Cross coupling of acyl and aminyl radicals: Direct synthesis of amides catalyzed by Bu4NI with TBHP as an oxidant

Article abstract of DOI:10.1002/anie.201108763

A radical solution: A Bu₄NI/tert-butyl hydroperoxide (TBHP) catalyzed synthesis of amides through a cross-coupling reaction between acyl and aminyl radicals is described. This method involves the combination of aldehyde C-H bond functionalization and decarbonylation of N,N-disubstituted formamides (see scheme). The cross-coupling is metal-free, has a wide substrate scope, operational simplicity, and gives high yields on scale-up. Copyright

Full text of DOI:10.1002/anie.201108763

Angewandte
Chemie
DOI: 10.1002/anie.201108763
Synthetic Methods
Cross Coupling of Acyl and Aminyl Radicals: Direct Synthesis of
Amides Catalyzed by Bu4NI with TBHP as an Oxidant**
Zhaojun Liu, Jie Zhang, Shulin Chen, Erbo Shi, Yuan Xu, and Xiaobing Wan*
Dedicated to Professor Christian Bruneau on the occasion of his 60th birthday
Amides are prevalent structural motifs that are found in
biologically relevant molecules, such as proteins, as well as
natural products, marketed drugs, and synthetic intermedi-
ates.[1] As a result, the synthesis of amides has attracted
considerable interest and a number of methods have been
devised. Conventionally, amides are synthesized by coupling
a carboxylic acid or a carboxylic acid derivative with an
amine.[1a,b,2,3] In addition, the aminocarbonylation of aryl
halides has been developed for the chemoselective formation
of amides.[4] Transition-metal-catalyzed oxidative coupling
between alcohols and amines also offers elegant and direct
access to amides.[5] Alternatively, the use of thioacids or
thioesters as acylation reagents has emerged as a powerful
method for amide synthesis.[6] Other attractive approaches
include the hydration of nitriles,[7] rearrangement of oximes,[8]
acylation of amines,[9] the modified Staudinger reaction,[10]
carbonylation of alkenes[11] or alkynes,[12] amidation of
was required. As shown in Table 1, a variety of amine
derivatives, which include N-chlorosuccinimide (NCS), N-
bromosuccinimide (NBS), N-iodosuccinimide (NIS), Chlor-
amine-T, NH2NH2, and NH2OH, were used as potential
Table 1: Screening for aminyl radical precursors.[a]
Entry
R1R2N-X
Yield [%][b]
1
2
3
4
5
6
7
NCS
NBS
NIS
Chloramine-T
NH2NH2
NH2OH
DMF
<5
<5
<5
<5
<5
<5
89
nitriles,[13] or transition-metal-catalyzed C C bond cleav-
À
age.[14] Although great progress has been achieved in this
field, there still remains significant challenges for synthetic
organic chemists in both academic and industrial teams
worldwide.
[a] Reaction conditions: A mixture of 1-naphthaldehyde (1a, 0.5 mmol),
amino radical precursors 2 (7.5 mmol), Bu4NI (20 mol%), TBHP
(2.9 mmol, 0.4 mL of a 70% aqueous solution) in 1,1,2-trichloroethane
(2.0 mL) was stirred at 908C for 24 h. [b] Yield of isolated product.
Currently, the synthesis of amides relies heavily on ionic
reactions. Undoubtedly, a radical process,[15] for example the
coupling of acyl- and nitrogen-centered radicals, is a funda-
mentally different method for the formation of amide bonds.
Recently, we developed a Bu4NI-catalyzed tert-butyl perester
synthesis,[16d] in which acyl radicals, which are generated
in situ from aldehydes, could be trapped by 2,2,6,6-tetrame-
thylpiperidine 1-oxyl (TEMPO). Inspired by this success, we
envisioned the coupling of a nitrogen-centered radical,
instead of TEMPO, with the acyl radical to provide
a method for amide synthesis.
donors of nitrogen-centered radicals.[17] Unfortunately, no
significant formation of the amide bond was detected in these
reactions. When the reaction was performed in N,N-dime-
thylformamide (DMF), however, N,N-dimethyl-1-naphtha-
mide (3a) was detected, which indicates that DMF is an
effective source of aminyl radicals. The success of the reaction
with DMF might be a consequence of the longer lifetime of
aminyl radicals relative to amidyl radicals.[18] Through system-
atic screening of the reaction conditions, a stirred solution of
1-naphthaldehyde 1a, DMF, Bu4NI (20 mol%), and tert-butyl
hydroperoxide (TBHP, 5.8 equiv) in 1,1,2-trichloroethane at
908C for 24 h gave 3a in 89% yield, with no formation of 1,2-
diketones or tert-butyl peresters (Table 1, entry 7; for opti-
mization of the reaction conditions, see Table S1 in the
Supporting Information). A trace amount of hydrazine was
formed in the transformation, which indicates that the aminyl
radical was generated in situ from DMF. The high selectivity
could be a result of the persistent radical effect (PRE).[19]
Further investigations on the mechanism were performed.
A trace amount of carboxylic acid was detected in the
reaction mixture. When 1-naphthoic acid (4) was used in the
optimized conditions, no 3a was detected (Scheme S1a in the
Supporting Information). Furthermore, the use of tert-butyl
perester 5 as reaction partner suppressed the amide synthesis
To achieve this goal, an appropriate nitrogen-centered
radical precursor that favors the formation of the amide bond
[*] Z. Liu, J. Zhang, S. Chen, E. Shi, Y. Xu, Prof. Dr. X. Wan
Key Laboratory of Organic Synthesis of Jiangsu Province
College of Chemistry, Chemical Engineering and Materials Science
Soochow University, Suzhou 215123 (China)
E-mail: wanxb@suda.edu.cn
Prof. Dr. X. Wan
State Key Laboratory of Applied Organic Chemistry
Lanzhou University (China)
[**] A Project Funded by the Priority Academic Program Development of
Jiangsu Higher Education Institutions (PAPD) and NSFC
(20802047, 21072142).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201108763.
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(Scheme S1b in the Supporting Information). Based on these
two results, both the carboxylic acid and tert-butyl perester
can be excluded as reaction intermediates. Recently, hyper-
valent iodine reagents have attracted much interest owing to
their efficiency and the mild reaction conditions under which
they can be used.[20] It was possible that a hypervalent iodine
reagent might be formed in situ from Bu4NI and TBHP, which
would then serve as the oxidant in the transformation.
However, both PhI(OAc)2 and 2-iodoxybenzoic acid (IBX)
completely suppressed the reaction (Scheme S1c in the
Supporting Information).
Scheme 2. Trapping the aminyl radical.
As anticipated, the TEMPO adduct 6 was formed instead
of the amide in 64% yield under the optimized conditions
(Scheme 1a). A 13C-isotope labeling experiment proved that
the carbonyl group comes from the aldehyde, not from the
DMF (Scheme 1b). Based on these results, the acyl radical is
initially generated by hydrogen abstraction from the alde-
hydes, and then serves as the acylation reagent in the amide
(Scheme 2). This result strongly suggests that an aminyl
radical, not an amine, was the intermediate in the trans-
formation. DMF has previously been employed as the amide
source for aminocarbonylation of aryl halides;[4g–i] however,
the expense of the transition-metal catalysts and the hazards
of POCl3 or other strong bases limit their applications. To the
best of our knowledge, the use of DMF as a source of an
aminyl radical has not been reported before.
On the basis of these results and previous publications,
a plausible catalytic cycle is presented in Scheme 3. In the first
step, the tert-butoxyl and tert-butylperoxyl radicals form
catalytically (Scheme 3a).[25] These radicals then abstract
hydrogen from the aldehyde and DMF to generate acyl
radical A[16d,26] and aminyl radical B,[17] respectively (Sche-
me 3b and c). Finally, the acyl radical A and aminyl radical B
couple to form the desired amide (Scheme 3d).
À
synthesis. Whereas both the functionalization of the C H
bond in aldehydes[21,22] and the decarbonylation of DMF[23]
have been well-documented, combining them into one
reaction under metal-free conditions has remained virtually
unexplored.
Scheme 1. Investigations into the reaction mechanism.
The acylation of amines has proved to be a reliable
method for the construction of amide bonds.[9] Nucleophilic
addition of an amine to an aldehyde and oxidation of the
resulting carbinolamine was proposed as a mechanism. Our
reaction would involve dimethylamine that is generated
in situ from DMF. To rule out this pathway, dimethylamine
was used instead of DMF under otherwise the same
conditions (Scheme 1c), and only trace amount of amide 3a
was detected. Tert-butyl dimethylcarbamoperoxoate (7)
decomposes to form an aminyl radical, a tert-butoxyl radical,
and CO2 when heated.[24] Thus, it is logical to assume that the
aminyl radical, which is generated in situ from 7, could couple
with an acyl radical to generate an amide bond. To confirm
this hypothesis, tert-butyl dimethylcarbamoperoxoate 7 was
prepared and subjected to the amide synthesis reaction. As
anticipated, amide 3a was generated in 73% yield
Scheme 3. Proposed reaction mechanism.
A variety of substituted aryl aldehydes were subjected to
the optimized conditions, and representative results are
summarized in Scheme 4. The results indicate that aldehydes
with electron-withdrawing or electron-donating groups were
well tolerated and provided the corresponding amides in
moderate to excellent yields. Generally, aldehydes bearing
electron-withdrawing substituents gave the correct products
but with decreased yields. For example, when 4-nitrobenzal-
dehyde was coupled with DMF, the effect of the electron-
withdrawing group was noticeable, and the reaction produced
3d in low yield. Steric effects also influence the reaction.
Slightly decreased but acceptable yields were achieved for
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mides were required in the reaction,
a range of N,N-disubstituted forma-
mides, which includes cyclic and acyclic
formamides, were suitable for the for-
mation of the corresponding amides
9a–9k in moderate to high yields.
Other than alkyl substituted forma-
mides, the synthetically more impor-
tant benzyl- and allyl-substituted for-
mamides gave good yields (9e and 9 f).
Unprotected hydroxy groups and the
removable Boc group were tolerated in
the amide formation reaction (9g and
9h). Pyrazole was also a compatible
substrate for this transformation and
gave the desired amide 9i in moderate
yield. Notably, the method also proved
applicable to amino acid derivatives
(9j). N,N-Diphenylformamide did not
form the desired product (9l). The
strong conjugation between the amide
group and phenyl ring most likely
Scheme 4. Scope of the reaction with aryl aldehydes.
reactions that involved ortho-substituted aldehydes (3s and
3t). A wide variety of functional groups, including benzylic
À
C H (3b), CN (3c and 3t), CF3 (3h), alkyne (3j), O-(4-
toluenesulfonyl) (OTs, 3n), ether (3r), ester (3l, 3m, and 3o),
O-tert-butyloxycarbonyl (Boc, 3q), and amide (3p), were
tolerated under the optimized conditions. The presence of
halide substituents on the aromatic groups did not interfere
with the formation of the amide bond, and these reactions
afforded the corresponding products, which could be further
manipulated by traditional cross-coupling reactions (3 f and
3g). Even functional groups that are sensitive to oxidation,
such as sulfides and double bonds, were not affected during
the reaction (3i, 3k, and 3l). The reaction could be scaled up
to 100 mmol (1-naphthaldehyde (1a), 15.6 g), and the desired
amide 3a was produced in 76% yield. When aliphatic
aldehydes were subjected to the reaction, only small
amount of the corresponding amides
Scheme 5. Scope of the reaction with other aromatic aldehydes.
were obtained.[27]
To show the synthetic utility of the
method, a variety of heteroaryl alde-
hydes, including furan, thiophene, thia-
zole, and pyridine, were subjected to
the optimized conditions. As shown in
Scheme 5, the desired amides 8a–8 f
were obtained in satisfactory yields.
The catalytic synthesis of a,b-unsatu-
rated amides remains a challenge in the
literature.[4–14] In this study, both enal
and ynal groups were suitable reaction
partners in the transformation, and led
to the corresponding amides 8g, 8h,
and 8i in good yields.
Scheme 6 presents the scope of the
N,N-disubstituted formamides which
can be used in this reaction. Although
large amounts (15 equiv relative to
Scheme 6. Scope of the reaction with N,N-disubstituted formamides. 2.0 mL of ethyl acetate
aldehydes) of N,N-disubstituted forma- was used for 9 f. N.O=not obtained
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amides. Further studies on the mechanistic details and
expansion of the scope of the reaction are currently underway
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Experimental Section
General procedures for amides 3a–3t, 8a–8I, and 9a–9k: The
aldehyde (0.5 mmol), N,N-disubstituted formamide (7.5 mmol),
Bu4NI (0.1 mmol, 20 mol%), TBHP (2.9 mmol, 0.4 mL of a 70%
aqueous solution), and 1,1,2-trichloroethane (2.0 mL) were added to
a test tube in air. The reaction mixture was heated in an oil bath at
908C for 24 h and was quenched with a saturated solution of Na2SO3
(for removal of excess TBHP) and extracted with ethyl acetate. The
organic solvent was removed under vacuum and purification by
chromatography on a silica gel column afforded the desired product.
Received: December 13, 2011
Revised: January 31, 2012
Published online: February 15, 2012
Keywords: aldehydes · amides · cross-coupling · formamides ·
.
radical reactions
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