Rhodium-catalyzed oxidative amidation of allylic alcohols and aldehydes: Effective conversion of amines and anilines into amides

Article abstract of DOI:10.1039/c5sc03103f

The rhodium-catalyzed oxidative amidation of allylic alcohols and aldehydes is reported. In situ generated [(BINAP)Rh]BF₄ catalyzes the one-pot isomerization/oxidative amidation of allylic alcohols or direct amidation of aldehydes using acetone or styrene as the hydrogen acceptor. The conditions are general, affording good to excellent yields with a wide array of amine and aniline nucleophiles, and chemoselective, other alcohols do not participate in the oxidation reaction. Utilization of biphasic conditions is critical, as they promote an equilibrium between the imine/enamine byproducts and the hemiaminal, which can undergo oxidation to the amide.

Full text of DOI:10.1039/c5sc03103f

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Chemical Science
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DOI: 10.1039/C5SC03103F
Journal Name
ARTICLE
Rhodium-catalyzed oxidative amidation of allylic alcohols and
aldehydes: effective conversion of amines and anilines into
amides
Received 00th January 20xx,
Accepted 00th January 20xx
Zhao Wu and Kami L. Hull*
DOI: 10.1039/x0xx00000x
The rhodium-catalyzed oxidative amidation of allylic alcohols and aldehydes is reported. In situ generated [(BINAP)Rh]BF4
catalyzes the one-pot isomerization/oxidative amidation of allylic alcohols or direct amidation of aldehydes using acetone
or styrene as the hydrogen acceptor. The conditions are general, affording good to excellent yields with a wide array of
amine and aniline nucleophiles, and chemoselective, other alcohols do not participate in the oxidation reaction. Utilization
of biphasic conditions is critical, as they promote an equilibrium between the imine/enamine byproducts and the
hemiaminal, which can undergo oxidation to the amide.
www.rsc.org/
reported an acceptorless oxidative amidation of alcohols using
Ru catalysis with pincer and NHC ligands, respectively.
Although no hydrogen acceptor is needed, substrate scopes
Introduction
Amides are a common functionality found throughout
natural products, pharmaceuticals, agrochemicals, and organic
materials.1 Approaches have been developed for the coupling
of carboxylic acids and amines to generate amides in high
yield.2 While these reactions are versatile and widely
employed, there are significant drawbacks associated with
them: they generate super-stoichiometric quantities of high
molecular weight byproducts and are not functional group
tolerant.3 The transition metal-catalyzed oxidative amidation
of alcohols4 and aldehydes5 is a promising alternative to
traditional coupling methods,6,7 as it allows for the generation
of amides along with molecular hydrogen as the only by-
are limited to unhindered alcohols and amines. Secondary
cyclic amines require a less-hindered pincer ligand8b and
acyclic amines are still challenging.8 Moreover, elevated
temperatures (> 110 °C) and refluxing solvents are needed to
favor the evolution of H2 gas4c-d, 4i-l or transfer hydrogenation
to ketones.4e Direct amidation of aryl aldehydes with external
oxidants have been reported by Rh and Cu catalysis. However,
yields are usually low when enolizable aldehydes are used due
to the formation of amine byproducts.5b Recently, Dong
reported a Ni-catalyzed C–H activation of aldehydes followed
by coupling with alcohols or amines to form esters and amides
respectively.5i A variety of aldehydes and amines are shown to
be reactive, but an additional equivalent aldehyde or
trifluoroacetophenone is required as the hydrogen acceptor.
Herein, we report an easily accessible, chemoselective, and
general catalytic method, which selectively couples allylic
alcohols or aldehydes with aliphatic and aryl amines to form
amides.
product (Scheme 1). For example, Misltein and Madsen
Scheme 1. Transition metal-catalyzed oxidative amidation of alcohols and aldehydes.
Previous Work:
Amidation of Alcohols (Milstein, Madsen, Grützmacher)
O
[Ru], [Rh]
R2
R2
2 H2
R1 OH
+
+
(1)
(2)
R4
R1
N
H2N
H
Amidation of Aldehydes (Beller, Li, Dong)
O
R2
[Rh], [Cu], [Ni]
[O]
O
Results and discussion
Research Hypothesis
R2
+
HN
R3
R1
N
R3
R1
H
This Work:
In seeking to develop general conditions for amide bond
formation, we proposed that allylic alcohols could serve as an
aldehyde precursor.9, 10 Such a system would be advantageous
as allylic alcohols have been previously shown to isomerize to
an aldehyde in the presence of a [Rh]-catalyst.10 Then, the in
situ generated aldehydes could undergo a Rh-catalyzed
oxidative amidation with an amine to afford the amide and a
Rh–H. Subsequent H2 formation or transfer hydrogenation
would regenerate the active catalyst species.4e, 5b
OH
O
O
R4
+ [Rh]
+ [Rh]
HN
+
R1
R1
R1
N
R3
R2
R1, R2 = H, alkyl, aryl
R2
R2 R3
R3 = H, alkyl
R4 = alkyl, aryl
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Table 1: Selected optimization of oxidative amidation of allyl alcohol with
secondary amine.a
Table 2: Selected optimization of oxidative amidation of allyl alcohol with
primary amine.a
View Article Online
DOI: 10.1039/C5SC03103F
O
O
3 mol % [(COD)2Rh]BF4
3 mol % [(COD)2Rh]BF4
3 mol % BINAP
Ph
N
Ph
Ph
N
H
Me
N
3 mol % BINAP
Oxidant, Base
N
3a
OH
3h
OH
NH2
Oxidant, Base
Me
+
+
+
+
C6H6/H2O, 80°C, 24 h
Ph
Solvent, 80°C, 15 h
Ph
N
H
N
Ph
OH
1a
2h
4h
1a
2a
1h
% yield
3h
11
50
51
56
48
82
60
%yield
4h
89
30
19
10
6
0
11
0
% yield
1h
0
20
30
26
37
6
% yield
3a
% yield
1h
0
entry
base
oxidant
entry
solvent
base
oxidant
1
2
3
4
5
6
7
8
9c
CsOAc
Cs2CO3
KOH
KOH
KOH
KOH
Cs2CO3
KOH
styrene
styrene
styrene
norbornene
NMO
acetone
acetone
acetoneb
acetone
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
DME
none
none
none
none
KOH
NEt3
K2CO3
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAce
CsOAcf
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
cyclohexanone
norbornene
styrene
9
DME/H2O
C6H6/H2O
Tol/H2O
14
42
38
24
41
51
56
63
62
80
65
68
91
84
90
0
20
19
19
19
24
22
22
23
9
12
20
5
10
10
C6H6/H2O
C6H6/H2O
C6H6/H2O
C6H6/H2O
C6H6/H2O
C6H6/H2O
C6H6/H2O
C6H6/H2O
C6H6/H2O
C6H6/H2O
C6H6/H2O
C6H6/H2O
18
4
0
84
15
KOH
3
a
Unless otherwise noted, reaction conditions are: allyl alcohol (0.25 mmol, 1.0 equiv),
amine (3.0 equiv), base (1.5 equiv), oxidant (3.0 equiv), solvent (0.2 mL, 1.2 M), DI H2O
(0.2 mL). Yields are determined by GC analysis and comparison to an internal standard.
b 5.0 equiv. c No H2O added.
MMAb
styrenec
styrened
styrene
41% yields with 1h as the major byproduct (Table 1, entry 5-8;
Table S4). Next, hydrogen acceptors were investigated; styrene
proved to be superior, over acetone, affording 3a in 80% yield
and 1h in 9% yield (Table 1, entry 11). Cyclohexanone,
norbornene and MMA lead to lower yields of 3a (Table 1,
entries 9-12; Table S4). Finally, increasing the equivalents of
styrene and CsOAc slightly improved yields and shortened the
reaction time to 4 hours (Table 1, entries 13-16; Table S5, S7).
Interestingly, as seen in Table 2, under the optimized
conditions benzyl amine gave only 11% yield of amide 3h and
89% yield of imine 4h (Table 2, entry 1). Fortunately, by
changing the base and hydrogen acceptor to KOH and acetone,
respectively, the desired amide 3h is formed in 82% yield along
with only 6% yield of 1h (Table 2, entry 6).
styrene
a
Unless otherwise noted, reaction conditions are: allyl alcohol (0.25 mmol, 1.0 equiv),
amine (3.0 equiv), base (1.5 equiv), oxidant (3.0 equiv), solvent (0.2 mL, 1.2 M), DI H2O
(0.2 mL). Yields are determined by GC analysis and comparison to an internal standard.
b MMA = methyl methacrylate. c 1.0 equiv. d 5.0 equiv. e 2.0 equiv. f 2.5 equiv.
Optimization Studies
Initial efforts focused on developing a Rh-catalyzed oxidative
amidation of cinnamyl alcohol (1a) and N-methylpiperazine
(
2a). When they are combined with a cationic rhodium
catalyst, the enamine (E)-1-methyl-4-(3-phenylprop-1-en-1-
yl)piperazine 4a suggesting that
predominates,12
isomerization/condensation is significantly faster than the
subsequent oxidation of the hemiaminal (vide infra).
Moreover, reduced starting material 1h was also observed,
indicating that the cinnamyl alcohol was acting as the
hydrogen acceptor.12
As such, two main challenges in optimization of the desired
oxidative amidation reaction were to identify: (1) conditions
that promote amide over enamine formation and (2) an
oxidant that is selectively reduced over the allylic alcohol.
As summarized in Table 1, and further elaborated in Table
S1-S8, a variety of reaction conditions were explored: varying
solvent systems, bases, and oxidants. As enamine byproducts
do not undergo the oxidative amidation, it was postulated that
adding water to the reaction might promote reformation of
the hemiaminal; indeed, the addition of an equal volume of
H2O to non-polar solvents like benzene and toluene significant-
ly suppressed the formation of the enamine 4a (Table S3) and
favored the formation of the amide 3a (Table 1, entries 1-4;
Table S2). Bases were next investigated: addition of CsOAc
gave 56% yield of 3a; stronger bases lead to lower yields of the
desired amide, with KOH and Et3N affording 3a in 24% and
(
)
Substrate Scope
The optimization experiments suggest that the allylic alcohol
rapidly converts into the aldehyde under the reaction
conditions, which could then go on to form the amide. This
suggested that under the optimized conditions, aldehydes
should be effective substrates for the oxidative coupling
reaction. Indeed, when 3-phenylpropanal (5a) is subjected to
the optimized conditions amide 3a is formed in a 76% yield,
which is nearly identical to the 81% yield from the cinnamyl
alcohol (Table 3). The scope of amines was then explored with
both 1a and 5a (Table 3). Secondary cyclic amines, including 1-
methylpiperazine, morpholine, piperidine, pyrrolidine,
tetrahydroisoquinoline (2a-2e) and more sterically hindered
acyclic amines, such as dimethyl amine (2f) and N-benzyl
methyl amine (2g) are incorporated in very good, and nearly
equivalent, yields from either the 1a or 5a. cis cinnamyl alcohol
also undergoes the amidation reaction with morpholine to
afford 3b, although at a significantly reduced rate and in
moderately reduced yields.12 Likewise, primary amines
afforded 3h-3l in good to excellent yields.
2 | J. Name., 2012, 00, 1-3
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Table 3: Amine scope of allylic alcohol and aldehyde amidation a
View Article Online
DOI: 10.1039/C5SC03103F
3.0 mol % [(COD)2Rh]BF4
3.0 mol % BINAP
Oxidant, Base
Ph
OH
O
O
1a
R2
R2
+
HN
R1
2a-r
or
Ph
N
C6H6/H2O, 80 °C, 4-24 h
R1
Ph
3a-r
yield from 1a or 5a
5a
O
O
O
O
O
O
O
Me
Ph
N
Ph
N
Ph
N
Ph
N
Ph
N
Me
Ph
N
Me
Ph
N
N
O
Me
3g
76%, 76%
3a
81%, 76%
3b
91%, 88%b
3c
84%, 73%
3d
81%, 83%
3e
83%, 72%
3f
64%, 57%
O
O
O
N
O
O
O
O
NEt2
Ph
N
H
Ph
N
H
Ph
Ph
N
H
Me
Ph
N
H
Ph
N
H
3j
54%, 48%
3k
73%, 66%
3h
80%, 72%
3i
72%, 63%
3l
73%, 65%
3m
73%, 83%
Me
OMe
F
CF3
O
O
O
O
O
Ph
N
H
Ph
N
H
Ph
N
H
Ph
N
H
Ph
N
H
3n
55%, 59%
3o
64%, 53%
3p
53%, 59%
3q
66%, 56%
3r
41%, 37%
a Alcohol or aldehyde (0.25 mmol, 1.0 equiv), amine (3.0 equiv), [(COD)2Rh]BF4 (3.0 mol %), BINAP (3.0 mol %), oxidant (3.0-5.0 equiv): styrene (2° amine and aniline) or acetone (1°
amine), base(1.5-2.5 equiv), benzene (0.2 mL, 1.2 M), DI H2O (0.2 mL).12 b 82% yield was observed from (Z)-cinnamyl alcohol.12
Table 4: Allylic alcohol scope for amidation.a
The reaction is sensitive to steric hindrance of the amine,
as cyclohexylamine affords 54%/48% yield of amide 3j while n-
3.0 mol % [(COD)2Rh]BF4
3.0 mol % BINAP
Oxidant, Base
butylamine affords amide 3i in 72%/63% yield. Unlike other
oxidative amidation processes,4a, 4d-l electron rich and electron
poor aniline derivatives (2m-2r) were all effective nucleophiles
in the coupling reaction without requiring higher temperatures
or specialized reaction conditions.11 It is important to note,
that for all substrates, the allylic alcohol and the aldehyde gave
similar yields.
The allylic alcohols that undergo the oxidative amidation
reaction were explored, as seen in Table 4. Functional groups
such as ketones, esters, ethers, aryl bromides, and chlorides
are tolerant under the standard conditions based on a
chemical robustness screen.12 Products bearing active aryl
R2
R2
O
R5
+
HN
R4
R5
R1
OH
O
R1
N
C6H6/H2O, 80 °C, 24 h
R3
1b-f
R3 R4
6a-j
2
O
N
O
Me
Ar
N
Me
N
N
O
Ph
O
O
O
3ba: Ar=4-Br-C6H4-, 76%
3bb: Ar=4-MeO-C6H4-, 72%
6a
77%
6b
61%
O
O
Me
O
Me
N
Ph
Ph
N
N
Ph
O
Me
O
Ph
6c
61%
6d
86%
6e
52%
bromides could be synthesized in good yields (3ba, 3ha),
O
Me
O
Me
Me O
allowing for facile subsequent coupling reactions to increase
molecule complexity. 1,1-di, 1,2-di-, tri-, and tetra-substituted
allylic alcohols give the corresponding α- or/and β- branched
N
Me
N
O
Me
6h
O
6g
64%
6f
54%
41%(1.6:1 dr)
secondary (6i-6p) and tertiary (6a-6h) amides in moderate to
O
O
O
good yields with primary and secondary amines, respectively.
Notably, allylic alcohols known to be slow to isomerize, such as
1f afforded moderate yields (54%) of the oxidative amidation
product 6f after 24 hours.10c Notably, geraniol was coupled to
afford 6g and 6o in 64% and 65% yield, respectively; neither
reduction nor isomerization of the distal alkene was observed.
Tetra-substituted allylic alcohols react, affording 6h and 6p
in 41% and 31% yield, respectively, along with unreacted
starting material. Unfortunately, the diastereoselectivity of
these reactions was poor, affording the amines in only 1.6:1
and 1:1 dr.
Me
N
Ph
Ar
N
Ph
Me
Ph
N
H
Ph
Ph
H
H
Ph
6j
6i
87%
3ha: Ar=4-Br-C6H4-, 60%
3hb: Ar=4-MeO-C6H4-, 70%
74%
O
O
Me
O
Me
N
H
Ph
Ph
Ph
N
H
Ph
N
H
Me
Ph
6k
70%
6l
74%
6m
60%
O
Me
O
Me
Me
O
N
H
Ph
N
H
Ph
Me
N
H
Ph
Me
6p
31%(1:1 dr)
6n
67%
6o
65%
a Alcohol or aldehyde (0.25 mmol, 1.0 equiv), amine (3.0 equiv), [(COD)2Rh]BF4 (3.0 mol
%), BINAP (3.0 mol %), oxidant (3.0-5.0 equiv): styrene (2° amine) or acetone (1° amine
benzene (0.2 mL, 1.2 M), DI H2O (0.2 mL).12
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Chemical Science
Table 5: Aldehyde scope for amidation.a
Scheme 2. Competition Experiments. a
View Article Online
DOI: 10.1039/C5SC03103F
3.0 mol % [(COD)2Rh]BF4
3.0 mol % BINAP
5.0 equiv styrene
1. Allylic alcohol vs. aldehyde
O
O
O
R3
OH
HN
R2
2
R3
+
R1
N
Ph
N
R1
5b-m
1.0-2.5 equiv CsOAc
C6H6/H2O, 80 °C, 24 h
33%
25%
Ph
1.0 equiv
R2
1a
Me
N
N
3a
Conditionsa
7a-l
Me
Me
Me
+
+
O
O
O
O
3
O
N
H
O
N
N
N
N
5k
3
O
O
2a
3.0 equiv
N
O
O
1.0 equiv
Me
7b
99%
7a
91%
7c
99%
8
O
O
Me
O
2. Disubstituted vs. trisubstituted allylic alcohols:
N
N
N
O
OH
O
O
O
Br
7d
64%
Me
7e
Me
7f
88%
72%
Ph
N
Ph
1a
Me
N
N
84%
3a
Conditionsa
1.0 equiv
O
O
O
+
+
O
OH
N
H
N
N
N
O
O
O
N
not observed
F3C
Me
F
NC
2a
3.0 equiv
7g
85%
7h
48%
7i
72%
N
1d
Me
9
1.0 equiv
O
N
O
Me
O
Me
N
3. Allylic vs. benzylic alcohol:
Me
N
Me
N
O
O
OH
7j
97%
7k
78%
6g
63%
Ph
N
93%b
Ph
1.0 equiv
1a
Me
N
a Alcohol or aldehyde (0.25 mmol, 1.0 equiv), amine (3.0 equiv), [(COD)2Rh]BF4 (3.0 mol
%), BINAP (3.0 mol %), styrene (5.0 equiv), CsOAc (1.5-2.5 equiv), benzene (0.2 mL, 1.2
M), DI H2O (0.2 mL).12
3a
N
Conditionsa
+
+
OH
O
N
H
not observed
Ph
1.0 equiv
Ph
N
2a
3.0 equiv
N
Me
Finally, as seen in Table 5, the scope of aldehydes that
undergo the oxidative amidation reaction was investigated.
The reactions are tolerant of a variety of functionalities,
including ethers (7b), acetals (7c), aryl bromides (7d), aryl
10
4. Allylic vs homoallylic alcohol:
O
OH
82%
Ph
N
fluorides
(
7g), trifluromethyls
(
7i), nitriles
(7h), and
Ph
1.0 equiv
1a
Me
N
N
3a
Conditionsa
heteroaromatics (7j). Benzaldehyde derivatives with electron
donating groups, such as p-MeO, afford the desire amide in
excellent yield; electron poor benzaldehydes, such as p-CN or
Me
+
+
OH
O
N
H
< 5%
N
2a
3.0 equiv
p-F3C, undergo the oxidative amidation to afford 7h and 7i
,
1.0 equiv
N
Me
11
albeit in reduced yields. Steric hindrance of the aldehyde did
not affect its reactivity, as 2,6-dimethylbenzaldehyde afforded
amide 7f in 88% yield. Aliphatic aldehydes, which have proven
challenging for other oxidative amidation reactions, 5a-h also
afford the desired amides in good to very good yields (7k and
6g).
5. Allylic vs alphatic alcohol:
O
OH
Ph
N
88%c
Ph
1.0 equiv
1a
Me
N
N
3a
Conditionsa
Me
+
+
O
OH
N
H
Competition Experiments
N
3
3
not observed
12
1.0 equiv
2a
3.0 equiv
N
The synthetic utility of this oxidative amidation reaction
would be significantly increased if the reaction proved to be
chemoselective for allylic alcohols and aldehydes over other
oxidizable functionalities, i.e., simple primary alcohols. To
explore the chemoselectivity of the reaction conditions, a
series of competition studies were carried out (Scheme 2).
Me
8
a
Standard conditions are: alcohol/aldehyde 1 (1.0 equiv), alcohol/aldehyde 2 (1.0
equiv), 2a (3.0 equiv), [(COD)2Rh]BF4 (3.0 mol %), BINAP (3.0 mol %), styrene (3.0
equiv), CsOAc (2.5 equiv), benzene (0.2 mL, 1.2 M), DI H2O (0.2 mL), 80 °C, 4 hours.
benzyl 3-phenylpropanoate was formed in 7% yield. hexyl 3-phenyl-propanoate was
b
c
formed in 8% yield.
In Competition Experiment 1, cinnamyl alcohol
(1a)
oxidative amidation of the two aliphatic aldehydes then occurs
at similar rates.
Next, in Competition Experiment 2, the comparative
reactivity of two different allylic alcohols was explored. Under
the standard reaction conditions, cinnamyl alcohol (1a) reacts
competes against hexanal (5k) to compare the relative rates of
the two coupling partners. Unsurprisingly, given the rapid rate
of 1,3-hydride shift,10c the reaction is unselective, affording a
33% yield of 3a and a 25% yield of
8 after four hours. This lack
of selectivity supports the rapid Rh-catalyzed isomerization of
the cinnamyl alcohol to the corresponding aldehyde; the
selectively over cyclohex-1-en-1-ylmethanol
(1d). This
excellent chemoselectivity is consistent with the known rates
4 | J. Name., 2012, 00, 1-3
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Chemical Science
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Journal Name
ARTICLE
of the Rh-catalyzed isomerization of allylic alcohols.10c
Importantly, 1d was observed, unisomerized, at the end of the
reaction.
H
N
3.0 mol % [(COD)2Rh]BF4
3.0 mol % BINAP
View Article Online
O
OH
DOI: 10.1039/C5SC03103F
Ph
N
+
5.0 equiv Styrene
2.5 equiv CsOAc
C6H6/D2O (1:1), 80 °C
Ph
D D
N
Me
2a
N
Me
Competition Experiments 3-5 investigate the chemo-
selectivity of the oxidative amidation reaction with respect to
benzylic alcohols, homoallylic alcohols, and aliphatic alcohols.
When equimolar amounts of cinnamyl alcohol (1a) and benzyl
alcohol were treated with 3.0 equivalents of 2a under the
standard reaction conditions, product 3a was formed in 9
3% yield while 10 was not observed. This indicates that our
conditions are highly selective for allylic alcohols over easily
oxidizable benzylic alcohols.4h,4m Moreover, in Competition
Experiment 4, less than 5% amide product 11 was observed
when cinnamyl alcohol and 3-buten-1-ol are subjected to the
3a-d2
1a
83 % D Incorporation
kH/kD = 2.2
formation.4c-f, 4i-k Comparison of the initial rate of the reaction
in H2O and D2O revealed a kH/kD = 2.2, indicating the enamine-
hemiaminal equilibrium occurs at or before the turnover-
limiting step. Alternatively, the primary k.i.e. could be
attributed to cleavage of N-H(D) bond in hemiaminal
formation, due to the exchange of amine proton with D2O.
The proposed dual catalytic cycles for this oxidative amidation
reaction are shown in Scheme 4. First, a Rh-mediated 1,3-
hydride shift10 occurs to form an aldehyde from the allylic
alcohol. The aldehyde then condenses with the amine to
generate the enamine/imine, which is in equilibrium with the
hemiaminal. The oxidation of the hemiaminal could occur
through either a Rh(I)/Rh(III) or a redox neutral Rh(I) catalytic
cycle. In the first, oxidative addition of the hemiaminal OH into
reaction conditions, which afforded an 82% yield of 3a
.
Notably, 3-buten-1-ol affords <5% yield of 11 under the
standard reaction conditions, in the absence of cinnamyl
alcohol.12 Finally, Competition Experiment 5 demonstrates that
cinnamyl alcohol (1a) reacts selectively over hexan-1-ol (12), to
afford an 88% yield of 3a; 8 was not observed. These
experiments exhibit the excellent chemoselectivity of this Rh-
catalyzed oxidative amidation reaction for coupling allylic
alcohols and aldehydes selectively.
the Rh(I) generates a Rh(III)(H)OCHNR2
hydride elimination generates the amide and a Rh(III)–(H)2 (IV
complex which is reduced to Rh(I) through hydrogenation of
the styrene or acetone. Alternatively, in a redox neutral
(
III). Subsequent
β
-
)
Mechanistic Investigations
catalytic cycle, ligand exchange of the [Rh] (
hemiaminal affords the Rh–alkoxide (III) then undergoes
hydride elimination to generate the amide and the Rh–H (IV).
Insertion of the hydride into styrene/acetone followed by
protolytic cleavage or ligand exchange affords the ethyl
benzene/isopropanol, respectively,
I) with the
Next, the requirement of excess amine and super-
stoichiometric base was investigated. When a equimolar
amounts of amine and allyl alcohol/aldehyde are added to the
reaction the desired amide is formed in only 20% yield along
with 13% enamine along with both unreacted aldehyde and
aldol condensation products (Table S6, entry 1). However, in
the presence of excess amine excellent yields of the amide are
observed. It is proposed that the excess amine forces the
equilibrium, between aldehyde and enamine/imine, to the
enamine/imine thereby decreasing the concentration of
aldehyde and preventing the undesired aldol condensation
from occurring. The base additive, CsOAc or KOH, could serve
two possible roles, either acting as a proton shuttle or as a
ligand on the catalyst. The pH of the water layer in the
oxidative amidation reactions is 9.2; when the CsOAc solution
is replaced with various buffers (pH = 5.2, 7.5, or 9.0) the
reaction are equally efficient as to those in the absence of base
(Table S9). This suggests that the base is acting as a ligand to
the catalyst and that the requirement of excess base is due to
the solubility differential of the anion in water versus benzene.
To gain further mechanistic insight into this reaction, we
conducted an isotope incorporation experiment, replacing H2O
with D2O. After the reaction had gone to completion, 83%
deuterium was incorporated at the α-position of the product
(Scheme 3). Importantly, in the absence of catalyst and N-
methylpiperazine, no deuterium incorporation is observed into
amide 3a or 3-phenylpropanal. This suggests that water reacts
with the enamine/imine to reform the reactive hemiaminal,13
which is different from many Ru-catalyzed dehydrogenative
coupling of alcohols with amines, where in-situ formed
β
-
Scheme 4. Proposed dual catalytic cycle.
Catalytic Cycle 1:
1,3-Hydride Shift
Catalytic Cycle 2:
Oxidative Amidation
Ph
or
Ph
or
O
hydrogenation
OH
HO
R
C–H
activation
H
[Rh]
IV
O
R1
N
R
R2
HO
R
H
β-hydride
elimination
[Rh]
[Rh]
O
[Rh]
II
R1
I
N
R
R2
III
reductive
elimination
oxidative addition or
ligand exchange
– HNR1R2
+ HNR1R2
HO
R
O
R
HNR1R2
+ H2O – H2O
1R2RNH
R1N
R
R
or
R2 = H
aldehydes stay bounded to metal center to avoid the imine
Scheme 3. Deuterium studies.
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J. Name., 2013, 00, 1-3 | 5
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Chemical Science
Page 6 of 6
EDGE ARTICLE
Chemical Science
Eur. J., 2013, 19, 82. (i) Whittaker, A. M.; Dong,VVie.wMAr.ticAlenOgneliwne.
and either [Rh] complex
I or III. Currently, we can not
Chem. Int. Ed., 2015, 54, 1312.
DOI: 10.1039/C5SC03103F
distinguish between the two possible mechanistic pathways
6
For recent reviews, see: (a) Dobereiner, G. E.; Crabtree, R. H.
Chem. Rev., 2010, 110, 681. (b) Pattabiraman, V. R.; Bode, J.
W. Nature, 2011, 480, 471. (c) Allen, C. L.; Williams, J. M. J.
Chem. Soc. Rev., 2011, 40, 3405. (d) Singh, C.; Kumar, V.;
and further mechanistic investigations are ongoing.14
Conclusions
Sharma, U.; Kumar, N.; Singh, B. Curr. Org. Synth., 2013, 10
,
241. (e) Crochet, P.; Cadierno, V. Top. Organomet. Chem.,
2014, 48, 81.
In conclusion, conditions have been developed for the
chemoselective oxidative amidation of allylic alcohols or
aldehydes, using styrene or acetone as hydrogen acceptors.
This methodology presents a general protocol for the synthesis
of amides, which is effective for both primary and secondary
alkyl/aryl amines. Current efforts are focusing on expanding
the scope of nucleophiles and developing asymmetric
conditions15 for the transformation.
7
8
9
For related NHC catalyzed amidation see: (a) Vora, H. U.;
Rovis, T. J. Am. Chem. Soc., 2007, 129, 13796. (b) Bode, J. W.;
Sohn, S. S. J. Am. Chem. Soc., 2007, 129, 13798. (c) Sarkar, S.
D.; Studer, A. Org. Lett., 2010, 12, 1992.
Formation of tertiary amides: (a) Chen, C.; Zhang, Y.; Hong, S.
H. J. Org. Chem., 2011, 76, 10005. (b) Srimani, D.; Balaraman,
E.; Hu, P.; Ben-David, Y.; Milstein, D. Adv. Synth. Catal., 2013,
355, 2525.
Transition metal-catalyzed functionalization of allylic alcohol:
(a) Hirai, K.; Takahashi, Y.; Ojima, I. Tetrahedron Letters,
1982, 23, 2491. (b) Watanabe, Y.; Tsuji, Y.; Ohsugi, Y.; Shida,
J. Bull. Chem. Soc. Jpn. 1983, 56, 2452.
Acknowledgements
10 Rh-catalyzed allylic alcohol isomerization: (a) Tanaka, K.; Fu,
G. C. J. Org. Chem., 2001, 66, 8177. (b) Tanaka, K.; Qiao, S.;
Tobisu, M.; Lo, M. M.-C.; Fu, G. C. J. Am. Chem. Soc., 2000,
122, 9870. (c) Bergens, S. H.; Bosnich, B. J. Am. Chem. Soc.,
1991, 113, 958. (d) Tani, K. Pure Appl. Chem., 1985, 57, 1845.
11 Anilines have been demonstrated to undergo oxidative
amidation with heterogeneous gold catalysts, see reference
4k.
The authors would like to thank the University of Illinois,
Urbana-Champaign for their generous support.
Notes and references
1
(a) Zabicky, J. The Chemistry of Amides; Wiley-VCH: New
York, 1970. (b) Greenberg, A.; Breneman, C. M. The Amide
Linkage: Structural Significance in Chemistry, Biochemistry
and Material Science. Wiley-VCH: New York, 2000. (c) Carey,
J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org. Biomol.
12 See Supporting Information.
13 Amide formation using H2O as the oxygen atom source: (a)
Khusnutdinova, J. R.; Ben-David, Y.; Milstein, D. J. Am. Chem.
Soc. 2014, 136, 2998. (b) Gellrich, U.; Khusnutdinova, J. R.;
Chem. 2006, 4, 2337.
Leitus, G. M.; Milstein, D. J. Am. Chem. Soc. 2015, 137, 4851.
2
3
For a review: Valeur, E.; Bradley, M. Chem. Soc. Rev., 2009,
38, 606.
1
14 When the reaction is monitored by both H and 31P NMR no
Rh–H are observed. This suggests that either oxidative
(a) Coin, I.; Beyermann, M.; Bienert, M. Nature Protocols,
addition or
β-hydride elimination is between the turnover
2007, 2, 3247. (b) Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.;
limiting step and the catalyst resting state if the reaction is
occurring through the Rh(I)/(III) or Rh(I) catalytic cycles,
respectively.
Humphrey, G. R.; Leazer, Jr. J. L.; Linderman, R. J.; Lorenz, K.;
Manley, J.; Pearlman, B. A.; Wells, A.; Zaks, A.; Zhang, T. Y.
Green Chem, 2007,
From alcohols: (a) Naota, T.; Murahashi, S. I. Synlett, 1991
10, 693. (b) Fujita, K.; Takahashi, Y.; Owaki, M.; Yamamoto,
K.; Yamaguchi, R. Org. Lett., 2004, , 2785. (c) Gunanathan,
9, 411.
15 Under standard condition, reaction of prochiral (E)-3-
phenylbut-2-en-1-ol with morpholine affords 1-morpholino-
3-phenylbutan-1-one in 86% yield and 3:1 er by using R-
BINAP as chiral ligand. For comparison, [((R)-BINAP)Rh]ClO4
catalyzes the asymmetric isomerization of (E)-3-phenylbut-2-
en-1-ol to afford the β-chiral aldehyde in 70% yield and 3.3:1
er. See reference 10d.
4
,
6
C.; Ben-David, Y.; Milstein, D. Science, 2007, 317, 790. (d)
Owston, N. A.; Parker, A. J.; Williams, J. M. J. Org. Lett. 2007,
9
, 73. (e) Nordstrom, L. U.; Vogt, H. Madsen, R. J. Am. Chem.
Soc., 2008, 130, 17672. (f) Watson, A. J. A.; Maxwell, A. C.;
Williams, J. M. J. Org. Lett., 2009, 11, 2667. (g) Zweifel, T.;
Naubron, J.-V.; Grützmacher, H. Angew. Chem. Int. Ed., 2009,
48, 559. (h) Shimizu, K.-i.; Ohshima, K.; Satsuma, A. Chem.
Eur. J., 2009, 15, 9977. (i) Ghosh, S. C.; Muthaiah, S.; Zhang,
Y.; Xu, X.; Hong, S. H. Adv. Synth. Catal., 2009, 351, 2643. (j)
Zhang, Y.; Chen, C.; Ghosh, S. C.; Li, Y.; Hong. S. H.
Organometallics, 2010, 29, 1374. (k) Muthaiah, S.; Ghosh, S.
C.; Jee, J.-E.; Chen, C.; Zhang, J.; Hong, S. H. J. Org. Chem.,
2010, 75, 3002. (l) Dam, J. H.; Osztrovszky, G.; Nordstrom L.
U.; Madsen, R. Chem. Eur. J., 2010, 16, 6820. (m) Wang, Y.;
Zhu, D.; Tang, L.; Wang, S.; Wang, Z. Angew. Chem. Int. Ed.,
2011, 50, 8917.
5
From aldehydes: (a) Tamaru, Y.; Yamada, Y.; Yoshida, Z.-i.
Synthesis, 1983, 474. (b) Tillack, A.; Rudloff, I.; Beller, M. Eur.
J. Org. Chem., 2001, 523. (c) Yoo, W.-J.; Li, C.-J. J. Am. Chem.
Soc., 2006, 128, 13064. (d) Chang, J. W. W.; Chan, P. W. H.
Angew. Chem. Int. Ed., 2008, 47, 1138. (e) Seo, S. Y.; Marks,
T. J. Org. Lett., 2008, 10, 317. (f) ref 4i. (g) Ghosh, S. C.;
Ngiam, J. S. Y.; Seayad, A. M.; Tuan, D. T.; Chai, C. L. L.; Chen,
A.; J. Org. Chem., 2012, 77, 8007. (h) Li, Y.; Jia, F.; Li, Z. Chem.
6 | J. Name., 2012, 00, 1-3
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