Facile Intramolecular O→C Ester Migration in Benzylphosphonium Salts

Full text of DOI:10.1021/jo000532y

7660
J . Org. Chem. 2000, 65, 7660-7662
Sch em e 1. F or m a tion of 3a fr om Eith er 1 or 4a a s
F a cile In tr a m olecu la r OfC Ester
Migr a tion in Ben zylp h osp h on iu m Sa lts
P r ecu r sor
Peter Nussbaumer* and Melitta Bilban
NOVARTIS Research Institute, Brunnerstrasse 59,
A-1235 Vienna, Austria
peter.nussbaumer@pharma.novartis.com
Received April 10, 2000
Compared to aldehydes and ketones, esters are usually
poor substrates for Wittig reactions unless an intra-
molecular process is involved. A typical example of an
efficient nonclassical Wittig reaction1 is the conversion
of (2-acyloxybenzyl)triphenylphosphonium salts into 2-sub-
stituted benzofurans.2 With regard to carbonates, there
are only two reports on olefinations with phosphonium
salts3,4 and in both cases an intramolecular Wittig
reaction is used to generate the cyclic ketene acetal
functionality of 2-phenoxy-4H-1-benzopyran-4-ones.
We now report that, in contrast to the observations
cited above, carbonate-containing benzylphosphonium
salts 4 do not undergo an intramolecular Wittig reaction
to produce 2-alkoxybenzofurans, but follow a different
reaction pathway on treatment with base (Scheme 1, 2).
When commercially available 1 was reacted with
methyl chloroformate (2a ) and excess triethylamine at
room temperature, we observed further transformation
of the initially formed acylated phosphonium salt 4a
already under these conditions. The reaction finally
yielded methyl (2-hydroxyphenyl)acetate 3a 5 and tri-
phenylphosphine oxide (Scheme 1). For confirmation, the
postulated intermediate 4a was prepared in pure state
using a different route (3 steps starting from o-cresol;
acylation with methyl chloroformate, NBS-bromination,
reaction with triphenylphosphine; 68% overall yield;
Scheme 1) and treated with triethylamine. Again 3a
(82%) was obtained after aqueous workup, ruling out the
possibility that the product was generated via direct
acylation at the benzylic position of the phosphonium
component.
Ta ble 1. Yield s Obta in ed in th e Rea ction of
P h osp h on iu m Sa lt 1 w ith Acyla tin g Agen ts 2a -g
R
ClCOOR or (ROCO)2Oa
product (% yield)b,c
methyl
2a
2b
2c
2d
2e
2f
3a (80)
3b (63)
3c (55)
3d (75)
3e (77)
5 (90)
i-propyl
tert-butyl
benzyl
allyl
phenyl
4-NO2-phenyl
2g
5 (83)
a
Compounds 2a ,b,d -g were used as chloroformates, 2c as
b
dicarbonate. Nonoptimized yields of isolated, analytically pure
products. c Analytical data of products 3a -d agreed with pub-
lished information; 3e and 5 were characterized by 1H NMR, 13C
NMR, and C, H analysis.
respectively, in the presence of excess triethylamine the
stabilized phosphonium ylide 5 was obtained in high
yield. The structure of 56 was confirmed by two indepen-
dent syntheses (Scheme 3) starting either with 3-bromo-
2(3H)benzofuranone (6) and triphenylphosphine or with
1 and carbonyldiimidazole.
Our mechanistic rationale for the formation of 3 and
5 is depicted in Scheme 2 and involves nonisolable
intermediates Ia -d . Acylation of the hydroxy group in
1 produces the carbonate-containing phosphonium salt
4. The mild reaction conditions (triethylamine, rt) are
sufficient to allow further transformation of 4. Deproto-
nation generates ylide Ia , which upon intramolecular
cyclization yields betaine Ib. This intermediate does not
eliminate triphenylphosphine oxide to give 2-alkoxyben-
zofurans as expected for a Wittig-type reaction. Instead,
opening of the heavily substituted five-membered ring
generates intermediate Ic, provided that R ) alkyl. The
The scope of the conversion of 1 into 3 was investigated
by variation of the R group in the acylating agent 2
(Scheme 2). As shown in Table 1, alkyl chloroformates
2a ,b,d ,e and dialkyl dicarbonate 2c gave the correspond-
ing alkyl (2-hydroxyphenyl)acetates 3a -e in moderate
to good yields. In some experiments trace amounts (<7%)
of apolar byproducts were obtained which were identified
as the O-acylated product analogues, resulting from
reaction of phenolic products 3 with residual acylating
agent 2. However, when 1 was treated with phenyl
chloroformate (2f) and 4-nitrophenyl chloroformate (2g),
(1) For recent reviews, see: (a) Murphy, P. J .; Lee, S. E. J . Chem.
Soc., Perkin Trans. 1 1999, 3049-3066. (b) Heron, B. M. Heterocycles
1995, 41 (10), 2357-2386. (c) Le Corre, M. J anssen Chim. Acta 1985,
3 (2), 4-8.
(2) Hercouet, A.; Le Corre, M. Tetrahedron 1981, 37, 2867-2873.
(3) Takeno, H.; Hashimoto, M. Chem. Commun. 1981, 282-283.
(4) Takeno, H.; Hashimoto, M.; Koma, J .; Horiai, H.; Kikuchi, H.
Chem. Comm. 1981, 474-475.
(6) The chemical shift of 13.3 ppm observed for stabilized ylide 5 in
the 31P NMR spectrum agreed well with published data of similar
structures: Saalfrank, R. W.; Ackermann, E.; Winkler, H.; Paul, W.;
Bo¨hme, R. Chem. Ber. 1980, 113, 2950-2958.
(5) Compound 3a proved to be analytically identical (TLC, mp, 1H
NMR, MS) to a sample prepared by esterification of (2-hydroxyphenyl)-
acetic acid.
10.1021/jo000532y CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/11/2000

Notes
J . Org. Chem., Vol. 65, No. 22, 2000 7661
Sch em e 2. P ostu la ted Mech a n ism for th e F or m a tion of 3 (R ) a lk yl) a n d 5 (R ) a r yl)
Sch em e 3. Alter n a tive Syn th eses of Sta bilized
Ylid e 5
able (2-hydroxybenzyl)triphenylphosphonium salt 1, un-
dergo base-induced rearrangement with concomitant
elimination of triphenylphosphine oxide under very mild
conditions to give alkyl (2-hydroxyphenyl)acetates 3 in
good yields. In contrast, the reaction of 1 with phenyl
chloroformates follows a different course producing the
stabilized phosphonium ylide 5 by elimination of the
corresponding phenols.
better leaving group character of the phenolate relative
to the alkoxide is believed to be the driving force behind
this pathway. In accordance with the mechanism dis-
cussed by Le Corre,2 intermediate Ic then rearranges into
the hydrolytically labile7,8 phenoxyphosphonium salt Id ,
which gives 3 and triphenylphosphine oxide on aqueous
workup. The formal result of this sequence is an oxygen
to carbon (O f C) migration of an alkyl ester fragment
in 4 with concomitant loss of triphenylphosphine oxide.
When R ) phenyl in intermediate Ib, irreversible
elimination of the unsubstituted phenolate residue (in-
troduced by the acylating agent 2) generates a phospho-
nium salt which is deprotonated by excess triethylamine
to yield the stabilized ylide 5.
Thus, formation of both products 3 and 5 can be
explained from one common intermediate, i.e., Ib. The
course of the reaction appears to be rather selective, since
production of 5 was never observed in the alkyl series
(products 3a -e) and the treatment of 1 with either 2f
(R ) phenyl) or 2g (R ) 4-nitrophenyl) produced 5 in high
yield with no detectable amount of the corresponding
phenylacetate.
Exp er im en ta l Section
(2-Hydroxybenzyl)triphenylphosphonium bromide, alkyl and
aryl chloroformates, di-tert-butyl dicarbonate, and 3-bromo-
2(3H)benzofuranone were purchased from Aldrich.
Gen er a l P r oced u r e for th e Syn th esis of Alk yl (2-Hy-
d r oxyp h en yl)a cet a t es 3. Syn t h esis of Allyl (2-H yd r oxy-
p h en yl)a ceta te (3e). Allyl chloroformate (2e; 130 mg dissolved
in 2 mL of dry dichloromethane, 1.1 mmol) was added via syringe
to a solution of (2-hydroxybenzyl)triphenylphosphonium bromide
(1; 500 mg, 1.1 mmol) and triethylamine (340 mg, 3.3 mmol) in
dry dichloromethane at room temperature under argon atmo-
sphere. The mixture was stirred for 16 h and then poured into
aqueous pH 7 buffer solution. Extraction with ethyl acetate
followed by chromatography on silica gel (cyclohexane/ethyl
acetate ) 4/1) gave pure 3e (160 mg, 77%) as light yellow oil:
1H NMR (CDCl3) δ 7.23 (dt, J ) 1.7, 7.9 Hz, 1H), 7.11 (dd, J )
1.7, 7.4 Hz, 1H), 6.94 (dd, J ) 1.2, 7.9 Hz, 1H), 6.88 (dt, J ) 1.2,
7.4 Hz, 1H), 5.90 (ddt, J ) 5.8, 10.4, 17.2 Hz, 1H), 5.33 (dqua, J
) 1.3, 17.2 Hz, 1H), 5.27 (dqua, J ) 1.3, 10.4 Hz, 1H), 4.64 (dt,
J ) 1.3, 5.8 Hz, 2H), 3.71 (s, 2H); 13C NMR (CDCl3) δ 173.46,
155.06, 131.37, 131.00, 129.17, 120.87, 120.54, 118.99, 117.51,
66.29, 37.69. Anal. Calcd. for C11H12O3 (mw 192.22): 68.73, C;
6.29, H. Found: 69.01, C; 6.15, H.
In analogy to the synthesis decribed for 3e the following
compounds were obtained starting from 1 and the respective
acylating agents 2a -d .
Meth yl (2-h yd r oxyp h en yl)a ceta te (3a ): colorless crystals,
mp 69-71 °C (lit.9 mp 69-71 °C); 1H NMR (CDCl3) δ 7.35 (br s,
1H), 7.20 (dt, J ) 1.6, 7.7 Hz, 1H), 7.10 (dd, J ) 1.6, 7.4 Hz,
1H), 6.94 (dd, J ) 1.2, 7.7 Hz, 1H), 6.89 (dt, J ) 1.2, 7.4 Hz,
1H), 3.75 (s, 3H), 3.69 (s, 2H); 13C NMR (CDCl3) δ 174.20, 155.00,
130.94, 129.12, 120.81, 120.53, 117.40, 52.64, 37.44.
In summary, we discovered that (2-alkoxycarbonyloxy-
benzyl)triphenylphosphonium bromides (4, R ) alkyl),
which can be generated in situ from commercially avail-
(7) Sensitivity of phenoxyphosphonium salts to hydrolysis: Appel,
R.; Warning, K.; Ziehn, K. D. Liebigs Ann. Chem. 1975, 406-409.
(8) TLC analysis supported the presence of a hydrolytically labile
intermediate (i.e., Id ) when comparing samples taken directly from
the reaction mixture and run without aqueous treatment in aprotic
and protic solvent systems.
(9) Gringauz, A. J . Med. Chem. 1968, 611-612.

7662 J . Org. Chem., Vol. 65, No. 22, 2000
Notes
2-P r op yl (2-h yd r oxyp h en yl)a ceta te (3b): colorless oil; 1H
NMR (CDCl3) δ 7.20 (dt, J ) 1.6, 7.7 Hz, 1H), 7.10 (dd, J ) 1.6,
7.4 Hz, 1H), 6.96 (dd, J ) 1.2, 7.7 Hz, 1H), 6.88 (dt, J ) 1.2, 7.4
Hz, 1H), 5.04 (hept, J ) 6.3 Hz, 1H), 3.64 (s, 2H), 1.27 (d, J )
6.3 Hz, 6H); 13C NMR (CDCl3) δ 173.63, 155.33, 130.93, 129.11,
120.75, 117.71, 69.72, 38.47, 21.65.
ter t-Bu tyl (2-h yd r oxyp h en yl)a ceta te (3c): reaction time
72 h, colorless oil; 1H NMR (CDCl3) δ 7.98 (br s, 1H), 7.20 (dt, J
) 1.7, 7.7 Hz, 1H), 7.08 (dd, J ) 1.7, 7.4 Hz, 1H), 6.97 (dd, J )
1.2, 7.7 Hz, 1H), 6.88 (dt, J ) 1.2, 7.4 Hz, 1H), 3.59 (s, 2H), 1.47
(s, 9H); 13C NMR (CDCl3) δ 173.60, 155.44, 130.96, 129.04,
121.06, 120.70, 117.78, 82.89, 39.62, 27.95.
graphic purification on silica gel (cyclohexane/ethyl acetate )
4/1) yielded 5 in 64% yield.
Syn t h esis of (2-Met h oxyca r b on yloxyp h en yl)t r ip h en -
ylp h osp h on iu m Br om id e (4a ). Methyl chloroformate (2.88 g,
30.5 mmol) was added to a solution of o-cresol (3 g, 27.7 mmol)
and triethylamine (3.36 g, 33.3 mmol) in dry dichloromethane
(50 mL) at 5 °C under argon atmosphere. The mixture was
stirred for 30 min at this temperature and then for 1 h at room
temperature. The solvent was distilled off in vacuo, and the
residue was partitioned between ethyl acetate and water. The
organic layer was separated, washed with brine, dried over
magnesium sulfate, and evaporated to dryness to give crude
methyl 2-methylphenyl carbonate (4.4 g, 95%). Without further
purification the crude intermediate, N-bromosuccinimide (4.7 g,
26.5 mmol) and a catalytic amount of benzoyl peroxide were
heated in tetrachloromethane for 4 h at 80 °C. After the reaction
was cooled, the succinimide was removed by filtration and the
filtrate was evaporated in vacuo. The crude methyl 2-bromo-
methylphenyl carbonate (6 g) thus obtained was dissolved in dry
toluene (50 mL) and heated together with triphenylphosphine
(6.43 g, 24.5 mmol) to 80 °C for 6 h, followed by heating to 100
°C for 1 h. After this solution was cooled, the precipitate was
collected by filtration, washed with diethyl ether, and dried in
vacuo to yield pure 4a (9.56 g, 68% over all steps starting from
o-cresol) as colorless crystals: mp 147-148 °C; 1H NMR (CDCl3)
δ 7.54-7.83 (m, 15H), 7.42-7.50 (m, 1H), 7.23-7.32 (m, 1H),
7.18 (d, J ) 8 Hz, 1H), 7.05 (t, J ) 7.5 Hz, 1H), 5.41 (d, J ) 14.3
Hz, 2H), 3.70 (s, 3H); 13C NMR (CDCl3) δ 152.33, 149.78, 149.69,
135.08, 135.03, 134.33, 134.17, 133.17, 133.09, 130.28, 130.08,
129.80, 129.74, 126.31, 126.26, 121.32, 121.27, 119.05, 118.92,
118.17, 116.82, 55.54, 25.99, 25.22; 31P NMR (CDCl3) δ 22.8.
Anal. Calcd for C27H24O3P‚Br (mw 507.37): 63.92, C; 4.77, H;
Found: 63.64, C; 4.91, H.
Ben zyl (2-h yd r oxyp h en yl)a ceta te (3d ): colorless crystals,
1
mp 99-100 °C (lit.9 mp 98-100 °C); H NMR (CDCl3) δ 7.30-
7.42 (m, 5H), 7.21 (dt, J ) 1.6, 7.7 Hz, 1H), 7.11 (dd, J ) 1.6,
7.5 Hz, 1H), 6.84 (dd, J ) 1.2, 7.7 Hz, 1H), 6.89 (dt, J ) 1.2, 7.5
Hz, 1H), 5.18 (s, 2H), 3.72 (s, 2H); 13C NMR (CDCl3) δ 173.63,
155.07, 135.06, 131.01, 129.19, 128.61, 128.50, 128.32, 120.89,
120.51, 117.56, 67.50, 37.78.
Syn t h esis of 3-(Tr ip h en ylp h osp h or a n ylid en e)-2(3H )-
ben zofu r a n on e (5). Following the procedure described for the
synthesis of 3e the reaction of equimolar amounts of phospho-
nium salt 1 with either phenyl chloroformate (2f), 4-nitrophenyl
chloroformate (2g), or 1,1′-carbonyldiimidazole yielded 5 in 90,
83, and 79% yields, respectively, as yellowish crystals: mp 206-
209 °C; 1H NMR (CDCl3) δ 7.63-7.81 (m, 9H), 7.52-7.60 (m,
6H), 7.04-7.12 (m, 1H), 6.82 (dt, J ) 1.3, 7.6 Hz, 1H), 6.62 (dt,
J ) 1.2, 7.6 Hz, 1H), 5.64 (dd, J ) 1.2, 7.6 Hz, 1H); 13C NMR
(CDCl3) δ 171.82, 171.50, 149.37, 149.12, 134.11, 133.95, 133.33,
133.28, 132.36, 132.15, 129.39, 129.18, 123.90, 122.42, 121.36,
119.09, 114.04, 108.78, 48.74, 46.56; 31P NMR (CDCl3) δ 13.3.6
Anal. Calcd for C26H19PO2 (mw 394.41): 79.18, C; 4.86, H.
Found: 79.21, C; 5.26, H.
Reaction of commercially available 3-bromo-2(3H)benzofura-
none (6) with equimolar amounts of triphenylphosphine and
triethylamine in toluene at 80 °C for 6 h followed by chromato-
J O000532Y