Highly efficient dehydrogenative cross-coupling of aldehydes with amines and alcohols

Article abstract of DOI:10.1039/c5ra17425b

A common protocol for the synthesis of amides, esters and α-ketoesters via cross dehydrogenative coupling of aldehydes and amines/alcohols has been developed. The method is applicable to a wide variety of alcohols and amines as well as aliphatic and aromatic aldehydes. Also, the use of acetaldehyde for acetylation and ethyl glyoxalate to access 2-oxo-amino esters is presented for the first time.

Full text of DOI:10.1039/c5ra17425b

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Highly Efficient Dehydrogenative Cross-
Coupling of Aldehydes with Amines and
Alcohols
Cite this: DOI: 10.1039/x0xx00000x
Ramesh Deshidi,a Masood Ahmad Rizvia and Bhahwal Ali Shah*,a
Received 00th January 2012,
Accepted 00th January
DOI: 10.1039/x0xx00000x
www.rsc.org/
A common protocol for the synthesis of amides, esters and α- over the previous methods, but still a general method applicable
ketoesters via cross dehydrogenative coupling of aldehydes to synthesis of amides as well as esters from aldehydes was
and amines/alcohols has been developed. The method is lacking until recently, when a Ni(cod)2/IPr catalyzed coupling of
applicable to a wide variety of alcohols and amines as well as aldehdyes amines, anilines and alcohol for synthesis of esters
aliphatic and aromatic aldehydes. Also, the use of and amides was reported.9 The method nevertheless employed
acetaldehyde for acetylation and ethyl glyoxalate to access 2- expensive nickel catalyst. Towards addressing this challenge
oxo-amino esters is presented for the first time.
and in continuation of our interests,10 we made a conscious effort
to develop a metal free catalytic system, which was not only
applicable to amines and alcohols but also to aromatic/aliphatic
aldehydes and 2-oxo aldehdyes to give amides, esters and α-
keto esters.
Direct acyl C-H functionalization of aldehydes to access amides
and esters represent an interesting and challenging strategy.1
The C-H functionalization is also fascinating because of the fact
that it circumvents the need of prefunctionalization and hence,
has more step as well as atom economy.2 However, the limiting
factor behind their use is overcoming high bond energies of C-H
bonds. In recent past this limitation has been addressed via
employment of transition metal catalyst, which can facilitate the
coupling of C-H of aldehydes with amines and alcohols.3
Examples include CuI/AgIO3 catalyzed oxidative amidation of
aldehydes with primary amines,4 utilization of FeCl3/TBHP
system5 and PdCl2/Xanthphos catalyzed synthesis of amides
from amines and aldehydes.6 The drawback of these protocols
was the use of toxic and expensive metals, limited substrate
scope and protection of amines as either amine hydrochloride or
chloramines to prevent oxidation of amines. To deal with these
impediments alternative strategies were explored, which avoided
the use of metal catalysts. For example, Wan and co-workers
developed a metal fee reaction of TBAI/TBHP catalyzed cross-
coupling of aldehydes, however, it required use of preformed
amides viz., N,N-disubstituted formamides and was limited to
aromatic aldehydes/secondary amines.7 Subsequently another
method employing TBAI/TBHP as catalyst was developed using
free amine, but, instead required the activation of aldehydes with
N-hydroxy succinimde (NHS) and had broader substrate scope
as it was applicable to primary amines as well as anilines.8
Though all the methods presented some sort of improvements
Figure 1. This work
To begin with we contemplated using pyridine in combination
with tert-butyl hydroperoxide (TBHP), as it can facilitate its
cleavage to generate a tert-butyloxy anion, which can further
attack the C=N system to give corresponding amide.11 The
optimization studies were performed with benzaldehyde and
morpholine as substrates. To our delight the reaction in presence
of pyridine (1 equiv.) and TBHP (1.5 equiv) at 80 oC in ACN gave
corresponding amide 3a in 82% yields (table 1, entry 1).
Lowering the temperature to rt resulted in drop of yields to 56%
(table 1, entry 2). We also tried reaction with other bases, while
triethyl amine (TEA) and K2CO3 gave 3a in 42 and 51% yields,
the use of KOH failed to give product (table 1, entry 3-5). Next,
we screened other oxidants such as H2O2, m-CPBA and cumene
hydroperoxide (CuHP), wherein in only CuHP gave 3a in 71%
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yields (table 1, entry 6-8). The reaction in other solvents gave imnium ion formation and instead proceeds through a radical
product in comparatively lesser yields (table 1, entry 9-11).
mechanism. Thus, we used I2, which is known to generate tert-
butoxyl and tert-butylperoxyl radicals instead of tert-butoxyl
anion.12 The reaction of benzaldehyde with aniline in presence of
I2/TBHP was chosen as model reaction. The reaction lead to the
formation of desired product 3s in 65% yields (table 2 entry 5).
We deliberated the screening of other iodine sources such as
NIS, KI, TBAI and PhI(OAc)2. While there was no product
formation with PhI(OAc)2, the yields with NIS and KI were
comparable to that of I2 (table 2 entry 2-4). However, to our
surprise the TBAI was found to be catalyst of choice giving
corresponding amide 3s in 74% yields (table 2 entry 5). The
reaction in other solvents though gave product, but in
comparatively lesser yields (table 2, entry 6-9).
Table 1. Optimization of the reaction conditions[a]
entry
1
solvent
CH3CN
base
pyridine
oxidant
TBHP
temp (oC)
80
yield [%]
82
2
3
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Toluene
THF
pyridine
TEA
TBHP
TBHP
TBHP
TBHP
H2O2
rt
56
42
51
-
80
80
80
80
80
80
80
80
80
4
K2CO3
5
KOH
6
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
-
Table 2. Optimization of the reaction conditions[a]
7
m-CPBA
CuHP
TBHP
TBHP
TBHP
-
8
71
45
58
54
9
10
11
entry
1
solvent
CH3CN
catalyst
I2
oxidant
TBHP
temp (oC)
80
yield [%]
65
DCE
[a] Reactants: 1 (1 mmol); 2 (1 mmol); base (1 equiv); oxidant (1.5 equiv)
2
3
4
5
6
7
8
9
CH3CN
CH3CN
CH3CN
CH3CN
Toluene
THF
NIS
KI
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
80
80
80
80
80
80
80
80
61
59
-
Having conditions optimized, we explored the scope of different
aldehydes with amines (Scheme 1). The reaction proceeds
readily with a range of amines secondary amines to give
corresponding products. The reaction of benzaldehyde with
different secondary amines including heterocyclic amines such
as thiomorpholine, piperidine, 4-phenyl piperidine, pyrrolidine,
diethyl amines gave corresponding amides (3b-3f) in excellent
PhI(OAc)2
TBAI
TBAI
TBAI
TBAI
TBAI
74
45
58
54
52
DCE
DMSO
yields (scheme-1). Furthermore, the reaction of 4-bromo and 4- [a] Reactants: 1 (20 mmol); 2 (1 mmol); catalyst (30 mol%); oxidant (3 equiv)
nitro benzaldehyde with morpholine also gave amides 3g and 3h
Next, we investigated the scope of reaction with different
aldehydes and amines (scheme 2). To begin with, we tested the
catalytic system with acetaldehyde as the coupling partner,
which would probably be the simplest way for acetylation and
has no precedence in literature. The reaction of acetaldehyde
under optimized conditions proceeded smoothly with different
amines i.e., aniline, 4-methyl, 4-bromo and 4-(trifluoromethoxy)
anilines to give corresponding products 3i-3l in good yields.
Interestingly, the reaction of acetaldehyde with p-hydroxy and p-
ethoxy aniline as coupling partners accomplishes possibly the
in 73% and 78% yields respectively. However, the reaction failed
to give desired product when aniline was used as a coupling
partner.
simplest synthesis of paracetamol (3m, 60
%) and phenacetin
(
6n 65 respectively. Notably, previously the use of
,
%)
acetaldehyde has proven difficult as a result of its tendency to
polymerise, low-boiling point and the formation of side-
products.13 Intriguingly, with present catalytic system, there was
no side product formation observed as well as reaction could be
carried out in open flask. Since, the reaction was amenable to
aliphatic aldehydes we thought of using ethyl glyoxalate, as it
would give access to 2-oxo-amino esters, which are also hitherto
unreported. The advantage of having a vicinal ester group is that
it can be used as a handle for further diversification. The reaction
of ethylglyoxalate as expected with aniline, 4-bromo, 4-methyl, 4-
(trifluoromethyl) anilines gave corresponding 2-oxo-amino esters
3o-3r in excellent yields. The scope of the reaction with respect
Scheme 1. Generality of the reaction in terms of aldehydes and 2o amines
Thus, further optimization studies were performed to expand its
scope to primary amines and anilines. We reasoned that it’s
probably iminium ion formation with secondary amine that is
facilitating the oxidation of C=N system, hence, we envisaged
finding alternate catalytic system, which circumvents the need of
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to different aromatic aldehydes having electron withdrawing and in 66, 62 and 69% yields. Importantly, there was no side product
releasing function was also investigated. The reaction with formation with alcohol of leucinol possibly due to more
different aromatic aldehydes such as benzaldehyde, 4-methoxy, nucleophilicity of amine and its stoichiometric use. The use of 2-
4-(trifluoromethoxy), 3,4-methylenedioxy, 4-nitro benzaldehyde ethoxybenzaldehyde and ammonia as coupling partners leads to
and 2-napthaldehyde gave the corresponding products (3s-3v the synthesis of ethenzamide (3av) in 62% yields. It would be
and 3z-3aa) in good yields. Furthermore, the reaction with pertinent to mention here that the reaction with secondary
halogenated aldehydes such as 4-fluoro, 2,4-dichloro and 3- amines failed to proceed with TBAI/TBHP catalytic system.
bromo benzaldehyde to give (3w-3y) in excellent yields and To the best of our knowledge there is only a single method
providing possibility for further functionalization. The method also known, capable of transforming aldehydes into esters and
proceeds efficiently with heterocyclic aldehydes like 2-furyl and amides using alcohols and amines.9 Thus, using our optimized
2-thiophenyl carboxaldehyde to give corresponding products 3ab conditions we carried out the reaction of benzaldehyde with
and 3ac in 56 and 63% yields respectively.
methanol to delightfully get methyl benzoate 5a in 78% yields
(scheme 3). Furthermore, the methanol could easily be coupled
with different aromatic aldehydes such as 4-methoxy, 3,4-di-
methoxy, 4-nitro, 3-nitro, 3-bromo-4-methoxy, 4-chloro, 3,4-
methylenedioxy benzaldehyde and 2-napthaldehyde to get the
corresponding esters (5b-5i) in excellent yields. Importantly,
heterocyclic aldehydes such as 2-pyridine and 2-thiophene
carboxaldehdye could also be easily transformed into esters 5j
and 5k in 74 and 68% yields respectively. Also, ethanol and
butanol could be utilized as coupling partners with benzadehyde
to get corresponding esters 5l and 5m in 62 and 54% yields. We
also explored the substrate scope of 2-oxoaldehydes for
synthesis of corresponding α-ketoesters, which find pervasive
presence in a large number of bioactive compounds and have
lead to the development of copious methods for their synthesis in
recent years.14 Likewise, the reaction of 2-oxo-phenyl
acetaldehyde and methanol under optimized condition gave
corresponding α-ketoester 5n in 56% yield. Similarly, other
substituted 2-oxoaldehydes such as 4-OMe, 4-Br and 4-Cl gave
corresponding α-ketoesters (5o-5q) in good yields. The reaction
of 2-oxo-phenyl acetaldehyde with ethanol and butanol also gave
corresponding products 5r and 5s in 50 and 42% yields
respectively.
Scheme 2. Synthesis of various amides
Next, we expanded the scope to various primary amines aliphatic
as well aromatic (scheme 2). Aliphatic amines such as n-propyl,
iso-propyl, cyclopropyl, cyclopentyl and benzyl amines reacted
efficiently with benzaldehyde to give corresponding products
(
3ad-3ah) in good yields. Also, the reaction with different
aromatic amines viz., 4-methyl, 2-methyl 4-methoxy, 4-OCF3 and
4-CF3 aniline proceeded gave amides (3ai-3am) in excellent
yields. In addition the reaction of halogenated amines such as
3,4-difluoro, 4-fluoro and 4-chloro anilines also gave the
corresponding products (3an-3ap) in good yields respectively,
which not to mention provide the possibility of further
functionalization. Furthermore, heterocyclic amines like 2-amino
pyridine and 2-amino benzothiazole were also found suitable for
this transformation to give 3aq and 3ar in 53 and 57% yields. We
also extended the reaction to different aminoacids, which have
very few literature reports. To our delight the reaction of amino
acid methyl esters such as leucine and phenylalanine as well as
Scheme 3. Synthesis of esters and α-keto-esters
The reaction possibly proceeds via two different routes for
secondary amines and primary amines with pyridine and TBAI as
catalyst. For route A; benzaldehyde possibly reacts with
secondary amine to form iminium ion intermediate
Subsequently, tert-butylperoxy anion generated by abstraction of
a proton from TBHP by pyridine,11 attacks the iminium ion (
) to
(I).
I
amino alcohol, leucinol gave corresponding products (3as-3au
)
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give intermediate (II). The pyridine also further abstracts a proton
from intermediate (II) to eliminate tert-butanol and give the
desired product (III). For route B; on the basis of previous
publications,7,8,12 we assume the TBAI catalyses the formation of
tert-butoxyl and tert-butylperoxyl radicals from TBHP. The acetal
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(
II) consequently oxidizes to the corresponding amide or ester.
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In summary, we have developed an efficient cross-coupling
strategy for the synthesis of amides, esters and α-ketoesters
from aldehydes. The method also presents a first use of
acetaldehyde for acetylation and ethyl glyoxalate for 2-oxo-amino
esters respectively. The method employs a simple experimental
procedure, broad substrate scope and sustainable to wide range
of functionalities.
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aAcademy of Scientific and Innovative Research (AcSIR); Natural
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Road, Jammu-Tawi, 180001; bDepartment of Chemistry, University of
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