Practical Synthesis of N -(Diphenylmethyl)- and N -(1-Adamantyl)amides Directly from Aldehydes via a One-Pot Schmidt and Ritter Reaction Sequence

Article abstract of DOI:10.1055/s-0034-1380754

Nonoxidative and noncoupling reaction conditions have been developed for the synthesis of N-(diphenylmethyl)- and N-(1-adamantyl)amide derivatives directly from aldehydes by employing the concept of a Schmidt and Ritter reaction sequence in a one-pot operation. The reagent mixture consisting of sodium azide and HBF₄·OEt₂ in acetic acid converts the aldehydes into their respective nitrile analogues which in situ undergo the Ritter reaction with diphenylmethanol or 1-adamantanol to afford the corresponding N-(diphenylmethyl)- or N-(1-adamantyl)amide derivatives in very good yields. The method does not require column chromatographic purification for isolation of the products. With its simple reaction procedure and easy product purification technique, this method outshines earlier conventional two-step methods.

Full text of DOI:10.1055/s-0034-1380754

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 2851–2859
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Synthesis
Practical Synthesis of N-(Diphenylmethyl)- and N-(1-Adaman-
tyl)amides Directly from Aldehydes via a One-Pot Schmidt and
Ritter Reaction Sequence
Nabajyoti Hazarikaa
Gakul Baishya*a
Prodeep Phukanb
O
O
Ph
i. NaN3, HBF4•OEt2 (2–3 equiv), AcOH
CHO
or
R
R
N
H
R
N
Ph
ii. benzhydrol or 1-adamantanol, HBF4•OEt2 (2–3 equiv)
iii. NaHCO3 (aq)
H
71–86%
70–76%
a Natural Products Chemistry Division, CSIR-North East Institute
of Science & Technology, Jorhat 785006, Assam, India
b.gakul@gmail.com
b Department of Chemistry, Gauhati University, Guwahati
781014, Assam, India
R = aryl, heteroaryl, alkyl, styryl
17 examples
Received: 04.03.2015
Accepted after revision: 16.04.2015
Published online: 23.06.2015
Among all carbon–heteroatom bonds, the amide bond
bears a remarkable synthetic prospective and great interest
in organic chemistry.2 Traditionally, amides have been pre-
pared by the reaction of amines either with carboxylic acids
in the presence of a coupling reagent or with carboxylic
acid derivatives such as acyl halides, anhydrides and esters
in the presence of a tertiary amine.3 Although amide bonds
are found in many natural products, peptides and peptido-
mimetics, some such functionalities can be used as protect-
ing groups in multiple-step organic syntheses.4 For exam-
ple, NHBoc5 and NHCbz6 have been extensively used as
amine protecting groups. Other than these two protecting
groups, the N-(diphenylmethyl)amide functionality has
also been used as an acid-labile protecting group for am-
ides.7a N-(Diphenylmethyl)amides were achieved by the re-
action of benzhydrol (diphenylmethanol) with the corre-
sponding amides in the presence of an acid promoter (such
as p-TsOH, H2SO4, MsOH and AcOH) under heating condi-
tions.7b These amides have also been prepared via the direct
amidation of benzylic sp3 C–H bonds using the reagent sys-
tem comprised of N-bromosuccinimide with iron(II) chlo-
ride7c,d and in Grignard reactions with tert-butylperoxyam-
ido acetals.7e It is also well established that the Ritter reac-
tion can easily afford this type of amide derivative in a
single-step chemical process.8 Under the Ritter reaction
conditions an appropriate nitrile entity is reacted with a
source of carbocation, such as benzhydrol, 1-adamantanol,
tert-butyl alcohol or tert-butyl acetate, in the presence of a
strong acid promoter to afford the corresponding amide de-
rivatives in very good yields.9,10
DOI: 10.1055/s-0034-1380754; Art ID: ss-2015-z0137-op
Abstract Nonoxidative and noncoupling reaction conditions have
been developed for the synthesis of N-(diphenylmethyl)- and N-(1-ada-
mantyl)amide derivatives directly from aldehydes by employing the
concept of a Schmidt and Ritter reaction sequence in a one-pot opera-
tion. The reagent mixture consisting of sodium azide and HBF4·OEt2 in
acetic acid converts the aldehydes into their respective nitrile ana-
logues which in situ undergo the Ritter reaction with diphenylmethanol
or 1-adamantanol to afford the corresponding N-(diphenylmethyl)- or
N-(1-adamantyl)amide derivatives in very good yields. The method
does not require column chromatographic purification for isolation of
the products. With its simple reaction procedure and easy product pu-
rification technique, this method outshines earlier conventional two-
step methods.
Key words Schmidt reactions, Ritter reactions, N-(diphenylmeth-
yl)amides, N-(1-adamantyl)amides, aldehydes, tetrafluoroboric acid–di-
ethyl ether complex, one-pot reactions
In recent years, one-pot multicomponent reactions
(MCRs) and multicatalysis cascade reactions (MCCs) have
shown their importance in different areas of synthetic or-
ganic chemistry including drug development processes and
combinatorial library syntheses.1 As MCRs can incorporate
a multistep chemical process in a single operation and in a
single flask, this type of method can easily minimize the
costs involved as well as undesired chemical wastes. Thus,
MCRs and MCCs have emerged as a new technology in the
area of synthetic organic chemistry and have become more
attractive than traditional chemical processes. Consequent-
ly, the high demand for environmentally benign and eco-
nomically friendly synthetic chemical processes has been
inspiring researchers to develop different one-pot multi-
component sequential reactions for the design of and in or-
der to obtain desired organic molecules in the most effi-
cient way.
In recent years, numerous publications have drawn at-
tention to the use of tetrafluoroboric acid–diethyl ether
complex (HBF4·OEt2) as an efficient catalyst cum fluorinat-
ing agent as well as an acid promoter in different organic
transformations.11 This reagent has also been established as
a fluorinating agent cum catalyst in the Hosomi–Sakurai–
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O
i. NaN3, HBF4•OEt2 (2 equiv), AcOH
CHO
N
R
H
ii. tert-butyl acetate, HBF4•OEt2 (2 equiv)
R
iii. NaHCO3 (aq)
Scheme 1 Synthesis of N-tert-butylamides from aldehydes via a Schmidt and Ritter reaction sequence14
Prins, Prins cyclization and aza-Prins cyclization reactions
for the generation of different libraries of 4-fluorotetrahy-
dropyran and 4-fluoropiperidine derivatives.12 Very recent-
ly, we have reported that HBF4·OEt2 is a better catalyst than
various Brønsted and Lewis acid catalysts (such as TFA,
TfOH, TMSOTf, I2 and BF3·OEt2) in the Prins arylthiolation
reaction of (–)-isopulegol to afford diverse 4-(arylthio)octa-
hydro-2H-chromene derivatives.13
Recently, we have disclosed an efficient direct method
for the synthesis of N-tert-butylamide derivatives from al-
dehydes via a novel one-pot Schmidt and Ritter reaction se-
quence (Scheme 1).14 In this method, it has been clearly
demonstrated that the Schmidt reaction of aryl aldehydes
with sodium azide and HBF4·OEt2 in acetic acid efficiently
produces the corresponding nitrile derivatives, which in
situ undergo the Ritter reaction with tert-butyl acetate to
afford the respective N-tert-butylamide derivatives.
It can be easily understood from the mechanism of the
Schmidt and Ritter reactions that the initially formed nitrile
will react with the tert-butyl carbocation generated from
tert-butyl acetate to give the nitrilium ion which under
quenching with water forms the amide. The equilibrium
formed between tert-butyl acetate and isobutylene in the
acetic acid medium facilitates the Ritter reaction of the ni-
trile compound with the tert-butyl carbocation to provide
the N-tert-butylamide analogue.9l Therefore, we thought of
performing the same reaction sequence with other carbo-
cation sources such as the trityl cation, diphenylmethyl cat-
ion and adamantyl cation where the formation of such a
type of equilibrium is not possible. However, to our knowl-
edge, there is no report of the direct conversion of alde-
hydes into their corresponding N-(diphenylmethyl)amides
and N-(1-adamantyl)amides via a Schmidt and Ritter reac-
tion sequence. In this paper, we wish to report a one-pot se-
quential Schmidt and Ritter reaction for the synthesis of N-
(diphenylmethyl)- and N-(1-adamantyl)amides directly
from aldehydes using sodium azide and HBF4·OEt2 with
benzhydrol or 1-adamantanol in acetic acid (Scheme 2).
Following the optimal reaction conditions of our earlier
report14 for this sequential reaction, we first attempted the
reaction of p-anisaldehyde (1c, 1.0 mmol) with sodium
azide (1.5 mmol) using 2.0 equivalents of HBF4·OEt2 as a
promoter in acetic acid at room temperature, followed by
the addition of benzhydrol (2, 1.0 mmol) and an additional
2 equivalents of HBF4·OEt2. The reaction mixture was al-
lowed to stir at ambient temperature for a stipulated time.
After the reaction mixture was quenched with saturated
aqueous sodium bicarbonate solution, the product precipi-
tated out from the solution and was isolated by a simple fil-
tration method, then further recrystallized from ethanol to
obtain an 86% yield of the product 3c. Once the reaction
was optimized with p-anisaldehyde (1c), we explored the
general applicability and scope of this protocol with various
aromatic, conjugated and aliphatic aldehydes; the results
are presented in Table 1.
Aromatic aldehydes with electron-donating substitu-
ents underwent the Schmidt and Ritter reactions efficiently
with sodium azide, HBF4·OEt2, benzhydrol (2) and acetic
acid, and provided the corresponding N-(diphenylmeth-
yl)amide derivatives in very good yields (Table 1, entries 3–
7). Again, all products were isolated by a simple filtration
process and further purified by recrystallization from etha-
nol. Among the various aromatic aldehydes bearing elec-
tron-donating substituents, p-anisaldehyde (1c) and piper-
onal (1d) were found to be highly active under the reaction
conditions and yielded the respective products 3c and 3d in
excellent yields (Table 1, entries 3 and 4). Similarly, 3,4-di-
methoxybenzaldehyde (1e) also proved a very effective
O
Ph
CHO
i. NaN3, HBF4•OEt2 (2–3 equiv), AcOH
N
H
Ph
R
R
R
R
ii. benzhydrol, HBF4•OEt2 (2–3 equiv)
iii. NaHCO3 (aq)
O
CHO
i. NaN3, HBF4•OEt2 (2–3 equiv), AcOH
N
H
ii. 1-adamantanol, HBF4•OEt2 (2–3 equiv)
iii. NaHCO3 (aq)
R = electron-donating and electron-withdrawing groups
Scheme 2 Schmidt and Ritter reaction sequence for the synthesis of N-(diphenylmethyl)- and N-(1-adamantyl)amides directly from aldehydes
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starting compound for this one-pot sequential reaction (Ta-
ble 1, entry 5). Unfortunately, under the optimal reaction
conditions, p-hydroxybenzaldehyde (1n) gave a mixture of
products (as monitored by TLC; Table 1, entry 14). p-Tolual-
dehyde (1f) and p-isopropylbenzaldehyde (1g) were also
reacted with sodium azide, HBF4·OEt2 and benzhydrol (2) in
acetic acid at ambient temperature to furnish the corre-
sponding N-(diphenylmethyl)amide derivatives 3f and 3g
in very good yields (Table 1, entries 6 and 7).
After the successful execution of this protocol with aro-
matic aldehydes bearing electron-donating substituents,
we turned our interest to aromatic aldehydes bearing elec-
tron-withdrawing substituents (Table 1, entries 8–12 and
15). We first attempted the reaction of p-chlorobenzalde-
hyde (1h) with sodium azide, HBF4·OEt2 and benzhydrol (2)
in acetic acid at room temperature under the optimal reac-
tion conditions; however, in this case the reaction did not
proceed to completion (as monitored by TLC). Consequent-
ly, the product could not be isolated by a simple filtration
process. Therefore, we turned our attention to the amount
of the acid promoter HBF4·OEt2 used in the reaction mix-
ture. We observed that the addition of 3 equivalents of
HBF4·OEt2 to the reaction mixture in each step of the se-
quence produced the corresponding N-(diphenylmeth-
yl)amide 3h in good yield (Table 1, entry 8). Similarly, p-
bromobenzaldehyde (1i), p-fluorobenzaldehyde (1j) and p-
(trifluoromethyl)benzaldehyde (1k) also underwent the re-
action and their respective N-(diphenylmethyl)amide de-
rivatives 3i, 3j and 3k were obtained in good yields (Table 1,
entries 9–11). However, p-nitrobenzaldehyde (1l) did not
undergo the sequential reaction to afford its amide deriva-
tive (Table 1, entry 12) because the first step of the se-
quence to afford the nitrile analogue did not succeed under
the optimal reaction conditions. This is due to the presence
of the strong electron-withdrawing substituent (NO2) on
the arene ring which decreases the reactivity. Similarly, the
desired reaction was not successful with 2,4-dichlorobenz-
aldehyde (1o) under the standard reaction conditions due
to the presence of two strong electron-withdrawing groups
(Cl), and an unidentified mixture of products was obtained
(Table 1, entry 15).
Table 1 Scope and Generalization of the Schmidt and Ritter Reactions for the Synthesis of N-(Diphenylmethyl)amides
NaN3
benzhydrol (2)
HBF4•OEt2 (2–3 equiv)
O
Ph
HBF4•OEt2 (2–3 equiv)
CHO
R
R
N
Ph
NaHCO3 (aq)
AcOH
H
1a–r
3a–r
R = aryl, heteroaryl, styryl, alkyl
Entry
1
Aldehyde
Producta
Time (h)
Yieldb (%)
O
Ph
CHO
CHO
N
Ph
4
81
H
1a
3a
2
3
4
no reaction
12
–
1b
O
Ph
CHO
N
H
Ph
3
86
84
MeO
1c
MeO
3c
O
Ph
CHO
O
O
N
Ph
3.5
H
O
1d
O
3d
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Table 1 (continued)
Entry
Aldehyde
Producta
Time (h)
Yieldb (%)
O
Ph
MeO
CHO
MeO
N
H
Ph
5
6
3
86
MeO
1e
MeO
3e
O
Ph
CHO
N
Ph
4.5
81
81
H
1f
3f
O
Ph
CHO
N
H
Ph
7
5
1g
3g
O
Ph
CHO
CHO
CHO
N
73c
76c
71c
73c
Ph
8
9
6
6
6
6
H
Cl
Cl
1h
3h
O
Ph
N
H
Ph
Br
1i
Br
3i
O
Ph
N
Ph
10
11
H
F
1j
F
3j
O
Ph
CHO
CHO
N
Ph
H
F3C
1k
F3C
3k
c
12
13
14
no reaction
6
5
–
O2N
1l
O
Ph
CHO
N
Ph
77
–
H
S
S
1m
3m
CHO
mixture of products
12
HO
1n
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Table 1 (continued)
Entry
Aldehyde
Producta
Time (h)
12
Yieldb (%)
Cl
CHO
c
15
16
mixture of products
–
Cl
1o
O
O
Ph
CHO
CHO
5
79
Ph
1p
Ph
N
H
Ph
Ph
3p
Ph
17
18
5
6
80
–
Ph
1q
Ph
N
H
3q
CHO
mixture of products
1r
a Products were characterized by 1H and 13C NMR, IR and mass spectrometric analysis.
b Isolated yield after recrystallization.
c HBF4·OEt2 (3 equiv) was used in each step of the sequence.
We also investigated the scope of our protocol with a
Furthermore, it was proved that this reaction also pro-
heteroaromatic aldehyde under the optimal reaction condi-
tions. Thus, thiophene-2-carbaldehyde (1m) was treated
with sodium azide and HBF4·OEt2 in acetic acid at room
temperature to give the nitrile analogue which was in situ
reacted with benzhydrol (2) at 50 °C to afford the respective
amide derivative 3m in very good yield (Table 1, entry 13).
The product 3m was isolated by a simple filtration process
and purified by recrystallization from ethanol, followed by
a wash with hot hexane. In a similar fashion, the Schmidt
and Ritter reaction sequence was also executed with trans-
cinnamaldehyde (1p); as expected, the corresponding N-
(diphenylmethyl)amide 3p was isolated without column
chromatographic purification in very good yield (Table 1,
entry 16). An unsubstituted aromatic aldehyde, namely
benzaldehyde (1a), also led to its respective product 3a un-
der the standard reaction conditions (Table 1, entry 1). On
the other hand, the sterically hindered anthracene-9-car-
baldehyde (1b) did not yield the corresponding N-(di-
phenylmethyl)amide derivative after a 12-hour reaction
time (Table 1, entry 2). In this case, the Schmidt reaction of
1b with sodium azide and HBF4·OEt2 in acetic acid was not
successful due to steric hindrance of the bulky anthracene
ring at the aldehyde functionality.
ceeds well with an aliphatic aldehyde, namely 3-phenylpro-
pionaldehyde (1q), to furnish the corresponding N-(di-
phenylmethyl)amide derivative 3q in 80% yield. Like the ar-
omatic aldehydes, the product obtained in this case was
also purified by recrystallization (Table 1, entry 17). In con-
trast, the reaction with isobutyraldehyde (1r) produced a
mixture of products (Table 1, entry 18).
In further experiments, we explored the Schmidt and
Ritter reaction sequence with another source of carbocat-
ion, namely trityl alcohol (4), for the one-pot synthesis of
N-tritylamide derivatives 5 directly from aldehydes. Thus,
p-anisaldehyde (1c) was treated with sodium azide,
HBF4·OEt2, trityl alcohol (4) and acetic acid under the opti-
mal reaction conditions, but the reaction did not yield the
corresponding N-tritylamide derivative 5c. Similarly, benz-
aldehyde (1a) and p-chlorobenzaldehyde (1h) did not un-
dergo the sequential reaction to afford the corresponding
amide derivatives 5a and 5h (Scheme 3). An explanation is
that steric hindrance of the trityl carbocation deactivates
the attack of a nitrile molecule to form the nitrilium ion un-
der the Ritter reaction conditions.
O
Ph
Ph
Ph
i. NaN3, HBF4•OEt2 (2 equiv), AcOH
CHO
N
H
ii. trityl alcohol (4), HBF4•OEt2 (2 equiv)
R
R
iii. NaHCO3 (aq)
1a, 1c, 1h
5a, 5c, 5h
not formed
R = H, OMe, Cl
Scheme 3 Exploration of the Schmidt and Ritter reactions with trityl alcohol (4)
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Table 2 Schmidt and Ritter Reactions for the Synthesis of N-(1-Adamantyl)amides
O
CHO
i. NaN3, HBF4•OEt2 (2–3 equiv), AcOH
ii. 1-adamantanol (6), HBF4•OEt2 (2–3 equiv)
iii. NaHCO3 (aq)
R
R
N
H
1
7
Entry
R
Producta
Time (h)
Yieldb (%)
4-MeOC6H4
1c
1
2
3
7c
7f
7i
4
4
4
76
74
70c
4-Tol
1f
4-BrC6H4
1i
4
7p
5
71
Ph
1p
a Products were characterized by 1H and 13C NMR, IR and mass spectrometric analysis.
b Isolated yield after recrystallization.
c HBF4·OEt2 (3 equiv) was used in each step of the sequence.
It has been well documented that N-adamantylamide
derivatives show versatile biological activities such as anti-
arrhythmic15 and tumor necrosis activities.16 These com-
pounds are also known as promising mGluR5 allosteric
modulators for the treatment of CNS disorders.17 Usually, N-
(1-adamantyl)amides are prepared from 1-adamantanol
and the corresponding nitriles through a Ritter reaction.18
In another method, these derivatives have also been syn-
thesized directly from adamantane.19 Our Schmidt and
Ritter reaction sequence has also been successfully execut-
ed for the synthesis of N-(1-adamantyl)amides directly
from aldehydes. For example, p-anisaldehyde (1c), p-tolual-
dehyde (1f), p-bromobenzaldehyde (1i) and trans-cin-
namaldehyde (1p) underwent the sequential reaction pro-
cess with 1-adamantanol (6) to afford the corresponding
amide derivatives in very good yields (Table 2, entries 1–4).
Products 7c, 7f, 7i and 7p were also isolated by simple fil-
tration, and purified further by recrystallization from hex-
ane.
The reaction of p-anisaldehyde (1c) was also performed
with an unactivated alcohol, namely ethanol, under the
standard reaction conditions, but it did not proceed to give
the respective amide analogue 8c (Scheme 4).
The proposed mechanism of the overall process is out-
lined Scheme 5 where the established mechanisms of each
step, the Schmidt20 and Ritter8,9 reactions, of this novel re-
action sequence clearly confirm the formation of N-(di-
phenylmethyl)amides in a one-pot operation.
O
CHO
i. NaN3, HBF4•OEt2 (2 equiv), AcOH
N
H
MeO
ii. EtOH, HBF4•OEt2 (2 equiv)
iii. NaHCO3 (aq)
MeO
1c
8c
not formed
Scheme 4 Exploration of the Schmidt and Ritter reactions of 1c with ethanol
H+
H
HO
H
CHO
CN
– H2O
– N2
– H+
HN3
H+
+
N
N
+
N
N
N
N
H
Ph
CN
O
Ph
+OH2
Ph
+N
Ph
H+
AcOH
OH
+
H2O
N
Ph
H
Ph
Ph
– H2O
Ph
Ph
Ph
Scheme 5 Proposed reaction mechanism of the Schmidt and Ritter reaction sequence
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In summary, we have revealed the utility of a Schmidt
and Ritter reaction sequence for the synthesis of N-(di-
phenylmethyl)- and N-(1-adamantyl)amide derivatives in
very good yields under nonoxidative and noncoupling reac-
tion conditions. A variety of aryl aldehydes with electron-
donating or electron-withdrawing groups react with sodi-
um azide and HBF4·OEt2 in acetic acid to produce the re-
spective nitrile analogues which in situ undergo the Ritter
reaction with diphenylmethanol or 1-adamantanol to af-
ford the corresponding amide derivatives in a single-step
chemical process. This protocol was also found to be effec-
tive with 3-phenylpropionaldehyde and trans-cinnamalde-
hyde. Several features such as short reaction times, opera-
tional simplicity, one-pot reaction and no column chro-
matographic purification of the products make this method
superior to, and more practical than, any other two-step
method previously reported.
Anal. Calcd for C21H17NO3: C, 76.12; H, 5.17; N, 4.23. Found: C, 76.16;
H, 5.21; N, 4.26.
N-Benzhydryl-3,4-dimethoxybenzamide (3e)
Off-white solid; yield: 298 mg (86%); mp 196 °C.
IR (CHCl3): 3294.8, 3060.8, 2935.0, 2837.5, 1628.9 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.48 (s, 1 H), 7.31–7.26 (m, 11 H), 6.87
(d, J = 8.2 Hz, 1 H), 6.63 (br d, J = 6.9 Hz, 1 H), 6.45 (d, J = 7.5 Hz, 1 H),
3.92 (s, 6 H).
13C NMR (125 MHz, CDCl3): δ = 165.98, 152.10, 148.99, 141.41,
128.65, 127.47, 127.42, 126.68, 119.05, 110.80, 110.03, 57.40, 55.96,
55.94.
MS (EI): m/z = 347 [M]+, 348 [M + H]+.
Anal. Calcd for C22H21NO3: C, 76.06; H, 6.09; N, 4.03. Found: C, 76.10;
H, 6.03; N, 4.09.
N-Benzhydryl-4-isopropylbenzamide (3g)
White solid; yield: 266 mg (81%); mp 150 °C.
IR (CHCl3): 3323.1, 3029.2, 2906.9, 1633.3 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.81 (d, J = 8.2 Hz, 2 H), 7.31–7.08 (m,
12 H), 6.70 (br d, J = 6.1 Hz, 1 H), 6.45 (d, J = 7.7 Hz, 1 H), 2.96 (septet,
J = 6.8 Hz, 1 H), 1.29 (d, J = 9.2 Hz, 6 H).
13C NMR (125 MHz, CDCl3): δ = 166.35, 152.90, 141.45, 131.64,
128.86, 128.74, 128.68, 128.62, 128.40, 126.14, 57.27, 34.00, 23.67.
Melting points were measured with a Büchi B-540 melting point ap-
paratus and are uncorrected. IR spectra were recorded on a Shimadzu
FTIR-8400 spectrometer. NMR spectra were recorded on Bruker DPX
300 MHz and AV500 Advance-III 500 MHz FT-NMR spectrometers us-
ing TMS as an internal standard. All commercially available reagents
were used without further purification. All experiments were moni-
tored by thin-layer chromatography using aluminum precoated silica
gel TLC plates (Merck). After elution, plates were visualized under UV
illumination at 254 nm for UV-active materials. Further visualization
was achieved by staining with anisaldehyde charring solution.
MS (EI): m/z = 330 [M + H]+.
Anal. Calcd for C23H23NO: C, 83.85; H, 7.04; N, 4.25. Found: C, 83.91;
H, 7.10; N, 4.20.
N-Benzhydryl-4-(trifluoromethyl)benzamide (3k)
N-(Diphenylmethyl)amides 3 and N-(1-Adamantyl)amides 7 via
the Schmidt and Ritter Reaction Sequence; General Procedure
White solid; yield: 259 mg (73%); mp 196 °C.
IR (CHCl3): 3307.4, 3056.0, 1644.9, 1534.5, 1326.3 cm–1
.
To a solution of an aldehyde (1 mmol, 1 equiv) and NaN3 (1.5 mmol,
1.5 equiv) in AcOH (2 mL) was added HBF4·OEt2 (2–3 mmol, 2–3
equiv), and the reaction mixture was stirred for 1 h. To this reaction
mixture was added benzhydrol (2) or 1-adamantanol (6; 1.0 mmol,
1.0 equiv) and HBF4·OEt2 (2–3 mmol, 2–3 equiv). Then, the reaction
mixture was allowed to stir for an additional 2–4 h. After completion
of the reaction (TLC), sat. aq NaHCO3 solution (20 mL) was added to
the mixture. The solid product which precipitated from the reaction
mixture was filtered and washed thoroughly with distilled water (50
mL). The solid was dried under reduced pressure to give the product
which was further purified by recrystallization from ethanol [N-(di-
phenylmethyl)amides] or hexane [N-(1-adamantyl)amides]. Com-
pounds 3a, 3c, 3f, 3h, 3i and 3j are known in the literature,7 and their
structures have been confirmed by comparison of the corresponding
analytical data. Full spectroscopic data of all new compounds are pro-
vided below.
1H NMR (300 MHz, CDCl3): δ = 7.93 (d, J = 7.9 Hz, 2 H), 7.70 (d, J = 8.0
Hz, 2 H), 7.35–7.25 (m, 10 H), 6.45 (br d, J = 7.6 Hz, 1 H), 6.25 (d, J = 7.9
Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 165.14, 141.90, 137.34, 128.75,
128.59, 127.68, 127.45, 127.35, 125.62, 125.59, 57.59.
MS (EI): m/z = 355 [M]+, 356 [M + H]+.
Anal. Calcd for C21H16F3NO: C, 70.98; H, 4.54; N, 3.94. Found: C, 71.04;
H, 4.60; N, 3.91.
N-Benzhydrylthiophene-2-carboxamide (3m)
Brown solid; yield: 225 mg (77%); mp 161 °C.
IR (CHCl3): 3307.4, 3056.0, 1644.9, 1534.5, 1326.3 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.37 (d, J = 5.0 Hz, 1 H), 7.35 (d, J = 6.5
Hz, 1 H), 7.30–7.20 (m, 10 H), 7.06 (t, J = 5.0 Hz, 1 H), 6.55 (br d, J = 7.6
Hz, 1 H), 6.40 (d, J = 7.6 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 160.86, 141.13, 138.46, 130.16,
128.66, 128.63, 128.62, 128.23, 127.56, 127.54, 127.42, 57.26.
N-Benzhydrylpiperonamide (3d)
White solid; yield: 278 mg (84%); mp 165 °C.
IR (CHCl3): 3351.0, 3030.4, 2924.2, 1628.3 cm–1
.
MS (EI): m/z = 294 [M + H]+.
1H NMR (500 MHz, CDCl3): δ = 7.39–7.24 (m, 12 H), 6.85 (d, J = 12.0
Hz, 1 H), 6.56 (br d, J = 7.0 Hz, 1 H), 6.41 (d, J = 7.5 Hz, 1 H), 6.01 (s, 2
H).
Anal. Calcd for C18H15NOS: C, 73.69; H, 5.15; N, 4.77. Found: C, 73.75;
H, 5.20; N, 4.72.
13C NMR (125 MHz, CDCl3): δ = 165.64, 150.40, 147.93, 141.38,
128.64, 128.33, 127.45, 127.37, 121.50, 107.91, 107.67, 101.62, 57.39.
MS (EI): m/z = 331 [M]+.
N-Benzhydryl-3-phenylacrylamide (3p)
White solid; yield: 247 mg (79%); mp 170 °C.
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IR (CHCl3): 3273.8, 3028.2, 2918.0, 2850.3, 1651.6, 1613.3 cm–1
.
Anal. Calcd for C17H20BrNO: C, 61.09; H, 6.03; N, 4.19. Found: C, 61.15;
H, 6.10; N, 4.15.
1H NMR (500 MHz, CDCl3): δ = 7.68 (d, J = 16 Hz, 1 H), 7.49 (d, J = 5 Hz,
2 H), 7.35–7.22 (m, 13 H), 6.49 (d, J = 16 Hz, 1 H), 6.45 (d, J = 4.5 Hz, 1
H), 6.36 (d, J = 8.0 Hz, 1 H).
N-(1-Adamantyl)-3-phenylacrylamide (7p)
13C NMR (125 MHz, CDCl3): δ = 164.83, 141.76, 141.33, 134.62,
129.68, 128.72, 128.60, 127.74, 127.42, 127.40, 120.14, 57.11.
White solid; yield: 199 mg (71%); mp 143 °C.
IR (CHCl3): 3287.8, 2906.6, 2850.2, 1656.6, 1615.5, 1547.0 cm–1
.
MS (EI): m/z = 313 [M]+, 314 [M + H]+.
1H NMR (500 MHz, CDCl3): δ = 7.56 (d, J = 15.5 Hz, 1 H), 7.51 (d, J = 7.6
Hz, 2 H), 7.39–7.31 (m, 3 H), 6.35 (d, J = 15.5 Hz, 1 H), 5.33 (br s, 1 H),
2.10–2.04 (m, 7 H), 1.73–1.68 (m, 8 H).
Anal. Calcd for C22H19NO: C, 84.31; H, 6.11; N, 4.47. Found: C, 84.35;
H, 6.05; N, 4.50.
13C NMR (125 MHz, CDCl3): δ = 164.77, 140.08, 134.91, 129.31,
128.64, 127.60, 122.02, 52.10, 41.58, 36.25, 29.34.
N-Benzhydryl-3-phenylpropionamide (3q)
White solid; yield: 252 mg (80%); mp 138 °C.
MS (EI): m/z = 281 [M]+, 282 [M + H]+.
IR (CHCl3): 3412.4, 3305.6, 3060.9, 2930.3, 1644.5 cm–1
.
Anal. Calcd for C19H23NO: C, 81.10; H, 8.24; N, 4.98. Found: C, 81.15;
H, 8.30; N, 4.94.
1H NMR (500 MHz, CDCl3): δ = 7.49–7.28 (m, 12 H), 7.18–7.03 (m, 3
H), 6.25 (d, J = 6.7 Hz, 1 H), 5.94 (br s, 1 H), 3.11–2.88 (m, 2 H), 2.61–
2.20 (m, 2 H).
Acknowledgment
13C NMR (125 MHz, CDCl3): δ = 170.93, 141.28, 140.55, 128.61,
128.51, 128.37, 128.30, 127.45, 127.29, 127.15, 127.03, 126.19, 56.75,
38.38, 31.54.
We acknowledge CSIR, New Delhi for financial support. The authors
are grateful to the Director, CSIR-NEIST, Jorhat for his support and
keen interest.
MS (EI): m/z = 315 [M]+, 316 [M + H]+.
Anal. Calcd for C22H21NO: C, 83.78; H, 6.71; N, 4.44. Found: C, 83.84;
H, 6.75; N, 4.50.
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N-(1-Adamantyl)-4-methoxybenzamide (7c)
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White solid; yield: 216 mg (76%); mp 149 °C.
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White solid; yield: 199 mg (74%); mp 151 °C.
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Hz, 2 H), 5.77 (br s, 1 H), 2.38 (s, 3 H), 2.16 (m, 7 H), 1.72 (m, 8 H).
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2851–2859