Synthesis of δ- And ε-cyanoesters by zinc-catalyzed ring-opening of cyclic ethers with acid chlorides and subsequent cyanation

Article abstract of DOI:10.1007/s10562-011-0744-6

In the present study, the zinc-catalyzed cleavage of cyclic ethers with acid halides as nucleophiles to yield chloroesters with different chain length has been investigated in detail. In the presence of straightforward and commercially available zinc salts as pre-catalysts excellent yields and selectivities were feasible. After studying the reaction conditions and the scope of the method, several efforts were carried out to understand the reaction mechanism. The obtained chloroesters were subsequently converted to δ- and ε-cyano esters, which are useful precursors in natural product synthesis. Graphical Abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s10562-011-0744-6

Catal Lett (2012) 142:168–175
DOI 10.1007/s10562-011-0744-6
Synthesis of d- and e-Cyanoesters by Zinc-Catalyzed
Ring-Opening of Cyclic Ethers with Acid Chlorides
and Subsequent Cyanation
•
Stephan Enthaler Maik Weidauer
Received: 10 October 2011 / Accepted: 13 November 2011 / Published online: 29 November 2011
Ó Springer Science+Business Media, LLC 2011
Abstract In the present study, the zinc-catalyzed cleav-
age of cyclic ethers with acid halides as nucleophiles to
yield chloroesters with different chain length has been
investigated in detail. In the presence of straightforward
and commercially available zinc salts as pre-catalysts
excellent yields and selectivities were feasible. After
studying the reaction conditions and the scope of the
method, several efforts were carried out to understand the
reaction mechanism. The obtained chloroesters were sub-
sequently converted to d- and e-cyano esters, which are
useful precursors in natural product synthesis.
nucleophilic ring opening of ethers and subsequent cya-
nation can be an interesting possibility (Fig. 1). In more
detail, on the one hand, a Lewis acid catalyzed ring-opening
of cyclic ethers with acid chlorides as nucleophiles has the
advantage of providing a variety of chloroesters with easy
tunable chain lengths, since a great number of ethers are
commercially available. During the years various methods
based on Lewis acids have been introduced for the ring
opening of cyclic ethers [8–20]. Among those protocols the
application of zinc-salts as catalysts is advantageously,
because it is abundant, cheap and low toxic. However, even
if the zinc-catalyzed ring-opening of cyclic ethers has been
reported a scope and limitations of the method is desired
[21–27]. In addition, so far no mechanistical investigations
have been accounted. On the other hand, the formation
of a halide functionality allows a straightforward trans-
formation to the corresponding nitriles [28, 29]. Finally, the
cyanoesters are deprotected to provide the requested
hydroxynitriles.
Keywords Homogeneous catalysis Á Zinc Á Ether Á
Ring-opening Á Nitriles Á Cyanation
1 Introduction
Nitrile functionalities are extensively applied in organic
chemistry and represent building blocks for the production
of pharmaceuticals, agrochemicals, and polymers [1].
Especially, nitriles with additional functional groups allow
for a broad scope of purposes. Here an interesting sub-class
is represented by hydroxynitriles, which have been applied
e.g. in the synthesis of natural products [2–5]. However, a
general method for the synthesis of hydroxynitriles, which
allows the easy adjustment of the carbon spacer between
the hydroxyl and nitrile functionality is highly requested [6,
7]. In this regard, a three step synthesis based on the
Herein we present based on our ongoing interest in zinc-
chemistry an efficient and straightforward two step proto-
col based on zinc-catalyzed ring opening of cyclic ethers
and subsequent cyanation to access protected hydroxy-
nitriles with tunable chain length [30–36].
2 Results and Discussion
Initially, the ring-opening of THF with benzoyl chloride (1)
was investigated as a model reaction to evaluate appro-
priate reaction conditions and to examine the influence of
different reaction parameters (Table 1). As expected no
formation of the d-chloroester 2 was noticed in the absence
of any zinc source applying THF as solvent at 70 °C
(Table 1, entry 1). On the contrary, in the presence of
S. Enthaler (&) Á M. Weidauer
Department of Chemistry, Cluster of Excellence ‘‘Unifying
¨
Concepts in Catalysis’’, Technische Universitat Berlin, Straße
des 17. Juni 135/C2, 10623 Berlin, Germany
e-mail: stephan.enthaler@tu-berlin.de
123

Synthesis of d- and e-Cyanoesters
169
electron-donating groups (Table 2, entries 1–7). In addition
the reaction of alkyl acid chlorides with THF resulted in
excellent yields (Table 2, entries 8 and 9). By changing
the source of cyclic ether towards tetrahydropyrane,
2,5-dimethyltetrahydrofuran and 3,3-dimethyloxetane lower
yields were obtained (Table 2, entries 10–12). In case of 22
two isomers were found in a ratio of *1:1. Moreover,
sulfonic acid chlorides were reacted with THF in the
presence of ZnCl2. Moderate yields were monitored for
p-toluenesulfonic acid chloride, whilst for p-nitrophenyl-
sulfonic acid chloride no product formation was observed
(Table 2, entries 13–14). Finally, also a heteroaromatic
acid chloride was converted to the desired product in
excellent yield (Table 2, entry 15).
Fig. 1 Synthetic strategy for the synthesis of hydroxynitriles starting
from cyclic ethers
5.0 mol% of commercially available ZnCl2 an excellent
yield ([99%) and chemoselectivity ([99%) was realized
under non-inert conditions (Table 1, entry 2). Additionally,
the effect of various zinc sources such as ZnBr2, Zn(OAc)2,
Zn(acac)2, and Zn(OTf)2 on the formation of 2 was
investigated (Table 1, entries 3–6). Interestingly, all
applied zinc sources lead to a quantitative conversion of 1.
The loading of Zn(OTf)2 was decreased to 1.0 and
0.5 mol% respectively, resulting in diminished yields of 2
for 0.5 mol% loading, while with 1.0 mol% excellent
yields were feasible even after 1 h reaction time with
turnover frequencies of [99 h-1 (Table 1, entry 6–8 and
11). Besides THF, toluene has been applied as solvent, but
lower yields were achieved (Table 1, entry 10).
After having established an appropriate catalyst system
for the ring-opening of cyclic ethers to the corresponding
chloroesters we became intrigued in studying the under-
lying reaction mechanism. As elucidated in Table 1 entry 1
catalytic amounts of zinc salts are necessary to promote the
reaction, while in the absence of any zinc the reaction did
not proceed. To investigate the effect of the anion con-
nected to the zinc stoichiometric amounts of ZnBr2 (1.0
equiv) or ZnF2 (1.0 equiv), respectively, were added to a
mixture of THF (excess) and 1 (1.0 equiv). After refluxing
the reaction for 1 h the outcome was analyzed by GC–MS
revealing the exclusive formation of chloroester 2, while
the corresponding bromo- or fluoroester was not observed.
With respect to this result an abstraction of the chloride
from the benzoyl chloride by the zinc is unlikely and the
zinc acts probably as a Lewis acid [17]. Moreover, the
To explore the scope and limitation of the zinc catalyst,
the ring-opening of a range of cyclic ethers with different
benzoyl chlorides was performed (Table 2). The reaction
conditions are in accordance to optimized conditions dis-
covered in Table 1, means the corresponding ethers were
converted in the presence of 1.0 mol% ZnCl2. First an
excess of THF was reacted with substituted benzoyl chlo-
rides at 70 °C for 2 h (Table 2, entries 1–4). In all exper-
iments excellent yields were observed. Furthermore, no
difference was detected for electron-withdrawing as well as
Table 1 Zinc-catalyzed synthesis of d-chloroester 2
Entry
Zinc source (mol%)
Time (h)
T (°C)
Solvent
Yield (%)a
1
–
6
6
6
6
6
6
6
6
6
6
1
70
70
70
70
70
70
70
70
r.t.
70
70
THF
THF
THF
THF
THF
THF
THF
THF
THF
Toluene
THF
\1
2
ZnCl2 (5)
[99
[99
[99
[99
[99
[99
72
3
ZnBr2 (5)
4
Zn(OAc)2 (5)
Zn(acac)2 (5)
Zn(OTf)2 (5)
Zn(OTf)2 (1.0)
Zn(OTf)2 (0.5)
Zn(OTf)2 (5)
Zn(OTf)2 (1.0)
Zn(OTf)2 (1.0)
5
6
7
8
9
10b
7
59
11
[99
Reaction conditions: 1 (0.72 mmol), Zn-precursor (0.5–5.0 mol%), solvent (2.0 mL), THF (1.1 equiv.–excess), r.t.-70 °C, 1–6 h
a
Determined by GC methods applying anisol as internal standard
b
1.1 equiv. of THF (0.79 mmol)
123

170
S. Enthaler and M. Weidauer
Table 2 Zinc-catalyzed
synthesis of various
chloroesters
Entry
1
Substrates
Product
Yield [%][a
>99 (97)
2
3
>99 (89)
>99 (73)
4
5
6
7
>99
>99 (92)
>99 (85)
>99 (79)
8
>99 (90)
9
>99 (87)
86 (77)
10[b]
11
69 (60)
12
13
93 (84)
36
Reaction conditions:
substrate
(3.2–37 mmol), ZnCl2
(1.0 mol%), ether
(2.0–10 mL), 70 °C, 2 h
In brackets the
isolated yield is stated
14
15
<1
a
>99 (98)
b
24 h at 100 °C
function of the zinc was studied by NMR techniques. For
this purpose Zn(OTf)2 was applied as probe for 19F NMR.
Zn(OTf)2 was dissolved in THF-d8 and a 19F NMR
spectrum was recorded showing a single peak at -79.1 ppm.
The signal was assigned to the already known complex
Zn(OTf)2(thf)4 (31), which was reported by Nefedov and
123

Synthesis of d- and e-Cyanoesters
171
co-workers and more recently by us (Fig. 1) [33, 37]. The
octahedral zinc is axial coordinated by the triflate groups
and in the equatorial plane four THF molecules are located.
Subsequently, acid chloride 5 (10 equiv.) was added to the
solution at room temperature, resulting in the formation of a
new signal for 5 at d = -104.4 ppm (sept, J = 4.51 Hz),
while the signal for Zn(OTf)2 (d = -81.1 ppm) is slightly
shifted. Afterwards the mixture was heated to 70 °C for 1 h
3 Conclusions
In summary, we have studied the zinc-catalyzed cleavage
of cyclic ethers with acid halides as nucleophiles to yield
chloroesters with different chain length. In the presence of
straightforward and commercially available zinc salts as
pre-catalysts excellent yields and selectivities were
achieved. After studying the reaction conditions and the
scope of the method, several efforts were carried out to
understand the reaction mechanism. The obtained chloro-
esters were subsequently converted to d- and e-cyanoesters,
which are useful precursors in natural product synthesis.
and cooled to room temperature followed by recording 19
F
NMR spectrum. On the one hand the signal for Zn(OTf)2
(d = -81.1 ppm) is unaltered on the NMR time-scale,
which proves the assumption for a Lewis acid mechanism.
On the other hand a new multiplet at d = -109.3 to
-109.5 ppm occurred, which was dedicated to the product
8. The product 8 was compared with the undeuterated
compound 6 and affirmed by MS-methods. Based on the
findings (vide supra) a reaction mechanism according to
Scheme 1 is assumed. First the Zn(OTf)2 is dissolved in
THF and the complex 31 is formed. The coordination of the
oxygen functionality of the ether to the zinc allows an
activation of the oxygen and the adjacent carbon. In the next
step one THF ligand dissociates and enables the coordina-
tion of the benzoyl chloride via the oxygen. Subsequently
the chloride attacks the carbon and the benzoyl group is
transferred to the former THF oxygen. The chloroester is
discharged and a new molecule of THF coordinates to the
zinc forming complex 31, which can perform the next cat-
alytic cycle.
4 Experimental Section
4.1 General
All compounds were used as received without further
purification. THF and toluene were dried applying standard
procedures. 1H, 19F and 13C NMR spectra were recorded on
a Bruker AFM 200 spectrometer (1H: 200.13 MHz; 13C:
50.32 MHz; 19F: 188.31 MHz) using the proton signals of
the deuterated solvents as reference. GC–MS measurements
were carried out on a Shimadzu GC-2010 gas chromato-
graph (30 m Rxi-5 ms column) linked with a Shimadzu
GCMA-QP 2010 Plus mass spectrometer. IR spectra were
recorded on a Perkin Elmer Spectrum 100 FT-IR.
After studying the zinc-catalyzed ring-opening of
cyclic ethers we focused on the cyanation of the obtained
chloroesters. In accordance to the work of Stirling and
co-workers the chloroester and potassium cyanide were
dissolved in dimethyl sulfoxide and stirred for 24 h at
80 °C [28]. In all experiments excellent yields have been
observed for various substitution patterns (Table 3).
Moreover, attempts to connect the zinc-catalyzed ring-
opening and the cyanation protocol, means a one-pot pro-
cedure or a sequential process, failed so far.
4.2 General Procedure for the Zinc-Catalyzed
Ring-Opening of Cyclic Ethers
A pressure tube was charged with an appropriate amount of
ZnCl2 (1.0 mol%), the corresponding ether (2.0–10 mL)
and the acid chloride (3.2–37 mmol). The reaction mixture
was stirred in a preheated oil bath at 70 °C for 2 h. The
mixture was cooled on an ice bath. The solvent was
removed in vacuum and the residue was dissolved in
dichloromethane (20 mL) and washed with water, brine
and dried with Na2SO4. After filtration the solvent was
removed to obtain colourless oils. The analytical properties
of the corresponding chloroesters are in agreement with
literature.
1
d-Chlorobutyl benzoate (2) [16] m = 7.6 g (97%); H
NMR (CDCl3, 200 MHz) d = 7.94–8.07 (m, 2H);
7.33–7.58 (m, 3H), 4.26–4.40 (m, 2H), 3.50–3.65 (m, 2H),
1.84–1.98 (m, 4H) ppm; 13C NMR (CDCl3, 50 MHz)
d = 166.3, 132.8, 130.1, 129.4, 128.2, 63.9, 44.3, 29.1,
26.2 ppm; IR (KBr): m = 3805 (w), 3660 (w), 3424 (m),
3065 (w), 2959 (m), 2871 (w), 2346 (w), 1720 (s), 1602
(w), 1584 (w), 1451 (s), 1387 (m), 1315 (s), 1275 (s), 1176
Scheme 1 Proposed catalytic cycle for the synthesis of chloroesters
123

172
S. Enthaler and M. Weidauer
Table 3 Cyanation of chloroesters
Yield [%][a]
Substrate
Product
Entry
>99 (81)
1
>99 (87)
>99 (86)
>99 (91)
>99 (80)
>99 (94)
2
3
4
5
6
>99 (78)
7
Reaction conditions: substrate (4.7 mmol), KCN (5.7 mmol), DMSO (2.0 mL), 80 °C, 24 h
a
In brackets the isolated yield is stated
(m), 1116 (s), 1070 (s), 1027 (s), 895 (w), 806 (w), 712 (s),
687 (m), 675 (m), 651 (m) cm-1; MS (ESI) m/z = 212 (3,
M?), 177 (11), 122 (53), 105 (100), 77 (47) 51 (16).
d-Chlorobutyl 4-methylbenzoate (4) [18] m = 6.0 g
2H), 6.99–7.13 (m, 2H), 4.24–4.35 (m, 2H), 3.32–3.62 (m,
3H), 1.84–1.96 (m, 3H) ppm; 13C NMR (CDCl3, 50 MHz)
d = 168.2, 165.5, 132.1, 131.9, 126.5, 126.4, 115.6, 115.2,
64.2, 44.3, 29.2, 26.1 ppm; 19F NMR (CDCl3, 188 MHz)
d = -105.9 to -105.6 (m); IR (KBr): m = 2960 (w), 2873
(w), 1718 (s), 1604 (s), 1508 (m), 1412 (w), 1274 (s), 1239
(m), 1154 (m), 1117 (m), 1091 (m), 1015 (w), 855 (m), 768
(m), 687 (w), 608 (w) cm-1; MS (ESI) m/z = 230 (1, M?),
195 (13), 140 (58), 123 (100), 96 (38), 75 (15), 55 (21).
d-Chlorobutyl 4-chlorobenzoate (10) [14] m = 1.3 g
1
(89%); H NMR (CDCl3, 200 MHz) d = 7.84–7.94 (m,
2H), 7.13–7.24 (m, 2H), 4.24–4.36 (m, 2H), 3.49–3.62 (m,
2H), 2.36 (s, 3H, CH3), 1.82–1.96 (m, 4H) ppm; 13C NMR
(CDCl3, 50 MHz) d = 166.6, 143.6, 129.6, 129.1, 127.5,
63.9, 44.5, 29.3, 26.2, 21.6 ppm; IR (KBr): m = 3423 (w),
2957 (s), 2867 (m), 2346 (w), 1717 (s), 1612 (s), 1578 (w),
1510 (m), 1446 (m), 1407 (m), 1385 (m), 1275 (s), 1208
(m), 1178 (s), 1110 (s), 1021 (m), 842 (m), 745 (s), 691
(w), 651 (w), 609 (w), 475 (w) cm-1; MS (ESI) m/z = 226
(4, M?), 191 (19), 136 (84), 119 (100), 91 (49), 65 (19), 55
(15).
1
(92%); H NMR (CDCl3, 200 MHz) d = 7.85–8.00 (m,
2H), 7.31–7.43 (m, 2H), 4.23–4.39 (m, 2H), 3.35–3.82 (m,
2H), 1.62–2.01 (m, 4H) ppm; 13C NMR (CDCl3, 50 MHz)
d = 166.7, 139.4, 131.0, 128.7, 128.6, 64.4, 44.4, 29.2,
26.2 ppm; IR (KBr): m = 2959 (m), 2871 (w), 1721 (s),
1595 (s), 1530 (m), 1488 (m), 1446 (w), 1402 (m), 1272
(s), 1172 (m), 1118 (s), 1015 (m), 895 (w), 850 (m), 760
d-Chlorobutyl 4-fluorobenzoate (6) m = 533 mg
1
(73%); H NMR (CDCl3, 200 MHz) d = 7.95–8.07 (m,
123

Synthesis of d- and e-Cyanoesters
173
(s), 721 (w), 685 (m), 652 (w), 524 (w), 479 (w) cm-1; MS
(ESI) m/z = 246 (3, M?), 211 (14), 156 (78), 139 (100),
111 (34), 75 (21), 55 (38).
754 (w), 712 (s), 687 (m), 675 (m), 651 (m) cm-1; MS
(ESI) m/z = 226 (2, M?), 123 (67), 105 (100), 77 (47), 51
(15).
d-Chlorobutyl 4-methoxybenzoate (12) [38] m = 6.2 g
(85%); 1H NMR (CDCl3, 200 MHz) d = 7.90–8.01 (m, 2H),
6.84–6.92 (m, 2H), 4.23–4.34 (m, 2H), 3.82 (s, 3H, CH3O),
3.36–3.63 (m, 3H), 1.84–1.94 (m, 3H) ppm; 13CNMR(CDCl3,
50 MHz) d = 166.3, 163.4, 131.6, 122.7, 113.6, 63.8, 55.4,
44.5, 29.3, 26.3 ppm; IR (KBr): m = 3851 (w), 3748 (w), 3736
(w), 3673 (w), 3650 (w), 3421 (w), 2959 (s), 2843 (m), 2346
(m), 1712 (s), 1607 (s), 1581 (m), 1512 (s), 1461 (s), 1421 (m),
1386 (m), 1312 (s), 1275 (s), 1253 (s), 1158 (s), 1103 (s), 1030
(s), 897 (w), 848 (m), 771 (s), 696 (m), 651 (w), 613 (m), 512
(w) cm-1; MS (ESI) m/z = 242 (14, M?), 207 (22), 152 (77),
135 (100), 107 (13), 92 (13), 77 (21), 56 (15).
1-Methyl-4-chloropentylbenzoate (22) [15] m = 2.9 g
1
(60%); H NMR (CDCl3, 200 MHz) d = 7.80–8.17 (m,
2H), 7.35–7.68 (m, 3H), 5.07–5.23 (m, 1H), 3.95–4.15 (m,
1H), 1.28–2.04 (m, 10H) ppm; 13C NMR (CDCl3, 50 MHz)
d = 166.15, 166.18, 134.5, 133.7, 132.9, 130.7, 130.6,
130.2, 129.4, 128.9, 128.5, 128.4, 71.3, 70.8, 58.6, 58.5,
58.3, 57.9, 37.6, 36.9, 36.4, 36.0, 33.3, 33.1, 25.5, 25.4,
20.2, 20.16 ppm; IR (KBr): m = 2975 (m), 1790 (w), 1717
(s), 1602 (w), 1584 (w), 1491 (w), 1451 (m), 1379 (w),
1354 (w), 1314 (m), 1276 (s), 1212 (w), 1176 (w), 1112
(m), 1070 (m), 1026 (m), 921 (w), 853 (w), 755 (w), 712
(s), 687 (w), 616 (w) cm-1; MS (ESI) m/z = 240 (1, M?),
123 (40), 105 (100), 82 (34), 77 (33), 55 (23).
d-Chlorobutyl 4-nitrobenzoate (14) [14] m = 1.0 g
1
(79%); H NMR (CDCl3, 200 MHz) d = 7.86–7.98 (m,
4-Chloro-2,2-dimethylbutyl benzoate (24) m = 4.41 g
1
(84%); H NMR (CDCl3, 200 MHz) d = 7.97–8.17 (m,
2H), 7.30–7.44 (m, 2H), 4.20–4.39 (m, 2H), 3.35–3.90 (m,
3H), 1.84–1.96 (m, 3H) ppm; 13C NMR (CDCl3, 50 MHz)
d = 165.7, 139.4, 131.0, 128.7, 128.6, 65.1, 44.4, 29.2,
26.2 ppm; IR (KBr): m = 3112 (w), 2960 (m), 2870 (w),
1725 (s), 1608 (m), 1529 (s), 1446 (w), 1411 (w), 1350 (m),
1320 (w), 1275 (s), 1168 (w), 1104 (m), 1015 (w), 874 (m),
843 (w), 784 (w), 720 (s), 651 (w), 504 (w) cm-1; MS
(ESI) m/z = 257 (2, M?), 168 (45), 150 (83), 120 (22), 104
(36), 92 (25), 76 (31), 65 (12), 54 (100).
2H), 7.35–7.76 (m, 3H), 4.16 (s, 2H), 3.51 (s, 2H), 1.10 (s,
6H, 2xCH3) ppm; 13C NMR (CDCl3, 50 MHz) d = 166.3,
133.1, 131.4, 129.6, 128.5, 69.7, 52.2, 36.4, 22.7 ppm; IR
(KBr): m = 3065 (w), 2967 (m), 1721 (s), 1602 (w), 1528
(w), 1472 (w), 1451 (m), 1394 (w), 1373 (m), 1314 (w),
1273 (s), 1176 (w), 1114 (m), 1070 (w), 1026 (m), 972 (w),
935 (w), 851 (w), 805 (w), 772 (w), 711 (s), 687 (w), 672
(w) cm-1; MS (ESI) m/z = 226 (1, M?), 123 (25), 105
(100), 77 (29), 56 (13).
d-Chlorobutyl isobutyrate (16) [26] m = 4.0 g (90%);
1H NMR (CDCl3, 200 MHz) d = 3.98–4.13 (m, 2H),
3.31–3.70 (m, 2H), 2.35–2.60 (m, 1H), 1.65–1.90 (m, 4H),
1.05–1.17 (m, 6H) ppm; 13C NMR (CDCl3, 50 MHz)
d = 177.1, 63.4, 44.4, 34.0, 29.2, 26.1, 19.0 ppm; IR
(KBr): m = 2974 (m), 2877 (w), 2345 (w), 1735 (s), 1471
(m), 1390 (w), 1345 (w), 1259 (w), 1194 (m), 1157 (m),
1118 (w), 1078 (w), 890 (w), 754 (w), 669 (w), 653
(w) cm-1; MS (ESI) m/z = 178 (1, M?), 168 (45), 89 (70),
71 (91), 54 (79), 43 (100).
4-Chlorobutyl tosylate (26) MS (ESI) m/z = 262 (2,
M?), 172 (40), 155 (48), 107 (10), 91 (100), 65 (29), 54
(25).
d-Chlorobutyl thiophenecarboxylate (30) m = 1.46 g
1
(98%); H NMR (CDCl3, 200 MHz) d = 7.73–7.78 (m,
1H), 7.48–7.54 (m, 1H), 7.02–7.09 (m, 1H), 4.23–4.34 (m,
2H), 3.35–3.63 (m, 3H), 1.81–1.92 (m, 3H) ppm; 13C NMR
(CDCl3, 50 MHz) d = 162.0, 133.3, 132.2, 127.7, 64.2,
44.4, 29.1, 26.1 ppm; IR (KBr): m = 2959 (w), 2871 (w),
1710 (s), 1526 (m), 1446 (w), 1420 (m), 1358 (m), 1260
(s), 1225 (w), 1153 (w), 1102 (s), 1076 (m), 1039 (w), 860
(w), 750 (m), 722 (m), 652 (w) cm-1; MS (ESI) m/z = 218
(5, M?), 183 (13), 128 (82), 111 (100), 55 (21).
d-Chlorobutyl 4-acetate (18) [39] m = 3.3 g (87%);
1H NMR (CDCl3, 200 MHz) d = 3.95–4.10 (m, 2H),
3.46–3.58 (m, 2H), 2.00 (s, 3H), 1.60–1.89 (m, 4H) ppm;
13C NMR (CDCl3, 50 MHz) d = 171.0, 63.6, 44.4, 29.1,
26.1, 20.9 ppm; IR (KBr): m = 2960 (m), 2871 (w), 1740
(s), 1446 (w), 1367 (m), 1241 (s), 1116 (m), 1047 (m), 755
(w), 650 (w), 607 (w) cm-1; MS (ESI) m/z = 150 (1, M?),
73 (14), 61 (16), 54 (36), 43 (100).
4.3 General Procedure for the Cyanation
of Chloroesters
e-Chloropentyl benzoate (20) [17] m = 6.2 g (77%);
1H NMR (CDCl3, 200 MHz) d = 7.94–8.06 (m, 2H),
7.30–7.55 (m, 3H), 4.21–4.34 (m, 2H), 3.41–3.57 (m, 2H),
1.40–1.90 (m, 6H) ppm; 13C NMR (CDCl3, 50 MHz)
d = 166.5, 132.9, 130.4, 129.5, 128.4, 64.6, 44.7, 32.2,
28.1, 23.5 ppm; IR (KBr): m = 3360 (w), 3423 (w), 3065
(w), 2955 (s), 2868 (m), 2346 (w), 1720 (s), 1602 (m), 1584
(m), 1492 (w), 1452 (s), 1387 (m), 1314 (s), 1275 (s), 1176
(s), 1116 (s), 1070 (s), 1026 (s), 961 (w), 849 (w), 806 (w),
The corresponding chloroester (4.7 mmol) and potassium
cyanide (5.7 mmol, 1.2 equivalents) were dissolved in
DMSO (2.0 mL) and stirred for 24 h at 80 °C. After
cooling to room temperature water (20 mL) was added and
the mixture was extracted with dichloromethane
(2 9 20 mL). The organic layer was washed with water,
brine and dried over Na2SO4. After filtration over a short
plug of silica gel the solvent was removed in vacuum to
obtain yellow oils.
123

174
S. Enthaler and M. Weidauer
d-Cyanobutyl benzoate (34) [40] m = 770 mg (81%);
725 (w), 685 (w), 528 (w) cm-1; MS (ESI) m/z = 233 (20,
1H NMR (CDCl3, 200 MHz) d = 7.96–8.05 (m, 2H),
7.35–7.57 (m, 3H), 4.28–4.38 (m, 2H), 2.35–2.46 (m, 2H),
1.60–2.01 (m, 4H) ppm; 13C NMR (CDCl3, 50 MHz)
d = 166.5, 133.1, 130.1, 129.6, 128.5, 128.4, 63.6, 527.8,
22.4, 17.0 ppm; IR (KBr): m = 2958 (m), 2346 (w), 2246
(w), 1718 (s), 1601 (w), 1684 (w), 1528 (w), 1452 (m),
1387 (w), 1315 (w), 1276 (s), 1176 (w), 1118 (m), 1071
(w), 1026 (w), 713 (s), 687 (w), 675 (w) cm-1; MS (ESI)
m/z = 203 (5, M?), 122 (58), 105 (100), 77 (41), 51 (14).
d-Cyanobutyl 4-methylbenzoate (35) m = 890 mg
M?), 152 (56), 135 (100), 107 (11), 92 (12), 77 (18).
1
e-Cyanopentyl benzoate (39) m = 960 mg (94%); H
NMR (CDCl3, 200 MHz) d = 7.95–8.04 (m, 2H),
7.34–7.57 (m, 3H), 4.24–4.34 (m, 2H), 2.28–2.38 (m, 2H),
1.47–1.92 (m, 6H) ppm; 13C NMR (CDCl3, 50 MHz)
d = 166.5, 133.0, 130.3, 129.5, 128.4, 119.5, 64.4, 28.0,
25.3, 25.1, 17.1 ppm; IR (KBr): m = 2952 (m), 2870 (w),
2246 (w), 1718 (s), 1602 (w), 1584 (w), 1452 (m), 1375
(w), 1315 (w), 1276 (s), 1176 (w), 1119 (m), 1071 (w),
1026 (w), 713 (s), 688 (w), 674 (w) cm-1; MS (ESI) m/
z = 217 (1, M?), 177 (12), 122 (38), 105 (100), 77 (40), 55
(12).
1
(87%); H NMR (CDCl3, 200 MHz) d = 7.83–7.92 (m,
2H), 7.14–7.23 (m, 2H), 4.25–4.35 (m, 2H), 2.35 (s, 3H),
2.32–2.44 (m, 2H), 1.68–1.97 (m, 4H) ppm; 13C NMR
(CDCl3, 50 MHz) d = 166.7, 143.8, 129.6, 129.2, 127.3,
119.4, 63.5, 27.8, 22.4, 21.6, 16.9 ppm; IR (KBr):
m = 2956 (m), 2342 (w), 2246 (w), 1717 (s), 1612 (m),
1509 (w), 1452 (w), 1375 (w), 1313 (w), 1276 (s), 1208
(w), 1178 (m), 1113 (m), 1071 (w), 1021 (w), 842 (w), 755
(m), 714 (m), 690 (w), 476 (w) cm-1; MS (ESI) m/z = 217
(10, M?), 136 (61), 114 (100), 91 (43), 65 (17).
d-Cyanobutyl 3-thiophenecarboxylate (40)
m = 766 mg (78%); 1H NMR (CDCl3, 200 MHz)
d = 7.69–7.76 (m, 1H), 7.46–7.53 (m, 1H), 6.98–7.07 (m,
1H), 4.20–4.31 (m, 2H), 2.32–2.43 (m, 2H), 1.59–1.92 (m,
4H) ppm; 13C NMR (CDCl3, 50 MHz) d = 162.0, 133.5,
132.6, 127.9, 119.3, 63.8, 27.7, 22.3, 16.9 ppm; IR (KBr):
m = 2957 (w), 2873 (w), 1711 (s), 1604 (m), 1526 (m),
1508 (w), 1457 (m), 1420 (m), 1380 (w), 1358 (w), 1283
(s), 1262 (s), 1226 (m), 1154 (w), 1094 (s), 1076 (m), 1040
(w), 860 (m), 769 (m), 752 (m), 728 (m), 688 (w), 608
(w) cm-1; MS (ESI) m/z = 209 (11, M?), 128 (61), 111
(100).
d-Cyanobutyl 4-fluorobenzoate (36) m = 893 mg
1
(86%); H NMR (CDCl3, 200 MHz) d = 7.92–8.03 (m,
2H), 6.97–7.10 (m, 2H), 4.24–4.33 (m, 2H), 2.33–2.43 (m,
2H), 1.55–1.95 (m, 4H) ppm; 13C NMR (CDCl3, 50 MHz)
d = 168.3, 165.4, 163.3, 132.2, 132.0, 126.3, 119.3, 115.8,
115.3, 63.8, 40.9, 27.7, 22.3, 16.9 ppm; 19F NMR (CDCl3,
188 MHz) d = -105.6 to -105.3 (m); IR (KBr):
m = 2959 (w), 2874 (w), 1718 (s), 1604 (s), 1508 (s), 1458
(w), 1412 (w), 1388 (w), 1274 (s), 1239 (s), 1118 (s), 1091
(s), 1060 (w), 1015 (w), 951 (w), 929 (w), 856 (m), 768 (s),
688 (m), 608 (m), 504 (w) cm-1; MS (ESI) m/z = 221 (3,
M?), 140 (57), 123 (100), 95 (37), 75 (13).
Acknowledgments Financial support from the Cluster of Excel-
lence ‘‘Unifying Concepts in Catalysis’’ (funded by the Deutsche
Forschungsgemeinschaft and administered by the Technische Uni-
¨
versitat Berlin) is gratefully acknowledged. Furthermore, S. Hennig
and R. Skobalj (Technische Universitat Berlin) are thanked for their
¨
support.
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