Anilines made easily: From aldehydes to tri-, tetra-, and pentasubstituted anilines in two steps

Article abstract of DOI:10.1002/anie.200351484

Easy as one, two, three. Highly substituted anilines are accessible with unprecedented efficiency from the three-component-coupling reaction of O-benzyl carbamate, aldehydes, and dienophiles followed by a new domino aromatization/deprotection reaction inv

Full text of DOI:10.1002/anie.200351484

Angewandte
Chemie
Aniline Synthesis
Anilines Made Easily: From Aldehydes to Tri-,
Tetra-, and Pentasubstituted Anilines in Two
Steps**
Helfried Neumann, Axel Jacobi von Wangelin,
Stefan Klaus, Dirk Strübing, Dirk Gördes, and
Matthias Beller*
Dedicated to Professor Boy Cornils
on the occasion of his 65th birthday
Polysubstituted anilines play a central role as building blocks
in synthetic chemistry. Major technical applications include
their use as intermediates in the manufacture of agrochem-
icals, pharmaceuticals, dyes, pigments, and rubber chemi-
cals.[1] Although anilines have become accessible by new
methods—in particular catalyzed by transition metals—in
recent years, most technically feasible syntheses still rely on
classical approaches. While sequential electrophilic nitration
and reduction suffers from the relatively harsh reaction
conditions,[2] nucleophilic aromatic amination requires the
presence of special substituents.[3] The recently developed
palladium-catalyzed[4] (Buchwald–Hartwig amination) and
copper-catalyzed[5] aminations of aryl halides provide a
general entry to this class of compounds. However, for these
reactions as well as for other known syntheses of polysub-
stituted anilines, aromatic reactants with a defined substitu-
tion pattern are needed. In most cases, these starting materials
are synthesized in numerous steps generating several equiv-
alents of waste and salt as by-products.
Over the last years we have been involved in the
development of newsyntheses of amino compounds with
special regard to transition-metal-catalyzed hydroamina-
tions,[6] hydroaminomethylations,[7] and amidocarbonyla-
tions.[8] Recently, we reported on novel multicomponent
reactions (MCRs)[9] of amides and aldehydes with dienophiles
for the straightforward synthesis of a large variety of carbo-
and heterocyclic amides.[10] As shown in Scheme 1, the
underlying mechanism involves the intermediacy of an
Oppolzer–Overman-type
1-(N-acylamino)-1,3-butadiene,
which easily undergoes Diels–Alder addition with an elec-
tron-deficient dienophile.[11] The synthesized three-compo-
nent adducts exhibit a high degree of diversity, which is based
[*] Prof. Dr. M. Beller, Dr. H. Neumann, Dr. A. Jacobi von Wangelin,
S. Klaus, D. Strübing, Dr. D. Gördes
Leibniz-Institut für Organische Katalyse
Universität Rostock e.V. (IfOK)
Buchbinderstrasse 5–6, 18055 Rostock (Germany)
Fax: (+49)381-466-9324
E-mail: matthias.beller@ifok.uni-rostock.de
[**] The authors thank S. Giertz and S. Buchholz for excellent technical
and analytical assistence. Generous financial support from the state
Mecklenburg-Western Pomerania (Landesforschungsschwerpunkt),
the Fonds der Chemischen Industrie, and the Bundesministerium
für Bildung und Forschung (BMBF) is gratefully acknowledged.
Angew. Chem. Int. Ed. 2003, 42, 4503 –4507
DOI: 10.1002/anie.200351484
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Communications
afforded (Table 1). Three isomeric amino-
substituted cyclohexenes (formed in 26%
overall yield (6:7:13)) and the targeted
oxidized species, aniline 2a (28%), were
identified as major products. When the
reaction conditions were optimized, 2a was
obtained in excellent yield (91%).
In the presence of stronger hydrogen
donors (H2,[16] HCO2H[17]), saturated cyclo-
hexane 4a was formed in moderate yield. A
significant increase in the yield of aniline 2a
was observed when triglyme was employed
as the solvent and the reaction was con-
ducted at higher temperatures. The cyclo-
hexene moiety in 1a itself can act as an
efficient hydrogen donor for the debenzyla-
tion of the carbamate (Table 1, entries 8–10),
Scheme 1. Three-component-coupling reaction of amides, aldehydes, and dienophiles and the envi-
sioned aromatization to give anilines.
upon structural variations of the simple, ubiquitous compo-
nents—carboxamides, aldehydes, and olefins.
We considered the newthree-component coupling prod-
ucts useful intermediates for the synthesis of anilines.
Obviously, such a strategy constitutes a short and highly
convergent synthetic approach. Although syntheses of arenes
based on transition-metal-catalyzed cyclization reactions with
alkynes[12] and Diels–Alder reactions with heterodienes[13]
have been reported in the past, the operational difficulty
and the laborious synthesis of the precursors diminish their
general use. Here, we wish to report a novel reaction
sequence for the synthesis of substituted anilines by the
combination of a three-component-coupling reaction and a
newtransition-metal-catalyzed
aromatization step (Scheme 1). To
the best of our knowledge, such a
strategy has not been used previ-
ously for the synthesis of anilines.
Initial studies on the aromati-
Table 1: Palladium-catalyzed aromatization of 4-N-(benzyloxycarbonyl)aminohexahydro-1H-isoindole
1a (GC yields).
Entry
Pd [mol%]
Solvent
H2 donor
t [h]
T [8C]
Yield [%] 2a
Yield [%] 3a/4a/5a
[a]
1
2
3
4
5
6
7
8
9
32
32
32
32
16
8
8
8
8
8
EtOH
EtOH
MeOH
MeOH
EtOH
EtOH
EtOH
triglyme
triglyme
triglyme
triglyme
C6H10
0.16
16
24
80
80
25
25
80
120
120
120
140
140
140
28
37
–
26/–/–
13/–/7
–/35/–
–/25/–
zation of three-component cou-
pling products of different aliphatic
and aromatic amides in the pres-
ence of stoichiometric quantities of
sulfur or catalytic amounts of Pd/C
and various other oxidants gave
lowconversion or complex product
mixtures (yield of anilines < 5%).
Therefore, we considered facilita-
tion of the aromatization process
by using a quasi-intramolecular[14]
hydrogen transfer onto a powerful
hydrogen acceptor within the mol-
ecule. The use of O-benzyl carba-
[a]
C6H10
[b]
H2
HCO2H[c]
0.16
–
[a]
C6H10
24
24
24
24
24
24
24
40
36
30
50
71
95[d]
65[d]
[a]
C6H10
–
–
–
–
–
10
11
4
Conditions: 1a (0.5 mmol), 10% Pd/C, solvent(10 mL), ACE pressure tube; [a] 200 mmol; [b] 15 bar;
[c] 10 equiv; [d] Large scale: 1a (3 mmol).
mate as the amide component could yield a coupling product
that would fulfill this requirement. Reaction of propional-
dehyde, O-benzyl carbamate (CbzNH2, R1 = BnO), and
maleimide furnished 4-N-(benzyloxycarbonyl)aminohexahy-
dro-1H-isoindole (1a) in 79% yield. Next, imide 1a was
subjected to different cleavage procedures [Eq. (1)]. When 1a
was heated at reflux in the presence of Pd/C and cyclohexene
(as a hydrogen donor) in ethanol,[15] a mixture of products was
which supersedes the use of an extra hydrogen donor. This
unprecedented reaction pattern involves H2 elimination and
Cbz cleavage. As Cbz cleavage cannot be effected without
concomitant supply of hydrogen atoms from the ring aroma-
tization, we propose the operation of a domino dehydrogen-
ation/Cbz-cleavage process.[18] While both the palladium-
catalyzed dehydrogenation[19] and the palladium-catalyzed
Cbz-cleavage from amines[15–20] have been investigated as
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Table 2: Pd/C-catalyzed synthesis of polysubstituted anilines.
Entry Aldehyde Dienophile Coupling product
separate processes, no procedure involving
the concurrent operation of both transfor-
mations has been reported so far.
Yield [%]
Aniline
Yield [%]
91
We set out to extend the methodology to
other N-(Cbz)aminocyclohexenes. There-
fore, a variety of three-component adducts
of O-benzyl carbamate, aldehydes, and
dienophiles were prepared. Table 2
(middle) shows a selection of 10 adducts
with diverse substituents. Regarding the
aldehyde component, simple aliphatic
(with an a-CH2 moiety) and a,b-unsatu-
rated (with a g-hydrogen) aldehydes bear-
ing linear or branched alkyl, aryl, or heter-
oaryl substituents were employed. While
simple aldehydes lead to adducts with
equivalent substituents on C4 and C6,
reactions with a,b-unsaturated aldehydes
are not subject to this restriction. Com-
pounds 1 f and 1g (Table 2, entries 6 and 7)
illustrate the potential for the construction
of anellated ring systems. Further diversity
of the three-component adducts was
attained by employing different dienophiles
such as N-methyl maleimide, acrylonitrile,
and diethyl fumarate. Apart from benzo-
thiazole 1 f (44%), the three-component
adducts were isolated in good yields (65–
89%) without further optimization. NMR
spectra established the syn configuration of
the cycloadducts, as expected from a selec-
tive endo Diels–Alder reaction of the all-
trans aminodiene.[21] However, reactions
with diethyl fumarate gave an equimolar
mixture of two isomers with an overall yield
of 67% (Table 2, entry 10).
The domino dehydrogenation/Cbz-
cleavage reaction of 1a–j cleanly afforded
the desired anilines (Table 2). Aromatiza-
tion of imides 1a–f yielded substituted 4-
amino-1,3-dioxo-2,3-dihydro-1H-isoindoles
2a–g (entries 1–7). The employment of 2-
cyclohexylidenepropionaldehyde[22] proves
the possibility to access hexasubstituted
aminobenzenes in only two (!) reaction
steps (entry 7). With dienophilic acryloni-
trile, substituted 2-aminobenzonitriles (2h,
2i) were accessed in a straightforward
manner (entries 8, 9). These compounds
constitute important intermediates for the
synthesis of pharmaceuticals; for example,
simple reaction with a-halocarboxylic acids
and subsequent reduction affords 1,4-ben-
zodiazepines.[23] Both isomers of diester 1j
gave the desired aniline in equivalent yields
(entry 10).
1
79
2
3
4
5
6
7
88
74
73
87
44
45
79
80
91
64
78
40
8
9
68
66
67
63
62
10
78
In conclusion, we have developed a new,
highly efficient strategy for the synthesis of
substituted anilines. A palladium-catalyzed
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Communications
d = 7.07 (s, 1H, Ph), 6.01 (s, 2H, NH2), 2.91 (s, 3H, NMe), 2.35 (s, 3H,
Me), 2.13 ppm (s, 3H, Me); 13C{1H} d = 169.6 and 169.5 (2CO), 143.2,
130.2, 125.8, 124.3, and 109.2 (5C of Ph), 137.7 (CH of Ph), 23.0, 17.0,
and 15.9 ppm (3Me).
aromatization of three-component-coupling products, which
is based on a newtransfer hydrogenation reaction, is the key
step of the described method. The sequential combination of
a three-component-coupling reaction and a domino depro-
tection/aromatization reaction leads to the straightforward
synthesis of polysubstituted anilines with diverse substitution
patterns.[24] The overall procedure utilizes simple, readily
available starting materials and is unique in that it allows the
(regio)selective introduction of substituents in one ortho, one
meta, and para position, as well as electron-deficient sub-
stituents in the other ortho and meta positions. To the best of
our knowledge, this type of tri-, tetra-, and pentasubstituted
anilines cannot be accessed by any other methods with similar
efficiency.
Received: March 25, 2003 [Z51484]
Keywords: anilines · multicomponent reactions · palladium ·
.
transfer hydrogenation
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Experimental Section
General procedure for the preparation of 1: A mixture of O-benzyl
carbamate (15 mmol), p-toluenesulfonic acid·H2O (2 mol%), alde-
hyde (15 mmol), Ac2O (15 mmol), maleimide (11 mmol), and N-
methylpyrrolidone (10 mL) was sealed in an ACE pressure tube and
stirred at 1208C. After 24 h the solvent and other volatile compounds
were removed by high-vacuum distillation. Silica gel flash chroma-
tography (heptane/ethyl acetate) of the residue afforded the three-
component-reaction adducts as air-stable solids.
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With a,b-unsaturated aldehydes, reactions were run in the
presence of 7.5 mmol aldehyde and without Ac2O. Reactions with
acrylonitrile used a fourfold excess of the dienophile and required 4 d
for completion.
General procedure for the synthesis of 2: A 100-mL flask was
charged with a mixture of carbamate 1 (2.9 mmol), Pd/C (10% Pd on
C, 8 mol%), and triglyme (20 mL), equipped with a reflux condenser,
and heated to 1408C. After 6–64 h the solution was filtered through a
Celite pad, and solvent and other volatile compounds were removed
by high-vacuum distillation. The residue was subjected to silica gel
flash chromatography (heptane/ethyl acetate).
1a: According to the general procedure for 1, O-benzyl
carbamate (2.27 g, 15 mmol), propionaldehyde (0.87 g, 15 mmol),
acetic anhydride (1.4 mL, 15 mmol), and N-methylmaleimide (1.28 g,
11.25 mmol) were employed. SiO2 chromatography (hept/EtOAc
3:1): Rf = 0.15. 79% yield of isolated product (white solid). M.p. 62–
~
668C. IR (KBr): n = 3395 brvs, 3064 w, 3033 w, 2937 m, 1769 m, 1705
brvs, 1514 vs, 1437 s, 1384 s, 1336 s, 1287 s, 1232 s, 1045 s, 912 w, 836 m,
781 m, 749 m, 699 s, 662 w, 594 m, 531 cmÀ1; MS (EI): 342 ([M]+, 1%),
251 ([MÀBn]+, 5%), 233 ([MÀBnO]+, 4%), 207 (93%), 122 (23%),
107 ([BnO]+, 17%), 91 ([Bn]+, 100%, no other peaks of > 5%;
HRMS: calcd for C19H22N2O4: 342.15796; found: 342.15788; NMR
([D6]DMSO): 1H d = 7.44–7.34 (m, 5H, Ph), 6.96 (d, 9.3 Hz, 1H, NH),
[7] a) A. Seayad, M. Ahmed, H. Klein, R. Jackstell, T. Gross, M.
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=
5.36 (s, 1H, C ), 5.15 (s, 2H, CH2), 4.36 (m, 1H, NHCH), 3.33 (dd,
6.2/8.4 Hz, 1H, NHCHCH), 3.11 (t*, 7.7 Hz, 1H, CH3CHCHCO),
=
2.78 (s, 3H, NMe), 2.49–2.43 (m, 1H, MeCH), 1.62 (s, 3H, MeC ),
1.28 ppm (d, 7.4 Hz, 3H, MeCH); 13C{1H} d = 178.9 and 177.1 (2 CO);
=
=
155.6 (CO2), 137.3 (MeC ), 136.9, 128.4, 127.9, 127.7, and 127.1 (CH
and Ph), 65.8 (CH2O), 49.7 (NHCH), 44.1 and 43.9 (NHCHCHCH),
=
29.6 (MeCH), 24.3 (NMe), 18.0 and 16.8 ppm (MeC and MeCH).
2a: According to the general procedure for 2, carbamate 1a
(1.0 g, 2.9 mmol) and Pd/C (0.25 g, 10% Pd on C) were employed.
SiO2 chromatography (hept/EtOAc 3:1): Rf = 0.15. 91% yield of
~
isolated product (yellowish solid). M.p. 185–1878C. IR (KBr): n =
3475, 3370 vs, 3200, 2924 w, 1740 s, 1690 s, 1642 s, 1614 m, 1596 m, 1492
s, 1441 s, 1382 m, 1370 m, 1313 w, 1268 s, 1235 m, 1159 w, 1125 w, 1024 s,
996 s, 761 s, 615 m, 560 cmÀ1; MS (EI): 204 ([M]+, 100%), 189
([MÀNH]+,
18%),
147
([MÀCOÀNMe]+,
19%),
119
([MÀ2COÀNMe]+, 42%), no other peaks of > 5%. HRMS: calcd
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for C11H12N2O2: 204.08890; found: 204.08987; NMR ([D6]DMSO): 1H
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