P2-Et-mediated deprotonation of ortho-halobenzyl sulfones: Synthetic applications as zwitterionic synthons

Article abstract of DOI:10.1055/s-2001-18740

α-Sulfonyl benzylic carbanions, derived from ortho-halobenzyl sulfones 5 (Hal = Br, I), can be easily generated by the phosphazene base P₂-Et and react with different electrophiles such as alkyl halides, aldehydes and ethyl acrylate. Palladium

Full text of DOI:10.1055/s-2001-18740

LETTER
1881
P2-Et-Mediated Deprotonation of ortho-Halobenzyl Sulfones: Synthetic
Applications as Zwitterionic Synthons
P
-Et-Mediated D
e
n
protonation
a
of ortho-Haloben
C
2
Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Alicante, Apdo. 99, 03080-Alicante, Spain
Fax +34(96)5903549; E-mail: cnajera@ua.es
Received 1 August 2001
N-t-Bu
Abstract: -Sulfonyl benzylic carbanions, derived from ortho-ha-
t-Bu-N
P
N
P(NMe2)3
(Me2N)3P
N
P
(NMe2)2
3
lobenzyl sulfones 5 (Hal = Br, I), can be easily generated by the
phosphazene base P2-Et and react with different electrophiles such
as alkyl halides, aldehydes and ethyl acrylate. Palladium catalysed
cross-coupling reactions performed at the halogen atom, followed
by P2-Et-mediated alkylation-dehydrosulfinylation process using
bromoacetates as electrophiles allow the preparation of ortho-sub-
stituted cinnamates.
1 (P4-t-Bu)
4 (P2-Et)
_
SO2R
+
Hal
2
3
Key words: sulfones, phosphazene bases, alkylations, aldol reac-
tion, Heck reaction, cross-coupling
Figure
For the preparation of ortho-halobenzyl sulfones 5, 2-ha-
lobenzyl bromides9 were treated with sodium para-tolue-
nesulfinate in refluxing methanol to give the bromo
derivative 5a and the ortho-iodobenzyl sulfone 5b in 80%
and 85% overall yield, respectively.10 Initially, the alkyla-
tion reaction of sulfones 5 using P4-t-Bu or BEMP,2,4 as
phosphazene bases, failed. However, P2-Et gave satisfac-
tory results for the alkylation of compounds 5 with alkyl
halides at room temperature in dry THF and in absence of
an inert atmosphere (Scheme 1, Table, entries 1–5).11 The
Michael addition reaction with ethyl acrylate could be car-
ried out with 10 mol% of P2-Et to give adducts 6ad and
6bd, both in 75% yields (Table, entries 6 and 7).11 When
ethyl bromoacetate was used as electrophile sequential
alkylation- -elimination reaction of para-toluenesulfinic
acid took place affording ethyl ortho-cinnamates 7a and
7b, the presence of two equivalents of base being neces-
sary (Table, entries 8 and 9).11
-Sulfonyl carbanions1 are usually generated by means of
alkyllithium and Grignard reagents, lithium amides and
other strong bases as alkali hydrides or alkoxydes under
strict anhydrous conditions and low temperatures. Solla-
dié-Cavallo et al. have described2 the diastereoselective
aldol reaction of -sulfonyl carbanions derived from ben-
zyl sulfones employing phosphazene base P4-t-Bu 1.3,4
This base gave better results than n-butyllithium or ethyl-
magnesium bromide in the case of butyraldehyde and
chiral isopropylidene glyceraldehyde.2 Phosphazene base
P4-t-Bu has also been employed in the alkylation reaction
of episulfones.5 In general, these cation free Schwesinger
bases3 are strong non-ionic systems, which allow the
deprotonation of a wide range of acidic protons (MeCNpKa
= 27–42)3 to give high reactive naked carbanions.6 They
can be managed under simpler reaction conditions than
the above mentioned bases and the high cost of phosp-
hazene bases is partially overcome because recovery from
the reaction mixture after acidic treatment can be made.3,4
For the aldol reactions the temperature was kept at -78 ºC
for times depicted in Table, depending on the aldehyde
structure, in order to isolate the addition products 8.11
Higher temperatures led to retro-aldol reaction and the
formation of vinyl sulfones. The relative configuration of
the major -or exclusively obtained- diastereomer anti-8
was deduced from the coupling constants between CHS
and CHO12 (Scheme 1, Table, entries 10–14). The anti/
syn ratio increased notably with the bulkiness of the alde-
hyde and with the size of the halogen of the sulfone (Ta-
ble, entries 12–14). The anti-aldol products are the
favoured ones as it was demonstrated previously by Sol-
ladié et al.2 obtaining the best diastereoselection (89:11
dr) using t-butyl benzyl sulfone /P4-t-Bu and isopropy-
lideneglyceraldehyde. They justified it by the interaction
between the extra -oxygen atom of the aldehyde moiety
and the conjugated acid of the phosphazene base (P4-t-
BuH+). In our reaction, according to the achieved results,
the iodine atom in 5b caused higher diastereoselection to-
We envisaged that ortho-halobenzyl sulfones 2 can be ap-
propriate equivalents of the zwitterionic synthon 3, useful
for the synthesis of interesting disubstituted benzenes
through a sequence comprised of electrophilic functional-
isation at the benzylic position and palladium cross-cou-
pling reactions of the halogen atom or the reverse
sequence. In this way, we have found that phosphazene
base P2-Et 4,3,4 a moderate hindered base7 whose MeCNpKa
is similar to 33, is the most suitable base for the proton ab-
straction of ortho-halobenzyl sulfones 2 and further reac-
tion with different electrophiles8 under very simple
reaction conditions.
Synlett 2001, No. 12, 30 11 2001. Article Identifier:
1437-2096,E;2001,0,12,1881,1884,ftx,en;D19701ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1882
A. Costa et al.
LETTER
Ts
Ts
R
R
RCHO
-78ºC
+
OH
OH
X
Hal
Hal
anti-8
syn-8
P2-Et
P2-Et
Ts
Ts
RHal or
CO2Et
Ts
Hal
Hal
6
5a, Hal = Br
5b, Hal = I
(CH2O)n
0ºC to rt
Br
P2-Et
Ts = p-TolSO2
9
BrCH2CO2Et
Ts
Ts
CO2Et
Hal
Br Br
7
10
Scheme 1
wards the anti isomer. Probably, the main reason is the droxylase inhibitors20 and drugs for treatment of obesity
difference in energy in the opened transition states, such and diabetes.21 Biaryl acrylate 12 was obtained, in 67%
as it was confirmed by preliminary search employing ab yield, employing the Suzuki-Miyaura cross-coupling
initio calculations.13 The analogous condensation reaction reaction22,23 of 5a with phenylboronic acid and potassium
was performed with paraformaldehyde and 5a obtaining carbonate in DMF at 120 ºC for 19 h followed by P2-Et-
an equimolar mixture of vinyl sulfone 9a and the Michael mediated alkylation-elimination with ethyl bromoacetate.
addition product 10a as mixture of diastereomers.14 This Enyne 13 was isolated in 71% yield through a
very reactive alkenyl sulfone had to be generated in the Sonogashira24 reaction of 5b with phenylacetylene in the
presence of an excess of paraformaldehyde avoiding large presence of catalytic amounts of CuI under refluxing di-
amounts of -sulfonyl carbanion in the reaction mixture. ethylamine for 24 h and further synthesis of the acrylic es-
So, adding the sulfone 5a or 5b very slowly (2 h, via sy- ter moiety (Scheme 2).
ringe pump) to a suspension of paraformaldehyde (10
equiv) and P2-Et (1 equiv) at 0 ºC, vinyl sulfone 9a and
1) Pd(OAc)2/PPh3, K2CO3
9b11 were exclusively obtained in 54% and 70% yield, re-
MeCN, 80ºC, 19h
CO2Et
CO2But
spectively (Scheme 1, Table, entries 15 and 16). The
chemoselectivity and basicity of phosphazene base P2-Et
represented a very interesting alternative to strong bases
operating at very low temperatures and under strict anhy-
drous conditions. For instance, when the aldol reaction
was carried out using n-butyllithium as base in the case of
5a no reaction was observed and 5b gave a complex mix-
ture of products.
2) P2-Et, BrCH2CO2Et
CO2But
Hal = I, 11 (65%)
1) Pd(OAc)2/PPh3, K2CO3
DMF, 120ºC, 19h
PhB(OH)2
CO2Et
Ts
2) P2-Et, BrCH2CO2Et
Ph
Hal
5a,b
Hal = Br, 12 (67%)
A combination of Heck reaction/cross-coupling-alkyla-
tion- -elimination sequence15 was used for preparing cin-
namic esters derivatives 11–13. The synthesis of diene 11
was accomplished, in 65% yield, by Heck reaction16 with
ethyl acrylate under Jeffery’s PTC conditions17 (using po-
tassium carbonate as base, 10 mol% of tetra-n-butylam-
monium bromide, in refluxing acetonitrile for 19 h),
followed by the mentioned alkylation-elimination proto-
col with t-butyl bromoacetate (Scheme 2). The not easy
preparation of 1,2-disubstituted benzenes, bearing two
different , -unsaturated carbonyl compounds or related
derivatives, make this methodology an elegant way to ac-
cess them.18,19 Compounds of the type 11 have been em-
ployed in electrocyclic reactions,18c,19a,c in the synthesis of
cispentacin derivatives,18b 1,3-dihydroisobenzofuranes18a
and annulenes,19b in the preparation of dopamine -hy-
1) Pd(OAc)2/PPh3, Et2NH
reflux, 24h,CuI (cat)
CO2Et
Ph
2) P2-Et, BrCH2CO2Et
Ph
Hal = I, 13 (71%)
Scheme 2
As summary, we have found that ortho-halobenzyl sul-
fones are appropriate zwitterionic synthons for the prepa-
ration of ortho-disubstituted benzenes by sequential
cross-coupling reaction at the halogen atom and P2-Et-
mediated alkylation at the benzylic position. Further ap-
plications of these sulfones are underway.
Synlett 2001, No. 12, 1881–1884 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
P2-Et-Mediated Deprotonation of ortho-Halobenzyl Sulfones
1883
Table P2-Et Mediated Alkylation and Aldol Reaction of ortho-Halobenzyl Sulfones 5a and 5ba
Entry
1
Sulfone 5
5a
Electrophile
EtI
T (ºC)
25
Time (h)
16
Productb
6aa
6ba
6ab
6bb
6ac
6ad
6bd
7a
X or R
Yield (%)c
Et
70
78
80
65
90
75
75
70
66
75
90
55
86
70
54
70
2
5b
EtI
25
16
Et
3
5a
CH2=CHCH2Br
CH2=CHCH2Br
HC CCH2Br
CH2=CHCO2Et
CH2=CHCO2Et
BrCH2CO2Et
BrCH2CO2Et
n-PrCHO
25
16
CH2=CHCH2
CH2=CHCH2
HC CCH2
CH2CH2CO2Et
4
5b
25
16
5
5a
25
16
6
5a
25
12
7
5b
25
12
CH2CH2CO2Et
___
8
5a
25
19
___
9
5b
25
19
7b
10
11
12
13
14
15
16
5a
–78
–78
–78
–78
–78
0g
0.5
0.5
0.5
19
8aa
8ba
8ab
8ac
8bc
9ª
n-Prd
n-Prd
t-Bue
5b
n-PrCHO
5a
t-BuCHO
f
5a
n-C6H13CHO
n-C6H13CHO
(CH2O)n
n-C6H13
e
5b
19
n-C6H13
___
5a
2
___
5b
(CH2O)n
0g
2
9b
a For experimental procedures see ref. 11.
b All products gave satisfactory physical and spectroscopic data.
c Isolated yield after column chromatography (silica gel).
d Obtained as a 7:1 anti:syn mixture.
e Obtained as a 1:0 anti:syn mixture.
f Obtained as a 3:1 anti:syn mixture.
g Slow addition of the sulfone 5 (see text).
(6) For structural studies about metal-free a-sulfonyl carbanions
of benzyl sulfones see: Reetz, M. T.; Hütte, S.; Goddard, R.
Eur. J. Org. Chem. 1999, 2475.
Acknowledgement
The authors wish to thank to the Spanish Ministerio de Educación y
Cultura (M.E.C.) (PB97-0123) for the financial support.
(7) P2-Et has been used for E2 elimination reactions of
secondary halides: (a) Schwesinger, R.; Willaredt, J.;
Schlemper, H.; Keller, M.; Schmitt, D. Chem. Ber. 1994,
127, 2435. (b) It also promoted the double bond
isomerisation of a vinyl sulfone to an allyl sulfone: Kim, S.
H.; Jin, Z.; Fuchs, P. L. Tetrahedron Lett. 1995, 36, 4537.
(8) A preliminary account of this work was presented at the
6th International Symposium on Carbanion Chemistry;
Marburg, Germany, July 28-August 1, 2001; SL-15.
(9) 2-Bromobenzyl bromide is commercially available
(Aldrich) and 2-iodobenzyl bromide was prepared by
reaction of 2-iodobenzyl alcohol with concentrated HBr in
AcOH: Vögtle, F.; Eisen, N.; Franken, S.; Büllesbach, P.;
Puff, H. J. Org. Chem. 1987, 52, 5560.
(10) ortho-Bromobenzyl phenyl sulfone has been previously
prepared and deprotonated using LiHMDS: Orita, A.;
Yoshioka, N.; Struwe, P.; Braier, A.; Beckmann, A.; Otera,
J. Chem.–Eur. J. 1999, 5, 1355.
(11) A typical procedure for the -alkylation of benzyl sulfones 5
follows:
References
(1) For a recent review, see: (a) Prilezhaeva, E. N. Russ. Chem.
Rev. 2000, 69, 367. (b) Nájera, C.; Sansano, J. M. Rec. Res.
Devel. Org. Chem. 1998, 2, 637.
(2) Solladié-Cavallo, A.; Roche, D.; Fischer, J.; De Chian, A. J.
Org. Chem. 1996, 61, 2690.
(3) Schwesinger, R.; Schlemper, H.; Hasenfratz, C.; Willaredt,
J.; Dambacher, T.; Breuer, T.; Ottaway, C.; Fletschinger, M.;
Boele, J.; Fritz, H.; Putzas, D.; Rotter, H. W.; Bordwell, F.
G.; Satish, A. V.; Ji, G.-Z.; Peters, E. M.; Peters, K.; von
Schnering, H. G.; Walz, L. Liebigs Ann. 1996, 1055.
(4) Encyclopedia of Reagents for Organic Synthesis, Vol. 6;
Paquette, L. A., Ed.; John Wiley & Sons: Chichester, 1995,
4110.
(5) Episulfones derived from -sulfonyl carbanions have been
generated with phosphazene base P4-t-Bu and alkylated
with benzyl bromide and benzaldehyde obtaining alkenes by
loss of SO2: Muccioli, A. B.; Simpkins, N. S.; Mortlock, A.
J. Org. Chem. 1994, 59, 5141.
To a solution of the benzyl sulfone 5 (0.2 mmol) and P2-Et
(79 L, 0.24 mmol for compounds 6aa–6ac, 6ba and 6bb;
Synlett 2001, No. 12, 1881–1884 ISSN 0936-5214 © Thieme Stuttgart · New York

1884
A. Costa et al.
LETTER
(15) The sequence alkylation- -elimination-Heck/coupling
237 L, 0.72 mmol for compound 7; 7 L, 0.02 mmol for
compounds 6ad and 6bd) in dry THF (3 mL), at 0 °C, the
corresponding electrophile (0.24 mmol) was added. After
stirring at this temperature, for reaction times depicted in
Table, an aqueous 2 M solution of hydrochloric acid (2 mL)
was poured into the flask. The aqueous phase was extracted
with EtOAc (3 10 mL) and the combined organic layers
were washed successively with aqueous 2 M HCl (2 10
mL) and brine (10 mL), dried (Na2SO4) and evaporated
under vacuo. The crude products were purified by flash
chromatography (silica gel) using mixtures of n-hexane/
ethyl acetate as eluent, obtaining products 6 or 7 in yields
showed in Table.
reaction gave slightly lower yields because a little
intramolecular Heck reaction onto o-halocinnamic ester
occurred.
(16) For a recent review, see: Beletskaya, I. P.; Cheprakov, A. V.
Chem. Rev. 2000, 100, 3009.
(17) For recent publications regarding the efficiency of
tetraalkylammonium salts in Heck reaction, see: (a) Jeffery,
T. Tetrahedron Lett. 1999, 40, 1673. (b) Jeffery, T.
Tetrahedron 1996, 52, 10113; and references cited therein.
(18) Symmetrical ortho-distyrylbenzenes have been obtained by
a double Heck reaction: (a) Chao, B.; Dittmer, D. C.
Tetrahedron Lett. 2000, 41, 6001. (b) Voigt, K.; Lansky, A.;
Noltemeyer, M.; de Meijere, A. Liebigs Ann. 1996, 899.
(c) Lansky, A.; Reiser, O.; de Meijere, A. Synlett 1990, 405.
(d) Tao, W.; Nesbitt, S.; Heck, R. F. J. Org. Chem. 1990, 55,
63.
(19) As well, symmetrical ortho-distyrylbenzenes have been
obtained by a double Wittig or a double Horner-Wadsworth-
Emmons reaction from the corresponding phthalaldehydes:
(a) Kaupp, G.; Frey, H.; Behmann, G. Chem. Ber. 1988, 121,
2135. (b) Darby, N.; Cresp, T. M.; Sondheimer, F. J. Org.
Chem. 1977, 42, 1960. (c) Tavares, D. F.; Ploder, W. H.
Tetrahedron Lett. 1970, 1567.
(20) (a) Martínez, G. R.; Gooding, O. W.; Repke, D. B.;
Teitelbaum, P. J.; Walker, K. A. M.; Whiting, R. L. U. S.
Patent 19960723, 1996. (b) Chem. Abstr. 1996, 125,
195657. (c) Martínez, G. R.; Repke, D. B.; Teitelbaum, P. J.;
Walker, K. A. M.; Gooding, O. W.; Whiting, R. L.; Bansal,
R. P.; Muehldorf, A. V.; O’yang, C. U. S. Patent 19951102,
1995. (d) Chem. Abstr. 1995, 124, 176116.
(21) (a) Bousard, M.-F.; Guette, J. P.; Wierzbicki, M.; Beal, P.;
Fournier, J.; Boulanger, M.; Della-Zuana, O.; Duhault, J.
Arzneim.-Forsch. 2000, 50, 1084. (b) Wierzbicki, M.;
Hugon, P.; Duhault, J.; Lacour, F. FR. Patent 19900105,
1990. (c) Chem. Abstr. 1990, 113, 230948.
A typical procedure for compounds 8 follows:
To a solution of the benzyl sulfone 5 (0.2 mmol) and P2-Et
(79 L, 0.24 mmol)in dry THF (3 mL), at -78 °C, under an
inert atmosphere (N2) was added the corresponding aldehyde
(0.24 mmol). After stirring at this temperature, for reaction
times depicted in Table, an aqueous 2 M solution of
hydrochloric acid (2 mL) was poured into the flask. The
aqueous phase was extracted with EtOAc (3 10 mL) and
the combined organic layers were washed successively with
aqueous 2 M HCl (2 10 mL) and brine (10 mL), dried
(Na2SO4) and evaporated under vacuo. The crude products
were purified by flash chromatography (silica gel) using
mixtures of n-hexane/ethyl acetate as eluent, obtaining
aldols 8 in yields showed in Table.
A typical procedure for compounds 9 follows:
To a solution of paraformaldehyde (34 mg, 1.08 mmol) and
benzyl sulfone 5 (0.2 mmol) in dry THF (10 mL), at 0 ºC,
was slowly added (2 h) a solution of P2-Et (145 L, 0.43
mmol) in dry THF (5 mL). The resulting mixture was stirred
at room temperature overnight and an aqueous 2 M HCl
solution (2 mL) was added. The mixture was treated as
described previously affording, after purification by flash
chromatography (silica gel), compound 9a or 9b in 54% and
70% yield, respectively (see Table).
(22) For reviews, see: (a) Suzuki, A. J. Organomet. Chem. 1999,
576, 147. (b) Suzuki, A. Metal Catalyzed Cross Coupling
Reactions; Diederich, F.; Stang, P. J., Eds.; Wiley-V.C.H.:
Weinheim, 1998, Chap. 2, 49–97.
(23) In the case of ortho-iodobenzyl chloride Cu-thiophene-2-
carboxylate (CuTC)-mediated coupling of boronic acids
under non-basic/room temperature conditions has been
reported as alternative to the traditional Suzuki–Miyaura
conditions: Savarin, C.; Liebeskind, L. S. Org. Lett. 2001, 3,
2149.
9a: 1H NMR (300 MHz, CDCl3) : 2.41 (s, 3 H, CH3Ar),
5.93, 6.82 (2 s, 2 H, CH2=C), 7.19–7.31 (m, 4 H, ArH) and
7.42–7.52 (m, 4 H, ArH). 13C NMR (75 MHz, CDCl3) :
21.6 (CH3Ar), 124.4 (ArCBr), 127.6, 128.7, 129.1, 130.4,
131.0, 134.7, 136.7, 139.7, 140.1, 144.7 and 148.9 (ArC and
CH2=C). IR (neat): 3101, 1596, 1316, 1303, 1149, 800
cm–1. MS (EI, 70 eV) m/z: 338, 336 (M+, 3%), 259 (11), 258
(80), 257 (96), 199 (54), 197 (49), 184 (39), 182 (78), 181
(100), 140 (27), 103 (31), 102 (44)and 101 (45).
(12) Truce, W. E.; Klingler, T. C. J. Org. Chem. 1970, 35, 1834.
(13) Chinchilla, R. private communication.
(14) Compound 10a was obtained from the crude reaction
mixture as a 5:1 mixture of diastereomers.
(24) Sonogashira, K. Metal Catalyzed Cross Coupling Reactions;
Diederich, F.; Stang, P. J., Eds.; Wiley-V.C.H.: Weinheim,
1998, Chap. 5, 203–229.
Synlett 2001, No. 12, 1881–1884 ISSN 0936-5214 © Thieme Stuttgart · New York