A new and efficient method for the isomerization of secondary functional allylic alcohols into their primary isomers

Article abstract of DOI:10.1055/s-1998-2220

The first efficient tandem: 'bromination-formylation-hydrolysis' for the 1,3-transposition of acyclic allylic alcohols 1 and 2 bearing a nitrile and an ester group is reported.

Full text of DOI:10.1055/s-1998-2220

SYNTHESIS
December 1998
1765
A New and Efficient Method for the Isomerization of Secondary Functional Allylic
Alcohols into their Primary Isomers
Imen Beltaïef,a Souhaïra Hbaïeb,a Rafaâ Besbes,a Hassen Amri,a Monique Villiéras,b Jean Villiérasb
a Laboratoire de Chimie Organique et Organométallique, Faculté des Sciences, Campus Universitaire, 1060-Tunis, Tunisia
Fax +216(1)885008; E-mail: hassen.Amri@fst.rnu.tn
b Laboratoire de Synthèse Organique, associé au CNRS, Faculté des Sciences et des Techniques, BP 92208, 2, rue de la Houssinière,
F-44322 Nantes Cedex 03, France
Fax +33(2)51125412; E-mail: villiera@chimi.e.univ-nantes.fr
Received 18 February 1998; revised 6 April 1998
Abstract: The first efficient tandem: “bromination–formylation–
hydrolysis” for the 1,3-transposition of acyclic allylic alcohols 1
and 2 bearing a nitrile and an ester group is reported.
Key words: Baylis–Hillman reaction, (E/Z)-2-cyano-2-(hydro-
xymethyl)alk-2-enes, ethyl (E)-2-(hydroxymethyl)alk-2-enoates,
isomerization, tandem bromination–formylation–hydrolysis
While the Baylis–Hillman reaction produces highly func-
tionalized alkenes1 of types 1 and 2, which have been
demonstrated to be versatile and useful intermediates in
the synthesis of natural products2 and biologically active
compounds,3 this methodology is not efficient for the pro-
duction of the corresponding 3-substituted allylic alcohols
3 and 4. The latter compounds are important raw materials
for the food industry,4 as well as intermediates for the syn-
thesis of Nuciferol derivatives,5 sesquiterpenes lactones,6
and antifungal and antibacterial products.7 To our knowl-
edge, few preparations of 38 or 49 (Scheme 1) have been
described.
i: PBr3, Et2O, 0°C; ii: TEAF, MeCN, r.t. or reflux; iii: H+ cat., MeOH,
r.t.
Scheme 2
ium formate (TEAF; 2 Et3N–5 HCO2H) as formylating
reagent13, has been carried out in refluxing acetonitrile.
The formyloxy nitriles and esters 6 are hydrolyzed to the
corresponding alcohols 3a–g and 4a–h upon hydrolysis in
the presence of one drop of concentrated hydrochloric
acid at room temperature. 2-(Hydroxymethyl)alk-2-ene-
nitriles 3a–g and ethyl 2-(hydroxymethyl)alk-2-enoates
4a–h prepared are summarized in Table 1.
Scheme 1
A recent publication10 on the first synthesis of 3-substitut-
ed 2-cyanoallylic alcohols 3 based on reduction of 2-cy-
ano-2,3-epoxy esters prompts us to describe our own re-
sults. As part of our ongoing work on the synthesis of nov-
el 2-functional allylic alcohols 3 and 4, we report here a
general and convenient method to accomplish the rear-
rangement of Baylis–Hillman products 1 and 2 to the cor-
responding primary allylic alcohols 3 and 4 using a three-
step reaction sequence (bromination–formylation–hydro-
lysis).11 The sequence involves a regiospecific 1,3-allylic
transposition of the hydroxy group (Scheme 2).
The E- and Z-structure is determined from spectroscopic
data4, 5, 10, 14 of the functional allylic alcohols 3 and 4 and
by comparison with data of various authentic samples.15
From Table 1, it is clear that the stereochemistry of the
formylation reaction is dependent on the nature of elec-
tron-withdrawing group. With EWG = CN, the stereose-
lectivity of the new allylic alcohols 3a–g seems to depend
both on steric and electronic effects and gives E-function-
al olefins for an electron-withdrawing group (R =
p-CF3C6H4). In contrast, the transformation of secondary
alcohols 2 into the corresponding primary alcohols 4a–h
is highly stereoselective, independent of the nature of the
R group and leading to the more stable E-isomers.
Our methodology is based on the treatment of 2-(hy-
droxyalkyl)acrylic compounds 1 and 2 with PBr3 in dieth-
yl ether at 0°C leading respectively to allylic bromides 5
as a mixture of E,Z-isomers in which the E-isomer is
strongly predominant (EWG = CN) and exclusively the Z-
isomer when EWG = CO2Et. The stereochemistry of allyl
In summary, to the best of our knowledge, these prelimi-
nary results are the first examples of successful tandem:
“bromination–formylation–hydrolysis” of readily avail-
able Baylis–Hillman products 1 and 2 giving rise to the
synthesis of 2-(hydroxymethyl)alk-2-enenitriles 3 and
bromides was assigned by comparing H and 13C NMR
1
spectral data of these molecules reported in literature.12
Thus, the displacement of bromide using triethylammon-

SYNTHESIS
Papers
Table 1. 3-Substituted 2-Cyano/(Ethoxycarbonyl)allylic Alcohols 3a–g and 4a–h
1766
R
Products
Products
3a–g
(EWG = CN)
Isomer Ratio
Yield (%)b
4a–h
(EWG = CO2Et)
Yield (%)b
E/Za
Me
Et
Pr
nC5H11
Ph
o-FC6H4
p-CF3C6H4
PhCH = CH
3a (E, Z)
3b (E, Z)
3c (E, Z)
3d (E, Z)
3e (E, Z)
3f (E, Z)
3g (E)
61 : 39
60 : 40
75 : 25
66 : 34
90 : 10
84 : 16
100 : 0
–
62
72
86
66
57
80
82
–
4a (E)
4b (E)
4c (E)
4d (E)
4e (E)
4f (E)
4g (E)
4h (E)
63
68
80
73
61
85
81
68
–
a
Determined by 1H NMR spectral analysis of the crude reaction mixture.
Yields are based on the starting formates 6.
b
Table 2. 2-(Hydroxymethyl)alkenenitriles 3a–g (E, Z) Prepareda
Com-
pound
IR (Film)
Molecular
Formula
1H NMR (CDCl3/TMS),
δ, J (Hz)
13C NMR (CDCl3/TMS),
δ, J (Hz)
MS (70eV),
m/z (%)
ν (cm–1)
3a (E, Z)
3b (E, Z)
3436,
2221,
1642
C5H7NO
(97.12)
6.58 (q, 1H, J = 7.3, Z), 6.55 14.3 (CH3CH=C, Z), 16.8 (CH3CH=C, E), 97 (M+, 26), 82
(q, 1H, J = 7.0, E), 4.26 (s, 56.9 (CH2OH, E), 62.5 (CH2OH, Z), 115.5 (39), 68 (100), 52
2H, Z), 4.19 (s, 2H, E), 2.03 (CH=C, E), 116.4 (CH=C, Z), 116.4 (CN, E), (48), 41 (42)
(d, 3H, J = 7.3, Z), 1.91 (d, 118.9 (CN, Z), 144.4 (CH=C, Z), 145.6
3H, J = 7.0, E)
(CH=C, E)
3437,
2221,
1638
C6H9NO
(111.14)
6.48 (t, 1H, J = 7.6, E), 6.46 12.8 (CH3CH2, E), 12.9 (CH3CH2, Z), 22.0 111 (M+, 13), 93
(t, 1H, J = 7.6, Z), 4.26 (s, (CH2CH3, Z), 24.7 (CH2CH3, E), 57.4 (52), 80 (48), 66
2H, Z), 4.20 (s, 2H, E), 2.42 (CH2OH, E), 62.8 (CH2OH, Z), 114.0 (100), 54 (67), 39
(m, 2H, Z), 2.28 (m, 2H, E), (CH=C, Z), 114.4 (CH=C, E), 116.5 (CN, E), (35), 27 (20)
1.09 (t, 3H, J = 7.5, Z), 1.07 119.0 (CN, Z), 150.6 (CH=C, E), 152.0
(t, 3H, J = 7.5, E)
(CH=C, Z)
3c (E, Z)
3d (E, Z)
3431,
2220,
1639
C7H11NO
(125.17)
6.48 (2t, 1H, Z, 1H, E), 4.25 13.3 (CH3CH2CH2), 21.4 (CH3CH2CH2), 125 (M+, 4), 107
(s, 2H, Z), 4.19 (s, 2H, E), 30.2 (CH3CH2CH2, Z), 33.0 (CH3CH2CH2, (25), 92 (22), 84
2.37 (m, 2H, E), 2.24 (m, E), 57.1 (CH2OH, Z), 62.5 (CH2OH, E), 114.6 (100), 81 (30), 80
2H, Z), 1.51 (m, 2H), 0.96 (CH=C), 116.5 (CN, E), 118.9 (CN, Z), 149.1 (57), 79 (54), 66
(t, 3H, J = 7.3, E), 0.94 (t, (CH=C, E), 150.4 (CH=C, Z)
3H, J = 7.4, Z)
(59), 42 (57)
3431,
2220,
1639
C9H15NO
(153.22)
6.49 (t, 1H, J = 7.9, Z), 6.47 13.8 (CH3CH2CH2), 22.2 (CH3CH2CH2), 153 (M+, 4), 107
(t, 1H, J = 7.8, E), 4.25 (s, 27.9 (CH3CH2CH2), 28.5 (CH2CH2CH=Z), (20), 94 (30), 81
2H, Z), 4.20 (s, 2H, E), 2.39 31.0 (CH2CH2CH=), 31.2 (CH2CH2CH =, E), (100), 55 (70), 41
(m, 2H, E), 2.37 (m, 2H, Z), 57.4 (CH2OH, Z), 62.7 (CH2OH, E), 114.5 (96), 29 (60)
1.46 (m, 2H), 1.32 (m, 4H), (CH=C, E), 114.7 (CH=C, Z), 119.9 (CN, E),
0.91 (t, 3H, J = 7.1)
119.9 (CN, Z), 149.4 (CH=C, E), 150.8
(CH=C, Z)
3e (E, Z)
3f (E, Z)
3g (E)
3429,
2215,
1625
C10H9NO
(159.19)
7.70 (m, 5H, Z), 7.4 (m, 5H, 59.0 (CH2OH, Z), 64.1 (CH2OH, E), 110.4 159 (M+, 100),
E), 7.37 (s, 1H, E), 7.18 (s, (CH=C, E), 114.7 (CH=C, Z), 117.0 (CN, E), 140 (24), 131 (24),
1H, E), 4.41 (s, 2H, Z), 4.36 119.5 (CN, Z), 128.1, 129.4, 130.4 (5CHarom), 130 (98), 103 (27),
(s, 2H, E)
132.9 (Carom), 143.9 (CH=C, E), 146.2 91 (44), 78 (33)
(CH=C, Z)
3415,
2217,
1631
C10H8FNO
(177.18)
8.04, 7.35, 7.18, 7.09 (4m, 58.5 (CH8OH, Z), 63.8 (CH2OH, E), 112.8 177 (M+, 100), 158
4H), 7.40 (s, 1H, Z), 7.30 (s, (CH=C), 115.7, 115.9, 124.3 (4CHarom), 117.3 (23), 148 (84), 120
1H, E), 4.40 (s, 2H, Z), 4.36 (CN, E), 120.9 (CN, Z), 128,2 (CCF), 133.7 (d, (33), 109 (75)
(s, 2H, E)
CF, J = 246.7, Z), 133.8 (d, CF, J = 244.1, E),
158.6 (CH=C, Z), 161.9 (CH=C, E)
3390,
2217,
1617
C11H8F3NO 7.27 (s, 1H), 7.50, 7.27 (2d, 63.9 (CH2OH), 113.4 (CH=C), 117.1 (CN), 227 (M+, 100), 198
(227.18) 4H, J = 8.3, J = 7.3), 4.44 125.0 (q, CF3, J = 289.3), 125.8, 128.9 (81), 178 (72), 159
(s, 2H) (CHarom), 132.1 (Carom), 136.2 (q, CCF3, J = (60), 158 (47), 130
21.6), 141.8 (CH=C)
(25), 68 (31), 54
(49)
aThe microanalyses were in fair agreement with the calculated values (C ± 0.17, H ± 0.07, N ± 0.11, F ± 0.19)

SYNTHESIS
December 1998
1767
Table 3. Ethyl 2-(Hydroxymethyl)alkenoates 4a–h (E) Prepareda
Compound
IR (Film)
Molecular
Formula
1H NMR (CDCl3/TMS),
δ, J (Hz)
13C NMR (CDCl3/TMS),
δ, J (Hz)
MS (70eV),
m/z (%)
ν (cm–1)
4a (E)
3590,
1693,
1651
C7H12O3
(144.2)
6.95 (q, 1H, J = 7.3), 4.33 13.9 (CH3CH2O), 14.0 (CH3CH=C), 56.4 144 (M+, 6), 129
(s, 2H), 4.20 (q, 2H, J = 7), (CH2O), 60.5 (CH2OH), 131.8 (CH=C), (73) 115 (89), 99
2.80 (s, 1H), 1.88 (d, 3H, J 140.4 (CH =), 167.3 (CO)
= 7.3), 1.28 (t, 3H, J = 7)
(98), 87 (54), 69
(87), 41 (100)
4b (E)
4c (E)
4d (E)
3592,
1693,
1647
C8H14O3
(158.2)
6.85 (t, 1H, J = 7.5), 4.33 (s, 13.1 (CH3CH2CH), 14.0 (CH3CH2O), 21.5 158 (M+, 2), 140
2H), 4.26 (q, 2H, J = 7), (CH2CH =), 56.7 (CH2O), 60.5 (CH2OH), (19), 129 (100),
2.73 (s, 1H), 2.30 (m, 2H), 130.4 (CH=C), 146.9 (CH =), 167.5 (CO)
113 (59), 101
(51), 83 (67), 55
(51)
1.32 (t, 3H, J = 7), 1.08 (t,
3H, J = 7.3)
3592,
1694,
1646
C9H16O3
(172.2)
6.88 (t, 1H, J = 7.6), 4.34 (s, 13.6 (CH3CH2CH2), 14.0 (CH3CH2O), 21.9 172 (M+, 3), 154
2H), 4.23 (q, 2H, J = 7), (CH3CH2CH2), 30.1 (CH2CH=), 56.8 (21), 143(36), 127
2.88 (s, 1H), 2.27 (m, 2H), (CH2O), 60.5 (CH2OH), 131.1 (CH C), 145.4 (57), 111 (67), 81
1.50 (m, 2H), 1.31 (t, 3H, J (CH =), 167.5 (CO)
= 7), 0.95 (t, 3H, J = 7.4)
(83), 29 (100)
3592,
1692,
1646
C11H20O3
(200.3)
6.89 (t, 1H, J = 7.8), 4.33 (s, 13.7 (CH3CH2CH2), 14.0 (CH3CH2O), 22.2 200 (M+, 1), 182
2H), 4.23 (q, 2H, J = 7), (CH3CH2CH2), 28.1 (CH3CH2CH2), 28.3 (17), 171(14), 155
2.95 (s, 1H), 2.28 (td, 2H, (CH2CH2CH =), 31.3 (CH2CH=), 56.8 (33), 139(35), 109
J = 7.8), 1.46 (m, 2H), 1.32 (CH2O), 60.5 (CH2OH), 130.9 (CH=C), (40)
(m, 7H), 0.89 (t, 3H, J = 145.6 (CH =), 167.4 (CO)
6.7)
4e (E)
4f (E)
4g (E)
3595,
1694,
1633
C12H14O3
(206.2)
7.72 (s, 1H), 7.38 (m, 5H), 14.2 (CH3CH2), 57.7 (CH2O), 61.0 (CH2OH), 206 (M+, 15), 188
4.40 (s, 2H), 4.23 (q, 2H, J 128.4, 129.0, 129.5 (5CHarom), 131.1 (8), 177 (32), 160
= 7), 2.65 (s, 1H), 1.33 (t, (CH=C), 134.5 (Carom), 142.3 (CH =), 167.9 (23), 131 (100),
3H, J = 7)
(CO)
103 (59)
3592,
1694,
1639
C12H13FO3 7.78 (s, 1H), 7.25 (m, 4H), 14.1 (CH3CH2), 58.0 (CH3CH2), 61.2 224 (M+, 18), 195
(224.2)
4.37 (s, 2H), 4.24 (q, 2H, J (CH2OH), 115.5 (CHCF, d, 2J = 13.1), 124.1, (71), 179(22), 149
= 7), 2.75 (s, 1H), 1.33 (t, 130.8, 131.0 (3CHarom), 132.9 (CH=C), 134.6 (100), 133 (67),
3H, J = 7)
(CH =), 160.3 (CF, d, J = 250.7), 167.4 (CO) 121 (48), 101 (70)
3594,
1695,
1638
C13H13F3O3 7.82 (s, 1H), 7.67, 7.58 14.2 (CH3CH2), 57.6 (CH3CH2), 61.4 274 (M+, 14), 245
(274.2)
(A2B2, 4H, J = 8.4), 4.43 (d, (CH2OH), 124.0 (CF3, 1, 1J = 271.7), 125.5, (67), 229(34), 199
2H, J = 6.5), 4.34 (q, 2H, 129.7 (4CHarom), 130.8 (CCF3, q, 2J = 34.5), (92), 151(71), 131
J = 7), 2.82 (t, 1H, J = 6.5), 133.1 (CH=C), 138.1 (Carom), 140.5 (CH=), (77)
1.38 (t, 3H, J = 7)
167.5 (CO)
4h (E)
3592,
1694,
1681,
1622
C14H16O3
(232.3)
7.47, 7.33 (2m, 5H), 7.42 (d, 14.1 (CH3CH2), 57.1 (CH3CH2), 60.7 232 (M+, 41), 214
1H, J = 11.6), 7.18 (dd, 1H, (CH2OH), 122.6 (C6H5CH=CH), 127.2, (15), 186(14), 158
J = 11.6, 15.3), 6.92 (d, 1H, 128.7, 129.0 (5CHarom), 129.3 (Carom), 135.9 (43), 141(56), 129
J = 15.3), 4.53 (s, 2H), 4.26 (CH=C), 140.9, 141.4 (C6H5CH =, CH=C), (77), 115 (64), 91
(q, 2H, J = 7.2), 2.93 (s, 167.7 (CO)
1H), 1.33 (t, 3H, J = 7.2)
(79)
a The microanalyses were in fair agreement with the calculated values (C ± 0.21, H ± 0.05, F ± 0.14).
ethyl 2-(hydroxymethyl)alk-2-enoates 4 which are diffi-
cult to obtain by other methods.
continued for 1 h. Water (25 mL) was then added at –10°C and the
mixture was extracted with hexane (3 × 20 mL). The organic phase
was washed with brine (2 × 15 mL) and dried (MgSO4). The solvent
was evaporated and the remaining oil was distilled in vacuo.
Reactions’ progress were controlled using an Intersmat 20M GC with
a 3 m × 3 mm column packed with 10% SE 30 or by TLC on silica gel
plates (Fluka Kieselgel 60 F254). For column chromatography, Fluka
Kieselgel 70–230 mesh was used. IR were determined on a Perkin–
Elmer Paragon 1000PC spectrophotometer. 1H and 13C NMR spectra
were recorded on Bruker AM 300 and 400 spectrometers with TMS
as internal standard and CDCl3 as solvent. MS are obtained using a
Hewlett Packard 5989A spectrometer at 70 eV.
Allyl Formates 6; General Procedure:
To a solution of triethylammonium formate (3.67g, 25 mmol) in
MeCN (7.5 mL) was added allyl bromide 5 (10 mmol) and the solu-
tion was stirred at reflux (12 h, EWG = CN) or (2 h, EWG = CO2Et).
The mixture was extracted with Et2O (3 × 30mL). The combined or-
ganic layers were dried (MgSO4) and evaporated at reduced pressure
to give the crude formate 6 which can be utilized for the next step.
Allyl Bromides 5; General Procedure:
3-Substituted Allyl Alcohols 3 and 4; General Procedure:
To a solution of formate 6 in MeOH (10 mL) were added one drop of
concd HCl and the mixture was stirred at r.t. for 3 h. The mixture was
PBr3 (5.7 g, 1.9 mL, 20 mmol) was added to a stirred solution of 2-
(hydroxyalkyl)acrylic compound 1 or 2 in anhyd Et2O (40 mL) at
–10°C. The temperature was allowed to rise to 20°C and stirring was

SYNTHESIS
Papers
1768
diluted with Et2O and dried (MgSO4). The solvent was removed in
vacuo to give the allylic alcohol 3 (or 4) which was purified by distil-
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