Asymmetric Heck reaction of (R) 1-tert-butylsulfinylcyclopentene with arenediazonium salts

Article abstract of DOI:10.1055/s-1999-2890

The asymmetric Heck reaction of the readily available (R) l-tert- butylsulfinyl-l-cyclopentene with a variety of para- and meta- substituted arenediazonium tetrafluoroborates is described. In the presence of Ag₂CO₃ as base, in CH₃CN at rt, the reactions occur in good yields (72-79%) with high diastereoselectivities (de = 82-92%) to afford (3S, SR)-3-aryl-2-tert- butylsulfinyl-1-cyclopentenes as the major adducts. In contrast, poor results were obtained from ortho-substituted arenediazonium salts.

Full text of DOI:10.1055/s-1999-2890

LETTER
1603
Asymmetric Heck Reaction of (R) 1-tert-Butylsulfinylcyclopentene with
Arenediazonium Salts
Julián Priego, Juan Carlos Carretero*
Departamento de Química Orgánica, Facultad de Ciencias, Universidad Autónoma de Madrid, 28049 Madrid, Spain
Fax 34 913973966; E-mail: juancarlos.carretero@uam.es
Received 6 July 1999
Abstract: The asymmetric Heck reaction of the readily available
(R) 1-tert-butylsulfinyl-1-cyclopentene with a variety of para- and
meta- substituted arenediazonium tetrafluoroborates is described.
In the presence of Ag2CO3 as base, in CH3CN at rt, the reactions oc-
cur in good yields (72-79%) with high diastereoselectivities
(de = 82-92%) to afford (3S, SR)-3-aryl-2-tert-butylsulfinyl-1-cy-
clopentenes as the major adducts. In contrast, poor results were ob-
tained from ortho-substituted arenediazonium salts.
Key words: Heck reaction, asymmetric synthesis, sulfoxides, diaz-
oniums salts, chiral cyclopentenes
The impressive development achieved over the last two
decades in the palladium-catalyzed arylation and alkenyl-
ation of olefins (the Heck reaction) demonstrates the ver-
satility of such reactions in organic synthesis.1 However,
efficient enantioselective variants of this process (asym-
metric Heck reactions) have only been developed during
the last decade, mainly using enantiopure phosphane
ligands as source of chiral induction.2 Motivated by our
recent results on the use of substituted aryl sulfoxides as
chiral auxiliaries in the asymmetric Heck reactions of 4-
arylsulfinyl-2,3-dihydrofurans with iodoarenes,3 we en-
visaged that the use of sterically more demanding sulfox-
ides, such as the tert-butylsulfinyl group, could afford
even higher diastereoselectivities.4
To test this hypothesis, (R) 1-tert-butylsulfinyl-1-cyclo-
pentene (1) was readily prepared in 67% yield with high
optical purity (ee = 96% by HPLC, Chiralpak AS) by
sulfinylation of cyclopentenyllithium (generated in situ
from 1-bromocyclopentene and t-BuLi in THF at –78ºC)
with (R) tert-butyl tert-butanethiosulfinate5 (ee = 97% by
HPLC, Chiralpak AS). Disappointingly, the reaction of 1
with aryl iodides under the optimum conditions previous-
Despite the fact that the Heck reactions of arenediazonium
salts with unhindered alkenes usually occur rapidly in al-
coholic solvents in the absence of added bases,7 no reac-
tion was observed after treatment of 1 with p-
methoxyphenyldiazonium tetrafluoroborate in the pres-
ly found for the Heck reactions of 4-arylsulfinyl-2,3- ence of 10 mol% Pd(OAc)2 in methanol at rt for 24 h (en-
dihydrofurans3 [Pd(OAc)2, Ag2CO3, dppp, DMF, 100ºC] try 1), whereas only a sluggish reaction was detected in
gave a complex mixture of products, due in part to the
thermal instability of the alkyl sulfoxides. On the other
hand, at lower temperatures (60ºC) a very sluggish reac-
tion was observed even after several days.6 Taking into
account the reluctance of the hindered substituted cyclo-
pentene 1 to undergo Heck reactions with iodoarenes, we
turned towards the use of the more reactive arenediazoni-
um salts.7
acetonitrile (entry 2). The use of different bases, such as
NaOAc, K2CO3, AgBF4 and Tl(OAc)3 gave no reaction at
all or very low conversions (entries 3-6). Most gratifying,
using Ag2CO3 (2.0 equiv.) as base8 and CH3CN as solvent
(entry 7), a clean and complete reaction took place, lead-
ing to the Heck adducts 2 in good yield (78%) and in a
highly stereoselective manner (2A:2B = 9:91, entry 7).
Further studies showed the solvent dependence of this re-
action with regard to both the stereoselectivity
(2A:2B = 37:63 in DMF, entry 8) and the reactivity (27%
conversion in DMSO, entry 9) of the process.9
The results obtained for palladium catalyzed [Pd(OAc)2]
reaction of 1 with p-methoxyphenyldiazonium tetrafluo-
roborate (2.0 equiv) under different experimental condi-
tions are shown in Table 1.
Synlett 1999, No. 10, 1603–1605 ISSN 0936-5214 © Thieme Stuttgart · New York

1604
J. Priego, J. C. Carretero
LETTER
The scope of this reaction was studied with a wide array
of electronically and structurally diverse arenediazonium
salts under the optimum conditions10 [Pd(OAc)2 (20
mol%),11 Ag2CO3 (2.0 equiv.), CH3CN, rt]. As described
in Table 2, the Heck reaction occurred cleanly using phe-
nyldiazonium tetrafluoroborate (entry 2) or the para-sub-
stituted arenediazonium salts bearing either electron-
donating (entries 1 and 3) or weakly electron-withdrawing
functional groups (entry 4). In all these cases we observed
complete disappearance of 1 (conversion >98% after 8-
10h) and the formation of the Heck adducts as the main
products (72-79% yields after chromatographic purifica-
tion) devoid of any double bond isomerized cyclopentene
byproducts.12 However, the most interesting result con-
cerns the remarkable stereoselectivity of the process,
which affords stereoisomer B as the major adduct13 (A:B
ratio ranging from 9:91 to 4:96).
Scheme 1
This high p-facial stereoselectivity could be rationalized
on steric grounds invoking that the aryl insertion step
would take place from the least hindered face of substrate
1, that in the face opposite to the bulky tert-butyl group,
in its most stable s-cis conformation19 (shown in Table 2).
However, very low conversions were observed when
para-nitrophenyldiazonium tetrafluoroborate20 (entry 5)
or ortho-substituted arenediazonium salts (entries 7 and 8)
were used. In these cases the Heck adducts were detected
as minor products (yields ≤20%) due to the formation of
complex mixtures of aromatic compounds, likely as a re-
sult of the competitive coupling reaction of arenediazoni-
um salts or other palladium catalyzed side reactions. An
intermediate behaviour was observed for the meta-tolyl-
diazonium tetrafluoroborate (entry 6), which led to the
corresponding Heck adducts 7 (7A:7B = 7:93) in moder-
ate yield (54%) because of the incomplete consumption of
1 (64% conversion).
In summary, the results shown here indicate the useful-
ness of the t-butylsulfinyl group as a novel chiral auxiliary
in asymmetric Heck reactions when arenediazonium salts
are used as arylating reagents. Good yields (72-79%) and
high diastereoselectivities (de = 82-92%) were obtained
in the Heck reactions of 1-sulfinylcyclopentane 1 with a
variety of arenediazonium tetrafluoroborates. The exten-
sion of this procedure to other cyclic alkenes is in progress
in our laboratory.
Acknowledgement
We thank the DGICYT (project PB96-0021) for financial support.
J.P. also acknowledges the Ministerio de Educación y Cultura for a
fellowship.
References and Notes
(1) Recent reviews on the Heck reaction: a) Gibson, S. E.;
Middleton, R. J. Contemp. Org. Synth., 1996, 3, 447. b) Cabri,
W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2. c) de Meijere,
A.; Meyer, F. E. Angew. Chem. Int. Ed. Engl. 1994, 36, 2379.
d) Bräse, S.; de Meijere, A. In Metal-catalyzed Cross-
coupling Reactions; Diederich, F.; Stang, P. J., Eds.; Wiley-
VCH: Weinheim, 1998; Chapter 3.
(2) For a review on the asymmetric Heck reaction, see: Shibasaki,
M.; Boden, C. D. J.; Kojima, A. Tetrahedron 1997, 53, 7371.
For some recent references, see: a) Ashimori, A.; Bachand, B.;
Overman, L. E.; Poon, D. J. J. Am. Chem. Soc. 1998, 120,
6477. b) Kojima, A.; Takemoto, T.; Sodeoka, M.; Shibasaki,
M. Synthesis 1998, 581. c) Loiseleur, O.; Hayashi, M.;
Schmees, N.; Pfaltz, A. Synthesis 1997, 1338. c) Cheng, C.-
Y.; Liou, J.-P.; Lee, M.-J. Tetrahedron Lett. 1997, 38, 4571.
d) Trabesinger, G.; Albinati, A.; Feiken, N.; Kunz, R. W.;
Pregosin, P. S.; Tschoerner, M. J. Am. Chem. Soc. 1997, 119,
6315.
The stereochemical assignments of A and B isomers were
first established by 1H NMR14 and later confirmed by con-
version of 3B (ee = 96% by HPLC, Chiralcel OD) into the
known (R) 3-phenylcyclopentene15 by a two-step reduc-
tive cleavage of the sulfinylated chiral auxiliary16
(Scheme 1). Thus, the oxidation of 3B with MCPBA (1
equiv, CH2Cl2, 0ºC) afforded quantitatively the vinyl sul-
fone 10, which was reductively desulfonylated by treat-
ment with excess of i-PrMgBr in the presence of a
catalytic amount of Pd(acac)217 (5 mol%) to give cleanly
the (R) 3-phenylcyclopentene (11) in 53% overall yield18
and in high optical purity [[a]D = +194 (c 1, CHCl3),
ee = 96%; [a]DLit. ref 15 = +184 (c 1, CHCl3), ee = 91%].
Synlett 1999, No. 10, 1603–1605 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Heck Reaction of (R) 1-tert-Butylsulfinylcyclopentene with diazonium Salts
1605
(3) Díaz Buezo, N.; Alonso, I.; Carretero, J. C. J. Am. Chem. Soc.
1998, 120, 7129.
1989, 30, 2603. c) Prashad, M.; Tomesch, J. C.; Wareing, J.
R.; Smith, H. C.; Cheon, S. H. Tetrahedron Lett. 1989, 30,
2877. d) Kikukawa, K.; Nagira, K.; Wada, F.; Matsuda, T.
Tetrahedron 1981, 37, 31
(4) For some recent results on the use of the tert-butylsulfinyl
group as a chiral auxiliary in other reactions, see: a) Cogan D.
A.; Ellman, J. A. J. Am. Chem. Soc. 1999, 121, 268. b) Tang,
T. P.; Ellman, J. A. J. Org. Chem. 1999, 64, 12. c) Adrio, J.;
Carretero, J. C. J. Am. Chem. Soc. 1999, 121, 7411.
(5) Cogan, D. A.; Liu, G.; Kim, K.; Backes, B. J.; Ellman, J. A. J.
Am. Chem. Soc. 1998, 120, 8011.
(13) We confirmed that, as expected, substrate 1 (ee = 96%,
HPLC, chiralpak AS) did not suffer racemization at sulfur
under these experimental Heck reactions, as it was proved by
the preservation of the same high optical purity in the adduct
3B (ee = 96% by HPLC, Chiralcel OD).
(6) Only 35% conversion was observed in the reaction of 1 with
p-methoxyiodobenzene [Pd(OAc)2 10 mol%, dppp 10 mol%,
Ag2CO3 (2 equiv)] in acetonitrile at 60ºC for 72h.
Furthermore, the stereoselectivity was significantly lower
than from p-methoxybenzenediazonium tetrafluoroborate
(2A:2B = 17:83 instead of 9:91).
(7) For recent references on aryldiazonium salts in Heck
reactions, see: a) Oliveira, D. F.; Severino, E. A.; Correia, C.
R. D. Tetrahedron Lett. 1999, 40, 2083. b) Sengupta, S.;
Sadhukhan, S. K. Tetrahedron Lett. 1998, 39, 715.
c) Sengupta, S.; Bhattacharyya, Sadhukhan, S. K. J. Chem.
Soc., Perkin Trans. 1 1998, 275. d) Sengupta, S.; Sadhukhan,
S. K.; Bhattacharyya, S. Tetrahedron 1997, 53, 2213.
(8) To the best of our knowledge the use of Ag2CO3 as additive in
the Heck reaction of arenediazonium salts had not been
described previously.
(14) As in the case of Heck adducts of sulfinylated dihydrofuran
(reference 3), the chemical shifts differences of the protons
contiguous to the sulfur atom (H1 and H3) in both A and B
isomers constitute an excellent criteria for its configurational
assignment. Thus, H1 appears significantly more deshielded in
isomers A than in isomers B, whereas the opposite was
observed for H3. These effects can be explained as shown in
the figure below on the basis of the highly deshielding effect
induced by the sulfinylic oxygen on the hydrogens in 1,3-
parallel relationship in the presumed most stable
conformations of isomers A and B (for NMR effects of the
sulfinyl group, see: Lett, R.; Marquet, A. Tetrahedron 1974,
30, 3379).
(9) We also found that the addition of a catalytic amount of
phosphane ligands (PPh3 or dppp) had a detrimental effect on
the reactivity.
General procedure: In a one-necked round bottom flask were
sequentially added the sulfinylcyclopentene 1 (172 mg, 1
mmol), p-methoxyphenyldiazonium tetrafluoroborate (445
mg, 2 mmol), Ag2CO3 (552 mg, 2 mmol), Pd(OAc)2 (45 mg,
0.2 mmol) and dry acetonitrile (2 mL). The reaction was
degassed and stirred vigorously at rt under argon. The reaction
was followed by TLC until disappearance of 1 (8-10 h). Then,
the mixture was diluted with ether (12 mL), filtered and
washed with water. The organic layer was dried (MgSO4) and
evaporated to give the crude Heck adducts 2A+2B (9:91
ratio), which were purified by flash chromatography (2:1 ethyl
acetate: CH2Cl2 as eluent, 78% yield).
Dd1 = d1A-d1B = + [0.3-0.4] ppm; Dd3 = d3A-d3B = [0.3-0.5]
ppm (values in CDCl3)
(15) Loiseleur, O.; Hayashi, M.; Schmees, N.; Pfaltz, A. Synthesis
1997, 1338.
(16) All attempts to remove the tert-butylsulfinyl group by reaction
with different desulfinylating agents were unsuccessful, due
to the competitive reduction to the thioether (activated zinc,
NH4Cl), overreduction to cyclopentanes (Raney Ni, EtOH) or
lack of reaction [SmI2/THF/MeOH or Ni(OAc)2/NaH/t-
AmOH].
(17) Fabre, J. L.; Julia, M. Tetrahedron Lett. 1983, 4311.
(18) This moderate yield was mainly due to the high volatility of
cyclopentene 11.
(19) Recent ab initio calculations performed on different
substituted a,b-unsaturated sulfoxides indicate that the s-cis
conformation is significantly more stable than any other
(Tietze, L. F.; Schuffenhauer, A.; Schreiner, P. R. J. Am.
Chem. Soc. 1998, 120, 7952).
(20) For a similar result in the Heck reactions of nitro-substituted
diazonium compounds, see: Sengupta, S.; Bhattacharya, S. J.
Chem. Soc. Perkin Trans. 1 1993, 1943.
2B. [a]D = +32.4 (c 0.46, CHCl3). Rf = 0.35 (2:1 ethyl acetate:
CH2Cl2). 1H NMR (200 MHz, C6D6): d = 7.16 (AA’BB’, 2H),
6.83 (AA’BB’, 2H), 6.09 (br s, 1H), 4.12 (br s, 1H), 3.37 (s,
3H), 2.29-2.41 (m, 1H), 1.98-2.19 (m, 2H), 1.73-1.81 (m, 1H),
1.03 (s, 9H). 13C NMR (75 MHz, CDCl3): d = 158.0, 147.6,
139.0, 135.5, 127,9, 113.7, 56.0, 55.0, 50.7, 34.5, 31.7, 23.1.
Anal. Calcd. for C16H22O2S: C 69.03; H 7.96; S 11.52. Found:
C 69.02; H 7.65; S 11.97.
2A. Rf = 0.29 (2:1 ethyl acetate: CH2Cl2). 1H NMR (200
MHz, C6D6), significant signals: d = 6.09 (br s, 1H), 4.11 (br
s, 1H), 1.08 (s, 9H).
(11) Incomplete conversions were observed in the presence of 10
mol% Pd(OAc)2 for the case of the diazonium salts of entries
3 and 4 of Table 2.
(12) For examples of Heck reactions of cyclopentene, see: a)
Larock, R. C.; Baker, B. E. Tetrahedron Lett. 1988, 29, 905.
b) Larock, R. C.; Gong, W. H.; Baker, B. E. Tetrahedron Lett.
Article Identifier:
1437-2096,E;1999,0,10,1603,1605,ftx,en;G17899ST.pdf
Synlett 1999, No. 10, 1603–1605 ISSN 0936-5214 © Thieme Stuttgart · New York