Synthesis of substituted benzhydrylamines

Article abstract of DOI:10.1055/s-2002-19328

The synthesis of para di- and monosubstituted benzhydrylamines by addition of Grignard reagents to benzonitriles and subsequent reduction, is evaluated and discussed. The reduction step with sodium borohydride allows simple handling and mild conditions. An optimized synthesis of 4,4'-dimethoxybenzhydrylamine by this method is disclosed.

Full text of DOI:10.1055/s-2002-19328

LETTER
113
Synthesis of Substituted Benzhydrylamines
S
ynthesis of substi
v
tuted Benzhy
e
drylamines Dejaegher, Sven Mangelinckx, Norbert De Kimpe*
Department of Organic Chemistry, Faculty of Agricultural and Applied Biological Sciences, Ghent University, Coupure Links 653,
9000 Ghent, Belgium
Fax +32(9)2646243; E-mail: norbert.dekimpe@rug.ac.be
Received 26 July 2001
In this letter, the synthesis of para di- and monosubstitut-
ed benzhydrylamines, including an optimized procedure
for the synthesis of 4,4’-dimethoxybenzhydrylamine, by
reaction of bromobenzene derived Grignard reagents with
Abstract: The synthesis of para di- and monosubstituted benzhy-
drylamines by addition of Grignard reagents to benzonitriles and
subsequent reduction, is evaluated and discussed. The reduction
step with sodium borohydride allows simple handling and mild con-
ditions. An optimized synthesis of 4,4’-dimethoxybenzhydrylamine benzonitriles and subsequent reduction with sodium boro-
by this method is disclosed.
hydride, is disclosed. A one-pot synthesis of 4,4’-
dimethoxybenzhydrylamine is also described.
Key words: benzhydrylamines, Grignard reactions, diphenylmeth-
ylidenamines, diarylketimines, reductions, protecting groups
For the synthesis of the diphenylmethylidenamine deriva-
tives 2, the work published by Pickard et al. was used as a
starting point.9a,b To an ethereal solution of the Grignard
reagents, derived from bromobenzenes 1, benzonitriles,
dissolved in diethyl ether, were added. After 5 hours of re-
flux, the mixture was cooled and dry methanol was added.
Filtration and evaporation of the solvent yielded the
diphenylmethylidenamine derivatives 2 in good yields
and purity (see Scheme and Table). Although further pu-
rification was not really necessary to perform the reduc-
tion step, this could be performed either by distillation
(entry a, c, d) or crystallization from toluene (entry b, e)
or from hexane/cyclohexane (1:1) (entry e).
Benzhydrylamine and its substituted derivatives form an
important class of compounds in organic synthesis be-
cause of their use as protecting groups.1 The benzhydryl-
amine moiety can be cleaved by hydrogenation, acid hy-
drolysis or radical reaction with ceric ammonium nitrate
(in the case of 4,4’-dimethoxybenzhydrylamine). Further-
more, these diarylmethylamines are present in a wide va-
riety of physiologically interesting compounds.2
A wide array of syntheses of benzhydrylamines are
known, based on transformations of the corresponding
benzhydrols,1a,b,3 reduction of the oxime derivatives,4 re-
ductive amination of benzophenone precursors,1c,5 and ad-
dition of organometallic reagents to either aldimines,6 N-
boryl imines,7 quaternary hydrazonium salts8 or nitriles.9
In the case of bis(4-methoxyphenyl)methanimine 2e, a
precipitate was formed directly after the addition of the 4-
methoxybenzonitrile to the corresponding Grignard re-
agent, derived from 1-bromo-4-methoxybenzene. During
further reflux, this precipitate dissolved. It is believed that
this possibly accounted for the lower yield observed in
this case, corresponding to literature data.10,11 Performing
the reaction in tetrahydrofuran, there was no precipitate
formed. However, after quenching with methanol, partial
evaporation of tetrahydrofuran and addition of diethyl
ether, a precipitate was formed, that we assumed to be
methoxymagnesium bromide. After filtration and evapo-
ration of the solvent, the imine 2e was obtained in only
45% yield. It was observed that the solubility of 2e in di-
However, while using the latter method in our own re-
search, we found some inadequacies in the literature con-
cerning this topic. In most of the papers discussing
Grignard addition of bromobenzene derivatives to substi-
tuted benzonitriles, the synthesis of bis(4-methoxyphe-
nyl)methylidenamine (precursor to the more interesting
4,4’-dimethoxybenzhydrylamine) is not performed nor
discussed.9 In other papers, this latter experiment has been
performed, but only with very low or moderate yields
(10–20%,10 54%11).
1) Mg, Et2O
2)
CN
NH
NH2
Br
R2
Et2O, ∆, 5h
3) MeOH
NaBH4, MeOH
∆, 2h
R1
R1
R1
R2
R2
3
1
2
Scheme
Synlett 2002, No. 1, 28 12 2001. Article Identifier:
1437-2096,E;2002,0,01,0113,0115,ftx,en;G16101ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

114
Y. Dejaegher et al.
LETTER
Table Substitution Pattern and Yields of Imines 2 and Amines 3
0 °C, dry methanol was added, and after 20 minutes, also
sodium borohydride (2 molar equiv) was added. After
stirring for 1 hour at room temperature and 1 hour of re-
flux, the amine 3e was obtained with an overall yield of
85%. Accordingly, this highly valuable amine 3e in N-
protection/N-deprotection protocols becomes now readily
available.
Entry R1
R2
Yield 2 b.p. (°C/mmHg) Yield 3
(%)
70a
75b
50a
50a
51c
(%)
99
95
98
98
94
a
b
c
d
e
H
H
166 / 11.5
Me
H
Me
Me
Me
MeO
–
91/0.04
135/0.08
–
References
MeO
MeO
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a Yields before distillation were 90–95% with > 90% purity based on
1H NMR; yields dropped because of small scale distillation.
b Yield after crystallization from toluene.
c Yield of the crude reaction product.
(2) (a) Estiu, G. L.; Cachau, R. E.; Castro, E. A. Il Farmaco
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ethyl ether is very low, so bis(4-methoxyphenyl)meth-
ylidenamine 2e was probably also partially precipitated
after the removal of tetrahydrofuran and addition of dieth-
yl ether. For this reason, the application of an alternative
work-up procedure (extraction with water/diethyl ether or
dichloromethane) was performed. Now, it was observed
that the crude yields of the reaction product 2e improved
to almost 100%, either using diethyl ether or tetrahydro-
furan as solvent. However, recrystallization from toluene
or hexane–cyclohexane (1:1) decreased the yield of the
pure product to 50%, as was already observed in the afore-
mentioned publications. Taking advantage of observing
the low solubility of the imine 2e in diethyl ether, the latter
compound was dissolved in a minimal amount of dichlo-
romethane and diethyl ether was added until precipitation
started. This increased the overall yield of the reaction to
80% after purification. In conclusion, changing the work-
up procedure and solvents for crystallization allowed to
increase the yield of bis(4-methoxyphenyl)methanimine
2e from 51% to 80% for the pure compound.
(5) Wakamiya, T.; Kamata, M.; Kusumoto, S.; Kobayashi, H.;
Sai, Y.; Tamai, I.; Tsuji, A. Bull. Chem. Soc. Jpn. 1998, 71,
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(6) Katritzky, A. R.; Xie, L.; Zhang, G. Tetrahedron Lett. 1997,
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The subsequent reduction of the diphenylmethanimine
derivatives 2 with sodium borohydride in methanol is very
mild and effective (see Scheme). The resulting benzhy-
drylamines 3 were obtained in excellent yields (see Ta-
ble). Previously, reduction of substituted diphenyl-
methylidenamines 2 to the corresponding amines 3 had
only been performed with less common and sometimes
not easy-to-handle reductive systems, including zinc pow-
der in aqueous sodium hydroxide solution,12 diphenylsi-
lane in the presence of various titanocene complexes,13
ytterbium in THF/HMPA,14 irradiation in isopropanol,15
lithium in HMPT16 and hydrogenation in the presence of
nickel.17 Three tandem alkylation-reduction methods have
also been described in the literature. The reduction was
performed with lithium in ammonia,9c,d lithium alumini-
um hydride18 and zinc borohydride, respectively.19 How-
ever, none of these methods was performed towards the
synthesis of amine 3e. Finally, this tandem arylation-re-
duction method was applied to the synthesis of bis(4-
methoxyphenyl)methylidenamine 2e.20 After the Grig-
nard addition, the reaction mixture was cooled down to
(7) Itsuno, S.; Hachisuka, C.; Ito, K. J. Chem. Soc., Perkin
Trans. 1 1991, 1767.
(8) Smith, P. A. S.; Tan, H. H. J. Org. Chem. 1967, 32, 2586.
(9) (a) Pickard, P. L.; Tolbert, T. L. Organic Synthesis,
Collective Volume V; Baumgarten, H. E., Ed.; Wiley: New
York, 1973, 520. (b) Pickard, P. L.; Tolbert, T. L. J. Org.
Chem. 1961, 26, 4886. (c) Weiberth, F. J.; Hall, S. S. J. Org.
Chem. 1986, 51, 5338. (d) Weiberth, F. J.; Hall, S. S. J. Org.
Chem. 1987, 52, 3901.
(10) Knoop, F. W. E.; Buck, H. M.; Oosterhoff, L. J. Recl. Trav.
Chim. Pays-Bas 1968, 87, 847.
(11) Thoman, C. J.; Hunsberger, I. M. J. Org. Chem. 1968, 33,
2852.
(12) Tsukinoki, T.; Mitoma, Y.; Nagashima, S.; Kawaji, T.;
Hashimoto, I.; Tashiro, M. Tetrahedron Lett. 1998, 39,
8873.
(13) Tillack, A.; Lefeber, C.; Peulecke, N.; Thomas, D.;
Rosenthal, U. Tetrahedron Lett. 1997, 38, 1533.
(14) Takaki, K.; Tsubaki, Y.; Tanaka, S.; Beppu, F.; Fujiwara, Y.
Chem. Lett. 1990, 203.
(15) Fischer, M. Chem. Ber. 1967, 3599.
(16) Larcheveque, M. Bull. Soc. Chim. Fr. 1968, 3387.
(17) Cantarel, R. Compt. Rend. 1940, 210, 403; Chem. Abstr.
1940, 34, 3712.
Synlett 2002, No. 1, 113–115 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of Substituted Benzhydrylamines
115
(18) Pohland, A.; Sullivan, H. R. J. Am. Chem. Soc. 1953, 75,
5898.
The solution is stirred for 1 h at r.t. and 1 h reflux.
Subsequently, the mixture is filtered over Celite and the
(19) Kotsuki, H.; Yoshimura, N.; Kadota, I.; Ushio, Y.; Ochi, M.
Synthesis 1990, 401.
filtrate partially evaporated. The remaining liquid is poured
into 200 mL 0.5 N HCl solution and extracted 3 times with
25 mL diethyl ether. After addition of 2 N NaOH untill pH
9–10, the water phase is extracted with 3 times 50 mL
CH2Cl2. The combined organic phases are dried (MgSO4).
After filtration and evaporation of the solvent, 7.71 g of
amine 3e is obtained. Yield: 85%. Spectroscopic data for
compound 3e: 1H NMR (270 MHz, CDCl3): = 1.79 (2 H,
br s, NH2); 3.78 (6 H, s, 2 OMe); 5.13 (1 H, s, CHNH2);
6.84 and 7.27 (4 H each, d each, J = 8.6 Hz, CHar); 13C NMR
(68 MHz, CDCl3): = 55.24 (2 OMe); 58.45 (CHNH2);
113.76 and 127. 83 (CHar); 138.15 and 158.45 (Car,quat.); IR
(KBr, cm–1): 3370, 1608, 1585, 1509, 1466;3c MS (70eV):
m/z (%) = 243(10) [M+], 242(54), 241(34), 227(9), 226(39),
211(14), 183(6), 135(81), 134(100), 133(47), 109(9); mp
(Büchi 540 melting point apparatus, uncorrected): 58–59 °C.
(20) General Procedure for the one-pot synthesis of 4,4’-
Dimethoxybenzhydrylamine 3e : In an oven-dry bulb, 1.01
g (43 mmol) of magnesium is suspended in 15 mL dry THF.
At r.t., some drops of 4-bromoanisole are added. In order to
initiate the reaction, the resulting mixture is scratched with a
spatula. If necessary, a crystal of iodine might be added, and
the solution might be heated. Once initiated, the remaining
of 7.73 g (41 mmol) of 4-bromoanisole were added in 8 mL
THF, in order to maintain gentle reflux. When the addition
is completed, the mixture is refluxed for another 45 min.
After cooling to r.t., 5 g (37.5 mmol) of anisonitrile in 8 mL
dry THF is added over 20 min. After additional reflux for 5
h, the reaction mixture is cooled in an ice bath and 30 mL
dry methanol is carefully added. After stirring for 20 min,
2.86 g (75 mmol) sodium borohydride is added in portions.
Synlett 2002, No. 1, 113–115 ISSN 0936-5214 © Thieme Stuttgart · New York