A practical route to tertiary diarylmethylamides or -carbamates from imines, organozinc reagents and acyl chlorides or chloroformates

Article abstract of DOI:10.3762/bjoc.7.112

A practical route to tertiary diarylmethylamides or -carbamates from imines, organozinc reagents and acyl chlorides or chloroformates is described. This route involves the formation of an imine, which is used without isolation, followed by its activation

Full text of DOI:10.3762/bjoc.7.112

A practical route to tertiary diarylmethylamides
or -carbamates from imines, organozinc reagents
and acyl chlorides or chloroformates
Erwan Le Gall*, Antoine Pignon and Thierry Martens
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 997–1002.
Électrochimie et Synthèse Organique, Institut de Chimie et des
Matériaux Paris-Est, UMR 7182 CNRS - Université Paris-Est Créteil,
2-8 rue Henri Dunant, 94320 Thiais, France
doi:10.3762/bjoc.7.112
Received: 07 April 2011
Accepted: 22 June 2011
Published: 20 July 2011
Email:
Erwan Le Gall* - legall@glvt-cnrs.fr
This article is part of the Thematic Series "Multicomponent reactions".
Guest Editor: T. J. J. Müller
* Corresponding author
Keywords:
acyliminium; amides; carbamates; multicomponent reactions;
organozinc reagents
© 2011 Le Gall et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
A practical route to tertiary diarylmethylamides or -carbamates from imines, organozinc reagents and acyl chlorides or chlorofor-
mates is described. This route involves the formation of an imine, which is used without isolation, followed by its activation by the
carbonyl-containing electrophile and the trapping of the acyliminium by an organozinc reagent. Most steps are conducted concomi-
tantly to render the procedure as practical and straightforward as possible. Therefore, the whole experimental protocol takes less
than two hours.
Introduction
Diarylmethylamines constitute an important class of nitrogen- Indeed, while the synthesis of secondary N-protected diaryl-
containing compounds displaying antihistaminic, anti- methylamines generally relies on the addition of organometallic
arrhythmic, diuretic, antidepressant, laxative, anesthetic and reagents to electron-deficient (activated) imines [3-7], the
anticholinergic properties [1,2]. In this context, diarylmethyl- preparation of tertiary diarylmethylamides or -carbamates may
amides and -carbamates represent reliable N-protected diaryl- be conducted through the addition of aromatic nucleophiles
methylamine derivatives and should thus serve as valuable onto N-acyliminium intermediates, formed in situ by reaction of
precursors in the preparation of compounds of pharmaceutical imines with carbonyl-containing electrophiles. In this latter
interest. Several procedures enabling the construction of the di- area, several studies have shown that some electron-enriched
arylmethylamide and -carbamate core have been described. arenes can be used as nucleophiles and add efficiently onto the
However, with respect to the substitution pattern of the iminium carbon, either inter- or intramolecularly [8-16].
expected final compound, available methods differ notably. However, an increased range of aromatic moieties can be intro-
997

Beilstein J. Org. Chem. 2011, 7, 997–1002.
duced through the use of organometallic compounds. The most
commonly employed reagents are organoindium [17,18],
organolithium [19,20], organomagnesium [21,22], organotin
[23], or organozinc compounds [24,25]. However, although
these are recognized as mild multi-purpose reagents, sole exam-
ples of their use in nucleophilic additions on acylimium salts
consist, to the best of our knowledge, of the phenylation of
quinolinium salts using diphenylzinc [26,27].
Recently, our group has been involved in various projects
pertaining to the development of multicomponent reactions
(MCRs) involving organometallic reagents, in particular
organozinc reagents, due to their ability to react in very mild
Scheme 1: Addition of nucleophiles onto activated imines (A) or
iminiums (B).
conditions and generally preserve most common functional initially envisaged the use of Lewis acid catalysis. Indeed, we
groups. Moreover, used in stoichiometric amounts, organozinc assumed that under these conditions, the formation of N–AG
reagents are more cost-effective and produce less toxic wastes (AG = activating group) bonds would be reversible, thus
than other common nucleophiles, such as, e.g., organoindium or cleavage would be effective in situ and only relatively small
organotin reagents. Our main contribution to the field was with amounts of the Lewis acid would be necessary. While several
regards to the use of arylzinc reagents in Mannich-type reac- common Lewis acids (TiCl4, AlCl3, CeCl3 and BF3·Et2O) were
tions with secondary amines and aldehydes to furnish tertiary trialled unsuccessfully, a different strategy based on the forma-
diarylmethylamines [28-33]. However, while a large range of tion of solid bonds indicated that carbonyl derivatives such as
starting compounds could be used successfully in the process, acetyl chloride or methyl chloroformate were, in contrast, effi-
we noticed that primary amines are ineffective, probably due to cient activators of the C=N double bond, albeit used in stoichio-
a weaker electrophilicity of the in situ-formed imines compared metric amounts. This result is consistent with some previous
to iminium ions. Consequently, we report herein the use of pri- studies reporting the activation of imines under an acyliminium
mary amines in a sequential one-pot process, based on the form and the subsequent addition of either aromatic
preliminary activation of an aldimine with an acyl chloride or a [17-23,26,27] or non-aromatic [34,35] organometallic nucleo-
chloroformate, and the subsequent trapping of the resulting philes onto carbon.
acyliminium ion with an aromatic organozinc reagent, to
generate a range of diarylmethylamides and -carbamates in Our preliminary investigations were then conducted on
satisfactory to good yields.
N-benzylidenepropan-1-amine, taken as a model aldimine,
which was preformed and purified prior to use. This compound
was subjected to consecutive reactions with acetyl chloride and
Results and Discussion
The limited intrinsic reactivity of imines towards the addition of phenylzinc bromide, furnishing the corresponding diarylmethyl-
nucleophiles has long been recognized as a major issue in amide in good yield (80%). However, as supplementary experi-
nitrogen chemistry, but one which can be circumvented through ments indicated that the starting imine 1 can be used without
several strategies, mainly intended to withdraw electrons and preliminary purification, we chose to simplify the process by
render the carbon more electrophilic [3-7]. Depending on the operating from the crude imine, although slightly lower yields
substitution pattern of the expected final amines, the increase of (10–15% decreasing) were hence obtained. Thus, in a typical
the electrophilicity should be implemented through the use of experiment, the amine and the aldehyde were heated in toluene
activated imines (Scheme 1, pathway A) or by quaternarization in the presence of 4 Å molecular sieves for a few minutes. After
of the nitrogen atom with an electrophilic species (Scheme 1, cooling to room temperature, the toluene solution containing the
pathway B). The activating group (AG) should then be released imine 1 was transferred into another flask in which a slight
by a final deprotection to deliver the free amine (Scheme 1).
excess of the electrophile (acyl chloride or chloroformate 2)
was added. After a limited period under heating, the arylzinc
During the course of preceding works, we noticed that the add- reagent 3, prepared in parallel via a cobalt-catalyzed procedure
ition of aromatic organozinc reagents onto N-substituted [36] was added and the resulting solution was stirred for 30
aldimines, formed in situ upon reaction of primary amines with minutes at ambient temperature. The chromatographic purifica-
aromatic aldehydes, cannot be undertaken under our estab- tion of the crude oil afforded the expected diarylmethylamide
lished conditions. Thus, we intended to activate the C=N double or -carbamate 4. Representative experimental results are
bond by rendering the carbon more electrophilic and we reported in Table 1.
998

Beilstein J. Org. Chem. 2011, 7, 997–1002.
Table 1: Formation of diarylmethylamides and -carbamates.a
Entry
R1
R2
Ph
R3
R4
Ph
Product
Isolated yield (%)
1
n-Pr
Me
64
4a
4b
4c
2
3
n-Pr
n-Pr
3-O2N–C6H4–
3-O2N–C6H4–
Me
Ph
Ph
55
59
MeO
4
n-Pr
2-F3C–C6H4–
MeO
Ph
67
4d
4e
4f
5
6
n-Pr
n-Pr
thiophen-3-yl
MeO
MeO
Ph
42
68
Ph
3-F3C–C6H4–
7
n-Pr
Ph
MeO
4-EtO2C–C6H4–
57
4g
999

Beilstein J. Org. Chem. 2011, 7, 997–1002.
Table 1: Formation of diarylmethylamides and -carbamates.a (continued)
8
9
n-Pr
n-Pr
Ph
Ph
MeO
MeO
4-Cl–C6H4–
71
4h
4-MeO–C6H4–
63
4i
10
11
Ph
Bn
Ph
Ph
Me
Me
Ph
Ph
69
4j
36
4k
aExperiments were conducted with ~10 mmol of imine, 12 mmol of acyl chloride or chloroformate, 13–16 mmol of the organozinc reagent, prepared
from 20 mmol of aryl bromide.
Under these conditions, coupling products 4 are formed in low
to high yields. The use of acetyl chloride (Table 1, entries 1, 2,
10 and 11) provided similar results to those observed with
methyl chloroformate (Table 1, entries 3–9). It can be seen that
more limited yields were obtained when a thiophene-derived
aldehyde (Table 1, entry 5) or benzylamine was employed as
the starting amine (Table 1, entry 11). However, these last two
results could not be explained.
We next tried to extend the reaction to other electrophilic com-
pounds that are known to easily form N–AG bonds with imines
and furnish analogous iminium salts. The case of methanesul-
fonyl chloride (MsCl) was dealt with first (Scheme 2).
Scheme 2: Activation of the aldimine with MsCl.
Unfortunately, while the reaction of benzylzinc bromide proved
efficient under MsCl activation, phenylzinc bromide did not
undergo the coupling at all [37]. This was also the case with These results, combined with the above reported observations
trimethylsilyl chloride as an activator, whose reaction with the with common Lewis acids, may indicate that acylating reagents
model aldimine and phenylzinc bromide did not afford the are particularly reliable for the activation of aldimines toward
expected compound. On the other hand, a preliminary experi- arylzinc additions. However, the use of carbonyl-containing
ment indicated that trifluoracetic anhydride was a very reliable electrophiles obviously constitutes an important drawback of
activator of the imine towards phenylzinc bromide addition. the procedure. Indeed, although TBAF has been reported to
1000

Beilstein J. Org. Chem. 2011, 7, 997–1002.
constitute a mild deprotection reagent for a range of carbamates BrCH2CH2Br (0.2 mL) were added consecutively under
[38,39], the cleavage of the N–C=O bond, which is formed vigorous (~500 rpm) stirring. The mixture was heated until gas
during the process, might be commonly achieved under rather was evolved (at 50–70 °C), then allowed to cool to rt under
harsh conditions. This is not the case with other potential acti- continuous stirring. The aryl bromide (15 mmol) and anhy-
vating agents such as sulfinic or phosphinic chloride deriva- drous cobalt bromide (330 mg) were then added to the mixture,
tives (ClS(O)R and ClP(O)R2), whose N–AG bond might be which was stirred at rt for additional 20 min. Stirring was then
cleaved easily upon acidic work-up. In addition, chiral versions stopped and the surrounding solution was taken-up with a
of such activators would be of further interest for potential syringe. The solution was then added to the flask containing the
asymmetric couplings (at least with benzylzinc reagents), as the imine/carbonyl-containing compound mixture and the resulting
stereogenic center would be located very close to the impending mixture was stirred at rt for 30 min. The solution was poured
asymmetric carbon and may thus serve as a valuable chiral into a sat. NH4Cl solution (100 mL), extracted with diethyl
auxiliary. Consequently, we envisage the implementation a ether (2 × 75 mL) and the combined organic fractions were
further study which would be dedicated to the evaluation of dried with magnesium sulfate, filtrated and then concentrated
well-recognized chiral inductors such as Ellman- [40,41] or under reduced pressure. The crude oil was purified by column
Davis-type [42,43] sulfinyl derivatives in the process.
chromatography over silica gel with a pentane/diethyl ether
mixture (1:0 to 0:1) as an eluant to afford the diarylmethyl-
amide or carbamate 4.
Conclusion
In conclusion, the results reported in this study indicate that the
formation of acyliminium cations constitutes a very convenient NMR data for selected compounds
approach to the activation of imines toward the addition of Methyl phenyl(2-(trifluoromethyl)phenyl)methyl(propyl)carba-
aromatic organozinc reagents. Indeed, we could prepare a range mate (4d) 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 7.8 Hz,
of diarylmethylamides or diarylmethylcarbamates by a sequen- 1H), 7.51 (t, J = 7.5 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.37–7.25
tial multicomponent process involving the preliminary forma- (m, 4H), 7.12 (d, J = 7.2 Hz, 2H), 6.94 (s, 1H), 3.71 (s, 3H),
tion of an imine, which can be used without isolation, its acti- 3.45–3.31 (m, 1H), 3.23–3.11 (m, 1H), 1.27–1.11 (m, 1H), 0.79
vation by an acyl chloride or a chloroformate and the final trap- (br s, 1H), 0.56 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz,
ping of the resulting acyliminium salt by an arylzinc reagent. CDCl3) δ 156.9, 139.9, 139.5, 131.7, 131.0, 129.5 (q, J = 30.3
However, the harsh conditions which would probably be Hz), 128.4, 128.0, 127.9, 127.4, 126.4 (q, J = 6.0 Hz), 124.2 (q,
required for the deprotection of the amide or carbamate func- J = 274.4 Hz), 59.4, 52.7, 47.5, 21.9, 11.11.
tion prompt us to undertake complementary experiments dedi-
cated to the assessment of easier-to-cleave activating groups. N-Benzhydryl-N-phenylacetamide (4j) 1H NMR (400 MHz,
Consequently, the evaluation of sulfinyl- or phosphinyl deriva- CDCl3) δ 7.19–7.10 (m, 15H), 6.74 (s, 1H), 1.86 (s, 3H);
tives in the process has been undertaken recently and will be 13C NMR (100 MHz, CDCl3) δ 170.8, 140.9, 139.2, 130.2,
reported in due course.
129.7, 128.9, 128.1, 128.0, 127.4, 64.1, 23.7.
Experimental
Typical procedure for the preparation of di-
arylmethylamides and carbamates
N-Benzhydryl-N-benzylacetamide (4k) 1H NMR (400 MHz,
CDCl3) δ 7.15–6.96 (m, 14H), 6.67–6.64 (m, 2H), 4.57 (s, 2H),
2.04 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 172.2, 139.3,
137.4, 129.2, 128.5, 128.2, 127.9, 127.6, 125.8, 66.4, 48.0, 22.8.
The aldimine (~10 mmol) was prepared from the aromatic alde-
hyde (12 mmol) and the amine (12 mmol) in toluene (10 mL) in
the presence of 4 Å molecular sieves (10 g) and para-toluene-
sulfonic acid (10 mg). After 30 min stirring at 80 °C and
cooling to rt, the solution was taken-up with a syringe and the
sieves washed with 5 mL toluene. The combined toluene frac-
tions were placed in another flask, which was flushed with
argon prior to addition, and acetyl chloride or methyl chlorofor-
mate (12 mmol) was added. The resulting mixture was stirred at
rt (ClCOCH3) or at 50 °C (ClCOOCH3) for 30 min, a period
during which the aromatic organozinc reagent (13–16 mmol,
depending on the starting halide) was prepared concomitantly as
Acknowledgements
Financial support of this work by the CNRS and the University
Paris-Est (PhD grant) is gratefully acknowledged.
References
1. Spencer, C. M.; Faulds, D.; Peters, D. H. Drugs 1993, 46, 1055–1080.
2. Sakurai, S.; Ogawa, N.; Suzuki, T.; Kato, K.; Ohashi, T.; Yasuda, S.;
Kato, H.; Ito, Y. Chem. Pharm. Bull. 1996, 44, 765–777.
3. Enders, D.; Reinhold, U. Tetrahedron: Asymmetry 1997, 8, 1895–1946.
doi:10.1016/S0957-4166(97)00208-5
4. Bloch, R. Chem. Rev. 1998, 98, 1407–1438. doi:10.1021/cr940474e
follows: A 100 mL round bottom flask was flushed with argon, 5. Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069–1094.
doi:10.1021/cr980414z
then acetonitrile (20 mL), zinc dust (3 g), TFA (0.2 mL) and
1001

Beilstein J. Org. Chem. 2011, 7, 997–1002.
6. Friestad, G. K.; Mathies, A. K. Tetrahedron 2007, 63, 2541–2569.
doi:10.1016/j.tet.2006.11.076
33.Le Gall, E.; Troupel, M.; Nédélec, J.-Y. Tetrahedron Lett. 2006, 47,
2497–2500. doi:10.1016/j.tetlet.2006.02.056
7. Hermanns, N.; Dahmen, S.; Bolm, C.; Bräse, S. Angew. Chem. 2002,
114, 3844–3846.
34.Black, D. A.; Arndtsen, B. A. Org. Lett. 2004, 6, 1107–1110.
doi:10.1021/ol036462+
doi:10.1002/1521-3757(20021004)114:19<3844::AID-ANGE3844>3.0.
CO;2-R
35.Fischer, C.; Carreira, E. M. Org. Lett. 2004, 6, 1497–1499.
doi:10.1021/ol049578u
8. Zhang, Y.; Kindelin, P. J.; DeSchepper, D. J.; Zheng, C.; Klumpp, D. A.
Synthesis 2006, 1775–1780. doi:10.1055/s-2006-942387
9. Kitabatake, M.; Saitoh, T.; Sano, T.; Horiguchi, Y. Heterocycles 2009,
78, 1177–1181. doi:10.3987/COM-08-11621
36.Fillon, H.; Gosmini, C.; Périchon, J. J. Am. Chem. Soc. 2003, 125,
3867–3870. doi:10.1021/ja0289494
37.The more important reactivity of benzylzinc vs arylzinc reagents has
been noticed on several occasions. For instance, we have already
shown that benzyl bromides react, under Barbier-like conditions, with
aldehydes and primary amines whereas aryl bromides do not undergo
the coupling at all. This result is consistent with a possible nucleophilic
addition of benzylzinc reagents onto imines without mandatory
activation of the latter. See ref. [29] for details.
10.Zhang, Y.; DeSchepper, D. J.; Gilbert, T. M.; Sai, K. K. S.;
Klumpp, D. A. Chem. Commun. 2007, 4032–4034.
doi:10.1039/b708760h
11.Romero, M.; Caignard, D.-H.; Renard, P.; Pujol, M. D. Tetrahedron
2008, 64, 11020–11027. doi:10.1016/j.tet.2008.09.097
12.Klumpp, D. A.; Zhang, Y.; O’Connor, M. J.; Esteves, P. M.;
de Almeida, L. S. Org. Lett. 2007, 9, 3085–3088.
doi:10.1021/ol0711570
38.Routier, S.; Saugé, L.; Ayerbe, N.; Coudert, G.; Mérour, J.-Y.
Tetrahedron Lett. 2002, 43, 589–591.
doi:10.1016/S0040-4039(01)02225-0
13.Venkov, A. P.; Statkova-Abeghe, S. Synth. Commun. 1996, 26,
127–134. doi:10.1080/00397919608003871
39.Jacquemard, U.; Bénéteau, V.; Lefoix, M.; Routier, S.; Mérour, J.-Y.;
Coudert, G. Tetrahedron 2004, 60, 10039–10047.
doi:10.1016/j.tet.2004.07.071
14.Venkov, A. P.; Statkova, S. M.; Ivanov, I. I. Synth. Commun. 1992, 22,
125–134. doi:10.1080/00397919208021083
40.Liu, G.; Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1997, 119,
9913–9914. doi:10.1021/ja972012z
15.Venkov, A. P.; Statkova, S. M. Synth. Commun. 1991, 21, 1511–1520.
doi:10.1080/00397919108016425
41.Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35,
984–995. doi:10.1021/ar020066u
16.Venkov, A. P.; Mollov, N. M. Synthesis 1982, 216–217.
doi:10.1055/s-1982-29752
42.Davis, F. A. J. Org. Chem. 2006, 71, 8993–9003.
doi:10.1021/jo061027p
17.Black, D. A.; Arndtsen, B. A. Org. Lett. 2006, 8, 1991–1993.
doi:10.1021/ol060277p
43.Zhou, P.; Chen, B.-C.; Davis, F. A. Tetrahedron 2004, 60, 8003–8030.
doi:10.1016/j.tet.2004.06.071
18.Beveridge, R. E.; Black, D. A.; Arndtsen, B. A. Eur. J. Org. Chem.
2010, 3650–3656. doi:10.1002/ejoc.201000231
19.Lamblin, M.; Couture, A.; Deniau, E.; Grandclaudon, P.
Tetrahedron: Asymmetry 2008, 19, 111–123.
License and Terms
doi:10.1016/j.tetasy.2007.11.014
20.Alexakis, A.; Amiot, F. Tetrahedron: Asymmetry 2002, 13, 2117–2122.
doi:10.1016/S0957-4166(02)00531-1
This is an Open Access article under the terms of the
Creative Commons Attribution License
21.Venkov, A. P.; Statkova-Abeghe, S. M. Synth. Commun. 1995,
1817–1824. doi:10.1080/00397919508015425
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
22.Pegoraro, S.; Lang, M.; Dreker, T.; Kraus, J.; Hamm, S.; Meere, C.;
Feurle, J.; Tasler, S.; Prütting, S.; Kuras, Z.; Visan, V.; Grissmer, S.
Bioorg. Med. Chem. Lett. 2009, 19, 2299–2304.
doi:10.1016/j.bmcl.2009.02.077
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
23.Black, D. A.; Arndtsen, B. A. J. Org. Chem. 2005, 70, 5133–5138.
doi:10.1021/jo0503557
24.Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93, 2117–2188.
doi:10.1021/cr00022a008
(http://www.beilstein-journals.org/bjoc)
25.Knochel, P.; Jones, P., Eds. Organozinc Reagents, A Practical
Approach; The Practical Approach in Chemistry Series; Oxford
University Press: Oxford, 1999.
The definitive version of this article is the electronic one
which can be found at:
doi:10.3762/bjoc.7.112
26.Ludwig, M.; Polborn, K.; Wanner, K. T. Heterocycles 2003, 61,
299–326. doi:10.3987/COM-03-S40
27.Bender, C.; Liebscher, J. ARKIVOC 2009, (vi), 111–136.
28.Haurena, C.; Le Gall, E.; Sengmany, S.; Martens, T. Tetrahedron 2010,
66, 9902–9911. doi:10.1016/j.tet.2010.10.058
29.Le Gall, E.; Haurena, C.; Sengmany, S.; Martens, T.; Troupel, M.
J. Org. Chem. 2009, 74, 7970–7973. doi:10.1021/jo901704s
30.Sengmany, S.; Le Gall, E.; Troupel, M. Synlett 2008, 1031–1035.
31.Sengmany, S.; Le Gall, E.; Le Jean, C.; Troupel, M.; Nédélec, J.-Y.
Tetrahedron 2007, 63, 3672–3681. doi:10.1016/j.tet.2007.02.086
32.Le Gall, E.; Troupel, M.; Nédélec, J.-Y. Tetrahedron 2006, 62,
9953–9965. doi:10.1016/j.tet.2006.08.008
1002