Synthesis of N-(adamantan-1-yl)amides by reaction of carboxylic acid amides with 1-bromo(chloro)adamantane catalyzed by manganese compounds

Article abstract of DOI:10.1134/S107042801504003X

Abstract N-(Adamantan-1-yl)amides were synthesized in 70-90% yield by reaction of 1-bromoadamantane with carboxylic acid amides in the presence of manganese salts and complexes.

Full text of DOI:10.1134/S107042801504003X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2015, Vol. 51, No. 4, pp. 476–479. © Pleiades Publishing, Ltd., 2015.
Original Russian Text © R.I. Khusnutdinov, N.A. Shchadneva, L.F. Khisamova, 2015, published in Zhurnal Organicheskoi Khimii, 2015, Vol. 51, No. 4,
pp. 495–497.
Synthesis of N-(Adamantan-1-yl)amides by Reaction
of Carboxylic Acid Amides with 1-Bromo(chloro)adamantane
Catalyzed by Manganese Compounds
R. I. Khusnutdinov, N. A. Shchadneva, and L. F. Khisamova
Institute of Petrochemistry and Catalysis, Russian Academy of Sciences,
pr. Oktyabrya 141, Ufa, 450075 Bashkortostan, Russia
e-mail: ink@anrb.ru
Received January 17, 2015
Abstract—N-(Adamantan-1-yl)amides were synthesized in 70–90% yield by reaction of 1-bromoadamantane
with carboxylic acid amides in the presence of manganese salts and complexes.
DOI: 10.1134/S107042801504003X
Adamantane and its derivatives are widely used in
the synthesis of valuable chemical substances needed
in various industries. An important field of application
of adamantane derivatives is the synthesis of antiviral
and neurotropic drugs. N-(Adamantan-1-yl) carboxylic
acid amides are closest precursors of biologically
active adamantanamines which exhibit antimicrobial
activity and are used for the treatment and prophy-
lactics of severe diseases such as influenza, herpes,
pneumonia, etc. [1–3].
ric amount of silver sulfate Ag2SO4 [11]. In both cases,
the yield of adamantylamides did not exceed 45%.
Taking into account practical importance of
N-(adamantan-1-yl)amides, we have developed a new
efficient procedure for their preparation using metal-
complex catalysts. The reaction of 1-bromoadaman-
tane (1) with formamide in the presence of manganese
catalysts [MnCl2, MnBr2, Mn(OAc)2, Mn(acac)3,
Mn2(CO)10] was carried out by heating for 2–3 h at
120–130°C, the molar ratio 1-bromoadamantane–
formamide–catalyst being 100 :(200–300):(1–3).
Under the optimal conditions, the conversion of
1-bromoadamantane (1) was complete, and the only
product was N-(adamantan-1-yl)formamide (2). Other
carboxylic acid amides, in particular acetamide, pro-
pionamide, N-methylformamide, and benzamide, also
readily reacted with bromide 1 under the above condi-
tions to afford N-(adamantan-1-yl)amides 3–5 in 78–
100% yield. The nature of organic amide did not affect
the reaction selectivity and yield.
1-Bromoadamantane (1) is used most frequently in
laboratory and large-scale syntheses of various
N-(adamantan-1-yl)amides. Adamantyl cation is gen-
erated therefrom by the action of concentrated sulfuric
[4] or nitric acid [5], oleum [6], equimolar mixture of
trifluoroacetic acid and boron trifluoride–diethyl ether
complex [7], or liquid bromine [8]. These reagents are
taken in a large excess with respect to 1-bromoada-
mantane (1), which complicates the isolation of target
products [9]. N-(Adamantan-1-yl)amides were also
synthesized by reaction of 1-bromoadamantane (1)
with formamide or acetamide at elevated temperature
(185–195°C) [10] or in the presence of a stoichiomet-
The progress of the reaction was monitored by
GLC. The optimal reactant concentrations and condi-
tions for the synthesis of N-(adamantan-1-yl)amides 2–
Scheme 1.
[Mn], 3 mol %
120–130°C, 2–3 h
+ RCONH2
COR
Br
N
H
1
2–5
2, R = H; 3, R = Me; 4, R = Et; 5, R = Ph.
476

SYNTHESIS OF N-(ADAMANTAN-1-YL)AMIDES
477
Scheme 2.
[Mn], 3 mol %
120–130°C, 2–3 h
O
O
+
Me
Me
N
Br
N
Me
H
Me
1
7
7 were found. Carboxylic acid amides were taken in
2–3-fold excess since they acted simultaneously as
reagent and solvent; the reactions with solid amides
were carried out in melt.
N-(adamantan-1-yl)amides 2–7 with high selectivity.
The conversion of adamantyl halides 1 and 8 and the
yields of amides 2–7 depended on the catalyst nature.
Among the examined manganese compounds
[Mn2(CO)10, Mn(OAc)2 ·4 H2O, Mn(acac)3, MnBr2,
MnCl2], Mn2(CO)10 turned out to be the best catalyst.
Malonamide reacted with 1-bromoadamantane at
one amide group. However, the yield of N-(adamantan-
1-yl)propanediamide (6) did not exceed 10% even on
prolonged heating (130°C, 8 h). Benzamide vigorously
reacted with bromide 1 to produce N-(adamantan-1-
yl)benzamide (5) in quantitative yield. The reaction of
1-bromoadamantane (1) with N-methylacetamide was
fairly active, and N-(adamantan-1-yl)-N-methylacet-
amide (7) was formed in 75% yield (Scheme 2).
N-(Adamantan-1-yl)amides 2–7 were purified from
concomitant impurities by silica gel column chroma-
tography using hexane–ethyl acetate as eluent. Amides
2–7 were identified by spectral methods and by com-
paring their properties with those of authentic samples
and with published data [12].
Thus, manganese-containing catalysts ensure
amidation of 1-bromo- and 1-chloroadamantanes with
aliphatic and aromatic carboxylic acid amides under
solvent-free conditions (see table).
The reactivity of 1-chloroadamantane (8) in analo-
gous reactions was similar to that of bromide 1, and
the reactions of 8 with amides afforded 45–90% of
Synthesis of N-(adamantan-1-yl)amides 2–7 from 1-bromoadamantane (1) and carboxylic acid amides in the presence of
manganese compounds
Molar ratio
1–amide–Mn
Temperature,
°C
Yield of amide
Initial amide
MeCONH2
Catalyst
Reaction time, h
2–7, %
MnCl2
100:300:3
100:300:3
100:300:3
100:300:3
100:200:3
100:300:2
100:300:3
100:300:3
100:300:3
100:200:3
100:300:1
100:300:2
100:300:3
100:300:3
100:300:3
100:300:3
100:300:3
130
130
130
130
130
130
120
130
120
120
120
120
120
120
120
120
120
2
2
2
2
2
2
3
2
3
3
3
3
3
3
3
3
3
36
45
87
80
65
72
95
96
95
93
88
90
97
92
99
10
75
MnBr2
Mn(OAc)2
Mn(acac)3
Mn(acac)3
Mn(acac)3
Mn(acac)3
Mn2(CO)10
Mn2(CO)10
Mn2(CO)10
Mn2(CO)10
Mn2(CO)10
Mn2(CO)10
Mn2(CO)10
Mn2(CO)10
Mn2(CO)10
Mn2(CO)10
HCONH2
EtCONH2
PhCONH2
CH2(CONH2)2
MeCONHMe
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 4 2015

KHUSNUTDINOV et al.
mp 147–147.5°C. IR spectrum, ν, cm–1: 3220 (N–H),
478
EXPERIMENTAL
1645 (C=O), 1545 (δN–H). 13C NMR spectrum, δC,
ppm: 25.42 (CH3), 30.85 (C3, C5, C7), 36.42 (C4, C6,
C10), 41.54 (C2, C8, C9), 51.62 (C1), 160.86 (C=O).
Mass spectrum, m/z (Irel, %): 193 (43) [M]+, 192 (9),
150 (7), 137 (8), 136 (100), 135 (24), 134 (25), 100
(8), 94 (45), 93 (18), 92 (16), 91 (17), 79 (15), 77 (14),
58 (8), 55 (7), 43 (31), 42 (12), 41 (21), 39 (14).
Found, %: C 74.60; H 9.88; N 7.18. C12H19NO. Cal-
culated, %: C 74.56; H 9.91; N 7.25.
The IR spectra were recorded in KBr or mineral oil
on a Bruker Vertex 70V spectrometer. The 13C NMR
spectra were recorded on a Bruker Avance-400
spectrometer at 100.62 MHz from solutions in CDCl3.
The mass spectra were obtained on a Shimadzu
GCMS-QP2010Ultra instrument (Supelco PTE-5
capillary column, 60 m×0.25 mm; carrier gas helium;
oven temperature programming from 40 to 280°C at
a rate of 8 deg/min; injector temperature 260°C; ion
source temperature 200°C; electron imact, 70 eV). The
elemental compositions were determined on a Carlo
Erba 1106 elemental analyzer.
N-(Adamantan-1-yl)propanamide (4). Yield 88%,
mp 103.5–104°C (from MeOH); published data [12]:
mp 104.2°C. IR spectrum, ν, cm–1: 3300 (N–H), 1650
(C=O), 1550 (δN–H). 13C NMR spectrum, δC, ppm:
22.32 (CH3), 28.35 (CH2), 29.18 (C3, C5, C7), 36.12
(C4, C6, C10), 41.29 (C2, C8, C9), 51.73 (C1), 172.21
(C=O). Found, %: C 78.95; H 10.68; N 7.09.
C13H21NO. Calculated, %: C 79.13; H 10.73; N 7.10.
The progress of reactions and the purity of products
were monitored by GLC on Shimadzu GC-9A and
GC-2014 instruments (2 m×3-mm column, stationary
phase 5% of SE-30 on Chromaton N-AW-HMDS;
oven temperature programming from 50 to 270°C at
a rate of 8 deg/min; carrier gas helium, 47 mL/min).
The yields of amides 2–7 were determined by GLC
analysis of the reaction mixtures using undecane as
internal standard; the calibration factors for 1-bromo-
adamantane and N-(adamantan-1-yl)acetamide were
1.53 and 1.68, respectively.
N-(Adamantan-1-yl)benzamide (5). Yield 92%,
mp 148–149°C (from MeOH); published data [4]:
mp 149–150°C. IR spectrum, ν, cm–1: 3440 (N–H),
1655 (C=O), 1650 (C=O), 1580 (C=Carom), 1515
(δN–H). 13C NMR spectrum, δC, ppm: 29.51 (C3, C5,
C7), 36.71 (C4, C6, C10), 41.61 (C2, C8, C9), 52.43 (C1),
126.80, 128.42, 130.12, 135.88 (Carom), 167.08 (C=O).
Found, %: C 79.88; H 8.25; N 5.46. C17H21NO. Cal-
culated, %: C 79.96; H 8.29; N 5.48.
Synthesis of N-(adamantan-1-yl)amides 2–7 (gen-
eral procedure). A 17-mL stainless-steel high-pressure
micro reactor or a glass ampule (the results of parallel
runs differed insignificantly) was charged under argon
with 0.3 mmol of manganese compound, 10 mmol of
1-bromoadamantane (1), and 30 mmol of the corre-
sponding amide. The reactor was hermetically closed
(the ampule was sealed), and the mixture was heated
for 2–3 h at 120–130°C under continuous stirring.
When the reaction was complete, the reactor (ampule)
was cooled to room temperature and opened, and
the mixture was washed with water and extracted
with methylene chloride (3×5 mL). The solvent was
removed under reduced pressure, and the residue was
recrystallized.
N-(Adamantan-1-yl)propanediamide (6). Yield
10%. IR spectrum, ν, cm–1: 3300 (N–H), 1650 (C=O),
1550 (δN–H). 13C NMR spectrum, δC, ppm: 28.82 (C3,
C5, C7), 36.03 (C4, C6, C10), 40.94 (C2, C8, C9), 43.80
(CH2), 50.78 (C1), 165.67 (C=O), 175.04 (C=O).
Found, %: C 65.98; H 8.48; N 11.79. C13H20N2O2. Cal-
culated, %: C 66.07; H 8.53; N 11.85.
N-(Adamantan-1-yl)-N-methylacetamide (7).
Yield 75%. IR spectrum, ν, cm–1: 3270 (N–H), 1650
(C=O). 13C NMR spectrum, δC, ppm: 23.05 (CH3),
29.56 (CH3), 30.76 (C3, C5, C7), 37.08 (C4, C6, C10),
39.84 (C2, C8, C9), 54.95 (C1), 171.87 (C=O). Found,
%: C 75.25; H 10.18; N 6.69. C13H21NO. Calculated,
%: C 75.32; H 10.21; N 6.76.
N-(Adamantan-1-yl)formamide (2). Yield 94%,
mp 139–140°C (from MeOH). IR spectrum, ν, cm–1:
3278 (N–H), 1643 (C=O), 1559 (δN–H). 13C NMR
spectrum, δC, ppm: 29.11 (C3, C5, C7), 36.15 (C4, C6,
C10), 43.48 (C2, C8, C9), 51.62 (C1), 162.08 (C=O).
Found, %: C 73.62; H 9.53; N 7.77. C11H17NO. Cal-
culated, %: C 73.70; H 9.56; N 7.81.
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 14-03-97029r_povolzh’e-a) and by the program of
the President of the Russian Federation for young
scientists and post-graduate students engaged in
promising researches and developments in the priority
fields of modernization of the Russian economics
(project no. SP-4810.2013.4 for 2013–2015).
N-(Adamantan-1-yl)acetamide (3). Yield 91%,
mp 147–148°C (from MeOH); published data [12]:
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 4 2015

SYNTHESIS OF N-(ADAMANTAN-1-YL)AMIDES
479
6. Butenko, L.N. and Khardin, A.P., USSR Inventor’s
Certificate no. 491616, 1976.
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