Synthesis of N-tert-butyl amides by reaction of tert-butyl bromide with amides in the presence of manganese compounds

Full text of DOI:10.1134/S1070428015100255

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2015, Vol. 51, No. 10, pp. 1502–1504. © 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. 10,
pp. 1532–1534.
SHORT
COMMUNICATIONS
Synthesis of N-tert-Butyl Amides by Reaction of tert-Butyl
Bromide with Amides in the Presence of 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: inklab4@gmail.com
Received May 11, 2015
DOI: 10.1134/S1070428015100255
N-tert-Butyl amides are important compounds for
pharmaceutical industry and are precursors of impor-
tant drugs, such as Finasteride, Nelfinavir, Saquinavir,
and some diarylbutanol derivatives, that are used for
the treatment of prostatic hyperplasia and inhibit HIV
protease [1].
an equimolar amount of silver sulfate afforded 45%
of the corresponding N-(adamantan-1-yl)-substituted
amide [15].
We have recently shown that N-(adamantan-1-yl)
amides are formed in 70–90% yield in the reactions of
1-bromoadamantane with carboxylic acid amides in
the presence of manganese-containing catalysts at
120–130°C [16]. Taking into account practical impor-
tance of N-tert-butyl amides, we set ourselves the task
of developing a procedure for their preparation via
reaction of tert-butyl bromide with amides in the
presence of metal complexes. As the latter we used the
following manganese compounds: MnCl2, MnBr2,
Mn(OAc)2, Mn(acac)3, and Mn2(CO)10. The conver-
sion of tert-butyl bromide (1) and the yield of N-tert-
butyl amides 2–7 depended on the catalyst. Among the
examined manganese compounds, the best catalyst was
Mn2(CO)10. The reactions with formamide were
carried out at 120–130°C (2–3 h), the molar ratio
t-BuBr–amide–catalyst being 100:(200 to 300):(1 to 3).
Under the optimal conditions, the conversion of tert-
butyl bromide (1) was 75%, and the only product was
N-tert-butylformamide (2). Other carboxylic acid
A known method for the synthesis of N-tert-butyl
amides is based on the Ritter reaction of nitriles with
tert-butyl cation generated in situ from isobutylene or
tert-butyl alcohol in the presence of a strong acid.
However, these procedures are not free from some
limitations; for instance, isobutylene is a gaseous sub-
stance under normal conditions, and it polymerizes on
heating, while tert-butyl alcohol is a solid at room
temperature. The most convenient reagent is tert-butyl
acetate which reacts with nitriles at 20°C in the pres-
ence of stoichiometric amounts of sulfuric and acetic
acids [2–4]. Analogous reaction was also accomplished
in the presence of FeCl3·6H2O (10 mol %) at 150°C
[5] and I2 (20 mol %) (110°C, 4–6 h) [6] or trifluoro-
acetic acid (3–4 equiv) [7]. The reaction catalyzed by
a stoichiometric amount of the boron trifluoride com-
plex with poly(vinylpyrrolidone) PVP–BF3 occurred
under milder conditions (70°C) [8]. Syntheses of
N-tert-butyl amides by reactions of alcohols or ethers
with nitriles in the presence of heterogeneous catalysts,
in particular ZnCl2/SiO2 (15 mol %) [9], P2O5/SiO2
(60 wt %) [10], heteropolyacids, Amberlyst-15, Mont-
morillonite KSF, Zeolite HZSM-5 [11, 12], and ionic
liquids [13], have also been reported.
[Mn] (3 mol %)
120–130°C, 2–3 h
O
O
t-BuBr
+
Bu-t
–HBr
R
NH2
Me
R
N
H
1
2–6
O
[Mn] (3 mol %)
130°C, 2 h
O
Bu-t
1
+
Me
N
–HBr
Amides are known to react with tertiary hydro-
carbyl halides. For example, the reaction of 1-bromo-
adamantane with formamide or acetamide at elevated
temperature (185–195°C) [14] or in the presence of
Me
N
H
Me
7
2, R = H; 3, R = Me; 4, R = Et; 5, R = Ph; 6, R = H2NC(O)CH2.
1502

SYNTHESIS OF N-tert-BUTYL AMIDES
1503
Reaction of tert-butyl bromide (1) with carboxylic acid amides in the presence of manganese compounds
Molar ratio
1–amide–Mn
Temperature,
°C
Reaction
time, h
Product no.
(yield, %)
Catalyst
Amide
MnCl2
MeCONH2
MeCONH2
MeCONH2
MeCONH2
MeCONH2
MeCONH2
MeCONH2
MeCONH2
MeCONH2
MeCONH2
MeCONH2
MeCONH2
HCONH2
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
130
130
130
130
130
3
3
2
2
2
2
3
2
3
3
4
4
2
2
2
2
2
3 (54)
3 (67)
3 (90)
3 (91)
3 (82)
3 (79)
3 (92)
3 (93)
3 (89)
3 (75)
3 (68)
3 (79)
2 (75)
4 (92)
5 (95)
6 (64)
7 (60)
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
EtCONH2
PhCONH2
CH2(CONH2)2
MeCONHMe
amides, such as acetamide, propanamide, and benz-
amide, also readily reacted with tert-butyl bromide (1)
under the above conditions, yielding 64–95% of the
corresponding N-substituted amides 3–5 (see table).
The amide nature appreciably affected the reaction
selectivity and yield of the target product. Benzamide
possessing a bulky benzene ring reacted with 1 to give
N-tert-butylbenzamide (5) in 95% yield. The reaction
of malonamide with t-BuBr was highly selective, and
N-tert-butylmalonamide (6) was obtained in 64%
yield. In all cases, liberated hydrogen bromide did not
form salts with amides but evolved as gaseous product.
The reaction of 1 with N-methylacetamide gave 60%
of N-tert-butyl-N-methylacetamide (7).
N-tert-Butyl amides 2–7 (general procedure).
A 17-mL stainless steel high-pressure micro reactor or
a glass ampule (the results of parallel runs differed in-
significantly) was charged under argon with 0.3 mmol
of manganese catalyst, 10 mmol of tert-butyl bromide
(1), and 30 mmol of the corresponding amide. The
reactor was hermetically closed (the ampule was
sealed) and heated for 3–4 h at 120–130°C under con-
tinuous stirring. When the reaction was complete, the
reactor (ampule) was cooled to room temperature and
opened, the mixture was washed with water and ex-
tracted with methylene chloride (3×5 mL), the extract
was evaporated under reduced pressure, and the resi-
due was recrystallized.
N-tert-Butylformamide (2). Yield 75%, bp 81–
82°C (10 mm); published data [17]: bp 82–85°C
(14 mm). IR spectrum (film), ν, cm–1: 3278 (NH),
1643 (C=O), 1559 (NH). 13C NMR spectrum, δC, ppm:
30.79 (CH3), 50.90 (CNH), 163.33 (C=O).
N-tert-Butylacetamide (3). Yield 93%, mp 97–
98°C (from EtOH) [17]. IR spectrum (mineral oil), ν,
cm–1: 3284 (NH), 1640 (C=O), 1555, 1223, 606 (NH).
13C NMR spectrum, δC, ppm: 25.22 (COCH3), 29.04
(CH3), 50.97 (CNH), 171.75 (C=O).
The progress of the reaction was monitored by
GLC. Optimal reactant concentrations and reaction
conditions were found. Initial amides were taken in
2–3-fold excess, for they simultaneously acted as sol-
vent (the reactions with solid amides were carried out
in melt). The structure of amides 2–7 was confirmed
by spectral data (IR, 13C NMR, GC/MS) and compari-
son with authentic samples and published data. N-tert-
Butyl amides 2–7 were purified from impurities by
silica gel column chromatography using hexane–ethyl
acetate as eluent; the yields are given for the isolated
product.
N-tert-Butylpropanamide (4). Yield 92%, mp 83–
84°C (from EtOH) [18]. IR spectrum (mineral oil), ν,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 10 2015

KHUSNUTDINOV et al.
1504
cm–1: 3300 (NH), 1650 (C=O), 1550 (NH). 13C NMR
spectrum, δC, ppm: 8.26 (CH3CH2), 28.92 (CH3), 31.42
(CH2), 51.28 (CNH), 172.53 (C=O).
no. 14-03-97029r_povolzh’e-a) and by the Council for
Grants at the President of the Russian Federation
(project no. SP-4810.2013.4)
N-tert-Butylbenzamide (5). Yield 95%, mp 135–
136°C (from EtOH) [8]. IR spectrum (mineral oil), ν,
cm–1: 3438 (NH), 1655, 1663 (C=O), 1580 (C=Carom),
1515 (δNH). 13C NMR spectrum, δC, ppm: 29.32
(CH3), 51.53 (CNH); 126.83, 128.59, 131.36, 135.92
(Carom); 168.06 (C=O).
REFERENCES
1. Hazarika, N. and Baishya, G., Eur. J. Org. Chem., 2014,
p. 5686.
2. Colombo, M.I., Bohn, M.L., and Rúveda, E.A.,
J. Chem. Educ., 2002, vol. 79, p. 484.
N-tert-Butylpropanediamide (6). Yield 64%,
mp 145–146°C. IR spectrum (mineral oil), ν, cm–1:
3284 (NH), 1650 (C=O), 1555 (NH). 13C NMR spec-
trum, δC, ppm: 29.84 (CH3), 45.05 (CH2), 50.12
(CNH), 165.23 (C=O), 175.36 (C=O). Found, %:
C 52.82; H 8.78; N 17.44. C7H14N2O2. Calculated, %:
C 53.15; H 8.92; N 17.71.
3. Baum, J.C., Milne, J.E., Murry, J.A., and Thiel, O.R.,
J. Org. Chem., 2009, vol. 74, p. 2207.
4. Reddy, K.L., Tetrahedron Lett., 2003, vol. 44, p. 1453.
5. Anxionnat, B., Guérinot, A., Reymond, S., and
Cossy, J., Tetrahedron Lett., 2009, vol. 50, p. 3470.
6. Theerthagiri, P., Lalitha, A., and Arunachalam, P.N.,
Tetrahedron Lett., 2010, vol. 51, p. 2813.
7. Plakhotnik, V.M., Kovtun, V.Yu., and Yashunskii, V.G.,
Zh. Org. Khim., 1982, vol. 18, p. 1001.
8. Mokhtary, M. and Najafizaden, F., E-J. Chem., 2012,
N-tert-Butyl-N-methylacetamide (7). Yield 60%,
bp 70–71°C (14 mm); published data [19]: bp 56.5°C
(5 mm). IR spectrum (film), ν, cm–1: 3290 (NH), 1645
(C=O), 1555 (NH). 13C NMR spectrum, δC, ppm:
26.48 (CH3), 28.85 (CH3), 30.96 [C(CH3)3], 54.96
(CNH), 174.50 (C=O).
vol. 9, p. 576.
9. Tamaddon, F. and Tavakoli, F., J. Mol. Catal. A: Chem.,
2011, vol. 337, p. 52.
10. Tamaddon, F., Khoobi, M., and Keshavarz, E., Tetra-
hedron Lett., 2007, vol. 48, p. 3643.
11. Yadav, J.S., Reddy, B.V.S., Pandurangan, T.,
Reddy, Y.J., and Gupta, M.K., Catal. Commun., 2008,
vol. 9, p. 1297.
12. Guérinot, A., Reymond, S., and Cossy, J., Eur. J. Org.
Chem., 2012, p. 19.
13. Kalkhambkar, R.G., Waters, S.N., and Laali, K.K.,
Tetrahedron Lett., 2011, vol. 52, p. 867.
14. Polis, Ya.Yu., USSR Inventor’s Certificate no. 1609406,
1977.
15. Paulshock, M. and Watts, J.C., US Patent no. 3310469,
1967.
16. Khusnutdinov, R.I., Shchadneva, N.A., and Khisamo-
The IR spectra were recorded on a Bruker Vertex
70V spectrometer. The 13C NMR spectra were mea-
sured on a Bruker Avance-400 spectrometer at
100.62 MHz using CDCl3 as solvent. The mass spectra
were obtained on a Shimadzu GCMS-QP2010 Ultra
instrument (Supelco PTE-5 capillary column, 60 m×
0.25 mm; carrier gas helium; oven temperature pro-
gramming from 40 to 280°C at a rate of 8 deg/min;
injector temperature 260°C; ion source temperature
200°C; electron impact, 70 eV). The elemental com-
positions were determined on a Carlo Erba 1106
analyzer. The progress of reactions was monitored,
and the purity of products was checked, by GLC on
Shimadzu GC-9A and GC-2014 instruments (2-m×
3-mm column packed with 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,
flow rate 47 mL/min).
va, L.F., Russ. J. Org. Chem., 2015, vol. 51, p. 476.
17. Merger, F., Nestler, G., and Kempe, U., US Patent
no. 4273938, 1984.
18. Audiger, L., Watts, K., Elmore, S.C., Robinson, R.I.,
and Wirth, T., ChemSusChem, 2012, vol. 5, p. 257.
This study was performed under financial support
by the Russian Foundation for Basic Research (project
19. LaPlanche, L.A. and Rogers, M.T., J. Am. Chem. Soc.,
1963, vol. 85, p. 3728.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 10 2015