Tin-free, radical-mediated γ-alkylations of α,β- unsaturated esters via O-tert-alkyl dienol ethers

Article abstract of DOI:10.1055/s-2007-992385

Tin-free, radical-mediated γ-alkylation of α,β-unsaturated esters is accomplished by radical addition and β-fragmentation of O-tert-alkyl dienol ethers and subsequent iodine atom transfer process. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-992385

LETTER
49
Tin-Free, Radical-Mediated g-Alkylations of a,b-Unsaturated Esters via
O-tert-Alkyl Dienol Ethers
g
-Alkylati
ions of
n
,
b
-UnsaturatedEs
Y
ters via O-tert-Alk
o
yl
D
ienol
E
t
u
hers ng Lee, Sunggak Kim*
Center for Molecular Design & Synthesis and Department of Chemistry, School of Molecular Science (BK-21), Korea Advanced Institute
of Science and Technology, Daejeon 305-701, Korea
Fax +82(42)8698370; E-mail: skim@kaist.ac.kr
Received 19 September 2007
OTBS
N
OTBS
N
Abstract: Tin-free, radical-mediated g-alkylation of a,b-unsaturat-
ed esters is accomplished by radical addition and b-fragmentation
of O-tert-alkyl dienol ethers and subsequent iodine atom transfer
process.
R1
OTBDPS
R1
OTBDPS
1
R
Cbz
Cbz
OTBS
R
R1
Key words: alkylation, carboxylic ester, fragmentation, radicals,
tin-free
N
R
Cbz
RI
Ph2(t-Bu)SiO
Ph(PhO)(t-Bu)Si
3
4
O
Reaction of an enolate anion of an a,b-unsaturated carbo-
nyl compound with an alkylating agent generally affords
an a-alkylation product as a major product.1 Thus, the g-
alkylation of a,b-unsaturated carbonyl compounds has
been a very challenging problem in synthetic organic
chemistry. Several methods to effect the g-alkylation of
a,b-unsaturated carbonyl compounds have been devel-
oped over the years and include the use of g-arylsulfonyl
group as a regiospecific control group,2 copper dieno-
lates,3 and zinc bromide catalyzed alkylation of O-silylat-
ed dienolates.4,5 However, those methods have
R1
NHCbz
R
2
Scheme 1 Radical-mediated g-functionalization of a,b-unsaturated
carboxylic amides
Ot-Bu
O
Ot-Bu
AIBN
+ RI
R
t-Bu
+
R
OR
OR
OR
Scheme 2 Radical addition–fragmentation of O-tert-alkyl enol
limitations, depending critically on the nature of alkyla- ethers
tion agents and dienolates.
OTBS
OTBS
Previously, we reported a radical-mediated g-functional-
ization approach based on the addition of an alkyl radical
R1
R1
X
OR
OR
α-attack
5
to diene ketene O,N-acetal 1 followed by the cleavage of
N–O bond to afford g-alkylated carboxylic imide 2 after
aqueous workup (Scheme 1).6,7 In this approach, the radi-
cal rearrangement of silyloxy radical 3 into silyl radical 4
X
7
γ-attack
X
OTBS
OR
OTBS
R1
was utilized to achieve tin-free conditions.8,9
R1
OR
X
During our studies on the radical alkylation using ketene
X
6b
6a
enol ethers, Roberts reported a similar approach involving
Scheme 3 Radical approach to the g-alkylation of a,b-unsaturated
radical addition–fragmentation approach using O-tert-
alkyl enol ethers as shown in Scheme 2.10 In our continued
effort to develop a tin-free approach to achieve g-alkyla-
tion of a,b-unsaturated carboxylic esters, we have studied
the radical reaction of silyl dienol ethers 5 derived from
a,b-unsaturated esters.
carboxylic ester.
features in this approach is a facile b-fragmentation of in-
termediate 11 to yield alkylation product 10 along with
liberation of tert-alkyl radical 12. Finally, to achieve the
tin-free conditions, Curran’s iodine-atom-transfer process
was employed.11 A noteworthy feature in this approach is
to generate reactive primary alkyl radical 13 by a radical
cyclization of tert-alkyl radical 12 for an efficient iodine-
atom transfer (Scheme 4).
Our approach is based on three factors. First, our idea to
accomplish the g-alkylation relies on the stability of radi-
cal intermediates derived from a- and g-attack of the alkyl
radical onto silyl dienol ether 5. It is evident that interme-
diate 6 should be more stable than intermediate 7 due to
the allylic nature of 6 (Scheme 3). Second, one of the key
In order to test our rationale, we initially prepared 15a
from 14a to facilitate the b-fragmentation process by gen-
eration of a very stable tert-benzylic radical. Radical reac-
tion of 15a with iodomethyl phenyl sulfone in refluxing
SYNLETT 2008, No. 1, pp 0049–0054
x
x.
x
x.
2
0
0
7
Advanced online publication: 03.12.2007
DOI: 10.1055/s-2007-992385; Art ID: U08507ST
© Georg Thieme Verlag Stuttgart · New York

50
J. Y. Lee, S. Kim
LETTER
O
OTBS
O
O
R1
R1
R
RI
O
OTBS
R1
10
8
9
OTBS
O
10
R
R1
12
11
5-exo
cyclization
8
R
I
RI
13
Scheme 4 Radical approach for the g-alkylation of 8 via 9
OTBS
O
O
R
R
LDA, HMPA, TBSCl
THF, –78 °C
O
15a: R = Ph, 95%
15b: R = Me, 91%
14a: R = Ph
14b: R = Me
O
O
15a or 15b
Bu4NF, MeI
PhO2S
I
THF
PhO2S
OMe
PhO2S
OTBS
17
16
8%
for 15a
conditions A
conditions B
38%
72%
70%
conditions A
conditions B
for 15b
conditions A: DLP (0.1 equiv), C6H6, 90 °C, 5 h
conditions B: (Me3Sn)2 (0.1 equiv), C6H6, hν, 1 h
Scheme 5 Radical alkylation of ketene enol ether 15. Conditions A: DLP (0.1 equiv), C6H6, 90 °C, 5 h. Conditions B: (Me3Sn)2 (0.1 equiv),
C6H6, hn, 1 h.
benzene using lauroyl peroxide (DLP) for five hours af- ium followed by the addition of crotonyl chloride and 2-
forded the desired product in a very low yield (8%).
pentenoyl chloride afforded the corresponding esters 8a
and 8b in 85% and 77% yield, respectively. When ester 8a
was treated with LDA in the presence of tert-butyldimeth-
ylsilyl chloride (TBSCl) in THF containing a small
amount of HMPA, silyl dienol ether 9a was prepared in
90% yield.
The yield was improved to some extent by performing the
reaction in benzene using a catalytic amount of hexameth-
ylditin (0.1 equiv) under irradiation (300 nm) for one
hour. It appeared that the low yield resulted from instabil-
ity of 15a under thermally and photochemically initiated
conditions. To increase the stability of ketene enol ether Compound 9a was thermally stable but was decomposed
15, we introduced a methyl group instead of the phenyl to some extent during a column-chromatographic separa-
group in 15a. When the reaction was repeated with 15b tion on silica gel. Thus, remaining reactions were carried
under the similar conditions, 17 was isolated in 72% and out with the crude products without isolation of 9
70% yield, respectively (Scheme 5). Due to instability of (Scheme 6).
TBS esters 16 on silica gel, 16 was converted into the cor-
responding methyl ester by treatment of 16 with tetrabu-
When a benzene solution of 9a (1.5 equiv), iodomethyl
phenyl sulfone (1.0 equiv), DLP initiator (0.1 equiv) was
tylammonium fluoride and methyl iodide in THF at room
refluxed at 90 °C for five hours, 20a was isolated in 89%
temperature for two hours.12
yield via 19 (Scheme 7).13 To determine the efficiency
The silyl dienol ethers 9a and 9b were prepared by a two- and scope of the present method, we performed additional
step sequence. Treatment of tert-alcohol 18 with butyllith- experiments with several different alkyl iodides and bro-
Synlett 2008, No. 1, 49–54 © Thieme Stuttgart · New York

LETTER
g-Alkylations of a,b-Unsaturated Esters via O-tert-Alkyl Dienol Ethers
Table 1 Tin-Free Radical g-Alkylationa
51
OH
O
BuLi
THF
R1
Entry Substrate
Product
Yield (%)b
20a 20b
Cl
18
R1 = H, Me
OTBS
O
O
1
89
75
O
O
PhO2S
I
R1
R1
LDA, HMPA, TBSCl
O
PhO2S
PhO2S
OMe
THF
R1
–78 °C
2
88
76c
9a: R1 = H, 90%
9b: R1 = Me, 93%
8a: R1 = H, 85%
8b: R1 = Me, 77%
OMe
OMe
PhO2S
I
R1
R1
Scheme 6 Preparation of silyl dienol ethers
3
4
5
6
7
84
89
82
74
73
82
O
O
I
EtO
NC
EtO
O
DLP
O
9a or 9b
EWG
I
EWG
OTBS
benzene
90 °C
77
O
Br
R1
19
EWG: electron-withdrawing group
NC
OMe
R1
O
73d
75e
71
O
R1
Bu4NF, MeI
THF
O
EWG
OMe
I
OMe
EtO
Ph
EtO
Ph
R1
O
20a: R1 = H
O
R1
O
20b: R1 = Me
I
OMe
Scheme 7 Tin-free radical g-alkylations
O
CO2Et
Br
CO2Et
R1
O
mides using 9a and 9b. As shown in Table 1, several acti-
vated alkyl iodides and bromides bearing a-electron-
withdrawing substituents worked well, yielding the g-
alkylation products exclusively. It is also noteworthy that
methyl-substituted dienol ether 9b worked well without
affecting the chemical yields significantly. Of synthetic
importance is the exclusive formation of g-alkylation
products under tin-free radical conditions and there was
no indication of the formation of a-alkylation products.
EtO2C
EtO2C
OMe
a The reaction was carried out with lauroyl peroxide initiator in ben-
zene at 90 °C for 5 h.
b Yield of isolated products.
c Ratio syn/anti = 1:1.7.
d Ratio syn/anti = 1:1.
e Ratio syn/anti = 1:1.7.
However, this method proved to be limited with respect to
nucleophilic alkyl radicals. Irradiation (300 nm) of a ben-
zene solution of 9a with an equimolar amount of 1-io-
doadamantane and DLP gave the starting iodide (95%).
To further study the g-radical alkylation, we prepared a
cyclic silyl dienol ether 21. When the ester was treated
with LDA in the presence of TBSCl in THF containing a
small amount of HMPA, 21 was obtained in 89% yield.
When the radical reaction was carried out with 21 and io-
domethyl phenyl sulfone in the presence of DLP initiator
in benzene at 90 °C for five hours, the desired g-alkylated
product 23 was isolated in 77% yield (Scheme 8).
OTBS
O
O
I
SO2Ph
O
1) LDA, THF
2) TBSCl
DLP, benzene
90 °C
21 89%
O
O
Bu4NF, MeI
OTBS
OMe
THF
2 h
SO2Ph
SO2Ph
23 77%
A sequential radical reaction involving the radical g-alky-
lation and cyclization sequence was examined
(Scheme 9). Treatment of 24 with 21 (1.5 equiv), DLP
(0.1 equiv) in benzene at 90 °C for five hours afforded 25.
22
Scheme 8 Radical g-alkylation of cyclic diene enol ether 21
Treatment of 25 with benzenethiol and V-40 [1,1¢-azo- provided 28 in 79% yield (Scheme 9). From the H–1H
1
COSY NMR spectrum and the decoupling technique, an
NOE experiment of 28 showed 6.56% NOE between Ha
(d = 3.36 ppm) and Hb (d = 2.65–2.73 ppm), indicative of
a cis-fused bicyclic product.
bis(cyclohexanecarbonitrile)] initiator followed by addi-
tion of tetrabutylammonium fluoride and methyl iodide
afforded 26 in 66% yield along with 27 (12%). Further
treatment of 26 with MCPBA and subsequent elimination
Synlett 2008, No. 1, 49–54 © Thieme Stuttgart · New York

52
J. Y. Lee, S. Kim
LETTER
O
E
E
I
OTBS
V-40, PhSH
chlorobenzene
110 °C
Bu4NF, MeI
21, DLP
THF
2 h
benzene, 90 °C
E
E = CO2Et
E
24
25
O
O
O
OMe
+
OMe
OMe
1,2-dichlorobenzene
reflux
MCPBA
Ha
CH2Cl2
0 °C
Hb
E
E
E
SPh
E
E
E
26 66%
27 12%
28 (79% from 26)
Scheme 9 Radical cyclization via g-alkylation
N.; Saito, H.; Wang, D.; Hosomi, A. Org. Lett. 2001, 3,
2591. (d) Roepel, M. G. Tetrahedron Lett. 2002, 43, 1973.
(e) Cai, Y.; Roberts, B. P. Tetrahedron Lett. 2003, 44, 4645.
(8) (a) Dannley, R. L.; Jalics, G. J. Org. Chem. 1965, 30, 3848.
(b) Shubber, A. K.; Dannley, R. L. J. Org. Chem. 1971, 36,
3784.
In conclusion, we have developed the radical-mediated g-
alkylation of a,b-unsaturated carboxylic esters via O-tert-
alkyl dienol ethers under tin-free conditions, which ap-
pears to be a synthetically useful process.
(9) For tin-free radical reactions, see: (a) Baguley, P. A.;
Walton, J. C. Angew. Chem. Int. Ed. 1998, 37, 3072; and
references therein. (b) Kim, S.; Song, H.-J.; Choi, T.-L.;
Yoon, J.-Y. Angew. Chem. Int. Ed. 2001, 40, 2524.
(c) Kim, S.; Lim, C. J. Angew. Chem. Int. Ed. 2002, 41,
3265. (d) Kim, S.; Lim, C. J. Bull. Korean Chem. Soc. 2003,
20, 1219.
Acknowledgment
We are grateful to the Center for Molecular Design & Synthesis,
KEPCO, and BK21 for financial support.
References and Notes
(10) Cai, Y.; Roberts, B. P.; Tocher, D. A.; Barnett, S. A. Org.
Biomol. Chem. 2004, 2, 2517.
(11) (a) Curran, D. P.; Kim, D. Tetrahedron 1991, 47, 6171.
(b) Curran, D. P.; Kim, D.; Ziegler, C. Tetrahedron 1991, 47,
6189. (c) Curran, D. P.; Thoma, G. J. Am. Chem. Soc. 1992,
114, 4436. (d) Curran, D. P.; Thoma, G. Tetrahedron Lett.
1991, 32, 6307.
(1) (a) Fleming, I. Frontier Orbitals and Organic Chemical
Reactions; Wiley-Interscience: New York, 1996.
(b) Herrmann, J. L.; Kieczykowski, G. R.; Schlessinger, R.
H. Tetrahedron Lett. 1973, 26, 2433.
(2) (a) Lansbury, P. T.; Erwin, R. W. Tetrahedron Lett. 1978,
19, 2675. (b) Lansbury, P. T.; Erwin, R. W.; Jeffrey, D. A.
J. Am. Chem. Soc. 1980, 102, 1602. (c) Lansbury, P. T.;
Bebernitz, G. E.; Maynard, S. C.; Spagnuolo, C. J.
Tetrahedron Lett. 1985, 26, 169. (d) Lansbury, P. T.;
Spagnuolo, C. J.; Grimm, E. L. Tetrahedron Lett. 1986, 27,
2725.
(3) (a) Katzenellenbogen, J. A.; Crumrine, A. L. J. Am. Chem.
Soc. 1974, 96, 5662. (b) Katzenellenbogen, J. A.; Crumrine,
A. L. J. Am. Chem. Soc. 1976, 98, 4925. (c) Pitzele, B. S.;
Baran, J. S.; Steinman, D. H. Tetrahedron 1976, 32, 1347.
(d) Savu, P. M.; Katzenellenbogen, J. A. J. Org. Chem.
1981, 46, 239.
(4) (a) Fleming, I.; Goldhill, J.; Paterson, I. Tetrahedron Lett.
1979, 20, 3209. (b) Fleming, I.; Lee, T. V. Tetrahedron Lett.
1981, 22, 705.
(5) For other approaches, see: (a) Bryson, T. A.; Gammill, R. B.
Tetrahedron Lett. 1974, 15, 3963. (b) Pitzele, B. S.; Baran,
J. S. D.; Steinman, H. Tetrahedron 1976, 32, 1347.
(c) Wenkert, E.; Goodwin, T. E.; Ranu, B. C. J. Org. Chem.
1977, 42, 2137. (d) Majewski, M.; Mpango, G. B.; Thomas,
M. T.; Wu, A.; Snieckus, V. J. Org. Chem. 1981, 46, 2029.
(e) Paquette, L. A.; Kinney, W. A. Tetrahedron Lett. 1982,
23, 131.
(6) (a) Kim, S.; Lim, C. J.; Song, C.; Chung, W.-j. J. Am. Chem.
Soc. 2002, 124, 14306. (b) Kim, S.; Lim, C. J. Angew.
Chem. Int. Ed. 2004, 43, 5378.
(7) For other radical-mediated alkylations, see: (a) Watanabe,
Y.; Yoneda, T.; Ueno, Y.; Toru, T. Tetrahedron Lett. 1990,
31, 6669. (b) Renaud, P.; Vionnet, J.-P.; Vogel, P.
Tetrahedron Lett. 1991, 32, 3491. (c) Miura, K.; Fujisawa,
(12) Sakaitani, M.; Ohfune, Y. J. Org. Chem. 1990, 55, 870.
(13) Typical Experimental Procedure
A benzene solution (1 mL, 0.2 M in iodide) of iodomethyl
phenyl sulfone (56 mg, 0.2 mmol), O-tert-alkyl dienol ether
(9a, 93 mg, 0.3 mmol), and DLP (8 mg, 0.02 mmol) was
degassed with nitrogen for 10 min and then the solution was
stirred at 90 °C under nitrogen for 5 h. The solvent was
evaporated under reduced pressure and the residue was
diluted with THF (1 mL). Then, TBAF (240 mL, 0.24 mmol)
and MeI (50 mL, 0.8 mmol) were added successively. The
reaction mixture was allowed to stir at r.t. for 2 h. The
reaction mixture was diluted with Et2O, quenched with aq
NH4Cl and washed with H2O and brine. The organic layer
was dried over anhyd MgSO4, filtered, and concentrated
under reduced pressure. The crude product was purified by
silica gel column chromatography using EtOAc–n-hexane
(1:10) as eluant to give 5-benzenesulfonylpent-2-enoic acid
methyl ester (20a, 45 mg, 89%). 1H NMR (400 MHz,
CDCl3): d = 2.57–2.63 (m, 2 H), 3.16–3.20 (m, 2 H), 3.67 (s,
3 H), 5.79 (dt, J = 15.6, 1.3 Hz, 1 H), 6.78 (dt, J = 15.6, 6.8
Hz, 1 H), 7.53–7.57 (m, 2 H), 7.62–7.66 (m, 1 H), 7.86–7.89
(m, 2 H). 13C NMR (100 MHz, CDCl3): d = 25.3, 51.5, 54.2,
123.1, 128.0 (C2), 129.4 (C2), 133.9, 138.6, 143.3, 166.0. IR
(KBr): 1728, 1659, 1447, 1323, 1204, 766, 748 cm–1.
HRMS: m/z calcd for C12H14O4S [M+]: 254.0613; found:
254.0613.
Compound 20a (entry 2): MW (C14H18O4S): 282.35. 1H
NMR (400 MHz, CDCl3): d = 0.95 (t, J = 7.5 Hz, 3 H), 1.60–
Synlett 2008, No. 1, 49–54 © Thieme Stuttgart · New York

LETTER
g-Alkylations of a,b-Unsaturated Esters via O-tert-Alkyl Dienol Ethers
53
1.66 (m, 1 H), 1.84–1.87 (m, 1 H), 2.48–2.52 (m, 1 H), 2.68–
J = 15.7, 1.4 Hz, 1 H), 6.99 (dd, J = 15.7, 7.0 Hz, 1 H), 7.51–
7.55 (m, 2 H), 7.60–7.63 (m, 1 H), 7.84–7.87 (m, 2 H);
d(syn) = 0.85 (t, J = 7.5 Hz, 3 H), 1.21 (d, J = 7.0 Hz, 3 H),
1.67–1.70 (m, 1 H), 1.84–1.88 (m, 1 H), 2.95–2.99 (m, 1 H),
3.05–3.12 (m, 1 H), 3.68 (s, 3 H), 5.76 (dd, J = 15.7, 1.7 Hz,
1 H), 6.83 (dd, J = 15.7, 6.3 Hz, 1 H), 7.51–7.55 (m, 2 H),
7.60–7.63 (m, 1 H), 7.84–7.87 (m, 2 H). 13C NMR (100
MHz, CDCl3): d = 12.9, 13.0, 13.1, 13.4, 17.8, 18.9, 34.5,
34.8, 51.5, 51.6, 69.1, 70.5, 121.1, 121.9, 128.4 (C2), 128.6
(C2), 129.2 (C2), 129.3 (C2), 133.6, 133.7, 138.7, 138.9,
148.3, 150.5, 166.4, 166.5. IR (KBr): 1727, 1656, 1447,
1303, 1197, 765, 728 cm–1. HRMS: m/z calcd for C15H20O4S
[M+]: 296.1082; found: 296.1089.
2.72 (m, 1 H), 2.97–3.00 (m, 1 H), 3.67 (s, 3 H), 5.80 (dt,
J = 15.6, 1.3 Hz, 1 H), 6.78 (dt, J = 15.6, 7.37 Hz, 1 H),
7.51–7.55 (m, 2 H), 7.60–7.64 (m, 1 H), 7.83–7.85 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 11.0, 20.7, 30.0, 51.5,
64.6, 123.8, 128.7 (C2), 129.2 (C2), 133.8, 137.6, 143.4,
166.0. IR (KBr): 1729, 1658, 1447, 1320, 1214, 731, 691
cm–1. HRMS: m/z calcd for C14H18O4S [M+]: 282.0926;
found: 282.0929.
Compound 20a (entry 3): MW (C10H16O4): 186.21. 1H NMR
(400 MHz, CDCl3): d = 1.21 (t, J = 7.1 Hz, 3 H), 2.39–2.43
(m, 2 H), 2.46–2.51 (m, 2 H), 3.67 (s, 3 H), 4.10 (q, J = 7.1
Hz, 2 H), 5.82 (dt, J = 15.7, 1.5 Hz, 1 H), 6.91 (dt, J = 15.7,
6.3 Hz, 1 H). 13C NMR (100 MHz, CDCl3): d = 14.1, 27.2,
32.4, 51.4, 60.5, 121.7, 146.9, 166.7, 172.1. IR (KBr): 1742,
1720, 1659, 1436, 1179, 1039, 859 cm–1. HRMS: m/z calcd
for C9H14O4 [M+]: 186.0892; found: 186.0893.
Compound 20b (entry 3): MW (C10H16O4): 200.23. 1H NMR
(400 MHz, CDCl3): d = 1.07 (d, J = 6.7 Hz, 3 H), 1.20 (t,
J = 7.1 Hz, 3 H), 2.27 (dd, J = 15.3 Hz, 7.2 Hz, 1 H), 2.36
(dd, J = 15.3, 7.1 Hz, 1 H), 2.77–2.84 (m, 1 H), 3.67 (s, 3 H),
4.08 (q, J = 7.1 Hz, 2 H), 5.79 (dd, J = 15.7, 1.2 Hz, 1 H),
6.86 (dd, J = 15.7, 7.3 Hz, 1 H). 13C NMR (100 MHz,
CDCl3): d = 14.1, 18.9, 32.9, 40.3, 51.4, 60.4, 119.8, 152.0,
166.9, 171.5. IR (KBr): 1738, 1722, 1658, 1276, 1177, 765,
748 cm–1. HRMS: m/z calcd for C10H16O4 [M+]: 200.1049;
found: 200.1048.
Compound 20a (entry 4): MW (C7H9NO2): 139.15. 1H NMR
(400 MHz, CDCl3): d = 2.47–2.55 (m, 4 H), 3.72 (s, 3 H),
5.93 (dt, J = 15.7, 1.54 Hz, 1 H), 6.89 (dt, J = 15.7, 6.5 Hz,
1 H). 13C NMR (100 MHz, CDCl3): d = 16.1, 27.7, 51.6,
118.2, 123.6, 143.3, 166.1. IR (KBr): 1730, 1663, 1437,
1275, 1213, 1162, 766, 748 cm–1. HRMS: m/z calcd for
C7H9NO2 [M+]: 139.0633; found: 139.0642.
Compound 20b (entry 4): MW (C8H11NO2): 153.17. 1H
NMR (400 MHz, CDCl3): d = 1.21 (d, J = 6.8 Hz, 3 H),
2.35–2.46 (m, 2 H), 2.68–2.75 (m, 1 H), 3.70 (s, 3 H), 5.87
(dd, J = 15.7, 1.2 Hz, 1 H), 6.82 (dd, J = 15.7, 7.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 18.6, 23.6, 33.1, 51.6,
117.5, 121.6, 148.7, 166.3. IR (KBr): 1728, 1659, 1436,
1277, 1197, 765, 749 cm–1. HRMS: m/z calcd for C8H11NO2
[M+]: 153.0790; found: 153.0781.
Compound 20b (entry 5): MW (C11H18O4): 214.25. Ratio
syn/anti = 1:1 (from 1H NMR). 1H NMR (400 MHz, CDCl3):
d(syn) = 1.02 (d, J = 3.4 Hz, 3 H), 1.07 (t, J = 7.4 Hz, 3 H),
1.19 (t, J = 7.1 Hz, 3 H), 2.31–2.38 (m, 1 H), 2.55–2.65 (m,
1 H), 3.68 (s, 3 H), 4.06–4.14 (m, 2 H), 5.78 (dd, J = 15.7,
11.7 Hz, 1 H), 6.87 (dd, J = 15.7, 7.7 Hz, 1 H); d(anti) = 1.03
(d, J = 3.2 Hz, 3 H), 1.07 (t, J = 7.4 Hz, 3 H), 1.22 (t, J = 7.1
Hz, 3 H), 2.41–2.48 (m, 1 H), 2.55–2.65 (m, 1 H), 3.69 (s, 3
H), 4.06–4.14 (m, 2 H), 5.79 (dd, J = 15.6, 10.8 Hz, 1 H),
6.77 (dd, J = 15.6, 8.6 Hz, 1 H). 13C NMR (100 MHz,
CDCl3): d = 13.4, 14.1, 14.2, 14.8, 15.5, 17.6, 38.9, 39.5,
43.9, 44.5, 51.4, 51.5, 60.3, 60.4, 120.6, 121.3, 150.9, 151.4,
166.8, 166.9, 174.8, 175.0. IR (KBr): 1735, 1723, 1658,
1435, 1277, 1243, 765, 748 cm–1. HRMS: m/z calcd for
C11H18O4 [M+]: 214.1205; found: 214.1203.
Compound 20a (entry 5): MW (C10H16O4: 200.23. 1H NMR
(400 MHz, CDCl3): d = 1.15 (d, J = 14.3 Hz, 3 H), 1.20 (t,
J = 7.1 Hz, 3 H), 2.25–2.30 (m, 1 H), 2.50–2.57 (m, 2 H),
3.68 (s, 3 H), 4.09 (q, J = 7.1 Hz, 2 H), 5.82 (dt, J = 15.6, 1.1
Hz, 1 H), 6.84 (dt, J = 15.6, 6.9 Hz, 1 H). 13C NMR (100
MHz, CDCl3): d = 14.1, 25.5, 35.8, 38.4, 51.4, 60.4, 122.8,
145.8, 166.6, 175.2. IR (KBr): 1740, 1720, 1659, 1436,
1275, 1196, 1180 cm–1. HRMS: m/z calcd for C10H16O4
[M+]: 200.1049; found: 200.1041.
Compound 20a (entry 6): MW (C14H16O3): 232.27. 1H NMR
(400 MHz, CDCl3): d = 1.21 (d, J = 7.0 Hz, 3 H), 2.30–2.36
(m, 1 H), 2.66–2.72 (m, 1 H), 3.54–3.59 (m, 1 H), 3.67 (s, 3
H), 5.84 (dt, J = 15.6, 1.5 Hz, 1 H), 6.91 (dt, J = 15.6, 6.9 Hz,
1 H), 7.43–7.46 (m, 2 H), 7.52–7.54 (m, 1 H), 7.90–7.92 (m,
2 H). 13C NMR (100 MHz, CDCl3): d = 17.5, 35.4, 39.8,
51.4, 122.8 (C2), 128.7 (C2), 133.1, 135.8, 146.3, 166.6,
202.4. IR (KBr): 1733, 1712, 1688, 1449, 1434, 971, 705
cm–1. HRMS: m/z calcd for C14H16O3 [M+]: 232.1099;
found: 232.1086.
Compound 20a (entry 7): MW (C12H18O6): 258.26. 1H NMR
(400 MHz, CDCl3): d = 1.23 (t, J = 7.1 Hz, 6 H), 2.73–2.77
(m, 2 H), 3.44 (t, J = 7.44 Hz, 1 H), 3.68 (s, 3 H), 4.18 (q,
J = 7.1 Hz, 4 H), 5.87 (dt, J = 15.6, 1.5 Hz, 1 H), 6.86 (dt,
J = 15.6, 7.1 Hz, 1 H). 13C NMR (100 MHz, CDCl3):
d = 14.0 (C2), 31.0, 50.6, 51.5, 61.7 (C2), 123.8, 144.0,
166.3, 168.2 (C2). IR (KBr): 1755, 1720, 1661, 1436, 1151,
1036, 774 cm–1. HRMS: m/z calcd for C12H18O6 [M+]:
258.1103; found: 258.1128.
Compound 20b (entry 6): MW (C15H18O3): 246.30. Ratio
syn/anti = 1.67:1 (from 1H NMR). 1H NMR (400 MHz,
CDCl3): d(anti) = 1.03 (d, J = 6.8 Hz, 3 H), 1.15 (d, J = 6.9
Hz, 3 H), 2.76–2.84 (m, 1 H), 3.47–3.54 (m, 1 H), 3.66 (s, 3
H), 5.77–5.85 (m, 1 H), 6.94 (dd, J = 15.7, 7.4 Hz, 1 H),
7.42–7.47 (m, 2 H), 7.51–7.55 (m, 1 H), 7.87–7.93 (m, 2 H);
d(syn) = 1.02 (d, J = 6.6 Hz, 3 H), 1.11 (d, J = 6.9 Hz, 3 H),
2.76–2.84 (m, 1 H), 3.38–3.41 (m, 1 H), 5.77–5.85 (m, 1 H),
6.87 (dd, J = 15.6, 8.9 Hz, 1 H), 7.42–7.47 (m, 2 H), 7.51–
7.55 (m, 1 H), 7.87–7.93 (m, 2 H). 13C NMR (100 MHz,
CDCl3): d = 13.4, 14.9, 16.0, 18.4, 38.2, 39.4, 44.6, 45.2,
51.4, 51.5, 120.5 (C2), 121.3, 128.1 (C2), 128.7 (C2), 133.0,
133.1, 136.4, 136.8, 151.3, 151.9 (C2), 166.8, 166.9, 202.6,
203.2. IR (KBr): 1722, 1681, 1655, 1449, 1277, 765, 748
cm–1. HRMS: m/z calcd for C15H18O3 [M+]: 246.1256;
found: 246.1255.
Compound 20b (entry 1): MW (C13H16O4S): 268.32. 1H
NMR (400 MHz, CDCl3): d = 1.19 (d, J = 8.9 Hz, 3 H),
2.90–2.96 (m, 1 H), 3.06 (dd, J = 14.1, 6.3 Hz, 1 H), 3.17
(dd, J = 14.1, 6.6 Hz, 1 H), 3.65 (s, 3 H), 5.72 (dd, J = 15.6,
1.0 Hz, 1 H), 6.71 (dd, J = 15.6, 7.6 Hz, 1 H), 7.50–7.55 (m,
2 H), 7.59–7.63 (m, 1 H), 7.84–7.90 (m, 2 H). 13C NMR (100
MHz, CDCl3): d = 19.5, 31.6, 51.5, 60.9, 120.9, 127.8 (C2),
129.2 (C2), 133.7, 139.4, 149.5, 166.3. IR (KBr): 1721,
1659, 1447, 1305, 1209, 766, 747 cm–1. HRMS: m/z calcd
for C13H16O4S [M+]: 268.0769; found: 2268.0751.
Compound 20b (entry 2): MW (C15H20O4S): 296.38. Ratio
syn/anti = 1.67:1 (from 1H NMR). 1H NMR (400 MHz,
CDCl3): d(anti) = 0.90 (t, J = 7.5 Hz, 3 H), 1.19 (d, J = 7.0
Hz, 3 H), 1.67–1.70 (m, 1 H), 1.84–1.88 (m, 1 H), 2.88–2.91
(m, 1 H), 3.05–3.12 (m, 1 H), 3.69 (s, 3 H), 5.77 (dd,
Compound 20b (entry 7): MW (C13H20O6): 272.29. 1H NMR
(400 MHz, CDCl3): d = 1.12 (d, J = 6.8 Hz, 3 H), 1.20 (t,
J = 7.1 Hz, 3 H), 1.23 (t, J = 7.1 Hz, 3 H), 3.04–3.10 (m, 1
H), 3.30 (d, J = 8.5 Hz, 1 H), 3.68 (s, 3 H), 4.13 (t, J = 7.1
Hz, 2 H), 4.17 (t, J = 7.1 Hz, 2 H), 5.83 (dd, J = 15.6, 0.7 Hz,
Synlett 2008, No. 1, 49–54 © Thieme Stuttgart · New York

54
J. Y. Lee, S. Kim
LETTER
1 H), 6.87 (dd, J = 15.6, 8.1 Hz, 1 H). 13C NMR (100 MHz,
CDCl3): d = 13.9, 14.0, 17.3, 36.2, 51.4, 56.7, 61.4, 61.5,
121.4, 149.3, 166.6, 167.6, 167.7. IR (KBr): 1756, 1722,
1658, 1436, 1300, 1278, 1234, 988 cm–1. HRMS: m/z calcd
for C13H20O6 [M+]: 272.1260; found: 272.1271.
139.0, 139.7, 167.3. IR (KBr): 1715, 1447, 1276, 1255,
1151, 1086, 719 cm–1. HRMS: m/z calcd for C15H18O4S
[M+]: 294.0926; found: 294.0936.
Compound 28: MW (C18H26O6): 338.39. 1H NMR (400
MHz, CDCl3): d = 0.84–0.95 (m, 1 H), 1.17–1.25 (m, 8 H),
1.49–1.59 (m, 1 H), 1.74–1.80 (m, 2 H), 2.62–2.73 (m, 2 H),
2.79–2.84 (m, 1 H), 3.28–3.36 (m, 2 H), 3.65 (s, 3 H), 4.07–
Compound 23: MW (C15H18O4S): 294.37. 1H NMR (400
MHz, CDCl3): d = 1.36–1.44 (m, 1 H), 1.50–1.56 (m, 1 H),
1.68–1.74 (m, 1 H), 1.87–1.93 (m, 1 H), 2.10–2.17 (m, 1 H),
2.21–2.27 (m, 1 H), 2.85–2.89 (m, 1 H), 3.04 (dd, J = 14.1,
6.9 Hz, 1 H), 3.13 (dd, J = 14.1, 6.1 Hz, 1 H), 3.66 (s, 3 H),
6.74–6.75 (m, 1 H), 7.52–7.56 (m, 2 H), 7.60–7.64 (m, 1 H),
7.88–7.90 (m, 2 H). 13C NMR (100 MHz, CDCl3): d = 20.3,
23.8, 27.8, 31.1, 51.6, 60.4, 127.8, 129.3, 132.1, 133.7,
4.22 (m, 4 H), 4.55–4.57 (m, 1 H), 4.90–4.91 (m, 1 H). 13
C
NMR (100 MHz, CDCl3): d = 13.9, 14.0, 21.5, 23.2, 24.6,
37.8, 41.9, 44.4, 45.4, 51.5, 60.9, 61.4, 61.5, 107.4, 145.4,
169.5, 171.7, 174.9. IR (KBr): 1731, 1446, 1268, 1254,
1224, 1058, 1038, 1015 cm–1. HRMS: m/z calcd for
C18H26O6 [M+]: 338.1729; found: 338.1750.
Synlett 2008, No. 1, 49–54 © Thieme Stuttgart · New York

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