Mild and practical stereoselective synthesis of (Z)- and (E)-allyl bromides from Baylis-Hillman adducts using Appel agents (PPh3/CBr4): a facile synthesis of semiplenamides C and E

Article abstract of DOI:10.1016/j.tetlet.2009.02.132

Appel agents (PPh₃/CBr₄) have been utilized for high-yielding stereoselective synthesis of (Z)- and (E)-allyl bromides from Baylis-Hillman adducts at room temperature. The method has been applied for the synthesis of naturally occurr

Full text of DOI:10.1016/j.tetlet.2009.02.132

Tetrahedron Letters 50 (2009) 2072–2074
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Mild and practical stereoselective synthesis of (Z)- and (E)-allyl bromides from
Baylis–Hillman adducts using Appel agents (PPh3/CBr4): a facile synthesis
of semiplenamides C and E q
*
Biswanath Das , Kongara Damodar, Nisith Bhunia, Boddu Shashikanth
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Appel agents (PPh3/CBr4) have been utilized for high-yielding stereoselective synthesis of (Z)- and (E)-
allyl bromides from Baylis–Hillman adducts at room temperature. The method has been applied for
the synthesis of naturally occurring bioactive fatty acid amides, semiplenamides C and E.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 2 January 2009
Revised 23 January 2009
Accepted 15 February 2009
Available online 21 February 2009
Keywords:
(Z)- and (E)-Allyl bromides
Baylis–Hillman adduct
Appel agents
PPh3/CBr4
Semiplenamides C and E
Baylis–Hillman adducts are important precursors for stereose-
lective synthesis of various functionalized molecules.1 The allyl ha-
lides derived from these adducts have been employed for the
synthesis of several bioactive compounds and their analogues such
The aromatic aldehydes containing both electron-donating and
electron-withdrawing groups were used for the preparation of
Baylis–Hillman adducts. Several functionalities such as halogen,
nitro and ether groups remained unaffected. The structures of
the products were settled from their spectral (IR, 1H and 13C
NMR and MS) and analytical data.
The present conversion is highly stereoselective. The allyl bro-
mides with ester moieties were obtained with (Z)-configuration
as the sole products while those with nitrile group were formed
with (E)-configuration as the major products (Table 1). The ratio
of the (Z)- and (E)-isomers was determined from the 1H NMR spec-
tra of the crude products. The 1H NMR spectra of the E and Z-iso-
mers are according to the ones reported in the literature.3d These
reported chemical shift values were helpful to determine the ste-
reochemistry of the prepared allyl bromides.
as
a-methylene-c-butyrolactones, a-alkylidene-b-lactams and
flavonoids.2 The conversion of the Baylis–Hillman adducts into
their corresponding allyl bromides has generally been carried out
by using a strong acid (HBr–H2SO4)2b or a metal halide (NaBr, LiBr,
CuBr2 or MgBr2).3 Some other mild methods using alternative re-
agents (PBr3, PPh3/NBS, HBr/SiO2, PPh3/Br2 and DMS/NBS)4 have
also been developed to carry out this conversion. Herein, we wish
to report the application of Appel agents (PPh3/CBr4)5 for this con-
version under very mild and metal-free conditions.
In connection to our works6 on the Baylis–Hillman adducts, we
have observed that the treatment of these adducts (1) with PPh3/
CBr4 in CH2Cl2 afforded the corresponding allyl bromides (2) in
high yields at room temperature (Scheme 1).
A series of allyl bromides were prepared from different Baylis–
Hillman adducts containing both ester (–COOMe, –COOEt) and
nitrile moieties (Table 1). The conversion was complete within
1.5–2 h and the products were formed in excellent yields
(91–99%). The adducts derived from various aliphatic as well as
aromatic aldehydes underwent the present conversion smoothly.
OH
PPh3/CBr4
EWG
Br
EWG
R
R
CH2Cl2, r.t.
1.5 - 2 h
2
1
91 - 99%
R = alkyl, aryl
EWG = COOMe, COOEt or CN
* Corresponding author. Tel./fax: +91 40 7160512.
E-mail address: biswanathdas@yahoo.com (B. Das).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.132

B. Das et al. / Tetrahedron Letters 50 (2009) 2072–2074
2073
Table 1
II. Bromide ion then attacks this intermediate to afford the allyl
bromide and Ph3PO via a general transition state III (Scheme 2).
The configuration of 2 can possibly be rationalized by consider-
ing the transition state models A–C (Fig. 1). Model A is more fa-
voured than B when EWG is an ester and (Z)-products are
formed predominantly. On the other hand, model C is more fa-
voured than A when EWG is –CN (which is linear) and thus (E)-
compounds are the major products.
Thepresentmethodhasbeenappliedforthesynthesisof twonat-
urally occurring fatty acid amides, semiplenamides C (3) and E (4).7
These two amides were isolated from the marine cyanobacterium
Lyngia semiplena and were shown to display toxicity towards the
brine shrimp model system. For the synthesis of 3 and 4, the Bay-
lis–Hillman adducts 5 and 6 (derived from tetradecanal and hexade-
canal, respectively, and ethyl acrylate) were used as starting
materials (Scheme 3). These adducts on treatment with PPh3/CBr4
in CH2Cl2 afforded the corresponding allyl bromides 7 and 8 which
were subsequently reduced with Zn/CH3COOH to afford the esters
9 and 10, respectively.8 These esters were then hydrolyzed with
85% methanolic KOH to form the corresponding acids 11 and 12
which on treatment with (S)-alaninol in the presence of HOBt
(1-hydroxybenzotriazole hydrate), DIEA (diisopropylethylamine)
and EDCI (N-(3-dimethylaminopropyl)-N0ethylcarbodiimide hydro-
chloride) afforded the amides 3 and 13, respectively.9 Compound 13
was further acetylated with acetic anhydride using pyridine and
a
Synthesis of allyl bromides using PPh3/CBr4
Entry
R
EWG
Productb
Time (h)
Yield (%)
Z:Ec
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
C6H5
4-Cl–C6H4
4-MeO–C6H4
4-NO2–C6H4
3-NO2–C6H4
CH3CH2
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
COOEt
COOEt
COOEt
COOEt
COOEt
CN
2a
2b
2c
2d
2e
2f
2g
2h
2i
1.5
1.5
1.5
2.0
2.0
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
2.0
1.5
96
97
99
91
93
97
97
97
97
99
98
98
98
98
94
92
95
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
6:94
(CH3)2CH
H3C(CH2)3CH2
H3C(CH2)5CH2
4-MeO–C6H4
4-(CH3)2CH–C6H4
H3C(CH2)11CH2
H3C(CH2)13CH2
H3C(CH2)15CH2
C6H5
2j
2k
7
8
2n
2o
2p
2q
3-NO2–C6H4
4-Cl–C6H4
CN
CN
10:90
7:93
a
Experimental conditions: Baylis–Hillman adduct 1 (1 mmol), PPh3 (2 mmol),
CBr4 (2 mmol), CH2Cl2 (10 mL) and the reaction mixture were stirred at room
temperature.
b
The structures of the products were settled from their spectral (IR, 1H and 13C
NMR and MS) and analytical data.
c
Determined from the 1H NMR spectra of the crude products.
The mechanism of the conversion involves the interaction of
PPh3 with CBr4 to form the intermediate I which reacts with a Bay-
lis–Hillman adduct to produce the oxyphosphonium intermediate
DMAP to furnish product 4. The physical (mp and [a]D) and spectral
data suggested that the amides 3 and 4 were identical to the natu-
rally occurring semiplenamides C and E, respectively.
Br
..
-
+
Br
C
+
Ph3P
Br
+
Br PPh3
CBr3
I
Br
..
.
.
OH
EWG
R
CHBr3
+
PPh3
EWG
.. PPh3
+
+
.
.
.
.
O
.
O
EWG
Br
OPPh
.
3
R
EWG
EWG
R
R
R
-
-
Br
Ph3P=O
Br
III
II
2
Scheme 2. A plausible reaction mechanism.
+
+
_
O
OPPh3
OPPh3
R
H
Br
Br
EWG
C
N
COOMe
Br
R
_
R
_
H
H
O
O
OPPh
+
3
Figure 1. Conformational transition-state analysis for the rationalization of the observed stereoselectivity in the reaction leading to the allyl bromides 2.

2074
B. Das et al. / Tetrahedron Letters 50 (2009) 2072–2074
OH
O
O
O
i
ii
R
OEt
R
OEt
R
OEt
Br
9, 10
5, 6
7, 8
iii
O
O
O
iv
v
OH
O
CH3
R
OH
R
N
R
N
H
H
O
11, 12
3, 13
4
for 5, 7, 9, 11 and 3: R = Me (CH2)11 CH2-
and for 6, 8, 10, 12, 13 and 4: R = Me (CH2)13 CH2-
Scheme 3. Synthesis of Semiplenamides C and E. Reagents and conditions: (i) PPh3/CBr4, CH2Cl2, rt, 1.5 h, (7, 8 98%); (ii) Zn (3 equiv), CH2Cl2, rt, 30 min, then CH3COOH
(slowly), 0 °C; rt, 30 min, (9 89%, 10 87%); (iii) 85% methanolic KOH, rt, 5 h, (11 84%, 12 83%); (iv) (S)-alaninol, HOBt, DIEA, EDCI, 0 °C, 15 min; rt, 24 h, (3 81%, 13 79%); (v)
Ac2O, Py, DMAP, rt, 4 h, 92%
In conclusion, we have developed a simple, mild and efficient
practical method for the stereoselective synthesis of (Z)- and (E)-al-
lyl bromides starting from Baylis–Hillman adducts by treatment
with Appel agents (PPh3/CBr4) at room temperature. The method
has successfully been applied for the facile synthesis of two natu-
rally occurring bioactive fatty acid amides, semiplenamides C and E.
General experimental procedure: To a stirred solution of Baylis–
Hillman adduct 1 (1 mmol) and PPh3 (2 mmol) in dry CH2Cl2
(10 ml), CBr4 (2 mmol) was added under nitrogen atmosphere.
The mixture was stirred at room temperature and the reaction
was monitored by TLC. After completion, the reaction mixture
was quenched with cold water (10 mL) and extracted with CH2Cl2
(3 ꢀ 10 mL). The organic layer was dried over anhydrous Na2SO4
and concentrated. The crude product was purified by column chro-
matography over silica gel using hexane–EtOAc (19:1–9:1) as elu-
ent to yield the corresponding allyl bromide 2.
tary data associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2009.02.132.
References and notes
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Acknowledgements
The authors thank CSIR and UGC, New Delhi, for financial assis-
tance. They are also thankful to NMR, Mass and IR divisions of IICT
for recording spectra.
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Supplementary data
Copies of 1H and 13C NMR spectra for selected compounds and
spectral (IR, 1H and 13C NMR and MS) and analytical data of the un-
known allyl bromides (2g, 2h, 7, 8, 2n, 2q) and of all the products
involved in the synthesis of semiplenamides C and E.. Supplemen-