A radical clock for reactions of epoxy derivatives induced by titanocene chloride

Article abstract of DOI:10.1055/s-0028-1087410

A new radical clock based on pinene derivatives has been designed to measure the radical cyclization rate onto cyano and carbonyl groups and the radical elimination rate of OR and CN. In this system, the known rate constant of cyclobutylcarbinyl radical cleavage is used as the internal clock. At room temperature, the cyclization rate constants for 4-exo and 5-exo processes onto nitrile and aldehyde carbonyl groups are in the order of 10⁷ to 10⁸ s^-1. The radical elimination rate constants for CN, OH, OCHO, and OAc are in the order of 10⁵ to 10⁸ s ^-1. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087410

3208
LETTER
A Radical Clock for Reactions of Epoxy Derivatives Induced by Titanocene
Chloride
Radical
Clock
for
.Reactions of
F
Epoxy Deriva
e
tives rnández-Mateos,* P. Herrero Teijón, R. Rabanedo Clemente, R. Rubio González
Departamento de Química Orgánica, Facultad de C. Químicas, Universidad de Salamanca, Plaza de los Caídos 1-5, 37008 Salamanca, Spain
E-mail: afmateos@usal.es
Received 3 September 2008
O
O
Abstract: A new radical clock based on pinene derivatives has
been designed to measure the radical cyclization rate onto cyano
and carbonyl groups and the radical elimination rate of OR and CN.
In this system, the known rate constant of cyclobutylcarbinyl radi-
cal cleavage is used as the internal clock. At room temperature, the
cyclization rate constants for 4-exo and 5-exo processes onto nitrile
and aldehyde carbonyl groups are in the order of 107 to 108 s–1. The
radical elimination rate constants for CN, OH, OCHO, and OAc are
in the order of 105 to 108 s–1.
H
k1 = 8.7⋅105 s–1 (80 °C)
k–1 = 4.7⋅108 s–1 (80 °C)
ref. 3p
A
A1
O
O
H
k2 = 1.0⋅106 s–1 (80 °C)
ref. 3q
k
–2 = 1.1⋅107 s–1 (80 °C)
B
C
D
B1
Key words: epoxides, titanium(III), radical clock, titanocene chlo-
ride, epoxynitriles, epoxyaldehydes, epoxyketones, epoxyesters
k
3 = 2.5⋅105 s–1 (25 °C)
ref. 3p,q
Radical reactions have become increasingly important in
the last two decades,1 and the knowledge of the rate con-
stants of radical reactions is a crucial issue in mechanistic
studies and synthetic applications.2 Accordingly, standard
methods for measuring the rates of radical reactions, such
as electron spin resonance (ESR), laser flash photolysis
and pulse radiolysis, have been extensively used.2 Al-
though direct methods are required for any kinetic scale,
indirect competition methods have been developed to
measure unknown rates. Radical clocks are used to de-
scribe a unimolecular radical reaction that is calibrated ki-
netically and, they can be applied in competition studies
to time a particular reaction.2 The kinetic method can now
exceed the limits of picosecond laser-flash methods.2
C1
N
N
k
k
4 = 4.0⋅103 s–1 (25 °C)
ref. 3p,q
ref. 3p,q
D1
5 = 1.0⋅104 s–1 (25 °C)
E
E1
Scheme 1 Rate constants
epoxides with titanocene chloride.4 However, no kinetic
studies of this process have been carried out. In this paper
we present a new radical clock to measure the rate of some
radical reactions induced by titanocene, such as the cy-
clizations shown in Scheme 2.5
Recently, the applications of radical methodology for the
production of carbocycles in the synthesis of complex
molecules have attracted much attention.1 Carbonyl and
cyano groups play an important role in organic chemistry.
Radical cyclizations involving carbonyl and cyano groups
have been studied from the synthetic and kinetic points of
view.3
TiIV
O
TiIV
O
O
X
X
X
Scheme 1 shows the experimental rate constant for sever-
al related processes. The generation of the radicals for all
these processes was done from alkyl halides with Bu3SnH
and AIBN. As shown in Scheme 1, the ring closure of rad-
ical A or B is slower than the cleavage of A1 or B1. The
last three processes are not reversible, and the latter two
reactions are very slow.
n
n
n
X = O, N
Scheme 2 Radical cyclizations onto polar multiple bonds
Our radical clock consists of the irreversible cleavage of
the cyclobutylcarbinyl radical.6
Over the last ten years the attention of organic chemists
has been drawn to the reactions of radicals generated from
To check the kinetics of the radical cyclizations of alde-
hydes, ketones, and nitriles,5 we decided to use intramo-
lecular competition systems, such as the radical F, shown
in Scheme 3, as our tools.
SYNLETT 2008, No. 20, pp 3208–3212
1
6
.1
2
.2
0
0
8
Advanced online publication: 26.11.2008
DOI: 10.1055/s-0028-1087410; Art ID: G29508ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Radical Clock for Reactions of Epoxy Derivatives
3209
X
X
k8 = 1.5⋅106 s–1 (60 °C)
X
k6
k7
n
H1
H
n
n
F2
F
F1
k9 = 3.0⋅105 s–1 (25 °C)
OH
X
X
OTiIV
n O
n
I
I1
n
1) elongation
2) epoxidation
TiIII
product
O
OTiIV
OTiIV
TiIII
k7
F´
1 n = 2
2 n = 1
G
n = 1–4
3
4
6
Scheme 3 Intramolecular competition system
1. TiIII
2. H3O+
k6
In F, the radical could be added to the polar multiple bond
(aldehyde, ketone, nitrile) to give F1 or the cyclobutane
could be cleaved to give F2. The ratio of the C≡X addition
product F1, relative to the cleavage product F2, should re-
flect the ratio of the rate constants of the two processes: k6/
k7 = [F2]/[F1].
OTiIV
OH
H3O+
OH
7
5
8
Our substrates G, the precursors of the radical F¢, were
prepared according to standard procedures from (1R)-(–)-
nopol (1, n = 2) and (1R)-(–)-myrtenol (2, n = 1), two
readily available terpenoids. These starting materials were
selected because their hydroxyl function permits easy
elongation of the chain and the incorporation of any func-
tional group, and also owing to the strategic situation of
the C=C double bond, which affords an epoxide at the cor-
rect site. In all cases, the epoxydation step was absolutely
stereoselective and was cis with respect to the methylene
bridge.7 The homolytic cleavage of the oxirane ring in the
above substrates with titanocene chloride would be totally
regioselective in the direction towards the tertiary radical,
as has been reported for trisubstituted epoxides.4,5
Scheme 4 Radical reaction of epoxide 3 with TiIII
Experimentally, the only product obtained in this reaction
was the menthane derivative 7.8 This means that the rate
constant k6, of the cyclobutane cleavage of 4 is higher than
that of the model k8. Otherwise, the ratio of the expected
compounds 7/8 would be 5:1 (k6/k7 = 5:1). To calculate
the rate constant k6, we used the faster radical clock J →
J1 (Scheme 5).2b
The reaction of 9 with TiIII gave a mixture of the cycliza-
tion product 10 and the cleavage product 11 at a ratio of
56:44, respectively.8 Thus, the cyclobutane cleavage in
substrate
9 was determined to be k6 = k10·[11]/
[10] = 1.4·107 s–1·44/56 = 1.1·107 s–1. Henceforth, this rate
constant was used as our internal radical clock to measure
other radical reaction rates. The practical limits of this
clock would be situated between 3·105 s–1 and 4·108 s–1;
that is, 36 times below and above 1.1·107 s–1 (k6/k10).
The rate constant for the cleavage of the radical cyclobu-
tylcarbinyl model H has been reported6 (Scheme 4). It
should be possible to use this known cleavage system as
an intramolecular radical clock to extrapolate the radical
cyclization rate constants of aldehydes, ketones, and ni-
triles.
Radical cyclizations rates: The reactions of the epoxy
derivatives were performed by slow addition of a THF so-
lution of titanocene chloride to a solution of the epoxy
substrates at room temperature. The results for the
However, the radical H is not exactly the same as F¢, gen-
erated by cleavage of the epoxy myrtenol substrates. In
the case of F¢, the radical is tertiary and the cyclobutane is
inserted in a cyclohexane. These characteristics could
modify the rate of the cyclobutane cleavage. To determine
this cyclobutane-cleavage rate more accurately, we pre-
pared epoxy alkene 3. The internal radical clock would be
the 5-exo cyclization I → I1: after treatment of 3 with TiIII,
the radical 4 would be obtained (Scheme 4). The compet-
itive pathways are the cyclobutane cleavage to the tertiary
radical 5 (k6), which further evolves through a loss of a
hydrogen atom to 7, and the irreversible 5-exo cyclization
onto C=C to the primary radical 6 (k7), which is further re-
duced to the tricyclic alcohol 8.
k10 = 1.4⋅107 s–1 (25 °C)
O
O
J
J1
O
O
O
O
OH
1. TiIII
OH
+
2. H3O+
9
10
11
Scheme 5 Radical reaction of epoxide 9 with TiIII
Synlett 2008, No. 20, 3208–3212 © Thieme Stuttgart · New York

3210
A. Fernández-Mateos et al.
LETTER
Table 1 Radical Cyclization Rates onto Nitrilea
5-exo cyclizations onto ketone carbonyls are slow pro-
cesses, like 6-exo cyclization onto the aldehyde carbonyl.
CN
n
a
The rate constants extrapolated for 5-exo cyclization
(Table 2, entry 2) are distant from those reported for the
same reaction induced by Bu3SnH (see k1, Scheme 1). The
b-scission of the alkoxy radicals generated in the cycliza-
tion onto carbonyl, which occurred for the reactions in-
duced by Bu3SnH, does not take place with titanocene. As
seen with cyano compounds, the coordination between the
carbonyl group and TiIII should occur. The trapping rate of
the alkoxy radical by TiIII should be faster than the b-scis-
sion (see k-1, Scheme 1).
n
n
+
O
O
CN
OH
OH
12
13
14
d
Entry 12
Yield of Yield of kCN
/
Extrapolated
kCN
13 (%)
14 (%)
kcleav
0.18
3.82
0
1
2
3
12a n = 1
12b n = 2
12c n = 3
12
42
0
67
0.2·107
4.2·107
<3·105
11
76
Radical fragmentation rates: It has been reported that
radicals generated by homolytic cleavage of epoxides
with titanocene afford alkenes through the elimination of
certain atoms or functional groups, such as H, CN, OH,
OCHO, and OAc, following the mechanism shown in
Scheme 6.10
a Conditions: (a) 1. TiIII, THF; 2. H3O+.
epoxynitriles are summarized in Table 1. The structures
of 12, 13, and 14 were formulated on the basis of NMR
data.8
The data from Table 1 indicate that 4-exo and 5-exo cy-
clizations onto nitrile are fast reactions and lie in the order
of 107 s–1, while 6-exo cyclization is a slower process:
<105 s–1. The rate constant values found for 5-exo cycliza-
tion onto nitrile in our reaction conditions are very differ-
ent from the reported k = 4·103 s–1 (25 °C)9 for the same
cyclization induced by Bu3SnH. The acceleration of the ti-
tanocene-induced cyclization must be due to a coordina-
tion of TiIII with the cyano group, which enhances the
radical-acceptor character of the cyano group by lowering
its LUMO.5e
The kinetics of these fragmentation reactions corresponds
to a radical reaction, as will be seen with our radical clock
based on pinene derivatives.5e
TiIV
O
O
TiIV
O
X
TiIII
X
+
XTiIV
X = CN, OH, OCHO, OAc
Scheme 6 Radical fragmentation
The results for epoxycarbonyl compounds are summa-
rized in Table 2.
The substrates for the kinetic study were obtained from
(1S)-(–)-a-pinene or from (1R)-(–)-myrtenol (2) by stan-
dard methods. The reactions of the epoxy derivatives were
performed by slow addition of a THF solution of ti-
tanocene chloride to a solution of the epoxides. The re-
sults are summarized in Table 3.
Table 2 Radical Cyclization Rates onto Carbonyl Groupa
R
O
n
Table 3 Radical Elimination Ratesa
n OH
a
n
+
O
R
R
OH
a
O
X
X
OH
+
O
16
15
17
OH
OH
18
20
Entry 15
Yield of
16 (%)
Yield of
17 (%)
Extrapolated
kCO
19
Entry 18
Yield of Yield of kelim
/
Extrapolated
>4·108
>4·108
<3·105
<3·105
<3·105
19 (%)
20 (%) kcleav kelim
1
2
3
4
5
15a n = 1, R = H
15b n = 2, R = H
15c n = 3, R = H
15d n = 1, R = Me
15e n = 2, R = Me
78
73
0
0
0
1
2
3
4
5
18a X = CN
20
47
0
0.42
–
4.6·106
>4·108
5.7·106
2.2·106
<3·105
18b X = OH
18c X = OCHO
18d X = OAc
18e X = OBz
90
76
75
75
25
45
62
73
0.55
0.24
0
0
13
0
a Conditions: (a) 1. TiIII, THF; 2. H3O+.
0
a Conditions: (a) 1. TiIII, THF; 2. H3O+.
The data from Table 2 show that 4-exo and 5-exo cycliza-
tions onto aldehyde carbonyl are very fast processes: lie
above 4·108 s–1 (25 °C). On the other hand, the 4-exo and
The data from Table 3 show that the fastest elimination
corresponds to the hydroxyl group followed by the for-
mate and cyano groups. It is interesting to note that, owing
Synlett 2008, No. 20, 3208–3212 © Thieme Stuttgart · New York

LETTER
Radical Clock for Reactions of Epoxy Derivatives
3211
Gansäuer, A.; Barchuk, A.; Keller, F. Angew. Chem. Int. Ed.
2006, 45, 2041; Angew. Chem. 2006, 118, 2095.
to its kinetics, benzoate elimination is a slow reaction:
<105 s–1. An explanation for the rate of ester eliminations
could be the stronger coordination of the oxygen carbonyl
to TiIII passing from benzoate to formate. Using intramo-
lecular competition experiments, we have determined the
approximate rates of radical cyclizations to carbonyl and
cyano groups and the radical elimination rates of CN, OH,
OCHO, and OAc.
(d) Gansäuer, A.; Bluhm, H. Chem. Rev. 2000, 100, 2771.
(e) Gansäuer, A.; Lauterbach, T.; Narayan, S. Angew. Chem.
Int. Ed. 2003, 42, 5556; Angew. Chem. 2003, 115, 5714.
(f) Barrero, A. F.; Quilez del Moral, J. F.; Sánchez, E. M.;
Arteaga, J. F. Eur. J. Org. Chem. 2006, 1627. (g) Cuerva, J.
M.; Justicia, J.; Oller-López, J. L.; Bazdi, B.; Oltra, J. E.
Mini-Rev. Org. Chem. 2006, 3, 23. (h) Gansäuer, A.;
Bluhm, H.; Pierobon, M. J. Am. Chem. Soc. 1998, 120,
12849. (i) Cuerva, J. M.; Justicia, J.; Oller-López, J. L.;
Oltra, J. E. Top. Curr. Chem. 2006, 264, 63.
Acknowledgment
(5) (a) Fernández-Mateos, A.; Martín de la Nava, E. M.;
Pascual Coca, G.; Rubio González, R. Org. Lett. 1999, 1,
607. (b) Fernández-Mateos, A.; Mateos Burón, L.;
Rabanedo Clemente, R.; Ramos Silvo, A. I.;
Financial support for this work from the MCyT of Spain (PPQ2002-
00290) (CTQ2005-05026/BQU) and the JCyL (SA079A06) is gra-
tefully acknowledged. We also thank the MCyT of Spain and the
Universidad de Salamanca for fellowships to R.R.C. and P.H.T.
Rubio González, R. Synlett 2004, 1011. (c) Fernández-
Mateos, A.; Martín de la Nava, E. M.; Mateos Burón, L.;
Rabanedo Clemente, R.; Rubio González, R.;
Sanz González, F. Synlett 2004, 2553. (d) Fernández-
Mateos, A.; Herrero Teijón, P.; Rabanedo Clemente, R.;
Rubio González, R. Tetrahedron Lett. 2006, 47, 7755.
(e) Fernández-Mateos, A.; Herrero Teijón, P.;
Rabanedo Clemente, R.; Rubio González, R. J. Org. Chem.
2007, 72, 9973. (f) Fernández-Mateos, A.; Herrero Teijón,
P.; Rabanedo Clemente, R.; Rubio González, R. Synlett
2007, 2718.
References and Notes
(1) (a) Curran, D. P. In Comprehensive Organic Synthesis, Vol.
4; Trost, B. M.; Fleming, I.; Paquette, L. A., Eds.; Pergamon:
Oxford, 1991, Chap. 4.2.1. (b) Giese, B.; Kopping, B.;
Göbel, T.; Thoma, G.; Dickhaut, J.; Kulicke, K. J.; Trach, F.
In Organic Reactions, Vol. 48; Paquette, L. A., Ed.; Wiley:
New York, 1996, 307. (c) Dhimane, A. L.; Fensterbank, L.;
Malacria, M. In Radicals in Organic Synthesis, Vol. 2;
Renaud, M.; Sibi, M. P., Eds.; Wiley-VCH: Weinheim,
2001.
(6) (a) Beckwith, A. L. J.; Moad, G. J. Chem. Soc., Perkin
Trans. 2 1980, 1083. (b) Maillard, B.; Walton, J. C.
J. Chem. Soc., Perkin Trans. 2 1985, 443.
(2) (a) Griller, D.; Ingold, K. U. Acc Chem. Res. 1980, 13, 317.
(7) (a) Il’ina, I. V.; Volcho, K. P.; Korchagina, D. V.; Barkash,
V. A.; Salakhutdinov, N. F. Helv. Chim. Acta 2007, 90, 353.
(b) Il’ina, I. V.; Volcho, K. P.; Korchagina, D. V.;
Salakhutdinov, N. F.; Barkash, V. A. Russ. J. Org. Chem.
2004, 40, 1483.
(b) Newcomb, M. Tetrahedron 1993, 49, 1151.
(c) Newcomb, M. In Radicals in Organic Synthesis, Vol. 1;
Renaud, M.; Sibi, M. P., Eds.; Wiley-VCH: Weinheim,
2001, 317–336.
(3) (a) Tsang, R.; Fraser-Reid, B. J. Am. Chem. Soc. 1986, 108,
2116. (b) Tsang, R.; Fraser-Reid, B. J. Am. Chem. Soc. 1986,
108, 8102. (c) Tsang, R.; Dickson, J. K. Jr.; Pak, H.; Walton,
R.; Fraser-Reid, B. J. Am. Chem. Soc. 1987, 109, 3484.
(d) Fraser-Reid, B.; Vite, G. D.; Yeung, B.-W. A.; Tsang, R.
Tetrahedron Lett. 1988, 29, 1645. (e) Dickson, J. K. J. r. Jr.;
Tsang, R.; Llera, J. M.; Fraser-Reid, B. J. Org. Chem. 1989,
54, 5350. (f) Walton, R.; Fraser-Reid, B. J. Am. Chem. Soc.
1991, 113, 5791. (g) Paquette, L. A.; Ra, C. S.; Silvestri,
T. W. Tetrahedron 1989, 45, 3099. (h) Knapp, S.; Gibson,
F. S.; Choe, Y. H. Tetrahedron Lett. 1990, 38, 5397.
(i) Knapp, S.; Gibson, F. S. J. Org. Chem. 1992, 57, 4802.
(j) Grissom, J. W.; Klingberg, D. J. Org. Chem. 1993, 58,
6559. (k) Grissom, J. W.; Klingberg, D.; Meyenburg, S.;
Stallman, B. L. J. Org. Chem. 1994, 59, 7876. (l) Clive,
D. L. J.; Postema, M. H. D. J. Chem. Soc., Chem. Commun.
1993, 429. (m) Jung, M. E.; Choe, S. W. T. Tetrahedron
Lett. 1993, 34, 6247. (n) Hays, D. S.; Fu, G. C. J. Am. Chem.
Soc. 1995, 117, 7283. (o) Davin, P.; Fensterbank, L.;
Malacria, M. Tetrahedron Lett. 1998, 39, 833.
(8) Reaction of Epoxides with Cp2TiCl
A mixture of Cp2TiCl2 (3.3 mmol) and Zn (6.60 mmol) in
strictly deoxygenated THF (4 mL) was stirred at r.t. until the
red solution turned green. In a separate flask, the epoxy
compound (1 mmol) was dissolved in strictly deoxygenated
THF (10 mL). The green TiIII solution was slowly added via
cannula to the epoxide solution. After 30 min, an excess of
sat. NaH2PO4 was added, and the mixture was stirred for 20
min. The product was extracted into Et2O, washed with sat.
NaHCO3 and brine, dried (Na2SO4), and filtered. After
removal of the solvent, the crude product was purified by
flash chromatography.
Compound 10: diastereomeric mixture (60:40). IR: 3408,
2923, 1462, 1053 cm–1. MS (EI): m/z (%) = 192 (14) [M+ –
18], 177 (7), 163 (3), 149 (12), 135 (17), 121 (16), 119 (25),
95 (31), 91 (82), 70 (65), 55 (100). HRMS (EI): m/z calcd for
C13H22O2Na [M+ + Na]: 233.1517; found: 233.1514. 1H
NMR (400 MHz, CDCl3): d (major isomer) = 0.94 (3 H, s),
1.10 (3 H, d, J = 7.2 Hz), 1.22 (3 H, s), 1.60–2.60 (7 H, m),
3.47 (1 H, dd, J1 = 3.3 Hz, J2 = 8.5 Hz), 3.51 (1 H, d, J = 9.1
Hz), 3.95 (1 H, dd, J1 = 6.8 Hz, J2 = 8.5 Hz), 4.22 (1 H, d,
J = 9.1 Hz), 4.53 (1 H, dd, J1 = 5.2 Hz, J2 = 9.3 Hz) ppm.
13C NMR (100 MHz, CDCl3): d = 16.17 (CH3), 23.83 (CH3),
27.77 (CH3), 30.66 (CH2), 38.15 (C), 39.31 (CH2), 40.14
(CH), 41.77 (CH), 51.50 (CH), 55.05 (C), 64.65 (CH), 72.86
(CH2), 75.30 (CH2) ppm. 1H NMR (400 MHz, CDCl3):
d (minor isomer) = 0.87 (3 H, d, J = 7.4 Hz), 0.88 (3 H, s),
1.21 (3 H, s), 1.60–2.90 (7 H, m), 3.31 (1 H, dd, J1 = 3.7 Hz,
J2 = 8.4 Hz), 3.37 (1 H, d, J = 8.6 Hz), 3.77 (1 H, d, J = 8.6
Hz), 4.02 (1 H, dd, J1 = 7.4 Hz, J2 = 8.4 Hz), 4.28 (1 H, dd,
J1 = 5.3 Hz, J2 = 9.3 Hz), ppm. 13C NMR (100 MHz,
CDCl3): d = 16.60 (CH3), 23.91 (CH3), 27.63 (CH3), 30.51
(p) Beckwith, A. L. J.; Hay, B. P. J. Am. Chem. Soc. 1989,
111, 230. (q) Beckwith, A. L. J.; Hay, B. P. J. Am. Chem.
Soc. 1989, 111, 2674. (r) Beckwith, A. L. J.; Raner, K. D.
J. Org. Chem. 1992, 57, 4954. (s) Bowman, W. R.; Bridge,
C. F.; Brookes, P. Tetrahedron Lett. 2000, 41, 8989; and
references therein. (t) Fallis, A. G.; Brinza, I. M.
Tetrahedron 1997, 52, 17543. (u) Curran, D. P.; Liu, W.
Synlett 1999, 117.
(4) (a) RajanBabu, T. V.; Nugent, W. A. J. Am. Chem. Soc.
1994, 116, 986. (b) RajanBabu, T. V.; Nugent, W. A. J. Am.
Chem. Soc. 1988, 110, 8561. (c) Daasbjerg, K.; Svith, H.;
Grimme, S.; Gerenkamp, M.; Muck-Lichtenfeld, C.;
Synlett 2008, No. 20, 3208–3212 © Thieme Stuttgart · New York

3212
A. Fernández-Mateos et al.
LETTER
(CH2), 36.37 (CH), 38.15 (C), 38.68 (CH2), 39.46 (CH),
40.92 (CH), 55.32 (C), 72.69 (CH), 72.76 (CH2), 79.34
(CH2) ppm.
1H NMR (400 MHz, CDCl3): d = 0.90 (3 H, s), 1.21 (3 H, s),
1.66 (4 H, m), 1.90 (1 H, m), 1.98 (1 H, t, J = 5.8 Hz), 2.10–
2.60 (4 H, m), 3.93 (1 H, t, J = 6.1 Hz), 4.68 (1 H, dd,
J1 = 9.2 Hz, J2 = 5.4 Hz) ppm. 13C NMR (100 MHz, CDCl3):
d = 22.62 (CH2), 23.16 (CH3), 27.49 (CH3), 27.85 (CH2),
29.90 (CH2), 38.35 (CH2, C), 40.76 (CH), 53.12 (CH, C),
62.02 (CH), 74.68 (CH) ppm. MS (EI): m/z (%) = 177 (3)
[M+ – 19], 163 (3), 149 (13), 134 (14), 121 (3), 108 (35), 92
(72), 91 (100), 67 (23), 55 (23). HRMS (EI): m/z calcd for
C12H20O2Na [M+ + Na]: 219.1356; found: 219.1338. Mp
146–150 °C; [a]D20 –7.4 (c 0.6, CHCl3).
Compound 11: IR: 3400, 1645 cm–1. 1H NMR (400 MHz,
CDCl3): d = 1.76 (3 H, s), 1.80–2.50 (5 H, m), 4.01 (1 H, m),
4.03 (2 H, s), 4.29 (1 H, s), 4.73 (1 H, s), 4.75 (1 H, s), 5.19
(1 H, d, J = 10.4 Hz), 5.27 (1 H, d, J = 15.6 Hz), 5.87 (1 H,
br s), 5.89 (1 H, m) ppm. 13C NMR (100 MHz, CDCl3):
d = 20.87 (CH3), 30.86 (CH2), 30.15 (CH), 35.57 (CH2),
60.30 (CH), 71.38 (CH2), 74.45 (CH2), 109.03 (CH2), 117.24
(CH2), 129.49 (CH), 134.34 (CH), 134.94 (C), 149.01 (C)
ppm. MS (EI): m/z (%) = 150 (22) [M+ – 58], 135 (20), 131
(13), 108 (69), 93 (68), 91 (100), 68 (79), 55 (98). HRMS
(EI): m/z calcd for C13H20O2Na [M+ + Na]: 231.1355; found:
231.1353; [a]D20 –49.2 (c 1.3, CHCl3).
Compound 16a2: IR: n = 3445, 2929, 1453, 1260, 1051 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.81 (3 H, s), 1.29 (3 H, s),
1.44 (2 H, m), 1.60–1.90 (4 H, m), 2.09 (1 H, m), 2.34 (2 H,
m), 2.46 (1 H, m), 3.94 (1 H, d, J = 8.2 Hz), 4.69 (1 H, dd,
J1 = 10.4 Hz, J2 = 10.4 Hz) ppm. 13C NMR (100 MHz,
CDCl3): d = 23.04 (CH3), 26.44 (CH2), 27.00 (CH3, CH2),
27.71 (CH2), 38.81 (CH2), 39.50 (CH), 39.54 (C), 43.99
(CH), 55.52 (C), 69.39 (CH), 71.48 (CH) ppm. MS (EI):
m/z (%) = 163 (3) [M+ – 33], 163 (2), 149 (1), 134 (10), 121
(4), 117 (27), 92 (51), 91 (100), 70 (23), 55 (43). HRMS (EI):
m/z calcd for C12H20O2Na [M+ + Na]: 219.1356; found:
219.1344. Mp 166–168 °C; [a]D20 +33.5 (c 0.7, CHCl3).
Compound 17c: IR: 3383, 2923, 2858, 1729, 1469, 1391,
1372 cm–1. 1H NMR (400 MHz, CDCl3): d = 0.89 (3 H, d,
J = 6.6 Hz), 0.91 (3 H, d, J = 6.6 Hz), 1.20–2.20 (12 H, m),
2.44 (2 H, t, J = 8.9 Hz), 4.05 (1 H, br s), 5.56 (1 H, m), 9.77
(1 H, s) ppm. 13C NMR (100 MHz, CDCl3): d = 19.45 (CH3),
19.89 (CH3), 21.78 (CH2), 27.55 (CH2), 28.99 (CH2), 31.94
(CH), 33.99 (CH2), 34.06 (CH), 35.48 (CH2), 43.71 (CH2),
67.13 (CH), 125.69 (CH), 137.92 (C), 202.57 (CH) ppm. MS
(EI): m/z (%) = 206 (9) [M+ – 18], 188 (3), 163 (9), 153 (13),
145 (33), 121 (12), 117 (29), 93 (35), 91 (100), 67 (67), 55
(90). HRMS (EI): m/z calcd for C14H24O2Na [M+ + Na]:
247.1674; found: 247.1681; [a]D20 –51.9 (c 2.1, CHCl3).
Compound 20d: IR: 3407, 2927, 1729, 1457, 1247, 1040
cm–1. 1H NMR (400 MHz, CDCl3): d = 1.73 (3 H, s), 1.50–
2.40 (5 H, m), 2.07 (3 H, s), 4.20 (1 H, br s), 4.51 (1 H, d,
J = 6.2 Hz), 4.72 (1 H, s), 4.73 (1 H, d, J = 6.2 Hz), 4.75 (1
H, s), 5.94 (1 H, br s) ppm. 13C NMR (100 MHz, CDCl3):
d = 20.78 (CH3), 20.94 (CH3), 30.80 (CH2), 34.99 (CH),
35.99 (CH2), 64.78 (CH), 66.58 (CH2), 109.27 (CH2), 130.74
(CH), 133.76 (C), 148.61 (C), 171.11 (C) ppm. MS (EI):
m/z (%) = 192 (2) [M+ – 18], 167 (1), 150 (25), 132 (20), 117
(96), 91 (100), 68 (50), 53 (70). HRMS (EI): m/z calcd for
Compound 13a1: IR: 3451, 2928, 2899, 1761, 1252, 1042
cm–1. 1H NMR (400 MHz, CDCl3): d = 0.96 (3 H, s), 1.13 (1
H, d, J = 10.2 Hz), 1.21 (3 H, s), 1.64 (2 H, m), 1.94 (1 H,
m), 2.24 (1 H, t, J = 5.7 Hz), 2.33 (1 H, m), 2.56 (2 H, m),
2.70 (1 H, m), 3.03 (1 H, m), 4.59 (1 H, dd, J1 = 9.3 Hz,
J2 = 4.9 Hz) ppm. 13C NMR (100 MHz, CDCl3): d = 18.56
(CH2), 23.35 (CH3), 27.07 (CH3), 29.82 (CH2), 38.35 (CH2),
38.53 (C), 40.44 (CH), 41.63 (CH2), 50.24 (CH), 62.53
(CH), 75.80 (C), 212.49 (C) ppm. MS (EI): m/z (%) = 179
(2) [M+ – 15], 161 (2), 134 (4), 133 (17), 119 (26), 105 (100),
91 (96), 77 (30), 67 (28), 55 (68). HRMS (EI): m/z calcd for
C12H18O2Na [M+ + Na]: 217.1199; found: 217.1206; [a]D
–10.1 (c 1.4, CHCl3).
20
Compound 13a2: IR: n = 3451, 2928, 2894, 1765, 1217 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.87 (3 H, s), 1.20 (1 H, d,
J = 10.1 Hz), 1.28 (3 H, s), 1.50–2.40 (6 H, m), 2.54 (1 H,
m), 3.01 (2 H, t, J = 8.9 Hz), 4.38 (1 H, dd, J1 = 9.1 Hz,
J2 = 3.7 Hz) ppm. 13C NMR (100 MHz, CDCl3): d = 22.65
(CH3), 26.59 (CH3), 27.16 (CH2), 27.88 (CH2), 39.16 (CH2),
39.65 (C), 39.80 (CH), 42.98 (CH2), 48.56 (CH), 53.40 (C),
70.61 (CH), 213.39 (C) ppm. MS (EI): m/z (%) = 179 (3) [M+
– 15], 151 (3), 134 (6), 133 (24), 119 (26), 105 (100), 91
(80), 77 (40), 67 (42), 55 (89). HRMS (EI): m/z calcd for
C12H18O2Na [M+ + Na]: 217.1199; found: 217.1195; [a]D
+40.7. (c 1.9, CHCl3).
20
Compound 14a: IR: n = 3455, 2920, 2249, 1645, 1441, 1217,
1053 cm–1. 1H NMR (400 MHz, CDCl3): d = 1.62 (1 H, dt,
J1 = 4.0 Hz, J2 = 13.3 Hz), 1.73 (3 H, s), 1.90 (4 H, m), 2.10–
2.60 (4 H, m), 4.09 (1 H, br s), 4.72 (1 H, s), 4.75 (1 H, s),
5.73 (1 H, m) ppm. 13C NMR (100 MHz, CDCl3): d = 16.71
(CH2), 20.82 (CH3), 30.47 (CH2), 30.81 (CH2), 35.04 (CH),
36.85 (CH2), 66.90 (CH), 109.37 (CH2), 119.73 (C), 128.03
(CH), 134.77 (C), 148.52 (C) ppm. MS (EI): m/z (%) = 173
(6) [M+ – 18], 158 (6), 131 (9), 117 (22), 105 (21), 91 (100),
77 (23), 65 (22), 51 (23); HRMS (EI): m/z calcd for
C12H17NONa [M+ + Na]:214.1208; found: 214.1205.
Compound 16a1: IR: n = 3439, 2929, 1455, 1260, 1052 cm–1.
20
C12H18O3Na [M+ + Na]: 233.1148; found: 233.1161; [a]D
–108.5 (c 0.3, CHCl3).
(9) Yamamoto, Y.; Matsumi, D.; Hattori, R.; Itoh, K. J. Org.
Chem. 1999, 64, 3224.
(10) Cuerva, J. M.; Campaña, A. G.; Justicia, J.; Rosales, A.;
Oller-López, J. L.; Robles, R.; Cárdenas, D. J.; Buñuel, E.;
Oltra, J. E. Angew. Chem. 2006, 118, 5522.
Synlett 2008, No. 20, 3208–3212 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.