A three-component coupling process based on vicarious nucleophilic substitution (VNSAR)-alkylation reactions: An approach to indoprofen and derivatives

Article abstract of DOI:10.1021/jo0159901

The intermediate anion derived from the vicarious nucleophilic substitution (VNS) of hydrogen reacts with a series of alkyl halides to generate the corresponding α-alkylated conventional VNS product in a one-pot process. This one-pot VNS-alkylation reaction offers a convenient route to a range α-substituted nitrobenzyl phosphine oxides, sulfones, and esters via a three-component coupling reaction. Reactions of α-chloroethyl phenyl sulfone (14) and ethyl 2-chloropropionate (16) with nitrobenzene followed by subsequent addition of an alkylating agent give a series of sulfones and esters bearing an α-aryl quaternary center. The VNS-alkylation protocol has been applied to the synthesis of derivatives of Indoprofen from nitrobenzene using readily available inexpensive starting materials. Indoprofen itself was prepared using the conventional VNS reaction in four steps and 24% overall yield from nitrobenzene.

Full text of DOI:10.1021/jo0159901

J . Org. Chem. 2002, 67, 457-464
457
A Th r ee-Com p on en t Cou p lin g P r ocess Ba sed on Vica r iou s
Nu cleop h ilic Su bstitu tion (VNSAR)-Alk yla tion Rea ction s: An
Ap p r oa ch to In d op r ofen a n d Der iva tives
Nicholas J . Lawrence,*,† J ohn Liddle,† Simon. M. Bushell,† and David A. J ackson‡,§
Department of Chemistry, University of Manchester Institute of Science and Technology,
Manchester M60 1QD, U.K., and Zeneca Process Technology Department, Huddersfield Works,
PO Box A38, Leeds Road, Huddersfield HD2 1FF, U.K.
Lawrencenj1@cardiff.ac.uk
Received J uly 31, 2001
The intermediate anion derived from the vicarious nucleophilic substitution (VNS) of hydrogen
reacts with a series of alkyl halides to generate the corresponding R-alkylated conventional VNS
product in a one-pot process. This one-pot VNS-alkylation reaction offers a convenient route to a
range R-substituted nitrobenzyl phosphine oxides, sulfones, and esters via a three-component
coupling reaction. Reactions of R-chloroethyl phenyl sulfone (14) and ethyl 2-chloropropionate (16)
with nitrobenzene followed by subsequent addition of an alkylating agent give a series of sulfones
and esters bearing an R-aryl quaternary center. The VNS-alkylation protocol has been applied to
the synthesis of derivatives of Indoprofen from nitrobenzene using readily available inexpensive
starting materials. Indoprofen itself was prepared using the conventional VNS reaction in four
steps and 24% overall yield from nitrobenzene.
In tr od u ction
both ortho and para to the nitro group, when these
positions are available. The ratio of para:ortho substitu-
tion increases with the size of the leaving group. Tertiary
carbanions replace hydrogen in the VNS reaction exclu-
sively in the para position. The selection of base and
solvent is important for the VNS reaction; it should
ensure efficient deprotonation of the CH acid and fast
â-elimination of HX from the intermediate σ-adduct 2.
The majority of examples of VNS of hydrogen involve the
use of KOH, NaOH, t-BuOH, or NaH in DMSO, liquid
ammonia, or DMF. Ma¸kosza and co-workers have el-
egantly shown that the VNS reaction can be applied to a
large number of substituted nitrobenzenes and several
five- and six-membered heterocyclic systems including
nitrothiophenes,4,5 nitrofurans,6 nitropyrroles,5,6 and ni-
tropyridines.4,7
In 1978 Ma¸kosza found that carbanions 1 possessing
a nucleofugal group at the nucleophilic center react with
aromatic nitro compounds replacing hydrogen atoms
ortho or para to the nitro group (Scheme 1).1 These
reactions were named vicarious nucleophilic substitution
(VNSAR) of hydrogen to specify that although hydrogen
in the aromatic ring is replaced by the carbanion moiety,
the leaving group departing from the intermediate σ-ad-
duct 2 is that originally present in the reacting carbanion.
The general mechanistic pathway of the reaction has
been established as a fast and reversible addition of the
carbanion to the nitroarene, resulting in the formation
of the σ-adduct 2, from which base-induced â-elimination
takes place to generate the anion 3a .2 In typical VNS
reactions, nitroarenes react with carbanions that are
generally prepared in situ by action of base on the
corresponding CH acids.3 Base is also consumed in the
elimination step, and therefore at least 2 mol of base is
required for each 1 mol of CH acid. Since the product of
the reaction mixture prior to workup is a highly colored
nitrobenzylic carbanion 3, only monosubstitution takes
place. The regioselectivity of the reaction is overwhelm-
ingly controlled by steric factors. Carbanions derived from
a methylene group bearing both a leaving group and
electron-withdrawing group generally replace hydrogen
Subsequent transformation of the products of VNS
reactions often exploits the nucleophilic reactivity of the
newly created benzylic center. Several examples of the
stepwise deprotonation and alkylation of VNS products,
performed in two separate operations, have been re-
ported.8 As part of a study aimed at controlling the
stereochemistry of the process, we first wished to develop
a one pot VNS-alkylation process. We were hopeful also
to show that the anion 3a would embody a rich chemistry
(4) Ma¸kosza, M.; Owczarczyk, Z. J . Org. Chem. 1989, 54, 5094.
(5) Ma¸kosza, M. Synthesis 1991, 103.
(6) Ma¸kosza, M.; Kwast, E. Tetrahedron 1995, 51, 8339.
(7) Ma¸kosza, M.; Chylinska, B.; Mudryk, B. Liebigs Ann. Chem.
1984, 8.
(8) (a) Ma¸kosza, M.; Tyrala, A. Synth. Commun. 1986, 16, 419. (b)
Ma¸kosza, M.; Danikiewicz, W.; Wojciechowski K. Liebigs Ann. Chem.
1988, 203. (c) Macor, J . E.; Wehner, J . M. Heterocycles 1993, 35, 349.
(d) Wro´bel, Z.; Ma¸kosza, M. Tetrahedron 1997, 53, 5501. (e) Macor, J .
E.; Wehner, J . M. Tetrahedron Lett. 1991, 32, 7195. (f) Wro´bel, Z.;
Ma¸kosza, M. Synlett 1993, 597. (g) Ma¸kosza, M.; Tyrala, A. Acta Chem.
Scand. 1992, 46, 689. (h) Ma¸kosza, M.; Stalewski, J . Tetrahedron 1995,
51, 7263. (i) Ma¸kosza, M.; Stalewski, J ., Maslennikova, O. Synthesis
1997, 1131.
* Address correspondence to this author. Present address: Depart-
ment of Chemistry, Cardiff University, PO Box 912, Cardiff CF10 3TB,
U.K. Fax: (+44)29 2087 4030.
† University of Manchester Institute of Science and Technology.
‡ Huddersfield Works.
§ Now of Syngenta at the same address.
(1) Golinski, J .; Ma¸kosza, M. Tetrahedron Lett. 1978, 3495.
(2) Ma¸kosza, M.; Glinka, T. J . Org. Chem. 1983, 48, 3860.
(3) (a) Ma¸kosza, M. J . Pol. Chem. 1992, 66, 1. (b) Ma¸kosza, M.;
Winiarski, J . Acc. Chem. Res. 1987, 20, 282. (c) Ma¸kosza, M. Russ.
Chem. Rev. 1989, 58, 747. (d) Ma¸kosza, M.; Wojciechowski, K.
Heterocycles 2001, 54, 445.
10.1021/jo0159901 CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/03/2002

458 J . Org. Chem., Vol. 67, No. 2, 2002
Sch em e 1. Gen er a l Mech a n ism of th e VNS Rea ction
Lawrence et al.
Sch em e 2. P r op osed Th r ee-Com p on en t
Sch em e 3. VNS-Alk yla tion Ea ction s of
P h osp h in e Oxid es, Su lfon es, a n d Ester
Nu cleop h iles
VNS-Alk yla tion Cou p lin g Rea ction
similar to that of malonate anions given the similar
acidities of 4 (R ) H and EWG ) CO2Et)9,10 and diethyl
malonate.11
In a general sense, this approach is represented in
Scheme 2. This represents a potentially useful and
convenient method for the rapid construction of arenes
bearing a quaternary center via a three-component
coupling reaction. We now describe in detail that the
intermediate anions 3 may indeed be alkylated directly
in the VNS reaction.12
Resu lts a n d Discu ssion
NMR revealed that the products of methylation, allyla-
tion, and benzylation (7a -c) were prepared efficiently
with yields similar to that of the product of protonation
(74%)14 (Scheme 3). It is noteworthy that although a
slight excess of both base and the alkyl halide were used
(2.5 and 1.1 mol equiv, respectively), dialkylation was not
observed.15
The success of this one-pot VNS-alkylation reaction
was not restricted to the use of phosphine oxide 6. The
phenylsulfonyl group is a well-studied electron-withdraw-
ing group in the nucleophilic partner of the VNS reaction.
Chloromethyl phenyl sulfone16 (9) reacts efficiently with
4-chloronitrobenzene (8) with substitution of hydrogen
taking place in the ortho position (69%).16 Using 9, the
alkylation of the intermediate nitrobenzylic anion derived
from 8 proceeded efficiently with the same three alky-
lating agents. In all cases dialkylation was not observed
(Scheme 3).15 The yields of the alkylated product are
similar to that of the corresponding normal VNS reaction,
indicating that again the alkylation reaction is efficient.
We next applied the VNS-alkylation process to the
synthesis of a range of structurally similar esters, which
arguably are synthetically more useful. In the VNS
reactions of acetate esters, a thiophenoxy leaving group
We have previously shown that the sodium anion of
(chloromethyl)diphenylphosphine oxide13 (6) reacts readily
and efficiently with 4-chloro-3-(trifluoromethyl)nitroben-
zene (5) replacing hydrogen in the 6 position.14 The
nitroarene 5 was therefore an ideal substrate with which
to develop the prototypical VNS-alkylation process. The
reaction was performed using sodium hydride as the
base, in DMSO at room temperature, and then quenched
with a variety of alkylating reagents. When the initial
1
substitution reaction was complete (as judged by the H
NMR of an aliquot of proton-quenched reaction mixture),
the appropriate alkyl halide was added and the reaction
mixture left stirring for an additional 30 min. Proton
(9) The p-nitro-substituted aryl group renders the hydrogen adjacent
to the electron-withdrawing group particularly acidic and stabilizes
the anion 3b: ethyl (p-nitrophenyl)acetate, pKa (DMSO) ) 15.1;10a ethyl
phenylacetate, pKa (DMSO) ) 22.7.10b
(10) (a) Kabachnik, M. I.; Lobanov, D. I.; Matveeva, A. G.; Kovsheva,
O. E.; Terekhova, M. I.; Petrov, E. S.; Petrovskii, P. V.; Matrosov, E.
I. Izv. Akad. Nauk SSSR, Ser. Khim. 1991, 1598. (b) Bordwell, F. G.;
Branca, J . C.; Bares, J . E.; Filler, R. J . Org. Chem. 1988, 53, 780.
(11) Olstead, W. N.; Bordwell, F. G. J . Org. Chem. 1980, 45, 3299:
diethyl malonate, pKa (DMSO) ) 16.4.
(12) For a preliminary report, see: (a) Lawrence, N. J .; Liddle, J .;
J ackson, D. A. Synlett 1996, 55. (b) Drew, M. D.; J ackson, D. A.;
Lawrence, N. J .; Liddle, J .; Pritchard, R. G. Chem. Commun. 1997,
189.
(13) Marmor, R. S.; Seyferth, D. J . Org. Chem. 1969, 34, 748.
(14) Lawrence, N. J .; Liddle, J .; J ackson, D. A. Tetrahedron Lett.
1995, 36, 8477.
(15) The amount of dialkylation is estimated as being <5%. No
material corresponding to dialkylated product was seen in the 1H NMR
spectrum of the crude reaction mixture.
(16) Ma¸kosza, M.; Golinski, J . J . Org. Chem. 1984, 49, 1488.

One-Pot VNS of Hydrogen-Alkylation Reactions
J . Org. Chem., Vol. 67, No. 2, 2002 459
Sch em e 4. Syn th esis of Qu a ter n a r y Cen ter s via
base-catalyzed self-condensation of the R-chloroester 16
is slow compared to the rate of the VNS reaction,
presumably for steric reasons. This particular VNS
reaction was found to be highly exothermic, and hence,
the addition of 16 and nitrobenzene to the sodium
hydride is carried out at 0 °C. The reaction was quenched
with the usual three electrophiles to generate the esters
15d -f bearing the quaternary center in moderate yield.
Other electrophiles were also used. The R-aryl succinate
derivative 15g was produced from the use of ethyl
bromoacetate. We have also shown that the less reactive
electrophiles n-butyl bromide and ethyl bromide behave
well in the VNS reaction of ethyl 2-chloropropionate.
Clearly in these cases (15h ,i), alkylation is more favor-
able than elimination. The use of an R-haloketone as the
electrophile gives rise to the efficient synthesis of the
corresponding 1,4-keto ester bearing a quaternary center,
such as 15j. Our hope that the (nitrophenyl)acetate anion
would react like a malonate enolate was well met by the
reaction with methyl acrylate. In a process that is similar
to the true Michael reaction, conjugate addition produces
the mixed glutaric acid diester 15k . For this reaction, it
was necessary to cool the reaction mixture to -68 °C after
the VNS reaction and prior to and during the addition
of the methyl acrylate. If both processes were performed
at 0 °C very little diester 15k was formed; the enolate
formed from the Michael reaction presumably reacts with
more acrylate. Chloroacetonitrile reacts well (when added
to the reaction at -68 °C) in the reaction to generate a
potentially useful cyanopropionate derivative 15l. It is
noteworthy that in all these VNS-alkylation processes
the product of type 15 is not directly accessible via a
single VNS reaction from a nucleophile already bearing
two alkyl groups. The one-pot VNS-alkylation reaction
this methodology in principle also offers a convenient way
to regioselectively alkylate nitrobenzenes. Decarboxyla-
tion of the R-ester group in 15d -l using the procedure
developed by Bull et al.21 will produce R-branched alkyl-
nitroarenes.
th e VNS-Alk yla tion Rea ction
Ta ble 1. Syn th esis of Qu a ter n a r y Cen ter s via th e
VNS-Alk yla tion Rea ction
15
EWG
R
RX
yield (%)
a
b
c
d
e
f
g
h
i
SO2Ph
SO2Ph
SO2Ph
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
Me
allyl
PhCH2
Me
allyl
PhCH2
CH2CO2Et
Et
(CH2)3Me
PhCOCH2
(CH2)2CO2Me
CH2CN
MeI
allyl Br
PhCH2Br
MeI
allyl Br
PhCH2Br
BrCH2CO2Et
EtBr
Me(CH2)3Br
PhCOCH2Br
H2CdCHCO2Me
ClCH2CN
74
80
72
60
67
63
80
54
59
65
56
56
j
k
l
is normally used since the enolate of ethyl R-chloroacetate
undergoes facile self-condensation.17 The analogous
thiophenoxyacetate 12 was prepared from commercially
available ethyl chloroacetate via displacement of chloride
with thiophenol.18 The enolate of ethyl thiophenoxy-
acetate was found to react exclusively in the para position
when treated with 3-chloronitrobenzene (11). The regio-
selectivity is the same as that reported in the reaction of
tert-butyl thiophenoxyacetate with 3-chloronitrobenzene
(11).17 The reaction was quenched with the same series
of alkyl halides to give the R-alkylated esters 13a -c in
moderate yield (Scheme 3). The alkylation with methyl
iodide gave the expected product 13a (R ) Me) ac-
companied by a small amount of the dimethylated
product (10%). Dialkylation was not observed when the
electrophiles allyl bromide and benzyl bromide were used.
We realized that the one-pot VNS-methylation process
incorporating ester nucleophiles represents a useful route
to a number of the medicinally important R-phenyl-
propionic acids.19 The route to one member of this class
of compounds is disclosed at the end of this discussion.
The one-pot VNS-alkylation reaction may be used in
the synthesis of R-aryl quaternary centers. This is
illustrated by the reaction of the anion of R-chloroethyl
phenyl sulfone20 (14) and the enolate of ethyl 2-chloro-
propionate (16) with nitrobenzene using the same range
of electrophiles (Scheme 4 and Table 1). As expected the
tertiary anion of 14 replaces the para hydrogen of
nitrobenzene exclusively.20 The subsequent alkylation,
using the standard alkylating agents, proceeded in good
yields to give the corresponding sulfones 15a -c possess-
ing a nitroaryl group bearing a quaternary center at the
para position.
Other electrophiles react with the anion 3. We have
shown that the VNS reaction of (chloromethyl)diphen-
ylphosphine oxide13 (6) and several nitrobenzenes may
be quenched with substituted benzaldehydes to generate
the corresponding E-stilbene.14 However, the anion 3
derived from ester nucleophiles does not react efficiently
with substituted benzaldehydes. This is probably because
the reaction is reversible and favors the stabilized anion
3. Indeed when addressing this problem, we serendipi-
tously found that the VNS reactions of ethyl 2-chloro-
propionate and various nitrobenzenes may be quenched
with benzaldehyde, in the presence of air, to give R-aryl-
R-hydroxy esters.22
We have sought to illustrate the potential of the one
pot VNS-alkylation protocol by the synthesis of some
biologically active molecules. We have already reported
the full details of a synthesis of the anticancer drug (()-
aminoglutethimide.23 We now report the synthesis of a
second drug. This time we used the VNS-alkylation
protocol to make Indoprofen (21), a member of the
Similarly, the sodium enolate of ethyl 2-chloropropi-
onate (16) reacted efficiently in the para position of
nitrobenzene using DMF as solvent. In this reaction a
thiophenoxy-substituted ester is not required since the
(17) Ma¸kosza, M.; Winiarski, J . J . Org. Chem. 1984, 49, 1494.
(18) Ono, N.; Miyake, H.; Saito, T.; Kaji, A. Synthesis 1980, 952.
(19) Rieu, J . P.; Boucherlr, A.; Cousse, H.; Mouzin, G. Tetrahedron
1986, 42, 4095.
(20) Ma¸kosza, M.; Glinka, T.; Kinowski, A. Tetrahedron 1984, 40,
1863.
(21) Bull, D. J .; Fray, M. J .; Mackenny, M. C.; Malloy, K. A. Synlett
1996, 647.
(22) Lawrence, N. J .; Lamarche, O.; Thurrab, N. Chem. Commun.
1999, 689.
(23) Bushell, S. M.; Crump, J . P.; Lawrence, N. J .; Pineau, G.
Tetrahedron 1998, 54, 2269.

460 J . Org. Chem., Vol. 67, No. 2, 2002
Lawrence et al.
Sch em e 5. Retr osyn th etic Rou te to In d op r ofen
(21)
duced the corresponding aniline 18 in reasonable yield.
The Takahashi protocol for phthalimidine synthesis
produced the ethyl Indoprofen (19) without problems.
Saponification of the ester 19 gave Indoprofen in an
overall 24% yield from nitrobenzene. The same approach
was applied to the R-methyl Indoprofen derivative 22,
as a representative analogue accessible by our VNS-
alkylation procedure. The VNS reaction of ethyl 2-chlo-
ropropionate (16) with nitrobenzene followed by reaction
with iodomethane gave the ester 15d (60%). The aniline
20 was obtained by treatment of 15d with Pd/C and
hydrogen (63%). The oxoisoindole 22 was prepared in the
same fashion from 20 (65%). Since we have prepared a
variety of adducts 15d -l from ethyl 2-chloropropionate
(16) and nitrobenzene followed by an electrophilic quench,
a similar number of Indoprofen analogues in principle
could be derived in the same manner.
Sch em e 6. VNS Syn th esis of In d op r ofen a n d
Der iva tives
In summary, we have demonstrated that VNS reac-
tions may be quenched with a series of alkyl halides and
this approach may be used to construct R-aryl quaternary
centers. This one-pot VNS-alkylation reaction offers a
convenient route to a range R-substituted nitrobenzyl
phosphine oxides, sulfones, and esters. This type of
process may form a variety of products from a single VNS
nucleophile, possibly allowing the introduction of func-
tionality that would not be compatible with the basic
conditions of the initial VNS reaction. We have also
developed a route to Indoprofen in four steps and 24%
overall yield from nitrobenzene using readily available
inexpensive starting materials, in a way that will allow
the rapid construction of many analogues. This clearly
illustrates the potential of the one-pot VNS-alkylation
reaction.
Exp er im en ta l Section
arylpropionic acid nonsteroidal antiinflammatory drugs.24
Indoprofen is amenable to synthesis via our methodology
since the para-amino functionality can be derived from
a nitro group.
Gen er a l In for m a tion . The 200 MHz 1H NMR spectra were
recorded using a Bruker AC 200 NMR spectrometer while all
300 MHz 1H and 75 MHz 13C NMR spectra were recorded
using a Bruker AC 300 spectrometer. 13C NMR spectra were
recorded using distortionless enhancement by polarization
transfer. Both 1H and 13C spectra were recorded using CHCl3
as internal standard. Chemical ionization (CI) mass spectra
were recorded using a Kratos MS25 mass spectrometer; fast
atom bombardment (FAB) mass spectra were recorded with a
Kratos MS50 with a meta-nitrobenzyl alcohol matrix. Accurate
mass determinations were carried out on a Kratos Concept
IS spectrometer. Elemental analyses were performed using a
Carlo-Erba 1106 elemental analyzer. Infrared spectra were
recorded using a Perkin-Elmer 783 spectrometer equipped
with a PE 600 data station. Melting points were determined
using an electrothermal melting point apparatus and were
uncorrected. Column chromatography was conducted using
silica gel 60 230-400 mesh (Merck & Co.). Silica TLC was
conducted on precoated aluminum sheets (60 F254) with a 0.2
mm thickness (Aldrich Chemical Co.). DMSO was distilled
from calcium hydride and stored under nitrogen prior to use.
Anhydrous methanol and DMF were obtained from Aldrich
Chemical Co. and used as supplied.
Dip h en yl-1-{1-[3′-ch lor o-6′-n itr o-4′-(tr iflu or om eth yl)-
p h en yl]eth yl}p h osp h in e Oxid e (7a ). Sodium hydride (60%
dispersion in oil, 400 mg, 10.00 mmol) was added to anhydrous
DMSO (5 mL) and the mixture flushed with nitrogen. (Chlo-
romethyl)diphenylphosphine oxide13 (6) (1.0 g, 3.99 mmol) and
4-chloro-3-(trifluoromethyl)nitrobenzene (5) (1.0 g, 4.43 mmol)
were dissolved in anhydrous DMSO (5 mL) and added drop-
wise to the sodium hydride slurry. The mixture was stirred
at ambient temperature for 6 h before methyl iodide (3.0 mL,
48.17 mmol) was added and the resulting mixture stirred for
a further 30 min. The reaction was quenched with distilled
We envisaged that the ester 17 would serve as a
convenient precursor (Scheme 5). The method of Taka-
hashi and co-workers25 provides a useful way to construct
a phthalimidine derivative from a substituted aniline by
1,2,3-1H-benzotriazole- and 2-mercaptoethanol-mediated
condensation with o-phthalaldehyde. In our general
strategy to Indoprofen and analogues, the carbon-carbon
bond positioned para to the nitro group can be con-
structed by VNS of the para hydrogen atom of nitroben-
zene (disconnection a). The second carbon-carbon bond
can be made by the alkylation of the VNS intermediate
anion via disconnection b, using a substituted acetate
derivative in the usual way.
We first showed that the product 17 previously pre-
pared by the VNS reaction of ethyl 2-chloropropionate
(16) with nitrobenzene could be efficiently converted to
the ethyl ester of Indoprofen (21) (Scheme 6). Reduction
of the nitroarene 17, via catalytic hydrogenation, pro-
(24) (a) Emanueli, A.; Mandelli, V.; Mascellani, G.; Sacchetti, G.
Curr. Med. Res. Opin. 1979, 6, 124. (b) Buttinoni, A.; Ferrari. M.;
Colombo. M.; Ceserani. R. J . Pharm. Pharmacol. 1983, 35, 603. (c)
Brockutne, J . G.; Love, A. J .; Mankowitz, E.; Downing, J . W. S. Afr.
Med. J . 1985, 68, 803. (d) Ravikumar, K. Acta Crystallogr., Sect. C:
Cryst. Struct. Commun. 1994, 50, 589.
(25) (a) Takahashi, I.; Kawakami, E.; Hirano, E.; Yokota, H.;
Kitajima, Synlett 1996, 353. (b) Takahashi, I.; Hirano, E.; Kawakami,
T.; Kitajima, H.. Heterocycles 1996, 43, 2343.

One-Pot VNS of Hydrogen-Alkylation Reactions
J . Org. Chem., Vol. 67, No. 2, 2002 461
water, acidified with hydrochloric acid (1 M solution), and
extracted with chloroform (3 × 20 mL). The combined extracts
were washed with distilled water (3 × 20 mL), dried (magne-
sium sulfate), and filtered, and the solvent was removed under
reduced pressure to yield the phosphine oxide (7a ) (1.36 g,
75%) as a yellow colored solid, mp 127-128 °C after chroma-
tography (silica, 9:1, chloroform-ethyl acetate). Anal. Found:
moved under reduced pressure to yield 10a (0.97 g, 57%) as a
white solid, mp 110-112 °C (lit.8a mp 114 °C) after chroma-
tography (silica, 7:3, chloroform-hexane) and recrystallization
from ethyl acetate. Anal. Found: C, 51.7; H, 3.8; N, 4.2; Cl,
10.8; S, 9.5. Calcd for C14H12ClNO4S: C, 51.6; H, 3.7; N, 4.3;
Cl, 10.9; S, 9.8. Rf ) 0.41 (silica, 7:3, chloroform-hexane). νmax
1
(KBr disk)/cm-1: 1535, 1360. H NMR (300 MHz; CDCl3): δ
C, 55.9; H, 3.5; N, 3.2; Cl, 7.8; F, 12.3; P, 6.7. Calcd for C21H16
-
1.77 (3H, d, J ) 7.0 Hz), 5.47 (1H, q, J ) 7.0 Hz), 7.44-7.52
(3H, m), 7.62-7.69 (3H, m), 7.75 (1H, d, J ) 2.2 Hz), 7.79 (1H,
d, J ) 8.7 Hz). 13C NMR (75 MHz; CDCl3): δ 14.4, 58.1, 126.5,
129.0, 129.3, 129.8, 130.3, 130.4, 134.3, 136.7, 139.7, 148.3.
MS (m/z) (FAB): 348 [(M + Na)+, 27%], 326 [(M + H)+, 67],
184 (100).
ClF3NO3P: C, 55.6; H, 3.6; N, 3.1; Cl, 7.8; F, 12.6; P, 6.8. Rf )
0.62 (silica, 9:1, chloroform-ethyl acetate). νmax (KBr disk)/
1
cm-1: 1620, 1530, 1440. H NMR (300 MHz; CDCl3): δ 1.61
(3H, dd, J ) 7.1 and 15.2 Hz), 4.73 (1H, quin, J ) 7 Hz), 7.25-
7.31 (2H, m), 7.37-7.49 (3H, m), 7.55-7.65 (3H, m), 7.91-
8.00 (3H, m), 8.28 (1H, d, J ) 1.1 Hz). 13C NMR (75 MHz;
CDCl3): δ 15.50 (d, J PC ) 3 Hz), 34.63 (d, J PC ) 64 Hz), 121.44
(q, J FC ) 274 Hz), 123.9, 124.0, 128.4, 128.6, 128.9, 129.0,
129.4, 130.0, 130.2, 130.4, 130.7, 131.0, 131.1, 131.4, 132.0,
132.0, 132.3, 132.4, 134.2, 134.3, 137.1, 139.4, 139.5, 146.6,
146.6. MS (m/z) (CI using ammonia): 454 [(M + H)+, 100].
Dip h en yl-1-{1-[3′-ch lor o-6′-n itr o-4′-(tr iflu or om eth yl)-
p h en yl]bu t-3-en yl}p h osp h in e Oxid e (7b). 7b was prepared
from (chloromethyl)diphenylphosphine oxide13 (6) (1.0 g, 3.99
mmol), 4-chloro-3-(trifluoromethyl)nitrobenzene (5) (1.0 g, 4.43
mmol), and allyl bromide (0.5 mL, 5.78 mmol) in a way to
similar to that for 7a . The phosphine oxide 7b (1.27 g, 66%)
was obtained as a white solid, mp 116-118 °C after chroma-
tography (silica, 9:1, chloroform-ethyl acetate) and recrystal-
lization from ethyl acetate-hexane. Anal. Found: C, 57.3; H,
3.6; N, 3.0; Cl, 7.4; F, 12.1; P, 6.1. Calcd for C23H18ClF3NO3P:
C, 57.6; H, 3.8; N, 2.9; Cl, 7.4; F, 11. 9; P, 6.5. Rf ) 0.58 (silica,
9:1, chloroform-ethyl acetate). νmax (KBr disk)/cm-1: 1530,
1440, 1350. 1H NMR (300 MHz; CDCl3): δ 2.68-2.90 (2H, m),
4.85-4.93 (3H, m), 5.47-5.61 (1H, m), 7.24-7.62 (8H, m),
7.92-8.01 (3H, m), 8.27 (1H, s). 13C NMR (75 MHz; CDCl3): δ
34.5, 40.10 (d, J PC ) 63 Hz), 118.60, 121.40 (q, J FC ) 274 Hz),
124.0, 124.0, 128.4, 128.6, 129.0, 129.1, 129.4, 129.9, 130.2,
130.3, 130.7, 131.0, 131.1, 131.3, 132.0, 132.0, 132.4, 132.5,
133.1, 133.3, 134.2, 134.3, 137.0, 137.5, 137.6, 147.4, 147.5.
MS (m/z) (FAB): 480 [(M + H)+, 95], 201 (100).
1-[1-(3′-Ch lor o-6′-n itr op h en yl)bu t-3-en yl] P h en yl Su l-
fon e (10b). 10b was prepared from chloromethyl phenyl
sulfone16 (9) (1.0 g, 5.25 mmol), 4-chloronitrobenzene (8) (910
mg, 5.78 mmol), and allyl bromide (0.50 mL, 5.78 mmol) in a
way similar to that for 10a . The sulfone 10b (1.21 g, 66%) was
obtained as yellow crystals, mp 103-104 °C after column
chromatography (silica, 7:3, chloroform-hexane) and recrys-
tallization from ethanol. Anal. Found: C, 54.3; H, 4.3; N, 4.3;
Cl, 10.1; S, 9.0. Calcd for C16H14ClNO4S: C, 54.6; H, 4.0; N,
4.0; Cl, 10.1; S, 9.1. Rf ) 0.46 (silica, 7:3, chloroform-hexane).
νmax (KBr disk)/cm-1
:
1530, 1350. 1H NMR (300 MHz;
CDCl3): δ 2.85-2.96 (1H, m), 3.11-3.19 (1H, m), 5.01 (1H, d,
J ) 10.8 Hz), 5.06 (1H, d, J ) 18.2 Hz), 5.48 (1H, dd, J ) 4.2
Hz, 11.3 Hz), 5.53-5.61 (1H, m), 7.42-7.50 (3H, m), 7.61-
7.66 (3H, m), 7.72-7.76 (2H, m). 13C NMR (75 MHz; CDCl3):
δ 32.3, 62.1, 119.5, 126.3, 128.7, 128.8, 129.2, 129.6, 130.4,
131.4, 134.2, 136.8, 139.5, 148.8. MS (m/z) (FAB): 352 [(M +
H)+, 100].
1-[1-(3′-Ch lor o-6′-n itr op h en yl)-2-p h en yleth yl] P h en yl
Su lfon e (10c). 10c was prepared from chloromethyl phenyl
sulfone16 (9) (1.0 g, 5.25 mmol), 4-chloronitrobenzene (8) (910
mg, 5.78 mmol), and benzyl bromide (0.70 mL, 5.89 mmol) in
a way similar to that for 10a . The sulfone 10c (1.40 g, 66%)
was obtained as pale yellow needles, mp 137-139 °C after
column chromatography (silica, 3:2, dichloromethane-hexane)
and recrystallization from ethanol. Anal. Found: C, 59.5; H,
4.0; N, 3.5; Cl, 8.9; S, 8.0. Calcd for C20H16ClNO4S: C, 59.8;
H, 4.0; N, 3.5; Cl, 8.8; S, 8.0. Rf ) 0.46 (silica, 7:3, chloroform-
Dip h en yl-1-{1-[3′-ch lor o-6′-n itr o-4′-(tr iflu or om eth yl)-
p h en yl]-2-p h en yleth yl}p h osp h in e Oxid e (7c). 7c was
prepared from (chloromethyl)diphenylphosphine oxide13 (6)
(1.0 g, 3.99 mmol), 4-chloro-3-(trifluoromethyl)nitrobenzene (5)
(1.0 g, 4.43 mmol), and benzyl bromide (0.71 mL, 5.97 mmol)
in a way similar to that for 7a . The phosphine oxide 7c (1.20
g, 79%) was obtained as a cream solid, mp 144-145 °C after
chromatography (silica, 19:1, chloroform-ethyl acetate) and
recrystallization from ethyl acetate-hexane. Anal. Found: C,
hexane). νmax (KBr disk)/cm-1
:
1530, 1355, 1310, 1150. 1H
NMR (300 MHz; CDCl3): δ 3.37 (1H, dd, J ) 11.5 and 14.2
Hz), 3.78 (1H, dd, J ) 4.2 and 14.2 Hz), 5.82 (1H, dd, J ) 4.2
and 11.5 Hz), 7.00 (2H, d, J ) 7.6 Hz), 7.04-7.18 (3H, m),
7.35 (1H, dd, J ) 2.2 and 8.7 Hz), 7.46 (2H, t, J ) 7.6 Hz),
7.59-7.64 (2H, m), 7.70 (2H, d, J ) 7.6 Hz), 7.93 (1H, d, J )
2.2 Hz). 13C NMR (75 MHz; CDCl3): δ 34.3, 63.6, 126.3, 127.0,
128.6, 128.8, 129.1, 129.5, 130.3, 134.2, 134.8, 136.9, 139.4,
148.5; m/z (FAB) 402 [(M + H)+, 100].
61.3; H, 3.6; N, 2.8; Cl, 6.8; F, 10.7; P, 5.7. Calcd for C27H20
-
ClF3NO3P: C, 61.2; H, 3.8; N, 2.6; Cl, 6.7; F, 10.8; P, 5.9. Rf )
0.49 (silica, 19:1, chloroform-ethyl acetate). νmax (KBr disk)/
cm-1: 1530, 1440. 1H NMR (300 MHz; CDCl3): δ 3.20-3.39
(2H, m), 5.18-5.25 (1H, m), 6.82-6.85 (2H, m), 7.08-7.11 (3H,
m), 7.25-7.30 (2H, m), 7.35-7.40 (1H, m), 7.56-7.64 (5H, m),
7.84 (1H, s), 8.01-8.08 (2H, m), 8.45 (1H, s). 13C NMR (75
Eth yl 2-(2′-Ch lor o-4′-n itr op h en yl)p r op ion a te (13a ). So-
dium hydride (60% dispersion in oil, 430 mg, 10.75 mmol) was
added to anhydrous DMSO (5 mL) and the mixture flushed
with nitrogen. Ethyl thiophenoxyacetate26 (12) (1.0 g, 5.10
mmol) and 3-chloronitrobenzene (11) (880 mg, 5.59 mmol) were
dissolved in anhydrous DMSO (5 mL) and added dropwise to
the sodium hydride slurry. The reaction mixture was stirred
at ambient temperature for 2 h before methyl iodide (0.32 mL,
5.14 mmol) was added and the resulting mixture stirred for a
further 30 min. The reaction was then poured into distilled
water (100 mL), acidified with hydrochloric acid (1 M solution),
and extracted with chloroform (3 × 20 mL). The combined
extracts were washed with distilled water (3 × 50 mL) and
saturated aqueous sodium bicarbonate solution (3 × 50 mL),
dried (magnesium sulfate), and filtered, and the solvent was
removed under reduced pressure to yield 13a as a yellow oil
(550 mg, 42%) after chromatography (silica, 3:2, hexane-
chloroform): Rf ) 0.16 (silica, 3:2, hexane-chloroform); νmax
(liquid film on CsI plates)/cm-1 1740, 1530, 1350; 1H NMR (300
MHz; CDCl3) δ 1.22 (3H, t, J ) 7.1 Hz), 1.54 (3H, d, J ) 7.2
Hz), 4.12-4.20 (2H, m), 4.25 (1H, q, J ) 7.2 Hz), 7.53 (1H, d,
J ) 8.6 Hz), 8.11 (1H, dd, J ) 2.4 and 8.6 Hz), 8.26 (1H, d, J
MHz; CDCl3): δ 36.3, 41.5 (d, J PC ) 62 Hz), 121.2 (q, J FC
)
274 Hz), 123.9, 124.0, 124.0, 124.1, 126.9, 128.3, 128.4, 128.6,
129.0, 129.2, 129.8, 130.2, 130.3, 130.4, 130.9, 131.0, 131.2,
131.5, 132.0, 132.0, 132.4, 132.4, 134.2, 134.2, 136.7, 136.8,
137.1, 137.9, 137.9, 147.2, 147.3. MS (m/z) (FAB): 530 [(M +
H)+, 100].
1-[1-(3′-Ch lor o-6′-n itr op h en yl)eth yl] P h en yl Su lfon e
(10a ). Sodium hydride (60% dispersion in oil, 470 mg, 11.75
mmol) was added to anhydrous DMSO (5 mL) and the flask
flushed with nitrogen. Chloromethyl phenyl sulfone16 (9) (1.0
g, 5.25 mmol) and 4-chloronitrobenzene (8) (910 mg, 5.78
mmol) were dissolved in anhydrous DMSO (5 mL) and added
dropwise to the sodium hydride slurry. The mixture was
stirred at ambient temperature for 2 h before methyl iodide
(0.4 mL, 6.42 mmol) was added and the resulting mixture
stirred for a further 30 min. The reaction was quenched with
distilled water, acidified with hydrochloric acid (1 M solution),
and extracted with chloroform (3 × 20 mL). The combined
extracts were washed with distilled water (3 × 20 mL), dried
(magnesium sulfate), and filtered, and the solvent was re-
(26) Dressler, H.; Graham, J . E. J . Org. Chem. 1967, 32, 985.

462 J . Org. Chem., Vol. 67, No. 2, 2002
Lawrence et al.
) 2.4 Hz); 13C NMR (75 MHz; CDCl3) δ 13.9, 17.2, 42.3, 61.3,
121.9, 124.6, 129.1, 134.6, 145.6, 147.0, 172.5; found (CI) (M
+ H)+ m/z 258.0533, calcd for C11H13ClNO4 (M + H)+ m/z
258.0533; m/z (FAB) 258 [(M + H)+, 100].
hexane). νmax (KBr disk)/cm-1: 1540, 1515, 1350. 1H NMR (300
MHz; CDCl3): δ 1.76 (3H, s), 2.89 (1H, dd, J ) 7.9 and 14.1),
3.42 (1H, dd, J ) 5.7 and 14.1 Hz), 5.07 (1H, d, J ) 9.7 Hz),
5.17 (1H, d, J ) 16.9 Hz), 5.27-5.40 (1H, m), 7.36-7.42 (4H,
m), 7.53 (2H, d, J ) 9.0 Hz), 7.54-7.62 (1H, m), 8.13 (2H, d,
J ) 9.0 Hz). 13C NMR (75 MHz; CDCl3): δ 19.6, 38.3, 68.7,
120.8, 122.8, 128.5, 130.2, 133.9, 134.3, 142.3 147.5. MS (m/z)
(FAB): 332 [(M + H)+, 32], 314 (100).
Eth yl 2-(2′-Ch lor o-4′-n itr op h en yl)p en t-4-en oa te (13b).
This was prepared from ethyl thiophenoxyacetate26 (12) (1.0
g, 5.10 mmol), 3-chloronitrobenzene (11) (880 mg, 5.59 mmol),
and allyl bromide (0.5 mL, 5.78 mmol) in a way similar to that
for 13a . The ester 13b (800 mg, 55%) was obtained as a yellow
oil after chromatography (silica, 1:1, chloroform-hexane): Rf
) 0.36 (silica, 1:1, chloroform-hexane); νmax (liquid film on CsI
plates)/cm-1 1740, 1430; 1H NMR (300 MHz; CDCl3) δ 1.22
(3H, t, J ) 7 Hz), 2.51-2.61 (1H, m), 2.80-2.85 (1H, m), 4.11-
4.23 (2H, m), 4.30 (1H, t, J ) 7.5 Hz), 5.01-5.09 (2H, m), 5.65-
5.79 (1H, m), 7.59 (1H, d, J ) 8.6 Hz), 8.11 (1H, dd, J ) 2.3
and 8.6 Hz), 8.27 (1H, d, J ) 2.3 Hz); 13C NMR (75 MHz;
CDCl3) δ 14.1, 36.6, 47.4, 61.4, 118.0, 121.9, 124.7, 129.8, 133.8,
135.0, 143.7, 147.1, 171.5; found (CI) (M + H)+ m/z 284.0696,
calcd for C13H15ClNO4 (M + H)+ m/z 284.0690; m/z (FAB) 284
[(M + H)+, 80%], 129 (100).
Eth yl 2-(2′-Ch lor o-4′-n itr op h en yl)-3-p h en ylp r op ion a te
(13c). This was prepared from ethyl thiophenoxyacetate26 (12)-
(1.0 g, 5.10 mmol), 3-chloronitrobenzene (11) (880 mg, 5.59
mmol), and benzyl bromide (0.7 mL, 5.89 mmol) in a way
similar to that for 13a . The ester 13c (1.0 g, 59%) was obtained
as a cream colored solid, mp 57-59 °C after chromatography
(silica, 3:2, hexane-chloroform) and recrystallization from
hexane. Anal. Found: C, 60.9; H, 5.0; N, 4.5; Cl, 10.7. Calcd
for C17H16ClNO4: C, 61.2; H, 4.8; N, 4.2; Cl, 10.6. Rf ) 0.37
(silica, 1:1, chloroform-hexane). νmax (KBr disk)/cm-1: 1740,
1530, 1350. 1H NMR (300 MHz; CDCl3): δ 1.15 (3H, t, J ) 7.1
Hz), 3.07 (1H, dd, J ) 7.8 and 13.8 Hz), 3.40 (1H, dd, J ) 7.8
and 13.8 Hz), 4.04-4.17 (2H, m), 4.50 (1H, t, J ) 7.8 Hz), 7.12-
7.27 (5H, m), 7.62 (1H, d, J ) 8.7 Hz), 8.08 (1H, dd, J ) 2.3
and 8.7 Hz), 8.24 (1H, d, J ) 2.3 Hz). 13C NMR (75 MHz;
CDCl3): δ 14.1, 38.8, 49.8, 61.5, 121.9, 124.9, 126.9, 128.6,
129.0, 129.9, 135.0, 137.7, 143.8, 147.3, 171.7. MS (m/z)
(FAB): 334 [(M + H)+, 65%], 91 (100).
2-[2-(4′-Nitr op h en yl)p r op yl] P h en yl Su lfon e (15a ). So-
dium hydride (60% dispersion in oil, 490 mg, 12.25 mmol) was
added to anhydrous DMSO (5 mL) and the flask flushed with
nitrogen. 1-(1-Chloroethyl)phenyl sulfone20 (14) (1.0 g, 4.89
mmol) and nitrobenzene (660 mg, 5.37 mmol) were dissolved
in anhydrous DMSO (5 mL) and added dropwise to the sodium
hydride slurry. The mixture was stirred at ambient temper-
ature for 2 h before methyl iodide (0.4 mL, 6.42 mmol) was
added and the resulting mixture stirred for a further 30 min.
The reaction was quenched with distilled water, acidified with
hydrochloric acid (1 M solution), and extracted with chloroform
(3 × 20 mL). The combined extracts were washed with distilled
water (3 × 20 mL), dried (magnesium sulfate), and filtered,
and the solvent was removed under reduced pressure to yield
15a (1.10 g, 74%) as orange colored crystals, mp 129-130 °C
(lit.27 mp 130-131 °C) after chromatography (silica, chloro-
form) and recrystallization from ethanol. Anal. Found: C, 59.3;
H, 5.1; N, 4.7; S, 10.4. Calcd for C15H15NO4S: C, 59.0; H, 5.0;
N, 4.6; S, 10.5%. Rf ) 0.40 (silica, chloroform). νmax (KBr disk)/
cm-1: 1520, 1360. 1H NMR (300 MHz; CDCl3): δ 1.85 (6H, s),
7.37-7.44 (4H, m), 7.54-7.62 (3H, m), 8.12 (2H, d, J ) 9.0
Hz). 13C NMR (75 MHz; CDCl3): δ 22.7, 65.6, 122.9, 128.6,
129.7, 130.3, 134.0, 134.4, 144.5, 147.6. MS (m/z) (FAB): 306
[(M + H)+, 47], 288 (100).
2-[2-(4′-Nitr op h en yl)-1-p h en ylp r op yl] P h en yl Su lfon e
(15c). 15c was prepared from 1-(1-chloroethyl)phenyl sulfone20
(14) (1.0 g, 4.89 mmol), nitrobenzene (660 mg, 5.37 mmol), and
benzyl bromide (0.6 mL, 5.05 mmol) in a way similar to that
for 15a . The sulfone 15c (1.35 g, 72%) was obtained as a cream
solid, mp 141-142 °C after column chromatography (silica,
4:1, chloroform-hexane) and recrystallization from ethanol.
Anal. Found: C, 66.4; H, 5.3; N, 3.7; S, 8.1. Calcd for C21H19
-
NO4S: C, 66.1; H, 5.0; N, 3.7; S, 8.4. Rf ) 0.49 (silica, 4:1,
chloroform-hexane). νmax (KBr disk)/cm-1: 1520, 1350, 1305,
1
1290, 1140. H NMR (300 MHz; CDCl3): δ 1.63 (3H, s), 3.53
(1H, d, J ) 13.6 Hz), 4.03 (1H, d, J ) 13.6 Hz), 6.82 (2H, dd,
J ) 2.2 and 7.2 Hz), 7.07-7.17 (3H, m), 7.34-7.44 (4H, m),
7.54-7.59 (1H, m), 7.67 (2H, d, J ) 8.8 Hz), 8.14 (2H, d, J )
8.8 Hz). 13C NMR (75 MHz; CDCl3): δ 19.4, 39.3, 69.9, 122.9,
127.2, 128.6, 130.3, 130.4, 130.5, 134.0, 134.1, 134.7, 142.7,
147.6. MS (m/z) (FAB): 382 [(M + H)+, 56], 240 (100).
Eth yl 2-Meth yl-2-(4′-n itr op h en yl)p r op ion a te (15d ). So-
dium hydride (60% dispersion in oil, 730 mg, 18.25 mmol) was
added to anhydrous DMF (5 mL) and the mixture flushed with
nitrogen and cooled to 0 °C. Ethyl 2-chloropropionate (16) (1.0
g, 7.33 mmol) and nitrobenzene (0.83 mL, 0.99 g, 8.07 mmol)
were dissolved in anhydrous DMF (5 mL) and added dropwise
to the sodium hydride slurry. The reaction mixture was stirred
at 0 °C for 30 min. and then allowed to warm to rt (room
temperature). Methyl iodide (0.32 mL, 5.14 mmol) was then
added and the resulting mixture stirred for a further 30 min.
The reaction mixture was poured onto ice/hydrochloric acid
(1 M solution) and extracted with dichloromethane (3 × 30
mL). The combined organic extracts were washed well with
distilled water (5 × 50 mL), saturated aqueous sodium
bicarbonate solution (3 × 50 mL), and dried (magnesium
sulfate), and the solvent was removed under reduced pressure
to give 15d (1.05 g, 60%) as a yellow colored oil after
chromatography (silica, 3:2, chloroform-hexane): Rf ) 0.26
(silica, 1:1, chloroform-hexane); νmax (liquid film on CsI plates)/
cm-1 1730, 1525, 1350; 1H NMR (300 MHz; CDCl3) δ 1.18 (3H,
t, J ) 7.1 Hz), 1.65 (6H, s), 4.13 (2H, q, J ) 7.1 Hz), 7.50 (2H,
d, J ) 9.0 Hz), 8.18 (2H, d, J ) 9.0 Hz); 13C NMR (75 MHz;
CDCl3) δ 13.8, 26.2, 46.7, 61.1, 123.4, 126.7, 146.5, 152.0, 175.3;
found (CI) (M + H)+ m/z 238.1081, calcd for C12H16NO4 (M +
H)+ m/z 238.1079; m/z (FAB) 238 [(M + H)+, 100].
Eth yl 2-Meth yl-2-(4′-n itr op h en yl)p en t-4-en oa te (15e).
15e was prepared from ethyl 2-chloropropionate (16) (1.0 g,
7.33 mmol), nitrobenzene (0.83 mL, 8.07 mmol), and allyl
bromide (0.7 mL, 8.10 mmol) in a way similar to that for 15e.
The ester 15e (1.30 g, 67%) was obtained as a yellow oil after
chromatography (silica, 1:1, chloroform-hexane): Rf ) 0.32
(silica, 1:1, chloroform-hexane); νmax (liquid film on CsI plates)/
cm-1 1730, 1525, 1350; 1H NMR (300 MHz; CDCl3) δ 1.17 (3H,
t, J ) 7.1 Hz), 1.55 (3H, s), 2.66 (1H, dd, J ) 7.1 and 13.8 Hz),
2.81 (1H, dd, J ) 7.4 and 13.8 Hz), 4.13 (2H, q, J ) 7.1 Hz),
5.01-5.07 (2H, m) 5.48-5.62 (1H, m), 7.46 (2H, d, J ) 8.9 Hz),
8.15 (2H, d, J ) 8.9 Hz); 13C NMR (75 MHz; CDCl3) δ 13.8,
22.4, 43.4, 50.2, 61.1, 119.1, 123.3, 127.1, 132.8, 146.5, 150.6,
174.4; found (CI) (M + H)+ m/z 264.1232, calcd for C14H18NO4
(M + H)+ m/z 264.1236; m/z (FAB) 264 [(M + H)+, 100].
Eth yl 2-Meth yl-2-(4′-n itr op h en yl)-3-p h en ylp r op ion a te
(15f). 15f was prepared from ethyl 2-chloropropionate (16) (1.0
g, 7.33 mmol), nitrobenzene (0.83 mL, 8.07 mmol), and benzyl
bromide (0.95 mL, 7.99 mmol) in a way similar to that for 15d .
The ester 15f (1.45 g, 63%) was obtained as a yellow oil after
chromatography (silica, 1:1, chloroform-hexane): Rf ) 0.32
(silica, 1:1, chloroform-hexane); νmax (liquid film on CsI plates)/
cm-1 1730, 1530, 1350; 1H NMR (300 MHz; CDCl3) δ 1.20 (3H,
t, J ) 7.1 Hz), 1.54 (3H, s), 3.22 (1H, d, J ) 13.4 Hz), 3.40
(1H, d, J ) 13.4 Hz), 4.10-4.22 (2H, m), 6.83-6.86 (2H, m),
2-[2-(4′-Nitr op h en yl)p en t-4-en yl] P h en yl Su lfon e (15b).
15b was prepared from 1-(1-chloroethyl)phenyl sulfone20 (14)
(1.0 g, 4.89 mmol), nitrobenzene (660 mg, 5.37 mmol), and allyl
bromide (0.5 mL, 5.78 mmol) in a way similar to that for 15a .
The sulfone 15b (1.30 g, 80%) was obtained as an orange solid,
mp 122-124 °C after column chromatography (silica, 4:1,
chloroform-hexane) and recrystallization from ethanol. Anal.
Found: C, 61.3; H, 5.5; N, 4.3; S, 9.3. Calcd for C17H17NO4S:
C, 61.6; H, 5.2; N, 4.2; S, 9.7. Rf ) 0.49 (silica, 4:1, chloroform-
(27) Kornblum, N.; Ackermann, P.; Swiger, R. T. J . Org. Chem. 1980,
45, 5294.

One-Pot VNS of Hydrogen-Alkylation Reactions
J . Org. Chem., Vol. 67, No. 2, 2002 463
7.15-7.19 (3H, m), 7.42 (2H, d, J ) 9.0 Hz), 8.17 (2H, d, J )
9.0 Hz); 13C NMR (75 MHz; CDCl3) δ 13.82, 21.8, 45.1, 51.4,
61.2, 123.2, 126.6, 127.4, 127.8, 130.2, 136.1, 146.5, 150.5,
174.5; found (CI) (M + H)+ m/z 314.1388, calcd for C18H20NO4
(M + H)+ m/z 314.1392; m/z (FAB) 314 [(M + H)+, 97], 91 (100).
Dieth yl 1-Meth yl-1-(4′-n itr oph en yl)su ccin ate (15g). 15g
was prepared from ethyl 2-chloropropionate (16) (2.2 g, 16.12
mmol), nitrobenzene (1.0 g, 8.13 mmol), and ethyl bromoac-
etate (1.00 mL, 9.02 mmol) in a way similar to that for 15d .
The ester 15g (2.0 g, 80%) was obtained as a yellow oil
after chromatography (silica, 7:3, chloroform-hexane). Anal.
Found: C, 58.0; H, 6.4; N, 4.6. Calcd for C15H19NO6: C, 58.2;
H, 6.2; N, 4.5. Rf ) 0.22 (silica, 7:3, chloroform-hexane). νmax
(0.9 g, 8.0 mmol) was added to the mixture that was allowed
to slowly warm to room temperature. After being stirred for 1
h at rt, the reaction was worked up in the same way as used
in the preparation of 15d . The diester 15k (1.4 g, 56%) was
obtained as a yellow oil after chromatography (silica, CHCl3).
Anal. Found: C, 58.4; H, 6.4; N, 4.4. Calcd for C15H19NO6: C,
58.2; H, 6.2; N, 4.5%. Rf ) 0.37 (chloroform). νmax (liquid film
on NaCl plates)/cm-1: 2960 (m), 1720 (s), 1600 (s), 1350 (s),
1010 (s), 900 (s), 750 (m), 700 (m). 1H (300 MHz, CDCl3): δ
1.19 (3H, m), 1.60 (3 H, s), 2.14-2.40 (4H, m), 3.60 (3H, s),
4.02-4.18 (2H, m), 7.46 (2H, d, J ) 7.7 Hz), 8.16 (2H, d, J )
7.7 Hz). 13C (75 MHz, CDCl3): 14.0, 22.7, 29.7, 34.0, 50.1, 51.7,
61.5, 123.6, 127.2, 146.7, 150.2, 173.2, 174.3. MS (m/z) (FAB):
310 ([M + H]+, 88), 278 (59), 264 (29), 250 (92), 236 (68), 204
(31), 137 (39), 130 (100), 107 (48), 95 (36), 91 (68), 85 (27).
Eth yl 3-Cya n o-2-m eth yl-2-(4′-n itr op h en yl)p r op ion a te
(15l). 15l was prepared from ethyl 2-chloropropionate (16)
(1.81 g, 13.2 mmol), nitrobenzene (1.48 g, 12 mmol), and
chloroacetonitrile (0.9 g, 12 mmol) in a way similar to that for
15k . The cyanoester 15l (1.75 g, 56%) was obtained as a yellow
colored oil after chromatography (silica, 5:3:2, hexane-
chloroform-ether). Anal. Found: C, 59.9; H, 5.6; N, 10.8. Calcd
for C13H14N2: C, 59.6; H, 5.4; N, 10.7. Rf ) 0.27 (silica, 5:3:2,
hexane-chloroform-ether). νmax (liquid film on NaCl plates)/
cm-1: 3000-2800, 2250, 1750, 1600, 1350, 990. 1H NMR (300
MHz; CDCl3): δ 1.22 (3H, t, J ) 7.1 Hz), 1.83 (3H, s), 2.98
(1H, d, J ) 17.0 Hz), 3.07 (1H, d, J ) 17.0 Hz), 4.20 (2H, q, J
) 7.1 Hz), 7.52 (2H, d, J ) 8.9 Hz), 8.15 (2H, d, J ) 8.9 Hz).
13C NMR (75 MHz; CDCl3): δ 13.9, 22.5, 28.9, 48.7, 66.0, 123.4,
116.8, 124.1, 127.1, 146.9, 147.5, 172.5. MS (m/z) (FAB): 263
[(M + H)+, 100], 246 (40), 235 (50), 189 (18), 154 (15), 136 (20),
91 (12).
(KBr disk)/cm-1
:
1740, 1530, 1350. 1H NMR (300 MHz;
CDCl3): δ 1.20 (6H, t, J ) 7.1 Hz), 1.74 (3H, s), 2.90 (1H, d, J
) 16.2 Hz), 3.21 (1H, d, J ) 16.2 Hz), 4.09 (2H, q, J ) 7.1 Hz),
4.18 (2H, q, J ) 7.1 Hz), 7.53 (2H, d, J ) 9.0 Hz), 8.19 (2H, d,
J ) 9.0 Hz). 13C NMR (75 MHz; CDCl3): δ 13.7, 13.9, 23.2,
43.1, 48.4, 60.5, 61.4, 123.4, 126.9, 146.7, 149.7, 170.1, 173.5.
MS (m/z) (FAB): 310 [(M + H)+, 95], 264 (100).
Eth yl 2-Meth yl-2-(4′-n itr op h en yl)bu tyr a te (15h ). 15h
was prepared from ethyl 2-chloropropionate (16) (1.0 g, 7.33
mmol), nitrobenzene (0.83 mL, 8.07 mmol), and ethyl bromide
(0.60 mL, 8.04 mmol) in a way similar to that for 15d . The
ester 15h (1.10 g, 54%) was obtained as a yellow oil after
chromatography (silica, 1:1, chloroform-hexane): Rf ) 0.48
(silica, 1:1, chloroform-hexane); νmax (liquid film on CsI plates)/
cm-1 1730, 1525, 1350; 1H NMR (300 MHz; CDCl3) δ 0.83 (3H,
t, J ) 7.4 Hz), 1.19 (3H, t, J ) 7.1 Hz), 1.56 (3H, s), 1.92-2.16
(2H, m), 4.14 (2H, q, J ) 7.1 Hz), 7.47 (2H, d, J ) 9.0 Hz),
8.18 (2H, d, J ) 9.0 Hz); 13C NMR (75 MHz; CDCl3) δ 8.8,
13.9, 22.0, 31.7, 50.9, 61.0, 123.3, 127.1, 146.5, 151.2, 174.9;
found (CI) (M + H)+ m/z 252.1236, calcd for C13H18NO4 (M +
H)+ m/z 252.1236; m/z (FAB) 252 [(M + H)+, 80].
Eth yl 2-(4′-Nitr op h en yl)p r op ion a te (17). Sodium hy-
dride (60% dispersion in oil, 2.69 g, 67 mmol) was added to
anhydrous DMF (30 mL) at 0 °C and the flask flushed with
nitrogen. Ethyl 2-chloropropionate (16) (2.86 mL, 22 mmol)
and nitrobenzene (2.29 mL, 22 mmol) were dissolved in
anhydrous DMF (15 mL) and added dropwise to the sodium
hydride slurry. The mixture was stirred at 0 °C for a further
0.5 h before warming to room temperature over 2 h. The
mixture was poured onto an HCl (1 M)/ice slurry and extracted
with chloroform (3 × 50 mL). The combined extracts were
washed well with distilled water (5 × 100 mL) and dried
(magnesium sulfate), and the solvent was removed under
reduced pressure to give the nitrobenzyl ester28 17 (3.21 g,
72%) as a yellow oil after chromatography (silica, 2:3, hexane-
chloroform): Rf ) 0.3 (silica, 1:1, hexane-chloroform); νmax
(liquid film on NaCl plates)/cm-1 3000-2800, 1750, 1600, 1350;
1H NMR (300 MHz; CDCl3) δ 1.19 (3H, t, J ) 7.1 Hz), 1.52
(3H, d, J ) 6.6 Hz), 3.82 (1H, q, J ) 6.6 Hz), 4.08-4.19 (2H,
m), 7.49 (2H, d, J ) 8.4 Hz) 8.17 (2H, d, J ) 8.4 Hz); 13C NMR
(75 MHz; CDCl3) δ 14.1, 16.4, 45.5, 61.3 123.9, 28.5, 147.1,
147.9, 173.2; found (CI) [M + H]+ m/z 224.0919, calcd for
Eth yl 2-Meth yl-2-(4′-n itr op h en yl)h exa n oa te (15i). 15i
was prepared from ethyl 2-chloropropionate (16) (1.0 g, 7.33
mmol), nitrobenzene (0.83 mL, 8.07 mmol), and bromobutane
(0.80 mL, 7.42 mmol) in a way similar to that for 15d . The
ester 15i (1.20 g, 59%) was obtained as
a yellow oil
after chromatography (silica, 1:1, chloroform-hexane). Anal.
Found: C, 64.8; H, 7.3; N, 5.1. Calcd for C15H21NO4: C, 64.5;
H, 7.6; N, 5.0. Rf ) 0.40 (silica, 1:1, chloroform-hexane). νmax
(liquid film on CsI plates)/cm-1: 2960, 1730, 1530, 1350. 1H
NMR (300 MHz; CDCl3): δ 0.87 (3H, t, J ) 7.1 Hz), 1.07-
1.20 (5H, m), 1.30 (2H, quin, J ) 7 Hz), 1.57 (3H, s), 1.87-
2.10 (2H, m), 4.13 (2H, q, J ) 7.1 Hz), 7.47 (2H, d, J ) 8.9
Hz), 8.17 (2H, d, J ) 8.9 Hz). 13C NMR (75 MHz; CDCl3): δ
13.8, 13.9, 22.7, 23.0, 26.7, 38.7, 50.6, 61.1, 123.4, 127.1, 146.5,
151.6, 175.0. MS (m/z) (FAB): 280 [(M + H)+, 100].
Eth yl 2-Meth yl-2-(4-n itr op h en yl)-4-oxo-4-p h en ylbu ty-
r a te (15j). 15j was prepared from ethyl 2-chloropropionate
(16) (1.20 g, 8.8 mmol), nitrobenzene (0.99 g, 8.0 mmol), and
R-bromoacetophenone (1.60 g, 8.0 mmol) in a way similar to
that for 15d . The ester 15j (1.78 g, 65%) was obtained as
colorless crystals, mp 105-106 °C, after chromatography
(silica, 5:4:1, hexane-chloroform-ether, v/v). Anal. Found: C,
67.0; H, 5.8; N, 4.2. Calcd for C19H19NO5: C, 66.9; H, 5.6; N,
4.1. Rf ) 0.57 (5:4:1, hexane-chloroform-ether, v/v). νmax (KBr
disk)/cm-1: 3000-2800 (m), 1750 (s), 1690 (s), 1600 (s), 1350
C
11H13NO4 m/z 224.0917; m/z (FAB) 224 ([M + H]+, 40), 95
(100).
Eth yl 2-(4′-Am in op h en yl)p r op ion a te (18). A solution of
the nitrobenzyl ester 17 (3.0 g, 13.4 mmol) in anhydrous
methanol (15 mL) ws added to a stirred slurry of palladium
on charcoal (10% Pd/C, 1.0 g) in anhydrous methanol (15 mL)
under an atmosphere of hydrogen. The resulting mixture was
stirred at room temperature until reduction was complete (by
TLC). The reaction mixture was filtered over a bed of Celite
and the solvent removed under reduced pressure to yield the
aminobenzyl ester25b 18 (1.68 g, 65%), as a brown oil after
chromatography (silica, chloroform): Rf ) 0.4 (silica, chloro-
form); νmax (liquid film on NaCl plates)/cm-1 3500, 3400, 3000-
2800, 1750, 1600; 1H NMR (300 MHz; CDCl3) δ 1.18 (3H, t, J
) 7.1 Hz), 1.43 (3H, d, J ) 7.6 Hz), 3.56 (1H, q, J ) 7.6 Hz)
overlapping 3.50-3.60 (2H, s), 4.04-4.18 (2H, m), 6.69 (2H,
d, J ) 8.4 Hz), 7.10 (2H, d, J ) 8.4 Hz); 13C NMR (75 MHz;
CDCl3) δ 14.2, 18.7, 44.7, 60.6, 115.3, 128.4, 130.8, 145.4, 175.1;
found (CI) [M + H]+ m/z 194.1184, calcd for C11H15NO2 m/z
194.1186; m/z (FAB) 194 ([M + H]+, 80), 120 (100).
1
(s), 1100 (s). H (200 MHz, CDCl3): δ 1.20 (3H, t, J ) 7.1 Hz),
1.80 (3H, s), 3.65 (1H, d, J ) 17.8 Hz), 3.90 (1H, d, J ) 17.8
Hz), 4.20 (2H, q, J ) 7.1 Hz), 7.43-7.60 (3H, m), 7.63 (2H, d,
J ) 8.9 Hz), 7.94-7.99 (2H, m), 8.21 (2H, d, J ) 8.9 Hz). 13C
(75 MHz, CDCl3): 14.0, 23.6, 47.7, 48.4, 61.5, 123.6, 127.8,
127.9, 128.7, 133.5, 136.7, 146.8, 150.7, 174.6, 196.3. MS (m/
z) (FAB): 342 ([M + H]+, 70), 296 (54), 256 (7), 137 (11), 105
(100), 89 (13).
1-Eth yl 5-Meth yl 2-m eth yl-2-(4-n itr oph en yl)pen tan edio-
a te (15k ). A mixture of ethyl 2-chloropropionate (16) (1.2 g,
8.8 mmol) and nitrobenzene (0.99 g, 8.0 mmol) in dry DMF
(20 mL) was added to a slurry of sodium hydride (80%
dispersion in oil, 0.6 g, 20 mmol) in dry DMF (20 mL). The
resulting deep purple colored mixture was stirred for 1 h at 0
°C and 2 h at ambient temperature. The mixture was cooled
to -68 °C using a methanol/CO2 cooling bath. Methyl acrylate
(28) DeBoos, G. A.; Milner, D. J . Synth. Commun. 1994, 24, 965.

464 J . Org. Chem., Vol. 67, No. 2, 2002
Lawrence et al.
Eth yl 2-(4′-(1-Oxo-2-isoin dolin yl)ph en yl)pr opion ate (19).
To a stirred solution of ortho-benzyldicarboxaldehyde (0.35 g,
2.6 mmol) in acetonitrile (10 mL) was added successively
2-mercaptoethanol (1.16 mL, 22.36 mmol), a solution of the
amino ester 18 (0.5 g, 2.6 mmol) in acetonitrile (2.6 mL), benzo-
1,2,3-1H-triazole, (0.31 g, 2.6 mmol), and pH 9.6 buffer solution
(0.05 M, H3BO3-KCl-NaOH, 1.3 mL), over 1 min each. The
resulting homogeneous brown solution was stirred for a further
13 h, evaporated in vacuo, triturated with diethyl ether, and
filtered, and the solvent was removed under reduced pressure
to give the phthalimidine25b 19 (0.55 g, 68%) as needles, mp
102-106 °C, after chromatography (silica, dichloromethane)
and recrystallization from dioxane: Rf ) 0.1 (silica, 2:3,
chloroform-hexane); νmax (KBr disk) 3500, 2970, 1750, 1600,
Eth yl 2-Meth yl-2-(4′-a m in op h en yl)p r op ion a te (20). 20
was prepared from the nitrophenyl ester 15d in a way similar
to that for the aniline 18. The aniline30
20 (1.38 g, 63%) was
obtained as a brown oil: Rf ) 0.4 (silica, chloroform); νmax
(liquid film on NaCl plates)/cm-1 3500, 3400, 3000-2800, 1750,
1600, 1200; 1H NMR (200 MHz; CDCl3) δ 1.18 (3H, t, J ) 7.1
Hz), 1.52 (6H, s), 3.41-3.52 (2H, m), 4.10 (2H, q, J ) 7.1 Hz),
6.65 (2H, d, J ) 8.4 Hz), 7.14 (2H, d, J ) 8.4 Hz); 13C NMR
(75 MHz; CDCl3) δ 14.2, 26.6, 45.6, 60.7, 115.1, 126.7, 135.0,
144.8, 177.2; found (CI) [M + H]+ m/z 208.1340, calcd for
C
12H17NO2 m/z 208.1337; m/z (FAB), 208 ([M + H]+, 100).
Eth yl 2-Meth yl-2-(4′-(1-Oxo-2-isoin d olin yl)p h en yl)p r o-
p ion a te (22). 22 was prepared from the aniline 20 (0.54 g,
2.6 mmol), ortho-benzyldicarboxaldehyde (0.35 g, 2.6 mmol),
2-mercaptoethanol (1.16 mL, 22.36 mmol), benzo-1,2,3-1H-
triazole, (0.31 g, 2.6 mmol), and pH 9.6 buffer solution (0.05
M, H3BO3-KCl-NaOH, 1.3 mL) in a way similar to that for
19. The ester 26 (0.5 g, 65%) was obtained as needles, mp 119-
120 °C, after chromatography (silica, 3:1, chloroform-hexane)
and recrystallization from dioxane: Rf ) 0.15 (silica, 3:1,
chloroform-hexane); νmax (KBr disk)/cm-1 3400, 2970, 1750,
1600, 1580, 1500; 1H NMR (300 MHz; CDCl3) δ 1.20 (3H, t, J
) 7.2 Hz), 1.59 (6H, s), 4.13 (2H, q, J ) 7.2 Hz), 7.41 (2H, d,
J ) 8.8 Hz), 7.49-7.53 (1H, m), 7.59 (1H, t, J ) 7.0 Hz), 7.82
(2H, d, J ) 8.8 Hz), 7.73 (1H, d, J ) 7 Hz); 13C NMR (75 MHz;
CDCl3) δ 14.2, 26.6, 46.2, 50.8, 61.0, 119.4, 122.7, 124.3, 126.6,
128.5, 132.2, 138.1, 140.2, 141.0, 155.0, 176.7, 182.8; found (CI)
[M + H]+ m/z 324.1595, calcd for C20H21NO3 m/z 324.1600; m/z
(FAB), 324 ([M + H]+, 80).
1
1650; H NMR (300 MHz; CDCl3) δ 1.21 (3H, t, J ) 7.1 Hz),
1.50 (3H, d, J ) 7.1 Hz), 3.71 (1H, q, J ) 7.1 Hz), 4.06-4.18
(2H, m), 4.83 (2H, s), 7.37 (2H, d, J ) 8.7 Hz), 7.50 (1H, d, J
) 8.7 Hz), 7.56 (1H, d, J ) 7.3 Hz), 7.81 (2H, d, J ) 8.7 Hz),
7.90 (1H, d, J ) 7.3 Hz); 13C NMR (75 MHz; CDCl3) δ 14.0,
18.4, 44.8, 50.5, 60.6, 119.4, 122.5, 123.9, 128.1, 128.2, 131.9,
132.9, 136.6, 138.2, 139.9, 167.3, 174.3; found (CI) [M + H]+
m/z 310.1436, calcd for C19H19NO3 m/z 310.1435; m/z (FAB)
310 [M + H]+, 100).
2-(4′-(1-Oxo-2-isoin d olin yl)p h en yl)p r op ion ic Acid (21).
To a stirred solution of 10% sodium hydroxide (10 mL) in
ethanol (10 mL) was added the ester 19 (0.5 g, 1.62 mmol),
and the resulting mixture was refluxed for 2.5 h. The resulting
colorless solution was cooled to room temperature, extracted
with diethyl ether, dried (magnesium sulfate), and filtered,
and the solvent was removed under reduced pressure to give
Indoprofen (21) (0.34 g, 75%) as needles, mp 213-214 °C (lit.29
mp 213-214 °C) after recrystallization from hexane: νmax (KBr
disk)/cm-1 3500, 2800, 1740, 1420; 1H NMR (300 MHz; DMSO-
d6) δ 1.38 (3H, d, J ) 7.0 Hz), 3.69 (1H, q, J ) 7.0 Hz), 5.01
(2H, s), 7.35 (2H, d, J ) 8.7 Hz), 7.51-7.57 (1H, m), 7.67-
7.69 (1H, m), 7.78 (2H, d, J ) 7.6 Hz), 7.85 (2H, d, J ) 8.7
Hz); 13C NMR (75 MHz; DMSO-d6) δ 22.4, 48.0, 54.4, 123.4,
127.1, 127.2, 131.9, 132.1, 136.1, 136.3, 140.9, 142.0, 144.9,
170.5, 179.3; found (CI) [M + H]+ m/z 282.1122, calcd for
C17H15NO3 m/z 282.1130; m/z (FAB), 307 (40), 282 ([M + H]+,
100).
Ack n ow led gm en t. We thank the EPSRC and Ze-
neca for a CASE studentship (to J .L.) and for Research
Grants (GR/L52246, NMR spectrometer; GR/L84391,
chromatographic equipment) and the EPSRC Chemical
Database Service at Daresbury.31
Su p p or tin g In for m a tion Ava ila ble: Figures showing
NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O0159901
(30) Picciola, G.; Ravenna, F.; Carenini, G.; Gentili, P.; Riva, M.
Farmaco, Ed. Sci. 1981, 36, 1037.
(31) Fletcher, D. A.; McMeeking, R. F.; Parkin, D. J . J . Chem. Inf.
Comput. Sci. 1996, 36, 746.
(29) Kametani, T.; Kigasawa, K.; Hiiragi, M.; Ishimaru, H.; Haga,
S.; Shirayama, K. J . Heterocycl. Chem. 1978, 15, 369.