Benzotriazole-mediated alkoxyalkylation and acyloxyalkylation

Article abstract of DOI:10.1016/j.tet.2007.04.021

Reactions of readily available and stable 1-(α-alkoxyalkyl)benzotriazoles type 9a,b and 10a-d with a variety of silyl enol ethers 11 or 1,3-dicarbonyl compounds 13 give the expected ketones 12a-l (60-92%), β-keto esters 14a,b (62-67%), and malonates 14c,d

Full text of DOI:10.1016/j.tet.2007.04.021

Tetrahedron 63 (2007) 6477–6484
Benzotriazole-mediated alkoxyalkylation and acyloxyalkylation
Alan R. Katritzky,a, Ashraf A. A. Abdel-Fattah,a,b Krzysztof R. Idzik,a,c
*
Bahaa El-Dien M. El-Gendya,b and Jadwiga Soloduchoc
aCenter for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA
bDepartment of Chemistry, Faculty of Science, Benha University, Benha, Egypt
cDepartment of Chemistry, Faculty of Medicinal Chemistry and Microbiology, Wroclaw University of Technology,
Wybrzeze Wyspianskiego 27, 50-370 Wroclaw, Poland
Received 8 January 2007; revised 23 March 2007; accepted 9 April 2007
Available online 14 April 2007
Abstract—Reactions of readily available and stable 1-(a-alkoxyalkyl)benzotriazoles type 9a,b and 10a–d with a variety of silyl enol ethers
11 or 1,3-dicarbonyl compounds 13 give the expected ketones 12a–l (60–92%), b-keto esters 14a,b (62–67%), and malonates 14c,d (79–88%)
in which a tetrahydrofuran or tetrahydropyran moiety has been introduced at the a position. 1-(Benzotriazol-1-yl)alkyl esters 7 are converted
by cyanide anion into cyanohydrin esters 15a–i (55–98%).
Ó 2007 Published by Elsevier Ltd.
1. Introduction
malonates 14c,d. We now also disclose the acyloxy-
alkylations of cyanide anion by 7 to provide cyanohydrin
esters 15.
N-Substituted benzotriazoles of type Bt–C–X, where X is
halogen,1 nitrogen,2 sulfur,3 and oxygen4 can ionize either
(i) by Bt–C bond scission to form alkyleneonium cations
C]X+ and Btꢀ or (ii) by C–X bond scission to give Xꢀ
anion and a benzotriazole stabilized carbocation Bt–C+.
Reports from our laboratory have described the use of Bt–
C–X (X]O) as precursors for the synthesis of complex
organic compounds including classes difficult to prepare.5
For example, replacement of the benzotriazole moiety in
simple 1-(1-alkoxyalkyl)benzotriazoles 1, or the products
of their addition to enol ethers 3, gives a wide range of a-
substituted ethers 2 or 1,3-diethers 4 and 5 (Scheme 1).6
Compounds of the type of 1 undergo deprotonation followed
by quenching with electrophiles and the products undergo
acid-catalyzed hydrolysis of the benzotriazole and the alk-
oxy group to provide ketones 6 (Scheme 1).7 The Bt–C–
OCO compounds 75 are intermediates for the synthesis of
carboxylic esters 88 by substitution of benzotriazolyl moiety
with an alkyl, alkenyl or aryl group from the corresponding
organozinc reagents (Scheme 2).
2. Results
2.1. Synthesis of b-alkoxy ketones 12
b-Alkoxy ketone units frequently occur in antibiotics9 and
steroidal frameworks10 and are precursors for b-hydroxy
ketone and syn-1,3-diol units, common structural features
imbedded in numerous natural products, e.g., rutamycin B
and oligomycin C,11 erythromycins,12 amphotericin B,13
and rofllamycoin.14 b-Alkoxy ketones are typically prepared
by: (i) oxidative C–C bond formation reactions of electron-
rich alkylbenzyl ethers with trimethylvinyloxysilane
(derived from PhCOCH3) catalyzed by 2,3-dichloro-5,6-
dicyanobenzoquinone (DDQ);15 (ii) direct alcohol addition
to enones;16 and (iii) Mukaiyama aldol-type condensation
of silyl enol ethers. Method iii has been a subject of exten-
sive investigations in which silyl enol ethers undergo a Lewis
acid-catalyzed coupling to an acetal (Scheme 3).17
We have now found that Lewis acid-catalyzed alkoxyalkyla-
tions by 9a,b or 10a–d of silyl enol ethers 11, and 1,3-
dicarbonyl compounds 13 provide convenient access to
a-substituted ketones 12a–l, b-keto esters 14a,b, and
We have previously demonstrated that 1-a-benzotriazolyl-
alkyl alkyl ethers 1 behave analogously to acetals, but be-
cause the benzotriazolyl substituent is a better leaving
group, compounds of type 1 are frequently effective for
alkoxyalkylation of ketones and Grignard reagents where the
corresponding acetals fail.6a,18 We now find that the use of
benzotriazole adducts (type 9a,b and 10a–d) in the place
* Corresponding author. Tel.: +1 352 392 0554; fax: +1 352 392 9199;
e-mail: katritzky@chem.ufl.edu
0040–4020/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tet.2007.04.021

6478
A. R. Katritzky et al. / Tetrahedron 63 (2007) 6477–6484
R3
R2
R3
R2
R2
O
R4
OEt
Bt
O
R1
O
R4MgX
R3
Bt
(R1 = H)
OEt
OEt
3
1
5
LAH
R4MgX
Bt = Benzotriazolyl
R3
O
R4
O
R3
4
R2
OEt
R2
2
i) n-BuLi, E+
O
ii) H+
6
1
R2
E
Scheme 1.
Bt–C–O compounds 1 are readily available,7c,18 and stable
(shelf life more than 8 months). Colorless viscous liquids
9a,b were prepared in 95–100% yields as mixtures of
benzotriazol-1-yl and -2-yl isomers by the addition of
benzotriazole to 2,3-dihydrofuran or 3,4-dihydro-2H-pyran,
respectively, in CCl4.18
R3
O
O
R
R3ZnX
Bt
O
O
R1
R
R1
8
7
Scheme 2.
O
Earlier reports from our laboratory suggested that lithio-
derivatives 1 (R1¼Li) could not be generated unless
R2¼hetero(aromatic),7c alkenyl,7a alkynyl,7b or R3¼aryl.7d
Rather surprisingly we now find that treatment of 9b with
1.2 M equiv of n-BuLi at ꢀ78 ꢁC and then quenching the
resultant carbanion with a series of alkyl bromides provides
the alkylated products 10a–d in 40–90% yields. The struc-
tures of 10a–d were confirmed by their spectral data together
with elemental analyses or HRMS.
R3
R1
R4
R2OH
(ii)
R4 = H
OR2
R1
OTMS
R1
OTMS
OR2
R1CHOR2
O
R2
R3
R3
R3
O
(iii)
R1 = H
R4
R3 = Ph, R4 = H
R4
R4
(i)
The aldol-type reaction of silyl enol ether 11a with 9a in
CH2Cl2 with 2 M equiv of ZnBr2 under reflux proceeded
smoothly to provide 1-phenyl-2-(tetrahydrofuran-2-yl)-
ethanone (12a) (86%). No product was obtained with
(CH3)3SiOTf at ꢀ78 ꢁC to reflux, TiCl4 at ꢀ78 ꢁC to rt, or
AlCl3 at rt to reflux. Silyl enol ethers 11a–h reacted with
9a,b or 10a–d under the same reaction conditions to give
Scheme 3.
of acetals in Mukaiyama aldol-type reactions of silyl enol
ethers 11 allows the preparation of b-alkoxy ketones 12 in
good to excellent yields (Scheme 4 and Table 1).
( )n
( )n
9b
R
Table 1. Synthesis of a-substituted ketones 12a–l
10a: R = Et
Bt
O
9a,b
n-BuLi, RBr
Bt
Start 11 Product 12
n
R
R1
R2
Yield (%)
O
10a-d
10b: R = n-Propyl
10c: R = n-Butyl
10d: R = n-Hexyl
9a: n = 0
9b: n = 1
11a
12a
12b
12c
12d
12e
12f
12g
12h
12i
0
1
0
0
0
0
1
1
1
1
1
1
H
H
H
H
H
H
H
H
Ph
H
H
H
H
86
71
80
65
11e
11c
11f
11b
11f
11g
11b
11e
11f
11d
11f
2-Naph
4-BrC6H4
2-Thienyl
OTMS
( )n
R
R2
9a,b, 10a-d
ZnBr2, CH2Cl2
R1
Ph
Me 79b
91
O
12a-l
a
R2
R1
a
80c
O
11a-h
Ph
Me 92d
)
11g: R1R2
11h: R1R2
=
n-Pr
n-Bu
Et
2-Naph
2-Thienyl
4-MeOC6H4
H
H
H
H
60
62
65
65
11a: R1 = Ph, R2 = H
11b: R1 = Ph, R2 = Me
)
12j
12k
12l
11c: R1 = 4-BrC6H4, 2 = H
R
=
n-Hex 2-Thienyl
11d: R1 = 4-MeOC6H4, R2 = H
11e: R1 = 2-Naph, R2 = H
11f: R1 = 2-Thienyl, R2 = H
)
MeO
a
See Scheme 4.
b
c
d
Isolated as diastereoisomeric mixture in a 2:1 ratio.
Isolated as diastereoisomeric mixture in a 3:1 ratio.
Isolated as diastereoisomeric mixture in a 1:1 ratio.
Scheme 4. For designation of R, R1, and R2 in 11 and 12, see Table 1.

A. R. Katritzky et al. / Tetrahedron 63 (2007) 6477–6484
Table 2. Alkoxyalkylations of 1,3-dicarbonyl compounds
6479
b-alkoxy ketones 12b–l in yields ranging from 60 to 92%
(Scheme 4 and Table 1).
Compd
n
R1
R2
Yield (%)
14a
14b
14c
14d
0
1
0
1
Ph
Ph
OMe
OMe
OEt
OEt
OMe
OMe
67
62a
79
88
Although the reactions of 9a,b and 10a–d with 11a–h were
structurally tolerant for the silyl enol ether component,
some failures were noted. Silyl enol ether 11a gave no
product with 1-(ethoxy-1-benzotriazolylethane, 1-(ethoxy-
a
Total yield of two isolated diastereoisomers in a 1:1.2 ratio.
naphthalen-2-yl-methyl)benzotriazole,
1-(1-methoxy-1-
phenylethyl)-1-benzotriazole, or 1-(1-ethoxy-1-methyl-3-
phenylprop-2-ynyl)benzotriazole.
compounds demonstrates the general applicability of this
synthetic route and provided the previously unreported
analogs 14a–d in yields ranging from 62 to 88%.
The present approach for the preparation of a-substituted
ketones 12 utilizes inexpensive Lewis acid under mild con-
ditions and shows good generality for silyl enol ethers pre-
pared from acyclic (to give 12a–c,e,h,i,k), cyclic (to give
12f and g), and heteroaromatic ketones (12d,j and l). The
required benzotriazolylalkyl alkyl ethers type 9a,b and
10a–d are easily prepared and stable alkoxyalkylation
reagents are more convenient than the acetal analogs. Our
new methodology provided a wide range of a-substituted
ketones 12 bearing a tetrahydrofuran or tetrahydropyran
unit at positions in which they are structural subunits in many
naturally occurring nucleosides, glycolipids, polyether anti-
biotics, and pheromones.19
However attempts to react Bt–C–O compounds of type 9
or 10 with organostannanes, amines, thiols, phenols, allyl
trimethylsilane, terminal alkenes, aromatics, and heteroaro-
matics failed.
2.3. Synthesis of cyanohydrin esters
Cyanohydrins are of interest as pesticides,26 and synthetic
precursors.27 Cyanohydrin esters 15 are versatile synthetic
intermediates.28 Approaches for cyanohydrin esters include
(Scheme 6): (i) acylation of cyanohydrins with the appropri-
ate acyl halide or acid anhydride;27a (ii) cyanoacylation of
aldehydes by (a) acyl halides in aqueous cyanide solution,29
(b) acyl cyanides in aqueous K2CO3 solution,30 or (c) trime-
thylsilyl cyanide and acid anhydride under the influence of
iron(III) chloride.31 Method (ii)b is commonly used for the
synthesis of the title compounds, however, acyl cyanides
are susceptible to hydrolysis and particularly aliphatic alde-
hydes having a-hydrogen atom readily undergo aldol
condensation under alkaline conditions. Consequently, a
number of modifications for method iic have been proposed.
For example, phase-transfer catalyst32 and Bu3SnCN have
been utilized for the addition of acyl cyanide to aldehydes.33
We now report for acylated cyanohydrin 15 from 1-(benzo-
triazol-1-yl)alkyl esters 7 with cyanide without catalyst
(Scheme 6).
2.2. a-Alkoxyalkylations of 1,3-dicarbonyl compounds
Enolizable diketones can bind to both metal ions20 and
nonmetallic elements,21 and are used as subunits in supra-
molecular host molecules.22 Previous a-alkoxyalkylations
of 1,3-dicarbonyl compounds 13 have usually involved
either (i) treatment of chloromethyl methyl ether with organo-
metallic derivatives of 1323 (but this is limited to methoxy-
methylation and a-chloro ethers, which are cancerogenic);
(ii) addition of active methylenes to cyclic enol ethers em-
ploying AuCl3/AgOTf as a catalyst24 (limited to diketones
and requires expensive reagents); or (iii) Lewis acid-induced
alkoxyalkylation of 13 with acetal25 (valuable only to pre-
pare particular analogs of 13). We now report the use of of
1-benzotriazolylalkyl alkyl ethers 9a,b as alkoxyalkylating
reagents for converting 13 into alkoxyalkylated products 14.
i
OH
RCOX
NC
ii
a-c
O
O
O
NC
Trials with different Lewis acids revealed that 2.0 M equiv
of AlCl3 catalyzed the stoichiometric reaction of dimethyl
malonate 13b with 9a to provide 79% of 14c. The a-alkoxy-
alkylation reaction also gave 14a,b derived from b-keto
ester and 14d from malonate (Scheme 5 and Table 2). All
reactions proceeded smoothly to give the corresponding
condensation products 14a–d. The NMR of the crude prod-
ucts shows that benzotriazole is usually the only byproduct,
although adducts 14 are occasionally contaminated by a
small amount of unreacted 13. Success with 1,3-dicarbonyl
R1
X = halide or
RCOO
R1
R1
R
-
a) RCOX, CN
b) RCOCN, K2CO3
c) TMSCN, RCOX
15
Scheme 6.
1-(Benzotriazol-1-yl)alkyl esters 7 were prepared by
treating 1-(benzotriazol-1-yl)-1-chloroalkanes with sodium
carboxylates for 7a,b8 or by O-acylation of aldehydes with
N-acylbenzotriazoles in the presence of K2CO3 for 7c–g.34
Our treatment of 7a with 2 M equiv of KCN in DMSO at
rt afforded 97% of cyanomethyl benzoate (15a). Similarly,
1-(benzotriazol-1-yl)alkyl esters 7a–j were reacted with
KCN to provide the expected cyanohydrin esters 15b–j in
55–98% yields (Scheme 7 and Table 3). This approach im-
proved the previously reported yield30a of compound 15e
from 49 to 80%, and afforded 15a35 and 15c30b in yields
comparable to the literature. The structures of all final
products obtained have been confirmed by 1H and 13C
NMR data and elemental analyses. Data for known
9a,b
O
O
R1
R2
( )n
O
AlCl3
R1
R2
CH2Cl2, reflux
O
O
14a-d
13a,b
13a: R1 = Ph, R2 = OEt
13b: R1 = R2 = OMe
Scheme 5. For designation of R1 and R2 in 14, see Table 2.

6480
A. R. Katritzky et al. / Tetrahedron 63 (2007) 6477–6484
compounds 15a,c,e have been compared with those avail-
able in the literature.
4. Experimental
4.1. General methods
Bt
O
O
KCN
NC
O
O
Melting points were determined on a capillary point appara-
tus equipped with a digital thermometer. 1H (300 MHz) and
13C (75 MHz) NMR spectra were recorded on a 300 MHz
NMR spectrometer in CDCl3 unless stated. Column chroma-
tography was performed on silica gel 200–425 mesh. THF
was distilled from sodium-benzophenone ketyl and
CH2Cl2 was dried over molecular sieves prior to use. 1-(a-
Alkoxyalkyl)benzotriazoles 10a,b18 were prepared accord-
ing to literature procedures. 1-(Benzotriazol-1-yl)alkyl
esters 7a,b8 and 7c–g34 were prepared following literature
procedures.
R1
DMSO
R1
R
R
7a-i
15a-i
Scheme 7. For designation of R and R1 in 15, see Table 3.
Table 3. Synthesis of cyanohydrin esters 15a–i
Compd
R
R1
Yield (%)
15a
15b
15c
15d
15e
15f
15g
15h
15i
Ph
Ph
Ph
Ph
H
t-BuCH2
n-Pr
98 (97a)35
87
95 (94a)30b
89
Et
Ph
80 (49a)30a
4.2. General procedure for the preparation of
1-(a-alkoxyalkyl)benzotriazoles 10a–d
Ph
t-Bu
t-Bu
2-Thienyl
2-Furyl
3,4,5-(MeO)3C6H2
n-Pr
n-Pr
t-BuCH2
82
96
92
85
To a solution of 9b (0.408 g, 2 mmol) in dry THF (5 mL),
1.1 equiv of n-BuLi (1.4 mL, 1.6 M in pentane, 2.2 mmol)
was added at ꢀ78 ꢁC. The solution was stirred at ꢀ78 ꢁC
for 1 h, and the appropriate alkyl halide (2 mmol) was added.
The reaction mixture was stirred for 10 h while the temper-
ature was allowed to rise to 20 ꢁC. After quenching with
water (5 mL) and extraction with EtOAc (3ꢂ20 mL), the
combined organic layers were washed with water (25 mL),
dried over MgSO4, and the solvent was removed in vacuo.
The resultant oil was subjected to column chromatography
(eluent: ethyl acetate/hexanes¼1:10 then 1:5) to give the
pure product.
a
Literature yield.
Our approach allows the preparation of a variety of alk-
anoylated, aryolated or heteroaryolated cyanohydrins
derived from (i) formaldehyde 9a, which is inaccessible
from acyl cyanides and aldehydes by the reported
methods,27a,29,30a,b,31–33 (ii) aliphatic 9b–d and 9g–i, or
(iii) aromatic aldehydes 9e,f; the process requires mild con-
ditions with no catalyst.
Reactions of 7 with alcohols, thiols, or organosilanes failed
to provide the corresponding acyloxyalkylation products.
Instead, with alcohols or thiols we obtained ester or thio-
ester derivatives 16, respectively, in quantitative yields
(Scheme 8).
4.2.1. 1-(2-Ethyltetrahydropyran-2-yl)-1H-benzotri-
azole (10a). Colorless oil (40%). 1H NMR d 8.07 (d,
J¼8.2 Hz, 1H), 7.90 (d, J¼8.4 Hz, 1H), 7.44 (ddd,
J¼15.2, 7.0, 1.1 Hz, 1H), 7.36 (ddd, J¼15.2, 8.1, 1.1 Hz,
1H), 3.89–3.84 (m, 1H), 3.29–3.25 (m, 1H), 3.15 (td,
J¼11.8, 2.6 Hz, 1H), 2.15–1.88 (m, 2H), 1.86–1.71
(m, 4H), 1.47–1.40 (m, 1H), 0.68 (t, J¼7.6 Hz, 3H). 13C
NMR d 146.6, 132.2, 127.1, 123.8, 119.7, 113.0, 94.1,
63.4, 35.2, 30.6, 24.2, 18.6, 7.4. Anal. Calcd for
C13H17N3O: C, 67.51; H, 7.41; N, 18.17. Found: C, 67.65;
H, 7.71; N, 18.03.
O
R2
Bt
O
O
R2XH
X = O, S
X
R
R1
R
16
7
Scheme 8.
3. Summary
4.2.2. 1-(2-Propyltetrahydropyran-2-yl)-1H-benzotri-
azole (10b). Colorless oil (60%). 1H NMR d 8.07 (d,
J¼8.2 Hz, 1H), 7.90 (d, J¼8.4 Hz, 1H), 7.44 (ddd,
J¼15.2, 7.0, 1.0 Hz, 1H), 7.36 (ddd, J¼15.2, 7.1, 1.0 Hz,
1H), 3.88–3.83 (m, 1H), 3.29–3.24 (m, 1H), 3.14 (td,
J¼11.9, 2.5 Hz, 1H), 2.08–1.66 (m, 7H), 1.46–1.27 (m,
2H), 0.92–0.81 (m, 1H), 0.74 (t, J¼7.1 Hz, 3H). 13C NMR
d 146.5, 132.2, 127.1, 123.7, 119.6, 112.9, 93.7, 63.3,
44.6, 31.2, 24.1, 18.6, 16.2, 13.8. HRMS: m/z [M+H]+ calcd
for C14H19N3O: 246.16009; found: 246.16247.
In summary, novel and convenient routes have been devel-
oped for the preparation of a wide range of ketones 12,
b-keto esters 14a,b, and malonates 14c,d bearing tetrahydro-
furan or tetrahydropyran structural units at the a position.
Compared to acetal analogs,38 our use of a-benzotriazolyl-
alkyl ethers is advantageous since it requires inexpensive
Lewis acids and with benzotriazole adducts it is applicable
not only when R¼H but also when R¼alkyl.
Reactions of easily prepared 1-(benzotriazol-1-yl)alkyl es-
ters 7 with cyanide anion give acylated cyanohydrins 15.
The method utilizes nontoxic, and recyclable benzotriazole
as an auxiliary to provide a-cyano aliphatic-, aromatic-,
and heteroaromatic esters. In terms of yields, generality,
and experimental simplicity, the conversion of 7 to 15
represents an attractive alternative to earlier methods for
synthesizing acylated cyanohydrins.27a,29,30a,b,31–33
4.2.3. 1-(2-Butyltetrahydropyran-2-yl)-1H-benzotriazole
1
(10c). Colorless oil (90%). H NMR d 8.06 (d, J¼8.2 Hz,
1H), 7.90 (d, J¼8.2 Hz, 1H), 7.44 (ddd, J¼15.2, 7.0,
1.1 Hz, 1H), 7.36 (ddd, J¼15.2, 8.2, 1.1 Hz, 1H), 3.88–
3.83 (m, 1H), 3.29–3.25 (m, 1H), 3.14 (td, J¼11.8, 2.6 Hz,
1H), 2.10–1.66 (m, 7H), 1.50–1.23 (m, 2H), 1.18–1.08 (m,
2H), 0.74 (t, J¼7.3 Hz, 3H). 13C NMR d 146.5, 132.2,
127.1, 123.7, 119.6, 112.9, 93.7, 63.3, 42.1, 31.2, 24.9,

A. R. Katritzky et al. / Tetrahedron 63 (2007) 6477–6484
6481
24.1, 22.4, 18.6, 13.7. HRMS: m/z [M+Na]+ calcd for
C15H21N3O: 282.15768; found: 282.15996.
44.6, 31.6, 25.6. Anal. Calcd for C12H13BrO2: C, 53.55; H,
4.87. Found: 53.57; H, 4.78.
4.2.4. 1-(2-Hexyltetrahydropyran-2-yl)-1H-benzotri-
azole (10d). Colorless oil (80%). 1H NMR d 8.07 (d,
J¼8.2 Hz, 1H), 7.90 (d, J¼8.2 Hz, 1H), 7.44 (ddd, J¼
15.2, 7.0, 1.0 Hz, 1H), 7.35 (ddd, J¼15.2, 8.1, 0.8 Hz, 1H),
3.88–3.83 (m, 1H), 3.29–3.25 (m, 1H), 3.14 (td, J¼11.8,
2.6 Hz, 1H), 2.10–1.70 (m, 6H), 1.46–1.21 (m, 2H), 1.20–
1.14 (m, 2H), 1.11–1.07 (m, 5H), 0.77 (t, J¼7.0 Hz, 3H).
13C NMR d 146.5, 132.1, 127.0, 123.7, 119.6, 112.9, 93.7,
63.3, 42.3, 31.3, 31.1, 28.9, 27.3, 24.1, 22.7, 22.3, 18.6,
13.8. Anal. Calcd for C17H25N3O: C, 71.04; H, 8.77; N,
14.62. Found: C, 70.71; H, 9.08; N, 14.82.
4.3.4. 2-(Tetrahydrofuran-2-yl)-1-thiophen-2-ylethanone
(12d). Yellow Oil (65%). 1H NMR d 7.74 (d, J¼3.7 Hz, 1H),
7.65 (d, J¼4.8 Hz, 1H), 7.14 (t, J¼4.3 Hz, 1H), 4.45–4.35
(m, 1H), 3.94–3.85 (m, 1H), 3.79–3.72 (m, 1H), 3.35–
3.26 (m, 1H), 3.03–2.59 (m, 1H), 2.23–2.13 (m, 1H), 1.98–
1.90 (m, 2H), 1.67–1.62 (m, 1H). 13C NMR d 191.2, 144.6,
133.8, 132.3, 128.1, 75.5, 67.9, 45.3, 31.5, 25.6. Anal. Calcd
for C10H12O2S: C, 61.20; H, 6.16. Found: C, 60.88; H, 6.28.
4.3.5. 1-Phenyl-2-(tetrahydrofuran-2-yl)-propan-1-one
(12e) [two diastereoisomers 2:1]. Yellow oil (79%). H
1
NMR d 8.00–7.96 (m, 2H), 7.59–7.52 (m, 1H), 7.49–7.43
(m, 2H), 4.22–4.09 (m, 1H), 3.87–3.72 (m, 2H), 3.69–
3.55 (m, 1H), 2.08–1.98 (m, 1H), 1.96–1.80 (m, 2H), 1.70–
1.45 (m, 1H), 1.32 (d, J¼7.0 Hz, 2H), 1.16 (d, J¼6.9 Hz,
1H). 13C NMR d 203.1, 203.0, 137.0, 136.8, 133.0, 132.8,
128.6, 128.5, 128.4, 128.3, 81.0, 80.9, 68.1, 67.8, 45.8,
45.7, 29.7, 29.1, 25.7, 25.6, 15.4, 13.8. Anal. Calcd for
C13H16O2: C, 76.44; H, 7.89. Found: C, 76.20; H, 8.18.
4.3. General procedure for the preparation of b-alkoxy
ketones 12a–l
To a stirred solution of silyl enol ether 11 (1 mmol) and
1-(a-alkoxyalkyl)benzotriazoles 9a,b or 10a–d (1 mmol)
in dry dichloromethane (40 mL) was added ZnBr2
(0.495 g, 2.2 mmol) under nitrogen atmosphere at rt. The
mixture was refluxed for 8 h, and was monitored by
TLC. Ether (100 mL) was added, and the solution was
washed with cold water (3ꢂ25) and dried over MgSO4.
After removal of the solvent in vacuo, the resulting crude
product was purified by column chromatography on silica
gel and eluted with 9/1 hexanes/EtOAc to give the pure
product 12. Structures of 12a–l were supported by their
4.3.6. 2-(Tetrahydrofuran-2-yl)indan-1-one (12f). Yellow
1
oil (91%). H NMR d 7.75 (d, J¼7.8 Hz, 1H), 7.61–7.57
(m, 1H), 7.48 (d, J¼7.8 Hz, 1H), 7.39–7.34 (m, 1H), 4.37–
4.28 (m, 1H), 3.93–3.83 (m, 1H), 3.80–3.71 (m, 1H),
3.31–3.15 (m, 2H), 3.01 (dd, J¼17.1, 2.7 Hz, 1H), 1.97–
1.79 (m, 3H), 1.62–1.54 (m, 1H). 13C NMR d 206.4,
154.2, 137.3, 134.7, 127.2, 126.4, 123.7, 79.2, 68.3, 50.1,
29.0, 26.8, 25.8. Anal. Calcd for C13H14O2: C, 77.20; H,
6.98. Found: C, 77.00; H, 7.39.
1
1H and 13C NMR spectra. The H NMR spectra no longer
showed distinctive signals in the range 7.0–8.2 ppm corre-
sponding to the benzotriazolyl group. Similarly, 13C NMR
of 12a–l showed new signals at 196.0–199.6 ppm assign-
able to carbonyl carbon and no longer showed the charac-
teristic benzotriazole signals around 110, 120, and
146 ppm.
4.3.7. 7-Methoxy-2-(tetrahydropyran-2-yl)-3,4-dihydro-
2H-naphthalen-1-one (12g) [two diastereoisomers 3:1].
Yellow oil (80%). 1H NMR d 7.98 (dd, J¼8.7, 1.7 Hz,
1H), 6.79 (dt, J¼8.6, 2.6 Hz, 1H), 6.67 (s, 1H), 4.12–3.91
(m, 2H), 3.83 (s, 3H), 3.57–3.42 (m, 1H), 3.04–2.81 (m,
2H), 2.72 (dt, J¼12.4, 4.1 Hz, 0.5H), 2.41–2.14 (m, 2H),
2.01–1.83 (m, 1.5H), 1.58–1.49 (m, 5H). 13C NMR
d 196.9, 196.5, 163.3, 146.6, 146.5, 129.8, 129.6, 126.4,
126.3, 112.9, 112.9, 112.3, 112.2, 76.6, 75.1, 68.9, 68.7,
55.3, 55.2, 52.4, 52.3, 29.6, 29.3, 28.4, 26.6, 26.0, 25.9,
23.9, 23.5, 23.4, 23.2. Anal. Calcd for C16H20O3: C, 73.82;
H, 7.74. Found: C, 73.44; H, 8.10.
4.3.1. 1-Phenyl-2-(tetrahydrofuran-2-yl)ethanone (12a).
1
Colorless oil36 (86%). H NMR d 7.96 (d, J¼7.3 Hz, 2H),
7.58–7.53 (m, 1H), 7.48–7.43 (m, 2H), 4.44 (pentet,
J¼6.6 Hz, 1H), 3.93–3.85 (m, 1H), 3.78–3.71 (m, 1H),
3.39 (dd, J¼16.2, 6.0 Hz, 1H), 3.06 (dd, J¼16.5, 6.6 Hz,
1H), 2.19 (sextet, J¼6.3 Hz, 1H), 1.97–1.87 (m, 2H),
1.62–1.50 (m, 1H). 13C NMR d 198.3, 136.9, 133.0, 128.5,
128.1, 75.3, 67.7, 44.5, 31.5, 25.5.
4.3.2. 1-Naphthalen-2-yl-2-(tetrahydropyran-2-yl)etha-
none (12b). Colorless oil (89%). H NMR d 8.47 (s, 1H),
4.3.8. 1-Phenyl-2-(tetrahydropyran-2-yl)-propan-1-one
(12h) [two diastereoisomers 1:1]. Colorless oil (92%). H
1
1
8.03 (d, J¼8.4 Hz, 1H), 7.95 (d, J¼7.8 Hz, 1H), 7.88–7.83
(m, 2H), 7.60–7.50 (m, 2H), 4.05–3.94 (m, 2H), 3.52–3.39
(m, 2H), 3.03 (dd, J¼15.9, 5.7 Hz, 1H), 1.87–1.76 (m,
2H), 1.62–1.38 (m, 4H). 13C NMR d 198.2, 135.5, 134.5,
132.4, 130.0, 129.5, 128.4, 128.3, 127.6, 126.6, 123.9, 74.4,
68.6, 45.3, 31.9, 25.8, 23.3. Anal. Calcd for C17H18O2: C,
80.28; H, 7.13. Found: C, 80.16; H, 7.06.
NMR d 8.00–7.94 (m, 2H), 7.57–7.41 (m, 3H), 4.02–3.97
(m, 0.5H), 3.85–3.81 (m, 0.5H), 3.73–3.66 (m, 0.5H),
3.63–3.52 (m, 1.5H), 3.45–3.32 (m, 1H), 1.89–1.85 (m,
0.5H), 1.76–1.72 (m, 1H), 1.61–1.43 (m, 3.5H), 1.34–1.20
(m, 2.5H), 1.10 (d, J¼6.9 Hz, 1.5H). 13C NMR d 203.7,
202.9, 137.2, 136.9, 132.8, 132.6, 128.4, 128.3, 128.3,
128.2, 79.7, 79.2, 68.6, 68.4, 46.1, 45.9, 29.8, 28.5, 25.9,
25.8, 23.2, 23.2, 14.3, 13.2. Anal. Calcd for C14H18O2: C,
77.03; H, 8.31. Found: C, 77.27; H, 8.61.
4.3.3. 1-(4-Bromophenyl)-2-(tetrahydrofuran-2-yl)etha-
1
none (12c). Gray prisms (80%), mp 40–41 ꢁC. H NMR
d 7.83 (d, J¼8.5 Hz, 2H), 7.60 (d, J¼8.5 Hz, 2H), 4.43–
4.34 (m, 1H), 3.92–3.85 (m, 1H), 3.79–3.71 (m, 1H), 3.34
(dd, J¼16.2, 6.3 Hz, 1H), 3.02 (dd, J¼19.2, 9.3 Hz, 1H),
2.25–2.14 (m, 1H), 1.98–1.88 (m, 2H), 1.67–1.50 (m, 1H).
13C NMR d 197.4, 135.7, 131.9, 129.7, 128.3, 75.3, 67.9,
4.3.9. 1-Naphthalen-2-yl-2-(2-propyltetrahydropyran-
2-yl)ethanone (12i). Yellow oil (60%). H NMR d 8.51 (s,
1H), 8.04 (dd, J¼8.6, 1.6 Hz, 1H), 7.97–7.92 (m, 1H),
7.88–7.85 (m, 2H), 7.61–7.51 (m, 2H), 3.69 (t, J¼5.4 Hz,
2H), 3.34 (dd, J¼27.7, 15.2 Hz, 2H), 1.90–1.59 (m, 6H),
1

6482
A. R. Katritzky et al. / Tetrahedron 63 (2007) 6477–6484
1.56–1.48 (m, 2H), 1.44–1.26 (m, 2H), 0.89 (t, J¼7.3 Hz,
3H). 13C NMR d 198.9, 135.7, 135.4, 132.5, 130.0, 129.6,
128.3, 128.2, 127.7, 136.6, 124.0, 75.4, 61.4, 44.7, 36.7,
33.5, 25.7, 19.0, 16.3, 14.5. Anal. Calcd for C20H24O2: C,
81.04; H, 8.16. Found: C, 80.86; H, 7.86.
4.4.2. 3-Oxo-3-phenyl-2-(tetrahydropyran-2-yl)pro-
pionic acid ethyl ester (14b) [two isolated diastereoiso-
mers]. First diastereoisomer: colorless oil (28%). 1H NMR
d 8.03–8.01 (m, 2H), 7.59–7.54 (m, 1H), 7.49–7.44 (m,
2H), 4.48 (d, J¼9.3 Hz, 1H), 4.25–4.10 (m, 3H), 3.87–3.82
(m, 1H), 3.43 (td, J¼11.1, 3.2 Hz, 1H), 1.89–1.80 (m, 2H),
1.69–1.32 (m, 4H), 1.81 (t, J¼7.1 Hz, 3H). 13C NMR
d 193.7, 167.1, 137.1, 133.3, 128.8, 128.6, 76.9, 68.7, 61.4,
59.8, 29.7, 25.7, 23.1, 14.0. Anal. Calcd for C16H20O4: C,
69.54; H, 7.29. Found: C, 69.59; H, 7.67. Second diastereo-
4.3.10. 2-(2-Butyltetrahydropyran-2-yl)-1-thiophen-2-yl-
ethanone (12j). Brown oil (62%). H NMR d 7.74 (dd,
1
J¼3.8, 1.0 Hz, 1H), 7.63–7.61 (m, 1H), 7.12 (dd, J¼4.9,
3.8 Hz, 1H), 3.67 (t, J¼5.4 Hz, 2H), 3.12 (AB system,
JAB¼33.0, 14.7 Hz, 2H), 1.89–1.75 (m, 1H), 1.73–1.58 (m,
5H), 1.55–1.49 (m, 2H), 1.35–1.27 (m, 4H), 0.88 (t,
J¼7.0 Hz, 3H). 13C NMR d 191.7, 146.1, 133.7, 132.3,
128.0, 75.1, 61.4, 45.8, 34.2, 33.4, 25.6, 25.2, 23.1, 19.0,
14.1. Anal. Calcd for C15H22NO2S: C, 67.63; H, 8.32.
Found: C, 67.79; H, 8.63.
1
isomer: yellow oil (34%). H NMR d 8.06–8.03 (m, 2H),
7.62–7.57 (m, 1H), 7.50–7.45 (m, 2H), 4.46 (d, J¼9.5 Hz,
1H), 4.26–4.10 (m, 3H), 4.03–3.98 (m, 1H), 3.51 (td,
J¼11.3, 2.9 Hz, 1H), 1.78–1.23 (m, 6H), 1.17 (t, J¼7.1 Hz,
3H). 13C NMR d 192.6, 167.8, 136.4, 133.7, 128.7, 128.7,
77.1, 68.9, 61.4, 60.6, 29.8, 25.7, 23.0, 13.9. Anal. Calcd
for C16H20O4: C, 69.54; H, 7.29. Found: C, 69.69; H, 7.63.
4.3.11. 2-(2-Ethyltetrahydropyran-2-yl)-1-(4-methoxy-
phenyl)ethanone (12k). Colorless oil (65%). 1H NMR
d 7.99–7.95 (m, 2H), 6.95–6.90 (m, 2H), 3.87 (s, 3H),
3.68–3.64 (m, 2H), 3.13 (dd, J¼32.3, 15.0 Hz, 2H), 1.94–
1.86 (m, 1H), 1.75–1.61 (m, 5H), 1.53–1.48 (m, 2H), 0.87
(t, J¼7.5 Hz, 3H). 13C NMR d 197.6, 163.2, 131.5, 130.6,
113.5, 75.4, 61.3, 55.4, 43.9, 33.1, 26.7, 25.7, 19.0, 7.4.
Anal. Calcd for C16H22O3: C, 73.25; H, 8.45. Found: C,
73.07; H, 8.83.
4.4.3. 3-Oxo-2-(tetrahydrofuran-2-yl)butyric acid
methyl ester (14c). Colorless oil (79%). H NMR d 4.50–
1
4.43 (m, 1H), 3.91–3.80 (m, 2H), 3.78 (s, 3H), 3.74 (s,
3H), 3.49 (d, J¼9.1 Hz, 1H), 2.23–2.12 (m, 1H), 1.97–
1.88 (m, 2H), 1.78–1.66 (m, 1H). 13C NMR d 167.9,
167.5, 76.9, 68.3, 57.0, 52.6, 52.5, 29.9, 25.4. Anal. Calcd
for C9H14O5: C, 53.46; H, 6.98. Found: C, 53.09; H, 7.23.
4.4.4. 3-Oxo-2-(tetrahydropyran-2-yl)butyric acid methyl
ester (14d). Colorless oil (79%). H NMR d 4.04–3.96 (m,
1
4.3.12. 2-(2-Hexyltetrahydropyran-2-yl)-1-thiophen-
2-yl-ethanone (12l). Brown oil (65%). H NMR d 7.74
1
1H), 3.80 (s, 3H), 3.75 (s, 3H), 3.61 (d, J¼9.3 Hz, 1H), 2.31–
2.18 (m, 1H), 1.94–1.70 (m, 3H), 1.65–1.53 (m, 2H), 1.45–
1.24 (m, 2H). 13C NMR d 172.2, 171.5, 72.8, 60.3, 52.7,
52.5, 31.3, 30.4, 23.0, 22.0. Anal. Calcd for C10H16O5: C,
55.54; H, 7.46. Found: C, 55.84; H, 7.76.
(dd, J¼3.8, 1.0 Hz, 1H), 7.62 (dd, J¼4.9, 1.0 Hz, 1H),
7.12 (dd, J¼4.9, 3.9 Hz, 1H), 3.67 (t, J¼5.4 Hz, 2H), 3.12
(AB system, JAB¼31.2, 14.4 Hz, 2H), 1.86–1.59 (m, 6H),
1.54–1.51 (m, 2H), 1.36–1.26 (m, 8H), 0.86 (t, J¼6.7 Hz,
3H). 13C NMR d 191.6, 146.1, 133.7, 132.3, 128.0, 75.1,
61.4, 45.8, 34.5, 33.4, 31.8, 29.7, 25.6, 22.9, 22.6, 19.0,
14.1. Anal. Calcd for C17H26NO2S: C, 69.34; H, 8.90.
Found: C, 69.25; H, 9.24.
4.5. General procedure for the preparation of cyano-
hydrin esters 15
A mixture of 1-(benzotriazol-1-yl)alkyl ester 7 (2 mmol)
and potassium cyanide (0.13 g, 2 mmol) in DMSO
(10 mL) was stirred for 4 h at 20 ꢁC. The mixture was poured
into water (40 mL) and extracted with ethyl acetate (3ꢂ
30 mL). The extracts were washed with water, dried over
MgSO4, and the solvent was removed under reduced pres-
sure. The residue was placed in a silica gel column and
eluted with hexanes/EtOAc 5:1 to give 15. Structures
15a–d were supported by their elemental analyses and spec-
4.4. General procedure for 14
To a stirred solution of 1,3-dicarbonyl compound 13
(2 mmol) and 1-(a-alkoxyalkyl)benzotriazoles 9a,b (2 mmol)
in dry dichloromethane (40 mL), anhydrous AlCl3 (0.534 g,
4 mmol) was added portion-wise under nitrogen atmosphere
at rt over a period of 5 min. The mixture was then heated
under reflux, monitored by TLC and continued for 8 h. Ether
(100 mL) was added and the solution was washed with cold
water (3ꢂ25) and dried over MgSO4. After removal of the
solvent in vacuo, the resulting crude product was purified
by column chromatography on silica gel and eluted with
hexanes/EtOAc 9:1 to give 14.
1
tral data. For example, in the H NMR spectrum of 15c a
new multiplet appeared at 3.91–3.80 ppm, confirming the
successful displacement of the benzotriazolyl group. Dis-
placement of nitrogen (benzotriazolyl group) by carbon
(dicarbonyl moiety) resulted in an upfield shift of the signal
of the ethereal tertiary a-carbon atom (from 94.0, Bt2, or
87.7, Bt1 to 76.9 ppm) in the 13C NMR spectrum of 15c.
4.4.1. 3-Oxo-3-phenyl-2-(tetrahydrofuran-2-yl)-pro-
pionic acid ethyl ester (14a). Colorless oil (67%). 1H
NMR d 8.05–8.01 (m, 2H), 7.62–7.56 (m, 1H), 7.51–7.45
(m, 2H), 4.74–4.64 (m, 1H), 4.43 (dd, J¼13.2, 9.1 Hz,
1H), 4.21–4.11 (m, 2H), 3.92–3.69 (m, 2H), 2.26–2.15 (m,
1H), 1.99–1.84 (m, 2H), 1.57–1.48 (m, 1H), 1.21–1.14 (m,
3H). 13C NMR d 193.6, 193.2, 167.9, 167.5, 136.7, 136.3,
133.7, 133.4, 128.8, 128.7, 128.6, 78.0, 77.7, 68.1, 68.0,
61.6, 61.4, 60.1, 59.3, 30.2, 29.9, 25.4, 25.4, 13.9, 13.9.
Anal. Calcd for C15H18O4: C, 68.68; H, 6.92. Found: C,
68.37; H, 7.20.
4.5.1. Benzoic acid cyanomethyl ester (15a). Colorless
1
oil35 (98%). H NMR d 8.07–8.04 (m, 2H), 7.66–7.61 (m,
1H), 7.51–7.46 (m, 2H), 4.96 (s, 1H). 13C NMR d 164.9,
134.1, 130.0, 128.6, 127.8, 114.5, 48.8. Anal. Calcd for
C9H7NO2: C, 67.08; H, 4.38; N, 8.69. Found: C, 67.03; H,
4.31; N, 8.72.
4.5.2. Benzoic acid 1-cyano-3,3-dimethylbutyl ester
(15b). Colorless oil (87%). H NMR d 8.07–8.04 (m, 2H),
1

A. R. Katritzky et al. / Tetrahedron 63 (2007) 6477–6484
6483
7.65–7.60 (m, 1H), 7.51–7.46 (m, 2H), 5.63 (dd, J¼7.5,
References and notes
6 Hz, 1H), 2.13–1.99 (m, 2H), 1.05 (s, 9H). 13C NMR
d 164.9, 134.0, 130.0, 128.7, 128.4, 117.9, 59.4, 45.8,
30.3, 29.6. Anal. Calcd for C14H14NO2: C, 72.70; H, 7.41;
N, 6.06. Found: C, 72.78; H, 7.59; N, 6.29.
1. Katritzky, A. R.; Szajda, M.; Lam, J. N. Pol. J. Chem. 1993, 67,
1243–1250.
2. (a) Katritzky, A. R.; Borowiecka, J.; Fan, W.-Q. Synthesis 1990,
1173–1176; (b) Katritzky, A. R.; Drewniak, M. J. Chem. Soc.,
Perkin Trans. 1 1988, 2339–2344.
3. Katritzky, A. R.; Perumal, S.; Kuzmierkiewicz, W.; Lue, P.;
Greenhill, J. V. Helv. Chim. Acta 1991, 74, 1924–1930.
4. Katritzky, A. R.; Rachwal, S.; Rachwal, B. J. Org. Chem. 1989,
54, 6022–6029.
5. Katritzky, A. R.; Manju, K.; Singh, S. K.; Meher, N. K.
Tetrahedron 2005, 61, 2555–2581.
6. (a) Katritzky, A. R.; Bayyuk, S. I.; Rachwal, S. Synthesis 1991,
279–281; (b) Katritzky, A. R.; Rachwal, S.; Rachwal, B.; Steel,
P. J. J. Org. Chem. 1992, 57, 4925–4931.
7. (a) Katritzky, A. R.; Zhang, G.; Jiang, J. J. Org. Chem. 1995,
60, 7589–7596; (b) Katritzky, A. R.; Lang, H. J. Org. Chem.
1995, 60, 7612–7618; (c) Katritzky, A. R.; Lang, H.; Wang,
Z.; Zhang, Z.; Song, H. J. Org. Chem. 1995, 60, 7619–7624;
(d) Katritzky, A. R.; Lang, H.; Wang, Z.; Lie, Z. J. Org.
Chem. 1995, 61, 7551–7557.
4.5.3. Benzoic acid 1-cyanobutyl ester (15c). Colorless mi-
1
crocrystals30b (95%), mp 48–49 ꢁC. H NMR d 8.06–8.04
(m, 2H), 7.64–7.59 (m, 1H), 7.49–7.44 (m, 2H), 5.58 (t,
J¼6.6 Hz, 1H), 2.07–1.99 (m, 2H), 1.66–1.56 (m, 2H),
1.03 (t, J¼7.4 Hz, 3H). 13C NMR d 164.6, 133.8, 129.8,
128.5, 128.1, 116.9, 61.3, 34.2, 17.9, 13.2. Anal. Calcd for
C12H13NO2: C, 70.92; H, 6.45; N, 6.89. Found: C, 70.83;
H, 6.66; N, 7.05.
4.5.4. Benzoic acid 1-cyanopropyl ester (15d). Colorless
1
oil37 (98%). H NMR d 8.07–8.04 (m, 2H), 7.65–7.60 (m,
1H), 7.51–7.45 (m, 2H), 5.54 (t, J¼6.5 Hz, 1H), 2.07 (q,
J¼7.2 Hz, 2H), 1.19 (t, J¼7.4 Hz, 3H). 13C NMR d 164.7,
133.9, 129.8, 128.6, 128.2, 116.7, 62.6, 25.9, 8.9. Anal.
Calcd for C11H11NO2: C, 69.82; H, 5.86; N, 7.40. Found:
C, 69.71; H, 5.86; N, 7.71.
8. Katritzky, A. R.; Rachwal, S.; Rachwal, B. Synthesis 1991,
69–73.
9. Ireland, R. E.; Thaisrivongs, S.; Vanier, N.; Wilcox, C. S.
J. Org. Chem. 1980, 45, 48–61.
10. Meza-Reyes, S.; Sandoval-Ramirez, J.; Montiel-Smith, S.;
Hernandez-Linares, G.; Vinas-Bravo, O.; Martinez-Pascual,
R.; Fernandez-Herrera, M. A.; Vega-Baez, J. L.; Merino-
Montiel, P.; Santillan, R. L.; Farfan, N.; Rincon, S.; del Rio,
R. E. ARKIVOC 2005, vi, 307–320.
4.5.5. Benzoic acid cyanophenylmethyl ester (15e). Color-
less microcrystals (80%), mp 52–53 ꢁC (lit.30a mp 59 ꢁC).
1H NMR d 8.08–8.05 (m, 2H), 7.64–7.59 (m, 3H), 7.49–
7.44 (m, 5H), 6.68 (s, 1H). 13C NMR d 164.6, 134.1,
131.8, 130.4, 130.0, 129.3, 128.6, 128.0, 127.8, 116.2,
63.3. Anal. Calcd for C15H11NO2: C, 75.94; H, 4.67; N,
5.90. Found: C, 75.91; H, 4.79; N, 5.95.
4.5.6. 2,2-Dimethylpropionic acid cyano(3,4,5-trimethoxy-
phenyl)methyl ester (15f). Colorless microcrystals (82%),
11. Panek, J. S.; Jain, N. F. J. Org. Chem. 2001, 66, 2747–2756.
12. Corey, E. J.; Trybulski, E. J.; Melvin, L. S., Jr.; Nicolaou, K. C.;
Secrist, J. A.; Lett, R.; Sheldrake, P. W.; Falck, J. R.; Brunelle,
D. J.; Haslanger, M. F.; Kim, S.; Yoo, S.-e. J. Am. Chem. Soc.
1978, 100, 4618–4620.
1
mp 86–87 ꢁC. H NMR d 6.71 (s, 2H), 6.36 (s, 1H), 3.89
(s, 6H), 3.87 (s, 3H), 1.26 (s, 9H). 13C NMR d 176.2,
153.6, 139.2, 127.3, 116.2, 104.5, 62.7, 60.7, 56.1, 38.7,
26.7. Anal. Calcd for C16H21NO5: C, 62.53; H, 6.89; N,
4.56. Found: C, 62.22; H, 7.11; N, 4.23.
13. Nicolaou, K. C.; Daines, R. A.; Ogawa, Y.; Chakraborty, T. K.
J. Am. Chem. Soc. 1988, 110, 4696–4705.
14. Rychnovsky, S. D.; Griesgraber, G.; Kim, J. J. Am. Chem. Soc.
1994, 116, 2621–2622.
15. Ying, B.-P.; Trogden, B. G.; Kohlman, D. T.; Liang, S. X.; Xu,
Y.-C. Org. Lett. 2004, 6, 1523–1526.
16. (a) Lee, A. S.-H.; Wang, S.-H.; Chang, Y.-T.; Chu, S.-F.
Synlett 2003, 2359–2363; (b) Stewart, I. C.; Bergman,
R. G.; Toste, F. D. J. Am. Chem. Soc. 2003, 125, 8696–
8697.
4.5.7. 2,2-Dimethylpropionic acid 1-cyanobutyl ester
1
(15g). Colorless oil (96%). H NMR d 5.32 (t, J¼6.7 Hz,
1H), 1.94–1.87 (m, 2H), 1.60–1.48 (m, 2H), 1.24 (s, 9H),
1.00 (t, J¼7.4 Hz, 3H). 13C NMR d 176.6, 117.0, 60.7,
38.7, 34.1, 26.8, 17.9, 13.2. Anal. Calcd for C10H17NO2:
C, 65.54; H, 9.35; N, 7.64. Found: C, 65.64; H, 9.70; N, 7.48.
4.5.8. Thiophene-2-carboxylic acid 1-cyanobutyl ester
(15h). Colorless microcrystals (92%), mp 49–50 ꢁC. 1H
NMR d 7.87 (dd, J¼3.8, 1.2 Hz, 1H), 7.66 (dd, J¼4.9, 1.2 Hz,
1H), 7.15 (dd, J¼4.8, 3.8 Hz, 1H), 5.56 (t, J¼6.7 Hz, 1H),
2.05–1.98 (m, 2H), 1.68–1.55 (m, 2H), 1.03 (t, J¼7.3 Hz,
3H). 13C NMR d 160.2, 134.8, 134.0, 131.3, 128.0, 116.7,
61.4, 34.2, 17.9, 13.3. Anal. Calcd for C10H11NO2: C,
57.39; H, 5.30; N, 6.69. Found: C, 57.58; H, 5.24; N, 6.70.
17. (a) Murata, S.; Suzuki, M.; Noyori, R. J. Am. Chem. Soc. 1980,
102, 3248–3249; (b) Kamata, M.; Yokoyama, Y.; Karasawa,
N.; Kato, M.; Hasegawa, E. Tetrahedron. Lett. 1996, 37,
3483–3486; (c) Kamata, M.; Nagai, S.; Kato, M.; Hasegawa,
E. Tetrahedron Lett. 1996, 37, 7779–7782; (d) Roux, C. L.;
Ciliberti, L.; Laurent, R. H.; Laporterie, A.; Dubac, J. Synlett
1998, 1249–1251; (e) Cossy, J.; Lutz, F.; Alauze, V.; Meyer,
C. Synlett 2002, 45–48; (f) Ishitani, H.; Iwamoto, M.
Tetrahedron Lett. 2003, 44, 299–301; (g) Li, L.-S.; Das, S.;
Sinha, S. C. Org. Lett. 2004, 6, 127–130.
18. Katritzky, A. R.; Rachwal, S.; Rachwal, B. J. Chem. Soc.,
Perkin Trans. 1 1990, 1717–1725.
19. (a) Kunz, K. R.; Iyengar, B. S.; Dorr, R. T.; Alberts, D. S.;
Remers, W. A. J. Med. Chem. 1991, 34, 2281–2286; (b)
Lockhoff, O.; Stadler, P. Carbohydr. Res. 1998, 314, 13–24; (c)
Frauenrath, H.; Philipps, T. Tetrahedron 1986, 42, 1135–1138;
4.5.9. Furan-2-carboxylic acid 1-cyano-2,2-dimethyl-
propyl ester (15i). Colorless oil (85%). H NMR d 7.66
1
(d, J¼0.83 Hz, 1H), 7.28 (d, J¼3.6 Hz, 1H), 6.57 (dd,
J¼3.4, 1.6 Hz, 1H), 5.60 (dd, J¼7.1, 6.0 Hz, 1H), 2.10–
1.98 (m, 2H), 1.04 (s, 9H). 13C NMR d 156.5, 147.5,
142.8, 119.8, 117.4, 112.2, 59.0, 45.5, 30.1, 29.4. Anal.
Calcd for C12H15NO3: C, 65.14; H, 6.83; N, 6.33. Found:
C, 65.25; H, 6.98; N, 6.72.

6484
A. R. Katritzky et al. / Tetrahedron 63 (2007) 6477–6484
(d) Frauenrath, H.; Sawicki, M. Tetrahedron Lett. 1990, 31,
649–650.
(d) Achard, T. R. J.; Clutterbuck, L. A.; North, M. Synlett
2005, 1828–1847.
20. Flavio, B. Organomet. Chem. Rev. 1966, 1, 379–389.
21. Pike, R. M. Coord. Chem. Rev. 1967, 2, 163–172.
22. (a) Kobuke, Y.; Satoh, Y. J. Am. Chem. Soc. 1992, 114, 789–
790; (b) Kobuke, Y.; Kokubo, K.; Munakata, M. J. Am.
Chem. Soc. 1995, 117, 12751–12758.
29. Francis, F.; Davis, O. C. M. J. Chem. Soc. 1909, 95, 1403–
1409.
30. (a) Marvel, C. S.; Brace, N. O.; Miller, F. A.; Johnson, A. R.
J. Am. Chem. Soc. 1949, 71, 34–36; (b) Okimoto, M.; Chiba,
T. Synthesis 1996, 1188–1190.
23. Berliner, M. A.; Belecki, K. J. Org. Chem. 2005, 70, 9618–
9621.
31. Iwanami, K.; Aoyagi, M.; Oriyama, T. Tetrahedron Lett. 2005,
46, 7487–7490.
24. Nguyen, R.-V.; Yao, X.-Q.; Bohle, D. S.; Li, C.-J. Org. Lett.
2005, 7, 673–675.
25. Antonioletti, R.; Bonadies, F.; Scettri, A. J. Org. Chem. 1988,
53, 5540–5542.
32. Hoffmann, H. M. R.; Ismail, Z. M.; Hollweg, R.; Zein, A. R.
Bull. Chem. Soc. Jpn. 1990, 63, 1807–1810.
33. Scholl, M.; Lim, C.-K.; Fu, G. C. J. Org. Chem. 1995, 60,
6229–6231.
26. Agrochemicals from Natural Products; Godfrey, C. R. A., Ed.;
Marcel Dekker: New York, NY, 1995; p 418.
34. Katritzky, A. R.; Pastor, A.; Voronkov, M. V. J. Heterocycl.
Chem. 1999, 36, 777–781.
27. (a) Effenberger, F. Angew. Chem. 1994, 106, 1609–1619; (b)
Inagaki, M.; Hiratake, J.; Nishioka, T.; Oda, J. J. Am. Chem.
Soc. 1991, 113, 9360–9361; (c) Chen, F.; Feng, X.; Jiang, Y.
35. Byers, J. H.; Baran, R. C.; Craig, M. E.; Jackman, J. T. Org.
Prep. Proced. Int. 1991, 23, 373–374.
36. Murata, S.; Suzuki, M.; Noyori, R. Tetrahedron 1988, 44,
4259–4275.
37. Chenevert, R.; Plante, R.; Voyer, N. Synth. Commun. 1983, 13,
403–409.
38. de Godoy, L. A. F.; Camilo, N. S.; Pilli, R. A. Tetrahedron Lett.
2006, 47, 7853–7856.
ꢀ
ARKIVOC 2003, ii, 21–31; (d) Cordoba, R.; Csaky, A. G.;
Plumet, J. ARKIVOC 2004, iv, 94–99.
ꢀ €
28. (a) Gregory, R. J. H. Chem. Rev. 1999, 99, 3649–3682; (b)
Brunel, J.-M.; Holmes, I. P. Angew. Chem., Int. Ed. 2004, 43,
2752–2778; (c) Chen, F.-X.; Feng, X. Synlett 2005, 892–899;