Direct Preparation of Amides from Amine Hydrochloride Salts and Orthoesters: A Synthetic and Mechanistic Perspective

Article abstract of DOI:10.1080/00397911.2015.1096943

The conversion of a wide range of primary and secondary aliphatic and a few arylamine hydrochloride salts to their corresponding acetamides with trimethyl orthoacetate is described. Mechanistic studies using NMR and gas chromatography-mass spectrometry techniques indicate these reactions proceed via an O-methylimidate intermediate that undergoes in situ demethylation by chloride, affording the corresponding acetamides. Synthetically, this reaction represents a practical, high-yielding protocol with a simple workup for the rapid conversion of amine hydrochloride salts to acetamides.

Full text of DOI:10.1080/00397911.2015.1096943

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
The Direct Preparation of Amides from Amine
Hydrochloride Salts and Orthoesters: A Synthetic
and Mechanistic Perspective
Martin J. Di Grandi, Caitlin Bennett, Kristen Cagino, Arnold Muccini, Corey
Suraci & Shahrokh Saba
To cite this article: Martin J. Di Grandi, Caitlin Bennett, Kristen Cagino, Arnold Muccini, Corey
Suraci & Shahrokh Saba (2015): The Direct Preparation of Amides from Amine Hydrochloride
Salts and Orthoesters: A Synthetic and Mechanistic Perspective, Synthetic Communications,
DOI: 10.1080/00397911.2015.1096943
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Date: 10 October 2015, At: 00:32

The Direct Preparation of Amides from Amine Hydrochloride Salts and Orthoesters:
A Synthetic and Mechanistic Perspective
1
2
2
2
2
Martin J. Di Grandi , Caitlin Bennett . Kristen Cagino , Arnold Muccini , Corey Suraci ,
2
Shahrokh Saba
1
Department of Natural Sciences, Fordham University, New York, NY, USA,
2
Department of Chemistry, Fordham University, Bronx, NY, USA
E-mail: saba@fordham.edu
Abstract
The conversion of a wide range of primary, secondary aliphatic and a few arylamine
hydrochloride salts to their corresponding acetamides with trimethyl orthoacetate
(
TMOA) is described. Mechanistic studies using NMR and GC-MS techniques indicate
these reactions proceed via an O-methylimidate intermediate that undergoes in situ
demethylation by chloride affording the corresponding acetamides. Synthetically, this
reaction represents a practical, high-yielding protocol with a simple workup for the rapid
conversion of amine hydrochloride salts to acetamides.
KEYWORDS: acylation, imidate ion, orthoesters, amine hydrochlorides, amides,
microwave heating
INTRODUCTION
1

Acetylation is a fundamentally important reaction in both biological systems and organic
chemistry. For instance, the post-translational acetylation of histone lysine residues or
those found in -tubulin is known to alter the function of these proteins and there is still a
[
1]
need to understand the function of N-terminal protein acetamides. From an organic
chemistry perspective, the preparation of amides from amines is a well-established
[
2]
reaction, but while there exists numerous methods for this conversion, there is interest
[
3]
still in methods that are simple, efficient, inexpensive, and solvent- and/or catalyst-free.
In light of this, we report herein our findings in the use of trimethyl orthoacetate (TMOA)
as an effective acetylating agent of aliphatic/aromatic amine hydrochloride salts under
either conventional heating or microwave irradiation conditions.
This work is an extension of our earlier publication that reported a highly efficient one-
[
4]
pot procedure for the preparation of a wide range of cyclic amidinium salts (Scheme 1).
The simplicity and efficiency of this chemistry allows for the easy preparation of various
,5-dihydroimidazolium salts, including those that feature bulky nitrogen substituents
4
2
5
[6]
(
Scheme 1: n = 0, R = H), which are N-heterocyclic carbene precursors. Using this
same methodology, we subsequently found that certain acylic di- and tetra-alkylated
amidinium salts with non-nucleophilic counterions could also be prepared from aliphatic
primary and secondary monoamines upon treatment with orthoesters in the presence of
[
7]
ammonium tetrafluoroborate or hexafluorophosphate.
Anticipating the effect of the nucleophilicity of the anionic counterpart of the ammonium
salt on the reaction course, and as part of our continued efforts on the use of simple
2

[8]
ammonium salts in synthetic transformations, we explored the reaction of the
hydrochloride salts of primary and secondary aliphatic amines as well as a few
representative anilines with TMOA. Herein, we present a simple and efficient protocol
1
2
for the reaction of a series of amine hydrochloride salts (2, R = alkyl/aryl, R = H or
alkyl) with TMOA that affords acetamides (Scheme 2).
DISCUSSION
With the exception of the commercially available hydrochloride salts of methylamine,
ethylamine and the anilines, all amine hydrochloride salts (2c-r) used in this work were
readily prepared by heating an equimolar mixture of the amine free base with ammonium
[
9]
chloride in ethanol (Scheme 2). These reactions were practically complete within 2
hours affording very high yields (> 90 %) of the hydrochloride salts upon removal of
ethanol under reduced pressure.
In our first attempt to prepare acetamides directly from these salts, amine hydrochlorides
were treated with a slight excess of TMOA at reflux under conventional heating. These
reactions generally reached completion within 1-4 hours and very high yields of nearly
pure acetamides were obtained upon removal of methanol and excess TMOA by rotary
[
10]
evaporation (Table 1).
Primary and secondary amine hydrochlorides afforded very
high yields of acetamides upon reaction with TMOA, but as expected, secondary amines
with relatively bulky substituents (e.g., diisopropylamine) produced only traces of
[
11]
1
13
product.
All acetamides were characterized by their H and C NMR spectra, which
exhibited features typical for these compounds: chemical shift nonequivalence of the N-
3

[
12]
alkyl residues for tertiary acetamides and CH-NH coupling for secondary
[
13]
acetamides.
Following the success of this reaction, we attempted the same conversion using
microwave irradiation. Gratifyingly, treatment of the same amine hydrochloride salts
with 1.5 equivalents of TMOA in methanol at 135 ºC for fifteen minutes cleanly afforded
[
9,14]
the corresponding acetamides (Table 1)
, in yields comparable to the thermal reaction
[
15]
but with substantially reduced reaction times.
The only exceptions to this were the
anilines (2s - u): these microwave reactions afforded highly colored crude products that
required further purification via recrystallization from water/ethanol mixtures. For this
reason, the anilines afforded acetanilides in lower yield, when compared to the reactions
performed under conventional thermal conditions.
In terms of a plausible mechanism, this reaction appears to be driven by loss of
chloromethane (Scheme 3). The ammonium chloride first catalyzes the formation of
imidate 4 after loss of methanol, which is followed by subsequent O-demethylation by
chloride, to afford the acetamide product. The intermediacy of an imidate ion was
verified by the reaction of hexamethyleneiminium tetrafluoroborate (5) with TMOA,
1
13
which produced the isolable salt 6 (Scheme 4). The H and C NMR spectra of this
compound showed signals expected for all nonequivalent hydrogens and carbons,
respectively, and the DEPT-135 spectrum of 6 displayed positive peaks for the carbons of
CH O- and CH - groups of this molecule (60.0 and 14.5 ppm, respectively) and negative
3
3
signals for all six methylene carbons (52.0, 50.0, 26.6, 26.3, 26.1, and 25.7 ppm,
4

respectively). Additionally, nucleophilic attack of the chloride ion on intermediate 4 was
also inferred by isolation of MeI as by-product of the reaction of the iodide salt of
hexamethyleneimine with TMOA, which was distilled from the reaction mixture and
1
characterized by H NMR and GC-MS analyses.
The literature on the reaction of aliphatic amines with TMOA is sparse and the products
obtained from the reported cases vary with the reaction conditions. Most recently,
Gopalan et al. reported the conversion of unprotected amino acids to ethyl ester
acetamides in refluxing toluene containing one equivalent of triethyl orthoacetate
[
16]
[17]
(TEOA).
Prior to this, Taylor and Ehrhart observed formation of amidines from the
reaction of 2 equivalents of cyclohexylamine or benzylamine with TEOA in either the
[18]
presence or absence of acetic acid as a catalyst. Swaringen, Jr. et al. reported a single
reaction between morpholine and TMOA affording a mixture of N-acetylmorpholine and
N-methylmorpholine. However, when the same amine was treated with triethyl
orthoformate and p-toluenesulfonic acid or acetic acid as catalyst, only
[
19]
trimorpholinomethane was obtained as the major product. McElvain and Tate also
reported a single reaction leading to N,N-dibutylacetamide by heating an excess of
dibutylamine with TEOA at 200-220 °C for 12 hours in a bomb. The methodology
reported here represents the first systematic study of this reaction and has yielded a
reproducible, expedient process for the acetylation of amines under relatively mildly
acidic conditions.
CONCLUSION
5

We have devised a practical, high-yielding protocol with short reaction times (for the
microwave assisted version) and a simple workup for acetylation of the hydrochloride
salts of primary and secondary amine as well as anilines using TMOA as the acetylating
reagent, and we provide some mechanistic insight for this reaction. Given the importance
of amine acylation as a fundamental reaction in organic synthesis and the paucity of
literature data on the reaction of acyclic and cyclic aliphatic amines with TMOA, the
procedure described herein highlights the utility of orthoesters as amine acylating
reagents. The reaction appears to be broadly applicable to a wide variety of amines, has
the distinct advantage of requiring only mildly acidic conditions and a simple workup.
EXPERIMENTAL
General Information
All solvents and reagents were obtained from commercial suppliers. With the exception
of methylamine hydrochloride, ethylamine hydrochloride, and aniline hydrochlorides, all
amine hydrochlorides were prepared by treatment of the amine free bases with
ammonium chloride (see general procedure for the preparation of amine hydrochloride
salts 2c-2r). Pyrrolidine, piperidine, and morpholine were distilled prior to conversion to
their hydrochloride salts but all the other amines were used without further purification.
1
13
H (300 MHz) and C (75 MHz) NMR spectra of acetamides 3a-3r and tetrafluoroborate
salt 6 were recorded on a Bruker Avance DPX 300 spectrometer in CDCl with TMS as
3
1
13
the internal standard. H (400 MHz) and C (100 MHz) NMR spectra of acetamides 3s-
3
u were recorded on a Bruker 400 spectrometer in CDCl with TMS as the internal
3
standard. Chemical shifts are reported in ppm (δ) and J values are in Hz.
6

General Procedure For The Preparation Of Acetamides 3a-U: N-Methylacetamide
3a)
(
Methylamine hydrochloride (0.68 g, 0.010 mol) and trimethyl orthoacetate (1.80 g, 0.015
mol) were combined in a 25 mL round bottomed flask and heated under gentle reflux
while being stirred for 2 hours. The homogeneous solution was then evaporated under
1
reduced pressure to yield 0.66 g (91%) of a clear liquid. H NMR 6.46 (br, 1H), 2.78 (d,
1
3
3
H, JCH-NH = 4.8 Hz ), 1.99 (s, 3H); C NMR 171.0, 26.2, 22.8.
ACKNOWLEDGMENTS
The authors gratefully acknowledge financial support from the National Science
Foundation Division of Undergraduate Education through Grant DUE #9650684 for the
Bruker Avance 300 MHz NMR spectrometer at Fordham University. The authors also
thank James A. Ciaccio for obtaining the GC-MS data and helpful comments on the
manuscript.
SUPPLEMENTAL MATERIAL
1
Full experimental details, IR, H NMR, and HRMS data for this article can be accessed
on the publisher’s website.
REFERENCES
7

[
1]
For reviews of lysine acetylation of histones, see: a) Turner, B. M. BioEssays
2
000, 22, 836-845; b) Choudhary, C.; Kumar, C.; Gnad, F.; Nielsen, M. L.; Rehman, M.;
Walther, T. C.; Olsen, J. V.; Mann, M. Science 2009, 325, 834-840; for reviews of -
tubulin acetylation, see: c) Al-Bassam, J.; Corbett, K. D. Proc. Nat. Acad. Sci. USA 2012,
1
09, 19515-19516; d) Rymut, S. M.; Kelley, T. J. Cell Health Cytoskel. 2015, 7, 71-82;
for the importance of N-terminal protein acetamides, see: e) Arnesen, T. PLoS Biology
2
011, 9, e1001074. doi:10.1371/journal.pbio.1001074.
[
2]
For extensive coverage of the multitude of ways to prepare amides, please see:
Wuts, G.M.P.; Greene, T.W. In: Greene’s Protective Groups in Organic Synthesis,
Fourth Ed; John Wiley & Sons, Inc: New Jersey, 2007, pp 773-802 and references cited
therein.
[
3]
a) Pelagalli, R.; Chiarotto, I.; Feroci, M.; Vecchio, S. Green Chem. 2012, 14,
251-2255; b) Mali, S.M.; Bhaisare, R.D.; Gopi, H.N. J. Org. Chem. 2013, 78, 5550-
555; c) Alalla, A.; Merabet-Khelassi, M.; Aribi-Zouioueche, L; Riant, O. Syn. Comm.
014, 44, 2364-2376.
2
5
2
[
4]
This method provides a highly efficient one-pot procedure for the preparation of a
–
–
wide range of cyclic amidinium tetrafluoroborate (BF ) and hexafluorophosphate (PF )
4
6
salts (Scheme 1) by treating primary or secondary diamines with an equimolar quantity
each of an orthoester and NH BF or NH PF ; see: Saba, S.; Brescia A.; Kaloustian, M.
4
4
4
6
Tetrahedron Lett. 1991, 32, 5031-5034.
[
5]
Benhamou, L.; Chardon, E.; Lavigne, G.; Bellemin-Laponnaz, S.; César, V.
Chem. Rev. 2011, 111, 2705-2733.
8

[
6]
Saba, S.; Kojtari, A.; Rivera, M.; D’Amico, P.; Canuso, D.; Kaloustian, M.
th
Abstracts of Papers, 37 Middle Atlantic Regional Meeting of the American Chemical
Society: New Brunswick, NJ, 2005.
[
7]
(a) Saba, S.; Vrkic, D.; Cascella, C.; DaSilva, I., Carta, K.; Kojtari, A. J. Chem.
Res. 2008, 301-304. (b) O’Connor, D.; Lauria, A.; Bondi, S. P.; Saba, S. Tetrahedron
Lett. 2011, 52, 129-132.
[
8]
Saba, S.; Hernandez, R.; Chin Choy, C.; Carta, K.; Bennett, Y.; Bondi, S.; Kolaj,
S.; Bennett, C. J. Fluorine Chem. 2013, 153, 168-171.
[
9]
Please see the Supporting Information for more details.
[10]
Diisopropylamine is known to perform poorly in acylation reactions; see
reference 3a.
[11]
[12]
[13]
Stewart, W. E.; Siddall III, T. H. Chem. Rev. 1970, 70, 517-551.
Gutowsky, H. S.; Holm, C. H. J. Chem. Phys. 1956, 25, 1228-1234.
The hydrochloride salts are only sparingly soluble in neat trimethyl orthoacetate,
and in a few instances, some insoluble salt remained after microwave heating for 15
minutes, which resulted in incomplete conversion. The addition of methanol afforded
homogeneous mixtures, thus allowing the reaction to go to completion.
[14]
Not surprisingly, this reaction is quite sensitive to moisture. Of all the amine salts
tested, pyrrolidine hydrochloride (2o) was the most hygroscopic, turning the crystalline
solid into an oil. If this oil was used under the described conditions, the reaction failed to
go to completion, even under prolonged heating. Presumably, in the presence of a weak
acid, adventitious water hydrolyzes TMOA, essentially terminating the reaction.
9

[15]
Gibson, S.; Romero, D.; Jacobs, H. K.; Gopalan, A. S. Tetrahedron Lett. 2010,
5
1, 6737–6740.
[16]
Taylor, E. C.; Ehrhart, W. A. A J. Org. Chem. 1963, 28, 1108-1112.
[17]
Swaringen, Jr., R. A.; Eaddy, J. F.; Henderson, T. R. J. Org. Chem. 1980, 45,
3
986-3989.
[18]
McElvain, S. M.; Tate, B. E. J. Am. Chem. Soc. 1945, 67, 202-204.
1
0

Table 1. Preparation of secondary and tertiary acetamides
Thermal
Reaction
Microwave
b
Reaction
a
Entry
Amine.HCl Salt
Product
Time
Yield
Yield (%)
a
(
h)
(%)
+
1
2
3
4
5
6
CH NH3
2a
2b
2c
2d
2e
2f
CH NHAc
3a
3b
3c
3d
3e
3f
2
91
100
95
3
3
+
CH CH NH
CH CH NHAc
2
2
85
93
90
98
99
3
2
3
3
2
+
3
(CH ) CHNH
(CH ) CHNHAc
82
3
2
3 2
+
(CH ) CNH
(CH ) CNHAc
2.5
2
94
3
3
3
3 3
+
PhCH NH3
PhCH NHAc
100
98
2
2
2
7
8
2g
2h
3g
3h
2.5
2
100
96
96
90
9
2i
3i
3
3
100
90
100
96
10
2j
3j
+
1
1
1
1
2
3
(CH CH ) NH
2k
(CH CH ) NAc
3k
4
4
88
99
94
77
90
82
3
2 2
2
3
2 2
+
2
(CH CH CH ) NH
2l (CH CH CH ) NAc 3l
3
2
2 2
3
2
2 2
2m
2n
3m
3n
3.5
1
1
4
5
3
4
98
90
96
90
2o
2p
2q
3o
3p
3q
1
1
6
7
4
2
95
99
89
86
18
2r
3r
2
97
96
+
1
2
2
9
0
1
C H NH
2s
2t
C H NHAc
3s
3t
1
1
1
83
84
78
50
54
48
6
5
3
6
5
+
4-CH C H NH
4-CH C H NHAc
3 6 5
3
6
5
3
+
4-CH OC H NH
2u 4-CH OC H NHAc 3u
3
6
5
3
3
6
5
a
b
Isolated yield; All microwave reactions were complete within 0.25 h
1
1

Scheme 1 The one-pot procedure for the preparation of cyclic amidinium salts (see
reference 4).
1
2

Scheme 2 The preparation of amine hydrochloride salts and their conversion to
acetamides in the presence of trimethylorthoacetate.
1
3

Scheme 3 A proposed mechanism for the conversion of amine hydrochloride salts to their
acetamides in the presence of trimethylorthoaceate.
1
4

Scheme 4 The preparation of isolable salt 6 from the reaction of hexamethyleneiminium
tetrafluoroborate with TMOA.
1
5