Di-tert-butyl dicarbonate: a versatile carboxylating reagent

Article abstract of DOI:10.1016/j.tet.2008.10.089

Carbon nucleophiles generated by a non-nucleophilic base (LDA) were effectively trapped with di-tert-butyl dicarbonate (Boc-anhydride) to provide the corresponding tert-butyl aryl acetates, di-tert-butyl aryl malonates, unsymmetrical aryl malonates and te

Full text of DOI:10.1016/j.tet.2008.10.089

Tetrahedron 65 (2009) 134–138
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Tetrahedron
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Di-tert-butyl dicarbonate: a versatile carboxylating reagent
,
b
,
b
a
a
John Kallikat Augustine a , Y. Arthoba Naik , Veeramani Vairaperumal , Sharmila Narasimhan
*
a Syngene International Ltd, Biocon Park, Plot No. 2 & 3, Bommasandra-Jigani Road, Bangalore 560 099, India
b Department of Studies in Chemistry, Kuvempu University, Shankaraghatta, Shimoga 577 451, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Carbon nucleophiles generated by a non-nucleophilic base (LDA) were effectively trapped with di-tert-
butyl dicarbonate (Boc-anhydride) to provide the corresponding tert-butyl aryl acetates, di-tert-butyl aryl
malonates, unsymmetrical aryl malonates and tert-butyl benzoates in high yields. This reaction repre-
sents another useful way to prepare a variety of tert-butyl carboxylates and highlights the synthetic
utility of di-tert-butyl dicarbonate as a versatile carboxylating reagent.
Received 15 September 2008
Received in revised form 27 October 2008
Accepted 29 October 2008
Available online 6 November 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Carbon nucleophile
Boc-anhydride
Carboxylating reagent
Non-nucleophilic base
Di-tert-butyl malonate
1. Introduction
n-butylmagnesium ate complex, followed by reacting with Boc-
anhydride.7 Interestingly the broad scope and synthetic utility of
Di-tert-butyl dicarbonate (Boc-anhydride) is a widely used re-
agent in organic chemistry. It is an extremely efficient reagent to
introduce the tert-butoxycarbonyl (BOC) protecting group for the
amine functionality.1 It is also an efficient tert-butoxycarbonylating
agent for alcohols and thiols.2 Boc-anhydride has been used for the
conversion of amines to corresponding isocyanates, carbamates
and urea derivatives.3 In some cases, it is used as an apparent
dehydrating agent when it reacts with carboxylic acids,4 primary
nitroalkanes,5 or with certain hydroxyl groups.6 It’s easy to in-
troduce and cleave as a protecting group add to its value as a ver-
satile reagent.
Compounds possessing tert-butyl carboxylate functionality are
useful building blocks in organic synthesis, preferably due to their
ease of de-protection to the corresponding carboxylic acid under
acidic medium. Esterification of a carboxylic acid with tert-butanol,
tert-butyl bromide or isobutylene is the most common method of
synthesis of a tert-butyl ester. As part of a research program aimed
at developing a one step organic transformation to achieve tert-
butyl acetates of some nitrogen heterocycles, we decided to explore
the possibility of using Boc-anhydride as a carboxylating agent.
Hongmei Li and Jaume Balsells have demonstrated the synthesis of
tert-butyl benzoates from haloarenes bearing multiple halogen
substituents via selective metal–halogen exchange with lithium tri-
this reagent as a carboxylating agent has not been explored for
substrates that could not produce triarenemagnesium ate com-
plexes. Herein, we report Boc-anhydride as a mild and efficient
carboxylating reagent by demonstrating the synthesis of tert-butyl
aryl acetates, substituted di-tert-butyl malonates and tert-butyl
benzoates by trapping the carbon nucleophiles generated by a non-
nucleophilic base such as LDA8 with Boc-anhydride.
2. Results and discussion
Our initial investigations were aimed at scrutinizing the feasi-
bility of trapping Boc-anhydride with carbanions generated by LDA.
Accordingly, the nitrogen heterocycle 1a was treated with a freshly
prepared solution of LDA (1.1 equiv)9 in THF at ꢀ78 ꢁC for 0.5 h and
to the resulting solution was added Boc-anhydride (1.1 equiv). To
our satisfaction, the product formed was found to be the expected
tert-butyl acetate 2a in 84% isolated yield (entry 1, Table 1). Sub-
sequently, we investigated the scope of this reagent as a tert-butyl
carboxylating agent on other nitrogen heterocycles (entries 2–11,
Table 1) having an active methyl group as shown in Scheme 1. This
procedure was found to exhibit excellent scope, and the reaction
condition was found to be optimal as we could obtain most of the
products in good to excellent yields as depicted in Table 1. Sur-
prisingly, 3-cyano-4-picoline did not react with LDA under this
reaction conditions and only starting material was recovered from
the reaction mixture (entry 8, Table 1). While pyridine and quino-
line substrates provided good yield of products, moderate yield was
* Corresponding author. Tel.: þ91 80 2808 3131; fax: þ91 80 2808 3150.
E-mail address: john.kallikat@syngeneintl.com (J.K. Augustine).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.10.089

J.K. Augustine et al. / Tetrahedron 65 (2009) 134–138
135
obtained for pyrazine (entry 5, Table 1). Interestingly, the use of
excess of LDA (2.2 equiv) and Boc-anhydride (2.2 equiv) led to the
formation of di-tert-butyl malonates (entries 9–11, Table 1). It fur-
ther emphasizes the synthetic utility of Boc-anhydride in producing
the tert-butyl malonates of substrates possessing an active methyl
group.
Table 1
Reaction of Boc-anhydride with carbon nucleophiles generated by LDA via Scheme 1
Entry
1
Substrate
Time (min)
Product
Yielda (%)
O
30
84
Cl
F
O
O
N
Cl
N
1a
B
B
O
2a
LDA (1.1 equiv)
FG
FG
Boc2O (1.1 equiv)
- 78 °C
A
A
A
O
O
2
30
86
O
O
N
N
N
F
2b
1b
B
B
O
O
LDA (2.2 equiv)
Boc2O (2.2 equiv)
- 78°C
FG
FG
N
A
3
4
45
30
91
83
Br
O
O
Br
O
1c
2c
A = Nitrogen; B = Carbon or Nitrogen
A = Carbon; B = Nitrogen
O
N
N
1d
Scheme 1.
2d
Having achieved the initial objective of tert-butyl acetate syn-
thesis using Boc-anhydride as a carboxylating reagent, we pro-
ceeded to study the generality and efficacy of this method. With the
optimal reaction conditions in hand, subsequently, we investigated
the scope of this reaction on active methylene compounds (Scheme
2). A variety of active methylene compounds bearing multiple
functional groups such as halo, methoxy, nitro, alkyl and tri-
fluoromethoxy (entries 1–9, Table 2) participated effectively in this
ester synthesis. Substrates having multiple reactive centres (entries
4 and 6, Table 2) were also studied. It is interesting to note that
substrates having two reactive centers such as 3d and 3f gave ex-
clusively 4d and 4f at ꢀ78 ꢁC. Further, unlike in the case of active
methyl substrates, the use of excess of LDA (2.2 equiv) and Boc-
anhydride (2.2 equiv) failed to introduce a second tert-butyl car-
boxylate group on substrates possessing an active methylene
group. As described in Table 2, this reaction was also found to be
useful for the synthesis of tert-butyl benzoates (Scheme 3). Com-
mercially available electron rich substrates such as 3j–3k were
reacted with Boc-anhydride under these conditions to provide the
corresponding tert-butyl benzoates in good yields. The tolerance of
functional group such as bromo under these conditions adds
a synthetic advantage to this protocol (entries 10–12, Table 2).
N
N
O
5
6
7
45
45
45
68
85
88
O
N
N
1e
2e
NC
Cl
NC
Cl
O
O
O
O
N
N
N
1f
2f
N
Cl
N
Cl
N
2g
1g
O
0b
O
8
9
45
30
CN
1h
CN
2h
N
O
F
O
93c
O
O
O
N
1i
F
LDA (1.1 equiv)
O
FG
2i
FG
O
O
O
EWG
N
O
O
O
O
O
EWG
- 78 °C
N
Br
O
10
45
89c
Br
EWG = Electron withdrawing group
1j
Scheme 2.
2j
O
N
O
3. Conclusion
11
45
81c
N
1k
O
O
In summary, carbanions generated by a non-nucleophilic base
(LDA) were effectively trapped with di-tert-butyl dicarbonate to
provide the corresponding tert-butyl carboxylates in high yields.
This reaction represents another useful way to prepare a variety of
tert-butyl aryl acetates, di-tert-butyl aryl malonates and tert-butyl
benzoates and highlights the synthetic utility of di-tert-butyl
dicarbonate as a versatile carboxylating reagent.
2k
a
Isolated yields.
b
c
Starting material was recovered.
Excess of LDA and Boc-anhydride (2.2 equiv each) were used.

136
J.K. Augustine et al. / Tetrahedron 65 (2009) 134–138
Table 2
Reaction of Boc-anhydride with carbon nucleophiles generated by LDA via Schemes
2 and 3
Table 2 (continued)
Entry
Substrate
Time (min)
70
Producta
Yieldb (%)
Entry
1
Substrate
Time (min)
Producta
Yieldb (%)
F
O
F
Br
O
Br
10
91
CN
N
N
Br
Br
4j
60
89
CN
3j
O
O
3a
4a
F
O
F
O
O
O2N
11
70
70
84
87
O2N
Br
Br
F
Br
F
4k
CN
2
3
90
60
90
86
3k
CN
O
O
3b
O
O
O
4b
Br
12
O
O
CN
O
CN
CN
O
F
O
F
4l
3l
O
a
Isolated yields.
3c
4c
b
Excess LDA and Boc-anhydride (2.1 equiv each) were used.
F
F
4. Experimental
4.1. General
CN
O
4
5
60
70
88
92
O
3d
4d
1H 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. 19F
NMR spectra were recorded on 376-MHz Bruker spectrometer.
Melting points were recorded (uncorrected) on Buchi Melting Point
B-545 instrument. Infrared spectra were recorded on a Thermo
Scientific Nicolet 6700 FT-IR spectrometer. Coupling constants
were reported wherever it was necessary in hertz (Hz). The mass
spectra were recorded on Agilent LC/MSD SL 1100 instrument.
Reactions were carried out in an oven dried three-necked round-
bottomed flask. Yields in table refer to isolated yields of compounds
with purity >95% as determined by 1H NMR and HPLC analysis.
COOMe
O
COOMe
COOMe
O
3e
4e
O
O
COOMe
O
O
6
70
85
O
O
4.2. General procedure for the preparation of 2a–2g and 4a–4l
4f
3f
F
F
To a solution of diisopropylamine (0.12 mol) in THF (100 mL) at
ꢀ78 ꢁC was added n-BuLi (0.11 mol, 3 M solution in hexane) in
drops over a period of 15 min and the resulting solution was stirred
at ꢀ78 ꢁC for additional 30 min. To the above LDA solution was
added substrates 1a–1g and 3a–3l (0.10 mol) in THF (20 mL) in
drops and the reaction mixture was stirred for 1 h. To this was
added Boc-anhydride (0.11 mol) and the reaction mixture was
slowly allowed to room temperature over a period of 2 h, and di-
luted with water (200 mL). The product was extracted with diethyl
ether (2ꢂ100 mL). The combined organic layer was washed with
water (100 mL), brine (50 mL) and dried over sodium sulfate. The
F
F
F
F
COOMe
O
7
8
70
70
91
84
COOMe
O
3g
4g
COOMe
O
S
COOMe
3h
S
O
4h
EDG
O
EDG
F
F
LDA (1.1 equiv)
O
F
F
FG
FG
O
F
O
F
O
O
EDG
EDG
O
O
O
- 78 °C
9
70
87
O
CN
3i
EDG = Electron donating group
NC
O
4i
Scheme 3.

J.K. Augustine et al. / Tetrahedron 65 (2009) 134–138
137
organic phase was concentrated under reduced pressure and the
residue was purified by flash chromatography (1–5% EtOAc/hex-
ane) to afford compounds 2a–2g and 4a–4l as colourless liquids.
The same protocol was used for the synthesis of 2i–2k, except
for the fact that 0.05 mmol of 1i–1k were used.
(400 MHz, CDCl3) 8.15–8.13 (1H, d, J 8.4 Hz, Ph), 7.83–7.81 (1H, dd, J
7.4,1.2 Hz, Ph), 7.74–7.72 (1H, dd, J 8.2,1.2 Hz, Ph), 7.52–7.50 (1H, d, J
8.4 Hz, Ph), 7.45–7.41 (1H, t, Ph), 4.05 (2H, s, CH2COOtBu), 1.49 (9H,
s, COOtBu); dC (100.6 MHz, CDCl3) 169.6, 156.4, 144.0, 136.6, 133.2,
129.6, 128.3, 126.6, 126.1, 122.7, 81.4, 45.9, 28.0; MS (ESI) 278
[MþH]þ.
4.2.1. tert-Butyl (6-chloropyridin-2-yl)acetate (2a)
Colourless liquid; Rf (10% EtOAc/hexane) 0.60; nmax (liquid film)
1726, 1584, 1439, 1134 cmꢀ1; [Found: C, 58.09; H, 6.25; N, 6.12.
C11H14ClNO2 requires: C, 58.03; H, 6.20; N, 6.15%.] dH (400 MHz,
CDCl3) 7.63–7.59 (1H, t, Ph), 7.23–7.21 (2H, m, Ph), 3.73 (2H, s,
CH2COOtBu), 1.44 (9H, s, COOtBu); dC (100.6 MHz, DMSO-d6) 169.3,
155.7, 150.6, 139.0, 122.5, 122.4, 81.5, 44.5, 28.0; MS (ESI) 228
[MþH]þ.
4.2.8. Di-tert-butyl (2-fluoropyridin-4-yl)malonate (2i)
Off-white solid; Rf (10% EtOAc/hexane) 0.70; mp 45.5–47.2 ꢁC;
nmax (KBr) 1733, 1610, 1414, 1285, 1139, 849 cmꢀ1; [Found: C, 61.77;
H, 7.19; N, 4.45. C16H22FNO4 requires: C, 61.72; H, 7.12; N, 4.50%.] dH
(400 MHz, CDCl3) 8.22–8.21 (1H, d, J 5.1 Hz, Ph), 7.23–7.21 (1H, m,
Ph), 7.01 (1H, s, Ph), 4.4 (2H, s, CH(COOtBu)2), 1.48 (18H, s,
CH(COOtBu)2); dC (100.6 MHz, CDCl3) 165.5, 164.9, 162.6, 147.6,
147.5, 147.4, 122.2, 122.1, 110.6, 110.2, 83.1, 59.2, 59.1, 28.0; dF
(376.5 MHz, CDCl3) ꢀ67.73 (1F, s); MS (ESI) 312 [MþH]þ.
4.2.2. tert-Butyl (2-fluoropyridin-4-yl)acetate (2b)
Colourless liquid; Rf (10% EtOAc/hexane) 0.60; nmax (liquid film)
1726, 1612, 1465, 1280, 1137, 854 cmꢀ1; [Found: C, 62.61; H, 6.74; N,
6.60. C11H14FNO2 requires: C, 62.55; H, 6.68; N, 6.63%.] dH
(400 MHz, CDCl3) 8.18–8.16 (1H, d, J 5.1 Hz, Ph), 7.12–7.10 (1H, d, J
5.1 Hz, Ph), 6.88 (1H, s, Ph), 3.57 (2H, s, CH2COOtBu), 1.45 (9H, s,
COOtBu); dC (100.6 MHz, CDCl3) 168.6, 165.1, 162.7, 149.1, 149.1,
147.5, 147.4, 129.1, 127.6, 122.5, 122.2, 110.3, 109.9, 81.9, 41.7, 41.7,
27.9; dF (376.5 MHz, CDCl3) ꢀ68.34 (1F, s); MS (ESI) 212 [MþH]þ.
4.2.9. Di-tert-butyl (2-bromopyridin-4-yl)malonate (2j)
White solid; Rf (10% EtOAc/hexane) 0.75; mp 64.8–66.2 ꢁC; nmax
(KBr) 1739, 1731, 1588, 1456, 1369, 1134, 1085, 843 cmꢀ1; [Found: C,
51.67; H, 6.03; N, 3.70. C16H22BrNO4 requires: C, 51.62; H, 5.96; N,
3.76%.] dH (400 MHz, CDCl3) 8.37–8.35 (1H, d, J 5.1 Hz, Ph), 7.53 (1H,
s, Ph), 7.33–7.32 (1H, dd, J 5.1, 1.2 Hz, Ph), 4.38 (1H, s, CH(COOtBu)2),
1.47 (18H, s, CH(COOtBu)2); dC (100.6 MHz, CDCl3) 165.5, 149.9,
144.8, 142.2, 128.8, 123.5, 83.2, 58.9, 27.8; MS (ESI) 374 [Mþ2]þ.
4.2.3. tert-Butyl (2-bromopyridin-4-yl)acetate (2c)
Colourless liquid; Rf (10% EtOAc/hexane) 0.60; nmax (liquid film)
1725, 1588, 1416, 1380, 1140, 834 cmꢀ1; [Found: C, 48.60; H, 5.23; N,
5.13. C11H14BrNO2 requires: C, 48.55; H, 5.19; N, 5.15%.] dH
(400 MHz, CDCl3) 8.32–8.31 (1H, d, J 5.0 Hz, Ph), 7.43 (1H, s, Ph),
7.20–7.18 (1H, dd, J 5.0, 1.2 Hz, Ph), 3.51 (2H, s, CH2COOtBu), 1.45
(9H, s, COOtBu); dC (100.6 MHz, CDCl3) 168.5, 149.9, 146.4, 142.3,
128.8, 123.6, 82.0, 41.4, 27.9; MS (ESI) 274 [Mþ2]þ.
4.2.10. Di-tert-butyl (pyridin-2-yl)malonate (2k)
Colourless liquid; Rf (10% EtOAc/hexane) 0.70; nmax (liquid film)
1725, 1472, 1367, 1128, 757 cmꢀ1; [Found: C, 65.60; H, 8.03; N, 4.69.
C16H23NO4 requires: C, 65.51; H, 7.90; N, 4.77%.] dH (400 MHz,
CDCl3) 8.56–8.55 (1H, m, Ph), 7.73–7.68 (1H, m, Ph), 7.52–7.50 (1H,
dd,
J 7.9, 0.7 Hz, Ph), 7.25–7.21 (1H, m, Ph), 4.76 (1H, s,
CH(COOtBu)2), 1.47 (18H, s, CH(COOtBu)2); dC (100.6 MHz, CDCl3)
166.8, 153.8, 149.1, 136.4, 123.6, 122.7, 82.2, 62.7, 27.7; MS (ESI) 294
[MþH]þ.
4.2.4. tert-Butyl (3,5-dimethylpyridin-2-yl)acetate (2d)
Colourless liquid; Rf (10% EtOAc/hexane) 0.65; nmax (liquid film)
1727, 1472, 1366, 1143, 884 cmꢀ1; [Found: C, 70.59; H, 8.70; N, 6.30.
C13H19NO2 requires: C, 70.56; H, 8.65; N, 6.33%.] dH (400 MHz,
DMSO-d6) 8.11 (1H, s, Ph), 7.37 (1H, s, Ph), 3.68 (2H, s, CH2COOtBu),
2.22 (3H, s, PhMe), 2.19 (3H, s, PhMe), 1.37 (9H, s, COOtBu); dC
(100.6 MHz, CDCl3) 170.0, 150.7, 147.0, 138.6, 131.6, 131.5, 81.0, 42.7,
28.0, 18.6, 17.9; MS (ESI) 222 [MþH]þ.
4.2.11. tert-Butyl (4-bromophenyl)(cyano)acetate (4a)
Colourless liquid; Rf (10% EtOAc/hexane) 0.85; nmax (liquid film)
1738, 1488, 1369, 1142, 1072, 1012, 829 cmꢀ1; [Found: C, 52.76; H,
4.81; N, 4.68. C13H14BrNO2 requires: C, 52.72; H, 4.76; N, 4.73%.] dH
(400 MHz, CDCl3) 7.57–7.54 (2H, d, J 11.1 Hz, Ph), 7.34–7.31 (2H, d, J
11.1 Hz, Ph), 4.5 (1H, s, CHCOOtBu), 1.48 (9H, s, COOtBu); dC
(100.6 MHz, CDCl3) 163.3, 132.4, 132.2, 131.3, 129.4, 123.3, 115.5,
84.9, 44.2, 27.6; MS (ESI) 298 [Mþ2]þ.
4.2.5. tert-Butyl 2-pyrazin-2-ylpropanoate (2e)
Colourless liquid; Rf (10% EtOAc/hexane) 0.50; nmax (liquid film)
1726, 1403, 1367, 1142, 1081, 847 cmꢀ1; [Found: C, 63.51; H, 7.83; N,
13.39. C11H16N2O2 requires: C, 63.44; H, 7.74; N, 13.45%.] dH
(400 MHz, CDCl3) 8.58–8.58 (1H, d, J 1.4 Hz, Ph), 8.53–8.52 (1H, dd, J
2.4, 1.6 Hz, Ph), 8.47–8.46 (1H, d, J 2.5 Hz, Ph), 3.90–3.85 (1H, q,
PhCHMe), 1.56–1.55 (3H, d, PhCHMe), 1.41 (9H, s, COOtBu); dC
(100.6 MHz, CDCl3) 171.8, 156.0, 144.2, 143.9, 142.9, 81.4, 46.5, 27.9,
16.6; MS (ESI) 209 [MþH]þ.
4.2.12. tert-Butyl cyano (4-nitrophenyl)acetate (4b)
Colourless liquid; Rf (10% EtOAc/hexane) 0.8; nmax (liquid film)
1738, 1523, 1370,1346, 1142, 833 cmꢀ1; [Found: C, 59.60; H, 5.42; N,
10.58. C13H14N2O4 requires: C, 59.54; H, 5.38; N, 10.68%.] dH
(400 MHz, CDCl3) 8.30–8.28 (2H, d, J 8.8 Hz, Ph), 7.67–7.65 (2H, d, J
8.6 Hz, Ph), 4.76 (1H, s, CHCOOtBu), 1.46 (9H, s, COOtBu); dC
(100.6 MHz, CDCl3) 162.5, 148.3, 137.0, 129.0, 124.3, 114.8, 85.7, 44.4,
27.6; MS (ESI) 263 [MþH]þ.
4.2.6. tert-Butyl (6-chloro-5-cyanopyridin-2-yl)acetate (2f)
Colourless liquid; Rf (10% EtOAc/hexane) 0.65; nmax (liquid film)
1727, 1585, 1366, 1142, 1072, 785 cmꢀ1; [Found: C, 57.10; H, 5.23; N,
11.01. C12H13 ClN2O2 requires: C, 57.04; H, 5.19; N, 11.09%.] dH
(400 MHz, CDCl3) 7.97–7.95 (1H, d, J 8 Hz, Ph), 7.41–7.39 (1H, d, J
8 Hz, Ph), 3.82 (2H, s, CH2COOtBu), 1.46 (9H, s, COOtBu); dC
(100.6 MHz, CDCl3) 168.0, 159.7, 152.0, 142.5, 122.6, 114.7, 108.9,
82.3, 44.7, 27.9; MS (ESI) 253 [MþH]þ.
4.2.13. tert-Butyl cyano (3-methoxyphenyl)acetate (4c)
Colourless liquid; Rf (10% EtOAc/hexane) 0.85; nmax (liquid film)
1737, 1601, 1490, 1394, 1141, 1044, 769 cmꢀ1; [Found: C, 68.07; H,
7.00; N, 5.62. C14H17NO3 requires: C, 68.00; H, 6.93; N, 5.66%.] dH
(400 MHz, CDCl3) 7.32–7.30 (1H, t, Ph), 7.03–6.91 (3H, m, Ph), 4.58
(1H, s, CHCOOtBu), 3.83 (3H, s, OCH3), 1.48 (9H, s, COOtBu); dC
(100.6 MHz, CDCl3) 163.7, 160.0, 131.7, 130.2, 120.0, 115.9, 114.6,
113.3, 84.5, 55.3, 44.7, 27.6; MS (ESI) 248 [MþH]þ.
4.2.7. tert-Butyl (8-chloroquinolin-2-yl)acetate (2g)
Colourless liquid; Rf (10% EtOAc/hexane) 0.70; nmax (liquid film)
1725, 1625, 1408, 1135, 998, 755 cmꢀ1; [Found: C, 64.90; H, 5.89; N,
4.99. C15H16 ClNO2 requires: C, 64.87; H, 5.81; N, 5.04%.] dH
4.2.14. tert-Butyl cyano (2,4-difluorophenyl)acetate (4d)
Colourless liquid; Rf (10% EtOAc/hexane) 0.85; nmax (liquid film)
1742, 1616, 1506, 1395, 1278, 1141, 967, 850 cmꢀ1; [Found: C, 61.70;

138
J.K. Augustine et al. / Tetrahedron 65 (2009) 134–138
H, 5.23; N, 5.47. C13H13F2NO2 requires: C, 61.66; H, 5.17; N, 5.53%.] dH
(400 MHz, CDCl3) 7.52–7.46 (1H, m, Ph), 7.00–6.97 (1H, m, Ph),
6.96–6.88 (1H, m, Ph), 4.87 (1H, s, CHCOOtBu), 1.48 (9H, s, COOtBu);
dC (100.6 MHz, CDCl3) 164.7, 164.6, 162.6, 162.2, 162.1, 161.4, 161.3,
158.9, 158.8, 130.6, 130.5, 130.5,115.0, 114.6, 114.4, 112.4, 112.3, 112.1,
112.1, 104.8, 104.5, 104.3, 85.2, 37.8, 37.8, 27.6; dF (376.5 MHz, CDCl3)
ꢀ107.32 (1F, d, JFF 9.0 Hz), ꢀ112.12 (1F, d, JFF 9.0 Hz); MS (ESI) 254
[MþH]þ.
4.10; N, 5.00. C10H11BrFNO2 requires: C, 43.50; H, 4.02; N, 5.07%.] dH
(400 MHz, CDCl3) 8.58 (1H, s, Ph), 8.47 (1H, s, Ph), 1.62 (9H, s,
COOtBu); dC (100.6 MHz, CDCl3) 160.6, 156.3, 153.7, 147.8, 147.8,
137.2, 137.0, 132.1, 132.0, 116.9, 85.4, 28.0; dF (376.5 MHz, CDCl3)
ꢀ127.24 (1F, s); MS (ESI) 278 [Mþ2]þ.
4.2.21. tert-Butyl 4-bromo-2,6-difluorobenzoate (4k)
Colourless liquid; Rf (10% EtOAc/hexane) 0.85; nmax (liquid film)
1728, 1613, 1415, 1307, 1111, 839 cmꢀ1; [Found: C, 45.15; H, 3,82.
C11H11BrF2O2 requires: C, 45.08; H, 3.78%.] dH (400 MHz, CDCl3)
7.14–7.13 (1H, t, Ph), 7.11–7.10 (1H, t, Ph), 1.58 (9H, s, COOtBu); dC
(100.6 MHz, CDCl3) 161.5, 161.4, 159.8, 158.9, 158.9, 124.4, 124.3,
124.2, 116.0, 116.0, 115.9, 115.8, 115.7, 115.7, 112.2, 83.8, 28.0; dF
(376.5 MHz, CDCl3) ꢀ109.94 (2F, s); MS (ESI) 295 [Mþ2]þ.
4.2.15. tert-Butyl methyl (3,5-dimethylphenyl)malonate (4e)
Colourless liquid; Rf (10% EtOAc/hexane) 0.85; nmax (liquid film)
1730, 1606, 1253, 1131, 849 cmꢀ1; [Found: C, 69.09; H, 8.03.
C16H22O4 requires: C, 69.04; H, 7.97%.] dH (400 MHz, CDCl3) 6.98
(2H, s, Ph), 6.96 (1H, s, Ph), 4.48 (1H, s, CHCOOtBu), 3.75 (3H, s,
COOMe), 3.32 (6H, s, PhMe), 1.47 (9H, s, COOtBu); dC (100.6 MHz,
CDCl3) 169.2, 167.2, 138.0, 132.8, 129.8, 128.9, 82.2, 58.6, 52.6, 27.8,
21.2; MS (ESI) 279 [MþH]þ.
4.2.22. tert-Butyl 3-bromo-2,6-dimethoxybenzoate (4l)
Colourless liquid; Rf (10% EtOAc/hexane) 0.85; nmax (liquid film)
1721, 1583, 1462, 1296, 1087, 742 cmꢀ1; [Found: C, 49.29; H, 5.45.
C13H17BrO4 requires: C, 49.23; H, 5.40%.] dH (400 MHz, CDCl3) 7.47–
7.45 (1H, d, J 8.9 Hz, Ph), 6.60–6.58 (1H, d, J 8.9 Hz, Ph), 3.90 (3H, s,
PhOMe), 3.81 (3H, s, PhOMe), 1.59 (9H, s, COOtBu); dC (100.6 MHz,
CDCl3) 164.4, 156.4, 154.1, 133.6, 121.8, 108.5, 107.7, 82.5, 62.0, 56.2,
28.1; MS (ESI) 319 [Mþ2]þ.
4.2.16. tert-Butyl methyl (3,5-dimethoxyphenyl)malonate (4f)
Colourless liquid; Rf (10% EtOAc/hexane) 0.80; nmax (liquid film)
1730, 1596, 1431, 1298, 1135, 783 cmꢀ1; [Found: C, 64.56; H, 6.93.
C15H19O5 requires: C, 64.50; H, 6.86%.] dH (400 MHz, CDCl3) 6.54–
6.53 (2H, d, J 2.2 Hz, Ph), 6.43–6.42 (1H, d, J 2.2 Hz, Ph), 4.47 (1H, s,
CHCOOtBu), 3.78 (6H, s, PhOMe), 3.75 (3H, s, COOMe), 1.46 (9H, s,
COOtBu); dC (100.6 MHz, CDCl3) 168.8, 166.8, 160.6, 134.9, 107.3,
100.2, 82.4, 58.8, 55.3, 52.6, 27.8; MS (ESI) 311 [MþH]þ.
Acknowledgements
The authors thank Dr. Ashis Baran Mandal for helpful discus-
sions and gratefully acknowledge Dr. Goutam Das, COO, Syngene
International Ltd for his invaluable support.
4.2.17. tert-Butyl methyl [3-(trifluoromethyl)phenyl]malonate (4g)
Colourless liquid; Rf (10% EtOAc/hexane) 0.85; nmax (liquid film)
1730, 1453, 1328, 1121, 700 cmꢀ1; [Found: C, 56.67; H, 5.43.
C15H17F3O4 requires: C, 56.60; H, 5.38%.] dH (400 MHz, CDCl3) 7.65
(1H, s, Ph), 7.62–7.59 (2H, m, Ph), 7.51–7.48 (1H, t, Ph), 4.61 (1H, s,
CHCOOtBu), 3.77 (3H, s, COOMe), 1.46 (9H, s, COOtBu); dC
(100.6 MHz, CDCl3) 168.3, 166.4, 133.9, 132.7, 131.0, 130.7, 128.9,
126.2, 126.2, 125.2, 125.0, 124.9, 122.5, 83.0, 58.5, 52.8, 27.7; MS
(ESI) 319 [MþH]þ.
References and notes
1. For N-BOC protection, see: Greene, T. W.; Wuts, P. G. M. Protective Group in
Organic Synthesis, 3rd ed.; Wiley: New York, NY, 1999; pp 518–525.
2. Wakselman, M. In Encyclopedia of Reagents for Organic Synthesis; Paquette, L. A.,
Ed.; John Wiley and Sons: New York, NY, 1995; Vol. 3, pp 1602–1608; and ref-
erences therein.
3. (a) Kno¨lker, H.-J.; Braxmeier, T.; Schlechtingen, G. Angew. Chem. 1995, 107, 2746–
2749; Angew. Chem., Int. Ed. Engl. 1995, 34 2497–2500; (b) Kno¨lker, H.-J.; Brax-
meier, T.; Schlechtingen, G. Synlett 1996, 502–504; (c) Kno¨lker, H.-J.; Braxmeier, T.
Tetrahedron Lett. 1996, 37, 5861–5864; (d) Kno¨lker, H.-J.; Braxmeier, T. Tetra-
hedron Lett. 1998, 39, 9407–9410.
4. (a) Pozdnev, V. F. Tetrahedron Lett. 1995, 36, 7115–7118; (b) Pozdnev, V. F. Int.
J. Pept. Protein Res. 1994, 44, 36–48; (c) Takeda, K.; Akiyama, A.; Nakamura, H.;
Takizawa, S.; Mizuno, Y.; Takayanagi, H.; Harigaya, Y. Synthesis 1994, 1063–1066.
5. Basel, Y.; Hassner, A. Synthesis 1997, 309–312.
6. (a) Mattern, R.-H. Tetrahedron Lett. 1996, 37, 291–294; (b) Nagarajan, M.; Kumar,
V. S.; Rao, B. V. Tetrahedron Lett. 1997, 38, 5835–5838; (c) Mohapatra, D. K.; Datta,
A. Synlett 1996, 1129–1130; (d) Mohapatra, D. K.; Datta, A. Bioorg. Med. Chem.
Lett. 1997, 7, 2527–2530.
4.2.18. tert-Butyl methyl 2-thienylmalonate (4h)
Colourless liquid; Rf (10% EtOAc/hexane) 0.80; nmax (liquid film)
1730, 1394, 1239, 1134, 700 cmꢀ1; [Found: C, 56.30; H, 6.34.
C12H16O4S requires: C, 56.23; H, 6.29%.] dH (400 MHz, CDCl3) 7.32–
7.30 (1H, dd, J 5.2, 1.1 Hz, Ph), 7.09–7.07 (1H, m, Ph), 7.00–6.98 (1H,
dd, J 5.1, 3.61 Hz, Ph), 4.85 (1H, s, CHCOOtBu), 3.78 (3H, s, COOMe),
1.47 (9H, s, COOtBu); dC (100.6 MHz, CDCl3) 168.1, 166.1, 133.8, 127.7,
126.4, 126.2, 82.2, 54.0, 52.9, 27.7; MS (ESI) 257 [MþH]þ.
4.2.19. tert-Butyl cyano [4-(trifluoromethoxy)phenyl]acetate (4i)
Colourless liquid; Rf (10% EtOAc/hexane) 0.85; nmax (liquid film)
1740, 1508, 1253, 1142, 835 cmꢀ1; [Found: C, 55.89; H, 4.73; N, 4.60.
C14H14F3NO3 requires: C, 55.82; H, 4.68; N, 4.65%.] dH (400 MHz,
CDCl3) 7.51–7.48 (2H, dd, J 8.6, 1.9 Hz, Ph), 7.29–7.29 (2H, m, Ph),
4.64 (1H, s, CHCOOtBu), 1.48 (9H, s, COOtBu); dC (100.6 MHz, CDCl3)
163.3, 149.6, 129.4, 129.0, 121.5, 119.0, 115.5, 85.0, 44.0, 27.6; MS
(ESI) 302 [MþH]þ.
7. Hongmei, L.; Jaume, B. Tetrahedron Lett. 2008, 49, 2034–2037.
8. For examples of carbanion generation using LDA and their reaction with elec-
trophiles: (a) Hiyoshizo, K.; Hiroyuki, H.; Hirotaka, T.; Masahiro, W.; Motoo, S.
Tetrahedron: Asymmetry 1998, 9, 3203–3212; (b) Swaminathan, R. N.; Meng-
Hsin, C.; Stephen, T. H.; Robert, M. T.; Ellen, M. C.; Cui, M.; Han, K.; Jingchao, D.;
Bin, H.; Wu, H.; Shu-Hui, C. Tetrahedron Lett. 2006, 47, 5063–5067; (c) Liusheng,
Z.; Marc, V.; Sean, P. B.; Julio, C. M. Tetrahedron Lett. 2008, 49, 1768–1770; (d)
Sumalee, K.; Rachel, Q.; Netnapa, C.; Rachel, P.; Tirayut, V.; Jarunee, V.; Bong-
koch, T.; Worachart, S.; Gordon, L.; Yongyuth, Y. J. Med. Chem. 2004, 47, 673–680;
(e) Bongkoch, T.; Chawanee, S.; Worrapong, P.; Chakapong, I.; Worachart, S.;
Sumalee, K.; Jarunee, V.; Yodhathai, T.; Yongyuth, Y. J. Med. Chem. 2002, 45,
1244–1252; (f) Toshiyuki, I.; Keiko, K.; Miki, T.; Yumiko, T. J. Org. Chem. 1991, 56,
797–804; (g) Gu, Y. G.; Bayburt, E. K. Tetrahedron Lett. 1996, 37, 2565–2568.
9. Commercial LDA was found to provide quantitative yields when used in slight
excess (1.4 equiv).
4.2.20. tert-Butyl 3-bromo-5-fluoroisonicotinate (4j)
Colourless liquid; Rf (10% EtOAc/hexane) 0.75; nmax (liquid film)
1736, 1548, 1403, 1292, 1160, 1106, 885 cmꢀ1; [Found: C, 43.55; H,