Direct amidation of alcohols with N-substituted formamides under transition-metal-free conditions

Article abstract of DOI:10.1002/chem.201201203

Go tandem! The first example of the direct amidation of alcohols with N-substituted formamides has been developed. A series of tertiary amides, including the challenging N,N-dimethyl-substituted amides, were obtained in moderate to good yields under transition-metal-free conditions (see scheme). TBHP=tert-butyl hydroperoxide. Copyright

Full text of DOI:10.1002/chem.201201203

COMMUNICATION
DOI: 10.1002/chem.201201203
Direct Amidation of Alcohols with N-Substituted Formamides under
Transition-Metal-Free Conditions
Kun Xu, Yanbin Hu, Sheng Zhang, Zhenggen Zha, and Zhiyong Wang*[a]
Amides are one of the most important units in a wide
range of natural and designed compounds with biologically
relevant properties.[1] The importance of the amide motif ne-
cessitates the development of efficient methods for their
preparation. Recently, Li etal. described an elegant proce-
dure for the direct amidation of simple aldehydes with
amines.[2] With the aim to construct an amide bond in
a clean atom-economical manner, several transition-metal-
based homogeneous[3,4] and heterogeneous catalysts[5] have
emerged as attractive tools for the direct synthesis of amides
from alcohols and amines. Other alternatives, such as the
hydration of nitriles,[6] rearrangement of aldoximes,[7] transa-
midation,[8] and C H oxidative amidation,[9] have also
À
proven to be efficient methods for the construction of amide
bonds.
Although considerable progress has been made towards
methods facilitating amide formation, efficient and low cost
syntheses of N,N-dimethyl-substituted amides under metal-
free conditions are still less explored. In general, the tradi-
tional syntheses of N,N-dimethyl-substituted amides are lim-
Scheme 1. Typical pathways for the N,N-dimethyl-substituted amide syn-
theses.
ited by the need for prior activation of carboxylic acids
(Scheme 1a).[10] Alternative methods, such as aminocarbony-
lation or carbamoylation of aryl halides[11,12] and oxidative
amination of aldehydes,[13] have also been developed
(Scheme 1b and c). Recently, our group has developed
a new protocol for the direct synthesis of N,N-dimethylben-
zamide from benzyl alcohol by using a Au/DNA nanohybrid
as the catalyst (Scheme 1d).[5c] As a logical extension of this
catalytic method, and encouraged by our previous work on
I2/tert-butyl hydroperoxide (TBHP)-mediated catalytic oxi-
dative transformations,[14] we have developed a metal-free
transformation of alcohols to N,N-dimethyl-substituted
amides.[15]
TBHP as an external oxidant (see Table S1 in the Support-
ing Information for details). Firstly, a series of solvents, in-
cluding CH2Cl2, toluene, N,N-dimethylacetamide (DMA),
and 1,4-dioxane, were examined for the reaction; however,
all of these attempts were unsuccessful. Interestingly, when
the solvent was replaced by dimethylformamide (DMF),
N,N-dimethylbenzamide (3aa) was obtained in 37% yield.
This finding prompted us to explore the scope and limitation
of the unexpected reaction in DMF in more detail. By con-
sidering the amidation of benzyl alcohol (1a) with DMF
(2a) as a model reaction, a series of reaction conditions
were optimized (Table 1). Initial experiments were per-
formed to investigate the effect of a base on the reaction.
An excellent yield was obtained by using NaOH as the
base; however, lower yields were obtained when other hy-
droxide bases or alkoxide bases were employed (Table 1, en-
tries 1–4). Further studies indicated that 0.05mmol of
NaOH was optimal (Table 1, entries 5 and 6). Subsequently,
control experiments showed that the catalyst, oxidant, and
base were all essential for this transformation (Table 1, en-
tries 7–9). Replacement of the aqueous TBHP (70wt.% in
water) with anhydrous TBHP (5m in decane) led to a lower
Initially, our study focused on the I2-mediated amidation
of benzyl alcohol with aqueous dimethylamine by using
[a] K. Xu, Y. Hu, S. Zhang, Z. Zha, Prof. Z. Wang
Hefei National Laboratory for Physical Sciences at Microscale
CAS Key Laboratory of Soft Matter Chemistry and
Department of Chemistry
University of Science and Technology of China
Hefei, Anhui, 230026 (P.R. China)
Fax : (+86)551-3603185
yield (Table 1, entry 10), which revealed that
a small
E-mail: zwang3@ustc.edu.cn
amount of water was crucial for this reaction. Increasing the
temperature led to a lower yield due to the partial forma-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201203.
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Table 1. Optimization of the reaction conditions.[a]
Table 2. Reactions of alcohols with DMF.[a]
R1
Product
Yield [%][b]
Entry
Catalyst
Oxidant
Base
Yield [%][b]
Entry
1
2
3
I2
I2
I2
I2
I2
I2
–
I2
I2
I2
I2
PhI
I2
I2
I2
I2
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
–
TBHP
TBHP
TBHP
TBHP
DTBP
DDQ
O2
LiOH·H2O
NaOH
KOH
tBuOK
NaOH
NaOH
NaOH
NaOH
–
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
77
84
82
54
71
1
2
3
4
5
C6H5
4-FC6H4
3aa
3ba
3ca
3da
3ea
3 fa
3ga
3ha
3ia
3ja
3ka
3la
3ma
3na
3oa
3pa
3qa
84 (67)
89 (69)
85
82
85
83 (51)
84.
79
80
78
82
81
82
81
86
77 (42)
62
4-ClC6H4
4-BrC6H4
4-CNC6H4
4-CF3C6H4
4-MeC6H4
2-MeC6H4
2-BrC6H4
3-MeC6H4
3-ClC6H4
3,4-di-MeOC6H3
1-naphthyl
2-Py
4
5[c]
6[d]
7
73
6
7
n.r.
n.r.
59
46
79
8[c]
9
8
9
10[e]
11[f]
12
13
14
15
16
10
11
12
13
14
15
16
17[d]
(OAc)2
35
<10
<5
n.r.
<5
2-thio
2-furyl
(E)-cinnamyl
K2S2O8
[a] The reactions were carried out with 1a (0.5 mmol), I2 (0.1 mmol),
TBHP (2.0 mmol), NaOH (0.1 mmol), and 2a (0.5 mL) at 708C for 2 h;
then at 808C for 22 h. [b] Yield of the isolated product is based on the al-
cohol. [c] Using 0.25 mmol of NaOH. [d] Using 0.05 mmol of NaOH.
[e] Using anhydrous TBHP (5m in decane). [f] Reaction was carried out
at 908C. DTBP=di-tert-butyl peroxide, DDQ=2,3-dichloro-5,6-dicyano-
1,4-benzoquinone.
[a] The reactions were carried out with 1a–1q (0.5 mmol), I2 (0.1 mmol),
TBHP (2.0 mmol), NaOH (0.1 mmol), and 2a (0.5 mL) at 708C for 2 h;
then at 808C for 22 h. [b] Yield of the isolated product is based on the al-
cohol; yields in parentheses resulted from a reaction time of 2 h. [c] Re-
action was carried out at 708C for 2 h, then at 808C for 48 h. [d] Reaction
was carried out at 708C for 24 h.
tion of benzoic acid as a side product (Table 1, entry 11). It
is worth noting that the yield was decreased when hyperva-
lent iodine was employed in the reaction (Table 1, entry 12).
Further assessment of the reaction conditions indicated that
TBHP was the optimal oxidant; other organic and inorganic
oxidants showed low activity (Table 1, entries 13–16).
as 2-phenylethanol and cyclohexylmethanol, were employed
as the substrates, no corresponding amides were obtained.[16]
To further establish the general utility of this transforma-
tion, we examined the scope for other N-substituted forma-
mides. As presented in Table 3, when N,N-disubstituted for-
With the optimized conditions in hand, the substrate
scope of the reaction was investigated. As illustrated in
Table 2, the reaction proceeded smoothly with different sub-
strates to afford a wide range of N,N-dimethyl-substituted
amides in moderate to good yields. The electronic properties
of a series of aromatic alcohols were found to have little in-
fluence on the reaction (Table 2, entries 1–7). On the other
hand, the steric effects of substituents had some influence
on the reaction. For example, the reaction proceeded effi-
ciently when meta- and para-substituted benzyl alcohols
were employed (Table 2, entries 3, 4, 7, and 10–12); howev-
er, ortho substituents had a negative effect on the transfor-
mation (Table 2, entries 8 and 9). It is worth noting that
halo-substituted benzyl alcohols were well tolerated, be-
cause this is advantageous for further transformations.
When the aromatic ring was replaced by a hindered naph-
thyl group, the corresponding amide 3ma was obtained in
82% yield (Table 2, entry 13). Heteroaryl substrates were
also efficiently transformed, affording the potentially bio-
important amides in good yields (Table 2, entries 14–16).
However, the reaction of (E)-cinnamyl alcohol with DMF
afforded the amide 3qa in a lower yield (Table 2, entry 17),
which was attributed to the oxidative cleavage of the
carbon–carbon double bond. When aliphatic alcohols, such
Table 3. Reactions of benzylic alcohol with N-substituted formamides.[a]
Entry
R1
R2
Product
Yield [%][b]
1
2
Et
Et
–
–
3ab
3ac
3ad
3ae
80
81
87
41
piperidine
morpholine
CH3
3
4[c]
H
[a] The reactions were carried out with 1a (0.5 mmol), I2 (0.1 mmol),
TBHP (2.0 mmol), NaOH (0.1 mmol), and 2b–2e (0.5 mL) at 708C for
2 h; then at 808C for 22 h. [b] Yield of the isolated product is based on
the alcohol. [c] Reaction was carried out at 508C for 48 h.
mamides were employed, the corresponding amides were
formed in moderate to good yields (Table 3, entries 1–3).
Importantly, the challenging substrate N-methylformamide
(2e) worked effectively in the present system to deliver the
product 3ae in 41% yield (Table 3, entry 4). This indicated
that 2e can be a substrate under this catalytic system in
spite of the lower yield.
To gain an insight into the mechanism of the reaction,
a series of control experiments were set up under various
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Direct Amidation of Alcohols with Formamides
COMMUNICATION
conditions. When benzyl alcohol was treated with DMF in
the absence of a base, the corresponding amide 3aa was ob-
tained in a moderate yield; however, when benzaldehyde
was treated with DMF in the absence of base, the amide
3aa was obtained in excellent yield [Eq. (1)]. This indicates
that the base plays an important role in the oxidation of the
alcohol, rather than in the amidation step.
Scheme 2. A proposed mechanism accounting for the formation of 3aa.
When 1,1-diphenylethylene (a radical scavenger) was
added to the reaction mixture, the amidation process was
suppressed dramatically [Eq. (2)], which suggests that the
amidation step may involve a radical pathway.
cycle.[20] Simultaneously, a tert-butoxyl radical is generated,
which can trap the H radical to form the acyl radical
5a.[15,20a,21] Meanwhile, the aminyl radical 6a is generated ef-
ficiently from DMF with the assistance of the tert-butoxyl
radical.[22,23] Subsequent cross-coupling of the acyl radical 5a
with the aminyl radical 6a leads to formation of the corre-
sponding amide 3aa. This highly selective radical cross-cou-
pling might be explained by the persistent-radical effect
(PRE).[24,25]
In conclusion, the first efficient and direct synthesis of ter-
tiary amides from alcohols and dimethylformamide has
been developed. This transition-metal-free protocol provides
a practical synthetic tool for the construction of N-substitut-
ed amides, especially N,N-dimethyl-substituted amides. Fur-
ther studies to clearly understand the mechanism are ongo-
ing in our laboratory.
When DMF was replaced by dimethylamine, a trace
amount of amide was detected by GC–MS analysis [Eq. (3)]
(see Scheme S3 in the Supporting Information for details),
which implied that dimethylamine was not the reaction in-
termediate. A proposed pathway based on the reaction of
benzaldehyde with dimethylamine to form a hemiaminal in-
termediate, and the subsequent oxidation to the amide 3aa,
could therefore be ruled out.[17]
Experimental Section
General procedure: TBHP (2.0 mmol, 70 wt.% aqueous solution) was
added to
a mixture of alcohol (0.5 mmol), I2 (0.1 mmol), NaOH
(0.1 mmol), and DMF (0.5 mL) in a tube equipped with a condenser. The
mixture was allowed to stir at 708C for 2 h, and was then heated at 808C
for 22 h. After the reaction was complete, the mixture was cooled to
room temperature. Then, a saturated solution of Na2S2O4 (10 mL) was
added. The mixture was extracted with ethyl acetate (3ꢁ15 mL). The
combined organic phases were dried with Na2SO4 and evaporated under
vacuum. Purification of the residue by flash column chromatography (pe-
troleum ether/EtOAc=2:1–1:1) afforded the desired amide.
When tetrabutylammonium iodide (TBAI) and PhI were
employed as the catalysts, moderate yields of 3aa were ob-
tained [Eq. (4)]. However, hypervalent iodine (PhIACHTNUTRGNEUNG(OAc)2)
suppressed the transformation (Table 1, entry 12). These re-
sults showed that the IÀ–I2 catalytic cycle is likely to play an
important role in the reaction process.
Acknowledgements
We are grateful to the National Nature Science Foundation of China
(20932002, 20972144, 90813008, 21172205, 20772188, and J1030412) and
the 973 program (2010CB912103).
On the basis of the control experiments and previous
studies,
a possible reaction mechanism is shown in
Scheme 2. Initially, benzyl alcohol (1a) is oxidized to benzal-
dehyde (4a) under basic conditions.[18,19] Then, IÀ is oxidized
to I2 though a radical pathway to realize the catalytic
Keywords: alcohols · amides · dimethylformamide · radical
reactions · transition-metal-free reactions
Chem. Eur. J. 2012, 00, 0 – 0
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Direct Amidation of Alcohols with Formamides
COMMUNICATION
[24] Since the reaction is not a radical chain-reaction, the concentration
of the radical species is crucial for efficient coupling. Homocoupling
of the acyl radical might be far slower than the consumption of the
aminyl radical (see ref. [22]). When the acyl and aminyl radicals are
generated at comparable rates, the increase in the relative concen-
tration of the acyl radicals with respect to the aminyl radicals leads
to the selective cross-coupling.
[25] For reviews of the persistent-radical effect, see: a) H. Fischer, Chem.
Rev. 2001, 101, 3581–3610; b) A. Studer, Chem. Eur. J. 2001, 7,
1159–1164; c) A. Studer, Chem. Soc. Rev. 2004, 33, 267–273; d) A.
Studer, T. Schulte, Chem. Rec. 2005, 5, 27–35.
Received: April 9, 2012
Revised: May 17, 2012
Published online: && &&, 0000
Chem. Eur. J. 2012, 00, 0 – 0
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Z. Wang et al.
Amides
K. Xu, Y. Hu, S. Zhang, Z. Zha,
Z. Wang* ...................... &&&& — &&&&
Direct Amidation of Alcohols with N-
Substituted Formamides under Transi-
tion-Metal-Free Conditions
Go Tandem! The first example of the
direct amidation of alcohols with N-
substituted formamides has been
developed. A series of tertiary amides,
including the challenging N,N-
dimethyl-substituted amides, were
obtained in moderate to good yields
under transition-metal-free conditions
(see scheme). TBHP=tert-butyl hydro-
peroxide.
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ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!