Steric and Electronic Effects in the Synthesis and Regioselective Hydrolysis of Unsymmetrical Imides

Article abstract of DOI:10.1071/CH15504

The AgI-promoted coupling reaction of thioamides and carboxylic acids is shown to be a useful method for the generation of unsymmetrical imides. The reaction proceeds efficiently with unhindered and electron-rich or neutral coupling partners, but not with hindered thioamides (such as thiopivalamides) or electron deficient thioamides (such as trifluorothioacetamides). Intriguingly, thioformamides are also ineffective coupling partners, despite having minimal steric or electronic influence. Hindered carboxylic acid coupling partners (such as pivalic acid) are tolerated, but electron deficient acids, such as trifluoroacetic acid, are ineffective coupling partners. Furthermore, an interplay of both steric and electronic effects is observed in the subsequent hydrolysis of unsymmetrical imides. Imides with a dimethoxybenzoyl group give high regioselectivity upon hydrolysis, favouring cleavage of the distal acyl group. Imides with a p-nitrobenzoyl or pivaloyl group give reversed selectivity, favouring cleavage of the proximal acyl group.

Full text of DOI:10.1071/CH15504

RESEARCH FRONT
CSIRO PUBLISHING
Aust. J. Chem.
Full Paper
http://dx.doi.org/10.1071/CH15504
Steric and Electronic Effects in the Synthesis and
Regioselective Hydrolysis of Unsymmetrical Imides
A
A
A
Jing Shang, Aysa Pourvali, James R. Cochrane,
A B
,
and Craig A. Hutton
A
School of Chemistry and Bio21 Molecular Science and Biotechnology Institute,
The University of Melbourne, Melbourne, Vic. 3010, Australia.
Corresponding author. Email: chutton@unimelb.edu.au
B
The AgI-promoted coupling reaction of thioamides and carboxylic acids is shown to be a useful method for the generation
of unsymmetrical imides. The reaction proceeds efficiently with unhindered and electron-rich or neutral coupling partners,
but not with hindered thioamides (such as thiopivalamides) or electron deficient thioamides (such as trifluorothioace-
tamides). Intriguingly, thioformamides are also ineffective coupling partners, despite having minimal steric or electronic
influence. Hindered carboxylic acid coupling partners (such as pivalic acid) are tolerated, but electron deficient acids, such
as trifluoroacetic acid, are ineffective coupling partners. Furthermore, an interplay of both steric and electronic effects is
observed in the subsequent hydrolysis of unsymmetrical imides. Imides with a dimethoxybenzoyl group give high
regioselectivity upon hydrolysis, favouring cleavage of the distal acyl group. Imides with a p-nitrobenzoyl or pivaloyl
group give reversed selectivity, favouring cleavage of the proximal acyl group.
Manuscript received: 17 August 2015.
Manuscript accepted: 19 September 2015.
Published online: 15 October 2015.
Introduction
Selective imide hydrolysis with concomitant ester deprotection
then generates the homologated peptide acid 4, suitable for
iterative extension of the peptide chain.[2]
Despite the voluminous work on the synthesis of amide bonds,
the preparation of acyclic imides has received relatively little
attention.[1] We have recently developed a method for the syn-
thesis of peptide imides through the coupling of amino ester
thioacetamides 2 to the C-terminal carboxylic acid of a peptide
or protected amino acid 1 in a process promoted by silver(I).[2] In
its simplest sense, this process enables the high yielding prep-
aration of unsymmetrical imides, which are difficult to access
through the acylation of imides due to the propensity for acyl
scrambling.[3] In the context of peptide synthesis,[4,5] this new
method allows the N-to-C direction synthesis of peptides and
proceeds through a peptide imide intermediate 3 (Scheme 1).
To date this process has only been investigated with N-
thioacetyl amino acids. In our previous studies selective cleav-
age of the peptide imide 3 was postulated to proceed due to steric
factors, with hydrolysis or methanolysis of the imide occurring
at the less hindered acetyl carbonyl group.[2] However, we have
observed in occasional cases (e.g. see Scheme 2) that imide
cleavage is not selective or displays the opposite selectivity,
leading us to investigate the scope and limitations of both the
thioamide coupling step and the imide hydrolysis step, with
regard to steric and electronic effects of both coupling partners.
O
R1
R1
R1
H
H
N
Ag2CO3
CH2Cl2
CO2Me
LiOH
N
CO2Me
CO2H
N
ϩ
RCONH
RCONH
RCONH
CO2H
S
R2
O
R2
R2
O
1
2
3
4
Scheme 1. AgI-promoted synthesis of peptide imides.
CO2Me
AcHN
Ph
Ph
PhthN
O
NaHCO3
MeOH
H
N
8
CO2Me
CO2Me
ϩ
Ph
N
81 %
PhthN
O
O
15 %
PhthN
CO2Me
5
6
7
Scheme 2. Solvolysis of Phe–Gly dipeptide imide.
Journal compilation Ó CSIRO 2015
www.publish.csiro.au/journals/ajc

B
J. Shang et al.
Table 1. Preparation of thioamides 11
O
S
R1COX
LR
R1
R1
N
H
Ph
N
H
Ph
Ph
NH2
9
10
11
Entry
R1COX
Ac2O
R1
Yield 10 [%]
Yield 11 [%]
a
b
c
d
e
f
Me
tBu
CF3
83
74
97
98
89
95
89
91
97
91
65
47
53
51
66
50
83
97
62
60
pivalic acid (þ HBTUA)
(F3CCO)2O
(Cl3CCO)2O
CCl3
H
ethyl formate
benzoic acid (þ HBTU)
4-OMe-benzoyl chloride
2,4-(OMe)2-benzoyl chloride
4-NO2-benzoyl chloride
2,4-(NO2)2-benzoyl chloride
Ph
g
h
i
PMP
DMP
PNP
DNP
j
AHBTU ¼ O-(benzotriazol-1-yl)-N,N,N0,N0-tetramethyluronium hexafluorophosphate.
Factors Affecting AgI-Promoted Thioamide Coupling
Table 2. Preparation and corresponding isolated yields (%) of imides
13 from coupling of thioamides 11 with carboxylic acids 12
A range of N-benzylthioamides were chosen as model substrates
and prepared in two steps from benzylamine. Benzylamine (9)
was treated with a variety of acyl donors to generate the corre-
sponding amides 10a–j, which were then treated with
Lawesson’s reagent (LR) to generate the corresponding thio-
amides 11a–j in 35–88 % yield over two steps (Table 1). The
thioamides were chosen to provide substrates with a range
of steric bulk (e.g. formyl, acetyl, pivaloyl) and electron
donating/withdrawing capability (e.g. p-nitrophenyl (PNP) cf.
p-methoxyphenyl (PMP); acetyl cf. trifluoroacetyl) (Table 1).
Similarly, a range of carboxylic acids was chosen to investigate
steric and electronic effects of these coupling partners (Table 2).
The imides 13 were generated by treatment of one equiv. of
acid 12a–c with two equiv. of thioamide 11a–j and two equiv.
Ag2CO3 at room temperature overnight (Table 2).
First, a comparison of the reactivity of the thioamides 11a–j
was undertaken, in reactions with silver carbonate and acetic
acid (12a). Thioacetamide (11a) afforded the corresponding
imide 13aa in good yield (76 %, Table 2). However, hindered
thiopivalamide (11b) gave only trace amounts of the corre-
sponding imide 13ab, and strongly electron deficient thio-
amides 11c and 11d yielded no imide product. Interestingly,
use of thioformamide (11e) did not generate the corresponding
imide product with only starting material and amide 10e recov-
ered. Aryl thioamides 11f–i generally afforded the correspond-
ing imides 13 in good yields, although the electron deficient
thioamide 11j gave only a moderate yield of imide 13aj
(Table 2).
Next, the effect of the acid partners was investigated. Pivalic
acid (12b) was reasonably well tolerated, but generated the
imides 13b(a,f–i) in lower yield than the corresponding reac-
tions with acetic acid (12a). The combination of sterically
hindered pivalic acid (12b) and electron deficient dinitro-
benzoyl thioamide 11j gave no imide product. Trifluoroacetic
acid (12c) did not undergo coupling with any of the thioamides.
These results indicate that steric hindrance from either
coupling partner considerably reduces the yield of the imide
adduct, as does the presence of strongly electron withdrawing
substituents. Such findings are consistent with the proposed
mechanism in which the carboxylate is acting as a nucleo-
phile:[2,6,7] trifluoroacetate is presumably not nucleophilic
enough for the reaction to proceed. Furthermore, the thioamide
S
O
Ag2CO3
CH2Cl2
R2CO2H
R1
R1
N
N
H
ϩ
Ph
Ph
R2
12
O
11
13
R1 (11a–i)
R2 (12a–c)
tBu (b)
Me (a)
CF3 (c)
Me (a)
tBu (b)
CF3 (c)
CCl3 (d)
H (e)
76
trace
0
60
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Ph (f)
88
92
89
70
41
68
80
83
50
0
PMP (g)
DMP (h)
PNP (i)
DNP (j)
must first coordinate to the AgI ion, which is impeded by
electron withdrawing substituents on the thioamide partner.
Factors Affecting Imide Hydrolysis
In the context of using this method for the preparation of amide
bonds, regioselective hydrolysis of the imide adduct is essential.
To investigate the factors affecting the regioselectivity of
imide cleavage, the imides were treated with LiOH to generate a
mixture of amides 10 and 14 (Table 3).
Hydrolysis of the benzoyl/acetyl imide 12af proceeded with
low selectivity to give a 1.1 : 1 mixture of amides 10f and 14a.
Hydrolysis of p-methoxybenzoyl/acetyl imide 12ag displayed
marginal selectivity, favouring cleavage of the acetyl group to
give the benzamide 10g with 2 : 1 selectivity. The electron-
donating methoxy group presumably reduces the electrophili-
city of the carbonyl group, such that hydroxide preferentially
attacks the acetyl group. The dimethoxybenzoyl/acetyl imide
12ah gave excellent regioselectivity (20 : 1), generating
dimethoxybenzoyl amide 10h as the major product. Presumably
the o-methoxy group further disfavours attack at the benzoyl

Imide Synthesis and Solvolysis
C
Table 3. Regioselectivity in hydrolysis of imides 13A
Table 4. Regioselectivity in hydrolysis of imides 13xy upon treatment
with MeOH/NaHCOA3
O
O
O
R1
LiOH
N
Ph
Ph
R1
Ph
R2
ϩ
N
H
N
H
R2
R1
R2
O
Me (a)
tBu (b)
Ph (f)
PMP (g)
DMP (h)
PNP (i)
10
14
13
Me (a)
tBu (b)
1 : 12
–
3 : 2
5 : 2
–
–
1 : 1
5 : 6
2 : 1
R2
R1
Me (a) tBu (b) Ph (f) PMP (g) DMP (h) PNP (i) DNP (j)
ARatio of 10 : 14, determined from isolated yield.
Me (a)
tBu (b) (7 : 1)
1 : 7 1.1 : 1
3 : 1
2 : 1
3 : 1
20 : 1
18 : 1
1 : 3
6 : 5
6 : 5
–
being the bulkier acyl group. IR analysis again shows a shift of
carbonyl absorbance from ,1685 cmꢀ1 in acetimides 13ay, to
,1675 cmꢀ1 in pivalimides 13by, consistent with a switch to the
non-planar conformation 15c.
Imide solvolysis reactions were also investigated under mild
conditions using NaHCO3 in methanol (Table 4),[4,5] and gave
similar results to those observed for basic hydrolysis.
ARatio of 10 : 14, determined from isolated yield.
R1
O
O
R3
R3
R2
R3
R2
R1
R1
N
N
N
O
R2
O
O
O
15a
15b
15c
Conclusion
In summary, the AgI-promoted coupling reaction of thioamides
and carboxylic acids to generate unsymmetrical imides is
affected considerably by both steric and electronic factors.
Hindered thioamides such as thiopivalamides do not generate
the imide in good yield. Intriguingly, thioformamides are also
ineffective coupling partners, despite having minimal steric
influence. Hindered carboxylic acid coupling partners (such as
pivalic acid) are tolerated, although they result in lower yields
than acetic acid. Electron deficient acids, such as trifluoroacetic
acid, are ineffective coupling partners, presumably due to the
low nucleophilicity of the carboxylate.
Furthermore, an interplay of both steric and electronic effects
is observed in the subsequent hydrolysis of unsymmetrical
imides. Acetimides generally undergo cleavage of the less
hindered acetyl group. However, with acetyl/pivaloyl imide
13ab a change of conformation leads to a change in regioselec-
tivity, with pivaloyl cleavage predominating. Electronic effects
can be employed to manipulate regioselectivity of imide cleav-
age. Imides with an electron-rich dimethoxybenzoyl group give
high regioselectivity upon hydrolysis, favouring cleavage at the
distal acyl group. Contrastingly, imides with an electron poor
p-nitrobenzoyl group give either reversed selectivity, favouring
cleavage of the p-nitrobenzoyl group due to the increased
electrophilicity at this site, or are non-selective.
Fig. 1. Imide conformations.
group not only through increased electron donation but also due
to a steric effect.
Hydrolysis of the p-nitrobenzoyl/acetyl imide 12ai pro-
ceeded with moderate selectivity (1 : 3), with a reversal of
selectivity compared with the electron rich systems, with
predominant cleavage of the p-nitrobenzoyl group to give the
acetamide 14a. The electron-withdrawing nitro group presum-
ably increases the electrophilicity of the benzoyl group, favour-
ing attack by hydroxide at the benzoyl carbonyl group.
However, hydrolysis of the dinitrobenzoyl/acetyl imide 12aj
proceeded with low selectivity (1.2 : 1). In this case, the elec-
tronic effects of the nitro groups are counterbalanced by the
steric effect of the o-nitro substituent, such that low selectivity is
observed.
In hydrolysis of the acetyl/pivaloyl imide 12ab, unexpected
regioselectivity was observed, with moderate selectivity (7 : 1)
for cleavage of the more sterically hindered pivaloyl group to
yield acetamide 14a. Imides are known to adopt several con-
formations, with the predominant conformations being the
planar s-trans and s-cis conformations 15a and 15b (Fig. 1).[8]
In imides with bulky substituents (e.g. R2 ¼ tBu), the planar
conformations are disfavoured through steric effects, such that
the non-planar conformation 15c is favoured. Conformational
analysis of imides can be undertaken through IR spectroscopy:
s-trans imides 15a typically show a major IR absorbance at
,1695 cmꢀ1, with a shift to ,1680 cmꢀ1 upon conversion
into the non-planar conformation 15c.[8] IR analysis of imides
13aa and 13ab shows a shift in the carbonyl absorbance
from 1695 cmꢀ1 in bisacetimide 13aa, to 1676 cmꢀ1 in acetyl/
pivaloyl imide 13ab, consistent with a switch to the non-planar
conformation 15c.[8] In the acetyl/pivaloyl imide 13ab the
pivaloyl group is therefore perpendicular to the plane of the
N–C(CH3)¼O group and is not in conjugation, such that it is
more ketone-like and therefore more electrophilic. This ratio-
nalisation has also been invoked for the cleavage of imide 13ab
with ammonia, which similarly occurs with predominant piva-
loyl cleavage,[3] and of hydrolysis/acyl transfer reactions of
related twisted amide- and imide-type systems.[9–11]
Experimental
General Procedure A: Synthesis of Imides Using
Silver Carbonate
To a solution of the thioamide 11 (2 equiv.) and carboxylic acid
12 (1 equiv) in dichloromethane (1.5 mL mmolꢀ1), silver car-
bonate (2 equiv.) was added at room temperature. The solution
was stirred for 12 h at room temperature. The solvent was
removed under reduced pressure and the black residue purified
by flash chromatography to give the imide 13.
N-Acetyl-N-benzylacetamide (13aa)[12]
Silver(I) acetate (330 mg, 2 mmol) was added to a solution of
N-benzylthioacetamide 11a (165 mg, 1 mmol) in CH2Cl2
(4 mL). The solution was stirred under nitrogen for 18 h. The
solvent was evaporated and the residue was purified by chro-
matography on silica to give title compound 13aa as a colourless
oil (60 mg, 33 %). dH (600 MHz, CDCl3) 7.33–7.23 (3H, m,
Similar effects were observed with pivalimides 13b(f–i),
with moderate selectivity towards pivaloyl cleavage, despite it

D
J. Shang et al.
ArH), 7.13 (2H, m, ArH), 4.96 (2H, s, CH2), 2.41 (6H, s, 2Me).
dC (100 MHz, CDCl3) 173.6, 136.6, 128.6, 127.3, 125.8, 47.4,
26.4. m/z (ESI) 192 ([M þ H]þ, 100 %). HRMS m/z 192.1206;
calcd for C11H13NO2 192.1019. nmax (CHCl3)/cmꢀ1 3032, 1695,
1606, 1497, 1370, 1267, 1208, 975, 872, 717, 694.
calcd for C20H23NO3 326.1751. nmax (CHCl3)/cmꢀ1 2968, 2927,
1673, 1602, 1245, 1164.
N-Acetyl-N-benzyl-2,4-dimethoxybenzamide (13ah)
N-Benzyl-2,4-dimethoxythiobenzamide
(11h)
(83.2 mg,
0.3 mmol) and acetic acid (12a) (8.2 mL, 0.15 mmol) were
treated according to general procedure A to give the product
13ah (40.8 mg, 89 %) as a white solid. dH (400 MHz, CDCl3)
7.33–7.18 (8H, m, ArH), 4.92 (2H, s, CH2), 3.83 (3H, s, p-OMe),
3.75 (3H, s, o-OMe), 2.24 (3H, s, Me). dC (100 MHz, CDCl3)
173.4, 171.5, 163.6, 157.9, 137.8, 131.5, 128.3, 127.8, 127.1,
118.5, 105.1, 98.5, 55.6, 55.5, 48.6, 25.9. m/z (ESI) 314
([M þ H]þ, 100 %). HRMS m/z 314.1376; calcd for C18H19NO4
314.1387. nmax (CHCl3)/cmꢀ1 3007, 2970, 2941, 2841, 1698,
1648, 1606, 1210, 1164, 978.
N-Acetyl-N-benzylpivalamide (13ab)[13]
N-Benzylthiopivalamide 11b (80.0 mg, 0.4 mmol) and acetic
acid (11 mL, 0.2 mmol) were treated according to general pro-
cedure A to give the imide 13ab (37 mg, 82 %) as a colourless
oil. dH (400 MHz, CDCl3) 7.33–7.18 (5H, m, ArH), 4.83 (2H, s,
CH2), 2.22 (3H, s, Me), 1.25 (9H, s, tBu). dC (100 MHz, CDCl3)
187.5, 173.2, 137.2, 128.7, 127.4, 126.7, 49.1, 43.2, 28.1, 24.4;
MS (ESI) m/z: 234 ([M þ H]þ, 100 %). HRMS m/z 234.1417;
calcd for C14H19NO2 234.1489. nmax (CHCl3)/cmꢀ1 3304, 2966,
2928, 1676, 1373, 1336, 1159, 975, 733, 699.
N-Benzyl-N-pivaloyl-2,4-dimethoxybenzamide (13bh)
N-Acetyl-N-benzylbenzamide (13af)[14,15]
N-Benzyl-2,4-dimethoxythiobenzamide
(11h)
(85.2 mg,
N-Benzylthiobenzamide (11f) (71 mg, 0.3 mmol) and acetic
acid (12a) (8.2 mL, 0.15 mmol) were treated according to general
procedure A to give the product 13af (39 mg, 88 %) as a col-
ourless oil. dH (400 MHz, CDCl3) 7.56–7.22 (10H, m, ArH),
5.00 (2H, s, CH2), 2.16 (3H, s, Me). dC (100 MHz, CDCl3) 174.3,
173.2, 137.3, 135.8, 132.4, 128.8, 128.5, 128.4, 127.8, 127.4,
49.3, 26.4. m/z (ESI) 254 ([M þ H]þ, 100 %). HRMS m/z
254.1201; calcd for C16H15NO2 254.1176. nmax (CHCl3)/cmꢀ1
3031, 2971, 1686, 1659, 1215, 727, 696.
0.3 mmol) and pivalic acid (12b) (17.2 mL, 0.15 mmol) were
treated according to general procedure A to give the product
13bh (41.5 mg, 83 %) as a white solid. dH (400 MHz, CDCl3)
7.33–7.15 (6H, m, ArH), 6.48–6.44 (2H, m, ArH), 4.70 (2H, s,
CH2), 3.83 (3H, s, OMe), 3.79 (3H, s, OMe), 1.24 (9H, s, tBu).
dC (400 MHz, CDCl3) 187.4, 172.0, 163.5, 158.3, 137.7, 132.1,
128.2, 127.7, 127.1, 117.8, 104.9, 98.6, 55.5, 51.1, 43.4, 28.4.
m/z (ESI) 356 ([M þ H]þ, 100 %). HRMS m/z 356.1875; calcd
for C21H25NO4 356.1856. nmax (CHCl3)/cmꢀ1 3402, 3063,
3029, 3005, 2925, 2852, 1642, 1603, 1528, 1496, 1295, 1208,
1166, 1025, 699.
N-Benzyl-N-pivaloylbenzamide (13bf)[16]
N-Benzylthiobenzamide (11f) (85 mg, 0.3 mmol) and pivalic
acid (12b) (22.6 mL, 0.2 mmol) were treated according to gen-
eral procedure A to give the product 13bf (36.4 mg, 71.5 %) as a
white solid. dH (400 MHz, CDCl3) 7.69–7.20 (10H, m, ArH),
4.83 (2H, s, CH2), 1.21 (9H, s, tBu). dC (100 MHz, CDCl3)
187.4, 174.8, 137.2, 135.0, 132.5, 129.0, 128.7, 128.5, 127.7,
127.4, 51.3, 43.5, 28.5. m/z (ESI) 296 ([M þ H]þ, 100 %).
HRMS m/z 296.1653; calcd for C19H21NO2 296.1645. nmax
(CHCl3)/cmꢀ1 3065, 3031, 2970, 2924, 1676, 1655, 1342, 1239,
1167, 1125, 965, 721, 696.
N-Acetyl-N-benzyl-4-nitrobenzamide (13ai)
N-Benzyl-4-nitrothiobenzamide (11i) (101 mg, 0.35 mmol) and
acetic acid (12a) (11.1 mL, 0.2 mmol) were treated according to
general procedure A to give the product 13ai (38 mg, 70 %) as a
yellow solid. dH (400 MHz, CDCl3) 8.26–7.16 (9H, m, ArH),
4.99 (2H, s, CH2), 2.31 (3H, s, Me). dC (100 MHz, CDCl3) 173.1,
172.2, 149.4, 141.7, 136.5, 128.9, 128.6, 127.8, 127.1, 123.8,
49.1, 26.0. nmax (CHCl3)/cmꢀ1 3108, 3066, 3030, 2971, 2865,
1686, 1664, 1604, 1522, 1345, 1211.
N-Acetyl-N-benzyl-4-methoxybenzamide (13ag)[15]
N-Benzyl-N-pivaloyl-4-nitrobenzamide (13bi)
N-Benzyl-4-nitrothiobenzamide (11i) (103 mg, 0.4 mmol) and
pivalic acid (12b) (22.5 mL, 0.2 mmol) were treated according to
general procedure A to give the product 13bi (25.2 mg, 50 %) as
a yellow solid. dH (400 MHz, CDCl3) 8.20–7.08 (9H, m, ArH),
4.80 (2H, s, CH2), 1.19 (9H, s, tBu). dC (100 MHz, CDCl3)
186.9, 172.5, 149.5, 140.9, 136.5, 129.2, 128.8, 127.7, 127.1,
123.9, 50.6, 43.3, 28.4. nmax (CHCl3)/cmꢀ1 3316, 3030, 2971,
2927, 1738, 1644, 1600, 1523, 1247.
N-Benzyl-4-methoxythiobenzamide (11g) (70.2 mg, 0.3 mmol)
and acetic acid (12a) (8.2 mL, 0.15 mmol) were treated accord-
ing to general procedure A to give the product 13ag (39.6 mg,
92 %) as a colourless oil. dH (400 MHz, CDCl3) 7.58–6.90 (9H,
m, ArH), 5.00 (2H, s, CH2), 3.85 (3H, s, OMe), 2.11 (3H, s, Me).
dC (100 MHz, CDCl3) 173.9, 173.0, 163.3, 137.4, 131.1, 128.5,
127.9, 127.7, 127.4, 114.1, 55.5, 49.5, 26.1. m/z (ESI) 284
([M þ H]þ, 100 %). HRMS m/z 284.1287; calcd for C17H17NO3
284.1281. nmax (CHCl3)/cmꢀ1 3030, 2971, 2938, 1682, 1655,
1602, 1256, 1217, 1167, 1026, 844, 699.
N-Acetyl-N-benzyl-2,4-dinitrobenzamide (13aj)
N-Benzyl-2,4-dinitrothiobenzamide (11j) (63 mg, 0.2 mmol)
and acetic acid (12a) (6.0 mL, 0.1 mmol) were treated according
to general procedure A to give the product 13aj (32 mg, 41 %)
as a light yellow oil. dH (400 MHz, CDCl3) 9.08–9.06 (1H, m,
ArH), 8.51–8.48 (1H, m, ArH), 7.43–7.24 (6H, m, ArH), 5.14
(2H, s, CH2), 2.26 (3H, s, Me).
N-Benzyl-N-pivaloyl-4-methoxybenzamide (13bg)[16]
N-Benzyl-4-methoxythiobenzamide (11g) (48.5 mg, 0.2 mmol)
and pivalic acid (12b) (11.6 mL, 0.1 mmol) were treated
according to general procedure A to give the product 13bg
(27.4 mg, 84 %) as a white solid. dH (400 MHz, CDCl3) 7.70–
6.90 (9H, m, ArH), 4.83 (2H, s, CH2), 3.68 (3H, s, OMe), 1.21
(9H, s, tBu). dC (100 MHz, CDCl3) 186.7, 174.4, 163.3, 137.4,
131.5, 128.5, 127.6, 127.3, 127.0, 114.1, 55.5, 51.5, 43.3, 28.6.
m/z (ESI) 326 ([M þ H]þ, 100 %). HRMS m/z 326.1747;
General Procedure B
To a solution of imide 13 (0.3 mmol) in 1 : 1 dioxane/H2O
(6 mL) was added LiOHꢁH2O (41 mg, 0.9 mmol) and the

Imide Synthesis and Solvolysis
E
solution was stirred for 16 h at room temperature. The mixture
was partitioned between EtOAc (40 mL) and 1 M HCl (30 mL).
The aqueous phase was extracted with EtOAc (2 ꢂ 40 mL). The
combined organic fractions were washed with brine (50 mL) and
dried (MgSO4). The solvent was evaporated and the residue was
analysed by 1H NMR spectrometry to determine the ratio of the
two amides 10 and 14.
[2] A. Pourvali, J. R. Cochrane, C. A. Hutton, Chem. Commun. 2014, 50,
15963. doi:10.1039/C4CC07601J
[3] R. W. Darbeau, E. H. White, N. Nunez, B. Coit, M. Daigle, J. Org.
Chem. 2000, 65, 1115. doi:10.1021/JO991600N
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2009, 50, 2329. doi:10.1016/J.TETLET.2009.02.205
[6] M. Avalos, R. Babiano, C. J. Duran, J. Jiminez, J. C. Palacios, Tet-
rahedron Lett. 1994, 35, 477. doi:10.1016/0040-4039(94)85085-2
[7] M. Avalos, R. Babiano, P. Cintas, C. J. Dura´n, F. J. Higes, J. L.
Jimenez, I. Lopez, J. C. Palacios, Tetrahedron 1997, 53, 14463.
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B. D. Santarsiero, J. Am. Chem. Soc. 1990, 112, 6383. doi:10.1021/
JA00173A029
General Procedure C
To a solution of imide 13 (0.17 mmol) in methanol (3 mL) was
added NaHCO3 (28.0 mg, 0.34 mmol) and the solution was
stirred for 16 h at room temperature. The mixture was parti-
tioned between EtOAc (30 mL) and 1 M HCl (15 mL). The
aqueous phase was extracted with EtOAc (2 ꢂ 30 mL). The
combined organic fractions were washed with brine (50 mL)
and dried (MgSO4). The solvent was evaporated and the residue
was analysed by 1H NMR spectrometry to determine the ratio of
the two amides 10 and 14.
[10] V. Somayaji, R. S. Brown, J. Org. Chem. 1986, 51, 2676. doi:10.1021/
JO00364A012
[11] S. Yamada, T. Sugaki, K. Matsuzaki, J. Org. Chem. 1996, 61, 5932.
doi:10.1021/JO9522015
Supplementary Material
[12] H. J. Meyer, C. Nolde, I. Thomsen, S.-O. Lawesson, Bull. Soc. Chim.
Belg. 1978, 87, 621. doi:10.1002/BSCB.19780870807
[13] R. H. Taaning, K. B. Lindsay, B. Schiøtt, K. Daasbjerg, T. Skrydstrup,
J. Am. Chem. Soc. 2009, 131, 10253. doi:10.1021/JA903401Y
[14] T. Mukaiyama, J. Ichikawa, M. Asami, Chem. Lett. 1983, 12, 293.
doi:10.1246/CL.1983.293
Experimental procedures for the synthesis of amides 10 and
1
thioamides 11, and H, 13C NMR and IR spectra for imides
13a(a,b,f–j) and 13b(f–i) are available on the Journal’s website.
Acknowledgements
[15] J. Wang, C. Liu, J. Yuan, A. Lei, Chem. Commun. 2014, 50, 4736.
doi:10.1039/C4CC01447B
This work was supported by the Australian Research Council.
[16] R. W. Darbeau, R. E. Gibble, R. S. Pease, D. E. Bridges, L. M. Siso,
D. J. Heurtin, J. Chem. Soc., Perkin Trans. 2 2001, 1084. doi:10.1039/
B102014P
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