Tetraethylorthosilicate as a mild dehydrating reagent for the synthesis of N-formamides with formic acid

Article abstract of DOI:10.1016/j.tetlet.2017.01.056

The synthesis of N-formamides with formic acid as a formyl source under mild conditions was achieved using tetraethylorthosilicate (TEOS), a low cost and environmentally benign reagent. The mild conditions in this system enable the formylation of a variety of amino acid derivatives including stereochemically labile phenylglycine ethyl ester with 96% ee. This new protocol could also be applied to simple amines including weakly basic aniline derivatives, giving various primary and secondary formamides.

Full text of DOI:10.1016/j.tetlet.2017.01.056

Accepted Manuscript
Tetraethylorthosilicate as a mild dehydrating reagent for the synthesis of N-
formamides with formic acid
Yasuhiro Nishikawa, Hidetsugu Nakamura, Norimitsu Ukai, Wakana Adachi,
Osamu Hara
PII:
S0040-4039(17)30076-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.01.056
TETL 48559
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
24 November 2016
11 January 2017
17 January 2017
Please cite this article as: Nishikawa, Y., Nakamura, H., Ukai, N., Adachi, W., Hara, O., Tetraethylorthosilicate as
a mild dehydrating reagent for the synthesis of N-formamides with formic acid, Tetrahedron Letters (2017), doi:
http://dx.doi.org/10.1016/j.tetlet.2017.01.056
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Tetrahedron Letters
Tetraethylorthosilicate as a mild dehydrating reagent for the synthesis of N-
formamides with formic acid
Yasuhiro Nishikawa, Hidetsugu Nakamura, Norimitsu Ukai, Wakana Adachi, and Osamu Hara
Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tenpaku-ku, Nagoya, Aichi 468-8503, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The synthesis of N-formamides with formic acid as a formyl source under mild conditions was
achieved using tetraethylorthosilicate (TEOS), a low cost and environmentally benign reagent.
The mild conditions in this system enable the formylation of a variety of amino acid derivatives
including stereochemically labile phenylglycine ethyl ester with 96% ee. This new protocol
could also be applied to simple amines including weakly basic aniline derivatives, giving
various primary and secondary formamides.
Available online
Keywords:
Formylation
Silicate
2009 Elsevier Ltd. All rights reserved.
Dehydration
Amino acids
Amide bond
N-formylation is one of the important reactions available to
introduce an easily removable protecting group for various amine
functionalities.1 The resulting formamides serve as
pharmaceutically valuable compounds or as their intermediates in
several organic transformations, such as isonitriles used in the
Ugi multi-component reaction to make a diverse range of
compounds.2 In particular, the preparation of N-formylated amino
acid derivatives is highly important in the synthesis of peptides
and a wide variety of chiral sources. Thus, numerous efforts have
been dedicated to achieving more efficiency with less expensive
and environmentally benign reagents under mild reaction
conditions while retaining reactive functionalities and
stereochemical information.3-7 Recently, the incorporation of
carbon dioxide (CO2) into amines, thereby affording N-
formamides, has attracted much attention in synthetic chemistry
since CO2 is a low-cost, abundant and nontoxic raw material.3,4
However, the utilization of CO2 for N-formylation suffers from
the necessity of using expensive catalysts and reagents as well as
harsh reaction conditions that limit the scope of possible
reactions. In turn, formic acid, the reduced form of CO2, is also
one of the most attractive formyl sources because of its wide
availability and low cost.5 The condensation of formic acid and
amines without expensive coupling reagents under mild
conditions is highly desirable. While most methods that employ
formic acid need to be performed at high temperatures, some
more practical reagents have been reported. Reagents as varied
as ZnO,5a polyethylene glycol,5b hydroxyapatite-encapsulated--
used for N-formylation at room temperature. However, most of
these methods suffer from poor availability of reagents or a
limited substrate scope in which a only few examples of amino
acid derivatives occur.5a,5f Herein, we report a new protocol for
N-formylation of various amines, including amino acid esters,
with tetraethylorthosilicate as a mild dehydrating reagent.
Scheme 1. N-Formylation with HCO2H and Si(OEt)4 under
mild condition.
Tetraethylorthosilicate, Si(OEt)4 abbreviated as TEOS, is a
relatively stable and benign liquid often used as a crosslinking
agent in the silicone polymer industry.8 Its large industrial
consumption makes TEOS an inexpensive reagent comparable in
cost to conventional solvents. TEOS has also been utilized in
organic synthesis to form imines from aldehydes and amine
derivatives at high temperatures.9 In a preliminary study on N-
formylation, we found that the addition of TEOS accelarated N-
formylation of L-phenylalanine ethyl ester hydrochloride 2a with
Fe2O3,5e
nano
rod-shaped
Al2O3,5g
hydroxylamine
hydrochloride,5i and a sulfated ionic liquid5j can reportedly be
———
 Corresponding author. e-mail: yasuhiro@meijo-u.ac.jp (Y. Nishikawa)
 Corresponding author. e-mail: oshara@meijo-u.ac.jp (O. Hara)

2
Tetrahedron
formic acid and triethylamine in acetonitrile (Table 1, entries 1
ethyl ester 2j was selected to test the mildness of the reaction
conditions because 2j is known to be very labile to racemization.
A slight decrease in the optical purity of 3j was observed when
the standard conditions were applied to 2j. We found the Et3N
employed to neutralize amine hydrochloride salts caused
racemization. Hence, decreasing the amount of this base led to
suppression of the racemization to afford 3j with 96% ee in
moderate yield. To the best of our knowledge, this is the first
report of the N-formylation of phenylglycine derivatives with
formic acid without substantial loss of enantiopurity.
and 2). Increasing the relative amount of TEOS up to 9
equivalents, the same volume as the volume of acetonitrile
employed resulted in higher yields of the product 3a (entries 2-
4), although further excess amounts of TEOS was ineffective
(entry 5). After easy optimization of the amounts of formic acid
and triethylamine required, we succeeded in establishing a set of
reaction conditions affording N-formamide in 93% isolated yield
without any loss of its enantiopurity (entries 6 and 7).10
Furthermore, the facile separation between the polar product 3a
and excess amounts of non-polar TEOS is enabled by liquid-
liquid partition between 50% methanol/water and n-hexane.
After a conventional workup using acid/base washing, 3a was
obtained in almost pure form. Finally, gram-scale synthesis with
this protocol was achieved affording the comparable yield to
corroborate the utility of this reaction (entry 8).
Table 2. N-Formylation of amino acid ester hydrochlorides
with TEOS.a
Table1. N-Formylation of H-Phe-OEt•HCl (2a) with TEOS. a
Entry
1
H-AA-OEt•HCl
R
Yield (%)b
3a: 93
2a
2b
2c
2d
2e
2f
Phe
Gly
CH2Ph
2
H
3b: 72
3
Ala
CH3
3c: 74
Entry
HCO2H
Si(OEt)4
Et3N
(equiv)
1.5
3a
Yield (%)b
13
4
Val
iPr
CH2OTBS
CH2S(tBu)
CH2C6H4OH
CH2(3-indolyl)
-
3d: 86
(equiv)
(equiv)
5
Ser(OTBS)
Cys(tBu)
Tyr
3e: 95
1
2
2
2
2
2
2
3
3
3
0
1
6
3f: 82
1.5
48
7
2g
2h
2i
3g: 82
3
4.5
9
1.5
55
8c
Trp
3h: 90
4
1.5
88 (74)c
9
Pro
3i: 52
5
13.5
9
1.5
82
10
11
2j
Phg
Ph
3j: 73 (87)d
3j: 49 (96)d,e
6
1.5
87
2j
Phg
Ph
7
9
3
98 (93)c,d
(98) c,d
a Reactions were performed with 0.5 mmol of 2 in acetonitrile (1 mL) in the
presence of reagents as shown in the scheme at 25 ºC. See Supporting
Information for details.
8e
9
3
a Reactions were performed with 0.5 mmol of 2a in acetonitrile (1 mL) in the
presence of reagents as shown in the table. See Supporting Information for
details.
b Isolated yield.
c The reaction was performed with tryptophan methyl ester hydrochloride at
50 ºC.
b 1H-NMR yield.
d The value in parenthesis is % ee. The optical purity of isolated 3j was
confirmed by chiral HPLC analysis.
c The yield in parenthesis is isolated yield.
d The optical purity of isolated 3a was confirmed as >99%ee by chiral HPLC
analysis.
e 1 equivalent of Et3N was used.
e 5 mmol (1.18 g) of 2a was used.
After the successful demonstration of N-formylation of amino
acid derivatives under mild reaction conditions, we turned our
attention to a broad range of simple amines (Table 3). The N-
formylation of less basic aniline derivatives bearing electron
donating groups as well as an electron-withdrawing group
afforded the N-formamides (5a-5d) in good yields. In addition to
aniline derivatives, aliphatic amines were also converted to the
corresponding N-formamides (5e-f), even though higher
temperatures up to 50 ºC were necessary to complete the
reactions in the cases of 5e and 5g. Furthermore, secondary
aromatic and aliphatic amines also could be employed in this
system to afford 5h-j in moderate to good yields at room
temperature. The compatibility of alcohol in this system was
revealed in the selective N-formylation of the aniline derivative
4k having an aliphatic alcohol functionality, implying that a 1,2-
aminoalcohol such as serine ethyl ester is particularly unsuitable
for this formylation reaction (Table 2, entry 5 and Table 3, 5k).
With the optimized reaction conditions in hand, we examined
a range of substrates for the synthesis of N-formyl amino acid
derivatives (Table 2). Alkyl substituents at the  position of
amino acids, including the bulky isopropyl group, are tolerated in
this formylation, implying that various other types of steric bulk
at the  position would also be acceptable (entries 1-4). While
the formylation of unprotected serine and cysteine derivatives
gave poor results, leading to the recovery of the starting
compounds, protection of the alcohol and the thiol functionalities
improved the corresponding N-formylations producing N-formyl
derivatives 3e and 3f in high yields (entries 5, 6). On the other
hands, unprotected tyrosine ethyl ester reacted smoothly
producing the N-formyl derivative with the phenolic alcohol
intact (entry 7). An amino group in indole is also compatible
under these mild conditions resulting in preferential formylation
on the aliphatic amino group (entry 8). Secondary amino group,
as well as primary amino groups, could also be employed in this
reaction in moderate yield (entry 9). Next, (S)-phenylglycine
To gain mechanistic insights, we compared the results of the
N-formylation of 2a using either formic acid or ethyl formate as a

formyl source. No reaction was observed when ethyl formate was
used, indicating that the role of TEOS is not simply as a Lewis
acid and that the acidic proton in formic acid plays an important
role in this reaction.11 With these results in mind, we have
broad scope of this new formylation method was demonstrated
using various aromatic and aliphatic amines with diverse
electronic and steric characters.
Table 3. N-Formylation of a variety of amines with TEOSa
Scheme 2. Plausible reaction mechanism.
Acknowledgments
This research was partially supported by a Grant-in-Aid for
Young Scientists (B) (26810063) from the Japan Society for the
Promotion of Science (JSPS).
Supplementary data
Supplementary data (full experimental procedures and
1
characterization data including copies of the H and 13C NMR
a Reactions were performed with 0.5 mmol of amines in acetonitrile (1 mL) in
the presence of reagents at the temperature and reaction time shown in the
table. Isolated yields are shown in the table. See Supporting Information for
details.
spectra of the compounds that were produced by this procedure)
associated with this article can be found in the online version, at.
b The yields determined by 1H NMR of the crude products are shown in the
parenthesis.
References and notes
1.
2.
3.
4.
For a recent review on formylation of amines, see: Gerack, C.;
McElwee-White, L. Molecules 2014, 19, 7689–7713.
speculated a plausible mechanism (Scheme 2). We assumed that
formic acid could react with TEOS accompanied by the
elimination of ethanol to afford a small amount of triethoxysilyl
formate that has the potential to be a formylating agent.12,13
During the course of the reaction, the acidic proton of formic acid
would assist the elimination of ethanol by protonation to TEOS.
Even though the formation of the silyl formate should be
disadvantaged, the small amount of silyl formate produced could
be trapped immediately by an amine giving an N-formamide and
silanol. Probably, a large amount of TEOS would be required to
produce an appropriate amount of silyl formate to retain
acceptable reaction rate. In this scenario, TEOS functions as a
neutral and mild dehydrating reagent producing only ethanol and
silanol as by-products.
For the utility of isocyanate, see: (a) Kotha, S.; Halder, S. Synlett
2010, 337-354; (b) Dömling, A. Chem. Rev. 2006, 106, 17–89.
For a review on N-formylation with CO2, see: Tlili, A.; Blondiaux,
E.; Frogneux, X.; Cantat, T. Green Chemistry 2015, 157-168.
For recent examples of N-formylation with CO2, see: (a) Zhang,
L.; Han, Z.; Zhao, X.; Wang, Z.; Ding, K. Angew. Chem. Int. Ed.
2015, 54, 6186–6189; Angew. Chem. 2015, 127, 6284–6287; (b)
Nguyen, T. V. Q.; Yoo, W.-J.; Kobayashi, S. Angew. Chem. Int.
Ed. 2015, 54, 9209–9212; Angew. Chem. 2015, 127, 9341–9344;
(c) Chong, C. C.; Kinjo, R. Angew. Chem. Int. Ed. 2015, 54,
12116–12120; Angew. Chem. 2015, 127, 12284–12288; (d) Das,
S.; Bobbink, F. D.; Bulut, S.; Soudani, M. Chem. Commun. 2016,
52, 2497-2500.
N-formylation with formic acid, see: (a) Hosseini-Sarvari, M.;
Sharghi, H. J. Org. Chem. 2006, 71, 6652-6654; (b) Das, B.;
Krishnaiah, M.; Balasubramanyam, P. Tetrahedron 2008, 49,
2225-2227; (c) Kim, J.-G.; Jang, D. Synlett 2010, 1231-1234; (d)
Kim, J.-G.; Jang, D. Synlett 2010, 2093–2096; (e) Lei, M.; Ma, L.;
Hu, L. Tetrahedron Lett. 2010, 51, 4186–4188; (f) Ma’mani, L.;
Sheykhan, M.; Heydari, A.; Faraji, M.; Yamini, Y. App. Cat. A:
General 2010, 377, 64–69; (g) Pathare, S. P.; Sawant, R. V.;
Akamanchi, K. G. Tetrahedron Lett. 2012, 53, 3259-3263; (h)
Das, V. K.; Devi, R. R.; Raul, P. K.; Thakur, A. J. Green Chem.
2012, 14, 847-854; (i) Bahrami, K.; Khodaei, M. M.; Targhan, H.;
Sheikh Arabi, M. Tetrahedron Lett. 2013, 54, 5064–5068; (j)
Deepali, A.; Akansha, A.; Anamika, B. Res. J. Chem. Sci. 2014, 4,
5.
In conclusion, we have developed a simple protocol for N-
formylation using formic acid and inexpensive TEOS with high
yields under mild conditions. A variety of amino acid derivatives
bearing various functionalities could be converted to the
corresponding N-formamides at room temperature. It is
noteworthy that stereochemically labile L-phenylglycine could be
formylated without marked loss of its enantiopurity,
corresponding to the mild reaction conditions in our system. The

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Tetrahedron
54-57; (k) Satasia, S. P.; Kalaria, P. N.; Raval, D. K. J. Mol.
Catal. A 2014, 41-47; (l) Khojastehnezhad, A.; Rahimizadeh, M.
C. R. Chemie 2014, 459-464.
6.
7.
N-formylation with ammonium formate, see: (a) Ganapati Reddy,
P.; Kishore Kumar, G. D.; Baskaran, S. Tetrahedron Lett. 2000,
41, 9149–9151; (b) Kotha, S.; Behera, M.; Khedkar, P.
Tetrahedron Lett. 2004, 45, 7589–7590.
For recent examples of N-formylation by transamidation, see: (a)
Suchý, M.; Elmehriki, A. A. H.; Hudson, R. H. E. Org. Lett. 2011,
13, 3952–3955; (b) Atkinson, B. N.; Chhatwal, A. R.; Lomax, H.
V.; Walton, J. W.; Williams, J. M. J. Chem. Commun. 2012, 48,
11626-11628; (c) Nguyen, T. B.; Sorres, J.; Tran, M. Q.;
Ermolenko, L.; Al-Mourabit, A. Org. Lett. 2012, 14, 3202–3205;
(d) Joseph, S.; Das, P.; Srivastava, B.; Nizar, H.; Prasad, M.
Tetrahedron Lett. 2013, 54, 929–931; (e) Rao, S. N.; Mohan, D.
C.; Adimurthy, S. Org. Lett. 2013, 15, 1496–1499; (f) Lanigan, R.
M.; Starkov, P.; Sheppard, T. D. J. Org. Chem. 2013, 78, 4512–
4523; (g) Binh Nguyen, T.; Al-Mourabit, A.; Ermolenko, L.; Tran
Huu Dau, M.-E. Heterocycles 2014, 88, 403-416; (h) Lebleu, T.;
Kotsuki, H.; Maddaluno, J.; Legros, J. Tetrahedron Lett. 2014, 55,
362–364; (i) Becerra-Figueroa, L.; Ojeda-Porras, A.; Gamba-
Sánchez, D. J. Org. Chem. 2014, 79, 4544–4552; (j) Fu, R.; Yang,
Y.; Chen, Z.; Lai, W.; Ma, Y.; Wang, Q.; Yuan, R. Tetrahedron
2014, 70, 9492–9499; (k) Rasheed, S.; Rao, D. N.; Reddy, A. S.;
Shankar, R.; Das, P. RSC Adv. 2015, 5, 10567–10574; (l) Rao, S.
N.; Mohan, D. C.; Adimurthy, S. RSC Adv. 2015, 5, 95313-95317;
(m) Srinivas, M.; Hudwekar, A. D.; Venkateswarlu, V.; Reddy, G.
L.; Kumar, K. A. A.; Vishwakarma, R. A.; Sawant, S. D.
Tetrahedron Lett. 2015, 56, 4775–4779; (n) Gu, D.-W.; Guo, X.-
X. Tetrahedron 2015, 71, 9117–9122; (o) Dine, T. M.; Evans, D.;
Rouden, J. Chem. Eur. J. 2016, 22, 5894-5898.
8.
9.
Annekov, V. V.; Danilovtseva, E. N.; Filina, E.A. New Frontiers
in Polymer Research (Eds.: Bregg, R. K.), Nova Science
Publishers, Inc. New York, 2006, pp 173-199.
(a) Love, B. E.; Ren, J. J. Org. Chem. 1993, 58, 5556-5557; (b)
Love, B. E.; Raje, P. S.; Williams, T. C., II. Synlett 1994, 493–
494.
10. We could found that only two literatures (ref. 4b and 7o)
confirmed the enantiopurity of N-formyl amino acid derivatives by
chiral HPLC. In ref 7o, N-formyl phenylalanine methyl ester was
obtained with 96% ee.
11. (a) Niknam, K.; Saberi, D. Tetrahedron Lett. 2009, 50, 5210-5214;
(b) Tan, E.; Ung, S.; Corbet, M. Eur. J. Org. Chem. 2016, 1836-
1840.
12. Sattler, W.; Parkin, G. J. Am. Chem. Soc. 2012, 134, 17462–
17465.
13. We could not observe the formation of silyl formate by NMR
experiment in CD3CN.

2
Tetrahedron
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Tetraethylorthosilicate as a mild dehydrating
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with formic acid
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Yasuhiro Nishikawa, Hidetsugu Nakamura, Norimitsu Ukai, Wakana Adachi, and Osamu Hara

3
Research highlights
N-Formylation with formic acid and Si(OEt)4 under mild conditions was achieved.
Si(OEt)4 is inexpensive and environmentally benign dehydrating reagent.
A variety of amines including amino acid derivatives can be applied to this method.