gem-Dibromomethyl aromatics: Efficient aldehyde equivalents in the Knoevenagel-Doebner reaction

Article abstract of DOI:10.1055/s-0029-1216849

A valuable variation of the Knoevenagel - Doebner reaction for the efficient synthesis of cinnamic esters is described. This reaction provides cinnamic esters in a single step from gem-dibromomethyl aromatics, which otherwise require the hydrolytic conver

Full text of DOI:10.1055/s-0029-1216849

PAPER
2349
gem-Dibromomethyl Aromatics: Efficient Aldehyde Equivalents in the
Knoevenagel–Doebner Reaction
g
em
-
Dibro
o
m
omethyl
A
h
romatics as
E
n
fficient
A
ldehyde
K
Equivalents allikat Augustine,*a,b Yanjerappa Arthoba Naik,b Subba Poojari,a Nagaraja Chowdappa,a Bailur Sheena
Sherigara,b Kummara Areppaa
a
Syngene International Ltd., Biocon Park, Plot Nos. 2 & 3, Bommasandra IV Phase, Jigani Link Road, Bangalore 560099, India
Fax + 91(80)2808 3150; E-mail: john.kallikat@syngeneintl.com
b
Department of Chemistry, Kuvempu University, Shankaraghatta Post, Shimoga 577451, India
Received 3 March 2009; revised 18 March 2009
ichiometric byproduct formation can challenge waste
management. The decarboxylative Knoevenagel-type re-
action of malonic acid half esters with aldehydes to give
a,b-unsaturated esters is another alternative.11 Water and
Abstract: A valuable variation of the Knoevenagel–Doebner reac-
tion for the efficient synthesis of cinnamic esters is described. This
reaction provides cinnamic esters in a single step from gem-dibro-
momethyl aromatics, which otherwise require the hydrolytic con-
version of gem-dibromides into aldehydes, and demonstrates the carbon dioxide are produced as byproducts, hence it has a
significantly improved advantage.
use of an alternative reagent for noncommercial and expensive al-
dehydes. Further, the reaction of gem-dibromomethyl aromatics
with malonic acid and di-tert-butyl dicarbonate for the one-pot syn-
thesis of tert-butyl cinnamates is also described.
In a previous paper, we reported a valuable variation to
the Knoevenagel–Doebner reaction by using gem-dibro-
momethyl aromatics as a substitute for aldehydes for the
synthesis of cinnamic acids12 and now wish to report the
synthesis of cinnamic esters as an extension of this proce-
dure (Scheme 1). This eventually avoids the hydrolytic
cleavage of the gem-dibromides to aldehydes13 for their
use in the synthesis of cinnamic acid derivatives.
Key words: Knoevenagel–Doebner reaction, tert-butyl cinnam-
ates, gem-dibromomethyl aromatics, di-tert-butyl dicarbonate, hy-
drolytic
Cinnamic esters compose a relatively large family of or-
ganic compounds, which are important reagents in organ-
ic synthesis both as intermediates and final products. For
example, they have been incorporated into nylon monofil-
aments of toothbrush bristles as antimicrobial agents1 and
used to prepare compounds of biological relevance.2
Chlorogenic acid, a natural cinnamic ester, is a major phe-
nolic compound in coffee, that is widespread in plants,
and can be isolated from the leaves and fruit.3 This com-
pound, long known as an antioxidant, also slows the re-
lease of glucose into the bloodstream after a meal.4 This
substance is claimed to have antiviral,5 antibacterial,6 and
antifungal7 effects with relatively low toxicity and side ef-
fects. For use in the food, polymer, and perfume industries
and for their medical and technical applications, cinnamic
esters are synthesized on a commercial scale.
R
O
O
Br
HOOC
R
O
O
Br
FG
FG
pyridine
piperidine (cat.)
1
2
81–96%
R = H, Me, Et, t-Bu, Bn, etc.
O
Br
malonic acid
pyridine
O
Br
FG
FG
Boc2O
piperidine (cat.)
1
2
84–96%
Scheme 1
The synthesis of cinnamic esters from aldehydes is regu-
larly required and a variety of methods have been devel-
oped for this transformation.8 In the Wittig reaction, an
aldehyde reacts with a stabilized ylide to produce cinnam-
ic esters.9 In this reaction, triphenylphosphine oxide is a
stoichiometric byproduct and it has to be removed
chromatographically and disposed of. The Horner–
Wadsworth–Emmons variant has the advantage of pro-
ducing a water-soluble phosphate salt as the byproduct,
which can be removed via aqueous extraction.10 This vari-
ant, however, typically requires the use of a strong base
such as sodium hydride and, as in the Wittig reaction, sto-
In initial studies, we treated commercially available ben-
zal bromide (1a, 1.0 equiv) with ethyl hydrogen malonate
(1.2 equiv) in pyridine in the presence of a catalytic quan-
tity (0.04 equiv) of piperidine at reflux (Table 1, entry l);
this was the optimized method for the synthesis of cin-
namic acid from benzal bromide.12 The starting material
was consumed in 1.5 hours as indicated by TLC analysis.
After workup, ethyl cinnamate was isolated in 81% yield.
Screening of various base catalysts such as triethylamine,
N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]un-
dec-7-ene, pyrrolidine, and morpholine was carried out.
While pyrrolidine and morpholine catalyzed the reaction
in quantitative yields in 2–3 hours, other bases were found
to be inefficient in promoting this reaction. With a catalyt-
ic amount of piperidine, the reaction took barely an hour
for completion. Further, we have screened various malon-
SYNTHESIS 2009, No. 14, pp 2349–2356
x
x.
x
x
.
2
0
0
9
Advanced online publication: 29.05.2009
DOI: 10.1055/s-0029-1216849; Art ID: Z03309SS
© Georg Thieme Verlag Stuttgart · New York

2350
J. K. Augustine et al.
PAPER
ic acid half esters with benzal bromide (1a) for the synthe- the synthesis of tert-butyl cinnamates to demonstrate the
sis of corresponding cinnamates and the results are scope and generality of utilizing gem-dibromomethyl aro-
summarized in Table 1.
matics as a substitute for aldehydes. Various gem-dibro-
momethyl aromatics 1b–i (for which, either the
corresponding aldehydes are not available or expensive)
were prepared using known protocols14 and further sub-
jected to the modified Knoevenagel–Doebner reaction
with tert-butyl hydrogen malonate to yield the corre-
sponding tert-butyl cinnamates 2b–i in excellent yields
(Table 2). The reaction proceeded well with all substrates
we tried and an aqueous extraction was sufficient to ob-
tain the products with good purity; chromatographic puri-
fication was not required.
Table 1 Reaction of Benzal Bromide (1a) with Malonic Acid Half
Esters
HO
Br
R
R
O
Br
pyridine
piperidine (cat.)
1a
2
Entry
R
Time (h)
1.5
Yield (%)
1
2
3
4
5
CO2Et
CO2Me
CO2t-Bu
CO2Bn
CNa
81
84
93
82
76
Takeda and co-workers have reported the use of di-tert-
butyl dicarbonate as an esterification reagent to produce
tert-butyl cinnamates.15 It was of interest to explore if we
could use di-tert-butyl dicarbonate in a one-pot reaction
with gem-dibromomethyl aromatics for the synthesis of
tert-butyl cinnamates in the modified Knoevenagel–
Doebner reaction as shown in Scheme 1. Thus, 1a (1.0
equiv) was treated with malonic acid (2.0 equiv) and di-
tert-butyl dicarbonate (1.1 equiv) in anhydrous pyridine in
the presence of a catalytic quantity (0.04 equiv) of piperi-
dine at reflux (Scheme 1). As expected, the starting mate-
rial was completely consumed in 25 minutes to provide
tert-butyl cinnamate (2a) in 56% yield along with cinnam-
ic acid in 30% isolated yield. After few optimization reac-
tions, we could achieve 2a in 88% yield by allowing the
reaction to continue for two hours at reflux. When di-tert-
butyl dicarbonate was omitted in the above reaction, cin-
namic acid was isolated as the sole product in 92% yield.12
The use of two equivalents of malonic acid was found to
be optimal for the complete conversion of 1a into 2a.
1.5
0.5
1.5
2
a An active methylene compound.
While ethyl, methyl, and benzyl malonates provided good
yield of the corresponding cinnamates, tert-butyl hydro-
gen malonate (Table 1, entry 3) provided an excellent
yield in a shorter duration. It is worthy of note that cy-
anoacetic acid, an active methylene compound, also react-
ed under the above standard reaction conditions to provide
cinnamonitrile in moderate yield (Table 1, entry 5).
Compounds possessing the tert-butyl carboxylate func-
tionality are useful building blocks in organic synthesis,
due to their ease of deprotection to the corresponding car-
boxylic acid in acidic medium. So we decided to take up
Table 2 Reaction of gem-Dibromomethyl Aromatics 1a–i with tert-Butyl Hydrogen Malonate
Entry
Substrate
Product
Yielda (%)
Br
O
O
Br
1
93
1a
2a
O
Br
MeOOC
MeOOC
O
Br
Br
2
3
87
85
Br
Br
Br
1b
2b
O
O
MeOOC
MeOOC
1c
2c
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PAPER
gem-Dibromomethyl Aromatics as Efficient Aldehyde Equivalents
2351
Table 2 Reaction of gem-Dibromomethyl Aromatics 1a–i with tert-Butyl Hydrogen Malonate (continued)
Entry
4
Substrate
Product
Yielda (%)
Br
O
Br
NO2
O
89
MeO
NO2
MeO
1d
2d
O
Br
O
Br
5
6
91
Br
N
N
Br
1e
2e
O
Br
O
Br
O
94
O
NO2
B
NO2
B
O
O
1f
2f
Br
O
N
N
Br
O
7
8
88
91
NC
NC
2g
1g
Br
O
Cl
N
Cl
N
Br
Br
O
MeOOC
MeOOC
1h
2h
MeOOC
S
O
MeOOC
9
96
S
Br
O
1i
2i
a Isolated yields
Table 3 Reaction of gem-Dibromomethyl Aromatics 1a,j–r with Malonic Acid and Di-tert-butyl Dicarbonate
Entry
Substrate
Product
Yielda (%)
Br
O
Br
O
1
88
1a
2a
Br
I
O
Br
O
2
3
87
87
MeOOC
I
MeOOC
1j
2j
O
Br
Br
Br
O
Br
N
N
1k
2k
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2352
J. K. Augustine et al.
PAPER
Table 3 Reaction of gem-Dibromomethyl Aromatics 1a,j–r with Malonic Acid and Di-tert-butyl Dicarbonate (continued)
Entry
4
Substrate
Product
Yielda (%)
Br
O
Cl
Cl
N
N
O
Br
89
1l
2l
O
Br
O2N
O
O
O2N
Br
5
91
N
Cl
N
1m
2m
Br
O
Cl
N
Cl
N
Br
O
6
93
F
F
F
F
F
F
1n
2n
O
Br
Br
Br
O
Br
7
8
9
87
96
85
MeO
MeO
2o
1o
O
Br
Br
Br
O
Br
CN
CN
1p
2p
Br
O
F
F
Br
COOMe
O
COOMe
1q
2q
COOMe
COOMe
Br
Br
10
84
O
O
Br
O
Br
O
1r
2r
a Isolated yields.
Having obtained standard reaction conditions, we synthe- The reaction is believed to proceed through nucleophilic
sized a variety of aromatic and heteroaromatic tert-butyl catalysis between the bis-pyridinium cation12 and malonic
cinnamates 2j–r in good to excellent yields (Table 3). A acid half ester followed by decarboxylative elimination of
substrate possessing a reactive halogen on the aryl ring pyridine to produce the cinnamic esters (Scheme 2).
(Table 3, entry 5) provided the corresponding tert-butyl When malonic acid is used, the decarboxylative elimina-
ether 2m due to displacement of the chloro group with tion of pyridine provides cinnamic acid, which further re-
tert-butyl alcohol under basic conditions. From Tables 2 acts with di-tert-butyl dicarbonate under basic conditions
and 3, we can discern that this reaction tolerates a wide to provide the corresponding tert-butyl cinnamate.
range of functional groups, such as nitro, halo, cyano, car-
boxylate, methoxy, trifluoromethyl, and boronate
(Table 2, entry 6) to provide the corresponding cinnama-
tes in good yields. Similarly, electron-withdrawing or
electron-donating groups on the substrate did not affect
the yield of a,b-unsaturated carboxylates.
In conclusion, we have demonstrated a valuable variation
of the Knoevenagel–Doebner reaction wherein, gem-di-
bromomethyl aromatics are employed as aldehyde equiv-
alents for the efficient synthesis of tert-butyl cinnamates.
As this reaction provides cinnamic esters in a single step
from gem-dibromomethyl aromatics, which otherwise re-
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PAPER
gem-Dibromomethyl Aromatics as Efficient Aldehyde Equivalents
2353
4-(Dibromomethyl)-2-nitrophenylboronic Acid Pinacol Ester
(1f)
White solid; yield: 78%; mp 109 °C.
2Br–
N+
Br
N+
IR (KBr): 1706, 1618, 1530, 1334, 1097, 662 cm–1.
COOR
piperidine
HOOC
pyridine
Br
1H NMR (400 MHz, DMSO-d6): d = 1.30 (s, 12 H), 7.49 (s, 1 H),
8.05–8.09 (m, 2 H), 8.19–8.21 (t, 1 H).
FG
FG
– pyridine, HBr
13C NMR (100 MHz, DMSO-d6): d = 24.5, 36.0, 84.6, 129.3, 131.6,
137.5, 139.6, 144.2.
O
Br–
N+
Anal. Calcd for C13H16BBr2NO4: C, 37.10; H, 3.83; N, 3.33. Found:
C, 37.15; H, 3.88; N, 3.29.
R
– CO2
– pyridine, HBr
O
COOH
FG
FG
6-(Dibromomethyl)pyridine-3-carbonitrile (1g)
Colorless liquid; yield: 83%.
O
O
R
IR(neat): 2234, 1585, 1471, 1375, 649 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 7.40 (s, 1 H), 7.84 (d, J = 8.1
Hz, 1 H), 8.40 (dd, J = 6.1, 2.1 Hz, 1 H), 9.08 (s, 1 H).
Scheme 2
13C NMR (100 MHz, DMSO-d6): d = 41.9, 109.8, 116.3, 120.6,
141.9, 152.4, 160.9.
quire the hydrolytic conversion of gem-dibromides into
aldehydes, and demonstrates the use of an alternative re-
agent for noncommercial and expensive aldehydes, we
believe that this methodology would be of appreciable use
to the synthetic community. Further, this reaction pro-
vides an interesting insight into the chemistry of gem-di-
bromomethyl aromatics and represents a useful way of
utilizing them as aldehyde counterparts with active meth-
ylene compounds.
Anal. Calcd for C7H4Br2N2: C, 30.47; H, 1.46; N, 10.15. Found: C,
30.52; H, 1.53; N, 10.04.
Methyl 2-Chloro-6-(dibromomethyl)pyridine-3-carboxylate
(1h)
White solid; yield: 67%; mp 78 °C.
IR (KBr): 1720, 1575, 1434, 1264, 1058, 670 cm–1.
1H NMR (400 MHz, CD3OD): d = 3.95 (s, 3 H), 6.97 (s, 1 H), 7.82
(d, J = 7.9 Hz, 1 H), 8.31 (d, J = 7.9 Hz, 1 H).
1H NMR and 13C NMR spectra were recorded on 400 MHz and 100
MHz Bruker spectrometer respectively and elemental analysis was
performed on a Thermo Finnigan FLASH EA 1112 CHN analyzer.
Melting points were recorded (uncorrected) on Buchi Melting Point
B-545 instrument. IR spectra were recorded on a Thermo Scientific
Nicolet 6700 FT-IR spectrophotometer. Reactions were carried out
in an oven dried three-necked round-bottomed flask. Yields in the
tables refer to isolated yields of compounds with purity >96% as de-
termined by 1H NMR and HPLC analysis.
13C NMR (100 MHz, CD3OD): d = 40.0, 55.0, 121.0, 128.7, 143.2,
149.6, 162.3, 165.6.
Anal. Calcd for C9H8Br2ClNO2: C, 30.24; H, 2.26; N, 3.92. Found:
C, 30.30; H, 2.29; N, 3.89.
Methyl 5-(Dibromomethyl)thiophene-2-carboxylate (1i)12
Yield: 76%.
Methyl 4-(Dibromomethyl)-3-iodobenzoate (1j)
Colorless liquid; yield: 72%.
gem-Dibromomethyl Aromatics 1b–r; General Procedure
Without any critical deviation to the reported protocol,14 all the
gem-dibromomethyl aromatics were prepared and purified by chro-
matography.
IR (neat): 1708, 1636, 1494, 1225, 1055, 774 cm–1.
1H NMR (400 MHz, CD3OD): d = 3.93 (s, 3 H), 7.07 (s, 1 H), 8.05–
8.12 (m, 2 H), 8.39 (d, J = 1.5 Hz, 1 H).
13C NMR (100 MHz, CD3OD): d = 45.7, 53.1, 95.1, 131.1, 133.5,
141.3, 149.1, 165.8.
Methyl 4-Bromo-3-(dibromomethyl)benzoate (1b)
White solid; yield: 73%; mp 86 °C.
IR (KBr): 1717, 1590, 1432, 1299, 1110, 638 cm–1.
Anal. Calcd for C9H7Br2IO2: C, 24.92; H, 1.63. Found: C, 25.01; H,
1.70.
1H NMR (400 MHz, DMSO-d6): d = 3.89 (s, 3 H), 7.39 (s, 1 H),
7.80–7.85 (m, 2 H), 8.46 (s, 1 H).
2-Bromo-4-(dibromomethyl)pyridine (1k)14
Yield: 75%.
13C NMR (100 MHz, DMSO-d6): d = 40.3, 52.6, 125.1, 130.0,
131.6, 134.0, 140.3, 164.8.
8-Chloro-2-(dibromomethyl)quinoline (1l)
White solid; yield: 69%; mp 157 °C.
Anal. Calcd for C9H7Br3O2: C, 27.94; H, 1.82. Found: C, 27.99; H,
1.87.
IR (KBr): 1596, 1498, 1453, 1301, 1140, 989, 608 cm–1.
Methyl 4-(Dibromomethyl)naphthalene-1-carboxylate (1c)12
Yield: 75%.
1H NMR (400 MHz, DMSO-d6): d = 7.41 (s, 1 H), 7.65 (t, 1 H),
8.01–8.04 (m, 3 H), 8.61 (d, J = 8.6 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 44.1, 120.7, 127.8, 128.6,
129.4, 131.2, 132.7, 139.7, 141.9, 159.2.
1-(Dibromomethyl)-4-methoxy-2-nitrobenzene (1d)12
Yield: 82%.
Anal. Calcd for C10H6Br2ClN: C, 35.81; H, 1.80; N, 4.18. Found: C,
35.86; H, 1.87; N, 4.09.
2-Bromo-5-(dibromomethyl)pyridine (1e)14
Yield: 77%.
2-Chloro-5-(dibromomethyl)-3-nitropyridine (1m)
Colorless liquid; yield: 66%.
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2354
J. K. Augustine et al.
PAPER
IR (neat): 1591, 1557, 1532, 1345, 1061, 810 cm–1.
tert-Butyl Cinnamate (2a); Typical Procedure for 2a,j–r Using
Malonic Acid and Di-tert-Butyl Dicarbonate
1H NMR (400 MHz, DMSO-d6): d = 7.50 (s, 1 H), 8.83 (d, J = 2.2
Hz, 1 H), 8.94 (d, J = 2.2 Hz, 1 H).
To a mixture of 1a (5 g, 0.02 mol) and malonic acid (4.16 g, 0.04
mol) in pyridine (25 mL) was added Boc2O (4.8 g, 0.022 mol) fol-
lowed by piperidine (0.07 mL, 0.0008 mol) and the mixture was re-
fluxed for 2 h (completion confirmed by TLC). The brown mixture
was cooled and poured onto ice-water. The aqueous phase was ex-
tracted with Et2O (2 × 50 mL). The combined organic phases were
washed with H2O (1 × 100 mL) and brine (1 × 50 mL) and dried
(Na2SO4). The solvent was removed under vacuum and the crude
product was passed through a small plug of silica using hexane to
afford 2a (3.6 g, 88%) as colorless liquid.
13C NMR (100 MHz, DMSO-d6): d = 35.0, 133.6, 138.7, 142.1,
143.9, 150.0.
Anal. Calcd for C6H3Br2ClN2O2: C, 21.81; H, 0.92; N, 8.48. Found:
C, 21.88; H, 1.01; N, 8.41.
2-Chloro-6-(dibromomethyl)-4-(trifluoromethyl)pyridine (1n)
White solid; yield: 68%; mp 90 °C.
IR (KBr): 1597, 1478, 1443, 1140, 989, 878, 648 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 7.38 (s, 1 H), 7.99 (s, 1 H),
8.05 (s, 1 H).
Methyl 4-Bromo-3-(3-tert-butoxy-3-oxoprop-1-enyl)benzoate
(2b)
White solid; yield: 87%; mp 92 °C.
13C NMR (100 MHz, DMSO-d6): d = 40.6, 117.9, 122.4, 123.0,
123.4, 140.7, 141.0, 141.4, 141.7, 152.0, 161.7.
IR (KBr): 1723, 1638, 1435, 1143, 755 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.48 (s, 9 H), 3.86 (s, 3 H),
6.60 (d, J = 15.8 Hz, 1 H), 7.78 (d, J = 15.8 Hz, 1 H), 7.83–7.88 (m,
2 H), 8.28 (d, J = 1.9 Hz, 1 H).
Anal. Calcd for C7H3Br2ClF3N: C, 23.79; H, 0.86; N, 3.96. Found:
C, 23.86; H, 0.89; N, 3.89.
2-Bromo-4-(dibromomethyl)anisole (1o)
This compound is unstable and hence the crude dibromide was used
in the subsequent reaction.
13C NMR (100 MHz, DMSO-d6): d = 28.2, 52.9, 81.0, 124.7, 129.1,
129.9, 130.2, 132.0, 134.2, 134.6, 140.6, 165.2, 165.9.
Anal. Calcd for C15H17BrO4: C, 52.80; H, 5.02. Found: C, 52.87; H,
5.10.
1H NMR (400 MHz, CDCl3): d = 3.93 (s, 3 H), 6.59 (s, 1 H), 6.86
(d, J = 8.6 Hz, 1 H), 7.49 (dd, J = 8.6, 2.4 Hz, 1 H), 8.08 (s, 1 H).
Methyl 4-(3-tert-Butoxy-3-oxoprop-1-enyl)naphthalene-1-car-
boxylate (2c)
White solid; yield: 85%; mp 110 °C.
4-Bromo-2-(dibromomethyl)benzonitrile (1p)
White solid; yield: 77%; mp 120 °C.
IR (KBr): 2226, 1578, 1482, 1145, 826, 646, 552 cm–1.
IR (KBr): 1696, 1635, 1438, 1260, 1127, 766 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 7.39 (s, 1 H), 7.82 (dd, J = 8.2,
1.9 Hz, 1 H), 7.92 (d, J = 8.2 Hz, 1 H), 8.03 (s, 1 H).
1H NMR (400 MHz, DMSO-d6): d = 1.52 (s, 9 H), 3.94 (s, 3 H),
6.64 (d, J = 15.6 Hz, 1 H), 7.68–7.74 (m, 2 H), 7.99 (d, J = 7.6 Hz,
1 H), 8.08 (d, J = 7.6 Hz, 1 H), 8.25–8.27 (m, 1 H), 8.35 (d, J = 15.7
Hz, 1 H), 8.74 (d, J = 1.3 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 36.7, 109.6, 115.9, 127.6,
130.9, 134.1, 137.0, 145.4.
13C NMR (100 MHz, DMSO-d6): d = 27.8, 52.4, 80.4, 123.8, 124.1,
124.8, 125.7, 127.3, 127.9, 128.3, 129.1, 130.5, 130.9, 135.8, 139.2,
165.0, 167.0.
Anal. Calcd for C8H4Br3N: C, 27.16; H, 1.14; N, 3.96. Found: C,
27.20; H, 1.14; N, 3.89.
Methyl 2-(Dibromomethyl)-4-fluorobenzoate (1q)
White solid; yield: 73%; mp 54 °C.
Anal. Calcd for C19H20O4: C, 73.06; H, 6.45. Found: C, 73.11; H,
6.50.
IR (KBr): 1712, 1605, 1581, 1431, 1116, 703 cm–1.
tert-Butyl 3-(4-Methoxy-2-nitrophenyl)prop-2-enoate (2d)
Colorless liquid; yield: 89%.
1H NMR (400 MHz, DMSO-d6): d = 3.87 (s, 3 H), 7.36–7.41 (m, 1
H), 7.83–7.86 (m, 2 H), 7.89–7.92 (m, 1 H).
IR (neat): 1706, 1614, 1528, 1248, 1144, 756 cm–1.
13C NMR (100 MHz, DMSO-d6): d = 37.1, 52.7, 117.2, 117.4,
117.5, 117.7, 121.8, 121.8, 132.9, 133.0, 145.0, 145.1, 162.9, 165.2,
165.4.
1H NMR (400 MHz, CDCl3): d = 1.52 (s, 9 H), 3.88 (s, 3 H), 6.23
(d, J = 15.8 Hz, 1 H), 7.14 (dd, J = 8.7, 2.6 Hz, 1 H), 7.47 (d,
J = 2.68 Hz, 1 H), 7.57 (d, J = 8.7 Hz, 1 H), 7.92 (d, J = 15.8 Hz, 1
H).
Anal. Calcd for C9H7Br2FO2: C, 33.16; H, 2.16. Found: C, 33.20; H,
2.22.
13C NMR (100 MHz, CDCl3): d = 28.1, 56.0, 80.8, 109.3, 119.8,
122.6, 123.4, 129.9, 138.1, 149.2, 160.6, 165.3.
Methyl 5-Bromo-2-(dibromomethyl)furan-3-carboxylate (1r)12
Yield: 70%.
Anal. Calcd for C14H17NO5: C, 60.21; H, 6.14; N, 5.02. Found: C,
60.27; H, 6.20; N, 4.93.
tert-Butyl Cinnamate (2a); Typical Procedure for 2a–i Using
tert-Butyl Hydrogen Malonate
tert-Butyl 3-(6-Bromopyridin-3-yl)prop-2-enoate (2e)
White solid; yield: 91%; mp 117 °C.
To a mixture of 1a (10 g, 0.04 mol) and tert-butyl hydrogen mal-
onate (7.68 g, 0.048 mol) in pyridine (40 mL) was added piperidine
(0.14 mL, 0.0016 mol) and the mixture was refluxed for 1.5 h under
N2 (completion confirmed by TLC). The brown mixture was cooled
and poured onto ice-water. The aqueous phase was extracted with
Et2O (2 × 50 mL). The combined organic phases were washed with
H2O (1 × 100 mL), 10% aq NaHCO3 (1 × 50 mL), and brine (1 × 50
mL) and dried (Na2SO4). The solvent was removed under vacuum
to afford 2a16 (7.6 g, 93%) as a colorless liquid.
IR (KBr): 1696, 1638, 1457, 1368, 1145, 980, 825 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.47 (s, 9 H), 6.71 (d, J = 15.8
Hz, 1 H), 7.55 (d, J = 15.8 Hz, 1 H), 7.69 (d, J = 8.3 Hz, 1 H), 8.12
(dd, J = 8.4, 2.3 Hz, 1 H), 8.67 (d, J = 2.1 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 28.2, 80.8, 123.2, 128.6,
130.2, 138.2, 139.3, 142.9, 150.9, 165.4.
Anal. Calcd for C12H14BrNO2: C, 50.72; H, 4.97; N, 4.93. Found: C,
50.80; H, 5.01; N, 4.86.
Synthesis 2009, No. 14, 2349–2356 © Thieme Stuttgart · New York

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gem-Dibromomethyl Aromatics as Efficient Aldehyde Equivalents
2355
tert-Butyl 3-[2-Nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)phenyl]prop-2-enoate (2f)
Colorless liquid; yield: 94%.
IR (KBr): 1698, 1581, 1459, 1364, 1291, 1156, 707 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.46 (s, 9 H), 6.86 (d, J = 15.8
Hz, 1 H), 7.49 (d, J = 15.8 Hz, 1 H), 7.74 (dd, J = 5.1, 1.2 Hz, 1 H),
7.98 (s, 1 H), 8.40 (d, J = 5.1 Hz, 1 H).
IR (neat): 1712, 1531, 1343, 1343, 1145, 755 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.31 (s, 12 H), 1.47 (s, 9 H),
6.53 (d, J = 15.8 Hz, 1 H), 7.84 (d, J = 15.8 Hz, 1 H), 7.91–7.95 (m,
2 H), 8.30 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 27.6, 80.7, 121.5, 126.0,
126.4, 139.3, 142.2, 144.8, 150.8, 164.6.
Anal. Calcd for C12H14BrNO2: C, 50.72; H, 4.97; N, 4.93. Found: C,
50.81; H, 5.01; N, 4.85.
13C NMR (100 MHz, DMSO-d6): d = 24.5, 27.7, 80.6, 84.5, 125.0,
129.1, 129.7, 131.9, 138.4, 138.9, 147.8, 164.6.
tert-Butyl 3-(8-Chloroquinolin-2-yl)prop-2-enoate (2l)
White solid; yield: 89%; mp 100 °C.
Anal. Calcd for C9H26BNO6: C, 60.82; H, 6.98; N, 3.73. Found: C,
60.89; H, 7.04; N, 3.68.
IR (KBr): 1698, 1594, 1251, 1150, 971, 830, 750 cm–1.
tert-Butyl 3-(5-Cyanopyridin-2-yl)prop-2-enoate (2g)
White solid; yield: 88%; mp 127 °C.
1H NMR (400 MHz, DMSO-d6): d = 1.51 (s, 9 H), 7.03 (d, J = 15.8
Hz, 1 H), 7.59 (t, 1 H), 7.71 (d, J = 15.8 Hz, 1 H), 7.95–7.97 (m, 2
H), 8.03 (d, J = 8.5 Hz, 1 H), 8.48 (d, J = 8.5 Hz, 1 H).
IR (KBr): 2230, 1690, 1589, 1325, 1196, 857 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.48 (s, 9 H), 6.90 (d, J = 15.8
Hz, 1 H), 7.58 (d, J = 15.8 Hz, 1 H), 7.95 (d, J = 8.2 Hz, 1 H), 8.38
(dd, J = 8.1, 2.1 Hz, 1 H), 9.03 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 27.7, 80.6, 121.7, 125.9,
127.3, 127.4, 129.1, 130.1, 132.4, 137.7, 142.6, 143.2, 153.5, 164.9.
Anal. Calcd for C16H16ClNO2: C, 66.32; H, 5.57; N, 4.83. Found: C,
66.36; H, 5.62; N, 4.76.
13C NMR (100 MHz, DMSO-d6): d = 28.1, 81.2, 109.5, 117.4,
124.5, 127.0, 141.4, 141.6, 153.0, 155.9, 165.1.
tert-Butyl 3-(6-tert-Butoxy-5-nitropyridin-3-yl)prop-2-enoate
(2m)
Colorless liquid; yield: 91%.
Anal. Calcd for C13H14N2O2: C, 67.81; H, 6.13; N, 12.17. Found:
C, 67.88; H, 6.19; N, 12.10.
Methyl 6-(3-tert-Butoxy-3-oxoprop-1-enyl)-2-chloropyridine-3-
carboxylate (2h)
White solid; yield: 91%; mp 63 °C.
IR (neat): 1708, 1606, 1532, 1463, 1365, 778 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.46 (s, 9 H), 1.58 (s, 9 H),
6.65 (d, J = 15.7 Hz, 1 H), 7.57 (d, J = 15.7 Hz, 1 H), 8.72 (m, 2 H).
IR (KBr): 1731, 1699, 1579, 1366, 1057, 785 cm–1.
13C NMR (100 MHz, DMSO-d6): d = 28.2, 28.5, 80.6, 84.5, 121.9,
124.2, 132.9, 136.2, 138.6, 151.2, 155.4, 165.6.
1H NMR (400 MHz, CDCl3): d = 1.52 (s, 9 H), 3.96 (s, 3 H), 6.93
(d, J = 15.8 Hz, 1 H), 7.38 (d, J = 7.8 Hz, 1 H), 7.49 (d, J = 15.8 Hz,
1 H), 8.17 (d, J = 7.8 Hz, 1 H).
Anal. Calcd for C16H22N2O5: C, 59.62; H, 6.88; N, 8.69. Found: C,
59.66; H, 6.91; N, 8.56.
13C NMR (100 MHz, CDCl3): d = 28.0, 52.8, 81.2, 121.7, 126.2,
128.0, 139.3, 141.1, 150.1, 155.8, 164.6, 165.2.
tert-Butyl 3-[6-Chloro-4-(trifluoromethyl)pyridin-2-yl]prop-2-
enoate (2n)
White solid; yield: 93%; mp 72 °C.
Anal. Calcd for C14H16ClNO4:C, 56.48; H, 5.42; N, 4.70. Found: C,
56.52; H, 5.44; N, 4.65.
IR (KBr): 1701, 1557, 1333, 1304, 1132, 699 cm–1.
Methyl 5-(3-tert-Butoxy-3-oxoprop-1-enyl)thiophene-2-carbox-
ylate (2i)
White solid; yield: 96%; mp 50 °C.
1H NMR (400 MHz, DMSO-d6): d = 1.48 (s, 9 H), 6.89 (d, J = 15.8
Hz, 1 H), 7.60 (d, J = 15.8 Hz, 1 H), 8.01 (s, 1 H), 8.22 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 28.1, 81.2, 119.7, 119.8,
121.0, 121.6, 123.8, 126.9, 140.1, 140.9, 141.3, 151.8, 155.3, 164.9.
IR (KBr): 1698, 1627, 1477, 1283, 1136, 829 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.51 (s, 9 H), 3.88 (s, 3 H), 6.27
(d, J = 15.8 Hz, 1 H), 7.18 (d, J = 4.0 Hz, 1 H), 7.60 (d, J = 15.8 Hz,
1 H), 7.68 (d, J = 4.0 Hz, 1 H).
Anal. Calcd for C13H13ClF3NO2: C, 50.75; H, 4.26; N, 4.55. Found:
C, 50.81; H, 4.31; N, 4.49.
13C NMR (100 MHz, CDCl3): d = 28.1, 52.3, 81.0, 121.9, 129.9,
133.8, 134.5, 135.0, 145.6, 162.1, 165.4.
tert-Butyl 3-(3-Bromo-4-methoxyphenyl)prop-2-enoate (2o)
Colorless liquid; yield: 87%.
Anal. Calcd for C13H16O4S: C, 58.19; H, 6.01. Found: C, 58.23; H,
6.08.
IR (neat): 1701, 1557, 1367, 1333, 1134, 707 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.53 (s, 9 H), 3.92 (s, 3 H), 6.25
(d, J = 15.7 Hz, 1 H), 6.88 (d, J = 8.4 Hz, 1 H), 7.49–7.40 (m, 2 H),
7.73 (s, 1 H).
Methyl 4-(3-tert-Butoxy-3-oxoprop-1-enyl)-3-iodobenzoate (2j)
White solid; yield: 87%; mp 80 °C.
13C NMR (100 MHz, CDCl3): d = 28.1, 56.3, 80.4, 111.7, 112.1,
119.1, 128.7, 132.4, 141.6, 157.1, 166.2.
IR (KBr): 1720, 1698, 1319, 1251, 972, 763 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.55 (s, 9 H), 3.92 (s, 3 H), 6.32
(d, J = 15.8 Hz, 1 H), 7.59 (d, J = 7.8 Hz, 1 H), 7.81 (d, J = 15.8 Hz,
1 H), 7.98 (dd, J = 7.8, 1.6 Hz, 1 H), 8.53 (d, J = 1.5 Hz, 1 H).
Anal. Calcd for C14H17BrO3: C, 53.69; H, 5.47. Found: C, 53.72; H,
5.52.
13C NMR (100 MHz, CDCl3): d = 28.1, 52.5, 81.4, 100.2, 125.0,
126.9, 129.3, 134.4, 140.9, 142.1, 145.5, 165.0, 165.1.
tert-Butyl 3-(5-Bromo-2-cyanophenyl)prop-2-enoate (2p)
White solid; yield: 96%; mp 124 °C.
Anal. Calcd for C15H17IO4: C, 46.41; H, 4.41. Found: C, 46.46; H,
4.43.
IR (KBr): 2226, 1701, 1626, 1478, 1299, 1167, 819 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.48 (s, 9 H), 6.91 (d, J = 15.8
Hz, 1 H), 7.63 (d, J = 15.8 Hz, 1 H), 7.79–7.86 (m, 2 H), 8.38 (s, 1
H).
tert-Butyl 3-(2-Bromopyridin-4-yl)prop-2-enoate (2k)
White solid; yield: 87%; mp 68 °C.
Synthesis 2009, No. 14, 2349–2356 © Thieme Stuttgart · New York

2356
J. K. Augustine et al.
PAPER
(7) Bowels, B. L.; Miller, A. J. J. Food Sci. 1994, 59, 905.
13C NMR (100 MHz, DMSO-d6): d = 27.7, 80.8, 110.7, 116.7,
126.0, 127.9, 130.2, 133.4, 134.9, 136.8, 138.4, 164.6.
(8) For selected examples, see: (a) Maryanoff, B. E.; Reitz, A.
B. Chem. Rev. 1989, 89, 863. (b) Hatsuda, M.; Kuroda, T.;
Seki, M. Synth. Commun. 2003, 33, 427. (c) Kisanga, P.;
’Sa, B. D.; Verkade, J. Tetrahedron 2001, 57, 8047.
(d) Herrmann, W. A.; Wang, M. Angew. Chem., Int. Ed.
Engl. 1991, 30, 1641; Angew. Chem. 1991, 103, 1709.
(e) Ledford, B. E.; Carreira, E. M. Tetrahedron Lett. 1997,
38, 8125. (f) Barma, D. K.; Kundu, A.; Bandyopadhyay, A.;
Sangras, B.; Briot, A.; Mioskowski, R.; Falck, J. R.
Tetrahedron Lett. 2004, 45, 5917. (g) Taguchi, H.; Shimoji,
K.; Yamamoto, H.; Nozaki, H. Bull. Chem. Soc. Jpn. 1974,
47, 2529. (h) Matui, S.; Tanaka, K.; Kaji, A. Synthesis 1983,
127. (i) Huang, Y.; Shen, Y.; Chen, C. Tetrahedron Lett.
1986, 27, 2903. (j) Olah, G. A.; Wu, A. H.; Farooq, O.;
Prakash, G. K. Synthesis 1988, 537.
Anal. Calcd for C14H14BrNO2: C, 54.56; H, 4.58; N, 4.55. Found: C,
54.60; H, 4.62; N, 4.50.
Methyl 2-(3-tert-Butoxy-3-oxoprop-1-enyl)-4-fluorobenzoate
(2q)
Colorless liquid; yield: 85%.
IR (neat): 1711, 1579, 1489, 1252, 1149, 757 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.47 (s, 9 H), 3.84 (s, 3 H),
6.51 (d, J = 15.8 Hz, 1 H), 7.32–7.37 (m, 1 H), 7.72–7.75 (m, 1 H),
7.92–7.95 (m, 1 H), 8.19 (d, J = 15.8 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 27.7, 52.4, 80.2, 114.5, 116.5,
116.7, 123.7, 126.0 (d), 133.2 (d), 138.1 (d), 140.3 (d), 162.8, 165.0,
165.3, 165.8.
(9) For a two step process for recycling Ph3PO, see p. 7 in:
Hermeling, D.; Bassler, P.; Hammes, P.; Hugo, R.;
Lechtken, P.; Siegel, H. EP 0638580, 1995.
Anal. Calcd for C15H17FO4: C, 64.28; H, 6.11. Found: C, 64.33; H,
6.20.
(10) (a) Horner, L.; Hoffmann, H. M. R.; Wippel, H. G. Chem.
Ber. 1958, 91, 61. (b) Wadsworth, W. S. Jr.; Emmons, W.
D. Org. Synth. Coll. Vol. V; John Wiley & Sons: London,
1973, 547. (c) Nagaoka, H.; Kishi, Y. Tetrahedron 1981, 37,
3873. (d) Ando, K. J. Org. Chem. 1997, 62, 1934.
(11) (a) Galat, A. J. Am. Chem. Soc. 1946, 68, 376. (b) Martin,
C. J.; Schepartz, A. I.; Daubert, B. F. J. Am. Chem. Soc.
1948, 70, 2601. (c) Klein, J.; Bergmann, E. D. J. Am. Chem.
Soc. 1957, 79, 3452.
Methyl 5-Bromo-2-(3-tert-butoxy-3-oxoprop-1-enyl)furan-3-
carboxylate (2r)
Colorless liquid; yield: 84%.
IR (neat): 1719, 1552, 1432, 1380, 1252, 618 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.52 (s, 9 H), 3.88 (s, 3 H), 6.49
(d, J = 15.8 Hz, 1 H), 6.73 (s, 1 H), 7.87 (d, J = 15.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 28.1, 52.1, 81.0, 114.2, 120.5,
123.4, 124.9, 127.5, 155.2, 161.9, 165.4.
(12) Augustine, J. K.; Naik, Y. A.; Mandal, A. B.; Chowdappa,
N.; Praveen, V. B. J. Org. Chem. 2007, 72, 9854.
(13) For selected examples, see: (a) Larock, R. C.
Comprehensive Organic Transformations, 2nd Ed.; John
Wiley & Sons: Chichester, 1999, 1224. (b) Chung, S. J.;
Kim, D. H. Tetrahedron 1995, 51, 12549. (c) Sander, W.;
Exner, M. J. Chem. Soc., Perkin Trans. 2 1999, 2285.
(d) Tabushi, I.; Sasaki, T. Tetrahedron Lett. 1982, 23, 1913.
(e) Dann, O.; Char, H.; Griessmeier, H. Liebigs Ann. Chem.
1982, 1836. (f) Li, W.; Li, J.; DeVincentis, D.; Mansour, T.
S. Tetrahedron Lett. 2004, 45, 1071. (g) Coleman, G. H.;
Honeywell, G. E. Org. Synth. Coll. Vol. II; John Wiley &
Sons: London, 1943, 98–91. (h) Bankston, D. Synthesis
2004, 282. (i) Gillespie, J. S.; Acharya, S. P.; Shamblee, D.
A.; Davis, R. E. Tetrahedron 1975, 31, 3. (j)Zondervan,C.;
Beuken, E.; Kooijman, H.; Spek, A. L.; Feringa, B. L.
Tetrahedron Lett. 1997, 38, 3111. (k) Helms, A.; Heiler, D.;
McLendon, G. J. Am. Chem. Soc. 1992, 114, 6227.
(l) Waehaelae, K.; Ojanperae, I.; Haeyri, L.; Hase, T. A.
Synth. Commun. 1987, 17, 137. (m) Man, Y.-M.; Thomas,
C. W.; Wong, H. N. C. J. Org. Chem. 1990, 55, 3214.
(n) Jung, M. E.; Hogan, K. T. Tetrahedron Lett. 1988, 29,
6199.
Anal. Calcd for C13H15BrO5: C, 47.15; H, 4.57. Found: C, 47.22; H,
4.63.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Acknowledgment
The authors gratefully acknowledge Dr. Goutam Das, COO,
Syngene International Ltd for his invaluable support.
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Synthesis 2009, No. 14, 2349–2356 © Thieme Stuttgart · New York