Use of functionalized aromatic organozinc reagents in the three-component Mannich-type synthesis of diarylmethylamines

Article abstract of DOI:10.1016/j.tetlet.2006.02.056

Efficient syntheses of functionalized diarylmethylamines have been realized according to a one-step three-component coupling between an aromatic aldehyde, a secondary amine and an aromatic organozinc reagent. Phenyl rings can be substituted by functional

Full text of DOI:10.1016/j.tetlet.2006.02.056

Tetrahedron Letters 47 (2006) 2497–2500
Use of functionalized aromatic organozinc reagents in the
three-component Mannich-type synthesis of diarylmethylamines
*
Erwan Le Gall, Michel Troupel and Jean-Yves N e´ d e´ lec
Laboratoire d’Electrochimie, Catalyse et Synth e` se Organique, LECSO, CNRS-Universit e´ Paris 12 Val de Marne,
UMR 7582, 2-8 rue Henri Dunant, 94320 Thiais, France
Received 14 December 2005; revised 1 February 2006; accepted 13 February 2006
Available online 28 February 2006
Abstract—Efficient syntheses of functionalized diarylmethylamines have been realized according to a one-step three-component cou-
pling between an aromatic aldehyde, a secondary amine and an aromatic organozinc reagent. Phenyl rings can be substituted by
functional groups and either aromatic or non-aromatic amines can be used in this process.
Ó 2006 Elsevier Ltd. All rights reserved.
Diarylmethylamines constitute an important class of
amines, which are present in many structures showing
pharmacological activities and during the last years,
was also successfully employed in the synthesis of the
enantiomerically pure antihistamine agent cetirizine.
6
1
there was a growing interest in their enantioselective
syntheses. Although chiral reductions of benzophenone
chromium tricarbonyl complexes followed by amination
In the field of racemate synthesis, numerous diarylmeth-
ylamines and especially diarylmethylpiperazines with
potent biological activity were recently synthesized using
a three-step procedure involving the formation of diaryl-
2
have been used, most works in this field deal with ste-
3
7
reoselective additions of nucleophiles to imines. It was
methanol in an intermediate step. Reductive amination
previously shown that organometallic reagents react
with chiral imines to furnish diarylmethylamines in good
of carbonyl compounds using polymethylhydrosiloxane
was successfully employed for the synthesis of racemic
alkylarylmethylamines or diarylmethylamines in very
4
enantiomeric excess. Stereoselectivity can also be pro-
5
8
vided through the use of chiral mediators. Thus, it
good yield. Several reactions involving Grignard re-
was demonstrated that in the presence of chiral cata-
lysts, strong nucleophiles like organolithium compounds
agents as the nucleophile have also been reported. For
instance the arylation of iminium salts led to the corre-
sponding coupling product in low to moderate yields. It
5
a,b
9
add stereoselectively to aromatic imines.
When
milder nucleophiles are used, an activation of the
C@N bond can be realized using sulfinyl, sulfonyl,
formyl, or phosphonyl groups. Thus it was shown that
was also shown that the displacement of polymer-sup-
ported benzotriazole using aromatic Grignard reagents
allows the formation of diarylmethylamines in moderate
4
c
5d
10
organoboron or organostannane compounds associ-
ated with a rhodium catalyst react efficiently with acti-
vated imines to furnish coupling products in high yield
and enantiomeric excess. Organozinc reagents react in
a similar manner with activated imines in the presence
to good yield. Several years ago, Petasis et al. de-
scribed a one-step three-component reaction among
1
1
organoboronic acids, amines, and aldehydes. This
method was successfully applied to the synthesis of some
diarylmethylamines bearing a phenol moiety in good
yield. However, it was mentioned that only ortho-
hydroxylated benzaldehydes are efficient in this process.
Recently, organotrifluoroborates were used instead of
arylboronic acids in a Petasis-related reaction to provide
5
e
of a chiral catalyst to provide diarylmethylamines or
5
f
alkylarylmethylamines in excellent yields without
requiring the use of an additional transition metal like
rhodium. A resolution technique involving tartaric acid
1
2
some diarylmethylamines in good yield.
Keywords: Diarylmethylamines; Three-component reaction; Aromatic
organozinc reagents; Aromatic aldehydes; Secondary amines.
To our knowledge, the use of readily available function-
alized aromatic organozinc reagents in three-component
Mannich-type reactions has not been described to date.
*
Corresponding author. Tel.: +33 (0) 1 49 78 11 36; fax: +33 (0) 1 49
8 11 48; e-mail: legall@glvt-cnrs.fr
7
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.02.056

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E. Le Gall et al. / Tetrahedron Letters 47 (2006) 2497–2500
However, these compounds are very mild nucleophiles13
and thus, starting materials can bear various functional-
ities. This feature could potentially allow access to
highly functionalized diarylmethylamines through the
one-step coupling of these reagents with aromatic alde-
hydes and secondary amines. Then, as a part of our
work devoted to the study of organozinc reagents reac-
tivity, we investigated their possible use in Mannich-type
reactions and we report herein our preliminary results.
Organozinc reagents were synthesized efficiently in ace-
tonitrile from the corresponding aryl bromides accord-
Table 1. Three-component coupling between organozinc reagents, secondary amines, and aldehydes
FG1
FG2
R
R'
FG1
N
FG2
R
R'
ZnBr
+
N
H
+
CHO
MeCN
Entry
Organozinc reagent
Amine
Aldehyde
Coupling
method
Reaction
time (h)
Product
Isolated
yield (%)
a
N
1
3
H CO
ZnBr
CHO
A
3
1
88
N
H
OCH3
Cl
N
2
3
H CO
ZnBr
ZnBr
A
A
3
3
2
3
96
83
3
N
H
Cl
CHO
OCH
3
N
3
H CO
NC
CHO
N
H
NC
OCH3
N
4
5
H CO
ZnBr
ZnBr
CHO
CHO
A
A
3
3
4
5
80
96
3
N
H
OCH3
OCH3
S
N
S
3
H CO
N
H
F3C
N
N
6
7
8
CHO
CHO
CHO
B
B
B
4
4
4
6
7
8
83
70
77
N
H
ZnBr
CF
3
EtO C
ZnBr
2
N
H
2
CO Et
CH
3
N
CH3
N
H
ZnBr
a
In coupling method A, CuI (ca. 0.3 equiv vs ArZnX) was added into the organozinc solution before addition of the amine and the aldehyde. In
coupling method B, the organozinc was added dropwise into the pre-heated mixture of the amine and the aldehyde in acetonitrile. See note 15 for
experimental details.

E. Le Gall et al. / Tetrahedron Letters 47 (2006) 2497–2500
2499
ing to a method previously developed in the labora-
herein prompt us to examine the scope of the reaction
and to investigate the mechanism of this coupling.
Furthermore, in the field of asymmetric synthesis,
additional experiments might be realized in the presence
of chiral ligands in order to test the feasibility and
enantioselectivity of the reaction.
tory, which was used after some improvements.15 In
14
order to achieve the three-component coupling reaction,
1
6
two methods were used. The most simple procedure
coupling method A) consisted in the introduction of a
(
1
7
catalytic amount of cuprous iodide in the organo-
zinc-containing acetonitrile solution followed by the
addition of the aromatic aldehyde and the secondary
amine. The mixture was then allowed to react for a
few hours at room temperature. As shown in Table 1
References and notes
(
entries 1–5), this method is very efficient when the phe-
1
. (a) Bishop, M. J.; McNutt, R. W. Bioorg. Med. Chem.
Lett. 1995, 5, 1311–1314; (b) Hamlin, K. E.; Weston, A.
W.; Fischer, F. E.; Michaels, R. J., Jr. J. Am. Chem. Soc.
1949, 71, 2731–2734; (c) Ide, W. S.; Lorz, E.; Phillips, A.
P.; Russell, P. B.; Baltzly, R.; Blumfeld, R. J. Am. Chem.
Soc. 1959, 81, 459–463; (d) Spencer, C. M.; Foulds, D.;
Peters, D. H. Drugs 1993, 46, 1055–1080; (e) Sakurai, S.;
Ogawa, N.; Suzuki, T.; Kato, K.; Ohashi, T.; Yasuda, S.;
Kato, H.; Ito, Y. Chem. Pharm. Bull. 1996, 44, 765–777.
. For reviews on stereocontrolled additions to C@N bonds,
see: (a) Enders, D.; Reinhold, U. Tetrahedron: Asymmetry
nyl moiety of the organozinc compound is substituted
by electron donating groups. However, with an electron
withdrawing substituent on the organozinc reagent, the
dimeric by-product Ar–Ar arising from the starting
ArZnBr is also obtained. In order to avoid this side reac-
tion, the coupling procedure was modified according to
coupling method B in which the organozinc-containing
acetonitrile solution was added dropwise to a pre-heated
mixture of the aromatic aldehyde and the secondary
amine in acetonitrile. The corresponding results are re-
ported in entries 6 and 7 of Table 1. It should be noted
that coupling method B is more versatile since it can be
also applied to compounds bearing electron donating
groups as asserted by entry 8 of Table 1.
2
1
997, 8, 1895–1946; (b) Bloch, R. Chem. Rev. 1998, 98,
1407–1438; (c) Kobayashi, S.; Ishitani, H. Chem. Rev.
1999, 99, 1069–1094.
3. (a) Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1996, 37,
4
1
837–4840; (b) Corey, E. J.; Helal, C. J. Tetrahedron Lett.
995, 36, 9153–9156.
4
5
. (a) Plobeck, N.; Powell, D. Tetrahedron: Asymmetry 2002,
3, 303–310; (b) Delorme, D.; Berthelette, C.; Lavoie, R.;
In each case, the addition of at least 2 equiv of the
organozinc species is required to observe efficient cou-
plings. The need for such quantities of arylzinc reagent
is likely correlated to a base-assisted hydroxide elimina-
tion on the intermediate hemiaminal leading to a formal
iminium ion, which is further attacked by the remaining
organozinc compound. At this stage, the precise role of
each constituent of the reaction medium remains unclear
and efforts are in progress to understand precisely the
mechanism of the reaction.
1
Roberts, E. Tetrahedron: Asymmetry 1998, 9, 3963–3966.
. (a) Cabello, N.; Kizirian, J. C.; Gille, S.; Alexakis, A.;
Bernardinelli, G.; Pinchard, L.; Caille, J. C. Eur. J. Org.
Chem. 2005, 4835–4842; (b) Tomioka, K.; Inoue, I.;
Shindo, M.; Koga, K. Tetrahedron Lett. 1990, 31, 6681–
6684; (c) Weix, D. J.; Shi, Y.; Ellman, J. A. J. Am. Chem.
Soc. 2005, 127, 1092–1093; (d) Hayashi, T.; Ishigedani, M.
J. Am. Chem. Soc. 2000, 122, 976–977; (e) Hermanns, N.;
Dahmen, S.; Bolm, C.; Br a¨ se, S. Angew. Chem. 2002, 114,
3
844–3846; (f) Fujihara, H.; Nagai, K.; Tomioka, K. J.
Am. Chem. Soc. 2000, 122, 12055–12056.
. Opalka, C. J.; D’Ambra, T. E.; Faccone, J. J.; Bodson, S.;
Cossement, E. Synthesis 1995, 766–768.
. Plobeck, N.; Delorme, D.; Wei, Z. Y.; Yang, H.; Zhou, F.;
Schwarz, P.; Gawell, L.; Gagnon, H.; Pelcman, B.;
Schmidt, R.; Yue, S. Y.; Walpole, C.; Brown, W.; Zhou,
E.; Labarre, M.; Payza, K.; St-Onge, S.; Kamassah, A.;
Morin, P. E.; Projean, D.; Ducharme, J.; Roberts, E. J.
Med. Chem. 2000, 43, 3878–3894.
This three-component coupling reaction allows the for-
6
7
1
8
mation of diarylmethylamines in very high yields
70–96%) starting from readily available materials.
(
Experimental conditions are mild and reactions proceed
rather quickly (3–4 h). Electron withdrawing or donat-
ing groups are compatible with this process and it is
worth noting that either a non-aromatic amine (entries
1
–3 and 5–8) or an aromatic amine (entry 4) reacts in
8
9
. Chandrasekhar, S.; Raji-Reddy, C.; Ahmed, M. Synlett
the same manner, furnishing the coupling product in
high yield. Entries 2 and 3 of Table 1 show that func-
tionalized benzaldehydes also react very efficiently.
Highly substituted diarylmethylamines might therefore
be affordable using both substituted organozinc and
aldehyde. It is worth to note that, to our knowledge,
all compounds synthesized using this procedure, except
compound 8, are new products.
2
000, 1655–1657.
. B o¨ hme, H.; Plappert, P. Chem. Ber. 1975, 108, 2827–2833.
1
0. Schiemann, K.; Showalter, H. D. H. J. Org. Chem. 1999,
4, 4972–4975.
1. Petasis, N. A.; Boral, S. Tetrahedron Lett. 2001, 42, 539–
42.
6
1
5
12. Tremblay-Morin, J. P.; Raeppel, S.; Gaudette, F. Tetra-
hedron Lett. 2004, 45, 3471–3474.
1
3. (a) Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93, 2117–
188; (b) Knochel, P.; Jones, P. In Organozinc Reagents, A
2
In conclusion, preliminary results reported in this letter
demonstrate that organozinc aromatic reagents are suit-
able nucleophiles in Mannich-type reactions involving
secondary amines and benzaldehyde derivatives. This
three-component coupling seems sufficiently versatile
to allow numerous combinations between secondary
amines, aromatic aldehydes, and starting aromatic bro-
mides thus providing a potential access to highly substi-
tuted diarylmethylamines. Preliminary results presented
Practical Approach; Harwood, L. M., Moody, C. J., Eds.;
Oxford University Press: Oxford, 1999.
4. Fillon, H.; Gosmini, C.; P e´ richon, J. J. Am. Chem. Soc.
1
1
2
003, 125, 3867–3870.
5. Owing to the fact that in the original work, organozinc
reagents were prepared on a 15 mmol scale and that in this
work 30 mmol of the aryl bromide were used, optimiza-
tion of the original procedure was done: trifluorome-
thanesulfonic acid was used instead of trifluoroacetic acid

2500
E. Le Gall et al. / Tetrahedron Letters 47 (2006) 2497–2500
and the mixture was kept at room temperature using a
each case, the diarylmethylamine was separated from by-
products as its ammonium sulfate form by adding sulfuric
acid then taken-up in dichloromethane in alkaline condi-
tions. After drying over sodium sulfate and evaporation,
analytically pure diarylmethylamines (>97% GC) were
obtained as pale yellow liquids, which generally soon
crystallized.
water bath after addition of the aryl bromide. These
modifications of experimental conditions resulted in the
formation of organozinc species in better yields (typically
ranging from 80% to 95%) than using the original
procedure (+5–10%).
1
6. In a typical procedure, a dried 100 mL tricol was flushed
with argon and charged with acetonitrile (40 mL). Dode-
cane (0.20 mL, used as internal standard), cobalt bromide
17. The nucleophilicity of organozinc reagents can be enhanced
by copper I, see: Knochel, P.; Jones, P. In Organozinc
Reagents, A Practical Approach; Harwood, L. M., Moody,
C. J., Eds.; Oxford University Press: Oxford, 1999; pp 179–
212.
(
0.66 g, 3 mmol), zinc bromide (0.68 g, 3 mmol), phenyl
bromide (0.32 mL, 3 mmol), and zinc dust (6 g, 92 mmol)
were added to the solution. Trifluoromethanesulfonic acid
1
(
0.20 mL) was added to the mixture under vigorous stirring.
18. Coupling products were characterized using H NMR
1
3
After ca. 15 min, the aryl bromide (30 mmol) was added to
the solution and as soon as the exothermic reaction had
began (ca. 5 min), a water bath at room temperature was
used to moderate the temperature of the medium. The
reaction time, which was monitored using gas chromato-
graphy, did not exceed 30 min in most cases. Coupling
method A: The organozinc-containing solution was trans-
ferred via a syringe into a flask flushed with argon. Cuprous
iodide (6 mmol) was first added under stirring into the
solution followed by the addition of the aldehyde (10 mmol)
and the amine (10 mmol). The stirring was continued for
additional 3 h at room temperature. Coupling method B: A
three-necked flask was equipped with a vertical water-
cooled condenser and charged with acetonitrile (15 mL).
The secondary amine (10 mmol) and the aldehyde
(200 MHz, CDCl3), C NMR (50 MHz, CDCl ), HRMS
3
19
and when useful FT IR or F NMR (188 MHz, CDCl
All products gave satisfactory spectroscopic data.
3
).
Data for selected compounds: 4-(4-Methoxyphenyl(pip-
À1
eridin-1-yl)methyl)benzonitrile (3): IR, m (cm ): 2230;
1
H NMR, d (ppm): 1.30–1.60 (m, 6H), 2.20–2.40 (m, 4H),
3.74 (s, 3H), 4.23 (s, 1H), 6.81 (AB, J = 8.7 Hz, 2H), 7.22
1
3
(AB, J = 8.7 Hz, 2H), 7.52 (s, 4H); C NMR, d (ppm):
24.64, 26.24, 53.04, 55.23, 75.60, 110.34, 114.05, 119.07,
128.49, 129.19, 132.28, 133.60, 149.63, 158.86; MS, m/z
(relative intensity): 306 (9), 222 (100), 204 (20), 190 (9), 178
+
(7); HRMS calcd for C H N O [M+H] : 307.1810,
2
0
23
2
found: 307.1816.
1-(Phenyl(3-(trifluoromethyl)phenyl)methyl)piperidine (6):
1
H NMR, d (ppm): 1.30–1.60 (m, 6H), 2.20–2.40 (m, 4H),
1
3
(
10 mmol) were added into the solvent and the mixture
4.28 (s, 1H), 7.10–7.71 (m, 9H); C NMR, d (ppm): 24.59,
was heated at 70 °C. An addition funnel, connected above
the condenser, was charged with the organozinc-containing
solution. This solution was added dropwise (ca. 2 h) to the
pre-heated mixture and stirred for additional 2 h at 70 °C.
A typical acid-base workup was then applied to crude
light brown oils, which were dissolved in diethyl ether. In
26.17, 53.03, 76.15, 123.60, 124.70, 127.01, 128.04, 128.54,
1
9
130.31, 130.95, 142.14, 144.54; F NMR, d (ppm):
À62.18; MS, m/z (relative intensity): 319 (40), 242 (85),
235 (45), 215 (49), 195 (13), 174 (100), 165 (61), 84 (45);
+
HRMS calcd for C19
320.1634.
H
21
F
3
N [M+H] : 320.1626, found: