Bifunctional Ligand-Assisted Catalytic Ketone α-Alkenylation with Internal Alkynes: Controlled Synthesis of Enones and Mechanistic Studies

Article abstract of DOI:10.1021/jacs.5b10466

Here, we describe a detailed study of the rhodium(I)-catalyzed, bifunctional ligand-assisted ketone α-C-H alkenylation using internal alkynes. Through controlling the reaction conditions, conjugated enamines, α,β- or β,γ-unsaturated ketones, can be selectively accessed. Both aromatic and aliphatic alkynes can be employed as coupling partners. The reaction conditions also tolerate a broad range of functional groups, including carboxylic esters, malonates, secondary amides, thioethers, and free alcohols. In addition, excellent E-selectivity was observed for the tetra-substituted alkene when forming the α,β-unsaturated ketone products. The mechanism of this transformation was explored through control experiments, kinetic monitoring, synthesizing the rhodium-hydride intermediates and their reactions with alkynes, deuterium-labeling experiments, and identification of the resting states of the catalyst.

Full text of DOI:10.1021/jacs.5b10466

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Article
Bi-functional Ligand-assisted Catalytic Ketone #-Alkenylation with Internal
Alkynes: Controlled Synthesis of Enones and Mechanistic Studies
Fanyang Mo, Hee Nam Lim, and Guangbin Dong
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b10466 • Publication Date (Web): 13 Nov 2015
Downloaded from http://pubs.acs.org on November 13, 2015
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Biꢀfunctional Ligandꢀassisted Catalytic Ketone αꢀAlkenylation with
Internal Alkynes: Controlled Synthesis of Enones and Mechanistic
Studies
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Fanyang Mo,1,2 Hee Nam Lim1 and Guangbin Dong1*
1 Department of Chemistry, University of Texas at Austin, Austin, TX 78712, United States
2 Department of Energy and Resources Engineering, College of Engineering, Peking University, Beijing 100871, China
Supporting Information
ABSTRACT: Here we describe a detailed study of the rhodium(I)ꢀcatalyzed, biꢀfunctional ligandꢀassisted ketone αꢀC‒H alkenylaꢀ
tion using internal alkynes. Through controlling the reaction conditions, conjugated enamines, α,βꢀ or β,γꢀunsaturated ketones can
be selectively accessed. Both aromatic and aliphatic alkynes can be employed as coupling partners. The reaction conditions also
tolerate a broad range of functional groups, including carboxylic esters, malonates, secondary amides, thioethers and free alcohols.
In addition, excellent Eꢀselectivity was observed for the tetraꢀsubstituted alkene when forming the α,βꢀunsaturated ketone products.
The mechanism of this transformation was explored through control experiments, kinetic monitoring, synthesizing the rhodium–
hydride intermediates and their reactions with alkynes, deuteriumꢀlabeling experiments and identification of the resting states of the
catalyst.
and coꢀworkers.62d Later, Lim and Kang developed an rhodiumꢀ
catalyzed orthoꢀalkenylation of 2ꢀphenylpyridines with internal
INTRODUCTION
Unsaturated ketones (also known as enones), typically those
alkynes.62h Besides through a metalꢀhydride reaction pathway,
bearing α,βꢀ or β,γꢀC‒C double bonds, have rich biological and
more recently Schipper and Fagnou demonstrated a Rh(III)ꢀ
chemical properties. They are often observed in bioactive comꢀ
pounds and frequently employed as synthetic intermediates.1,2
catalyzed intermolecular hydroarylation of alkynes via arylꢀ
metalation followed by protonation.62o In addition, Jun and coꢀ
Undoubtedly, numerous methods have been developed to date for
enone synthesis.3ꢀ5 However, direct C‒C coupling between a keꢀ
workers have achieved a novel metalꢀorganic cooperative apꢀ
proach in the rhodiumꢀcatalyzed hydroacylation of alkynes, in
tone and an alkyne represents one of the most attractive approachꢀ
which an aldehyde was masked as an imine that can undergo diꢀ
es due to the atom/redoxꢀefficiency of the reaction and the wide
rected C−H activation.61a,62k These seminal works offer a solid
availability of both starting materials.6,7 For example, the intramoꢀ
foundation and important inspiration for our targeted catalytic
ketone αꢀalkenylation with unactivated alkynes.
lecular ketoneꢀalkyne cyclization, also known as “Coniaꢀene”
reaction, represents a distinct way to synthesize cyclic enones,
which can be catalyzed/mediated by a range of metals or enabled
by thermal conditions (Scheme 1a).8ꢀ38 In contrast, the intermoꢀ
lecular ketoneꢀalkyne coupling is primarily known with activated
methylene compounds as the substrates (Scheme 1b).39ꢀ53 To date,
only two approaches are available for intermolecular coupling of a
regular ketones and an alkyne. One seminal work by Yamaguchi
involves addition of silyl enol ethers into monoꢀsubstituted alꢀ
kynes mediated by stoichiometric Lewis acids, such as Ga(III)
and Sn(IV) salts.54ꢀ57 Recently, Trofimov and coworkers develꢀ
oped a strong baseꢀpromoted addition of potassium enolates into
aryl terminal acetylenes (Scheme 1c).58,59
Our laboratory recently developed a regioselective ketone αꢀ
alkylation reaction with unactivated αꢀolefins, wherein the vinyl
C−H bond of the enamine generated from the ketone and an
amine biꢀfunctional catalyst can be activated by Rh metal and
added across olefins to deliver an alkylated enamine, which upon
hydrolysis furnished the alkylation product and regenerate the
bifunctional catalyst.60 Accordingly, we envisioned a protocol for
formal ketone αꢀalkenylation with internal alkynes wherein a
conjugated enamine is formed as the key intermediate that can
undergo hydrolysis to give either α,βꢀ or β,γꢀenones (Scheme 1d).
Compared to the αꢀalkylation reaction, the challenges of the αꢀ
alkenylation reactions with internal alkynes are threeꢀfold. First,
assisted by low valent metals, alkynes can undergo facile homoꢀ
couplings to give dimer or trimer products.63,64 Second, due to
their low steric hindrance, more than one alkyne can coordinate to
a single metal center, which often generates multipleꢀinsertion
products.65 Third, chemoꢀ and stereoꢀselective hydrolysis of the
proposed conjugated enamine intermediate is expected to be nonꢀ
trivial (Scheme 1d).66 Particularly, control of the geometry for the
newly formed tetraꢀsubstitutedꢀalkene in the α,βꢀenone products
can be a significant concern.
To the best of our knowledge, the intermolecular coupling be-
tween a regular ketone and an internal alkyne remained an un-
known transformation. Towards our longꢀterm goal of developing
byproductꢀfree ketone/unsaturate couplings under pH and redoxꢀ
neutral conditions,60 here we describe our detailed development of
a catalytic ketone αꢀalkenylation reaction with unactivated diꢀ
substituted alkynes, which is enabled by a biꢀfunctional ligand
and a lowꢀvalent transitionꢀmetal catalyst (Scheme 1d).
The transitionꢀmetalꢀcatalyzed addition of sp2 C‒H bonds
across unactivated alkynes has recently emerged a powerful stratꢀ
egy to synthesize substituted alkenes in a byproductꢀfree fashꢀ
ion.61,62 For example, Murai and coꢀworkers reported the first
directed hydroarylation of alkynes using a ruthenium catalyst.62c
The related alkyne hydrovinylation was first established by Trost
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(without the alkyne) revealed that Wilkinson’s catalyst can signifꢀ
Scheme 1. C‒C Couplings between Ketones and Alkynes.
1
2
3
4
5
6
7
icantly accelerate the condensation between ketone 1a and L1 to
form the enamine intermediate (eq 1). Consequently, in the abꢀ
sence of this protic acid, the conjugated enmaine products (3a/3a’)
are stable under the reaction conditions.
a. previous work: intramolecular coupling (Conia-ene)
O
O
O
O
O
O
O
O
metal salt (catalytic
or stoichiometric)
or
R1
R1 R3
or
R3
or
R1
R1
R2
R2
Table 1. Evaluation of Biꢀfunctional Ligands for Rh(I)ꢀcatalyzed
~ 250 o
C
Coupling of Cyclopentanone and Diphenylacetylenea
R2
R2
b. previous work: intermolecular coupling with activated methylenes
8
9
O
O
In, Ir, Re, Ru
Mo, Au/Ga etc
O
O
R4
R5
R1
R2
+
R1
R2
R3
R5
R3
R4
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c.previous work: intermolecular coupling with terminal alkynes
O
stoichiometric
SnCl4 or GaCl3
then H3O+
O
Me
R3
OTMS
R2
R3
+
R1
R1
or
R1
R2
when R3 = TMS
R2
when R3 TMS
O
stoichiometric
KOtBu
DMSO, 100 o
O
R3
R1
+
R1
R3
C
R2
R2
d. this work: Intermolecular coupling with regular ketones and internal alkynes
R2
R1
O
HCl
toluene
RhI cat
O
R2
R1
R2
R1
,
-enone
N
neutral conditions
N
+
R2
O
Entry
Biꢀfunctional ligand
Yields of Products b
3a 46%, 3a’ 26%, 4a 17%
all together < 5%
all together < 5%
all together < 5%
all together < 5%
all together < 5%
all together < 5%
all together < 5%
AcOH
CHCl3
N
N
R1
H
recyclable or
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L8
isolatable
applied catalytically
, -enone
R2
R1
N
N
N
N
N
H
N
Rh
H
Rh
Rh
R2
H
R1
a
Conditions: cyclopentanone 1a (0.2 mmol), diphenylacetylene 2a (0.2
mmol).
tetrachloroethane as the internal standard.
RESULTS AND DISCUSSION
Yields were determined by 1H NMR using 1,1,2,2ꢀ
b
Reaction Condition Optimization. To probe the feasibility
of the ketoneꢀalkyne coupling, we initiated our studies with cyꢀ
clopentanone 1a and diphenylacetylene 2a as the standard subꢀ
strates. First, the effect of the biꢀfunctional ligands was examined.
Eight secondary and primary amine compounds (L1 to L8 in Taꢀ
ble 1) containing an adjacent directing group were subjected to
the reaction conditions (5 mol % of Wilkinson’s catalyst and 10
o
mol % of TsOH•H2O in toluene at 130 C for 12 h). In accord
with our previous study,60 7ꢀazaindoline (L1) exhibited unique
and high catalytic activity, whereas other directing ligands were
inactive. As a preliminary result, with 100 mol % loading of L1,
the reaction gave 46% of conjugated enamine product 3a, 26% of
its isomer (3a’) and 17% of the conjugated enone 4a (Table 1,
entry 1). All these products were isolated and fully characterized
[Rh(CO)2Cl]2 and [Rh(coe)2Cl]2 also delivered the desired
products albeit giving lower yields than Wilkinson’s catalyst (enꢀ
tries 2 and 3). Different phosphine ligands other than PPh3 were
also evaluated, whereas both electronꢀrich and deficient ones gave
much lower yields (entries 4 and 5).67 Use of 2 equivalents of
cyclopentanone led to a full conversion of L1 with 64% yield of
3a and 31% yield of 3a’ (entry 6). It is noteworthy that under the
conditions giving low yields (e.g. entries 4 and 5), 3a’ was not
detected in the reaction mixture. We rationalized that 3a was likeꢀ
ly the initial product formed, and 3a’ is the isomerized product of
1
by H/13C NMR, infrared (IR), and highꢀresolution mass specꢀ
trometry (HRMS). The structures of 3a and 4a’s hydrazone derivꢀ
atives were further unambiguously confirmed by Xꢀray crystallogꢀ
raphy (vide infra).
With an active biꢀfunctional ligand L1 in hand, we continued
our studies by investigating other reaction parameters shown in
Table 2. First, we found that the absence of TsOH•H2O led to an
increased yield of 3a with no 4a formed (Table 2, entry 1). In
contrast to our study with alkene couplings,60 TsOH•H2O, previꢀ
ously proposed to promote enamine formation, is not necessary in
this ketone/alkyne coupling reaction. Two control experiments
o
3a. Indeed, when pure 3a was heated at 130 C overnight, 40%
conversion to 3a’ was observed (eq 2). The 3a/3a’ ratio was highꢀ
er when the reaction was conducted at 100 C instead of 130 C
(entry 7), without losing reactivity. We further discovered that
o
o
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Table 2. Reaction Condition Screeninga
1
2
3
4
5
6
7
8
9
Yields of Products (%)b
Entry
Rh(I) (mmol %)
Ratio (1a : 2a : L1)
Temperature (oC)
Additives (mol %)
3a
3a’
4a
5a
Optimization for conjugated enamine product 3a
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1
2
3
4
5
6
7
8
9c
Rh(PPh3)3Cl (5)
[Rh(CO)2Cl]2 (2.5)
1 : 1 : 1
1 : 1 : 1
1 : 1 : 1
1 : 1 : 1
1 : 1 : 1
2 : 1 : 1
2 : 1 : 1
2 : 1 : 1
2 : 1 : 1
130
130
130
130
130
130
100
100
100
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
59
17
22
13
15
64
73
31
84
22
12
12
0
0
0
0
0
0
0
0
0
4
0
0
0
0
0
0
0
0
0
[Rh(coe)2Cl]2 (2.5)
[Rh(coe)2Cl]2 (5)+ PCy3 (20)
[Rh(coe)2Cl]2 (5)+ P(C6F5)3 (20)
Rh(PPh3)3Cl (5)
0
31
26
0
Rh(PPh3)3Cl (5)
Rh(PPh3)3Cl (1)
Rh(PPh3)3Cl (2)
11
Optimization for conjugated ketone product 4a
10
11
12d
Rh(PPh3)3Cl (5)
Rh(PPh3)3Cl (5)
Rh(PPh3)3Cl (5)
ꢀ
2 : 1 : 1
2 : 1 : 1
2 : 1 : 0.5
2 : 1 : 1
2:1:0
130
130
130
130
130
TsOH•H2O (10)
PhCO2H (10)
30
55
7
51
40
0
18
4
0
0
9
0
0
TsOH•H2O (10)
TsOH•H2O (10)
TsOH•H2O (10)
64
0
13
0
0
14
Rh(PPh3)3Cl (5)
ꢀ
ꢀ
0
a General conditions: 0.5 mmol scale, toluene 2.5 mL. b Yields were determined by 1H NMR using 1,1,2,2ꢀtetrachloroethane as the internal standard. c 48 h. d
24 h. After the reaction, HCl (conc. 40 L) was added; the reaction was further heated at 130 oC for 0.5 h.
lowering the catalyst loading to 1 mol % resulted in almost no
isomerization, but 3a was formed in only 31% yield, due to the
relatively low reaction rate (entry 8). However, by using 2 mol %
of Wilkinson’s catalyst at 100 C for 48 hours, a full conversion
with 84% yield of product 3a was obtained (entry 9).
The Scope of Conjugated Enamine Products. The scope of
forming conjugated enamines (from ketones, alkynes and L1) is
illustrated in Chart 1. As expected, the nature of the ketones and
alkynes influenced the yields of these reactions, thus the reaction
conditions, such as catalyst loading, temperature and concentraꢀ
tion, were slightly varied in each cases (see supporting inforꢀ
mation for details). In general, the five memberedꢀring ketones
were normally run at 100 to 120 C with 2 mol % Rhꢀcatalyst
loading, whereas the six memberedꢀring ketones need a relatively
higher temperature (150 C) and 5 mol % of catalyst to enhance
the enamine condensation and further coupling with alkynes. In
this study, one equivalent of the ketone substrate was used except
simple cyclopentanone and cyclohexanone. Regarding the alkyne
partners, aliphatic alkynes normally exhibit higher reactivity than
aromatic ones, thus requiring relatively lower temperatures and
dilute concentration. In addition, we found when the aliphatic
alkynes were run at the standard concentration (0.2 M), multiple
alkyne insertions took place, giving a complex mixture which was
not observed when the reaction was conducted at 0.1 M concenꢀ
tration.
o
o
o
With an optimal yield for conjugate enamine 3a in hand, we
next optimized the yield for enone 4a through adding an acid as a
coꢀcatalyst. Tosylic acid monohydrate and benzoic acid both
showed comparable conversions. However, formation of 4a was
more favorable when tosylic acid monohydrate was used (entries
10 and 11). In principle, L1 can be employed in a catalytic
amount for in situ hydrolysis of 3a would liberate L1. However,
due to the high stability of the conjugated enamine product 3a
(3a’), 50 mol % of L1 was used to ensure the reaction rate. At the
end of the reaction, simple workup with a small amount of HCl
aqueous solution for half an hour (to hydrolyze any remaining
conjugated enamines) afforded an acceptable yield of 4a along
with a small amount of vinyl ketone 5a (entry 12). Finally, control
experiments showed that the rhodium catalyst and bifunctional
ligand L1 are both pivotal to this transformation (entries 13 and
14). Another potential pathway to form 4a is aldol reaction beꢀ
tween ketone 1a and 2ꢀphenylacetophenone, which can possibly
come from the hydration of alkyne 2a. However, as indicated in a
A series of symmetrical diarylacetylenes were examined first,
and the corresponding conjugated enamine products were isolated
in good to excellent yields (3aꢀ3f). Thiophene and naphthalene
were tolerated under the reaction conditions (3e and 3f). Next, we
tested unsymmetrical alkynes containing one alkyl and one aryl
substituents, namely 1ꢀphenylꢀpropyne and 1ꢀphenylꢀ1ꢀhexyne
(3g and 3h). It is interesting to observe that both substrates prefer
to form C─C bond at the aryl site. While the selectivity is moderꢀ
ate,69 the major isomers can be cleanly isolated in synthetically
useful yields. Symmetrical aliphatic alkynes (3i and 3j) also
worked well when running at 0.1 M concentration. It was exciting
to find that electronꢀdeficient phenylpropiolic dimethyl amide was
also a suitable substrate giving a high selectivity for the “reverse
control
experiment,
replacing
alkyne
2a
with
2ꢀ
phenylacetophenone led to no desired coupling products, which
excluded the hydration passway.68
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Chart 1. Synthesis of Conjugated Enamine Productsa
1
Rh(PPh3)3Cl (2-5 mol %)
toluene, 100-150 oC,12-48 h
2
3
4
5
O
R'
N
R'
N
+
+
N
N
R
R
H
1
2
L1
1 equiv.
3a-3z
1 or 2 equiv.
1 equiv.
6
7
8
9
Me
Me
OMe
S
N
N
N
N
N
N
N
N
N
N
Ph
Ph
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
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45
46
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48
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50
51
52
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56
57
58
59
60
S
Me
3c, 71%
Me
OMe
3e, 65%
3a, 81%
3b, 80%
3d, 83%
(X-ray obtained)
N
N
N
N
N
N
N
Et
Et
Me
Ph
nBu
nBu
nBu
N
N
N
Ph
3j, 51%
3f, 75%
3g, 54% (yield of the major
3h, 62% (yield of the major
3i, 78%
isomer) 2.3:1 rr
isomer) 2.8:1 rr
N
N
N
Ph
Ph
OH
N
Ph
Ph
N
N
N
N
N
Ph
Ph
N
1
5
NMe2
3
O
MeS
Ph
3k, 50% (>10:1 rr)
(X-ray obtained)
3l, 50% (yield of the
major isomer) 5 :1 rr
(X-ray obtained)
3n, 57%
3o, 59%
3m, 85%
Br
N
N
N
Ph
Ph
N
Ph
Ph
N
N
N
Ph
Ph
N
Ph
N
N
Ph
Ph
Ph
MeO2C
AcHN
R
CO2Me
3t, 33%
(X-ray obtained)
R= Me, 3q, 76%
R= CO2Me, 3r, 79%
3u, 55%
3p, 72%
3s, 62%
Ph
Ph
H
H
Ph
Ph
Ph
N
N
N
Ph
Ph
N
N
N
Ph
Ph
N
N
H
H
Ph
N
N
H
N
O
Me
Ph
CO2Et
3z, 68%
3y, 74%
3x, 36%
3v, 50%
3w, 52%
a For unsubstituted cyclopentanones and cyclohexanones, 2 equivalents of the ketone were employed; for other ketones, 1 equivalent of
the ketone was employed. For detailed conditions, see supporting information. All the yields are isolated yields. rr: regioisomer ratio.
conjugate addition” product (3k) confirmed by the Xꢀray crystalꢀ
lography. Since propiolic acid derivatives are known as good
Michael acceptors, the lack of normal conjugate addition supports
a metal hydrideꢀinvolved mechanism (vide infra).70 Chemoselecꢀ
tivity of this transformation was further demonstrated by the comꢀ
patibility of unprotected alcohols. Phenylproparyl alcohol can be
directly coupled to give the enamineꢀallylꢀalcohol product (3l)
with good regioselectivity. Monoꢀsubstituted alkynes were found
not suitable under the current reaction conditions, as the hydroamꢀ
ination with L1 was the major side reaction.
occurred exclusively at the less hindered C5 position of the keꢀ
tones (3mꢀs). Substrates containing acidic C‒H bonds, such as
those α to a carboxylic ester (3r) and a malonate group (3s), were
well tolerated. Thioethers (3n), aryl bromides (3o) and amides (3p)
were compatible as well. The high chemoselectivity can be at-
tributed to the pH and redox-neutral conditions. 2ꢀIndanone can
also couple to give the desired product 3t in a moderate yield.
Although of lower reactivity, sixꢀmembered cyclic ketones (3uꢀz)
were suitable substrates at an elevated temperature. Cholesterolꢀ
derived substrates gave the desired vinylation product (3x) selecꢀ
tively at the less hindered site of the ketone albeit in a lower yield.
Heterocyclic ketones also underwent efficient couplings to give
the corresponding enamines (3y and 3z). Acyclic ketones, e.g.
acetophenone, also reacted; however, the pure form of the conjuꢀ
gated enamine product (observed from the crude NMR and Mass
Subsequently, the scope of the ketones was investigated (also
see Charts 2 and 3). A range of 3ꢀsubstituted cyclopentanones
were first utilized to examine the siteꢀselectivity (for the ketone)
and functional group tolerance. To our delight, the alkenylation
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a
Spec) proved to be difficult to isolate due to its lability (for a oneꢀ
Reaction conditions: 0.2 mmol scale, toluene 1 mL. All the
1
2
3
4
5
6
pot alkenylation with acetophenone, see Chart 3). It is not surprisꢀ
ing that, compared to cyclic ketones, acyclic ketones showed sigꢀ
nificantly diminished reactivity due to their increased difficulty to
form enamines.71 Thus, the general trend of reactivity is in an
order of 5ꢀmembered cyclic ketones>6ꢀmembered cyclic keꢀ
tones>linear ketones.
yields are isolated yields of the major E isomer. E/Z ratio is
around 10:1. b With 100 mol % L1.
Scheme 2. Rationalization of the alkene geometry
Scope of Conjugated Enone Products. The scope of directly
forming conjugated enones was next investigated (Chart 2). Under
the previously optimized conditions (vide supra, Table 1, entry
12), a variety of α,βꢀunsaturated ketones were synthesized in 50ꢀ
70% yields. This coupling also tolerated a number of functional
groups. Given the challenge of forming geometrically defined
tetraꢀsubstituted alkenes, it is particularly interesting to note that
all reactions with cyclic ketones gave E enone as the predominate
products (E:Z ~ 10:1). The high selectivity is likely controlled by
the preferred conformation of the conjugatedꢀenamine intermediꢀ
ate during the hydrolysis step, in which the 1,3ꢀdiene would adopt
an sꢀcis conformation to avoid the steric repulsion between the 7ꢀ
azaindoline and the aryl group (Scheme 2). Most of the enone
products were derivatized to the corresponding 2,4ꢀdinitrophenyl
hydrozones, and their structures were confirmed through Xꢀray
crystallography.
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Scheme 3. Derivatization of Enone Products
Chart 2. Synthesis of Conjugated Enonesa
Scope of Vinyl Ketone Products. Undoubtedly, the α,βꢀ
unsaturated enones are the thermodynamically more favorable
products during the enamine hydrolysis, thus it would be difficult
to obtain the less stable vinyl ketones (β,γꢀunsaturated enones)
selectively using the in situ hydrolysis protocol.66 However, the
problem can be solved via a mild hydrolysis protocol (e.g. relaꢀ
tively low temperature) of the conjugate enamine intermediates (3)
to acquire the kinetic products. By carefully tuning the hydrolysis
conditions, the vinyl ketone products (β,γꢀunsaturated enones) can
be accessed selectively with retention of the geometry of the vinyl
group (Chart 3). We found that a weak acid, such as acetic acid, in
chloroform at room temperature gave the highest selectivity for
the vinyl ketone. A number of conjugated enamines obtained from
the ketone/alkyne/L1 coupling were subjected to these conditions.
In general, the β,γꢀenones products were formed predominantly,
and the geometry of the vinyl group was conserved during the
hydrolysis. In the case of 3ꢀphenylcyclopentanone (5g), only one
diastereoisomer was observed and the stereochemistry was reꢀ
vealed by 2D NMR analysis showing that the phenyl and vinyl
substituents are in a cis relationship. In contrast, a pair of diasterꢀ
eoisomers was isolated for the sixꢀmembered ring substrates (5i
and 5j). Linear ketones such as acetophenone, also participated in
this transformation. Interestingly, using a oneꢀpot procedure, the
vinyl ketone products (5k and 5k’) were isolated as the major
products instead of the conjugated enones.
Furthermore, a larger scale experiment was conducted to examꢀ
ine the scalability of the reaction. Running the reaction at a 5
o
mmol scale with 2 mol % Rh catalyst at 100 C for 40 h gave 5a
in 65% yield after mild hydrolysis. The directing ligand L1 was
recovered in 76% yield, showing that it can be recycled (eq 3).
Chart 3. Synthesis of Vinyl Ketone Products a
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% (L1)
% (Enamine INT)
% (3a)
% (3a')
% (3a+3a')
100
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40
20
0
aReaction conditions: 0.2 mmol scale. 1 mL CHCl3 and 1 mL 10%
(v/v) aqueous acetic acid. All the yields are isolated yields.
Proposed Mechanism. While other possible mechanisms canꢀ
not be excluded at this stage,72 based on our previous work with
alkene insertion60 and the aforementioned control experiments, a
plausible catalytic cycle of the ketone αꢀC‒H alkenylation is illusꢀ
trated in Scheme 4. The reaction begins with the condensation of
the secondary amine L1 with the ketone to form an enamine inꢀ
termediate I (step A). During this step, the ketone α sp3 C–H bond
is converted into a sp2 C–H bond, thus enhancing the reactivity
towards oxidative addition by a lowꢀvalent transition metal.73,74
Meanwhile, the adjacent pyridine group to the amine domain
facilitates insertion of the rhodium(I) species into the resulting
enamine vinyl C–H bond giving a rhodium‒hydride species II
(Rh–H, step B). Upon alkyne coordination with the metal, subseꢀ
quent Rh–H migratory insertion (step D) or Rhꢀvinyl migratory
insertion (not drawn) and reductive elimination (step E) would
provide the final alkenylated conjugated enamine product. The
following efforts have been conducted to explore the feasibility of
the proposed mechanism.
0h 1h 2h 3h 4h 5h 6h 7h 8h 9h 10h 11h 12h
Reaction time
Figure 1. The reaction progress profile for conjugated enamine
formation monitored by H NMR. The reaction was conducted
1
with 5 mol % Wilkinson’s catalyst at 130 oC.
Identification, Synthesis and Characterization of Rhodiꢀ
um‒Hydride Complexes. Low valent transition metals, such as
Ru(0), Rh(I) and Ir(I), are known to undergo oxidative addition
into C‒H bonds to give metal‒hydride species.75 However, metꢀ
al‒hydride complexes are challenging to be captured and isolated
particularly during a C─H activation reaction, due to their high
reactivity and lability.69 Thus, we first explore the feasibility to
synthesize Rh‒H species with more stable enamine substrates.
Previously, we have demonstrated the 1,2ꢀdiketoneꢀderived
enamines can undergo C‒H coupling with alkenes and alꢀ
kynes.76,77 To our delight, treatment of enamines 8a and 8b with
Rh(PPh3)3Cl in C6D6 for 1 hour afforded the desired Rh‒H speꢀ
cies 9a and 9b respectively (eqs 4 and 5), which were unambiguꢀ
ously characterized by NMR, IR, HRMS and Xꢀray crystallogꢀ
raphy. From the Xꢀray structures, the two PPh3 ligands adopt a
trans geometry. Surprisingly, these rhodium(III) hydride species
can be isolated in high yields via benchꢀtop flash chromatography,
and they were stable in the air for several hours. The high effiꢀ
ciency of these C‒H oxidative addition reactions is likely due to
Kinetic Monitoring. The reaction progress for forming the conꢀ
jugate enamines (3a and 3a’) was monitored by 1H NMR (Figure
1). The enamine adduct between the ketone and L1 (INT, vide
supra, eq 1) was observed at 1 h and disappeared at 3 h, suggestꢀ
ing that it was a reactive intermediate during the reaction. The
reaction was completed at 5 h with full consumption of the biꢀ
functional ligand L1. The profile after 3 h clearly showed that the
conjugated enamine product 3a started to isomerize to 3a’, which
ultimately reached an equilibrium with a ratio of 3a/3a’ about 2:1.
Scheme 4. Proposed Catalytic Cycle.
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the strong electronꢀwithdrawing nature of the conjugated carbonyl
group, which may stabilize the Rh‒H intermediates.
1
PPh3
2
3
4
5
6
7
8
9
N
Cl
Rh
HN
(4)
O
H
N
H
PPh3
O
Me
+
Me
N
N
C6D6, 100 oC
1 h
9a, 90% (X-ray obtained)
8a
RhCl(PPh3)3
PPh3
N
O
Cl
(5)
N
Rh
N
Me
H
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O
PPh3
8b
The reaction between the monoꢀketoneꢀderived rhodiꢀ
um‒hydride complex (9c) and diphenylacetylene was tested subꢀ
sequently (eq 9). While showing almost no reactivity with alkenes,
9c reacted with the alkyne to give the corresponding conjugated
enamine (3t) in 51% yield at 130 oC.
Me
9b
X-ray obtained
, 91% (
)
Encouraged by these results, we continued our study with the
monoꢀketone derived enamine (8c). In this case, Wilkinson’s
catalyst did not yield any detectable metal‒hydride species moniꢀ
tored by in situ 1H NMR analysis. Failure to capture a stable metꢀ
al‒hydride species does not necessarily mean that Wilkinson’s
catalyst lacks the reactivity to insert into the C‒H bond. We hyꢀ
pothesized that due to the bulkiness and πꢀaccepting nature of the
triphenylphosphine ligand, the reverse reaction (C‒H reductive
elimination) would be more favorable during the activation of
enamine 8c. Consequently, the Rh‒H species derived from the
normal ketone enamine 8c could possibly be a high energy transiꢀ
ent intermediate. To test this hypothesis, a less bulky but more
electronꢀrich ligand, i.e. trimethylphosphine, was employed (eq 6),
which should help to facilitate the C‒H oxidative addition and
stabilize the Rh(III) intermediate by disfavoring the reductive
elimination. Indeed, after heating [Rh(ethylene)2Cl]2, 8c and
PMe3 at 130 oC for 1 h, a rhodium‒hydride complex (9c) is
formed, which was found more sensitive to air than complexes 9a
and 9b.78 Nevertheless, we were able to isolate complex 9c and
characterize the structure via the Xꢀray crystallography. This
Rh‒H complex holds a distorted octahedral geometry with two
phosphorus groups at the axial positions, and the Rh‒H bond
length is 1.505 Å. To the best of our knowledge, this represents
the first example of insertion of a lowꢀvalent transition metal into
a regular enamine vinyl C–H bonds via oxidative addition.
DeuteriumꢀLabeling Experiments. In the proposed cycle
(Scheme 4), metal‒hydride migratory insertion and reductive
elimination will transfer a ketone αꢀproton to the terminal vinyl
position of the conjugated enamine product. Indeed, when deuterꢀ
ated cyclopentanone 1a’ (α and α’ꢀdeuterated 92%) was allowed
to react under the standard conditions, the NMR analysis of the
product 3a’’ revealed 68% incorporation of deuterium at the terꢀ
minal vinyl position (eq 10).78 The erosion in deuterium incorpoꢀ
ration for enone 3a’’ is likely caused by an proton exchange beꢀ
tween the αꢀhydrogens of 1a’ and the NH hydrogen of L1. In
addition, the resulting E olefin geometry in the product supports a
synꢀmigratory insertion pathway.
Identification of the Resting States of the Catalyst. To gain a
better understanding of the catalytic cycle, we continued to identiꢀ
fy the resting states of the catalyst. When monitoring the standard
reaction of forming conjugated enamine 3a in tolueneꢀd8 at 130
oC, we observed two sets of discrete phosphineꢀligated rhodium
species, which should correlate to the resting states of the catalyst
(Figure 2A).79 A doublet at 36.8 ppm with a JRhꢀP value of 126 Hz
and two doublets of doublets at 59.3 ppm and 52.4 ppm with JRhꢀP
values of 200 Hz and 166 Hz respectively were found in the 31P
NMR spectrum.
Reactivity of Rhodium‒Hydride Complexes with Alkenes
and Alkynes. Having examined the feasibility of the oxidative
addition into the vinyl C‒H bond (step B, Scheme 4), we next
investigated the C‒C bond forming step through 2πꢀinsertion with
the rhodium‒hydride intermediate (migratory insertion and reducꢀ
tive elimination, steps D and E). Rhodium‒hydride complexes 9a
and 9b were employed initially (eqs 7 and 8). Treatment of 9a
with 5 equivalents of 3,3ꢀdimethylbutene (10) provided the deꢀ
sired alkylation product 11 in 90% yield. Through monitoring the
reaction at different temperatures, no significant conversion was
observed below 100 oC. However, when 9b reacted with 2 equivaꢀ
lents of diphenylacetylene 2a, the metal‒hydride peak disapꢀ
o
peared in less than 10 min at 50 C, suggesting a much higher
reactivity with alkynes. The alkenylation product (12) was obꢀ
tained in 91% yield at 100 oC within 0.5h. These observations are
consistent with our previously proposed rhodium‒hydrideꢀ
involved mechanism for alkylation and alkenylation of 1,2ꢀ
diketoneꢀderived enamines.76, 77
Figure 2. 31P NMR of mechanistic studies.
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In summary, we have developed a rhodium(I)ꢀcatalyzed biꢀ
1
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3
4
5
6
7
8
functional ligandꢀassisted ketone alkenylation using unactivated
diꢀsubstituted alkynes as the coupling partner. Through controlꢀ
ling the reaction conditions, selective synthesis of conjugated
enamines, α,βꢀand β,γꢀunsaturated ketones can be achieved. While
both cyclic and acyclic ketones can be used as the substrates,
cyclic ketones are more reactive. The intermolecular coupling of
ketones with internal alkynes shows high siteꢀ, chemoꢀ and stereꢀ
oselectivity. This transformation can also tolerate a range of funcꢀ
tional groups due to its near pH and redoxꢀneutral conditions.
Finally, the proposed reaction mechanism was carefully explored
through control experiments, kinetic monitoring, preparation of
the rhodium–hydride intermediates and their reactions with alꢀ
kynes, deuteriumꢀlabeling experiments and identification of the
resting states of the catalyst. We expect this detailed study would
shed light on the scope and potential of the dual activation strateꢀ
gy for catalytic ketoneꢀunsaturate couplings. Expansion to the
coupling of other types of unsaturated hydrocarbons, e.g. allenes
and 1,3ꢀdienes, is ongoing in our laboratory.
To identify these rhodium species, we carried out control experꢀ
iments by mixing Rh(PPh3)3Cl with each reagent one at a time.
We discovered that the doublet at 36.8 ppm in 31P NMR spectrum
appeared when Wilkinson’s catalyst and diphenylacetylene were
mixed and heated together (Figure 2B and eq 11). Fortunately, a
crystal was obtained from this reaction and the Xꢀray structure
was shown below as an alkyneꢀcoordinated complex (13). This
complex exhibits a pseudoꢀtrigonal bipyramidal geometry in
which the distorted diphenylacetylene and chloride form the triꢀ
angle base and the two phosphorus groups occupy the axial posiꢀ
tions. The bond distance between the rhodium and one of the
alkynyl carbon is 2.075 Å and the C‒Rh‒C angle is 35.6 °.
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ASSOCIATED CONTENT
Text, figures, tables, and CIF files giving experimental proceꢀ
dures, kinetics data, and crystallographic information. This mateꢀ
rial is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
gbdong@cm.utexas.edu
Author Contributions
The manuscript was written through contributions of all authors.
All authors have given approval to the final version of the manuꢀ
script.
Figure 3. Crystal structure of complex 13 at 50% probability level.
Hydrogen atoms are omitted for clarity. Selected bond lengths (Å):
Rh1‒P1 = 2.342, Rh1‒P2 = 2.342, Rh1‒C1 = 2.072, Rh1‒C2 =
2.072, Rh1‒Cl1 = 2.341. Selected bond angle (deg): C2‒Rh1‒C1
= 35.6.
Notes
The authors declare no competing financial interest.
Later, we found that the synthesis of complex 13 was first reꢀ
ported by Wilkinson in 1966,80 albeit that no structure was deꢀ
fined at that time. In accord with Wilkinson’s discovery, we also
observed that complex 13 dissociates when dissolved in solution
and cannot be recrystallized. This phenomenon implies that comꢀ
plex 13 is not stable without excess alkynes and phosphine ligꢀ
ands in solution, and thus may hold high catalytic activity. Indeed,
when complex 13 (5 mol%) was used as the catalyst instead of
Rh(PPh3)3Cl, the reaction gave 70% yield of 3a within 2 hours (eq
12). All together, we anticipate that complex 13 is one of the restꢀ
ing states of the catalyst.
ACKNOWLEDGMENT
We thank Cancer Prevention and Research Institute of Texas
(R1118) for a startꢀup fund and the Welch Foundation (Fꢀ1781)
and NSF (CAREER: CHEꢀ1254935) for research grants. Dr.
Lynch is acknowledged for Xꢀray crystallography. We thank B.
A. Shoulders, S. Sorey, and A. Spangenberg for NMR advice;
Johnson Matthey for a donation of Rh salts. We also thank Dr.
M.C. Young for proofreading the manuscript.
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