Mild, simple, and efficient method for N-formylation of secondary amines via Reimer-Tiemann reaction

Article abstract of DOI:10.1080/00397910903576644

A rapid and easy route for the N-formylation of secondary amines using chloroform and sodium ethoxide via dichlorocarbene by the Riemer-Tiemann reaction with excellent yield is reported.

Full text of DOI:10.1080/00397910903576644

This article was downloaded by: [Stanford University Libraries]
On: 27 August 2012, At: 04:35
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Mild, Simple, and Efficient Method for
N-Formylation of Secondary Amines via
Reimer–Tiemann Reaction
Lokesh A. Shastri a , Samundeeswari L. Shastri a , Chinna D. Bathula
b , Mahantesha Basanagouda a & Manohar V. Kulkarni a
a P.G. Department of Chemistry, Karnatak University, Dharwad,
Karnataka, India
b Sami Laboratory, Research and Development, Synthetic Chemistry,
Peenya, Bangalore, Karnataka, India
Version of record first published: 02 Feb 2011
To cite this article: Lokesh A. Shastri, Samundeeswari L. Shastri, Chinna D. Bathula, Mahantesha
Basanagouda & Manohar V. Kulkarni (2011): Mild, Simple, and Efficient Method for N-Formylation of
Secondary Amines via Reimer–Tiemann Reaction, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 41:4, 476-484
To link to this article: http://dx.doi.org/10.1080/00397910903576644
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation
that the contents will be complete or accurate or up to date. The accuracy of any
instructions, formulae, and drug doses should be independently verified with primary
sources. The publisher shall not be liable for any loss, actions, claims, proceedings,

demand, or costs or damages whatsoever or howsoever caused arising directly or
indirectly in connection with or arising out of the use of this material.

Synthetic Communications1, 41: 476–484, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903576644
MILD, SIMPLE, AND EFFICIENT METHOD FOR
N-FORMYLATION OF SECONDARY AMINES VIA
REIMER–TIEMANN REACTION
Lokesh A. Shastri,1 Samundeeswari L. Shastri,1
Chinna D. Bathula,2 Mahantesha Basanagouda,1 and
Manohar V. Kulkarni1
1P.G. Department of Chemistry, Karnatak University, Dharwad,
Karnataka, India
2Sami Laboratory, Research and Development, Synthetic Chemistry, Peenya,
Bangalore, Karnataka, India
Abstract A rapid and easy route for the N-formylation of secondary amines using chloro-
form and sodium ethoxide via dichlorocarbene by the Riemer–Tiemann reaction with
excellent yield is reported.
Keywords Dichlorocarbene; N-formylation; Reimer–Tiemann; secondary amines;
sodium ethoxide
INTRODUCTION
A number of formylating methods have been reported in the literature. Acetic
formic anhydride[1,2] continues to be the most widely used formylating reagent, but it
is sensitive to decomposition to acetic acid and carbon monoxide. Many other useful
formylation reagents have been reported such as chloral,[3] activated formic acid
using N,N0-dicyclohexylcarbodiimide (DCC)[4] or EDCI,[5] activated formic
esters,[6–8] PGE-400,[9] and ammonium formate.[10] Despite the usefulness of these
reactions, such as excellent yields and mild conditions, they are less practical: they
are either toxic or expensive and the preparation and use of these reagents require
strictly anhydrous conditions. Moreover, the formyl group is a useful amino-
protecting group in peptide synthesis[11] and N-formylamino acid esters can, for
Received September 15, 2009.
Address correspondence to Lokesh A. Shastri, P. G. Department of Chemistry, Karnatak
University, Dharwad, Karnataka, 580003, India. E-mail: chemilok@yahoo.co.in
476

N-FORMYLATION OF SECONDARY AMINES
477
example, serve as starting materials for peptide synthesis.[12] Thus, in a few minutes
on a multiple-gram scale, primary and secondary amines have been subjected to
N-formylation by microwave irradiation.[13,14] Alcohols and amines have been for-
mylated and acetylated in the presence of Silphos [PCl3-n(SiO2)n] in good yield,[15,16]
and various cyclic and aliphatic amines have been N-formylated using dense carbon
dioxide and ruthenium as catalyst.[17] The effect of solvent on N-formylation[18] using
aqueous formic acid have been reported. N-Formylation under solvent-free
conditions with excellent yields has been achieved using ZnO as catalyst.[19] In our
previous work, we reported the N-acylation of primary and secondary amines using
acetic, propionic acid, and hydrazine hydrate.[20] We now report a mild and simple
N-formylation procedure using chloroform and sodium ethoxide.
RESULTS AND DISCUSSION
Though numerous methods have been reported in the literature for formyla-
tion of primary and secondary amines, there are several factors in some cases that
limit their applications, for example, thermal instability, formation of by-products,
and difficult preparation of the formylating agents. The present formylation pro-
cedure via dichlorocarbene seems to be unknown for amines in the literature. Here,
we are reporting a general and very efficient procedure, which accommodates prac-
ticality and functionality. This particular procedure has high specific importance for
=
Scheme 1. R CH3, C2H5, isopropyl.
Scheme 2. ¼ Piperidine, 4–CH3-piperidine, 4–piperidone, 4–ph-piperidine, pyrrolidin, N-Boc-
piperzine, morpholine.
=
Scheme 3. R CH3.

478
L. A. SHASTRI ET AL.
Table 1. N-Formylation from chloroform and NaOEt (21%) via Riemer–Teimann reaction
Product
Entry
Substrate
Structure
Entry code
Yield (%)
68
1a
2a
1b
1c
2b
2c
62
65
3a
3b
4a
4b
92
94
3c
4c
95
3d
3e
4d
4e
96
95
(Continued )

N-FORMYLATION OF SECONDARY AMINES
479
Table 1. Continued
Product
Entry
Substrate
Structure
Entry code
Yield (%)
3f
4f
96
3g
4g
94
5a
5b
6a
6b
65
68
potential reactants. At the onset of our work, we explored the utility of the Riemer–
Teimann reaction via dichlorocarbene with secondary amines. We were surprised to
find N-formylated products with good yields. Absence of a NH stretching band and
presence of aldehyde carbonyl stretching band in the infrared (IR) spectrum could be
easily confirmed. Thus, among the obtained products there are very common sol-
vents synthesized such as N,N-dimethylformamide (2a) and N,N-diethylformamide
(3b) from N,N-dimethylamine and N,N-diethyl amine respectively. The spectral data
for the synthesized compounds are in good agreement with the reported literature.
We thought this procedure could be expanded to an array of amines. A series of
aliphatic open chain (Scheme 1), cyclic (Scheme 2), and aromatic (Scheme 3) second-
ary amines were converted into the corresponding N-formyl amines in good yields
(Table 1). The present reaction conditions for aliphatic open-chain amines and aro-
matic amines afforded the N-formylation product in relatively poor yield, while the
cyclic amines undergo very good conversion, more than 90%. The formylation reac-
tion could be considered to proceed through the Riemer–Teimann reaction. The for-
mylating agent chloroform excess was treated with a base such as sodium ethoxide
(21%) at 50 ꢀC to give chloroform carbanion, which quickly undergoes a-elimination
to afford dichlorocarbene. Dichlorocarbene reacts with a secondary amine, and a
plausible mechanism is depicted in Scheme 4.

480
L. A. SHASTRI ET AL.
Scheme 4. General mechanism. R,R ¼ alkyl or cyclic aliphatic secondary amines.
The applications in organic synthesis have not yet been fully explored. The
present conversion has been utilized efficiently for the preparation of N-formylation
of secondary amines without further purification. The experimental procedure is
highly convenient. In a forthcoming work, we will report results for primary amines.
1
The structures of the products were established from their spectral [IR, H NMR,
13C NMR, and, liquid chromatographic–mass spectrometric (LCMS)] data.
EXPERIMENTAL
General Experimental Information
All reactions were performed in flame-dried glassware under a nitrogen atmos-
phere. Reagents were used as purchased from Aldrich, and 1H and 13C NMR spectra
were obtained on a Varian VI-300 and Bruker 300- and 400-MHz spectrometers
using dimethylsulfoxide (DMSO-d6) and CDCl3 with tetromethylsilane (TMS) or
residual solvent as standard unless otherwise noted. IR spectra were obtained on a
Bruker Equinox 55 Fourier transform (FT)–IR instrument. Thin-layer chromato-
graphy (TLC) analysis was performed using Aldrich 254, nm polyester-backed plates
˚
(60 A, 250 mm) and visualized using ultraviolet and KMnO4 stains. LCMS mass spec-
tra were obtained using an MPS-SCIEX-API-2000 Instrument.
General Procedure for N-Formylation of Secondary Amines for
Liquid Compounds
To a mixture of secondary amines (1 eq.) and sodium ethoxide (21% obtained
from Sigma-Aldrich) (3 eq.) was added. The mixture was stirred at 50 ꢀC on an oil

N-FORMYLATION OF SECONDARY AMINES
481
bath for 15 min, and excess of chloroform was added slowly. Stirring was continued
for another 30 min. The progress of the reaction was monitored by TLC. After com-
pletion, the mixture was quenched with 10 mL of water, and stirring continued
another for 15 min. The reaction mixture was distilled under reduced pressure, and
the pure compound was collected at a constant boiling point. The data obtained
for the isolated product was compared with the literature.
Selected Data
N-Formyl-N,N-dimethyl amine (or N,N-dimethylformamide) (2a).
Colorless liquid, boiling point 151–154 ꢀC; IR cmꢁ1 1664, 2865, 2932, (3448 cmꢁ1
1
is due to moisture); H NMR (400 MHz, CDCl3) d 2.88 and 2.91 (2-s for 2-CH3),
8.02 (s, 1H, N-CHO); 13C NMR (400 MHz, CDCl3) d 31.27, 36.32, 162.39; LCMS
(method 0.1% HCOOH=ACN) m=z ¼ 147.2 (double the mass, instead of m=z 73,
100%). Calcd. for C3H7NO: 73.05; found: 147.2.
N-Formyl-N,N-diethyl amine (or N,N-dꢁie1thylformamide) (2b). Colorless
liquid boiling point 172 to 175 ꢀC; IR cm
1658, 2891, 2936; 1H NMR
(400 MHz, DMSO-d6) d 1.32 (t, 3H), 1.35 (t, 3H), 2.75 (q, 2H), 2.87 (q, 2H), 8.21
(s, 1H, N-CHO); 13C NMR (400 MHz, DMSO-d6) d 13.21, 13.25, 32.30, 35.41,
161,43; LCMS (method 0.1% HCOOH=MeOH) m=z ¼ 203.06 (98.6%). Calcd. for
C5H11NO: 101.08; found: 203.06.
N-Formyl-N,N-diisopropyl amine (or N,N-ꢁd1iisopropylformamide) (2c).
1
Colorless liquid boiling point 194 to 198 ꢀC; IR cm 1664, 2871, 2982; H NMR
(400 MHz, DMSO-d6) d 1.21 (t, 6H), 1.29 (t, 6H), 2.91 (m, 1H), 2.98 (m, 1H),
8.03 (s, 1H, N-CHO); 13C NMR (400 MHz, DMSO-d6) d 12.13, 12.15, 12.42,
1243, 31.41, 34.87, 162,10; LCMS (method 0.1% HCOOH=MeOH) m=z ¼ 130.08
(99.2%). Calcd. for C7H15NO: 129.12; found: 130.08.
N-Formylpiperidinꢁe1(or 1-formylpiperidine) (4a). Colorless liquid, boiling
1
point 220–225 ꢀC; IR cm 1659, 2860, 2939 (3447 cmꢁ1 is due to moisture); H
NMR (400 MHz, CDCl3) d 1.50–1.71 (m, 6H), 3.30 (t, 2H), 3.46 (t, 2H), 8.00 (s,
1H, N-CHO); 13C NMR (400 MHz, CDCl3) d 24.59, 24.99, 26.48, 40.53, 46.75,
160, 58; LCMS (method 0.1% HCOOH=MeOH) m=z ¼ 144.2 (99.0%, m þ 1). Calcd.
for C6H11NO: 113.08; found: 114.2.
N-Formyl-4-methylpiperidine (or 4-methyl-1-formylpiperidine) (4b).
1
Colorless liquid, boiling point 232–236 ꢀC; IR cmꢁ1 1663, 2872, 2954; H NMR
(400 MHz, CDCl3) d 1.21 (d, 3H), 1.52 (m, 1H), 1.71–1.78 (m, 4H), 3.62 (t, 2H),
3.68 (t, 2H), 8.12 (s, 1H, N-CHO); 13C NMR (400 MHz, CDCl3) d 12.31, 22.83,
22.88, 25.92, 41.02, 45.74, 162.31; LCMS (method 0.1% HCOOH=MeOH)
m=z ¼ 128.08 (98.4%, m þ 1). Calcd. for C7H13NO: 127.18; found: 128.08.
General Procedure for N-Formylation of Secondary Amines for Solid
Compounds: N-Formyl-4-piperidone (4c)
To a mixture of secondary amines (1 eq.) and sodium ethoxide (21% obtained
from Sigma-Aldrich) (3 eq.) was added. The mixture was stirred at 50 ꢀC on an oil

482
L. A. SHASTRI ET AL.
bath for 15 min, and excess of chloroform was added slowly. Stirring was continued
for another 15 min. The progress of the reaction was monitored by TLC. After com-
pletion, the mixture was cooled to room temperature, diluted with water (20 mL),
and extracted with chloroform. The chloroform layer was washed with 10 mL HCl
(1 N). The combined organic layer was dried over anhydrous Na2SO4 and concen-
trated. The residue obtained was pure N-formyl amine, whichꢁr1equired no further
purification. Pale yellow solid, melting point 83–86 ꢀC; IR cm 1720, 1657, 2867,
1
2985; H NMR (400 MHz, CDCl3) d 2.47 (t, 2H), 2.49 (t, 2H), 3.10 (t, 2H), 3.15
(t, 2H) 8.02 (s, 1H, N-CHO); 13C NMR (400 MHz, CDCl3) d 39.16, 39.18, 40.32,
45.53, 161.75, 192.53; LCMS (method 0.1% HCOOH=MeOH) m=z ¼ 128.2
(97.8%, m þ 1). Calcd. for C6H9NO2: 127.06; found: 128.2.
Selected Data
N-Boc-4-formylpiperazine (4d). Colorless solid, melting point 121–125 ꢀC;
1
IR cmꢁ1 1682, 1648, 2861, 2978; H NMR (400 MHz, CDCl3) d 1.43 (s, 6H), 2.76
(t, 2H), 2.79 (t, 2H), 3.52–3.58 (m, 4H), 8.00 (s, 1H, N-CHO); 13C NMR
(400 MHz, CDCl3) d 23.25, 40.02, 40.41, 44.48, 46.01, 158.96, 161.92; LCMS
(method 10 mM NH4OAc=MeOH) m=z ¼ 216.02 (96.7%, m þ 2). Calcd. for
C10H18N2O3: 214.13; found: 216.02.
N-Formylmorpholine (4e). Colorless liquid boiling point 234–238 ꢀC; IR
1
cmꢁ1 1663, 2857, 2991; H NMR (400 MHz, DMSO-d6) d 3.36 (t, 4H), 3.50 (t,
2H), 3.56 (t, 2H), 8.02 (s, 1H, N-CHO); 13C NMR (400 MHz, CDCl3) d 40.20,
45.86, 66.87, 67.08, 161.23. LCMS (method 10 mM NH4OAc=MeOH) m=z ¼ 116.2
(96.6%, m þ 1). Calcd. for C6H9NO2: 115.13; found: 116.2.
N-Formyl-4-phenylpiperdine (4f). Pale yellow color solid, melting point
72–75 ꢀC; IR (KBr pellet) cmꢁ1 1665, 2861, 2936 (3433 cmꢁ1 is due to moisture);
1H NMR (400 MHz, DMSO-d6) d 1.38–1.53 (2q, 2H), 1.75–1.82 (t, 2H), 2.63–2.68
(t, 1H), 2.77–2.79 (t, 1H), 3.09–3.15 (t, 1H), 3.74–3.78 (d, 1H, J ¼ 16 MHz),
4.27–4.31(d, 1H, J ¼ 16 MHz), 7.16–7.30 (m, 5H), 8.01 (s, 1H, N-CHO); 13C
NMR (300 MHz, CDCl3) d 33.30, 33.83, 40.19, 42.82, 46.40, 126.55, 126.58,
128.55, 144.80, 160.80; LCMS (method 0.1% HCOOH=MeOH) m=z ¼ 190.2
(98.5%, m þ 1), Calcd. for C12H15NO: 189.12; found: 190.2.
N-Formylpyrrolidine (4g). Colorless liquid, boiling point 91–95 ꢀC; IR cmꢁ1
1671, 2832, 2946; 1H NMR (400 MHz, CDCl3) d 1.80–1.85 (m, 4H), 3.48 (t, 2H), 3.51
(t, 2H), 8.21 (s, 1H, N-CHO); 13C NMR (400 MHz, CDCl3) d 25.63, 25.86, 41.65,
46.87, 162.51; LCMS (method 0.1% HCOOH=MeOH) m=z ¼ 99.28. Calcd. for
C5H9NO: 99.07; found: 99.28.
N-Methyl-N-formylaniline (6a). Colorless liquid, boiling point 242–245 ꢀC;
1
IR cmꢁ1 1683, 2819, 2924 (3432 cmꢁ1 is due to moisture); H NMR (400 MHz,
DMSO-d6) d 3.21 (s, 3H), 7.24–7.45 (m, 5H), 8.53 (s, 1H, N-CHO); 13C NMR
(400 MHz, DMSO-d6) d 31.80, 121.71, 122.10, 125.91, 128.72, 124.10, 141.80
162,10; LCMS (method 0.1% HCOOH=MeOH) m=z ¼ 136.2, (72.7%, m þ 1). Calcd.
for C8H9NO: 135.16; found: 136.2.

N-FORMYLATION OF SECONDARY AMINES
483
N-Formyl-n-methy-2-flouroaniline (6b). Colorless liquid, boiling point
1
128–132 ꢀC; IR cmꢁ1 1677, 2826, 2943; H NMR (400 MHz, DMSO-d6) d 2.69 (s,
3H), 6.52 (t, 1H), 6.63 (t, 1H), 6.97 (d, 1H, J ¼ 4.68 Hz), 6.99 (d, 1H, J ¼ 4.88 Hz),
8.24 (s, 1H, N-CHO); 13C NMR (400 MHz, DMSO-d6) d 32.73, 121.83, 123.03,
126.86, 130.12, 131.31, 144.62, 162,53; LCMS (method 10 mM NH4OAc=MeOH)
m=z ¼ 154.2 (77.9%, m þ 1). Calcd. for C8H8FNO: 153.15; found: 154.2.
ACKNOWLEDGMENT
We gratefully acknowledge the support of this work by the Department of
Chemistry, Karnatak University, Dharwad.
REFERENCES
1. Strazzolini, P.; Giumanini, A. G.; Cauci, S. Acetic formic anhydride: A review.
Tetrahedron. 1990, 46, 1081–1118.
2. Blicke, F. F.; Lu, C. J. 6-Amino-2,3-dimethylindole. J. Am. Chem. Soc. 1952, 74, 3933–3934.
3. Waki, J.; Meienhofer, J. Efficient preparation of Na-formylamino acid tert-butyl esters.
J. Org. Chem. 1977, 42, 2019–2020.
4. Chen, F. M. F.; Benoiton, N. L. A general method for formylating sensitive amino acid
estersy. Synthesis. 1979, 709–710.
5. Yale, H. L. Formylation of amines with phenyl formate. J. Org. Chem. 1971, 36, 3238–3240.
6. Kisfaludy, L.; Laszlo, O. Rapid and selective formylation with pentafluorophenyl for
mate. Synthesis. 1987, 510–511.
7. Neveux, M.; Bruneau, C.; Dixneuf, P. H. Enol formates: Ruthenium-catalysed formation
and formylating reagents. J. Chem. Soc., Perkin Trans. 1 1991, 1197–1199.
8. Duczek, W.; Deutsch, J.; Vieth, S.; Niclas, H. J. A simple and convenient synthesis of
N-formyl amino acid esters under mild conditions. Synthesis. 1996, 37–38.
9. Biswanath, D.; Maddeboina, K.; Boyapati, V.; Balasubramanyam, P.; Nandan Kumar,
D. A remarkably simple N-formylation of anilines using polyethylene glycol. Tetrahedron
Lett. 2008, 49, 2225–2227.
10. Reddy, P. G.; Kumar, G. D. K.; Baskaran, S. A convenient method for the N-formylation
of secondary amines and anilines using ammonium formate. Tetrahedron Lett. 2000, 41,
9149–9151.
11. Martinez, J.; Laur, J. Active esters of formic acid as useful formylating agents: Improve-
ments in the synthesis of formyl-amino acid esters, N-a-formyl-met-leu-Phe-OH, and
`
formyl-Met-Lys-Pro-Arg, a phagocytosis stimulating peptide. Syntheses 1982, 979–981.
12. Floresheimer, A.; Kula, M. R. The application of N-formyl amino acid esters in the
enzyme-catalyzed peptide synthesis. Monatsh. Chem. 1988, 119, 1323–1329.
13. Ajay, K. B.; Subhendu, N. G.; Maghar, S. M.; Atri, G.; Esteban, P. V. Microwave-
promoted energy-efficient N-formylation with aqueous formic acid. Tetrahedron Lett.
2006, 47, 4605–4607.
14. Desai, B.; Danks, T. N.; Wagner, G. Thermal and microwave-assisted N-formylation
using solid-supported reagents. Tetrahedron Lett. 2005, 46, 955–957.
15. Iranpoor, N.; Habib, F.; Arezu, J. Silphos [PCl3ꢁn(SiO2)n]: A heterogeneous phosphine
reagent for formylation and acetylation of alcohols and amines with ethyl formate and
acetate. Tetrahedron Let. 2005, 46, 7963–7966.
16. Hill, D. R.; Hsiao, C. N.; Kurukulasuriya, R.; Wittenburger, S. J. 2,2,2-Trifluoroethyl
formate: A versatile and selective reagent for the formylation of alcohols, amines, and
N-hydroxylamines. Org. Lett. 2002, 4, 111–113.

484
L. A. SHASTRI ET AL.
17. Schmid, L.; Canonica, A.; Baiker, A. Ruthenium-catalysed formylation of amines with
dense carbon dioxide as C1-source. Appl. Catal. A. 2003, 255, 23–33.
18. Jung, S. H.; Ahn, J. H.; Park, S. K.; Choi, J. K. A practical and convenient procedure for the
N-formylation of amines using formic acid. Bull. Korean Chem. Soc. 2002, 23, 149–150.
19. Savari, M. H.; Sharghi, H. ZnO as a new catalyst for N-formylation of amines under
solvent-free conditions. J. Org. Chem. 2006, 71, 6652–6654.
20. Basanagouda, M.; Kulkarni, M. V.; Kalkhambkar, R. G.; Kulkarni, G. M. New, efficient,
selective, and one-pot method for acylation of amines. Synthetic Commun. 2008, 38, 2929–2940.