Synthesis of secondary amides from N-Substituted amidines by tandem oxidative rearrangement and isocyanate elimination

Article abstract of DOI:10.1002/adsc.201400648

In this work an efficient tandem process transforming N-substituted amidines into secondary amides has been described. The process involves N-acylurea formation by reaction of the substrate with bis(acyloxy)(phenyl)-λ³-iodane followed by isocyanate elimination. The periodinane reagents are obtained from the commercially available phenyl-iodine(III) diacetate [PhI(OAc)₂, (PIDA)] by ligand exchange with carboxylic acids. The N-substituted amidine substrates are easily synthesized from readily available nitriles. The method is applicable for secondary amide synthesis, based on both aliphatic and (hetero)aromatic amines, including challenging amides consisting of sterically hindered acids and amines. Moreover, the protocol allows one to combine steric bulk with electron deficiency in the target amides (aniline based). Such compounds are difficult to synthesize efficiently based on classical condensation reactions involving carboxylic acids and amines. Overall, the synthetic protocol transforms a nitrile into a secondary amide in both aliphatic and (hetero)aromatic systems.

Full text of DOI:10.1002/adsc.201400648

UPDATES
DOI: 10.1002/adsc.201400648
Synthesis of Secondary Amides from N-Substituted Amidines by
Tandem Oxidative Rearrangement and Isocyanate Elimination
Pradip Debnath,+a Mattijs Baeten,+a Nicolas Lefꢀvre,a Stijn Van Daele,a
and Bert U. W. Maesa,*
a
Organic Synthesis, Department of Chemistry, University of Antwerp, Groenenborgerlaan 171, B-2020 Antwerp, Belgium
Fax : (+32)-(0)3-265-3233; phone: (+32)-(0)3-265-3205; e-mail: bert.maes@uantwerpen.be
+
Both authors contributed equally.
Received: July 4, 2014; Revised: September 5, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400648.
Abstract: In this work an efficient tandem process
transforming N-substituted amidines into secondary
amides has been described. The process involves N-
acylurea formation by reaction of the substrate with
bis(acyloxy)(phenyl)-l3-iodane followed by isocya-
nate elimination. The periodinane reagents are ob-
tained from the commercially available phenyl-
methods used to construct them mainly rely on con-
densation approaches and still involve reagents with
poor atom economy.[2b] Classically, secondary amides
can be synthesized, starting from the corresponding
amines by reaction with carboxylic acid derivatives
such as anhydrides and acid chlorides or with carbox-
ylic acids with the aid of coupling reagents.[3] For ster-
ically hindered amides these stoichiometric reagents
often just fail. Recently, new synthetic approaches
that do not require activation of the carboxylic acid
with a stoichiometric reagent, based on a Lewis acid
(e.g., boronic acids) or silica as catalyst were devel-
oped.[4,5] Catalyst poisoning as well as substrate scope
are the main challenges remaining in this attractive
approach. It is also possible to make secondary
amides from functionalized aldehydes and primary
amines with catalytic amounts of an N-heterocyclic
carbene.[6] Another method is the acylation of primary
amines with alcohols or aldehydes, such as the ruthe-
nium-catalyzed amide formation from amines and al-
cohols described by Milstein.[5,7] Transition metal-cata-
lyzed transformations of nitriles into secondary
amides using alcohols, alkyl halides or primary
amines and water have also been described.[5,8] Alter-
natively, secondary amides can be obtained starting
from a primary amide via alkylation with alkyl halides
or arylation with aryl halides under transition metal
catalysis.[5,9] Although the latter protocols are very ef-
fective under relatively mild conditions, they start
from a preformed amide as reagent. Other transition
metal-catalyzed approaches based on aryl halides in-
ACHTUNGTRENNUNGiodine(III) diacetate [PhI(OAc)2, (PIDA)] by ligand
exchange with carboxylic acids. The N-substituted
amidine substrates are easily synthesized from read-
ily available nitriles. The method is applicable for
secondary amide synthesis, based on both aliphatic
and (hetero)aromatic amines, including challenging
amides consisting of sterically hindered acids and
amines. Moreover, the protocol allows one to com-
bine steric bulk with electron deficiency in the
target amides (aniline based). Such compounds are
difficult to synthesize efficiently based on classical
condensation reactions involving carboxylic acids
and amines. Overall, the synthetic protocol trans-
forms a nitrile into a secondary amide in both ali-
phatic and (hetero)aromatic systems.
Keywords: amide synthesis; elimination; hyperva-
lent iodine compounds; oxidative rearrangement
Introduction
Amides are important structural motifs in pharma- volve the use of carbon monoxide and amines.[5,10]
ceuticals, agrochemicals and materials.[1] Nevertheless, Hence, there is still a huge interest in the develop-
the development of efficient methods to synthesize ment of new and efficient secondary amide syntheses
2
À
this functional group class remains an important chal- involving the construction of the C(sp ) nitrogen
lenge in synthetic organic chemistry.[2] Although bond. In the 1990s Ramsden and co-workers have de-
amides are the most frequently synthesized functional scribed the phenyliodine(III) diacetate (PIDA)-medi-
groups in the pharmaceutical process industry, the ated oxidative rearrangement of N-substituted ami-
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UPDATES
Pradip Debnath et al.
Scheme 1. Transformation of aliphatic and aromatic nitriles into secondary amides.
dines.[11] They observed that the product of the reac- iodine reagents than PIDA, although not investigated
tion of N-substituted amidines with PIDA is deter- yet, also other amides than secondary acetamides
mined by the nature of the amidine substituents. should be accessible. The required bis(acyloxy)(phen-
C-Alkyl-N-arylamidines cyclize with formation of 1H- yl)-l3-iodanes can be easily obtained by an exchange
benzimidazoles, while C,N-dialkylamidines, C,N-di- reaction of the acetate groups in PIDA with carboxyl-
ACHTUNGTRENNUNG
arylamidines and C-aryl-N-alkylamidines under simi- ic acids.[13] The N-substituted amidine substrates are
lar reaction conditions undergo an aza-Hofmann rear- easily accessible from nitriles via the corresponding
rangement to give N-acetylureas. By elimination of imidate salts (Pinner reaction) or via a direct ap-
isocyanate, secondary acetamides were obtained. proach using activation by Lewis acids.[14] As aliphatic
However, the yields were limited to maximum 50% and aromatic nitriles are readily available commer-
for C-aryl-N-alkylamidines and C,N-diarylamidines cially or through synthesis,[15] such an approach would
due to a competitive reaction of isocyanate with sub- deliver a general way to access secondary amides
strate (N’-carbamoylated N-substituted amidine for- from nitriles[8] and hypervalent iodine reagents
mation) (Scheme 1, A).[12] In the case of C,N-dialkyl- (Scheme 1). The process should also allow one to
ACHTUNGTRENNUNGamidines, a competitive reaction of isourea with obtain challenging amides based on hindered carbox-
acetic acid gives urea as major compound, also signifi- ylic acids or bulky or electron-deficient amines. It is
cantly reducing the yield of the acetamides well known that these cannot be obtained efficiently
(Scheme 1, B). Encouraged by these preliminary re- through classical condensation and to the best of our
sults, and taking into account the interest in alterna- knowledge only one method based on isocyanates and
tive amide syntheses, we wondered whether the Grignard reagents has described such challenging ex-
Ramsden protocol can be transformed into a general amples.[16]
high yielding tandem process allowing the efficient
and direct transformation of N-substituted amidines
(both benzenecarboximidamide and alkancarboximid- Results and Discussion
ACHTUNGTRENNUNGamide) into the corresponding secondary amides with-
out side-product formation (Scheme 1). We found N-Benzylbenzamidine (1a) was selected as model sub-
that by changing the way the experiment is executed strate. When 1a was heated with 2 equiv. PIDA in tol-
this can be achieved. By using other hypervalent uene at 1008C full conversion was obtained in only
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Synthesis of Secondary Amides from N-Substituted Amidines
Scheme 2. Acetanilide synthesis optimization.
10 min and 83% of N-(benzylcarbamoyl)-N-phenyl- (entry 2). On the other hand, Cs2CO3 was not benefi-
ACHTUNGTRENNUNGacetamide (2a) could be isolated (Scheme 2). When cial as an additive as only 42% NMR yield of target
2a was heated in toluene at 808C for 16 h elimination compound was observed (entry 3). Interestingly,
of benzyl isocyanate occurred and 40% of N-acylani- PhNH2 inhibited the reaction (entry 4). PIDA pre-
line (3a) was isolated, while 58% of the starting mate- sumably reacts with PhNH2 before it can react with
rial 2a could be recovered (Scheme 2). When the the amidine. Oxidations of aromatic amines with
elimination reaction was performed at 1008C, full PIDA are known in the literature.[17] Addition of
conversion was achieved in an overnight reaction NEt3 (entry 5) gave a similar result as observed with
(16 h) with a yield of 83% of 3a. To investigate if the Cs2CO3 (see the Supporting Information for details).
amidine 1a could be transformed into the acetanilide
Subsequently, the scope of the method was studied.
3a in a tandem process, reaction from 1a was done First the compatibility with substituents in the phenyl
overnight (16 h) at 1008C. Interestingly full conver- ring of the N-benzylbenzamidine was investigated
sion of substrate 1a and intermediate 2a to acetanilide (Table 2). Both electron-donating (entries 2 to 8) and
3a was observed and the anilide was isolated in 78% electron-withdrawing (entries 9 to 18) substituents are
yield. Use of different amounts of PIDA at 1008C in-
dicated that 1.2 equivalents of PIDA were sufficient
(Scheme 2).
Table 2. Substituent scope in the aryl ring of the N-benzyl-
benzamidine (1).
Next, we turned our attention to the influence of
base and acid additives on the tandem reaction
(Table 1). When no additive was added, the NMR
yield of the reaction after 6 h was 83% (74% isolated
yield) (entry 1). When acetic acid was added, a similar
yield and conversion was achieved in the same time
Entry
Substrate
R
Product
Yield [%][a]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
H
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
83[b]
80
84
94
78
85
66
70
68
66
72
70
72
68
68
71
70
78
Table 1. Effect of additives on the tandem oxidative rear-
rangement and isocyanate elimination of 1a.
p-OMe
m-OMe
p-OEt
p-SMe
p-Me
m-Me
o-Me
p-I
p-Br
m-Br
o-Br
p-Cl
o-Cl
9
10
11
12
13
14
15
16
17
18
Entry
Additive
NMR yield [%][a]
Conversion [%][c]
1
2
3
4
5
None
83[b]
84
42
3
88
86
98
8
AcOH
Cs2CO3
PhNH2
Et3N
p-F
45
100
p-CF3
m-CF3
p-CO2Et
[a]
Reaction conditions: 0.5 mmol substrate, 1.2 equiv. PIDA,
1.0 equiv. additive, 1 mL toluene, 1008C, 6 h, argon at-
mosphere. 1,3,5-Trimethoxybenzene was used as an inter-
nal standard.
Isolated yield was 74%.
Based on the consumption of 1a.
[a]
Reaction conditions: 0.5 mmol substrate, 1.2 equiv. PIDA,
1 mL toluene, 1008C, 15 h, argon atmosphere.
89% of the theoretically formed PhI (calculated for
1 equiv. PIDA) was recovered.
[b]
[c]
[b]
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Table 3. Effect of the N-alkyl group on the tandem oxidative
rearrangement and isocyanate elimination.
To confirm that the tert-butyl group on nitrogen is
also compatible with aryl ring substitution in the ben-
zamidine, as was the case for an N-benzyl (Table 2),
several functional groups were rescreened (Table 4).
Interestingly, at least similar (entries 1, 2, 7) but often
higher (entries 3–6) yields were achieved in a shorter
reaction time at a lower temperature.
With 7a other solvents were tested to perform the
tandem reaction (Table 5). The reaction gave similar
results when 2-methyltetrahydrofuran and n-butyl
acetate (entries 2 and 3) were used, which is interest-
ing as these solvents are considered to be environ-
mentally benign.[20] The reaction also proceeded in
DMSO, with a slight drop in yield to 64% (entry 4).
However, the reaction did not work well in ethanol,
with a yield of only 31% and some remaining sub-
strate (entry 5).
Entry
Substrate
R
T [8C]
t [h]
Yield [%][a]
1
2
3
4
5
6
7
8
1f
4a
5a
5a
5a
6a
6a
7a
7a
7a
7a
7a
Bn
hexyl
Cy
Cy
Cy
i-Pr
i-Pr
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
100
100
100
100
80
100
100
100
100
80
15
15
15
5
5
15
5
15
5
5
5
5
85
80
90
83
66[b]
86
83
89
88
9
When a C,N-diarylamidine was used, as exemplified
by N-(4-chlorophenyl)benzamidine (8a), a mixture of
two acetanilides was obtained and no formation of 2-
10
11
12
89
60
40
28[c,d]
11[c,e]
[a]
Reaction conditions: 0.5 mmol substrate, 1.2 equiv. PIDA,
1 mL toluene, T, t, argon atmosphere.
20% of N-(cyclohexylcarbamoyl)-N-(4-methylphenyl)-
Table 4. Substituent scope in the aryl ring of the N-tert-bu-
tylbenzamidine 7.
[b]
ACHTUNGTRENNUNGacetamide remaining.
[c]
[d]
NMR yield.
59% of N-(tert-butylcarbamoyl)-N-(4-methylphenyl)acet-
ACHTUNGTRENNUNGamide remaining.
[e]
79% of N-(tert-butylcarbamoyl)-N-(4-methylphenyl)acet-
amide remaining.
ACHTUNGTRENNUNG
Entry
Substrate
R
Product
Yield [%][a]
1
2
3
4
5
6
7
7b
7a
7c
7d
7e
7f
7g
p-SMe
p-Me
m-Me
o-Br
o-Cl
p-F
3e
3f
3g
3l
3n
3o
3r
72
89
86
89
87
89
81
well tolerated and this in ortho, meta and para posi-
tions. Even oxidation-sensitive functional groups such
as a thiomethyl group (entry 5) were compatible with
the reaction conditions.
Subsequently, the effect of substitution on the ami-
dine nitrogen was investigated using para-toluamidine
as template molecule (Table 3). Primary (entries 1
and 2), secondary (entries 3–7) as well as tertiary
alkyl groups (entry 8–10) all gave excellent yields.
The N-tert-butyl-para-toluamidine (7a) reacted signifi-
cantly faster than the corresponding amidine with an
N-benzyl substituent as the former already reached
full conversion after 5 h (entry 9). Therefore, it was
possible to additionally lower the reaction tempera-
ture to 808C for the tandem protocol (entry 10).
Lower reaction temperatures did not give full conver-
sion of the N-acetylurea (entries 11 and 12). The N-
cyclohexyl-para-toluamidine (5a) also reaches full
conversion in 5 h. However at 808C, still 20% of N-
(cyclohexylcarbamoyl)-N-(4-methylphenylacetamide
was still remaining. As for amide synthesis the amine
selected to synthesize the amidine (by reaction with
nitrile) will be finally eliminated as an isocyanate, it is
not built in the amide reaction product and can there-
fore be freely selected. Based on the higher reactivity
of a tert-butyl group it was chosen for further studies.
p-CO2Et
[a]
Reaction conditions: 0.5 mmol substrate, 1.2 equiv. PIDA,
1 mL toluene, 808C, 5 h, argon atmosphere.
Table 5. Solvent compatibility on the tandem oxidative rear-
rangement and isocyanate elimination of 7a.
Entry
Solvent
Yield [%][a]
1
2
3
4
5
toluene
Me-THF
n-BuOAc
DMSO
EtOH
89
89
78
64
31
[a]
Reaction conditions: 0.5 mmol substrate, 1.2 equiv. PIDA,
1 mL solvent, 808C, 5 h, argon atmosphere.
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Synthesis of Secondary Amides from N-Substituted Amidines
Table 6. Tandem oxidative rearrangement and isocyanate
elimination of N-benzyl- 9 and N-tert-butyl-heteroarenecarb-
oximidamides 10.
AHCTUNGTRENNUNG
Scheme 3. Reaction of N-(4-chlorophenyl)benzamidine (8a)
and N-phenylbenzamidine (8b) with PIDA.
phenyl-5-chloro-1H-benzimidazole
was
observed
(Scheme 3). Only when the C,N-diarylamidine (8b) is
symmetrical, one reaction product can be obtained
(3a). In 2012, Zhu reported selective 2-phenyl-5-
chloro-1H-benzimidazole formation from 8a by PIDA
promotion.[18] Tandem oxidative rearrangement and
2
À
isocyanate elimination versus direct C(sp ) H amida-
tion therefore seems to depend on the solvent select-
ed. As 2,2,2-trifluoroethanol (TFE) promotes radical
reactions, it explains the solvent dependent selectivity.
For C,N-diarylamidines Ramsden observed formation
of acetanilide and carbamoylated substrate as side
product. We did not observe the latter product under
our reaction conditions.
Up to this point, only N-substituted benzamidines
were used as substrates for the tandem protocol.
Therefore both N-benzyl- and N-tert-butyl-heteroar-
ene analogues of benzamidines were tested (Table 6).
Both pyridine- (9a, 10a, 9b) (entries 1–3) and thio-
phene-carboximidamides (9c, 10b, 9d, 10c) (entries 4–
7) were screened and gave high yields of the target
compounds. For furans (9e, 10d) moderate yields
were obtained (entries 8 and 9). As aminofurans and
aminothiophenes are unstable, a synthetic approach
to obtain them in a protected form is interesting.[21]
Moreover, these electron-rich systems are also chal-
lenging as they could potentially react with the oxi-
dant in a competitive reaction.
Next, the use of other hypervalent iodine com-
pounds than PIDA was tested as this would deliver
other amides than those based on acetic acid and
therefore broaden the scope of the methodology
(Table 7). These hypervalent iodine compounds were
easily prepared by an exchange reaction on PIDA
with the respective carboxylic acid.[13,22] Subsequently,
[a]
Reaction conditions: 0.5 mmol substrate, 1.2 equiv. PIDA,
1 mL toluene, T, t, argon atmosphere.
they were tested in a reaction with 7a as model sub- (12c) synthesis from 7a and bis(benzoyloxy)(phenyl)-
strate (Table 7). The reaction with bis[(2,2-dimethyl- l3-iodane (entries 4 and 5). Interestingly, sterically
propanoyl)oxy]-(phenyl)-l3-iodane gave 93% of N- hindered carboxylic acids such as 2,4,6-trimethylben-
pivaloyl-para-toluidine (12a) (entry 2). Similarly, an zoic acid can also be used (entries 6 and 7). When
isobutyroyl could be smoothly introduced (entry 3). bis(2,2,2-trifluoroacetoxy)(phenyl)-l3-iodane (PIFA)
Besides alkanecarboxylic acids, benzoic acids also can (entry 8) and bis(2,2,2-trichloroacetoxy)(phenyl)-l3-
be used as exemplified by N-benzoyl-para-toluidine iodane (entry 9) were used, the trihaloacetanilides
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UPDATES
Pradip Debnath et al.
Table 7. Hypervalent iodine reagent scope.
15 h, 82% of N-benzylacetamide (15a) could be isolat-
ed (entry 1). With N-cyclohexylcyclohexane-carboxi-
midamide (13b) as a starting material under the same
reaction conditions, 92% of N-cyclohexylacetamide
(15b) was obtained (entry 2). When the sterically hin-
dered
N-tert-butyl-2,2-dimethylpropanimidamide
(13c) was tested under the reaction conditions for N-
tert-butylbenzamidines (808C, 5 h), oxidative rear-
rangement into N-acyl-N,N’-di-tert-butylurea (14c) oc-
curred by reaction with PIDA but no subsequent
elimination occured (entry 3). Applying the reaction
conditions optimized for N-benzylbenzamidines
(1008C, 15 h) already gave 13% of the desired N-acyl-
2,2-dimethylpropanamide (15c), but still 59% of 14c
remained (entry 4). Increasing the reaction tempera-
ture further to 1308C allowed one to completely and
efficiently convert N-acetyl-N,N’-di-tert-butylurea into
the target compound 15c (entry 6). Attempts to use
additives to speed up the tert-butyl isocyanate elimi-
nation on 14c were unsuccessful. At 08C, alcoholates
like LiOBn and NaOMe led to formation of the 1,3-
di-tert-butylurea.[23] Lewis acids either led to decom-
position (AlCl3, FeCl3, ZnBr2) or formation of acet-
amide (GaCl3, CuBr2). Only Zr(acac)4 gave 67% of
Entry
Oxidant
Product
Yield [%][a]
1
2
3
4
5
6
7
8
9
PhI(OAc)2
PhI(OPiv)2
PhI[OCOCH(CH3)2]2
PhI(OBz)2
PhI(OBz)2
PhI(OCOMes)2
PhI(OCOMes)2
PhI(OCOCF3)2
PhI(OCOCl3)2
3f
89
93
12a
12b
12c
12c
12d
12d
12e
12f
57
61[b]
73[c]
45
46[c]
0
0
[a]
Reaction conditions: 0.5 mmol substrate, 1.2 equiv. hyper-
valent iodine compound, 1 mL toluene, 808C, 5 h, argon
atmosphere.
16% of N-(tert-butylcarbamoyl)-N-(4-methylphenyl)ben-
zamide remained.
[b]
[c]
The reaction was carried out at 1008C during 15 h.
were not formed. Instead, the trihaloacylated N-tert- the desired compound, but also 32% of 1,3-di-tert-bu-
butyl-para-toluamidines could be detected by LC-MS tylurea (see the Supporting Information for details).
analysis of the reaction mixture, together with re- Brønsted acids either also led to decomposition (ben-
maining substrate. Apparently, when the carbonyl of zenesulfonic acid) or left the N-acylurea 14c unreact-
the hypervalent iodine species is too electrophilic, the ed.
amidine will perform a nucleophilic attack on the car-
bonyl group, instead of a nucleophilic attack on the bination with other periodinanes (Table 8). With
iodine atom.
bis[(2,2-dimethylpropanoyl)oxy](phenyl)-l3-iodane as
The sterically hindered 13c was also tested in com-
Besides benzamidines, the suitability of C,N-dialky- oxidant 2,2-dimethylpropanoyl-2,2-dimethylpropana-
lamidines as substrates was also investigated mide (15d) was obtained in a good yield (entries 8
(Table 8). When N-benzyl-2-phenylacetimidamide and 9). Also, the reaction with bis(benzoyloxy)(phen-
(13a) was used as a substrate in a reaction with yl)-l3-iodane gave the target amide 15e but in a mod-
1.2 equivalents of PIDA in toluene at 1008C during erate yield (entry 10). For C,N-dialkylamidines,
Table 8. Tandem oxidative rearrangement and isocyanate elimination of C,N-dialkylamidines 13.
Entry
Substrate
R1
Oxidant
R2
T [8C]
t [h]
N-Acylurea
Yield [%]
Product
Yield [%][a]
1
2
3
4
5
6
7
8
9
10
13a
13b
13c
13c
13c
13c
13c
13c
13c
13c
Bn
Cy
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OPiv)2
PhI(OPiv)2
PhI(OBz)2
Me
Me
Me
Me
Me
Me
Me
t-Bu
t-Bu
Ph
100
100
80
100
120
130
140
140
140
140
15
15
5
15
6
6
6
6
2.5
2.5
14a
14b
14c
14c
14c
14c
14c
14d
14d
14e
0
0
62
59
62
0
0
0
0
0
15a
15b
15c
15c
15c
15c
15c
15d
15d
15e
82
92
0
13
9
77
72
84
86
48
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
[a]
Reaction conditions: 0.5 mmol substrate, 1.2 equiv PIDA, 1 mL toluene, T, t, argon atmosphere.
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Synthesis of Secondary Amides from N-Substituted Amidines
thylpropanimidamide (16) with PIDA at 808C during
5 h yielded 61% of 15a together with 10% of 15c
(Scheme 4). Interestingly, with N-tert-butyl-2-phenyle-
thanimidamide (17), in which both alkyl groups are
switched, the same products were obtained in similar
yields. Although the selection of the sterically hinderd
tert-butylamine to synthesize C,N-dialkylamidine
from aliphatic nitriles will allow one to achieve the N-
acylalkanamine based on the C-subsituent of the ami-
dine as the major reaction product, C,N-dialkylami-
dines featuring the same alkyl group will allow one to
generate only one N-acylalkanamine and are there-
fore preferred (Table 8).
Scheme 4. Reaction of isomeric C,N-dialkylamidines 16 and
17 featuring two different alkyl groups.
With a C-alkyl-N-arylamidine as substrate only 1H-
Ramsden observed formation of ureas. Our protocol benzimidazole was formed as was observed by Rams-
prevents formation of this side product and conse- den. Reaction of 2,2-dimethyl-N-phenylpropanimida-
quently gives high yields of secondary amides. This mide with PIDA under the optimal reaction condi-
can be demonstrated with 13b, which is one of the tions gave 92% of 2-tert-butyl-1H-benzimidazole. This
amidines that was also tested by Ramsden. Under yield is similar to the one obtained under the reaction
their conditions, N-cyclohexylacetamide (15b) (32%), conditions of Zhu (Scheme 5).[18]
N,N’-dicyclohexylurea (28%) and N-acetyl-N-N’-dicy-
clohexylurea (21%) were formed, while we obtained shown in Scheme 6.[11b] The substrate I reacts with hy-
92% of 15b. pervalent iodine reagent via its unsubstituted nitro-
A possible mechanism for this transformation is
When C,N-dialkylamidines with two different alkyl gen. Subsequently, this N-activated compound II elim-
groups were selected, mixtures of N-acetylalkana- inates carboxylic acid resulting in an ylide III which
mines were formed. Reaction of N-benzyl-2,2-dime- rearranges to a carbodiimide IV with concomitant for-
mation of iodobenzene. Protonation of the carbodii-
mide by carboxylic acid, followed by nucleophilic
attack of the carboxylate on the carbodiimidium leads
to the formation of an isourea V which subsequently
undergoes spontaneous O- to N-acyl migration, there-
by yielding an N-acylurea VI. Subsequently, elimina-
tion of isocyanate VIII from VI occurred yielding sec-
ondary amide VII.[11b] The basicity of the nitrogen
atoms of the carbodiimide IV determines the selectiv-
ity of the reaction. In case of C-aryl-N-alkylamidines,
an N-aryl-N’-alkylcarbodiimide is formed and proto-
nation will always occur on the more basic alkylimine
moiety, thereby regioselectively giving access to ani-
lides. In the case of C,N-diarylamidines and C,N-dia-
lkylamidines carbodiimides with respectively two aryl
or two alkyl groups on nitrogen are formed. As the
Scheme 5. Synthesis of 1H-benzimidazole 19 from C-alkyl-
N-arylamidine 18.
Scheme 6. Proposed reaction mechanism for the tandem oxidative rearrangement and isocyanate (VIII) elimination of N-
substituted amidines (I).[11b]
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Pradip Debnath et al.
Scheme 7. Conversion of 7a and 2b as a function of time.
basicity of both nitrogen atoms becomes very similar
mixtures of amides are expected. This was observed
for N-(4-chlorophenyl)benzamidine (8a) featuring
two different aryl groups (Scheme 3). Also, steric fac-
tors play a role in such cases as acyl migration will
preferentially occur to the less sterically hindered ni-
trogen. This is supported by the reactions starting
from isomeric C,N-dialkylamidines 16 and 17 deliver-
ing the same reaction mixture irrespective of the sub-
strate (Scheme 4). A kinetic analysis as function of
time of the tandem reaction starting from 7a revealed
that the starting material is very quickly converted to
N-acylurea intermediate 2b (around 2 min) while iso-
cyanate elimination is slower (Scheme 7). The obser-
vation that tertiary alkyl substituents give a faster re-
action than secondary and primary alkyl substituents
in N-alkylamidines therefore seems to be linked to an
easier elimination of tertiary isocyanates from N-acy-
lurea (VI) (Table 3). For 13c, the same kinetic analy-
sis was done (Scheme 8). In this case the starting ma-
terial is consumed more slowly. Migration of an alkyl
group on carbon seems to be slower than an aryl
Scheme 8. Conversion of 13c as a function of time.
group. This rationalizes why 8a and 8b undergo rear- midium species are known in the literature and have
rangement and 18 only yields benzimidazole. To fur- been obtained via alkylation of the corresponding car-
ther support this mechanism, an N,N-disubstituted bodiimides.[24]
amidine was used as substrate. After all, the reaction
As no nucleophile is added to react with the isocya-
should stop after the rearrangement step as the nate formed in the elimination step, we wondered
second substituent prevents elimination of isocyanate. about its final fate in our protocol. In the transforma-
This is demonstrated by the reaction of N-benzyl-N- tion of N-substituted amidine into N-acylurea, two
methylbenzamidine (20) with PIDA at 1008C where equivalents of carboxylic acid are formed. One of
N-(N’-benzyl-N’-methylcarbamoyl)-N-phenylaceta-
these is used to react with the carbodiimide inter-
mide (21) is formed in 87% yield. This product was mediate. However, the other one is not consumed in
stable towards further heating. In this case the rear- this process. When elimination of isocyanate occurs
rangement goes via an N-methyl-N-benzylcarbodiimi- the carboxylic acid can react with isocyanate, forming
dium intermediate (Scheme 9). N,N-Dialkylcarbodii- a mixed anhydride of a carboxylic acid and a carbamic
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Synthesis of Secondary Amides from N-Substituted Amidines
Scheme 9. Reaction of N,N-disubstituted amidine 20 with PIDA.
Scheme 10. Detection of benzyl isocyanate with online IR in the reactions starting from 1a and 2a.
acid IX (Scheme 12). This product is not stable and N-acetylurea 2a as substrate benzyl isocyanate
will lose carbon dioxide directly or via reaction with (2266 cmÀ1) was clearly formed (reaction B). When
carboxylic acid. Such reactions of isocyanates with performing the same reaction in the presence of
carboxylic acid are known in the literature.[11b,25] This 1 equivalent of acetic acid, no isocyanate could be de-
can either lead to formation of X or towards forma- tected (reaction C). This indicates that the formed
tion of an amine, which can react with isocyanate isocyanate rapidly reacts with acetic acid, so that it
VIII forming urea XI. Analysis of the reaction mix- cannot be detected by IR (low concentration). To
ture of 7a with PIDA (Table 4, entry 2) with LC-MS prove this, in the reaction starting from 2a acetic acid
showed both formation of 1,3-di-tert-butylurea (XI) was added after 15 h (reaction B). As expected, the
and N-tert-butylacetamide (X).
isocyanate is consumed upon addition of the acid. A
To further support the reaction mechanism, we reference reaction of benzyl isocyanate with acetic
tried to detect the isocyanate VIII with online IR acid confirmed the reaction between both compounds
monitoring. Starting from our amidine substrate 1a, (Scheme 11, reaction D).
we were not able to detect benzyl isocyanate
As mentioned previously, when the procedure of
(Scheme 10, reaction A). However, with intermediate Ramsden was used for the synthesis of secondary
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Scheme 11. Reaction of benzylisocyanate with acetic acid.
amides, low yields are obtained due to the formation concentration) therefore suppresses the reaction of
of undesired side products (Scheme 1, A and B). isourea with acetic acid (Scheme 12).
However, with our newly developed reaction protocol
With all this information in hand, we investigated
no side products were observed in these cases whether this new method can be used for the synthe-
(Scheme 1), with higher yields of the desired secon- sis of sterically hindered or electron-deficient secon-
dary amide as a consequence. The different outcome dary amides (Table 9). These are notorious for their
between our protocol and the Ramsden procedure is difficult synthesis.[2a] Recently, the synthesis of such
therefore due to the way in which the reaction is per- amides was described starting from Grignard reagents
formed. In the case of C,N-diarylamidines and C-aryl- and isocyanates.[16] To synthesize these amides using
N-alkylamidines, carbamoylated substrate was formed our method, we first made the N-tert-butylamidines
under the Ramsden conditions (Scheme 1, A). The by reaction of the corresponding nitriles with tert-bu-
difference can be rationalized by the slow addition of tylamine (see the Supporting Information). Subse-
substrate to a refluxing solution of PIDA in toluene
versus mixing of substrate and reagent at room tem-
perature followed by heating. In the former proce-
dure N-acetylurea is gradually formed allowing it to
eliminate isocyanate which in a competitive reaction
can react with the slowly added substrate. As the rear-
rangement is very fast, immediate mixing prevents
isocyanate elimination when substrate is still present
and therefore no side product formation occurs
(Scheme 7). For C,N-dialkylamidines, undesired urea
formation was observed by Ramsden (Scheme 1, B).
Here the pH presumably plays a crucial role in the
different outcome observed under our reaction condi-
tions. After all, a low versus high concentration of
amidine will generate a different pH when acetic acid
is formed by oxidative rearrangement. The buffering
role of substrate under our reaction conditions (high (VIII).
Scheme 12. Possible decomposition pathways for isocyanate
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tion.[26] When N-tert-butyl-2,6-dichlorobenzamidine
(22b) was used as substrate, 46% of the correspond-
ing amide was formed (entry 2). The same substrates
were also reacted with another sterically hindered pe-
riodane, namely bis[(2,2-dimethylpropanoyl)oxy]-
Table 9. Synthesis of sterically hindered and electron-defi-
cient secondary amides applying the tandem protocol.
AHCTUNGTRENNUNG
(phenyl)-l3-iodane, providing even higher yields than
obtained with bis[(mesitylcarbonyl)oxy](phenyl)-l3-
iodane (entries 3 and 4).
To demonstrate the applicability of the protocol,
we subsequently synthesized Boscalidꢂ in an alterna-
tive manner (Scheme 13). Chemically seen, the amide
is an interesting case as it involves a heteroaromatic
carboxylic acid. Boscalid is an important fungicide
with an annual production of more than 1000 tons.[27]
The required substrate was made in two steps with
60% overall yield.[28] This amidine smoothly under-
goes oxidative rearrangement by reaction with 26 and
by subsequent elimination Boscalidꢂ (27) was ob-
tained in 79% yield after crystallization of the crude
reaction product from methanol. We only used
1.0 equivalent of the hypervalent iodine compound 26
which demonstrates that it is not always necessary to
use 1.2 equivalents. By washing the crude reaction
product several times with heptane, we were able to
separate the iodobenzene formed during the reaction,
upon reduction of the bis(acyloxy)(phenyl)-l3-iodane.
Crude iodobenzene could be reused by oxidation into
PIDA with hydrogen peroxide and acetic acid.[20b] In
[a]
Reaction conditions: 0.5 mmol substrate, 1.2 equiv.
PhI(OCOR2)2, 1 mL toluene, 808C, 5 h, argon atmos-
phere.
quently, these amidines were allowed to react with this way we were able to recover 62% of the original-
bis[(mesitylcarbonyl)oxy](phenyl)-l3-iodane. When N- ly used amount of PIDA. The hypervalent iodine 26
tert-butylbiphenyl-2-carboximidamide (22a) was used could be easily synthesized in high yield from PIDA
as a substrate, 74% of the corresponding amide could and 2-chloronicotinic acid. Interestingly, nicotinic
be isolated (entry 1). N-Biphenyl-2-ylamides are inter- acid-based periodinanes are to the best of our knowl-
esting molecules because they can be used as sub- edge not yet described in literature.
À
strate for the synthesis of carbazoles via C H activa-
Scheme 13. Synthesis of Boscalidꢂ based on our tandem protocol.
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nies in kind contribution. The authors thank Philippe
Franck, Heidi Seykens and Norbert Hancke for technical as-
sistance and the company Bruker for the use of a Matrix MF
spectrometer.
For the substrate on which our optimization was
performed (1a) separation of iodobenzene was also
tested and 89% of the theoretically formed iodoben-
zene could be recovered (Table 1, entry 1). In this
case iodobenzene could be easily separated during
the automated column chromatography purification
on silica gel. It comes off as the first chromatographic
peak when eluting with 100% heptane.
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In conclusion, an efficient tandem oxidative rear-
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dines was developed which allows for the synthesis of
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General Procedure for the Tandem Oxidative
Rearrangement Isocyanate Elimination of N-
Substituted Amidines
An oven-dried microwave vial (10 mL) equipped with a mag-
netic stirring bar was charged with the N-substituted ami-
dine (0.5 mmol) and PhI(OCOR)2 (0.6 mmol). The vessel
was flushed with argon for 1 min and then sealed with
a crimp cap with septum. 1 mL of dry toluene was added via
a syringe to the vessel. The reaction mixture was heated at
1008C and stirred for 15 h for N-benzyl-substituted amidines
and at 808C for 5 h for N-tert-butyl-substituted amidines,
unless mentioned otherwise. After completion of the reac-
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room temperature and toluene was evaporated under re-
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Acknowledgements
This work was supported by the Research Foundation Flan-
ders (FWO-Flanders), the Agency for Innovation by Science
and Technology (IWT-Flanders), the University of Antwerp
(BOF) and the Hercules Foundation. The research leading to
these results has also received funding from the Innovative
Medicines Initiative (www.imi.euopa.eu) Joint Undertaking
under grant agreement no. 115360, resources of which are
composed of financial contribution from the European
Unionꢀs Seventh Framework Programme and EFPIA compa-
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14 Synthesis of Secondary Amides from N-Substituted
Amidines by Tandem Oxidative Rearrangement and
Isocyanate Elimination
Adv. Synth. Catal. 2014, 356, 1 – 14
Pradip Debnath, Mattijs Baeten, Nicolas Lefꢀvre,
Stijn Van Daele, Bert U. W. Maes*
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