Stille reaction over cis-halocyclohexadienediol derivatives

Article abstract of DOI:10.1016/j.tetlet.2008.09.049

Stille reaction was performed with several halo cis-diol derivatives by reaction with allyltributyltin in the presence of a palladium catalyst forming allyl cis-dihydrodiol derivatives. These couplings were conducted with conventional heating as well as w

Full text of DOI:10.1016/j.tetlet.2008.09.049

Tetrahedron Letters 49 (2008) 6787–6790
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Stille reaction over cis-halocyclohexadienediol derivatives
b
a
a
Viviana Heguaburu a, , Marcus Mandolesi Sá , Valeria Schapiro , Enrique Pandolfi
*
a Departamento de Química Orgánica, Facultad de Química, UdelaR, Montevideo, C.P. 11800, Uruguay
b Departamento de Química, Universidade Federal de Santa Catarina, Florianópolis, SC 88040-900, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 July 2008
Revised 5 September 2008
Accepted 10 September 2008
Available online 17 September 2008
Stille reaction was performed with several halo cis-diol derivatives by reaction with allyltributyltin in the
presence of a palladium catalyst forming allyl cis-dihydrodiol derivatives. These couplings were con-
ducted with conventional heating as well as with microwave irradiation. Allylbenzene cis-dihydrodiol
was obtained with excellent yield using mild conventional heating. However, if the diol moiety is pro-
tected with the isopropylidene group, the expected product is obtained only under microwave irradia-
tion. The unusual reactivity observed for the polyoxygenated derivatives suggests assistance of the free
hydroxyls in the catalytic cycle.
Keywords:
cis-Cyclohexadienediols
Stille reaction
Microwave
Ó 2008 Elsevier Ltd. All rights reserved.
Biotransformation of monosubstituted arenes by mutant strains
of Pseudomonas putida1 to produce cis-dihydrodiols is a valuable
process2 leading to homochiral synthons, which are useful in
asymmetric synthesis of natural products.3,4 Although there are
more than 400 cis-arene diols known, low production yields and
substrate specificity of the enzyme involved in this transformation
limit the synthetic possibilities of these multifunctional com-
pounds. In order to expand the utility of these cis-diols, it is highly
desirable to increase the variety of these compounds available,
with different motifs in their side chain. Up to now, there have
been only a few reports aiming at this goal, such as Boyd’s5,6 palla-
dium-catalyzed cross-coupling of unprotected cis-diols, Hudlicky’s
preparation of alkynes7 and Ley’s preparation of organostannanes
as Stille cross-coupling partners.8 Also, results concerning the side
chain modification of cis-diols on previously functionalized rings
have been reported.9–15
O
HO
OH
O
O
O
O
O
O
HO
HO
O
H
HO
OH
O
O
ECH
epoxyquinol A
X
X
OH
OH
P. putida F39/D
CO2Me
O
C5H11
X=Br, I
O
OH
OH
OH OH
O
ambuic acid
O
OH OH
jesterone
Scheme 1. Synthetic strategy for chiral epoxyenones by side chain modification of cis-diols.
* Corresponding author. Tel.: +598 2 9244066; fax: +598 2 9241906.
E-mail address: vheguab@fq.edu.uy (V. Heguaburu).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.049

6788
V. Heguaburu et al. / Tetrahedron Letters 49 (2008) 6787–6790
We based our study on Boyd’s work5 in which cis-cyclohexadi-
enediols reacted with allyltributyltin in the presence of a palla-
dium catalyst to replace bromine or iodine by an allyl group,
forming allyl cis-dihydrodiols in low to moderate yields. We stud-
ied this reaction over several cis-dihydrodiol derivatives in order to
obtain valuable synthons for our research program in natural prod-
ucts synthesis.16 Insertion of allylic side chain into cis-diol deriva-
tives combined with modern synthetic methodologies is currently
the focus of our research, in order to achieve the total synthesis of
chiral epoxyenones, such as epoxyquinols, ambuic acid, jesterone
and related compounds (Scheme 1).17 In this Letter, we present
our results involving the Stille cross-coupling of allyltributyltin
and several cis-diols and derivatives, under conventional heating
and microwave irradiation, to obtain proper synthons for our re-
search program.
Stille reactions were conducted with conventional heating (oil
bath) as well as with microwave irradiation.18 Allylbenzene cis-
dihydrodiol (Table 1, entry 1, 2a) was obtained with excellent yield
by reaction of iodo precursor 1a with allyltributyltin under mild
heating. Despite Boyd’s work in which bromo cis-cyclohexadiene-
diol 1b did not react at 35 °C, the product 2a could be obtained
at a higher temperature. However, the reaction yield was lower
than the one obtained with the iodo derivative. Compound 2a
showed to be unstable in mild acidic conditions rendering aro-
matic products. As functionalization grows on the cyclic structure,
this type of compounds becomes more stable. Protected cis-diols,
as well as further functionalized derivatives are also suitable syn-
thons for our synthetic purposes. A very common way to prevent
aromatization of cis-dihydrodiols is to protect the diol moiety with
the isopropylidene group (1c,d). The isopropylidene group also
blocks one face of the cyclohexadiene, hence directing the
stereochemical outcome of the reaction.3 However, when Stille
cross-coupling was performed with substrates containing the iso-
propylidene group, no reaction was achieved (Table 1, entries 3
and 4). These results suggest that steric hindrance of this protec-
tive group does not allow the reaction to occur. When iodo cis-
dihydrodiol is protected as its diacetate (1e), cross-coupling occurs
in 3 h at 35 °C in 72% yield (entry 5), supporting the hypothesis
that the steric effect plays an important role in this reaction. How-
ever, polyoxygenated derivatives 1f–i19–21 afforded the expected
products even when they are partially protected as acetonides.
These results indicate that an assistance of the free allylic hydroxyl
in the palladium catalytic cycle may occur.22,23 In an effort to con-
firm these hypothesis, compounds 1j and 1k were submitted to the
same cross-coupling conditions. Reaction of the sterically hindered
derivative 1k only afforded small amounts of 2k, and compound 1j
showed no reaction. A more detailed observation of the results in
Table 1
Stille cross-coupling of allyltributyltin and cis-cyclohexadienediols and derivatives
under conventional heating
Pd(PPh3)a4
SnBu3
1a-k
+
2a-k
THF
Entry
Reactant
(1a–k)
Temp
Time
(hs)
Product
(2a–k)
Yield
(%)
(°C)
I
OH
1
35
0.45
93
OH
OH
1a
Br
2a
2a
OH
OH
OH
2
3
Reflux
Reflux
8
20
OH
OH
1b
I
O
O
8
No reaction
O
O
1c
Br
2c
O
O
4
5
Reflux
8
3
No reaction
O
O
1d
2c
I
OAc
OAc
35
72
OAc
OAc
1e
2e
I
O
O
O
6
7
Reflux
Reflux
3
90
70
HO
HO
O
OH
1f
HO
HO
OH
OH
2f
Br
O
O
O
O
12
OH
1g
2f
Br
O
O
O
O
8
Reflux
Reflux
12
12
25
49
HO
HO
OH
1h
HO
HO
OH
OH
2h
Br
Table 2
O
O
Stille reaction of cis-diol 1b under various conditions
O
O
9
Br
OH
1i
OH
Pd catalyst
THF
SnBu3
2i
OH
OH
+
OH
Br
1b
2a
O
O
10
Reflux
Reflux
10
12
No reaction
O
O
Entry
Source of
heatinga
Pd catalyst
(mol %)
Temperature
(°C)
Time
(min)
Yield
O
1j
Br
O
2j
1
2
3
4
5
6
7
Oil bath
Pd(PPh3)4 (15%)
Pd(PPh3)4 (15%)
Pd(PPh3)4 (7%)
Pd(PPh3)4 (15%)
Pd(PPh3)4 (15%)
PdCl2(PPh3)2 (15%)
Pd(PPh3)4 (15%)
Reflux
90
90
480
5
5
10
6
6
20
15
7
38
42
12
13
Microwave
Microwave
Microwave
Microwave
Microwave
Microwave
O
O
11
Traces
90
O
O
100
100
120
O
O
O
O
2k
1k
6
a
a
Microwave reactions were carried out using 200 W power.
All reactions were carried out using 15 mol % of palladium catalyst.

V. Heguaburu et al. / Tetrahedron Letters 49 (2008) 6787–6790
6789
Table 1 (entries 7–9) shows that compounds 1g and 1i were con-
verted to the corresponding allyl derivatives in higher yields than
1h. These results outline the importance of the presence of an
allylic hydroxyl moiety at the coupling partner, specially when it
is arranged at the less hindered face, opposite to the isopropyli-
dene group.
Stille reactions were also conducted under microwave condi-
tions to study a possible improvement in the reaction rates and
yields. Reaction of 1b was studied in detail in order to define the
best conditions for microwave heating. Time, temperature, catalyst
and catalyst load were varied. These results are showed in Table 2.
Lowering the catalyst load affected the reaction course (entry 3).
The reaction yield can be improved by using a longer irradiation
time (entry 4), as well as raising the temperature to 100 °C (entry
5). However, at 120 °C the reaction yield decreased, probably due
to catalyst decomposition and formation of oxidative addition
products.24 When the catalyst was changed to PdCl2(PPh3)3, the
reaction did not work in a satisfactory manner (entry 6).
Once the reaction conditions for 1b were optimized, microwave
reactions were extended to a variety of derivatives. As shown in
Table 3, when the diol moiety was protected with isopropylidene
group (1c and d, entries 3 and 4) the expected product was ob-
tained in modest yields by microwave irradiation at higher tem-
peratures. In general, higher reaction times did not afford better
conversions. These preliminary results indicated that cross-cou-
pling can be significantly accelerated under microwave-assisted
conditions, but a finer tuning of the reaction parameters must be
performed in order to achieve higher yields.
Table 3
Stille cross-coupling of allyltributyltin and cis-cyclohexadienediols and derivatives
under microwave irradiation
Pd(PPh3)4
SnBu3
1a-j
+
2a-j
THF, μwa,b
In conclusion, Stille reaction has been successfully performed
with cis-dienediols and derivatives.25,26 These transformations
are promoted by oxygenated groups such as free hydroxyls or ace-
tates. Results obtained with polyoxygenated derivatives suggest an
assistance of the free allylic hydroxyl in the catalytic cycle. Also, it
is demonstrated that higher yields were obtained when the assist-
ing hydroxyl is placed at the less hindered face. However, if the diol
is protected with an isopropylidene group, the coordination to the
palladium species is more difficult due to steric restrictions and the
reaction did not take place under conventional heating. The use of
microwave irradiation improves reaction rates and yields in a sig-
nificant way for isopropylidene-protected cis-cyclohexadienediols,
in comparison with conventional heating.
Entry
Reactant (la–h)
Temp
(°C)
Time
(min)
Product (2a–h)
Yield (%)
I
OH
1
100
100
120
6
6
6
67
42
16
OH
OH
1a
OH 2a
Br
OH
2
3
OH
OH
1b
OH 2a
Stille cross-coupling proved to be a valuable tool to obtain prop-
er building blocks for the synthesis of chiral epoxyenones. Exten-
sion of this coupling protocol for the synthesis of natural
products of this type is currently under investigation and will be
reported in due course.
I
O
O
O
1c
O
2c
2c
Br
O
Acknowledgements
4
5
120
90
6
38
27
O
O
O
The authors are grateful to PEDECIBA (PNUD/URU/06/004) and
CSIC-UdelaR for financial support of this work. V.H. thanks PEDEC-
IBA and ANII for a doctoral fellowship. Research Grants from CNPq
and FAPESC (PRONEX-2003, Brazil) are also acknowledged. We are
also grateful to Diego Menesez and Dr. David González for helpful
discussions.
1d
I
OAc
10
OAc
OAc
OAc
1e
2e
Supplementary data
Br
O
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.09.049.
O
6
7
100
100
100
10
10
10
43
O
HO
HO
O
HO
HO
OH
Br
1g
1h
OH
OH
2f
References and notes
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2. Hudlicky, T.; Stabile, M.; Gibson, D. T.; Whited, G. M. Org. Synth. 1999, 76, 77–
85.
3. Hudlicky, T.; Gonzalez, D.; Gibson, D. T. Aldrichim. Acta 1999, 32, 35–61.
4. Johnson, R. A. Org. React. 2004, 63, 117–264.
O
O
O
O
21
OH
5. Boyd, D. R.; Hand, M. V.; Sharma, N. D.; Chimia, J.; Dalton, H.; Sheldrake, G. N. J.
Chem. Soc., Chem. Commun. 1991, 1630–1632.
2h
6. Boyd, D. R.; Sharma, N. D.; Byrne, B.; Hand, M. V.; Malone, J. F.; Sheldrake, G. N.;
Blacker, J.; Dalton, H. J. Chem. Soc., Perkin Trans.1 1998, 1935–1943.
7. Hudlicky, T.; Boros, E. Tetrahedron: Asymmetry 1992, 3, 217–220.
8. Ley, S.; Redgrave, A. J.; Taylor, S. T.; Ahmed, S.; Ribbons, D. W. Synlett 1991,
741–742.
9. Johnson, C. R.; Johns, B. A. J. Org. Chem. 1997, 62, 6046–6050.
10. Hudlicky, T.; Tian, X.; Konigsberg, K.; Rouden, J. J. Org. Chem. 1994, 59, 4037–
4039.
Br
O
O
8
No reaction
O
O
O
1j
O
2j
a
All reactions were carried out using 200 W power.
All reactions were carried out using 15 mol % of palladium catalyst.
11. Wendeborn, S.; De Mesmaeker, A.; Brill, W. K.; Berteina, S. Acc. Chem. Res. 2000,
33, 215–224.
b

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13. Gonzalez, D.; Schapiro, V.; Seoane, G.; Hudlicky, T. Tetrahedron: Asymmetry
1997, 8, 975–977.
14. Matveenko, M.; Banwell, M. G.; Willis, A. C. Tetrahedron 2008, 64, 4817–4826.
15. Bui, V. P.; Nguyen, M.; Hansen, J.; Baker, J.; Hudlicky, T. Can. J. Chem. 2002, 80,
708–713.
16. Schapiro, V.; Cavalli, G.; Seoane, G.; Faccio, R.; Mombrú, A. W. Tetrahedron:
Asymmetry 2002, 13, 2453–2459.
17. Labora, M.; Heguaburu, V.; Pandolfi, E.; Schapiro, V. Tetrahedron: Asymmetry
2008, 19, 893–895.
18. Larhed, M.; Moberg, C.; Hallberg, A. Acc. Chem. Res. 2002, 35, 717–727.
19. Fonseca, G.; Seoane, G. Tetrahedron: Asymmetry 2005, 16, 1393–1402.
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L.; Mariezcurrena, R. New J. Chem. 1999, 23, 549–556.
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microwave heating: To a solution of cis-dihydrodiol derivative (0.37 mmol)
and tetrakis(triphenylphosphine) palladium (0) (63 mg, 0.055 mmol) in
anhydrous THF (2 mL), allyltributyltin was added (0.12 mL, 0.40 mmol). The
mixture was irradiated in a microwave at 90–120 °C and 200 W for 5–10 min
in a sealed tube under a nitrogen atmosphere. Removal of the solvent and
purification by flash chromatography on silica gel (EtOAc/hexanes) gave the
cross-coupling product.
26. Spectral data for selected compounds: 2c: 1H NMR (CDCl3, 400 MHz) d 6.00 (dd,
J1 = 3.5 Hz, J2 = 9.8 Hz, 1H), 5.88 (m, 1H), 5.84 (dd, J1 = 4.4 Hz, J2 = 8.6 Hz, 1H),
5.76 (m, 1H), 5.17 (d, J = 1.7 Hz, 1H), 5.13 (m, 1H), 4.68 (dd, J1 = 3.9 Hz,
J2 = 8.6 Hz, 1H), 4.56 (d, J = 8.6 Hz, 1H), 3.00 (m, 2H), 1.43 (s, 3H), 1.42 (s, 3H)
ppm; Compound 2e: 1H NMR (CDCl3, 400 MHz)
d 6.10 (dt, J1 = 1.6 Hz,
J2 = 5.4 Hz, 1H), 5.94 (d, J = 5.3 Hz, 1H), 5.81 (m, 1H), 5.75 (dd, J1 = 3.0 Hz,
J2 = 10.0 Hz, 1H), 5.61 (m, 1H), 5.54 (d, J = 6.0 Hz, 1H), 5.14 (dd, J1 = 1.6 Hz,
J2 = 8.6 Hz, 1H), 5.10 (d, J = 1.3 Hz, 1H), 2.91 (d, J = 8.0 Hz, 2H), 2.08 (s, 3H), 2.07
(s, 3H) ppm; Compound 2f: 1H NMR (CDCl3, 400 MHz) d 5.84 (m, 1H), 5.62 (d,
J = 4.3 Hz, 1H), 5.16 (dd, J1 = 1.0 Hz, J2 = 6.7 Hz, 1H), 5.11 (d, J = 1.0 Hz, 1H), 4.55
(d, J = 5.9 Hz, 1H), 4.36 (t, J = 6.5 Hz, 1H), 4.30 (m, 1H), 3.93 (dd, J1 = 3.7 Hz,
J2 = 6.8 Hz, 1H), 2.97 (dd, J1 = 6.4 Hz, J2 = 16 Hz, 1H), 2.90 (dd, J1 = 7.5 Hz,
J2 = 16 Hz, 1H), 2.71 (br s, 2H), 1.44 (s, 3H), 1.40 (s, 3H) ppm; Compound 2h: 1
H
24. Grushin, V. V. Organometallics 2000, 19, 1888–1900.
25. The cis-dihydrodiol metabolites 1a–b were obtained using P. putida F39/D
under the biotransformation conditions previously reported.2 Compounds
1c–k were prepared according to previous reports.19–21 Conventional heating
reactions were performed according to Boyd’s protocol.5 Microwave reactions
NMR (CDCl3, 400 MHz) d 5.85 (m, 1H), 5.59 (s, 1H), 5.15 (dd, J1 = 1.4 Hz,
J2 = 4.9 Hz, 1H), 5.12 (s, 1H), 4.53 (d, J = 6.4 Hz, 1H), 4.08 (m, 2H) 3.60 (t,
J = 8.4 Hz, 1H), 2.96 (dd, J1 = 6.2 Hz, J2 = 16 Hz, 1H), 2.90 (dd, J1 = 7.6 Hz,
J2 = 16 Hz, 1H), 1.52 (s, 3H), 1.41 (s, 3H) ppm; Compound 2i: 1H NMR (CDCl3,
400 MHz) d 5.80 (m, 1H), 5.50 (d, J = 1.4 Hz, 1H), 5.14 (m, 1H), 5.10 (s, 1H), 4.53
(m, 2H), 4.39 (m, 1H), 3.60 (ddd, J1 = 1.2 Hz, J2 = 2.5 Hz, J2 = 7.7 Hz, 1H), 2.90 (m,
1H), 2.74 (d, J = 7.1 Hz, 1H), 2.55 (d, J = 4.4 Hz, 1H), 1.43 (s, 3H), 1.36 (s, 3H)
ppm.
were performed in
a commercially available monomode reactor (CEM
Explorer). Reactions were carried out in 10 mL Pyrex vials sealed with septa
and using magnetic stirring. General procedure for Stille reaction using