Facile regio- and stereoselective carbon-carbon coupling of phenol derivatives with aryl aziridines

Article abstract of DOI:10.1021/ol060822m

A chemo-, regio-, and stereoselective direct carbon-carbon coupling of readily available aryl borates with N-protected aryl aziridines provides a method for the synthesis of new 2-(o-hydroxyaryl)-2-aryl ethylamines which can be used, in a novel annulation

Full text of DOI:10.1021/ol060822m

ORGANIC
LETTERS
2006
Vol. 8, No. 12
2627-2630
Facile Regio- and Stereoselective
Carbon Carbon Coupling of Phenol
−
Derivatives with Aryl Aziridines
Mauro Pineschi,* Ferruccio Bertolini, Paolo Crotti, and Franco Macchia
Dipartimento di Chimica Bioorganica e Biofarmacia, UniVersita` di Pisa,
Via Bonanno 33, 56126 Pisa, Italy
pineschi@farm.unipi.it
Received April 5, 2006
ABSTRACT
A chemo-, regio-, and stereoselective direct carbon−carbon coupling of readily available aryl borates with N-protected aryl aziridines provides
a method for the synthesis of new 2-(o-hydroxyaryl)-2-aryl ethylamines which can be used, in a novel annulation sequence, to give stereodefined
substituted 3-aryl indolines.
Phenol derivatives are of considerable importance for the
chemical industry as pharmaceutical and fine chemicals.
Hence, the development of a direct regio- and stereoselective
C-C coupling reaction of phenols with readily available
carbon electrophiles is an important area in organic synthesis.
Aziridines are well-known carbon electrophiles capable of
undergoing ring-opening reactions with various nucleophiles
to give substituted amines.1 The chemistry of aziridines is
enriched with respect to that of epoxides by the presence of
an additional valency on the heteroatom, allowing modular
reactivity of these strained heterocycles.2 Although carbanion
nucleophilic addition to aziridines is well documented,3 we
are not aware of reactions of any kind of organometallic
reagent, derived from ortho metalation of (protected) phenols,
with aziridines to give arylated ethylamines. Furthermore,
no direct regio- and stereoselective arylation of aziridines
with phenol derivatives has been described. Only a few
Friedel-Crafts reactions of arenes with activated aziridines
to give mixtures of regioisomeric â-arylated ethylamines
have been reported so far.4 Recently, a practical synthesis
of a gonanotropin-releasing hormone (GnRH) antagonist
based on a regioselective opening of 2-alkyl nosylaziridines
by indoles was described by Farr and co-workers. The
reaction was mediated by BF3-Et2O and in the optimized
reaction conditions was completely anti stereoselective.5 On
the other hand, Durst et al. reported that highly substituted
aziridines could not be trapped in the C-3 position with
highly nucleophilic indoles by the use of common Lewis
acid catalysts such as BF3-Et2O and SnCl4.6 Very recently,
we have reported a novel intermolecular Friedel-Crafts
(1) For a recent review, see: Hu, X. E. Tetrahedron 2004, 60, 2701.
(2) Sweeney, J. B. Chem. Soc. ReV. 2002, 31, 247.
(4) (a) Stamm, H.; Onistaschenko, A.; Bucholz, B.; Mall, T. J. Org.
Chem. 1989, 53, 193 and references therein. (b) Yadav, J. S.; Subba Reddy,
B. V.; Srinivasa Rao, R.; Veerendhar, G.; Nagaiah, K. Tetrahedron Lett.
2001, 42, 8067.
(5) Farr, R. N.; Alabaster, R. J.; Chung, J. Y. L.; Craig, B.; Edwards, J.
S.; Gibson, A. W.; Ho, G.-J.; Humprey, G. R.; Johnson, S. A.; Grabowski,
E. J. J. Tetrahedron: Asymmetry 2003, 14, 3503.
(3) (a) Hassner, A.; Kascheres, A. Tetrahedron Lett. 1970, N, 4623. (b)
Eis, M. J.; Ganem, B. Tetrahedron Lett. 1985, 26, 1153. (c) Baldwin J. E.;
Adlington, R. M.; O’Neil, I. A.; Schofield, C.; Spivey, A. C.; Sweeney, J.
B. J. Chem. Soc., Chem. Commun. 1989, 1852. (d) Stamm, H.; Weib, R.
Synthesis 1986, 395. (e) Iwamoto, K.; Chatani, N.; Murai, S. J. Org. Chem.
2001, 66, 169. (f) Enders, D.; Janeck, C. F.; Raabe, G. Eur. J. Org. Chem.
2000, 3337. (g) Vicario, J. L.; Badia, D.; Carrillo, L. J. Org. Chem. 2001,
66, 5801.
(6) Reddy, R.; Jaquith, J. B.; Neelagiri, V. R.; Saleh-Hanna, S.; Durst,
T. Org. Lett. 2002, 4, 695.
10.1021/ol060822m CCC: $33.50
© 2006 American Chemical Society
Published on Web 05/09/2006

alkylation of phenolic substrates with aryl epoxides, in which,
unfortunately, consistent amounts of O-alkylated products
and low stereoselectivities were obtained in most cases.7
We report here a new carbon-carbon coupling reaction
of phenol derivatives with aryl aziridines, proceeding under
mild conditions, with a high regioselectivity and a high syn
stereoselectivity, without the need for any external transition-
metal catalysts or Lewis acids.
After the study of the epoxide ring opening, we hypoth-
esized that the use of different protecting groups on the
aziridine nitrogen might cause a different activation of the
strained ring in the reaction with the aryl borate, thus causing
a different chemo- (C- vs O-alkylation) and stereoselectivity,
with respect to the same reaction performed with epoxides.
To verify this working hypothesis, three different N-protected
enantiomerically pure aziridines 2a-c were prepared from
commercially available optically active (R)-(+)-styrene oxide
(99:1 er) via azidolysis and subsequent phosphine-mediated
ring closure of the obtained azido alcohols (Scheme 1). The
In this reaction, the correct choice of the N-protecting
group turned out to be important to determine the extent of
epimerization of the C-alkylation process. The lower extent
of epimerization (96% er) was found with aziridine 2c,
bearing the N-diphenylphosphinyl protecting group described
by Sweeney et al.8
The use of electron-rich borates such as 1b-d with
optically active aziridines 2a-c proved to be particularly
fruitful providing a dramatic increase in the C-alkylation
pathway and allowing a novel entry to the corresponding
optically active unsymmetrical 2,2-diaryl ethylamines of type
3 which are very difficult to obtain by other routes (Table
2).10 For example, the reactions of aziridines 2a-c with tris-
(3,5-dimethylphenyl)borate (1b) gave the corresponding
C-alkylated products 3ab, 3bb, and 3cb, with good yields
and a high chemoselectivity and syn stereoselectivity (entries
1-3, Table 1). Similar results were obtained with the
reactions of borates 1c and 1d on 2b (entries 4 and 5). The
syn-anti stereoselectivities, demonstrated by cyclization to
indolines (vide infra), were determined by HPLC on chiral
columns and were particularly high with N-diphenylphos-
phinyl-protected aziridine 2c (entry 3). On the other hand,
the use of p-methoxyphenyl borate 1e gave the corresponding
diaryl ethylamine 3be with a lower chemo- and stereose-
lectivity (entry 6). In borate 1a, the p-methoxy group reduces
the electron density at the reactive ortho position by means
of the associated inductive electron-withdrawing effect.11 In
contrast, in borates 1b-d in which the corresponding reactive
ortho positions are particularly electron-rich due to inductive
or mesomeric effects, a fast chemo- and stereoselective
C-alkylation reaction was obtained.
Scheme 1. Synthesis of Enantiomerically Enriched
N-Protected Aziridines 2a-c
Whereas substituted styrenyl aziridines bearing electron-
withdrawing groups (p-nitro, o-nitro, o-bromo) proved to be
unreactive, racemic p-fluorophenyl aziridine 2d and p-meth-
ylaziridine 2e underwent the reaction under mild conditions
and with a high chemo- and regioselectivity (Table 1, entries
7 and 8). The use of disubstituted trans-aryl aziridine 2f gave
the corresponding C-alkylated ring-opened product 3fd with
complete syn stereoselectivity and a high yield (entry 9).12
As aryl triflates can be readily obtained from the corre-
sponding phenols, they are valuable starting materials in
crude NH aziridines were not isolated but were directly
derivatized to give the corresponding protected N-tosyl (2a),
N-benzyloxy carbonyl (2b), and N-diphenyl phosphinyl
aziridine (2c) with no loss of optical purity.8
In preliminary experiments, we found that the reaction of
simple triphenyl borate 1a with optically pure N-protected
aziridines 2a-c occurred in CH2Cl2 at -78 °C to give an
almost equimolar mixture of C- and O-alkylated products
of type 3 and 4 (Scheme 2).9 The new carbon-carbon bond
was formed with complete regioselectivity at the benzylic
position of the aziridine ring and at the ortho position of the
phenol derivative.
(7) Bertolini, F.; Crotti, P.; Macchia, F.; Pineschi, M. Tetrahedron Lett.
2006, 47, 61.
(8) Osborn, H. M. I.; Sweeney, J. B.; Howson, B. Synlett 1994, 145.
(9) General Procedure: A solution of freshly prepared aryl borate 1a-e
(1.5 mmol) in CH2Cl2 (1.0 mL) was added to a solution of aziridine (1.0
mmol) in CH2Cl2 (3.0 mL) under Ar. The reaction was followed by TLC
and quenched with brine (4.0 mL). The solution was diluted with Et2O or
CH2Cl2 (40 mL) and washed with brine. Evaporation of the dried organic
solution afforded a crude reaction mixture that was purified by silica gel
chromatography to give the corresponding pure products.
Scheme 2. Friedel-Crafts Alkylation of the N-Protected
Aziridines 2a-c Derived from (R)-(+)-Styrene Oxide (99:1 er)
with Triphenyl Borate (1a)
(10) For a general approach to 2,2-diaryl ethylamines devoid of the
phenolic functionality, see: Maryanoff, B. E.; Nortey, S.; Gardocki, J. F.
J. Med. Chem. 1984, 27, 1067.
(11) Moreover, it should be considered that the electron density on
phenolic oxygen is low because of pπ-pπ back-bonding with the boron
atom. For a study of the Lewis acidity of the boron atom in triarylborates,
see: (a) Fenwick, J. T. F.; Wilson, J. W. Inorg. Chem. 1975, 14, 1602. For
a recent report on the catalytic activity of borate esters, see: (b) Yasuda,
M.; Yoshioka, S.; Yamasaki, S.; Somyo, T.; Chiba, K.; Baba, A. Org. Lett.
2006, 8, 761.
(12) However, with some disubstituted aziridines and aryl borates, lower
yields and stereoselectivities were obtained. For other examples of the use
of disubstituted aziridines, see Supporting Information.
2628
Org. Lett., Vol. 8, No. 12, 2006

Table 1. Synthesis of New Phenolic Ethylamines by Coupling of Protected Aziridines with Electron-Rich Aryl Boratesa
a All reactions were carried out in accordance with the general procedure.9 b Obtained from (R)-(+)-styrene oxide (see Scheme 1). c All phenols were
treated with BH3-Me2S to form the corresponding aryl borates immediately before use (see Supporting Information). d Determined by 1H NMR examination
of the crude reaction mixture. e Isolated yield after chromatography on silica gel. f Determined by chiral HPLC analysis on the basis of the initial enantiomer
distribution of the starting aziridine (99:1 er).
many types of metal-catalyzed coupling reactions.13 We
envisaged the possibility of an intramolecular ring closure
to give substituted 3-aryl indolines, which are important
chiral constituents of a number of biologically active
compounds.14 Despite the outstanding recent progress in
intermolecular C-N bond-forming reactions using aryl
halides and Pd-15 or Cu-catalyzed catalytic systems,16 only
a few examples of the coupling of amides with aryl triflates
(14) For a recent highly enantioselective synthesis of chiral 3-substituted
indolines by catalytic asymmetric hydrogenation of indoles, see: Kuwano,
R.; Kaneda, K.; Ito, T.; Sato, K.; Kurokawa, T.; Ito, Y. Org. Lett. 2004, 6,
2213 and pertinent references therein.
(15) For reviews, see: (a) Hartwig, J. F. Angew. Chem., Int. Ed. 1998,
37, 2046. (b) Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999,
576, 125.
(13) For a review, see: (a) Ritter, K. Synthesis 1993, 735. For recent
reports on their preparation, see: (b) Bengston, A.; Hallberg, A.; Larhed,
M. Org. Lett. 2002, 4, 1231. (c) Frantz, D. E.; Weaver, D. G.; Carey, J. P.;
Kress, M. H.; Dolling, U. H. Org. Lett. 2002, 4, 4717.
Org. Lett., Vol. 8, No. 12, 2006
2629

have been disclosed.17 Moreover, we are aware of only one
report on intramolecular amination using an aryl triflate.18
A solution was found in the CuI/CsOAc-mediated intramo-
lecular amination developed by Fukuyama and co-workers
for aryl bromides and iodides.19 In preliminary experiments,
the application of the original reaction conditions (DMSO,
room temperature or 90 °C) to aryl triflate 5ab gave the
corresponding indoline 6ab with very low yields (<10%),
but a simple increase in the reaction temperature to 120 °C
gave complete conversion in 12 h; indoline 6ab was isolated
in 72% yield after chromatographic purification (entry 1,
Table 2).
from the ring opening of a disubstituted aziridine such as 2f
afforded the corresponding trans 2,3-substituted indoline 6fd,
albeit with a lower isolated yield (entry 5).20 By means of
copper-mediated intramolecular amidation, it was also pos-
sible to establish unequivocally the relative and absolute
configuration of the original phenolic 2-aryl ethylamines of
type 3 (see Supporting Information for details).
To sum up, an easy regioselective C-functionalization of
hydroxy arenes to give 2-(o-hydroxyaryl)-2-aryl ethylamines
has been realized. The reaction occurs with aryl aziridines
at a remarkably low temperature and neutral conditions with
retention of configuration at the cleaved center. Starting from
readily available aryl borates and activated (enantiomerically
enriched) aryl aziridines, it is now possible to access
stereodefined substituted 3-aryl indolines by way of a novel
and versatile procedure.
Table 2. Synthesis of 3-Aryl Indolines by Intramolecular
Copper-Mediated Ring Closure of Sulfonamidic Aryl Triflatesa
Acknowledgment. This work was supported by Ministero
dell’Istruzione, del’Universita` e della Ricerca (M.I.U.R.
Rome, P.R.I.N. 2004), and by the University of Pisa. We
gratefully acknowledge Merck for the generous financial
support deriving from the 2005 ADP Chemistry Award.
entry
R1
R2
Ar (N°)
Ph (5ab)
Ph (5af)
Ph (5aa)
time (h) yield (%)b
Supporting Information Available: Experimental pro-
cedures and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
1
2
3
4
5
3,5-di-Me
4-Me
H
H
H
H
12
12
12
12
12
72 (6ab)
77 (6af)
45 (6aa)
90 (6db)
22 (6fd)
H
OL060822M
3,5-di-Me
3,5-di-OMe Me Ph (5fd)
p-F-C6H4 (5db)
(17) (a) Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 6043.
(b) Ganton, M. D.; Kerr, M. A. Org. Lett. 2005, 7, 4777.
a Reactions carried out at 120 °C in accordance with the general procedure
reported in the Supporting Information. b Isolated yields after chromato-
graphic purification on silica gel.
(18) Coleman, R. S.; Chen, W. Org. Lett. 2001, 3, 1141. In this case,
the mitomycin core ring system was obtained in moderate yields by means
of a Pd(OAc)2/BINAP catalytic system, but application of this reaction
procedure to a compound of type 5 bearing the free amine functionality
(Table 2, scheme) proved to be ineffective. Likewise, the use of enhanced
versions of the Goldberg amidation reaction developed by Buchwald and
co-workers16 proved to be unsuccessful for the intramolecular ring closure
of triflates 5.
The optimized reaction conditions were applied to other
sulfonamidic triflates of type 5, giving rapid and versatile
access to the corresponding 3-aryl indolines of type 6 (entries
2-4). The application of this procedure to triflate 5fd derived
(19) Yamada, K.; Kubo, T.; Tokuyama, H.; Fukuyama, T. Synlett 2002,
231.
(20) It should be noted that trans 2,3-substituted indolines are difficult
to obtain by other routes and cannot be obtained by catalytic hydrogenation
of the corresponding 2,3-substituted indoles. For an efficient synthesis of
2,3-disubstituted indoles, see: (a) Larock, R. C.; Yum, E. K.; Refvik, M.
D. J. Org. Chem. 1998, 63, 7652. (b) For a review of indole synthesis, see:
Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045.
(16) For a recent mechanistic study of the Goldberg amidation reactions,
see: Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem. Soc.
2005, 127, 4120 and references therein.
2630
Org. Lett., Vol. 8, No. 12, 2006