Nitriles and carbonyl groups as acceptors in titanocene-catalyzed radical cyclizations

Article abstract of DOI:10.1055/s-0028-1083174

A catalytic approach to the titanocene-mediated radical cyclization of epoxy nitriles and epoxy carbonyl compounds to hydroxy ketones and diols is described. The reaction is sensitive to the substitution pattern of the catalyst and especially useful for the preparation of cyclobutanones. It can also be used for nitrile group transfer. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083174

PAPER
3509
Nitriles and Carbonyl Groups as Acceptors in Titanocene-Catalyzed Radical
Cyclizations
Catalytic
Cyclizati
n
ons
w
ith Nit
d
r
iles
a
nd Car
r
bonyl
G
r
oups as Gansäuer,* Frederik Piestert, Inga Huth, Thorsten Lauterbach
Kekulé-Institut für Organische Chemie und Biochemie der Universität Bonn, Gerhard-Domagk-Str. 1, 53121 Bonn, Germany
Fax +49(228)734760; E-mail: andreas.gansaeuer@uni-bonn.de
Received 29 April 2008; revised 3 July 2008
OH
O
Abstract: A catalytic approach to the titanocene-mediated radical
cyclization of epoxy nitriles and epoxy carbonyl compounds to hy-
droxy ketones and diols is described. The reaction is sensitive to the
substitution pattern of the catalyst and especially useful for the
preparation of cyclobutanones. It can also be used for nitrile group
transfer.
2.2 equiv Cp2TiCl2,
3 equiv Zn
95%
OH
CHO
O
2.2 equiv Cp2TiCl2,
3 equiv Zn
73%
Key words: catalysis, cyclization, cyclobutanone, radical,
titanocene
CN
HO
HO
O
O
3.3 equiv Cp2TiCl2,
6.6 equiv Zn
38%
Since the discovery of the titanocene-mediated epoxide
opening through electron transfer by Nugent and Rajan-
Babu,1 there have been numerous applications of this
highly interesting reaction.2 The catalytic conditions of
this process as developed by us3 and the group of Oltra
and Cuerva4 have been especially useful in the field of
radical cyclizations. By using these complementary proto-
cols, a number of pertinent and unusual applications such
as the synthesis of small rings by 3-exo and 4-exo cycliza-
tions,5 the preparation of heterocycles,6 and catalytic
transannular4a as well as epoxypolyene cyclizations7 have
been described.
CN
( )2
O
H
Scheme 1 Fernández-Matéos stoichiometric cyclizations of epoxy
aldehydes and nitriles
HO
O
10 mol% catalyst,
2 equiv Mn, 2.5 equiv Coll⋅HCl
O
CN
Catalyst
Yield
1
2
Cp2TiCl2
0%
(c-C6H11C5H4)2TiCl2 91%
(t-BuC5H4)2TiCl2 0%
HO
The group of Fernandez-Matéos has introduced the use of
aldehydes, ketones, and nitriles as radical acceptors in this
context and thus developed highly useful synthetic ap-
proaches, stoichiometric in titanium to hydroxy ketones
and diols, as shown in Scheme 1.8 Recently, a mechanistic
study has amongst other things unraveled the rate con-
stants of these cyclizations and suggested a dual role for
Cp2TiCl2, epoxide opening, and activation of the radical
traps in these reactions.9 Probably because of this suggest-
ed dual activation no catalytic version of the reaction has
been developed even though the stoichiometric process
has already been used efficiently in the synthesis of natu-
ral products and biologically active substances.10
O
10 mol% (c-C6H11C5H4)2TiCl2,
2 equiv Mn, 2.5 equiv Coll⋅HCl
87%
O
CN
3
4
O
HO
EtO2C
EtO2C
10 mol% (c-C6H11C5H4)2TiCl2,
2 equiv Mn, 2.5 equiv Coll⋅HCl
59%
O
CN
CO2Et
CO2Et
6
5
O
EtO2C
EtO2C
10 mol% (c-C6H11C5H4)2TiCl2,
2 equiv Mn, 2.5 equiv Coll⋅HCl
47%
O
Here, we report our findings on the development of cata-
lytic conditions for the cyclizations with aldehydes, ke-
tones and nitriles that can proceed with different
chemoselectivity than the stoichiometric processes. Our
results concerning the synthesis of cyclic ketones are sum-
marized in Scheme 2.
EtO2C
CO2Et
CN
7
8
Scheme 2 Catalytic cyclizations of epoxy nitriles (Coll·HCl: 2,4,6-
collidine hydrochloride)
It turned out that Cp2TiCl2 is indeed not suitable
as catalyst. The same holds true for the very bulky
(t-BuC5H4)2TiCl2. While the former complex led to exten-
sive decomposition, the latter complex is too hin-
dered to open the epoxide efficiently. Gratifyingly,
(c-C6H11C5H4)2TiCl2 led to excellent results in the synthe-
SYNTHESIS 2008, No. 21, pp 3509–3515
x
x.
x
x
.
2
0
0
8
Advanced online publication: 16.10.2008
DOI: 10.1055/s-0028-1083174; Art ID: T07008SS
© Georg Thieme Verlag Stuttgart · New York

3510
A. Gansäuer et al.
PAPER
HO
HO
NC
O
10 mol% (c-C6H11C5H4)2TiCl2,
2 equiv Mn, 2.5 equiv Coll⋅HCl
Et CO2Et
CN
CO2Et
Et
O
+
33% 10, 53% 11
Et
CO2Et
10
9
11, dr = 52:48
HO
NC
10 mol% catalyst,
2 equiv Mn, 2.5 equiv Coll⋅HCl
CN
CN
O
CN
13, dr = 52:48
Catalyst
Yield
12
(c-C6H11C5H4)2TiCl2
(MenthylC5H4)2TiCl2, 14
30%
59%
HO
NC
O
10 mol% (c-C6H11C5H4)2TiCl2,
2 equiv Mn, 2.5 equiv Coll⋅HCl
CN
CN
40%
CN
15
16, dr = 55:45
Scheme 3 Nitrile translocation reactions
OH
10 mol% Cp2TiCl2,
O
2 equiv Mn, 2.5 equiv
Coll⋅HCl, 5 equiv Coll.
60%
OH
CHO
18
17
10 mol% Cp2TiCl2,
2 equiv Mn,
2.5 equiv
Coll⋅HCl,
O
HO
OH HO
47:53
OH
5 equiv Coll.
50%
Figure 1 Crystal structure of cyclobutanone 2
O
19
20b
20a
sis of the cyclobutanones 2 and 4 and gave a reasonable
yield of cyclopentanone 6. We have demonstrated this
particular complex to be useful in intermolecular addi-
tions because of the efficient shielding of the intermediate
b-metaloxy radicals.11 A rather surprising result was ob-
served with substrate 7. The isolated product 8 lacks the
CH2OH group and has thus undergone a retro-aldol addi-
tion after cyclization. We attribute the ease of this addi-
tional transformation to unfavorable 1,3-diaxial
interactions in the initially formed product. Such interac-
tions are absent in the cyclobutanones as depicted for 2 in
Figure 1 and hence no retro-aldol processes were ob-
served for 2 and 4.
Scheme 4 Cyclizations of the carbonyl substituted epoxides 17 and
19
brought forward as an especially convincing argument for
the dual activation of the substrates by Fernández-
Matéos.9 Hence, it seems that in our catalytic reaction this
pathway is not operating.
Finally, we investigated the use of aldehydes and ketones
as radical acceptors. To this end a 3-exo and a 5-exo cy-
clization as shown in Scheme 4 were carried out. In this
case Cp2TiCl2 led to satisfactory results. This is readily
explained by the higher rate of cyclization of radicals with
aldehydes14 than with nitriles.15 Thus, an additional
shielding of the intermediate b-titanoxy radicals is not
necessary.
The double role of the titanocene postulated for the stoi-
chiometric reaction seems less likely in our catalytic con-
ditions due to the relatively low catalyst loading. We
therefore propose that the reductive trapping of the inter-
mediate iminyl radicals is much faster than the relatively
slow epoxide opening.12 Further support of this notion
was obtained from the nitrile translocation reactions of 9,
12, and 14 shown in Scheme 3.
It should be noted that in the first reaction, the cyclopro-
panol 18 is rather acid sensitive and can decompose to the
b,g-substituted aldehyde 21 via a cyclopropyl substituted
carbenium ion during workup. In the second reaction, sub-
strate 19 readily rearranges to the ketal 22 in the presence
of Coll·HCl as shown in Scheme 5.
In the reaction of 12, Kagan’s complex 14,13 which is
bulkier than (c-C6H11C5H4)2TiCl2, gave a much better
yield than the latter complex. In sharp contrast to the stoi-
chiometric reactions under our catalytic conditions, the
translocation compounds 11, 13 and 16 were either the
only or the main product. The suppression of these reac-
tions with stoichiometric amounts of titanocene have been
Thus, it is essential to employ the buffered reaction
mixture16 and to carry out the workup with phosphate
buffer8,9 instead of the usual aqueous 2 M HCl to obtain
the desired products. However, once these precautions are
taken, the cyclizations work reasonably well. It seems
rather unlikely that two equivalents of the titanocene cat-
Synthesis 2008, No. 21, 3509–3515 © Thieme Stuttgart · New York

PAPER
Catalytic Cyclizations with Nitriles and Carbonyl Groups
3511
pressure and the crude product was purified by SiO2 chromatogra-
phy.
10 mol% Cp2TiCl2,
2 equiv Mn, 2.5 equiv
Coll⋅HCl, 5 equiv Coll.
HCl workup
O
Compound 1
CHO
CHO
95%
According to General Procedure A, 2,2,4-trimethylpent-4-ene-
nitrile20 (1.10 g, 8.93 mmol) and 70% m-CPBA (4.44 g, 18.0 mmol)
in CH2Cl2 (50 mL) yielded 1 (834 mg, 5.99 mmol, 67%) as a color-
less oil; Rf = 0.41 (80% pentane–20% Et2O).
21
17
O
O
IR (film): 2981, 2235, 1455, 1394, 1371, 1290, 1259, 1065, 887,
798, 707 cm–1.
Coll⋅HCl
O
O
1H NMR (300.13 MHz, C6D6): d = 2.19 (d, J = 5.0 Hz, 1 H), 2.13
(d, J = 5.0 Hz, 1 H), 1.30 (d, J = 14.1 Hz, 1 H), 1.29 (s, 3 H), 1.21
(d, J = 14.4 Hz, 1 H), 0.97 (s, 3 H).
19
22
Scheme 5 Acid-catalyzed side reactions of 17 and 19
13C NMR (75.48 MHz, C6D6): d = 125.9, 54.1, 53.3, 47.6, 30.4,
27.4, 27.2, 21.7.
alyst bind to the substrate before the cyclization. In anal-
ogy to the situation encountered with the nitriles we
suggest that reduction of the highly reactive alkoxyl radi-
cal formed during cyclization is much faster than epoxide
opening. While at present definitive evidence about the
reductant cannot be provided, we suggest THF as hydro-
gen atom donor. This is because hydrogen atom abstrac-
tions from THF, the solvent of the reaction, by alkoxyl
radicals are extremely fast.17
HRMS-ESI: m/z calcd for C8H14NO (M + H): 140.1075; found:
140.1075.
Compound 2
According to General Procedure B, 1 (139 mg, 1.00 mmol), anhy-
drous collidine hydrochloride (394 mg, 2.50 mmol), Mn (110 mg,
2.00 mmol), and (c-C6H11C5H4)2TiCl2 (41.3 mg, 0.100 mmol) in
THF (10 mL) yielded 2 (129 mg, 0.908 mmol, 91%) as a colorless
solid: Rf = 0.27 (80% pentane–20% Et2O).
IR (film): 2960, 1771, 1455, 1379, 1284, 1164, 1044, 947, 913, 877,
850 cm–1.
All reactions were performed in oven-dried (100 °C) glassware un-
der argon. THF was freshly distilled from K. CH2Cl2 was freshly
distilled from CaH2. The products were purified by flash chroma-
tography on Merck silica gel 50 (eluents given in brackets, EA re-
fers to EtOAc, CH to cyclohexane) according to the procedure of
Still.18 Yields refer to analytically pure samples. Isomer ratios were
determined by suitable 1H NMR integrals of cleanly separated sig-
nals. NMR (r.t.): Bruker DRX 300, AMX 300, AM 400; DRX500
1H NMR, CHCl3 (7.26 ppm) or C6D5H (7.16 ppm) in the indicated
solvent as internal standard in the same solvent; 13C NMR, CDCl3
(77.16 ppm) or C6D6 (128.06 ppm) as internal standard in the same
solvent;19 integrals in accordance with assignments, coupling con-
stants are measured in Hz and always constitute JH,H coupling con-
stants. IR spectra: PerkinElmer 1600 series FT-IR and Thermo
Nicolet 380 as neat films on KBr plates or via ATR measurements.
Mass Spectrometry: EI Thermoquest Finnigan MAT 95 XL, cali-
bration against PFK; ESI Bruker Daltonics microTOF-Q, calibra-
tion against HCO2Na. Combustion analytics were performed on a
vario micro cube from Elementar, Hanau.
1H NMR (400.13 MHz, CDCl3): d = 3.70 (d, J = 11.1 Hz, 1 H), 3.52
(d, J = 11.1 Hz, 1 H), 2.10 (d, J = 11.5 Hz, 1 H), 1.71 (s, 1 H), 1.70
(d, J = 11.5 Hz, 1 H), 1.26 (s, 3 H), 1.26 (s, 3 H), 1.18 (s, 3 H).
13C NMR (100.63 MHz, CDCl3): d = 222.4, 66.5, 61.4, 55.8, 37.7,
24.6, 21.9, 19.5.
HRMS-EI: m/z calcd for C8H14O2: 142.0994; found: 142.0992.
Compound 3
According to General Procedure A, 1-(2-methylallyl)cyclo-
hexanecarbonitrile20 (3.49 g, 21.4 mmol) and 70% m-CPBA (10.5
g, 42.8 mmol) in CH2Cl2 (100 mL) yielded 3 (2.53 g, 14.1 mmol,
66%) as a colorless oil; Rf = 0.27 (83% CH–17% EA).
IR (film): 2934, 2860, 2230, 1451, 1301, 1279, 1218, 1158, 1103,
1076, 895, 800, 668 cm–1.
1H NMR (300.13 MHz, C6D6): d = 2.24 (d, J = 5.1 Hz, 1 H), 2.16(d,
J = 5.1 Hz, 1 H), 1.81–1.71 (m, 1 H), 1.61–1.27 (m, 2 H), 1.41 (d,
J = 14.4 Hz, 1 H), 1.34 (s, 3 H), 1.23 (d, J = 14.4 Hz, 1 H), 0.79 (dt,
J = 3.5, 12.9 Hz, 1 H), 0.76 (tt, J = 3.5, 12.9 Hz, 1 H), 0.61 (dt,
J = 3.3, 13.5 Hz, 1 H).
Epoxidation of Alkenes with m-CPBA; General Procedure A
To a solution of the alkene in CH2Cl2 was added m-CPBA, and the
mixture was stirred at 0 °C for 1 h and then at r.t. for 6 h. Then,
CH2Cl2 was added and the solution was washed with aq 2 N NaOH,
dried (MgSO4), and the solvent was removed. The residue was pu-
rified by SiO2 chromatography.
13C NMR (75.48 MHz, C6D6): d = 123.3, 53.9, 53.4, 47.8, 37.0,
36.3, 36.22, 3.3, 23.0, 22.9, 22.1.
HRMS-EI: m/z calcd for C11H16NO: 178.1232; found: 178.1238.
Compound 4
Titanocene-Catalyzed Radical Cyclizations of Epoxides; Gen-
eral Procedure B
According to General Procedure B, 3 (179 mg, 1.00 mmol), anhy-
drous collidine hydrochloride (394 mg, 2.50 mmol), Mn (110 mg,
2.00 mmol), and (c-C6H11C5H4)2TiCl2 (41.3 mg, 0.100 mmol) in
THF (10 mL) yielded 4 (158 mg, 0.868 mmol, 87%) as a colorless
liquid; Rf = 0.36 (90% CH–10% EA).
Titanocene catalyst (100 mmol), collidine hydrochloride (394 mg,
2.50 mmol), and Mn dust (131 mg, 2.00 mmol) were heated under
vacuum until the collidine hydrochloride began to sublime slightly
prior to use. Then, anhyd THF (10 mL) and the epoxide (1.00
mmol) were added and the mixture stirred at r.t. for 16 h. After the
addition of aq 2 N HCl (10 mL), the mixture was extracted with
Et2O (2 × 10 mL). The combined organic layers were washed with
H2O (10 mL) and the aqueous layer was extracted with CH2Cl2 (10
mL). The combined organic layers were washed with brine (5 mL)
and dried (MgSO4). The solvents were removed under reduced
IR (film): 3500, 2930, 1770, 1454, 1127, 1048, 987, 908 cm–1.
1H NMR (300.13 MHz, C6D6): d = 3.58 (d, J = 11.1 Hz, 1 H), 3.41
(d, J = 11.0 Hz, 1 H), 1.96 (d, J = 11.7 Hz, 1 H), 1.74–1.57 (m, 5 H),
1.58 (d, J = 11.3 Hz, 1 H), 1.50–1.30 (m, 6 H), 1.13 (s, 3 H).
13C NMR (75.34 MHz, CDCl3): d = 222.1, 66.6, 61.4, 60.2, 35.8,
33.8, 31.0, 25.6, 22.6, 22.5, 19.5.
Synthesis 2008, No. 21, 3509–3515 © Thieme Stuttgart · New York

3512
A. Gansäuer et al.
PAPER
HRMS-EI: m/z calcd for C11H18O2: 182.1307; found: 182.1311.
Anal. Calcd for C13H20O6: C, 57.34; H, 7.40. Found: C, 57.32; H,
7.52.
Diethyl 2-[(2-Methyloxiran-2-yl)methyl]malonate
According to General Procedure A, diethyl 2-(2-methyl-
allyl)malonate21 (3.81 g, 17.8 mmol) and 70% m-CPBA (5.64 g,
25.0 mmol) in CH2Cl2 (50 mL) yielded the desired product (3.57 g,
15.5 mmol, 62%) as a colorless oil; Rf = 0.35 (75% CH–25% EA).
Diethyl 2-(2-Cyanoethyl)-2-(2-methylallyl)malonate
To a suspension of NaH (60% in mineral oil, 400 mg, 10.0 mmol)
in THF (50 mL) was added slowly diethyl 2-(2-cyanoethyl)mal-
onate (2.33 g, 10.0 mmol). After stirring for 2 h, 3-chloro-2-meth-
ylprop-1-ene (1.36 g, 15.0 mmol) in THF (10 mL) was added. The
mixture was stirred for 16 h and quenched with H2O (50 mL). After
extraction with TBME (3 × 50 mL), the combined organic layers
were dried (MgSO4) and the solvent was removed. The residue was
purified by flash chromatography to yield the desired product (1.82
g, 6.80 mmol, 68%) as a colorless oil; Rf = 0.56 (80% CH–20%
EA).
IR (film): 3630, 2983, 2360, 1732, 1447, 1392, 1370, 1156, 1073,
1034, 904, 859, 806 cm–1.
1H NMR (300.13 MHz, CDCl3): d = 3.96 (q, J = 7.1 Hz, 4 H), 3.44
(dd, J = 7.9, 6.8 Hz, 1 H), 2.35 (dd, J = 14.4, 7.8 Hz, 1 H), 2.32 (d,
J = 3.8 Hz, 1 H), 2.25 (dd, J = 14.5, 6.8 Hz, 1 H), 2.11 (d, J = 4.7
Hz, 1 H), 1.05 (s, 3 H), 0.93 (t, J = 7.1 Hz, 6 H), 0.92 (t, J = 7.1 Hz,
6 H).
IR (neat): 2983, 2941, 2250, 1732, 1645, 1447, 1369, 1266, 1188,
1093, 1072, 1025, 905, 743, 680, 607, 566, 418 cm–1.
13C NMR (75.34 MHz, CDCl3): d = 169.1, 169.0, 61.4, 61.3, 54.7,
52.7, 48.7, 35.3, 21.3, 14.0.
1H NMR (400.13 MHz, CDCl3): d = 4.90 (t, J = 1.6 Hz, 1 H), 4.75
(s, 1 H), 4.21 (q, J = 7.1 Hz, 6 H), 2.72 (s, 2 H), 2.36 (dd, J = 9.0,
6.6 Hz, 2 H), 2.21 (dd, J = 8.4, 7.6 Hz, 2 H), 1.64 (s, 3 H), 1.27 (t,
J = 7.2 Hz, 6 H).
HRMS-EI: m/z calcd for C11H18O5: 230.1154; found: 230.1154.
Anal. Calcd for C11H18O5: C, 57.38; H, 7.88. Found: C, 57.20; H,
7.93.
13C NMR (100.62 MHz, CDCl3): d = 170.6, 140.0, 119.3, 116.7,
62.0, 55.9, 41.4, 28.9, 23.1, 14.1, 13.2.
Compound 5
To a suspension of NaH (60% in mineral oil, 400 mg, 10.0 mmol)
in THF (50 mL) was added slowly diethyl 2-[(2-methyloxiran-2-
yl)methyl]malonate (2.30 g, 10.0 mmol). After stirring for 2 h,
chloroacetonitrile (906 mg, 12.0 mmol) in THF (10 mL) was added.
The mixture was stirred for 16 h and quenched with H2O (50 mL).
After extraction with tert-butyl methyl ether (TBME, 3 × 50 mL),
the combined organic layers were dried (MgSO4) and the solvent
was removed. The residue was purified by flash chromatography to
yield 5 (1.45 g, 5.39 mmol, 54%) as a colorless oil; Rf = 0.33 (65%
CH–35% EA).
HRMS-EI: m/z calcd for C14H21NO4: 267.1471; found: 267.1462.
Compound 7
According to General Procedure A, diethyl 2-(2-cyanoethyl)-2-(2-
methylallyl)malonate (1.82 g, 6.80 mmol) and 70% m-CPBA (2.46
g, 10.0 mmol) in CH2Cl2 (50 mL) yielded 7 (1.36 g, 4.81 mmol,
70%) as a colorless oil; Rf = 0.29 (70% CH–30% EA).
IR (film): 3521, 2983, 2359, 2249, 1732, 1455, 1372, 1188, 861
cm–1.
IR (film): 2985, 2250, 1732, 1446, 1371, 1196, 1050, 1016, 858
cm–1.
1H NMR (300.13 MHz, C6D6): d = 4.05 (q, J = 7.1 Hz, 4 H), 2.42
(d, J = 15.1 Hz, 1 H), 2.38 (t, J = 7.1 Hz, 2 H), 2.17 (t, J = 7.2 Hz,
2 H), 2.14 (q, J = 5.3 Hz, 1 H), 2.11 (d, J = 16.2 Hz, 1 H), 2.09 (d,
J = 4.9 Hz, 1 H), 1.09 (s, 3 H), 0.98 (t, J = 7.1 Hz, 6 H).
1H NMR (400.13 MHz, C6D6): d = 3.90 (dq, J = 3.6, 7.1 Hz, 2 H),
3.88 (dq, J = 7.1, 7.1 Hz, 2 H), 3.01 (d, J = 17.0 Hz, 1 H), 2.87 (d,
J = 17.0 Hz, 1 H), 2.47 (d, J = 15.1 Hz, 1 H), 2.40 (d, J = 15.2 Hz,
1 H), 2.26 (d, J = 5.0 Hz, 1 H), 2.04 (d, J = 5.0 Hz, 1 H), 1.01 (s, 3
H), 0.88 (t, J = 7.1 Hz, 3 H), 0.87 (t, J = 7.1 Hz, 3 H).
13C NMR (75.34 MHz, C6D6): d = 170.4, 170.0, 119.0, 61.8, 61.9,
55.8, 53.9, 53.8, 39.6, 29.5, 21.2, 13.8, 12.9.
HRMS-EI: m/z calcd for C14H21NO5: 282.1336; found: 282.1346.
13C NMR (100.62 MHz, C6D6): d = 168.8, 168.56, 116.8, 62.5,
62.4, 54.9, 54.4, 53.6, 38.8, 22.7, 22.0, 13.8, 13.8.
Anal. Calcd for C14H21NO5: C, 59.35; H, 7.47; N, 4.94. Found: C,
59.12; H, 7.54; N, 4.89.
HRMS-EI: m/z calcd for C13H19NO5: 269.1263; found: 269.1259.
Compound 8
Anal. Calcd for C13H19NO5: C, 57.98; H, 7.11; N, 5.20. Found: C,
57.88; H, 7.26; N, 4.80.
According to General Procedure B, 7 (283 mg, 1.00 mmol), anhy-
drous collidine hydrochloride (394 mg, 2.50 mmol), Mn (110 mg,
2.00 mmol), and (c-C6H11C5H4)2TiCl2 (41.3 mg, 0.100 mmol) in
THF (10 mL) yielded 8 (121 mg, 0.473 mmol, 47%) as a colorless
liquid; Rf = 0.27 (70% CH–30% EA).
Compound 6
According to General Procedure B, 5 (269 mg, 1.00 mmol), anhy-
drous collidine hydrochloride (394 mg, 2.50 mmol), Mn (110 mg,
2.00 mmol), and (c-C6H11C5H4)2TiCl2 (41.3 mg, 0.100 mmol) in
THF (10 mL) yielded 6 (161 mg, 0.592 mmol, 59%) as a colorless
liquid; Rf = 0.22 (60% CH–40% EA).
IR (film): 2980, 2936, 2875, 1732, 1455, 1368, 1335, 1235, 1117,
1027, 944, 901, 862, 779, 719 cm–1.
1H NMR (300.13 MHz, C6D6): d = 3.98 (q, J = 7.0 Hz, 2 H), 3.86
(q, J = 7.1 Hz, 2 H), 2.67 (ddd, J = 13.5, 5.5, 3.3 Hz, 1 H), 2.59–
2.50 (m, 1 H), 2.47–2.36 (m, 1 H), 2.28 (ddd, J = 13.9, 5.6, 0.5 Hz,
1 H), 2.22 (ddd, J = 14.6, 5.1, 3.3 Hz, 1 H), 1.89 (dt, J = 13.5, 5.0
Hz, 1 H), 1.70 (t, J = 13.4 Hz, 1 H), 0.97 (d, J = 6.6 Hz, 3 H), 0.90
(t, J = 7.2 Hz, 3 H), 0.85 (t, J = 7.2 Hz, 3 H).
IR (film): 3522, 2982, 1732, 1464, 1368, 1250, 1187, 1055, 860
cm–1.
1H NMR (400.13 MHz, CDCl3): d = 4.19 (q, J = 7.0 Hz, 3 H), 4.07
(q, J = 7.1 Hz, 3 H), 3.56 (dd, J = 10.4, 6.1 Hz, 1 H), 3.37 (dd,
J = 10.5, 3.5 Hz, 1 H), 3.01 (d, J = 18.8 Hz, 1 H), 2.82 (d, J = 3.1
Hz, 1 H), 2.78 (d, J = 2.4 Hz, 1 H), 2.38 (d, J = 13.8 Hz, 1 H), 2.0
(s, 1 H), 1.23 (t, J = 7.1 Hz, 3 H), 1.22 (t, J = 7.1 Hz, 3 H), (d, J = 1.1
Hz, 3 H).
13C NMR (75.48 MHz, C6D6): d = 208.5, 170.8, 170.4, 61.5, 61.4,
54.7, 41.1, 39.9, 38.0, 31.9, 14.6, 14.0, 13.9.
HRMS-ESI: m/z calcd for C13H20O5 + Na (M + Na): 279.1208;
found: 279.1201.
13C NMR (100.62 MHz, CDCl3): d = 218.5, 171.7, 171.30, 67.5,
62.3, 60.5, 54.1, 50.9, 45.4, 39.4, 20.6, 14.2, 14.0.
Anal. Calcd for C13H20O5: C, 60.92; H, 7.87. Found: C, 61.18; H,
7.95.
HRMS-EI: m/z calcd for C13H20O6: 272.1260; found: 272.1251.
Synthesis 2008, No. 21, 3509–3515 © Thieme Stuttgart · New York

PAPER
Catalytic Cyclizations with Nitriles and Carbonyl Groups
3513
Ethyl 2-Cyano-2-ethyl-4-methylpent-4-enoate
(d, J = 9.8 Hz, 1 H), 1.49–1.57 (m, 2 H), 1.01 (s, 3 H), 0.97 (t,
J = 7.1 Hz, 3 H), 0.78 (t, J = 7.5 Hz, 3 H); d (diastereomer B): 3.94
(m, 2 H), 3.10 (br s, 1 H), 2.46–2.56 (m, 1 H), 2.09 (d, J = 10.4 Hz,
1 H), 2.04 (d, J = 10.2 Hz, 1 H), 1.21–1.48 (m, 2 H), 0.96 (t, J = 7.1
H, 3 H), 0.95 (s, 3 H), 0.74 (t, J = 7.5 Hz, 3 H).
To a suspension of NaH (60% in mineral oil, 648 mg, 16.2 mmol)
in DMF (80 mL) was added slowly ethyl 2-cyanobutanoate (2.30 g,
16.2 mmol). After stirring the mixture for 1 h, 3-chloro-2-methyl-
prop-1-ene (1.46 g, 16.2 mmol) was added. The mixture was stirred
for 16 h and quenched with H2O (50 mL). After extraction with
TBME (3 × 50 mL), the combined organic layers were dried
(MgSO4) and the solvent was removed. The residue was purified by
flash chromatography to yield the desired product (2.51 g, 13.1
mmol, 79%) as a colorless oil; Rf = 0.73 (80% CH–20% EA).
13C NMR (75.48 MHz, C6D6): d (diastereomer A) = 176.1, 122.9,
67.9, 61.0, 43.7, 39.3, 37.3, 27.6, 21.8, 14.2, 11.3; d (diastereomer
B) = 175.6, 122.7, 66.8, 60.7, 43.5, 38.9, 37.0, 27.6, 20.7, 14.1,
11.5.
HRMS-EI: m/z calcd for C11H19NO3: 213.1365; found: 213.1374.
IR (ATR): 2976, 2243, 1738, 1459, 1241, 1215, 1020, 902 cm–1.
1H NMR (300.13 MHz, CDCl3): d = 4.94 (s, 1 H), 4.86 (s, 1 H), 4.25
(q, J = 7.2 Hz, 2 H), 2.62 (d, J = 14.0 Hz, 1 H), 2.45 (d, J = 14.0 Hz,
1 H), 1.79–2.05 (m, 2 H), 1.82 (s, 3 H), 1.31 (t, J = 7.2 Hz, 3 H),
1.07 (t, J = 7.4 Hz, 3 H).
2-Methyl-2-(2-methylallyl)malononitrile
To a solution of 2-(2-methylallyl)malononitrile (1.94 g, 16.1 mmol)
and MeI (2.50 g, 17.8 mmol) in THF (6 mL) was slowly added
K2CO3 (2.45 g, 17.8 mmol). The suspension was stirred for 16 h and
quenched with H2O (30 mL). After extraction with Et2O (3 × 50
mL), the combined organic layers were dried (MgSO4) and the sol-
vent was removed. The residue yielded the product (1.90 g, 14.1
mmol, 87%) and was used without any purification; Rf = 0.25 (85%
CH–15% EA).
13C NMR (75.48 MHz, CDCl3): d = 169.0, 139.5, 119.4, 116.2,
62.7, 50.1, 44.9, 31.8, 23.2, 14.2, 9.8.
HRMS-EI: m/z calcd for C11H17NO2: 195.1259; found: 195.1262.
Compound 9
IR (ATR): 2978, 2359, 1651, 1453, 1382, 1255, 1136, 910 cm–1.
According to General Procedure A, ethyl 2-cyano-2-ethyl-4-meth-
ylpent-4-enoate (2.37 g, 12.1 mmol) and 70% m-CPBA (4.46 g,
18.1 mmol) in CH2Cl2 (120 mL) yielded 9 (2.24 g, 10.6 mmol, 88%,
dr 51:49) as a colorless oil; Rf = 0.27 (80% CH–20% EA).
1H NMR (300.13 MHz, CDCl3): d = 5.16 (s, 1 H), 5.07 (s, 1 H), 2.63
(s, 2 H), 1.95 (s, 3 H), 1.81 (s, 3 H).
13C NMR (75.47 MHz, CDCl3): d = 137.3, 118.8, 116.4, 46.3, 30.9,
25.2, 23.1.
IR (ATR): 2978, 2245, 1738, 1460, 1240, 1211, 1027, 805 cm–1.
1H NMR (400.13 MHz, C6D6): d (diastereomer A) = 3.85–3.99 (m,
2 H), 2.78 (d, J = 4.5 Hz, 1 H), 2.22 (d, J = 4.9 Hz, 1 H), 1.79–1.88
(m, 2 H), 1.52–1.67 (m, 1 H), 1.31–1.44 (m, 1 H), 1.26 (s, 3 H), 0.91
(t, J = 7.49 Hz, 3 H), 0.84 (t, J = 7.4 Hz, 3 H); d (diastereomer
B) = 3.85–3.99 (m, 2 H), 2.40 (d, J = 4.5 Hz, 1 H), 2.14 (d, J = 4.5
Hz, 1 H), 1.52–1.67 (m, 1 H), 1.45–1.50 (m, 2 H), 1.31–1.44 (m, 1
H), 1.26 (s, 3 H), 0.89 (t, J = 7.2 Hz, 3 H), 0.83 (t, J = 7.4 Hz, 3 H).
HRMS-EI: m/z calcd for C8H10N2: 134.0844; found: 134.0844.
Compound 12
According to General Procedure A, 2-methyl-2-(2-methylallyl)ma-
lononitrile (1.55 g, 11.5 mmol) and 70% m-CPBA (11.4 g, 45.9
mmol) in CH2Cl2 (115 mL) yielded 12 (1.26 g, 8.39 mmol, 73%) as
a colorless oil; Rf = 0.20 (75% CH–25% EA).
13C NMR (100.62 MHz, C6D6): d (diastereomer A) = 168.9, 119.3,
62.6, 54.6, 54.0, 48.0, 44.0, 32.4, 22.7, 13.8, 9.5; d (diastereomer
B) = 168.7, 119.0, 62.4, 54.1, 52.5, 47.2, 42.9, 32.4, 21.5, 13.8, 9.4.
IR (ATR): 2978, 2250, 1452, 1396, 1159, 889, 808, 703 cm–1.
1H NMR (300.13 MHz, C6D6): d = 2.26 (s, 1 H), 2.09 (s, 1 H), 1.39
(d, J = 13.2 Hz, 1 H), 1.15 (d, J = 13.2 Hz, 1 H), 1.14 (s, 3 H), 0.89
(s, 3 H).
HRMS-EI: m/z calcd for C10H14NO3: 196.0974; found: 196.0973.
13C NMR (75.48 MHz, C6D6): d = 116.5, 116.3, 53.1, 53.0, 45.0,
28.8, 24.9, 21.1.
Compounds 10 and 11
According to General Procedure B, 9 (200 mg, 0.948 mmol), anhy-
drous collidine hydrochloride (372 mg, 2.37 mmol), Mn (102 mg,
1.98 mmol), and (c-C6H11C5H4)2TiCl2 (34.0 mg, 0.0948 mmol) in
THF (9.5 mL) yielded 10 (67.0 mg, 0.313 mmol, 33%, single dia-
stereomer) and 11 (107 mg, 0.502 mmol, 53%, dr 52:48) as color-
less oils.
HRMS-ESI: m/z calcd for C8H10N2O + Na (M + Na): 173.0685;
found: 173.0682.
Anal. Calcd for C8H10N2O: C, 63.98; H, 6.71; N, 18.65. Found: C,
64.19; H, 7.15; N, 18.64.
Compound 13
10
Rf = 0.16 (75% CH–25% EA).
According to General Procedure B, 12 (200 mg, 1.33 mmol), anhy-
drous collidine hydrochloride (522 mg, 3.33 mmol), Mn (144 mg,
2.66 mmol) and (c-C6H11C5H4)2TiCl2 (54.9 mg, 0.130 mmol) in
THF (9.5 mL) yielded 13 (60.9 mg, 0.400 mmol, 30%, dr 52:48) as
a colorless oil.
IR (ATR): 3512, 2967, 2359, 1777, 1718, 1233, 1150, 1013 cm–1.
1H NMR (400.13 MHz, CDCl3): d = 4.02–3.88 (m, 2 H), 3.54 (d,
J = 11.0 Hz, 1 H), 3.11 (d, J = 11.0 Hz, 1 H), 2.42 (d, J = 11.6 Hz,
1 H), 2.16 (d, J = 11.8 Hz, 1 H), 2.22 (ddd, J = 14.3, 7.3, 7.3 Hz, 1
H), 1.97 (ddd, J = 21.1, 7.3, 7.3 Hz, 1 H), 1.08 (s, 3 H), 0.91 (t,
J = 7.0 Hz, 3 H), 0.90 (t, J = 7.4 Hz, 3 H).
According to General Procedure B, 12 (200 mg, 1.33 mmol), anhy-
drous collidine hydrochloride (522 mg, 3.33 mmol), Mn (144 mg,
2.66 mmol), and 14 (70.0 mg, 0.133 mmol) in THF (9.5 mL) yielded
13 (119 mg, 0.782 mmol, 59%, dr 52:48) as a colorless oil; Rf = 0.11
(70% CH–30% EA).
13C NMR (100.63 MHz, CDCl3): d = 209.9, 170.0, 71.8, 65.3, 64.2,
61.3, 31.1, 25.3, 18.3, 14.1, 9.4.
IR (ATR): 3463, 2985, 2942, 2882, 2239, 1456, 1386, 1058 cm–1.
HRMS-EI: m/z calcd for C11H18O4: 214.1205; found: 214.1213.
1H NMR (300.13 MHz, C6D6): d (diastereomer A) = 3.38–3.46 (m,
1 H), 3.08–3.13 (m, 1 H), 2.35–2.49 (m, 1 H), 1.62 (dd, J = 9.9, 14.4
Hz, 1 H), 1.02 (dd, J = 4.3, 14.4 Hz, 1 H), 0.99 (s, 3 H), 0.83 (d,
J = 7.1 Hz, 3 H); d (diastereomer B) = 3.30–3.38 (m, 1 H), 3.16–
3.21 (m, 1 H), 2.35–2.49 (m, 1 H), 1.43 (dd, J = 4.2, 14.4 Hz, 1 H),
1.02 (dd, J = 9.8, 14.2 Hz, 1 H), 1.10 (s, 3 H), 0.84 (d, J = 7.2 Hz, 3
H).
11
Rf = 0.11 (75% CH–25% EA).
IR (ATR): 3479, 2967, 2236, 1727, 1460, 1381, 1183, 1062 cm–1.
1H NMR (300.13 MHz, C6D6): d (diastereomer A) = 3.94 (m, 2 H),
3.10 (br s, 1 H), 2.46–2.56 (m, 1 H), 1.92 (d, J = 10.0 Hz, 1 H), 1.87
Synthesis 2008, No. 21, 3509–3515 © Thieme Stuttgart · New York

3514
A. Gansäuer et al.
PAPER
13C NMR (75.48 MHz, C6D6): d (diastereomer A) = 122.6, 122.6,
68.0, 39.1, 38.5, 21.9, 19.1; d (diastereomer B) = 122.7, 122.4, 66.5,
39.1, 38.1, 22.1, 20.3.
mmol, 60%) as a colorless solid. The analytical data were in accord
with literature values.22
Compounds 20a and 20b
HRMS-EI: m/z calcd for C7H10N2 (M – CH2O): 122.0844; found:
122.0844.
According to General Procedure B, 1921 (284 mg, 2.00 mmol), an-
hydrous collidine hydrochloride (788 mg, 5.00 mmol), collidine
(1.21 g, 10.0 mmol), Zn dust (261 mg, 4.00 mmol), and Cp2TiCl2
(49.8 mg, 0.200 mmol) in THF (20.0 mL) yielded 20a (67.0 mg,
0.465 mmol, 23%) and 20b (77.0 mg, 0.534 mmol, 27%) as color-
less solids. The analytical data were in accord with literature val-
ues.22
2-Methyl-2-(3-methylbut-3-enyl)malononitrile
To a solution of 2-(3-methylbut-3-enyl)malononitrile (2.68 g, 20.0
mmol) and MeI (3.04 g, 22.0 mmol) in THF (8 mL) was added
K2CO3 (3.10 g, 20.0 mmol). The suspension was stirred for 16 h and
quenched with H2O (30 mL). After extraction with Et2O (3 × 20
mL), the combined organic layers were dried (MgSO4) and the sol-
vent was removed. The residue yielded the product (2.83 g, 19.1
mmol, 96%) and was used without any purification; Rf = 0.12 (95%
CH–5% EA).
Compound 22
To a suspension of anhyd collidine hydrochloride (197 mg, 1.25
mmol) in THF (5 mL) was added 19 (71.0 mg, 0.499 mmol). The
mixture was stirred for 16 h. After washing with H2O and removal
of the volatiles, the residue was purified via flash chromatography
to yield 22 (67.2 mg, 0.479 mmol, 95%) as a pale yellow oil. The
analytical data were in accord with literature values.22
IR (ATR): 3080, 2939, 2249, 1651, 1453, 1378, 1159, 895 cm–1.
1H NMR (300.13 MHz, CDCl3): d = 4.84 (s, 1 H), 4.78 (s, 1H),
2.33–2.39 (m, 2 H), 2.04–2.09 (m, 2 H), 1.82 (s, 3 H), 1.78 (s, 3 H).
13C NMR (75.47 MHz, CDCl3): d = 142.2, 116.1, 112.2, 37.5, 33.6,
31.7, 25.0, 22.5.
Acknowledgment
HRMS-EI: m/z calculated for C9H12N2: 148.1000; found: 148.0999.
We are indebted to the Fonds der Chemischen Industrie (Sachbei-
hilfen) and the SFB 624 ‘Template - vom Design chemischer Scha-
blonen zur Reaktionssteuerung’ for continued financial assistance.
Compound 15
According to General Procedure A, 2-methyl-2-(3-methylbut-3-
enyl)malononitrile (1.13 g, 7.99 mmol) and 70% m-CPBA (2.98 g,
11.9 mmol) in CH2Cl2 (80 mL) yielded 15 (1.14 g, 6.95 mmol, 87%)
as a colorless oil; Rf = 0.34 (70% CH–30% EA).
References
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IR (ATR): 2933, 2250, 1725, 1454, 1393, 1155, 897, 808 cm–1.
1H NMR (400.13 MHz, C6D6): d = 2.04–2.06 (m, 2 H), 1.36–1.60
(m, 2 H), 1.20–1.33 (m, 2 H), 0.83 (s, 3 H), 0.79 (s, 3 H).
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32.2, 31.5, 23.8, 20.8.
HRMS-EI: m/z calcd for C9H11N2O (M – H): 163.0871; found:
163.0871.
Anal. Calcd for C9H12N2O: C, 65.83; H, 7.37; N, 17.06. Found: C,
66.09; H, 7.60; N, 17.00.
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Compound 16
According to General Procedure B, 15 (200 mg, 1.22 mmol), anhy-
drous collidine hydrochloride (478 mg, 3.05 mmol), Mn (132 mg,
2.44 mmol), and (c-C6H11C5H4)2TiCl2 (50.3 mg, 0.122 mmol) in
THF (12 mL) yielded 16 (80.0 mg, 0.482 mmol, 40%, dr 55:45) as
a colorless oil; Rf = 0.15 (65% CH–35% EA).
IR (ATR): 3479, 2968, 2237, 1727, 1461, 1382, 1184, 1062 cm–1.
1H NMR (300.13 MHz, C6D6): d (diastereomer A) = 3.22–3.31 (m,
2 H), 1.86–2.01 (m, 1 H), 1.01–1.58 (m, 4 H), 0.95 (s, 3 H), 0.76 (d,
J = 7.2 Hz, 3 H); d (diastereomer B) = 3.22–3.31 (m, 2 H), 1.86–
2.01 (m, 1 H), 1.01–1.58 (m, 4 H), 0.92 (s, 3 H), 0.75 (d, J = 7.0 Hz,
3 H).
13C NMR (75.58 MHz, C6D6): d (diastereomer A) = 123.2, 122.5,
67.4, 39.3, 33.2, 29.5, 25.5, 20.3, 17.7; d (diastereomer B) = 123.1,
122.5, 67.7, 39.2, 33.1, 29.3, 25.6, 20.3, 17.5.
HRMS-ESI: m/z calcd for C9H14N2O + Na (M + Na): 189.1004;
found: 189.1009.
Compound 18
According to General Procedure B, 1721 (336 mg, 2.00 mmol), an-
hydrous collidine hydrochloride (788 mg, 5.00 mmol), collidine
(1.21 g, 10.0 mmol), Zn dust (261 mg, 4.00 mmol), and Cp2TiCl2
(49.8 mg, 0.20 mmol) in THF (20.0 mL) yielded 18 (205 mg, 1.20
Synthesis 2008, No. 21, 3509–3515 © Thieme Stuttgart · New York

PAPER
Catalytic Cyclizations with Nitriles and Carbonyl Groups
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