Acid-catalyzed ortho-alkylation of anilines with styrenes: An improved route to chiral anilines with bulky substituents

Article abstract of DOI:10.1021/ol051916j

(Chemical Equation Presented) Reaction of para-substituted anilines with styrene derivatives at elevated temperatures, when catalyzed by CF ₃SO₃H, results in highly chemoselective ortho-alkylation of the aniline. When R = H, dialkylation can be achieved by varying the ratio of styrene to aniline. Several different substituted anilines and styrenes were examined, and good yields (42-87%) were obtained, except in the case where electron-withdrawing substituents are present on the styrene.

Full text of DOI:10.1021/ol051916j

ORGANIC
LETTERS
2
005
Acid-Catalyzed ortho-Alkylation of
Anilines with Styrenes: An Improved
Route to Chiral Anilines with Bulky
Substituents
Vol. 7, No. 23
5
135-5137
Anna E. Cherian, Gregory J. Domski, Jeffrey M. Rose, Emil B. Lobkovsky, and
Geoffrey W. Coates*
Department of Chemistry and Chemical Biology, Baker Laboratory,
Cornell UniVersity, Ithaca, New York 14853-1301
gc39@cornell.edu
Received August 9, 2005
ABSTRACT
Reaction of para-substituted anilines with styrene derivatives at elevated temperatures, when catalyzed by CF
3
SO
3
H, results in highly
chemoselective ortho-alkylation of the aniline. When R
) H, dialkylation can be achieved by varying the ratio of styrene to aniline. Several
different substituted anilines and styrenes were examined, and good yields (42
−87%) were obtained, except in the case where electron-
withdrawing substituents are present on the styrene.
Advances in the field of homogeneous catalysis have led to
the synthesis of well-defined transition metal complexes
capable of catalyzing a wide range of organic transforma-
a challenging problem. We therefore hypothesized that
anilines with ortho-substituents containing stereogenic cen-
ters could be universal chiral building blocks for the genesis
of a wide array of stereoselective catalysts.
1
tions. The commercial availability of chiral ligands such as
bisoxazolines and binaphthyl derivatives provides a facile
route to stereoselective catalysts. Controlling the stereo-
The Lewis acid catalyzed Friedel-Crafts alkylation of
substituted aromatic rings is a highly versatile C-C bond-
forming method. Reactions are typically enhanced by
electron-donating substituents, such as amine groups. How-
ever, alkylation of aniline is difficult, as the Lewis acid
typically binds to the amine substituent, thereby deactivating
2
chemistry of polymerizations has also been the focus of a
3
significant amount of research, as it leads to polymers with
highly regular structures, often giving improved physical and
mechanical properties. Many catalyst structures based on
N-N and N-O chelating ligands derived from bulky anilines
such as 2,6-diisopropylaniline have been shown to exhibit
6
the aromatic ring toward substitution. Initial efforts in our
laboratory to synthesize anilines with bulky chiral substit-
uents relied on the zeolite-catalyzed reaction of phenyl-
4
excellent catalytic behavior. However, examples of stereo-
7
control are generally limited to those with chain-end control
acetylene and p-toluidine, followed by subsequent hydro-
5
mechanisms, while site-controlled stereoselectivity remains
genation of the 2,6-bis(1-phenylvinyl)anilines catalyzed by
(
1) (a) Herrmann, W. A.; Cornils, B. Applied Homogeneous Catalysis
(5) (a) Pellechia, C.; Zambelli, A.; Oliva, L.; Pappalardo, D. Macro-
molecules 1996, 29, 6990-6993. (b) McClain, S. J.; Feldman, J.; McCord,
E. F.; Gardner, K. H.; Teasley, M. F.; Coughlin, E. B.; Sweetman, K. J.;
Johnson, L. K.; Brookhart, M. Macromolecules 1998, 31, 6705-6707. (c)
Nozaki, K.; Hiyama, T. J. Organomet. Chem. 1999, 576, 248-253. (d)
Small, B. L.; Brookhart, M. Macromolecules 1999, 32, 2120-2130.
(6) March, J. AdVanced Organic Chemistry: Reactions, Mechanisms,
and Structure, 4th ed.; John Wiley & Sons: New York, 1992; p 536.
with Organometallic Compounds; Wiley-VCH: Weinheim, 2002. (b)
Parshall, G. W.; Ittel, S. D. Homogeneous Catalysis: The Applications and
Chemistry of Catalysis by Soluble Transition Metal Complexes, 2nd ed.;
Wiley & Sons: New York, 1992.
(
(
(
2) Yoon, T. P.; Jacobsen, E. N. Science 2003, 299, 1691-1693.
3) Coates, G. W. Chem. ReV. 2000, 100, 1223-1252.
4) Gibson, V. C.; Spitzmesser, S. K. Chem. ReV. 2003, 103, 283-315.
1
0.1021/ol051916j CCC: $30.25
© 2005 American Chemical Society
Published on Web 10/13/2005

2
Pd/C. This method provided a route to C -symmetric chiral
anilines with sec-phenethyl substituents, which were incor-
porated into an R-diimine Ni(II) catalyst (Figure 1) for the
Table 1. Alkylation of p-Toluidine with Styrene
a
product distribution (%)
entry [styrene]/[1] [1]/[CF3SO3H]
1
2
3
4
1
2
3
4
5
6
0.75
1.0
2.0
5.0
1.0
1.0
0.2
0.2
0.2
0.2
0.1
0.5
44
0
0
0
0
44
81
65
0
81
75
8
4
18
23
88
12
20
1
12
12
7
Figure 1. Enantiomerically pure R-diimine Ni(II) catalyst with
chiral aniline groups for isospecific alkene polymerization.
0
5
a
1
Determined by H NMR spectroscopy.
8
isospecific polymerization of trans-2-butene. However, the
scope of anilines that could be synthesized with this method
was limited, so we sought a general one-step method for
the ortho-alkylation of anilines.
deter polystyrene formation. The ratio of p-toluidine to
styrene has a large impact on the amounts of 2 and 3 formed.
Even with an excess of p-toluidine (1.3 equiv to styrene,
entry 1), some dialkylation occurred, giving 8% of 3. In this
entry alone, the reaction was incomplete, with residual
p-toluidine observed by NMR spectroscopy. Increasing the
ratio of styrene to p-toluidine to 1:1 results in a high
proportion of 2 (81%, entry 2). Further increases in the
amount of styrene resulted in an increase in dialkylation,
giving high proportions of 3: 88% when 5 equiv of styrene
was used (entry 4). It should be noted that in all cases 3 was
obtained as a ∼55/45 mixture of the racemic/meso dia-
Several methods have been reported for the ortho-
alkylation of anilines with styrenes. Hart and Kosak found
aniline could be ortho-alkylated to 2-(sec-phenethyl)aniline
at 220 °C in 82% yield in the presence of aniline hydro-
9
chloride and an excess of styrene and aniline. Bergman and
3 6 5 4
Arnold reported that [PhNH ][B(C F ) ] is a catalyst for the
hydroamination and hydroarylation of several different types
of alkenes with anilines.10 Several metal-mediated routes
have been recently reported, using catalysts such as alumi-
1
1
num phenoxide, [Rh(1,5-cyclooctadiene)]BF
4
/4 PPh
After screening a number of
Brønsted acids and transition metal catalysts for the ortho-
3
/
3 3
stereomers. Changes in the amount of CF SO H catalyst had
1
2
13
HBF
4
,
3
and Ru (CO)12.
little effect on the product distribution, possibly increasing
the formation of 4 with decreasing catalyst concentration
14
alkylation of p-toluidine with styrene, we found that
CF SO H, an inexpensive and readily available compound,
3 3
(entry 5).
15
A number of commercially available aniline and styrene
was an excellent catalyst for the reaction, prompting our
further study.
derivatives were studied in the synthesis of monoalkylated
products (Table 2). An equimolar ratio of aniline and styrene
As shown in Table 1, the reaction of p-toluidine (1) with
3 3
styrene in xylenes, in the presence of CF SO H catalyst (160
°
C, 16 h), resulted in three different products: mono-C-
Table 2. Monoalkylation of Substituted Anilines with Styrene
Derivativesa
alkylated (2), di-C-alkylated (3), and N-alkylated (4). The
high reaction temperature minimized the formation of 4,
possibly by its isomerization to 2. Solvent volume was kept
to a minimum (1 g of p-toluidine per 1 mL of xylenes) to
(
7) Arienti, A.; Bigi, F.; Maggi, R.; Marzi, E.; Moggi, P.; Rastelli, M.;
Sartori, R.; Tarantola, F. Tetrahedron 1997, 53, 3795-3804.
8) Cherian, A. E.; Lobkovsky, E. B.; Coates, G. W. Chem. Commun.
(
d
entry
R
Ar
product
isolated yield (%)
2
003, 20, 2566-2567.
a
(
9) Hart, H.; Kosak, J. R. J. Org. Chem. 1962, 27, 116-121.
1
H
H
H
H
Ph
2
5
6
7
8
53
63
42
45
76
43
65
65
0
(10) Anderson, L. L.; Arnold, J.; Bergman, R. G. J. Am. Chem. Soc.
b
2
4-MeC6H4
2
1
2
005, 127, ASAP.
11) Olifirov, D. I.; Koschii, V. A.; Kozlikovskii, Y. B. Zh. Org. Khim.
992, 28, 1206-1212.
12) Beller, M.; Thiel, O. R.; Trauthwein, H. Synlett. 1999, 2, 243-
45. This paper also reports the metal-free, HBF4-catalyzed alkylation of
a
3
4-t-BuC6H4
2-naphthyl
2,4,6-Me3C6H2
4-t-BuC6H4
2,4,6-Me3C6H2
2,4,6-Me3C6H2
C6F5
(
a
4
b
(
5
H
c
6
CH3
CH3
F
9
an activated aniline (p-anisidine) with styrene.
b
7
10
11
12
(
(
13) Uchimaru, Y. Chem. Commun. 1999, 1133-1134.
b
8
14) Other attractive routes to 2-(1-arylethyl)anilines include thermal
a
rearrangements of N-(1-arylethyl)anilines in the presence of Brønsted and
9
H
9
Lewis acids, and reduction of 2,1-benzothiazines. Harmata, M.; Kahraman,
a
Aniline/styrene/CF3SO3H ) 1:1:0.2. b Aniline/styrene/CF3SO3H ) 1.5:
M. Synthesis 1994, 142-144.
1:0.2. c Aniline/styrene/CF3SO3H ) 1:2:0.2. d Based on the limiting reagent.
(15) For the alkylation of aniline with propylene using CF3SO3H, see:
Burgoyne, W. F.; Dixon, D. D. Appl. Catal. 1990, 63, 117-127.
5136
Org. Lett., Vol. 7, No. 23, 2005

was used successfully in most cases. However, in the case
of more expensive styrenes, the aniline was used in excess.
Good yields were obtained in all cases, with the exception
of pentafluorostyrene (entry 9).
When the ratio of styrene to p-toluidine was increased,
dialkylation of p-toluidine occurred preferrentially (Table 3).
Table 3. Dialkylation of p-Toluidine with Styrene Derivativesa
entry
Ar
product
isolated yield (%)c
a
1
Ph
3
13
14
15
77
75
87
84
b
2
4-t-BuC6H4
2-naphthyl
2,4,6-(CH3)3C6H2
b
3
b
4
a
b
Aniline/styrene/CF3SO3H ) 1:10:0.2. Aniline/styrene/CF3SO3H )
c
1
:5:0.2. Based on p-toluidine.
Four different styrenes were used, and high yields were
obtained in all cases. Diastereomeric products were obtained
in all cases, and rac- and meso-13-15 could be efficiently
separated by flash chromatography. rac-3 and meso-3 eluted
too closely to be separated by this method. However, rac-3
and meso-3 could be separated by successive recrystallization
from EtOH, and the meso diastereomer was assigned by
X-ray crystallography (Figure 2). (R,R)-3, (S,S)-3, and meso-3
could be separated by semipreparative HPLC equipped with
a chiral column (RegisTech, (S,S) Whelk-01). A crystal
structure of one enantiomer of rac-3 (later determined to be
Figure 2. Molecular structures of meso-3 and (R,R)-3 with thermal
ellipsoids at the 40% probability level.
ing,8,17 and we will continue to explore the use of these new
chiral ligand components.
Acknowledgment. G.W.C. gratefully acknowledges sup-
port from the Packard and Sloan Foundations, as well as
support from Mitsubishi Chemicals. This material is based
upon work supported in part by the U.S. Army Research
Laboratory and the U.S. Army Research Office under grant
number DAAD19-02-1-0275 Macromolecular Architecture
for Performance (MAP) MURI. This research made use of
the Cornell Center for Materials Research Shared Experi-
mental Facilities supported through the NSF MRSEC
program (DMR-0079992).
(R,R)-3) was also obtained (Figure 2). The absolute config-
uration of (S,S)-3 was assigned on the basis of the absolute
structure (Flack) parameter of the X-ray crystal structure of
8,16
a ligated Ni complex containing the aniline. Enantiomers
of 3 and 5-11 and 13-15 were separated by semipreparative
chiral HPLC, and only rac-15 exhibited incomplete resolu-
tion with this method.
3 3
In summary, we report the CF SO H-catalyzed alkylation
of substituted anilines with styrene derivatives. Combined
with chiral chromatography separation techniques, this
method provides a facile route to anilines with chiral ortho-
substituents. Use of these anilines in stereoselective homo-
geneous catalysts in our group has already proven promis-
Supporting Information Available: Compound synthe-
sis, characterization, and X-ray crystal structures of (R,R)-3
and meso-3. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL051916J
(
16) Flack, H. D.; Bernardinelli, G. J. Appl. Crystallogr. 2000, 33, 1143-
(17) Cherian, A. E., Rose, J. M., Lobkovsky, E. B., Coates, G. W. J.
Am. Chem. Soc. 2005, 127, 13770-13771.
1
148.
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