Synthesis of functionalized dialkyl cyclobutane-1,1-dicarboxylates and Alkyl 5,6-Dihydro-4H-pyran-3-carboxylates via Michael-Induced Ring Closure of δ-chloro-α,β-unsaturated diesters and ketoesters

Article abstract of DOI:10.1055/s-0028-1083506

Michael-induced ring closure (MIRC) of dimethyl 2-(3-chloro-2,2- dimethylpropylidene)malonate, upon treatment with sodium tert-butylthiolate, sodium methoxide or sodium cyanide in methanol, provided a short and efficient synthesis of new 2-functionalized cyclobutane-1,1-dicarboxylic esters. Under similar conditions, methyl 2-acetyl-5-chloro-4,4-dimethylpent-2-enoate afforded 4-functionalized methyl 5,6-dihydro-4H-pyran-3-carboxylates as the MIRC products.

Full text of DOI:10.1055/s-0028-1083506

LETTER
2697
Synthesis of Functionalized Dialkyl Cyclobutane-1,1-dicarboxylates and Alkyl
5,6-Dihydro-4H-pyran-3-carboxylates via Michael-Induced Ring Closure of
d-Chloro-a,b-Unsaturated Diesters and Ketoesters
M
ichael-Induc
v
edRingClo
e
e
of
d
-C
n
hloro-
a
,
b
-Unsatura
M
te
d
D
iesters andKetoe
a
sters ngelinckx,1 Bruno Vermaut, Roland Verhé, Norbert De Kimpe*
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium
Fax +32(9)2646243; E-mail: norbert.dekimpe@UGent.be
Received 6 June 2008
ylates have been synthesized via radical addition of xan-
Abstract: Michael-induced ring closure (MIRC) of dimethyl 2-(3-
thates to dimethyl cyclobut-2-ene-1,1-dicarboxylate.10
chloro-2,2-dimethylpropylidene)malonate, upon treatment with so-
dium tert-butylthiolate, sodium methoxide or sodium cyanide in
methanol, provided a short and efficient synthesis of new 2-func-
tionalized cyclobutane-1,1-dicarboxylic esters. Under similar con-
Despite the versatility of the Michael-induced ring closure
(MIRC)11 of g- and w-halo-a,b-unsaturated esters to three-,
five-, six- and seven-membered ring esters,12 only few ex-
amples of syntheses of four-membered carbocycles via a
MIRC strategy are reported. Early research was per-
formed on the synthesis of 1,1-dicyanocyclobutanes and
alkyl 1-cyanocyclobutane-1-carboxylates by reaction of
doubly activated w-tosyloxyolefins with hydride or alk-
oxide,13 and on the synthesis of 2-methoxy- and 2-cyano-
cyclobutyl ketones, together with cyclohexenones and
dihydropyrans as side products, from 5,5-dimethyl-6-(to-
syloxy)-3-hexen-2-one.14 Dialkyl cyclobutane-1,1-dicar-
boxylates have not been prepared, because the required
dialkyl w-tosyloxyalkylidenemalonate could not be pre-
pared via standard Knoevenagel condensation of 3-tosyl-
oxy-2,2-dimethylpropanal with diethyl malonate which
was insufficiently reactive.13 Following this pioneering
research on MIRC-based cyclobutane synthesis, only two
additional isolated examples have been reported which in-
volved cyclization of alkyl 5-bromo- or 5-iodo-2-pen-
tenoates, i.e. monoactivated substrates for the MIRC
reaction,15 with carbanions.16 Surprisingly, no further in-
vestigations on the synthesis of cyclobutane-1,1-dicar-
boxylic esters via a MIRC strategy have been reported.
The lack of MIRC reactions leading to cyclobutanes can
be understood from the fact that these reactions involve
the intramolecular 1,4-substitution of an in situ generated
d-halocarbanion, which is not favored for enthalpy and
entropy reasons.17 Therefore, the MIRC reaction of a,b-
unsaturated esters bearing a d-leaving group with nucleo-
philes to cyclobutanes suffers from competitive side reac-
tions such as formation of the initial conjugate addition
products without cyclization,16 intramolecular proton
transfer in the initial Michael adducts followed by alterna-
tive intramolecular alkylations,18 direct nucleophilic dis-
placement of the d-leaving group,19 and b-elimination of
the d-leaving group.11 It was envisaged that doubly acti-
vated g,g-dimethyl-a,b-unsaturated esters with a d-chloro
substituent as a weaker leaving group would be good sub-
strates for MIRC reactions to alkyl cyclobutane(di)car-
boxylates. The weaker nucleofugacity of the d-chloro
group should disfavor direct SN2 displacement. The g,g-
dimethyl substitution blocks b-elimination of the d-leav-
ing group, disfavors direct SN2 displacement and favors
ditions,
methyl
2-acetyl-5-chloro-4,4-dimethylpent-2-enoate
afforded 4-functionalized methyl 5,6-dihydro-4H-pyran-3-carbox-
ylates as the MIRC products.
Key words: Michael-induced ring closure, cyclobutanes, dihydro-
pyrans, carboxylic esters, cyclizations
Cyclobutane derivatives constitute an important class of
small-membered ring compounds, which have received
increasing attention due to the importance of the cyclobu-
tane unit in biomolecules,2 and as versatile intermediates
in organic synthesis.3 More specifically, cyclobutane-1,1-
dicarboxylate derivatives have found pharmaceutical ap-
plications as antitumor platinum(II) complexes, e.g. car-
boplatin,4 and in the synthesis of biologically interesting
compounds such as 1-aminocyclobutane-1-carboxylic ac-
ids,5 dihydrooxacenes,6 and cyclobutylmethylsulfanyl-
substituted pyrimidines as dihydrofolate reductase inhibi-
tors.7
Among the synthetic methods available for the synthesis
of cyclobutane derivatives, [2+2] cycloadditions are the
most important.8 However, the formation of functional-
ized dialkyl cyclobutane-1,1-dicarboxylates via [2+2] cy-
cloaddition of nucleophilic olefins, such as enamines,
vinyl ethers and vinyl sulfides, with electrophilic geminal
diester-substituted olefins is complicated by several prob-
lems. Dialkyl ethylenedicarboxylates have a rather low re-
activity and under the applied [2+2] cycloaddition
conditions side reactions occur such as [4+2] cycloaddi-
tion, 2:1 cycloadduct formation, cycloreversion, co-poly-
merization and transformation of the kinetically formed
dialkyl cyclobutane-1,1-dicarboxylates to thermodynami-
cally more stable ring-opening and ring-expansion prod-
ucts.9 The latter transformations are favored by the use of
heat, polar solvents and strong Lewis acids. Alternatively,
xanthate-substituted dimethyl cyclobutane-1,1-dicarbox-
SYNLETT 2008, No. 17, pp 2697–2701
x
x
.x
x
.2
0
0
8
Advanced online publication: 01.10.2008
DOI: 10.1055/s-0028-1083506; Art ID: G20208ST
© Georg Thieme Verlag Stuttgart · New York

2698
S. Mangelinckx et al.
LETTER
Table 1 Reaction of Alkylidene Ester 3a with Different Nucleo-
philes
the cyclization of the initial Michael adducts due to the
gem-dimethyl effect or Thorpe–Ingold effect.20
Entry
Reaction conditions
Yield (%)a
4 (79)
The intended new electrophilic w-chloroalkylidenes 3
were, to our satisfaction, efficiently prepared via a modi-
fied Knoevenagel condensation through reaction of 3-
chloro-2,2-dimethylpropanal (1), obtained via oxidation
of 3-chloro-2,2-dimethylpropanol with pyridiniumchloro-
chromate,21 with dimethyl malonate (2a) or methyl ace-
toacetate (2b) in the presence of titanium(IV) chloride and
pyridine (Scheme 1).15,22,23
1
2
3
4
NaSt-Bu (1.0 equiv), MeOH, r.t., 4 h
NaOMe (1.0 equiv), MeOH, D, 4 h
NaCN (1.5 equiv), MeOH, D, 4 h
NaCN (1.5 equiv), MeOH, r.t., 14 h
5 (67)
6 (63)
7 (58)
a Isolated yield after distillation.
O
CO2Me
TiCl4 (2 equiv)
CO2Me
The reactivity of methyl 2-acetyl-5-chloro-4,4-dimethyl-
pent-2-enoate (3b) towards sodium tert-butylthiolate, so-
dium methoxide and sodium cyanide was also
investigated. In this case, the MIRC reaction proceeded
via preferential formation of a six-membered ring instead
of a four-membered ring involving O-alkylation instead
of C-alkylation of the intermediate w-chloroenolate. The
former cyclization resulted in the formation of 4-function-
alized methyl 5,6-dihydropyran-3-carboxylates 8–10
(Scheme 3, Table 2).25 The formation of these different
highly substituted dihydropyrans 8–10 bears analogy with
the described reaction of 2,2-dimethyl-3-(tosyloxy)propi-
onaldehyde with the anion of ethyl acetoacetate which
similarly gave the corresponding ethyl 4-hydroxy-5,6-di-
hydropyran-3-carboxylate as reaction product via O-alky-
lation of an intermediate w-tosyloxyenolate.26 The O-
alkylation to 3,3,6-trimethyl-3,4-dihydropyran-4-carbo-
nitrile has also been reported as a competitive reaction of
5,5-dimethyl-6-(tosyloxy)-3-hexen-2-one with potassium
cyanide.14
H
+
py (4 equiv)
THF, Δ, 6–8 h
Z
Z
Cl
Cl
1
2a Z = CO2Me
2b Z = COMe
3a 72%
3b 69% (E/Z = 39:61)
Scheme 1
The reactivity of the synthesized electrophilic alkylidenes
3 with different classes of nucleophiles was studied
(Scheme 2, Table 1). The reaction of dimethyl 2-(3-chlo-
ro-2,2-dimethylpropylidene)malonate (3a) with one equiv-
alent of sodium tert-butylthiolate in methanol at room
temperature for four hours efficiently afforded dimethyl
2-tert-butylsulfanyl-3,3-dimethylcyclobutane-1,1-dicarboxy-
late (4) via Michael addition and subsequent ring closure
with intramolecular nucleophilic substitution of the d-
chloro atom (Table 1, entry 1).24 Reaction of malonate 3a
with one equivalent of sodium methoxide in methanol at
room temperature afforded a mixture of unreacted mal-
onate 3a, unidentified methoxy compounds and dimethyl
2-methoxy-3,3-dimethylcyclobutane-1,1-dicarboxylate
(5). However, the cyclobutane 5 was obtained in pure
form upon reflux of malonate 3a in the presence of one
equivalent of sodium methoxide in methanol (entry 2). A
temperature effect was also observed in the reaction of
malonate 3a with cyanide. Addition of sodium cyanide in
methanol afforded the corresponding Michael adduct 7
upon stirring at room temperature (entry 4), while reflux
conditions resulted in the selective formation of dimethyl
2-cyanocyclobutane-1,1-dicarboxylate (6; entry 3). The
cyclobutanedicarboxylic esters 4–6 were stable enough
for purification via high-vacuum distillation.
In an effort to extend the scope of these MIRC reactions,
the reaction of w-chloroalkylidenes 3 with isopropyl-
amine and hydride was also studied. Reaction of malonate
3a with isopropylamine in diethyl ether at room tempera-
ture did not lead to the formation of the target cyclobutane
(Scheme 4). Instead, the initial Michael adduct 11 under-
went retro-Mannich reaction with formation of N-isopro-
pyl aldimine 12 and dimethyl malonate (2a). The structure
of b-chloro aldimine 12 was confirmed by comparison of
the spectroscopic data with literature data.27 Malonate 3a
failed to react with diisopropylamine upon stirring for 62
hours at room temperature in diethyl ether. Upon reaction
of methyl 2-acetyl-5-chloro-4,4-dimethylpent-2-enoate
(3b) with an excess of isopropylamine, only products re-
sulting from a retro-Mannich reaction after Michael addi-
tion were formed.
Nu
CO2Me
NaNu (1–1.5 equiv)
MeOH, r.t. to Δ, 4–14 h
(see Table 1)
CO2Me
CO2Me
4 Nu = St-Bu
5 Nu = OMe
6 Nu = CN
CO2Me
Cl
3a
Nu
CO2Me
COMe
NaNu (1–2 equiv)
Nu
MeOH, r.t. to Δ, 4–24 h
(see Table 2)
O
Cl
CO2Me
CO2Me
or
3b (E/Z = 39:61)
8 Nu = St-Bu
9 Nu = OMe
10 Nu = CN
CO2Me
Cl
7 Nu = CN
Scheme 3
Scheme 2
Synlett 2008, No. 17, 2697–2701 © Thieme Stuttgart · New York

LETTER
Michael-Induced Ring Closure of d-Chloro-a,b-Unsaturated Diesters and Ketoesters
2699
Table 2 Reaction of Alkylidene Ester 3b with Different Nucleo-
philes
References and Notes
(1) Postdoctoral fellow of the Research Foundation, Flanders
(FWO-Vlaanderen).
Entry Reaction conditions
Yield (%)a
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2004, 357, 4452.
(5) (a) Lasa, M.; López, P.; Cativiela, C. Tetrahedron:
Asymmetry 2005, 16, 4022. (b) Allan, R. D.; Hanrahan,
J. R.; Hambley, T. W.; Johnston, G. A. R.; Mewett, K. N.;
Mitrovic, A. D. J. Med. Chem. 1990, 33, 2905.
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Synlett 2006, 1394. (c) Roy, O.; Faure, S.; Aitken, D. J.
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P. J. Am. Chem. Soc. 1975, 97, 800. (c) Baar, M. R.;
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Chem. 1993, 58, 4185. (e) Srisiri, W.; Padias, A. B.; Hall, H.
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(10) (a) Ferjančić, Z.; Čeković, Ž.; Saičić, R. N. Tetrahedron
Lett. 2000, 41, 2979. (b) Legrand, N.;Quiclet-Sire, B.;Zard,
S. Z. Tetrahedron Lett. 2000, 41, 9815.
1
2
3
NaSt-Bu (1.0 equiv), MeOH, r.t., 4 h
8 (70)
NaOMe (2.0 equiv), MeOH, D, 4 h or r.t., 24 h 9 (61)
NaCN (2.0 equiv), MeOH, D, 4 h 10 (64)
a Isolated yield after distillation.
The reaction of alkylidenes 3 with sodium borohydride in
methanol resulted in the formation of complex reaction
mixtures under different reaction conditions (0 °C up to
reflux temperature) with different amounts of hydride (2–
4 equiv). From the reaction of malonate 3a with three mo-
lar equivalents of NaBH4 at 0 °C for 30 minutes, a sample
of dimethyl 2-(3-chloro-2,2-dimethylpropyl)malonate
(13), resulting from the reduction of the C=C bond of 3a,
was obtained via preparative GC of a fraction obtained via
distillation under high vacuum (bp 88–91 °C/0.02 Torr;
Scheme 4).28
H
i-Pr
N
CO2Me
i-PrNH2 (4 equiv)
CO2Me
CO2Me
Et2O, r.t., 48 h
71%
CO2Me
Cl
3a
Cl
11
NaBH4 (3 equiv)
MeOH, 0 °C, 30 min
i-Pr
N
CO2Me
CO2Me
2a
CO2Me
CO2Me
+
H
Cl
Cl
12
(11) Little, R. D.; Dawson, J. R. Tetrahedron Lett. 1980, 21,
2609.
(12) Caine, D. Tetrahedron 2001, 57, 2643.
(13) Zabel, K.; Weyerstahl, P.; Marschall, H.; Nerdel, F. Chem.
Ber. 1972, 105, 1053.
13 (isolated by prep. GC)
Scheme 4
In conclusion, Michael addition of S-, O- and C-centered
nucleophiles with d-chloro-a,b-unsaturated diesters and
ketoesters results in the efficient formation of new 2-func-
tionalized cyclobutane-1,1-dicarboxylic esters via in-
tramolecular C-alkylation and 4-functionalized 5,6-
dihydro-4H-pyran-3-carboxylic esters via intramolecular
O-alkylation, respectively. The b-functionalized dialkyl
cyclobutane-1,1-dicarboxylates belong to a biologically
important class of constrained carbocyclic compounds
and should have potential for further synthetic transfor-
mations to interesting functionalized cyclobutanes.
(14) Marschall, H.; Tantau, K.; Weyerstahl, P. Chem. Ber. 1974,
107, 887.
(15) Little, R. D.; Verhé, R.; Monte, W. T.; Nugent, S.; Dawson,
J. R. J. Org. Chem. 1982, 47, 362.
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2000, 65, 1758. (b) Pohlman, M.; Kazmaier, U. Org. Lett.
2003, 5, 2631.
(17) (a) Barbasiewicz, M.; Brud, A.; Mąkosza, M. Synthesis
2007, 1209; and references cited therein. (b) Knipe, A. C.;
Stirling, C. J. M. J. Chem. Soc. B 1968, 67. (c) Casadei,
M. A.; Galli, C.; Mandolini, L. J. Am. Chem. Soc. 1984, 106,
1051.
(18) (a) Matsumoto, T.; Masu, H.; Yamaguchi, K.; Takeda, K.
Org. Lett. 2004, 6, 4367. (b) Ishikawa, T.; Nagai, K.;
Senzaki, M.; Tatsukawa, A.; Saito, S. Tetrahedron 1998, 54,
2433.
(19) (a) Stille, J. R.; Grubbs, R. H. J. Org. Chem. 1989, 54, 434.
(b) Hellou, J.; Berube, G.; Newlands, M. J.; Fallis, A. G.;
Gabe, E. J. Can. J. Org. Chem. 1988, 66, 439. (c) Nangia,
A.; Anthony, A.; Prasuna, G. Indian J. Chem., Sect. B 1996,
35, 52; Chem. Abstr. 1996, 124, 201959. (d) Yonezawa, Y.;
Hirosaki, T.; Hayashi, T.; Shin, C.-G. Synthesis 2000, 144.
Acknowledgment
The authors are indebted to the Research Foundation, Flanders
(FWO-Vlaanderen) and the Ghent University (GOA) for financial
support of this research.
Synlett 2008, No. 17, 2697–2701 © Thieme Stuttgart · New York

2700
S. Mangelinckx et al.
LETTER
(20) Bachrach, S. M. J. Org. Chem. 2008, 73, 2466; and
references cited therein.
(21) (a) Pennings, M. L. M.; Reinhoudt, D. N. J. Org. Chem.
1983, 48, 4043. (b) Wilt, J. W.; Aznavoorian, P. H. J. Org.
Chem. 1978, 43, 1285.
(EI, 70 eV): m/z (%) = 288 (2) [M+], 258 (1), 232 (8), 231
(8), 201 (8), 176 (54), 145 (23), 144 (77), 116 (8), 113 (23),
88 (100), 59 (31), 57 (92). Anal. Calcd for C14H24O4S: C,
58.30; H, 8.39. Found: C, 58.15; H, 8.54.
Dimethyl 2-Methoxy-3,3-dimethylcyclobutane-1,1-
dicarboxylate (5): yield: 67%; bp 60 °C/0.02 Torr. 1H NMR
(270 MHz, CDCl3): d = 1.10 [s, 3 H, C(Me)Me], 1.14 [s, 3
H, C(Me)Me], 1.65 (d, 1 H, J = 12.2 Hz, CH(H)], 2.55 [d, 1
H, J = 12.2 Hz, CH(H)], 3.41 (s, 3 H, OMe), 3.74 (s, 3 H,
COOMe), 3.78 (s, 3 H, COOMe), 4.12 (s, 1 H, CHOMe). 13C
NMR (68 MHz, CDCl3): d = 20.9, 29.8, 35.9, 37.3, 52.58,
52.63, 56.0, 58.5, 85.1, 169.5, 171.9. IR (NaCl): 1730 (C=O)
cm–1. MS (EI, 70 eV): m/z (%) = no [M+], 199 (6), 143 (38),
113 (23), 86 (100), 75 (19), 71 (38), 59 (14), 46 (14), 45 (19).
Anal. Calcd for C11H18O5: C, 57.38; H, 7.88. Found: C,
57.09; H, 8.04.
Dimethyl 2-Cyano-3,3-dimethylcyclobutane-1,1-
dicarboxylate (6): yield: 63%; bp 85 °C/0.04 Torr. 1H NMR
(270 MHz, CDCl3): d = 1.25 [s, 3 H, C(Me)Me], 1.31 [s, 3
H, C(Me)Me], 2.11 [d, 1 H, J = 12.5 Hz, CH(H)], 2.79 [d, 1
H, J = 12.5 Hz, CH(H)], 3.78 (s, 3 H, COOMe), 3.80 (s, 1 H,
CHCN), 3.84 (s, 3 H, COOMe). 13C NMR (68 MHz, CDCl3):
d = 25.6, 29.7, 34.0, 38.7, 39.6, 49.7, 53.4, 53.5, 116.5,
168.5, 170.0. IR (NaCl): 2230 (C≡N), 1735 (C=O) cm–1. MS
(EI, 70 eV): m/z (%) = no [M+], 194 (17), 170 (39), 166
(100), 138 (33), 134 (61), 113 (28), 106 (25), 79 (25), 59
(28), 56 (61), 54 (72).
(22) Lehnert, W. Tetrahedron 1973, 29, 635.
(23) General Procedure: To a three-necked flask equipped with
a reflux condenser, dropping funnel and mechanical stirrer
was added anhyd THF (200 mL). At 0 °C, TiCl4 (0.2 mol) in
CCl4 (50 mL) was added, after which, a solution of 3-chloro-
2,2-dimethylpropanal (1; 0.1 mol) and dimethyl malonate
(2a) or methyl acetoacetate (2b; 0.1 mol) in anhyd THF (50
mL) was added dropwise. Subsequently, at 0 °C, anhyd
pyridine (0.4 mol) in anhyd THF (50 mL) was added
dropwise over a period of 45 min. The reaction was stirred
under reflux (6–8 h), poured into crushed ice (500 mL),
extracted with Et2O (3 × 100 mL) and washed with brine, sat.
NaHCO3 and brine again. After drying (MgSO4), filtration
and evaporation under reduced pressure the pure alkylidene
ester was obtained via high-vacuum distillation.
Dimethyl 2-(3-Chloro-2,2-
dimethylpropylidene)malonate (3a): yield: 72%; bp 85 °C/
0.01 Torr. 1H NMR (270 MHz, CDCl3): d = 1.23 (s, 6 H,
CMe2), 3.49 (s, 2 H, CH2), 3.78 (s, 3 H, COOMe), 3.83 (s, 3
H, COOMe), 6.94 (s, 1 H, CH=C). 13C NMR (68 MHz,
CDCl3): d = 24.3, 39.1, 52.4, 52.6, 54.4, 127.6, 150.9, 164.3,
166.8. IR (NaCl): 1730 (C=O), 1650 (C=C) cm–1. MS (EI, 70
eV): m/z (%) = 234 (9) [M+], 219 (39), 185 (35), 167 (83),
153 (100), 135 (78), 125 (39), 67 (39), 59 (57), 41 (52). Anal.
Calcd for C10H15ClO4: C, 51.18; H, 6.44. Found: C, 51.01;
H, 6.61.
Dimethyl 2-(3-Chloro-1-cyano-2,2-
dimethylpropyl)malonate (7): yield: 58%; bp 88–89 °C/
0.01 Torr. 1H NMR (270 MHz, CDCl3): d = 1.11 [s, 3 H,
C(Me)Me], 1.20 [s, 3 H, C(Me)Me], 3.47 [d, 1 H, J = 11.9
Hz, CH(H)Cl], 3.60 [d, 1 H, J = 11.6 Hz, CH(H)Cl], 3.67,
3.71 [2 × d, 2 × 1 H, J = 5.4 Hz, CH(CN)CH], 3.82 (s, 3 H,
COOMe), 3.83 (s, 3 H, COOMe). 13C NMR (68 MHz,
CDCl3): d = 22.4, 23.7, 38.3 (2 × C), 49.4, 52.8, 53.3, 53.6,
117.4, 167.0, 167.1. IR (NaCl): 2240 (C≡N), 1750, 1735
(C=O) cm–1. MS (EI, 70 eV): m/z (%): no [M+], 230 (7), 212
(17), 171 (50), 152 (17), 148 (14), 139 (10), 112 (100), 91
(10), 80 (16), 59 (16), 55 (28). Anal. Calcd for C11H16ClNO4:
C, 50.48; H, 6.16; N, 5.35. Found: C, 50.32; H, 6.33; N, 5.24.
(25) Methyl 4-tert-Butylsulfanyl-2,5,5-trimethyl-5,6-dihydro-
4H-pyran-3-carboxylate (8): yield: 70%; bp 80–83 °C/0.02
Torr. 1H NMR (270 MHz, CDCl3): d = 1.01 [s, 3 H,
C(Me)Me], 1.10 [s, 3 H, C(Me)Me], 1.34 (s, 9 H, SCMe3],
2.12 (s, 3 H, C=CMe], 3.45–3.46 (m, 1 H, CHSt-Bu), 3.54
[dd, 1 H, J = 10.7, 2.8 Hz, CH(H)O], 3.73 (s, 3 H, COOMe),
3.73 [d, 1 H, J = 10.8 Hz, CH(H)O]. 13C NMR (68 MHz,
CDCl3): d = 19.8, 24.1, 24.2, 31.9, 32.2, 44.0, 46.0, 51.0,
72.3, 105.5, 160.0, 168.3. IR (NaCl): 1700 (C=O), 1615
(C=C) cm–1. MS (EI, 70 eV): m/z (%) = 272 (8) [M+], 183
(100), 182 (31), 151 (41), 141 (31), 109 (23), 90 (21), 59
(18), 57 (44), 43 (79), 41 (67). Anal. Calcd for C14H24O3S:
C, 61.73; H, 8.88. Found: C, 61.54; H, 8.97.
Methyl 2-Acetyl-5-chloro-4,4-dimethylpent-2-enoate
(3b): E/Z = 39:61; yield: 69%; bp 68 °C/0.02 Torr. 1H NMR
(270 MHz, CDCl3; Z-isomer): d = 1.25 (s, 6 H, CMe2), 2.32
(s, 3 H, COMe), 3.50 (s, 2 H, CH2), 3.84 (s, 3 H, COOMe),
6.75 (s, 1 H, CH=C). 1H NMR (270 MHz, CDCl3; E-isomer):
d = 1.22 (s, 6 H, CMe2), 2.44 (s, 3 H, COMe), 3.48 (s, 2 H,
CH2), 3.79 (s, 3 H, COOMe), 6.78 (s, 1 H, CH=C). 13C NMR
(68 MHz, CDCl3; Z-isomer): d = 25.3, 31.8, 39.3, 52.5, 54.5,
135.4, 149.8, 164.8, 203.1. 13C NMR (68 MHz, CDCl3; E-
isomer): d = 24.4, 26.1, 39.0, 52.3, 54.6, 136.5, 149.6, 167.8,
195.2. IR (NaCl): 1675–1730 (C=O), 1635 (C=C) cm–1. MS
(EI, 70 eV): m/z (%) = 218 (<1) [M+], 203 (4), 183 (5), 171
(6), 169 (3), 167 (4), 151 (9), 137 (4), 135 (4), 109 (7), 95
(6), 71 (6), 67 (5), 59 (4), 43 (100). Anal. Calcd for
C10H15ClO3: C, 54.92; H, 6.91. Found: C, 54.78; H, 7.07.
(24) Synthesis of Dimethyl 2-tert-Butylsulfanyl-3,3-
dimethylcyclobutane-1,1-dicarboxylate (4);
Representative Procedure: A solution of 2 M NaOMe in
MeOH (2.5 mL, 5 mmol) was added to tert-butanethiol (5
mmol). The obtained solution of sodium tert-butylthiolate
was added at r.t. to a solution of dimethyl 2-(3-chloro-2,2-
dimethylpropylidene)malonate (3a; 5 mmol) in anhyd
MeOH (5 mL). The reaction mixture was stirred for 4 h,
during which NaCl precipitated, poured into H2O (100 mL)
and extracted with Et2O (3 × 50 mL). The combined organic
layers were dried (MgSO4), filtered and evaporated under
reduced pressure. High-vacuum distillation afforded the
pure dimethyl 2-tert-butylsulfanyl-3,3-dimethylcyclo-
butane-1,1-dicarboxylate(4); yield: 79%; bp 64–65 °C/0.02
Torr. 1H NMR (270 MHz, CDCl3): d = 1.12 [s, 3 H,
C(Me)Me], 1.16 [s, 3 H, C(Me)Me], 1.31 (s, 9 H, SCMe3),
1.95 [d, 1 H, J = 12.2 Hz, CH(H)], 2.63 [dd, 1 H, J = 12.4,
0.8 Hz, CH(H)], 3.75 (s, 3 H, COOMe), 3.77 (s, 3 H,
COOMe), 3.99 (s, 1 H, CHSt-Bu). 13C NMR (68 MHz,
CDCl3): d = 24.1, 30.3, 31.4, 36.9, 39.7, 42.8, 50.9, 52.1,
52.6, 56.5, 170.3, 172.3. IR (NaCl): 1735 (C=O) cm–1. MS
Methyl 4-Methoxy-2,5,5-trimethyl-5,6-dihydro-4H-
pyran-3-carboxylate (9): yield: 61%; bp 52–54 °C/0.02
Torr. 1H NMR (270 MHz, CDCl3): d = 0.84 [s, 3 H,
C(Me)Me], 1.01 [s, 3 H, C(Me)Me], 2.23 [s, 3 H, C=C(Me)],
3.46 [s, 3 H, OMe], 3.58 [dd, 1 H, J = 10.2, 2.0 Hz,
CH(H)O], 3.66 (br s, 1 H, CHOMe), 3.74 (s, 3 H, COOMe),
3.83 [d, 1 H, J = 10.2 Hz, CH(H)O]. 13C NMR (68 MHz,
CDCl3): d = 20.2, 20.9, 22.5, 33.2, 51.0, 59.6, 71.5, 77.6,
102.9, 165.9, 169.0. IR (NaCl): 1710 (C=O), 1620 (C=C)
cm–1. MS (EI, 70 eV): m/z (%) = 214 (7) [M+], 183 (33), 159
(26), 155 (7), 151 (11), 143 (56), 127 (44), 85 (26), 75 (41),
59 (7), 43 (100). Anal. Calcd for C11H18O4: C, 61.66; H,
8.47. Found: C, 61.51; H, 8.59.
Synlett 2008, No. 17, 2697–2701 © Thieme Stuttgart · New York

LETTER
Michael-Induced Ring Closure of d-Chloro-a,b-Unsaturated Diesters and Ketoesters
2701
Methyl 4-Cyano-2,5,5-trimethyl-5,6-dihydro-4H-pyran-
3-carboxylate(10): yield: 64%; bp 82–83 °C/0.01 Torr. 1H
(27) Sulmon, P.; De Kimpe, N.; Verhé, R.; De Buyck, L.;
Schamp, N. Synthesis 1986, 192.
NMR (270 MHz, CDCl3): d = 1.03 [s, 3 H, C(Me)Me], 1.24
[s, 3 H, C(Me)Me], 2.31 (s, 3 H, C=CMe), 3.31 (br s, 1 H,
CHC≡N), 3.74 (dd, 1 H, J = 11.2, 2.3 Hz, OCHH], 3.77 (s, 3
H, COOMe), 3.86 (d, 1 H, J = 11.2 Hz, OCHH). 13C NMR
(68 MHz, CDCl3): d = 20.2, 23.1, 23.3, 29.8, 36.2, 51.6,
72.6, 96.6, 119.6, 166.7, 167.0. IR (NaCl): 2235 (C≡N),
1710 (C=O), 1610 (C=C) cm–1. MS (EI, 70 eV): m/z (%) =
209 (18) [M+], 194 (15), 178 (15), 154 (15), 150 (10), 122
(5), 113 (6), 97 (10), 56 (100). Anal. Calcd for C11H15NO3:
C, 63.14; H, 7.23; N, 6.69. Found: C, 63.01; H, 7.51; N 6.56.
(26) Lucas, K.; Weyerstahl, P.; Marshall, H.; Nerdel, F. Chem.
Ber. 1971, 104, 3607.
(28) Dimethyl 2-(3-Chloro-2,2-dimethylpropyl)malonate
(13): Sample was isolated via preparative GC from a
distillation fraction (bp 88–91 °C/0.02 Torr). 1H NMR (270
MHz, CDCl3): d = 0.98 (s, 6 H, CMe2), 2.08 (d, 2 H, J = 6.6
Hz, CH2CH), 3.34 (s, 2 H, ClCH2), 3.42 (t, 1 H, J = 6.4 Hz,
CH2CH), 3.75 [s, 6 H, (COOMe)2]. 13C NMR (68 MHz,
CDCl3): d = 24.7, 35.2, 37.5, 47.9, 52.8, 54.9, 170.2. IR
(NaCl): 1735 (C=O) cm–1. MS (EI, 70 eV): m/z (%) = no
[M+], 221 (<1), 205 (15), 187 (100), 155 (26), 145 (78), 127
(96), 123 (56), 95 (48), 59 (44), 55 (96), 41 (67).
Synlett 2008, No. 17, 2697–2701 © Thieme Stuttgart · New York

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