A solid-phase version of the palladium-catalyzed carbonyl allylation by allylic alcohols with SnCl2

Article abstract of DOI:10.1016/S0040-4039(01)00434-8

A solid-phase version of the palladium-catalyzed carbonyl allylation of aldehydes by allylic alcohols is described. Preliminary studies have been carried out with resin bound aldehydes 1a-c and different allylic alcohols. Solvent effects as well as the regio- and diastereoselectivity of our solid-phase conditions are compared with solution-phase protocols.

Full text of DOI:10.1016/S0040-4039(01)00434-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3299–3302
A solid-phase version of the palladium-catalyzed carbonyl
allylation by allylic alcohols with SnCl2
a,b
b
a,b,
Lydia Carde, Amadeu Llebaria and Antonio Delgado
*
a
Universitat de Barcelona, Facultat de Farm a` cia, Unitat de Qu ´ı mica Farmac e` utica, Avgda. Joan XXIII, s/n,
8028 Barcelona, Spain
Departament de Qu ´ı mica Org a` nica Biol o` gica,
0
b
Institut d’Investigacions Qu ´ı miques i Ambientals de Barcelona (I.I.Q.A.B.-C.S.I.C), Jordi Girona 18-26, 08034 Barcelona, Spain
Received 3 March 2001; revised 12 March 2001; accepted 14 March 2001
Abstract—A solid-phase version of the palladium-catalyzed carbonyl allylation of aldehydes by allylic alcohols is described.
Preliminary studies have been carried out with resin bound aldehydes 1a–c and different allylic alcohols. Solvent effects as well
as the regio- and diastereoselectivity of our solid-phase conditions are compared with solution-phase protocols. © 2001 Elsevier
Science Ltd. All rights reserved.
The allylation of aldehydes to give homoallylic alcohols
is a well-precedented synthetic transformation. Car-
temperature for 24 h under non-inert conditions (Table
1). Condensations on the solid support were monitored
by IR and were judged to be complete after disappear-
1
bonyl allylation via an umpolung of p-allylpalladium
−
1
complexes has been extensively studied over recent
ance of the aldehyde CꢀH stretching band at 2385 cm .
After a thorough study of some of the reaction parame-
ters (solvent, temperature and stoichiometry of allyl
alcohol, palladium catalyst, SnCl and H O), the best
2
years. In particular, palladium-catalyzed carbonyl ally-
3
lation by allylic alcohols with SnCl2 is especially
attractive for combinatorial chemistry due to the wide
range of commercially available allylic alcohols and
aldehydes as well as for synthetic versatility of the
resulting adducts. In this context, we wish to report our
results on the palladium-catalyzed allylation of resin-
2
2
conditions were those indicated in entry 7. Addition of
H O had no significant effects (compare entries 7 and
2
8), whereas an increase of the reaction temperature was
detrimental (entries 4 and 5). Shorter reaction times (5
h) proved equally effective under these optimized condi-
4
bound aldehydes 1a–c by allylic alcohols 2a–l with
5
SnCl to give homoallylic alcohols 3–11 after reductive
tions. Homoallylic alcohol 3 was also obtained from
2
cleavage from the resin (Scheme 1).
the more expensive resin 1b in 89% yield (entry 10) and
from resin 1c in less than 50% yield (entry 11). In the
light of these results, resin 1a was chosen for further
reaction development.
Preliminary experiments were carried out from allyl
alcohol (2a) and resin-bound aldehydes 1a–c at room
R2
R1
OH
O
R2
OH R2
OH
DIBAL, toluene
-78ºC to 0ºC
2
a-l
R3
R3
R3
H
O
R1
HO
R1
O
X
cat. Pd(0), SnCl2
X
O
O
O
1a-c
1a'-c'
3-11
(Merrifield)
(Wang)
(TentaGel S PHB)
1a, 1a': X=
1b, 1b': X=
1c, 1c': X=
PEG
O
Scheme 1.
*
Corresponding author. E-mail: adelgado@far.ub.es, adcqob@cid.csic.es
0
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00434-8

3
300
L. Carde et al. / Tetrahedron Letters 42 (2001) 3299–3302
a
Table 1. Condensation-cleavage of 2a with resin-bound aldehydes 1a–c to give 3
SnCl2 (equiv.)b
PdCl (PhCN) (equiv.)b
Alcohol (equiv.)b
H O (equiv.)b
Solvent
Yield (%)
c
Entry
Resin
2
2
2
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
6
6
6
6
6
0.04
0.04
0.04
0.04
0.04
0.04
0.06
0.06
0.06
0.06
0.06
3
3
3
3
3
3
7
7
7
7
7
0
0
0
0
0
0
0
100
DMF
THF
THF
THF
THF
THF
THF
THF
DMSO
THF
THF
23
38
38
25
13
45
78
75
61
89
41
d
e
9
21
21
21
21
21
0
0
0
1
0
1
1
a
b
c
Reactions were carried out at room temperature unless otherwise mentioned.
Number of equivalents relative to the resin.
Isolated yield of 3 after cleavage from the resin.
The reaction was carried out at 40°C.
d
e
The reaction was carried out at 80°C.
Table 2. Allylation–cleavage of resin-bound aldehyde 1a with allylic alcohols (see Scheme 1)
R3
OH R2
R1
OH
OH
R1
OH
R3
R3
R2
R2
R2
R1
HO
R1
HO
1
2
3
2
2
2
2
2
2
2
a: R =R =R =H
1
2
3
1
2
3
1
3
2
b: R =CH3; R =R =H
2c: R =R =H; R =CH3
1
2
6: R =R =H; R =CH
3
3
4
5
7
: R =R =H;
1
2
3
1
2
3
1
2
d: R =Et; R =R =H
2g: R =H; R =R =CH3
1
2
8: R =Ph; R =H
: R =CH3; R =H
1
2
3
1
2
3
e: R =R =H; R =CH3
2i: R =R =H; R =Ph
1
2
1
3
2
: R =Et; R =H;
2
9: R =R =H; R =SO Ph
1
2
3
f: R =R =CH3; R =H
2k: R1=Ph; R2=CH3; R3=H
2l: R1=CH3; R2=Ph; R3=H
1
2
1
3
: R =R =CH3
1
0: R =Ph; R =CH3 (γ adduct)
1
2
3
h: R =Ph; R =R =H
1
3
1
1: R =CH3; R =Ph (α adduct)
syn/antic
1
2
3
j: R =R =H; R =SO2Ph
a
Productb
Yieldd
Entry
Alcohol
Solvent/(H O)
2
1
2
3
4
5
6
7
8
9
2a
2b
2b
2b
2b
2b
2c
2d
2e
2f
THF/(0)
THF/(0)
3
4
4
4
4
4
4
5
6
7
7
7
8
8
8
8
–
78
78
77
78
35
31
72
75
89
80
80
70
75
65
41
40
68
77
72
75
67
67
75
60
30:70
28:72
38:62
60:40
20:80
33:67
20:80
–
THF/(25)
THF/(75)
DMSO/(0)
DMSO/(200)
THF/(0)
THF/(0)
THF/(0)
THF/(0)
THF/(25)
THF/(0)
THF/(0)
THF/(0)
DMSO/(200)
DMSO/(0)
THF/(0)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
–
–
–
2f
2g
2h
2i
2i
2i
0:100
0:100
0:100
50:50
–
40:60 )
35:65
60:40
18:82
2j
9
e
f
2k
2k
2k
2k
2l
2l
2l
THF/(0)
10/11
10/11
10/11
10
10/11
10/11
10
g
h
f
THF/(200)
DMSO/(0)
DMSO/(200)
THF/(200)
DMSO/(0)
DMSO/(200)
f
g
f
35:65
65:35
20:80
h
f
a
b
c
Equivalents of H O relative to the resin.
2
See Ref. 5.
Determined by 1H NMR.
Isolated yield.
d
e
Ratio 10/11: 75/25.
syn/anti ratio for compound 10.
Ratio 10/11: 95/5.
f
g
h
Ratio 10/11: 80/20.

L. Carde et al. / Tetrahedron Letters 42 (2001) 3299–3302
3301
Cleavage with DIBAL in toluene at low temperature
Tetrahedron 1998, 54, 14999–15016. Resin 1b: Wang resin
(Rapp polymer, 0.98 mmol/g, 4 g) was suspended in
CH Cl /DMF (9:1, 60 mL). In a separate flask 1-hydroxy-
afforded homoallylic alcohol 3 in good overall yields
6
(
Table 2, entry 1). This allylation–cleavage sequence
2
2
was succesfully applied to a series of allylic alcohols
benzotriazole (HOBt) (1.6 g, 12 mmol) was added to a
solution of 4-carboxybenzaldehyde (1.80 g, 12 mmol) and
dissolved in the minimum amount of DMF (2 mL). The
mixture was stirred until all the HOBt was dissolved and
then added to the resin. N,N%-Diisopropylcarbodiimide
(1.5 g, 12 mmol) and 4-dimethylaminopyridine (58 mg,
0.48 mmol) were added to the resin and the mixture was
agitated for 3 h at room temperature. Acetic anhydride (1
mL, 9.6 mmol) and pyridine (0.85 mL, 9.6 mmol) were
added to the reaction flask and agitated for additional 30
min at room temperature. After filtration, the resin was
washed thoroughly (DMF, DMF/H O (1:1), MeOH/H O
7
2a–l to give compounds 3–11, as indicated in Table 1.
Our best results in solid phase are comparable in terms
of yields and diastereoselectivities with those described
3
in solution by Masuyama et al. Thus, the predomi-
nance of anti adducts in THF, THF–H O and DMSO–
2
H O and the reversal to syn adducts in DMSO (with no
2
H O added) (entries 5, 16, 20 and 23) is consistent with
2
a change from a ‘six-membered cyclic’ to an ‘open-
chain’ transition state, as postulated for the same pro-
3
cess in solution. Similarly, equilibration of the
2
2
transient p-allylpalladium intermediates seems to take
place, as evidenced by the similar reaction outcome
observed from some pairs of isomeric alcohols under
identical reaction conditions (compare entries 2 with 7,
(1:1), MeOH and THF) and dried under vacuum to give
1b (4.45 g, 0.85 mmol/g). Following the same procedure,
Tentagel resin (5 g, 0.23 mmol/g) afforded resin 1c (5 g,
0.21 mmol/g). For an alternative synthesis of 1b, see:
Sarshar, S.; Siev, D.; Mjalli, A. Tetrahedron Lett. 1996, 37,
835–838.
1
3 with 14 and 19 with 22). However, higher regiocon-
trol on the allylation of terminally substituted p-allyl-
palladium species arising from allylic alcohols 2b–d,
5. Typical procedure for allylation–cleavage of 1a: Resin 1a
2
f–i and 2k,l is observed on solid support in compari-
(0.98 mmol/g, 200 mg) was suspended in THF (2 mL) and
3
a
−3
son with solution protocols. Thus, g adducts are the
SnCl (780 mg, 4.12 mmol), prop-2-en-1-ol (2a) (93×10
2
only (4, 5, 7, 8) or the major (10) adducts found under
mL, 1.37 mmol) and PdCl (PhCN) (4.5 mg, 0.012 mmol)
2
8
our solid-phase conditions (see Table 1).
were added to the solution. The reaction was agitated for
5
h at room temperature and the resin was filtered, washed
In summary, a new and efficient protocol for the allyla-
tion of resin-bound aldehydes with allylic alcohols
under mild conditions is reported. Further work to
widen the scope of this process to other aldehydes and
linkers is currently underway and will be reported in
due course.
(THF, THF/H O (1:1), MeOH/H O (1:1), MeOH and
2
2
toluene) and dried under vacuum to give the allylated resin
1
2
3
1a% (R =R =R =H, see Scheme 1, 208 mg, 0.94 mmol/
g). To a suspension, this resin (210 mg) in toluene (2 mL)
at −78°C under N , was added dropwise a solution of
2
DIBAL (1 M in hexane, 1.2 mL) and the mixture was
stirred for 6 h. The reaction was quenched with H O (2
2
®
mL) and filtered over a pad of Celite . The resulting
Acknowledgements
filtrate was evaporated to half volume and extracted with
EtOAc (3×10 mL) and the combined organic extracts were
dried over Na SO and evaporated under vacuum. Purifi-
This work was supported by grants from the European
Union (contract FMRXCT98-0235). Financial support
from Direcci o´ n General de Ense n˜ anza Superior, Minis-
terio de Educaci o´ n y Cultura (PB97-1171), and Comis-
sionat per a Universitats i Recerca, Generalitat de
2
4
cation by column chromatography (silica gel, hexane/
EtOAc (8:2)) led to alcohol 3 as a colorless liquid (28 mg,
81% based on the theoretical loading of the allylated resin
1a%); IR (film): 3373, 1642, 1512, 1218, 1040, 1009, 756
−
1 1
Catalunya
(Projects
1999SGR00080
and
cm . H NMR (CDCl ): l 7.32 (s, 4H, Ph); 5.68–5.89 (m,
3
1999SGR00187) is gratefully acknowledged.
1H, CHꢁCH ); 5.10–5.19 (m, 2H, CHꢁCH ); 4.72 (t, J=9,
2
2
1
2
H, CHOH); 4.64 (s, 2H, CH OH); 2.45–2.52 (t, J=10,
2
13
H, CH CHOH); 2.29 (br, 1H, OH), 2.1 (br, 1H, OH).
C
2
References
NMR (CDCl ): 143.3 (C, Ph); 140.2 (C, Ph); 134.4
3
(
CHꢁCH ); 127.1 (2×CH, Ph); 126 (2×CH, Ph); 118.4
2
1
. Hoppe, D. In Houben-Weyl; Methods of Organic Chem-
istry; Helmchen, G.; Hoffmann, R. W.; Mulzer, J.; Schau-
mann, E., Eds.; Thieme: New York, 1996; Vol. E21, pp.
(CHꢁCH ); 73.1 (CHOH); 64.8 (CH OH); 43.7 (CH ).
2
2
2
This protocol was also used for allylic alcohols 2b–l to give
alcohols 4–11 (Table 2). Selected spectroscopic data:
Compound 4 (mixture of syn and anti isomers): Colorless
liquid. IR (film): 3375, 1639, 1512, 1220, 1043, 1007, 755
1357–1602.
2
3
. Tamaru, Y. J. Organomet. Chem. 1999, 576, 215–231 and
references cited therein.
−
1 1
cm . H NMR (CDCl , 300 MHz): l 7.28–7.32 (m, 4H,
3
. (a) Takahara, J. P.; Masuyama, Y.; Kurusu, Y. J. Am.
Chem. Soc. 1992, 114, 2577–2586; (b) Masuyama, Y. In
Advances in Metal Organic Chemistry; Liebeskind, L., Ed.;
Jai Press: Greenwich, 1994; Vol. 3, pp. 255–303.
. Resins 1a–c were prepared from commercially available
Merrifield, Wang or Tentagel S PHB resins, respectively
Ph); 5.65–5.88 (m, 1H, CHꢁCH ); 4.92–5.23 (m, 2H,
2
CHꢁCH ); 4.66 (s, 2H, CH OH); 4.60 (d, J=8.4, 1H,
2
2
CHOH syn); 4.35 (d, J=11.4, 1H, CHOH anti); 2.38–
2.63 (m, 1H, CHCH ); 2.19 (br, 1H, OH), 2.1 (br, 1H,
3
4
OH); 1.0 (d, J=10.2, 3H, CH syn); 0.85 (d, J=10.2, 3H,
3
13
CH3 syn). C NMR (CDCl ): 142.7, 142.5, 141.2 and
3
(
Rapp Polymer), and 4-carboxybenzaldehyde. Resin 1a
140.2 (C, Ph); 139.8 and 138.7 (CHꢁCH ); 127.8 (2×CH,
2
was prepared as described in: Gennari, C.; Ceccarelli, S.;
Piarulli, U.; Aboutayab, K.; Donghi, M.; Paterson, I.
Ph); 126.8 (2×CH, Ph); 115.3 and 116.5 (CHꢁCH ); 76.9
2
and 75.9 (CHOH); 65.3 (CH OH); 46.5 (CH, anti); 44.9
2

3
302
L. Carde et al. / Tetrahedron Letters 42 (2001) 3299–3302
(
CH, syn); 16.8 (CH anti); 14.2 (CH syn).
5.8–6.30 (m, 1H, CHꢁCH(CH )); 5.30–5.60 (m, 1H,
3
3
3
Compound 5 (mixture of syn and anti isomers): Colorless
liquid. IR (film): 3373, 1636, 1512, 1220, 1045, 1002, 753
CHꢁCH(CH )); 4.69 (d, J=5, 1H, CHOH syn); 4.66 (s,
3
2H, CH OH); 4.59 (d, J=7, 1H, CHOH anti); 3.4–4.0 (m,
2
−
1 1
cm . H NMR (CDCl , 200 MHz): l 7.26–7.32 (m, 4H,
1H, CHPh); 2.20 (br, 1H, OH), 1.7 (dd, J=7.5 and 2.1,
3
Ph); 5.39–5.74 (m, 1H, CHꢁCH ); 4.96–5.30 (m, 2H,
3H, CH ); 1.6 (br, 1H, OH).
2
3
CHꢁCH ); 4.67 (s, 2H, CH OH); 4.62 (d, J=9, 1H,
2
2
Compound 11 (mixture of syn and anti isomers): Yellow
CHOH syn); 4.35 (d, J=12, 1H, CHOH anti); 2.11–2.43
m, 1H, CHCH ); 1.91 (br, 1H, OH), 1.68 (br, 1H, OH);
1
oil. H NMR (CDCl , 200 MHz): l 7.17–7.44 (m, 9H, Ph);
3
(
2
6.35–6.55 (m, 1H, CHꢁ); 6.10–5.20 (m, 1H, CHꢁ); 4.71 (d,
J=4.5, 1H, CHOH syn); 4.67 (s, 2H, CH OH); 4.52 (d,
J=7, 1H, CHOH anti); 2.65–2.78 (m, 1H, CHCH ); 2.15
(br, 1H, OH); 1.6 (br, 1H, OH); 0.95–1.12 (m, 3H, CH3).
1
.13–1.29 (m, 2H, CH ); 0.75–0.89 (m, 3H, CH ).
2 3
1
2
Compound 6: Yellow oil. H NMR (CDCl , 200 MHz): l
3
3
7
.3–7.4 (m, 4H, Ph); 4.84–4.78 (m, 3H, C(CH )ꢁCH and
3
2
CHOH); 4.67 (s, 2H, CH OH); 2.4 (d, J=9, 2H, CH );
2
2
6
. Optimum cleavage conditions of the ester linker of resins
2
.10 (br, 1H, OH), 1.87 (br, 1H, OH); 1.8 (s, 3H,CH ).
3
1
a–c and 1a%–c% were necessary in order to evaluate the
resin loading as well as the yield on homoallylic alcohols
–11. Attempts to cleave resin–aldehyde 1a in anhydrous
1
Compound 7: Yellow oil. H NMR (CDCl , 300 MHz): l
3
7.32 (s, 4H, Ph); 5.84–5.98 (dd, J=26, 16.2, 1H,
3
CHꢁCH ); 5.03–5.17 (m, 2H, CHꢁCH ); 4.67 (s, 2H,
2
2
MeOH–THF generated a mixture of the corresponding
ester and acid, whereas cleavage with NaOH in dioxane
led to decomposition. The ester linkage was conveniently
reduced with DIBAL in toluene, as described in Ref. 5.
Thus, resin 1a afforded 4-hydroxymethylbenzaldehyde in
good yield (95% based on the theoretical loading of resin).
. Allylic alcohols 2a–2i were commercially available. Allylic
alcohol 2j was synthesized following a described procedure
CH OH); 4.43 (s, 1H, CHOH); 2.17 (br, 1H, OH), 1.85
2
13
(
br, 1H, OH); 1.0 (s, 3H,CH ); 0.95 (s, 3H, CH ). C
3
3
NMR (CDCl ): 145 (CHꢁCH ); 140.2 (C, Ph); 139.9 (C,
3
2
Ph); 127.9 (2×CH, Ph); 126.2 (2×CH, Ph); 113.9
(
(
CHꢁCH ); 80.4 (CHOH); 65.1 (CH OH); 29.7 (C); 24.4
2
2
CH ); 20.9 (CH ).
3
3
7
Compound 8 (anti isomer): Colorless liquid. IR (film):
−
1
1
3
381, 1641, 1515, 1223, 1045, 1005, 753 cm . H NMR
(
4
Carpino, L. A.; Philbin, M. J. Org. Chem. 1999, 64,
315–4323); alcohol 2k was obtained by DIBAL reduction
(
CDCl , 200 MHz): l 7.07–7.32 (m, 9H, Ph); 6.15–6.38 (m,
3
1
H, CHꢁCH ); 5.17–5.35 (m, 2H, CHꢁCH ); 4.85 (d,
2
2
of commercially available benzylideneacetone as described
in: Kim, S.; Ahn, H. J. Org. Chem. 1984, 49, 1717–1724.
Alcohol 2l was synthesized following a described proce-
dure (Brown, C. D.; Chong, J. M.; Shen, L. Tetrahedron
1999, 55, 14233–14242).
J=12, 1H, CHOH); 4.62 (s, 2H, CH OH); 3.50 (t, J=12,
2
1
H, CHPh); 2.27 (br, 1H, OH), 1.95 (br, 1H, OH).
1
Compound 9: Yellow oil. H NMR (CDCl , 200 MHz): l
3
7
1
.5–7.68 (m, 9H, Ph); 6.17 (s, 1H, CHꢁ trans SO ); 5.88 (s,
2
H, CHꢁ cis SO ); 5.34 (m, 1H, CHOH); 4.60 (s, 2H,
2
CH OH); 2.40 (d, J=6.1, 2H, CH ); 2.20 (br, 1H, OH);
8. The presence of H O has been described as being crucial
2
2
2
1.8 (br, 1H, OH).
for the regiochemical outcome of the allylation of ben-
Compound 10 (mixture of syn and anti isomers): Yellow
zaldehyde with 2b in THF. Ratios syn/anti/a: 22/25/53
1
oil. H NMR (CDCl , 200 MHz): l 7.12–7.30 (m, 9H, Ph);
(THF); 17/83/0 (THF–H O, 25 mmol) (see Ref. 3a).
3
2
.
.