A copper(II)-catalyzed aza-friedel-crafts reaction of N-(2-Pyridyl)sulfonyl aldimines: Synthesis of unsymmetrical diaryl amines and triaryl methanes

Article abstract of DOI:10.1002/anie.200503305

(Chemical Equation Presented) The choice of the (2-pyridyl)sulfonyl moiety as an N-protecting group and Cu(OTf)₂/(±)-binap as catalyst system lead to a highly efficient aza-Friedel-Crafts reaction of electron-rich arenes (Ar²-H) and heteroarenes with N-sulfonyl imines. This protocol is also amenable to the synthesis of unsymmetrical triaryl methanes through a second electrophilic aromatic substitution with a different electron-rich arene (Ar³-H; see scheme).

Full text of DOI:10.1002/anie.200503305

Angewandte
Chemie
tolerance, either with regard to the arene nucleophile or the
electrophilic substrate, still remain for this transformation.
For instance, the mono Friedel–Crafts reaction of carbonyl
compounds and imines seems to be restricted to highly
electrophilic substrates[2] such as glyoxylates,[3] chloral (tri-
chloroacetaldehyde),[4] pyruvates,[5] trifluoromethyl imines,[6]
or a-imino esters.[3c,7] In contrast, aromatic aldehydes[8] and
their imines,[3c,9] generally evolve according to a double
Friedel–Crafts reaction to give symmetrical triaryl methanes
due to the intrinsic instability of the intermediate benzylic
alcohol (or amine derivative) under the acidic reaction
conditions (Scheme 1a). Triaryl methanes display varied
Scheme 1. Synthesis of triaryl methanes from aromatic aldehydes or
their imines by a Friedel–Crafts reaction. X=O, NR; LA=Lewis acid;
see text for details.
Homogeneous Catalysis
and interestingproperties and have received a great deal of
attention as leuco dyes,[10] photochromic agents,[11] suitable
DOI: 10.1002/anie.200503305
[12]
buildingblocks for egneratingdendrimers,
and as sub-
A Copper(ii)-Catalyzed Aza-Friedel–Crafts
Reaction of N-(2-Pyridyl)sulfonyl Aldimines:
Synthesis of Unsymmetrical Diaryl Amines and
Triaryl Methanes**
strates for theoretical[13] and biological[14] studies. While many
methods have been reported for the preparation of sym-
metrical triaryl methanes,[15] the synthesis of unsymmetrical
derivatives is much less developed.[16,17]
As part of an ongoing research program on metal-
controlled reactions of appropriately functionalized N-sulfon-
yl imines,[18] we describe here a broad-scope AFCR protocol
that allows the selective preparation of structurally diverse
unsymmetrical diaryl amines and triaryl methanes by sequen-
tial reaction with two different electron-rich aromatic com-
pounds (Scheme 1b).
Jorge Esquivias, Ramón Gómez Arrayµs,* and
Juan C. Carretero*
The Lewis acid-catalyzed addition of electron-rich aromatic
compounds to aldehydes, ketones and imines, the latter of
which is known as the aza-Friedel–Crafts reaction (AFCR), is
First, to study the effect of the sulfonyl substitution in
AFCR, a set of sulfonyl imines, 1a–e, of varied electronic and
coordination nature were readily prepared in good chemical
yields (87–94%) by direct condensation of benzaldehyde with
the correspondingsulfonamide (Scheme 2). [19]
À
a synthetically outstandingC C bond-formingprocess that
leads to functionalized alcohols and amines in a completely
atom-economical way.[1] However, despite its significance, a
number of unsolved aspects related to functional-group
We chose the electron-rich N-methylindole[20] as model
aromatic nucleophile for the AFCR of compounds 1, and
Cu(OTf) or Cu(OTf)2 as catalytic Lewis acids[21] (10 mol%).
[*] J. Esquivias, Dr. R. Gómez Arrayµs, Prof. Dr. J. C. Carretero
Departamento de Química Orgµnica
Facultad de Ciencias
Universidad Autónoma de Madrid
Cantoblanco 28049 Madrid (Spain)
Fax: (+34)91-497-3966
E-mail: ramon.gomez@uam.es
juancarlos.carretero@uam.es
[**] This work was supported by the Ministerio de Educación y Ciencia
(MEC, project BQU2003-0508) and the Consejería de Educación de
la Comunidad Autónoma de Madrid (Project GR/MAT/0016/2004).
J.E. and R.G.A. thank the MEC for a predoctoral fellowship and for a
Ramón y Cajal contract, respectively.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Scheme 2. Synthesis of N-sulfonyl imines 1a–e. M.S.=molecular
sieves.
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The effect of addingphosphane liagnds to the
reaction media was also examined [(Æ )-binap, dppf,
dppe, and PPh3], with binap beingthe most effi-
cient.[22] The results obtained by usingthe optimal
pair Cu(OTf)n/binap (10 mol%) are summarized in
Table 1.
Table 1: CuI- and CuII-catalyzed AFCR of sulfonyl imines 1a–e with N-
methylindole.
Scheme 3. Study of the substitution at the imine. Cy=cyclohexyl;
Naph=naphthyl.
regardless of the electronic and steric nature of the substitu-
tion, the Cu(OTf)2/(Æ)-binap-catalyzed AFCR provided
exclusively the pyridylsulfonamide products 11e–17e in
good yields (70–90%). Interestingly, this method can also
be applied to aliphatic imine electrophiles (product 17e),
which, to the best of our knowledge, have not been used
previously in the AFCR.
Table 2 shows the scope of the AFCR of imine 1e with
regard to the nucleophilic arene partner. Both heteroaromatic
and electron-rich aromatic compounds proved to be very
effective, affordingthe Friedel–Crafts addition product in
good yield as a single regioisomer. The reactions with a
representative selection of indole derivatives (entries 1–4), N-
methylpyrrole (entry 5), 2-methoxythiophene (entry 6), and
1,3,5-trimethoxybenzene (entry 10) were particularly fast
(ꢀ 5 min). Interestingly, substitution at C2 of the indole
seems to have no detrimental effect on the reactivity
(products 21e and 22e). Furan, which is known to be a
poorly reactive substrate,[1e,7e] provided the addition product
26e in 50% yield after 15 h, while the more nucleophilic 2-
methoxyfuran furnished the amine 27e in 69% yield after
Entry
Imine
R
Copper
salt
t
Yield [%][a]
2
3
1
2
3
4
5
6
7
8
9
1a
1a
1b
1b
1c
1c
1d
1d
1e
1e
Tol
Tol
Cu(OTf)
Cu(OTf)2
Cu(OTf)
Cu(OTf)2
Cu(OTf)
Cu(OTf)2
Cu(OTf)
Cu(OTf)2
Cu(OTf)
Cu(OTf)2
72 h
ꢀ5 min
69 h
2a, 41
–
2b, 47
–
2c, 50
–
2d, 45
–
–
72
–
85
–
80
–
82
–
–
(p-NO2)C6H4
(p-NO2)C6H4
2-thienyl
2-thienyl
NMe2
NMe2
2-pyridyl
2-pyridyl
ꢀ5 min
65 h
ꢀ5 min
70 h
ꢀ5 min
22 h
2e, 72
2e, 72
10
ꢀ5 min
[a] Yield of pure product isolated after chromatography.
90 min. Amongnonheteroaromatic nucleophiles,
N,N-
Three important conclusions can be drawn from this
study:
dimethyl-3-methoxyaniline, 1-methoxynaphthalene, and
1,3,5-trimethoxybenzene also underwent the AFCR and
gave satisfactory product yields (entries 8–10). However, no
reaction was observed with less activated aromatic rings, such
as N,N-dimethylaniline or anisole, even after prolonged
reaction times.
The synthetically relevant deprotection of these pyridyl-
sulfonamide products to give the corresponding diaryl
methylamines can be cleanly achieved by treatment with
magnesium turnings under neutral reaction conditions
(Scheme 4).[25]
To highlight the potential of the pyridylsulfonamide
adducts, we set out to develop a sequential, one-pot synthesis
of unsymmetrical triaryl methanes by promotinga second
electrophilic aromatic substitution with a different electron-
rich arene (Ar3-H). However, once the AFCR between imine
1e and N-methylindole reached completion (monitored by
TLC), the addition of 5-methoxy-1-methylindole to the
formed 2e resulted in no reaction at room temperature
after 24 h. Gratifyingly, this CuII-catalyzed sulfonamide dis-
placement proceeded smoothly when the reaction temper-
ature was increased to 408C and after 20 min triaryl methane
33 was isolated in 65% yield.[26]
a) The more-electrophilic CuII catalyst is around two orders
on magnitude more reactive than the analogous CuI
catalyst. For instance, the reaction of 1a catalyzed by
Cu(OTf) required 72 h to reach completion[23] (entry 1),
whereas in the presence of Cu(OTf)2 the reaction was
complete in less than 5 min (entry 2).
b) A different outcome was obtained with substrates 1a–d in
the reactions catalyzed by either Cu(OTf) or Cu(OTf)2.
Thus, with the CuI-based protocol the mono Friedel–
Crafts products 2a–d were selectively obtained in moder-
ate yield, while the CuII system provided selectively the
bis-indole 3 in good yields (72–85%) with very short
reaction times (ꢀ 5 min).
c) The 2-pyridylsulfonyl imine 1e behaves differently to the
rest of the sulfonyl imines[24] as the bis-indole product 3 is
not detected either in the presence of Cu(OTf) (entry 9)
or with Cu(OTf)2 (entry 10).
The role of the 2-pyridylsulfonyl group in controlling the
selectivity of the Cu(OTf)2-catalyzed AFCR in favor of the
sulfonamide product was confirmed by surveyinga variety of
substituted 2-pyridylsulfonyl imines. As shown in Scheme 3,
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Table 2: CuII-catalyzed AFCR of imine 1e with electron-rich arenes.
Entry
1
Ar
Product
t
Yield [%][a]
2e, R=Me
18e, R=H
72
82
ꢀ5 min
Scheme 4. Deprotection of N-(2-pyridyl)sulfonyldiaryl amines.
19e, R=H
20e, R=Me
89
93
2
ꢀ5 min
Table 3: One-pot synthesis of unsymmetrical (indolyl)diaryl methanes.
21e, R=Me
22e, R=Ph
80
70
3
4
ꢀ5 min
ꢀ5 min
23e
75
Entry
1
Ar1
Ar2
Ar3
Product Yield [%][a]
33
34
35
36
37
38
39
40
65
65
57
60
46
63
43
73
5
6
24e
25e
ꢀ5 min
ꢀ5 min
72
65
2
3
4
5
6
7
8
26e, R=H
27e, R=OMe
15 h
1.5 h
50
69
7
8
28e
29e
30e
8 h
6 h
73
65
76
9
10
ꢀ5 min
[a] Yield of pure product isolated after chromatography.
Table 3 shows the wide scope of this one-pot (indolyl)-
diaryl methane synthesis with regard to the nature of the
aromatic nucleophile Ar3-H (products 33–40). Even electron-
rich indole derivatives (entries 1 and 4), which are known to
polymerize easily under acidic conditions,[27] tolerate the mild
reaction conditions.
Disappointingly, this one-pot 2-pyridylsulfonamide dis-
placement did not take place with substrates lackingan
indolyl group, even under harsher conditions (DCE or
CH3CN, 608C). To further extend this methodology to the
[a] Overall yield of pure product isolated after chromatography.
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case of triaryl methanes that do not necessarily contain an
Keywords: amines · copper · homogeneous catalysis ·
nitrogen heterocycles · Schiff bases
.
indole moiety, the second electrophilic aromatic substitution
was investigated with isolated sulfonamide adducts. After
surveyingdifferent Lewis acids, we found that this reaction
occurs cleanly in the presence of Sc(OTf)3 (10 mol%) in
CH3CN at 608C. As shown in Table 4, a variety of unsym-
metrical triaryl methanes can be obtained in reasonable yields
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Table 4: Synthesis of unsymmetrical triaryl methanes.
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Entry
1
Ar1
Ar2
Ar3
Product Yield [%][a]
41
42
43
44
45
46
65
65
57
57
57
44
2
3
4
5
6
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has not been well established.[28]
In summary, we have developed an efficient Cu(OTf)2-
catalyzed AFCR of N-sulfonyl imines with electron-rich
aromatic and heteroaromatic compounds based on the use of
the 2-pyridylsulfonyl moiety as the key controllingunit. This
highly reactive protocol displays a wide tolerance both with
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Received: September 16, 2005
Published online: December 13, 2005
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[21] No reaction between 1a and N-methylindole was observed in the
absence of the Lewis acid.
[22] In the absence of (Æ )-binap the reaction between 1a and N-
methylindole catalyzed by Cu(OTf)2 becomes much slower (2 h
instead of 5 min). Unfortunately, the reaction of 1a or 1e in the
presence of enantiomerically pure (R)-binap, under different
reaction conditions, led to virtually racemic products 2a and 2e,
respectively (< 10% ee).
[23] A similar result and reactivity was observed in the presence of
other CuI salts such as [Cu(CH3CN)4](ClO4).
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Cu(OTf)2.
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[28] We have found only two examples of the synthesis of unsym-
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