and an alkene
with azobenzene. Alkenes were chosen as the third
reacting partner because they readily undergo 1,2- and
2,1-insertion reactions, but typically do not undergo
intermolecular [2+2] reactions with Ti imidos,10 thus
limiting the potential for unwanted alkene
homocoupling. Herein, we report our initial results on
the intra- and intermolecular oxidative multicomponent
coupling of alkynes, alkenes and diazenes, which
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yields formal alkyne carboamination products: either [py2TiCl2(NPh)]2 in the presence of
Page 2 of 5
equiv.
1
o
1
2
3
4
5
6
7
8
α,β-unsaturated
imines
or
α-functionalized
azobenzene at 115 C gave the α,β-unsaturated imine
1-(2-methylcyclopent-1-en-1-yl)-N-phenylpentan-1-
imine (2a) in 50% isolated yield (Figure 2).7
cyclopropanes.
Table 1. Scope of multicomponent carboamination of
tethered enynes with PhNNPh.a
This product likely forms through the expected
azatitanacyclohexene intermediate III, but instead of
C-N reductive coupling to form a dihydropyrrole, the
metallacycle collapses via β-H elimination to give IV,
followed by subsequent N-H reductive elimination to
Ph
PhNNPh
Ph
R1
N
2.2 equiv.
N
5% [py2TiCl2NPh]2
R2
R2
-or-
R2
R1
PhCF3, 115 oC
16 h
1a-m
2a-m
3a-m
9
V
and dieneamine isomerization (Figure 2).
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Substrate
% Isolated
Yieldb
(2:3)
1H NMR
% Yield
Alternately, direct β-H abstraction by the amide from
intermediate III could also form V.11 Unlike in the
previously reported pyrrole synthesis, it is likely that
the sp3-hybridized α-C is less prone to C-N reductive
elimination due to poor orbital overlap,12 which allows
for the β-H elimination pathway to kinetically
outcompete direct C-N elimination.
(2:3)
1a
1b
1c
1d
1e
1f
50
92
nBu
nBu
(>99:1)
86
(85:15)
92
D
(44:56)
37
(53:47)
d
N
-
Bn
Et
(>99:1)
13
(1: >99)e
N
29
Bn
nBu
(1: >99)
91
60
nBu
(>99:1)
69
(>99:1)
86
Figure 2. Tethered enynes yield α,β-unsaturated
imines upon catalysis with PhNNPh.
(>99:1)
50
(>99:1)
nBu
d
Ph
1g
-
In an attempt to shut down β-H elimination, we next
examined substrates that upon metallation would lack a
β-H to eliminate. Treatment of N-benzyl-N-(2-
methylallyl)hept-2-yn-1-amine (1d) under catalytic
conditions gave 1-(1-benzyl-5-methylenepiperidin-3-
yl)pentan-1-one (3d’) in low yield upon acidic workup.
This product arises from isomerization via retro-ene
ring opening of a cis-cyclopropane (3d), which is
generated via catalysis (Figure 3).
(>99:1)
nBu
d
1h
1i
54
-
nBu
(49:51)
d
57
-
Ph
Ar
Ar
(5:95)f
36
d
1j
-
Ar = p-CF3Ph
Ar = p-MeOPh
(1:>99)g
d
1k
37
-
(1:>99)h
0
1l
n.d.
n.d.
nBu
1m
0
tBu
aLoading of [py2TiCl2NPh]2 and reaction yields with respect to
PhNNPh. bIsolated as the ketone product after hydrolysis. See SI for
details. cDetermined by 1H NMR analysis of the crude reaction
d
1
mixture. Could not be determined due to peak overlap in the H
e
NMR spectrum. Isolated as the retro-ene product 3d’ (Figure 3).
Figure 3. Internally substituted alkenes yield α-
(iminomethyl)cyclopropanes upon catalysis with
PhNNPh as β-H elimination/abstraction is shut down.
fAs a mixture of 2i, 3i and 4i (Figure 5). gAs 4j. hAs a mixture of 3k
and 4k.
We initially focused on the [py2TiCl2(NPh)]2-catalyzed
reaction of tethered enynes with azobenzene,
envisioning that the intramolecular reactions would be
less likely to suffer from competitive pyrrole formation
or alkyne trimerization (Table 1). Reaction of 2.2
Remarkably, by shutting down the β-H elimination
process, the azatitanacyclohexene IIId collapses via
attack of the α-C on the γ-C,13 resulting in reductive
elimination of an α-imino functionalized cyclopropane.
In fact, this cyclopropanation can also be observed
equiv. undec-1-en-6-yne (1a) with
5
mol
%
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Interestingly, simply changing from a propyl linker
when using the deuterated analogue 1b: because β-D
1
2
3
4
5
6
(1a) to a butyl linker (1h) erodes selectivity for the
α,β-unsaturated imine 2h from 85:15 to 50:50,
indicating that there is a subtle steric balance between
β-H elimination and α,γ-coupling. Shorter tethers (1l),
as expected, do not undergo reaction and bulky
substituents on the alkyne (1m), which enforce the
wrong [2+2] regiochemistry necessary for alkene
insertion, also do not react productively.
elimination (which must occur in 1b) is typically
slower than β-H elimination (in 1a), there should be a
larger krel for forming the cyclopropane 3 versus the
α,β-unsaturated imine 2 in the reaction of 1b. This is
1
reflected in the H NMR product ratios, where 1a
forms an 85:15 ratio of 2a:3a, while at similar overall
conversion 1b forms a larger percentage of 3b, 50:50
2b:3b.
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The overall preliminary mechanistic manifold of these
carboaminations is presented in Figure 4.
Azatitanacyclohexenes (III) are prone to metallacycle
collapse via competitive α,γ-coupling (VI) or β-H
elimination/abstraction (IV). These pathways are
kinetically accessible because the α and β-carbons are
sp3-hybridized, making direct C-N reductive coupling
more challenging while opening up alternative
reductive cleavage pathways through the increased
flexibility of the metallacycle. This is characteristic of
all of the multicomponent reactions reported herein.
Aryl-substituted alkynes heavily favor α,γ-coupling
due to increased electrophilicity of the γ-C caused by
the aryl substituent (1i-1k). Furthermore, the resulting
electrophilic bicyclo[3.1.0]hexane arylimines (3i-3k)
undergo further reactivity in situ: titanium Lewis acid-
catalyzed carbocation rearrangement yields the fused
1-arylbicyclo[4.1.0]heptan-2-imines 4i-4k (Figure 5).
R
R
PhNNPh
2.2 equiv.
5% [py2TiCl2NPh]2
N
PhCF3, 115 oC
16 h
Ph
R = H (2i), CF3 (2j), OMe (2k)
4i-4k
R
LA
Ph
N
LA
N
Ph
3i-3k
R
Figure
5.
Phenyl-substituted
alkynes
yield
bicyclo[3.1.0]hexane imines that can undergo Lewis
acid-catalyzed carbocation rearrangement.
Next, intermolecular heterocouplings between internal
alkynes and terminal unactivated alkenes were
attempted (Table 2). Terminal alkenes compete
effectively with alkynes for the second insertion into
the azametallacyclobutene intermediate. Even at a 1:1
ratio of 1-octene : 3-hexyne, moderate yields of the
α,γ-unsaturated imine product were obtained, with the
remaining mass balance undergoing competitive
[2+2+1] pyrrole formation. The yield of the α,γ-
unsaturated product 6b could be increased from 31% to
61% by doubling the concentration of 1-octene. In all
cases, terminal alkenes react via 2,1-insertion,
indicating that this step is likely under steric control
where the alkene substituent orients preferentially
toward an uncrowded Ti center rather than a 2° carbon
substituent.
Figure 4. Proposed mechanism for Ti-catalyzed alkyne
carboaminations.
In order to probe the scope of carboamination and
selectivity for β-H elimination vs. α,γ-coupling, we
examined catalysis with several more tethered enynes
(Table 1). In most cases, isolated yields of the reactions
were moderate due to the difficulty in separating the
1
product isomers, but H NMR analysis of the crude
mixtures generally indicated that the reactions
proceeded to total conversion. Terminal and internal
alkenes were competent for catalysis, and there was
little difference in utilizing E or Z alkenes 1e and 1f.
Only internal alkynes are currently compatible because
their more-reactive terminal counterparts undergo
[2+2+1] pyrrole synthesis and alkyne trimerization too
rapidly.7
Table
2.
Intermolecular
multicomponent
carboamination of alkynes and alkenes with PhNNPh.a
R2
PhNNPh
5% [py2TiCl2NPh]2
Ph
R2
Ph
N
N
R1
R1
+
-or-
R2
PhCF3, 115 oC
16 h
R2
10 equiv. 5 equiv.
R2
R1
R2
6a-f
7a-f
Alkene R2
% Isolated
Yield (6:7)b
1H NMR %
Yield (6:7)c
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Hexn
Me 54 (40:60)
Et 61 (>99:1)
Me 42 (9:91)
n.d.
Corresponding Author
5a
5b
5c
1
2
3
4
5
6
7
8
Hexn
Ar
n.d.
63 (15:85)d
e-mail: itonks@umn.edu
Funding Sources
Ar = p-MeOPh
The authors declare no competing financial interests.
5d
5e f
5f
Et
Et
Et
51 (>99:1)
40 (>99:1)
0
70 (71:29)e
n.d.
Ar
ACKNOWLEDGMENT
Ar = p-MeOPh
Financial support was provided by the University of
Minnesota (start-up funds) and the National Institutes of
Health (1R35GM119457). Equipment for the Chemistry
Department NMR facility were supported through a grant
from the National Institutes of Health (S10OD011952)
with matching funds from the University of Minnesota.
9
tBu
n.d.
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aLoading of [py2TiCl2NPh]2 and reaction yields with respect to
PhNNPh. bIsolated as the ketone product after hydrolysis. See SI for
details. cDetermined by 1H NMR analysis of the crude reaction
d
e
mixture. 96 : 4 ratio of cis : trans cyclopropane product. 74 : 26
f
ratio of cis : trans cyclopropane product. Reaction run in neat
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(5) Rh-catalyzed alkyne carboaminations are two-step reactions
involving Cu-catalyzed alkyne/azide cycloaddition followed by Rh-
catalyzed iminovinylidene formation: Horneff, T.; Chuprakov, S.;
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As was the case in the intramolecular multicomponent
couplings, subtle structural changes in intermolecular
heterocouplings also lead to dramatic shifts in
selectivity between β-H elimination/abstraction and
α,γ-coupling products. This selectivity shift is apparent
in the reaction of 4-allylanisole with internal alkynes:
reaction with 3-hexyne gives a 71 : 29 ratio of 6d : 7d,
while reaction with 2-butyne inverts the selectivity and
1
yields a 15 : 85 ratio of 6c : 7c by H NMR analysis.
The cis:trans selectivity of the cyclopropanes also
varies heavily between the 3-hexyne product 7d
(74:26) and 2-butyne product 7c (96:4), which has
similarly been observed in Kulinkovich-type
cyclopropanation reactions.14
In addition to unsubstituted linear terminal alkenes,
terminal alkenes bearing 2° groups are also competent
for catalysis. 4-Vinylcyclohex-1-ene undergoes
reaction to give low yields of the product with
exclusive reactivity at the terminal alkene. Bulkier
alkenes, such as 3,3-dimethylbut-1-ene, fail to react.
In conclusion, we have demonstrated the first examples
of a three-component oxidative alkyne carboamination,
generating either α,β-unsaturated imines or α-
functionalized cyclopropanes. Preliminary mechanistic
studies indicate that these Ti-catalyzed reactions
proceed through a common azametallacyclohexene
intermediate. Somewhat remarkably, both intra- and
intermolecular reactions proceed in moderate to good
yields and selectivities despite the large potential for
the occurrence of undesired competitive processes such
as alkyne homocoupling. We are currently examining
new catalyst classes to further understand and increase
control over the rate and selectivity of these unique
transformations, as well as further pursuing new Ti
redox catalytic reactions promoted by diazene
oxidants.
Supporting Information. Full experimental
procedures, characterization data and spectra are available
in the Supporting Information. This material is available
free of charge via the Internet at http://pubs.acs.org.
(14) Kulnikovich, O.G.; de Meijere, A. Chem. Rev. 2000, 100,
2789-2834.
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