An expedient three-component approach to the synthesis of α,α-disubstituted amines under Barbier-like conditions

Article abstract of DOI:10.1055/s-2008-1072582

A series of α,α-disubstituted amines such as diarylmethylamines, 1,2-diarylethylamines, and amino esters have been prepared in acetonitrile using a simple and expedient three-component Mannich-type procedure involving organic halides, aldehyde derivatives

Full text of DOI:10.1055/s-2008-1072582

LETTER
1031
An Expedient Three-Component Approach to the Synthesis of
a,a-Disubstituted Amines under Barbier-like Conditions
A
pproach to th
t
e
Synt
é
hesis of
a
,
a
p
-Disubstitute
h
dAmines ane Sengmany, Erwan Le Gall,* Michel Troupel
Électrochimie et Synthèse Organique, Institut de Chimie et des Matériaux Paris Est (ICMPE), UMR 7182 CNRS – Université Paris,
12 Val de Marne, 2-8 Rue Henri Dunant, 94320 Thiais, France
Fax +33(1)49781148; E-mail: legall@glvt-cnrs.fr
Received 7 November 2007
hydes.9 Apart from this main purpose, it was also
disclosed the possibility to operate under Barbier-like
conditions, by means of a cobalt-catalyzed zinc-mediated
three-component coupling.9b Herein, we both confirm the
Abstract: A series of a,a-disubstituted amines such as diarylmeth-
ylamines, 1,2-diarylethylamines, and amino esters have been pre-
pared in acetonitrile using a simple and expedient three-component
Mannich-type procedure involving organic halides, aldehyde deriv-
atives, and amines. Reactions are conducted under Barbier-like con- possible in situ activation of aryl halides and further ex-
ditions using simple organic halides and zinc dust for the in situ
generation of organozinc reagents.
tend the procedure by reporting several examples of one-
pot reactions applied to the synthesis of a,a-disubstituted
amines like diarylmethylamines, 1,2-diarylethylamines,
and even amino esters.
Key words: amines, halides, multicomponent reactions, organo-
metallic reagents, zinc
With the ultimate goal to set up a useful three-component
method for the synthesis of various nitrogen derivatives,
we took as a starting point our previous studies dealing
with the use of preformed organozinc reagents in three-
component couplings with aldehydes and amines,9 and
envisaged to simplify the procedure by operating under
Barbier-like conditions. It was expected that such a mod-
ification of the procedure might be realizable provided
that the in situ formation of both organozinc reagents and
reactive nitrogen-containing intermediates (imines or imi-
nium ions equivalents) proceeds concomitantly. Indeed,
in such a case, the creation of the expected carbon–carbon
bond would likely happen instantly thus limiting risks of
byproduct formation. The relevance of this hypothesis
was supported by the fact that in acetonitrile such organo-
metallic formations are generally exothermic. This ther-
mal activation usually procures a positive outcome in the
simultaneous formation of electrophilic nitrogen-contain-
ing intermediates and their trapping by the organozinc re-
agent. Moreover, in the case of less reactive organic
halides, we envisaged an external heating to both acceler-
ate the formation of the organozinc reagent and its addi-
tion to the formal C=N double bond.
Multicomponent reactions constitute an attractive and
powerful tool of modern organic chemistry, allowing the
formation of complex structures in a single-step proce-
dure.1 One of the most renowned multicomponent proce-
dures is the Mannich reaction,2 which allows the
straightforward formation of numerous nitrogen-contain-
ing backbones. Accordingly, in the past decade, there has
been tremendous progress in the development of asym-
metric versions of the Mannich reaction for the synthesis
of nitrogen-containing molecules such as a-amino acid
derivatives,3 b-amino carbonyl compounds,4 or amino al-
cohols.5 Some other modern variants of the Mannich reac-
tion feature preformed organometallic reagents like
dialkylzinc as nucleophiles besides the amine and the al-
dehyde derivative.6 However, the in situ formation of or-
ganometallic intermediates under Barbier-like conditions
has been the subject of a significant interest during the last
past years owing to the versatility, the simplicity and the
cost-effectiveness of such procedures which were princi-
pally applied to the synthesis of propargylic amines.7 Re-
cently, Fan and co-workers described the efficient three-
component reaction of allyl or benzyl bromide with pri-
mary amines and aldehydes in THF resulting in the forma-
tion of several a,a-disubstituted amines.8 However, this
work was limited to the use of allyl and benzyl bromide as
starting halides and moreover, the use of secondary
amines was not mentioned.
A preliminary survey of three-component Barbier-type
couplings involving benzyl bromide as a model organic
halide revealed that reactions proceed very fast in acetoni-
trile compared to related THF solutions.10 It was also ob-
served that at least two equivalents of the organic halide
are necessary for the reaction to occur.11 This result ac-
counts for an acid–base reaction between the intermediate
hemiaminal and the in situ generated organozinc reagent
leading to a zinc-associated a-amino alcoholate which is
displaced by a further equivalent of the organozinc com-
pound. A possible mechanism for such a process has al-
ready been described elsewhere.8
As part of our program devoted to the arylation at the po-
sition a to the nitrogen, we recently reported a Mannich-
type three-component procedure allowing the preparation
of diarylmethylamines in acetonitrile, starting from pre-
formed arylzinc compounds, secondary amines, and alde-
SYNLETT 2008, No. 7, pp 1031–1035
x
x.
x
x.
2
0
0
8
In a typical experiment, zinc dust was placed in anhydrous
acetonitrile and activated using trifluoroacetic acid in the
Advanced online publication: 31.03.2008
DOI: 10.1055/s-2008-1072582; Art ID: D36507ST
© Georg Thieme Verlag Stuttgart · New York

1032
S. Sengmany et al.
LETTER
presence of a limited amount of the organic halide (0.4 A classical workup followed by a chromatographic purifi-
mL). After five minutes at room temperature, the alde- cation over neutral alumina afforded the expected com-
hyde and the amine were added along with the organic ha- pound.12 In the case of aryl bromides, which require
lide in the mixture. An exothermic reaction soon occurred catalysis to be converted into the related organozinc re-
resulting in an important rise of the medium temperature agents,13 cobalt bromide was added to the reaction mix-
(ambient to 50–60 °C), which was not controlled using a ture before the introduction of substrates. Results are
water bath. The resulting solution was stirred for one hour reported in Table 1.
at ambient temperature and the reaction was then
quenched with a saturated ammonium chloride solution.
Table 1 Three-Component Synthesis of a,a-Disubstituted Amines under Barbier-like Conditionsa
R2
R3
Zn
R2
R3
N
R1
X
R4 CHO
N
H
+
+
MeCN
R1
R4
Entry Organic halide
Amine
Aldehyde
Additional Time
conditions (h)
Product
Isolated
yield (%)
O
O
1
–
–
1
1
2
79
70
N
N
Br
H
H
H2N
H2N
2
0.5
Br
SMe
SMe
O
N
3
–
–
0.5
3
4
74
H
Br
N
H
O
O
4
1
58b
H
H
H
N
Me
Br
H2N
H2N
Me
Br
H
N
Br
5
–
–
1
1
5
6
65
87
Br
Cl
Cl
O
O
N
6
Br
N
H
H
H
CO2Et
CO2Et
Cl
Cl
H
7c
–
18
7
55
N
EtO2C
Br
EtO2C
H2N
Synlett 2008, No. 7, 1031–1035 © Thieme Stuttgart · New York

LETTER
Approach to the Synthesis of a,a-Disubstituted Amines
1033
Table 1 Three-Component Synthesis of a,a-Disubstituted Amines under Barbier-like Conditionsa (continued)
R2
R1
R3
R4
Zn
R2
R3
N
R1
X
R4 CHO
N
H
+
+
MeCN
Entry Organic halide
Amine
Aldehyde
Additional Time
conditions (h)
Product
Isolated
yield (%)
O
O
DMF,
H
N
8
Bu4NI
18
8
9
50
Cl
Br
H
H
60 °Cd
H2N
CoBr2,
ZnBr2
60 °Ce
9c
1
81
70
N
N
H
CHO
N
CHO
N
O
CoBr2,
ZnBr2
60 °Ce
Br
O
O
10
2
2
10
11
N
H
N
H
O
O
F
F
CHO
N
O
O
CoBr2,
ZnBr2
60 °Ce
Br
11
80
N
H
N
H
S
S
a Typical experimental conditions: anhyd MeCN (40 mL), Zn dust (2.7 g, 40 mmol), amine (10 mmol), aldehyde derivative (11 mmol), organic
halide (25 mmol).
b Yield for a mixture of diastereomers: dr = 75:25.
c Caution: vigorous reaction.
d DMF (5 mL) and Bu4NI (3.69 g, 10 mmol) were also used. The reaction mixture was heated at 60 °C for 18 h.
e Cobalt bromide (0.66 g, 3 mmol) and zinc bromide (0.68 g, 3 mmol) were also used. The reaction mixture was heated at 60 °C for 2 h.
Aromatic aldehydes, as well as an aliphatic aldehyde (en- volving simple aryl bromides as starting compounds and
try 1), undergo the coupling. It should be noted that ethyl consequently, a separate study has been undergone in or-
glyoxylate allows the three-component coupling in excel- der to determine the scope and limitations of this particu-
lent yield (entry 6). This result is of particular significance lar reaction.
for a further extension to the synthesis of non-natural a-
We also experimented with the use of an a-bromoester in
amino acid derivatives. Various amines are efficient in the
the procedure (entry 7). In that case, we did not remark
coupling and it is interesting to observe that aromatic
any important competition between the three-component
amines react as well as aliphatic amines. The cyclic char-
coupling (which is the almost sole reaction pathway) pro-
acter of the amine has no impact on the coupling and the
viding the b-amino ester 7, and the Reformatsky-type ad-
dition to the carbonyl compound furnishing an alcohol.
reaction performs well with both primary and secondary
amines. Benzyl bromides (entries 1–6) react faster than
Furthermore, contrary to other authors,14 we did not ob-
other organic halides (entries 7–11), which sometimes re-
serve a substantial formation of b-lactam by subsequent
cyclization of 7.
quire additional heating to undergo the coupling. It is
worth noting that aryl bromides react efficiently in the
In standard reaction conditions, alkyl halides like 1-bro-
presence of a substoichiometric amount of cobalt bromide
moheptane and 1-iodooctane do not solely undergo the
provided that a moderate heating is applied to the reaction
three-component coupling. The formation of various
mixture (entries 10, 11). This result is of particular signif-
byproducts by Würtz-like dimerization of the alkyl halide
icance since it appears, to the best of our knowledge, as
or a further N-alkylation of the three-component nitroge-
unprecedented examples of Mannich-type reactions in-
Synlett 2008, No. 7, 1031–1035 © Thieme Stuttgart · New York

1034
S. Sengmany et al.
LETTER
nated product (when a primary amine is employed) could
also be established upon analysis of the reaction mixture.
Acknowledgment
The authors thank Dr. Jacques Royer (University Paris 5, France)
and Pr. Lothar Wilhelm Bieber (Pernambuco University, Brazil) for
helpful discussions.
We also realized an experiment using a mixture of (Z)-
and (E)-1-bromoprop-1-ene as starting compound (entry
9). Regarding the chemical structure of this substrate, we
chose to use the conditions analogous to those employed
for the three-component coupling of aryl bromides. In that
case, an almost quantitative reaction is observed, with no
significant sign of disparity between the reactivity of both
stereoisomers, a mixture of E and Z three-component cou-
pling products being detected in the reaction mixture.
However, we could observe some slight fluctuations in
the stereoisomeric ratio of coupling products, with respect
to reaction time and/or temperature. This might indicate
that a stereoisomer is slightly more reactive than the other.
A further supplementary survey involving pure stereoiso-
mers could provide more indications about this observa-
tion.
References and Notes
(1) For recent reviews, see: (a) Guillena, G.; Ramon, D. J.; Yus,
M. Tetrahedron: Asymmetry 2007, 18, 693. (b) Dömling,
A. Chem. Rev. 2006, 106, 17. (c) Simon, C.; Constantieux,
T.; Rodriguez, J. Eur. J. Org. Chem. 2004, 4957. (d) Zhu, J.
Eur. J. Org. Chem. 2003, 1133. (e) Dömling, A.; Ugi, I.
Angew. Chem. Int. Ed. 2000, 39, 3168. (f) Ramón, D. J.;
Yus, M. Angew. Chem. Int. Ed. 2000, 44, 1602.
(2) (a) Arend, M.; Westermann, B.; Risch, N. Angew. Chem. Int.
Ed. 1998, 37, 1044. (b) Heaney, H. In Comprehensive
Organic Synthesis, Vol. 2; Trost, B. M.; Fleming, I., Eds.;
Pergamon Press: Oxford, 1991, 953–973. (c) Overman, L.
E.; Ricca, D. J. In Comprehensive Organic Synthesis, Vol. 2;
Trost, B. M.; Fleming, I., Eds.; Pergamon Press: Oxford,
1991, 1007–1046.
During the course of our preliminary investigation, we no-
ticed that the reaction cannot be conducted in acetonitrile
starting from allyl bromide which reacts vigorously fol-
lowing an exothermic reaction leading to the production
of volatile material, probably by a Würtz-like dimeriza-
tion of allyl bromide. Interestingly, allyl chloride reacts
smoother than allyl bromide, under thermal assistance and
in the additional presence of DMF and Bu4NI (entry 8).15
Under the experimental conditions described by Fan and
co-workers,8 allyl bromide was efficient in such cou-
plings, conducted in THF at room temperature for several
hours (typically 12–24 h). If one considers that our proce-
dure involving acetonitrile as the solvent leads generally
to exothermic reactions which are completed in less than
one hour and that, in addition, zinc-mediated chemical
syntheses of arylzinc compounds cannot be conducted in
THF solutions instead of acetonitrile,13 it appears that the
nature of the solvent has a great influence over the reac-
tion rate and that THF globally slows down the above-
mentioned processes compared to acetonitrile. In order to
define the reasons for which the solvent is of so crucial
importance, we envisage to implement a further mecha-
nistic investigation focused on transient organometallic
species by means of in situ ReactIR measurements and
electroanalytical investigations, which have already pro-
vided conclusive results on related systems.16
(3) (a) Westermann, B.; Neuhaus, C. Angew. Chem. Int. Ed.
2005, 44, 4077. (b) Kobayashi, S.; Matsubara, R.;
Nakamura, Y.; Kitagawa, H.; Sugiura, M. J. Am. Chem. Soc.
2003, 125, 2507. (c) Mitsumori, S.; Zhang, H.; Cheong, P.
H.-Y.; Houk, K. N.; Tanaka, F.; Barbas, C. F. III J. Am.
Chem. Soc. 2006, 128, 1040. (d) Cordova, A.; Barbas, C. F.
III Tetrahedron Lett. 2002, 43, 7749. (e) Dhawan, R.;
Dghaym, R. D.; Arndtsen, B. A. J. Am. Chem. Soc. 2003,
125, 1474. (f) Nanda, K. K.; Trotter, B. W. Tetrahedron
Lett. 2005, 46, 2025.
(4) (a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew.
Chem. Int. Ed. 2004, 43, 1566. (b) Kobayashi, S.; Ishitani,
H.; Yamashita, Y.; Ueno, M.; Shimizu, H. Tetrahedron
2001, 57, 861. (c) List, B. J. Am. Chem. Soc. 2000, 122,
9336. (d) Cordova, A.; Watanabe, S.-i.; Tanaka, F.; Notz,
W.; Barbas, C. F. III J. Am. Chem. Soc. 2002, 124, 1866.
(e) Ollevier, T.; Nadeau, E. J. Org. Chem. 2004, 69, 9292.
(5) (a) List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am.
Chem. Soc. 2002, 124, 827. (b) Trost, B. M.; Terrell, L. R.
J. Am. Chem. Soc. 2003, 125, 338. (c) Yamaguchi, A.;
Matsunaga, S.; Shibasaki, M. Tetrahedron Lett. 2006, 47,
3985.
(6) (a) Desrosier, J.-N.; Côté, A.; Charette, A. B. Tetrahedron
2005, 61, 6186. (b) Côté, A.; Charette, A. B. J. Org. Chem.
2005, 70, 10864. (c) Porter, J. R.; Traverse, J. F.; Hoveyda,
A. H.; Snapper, M. L. J. Am. Chem. Soc. 2001, 123, 10409.
(d) Akullian, L. C.; Snapper, M. L.; Hoveyda, A. H. Angew.
Chem. Int. Ed. 2003, 42, 4244.
(7) For recent examples of similar Mannich-type reactions
conducted in Barbier conditions, see: (a) Aschwanden, P.;
Stephenson, C. R. J.; Carreira, E. M. Org. Lett. 2006, 8,
2437. (b) Gommermann, N.; Knochel, P. Tetrahedron 2005,
61, 11418. (c) Estevam, I. H. S.; Bieber, L. W. Tetrahedron
Lett. 2003, 44, 667. (d) Wei, C.; Li, Z.; Li, C.-J. Org. Lett.
2003, 5, 4473. (e) Wei, C.; Li, C.-J. J. Am. Chem. Soc. 2003,
125, 9584. (f) Sakaguchi, S.; Kubo, T.; Ishii, Y. Angew.
Chem. Int. Ed. 2001, 40, 2534. (g) Gommermann, N.;
Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem. Int. Ed.
2003, 42, 5763. (h) Dube, H.; Gommermann, N.; Knochel,
P. Synthesis 2004, 2015. (i) Bieber, L. W.; Da Silva, M. F.
Tetrahedron Lett. 2004, 45, 8281.
In conclusion, the results reported in this preliminary
study prove that straightforward three-component reac-
tions between various organic halides, primary or second-
ary amines, and aldehyde derivatives can be conducted in
Barbier-like conditions. Consequently, we found a very
promising reaction system, able to provide a wide variety
of nitrogen-containing products under convenient reac-
tion conditions. Further developments, especially with
aryl bromides as starting compounds, are currently in
progress.
(8) Fan, R.; Pu, L.; Qin, L.; Wen, F.; Yao, G.; Wu, J. J. Org.
Chem. 2007, 72, 3149.
Synlett 2008, No. 7, 1031–1035 © Thieme Stuttgart · New York

LETTER
Approach to the Synthesis of a,a-Disubstituted Amines
1035
(9) (a) Le Gall, E.; Troupel, M.; Nédélec, J.-Y. Tetrahedron
Lett. 2006, 47, 2497. (b) Le Gall, E.; Troupel, M.; Nedelec,
J.-Y. Tetrahedron 2006, 62, 9953. (c) Sengmany, S.;
Le Gall, E.; Le Jean, C.; Troupel, M.; Nédélec, J.-Y.
Tetrahedron 2007, 63, 3672.
(10) During the course of a previous work dealing with the
synthesis of benzylzinc bromide (nonpublished results), we
could observe that the reaction is more rapid in MeCN than
in THF (>2 times faster). Additionally, it was observed by
Gosmini et al. that the solvent is of crucial importance in the
cobalt-catalyzed synthesis of arylzinc halides, which cannot
be conducted in THF (see ref. 13 for details).
3.01 (dd, J = 14.2, 6.5 Hz, 1 H), 2.92 (d, J = 6.8 Hz, 2 H),
1.50 (br s, 1 H). 13C NMR: d = 143.1, 137.7, 136.7, 131.4,
131.1, 128.4, 127.3, 127.2, 120.2, 115.8, 63.7, 50.0, 44.5.
MS: m/z (%) = 179 (5), 178 (6), 165 (5), 147 (11), 146 (100),
129 (8), 104 (7), 91 (35), 90 (8), 89 (5). Anal. Calcd for
C17H18BrN: C, 64.57; H, 5.74; N, 4.43. Found: C, 64.30; H,
5.75; N, 4.30.
Ethyl (N-Phenylamino)-3-phenylpropionate (7)
Pale yellow solid; yield 1.48 g (55%); mp 71–73 °C. ATR-
FTIR (neat, cm-1): 3384, 3025, 2980, 2925, 1712, 1602,
1218, 760, 689. 1H NMR: d = 7.42 (d, J = 7.5 Hz, 2 H), 7.36
(t, J = 7.3 Hz, 2 H), 7.28 (t, J = 7.0 Hz, 1 H), 7.14 (t, J = 7.6
Hz, 2 H), 6.71 (t, J = 7.3 Hz, 1 H), 6.60 (d, J = 7.8 Hz, 2 H),
4.87 (t, J = 6.6 Hz, 1 H), 4.64 (br s, 1 H), 4.14 (q, J = 7.1 Hz,
(11) This is consistent with previous works demonstrating that
organozinc reagents have to be used in sufficient excess (>2
equiv) to react efficiently with aldehydes and amines (see
ref. 9 for details).
2 H), 2.84 (d, J = 6.2 Hz, 2 H), 1.23 (t, J = 7.1 Hz, 3 H). 13
C
NMR: d = 171.2, 146.8, 142.2, 129.2, 128.8, 127.5, 126.3,
117.8, 113.7, 60.8, 55.0, 42.9, 14.2. MS: m/z (%) = 269 (20),
183 (14), 182 (100), 180 (9), 104 (17), 77 (6). Anal. Calcd
for C17H19NO2: C, 75.81; H, 7.11; N, 5.20. Found: C, 75.65;
H, 7.05; N, 5.07.
(12) Coupling products were characterized using 1H NMR (400
MHz, CDCl3), 13C NMR (100 MHz, CDCl3), mass
spectrometry, and when useful 19F NMR (376 MHz, CDCl3),
and IR spectroscopy.
Data for Selected Compounds N-(1-Phenyloctan-2-yl)-
aniline (1)
(13) The efficient chemical synthesis of arylzinc reagents has
been described in acetonitrile starting from aryl bromides
and using a cobalt-catalyzed process, see: Fillon, H.;
Gosmini, C.; Périchon, J. J. Am. Chem. Soc. 2003, 125,
3867.
(14) a-Bromo esters proved to react with preformed imines in the
presence of zinc dust under ultrasound activation to furnish
mixtures of b-amino esters and b-lactams, depending on the
reaction temperature, see: Ross, N. A.; MacGregor, R. R.;
Bartsch, R. A. Tetrahedron 2004, 60, 2035..
Colorless oil; yield 2.21 g (79%). ATR-FTIR (neat): 3405,
3025, 2926, 2855, 1600, 1504, 792, 691 cm–1. 1H NMR: d =
7.41–7.29 (m, 7 H), 6.79 (t, J = 7.3 Hz, 1 H), 6.72 (d, J = 8.0
Hz, 2 H), 3.75–3.73 (m, 1 H), 3.58 (br s, 1 H), 2.97 (dd,
J = 13.6,4.6 Hz, 1 H), 2.91 (dd, J = 13.6, 6.4 Hz, 1 H), 1.69–
1.40 (m, 10 H), 0.97 (t, J = 7.0 Hz, 3 H). 13C NMR: d =
147.7, 138.7, 129.7, 129.5, 128.4, 126.3, 117.0, 113.2, 53.7,
40.2, 34.2, 31.9 29.4, 26.2, 22.7, 14.2. MS: m/z (%) = 191
(13), 190 (100), 118 (9), 106 (39), 91 (6), 55 (6). Anal. Calcd
for C20H27N: C, 85.35; H, 9.67; N, 4.98. Found: C, 85.68; H,
9.99; N, 4.57.
(15) This constitutes nonoptimized reaction conditions, which
may likely be improved during the course of a separate
study.
Allyl-[2-(4-bromo-phenyl)-1-phenyl-ethyl]-amine (5)
Yellow oil; yield 2.05 g (65%). ATR-FTIR (neat): 3324,
3062, 3025, 2919, 2833, 1642, 1487, 1453, 1071, 1011, 915,
803, 756, 699 cm–1. 1H NMR: d = 7.40–7.26 (m, 7 H), 6.99
(d, J = 7.9 Hz, 2 H), 5.76–5.88 (m, 1 H), 5.09–5.05 (m, 2 H),
3.90 (t, J = 7.0 Hz, 1 H), 3.14 (dd, J = 14.2, 4.7 Hz, 1 H),
(16) (a) Buriez, O.; Cannes, C.; Nédélec, J.-Y.; Périchon, J. J.
Electroanal. Chem. 2000, 495, 57. (b) Buriez, O.; Nédélec,
J.-Y.; Périchon, J. J. Electroanal. Chem. 2001, 506, 162.
(c) Buriez, O.; Kazmierski, I.; Périchon, J. J. Electroanal.
Chem. 2002, 537, 119.
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