New Synthesis of Substituted Benzylamines. Novel Application of the Mitsunobu Reaction to Convert Substituted Benzyl Alcohols to Amines

Full text of DOI:10.1021/jo961738v

3754
J . Org. Chem. 1997, 62, 3754-3757
Sch em e 1
New Syn th esis of Su bstitu ted
Ben zyla m in es. Novel Ap p lica tion of th e
Mitsu n obu Rea ction To Con ver t
Su bstitu ted Ben zyl Alcoh ols to Am in es†
Sham S. Nikam,* Brian E. Kornberg, and
Michael F. Rafferty
Department of Chemistry, Parke-Davis Pharmaceutical
Research Division, Warner-Lambert Company, 2800
Plymouth Road, Ann Arbor, Michigan 48105
Received September 10, 1996
Sch em e 2. Syn th esis of Ben zyla m in es 2 u sin g
Ben zyl Alcoh ols 1 u n d er Mitsu n obu Rea ction
Con d ition s
In tr od u ction
Synthesis of amines from alcohols using the Mitsunobu
reaction is well-documented.1 In most cases, for the
success of the reaction it is important to have protected
amines as the acidic component (pKa ∼ 8) of the reaction
in the form of amides,2 phthalimides,3 N-alkylsulfona-
mides,4 N-methyltrifluoromethanesulfonamides,5 or hy-
drazoic acid6 which undergo deprotonation to generate
the reactive nucleophile. The yields are higher with
lower pKa of the amine component. The mechanism of
this conversion has been the topic of investigation for
several years and the one that best explains this trans-
formation involves the initial formation of a quaternary
phosphonium salt by addition of PPh3 to diethylazodi-
carboxylate (DEAD) followed by protonation of the salt
by the substituted amine moiety (Scheme 1).1 The
resulting complex reacts with the alcohol to give the
alkoxyphosphonium salt, which undergoes an SN1 or SN2
type displacement to give the desired amines. Thus, this
process essentially precludes the use of various basic
secondary amines as the amine component to synthesize
tertiary amines. There are very few examples in the
literature where the Mitsunobu reaction has been used
to form substituted amines, especially benzylic amines,
by reacting alcohols with secondary amines with pKa
higher than 8. In two reports7,8 an intramolecular
Mitsunobu reaction between benzylic amino alcohols
yielded cyclic amines with defined amine substituents,
which considerably narrowed the scope of the reaction.
Recently,9 Mitsunobu-mediated intramolecular cycliza-
tion of benzyl amines has been carried out using a variety
of azodicarboxamides. However, from this study it is
evident that there are several limitations for the success
of this reaction. In one of our ongoing projects, we have
a need for a variety of secondary and tertiary benzy-
lamines with 2-amino-3-nitro substitutions on the ben-
zene ring. In this context we successfully used the
Mitsunobu reaction conditions for the synthesis of these
substituted benzylamines 2 by reacting an activated
benzyl alcohol 110 with primary or secondary amines
(Scheme 2). These benzylamines 2 are also versatile
intermediates for the synthesis of a variety of biologically
active nitrogen heterocycles.11
Resu lts a n d Discu ssion
The benzylamines synthesized by the present method
are shown in Table 1. In a typical reaction a solution of
6-methyl-3-nitro-2-aminobenzyl alcohol (1) (1 equiv),
PPh3 (1.5 equiv), and an appropriate amine (1.5 equiv)
was treated with DEAD (1.5 equiv) at 5 °C. The reaction
mixture was allowed to warm to room temperature and,
after purification by chromatography, gave the corre-
sponding benzylamines 2 in fair to good yields. In
general, the yields suffered when the amines were less
basic (pKa < 9; amines listed in the table are in the range
of 10-12) or were sterically hindered. For example, the
reaction with morpholine (pKa ∼ 8, Table 1, no. 18) or
diisopropylamine (Table 1, no. 5) did not give the desired
product and mainly unreacted starting material was
recovered. These derivatives were made by reacting
these amines with the more reactive benzyl bromide 3,
which is generated by treating benzyl alcohol 1 with
CBr4/PPh3 in ether (Scheme 3). Efforts to improve the
yields by altering the sequence of addition of reagents
were not successful. For example, addition of the amine
and alcohol to the mixture of PPh3/DEAD complex or the
addition of the amine to a mixture of the alcohol 1 and
PPh3/DEAD complex did not improve the results obtained
using the procedure described earlier. Addition of the
amine to the mixture of alcohol 1 and PPh3/DEAD
complex gave mainly the hydrazine derivative 4. Hence,
it is important to have the desired nucleophilic amine in
† Dedicated to Dr. S. Ramanathan (Sandoz Research Labs, India),
on his 60th birthday.
* Phone: (313) 996-7452. Fax: (313)-996-5165. email: nikams@
aa.wl.com.
(1) Reviews on the Mitsunobu reaction: Mitsunobu, O. Synthesis
1981, 1. Hughes, D. L. Org. React. 1992, 42, 335.
(2) Comins, D. L.; Gao, J . Tetrahedron Lett. 1994, 35, 2819.
(3) Walker, M. A. J . Org. Chem. 1995, 60, 5352.
(4) Edwards, M. L.; Stemerick, D. M.; McCarthy, J . R. Tetrahedron
Lett. 1990, 31, 3417.
(5) Fukuyama, T.; J ow, C. K.; Cheung, M. Tetrahedron Lett. 1995,
36, 6373; Henry, J . R.; Marcin, L. R.; McIntosh, M. C.; Scola, P. M.;
Harris, G. D.; Weinreb, S. M. Tetrahedron Lett. 1989, 30, 5709.
(6) Fabiano, E.; Golding, B. T.; Sadeghi, M. M. Synthesis 1987, 190.
(7) Pfister, J . R. Synthesis 1984, 969.
(10) The activated benzyl alcohol was prepared from 2-amino-6-
methylbenzoic acid, following the procedure given: Utaka, M.; Takatsu,
M.; Takeda, A. Bull. Chem. Soc. J pn. 1977, 50, 3276.
(11) For reviews on the chemistry of benzimidazoles, see: Preston,
P. N.; Smith, D. M.; Tennant, G. in Heterocyclic compounds 1981, 40;
Quinoxalines. Cheeseman, G. W. H.; Werstiuk, E. S. G. In Advances
in Heterocyclic Chemistry; Katritzky, A. R., Boulton, A. J ., Eds.;
Academic Press: 1978; Vol. 22, pp 368-425. Condensed Pyrazines.
Cheeseman, G. W. H., Cookson, R. F. In Chemistry of Heterocyclic
Compounds, Weissburger, A., Taylor, E. C., Eds.; 1977; pp 1-261.
(8) Sammes, P. G.; Smith, S. J . Chem. Soc., Chem. Commun. 1983,
682.
(9) Tsunoda, T.; Ozaki, F.; Shirakata, N.; Tamaoka, Y.; Yamamoto,
H.; Ito, S. Tetrahedron Lett. 1996, 37, 2463.
S0022-3263(96)01738-0 CCC: $14.00 © 1997 American Chemical Society

Notes
J . Org. Chem., Vol. 62, No. 11, 1997 3755
Ta ble 1. Ben zyla m in es 2 Syn th esized via th e Mitsu n obu
P r otocol
Sch em e 4
entry
no.
yield
(%)
R1
R2
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
Me
Et
n-Pr
n-Bu
i-Pr
Me
Me
Me
Me
H
Me
Et
86
45
56
51
(82)a
43
64
60
63
50
33
80
62
65
84
49
74
76
(43)a
70
77
79
81
80
n-Pr
n-Bu
i-Pr
i-Pr
n-Bu
cyclohexyl
2-CH2-1,3-dioxolane
cyclohexyl
azetidinyl
pyrrolidinyl
Sch em e 5
2-methylpyrrolidinyl
2,5-dimethylpyrrolidinyl
piperidinyl
2-methylpiperidinyl
4-methylpiperidinyl
3,5-dimethylpiperidinyl
morpholinyl
thiomorpholinyl
4-methylpiperazinyl
azepinyl
octahydroquinolinyl
octahydroisoquinolinyl
give the desired benzylamines on reaction with piperidine
as the amine under the Mitsunobu reaction conditions
described earlier. These observations can be explained
by the mechanism postulated in Scheme 4. Thus, the
reaction of benzyl alcohol 1 with amines is probably a
typical conjugate addition of the nucleophilic amines to
an azaquinodimethane intermediate 6. The azaquin-
odimethane intermediate in turn could be generated via
the rearrangement of the PPh3 complex 5 by initial
deprotonation of the o-amino group. The significance of
the electron-withdrawing group ortho to the amine
functionality in 1 is thus obvious, in that it facilitates
deprotonation of the primary amino group by the hydra-
zine base to generate the azaquinodimethane intermedi-
ate 6. In support of this assumption is the observation
that the 3,5-dibromobenzyl alcohol derivative (entry no.
5, Table 2) also produced the desired amine under
identical Mitsunobu conditions in good yield. The reac-
tion of the N,N-dimethylamino compound (no. 6) with
piperidine under the reaction conditions mentioned above
did not give the desired benzylamine. This result con-
firms the importance of the deprotonation step and the
generation of the azaquinodimethane intermediate. As
noted in Scheme 5, appropriately substituted phenolic
alcohols also underwent this reaction to yield the desired
benzylamines. The success of this reaction further sup-
ports the mechanism postulated for the formation of the
benzylamines, which in this case probably proceeds via
the conjugate addition of piperidine to the o-quinone
methide intermediate 9. The desmethyl analog (Table
2, no. 4, R4 ) H) gave the desired benzylamine in
comparable yield to the corresponding methyl derivative
(Table 1, no. 14) indicating that the methyl group does
not play a major role in the formation of the products or
the overall mechanism of the reaction.
a
Yield starting from benzyl bromide derivative 3.
Sch em e 3. Syn th esis of Ben zyla m in es 2 via
Ben zyl Br om id e 3
Ta ble 2. Mitsu n obu Rea ction of P ip er id in e w ith
Va r iou sly Su bstitu ted Ben zyl Alcoh ols
entry no.
R1
R2
R3
R4
yield (%)
1
2
3
4
5
6
7
H
NH2
H
NH2
NH2
NMe2
OH
H
H
H
H
H
H
Br
H
H
H
H
H
H
H
Me
H
NRa
NR
NR
60
68
NR
27
NO2
NO2
Br
NO2
NO2
a
NR ) no reaction.
the reaction mixture before the hydrazine base is gener-
ated in the reaction.
Con clu sion
Several other experiments were carried out to inves-
tigate the mechanism of the reaction (Table 2). On the
basis of these results it was obvious that a meta electron-
withdrawing group and an amino group ortho to the
hydroxymethyl moiety are very important for the success
of these reactions. Unsubstituted benzyl alcohol, o-
aminobenzyl alcohol, or m-nitrobenzyl alcohol did not
In summary, we have developed a new method for the
synthesis of versatile multifunctional benzylamines using
mild Mitsunobu conditions which most likely proceeds
via conjugate addition of amines to the azaquinodimethane
or o-quinodimethane intermediates. On the basis of this
mechanism we are currently exploring alternate routes

3756 J . Org. Chem., Vol. 62, No. 11, 1997
Notes
No. 11: 1H-NMR δ 1.26 (m, 2H), 2.03 (quintet, 2H), 2.32 (s,
3H), 3.14 (t, J ) 7.1 Hz, 2H), 3.62 (s, 2H), 6.46 (d, J ) 8.8 Hz,
1H), 7.07 (bs, 2H), 7.98 (d, J ) 8.8 Hz, 1H); MS (CI) m/ z 222
(M + H).
to synthesize other 6-hetero-2-nitroanilines more ef-
ficiently.
No. 12: 1H-NMR δ 7.91 (d, J ) 8.8 Hz, 1H), 7.81 (bs, 2H),
6.42 (d, J ) 8.8 Hz, 1H), 3.68 (s, 2H), 2.48 (m, 4H), 2.30 (s, 3H),
1.75 (m, 4H), MS: (CI) m/ z 236 (M + H).
Exp er im en ta l Section
Ma ter ia ls. All chemicals were purchased from Aldrich and
were used without additional purification. 1H-NMR spectra
were recorded at 400 MHz in CDCl3. The starting material for
entry no. 7 in Table 2, 2-hydroxy-3-nitrobenzyl alcohol, was made
by reducing a solution of 3-nitrosalicyclic acid in THF with BH3‚-
THF (1.0 M solution). 2-(N,N-Dimethylamino)-6-methyl-3-ni-
trobenzyl alcohol (entry 6, Table 2) was made by treating the
O-TIPS ether of 1 with methyl iodide in the presence of NaH in
DMF and subsequent deprotection of the silyl ether with TBAF
solution in THF.
Gen er a l P r oced u r e for Syn th esis of Su bstitu ted Ben -
zyla m in es Sta r tin g fr om th e Cor r esp on d in g Ben zyl Alco-
h ols u n d er Mitsu n obu Con d ition s. To a stirred solution of
the benzyl alcohol (0.91 g, 5 mmol), PPh3 (1.96 g, 7.5 mmol),
and amine, e.g. N-methylisopropylamine (0.547 g, 7.5 mmol) in
benzene (10 mL) was added DEAD (1.31 g, 7.5 mmol) under N2
at 5 °C. The reaction mixture was allowed to warm to rt and
was stirred for additional 2 h. The reaction was monitored by
TLC (SiO2, petroleum ether/ethyl acetate, 1:1). The dark
reaction mixture was concentrated on a rotary evaporator (∼50
°C) to give a viscous oil. The product was purified by column
chromatography (SiO2, petroleum ether/ethyl acetate, 95:5 to 80:
20). The yield of the product (Table 1, entry no. 6) was 0.55 g,
43%: 1H-NMR δ 1.02 (d, 3H, J ) 6.6 Hz), 1.03 (d, 3H, J ) 6.6
Hz), 2.07 (s, 3H), 2.28 (s, 3H), 2.81 (m, 1H), 6.41 (d, 1H, J ) 9.1
Hz), 7.9 (d, 1H, J ) 9.1 Hz), 7.89-7.9 (bs, 2H); MS (CI) m/ z )
237.3 (M + H). Anal. Calcd for C12H19N3O2: C, 60.74; H, 8.07;
N, 17.71. Found: C, 60.9; H, 8.01; N, 17.8.
No. 13: 1H-NMR δ 1.17 (d, J ) 6.1 Hz, 1H), 1.37-1.45 (m,
1H), 1.6-1.68 (m, 2H), 1.93-2.01 (m, 1H), 2.08 (q, 1H), 2.3 (s,
3H), 2.35-2.42 (m, 1H), 2.77-2.82 (m, 1H), 6.42 (d, J ) 8.8 Hz,
1H), 7.85 (bs, 2H), 7.9 (d, J ) 8.8 Hz, 1H); MS (CI) m/ z 250
(M + H).
No. 14: 1H-NMR δ 0.97 (d, J ) 6.3 Hz, 3H), 0.98 (d, J ) 6.2
Hz, 3H), 1.29-1.42 (m, 2H), 1.81-1.9 (m, 2H), 2.32-1.42 (s, 3H),
2.57 (q, 2H), 3.71 (s, 2H), 6.41 (d, J ) 8.8 Hz, 1H), 7.86 (bs, 2H),
7.90 (d, J ) 8.8 Hz, 1H); MS (CI) m/ z 264 (M + H). Anal. Calcd
for C13H19N3O2, C, 63.85; H, 8.04; N, 15.96. Found: C, 63.82;
H, 7.94; N, 15.83.
No. 15: 1H-NMR δ 1.49 (m, 6H), 2.27 (s, 3H), 2.35 (bs, 4H),
3.52 (s, 2H), 6.42 (d, J ) 9 Hz, 1H), 7.84 (bs, 2H), 7.91 (d, J )
9 Hz, 1H); MS (CI) m/ z 250 (M + H). Anal. Calcd for
C
13H19N3O2, C, 62.63; H, 7.68; N, 16.85. Found: C, 62.75; H,
7.86; N, 16.62.
No. 16: 1H-NMR δ 1.19 (d, J ) 6.1 Hz, 3H), 1.41 (m, 5H),
1.64 (m, 2H), 1.91 (m, 1H), 2.27 (s, 3H), 2.63 (m, 1H), 3.33 (d, J
) 13.2 Hz, 1H), 4.0 (d, J ) 13.2 Hz, 1H), 6.41 (d, J ) 9 Hz, 1H),
7.90 (d, J ) 9 Hz, 1H), 7.95 (bs, 2H); MS (CI) m/ z 264 (M + H).
No. 17: 1H-NMR δ 0.88 (d, J ) 6.6 Hz, 3H), 1.14 (m, 2H),
1.35 (m, 1H), 1.59 (d, 2H, J ) 12.9 Hz), 1.95 (t, 2H, J ) 11.6
Hz), 2.79 (d, 2H, J ) 11.5 Hz), 3.53 (s, 2H), 6.42 (d, 1H, J ) 9
Hz), 7.83 (bs, 2H), 7.91 (d, 1H, J ) 8.8 Hz); MS (CI) m/ z 264
(M + H). Anal. Calcd for C14H21N3O2, C, 63.85; H, 8.04; N,
15.96. Found: C, 64.27; H, 8.18; N, 15.89.
No. 18: 1H-NMR δ 0.52 (q, 1H), 0.80 (d, 6H, J ) 6.3 Hz), 1.27
(m, 1H), 1.46 (t, 1H, J ) 10.9 Hz), 1.69 (m, 3H), 2.27 (s, 3H),
2.73 (d, 2H, J ) 8.8 Hz), 3.52 (s, 2H), 6.43 (d, 1H, J ) 8.8 Hz),
7.82 (bs, 2H), 7.92 (d, 1H, J ) 8.8 Hz); MS (CI) m/ z 278 (M +
H). Anal. Calcd for C15H13N3O2, C, 64.96; H, 8.36; N, 15.15.
Found: C, 64.87; H, 8.30; N, 14.88.
No. 19: 1H-NMR δ 2.34 (s, 3H), 2.37-2.48 (m, 4H), 3.63 (s,
3H), 3.71-3.73 (m, 4H), 6.49 (d, 1H, J ) 8.8 Hz), 7.65 (bs, 2H),
7.98 (d, 1H, J ) 8.8 Hz); MS (CI) m/ z 252 (M + H). Anal. Calcd
for C12H17N3O3, C, 57.36; H, 6.82; N, 16.72; Found: C, 57.72; H,
6.98; N, 16.5.
Spectral data for the compounds (entry nos) synthesized and
listed in Table 1 follow.
No. 1: 1HNMR δ 2.21 (s, 6H), 2.35 (s, 3H), 3.55 (s, 2H), 6.45
(d, J ) 6.5 Hz, 1H), 7.77 (bs, 2H), 7.95 (d, J ) 6.5 Hz, 1H); MS
(CI) m/ z 210 (M + H).
No. 2: 1H-NMR δ 1.03 (t, J ) 7.2 Hz, 6H), 2.28 (s, 3H), 2.46
(q, 4H), 3.63 (s, 2H), 6.41 (d, J ) 8.8H, 1 Hz), 7.90 (d, J ) 8.8 H,
1 Hz), 7.95 (bs, 2H); MS (CI) m/ z 238 (M + H).
No. 3: 1H-NMR δ 0.83 (t, J ) 7.3 Hz, 6H), 1.48 (septet, 4H),
2.27 (s, 3H), 2.32 (t, J ) 7.4 Hz, 4H), 3.62 (s, 2H), 6.42 (d, J )
8.8 Hz, 1H) 7.91 (d, J ) 8.8 Hz, 1H); MS (CI) m/ z 266 (M + H).
No. 4: 1H-NMR δ 0.84 (t, J ) 7.3 Hz, 6H), 1.23 (sextet, 4H),
1.43 (quintet, 4H), 2.27 (s, 3H), 2.35 (t, J ) 7.4 Hz, 4H), 3.62 (s,
2H), 6.42 (d, J ) 9 Hz, 1H), 7.91(d, J ) 8.8 Hz, 3H), 7.9-7.92
(bs, 2H); MS (CI) m/ z 294 (M + H).
No. 20: 1H-NMR δ 2.28 (s, 3H), 2.62-2.63 (m, 4H), 2.64-
2.69 (m, 4H), 3.58 (s, 2H), 6.45 (d, J ) 9 Hz, 1H), 7.58 (bs, 2H),
7.94 (d, J ) 8.9 Hz, 1H); MS (CI) m/ z 268 (M + H). Anal. Calcd
for C12H17N3O2S, C, 53.93; H, 6.36; N, 15.73. Found: C, 53.57;
H, 6.36; N, 15.29.
No. 5: 1H-NMR δ 1.10 (d, J ) 6.6 Hz, 12H), 2.34 (s, 3H), 3.03
(septet, 2H), 3.82 (s, 2H), 6.43 (d, J ) 8.8 Hz, 1H), 7.92 (d, J )
9.0 Hz, 1H), 8.15 (bs, 2H); MS (CI) m/ z 266 (M + H). Anal.
Calcd for C14H23N3O2, C, 63.37; H, 8.74; N, 15.84; Found: C,
63.36; H, 8.48; N, 15.84.
No. 6: 1H-NMR δ 1.02 (d, J ) 6.6 Hz, 3H), 1.03 (d, J ) 6.6
Hz, 3H), 2.07 (s, 3H), 2.28 (s, 3H), 2.81 (m, 1H), 6.41 (d, J ) 9.1
Hz, 1H), 7.9 (d, J ) 9.1 Hz, 1H), 7.89-7.9 (bs, 2H); MS (CI) m/ z
237.3 (M + H). Anal. Calcd for C12H19N3O2, C, 60.74; H, 8.07;
N, 17.8; Found: C, 60.9; H, 8.01; N, 17.71.
No. 21: 1H-NMR δ 2.09 (s, 3H), 2.25 (s, 3H), 2.35 (m, 8H),
3.51 (s, 2H), 6.49 (d, 1H, J ) 8.8 Hz), 7.62 (bs, 2H), 7.80 (d, 1H,
J ) 8.8 Hz); MS (CI) m/ z 265 (M + H).
No. 22: 1H-NMR δ 1.57 (bs, 8H), 2.27 (s, 3H), 2.54 (m, 4H),
3.64 (s, 2H), 6.42 (d, 1H, J ) 8.8 Hz), 7.91 (d, 1H, J ) 8.8 Hz),
7.95 (bs, 2H); MS (CI) m/ z 264 (M + H).
No. 23: 1H-NMR δ 0.84-0.97 (m, 3H), 1.06-1.24 (m, 4H),
1.45-1.68 (m, 6H), 1.92-1.99 (m, 1H), 2.63-2.66 (m, 1H), 2.82-
2.85 (m, 1H), 3.52 (s, 3H), 6.42 (d, 1H, J ) 8.8 Hz), 7.84 (bs,
2H), 7.91 (d, 1H, J ) 8.8 Hz); MS (CI) m/ z 304 (M + H).
No. 24: 1H-NMR δ 0.94-1.87 (m, 4H), 2.26 (s, 3H), 2.26 (s,
3H), 2.25-2.3 (m, 1H), 2.67-2.71 (m, 1H), 3.22 (d, 1H, J ) 13.2
Hz), 4.10 (d, 1H, J ) 13.2 Hz), 6.40 (d, 1H, 8.8 Hz), 7.89 (d, 1H,
8.8 Hz), 7.94 (bs, 2H); MS (CI) m/ z 304 (M + H).
No. 7: 1H-NMR δ 0.86 (t, J ) 7.3 Hz, 3H), 1.27 (sextet, 2H),
1.46 (quintet, 2H), 2.28 (s. 3H), 2.32 (t, J ) 7.4 Hz, 2H), 3.54 (s,
2H), 6.43 (d, J ) 8.8 Hz, 1H), 7.81 (bs, 2H), 7.92 (d, J ) 8.8 Hz,
1H); MS (CI) m/ z 252 (M + H).
No. 8: 1H-NMR δ 1.20 (m, 5H), 1.60 (d, J ) 12.5 Hz, 1H),
1.78 (m, 4H), 2.12 (s, 3H), 2.27 (s, 3H), 2.35 (m, 1H), 3.69 (s,
2H), 6.41 (d, J ) 8.8 Hz, 1H), 7.89-7.91 (bs, 2H), 7.90 (d, J )
8.8 Hz, 3H); MS (CI) m/ z 278 (M + H).
2-Am in o-6-m eth yl-3-n itr oben zyl Br om id e (3). To a mix-
ture of PPh3 (1.729 g, 6.6 mmol) and CBr4 (2.18 g, 6.6 mmol) in
anhydrous ether (50 mL) was added 2-amino-6-methyl-3-ni-
trobenzyl alcohol (1) (1.092 g, 6 mmol) with vigorous stirring at
rt. The reaction was monitored by TLC (SiO2, petroleum ether/
EtOAc, 1:1). On completion, the supernatant was decanted and
the yellow residue triturated with additional ether (2 × 100 mL).
The ether extracts were combined and evaporated to give a
sticky orange solid (4.43 g). The crude material was purified
by flash column chromatography (SiO2, petroleum ether/EtOAc,
9:1 to 8:2). The product was isolated as a yellow solid (0.925 g,
63%) and used immediately for coupling with the amines. The
product was unstable at rt and under N2 atmosphere and on
storage gave a polar orange residue.
No. 9: 1H-NMR δ 2.24 (s, 3H), 2.28 (s, 3H), 2.60 (d, J ) 4.1
Hz, 2H), 3.64 (s, 2H), 3.82-3.86 (m, 2H), 3.88-3.97 (m, 2H),
4.97 (t, J ) 4.1 Hz, 1H), 6.41 (d, J ) 8.8 Hz, 1H), 7.67 (bs, 2H),
7.92 (d, J ) 9 Hz, 1H); MS (CI) m/ z 282 (M + H). Anal. Calcd
for C13H19N3O4, C, 55.51; H, 6.81; N, 14.94; Found: C, 55.63; H,
6.77; N, 14.88.
No. 10: 1H-NMR δ 1.18 (m, 6H), 1.65 (m, 3H), 1.91 (m, 2H),
2.29 (s, 3H), 2.44 (m, 1H), 3.87 (s, 2H), 6.43 (d, J ) 8.8 Hz, 1H),
7.69 (bs, 2H), 7.91(d, J ) 8.8 Hz, 1H); MS (CI) m/ z 264
(M + H).

Notes
Gen er a l P r oced u r e for Syn th esis of Ben zyla m in es fr om
J . Org. Chem., Vol. 62, No. 11, 1997 3757
Ack n ow led gm en t. The authors wish to thank their
colleagues in the analytical department for the analyti-
cal and spectral data.
Ben zyl Br om id e. Syn th esis of 2-Am in o-6-m eth yl-3-n itr o-
N,N-d iisop r op ylben zyla m in e (Ta ble 1, n o. 5). To a solution
of benzyl bromide (0.925 g, 3.77 mmol) in anhydrous THF (5
mL) was added diisopropylamine (2 mL, 25 mmol) with stirring.
The reaction mixture was stirred overnight and filtered. The
filtrate was evaporated to dryness and extracted with EtOAc (2
× 50 mL). The EtOAc extracts were washed with water and
dried over MgSO4. The product was purified by column chro-
matography (SiO2, petroleum ether/EtOAc, 1:1) and isolated as
a yellow solid (0.811g 82%): 1H-NMR δ 1.10 (d, 12H, J ) 6.6
Hz), 2.34 (s, 3H), 3.03 (septet, 2H), 3.82 (s, 2H), 6.43 (d, 1H, J )
8.8 Hz), 7.92 (d, 1H, J ) 9.0 Hz), 8.15 (bs, 2H); MS (CI) m/ z
266 (M + H). Anal. Calcd for C14H23N3O2, C, 63.37; H, 8.74; N,
15.84; Found: C, 63.36; H, 8.48; N, 15.84.
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H-NMR
(400 MHz) spectra of new compounds (Table 1, entries 1-24,
and Table 2, entries 4, 5, and 7) (53 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
J O961738V