A novel direct conversion of primary amides to their corresponding methyl esters

Article abstract of DOI:10.1002/ejoc.200600853

A novel method was used to directly convert aliphatic and aromatic primary amides into their corresponding methyl esters in high yields (up to 99 %) under mild reaction conditions. Possible mechanisms were studied at the B3LYP/6-31++G(d,p) level of theory. Formation of the ester proceeded through a rearrangement of the -OMe and -NH₂ groups in the RC(O)NHS(O)OMe intermediate in a H⁺-catalyzed six-membered ring transition state structure. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200600853

FULL PAPER
DOI: 10.1002/ejoc.200600853
A Novel Direct Conversion of Primary Amides to Their Corresponding Methyl
Esters
Liang-Chun Li,[a,b] Jie Ren,[a] Tou-Gen Liao,[a,b] Ju-Xing Jiang,[a,b] and Hua-Jie Zhu*[a]
Keywords: Amides / Esters / Reaction Mechanisms / Density functional calculations
A novel method was used to directly convert aliphatic and
aromatic primary amides into their corresponding methyl es-
ters in high yields (up to 99%) under mild reaction condi-
tions. Possible mechanisms were studied at the B3LYP/6-
31++G(d,p) level of theory. Formation of the ester proceeded
through a rearrangement of the –OMe and –NH2 groups in
the RC(O)NHS(O)OMe intermediate in a H+-catalyzed six-
membered ring transition state structure.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
weight of 161 for the product, which confirms bis(ester) for-
mation.[15] The methanol solution of SOCl2 can catalyze the
conversions of seven aromatic primary amides (Entries 1–
10) and two aliphatic primary amides (Entries 11, 12) into
their corresponding methyl esters under the same reaction
conditions (Table 1). The structures of methyl esters were
Introduction
One of the most important tasks in chemistry is to per-
form functional group inter-conversions. Direct conversion
of organic esters (or acids) to their corresponding amides is
a common and convenient organic operation.[1–4] In con-
trast, the conversion of organic amides to the correspond-
ing esters is relatively difficult. Methods to convert second-
ary amides into their corresponding esters with the use of
NaNO2 heated at reflux in 1,4-dioxane have been re-
ported.[5–10] The conversions of primary amides to their
corresponding esters were reported by using resin,[11] con-
centrated HCl,[12] TiIV-catalysis,[13] or Me3SiCl.[14] Only the
use of resin and Me3SiCl in the conversion are relatively
mild. Herein, we report another novel efficient solution to
convert amides directly to their corresponding esters in high
yields under mild reaction conditions.
1
only identified by H NMR and 13C NMR spectroscopic
analysis because all of the esters are known products [Equa-
tion (1)].
Results and Discussions
The amino acid -asparagine was readily transformed
into its corresponding bis(methyl amino)ester by heating
thionyl chloride with methanol at 55 °C for 6 h [Equa-
tion (1)] or at room temperature for two days. The expected
amino ester was not found. The product has two singlets
with equal integrated areas at δ = 3.65 and 3.69 ppm in the
1H NMR spectra, respectively. The integration ratio of each
of these peaks to that of the α-proton (δ =3.78 ppm) is 3:1.
This demonstrated that two –COOMe groups were present
in the molecule. Mass spectra (EIMS) exhibited a molecular
(1)
HCl that is formed from SOCl2 and methanol may di-
rectly catalyze the conversion as shown in Figure 1.
However, 2 mol of dried HCl in methanol cannot cata-
lyze the conversion of 1 mol of -asparagine to the corre-
sponding methyl ester in reasonable yields in tightened
glassware in two days (Ͻ 5% at room temperature) in our
experiments. In contrast to this result, -asparagine could
be transformed into the methyl esters by using SOCl2 and
methanol at room temperature.[16] HCl may be involved in
the transition states. However, this direct conversion mecha-
nism cannot explain why the conversion of -asparagine to
bis(ester) can take place at room temperature in our studies.
Obviously, the reaction in our experiments must involve
[a] Organic Synthesis and Natural Product Laboratory, Kunming
Institute of Botany, CAS, Kunming,
650204, Yunnan, China
[b] Graduate School of the Chinese Academy of Sciences,
Beijing, 100039, China
E-mail: hjzhu@mail.kib.ac.cn
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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Conversion of Primary Amides to Their Corresponding Methyl Esters
FULL PAPER
Figure 1. HCl direct catalysis mechanism of amide to its methyl ester.
Table 1. The conversions of primary amides to the corresponding
methyl esters in methanol.[a]
Entry
R
Amide:SOCl2
[mol ratio]
T
[°C]
Yield
[%][b]
1
2
3
4
5
6
7
8
Ph-
Ph-
Ph-
Ph-
1:1.1
1:1.1
1:2.0
1:3.0
1:1.1
1:1.1
1:1.1
1:1.1
1:1.1
1:1.1
1:1.1
1:1.1
20
55
55
55
55
55
55
55
55
55
55
55
87
86
92
93
93
83
99
96
90
75
92
70[c]
3-F-C6H4-
(E)-PhCH=CH-
4-CH3-C6H4-
3-CH3-C6H4-
4-OH-C6H4-
2-NH2-C6H4-
(1-naphthyl)-CH2-
Me
9
10
11
12
Scheme 1.
[a] See ref.[16] in Supporting Information section for reaction pro-
cedure. [b] Isolated yields. [c] The boiling point of methyl acetate is
very low. Methyl acetate that was formed was converted to sodium
acetate by using NaOH in methanol at room temperature. The yield
was then computed on the basis of the dried quantity of NaOAc
obtained.
converted into methyl ester 6, the equilibrium between 2
and 3 would supply 2 for conversion to 5. Finally, the con-
version of 5 to 6 is the key TS step. This step proceeds
through TS-D.
some other complex mechanism even if the HCl catalysis
mechanism exists.
The proposed mechanism is shown in Scheme 1. Entire
molecules including the S and Cl atoms of SOCl2 are in-
volved in the transition state (TS) structures. This treatment
is the same as our previous reports.[17–19] The mechanism
was investigated by using DFT theory at the B3LYP/6-
31++G(d,p) level in the gas phase. Their energy magnitudes
in methanol were corrected with the use of the PCM model
by computing their single point energy by using the geome-
tries obtained in the gas phase.[20–26] The lowest energy con-
formers of substrate complexes (precursors of TS) were
used for barrier computations. The electronic energy data
were used in the barrier computations in this method. The
detailed energetics and structures and other information in-
volved in this mechanism are provided in the Supporting
Information.
The rapid formation of 2 from 1 occurs via TS-A over a
20.7 kcal/mol energy barrier in methanol (Figure 2). Re-
versible reaction to 1 is more difficult because this predicted
barrier is 23.6 kcal/mol. Compound 2 could either react
with another molecule of methanol to give 3 or react with
amide 4 to produce intermediate 5.[27] The barrier from 2 to
Figure 2. Transition state structures of TS-A to TS-C and their TS
barriers in methanol (energies in kcal/mol).
Four- and six-membered ring TS geometries, with or
3 is 18.1 kcal/mol, whereas the energy barrier for the reverse without H+ or HCl catalysis, were investigated. TS struc-
reaction (from 3 to 2) is only 18.8 kcal/mol. Thus, equilib- tures I, II, III, and IV were considered reasonable for struc-
rium exists between 2 and 3. When R = Me, the barrier ture studies of TS-D (Figure 3). The structures obtained for
predicted from 2 to intermediate 5 proceeds through TS-C TS-D with the lowest computed energies for each of the TS
with a magnitude of 19.7 kcal/mol, only 1.6 kcal/mol higher types (I, II, III, and IV), and their barriers, are illustrated
than the barrier to TS-B (Figure 2). Therefore, if 5 were in Figure 4.
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FULL PAPER
Figure 3. Four types of transition states involved in TS-D geome-
tries.
Figure 5. The TSs and their barriers in methanol in the reaction of
benzamide with thionyl chloride in methanol (energies in kcal/mol).
More experiments were carried out to test which TS ge-
ometry is possible. Reactions in THF showed that the pres-
ence of two or more mol of methanol per one mol of acet-
amide and benzamide is necessary for conversion of the
amides to their esters.[28] The effects of alcohol structure
and quantity on yields of benzamide conversion were
studied (Table 2). The low isopropyl ester yield obtained
(21%; Table 2, Entry 9) was expected because of the steric
factors of the isopropyl group. The yield is lower than that
of methyl ester by 44% (Table 2, Entry 7). Overall, an H+-
catalyzed six-membered ring TS, TS-D-4 (type IV), is the
possible TS geometry.
Figure 4. Four TS-D structures and their predicted barriers in con-
versions of acetamide to their corresponding methyl esters in
MeOH (energies in kcal/mol).
Table 2. Effect of the ratio of benzamide/SOCl2/ROH on the reac-
tion yields in dried THF solution.[29]
Entry
T
Ratio of
benzamide/SOCl2/ROH
Yield
[%][a]
Recovered
benzamide
[%]
[°C]
DFT calculations indicate that the lowest barriers found
without acid catalysis was 43.1 kcal/mol in methanol for
conversions proceeding through four-membered ring TSs
(TS-D-1). This is almost impossible in reactions. The HCl-
catalyzed four-membered TS structure TS-D-2 has an acti-
vation barrier of only 21.6 kcal/mol in methanol. In type
III, six-membered ring TS structure TS-D-3, a second mole-
cule of methanol was involved in the TS. The lowest energy
barrier, 35.7 kcal/mol in MeOH, was found. The barrier to
six-membered ring TS-D-4 of acetamide is 24.7 kcal/mol in
methanol. This value in methanol is 3.1 kcal/mol higher in
energy than that of HCl-catalyzed four-membered ring TS-
1
2
3
4
5
6
7
8
9
–5
–5
–5
–5
–5
–5
55
55
55
1:1.1:1.1 (R = Me)
1:1.1:2 (R = Me)
1:1.1:4–6 (R = Me)
1:1.1:8 (R = Me)
1:1.1:10 (R = Me)
1:1.1:14 (R = Me)
1:1.1:25 (R = Me)
1:1.1:25 (R = Et)
1:1.1:25 (R = iPr)
0
tiny
5–10
21
22
42
65
56
21
98
99
85–93
76
76
53
32
40
73
[a] Isolated yields.
In summary, a novel direct conversion of primary amides
D-2. TS-D-2 and TS-D-4 are both possible TS structures, to their corresponding methyl esters has been achieved in
and TS-D-2 looks favorable. high yields under mild reaction conditions by using thionyl
The H+-catalyzed four- and six-membered ring TSs, TS- chloride and methanol heated at 55 °C. Thus, the amide
D-2Ј and TS-D-4Ј, in the reaction of benzamide with thio- group could be conveniently used as an acid or ester syn-
nyl chloride in methanol were also investigated. The TSs thon. Aside from the HCl direct catalysis mechanism, the
and their barriers are illustrated in Figure 5. The barrier in likely TS geometries for these reactions have been predicted
methanol in four-membered ring TS-D-2Ј increased sharply by using the B3LYP/6-31++G(d,p) level of theory. The pos-
from 21.6 to 37.9 kcal/mol when acetamide was replaced by sible TS geometry in the conversions involves the H+-cata-
benzamide in the TS computations. In contrast, the barrier lyzed rearrangement of –OMe and –NH2 groups of the
in the six-membered ring only increased from 24.7 to RC(O)NHS(O)OMe intermediate via a six-membered ring
26.4 kcal/mol. Because the reactions take place at 50 °C, the TS structure in which a second molecule of methanol is
possible TS should theoretically be an H+-catalyzed six- needed. Secondary and tertiary amides cannot undergo this
membered ring structure in the reaction of amide with thio- conversion under these reaction conditions. Different che-
nyl chloride in methanol.
moselectivities will be discussed in subsequent studies.
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Eur. J. Org. Chem. 2007, 1026–1030

Conversion of Primary Amides to Their Corresponding Methyl Esters
FULL PAPER
Supporting Information (see footnote on the first page of this arti-
Experimental Section
cle): Experimental procedure, energy data and coordinates for all
1
TSs, IRC plots, and H NMR and 13C NMR spectroscopic data.
NMR spectra were recorded with a Bruker-AV-400 instrument with
the use of CDCl3 as the solvent, unless another solvent is specifi-
cally stated. Chemicals and silica gel (200–400 mesh) were bought
and used as received. Autospec was used for MS determination.
Acknowledgments
All compounds involved in the experiments are known. Thus, only
1H and 13C NMR spectra were determined. The general experimen-
tal procedure is summarized in the Supporting Information. The
NMR spectroscopic data of all compounds involved in this paper
are listed below.
This work was supported by CAS to H.-J. Z. (“Hundreds Talent
Program”) and by the Science and Technology Committee of Yun-
nan Province. The Super-Computational-Center in CAS is thanked
for partial computational support.
PhCOOMe (1): 1H NMR (400 MHz, CDCl3): δ = 8.08 (d, J =
7.6 Hz, 2 H), 7.57 (t, J = 7.2 Hz, 1 H), 7.46 (t, J = 7.6 Hz, 2 H),
3.93 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 166.9, 132.7,
129.9, 129.3, 128.2, 51.8 ppm.
[1] R. M. Propst III, L. S. Trzupek, J. Am. Chem. Soc. 1981, 103,
3233–3235.
[2] A. Solladié-Cavallo, M. Bencheqroun, J. Org. Chem. 1992, 57,
3-F-PhCOOMe (2): 1H NMR (400 MHz, CDCl3): δ = 7.96 (s, 1
H), 7.86 (d, J = 8.0 Hz, 1 H), 7.47 (dd, J = 8.0 Hz, 0.8 Hz, 1 H),
7.32 (t, J = 8.0 Hz, 1 H), 3.88 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 165.7, 134.4, 132.8, 132.7, 129.5, 127.5, 52.2 ppm.
5831–5834.
[3] J. J. Hans, R. W. Driver, S. D. Burke, J. Org. Chem. 1999, 64,
1430–1431.
[4] X. Huang, G. Y. Wang, Z. C. Chen, Newly Edited Chemistry of
Organic Synthesis, Chemical Industry Publisher, Beijing, 2005,
pp. 478–480. For examples of primary amides to acids, see: pp.
380–382.
[5] E. H. White, J. Am. Chem. Soc. 1954, 76, 4497–4498.
[6] E. H. White, C. A. Elliger, J. Am. Chem. Soc. 1967, 89, 165–
167.
(E)-PhCH=CHCOOMe (3): 1H NMR (400 MHz, CDCl3): δ = 7.70
(d, J = 16.0 Hz, 1 H), 7.52 (d, J = 3.6 Hz, 2 H), 7.39 (s, 3 H), 6.44
(d, J = 16.0 Hz, 1 H), 3.81 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 167.4, 144.8, 134.3, 130.2, 128.8, 128.0, 117.7,
51.7 ppm.
[7] W. J. Le Noble, E. H. White, P. M. Dzadzic, J. Am. Chem. Soc.
1976, 98, 4020–4221.
1
4-CH3-PhCOOMe (4): H NMR (400 MHz, CDCl3): δ = 7.94 (d,
J = 8.0 Hz, 2 H), 7.22 (d, J = 8.0 Hz, 2 H), 3.89 (s, 3 H), 2.39 (s,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 166.8, 143.2, 129.3,
128.8, 127.2, 51.6, 21.3 ppm.
[8] D. M. Shendage, R. Fröhlich, G. Haufe, Org. Lett. 2004, 6,
3675–3678.
[9] D. T. Glatzhofer, R. R. Roy, K. N. Cossey, Org. Lett. 2002, 4,
2349–2352.
[10] R. W. Darbeau, E. V. Perez, J. I. Sobieski, W. A. Rose, M. C.
Yates, B. J. Boese, N. R. Darbeau, J. Org. Chem. 2001, 66,
5679–5686.
[11] For ion-exchange resin uses in the conversion, see:W. L.
Greenlee, E. D. Thorsett, J. Org. Chem. 1981, 46, 5351–5353.
[12] a) H. A. Taylor, T. W. Davis, J. Phys. Chem. 1928, 32, 1467–
1480; b) E. Emmet Reid, Am. Chem. J. 1909, 41, 483–510.
[13] TiIV catalyzed conversion, see:L. E. Fisher, J. M. Caroon, S. R.
Stabler, S. Lundberg, S. Zaidi, Can. J. Chem. 1994, 72, 142.
[14] For chlorotrimethylsilane use in the transformation of amides
into esters, see: C.-H. Xue, F.-T. Luo, J. Chin. Chem. Soc. (Tai-
pei) 2004, 51, 359.
1
3-CH3-PhCOOMe (5): H NMR (400 MHz, CDCl3): δ = 7.89 (m,
2 H), 7.35 (m, 2 H), 3.90 (s, 3 H), 2.40 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 167.0, 137.9, 133.4, 129.9, 128.0, 126.5,
51.7, 20.9 ppm.
4-HO-PhCOOMe (6): 1H NMR (400 MHz, CD3COCD3): δ = 9.21
(s, 1 H), 7.87 (d, J = 8.4 Hz, 2 H), 6.91 (d, J = 8.8 Hz, 2 H), 3.81
(s, 3 H) ppm. 13C NMR (100 MHz, CD3COCD3): δ = 166.9, 132.3,
122.3, 115.9, 51.8 ppm.
1
2-NH2-PhCOOMe (7): H NMR (400 MHz, CDCl3): δ = 7.85 (m,
1 H), 7.25 (m, 1 H), 6.64 (t, J = 8.0 Hz, 2 H), 3.86 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 168.5, 150.3, 133.9, 131.1, 116.6,
116.2, 110.7, 51.38 ppm.
[15] This compound is known and only 1H NMR and mass spectra
were recorded. The NMR spectroscopic data was compared
with the known data. Details of the reaction procedure are
summarized in ref.[11] in the Supporting Information.
[16] See Supporting Information for reaction details.
[17] W. L. Xiao, H. J. Zhu, Y. H. Shen, R. T. Li, S. H. Li, H. D.
Sun, Y. T. Zheng, R. R. Wang, Y. Lu, C. Wang, Q. T. Zeng,
Org. Lett. 2005, 7, 2145.
[18] H. J. Zhu, J. X. Jiang, S. Saobo, C. U. Pittman Jr, J. Org. Chem.
2005, 70, 261–267.
[19] L. C. Li, J. X. Jiang, J. Ren, Y. Ren, C. U. Pittman Jr, H. J. Zhu,
Eur. J. Org. Chem. 2006, 1981–1990.
1-Naph-CH2COOMe (8): 1H NMR (400 MHz, CDCl3): δ = 8.01
(d, J = 8.0 Hz, 1 H), 7.88 (d, J = 8.0 Hz, 1 H), 7.81 (d, J = 7.6 Hz,
1 H), 7.58–7.43 (m, 4 H), 4.09 (s, 2 H), 3.70 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 172.0, 133.8, 132.0, 130.5, 128.7,
128.0, 127.9, 126.4, 125.7, 125.4, 123.7, 52.1, 39.0 ppm.
1
PhCOOCH2CH3 (9): H NMR (400 MHz, CDCl3): δ = 8.04 (d, J
= 7.2 Hz, 2 H), 7.55 (t, J = 7.6 Hz, 1 H), 7.44 (t, J = 7.6 Hz, 2 H),
4.38 (q, J = 5.6 Hz, 2 H), 1.39 (t, J = 5.7 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 166.6, 132.8, 130.5, 129.5, 128.3, 60.9,
14.3 ppm.
[20] M. J. Frisch, G. W. Trucks, H. B. Schlegel, Gaussian 03 UserЈs
Reference, Gaussian Inc., Carnegie, PA, 2003..
[21] S. Mirertus, E. Scrocco, J. Tomasi, Chem. Phys. Lett. 1996, 255,
327.
PhCOOCH(CH3)2 (10): 1H NMR (400 MHz, CDCl3): δ = 8.02 (d,
J = 8.0 Hz, 2 H), 7.52 (t, J = 7.6 Hz, 1 H), 7.41 (t, J = 8.0 Hz, 2
H), 5.25 (m, 1 H), 1.36 (d, J = 6.0 Hz, 6 H) ppm. 13C NMR [22] M. Cossi, V. Barone, J. Mennucci, J. Tomasi, Chem. Phys. Lett.
1998, 286, 253.
(100 MHz, CDCl3): δ = 165.9, 132.5, 130.7, 129.3, 128.1, 68.2,
[23] J. Tomasi, B. Mennucci, E. Cances, J. Mol. Struct.: THEO-
CHEM 1999, 464, 211.
[24] M. Cossi, G. Scalmani, N. Rega, V. Barone, J. Chem. Phys.
2002, 117, 43.
21.8 ppm.
MeOOCCH2CH(NH2)COOMe (11): 1H NMR (500 MHz,
CDCl3): δ = 3.78 (m, 1 H), 3.69 (s, 3 H), 3.65 (s, 3 H), 2.76 (dd, J
= 5.0 Hz, 16.5 Hz, 1 H), 2.66 (dd, J = 7.0 Hz, 17.2 Hz, 1 H) ppm.
MS: m/z = 161 [M]+.
[25]
[26]
C. Gonzalez, H. B. Schlegel, J. Chem. Phys. 1989, 90, 2154.
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[27] D. C. K. Chan, United States Patent 4,018,920, 1977. The reac-
tion of 2-hydroxylbenzamide with SOCl2 was found to form 2-
oxo-2,3-dihydro-2λ4-benzo[e][1,2,3]oxathiazin-4-one.
[28] Experiments were performed to define the smallest mol ratio
of MeOH/acetamide where 6 would still be formed. However,
because the methyl acetate formed has a low boiling point,
further studies to determine the yields were not performed.
[29] See the Supporting Information for reaction details.
Received: September 29, 2006
Published Online: December 21, 2006
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Eur. J. Org. Chem. 2007, 1026–1030