Preparation of 2- and 4-arylmethyl N-substituted and N,N-disubstituted anilines via a green , multicomponent reaction

Article abstract of DOI:10.1021/ol0501828

(Chemical Equation Presented) A new, green, regioselective, one-step, multicomponent reaction of an aldehyde possessing a nonenolizable carbonyl function, cyclohex-2-enone (or a derivative thereof), and primary or secondary amines afforded 2-N-substituted arylmethyl anilines or 4-N,N-disubstituted arylmethyl anilines, respectively. Yields and regioselectivities were good. Evidence for a pathway involving imine and iminium intermediates is presented along with examples demonstrating amenability of the process to combinatorial chemistry.

Full text of DOI:10.1021/ol0501828

ORGANIC
LETTERS
2005
Vol. 7, No. 8
1525-1528
Preparation of 2- and 4-Arylmethyl
N-Substituted and N,N-Disubstituted
Anilines via a “Green”, Multicomponent
Reaction
Anthony E. Rosamilia, Janet L. Scott, and Christopher R. Strauss*
ARC Special Research Centre for Green Chemistry, Monash UniVersity,
Clayton, Victoria 3800, Australia
chris.strauss@sci.monash.edu.au
Received January 28, 2005
ABSTRACT
A new, green, regioselective, one-step, multicomponent reaction of an aldehyde possessing a nonenolizable carbonyl function, cyclohex-2-
enone (or a derivative thereof), and primary or secondary amines afforded 2-N-substituted arylmethyl anilines or 4-N,N-disubstituted arylmethyl
anilines, respectively. Yields and regioselectivities were good. Evidence for a pathway involving imine and iminium intermediates is presented
along with examples demonstrating amenability of the process to combinatorial chemistry.
Aniline derivatives (4 and 5, see Scheme 1) possessing
arylmethyl substituents at the 2 or 4-position are employed
as antioxidants in lubricants1 and as synthetic precursors of
heterocyclic compounds2 or of 4,4-diphenylmethane diiso-
cyanate,3 while others have shown a diverse array of
biological activities with clinical potential in the treatment
of bone diseases, cancer, and ulcers.4
Our recent research has included reactions of nonenolizable
aldehydes and ketones to afford green processes and
products.7 We now report a new one-step multicomponent
reaction for the preparation of N-monosubstituted or N,N-
disubstituted aniline derivatives (4 and 5), which offers great
diversity and satisfies many of the principles of Green
Chemistry.8
Despite this broad range of applications, surprisingly few
members of the family have been reported. Coupling
reactions between substituted anilines and formaldehyde (or
an equivalent) are commonly employed, but they usually
afford symmetrical products.5 Other published routes to 4
and 5 require several steps and have variable yields.6 All of
these approaches offer limited scope for structural diversity.
Three different classes of reactants are employed: an
aldehyde 1 without an enolizable carbonyl function, cyclo-
hex-2-enone or a derivative thereof 2, and an amine 3, which
may be primary or secondary (see Scheme 1 and Table 1).
The examples of 1-3 in Scheme 1 are not limiting. In the
simplest manifestation, condensation of one molecule from
each of the three classes affords the substituted anilino
product plus two molecules of water. So far, reactions (Table
1) have been carried out preferably in refluxing toluene with
a Dean-Stark apparatus employed for water removal in situ.
(1) Roberts, J. T. U.S. Patent 4,411,805, 1983.
(2) (a) Wardrop, A. W. H.; Sainsbury, G. L.; Harrison, J. M.; Inch, T.
D. J. Chem. Soc., Perkin Trans. 1 1976, 12, 1279. (b) Moffett, R. B. J.
Heterocycl. Chem. 1980, 17, 341. (c) Nifant’ev, E. E.; Zavalishina, A. I.;
Orzhekovskaya, E. I.; Selezneva, N. M.; Vasyanina, L. K.; Vorontsov, E.
V.; Stash, A. I.; Bel’skii, V. K. Russ. J. Gen. Chem. 2002, 72, 193.
(3) Oh, J. S.; Kim, E. J. U.S. Patent 5,384,424, 1992.
(4) (a) Tani, K.; Kobayashi, K.; Maruyama, T. European Patent
1,258,473, 2001. (b) Patoiseau, J. P.; Autin, J. M.; Cousse, H.; Sales, V.;
Tisne-Versailles, J.; Bali, J. P. U.S. Patent 5,091,415, 1992.
(6) (a) Katritzky, A. R.; Lang, H.; Lan, X. Tetrahedron 1993, 49, 7445.
(b) Sisko, J.; Weinreb, S. M. Synth. Commun. 1988, 18, 1035. (c) Gassman,
P. G.; Drewes, H. R. J. Am. Chem. Soc. 1978, 100, 7600.
(7) (a) Kreher, U. P.; Rosamilia, A. E.; Raston, C. L.; Scott, J. L.; Strauss,
C. R. Org. Lett. 2003, 5, 3107. (b) Higham, L. T.; Kreher, U. P.; Raston,
C. L.; Scott, J. L.; Strauss, C. R. Org. Lett. 2004, 6, 3257.
(5) (a) Sukumar, R.; Sabu, K. R.; Lalithambika, M. Green Chem. 1999,
1, 191. (b) Rivera, A.; Torres, O. L.; Leito´n, J. D.; Morales-Rios, M. S.;
Joseph-Nathan, P. Synth. Commun. 2002, 32, 1407.
(8) Anastas, P. T.; Warner, J. C. Green ChemistrysTheory and Practice;
Oxford University Press: New York, 1998.
10.1021/ol0501828 CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/22/2005

Scheme 1. New Multicomponent Reaction
Mixtures of a tertiary amine and a weak acid can catalyze
at δ 4.42 ppm, diagnostic of a methylene group neighbored
these reactions, presumably by buffering the systems. Ph-
COOH and DABCO have proven effective in that regard.
Reactions can proceed, albeit more slowly, without acid and
catalytic base, or with either an acid or base alone (see
examples in Table 1). The presence of DABCO, however,
afforded improved yields and fewer byproducts.
by an imino nitrogen and a phenyl ring.
Regioselectivity usually was high under protocols pre-
sented herein. Influences included the catalysts employed
and the rate of addition of the enone, but regioselectivity
was dictated mainly by the nature of the participating amine.
Primary and secondary amines predominantly afforded
2-mono-N-substituted and 4-di-N-substituted anilines, re-
spectively.
The pathway was explored by NMR-monitoring of reac-
tions as they progressed, without water removal (see Scheme
2) and with variation in the order of combination of the
components, to deconvolute the effects of competing equi-
libria. Predictably, combination of aldehyde 1f and primary
amine 3b in toluene-d8 led to formation of imine 6 (acceler-
ated in the presence of DABCO/PhCOOH and/or heating).
After addition of cyclohexenone 2a the reaction progressed
smoothly. The increase in concentration of product 4fab was
concomitant with essentially collinear decrease in concentra-
tion of imine 6 and cyclohexanone 2a, as illustrated in Figure
1. The minor components provided clues as to the genesis
of the aniline functionality: in a minor alternative process,
cyclohexenone 2a reacted with amine 3b to afford an
unstable olefinic imine 8 directly. In the absence of aldehyde,
Figure 1. Relative concentrations in the reaction of furfural (1f)
with benzylamine (3b) and cyclohexenone (2a). The reaction was
carried out in toluene-d8 at 80 °C, and concentrations were inferred
1
from integrated areas of well-defined H NMR signals for each
compound. (Reaction mixture: 1.0 equiv of 1f, 1.2 equiv of 3b,
0.5 equiv of DABCO, and 0.55 equiv of PhCOOH in 1 mL of
toluene-d8. 1.0 equiv cyclohex-2-enone added at t ) 5 min.)
We propose that the enamine tautomer 9 of the olefinic
imine 6 was the key intermediate in the multicomponent
reaction. As suggested in Scheme 2, addition of tautomer 9
to imine 6, followed by elimination of one molecule of amine
3b and isoaromatization, would afford the product 4fab.
From Figure 1, the crossover point between formation of
1
a new resonance signal appeared in the H NMR spectrum
Scheme 2. Postulated Reaction Pathway and Intermediates
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Org. Lett., Vol. 7, No. 8, 2005

Table 1. Examples
a PhCOOH. b DABCO. c PhCOOH/DABCO (0.55:0.5 relative to aldehyde).
Org. Lett., Vol. 7, No. 8, 2005
1527

product 4fab and the depletion of imine 6 and enone 2a lay
midway, highlighting the cleanness of the reaction and the
absence of byproducts. The spectra confirmed that, until it
was converted to product 4fab, almost all of aldehyde 1f
was present as its imine derivative 6. Most of the cyclohex-
enone 2a, however, did not react with amine 3b, indicating
that the concentration of 8 (and therefore 9) was limiting
throughout.
Under the conditions, other equilibria were involved. In
the absence of aldehyde, it was found that amine 3b could
also add to enone 2a to form Michael product 7. When
furfural (1f) was introduced to a product mixture of amine
3b and cyclohexenone 2a in the presence of DABCO and
PhCOOH, however, the Michael adduct 7 dissociated and
imine 6 accumulated. Thus, under the conditions, 6 was more
stable than 7. This, combined with the aforementioned
evidence for low concentrations of enamine 9, is consistent
with the proposal that the reaction involves addition of an
enamine of the enone to an imine of the aldehyde, followed
by rapid elimination of an amine, to provide intermediate
10, which undergoes facile isoaromatization to aniline
products such as 4fab.
On occasions when a secondary amine was used, aminals
were observed.7a,9 Nonetheless, a set of competing equilibria
similar to those depicted in Scheme 2, with irreversible
isoaromatization leading to product accumulation, may be
envisaged.
Entries 6 and 2 in Table 1 indicated that reactivities of
3-arylcyclohexenone 2b and cyclohexenone 2a were com-
parable, thereby adding weight to the proposed pathway.10,11
Confirmation of assignment of regiochemistry of product
4abb arises from the crystal structure of this product
presented in Figure 2.
and bulkiness of the participating amine. With bulky disub-
stituted amines, nucleophilic attack on the iminium species
of the aldehyde (also sterically constrained) would be more
favored from the 4-position than from the crowded 2-position
of the tautomeric enamine of the starting enone.
With derivatives of benzaldehyde as starting materials, the
reaction has occurred regardless of electron-donating or
electron-withdrawing properties of the substituents. A diverse
range of aldehydes has been employed, including furfural
(1f), isophthalaldehyde (1e), and various heterocyclic ana-
logues. Applications of the products will be the subject of a
future communication. In the presence of cyclohexenone 2a
and benzylamine (3b), both carbonyl groups of 1e reacted
to produce a bis-anilino derivative, 1,3-bis(2-benzylami-
nobenzyl)benzene (4eab), in good yield (65%) given the
number of transformations involved and the potential scope
for competing processes (entry 17, Table 1).
Participating amines investigated successfully so far
include benzylamine, aniline, 2-aminomethylpyridine, methyl
aminoacetate, tryptamine (all primary) and di(2-methoxy-
ethyl)amine, morpholine, and di-n-butylamine (secondary).
To conclude, the new reaction can be performed simply,
under relatively uniform conditions and appears to be
convergent and predictable, regardless of the diverse array
of starting materials that can be employed. Therefore, it offers
opportunities for establishment of combinatorial libraries, an
aspect that we are exploring. In the context of Green
Chemistry, tandem, cascade, and/or multicomponent reac-
tions can be useful if they proceed in good yields with high
atom economy and generate little waste. This process could
become a useful tool toward establishment of a broader range
of significant, but heretofore not conveniently accessible,
aniline derivatives.
Acknowledgment. We thank the Australian Research
Council for funding the establishment and continuation of
the ARC Special Research Centre for Green Chemistry
(CGC) and for post-graduate scholarships to A.E.R. C.R.S.
thanks CSIRO Molecular Science for supporting his sec-
ondment to the CGC. Mr. Luke Higham’s contribution to
crystallographic analysis is acknowledged.
Supporting Information Available: Crystal data in CIF
format, experimental procedure and full characterization for
the all compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL0501828
Figure 2. Molecular diagrams from single-crystal structure analysis
of compounds 4baa, 5baa, 4abb (left to right) with ellipsoids are
depicted at the 50% probability level.
(10) Athough in principle, Baylis-Hillman reactions catalyzed by DABCO
could occur between an aryl aldehyde (such as benzaldehyde or furfural)
and cyclohexenone, such processes were not observed here in the presence
of participating amines. Baylis-Hillman reactions do not normally proceed
well with enones possessing a â-substituent and to our knowledge no
examples exist for substrates that are â,â-disubstituted. That the present
reaction proceeded readily and in good yield from 3-(4-methylphenyl)-
cyclohex-2-enone (entry 6, Table 1) further militates against involvement
of a Baylis-Hillman process.
The suggested pathway also accounts for the correlation
mentioned above, between regioselectivity of the reaction
(9) Katritzky, A. R.; Yannakopoulou, K.; Lang, H. J. Chem. Soc., Perkin
Trans. 2 1994, 1867.
(11) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. ReV. 2003, 103,
811.
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