TBSOTf-promoted versatile N-formylation using DMF at room temperature

Article abstract of DOI:10.1016/j.tetlet.2019.04.010

Hydrazides and amines were N-formylated by DMF in the presence of tert-butyldimethylsilyl triflate (TBSOTf) at room temperature, in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2019.04.010

Accepted Manuscript
TBSOTf-Promoted Versatile N-Formylation Using DMF at Room Temperature
Masayoshi Sakurai, Rina Kawakami, Nobuhiro Kihara
PII:
S0040-4039(19)30334-X
https://doi.org/10.1016/j.tetlet.2019.04.010
TETL 50725
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Reference:
Tetrahedron Letters
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Please cite this article as: Sakurai, M., Kawakami, R., Kihara, N., TBSOTf-Promoted Versatile N-Formylation Using
DMF at Room Temperature, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.04.010
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Tetrahedron Letters
TBSOTf-Promoted Versatile N-Formylation Using DMF at Room Temperature
Masayoshi Sakurai,a Rina Kawakami,a Nobuhiro Kiharaa
a Department of Chemistry, Faculty of Science, Kanagawa University, 2946 Tsuchiya, Hiratsuka 259-1293, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
2009 Elsevier Ltd. All rights reserved.
Hydrazides and amines were N-formylated by DMF in the presence of tert-butyldimethylsilyl
triflate (TBSOTf) at room temperature, in good to excellent yields.
Available online
Keywords:
Keyword_1 DMF
Keyword_2 hydrazides and amines
Keyword_3 tert-butyldimethylsilyl triflate
Keyword_4 N-formylation
52% yield as the only isolable product (Scheme 1), indicating
that even a primary amine can be formylated by the DMF-TBSCl
system. Soon after this observation, it was found that the DMF-
TBSOTf system is a simple and powerful N-formylation method
1. Introduction
Formamide is one of the most important members of the amide
family and has been used in various fields of organic chemistry.
N,N-Dimethylformamide (DMF) is a widely used because it is
one of the most important aprotic highly polar solvents.1 The
Vilsmeier reagent prepared from formamide serves as a powerful
tool for the preparation of aromatic aldehydes.2 The formamide
moiety is found in several pharmaceutical drugs and organic
catalysts.3
that can be extended to various amines.
Scheme 1
Although acid chloride and anhydride are usually employed as
the acylation agents for amines, both formyl chloride and formic
anhydride are too unstable to be used in formylation. Therefore,
various alternative methods have been developed for formylation.
The mixed anhydride of formic acid with a bulky acid is one of
the most powerful formylation agents,4 although it cannot be
stored for a long time. Ethyl formate is conveniently used for the
formylation of amines,5 although heating is generally necessary,
and the low boiling point of ethyl formate often limits its
availability.
DMF is the most widely used formic acid derivative, which also
finds application as a formylation agent.6 Because of the low
electrophilicity of DMF, heating is necessary to carry out
formylation, even in the presence of an effective activation
agent.7 Formylation by DMF using excess trimethylsilyl chloride
(TMSCl) or tert-butyldimethylsilyl chloride (TBSCl) in the
presence of imidazole or triethylamine at room temperature has
been reported,8 although this system is applicable only to
secondary amines and hence finds limited application.
During the course of our research on hydrazides,9 we
investigated the silylation of 1a with TBSCl in DMF at room
2. Results and Discussion
To optimize the reaction conditions for the N-formylation, 1b
was used as a simple hydrazide. Activating agents were added to
the DMF solution of 1b, and the reactions were carried out at
room temperature for 20 h. The results are summarized in Table
1.
When 1 equiv of TBSCl and imidazole were used to activate
DMF, 2b was obtained in 33% yield (entry 1). The yield
increased in the absence of imidazole (entry 2). Although TBSCl
has previously been used with tertiary amines to activate DMF,8
it was found that the tertiary amine deactivated TBSCl and
reduced its activation effect.7e No reaction occurred without
TBSCl, and other typical Lewis acids such as BF3·OEt2, AlCl3,
TiCl4 and SnCl4 gave 2b only in poor yields (entries 3-6). Thus,
other silane-based Lewis acids were examined to activate DMF.
While TMSCl turned out to be a poor activator (entry 7),
trimethylsilyl triflate (TMSOTf) gave 2b in excellent yield (entry
8), and tert-butyldimethylsilyl triflate (TBSOTf) gave the best
temperature. Unexpectedly, diacylhydrazine 2a was obtained in
———
 Corresponding author. Tel.: +81-463-59-4111; fax: +81-463-58-9684; e-mail: kihara@kanagawa-u.ac.jp

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Tetrahedron Letters
result (entry 9). The yield of 2b was almost proportional to the
Table 2. Formylation of hydrazides.a
amount of TBSOTf (entry 10). Therefore, we concluded that
TBSOTf acts as an activator but not as a catalyst.
Table 1. Optimization of the activating agent for DMF.
Entry Lewis acid (equiv)
Yield (%)a
1
TBSCl (1.0) + imidazole (1.0)
33
86
43
0
2
TBSCl (1.0)
BF3·OEt2 (1.0)
AlCl3 (1.0)
3
4
5
TiCl4 (1.0)
0
6
SnCl4 (1.0)
2
7
TMSCl (1.0)
TMSOTf (1.0)
TBSOTf (1.0)
TBSOTf (0.40)
18
95
97
44
8
9
10
aIsolated yield.
aIsolated yield.
The N-formylation was next carried out using various hydrazides.
The results are summarized in Table 2. Both aromatic and
aliphatic hydrazides, including the sterically hindered hydrazide
1j, gave the corresponding diacylhydrazines in good to excellent
yields. Carbazic acid ester 1k was also formylated smoothly.
Acid-sensitive protecting groups such as Boc and Cbz were
tolerated under these reaction conditions.
Next, the DMF-TBSOTf system was applied to the formylation
of amines. The results are summarized in Table 3. Primary
amines gave the corresponding formamides, as opposed to
previous studies, in which only a trace amount of formamide was
obtained from a primary amine in the presence of a tertiary
amine.8 The yield of formamides was moderate probably because
the highly basic and nucleophilic primary amine deactivated
TBSOTf in the absence of a tertiary amine. When a secondary
amine was used, formamide was obtained in good to excellent
yield. Anilines as well as aliphatic amines were N-formylated.
Despite the primary amino groups, amino acid derivatives gave
N-formylated products in high yields. No formylation of the
indole NH in 3m was observed.
Table 3. Formylation of amines.a

aIsolated yield. b2.0 equiv of imidazole was used.
When the reaction was carried out with 2.0 equiv of TBSOTf
but in the absence of imidazole, phthalide 7 was obtained from
1a in quantitative yield, and diacylhydrazine 8 without silylation
of the hydroxyl group was obtained from 5c in 92% yield
(Scheme 3). These results indicated that imidazole effectively
induces silylation of the hydroxy group for in situ protection. In
the absence of imidazole, activation of the carbonyl group in the
amide or hydrazide by TBSOTf occurred. In the case of 1a, the
activated hydrazide group was attacked by the neighboring
hydroxy group to induce cyclization.
aIsolated yield. b1.0 equiv of imidazole was added to neutralize
the ammonium group.
Scheme 3. Activation of hydrazide without protection of the
hydroxy group.
Then, a competitive reaction was carried out. When 3n was
subjected to the N-formylation conditions, 4n was obtained in
56% yield after treatment with Boc2O to protect the unreacted
hydrazide (Scheme 2). No formylation of the hydrazide was
observed, indicating that the amine is more reactive than the
hydrazide under these reaction conditions.
Scheme 2. Chemoselective formylation.
When a DMAc solution of 1b was treated with TBSOTf, the
corresponding acetylation product 9 was obtained in excellent
yield (Scheme 4). Thus, TBSOTf is expected to be used as an
activator for various amides.
The chemoselectivity in the formylation of aminoalcohols was
complicated because the hydroxy group was silylated by
TBSOTf in the presence of the amino group. To avoid this
complexity, the N-formylation of hydrazides and amines bearing
a hydroxy group was carried out using 2.0 equiv of TBSOTf and
1.0 equiv of imidazole, so that silylative protection of the
hydroxy group and formylation of the amino group occurred
simultaneously. The results are summarized in Table 4.
Formamide or formylated diacylhydrazine bearing a siloxy group
was obtained in moderate to high yields.
Scheme 4. Acetylation of hydrazide.
The outstanding effect of TBSOTf can be explained by its high
Lewis acidity and oxophilicity. The plausible mechanism
underlying the TBSOTf-promoted formylation is illustrated in
Scheme 5. Even in the presence of a nucleophilic amino group,
TBSOTf can selectively silylate DMF at the highly Lewis basic
amide carbonyl oxygen. The activated DMF is expected to be
attacked by the amine so that an efficient amide-exchange
reaction occurs. Hydrolysis of the exchange product gives
formamide.
Table 4. Silylative formylation of aminoalcohol.a
Scheme 5. Plausible mechanism of the TBSOTf-promoted
formylation.

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Tetrahedron Letters
8.
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9.
3. Conclusion
The TBSOTf-promoted N-formylation of hydrazides and
amines using DMF as the formylation agent is demonstrated.
The DMF-TBSOTf system can be used for the N-formylation of
various amines in the absence of a tertiary amine. Because of
the easy availability of DMF and TBSOTf, simple procedure,
mild reaction conditions, high chemoselectivity, and broad
scope for various acylation systems, the TBSOTf-promoted
trans-amidation can emerge as one of the most effective
methods for the N-formylation of hydrazides and amines.
Acknowledgments
We acknowledge the financial support from the MEXT-
Supported Program for the Strategic Research Foundation at
Private Universities, 2013-2017 (Creation of new fusion
materials by integration of highly ordered nano inorganic
materials and ultra-precisely controlled organic polymers).
Supplementary Material
Experimental procedure and spectral data are provided in the
Supplementary Material.
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7.

Graphical abstract

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Tetrahedron Letters
Highlights
Amines were formylated with DMF activated by
TBSOTf at room temperature.
Amino group was chemoselectively formylated in
the presence of hydrazide.
O-Silylative N-formylation of aminoalcohol
occurred in high yield.