Reaction of allylic and benzylic alcohols and esters with PPh 3/I2: One-pot synthesis of β,γ-unsaturated compounds

Article abstract of DOI:10.1016/j.tetlet.2005.03.132

The treatment of tertiary and secondary allylic alcohols containing a terminal double bond, and their acetyl derivatives, with triphenylphosphine and iodine under mild conditions leads regiospecifically and in high stereoselectivity to the corresponding primary allylic iodides, which can react 'in situ' with diverse nucleophiles. Primary allylic alcohols and benzyl alcohols and acetates are also transformed into the corresponding iodides under these conditions.

Full text of DOI:10.1016/j.tetlet.2005.03.132

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3755–3759
Reaction of allylic and benzylic alcohols and esters with
PPh /I : one-pot synthesis of b,c-unsaturated compounds
3
2
a,
E. J. Alvarez-Manzaneda, R. Chahboun, E. Cabrera Torres, E. Alvarez,
a
a
a
*
b
R. Alvarez-Manzaneda, A. Haidour and J. M. Ramos L o´ pez
a
a
a
Departamento de Qu ı´ mica Org a´ nica, Facultad de Ciencias, Instituto de Biotecnolog ı´ a, Universidad de Granada, 18071 Granada, Spain
b
Departamento de Qu ı´ mica Org a´ nica, Facultad de Ciencias, Universidad de Almer ı´ a, 04120 Almer ı´ a, Spain
Received 22 December 2004; revised 15 March 2005; accepted 21 March 2005
Available online 6 April 2005
Abstract—The treatment of tertiary and secondary allylic alcohols containing a terminal double bond, and their acetyl derivatives,
with triphenylphosphine and iodine under mild conditions leads regiospecifically and in high stereoselectivity to the corresponding
primary allylic iodides, which can react Ôin situÕ with diverse nucleophiles. Primary allylic alcohols and benzyl alcohols and acetates
are also transformed into the corresponding iodides under these conditions.
ꢀ
2005 Elsevier Ltd. All rights reserved.
1
. Introduction
storage. Because of this it would be advisable to prepare
allylic iodides under reaction conditions which enable
further synthesis in the same reaction vessel.
Allylic halides are versatile starting materials that are
widely used in synthetic organic chemistry. They are
usually prepared from the corresponding allylic alcohols
by the action of a great variety of reagents. Chlorides
Continuing our research into the development of new
synthetic methodologies and the utilization of the tri-
1
11
have been prepared utilizing chlorohydric acid, thionyl
2
phenylphosphine–iodine system,
behaviour of allylic alcohols against this reagent.
we studied the
3
4
chloride, titanium(IV) chloride, N-chlorosuccinimide
5
or chloromethylsilanes. Bromides are frequently syn-
6
thesized using phosphorous tribromide or bromohydric
7
Our investigation started with tertiary alcohols having a
terminal double bond, which are an important type of
allylic alcohols due to their presence in the structure of
many natural products. Linalool (1a), trans-nerolidol
acid. Some examples of preparation of iodides have
8
9
also been reported utilizing P I , magnesium iodide
2
4
1
0
or trimethylsilyl iodide.
(
2a), geranyl–linalool (3a) and alcohols 4a and 5a were
Allylic iodides are particularly interesting synthetic
intermediates. Their high reactivity makes them very
useful reagents, but this feature frequently becomes an
important drawback due to rapid decomposition during
treated with triphenylphosphine and iodine in dichloro-
methane affording in good yields the corresponding
E-allyl iodides 12–16, which were characterized by H
1
NMR after immediate flash column chromatography,
Ph
P
Ph
O
Ph
I
OH
-
HI
-Ph PO
3
+
Ph P-I
I
3
R
R
R
I
I
II
Scheme 1.
Keywords: Allylic alcohols; Allylic esters; Benzylic alcohols; Benzylic esters; Allyl iodides; Triphenylphosphine; Iodine.
*
Corresponding author. Tel./fax: +34 958 24 80 89; e-mail: eamr@ugr.es
0
040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.132

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E. J. Alvarez-Manzaneda et al. / Tetrahedron Letters 46 (2005) 3755–3759
Table 1. Reaction of allylic and benzylic alcohols and acetates with PPh
3
–I
2
and some nucleophiles
Nucleophile
Entry
1
Substrate
Time
Iodide (%)
Time
Product (%)
R
I
OR
1a R: H
1b R: Ac
0.5 h
13 h
12 (90)
(94)
NaSO
NaCN
NaN
K phthalimide
2
Ph
12 h
24 h
22 h
10 h
23a R: SO
23b R: CN (86)
23c R: N (82)
23d R: N-phthal (88)
2
Ph (84)
3
3
I
OR
2
2
a R: H
1.0 h
13 h
13 (94)
(96)
2
b R: Ac
I
OR
3
3
a R: H
1.0 h
11 h
14 (92)
(94)
3
b R: Ac
I
OR
4
COOMe
COOMe
4
a R: H
1.5 h
14 h
15 (95)
(97)
4
b R: Ac
5
I
OH
OR
5
a R: H
1.0 h
10 h
16 (96)
(98)
5
b R: Ac
I
R
6
OR
1
4
6
6
a R: H
b R: Ac
8 h
Complex mixture
NaSO
NaCN
NaN
K phthalimide
2
Ph
12 h
24 h
22 h
10 h
24a R: SO
2
Ph (78)
14
14
17 (92)
24b R: CN (73)
14
3
3
24c R: N (75)
14
24d R: N-phthal (85)

E. J. Alvarez-Manzaneda et al. / Tetrahedron Letters 46 (2005) 3755–3759
3757
Table 1 (continued)
Entry
Substrate
Time
Iodide (%)
Nucleophile
Time
Product (%)
7
I
OR
14
7
7
a R: H
b R: Ac
0.5 h
3 days
18 (96)
(90)
8
I
OR
8
a R: H
1.0 h
3 days
19 (92)
(87)
8
b R: Ac
9
OR
OR
I
9
a R: H
2.0 h
3 days
20 (88)
(Starting material)
9
b R: Ac
I
10
1
0a R: H
1.0 h
3 days
21 (90)
(86)
1
0b R: Ac
OR
I
11
MeO
MeO
1
1a R: H
1.0 h
2 days
22 (98)
(92)
1
1b R: Ac
as the main stereoisomers. Compounds 1a–3a, which
consist of a 1:1 mixture of epimers, gave a E/Z mixture
of allyl iodides in an approximate 4:1 ratio. Compounds
6b into 17 enables a very short synthesis of the above
mentioned terpenic acid from (ꢀ)-sclareol (6a).
4
a–5a, which are pure diastereoisomers, gave exclusively
Secondary and primary allylic alcohols, as well as their
acetyl derivatives, were also investigated. The secondary
alcohols 7a–8a, which consist of a mixture of epimers,
led to the corresponding E-ally iodides 18–19 in good
yields; the acetyl derivatives 7b–8b gave similar results
after prolonged reaction time. The primary alcohol 9a
was also transformed into iodide 20; however, its acetyl
derivative 9b remained unaltered after 3 days under the
same reaction conditions.
the E derivative, with simultaneous exocyclic double
bond isomerization. Sclareol (6a), under the same reac-
tion conditions, led to a complex mixture. This reaction
does not take place under CoreyÕs iodination conditions
(
triphenylphosphine–iodine–imidazole in acetonitrile–
1
2
water).
In view of the parallelism observed in the behaviour of
tertiary alcohols and their acetyl derivatives against the
PPh –I system, tertiary allyl acetates were also investi-
3
gated. Compounds 1b–5b, having the same stereochemis-
try as related alcohols 1a–5a, afforded similar results. It
should be emphasized that whereas sclareol (6a) gave a
complex mixture, its diacetyl derivative 6b was converted
into the E-allyl iodide 17; the related bromide was con-
1
1
A possible mechanism consistent with these results is
depicted in Scheme 1. The rearranged iodide could be
formed through the intermediate II, which results from
nucleophilic attack of the hydroxyl group on the phos-
phonium iodide I. In the case of acetyl derivatives, the
complexation of carbonyl oxygen with the phosphonium
iodide would allow the departure of the acetate group
2
1
3
verted into (+)-subersic acid, thus the conversion of

3758
E. J. Alvarez-Manzaneda et al. / Tetrahedron Letters 46 (2005) 3755–3759
previous to the nucleophilic attack of iodide anion; this
process is favoured when substitution on the carbon
bearing the oxygenated group is increased, which ex-
plains the high reactivity of tertiary esters and the lack
of reactivity of primary derivatives.
References and notes
1. Vani, P. V.; Chida, A. S.; Srinivasan, R.; Chandrasekha-
ram, M.; Singh, A. K. Synth. Commun. 2001, 31, 219–
2
. Jo, H.; Lee, J.; Kim, H.; Kim, S.; Kim, D. Tetrahedron
Lett. 2003, 44, 7043–7044.
. Takashi, T.; Furutani, A.; Seko, S.; PCT Int. Appl.
000061530.
. Xu, L.-H.; Kuendig, E. P. Helv. Chim. Acta 1994, 77,
480–1484.
24.
2
3
4
The above allyl iodides can be reacted Ôin situÕ with some
nucleophiles, by adding a solution of these in dimethyl-
sulfoxide, affording the corresponding b,c-unsaturated
compounds. Iodides 12 and 17 and sodium benzenesulf-
inate, sodium cyanide, sodium azide and potassium
phthalimide, as nucleophiles, were essayed.
2
1
5. Labrouillere, M.; Le Roux, C.; Gaspard-Iloughmane, H.;
Dubac, J. Synlett 1994, 723–724.
6
7
8
9
. Lambertin, F.; Taran, M.; Delmond, B. Tetrahedron 2002,
8, 6925–6930.
. Borowiecki, L.; Welniak, M. Pol. J. Chem. 1989, 63, 149–
56.
. Lasne, M. C.; Cairon, P.; Villemin, D. Synth. Commun.
990, 20(1), 41–44.
5
The triphenylphosphine–iodine system was also essayed
with benzyl alcohols and acetates (entries 10 and 11),
which also afforded the corresponding iodides. As can
be seen in Table 1, acetates required prolonged reaction
times.
1
1
. Garc ´ı a Mart ´ı nez, A.; Cruces Villalobos, A.; Oliver Ruiz,
M. Synthesis 1988, 58–60.
1
0. Kanai, T.; Irifune, S.; Ishii, Y.; Ogawa, M. Synthesis 1989,
283–286.
2
. Experimental
.1. Synthesis of allyl iodides
To a solution of PPh (3.3 mmol) in CH Cl (10 mL),
1
1. (a) Alvarez-Manzaneda, E. J.; Chahboun, R.; Cabrera
Torres, E.; Alvarez, E.; Alvarez-Manzaneda, R.; Haidour,
A.; Ramos, J. Tetrahedron Lett. 2004, 45, 4453–4455; (b)
Alvarez-Manzaneda, E. J.; Chahboun, R.; Cabrera Tor-
res, E.; Alvarez, E.; Alvarez-Manzaneda, R.; Haidour, A.;
Ramos, J. Tetrahedron Lett. 2005, 46, 1075–1077.
2. Corey, E. J.; Pyne, S. G.; Su, W. Tetrahedron Lett. 1983,
24, 4883–4886.
3. Basabe, P.; Diego, A.; Delgado, S.; Diez, D.; Marcos, I. S.;
Urones, J. G. Tetrahedron 2003, 59, 9173–9177.
2
3
2
2
resublimed iodine (3.3 mmol) was added and the mix-
ture was stirred at room temperature for 5 min. Then,
a solution of alcohol/acetate (3.2 mmol) in CH Cl
1
1
2
2
(
5 mL) was added and the mixture was further stirred
for the specified time. Then, it was diluted with ether
15 mL) and successively washed with aq 5% NaHCO3
and brine, dried over anhyd Na SO and evaporated
(
14. All new compounds were fully characterized spectroscop-
ically and had satisfactory high resolution mass spectros-
copy data. Selected data:
2
4
to give a crude which, after flash chromatography (hex-
ane), afforded the corresponding iodide.
1
Compound 17: H NMR (CDCl
J = 8.3 Hz, 1H), 3.92 (d, J = 8.3 Hz, 2H), 1.66 (s, 3H), 1.54
(
3
, 400 MHz): d 5.53 (t,
1
3
s, 3H), 0.91 (s, 3H), 0.86 (s, 3H), 0.80 (s, 3H). C NMR
CDCl , 100 MHz): d 40.4 (C-1), 19.1 (C-2), 41.8 (C-3),
3.2 (C-4), 51.9 (C-5), 19.1 (C-6), 37.1 (C-7), 126.3 (C-8),
43.4 (C-9), 39.1 (C-10), 26.4 (C-11), 33.7 (C-12), 139.9 (C-
3), 121.3 (C-14), 4.3 (C-15), 20.2* (C-16), 19.6* (C-17),
3.4 (C-18), 21.7 (C-19), 15.9 (C-20). (*Interchangeable
2
.2. ‘In situ’ reaction with nucleophiles
(
3
3
1
1
3
DMSO (3 mL) was added to the above reaction mixture
under stirring, and then a solution of the nucleophilic
reagent (4.8 mmol) in DMSO (5 mL). The stirring was
continued at room temperature for the specified time,
and then the mixture was diluted with ether (20 mL)
signals.)
Compound 18: H NMR (CDCl
3H), 1.21 (s, 3H), 1.25 (d, J = 6.9 Hz, 6H), 2.30 (d,
1
, 300 MHz): d 1.07 (s,
3
and washed with H O (6 · 10 mL) and brine
2
J = 12.9 Hz, 1H), 2.85 (m, 3H), 3.89 (d, J = 9.7 Hz, 1H),
3
(
rated to give a crude, which after column chromatogra-
2 · 10 mL). The organic phase was dried and evapo-
.93 (d, J = 9.7 Hz, 1H), 5.53 (d, J = 15.5 Hz, 1H), 5.69
dt, J = 15.5, 9.7 Hz, 1H), 6.88 (d, J = 1.1 Hz), 6.98 (dd,
(
J = 8.2, 1.1 Hz, 1H), 7.18 (d, J = 8.2 Hz, 1H). C NMR
phy gave the b,c-unsaturated compound.
1
3
a
a
(
CDCl , 75 MHz): d 39.5 (C-1), 18.8 (C-2), 38.4 (C-3),
3
In conclusion, allyl and benzyl alcohols and their acetyl
derivatives react with triphenylphosphine and iodine
under mild conditions affording in good yields the corre-
sponding primary allylic and benzylic iodides, which can
react Ôin situÕ with diverse nucleophiles. Primary allylic
acetates did not react under these conditions. The de-
scribed procedure constitutes a new methodology to
synthesize allylic and benzylic iodides, and makes
it possible to convert allylic alcohols or their acetyl
derivatives into b,c-unsaturated compounds.
b c c
1.9 (C-4), 48.4 (C-5), 30.2 (C-6), 30.3 (C-7), 134.9 (C-
4
8
1
b
d
), 145.6 (C-9), 37.2 (C-10), 124.1 (C-11), 123.8 (C-12),
d
d
47.3 (C-13), 124.9 (C-14), 33.4 (C-15), 24.0 (C-16), 24.0
e
e
e
(C-17), 147.7 (C-18), 25.3 (C-19), 17.9 (C-20), 126.9 (C-
0
0
a–e
1 ), 7.7 (C-2 ). ( Interchangeable signals.)
1
Compound 24a: H NMR (CDCl
J = 7.5 Hz, 2H), 7.60 (d, J = 7.4 Hz, 1H), 7.48 (dd, J = 7.5,
, 300 MHz): d 7.8 (d,
3
7
2
0
1
3
1
2
.4 Hz, 2H), 5.14 (t, J = 7.9 Hz, 1H), 3.76 (d, J = 7.9 Hz,
H), 1.49 (s, 3H), 1.27 (s, 3H), 0.88 (s, 3H), 0.83 (s, 3H),
.78 (s, 3H). C NMR (CDCl , 75 MHz): d 40.3 (C-1),
3
9.5 (C-2), 41.7 (C-3), 32.9 (C-4), 51.8 (C-5), 19.5 (C-6),
6.9 (C-7), 126.3 (C-8), 183.5 (C-9), 39.0 (C-10), 26.5 (C-
1), 33.5 (C-12), 147.2 (C-13), 109.8 (C-14), 56.1 (C-15),
0.1* (C-16), 19.6* (C-17), 33.2 (C-18), 21.7 (C-19), 16.1
1
3
Acknowledgements
(
133.5 (CH–SO Ph), 139.7 (C–SO Ph). (*Interchangeable
signals.)
C-20), 128.9 (2 · CH–SO
2
Ph), 128.6 (2 · CH–SO
2
Ph),
Financial support was received from Ministerio de
Ciencia y Tecnolog ´ı a (Project PPQ 2002-03308).
2
2

E. J. Alvarez-Manzaneda et al. / Tetrahedron Letters 46 (2005) 3755–3759
3759
1
Compound 24b: H NMR (CDCl
3
, 300 MHz): d 5.16 (t,
J = 6.8 Hz, 1H), 3.02 (d, J = 6.8 Hz, 2H), 1.68 (s, 3H), 1.54
116.3 (C-14), 48.1 (C-15), 20.1* (C-16), 19.5* (C-17), 33.3
(C-18), 21.8 (C-19), 16.5 (C-20). (*Interchangeable sig-
nals.)
1
3
(
NMR(CDCl
s, 3H), 0.92 (s, 3H), 0.86 (s, 3H), 0.81 (s, 3H).
C
1
3
, 75 MHz): d 39.9 (C-1), 19.1 (C-2), 41.8 (C-
Compound 24d: H NMR (CD
(s, 4H), 5.18 (t, J = 7.0 Hz, 1H), 4.23 (d, J = 7.0 Hz, 2H),
3
COCD
3
, 400 MHz): d 783
3
8
), 33.0 (C-4), 51.9 (C-5), 19.1 (C-6), 37.0 (C-7), 126.3 (C-
), 139.8 (C-9), 39.2 (C-10), 26.5 (C-11), 33.6 (C-12), 143.2
1.85 (s, 3H), 1.52 (s, 3H), 0.90 (s, 3H), 0.84 (s, 3H), 0.79 (s,
1
3
(
C-13), 111.0 (C-14), 16.2 (C-15), 20.0* (C-16), 19.6* (C-
7), 33.2 (C-18), 21.7 (C-19), 16.5 (C-20), 122.6 (C–CN).
3H). C NMR (CD COCD , 100 MHz): d 37.6 (C-1),
3 3
1
Compound 24c: H NMR (CDCl
J = 7.4 Hz, 1H), 3.68 (d, J = 7.4 Hz, 2H), 1.61 (s, 3H), 1.48
19.6 (C-2), 40.8 (C-3), 33.6 (C-4), 52.6 (C-5), 19.7 (C-6),
37.6 (C-7), 126.5 (C-8), 141.3 (C-9), 39.6 (C-10), 27.4 (C-
11), 36.1 (C-12), 140.7 (C-13), 118.9 (C-14), 42.4 (C-15),
23.4* (C-16), 20.4* (C-17), 33.6 (C-18), 21.9 (C-19), 16.4
(C-20), 169.2 (C-CO), 168.3 (C-CO), 133.9 (C), 133.1 (C),
134.9 (2 · CH), 123.6 (2 · CH). (*Interchangeable
signals.)
1
3
, 300 MHz): d 5.23 (t,
1
s, 3H), 0.84 (s, 3H), 0.77 (s, 3H), 0.72 (s, 3H). C NMR
CDCl , 75 MHz): d 40.3 (C-1), 19.1 (C-2), 41.8 (C-3), 33.0
C-4), 51.9 (C-5), 19.1 (C-6), 37.1 (C-7), 132.0 (C-8), 140.1
C-9), 39.1 (C-10), 26.9 (C-11), 33.7 (C-12), 144.2 (C-13),
3
(
(
(
(
3