Monoacylaminals by the benzotriazole-assisted aminoalkylation of amides

Article abstract of DOI:10.1055/s-1998-2164

A general synthesis of a range of monoacylaminals from the reaction of N-(α-aminoalkyl)benzotriazoles with amides in the presence of a base has been developed. In less reactive cases zinc bromide was used to facilitate the above reaction.

Full text of DOI:10.1055/s-1998-2164

SYNTHESIS
October 1998
1421
Monoacylaminals by the Benzotriazole-Assisted Aminoalkylation of Amides
Alan R. Katritzky,* Clara N. Fali, Weiliang Bao, Ming Qi
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA
E-mail: katritzky@chem.ufl.edu.
Received 5 February 1998; revised 27 March 1998
This paper is dedicated in friendship to Professor Klaus Burger (Leipzig) on the occasion of his 60th Anniversary
Abstract: A general synthesis of a range of monoacylaminals
and also provides further examples that represent an ex-
tension of Method (vi).
from the reaction of N-(α-aminoalkyl)benzotriazoles with amides
in the presence of a base has been developed. In less reactive cases
zinc bromide was used to facilitate the above reaction.
Monoacylaminals from aminoalkylation of amides:
1-aminoalkylbenzotriazoles 6 undergo reversible dissoci-
ation. The small equilibrium amounts of ion pair 817 me-
diate the displacement of benzotriazolyl moieties from 6
Key words: monoacylaminal, aminoalkylation, amide, benzotria-
zole, amine
Monoacylaminals are constituent units of retro-peptides,1, 2 by Grignard reagents, sodium borohydride, sulfur and
other nucleophiles (Scheme 2).18, 19 The analogous reac-
intermediates for the synthesis of heterocycles,3–5 and
have been utilized for the protection of amides6 and tion of N-aminoalkylbenzotriazoles 6 with amides in the
amines.7 Many synthetic routes have been documented
for monoacylaminals, including (i) Mannich reaction
presence of a base provides our new route to monoacyl-
aminals 7 (Scheme 2, Method A).
of amides by the conversion RCON(R)H
→
RCON(R)CH2NR2;8–12 (ii) reaction of a N-silylated amide
with a N-(chloromethyl)amine;13 (iii) reactions of N-
(chloromethyl)pyrrolidinone with amines;14 (iv) reactions
of two moles of an imine with one of a ketene;15 (v) in-
tramolecular acylation of a cyclic aminal;3 and (vi) amina-
tion of amidoalkylbenzotriazoles.2, 16 However, Method
(i) is usually restricted to monoacylformals and few exam-
ples were reported for Methods (ii–v). Method (vi) thus
represents the most general protocol previously available.
In Method (vi) compounds 7 are constructed from com-
pounds 1, 2 and 3 by first linking 1 and 2 with benzotria-
zole (4) to give intermediate 5 which reacts with 3 to give
7 (Scheme 1).2, 16 We now report that linking 2 and 3 with
benzotriazole (4) and subsequently reacting the interme-
diate 6 with amides 1 is also a feasible route for the prep-
aration of monoacylaminals 7 (also shown in Scheme 1),
Scheme 2
Treatment of pyrrolidin-2-one (1a) with 1-(piperidinome-
thyl)benzotriazole (6a) or N-(1-benzotriazol-1-yl-2-meth-
ylpropyl)-N-methylaniline (6b) in the presence of sodium
hydride (Method A, Scheme 2) gave products 7a,b, re-
spectively, in ca. 60% yield (Table 1). In a similar manner,
reaction of 4-(α-benzotriazol-1-ylbenzyl)morpholine
(6d) with pyrrolidin-2-one (1a) gave 1-(α-morpholi-
nobenzyl)pyrrolidin-2-one (10) in 70% yield (Scheme 3).
Similar reaction of 6d with formamide gave N-(α-mor-
pholinobenzyl)formamide (11),16 which did not survive
on a silica gel column, but was obtained pure by recrystal-
lization. In CDCl3 solution, 11 exists as a mixture of two
rotamers in a ratio of 3:1.20 In the minor rotamer, the alde-
hyde proton couples with the NH proton to give a doublet,
and the NH proton couples to both CH and the aldehyde
proton to give a double-doublet. In the major rotamer, these
protons appeared as a singlet and a doublet, respectively (in
DMSO-d6, the two rotamers are in the ratio of 6:1). N-(α-
Morpholinobenzyl)benzamide (12, 66%), was prepared
similarly from the reaction of 6d with benzamide. N-Meth-
ylformamide and hydantoin also reacted with 6d to give,
after column chromatography N-methyl-N-(α-morpholi-
nobenzyl)formamide (13) and 1-(α-morpholinobenzyl)-
hydantoin (14), respectively, in good yields.
Scheme 1

SYNTHESIS
Short Papers
Table. Preparation of Monoacylaminals 7
1422
aliphatic-substituted, can be converted into N-(α-ami-
noalkyl)amides by this new methodology.
Com- Method
pound
R
R1 R2
R3
R4
Ph
Yield
(%)
Mps were determined on a hot stage apparatus without correction. 1H
(300 MHz) and 13C NMR (75 MHz) spectra were recorded in CDCl3
(unless otherwise stated) with TMS or CDCl3, respectively, as the in-
ternal reference. Column chromatography was carried out on MCB
silica gel (230–400 mesh). THF was freshly distilled from Na/ben-
zophenone. All starting materials and other solvents are commercially
available (Aldrich, Fisher) and used as received. All reactions were
carried out under the protection of N2.
7a
7b
7c
7d
7e
7f
A
–(CH2)3–
–(CH2)3–
H
–(CH2)5–
60
60
A
i-Pr Me
B
Ph
H
H
H
H
H
–CH2CH2OCH2CH2– 72
B
PhCH2
Me
Et
H
H
H
H
H
H
–(CH2)5–
–(CH2)5–
86
61
B
B
–CH2CH2OCH2CH2– 81
7g
7h
7i
(vi)
(vi)
(vi)
Ph
Ph Ph
H
H
53
70
87
Preparation of 7a,b and 10–14; General Procedure (Method A):
To a suspension of NaH (0.16 g, 6.8 mmol) in anhyd THF (40 mL),
the appropriate amide (6.8 mmol) was added and stirred for 1 h at rt.
A solution of the appropriate N-(α-aminoalkyl)benzotriazole in THF
was then added and the mixture refluxed for 24 h. The mixture was
cooled and concentrated in vacuo to give a residue, which was dis-
solved in CH2Cl2 and washed with NaHCO3 soln. The organics were
dried (Na2SO4), concentrated, and triturated with EtOAc/hexane or
chromatographed on silica gel to afford the product.
Ph
H
Ph
Ph
Ph
–(CH2)5–
1-(Piperidinomethyl)pyrrolidin-2-one (7a): oil.
1H NMR: δ = 3.94 (s, 2H), 3.52 (t, 2H, J = 7.1 Hz), 2.47–2.37 (m, 6H),
2.05–2.00 (m, 2H), 1.57–1.52 (m, 4H), 1.45–1.43 (m, 2H).
13C NMR: δ = 175.2, 64.7, 51.4, 47.4, 30.7, 25.3, 23.8, 17.6.
Anal. Calcd for C10H18N2O: C, 65.90; H, 9.95; N, 15.37. Found: C,
65.95; H, 10.25; N, 15.49.
1-[2-Methyl-1-[methyl(phenyl)amino]propyl]pyrrolidin-2-one (7b):
oil.
1H NMR: δ = 7.26 (t, 2H, J = 8.9 Hz), 6.95 (d, 2H, J = 8.5 Hz), 6.79
(t, 1H, J = 7.3 Hz), 5.43 (d, 1H, J = 10.7 Hz), 3.45–3.34 (m, 1H),
3.25–3.16 (m, 1H), 2.99 (s, 3H), 2.42–2.35 (m, 3H), 1.96–1.94 (m,
2H), 0.99 (d, 3H, J = 6.7 Hz), 0.96 (d, 3H, J = 6.7 Hz).
13C NMR: δ = 175.1, 148.5, 129.2, 117.5, 112.7, 71.0, 43.6, 32.6,
30.7, 28.9, 19.2, 19.0, 18.1.
Scheme 3
HRMS (CI) calcd for C15H22N2O + H 246.1732, found 246.1705.
The reaction of acyclic amides with α-unsubstituted N-
(aminomethyl)benzotriazoles (i.e. 6, R2 = H) required the
addition of zinc bromide (Method B). Monoacylaminals
7c–f were thus synthesized in 61–86% yields (Scheme 2,
Table 1). Zinc bromide probably shifts the equilibrium be-
tween 6 and 8 and coordinates with benzotriazolyl anion,
helping to form the more reactive naked iminium cation.21
1-(α-Morpholinobenzyl)pyrrolidin-2-one (10): crystals; yield: 70%;
mp 140–141°C.
1H NMR: δ = 7.48–7.43 (m, 2H), 7.40–7.31 (m, 3H), 5.8 (s, 1H),
3.82–3.67 (m, 4H), 3.52–3.40 (m, 1H), 3.13–2.93 (m, 1H), 2.55–2.27
(m, 6H), 2.08–1.80 (m, 2H).
13C NMR: δ = 175.3, 136.3, 128.5, 128.3, 128.2, 74.0, 66.7, 50.4,
42.3, 31.4, 17.9.
Anal. Calcd for C15H20N2O2: C, 69.20; H 7.74; N 10.76. Found, C,
69.20; H, 8.01; N, 10.80.
Monoacylaminals from amidoalkylation of amines: in
our previous publications, only ammonia2 and a second-
ary amine (one example)16 were used as nucleophiles in
the reactions of an amine and an N-(α-amidoalkyl)benzo-
triazole. We have now found that Method (vi) also applies
to primary amines (Scheme 1). In particular, aniline react-
ed with N-[α-(phenylcarbamoyl)benzyl]benzotriazole
(5a) or N-[(phenylcarbamoyl)methyl]benzotriazole (5b)
to give compounds 7g,h (Scheme 1, Table 1), respective-
ly. α-Amidoalkylbenzotriazole 5a also reacted with the
secondary amine, piperidine, to give 7i in 87% yield.
N-(α-Morpholinobenzyl)formamide (11):16 mixture of two isomers
(3:1); white solid; yield: 65%; mp 141–142°C (EtOAc/hexane) [Lit.16
141–142°C].
1H NMR (peaks corresponding to the minor isomer in square brackets):
δ = 8.39 (s, 1H) [8.22 (d, 1H, J = 11.0 Hz)], 7.45–7.30 (m, 5H), 6.60 (d,
1H, J = 9.0 Hz) [7.02 (dd, 1H, J = 11.0, 9.9 Hz)], 5.82 (d, 1H, J = 9.9
Hz) [5.05 (d, 1H, J = 9.9 Hz)], 3.70–3.65 (m, 4H), 2.60–2.41 (m, 4H).
13C NMR: δ = 161.1 [164.1], 138.2 [137.9], 128.6 [128.8], 128.1
[128.4], 127.0 [126.9], 70.0 [76.0], 66.8 [66.7], 48.9 [48.5].
Anal. Calcd for C12H16N2O2: C, 65.43; H, 7.32; N, 12.72. Found: C,
65.78; H, 7.40; N, 12.91.
In conclusion, we have developed a general method for
the synthesis of N-(α-aminoalkyl)amides from readily
available and crystalline N-(aminoalkyl)benzotriazoles as
starting materials. Different types of amides, including
cyclic or acyclic, primary or secondary, and aromatic- or
N-(α-Morpholinobenzyl)benzamide (12): crystals; yield: 70%; mp
153–154°C.
1H NMR: δ = 7.84 (d, 2H, J = 5.0 Hz), 7.80–7.27 (m, 8H), 6.82 (d,
1H, J = 9.6 Hz), 5.96 (d, 1H, J = 9.6 Hz), 3.74–3.66 (m, 4H), 2.68–
2.52 (m, 4H).

SYNTHESIS
October 1998
1423
13C NMR: δ = 167.4, 138.6, 134.1, 131.7, 128.7, 128.6, 128.0, 127.1,
127.0, 71.8, 66.9, 49.2.
Anal. Calcd for C18H20N2O2: C, 72.95; H, 6.80; N, 9.45. Found: C,
73.13; H, 6.68; N, 9.78.
N-(α-Anilinobenzyl)benzamide (7g): solid; mp 118–119 °C.
1H NMR: δ = 7.75–7.83 (m, 2H), 7.33–7.56 (m, 8H), 7.18–7.25 (m,
2H), 6.64–6.83 (m, 5H), 4.36 (d, 1H, J = 5.1 Hz).
13C NMR: δ = 167.0, 145.3, 140.2, 132.0, 131.8, 129.5, 129.0, 128.7,
128.6, 127.2, 127.0, 126.2, 125.9, 119.1, 113.7, 111.2, 63.8.
Anal. Calcd for C20H18N2O: C, 79.44; H, 6.00; N, 9.26. Found: C,
78.96; H, 6.00; N, 9.20.
N-Methyl-N-(α-morpholinobenzyl)formamide (13): oil; yield: 60%.
1H NMR (mixture of two rotamers, peaks for the major isomer report-
ed here): δ = 8.49 (s, 1H), 7.52–7.30 (m, 5H), 5.30 (s, 1H), 3.89–3.64
(m, 4H), 2.75 (s, 3H), 2.50–2.40 (m, 4H).
N-(Anilinomethyl)benzamide (7h): solid; mp 111–113 °C.
1H NMR (mixture of two rotamers 5:1, peaks for the major isomer
reported here): δ = 7.71 (d, 2H, J = 6.9 Hz), 7.35–7.50 (m, 3H), 7.19
(t, 2H, J = 7.8 Hz), 6.71–6.85 (m, 4H), 4.88–4.94 (m, 2H), 4.68 (t, 1H,
J = 6.9 Hz).
13C NMR: δ = 162.8, 135.4, 128.7, 128.5, 127.9, 82.6, 66.6, 50.4,
26.5.
HRMS (FAB) calcd for C13H18N2O2 234.1368, found 234.1369.
13C NMR: δ = 168.2, 145.7, 134.0, 131.7, 129.5, 128.6, 126.9, 118.9,
113.6, 50.2.
1-(α-Morpholinobenzyl)hydantoin (14): crystals; yield: 60%; mp
155–157°C.
Anal. Calcd for C14H14N2O: C, 74.31; H, 6.24; N, 12.38. Found: C,
74.10; H, 6.40; N, 12.41.
1H NMR (DMSO-d6): δ = 10.90 (br s, 1H), 7.45–7.37 (m, 5H), 5.29
(s, 1H), 4.01 (d, 1H, J = 17.4 Hz), 3.62–3.59 (m, 4H), 3.54 (d, 1H, J
= 17.4 Hz), 2.51–2.31 (m, 2H), 2.29–2.24 (m, 2H).
13C NMR (DMSO-d6): δ = 171.2, 156.7, 136.0, 128.8, 128.5, 127.8,
73.7, 65.9, 50.1, 46.5.
N-(α-Piperidinobenzyl)benzamide (7i): solid; mp 132–134 °C.
1H NMR: δ = 7.81–7.86 (m, 2H), 7.45–7.56 (m, 5H), 7.27–7.39 (m,
3H), 6.57 (d, 1H, J = 9.3 Hz), 6.0 (d, 1H, J = 9.3 Hz), 2.54–2.65 (m,
4H), 1.59–1.60 (m, 4H), 1.45–1.48 (m, 2H).
Anal. Calcd for C14H17N3O3: C, 61.08; H, 6.22; N, 15.26. Found: C,
60.77; H, 6.46; N, 15.49.
13C NMR: δ = 167.3, 139.7, 132.0, 131.7, 128.7, 128.6, 128.5, 127.7,
127.3, 127.1, 127.0, 72.4, 50.0, 26.0, 24.5.
Anal. Calcd for C19H22N2O: C, 77.52; H, 7.53; N, 9.52. Found: C,
77.16; H, 7.64; N, 9.82.
Preparation of 7c–f; General Procedure (Method B):
These compounds were prepared following Method A, except that
CH2Cl2 was used as solvent and ZnBr2 (1 equiv) was added with the
N-(α-aminoalkyl)benzotriazoles.
(1) Goodman, M.; Chorev, M. Acc. Chem. Res. 1979, 12, 1.
(2) Katritzky, A. R.; Urogdi, L.; Mayence, A. J. Org. Chem. 1990,
55, 2206.
(3) Denzer, M.; Ott, H. J. Org. Chem. 1969, 34, 183.
(4) Bryant, L. R. B.; Coyle, J. D. J. Chem. Res. (S) 1982, 164.
(5) Hannoun, M.; Zinic, M.; Kolbah, D.; Blazevic, N.; Kajfez, F.
J. Heterocycl. Chem. 1981, 18, 963.
N-(Morpholinomethyl)benzamide (7c): solid; mp 68–69 °C.
1H NMR: δ = 7.80 (d, 2H, J = 7.8 Hz), 7.52–7.41 (m, 3H), 6.74 (br s,
1H), 4.29 (d, 2H, J = 6.3 Hz), 3.55–3.75 (m, 4H), 2.58–2.68 (m, 4H).
13C NMR: δ = 168.0, 131.7, 128.6, 127.3, 126.9, 66.8, 61.9, 50.5.
HRMS (FAB) calcd for C12H16N2O2 + H 221.1290, found 221.1255.
(6) Hamlet, A. B.; Durst, T. Can. J. Chem. 1983, 61, 411.
(7) Knapp, S.; Hale, J. J.; Bastos, M.; Gibson, F. S. Tetrahedron
Lett. 1990, 31, 2109.
(8) Sekiya, M.; Terao, Y. Chem. Pharm. Bull. 1970, 18, 947.
(9) Freyermuth, H. B.; Randall, D. I. German Patent D.O.S.
2114251; Chem. Abstr. 1972, 76, 34099y.
(10) Christjanson, P.; Suurpere, A.; Siimer, K. Tr. Tallin. Politekh.
Inst. 1975, 390, 89; Chem. Abstr. 1976, 85, 77113b.
(11) Graham, D. E.; Schneider, L. U.S. Patent 4202821; Chem. Ab-
str. 1981, 94, 15554y.
N-(Piperidinomethyl)phenylacetamide (7d): solid; mp 100–102 °C.
1H NMR: δ = 7.38–7.27 (m, 5H), 6.02 (br s, 1H), 4.08 (d, 2H, J = 6.3
Hz), 3.62 (s, 2H), 2.38–2.50 (m, 4H), 1.60–1.50 (m, 4H), 1.45–1.35
(m, 2H).
13C NMR: δ = 171.6, 134.7, 129.4, 129.0, 127.3, 61.8, 51.2, 43.9,
25.4, 23.9.
Anal. Calcd for C14H20N2O: C, 72.38; H, 8.68; N, 12.06. Found: C,
72.50; H, 9.10; N, 12.15.
(12) Katritzky, A. R.; Szajda, M.; Bayyuk, S. Synthesis 1986, 804.
(13) Anisimova, N. A.; Belavin, I. Yu.; Orlova, N. A.; Sergeev, V.
N.; Shipov, A. G.; Baukov, Yu. I. J. Gen. Chem. USSR 1983,
1066.
N-(Piperidinomethyl)acetamide (7e): colorless oil.
1H NMR: δ = 6.89 (br s, 1H), 4.08 (d, 2H, J = 6.3 Hz), 2.56–2.54 (m,
4H), 2.04 (s, 3H), 1.63–1.61 (m, 4H), 1.47–1.45 (m, 2H).
13C NMR: δ = 171.0, 61.6, 51.1, 25.2, 23.7, 23.0.
(14) Chen, P.; Suh, D.-J.; Smith, M. B. J. Chem. Soc., Perkin Trans.
1 1995, 1317.
HRMS (EI) calcd for C8H16N2O 156.1263, found 156.1248.
(15) Clemens, D. H.; Emmons, W. D. J. Org. Chem. 1961, 26, 949.
(16) Katritzky, A. R.; Xie, L.; Fan, W.-Q. Synthesis 1993, 45.
(17) Katritzky, A. R.; Rachwal, S.; Rachwal, B.; Frankenfeld, J. W.
Int. J. Chem. Kinet. 1995, 27, 351.
(18) Katritzky, A. R.; Rachwal, S.; Hitchings, G. J. Tetrahedron
1991, 47, 2683.
N-(Morpholinomethyl)propionamide (7f): solid; mp 38–39 °C.
1H NMR: δ = 6.08 (br s, 1H), 4.10 (d, 2H, J = 6.6 Hz), 3.72 (t, 4H, J
= 4.2 Hz), 2.57 (t, 4H, J = 4.2 Hz), 2.27 (q, 2H, J = 7.5 Hz), 1.19 (t,
3H, J = 7.5 Hz).
13C NMR: δ = 174.6, 66.7, 61.4, 50.4, 29.7, 9.8.
HRMS (FAB) calcd for C8H16N2O2 + H 173.1290, found 173.1295.
(19) Katritzky, A. R.; Lan, X.; Yang, J. Z.; Denisko, O. V. Chem.
Rev. 1998, 98, 409.
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stry; Barton, D.; Ollis, W. D. Eds.; Pergamon: Oxford, 1979;
Vol 2; 957.
(21) cf. Katritzky, A. R.; Nichols, D. A.; Qi, M.; Yang, B. J. Hetero-
cycl. Chem. 1997, 34, 1259.
Preparation of 7g–i; General Procedure (Method vi):
A
mixture of the appropriate N-(α-amidoalkyl)benzotriazole
(5 mmol), amine (6 mmol) and K2CO3 (2.0 g) in MeOH (40 mL) was
stirred at r.t. overnight. The mixture was worked up as for Method A
to afford the product.