Lewis acid-promoted cyclization reactions of alkenyl ethenetricarboxylates: Stereoselective synthesis of 2-oxotetrahydrofurans and 2-oxopyrrolidines

Article abstract of DOI:10.1021/jo401106m

Lewis acid-promoted intramolecular reactions of alkenyl ethenetricarboxylates and the corresponding amides have been examined. Reaction of allyl ethenetricarboxylates and the amides with Lewis acids (1-2 equiv) such as TiCl₄, TiBr₄, AlCl₃, and AlBr₃ gave 3,4-trans-halogenomethyl 2-oxotetrahydrofuran and pyrrolidine derivatives stereoselectively in high yields. The stereochemistries were determined by NOE experiments. Reaction of alkyl-substituted allylic ethenetricarboxylates with Lewis acids gave chloro 2-oxotetrahydrofurans and pyrans. For some alkyl-substituted substrates, cationic intermediates may be formed under the reaction conditions, and rearranged products have been obtained.

Full text of DOI:10.1021/jo401106m

Article
pubs.acs.org/joc
Lewis Acid-Promoted Cyclization Reactions of Alkenyl
Ethenetricarboxylates: Stereoselective Synthesis of
2‑Oxotetrahydrofurans and 2‑Oxopyrrolidines
Shoko Yamazaki,*,† Ken Fujinami,† Yuki Maitoko,† Khota Ueda,† and Kiyomi Kakiuchi‡
†Department of Chemistry, Nara University of Education, Takabatake-cho, Nara 630-8528, Japan
‡Graduate School of Materials Science, Nara Institute of Science and Technology (NAIST), Takayama, Ikoma, Nara 630-0192, Japan
S
* Supporting Information
ABSTRACT: Lewis acid-promoted intramolecular reactions of alkenyl
ethenetricarboxylates and the corresponding amides have been examined.
Reaction of allyl ethenetricarboxylates and the amides with Lewis acids (1−2
equiv) such as TiCl4, TiBr4, AlCl3, and AlBr3 gave 3,4-trans-halogenomethyl 2-
oxotetrahydrofuran and pyrrolidine derivatives stereoselectively in high yields.
The stereochemistries were determined by NOE experiments. Reaction of
alkyl-substituted allylic ethenetricarboxylates with Lewis acids gave chloro 2-oxotetrahydrofurans and pyrans. For some alkyl-
substituted substrates, cationic intermediates may be formed under the reaction conditions, and rearranged products have been
obtained.
acid-promoted reactions to give nitrogen-containing hetero-
cycles may also be of interest.
INTRODUCTION
■
Oxygen- and nitrogen-containing heterocyclic systems such as
five-membered rings, tetrahydrofurans and pyrrolidines, are
versatile core structures in organic chemistry because of their pre-
sence in many biologically active compounds.1,2 The develop-
ment of new efficient synthetic strategies for the construction of
these heterocycles is of considerable interest.3,4
Snider and Roush reported that Lewis acid-promoted intra-
molecular reactions of alkenyl and alkynyl ethenetricarboxylates
gave chlorinated γ-lactones (eq 1).5 We have developed Lewis
We have studied various Lewis acid-promoted intermolecular
reactions of ethenetricarboxylate derivatives and reported that
they function as highly electrophilic Michael acceptors.10 In this
work, Lewis acid-promoted intramolecular reaction of alkenyl
ester and amides of ethenetricarboxylate leading to five-mem-
bered heterocycles has been examined. Furthermore, the scope
and limitation of the Lewis acid-promoted intramolecular
reactions of alkyl-substituted allylic esters have been described.
RESULTS AND DISCUSSION
■
Cyclization of Alkenyl Ethenetricarboxylates and the
Amides. 2-Allyl 1,1-diethyl ethene-1,1,2-tricarboxylate (1) was
previously used in TiCl4-promoted intermolecular reaction with
aminoacetals.10a Competing intramolecular reaction was not
observed under the reaction conditions. After examining various
Lewis acids, it was found that reaction with AlCl3, AlBr3, TiCl4,
and TiBr4 (1−2 equiv) at room temperature gave diethyl
2-(trans-4-(chloro (or bromo)methyl)-2-oxotetrahydrofuran-3-yl)-
malonate (2a,b) in 57−90% yields (eq 3, Table 1). For AlCl3,
TiCl4, and TiBr4, use of 2 equiv of Lewis acids is required to
drive the reaction to completion.
The γ-lactone structure of 2a,b was suggested by the presence
of a characteristic CO absorption (1777−1779 cm−1). H, 13C
1
acid-promoted stereoselective cyclization of alkynyl ethenetricar-
boxylates with high generality (eq 2).6 Lewis acid-promoted
intramolecular ene reaction7 and related cyclization of silicon-
substituted allylic alkylidene 1,3-dioxo compounds to give
carbocycles8 have also been reported. Furthermore, Lewis acid-
promoted addition of simple alkenes to aldehydes proceeding
to form C−C bonds (Prins reaction) is well-known.9 However,
few Lewis acid-promoted Michael additions of simple alkenes
such as allyl moieties have been reported. Related Lewis
and 2D NMR spectra were in agreement with the five-membered
ring structure. The 3,4-stereochemistry of 2a,b was examined
by NOESY experiments. NOEs between H-3 and H-4 could be
observed for both 3,4-cis and trans diastereomers. The following
peaks were used for the assignment of the obtained single
Received: May 21, 2013
© XXXX American Chemical Society
A
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Table 1. Reactions of Allyl Ester 1
entry
MXn
MXn (equiv)
2
yield (%)
a
1
2
3
4
5
6
7
8
AlCl3
AlCl3
AlBr3
AlBr3
TiCl4
TiCl4
TiBr4
TiBr4
1
2
1
2
1
2
1
2
2a
2a
2b
2b
2a
2a
2b
2b
58
72
57
45
b
90
b
experiments. NOEs between H-3 and CHClMe and between
H-4 and CH(CO2Et)2 were observed. Thus, the cis stereo-
chemistry of 7b assigned in the literature is corrected to trans.13
The major products 7a and 7b are single diastereoisomers.
The relative configuration of CHClMe to C-3, C-4 for dia-
stereomers 7a,b could be deduced as (3S,4S)-4-((R)-1-
chloroethyl) (shown in eq 4) and (3R,4R)-4-((S)-1-chlor-
oethyl) by the similar reaction mechanism for the reaction of 1
(Scheme 1, vide post). The proposed reaction mechanism for
the reaction of 6 to 7 is shown in Supporting Information.
Amide substrates 8a−c were then prepared by the con-
densation reaction of 1,1-diethyl 2-hydrogen ethenetricabox-
ylate (prepared from 1,1-diethyl 2-tert-butyl ethenetricarbox-
ylate upon treatment with CF3CO2H) with the corresponding
amines in the presence of HOBT, EDCI and Et3N. Reaction of
diethyl 2-((N-allyl-N-methylcarbamoyl)methylene)malonate
(8a) with 1−2 equiv of TiCl4, FeCl3, AlCl3, TiBr4, and AlBr3
at room temperature and ZnI2 at 80 °C gave diethyl 2-(trans-4-
(chloro(or bromo/iodo)methyl)-1-methyl-2-oxopyrrolidin-3-
yl)malonate 9a−c in 69−98% yields (eq 5, Table 2). Use of
62
a
A small amount of the starting material 1 could not be removed.
The mixture including 1 and 2a/2b was obtained and could not be
b
purified.
diastereomer. NOEs between H-3 and CH2X (X = Cl, Br) and
between H-4 and CH(CO2Et)2 were observed. Thus, the 3,4-
trans stereochemistry of 2a,b was determined.
The reaction of 1 with 2 equiv of FeCl3 at room temperature
for 17 h gave the noncyclized H2O-adduct 3 in 42% yield as a
major product. The reaction of 1 with 2 equiv of ZnI2 at room
temperature gave 3 in 59% yield as a major product, and the
reaction at 80 °C in 1,2-dichloroethane gave only starting
material 1.11,12 The reaction of 1 with 2 equiv of TiCl4 at −40 °C
gave the noncyclized Cl-adduct 4 in 77% yield as a major pro-
duct. Formation of compounds 3 and 4 may be reversible as
they were converted to 2a by treatment with 2 equiv of TiCl4 at
room temperature in 61 and 86%, respectively. Alternatively,
compounds 3 and 4 may be intermediates en route to lactones 2.
2 equiv of Lewis acids such as FeCl3, AlCl3, and ZnI2 increased
product yields. SnCl4 and ZnBr2 are less effective than TiCl4 and
TiBr4 (entries 2,3,10). Reaction of N,N-diallyl and N-allyl-N-
propylcarbamoyl derivatives 8b,c also gave 3,4-trans-pyrrolidines
9d−i efficiently. The γ-lactam structures of 9a−i were suggested
by the presence of a characteristic CO absorption (1688−
1
1698 cm−1). H, 13C and 2D NMR spectra were in agreement
The reaction of 3-butenyl ester 5 with 1−2 equiv of TiCl4 or
AlCl3 was also examined. However, the reaction gave complex
mixtures. Six-membered ring formation from 5 was not an
efficient process.
with the 5-membered ring structure. The 3,4-trans stereo-
chemistry was determined by NOEs for I-adducts 9c,f,i in
CDCl3 and for Cl- and Br-adducts 9a,b,d,e,g,h in C6D6.14,15
NOEs between H-3 and CH2X (X = Cl, Br, I) and between H-4
and CH(CO2Et)2 were observed.
Thus, use of strong Lewis acids leads to efficient five-
membered cyclization of the allyl substrates. In the cyclization,
the 3,4-stereochemistry does not depend on Lewis acids.
The reaction mechanism to give the halogenated five-
membered heterocycles with 3,4-trans stereochemistry is
proposed and shown in Scheme 1. trans precursor A1 and cis
precursor A2 in Scheme 2 may be formed from 1 and Al2Cl6
reversibly. The reaction may start from the precursor A1
consisting of 1 and Al2Cl6. The C−C bond formation and Cl−
C bond formation from A1 may occur concertedly to lead to
cyclized intermediate B1. Intermolecular Cl− anti-attack leading
to 3,4-trans cyclized product is proposed by steric reason. One
molecule of Lewis acid (for example, AlCl3) may work as a
The reaction of (E)-2-butenyl esters 6a,b with Lewis acid was
next examined. The (E)-2-butenyl dimethyl ester 6b is the
substrate that Snider and Roush reported.5 The reaction with 1
equiv of AlCl3 or FeCl3 at room temperature overnight gave
diethyl 2-(4-(2-chloroethyl)tetrahydro-2-oxofuran-3-yl)malonates
7a,b as major products (eq 4). The H NMR and IR spectral
data for the product 7b are identical with the reported ones.
The 3,4-trans stereochemistry for 7a,b was suggested by NOESY
1
B
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Scheme 1. Proposed Reaction Mechanism for Cyclization of
Allyl Esters 1 (R = Et) and B3LYP/6-31G*-Optimized
Structures and Gibbs Free Energies (T = 298.15 K and P = 1
atm) for Intermediates and TS of the Model Compounds
Table 2. Reactions of Allyl Amides 8
MXn
(equiv)
temp
yield
entry
R″
MXn
(°C)
X
(%)
1
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
TiCl4
SnCl4
SnCl4
FeCl3
FeCl3
AlCl3
AlCl3
AlBr3
TiBr4
ZnBr2
ZnI2
1
1
2
1
2
1
2
1
1
1
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
9a
9a
9a
9a
9a
9a
9a
9b
9b
9b
9c
9c
9d
9e
9f
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
I
98
28
38
17
83
a
(1m (R = Me) + Al2Cl6)
2
3
4
5
a
6
65
7
76
69
87
47
73
69
86
71
59
77
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
b
1 × 2
c
ZnI2
2
1
1
80
I
CH2CHCH2
CH2CHCH2
CH2CHCH2
CH2CHCH2
CH2CH2CH3
CH2CH2CH3
CH2CH2CH3
CH2CH2CH3
CH2CH2CH3
CH2CH2CH3
TiCl4
TiBr4
ZnI2
rt
rt
rt
Cl
Br
I
b
1 × 2
c
ZnI2
2
1
2
2
1
80
9f
I
a
TiCl4
TiCl4
FeCl3
TiBr4
ZnI2
rt
rt
rt
rt
rt
9g
9g
9g
9h
9i
Cl
Cl
Cl
Br
I
48
98
54
88
67
87
b
1 × 2
2
c
ZnI2
80
9i
I
a
A small amount of starting material and impurity could not be
b
removed. The reaction with ZnI2 (1 equiv) for 17 h gave the crude
products including impurities (possibly noncyclized water-adducts)
after workup. The crude products were further treated with ZnI2 (1
c
equiv) to give the pure products 9c,f,i. In CH2ClCH2Cl.
the halogenated products. The reaction of 2a or 9a with
Bu3SnH and AIBN gave dechlorinated tetrahydrofuran 10 and
pyrrolidine 11, respectively (eq 6). The stereochemistry of 11
was determined as 3,4-trans by NOESY experiment.
a
TS geometry was characterized by vibrational analysis, which checked
whether the obtained geometry has single imaginary frequencies (ν‡).
From TS, reaction paths were traced by the intrinsic reaction
coordinate (IRC) method to obtain the energy-minimum geometries.
catalyst and could be released after the cyclization step.
Protonation and removal of AlCl2OH yield the product 2.
In order to support this hypothesis, the structures of the
intermediates and transition states (TS) of model compounds
(the corresponding methyl esters and Al2Cl6) were calculated
using B3LYP/6-31G*. ΔG‡ for TS1 leading to 3,4-trans-
tetrahydrofuran is found to be lower than that of TS2 leading to
3,4-cis-tetrahydrofuran (Scheme 2). According to the observed
trans selectivity and preferable use of excess Lewis acids in
some cases, the proposed mechanism involving Al2Cl6 is
likely.16 Cyclization mechanism and the stereochemistry of (E)-
2-butenyl esters (6 in eq 4) and allyl amides (8 in eq 5) were
also calculated by using the model compounds 6b and the
corresponding dimethyl ester of 8a with Al2Cl6. These
calculation results are similar to that for 1m + Al2Cl6. Thus,
formation of 3,4-trans five-membered rings are lower energy
process than that of 3,4-cis. The results are shown in
Supporting Information.
Cyclization of Alkyl Substituted Allylic Ethenetricar-
boxylates. Reactions of alkyl-substituted allylic ethenetricar-
boxylates with Lewis acids were investigated. The alkyl sub-
stitution pattern of allylic esters have been studied for mainly
R3/R3′ = Me or Ph (dimethyl esters) by Snider and Roush (eq 1)
and in this study (eq 4). In order to examine the effect of alkyl
substitution of R1/R1′, R2, the reaction of substrates shown
below under similar reaction conditions were carried out.
The reaction of 12 with AlCl3, TiCl4 and FeCl3 (1−2 equiv)
at room temperature gave mixtures of 5-methyl-2-oxotetrahy-
drofuran 13 and trans-4-(1-chloroethyl)-2-oxotetrahydrofuran
7a in ratios 1.3:1 to 0.3:1 (13:7a; eq 7). The isomeric mixture
Next, reductive dechlorination of tetrahydrofuran and
pyrrolidine was performed as an example of transformation of
C
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a
Scheme 2. Reaction Pathway Leading to 3,4-cis Intermediate B2 for Model Compounds (1m + Al2Cl6)
a
B3LYP/6-31G*-optimized structures of the model compounds are shown. The Gibbs free energies are relative to A1 (R = Me) in Scheme 1.
could not be separated. The compound 7a is the product by the
reaction of 6a shown in eq 4, i.e., the structural isomer of 12.
Similarly, the reaction of 14 with AlCl3, TiCl4 and FeCl3
(1 equiv) at room temperature overnight gave 4-trans-(2-chloro-2-
propanyl)-2-oxotetrahydrofuran 15 in low yields, along with
2-propenyl derivative 16 (eq 8). The compound 15 and the ene
product 16 were also obtained by the reaction of 17 (eq 9).
The reaction of 17 is similar to that of the corresponding
methyl ester that Snider and Roush reported.5 The stereo-
chemistry of the products 15 and 16 were determined as 3,4-
prior to cyclization of 14. The substrate 17 may be thermo-
dynamically more stable than 14, because of the more sub-
stituted alkenyl group.
Related Lewis acid-catalyzed C−O scission and subsequent
cycloaddition of 2-tertiary alkyl ester of ethenetricarboxylate has
been reported previously.18 B3LYP3/6-31G* optimized struc-
ture of model compound 14m (for ethenetricarboxylate 14)
with AlCl3 coordinated at 2-ester oxygen has longer C−O
trans by NOESY spectra.17
Formation of 7a from 12 and 15 from 14 may be explained
as follows. Secondary or tertiary allylic cation intermediate I
may be formed by Lewis acid in situ. The isomerization of the
ester 12 to 6a and the ester 14 to 17 may lead to cyclization of
6a to 7a and 17 to 15 (Scheme 3). The substrate 14 rearranges
to 17 via the stable tertiary allylic cation I (R1 = R1′ = Me)
D
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the stable tertiary cation six-membered ring intermediate C3.
The attack of chloride ion from anti and syn sides of the
malonate on the carbocation C3 may be reversible. The
observed diastereoselectivity of compound 19 may arise from
the stable 1,3-diequatorial (CH(CO2Et2)2 (on C-3) and larger
CH3 (on C-5)) of the six-membered ring with smaller chlorine
atom (on C-5) in the axial position. Thus, the attack of chloride
ion to C3 from anti-side of the malonate gives intermediate D3
(path a).
Scheme 3. Proposed Mechanism for Formation of 7a from
12 and 15 from 14
Alternatively, intramolecular reaction of alkene moiety gives
the stable tertiary cation six-membered ring intermediate C3
(path b), followed by Cl− attack leading to D3. Or, six-
membered formation along with attack of Cl− may lead to
intermediate D3 from A3 directly (path c). Dyotropic
rearrangement of the five-membered intermediate B3 to six-
membered ring intermediate D3 (path d) is also possible.19
The reaction paths were examined using model compounds
(the corresponding methyl esters and Al2Cl6). Only path a has
been obtained by the model calculations.20,21 The TS energies
of TS4 and TS5 are lower than the five-membered ring
formation TS3. Six-membered ring intermediate D3 may form
intermediate D′3 by removal of catalytic AlCl3. Intermediate
D′3 is slightly more stable than the five-membered
intermediate B′3, which may be formed from B3. Protonation
of the intermediate D′3 yields the product 19. The six-
membered diastereomers, E3 and E′3, which may be formed
reversibly, are thermodynamically less stable than D3 and D′3,
respectively, as discussed above. Further synthetic application
and detailed mechanistic study for the six-membered ring
formation are under investigation. Thus, for some alkyl-
substituted substrates, cationic intermediates may be formed
under the reaction conditions, and rearranged products have
been obtained.22
distance (1.586 Å) than that of 1m + AlCl3 (1.502 Å), which
shows the ion pair character of 14m + AlCl3.
Interestingly, the reaction of 18 with AlCl3 (1 equiv) gave
5-chloro-5-methyl-2-oxotetrahydro-2H-pyran 19 as an isolable
major product (eq 10). The δ-lactam structure of 19 was
In summary, a Lewis acid-promoted reaction of alkenyl
ethenetricarboxylates and the corresponding amides to give 3,4-
trans-halogenomethyl 2-oxotetrahydrofuran and pyrrolidine
derivatives has been found. The reaction proceeds stereo-
selectively. Strong Lewis acids such as TiCl4 and AlCl3 work
efficiently. The highly functionalized and halogenated five-
membered heterocyclic compounds generated in this reaction
should be useful synthetic intermediates. Studies of the detailed
reaction mechanism and transformations of the functionalized
cyclic compounds are under investigation.
EXPERIMENTAL SECTION
■
General Methods. 1H chemical shifts are reported in ppm relative
to Me4Si. 13C chemical shifts are reported in ppm relative to CDCl3
(77.1 ppm). 13C mutiplicities were determined by DEPT and HSQC.
Peak assignments are made by 2D COSY, HSQC, NOESY, and
HMBC spectra.
suggested by the observed CO absorptions (1738 cm−1
1
together with ethyl esters). H, 13C and 2D NMR spectra
were in agreement with the six-membered ring structure.
Assuming the stable C-3 equatorial (CH(CO2Et)2) conforma-
tion and the absence of NOE peaks between H-3 (axial) and 5-
CH3 suggest the stereochemistry of 19 as shown in eq 10. Use
of FeCl3 or TiCl4 also gave compound 19 in lower yield with a
complex mixture. The reaction of 18 with TiCl4 (1 equiv) at
−40 °C for 20 h gave the noncyclized Cl-adduct 20 in 42%
yield as a major product (eq 11), similar to the reaction of 1.
Treatment of 19 with AlCl3 (1 equiv) at room temperature
gave 20 in 50% yield.
Formation of 19 could be considered as follows (Scheme 4).
The first cyclization to give the five-membered ring
intermediate B3 may occur by kinetically favored process,
similar to Scheme 1. Alkyl group migration of B3 may lead to
Ethenetricarboxylate 1 was prepared according to the literature.10a
6b was prepared according to the literature.23
Ethenetricarboxylates 5, 6a, 12, 14, 15, 17 and 18 were prepared by
the reaction of diethyl ketomalonate with the corresponding
(triphenylphosphoranylidne)acetate according to the literature
procedure.10a,17 These (triphenylphosphoranylidne)acetate esters
were prepared by the corresponding chloroacetates and triphenyl-
phosphine in benezene and subsequent treatment with NaOH. The
chloroacetates were preprared by the reaction of the corresponding
alcohols (1 equiv) and chloroacetyl chloride (1 equiv) in the presence
of pyridine (1 equiv) in ether at 0 °C. Data of the ethenetricarbox-
ylates and chloroacetates for new (triphenylphosphoranylidne)acetate
esters are shown below.
3-Butenyl 2-chloroacetate. (69.3 mmol scale, 9.14 g, 89%);
colorless oil: bp 81−82 °C/4.2 mmHg; 1H NMR (400 MHz, CDCl3)
E
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a
Scheme 4. Proposed Mechanism for Formation of 19 from 18
a
Proposed reaction mechanism for cyclization of 18 (R = Et) and model compound 18m (R = Me) with Al2Cl6 and the B3LYP/6-31G* calculated
Gibbs free energies (T = 298.15 K and P = 1 atm) for intermediates and TS of the model compounds (18m + Al2Cl6). The B3LYP/6-31G*
calculated Gibbs free energies { } for B′3, D′3 and E′3 are relative to B′3.
δ (ppm) 2.43 (tddd, J = 6.8, 6.8, 1.4, 1.4 Hz, 2H), 4.07 (s, 2H), 4.25 (t,
J = 6.8 Hz, 2H), 5.10 (ddt, J = 10.3, 1.6, 1.3 Hz, 1H), 5.13 (ddt, J =
17.0, 1.6, 1.6 Hz, 1H), 5.78 (ddt, J = 17.0, 10.3, 6.8 Hz, 1H); 13C NMR
(100.6 MHz, CDCl3) δ (ppm) 32.9 (t), 40.9 (t), 65.2 (t), 117.7 (t),
133.4 (d), 167.4 (s); IR (neat) 3081, 2962, 1759, 1643, 1415, 1313,
1290, 1183, 989, 922 cm−1; MS (CI) m/z 151 ([M + 1]+, 35), 149
([M + 1]+, 100%); HRMS [M + 1]+ 149.0372, 151.0337 (calcd for
C6H10ClO2 [M + 1]+ 149.0369, 151.0340). Anal. Calcd for C6H9ClO2:
C, 48.50; H, 6.11. Found: C, 48.57; H, 6.20.
(ppm) 13.9 (q), 14.0 (q), 32.8 (t), 62.1 (t), 62.5 (t), 64.8 (t), 117.7
(t), 129.9 (d), 133.4 (d), 139.1 (s), 162.3 (s), 163.6 (s), 164.3 (s); IR
(neat) 2984, 1726, 1644, 1467, 1373, 1346, 1258, 1182, 1067, 1024
cm−1; MS (CI) m/z 271 ([M + 1]+); HRMS 271.1187 (calcd for
C13H19O6 [M + 1]+ 271.1182). Anal. Calcd for C13H18O6: C, 57.77; H,
6.71. Found: C, 57.60; H, 6.90.
1-((E)-2-Butenyl) 2,2-diethyl ethene-1,2,2-tricarboxylate
(6a). (15 mmol scale, 2.90 g, 72%); colorless oil: 1H NMR (400
MHz, CDCl3) δ (ppm) 1.32 (t, J = 7.1 Hz, 3H), 1.35 (t, J = 7.1 Hz,
3H), 1.73 (bd, J = 6.4 Hz, 3H), 4.30 (q, J = 7.1 Hz, 2H), 4.36 (q, J =
7.1 Hz, 2H), 4.61 (d-like, J = 6.6 Hz, 2H), 5.59 (dtq, J = 15.0, 6.6, 1.6
Hz, 1H), 5.83 (dqt, J = 15.1, 6.4, 1.1 Hz, 1H), 6.87 (s, 1H); 13C NMR
(100.6 MHz, CDCl3) δ (ppm) 13.95 (q), 14.01 (q), 17.8 (q), 62.1 (t),
62.5 (t), 66.5 (t), 124.2 (d), 130.0 (d), 132.7 (d), 139.1 (s), 162.3 (s),
163.4 (s), 164.3 (s); IR (neat) 2984, 1726, 1650, 1447, 1372, 1345,
1257, 1179, 1067, 1022, 969 cm−1; MS (CI) m/z 271 ([M + 1]+);
1-(3-Butenyl) 2,2-diethyl ethene-1,2,2-tricarboxylate (5).
1
(16.3 mmol scale, 2.88 g, 65%); colorless oil: H NMR (400 MHz,
CDCl3) δ (ppm) 1.32 (t, J = 7.1 Hz, 3H), 1.36 (t, J = 7.1 Hz, 3H),
2.43 (tddd, J = 6.8, 6.8, 1.4, 1.4 Hz, 2H), 4.24 (t, J = 6.8 Hz, 2H), 4.30
(q, J = 7.1 Hz, 2H), 4.38 (q, J = 7.1 Hz, 2H), 5.10 (ddt, J = 10.3, 1.6,
1.1 Hz, 1H), 5.13 (ddt, J = 17.0, 1.6, 1.6 Hz, 1H), 5.78 (ddt, J = 17.0,
10.3, 6.8 Hz, 1H), 6.87 (s, 1H); 13C NMR (100.6 MHz, CDCl3) δ
F
dx.doi.org/10.1021/jo401106m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
HRMS [M + 1]+ 271.1180 (calcd for C13H19O6 [M + 1]+ 271.1182).
Anal. Calcd for C13H18O6: C, 57.77; H, 6.71. Found: C, 57.70; H, 6.82.
3-Buten-2-yl 2-chloroacetate. (30.4 mmol scale, 4.25 g, 94%);
colorless oil: bp 65−66 °C/4.2 mmHg; 1H NMR (400 MHz, CDCl3)
δ (ppm) 1.37 (d, J = 6.6 Hz, 3H), 4.06 (s, 2H), 5.19 (ddd, J = 10.4,
1.2, 1.2 Hz, 1H), 5.30 (ddd, J = 17.2, 1.2, 1.2 Hz, 1H), 5.42 (qddd, J =
6.6, 6.0, 1.2, 1.2 Hz, 1H), 5.85 (ddd, J = 17.2, 10.4, 6.0 Hz, 1H); 13C
NMR (100.6 MHz, CDCl3) δ (ppm) 19.8 (q), 41.1 (t), 73.2 (d),
116.8 (t), 136.7 (d), 166.5 (s); IR (neat) 3091, 2987, 1753, 1647,
1452, 1414, 1288, 1187, 1138, 1044, 992, 953 cm−1; MS (CI) m/z 151
([M + 1]+, 30), 149 ([M + 1]+, 100%); HRMS [M + 1]+ 149.0358,
151.0307 (calcd for C6H10ClO2 [M + 1]+ 149.0369, 151.0340). Anal.
Calcd for C6H9ClO2: C, 48.50; H, 6.11. Found: C, 48.42; H, 6.21.
1-(3-Buten-2-yl) 2,2-diethyl ethene-1,2,2-tricarboxylate (12).
1,1-Diethyl 2-(2-methyl-2-propenyl) ethene-1,1,2-tricarbox-
ylate (18). (16 mmol scale, 3.47 g, 80%); colorless oil: 1H NMR (400
MHz, CDCl3) δ (ppm) 1.33 (t, J = 7.1 Hz, 3H), 1.34 (t, J = 7.1 Hz,
3H), 1.77 (bs, 3H), 4.31 (q, J = 7.1 Hz, 2H), 4.36 (q, J = 7.1 Hz, 2H),
4.61 (s, 2H), 4.97 (qt, J = 0.7, 0.7 Hz, 1H), 5.01 (bs, 1H), 6.91 (s,
1H); 13C NMR (100.6 MHz, CDCl3) δ (ppm) 13.9 (q), 14.0 (q), 19.5
(q), 62.2 (t), 62.6 (t), 69.1 (t), 114.1 (t), 129.8 (d), 139.0 (s), 139.3
(s), 162.3 (s), 163.3 (s), 164.3 (s); IR (neat) 2984, 1728, 1656, 1447,
1375, 1345, 1258, 1179, 1067, 1022 cm−1; MS (CI) m/z 271 ([M +
1]+); HRMS [M + 1]+ 271.1176 (calcd for C13H19O6 [M + 1]+
271.1182).
Typical Experimental Procedure (eq 3, Table 1, entry 6). To a
solution of 1 (128 mg, 0.5 mmol) in CH2Cl2 (2 mL) was TiCl4 (190
mg, 110 μL, 0.1 mmol). The mixture was stirred at room temperature
for 17 h. The reaction mixture was quenched by water and then
saturated aqueous NaHCO3. The mixture was extracted with
dichloromethane, and the organic phase was dried (Na2SO4) and
evaporated in vacuo to give 2a (134 mg, 90%).
1
(18.2 mmol scale, 3.07 g, 62%); colorless oil: H NMR (400 MHz,
CDCl3) δ (ppm) 1.32 (t, J = 7.1 Hz, 3H), 1.35 (t, J = 7.1 Hz, 3H),
1.36 (d, J = 6.4 Hz, 3H), 4.30 (q, J = 7.1 Hz, 2H), 4.36 (q, J = 7.1 Hz,
2H), 5.18 (ddd, J = 10.6, 1.2, 1.2 Hz, 1H), 5.28 (ddd, J = 17.2, 1.2, 1.2
Hz, 1H), 5.43 (qddd, J = 6.4, 6.0, 1.2, 1.2 Hz, 1H), 5.84 (ddd, J = 17.2,
10.6, 6.0, 1H), 6.87 (s, 1H); 13C NMR (100.6 MHz, CDCl3) δδ
(ppm) 13.96 (q), 14.03 (q), 19.8 (q), 62.1 (t), 62.5 (t), 72.8 (d),
116.8 (t), 130.3 (d), 136.7 (d), 138.9 (s), 162.4 (s), 162.8 (s), 164.3
(s); IR (neat) 2983, 1735, 1725, 1647, 1448, 1375, 1260, 1184, 1066
cm−1; MS (CI) m/z 271 ([M + 1]+); HRMS [M + 1]+ 271.1189
(calcd for C13H19O6 [M + 1]+ 271.1182). Anal. Calcd for C13H18O6:
C, 57.77; H, 6.71. Found: C, 57.52; H, 6.78.
2-Methyl-3-buten-2-yl 2-chloroacetate. (30.4 mmol scale, 3.73
g, 75%); colorless oil: bp 95−105 °C/53 mmHg; 1H NMR (400 MHz,
CDCl3) δ (ppm) 1.57 (s, 6H), 3.99 (s, 2H), 5.13 (dd, J = 10.9, 0.6 Hz,
1H), 5.23 (dd, J = 17.5, 0.6 Hz, 1H), 6.08 (dd, J = 17.5, 10.9 Hz, 1H);
13C NMR (100.6 MHz, CDCl3) δ (ppm) 26.3 (q), 41.9 (t), 83.3 (s),
113.8 (t), 141.5 (d), 166.0 (s); IR (neat) 2985, 1754, 1414, 1382,
1367, 1314, 1199, 1123 cm−1; MS (EI) m/z 165 ([M + 1]+, 39), 163
([M + 1]+, 100%); HRMS [M + 1]+ 163.0527 (calcd for C7H12ClO2
[M + 1]+ 163.0526), M+ 162.0452 (calcd for C7H11ClO2 M+
162.0448).
1,1-Diethyl 2-(2-methyl-3-buten-2-yl) ethene-1,1,2-tricar-
boxylate (14). (11.8 mmol scale, 1.39 g, 41%); colorless oil: 1H
NMR (400 MHz, CDCl3) δδ (ppm) 1.31 (t, J = 7.1 Hz, 3H), 1.34 (t, J
= 7.1 Hz, 3H), 1.56 (s, 6H), 4.29 (q, J = 7.1 Hz, 2H), 4.35 (q, J = 7.1
Hz, 2H), 5.12 (dd, J = 10.9, 0.7 Hz, 1H), 5.21 (dd, J = 17.4, 0.5 Hz,
1H), 6.08 (dd, J = 17.4, 10.9 Hz, 1H), 6.82 (s, 1H); 13C NMR (100.6
MHz, CDCl3) δ (ppm) 13.96 (q), 14.04 (q), 26.3 (q), 62.0 (t), 62.4
(t), 83.1 (s), 113.7 (t), 131.8 (d), 137.9 (s), 141.5 (d), 162.4 (s), 162.6
(s), 164.3 (s); IR (neat) 2984, 1725−1742, 1645, 1468, 1447, 1376,
1349, 1265, 1188, 1126, 1066, 1023 cm−1; MS (Ei) m/z 284 (M+, 0.4),
200 (42), 154 (68), 143 (80), 69 (100%); HRMS M+ 284.1261 (calcd
for C14H20O6 M+ 284.1260).
Diethyl 2-(trans-4-(chloromethyl)-2-oxotetrahydrofuran-3-
yl)malonate (2a). Colorless oil: 1H NMR (400 MHz, CDCl3) δ
(ppm) 1.29 (t, J = 7.1 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H), 3.09 (dd, J =
8.4, 4.1, 1H), 3.20 (ddddd, J = 8.7, 8.4, 7.1, 6.2, 4.0 Hz, 1H), 3.66 (dd,
J = 11.4, 6.2 Hz, 1H), 3.72 (dd, J = 11.4, 4.0 Hz, 1H), 4.06 (d, J = 4.1
Hz, 1H), 4.20 (dd, J = 9.2, 7.1 Hz, 1H), 4.21−4.33 (m, 4H), 4.55 (dd,
J = 9.2, 8.7 Hz, 1H); Selected NOEs are between δ 3.09 (H-3) and δ
3.66, 3.72 (CH2Cl) and between δ 3.20 (H-4) and δ 4.06
(CH(CO2Et)2), 4.55 (H-5b); 13C NMR (100.6 MHz, CDCl3) δ
(ppm) 13.97 (q), 14.01 (q), 39.3 (d), 42.0 (d), 45.5 (t), 50.9 (d),
62.31 (t), 62.32 (t), 69.5 (t), 167.3 (s), 167.8 (s), 175.8 (s); Selected
HMBC correlations are between δ 3.09 (H-3) and δ 45.5 (CH2Cl),
50.9 CH(CO2Et)2), 39.3 (C-4), between δ 3.20 (H-4) and δ 42.0 (C-
3), and between δ 4.20, 4.55 (H-5a,5b) and δ 45.5 (CH2Cl), 39.3 (C-
4); IR (neat) 2984, 1777, 1734, 1446, 1393, 1373, 1256, 1183, 1096,
1028 cm−1; MS (EI) m/z 294 (M+, 36%), 292 (M+, 100%); HRMS M+
292.0720, 294.0706 (calcd for C12H17ClO6 292.0714, 294.0684).
Diethyl 2-(trans-4-(bromomethyl)-2-oxotetrahydrofuran-3-
yl)malonate (2b). (Table 1, entry 3, 1 mmol scale, 193 mg, 57%);
1
colorless oil: H NMR (400 MHz, CDCl3) δ (ppm) 1.29 (t, J = 7.1
Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H), 3.07 (dd, J = 8.6, 4.2, 1H), 3.17
(ddddd, J = 8.6, 8.5, 7.3, 6.8, 3.8 Hz, 1H), 3.51 (dd, J = 10.6, 6.8 Hz,
1H), 3.60 (dd, J = 10.6, 3.8 Hz, 1H), 4.05 (d, J = 4.0 Hz, 1H), 4.15
(dd, J = 9.3, 7.3 Hz, 1H), 4.20−4.33 (m, 4H), 4.54 (dd, J = 9.3, 8.5 Hz,
1H); Selected NOEs are between δ 3.07 (H-3) and δ 3.51, 3.60
(CH2Br), between δ 3.17 (H-4) and δ 4.05 (CH(CO2Et)2), 4.54 (H-
5b), and between δ 4.15 (H-5a) and δ 3.51, 3.60 (CH2Br); 13C NMR
(100.6 MHz, CDCl3) δ (ppm) 13.9 (q), 14.0 (q), 34.5 (t), 39.0 (d),
43.4 (d), 50.8 (d), 62.3 (t × 2), 70.6 (t), 167.2 (s), 167.7 (s), 175.7
(s); Selected HMBC correlations are between δ 3.07 (H-3) and δ 34.5
(CH2Br), 50.8 CH(CO2Et)2), 39.0 (C-4), between δ 3.51, 3.60
(CH2Br) and δ 43.4 (C-3), 39.0 (C-4), and between δ 4.15, 4.54 (H-
5a,b) and δ 34.5 (CH2Br), 39.0 (C-4); IR (neat) 2983, 1779, 1740,
1475, 1446, 1391, 1373, 1234, 1183, 1029 cm−1; MS (EI) m/z 338
(M+, 100%), 336 (M+, 100%); HRMS M+ 336.0204, 338.0175 (calcd
for C12H17BrO6 336.0209, 338.0188).
3: (2 equiv of ZnI2, rt, 0.5 mmol scale, 81 mg, 59%); colorless oil;
1H NMR (400 MHz, CDCl3) δ (ppm) 1.28 (t, J = 7.1 Hz, 3H), 1.30
(t, J = 7.1 Hz, 3H), 3.33 (bs, 1H), 3.96 (d, J = 4.2 Hz, 1H), 4.21−4.30
(m, 4H), 4.699 (ddd, J = 5.9, 1.3, 1.3 Hz, 1H), 4.702 (ddd, J = 5.9, 1.3,
1.3 Hz, 1H), 4.76 (d, J = 4.2 Hz, 1H), 5.27 (dddd, J = 10.4, 1.2, 1.2, 1.2
Hz, 1H), 5.35 (dddd, J = 17.2, 1.5, 1.5, 1.5 Hz, 1H), 5.91 (dddd, J =
17.2, 10.4, 5.9, 5.9 Hz, 1H); 13C NMR (100.6 MHz, CDCl3) δ (ppm)
14.00 (q), 14.04 (q), 55.2 (d), 62.0 (t), 62.1 (t), 66.7 (t), 69.7 (d),
119.3 (t), 131.3 (d), 167.0 (s), 167.2 (s), 171.5 (s); IR (neat) 3501,
2986, 1739, 1651, 1466, 1448, 1372, 1260, 1177, 1031 cm−1; MS (EI)
m/z 275 ([M + 1]+, 14), 201 (50), 189 (100%); HRMS [M + 1]+
275.1129 (calcd for C12H19O7 [M + 1]+ 275.1131). Anal. Calcd for
C12H18O7: C, 52.55; H, 6.62. Found: C, 52.26; H, 6.80.
1,1-Diethyl 2-(3-methylbut-2-enyl) ethene-1,1,2-tricarboxy-
1
late (17). (14.9 mmol scale, 2.32 g, 55%); pale yellow oil: H NMR
(400 MHz, CDCl3) δ (ppm) 1.32 (t, J = 7.1 Hz, 3H), 1.35 (t, J = 7.1
Hz, 3H), 1.72 (narrow multiplet, 3H), 1.77 (narrow multiplet, 3H),
4.30 (q, J = 7.1 Hz, 2H), 4.36 (q, J = 7.1 Hz, 2H), 4.68 (bd, J = 7.5 Hz,
2H), 5.35 (tqq, J = 7.5, 1.4, 1.4 Hz, 1H), 6.87 (s, 1H); 13C NMR
(100.6 MHz, CDCl3) δ (ppm) 13.9 (q), 14.0 (q), 18.1 (q), 25.8 (q),
62.1 (t), 62.5 (t), 62.6 (t), 117.6 (d), 130.2 (d), 138.9 (s), 140.5 (s),
162.4 (s), 163.6 (s), 164.4 (s); IR (neat) 2983, 1725, 1648, 1466,
1447, 1377, 1348, 1258, 1178, 1066, 1022 cm−1; MS (EI) m/z 284
(M+, 14), 238 (43), 217 (100%); HRMS M+ 284.1264 (calcd for
C14H20O6 M+ 284.1260).
2-Methyl-2-propenyl 2-chloroacetate. (30.4 mmol scale, 4.30
g, 95%); colorless oil: bp 60−70 °C/5.1 mmHg; 1H NMR (400 MHz,
CDCl3) δ (ppm) 1.78 (narrow multiplet, 3H), 4.11 (s, 2H), 4.61 (bs,
2H), 4.98 (narrow multiplet, 1H), 5.02 (narrow multiplet, 1H); 13C
NMR (100.6 MHz, CDCl3) δ (ppm) 19.4 (q), 40.8 (d), 69.3 (d),
113.9 (d), 139.1 (s), 167.0 (s); IR (neat) 3085, 2951, 1762, 1660,
1452, 1413, 1312, 1171, 1031, 998 cm−1; MS (EI) m/z 150 (M+, 4.8),
148 (M+, 14), 77 (36), 72 (100%); HRMS M+ 148.0291, 150.0263
(calcd for C6H9ClO2 M+ 148.0291, 150.0262).
4: (2 equiv of TiCl4, −40 °C, 0.5 mmol scale, 113 mg, 77%);
compound 4 is unstable to column chromatography (SiO2) and partial
decomposition of 4 to starting material 1 was observed; colorless oil;
G
dx.doi.org/10.1021/jo401106m | J. Org. Chem. XXXX, XXX, XXX−XXX

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1H NMR (400 MHz, CDCl3) δ (ppm) 1.26 (t, J = 7.1 Hz, 3H), 1.31
5.70−5.84 (m, 1H), 7.27 (s, 1H × 0.55), 7.34 (s, 1H × 0.45); 13C
NMR (100.6 MHz, CDCl3) δ (ppm) 14.0 (q), 14.05 (q), 14.08 (q),
33.3 (q), 35.0 (q), 49.8 (t), 52.7 (t), 61.87 (t), 61.90 (t), 62.2 (t),
118.0 (t), 118.3 (t), 132.0 (d), 132.1 (d), 134.2 (d), 134.4 (s), 134.8
(d), 135.0 (s), 163.07 (s), 163.11 (s), 163.9 (s), 164.3 (s), 164.5 (s),
164.6 (s); IR (neat) 2986, 1734, 1657, 1468, 1448, 1408, 1375, 1257,
1069, 1023 cm−1; MS (EI) m/z 269 (M+, 17), 224 (36), 200 (86), 154
(100%); HRMS 269.1267 (calcd for C13H19NO5 M+ 269.1263).
8b: (3 mmol scale, 523 mg, 59%); colorless oil; 1H NMR (400 MHz,
CDCl3) δ (ppm) 1.31 (t, J = 7.1, 3H) 1.32 (t, J = 7.1 Hz, 3H), 3.93
(ddd, J = 5.1, 1.7, 1.7 Hz, 2H), 4.03 (ddd, J = 6.0, 1.3, 1.3 Hz, 2H),
4.29 (q, J = 7.1 Hz, 2H), 4.33 (q, J = 7.1 Hz, 2H), 5.16−5.28 (m, 4H),
5.71−5.83 (m, 2H), 7.27 (s, 1H); 13C NMR (100.6 MHz, CDCl3) δ
(ppm) 13.9 (q), 14.0 (q), 47.7 (t), 49.6 (t), 61.8 (t), 62.2 (t), 117.9
(t), 118.2 (t), 132.2 (d), 132.3 (d), 134.2 (d), 135.1 (s), 163.0 (s),
164.0 (s), 164.5 (s); IR (neat) 2984, 1733, 1655, 1466, 1445, 1417,
1374, 1256, 1206, 1069 cm−1; MS (EI) m/z 295 (M+); HRMS
295.1422 (calcd for C15H21NO5 M+ 295.1420).
(t, J = 7.1 Hz, 3H), 4.01 (d, J = 10.3 Hz, 1H), 4.17−4.31 (m, 4H),
4.700 (ddd, J = 5.8, 1.2, 1.2 Hz, 1H), 4.703 (ddd, J = 5.8, 1.2, 1.2 Hz,
1H), 4.82 (d, J = 10.3 Hz, 1H), 5.29 (dddd, J = 10.6, 1.2, 1.2, 1.2 Hz,
1H), 5.39 (dddd, J = 17.2, 1.5, 1.5, 1.5 Hz, 1H), 5.93 (dddd, J = 17.2,
10.6, 5.8, 5.8 Hz, 1H); 13C NMR (100.6 MHz, CDCl3) δ (ppm) 14.0
(q), 14.1 (q), 52.7 (d), 56.4 (d), 62.4 (t), 62.5 (t), 66.9 (t), 119.2 (t),
131.0 (d), 165.6 (s), 166.0 (s), 167.5 (s); IR (neat) 2985, 1741, 1650,
1447, 1306, 1166, 1096, 1029 cm−1; MS (EI) m/z 294 (M+, 36), 292
(100%); HRMS M+ 292.0717, 294.0706 (calcd for C12H17ClO6 M+
292.0714, 294.0684).
Diethyl 2-(trans-4-(1-chloroethyl)-2-oxotetrahydrofuran-3-
yl)malonate (7a). (1 equiv of FeCl3, 1.05 mmol scale, 285 mg,
80%); including a small amount of impurity, possibly containing ene
5
1
adduct; colorless oil: H NMR (400 MHz, CDCl3) δ (ppm) 1.28 (t,
J = 7.1 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H), 1.49 (d, J = 6.8 Hz, 3H), 3.09
(dddd, J = 9.0, 8.0, 6.8, 3.1 Hz, 1H), 3.19 (dd, J = 8.0, 3.9 Hz, 1H),
4.07 (d, J = 3.9 Hz, 1H), 4.19−4.32 (m, 5H), 4.37 (dd, J = 9.2, 6.8 Hz,
1H), 4.48 (dd, J = 9.2, 9.0 Hz, 1H); Selected NOEs are between δ 3.19
(H-3) and δ 1.49 (CHCH3Cl), 4.19−4.32 (CHCH3Cl, overlapped),
between δ 3.09 (H-4) and δ 4.07 (CH(CO2Et)2), 4.48 (H-5b); 13C
NMR (100.6 MHz, CDCl3) δ (ppm) 14.0 (q), 14.1 (q), 23.0 (q), 42.4
(d), 44.1 (d), 51.0 (d), 58.7 (d), 62.30 (t), 62.33 (t), 67.1 (t), 167.5
(s), 168.0 (s), 176.1 (s); Selected HMBC correlations are between δ
3.19 (H-3) and δ 51.0 CH(CO2Et)2), 44.1 (C-4), between δ 3.09 (H-
4) and δ 42.4 (C-3), 51.0 (CH(CO2Et)2), 58.7 (CHCH3Cl), 67.1 (C-
5), and between δ 4.37, 4.48 (H-5a,b) and δ 58.7 (CHCH3Cl), 44.1
(C-4); IR (neat) 2984, 1777, 1733, 1467, 1446, 1373, 1265, 1182,
1033 cm−1; MS (CI) m/z 309 ([M + 1]+, 36%), 307 ([M + 1]+,
100%); HRMS [M + 1]+ 307.0954, 309.0949 (calcd for C13H20ClO6
307.0948, 309.0919).
N-Allylpropylamine was prepared by reaction of propylamine with
allylbromide in ethanol according to the literature procedure.24
8c: (3 mmol scale, 741 mg, 83%); colorless oil; 1H NMR (400 MHz,
CDCl3) (2 rotamers, ratio 1:1) δ (ppm) 0.90 (t, J = 7.2, 3H × 0.5),
0.92 (t, J = 7.1 Hz, 3H × 0.5), 1.29−1.34 (m, 6H), 1.54−1.66 (m,
2H), 3.26 (dd, J = 7.6, 7.6 Hz, 2H × 0.5), 3.21−3.36 (m, 2H × 0.5),
3.94 (ddd, J = 4.9, 1.6, 1.6 Hz, 2H × 0.5), 4.03 (ddd, J = 6.0, 1.4, 1.4
Hz, 2H × 0.5), 4.26−4.36 (m, 4H), 5.16−5.27 (m, 2H), 5.72−5.85
(m, 1H), 7.26 (s, 1H × 0.5), 7.34 (s, 1H × 0.5); 13C NMR (100.6
MHz, CDCl3) δ (ppm) 11.2 (q), 11.4 (q), 14.0 (q), 14.1 (q), 20.7 (t),
22.2 (t), 47.6 (t), 47.9 (t), 49.4 (t), 50.7 (t), 61.9 (t), 62.17 (t), 62.23
(t), 117.7 (t), 117.8 (t), 132.6 (d), 132.7 (d), 134.2 (d), 134.6 (d),
134.7 (s), 135.0 (s), 163.1 (s), 163.2 (s), 163.7 (s), 164.1 (s), 164.7
(s); IR (neat) 2984, 1731, 1650, 1466, 1375, 1257, 1212, 1069 cm−1;
MS (EI) m/z 297 (M+, 0.5), 273 (4.7), 257 (70), 227 (75), 183 (74),
160 (100%); HRMS 297.1576 (calcd for C15H23NO5 M+ 297.1576).
Typical Experimental Procedure (eq 5, Table 2, entry 1). To a
solution of 8a (135 mg, 0.5 mmol) in CH2Cl2 (1 mL) was TiCl4 (95 mg,
55 μL, 0.5 mmol). The mixture was stirred at room temperature for 17
h. The reaction mixture was quenched by water and then saturated
aqueous NaHCO3. The mixture was extracted with dichloromethane,
and the organic phase was dried (Na2SO4), and evaporated in vacuo.
The residue was purified by column chromatography over silica gel
with hexane−ether (1:4) as eluent to give 9a (150 mg, 98%).
Diethyl 2-(trans-4-(chloromethyl)-1-methyl-2-oxopyrrolidin-
Dimethyl 2-(trans-4-(1-chloroethyl)-2-oxotetrahydrofuran-
3-yl)malonate (7b). (eq 4, 0.54 mmol scale, 78 mg, 52%); pale
yellow oil: 1H NMR (400 MHz, CDCl3) δ (ppm) 1.50 (d, J = 6.8 Hz,
3H), 3.07 (dddd, J = 8.9, 8.1, 6.8, 3.2 Hz, 1H), 3.20 (dd, J = 8.1, 3.9
Hz, 1H), 3.78 (s, 3H), 3.82 (s, 3H), 4.11 (d, J = 3.9 Hz, 1H), 4.27 (qd,
J = 6.8, 3.2 Hz, 1H), 4.36 (dd, J = 9.1, 6.8 Hz, 1H), 4.48 (dd, J = 9.1,
8.9 Hz, 1H); Selected NOEs are between δ 3.20 (H-3) and δ 1.50
(CHCH3Cl), 4.27 (CHCH3Cl), between δ 3.07 (H-4) and δ 4.11
(CH(CO2Me)2), 4.48 (H-5b); 13C NMR (100.6 MHz, CDCl3) δ
(ppm) 23.0 (q), 42.4 (d), 44.2 (d), 50.7 (d), 53.1 (q), 53.2 (q), 58.6
(d), 67.2 (t), 167.9 (s), 168.4 (s), 175.9 (s); Selected HMBC
correlations are between δ 3.20 (H-3) and δ 58.6 (CHCH3Cl), 44.2
(C-4), between δ 3.07 (H-4) and δ 42.4 (C-3), and between δ 4.36,
4.48 (H-5a,b) and δ 58.6 (CHCH3Cl); IR (neat) 2957, 1779, 1742,
1436, 1359, 1197, 1163, 1035 cm−1; MS (EI) m/z 281 ([M + 1]+, 6.9),
279 ([M + 1]+, 22), 85 (93), 83 (100%); HRMS M+ 278.0556 (calcd
for C11H15ClO6 278.0557).
1
3-yl)malonate (9a). Colorless oil: H NMR (400 MHz, CDCl3) δ
(ppm) 1.26 (t, J = 7.1 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H), 2.87 (s, 3H),
2.89−2.99 (m, 2H), 3.29 (dd, J = 9.8, 5.2 Hz, 1H), 3.56 (dd, J = 9.8,
9.8 Hz, 1H), 3.58 (dd, J = 11.0, 6.8 Hz, 1H), 3.72 (dd, J = 11.0, 3.9 Hz,
1H), 4.05 (d, J = 4.0 Hz, 1H), 4.13−4.30 (m, 4H); 13C NMR (100.6
MHz, CDCl3) δ (ppm) 14.0 (q), 14.1 (q), 29.9 (q), 36.1 (d), 44.8 (d),
47.5 (t), 51.3 (d), 51.7 (t), 61.8 (t), 61.9 (t), 167.9 (s), 168.6 (s),
172.2 (s); Selected HMBC correlations are between δ 4.05
(CH(CO2Et)2) and δ 44.8 (C-3), 36.1 (C-4), between δ 3.58, 3.72
(CH2Cl) and δ 36.1 (C-4), 44.8 (C-3), and between δ 3.29, 3.56 (H-5)
and δ 47.5 (CH2Cl), 36.1 (C-4); 1H NMR (400 MHz, C6D6) δ (ppm)
0.863 (t, J = 7.1 Hz, 3H), 0.912 (t, J = 7.1 Hz, 3H), 2.45 (d, J = 0.7 Hz,
3H), 2.59 (dd, J = 9.6, 5.8 Hz, 1H), 2.73 (dd, J = 7.5, 4.5 Hz, 1H), 2.85
(ddddd, J = 9.1, 8.2, 7.5, 5.8, 3.8 Hz, 1H), 2.96 (dd, J = 10.1, 8.2 Hz,
1H), 3.00 (dd, J = 9.6, 9.1 Hz, 1H), 3.26 (dd, J = 10.1, 3.8 Hz, 1H),
3.80−3.97 (m, 4H), 4.21 (d, J = 4.5 Hz, 1H); Selected NOEs are
between δ 2.73 (H-3) and δ 2.96, 3.26 (CH2Cl) and between δ 2.85
(H-4) and δ 4.21 (CH(CO2Et)2); 13C NMR (100.6 MHz, C6D6) δ
(ppm) 13.8 (q), 13.9 (q), 29.3 (q), 36.3 (d), 36.8 (t), 46.3 (d), 51.6
(d), 52.4 (t), 61.5 (t), 61.6 (t), 168.0 (s), 168.7 (s), 171.6 (s); IR
(neat) 2986, 2942, 1738, 1688, 1504, 1448, 1375, 1272, 1178, 1100,
1033 cm−1; MS (EI) m/z 307 (M+, 29), 305 (M+, 80), 260 (43), 256
(100%); HRMS M+ 305.1037, 307.1010 (calcd for C13H20ClNO5
305.1030, 307.1001).
Preparation of Substrates 8a−c. To a solution of 1,1-diethyl 2-
hydrogen ethenetricarboxylate (649 mg, 3 mmol) (prepared from 1,1-
diethyl 2-tert-butyl ethenetricarboxylate upon treatment with
CF3CO2H) in THF (4.1 mL) were added N-allylmethylamine (0.29
mL, 213 mg, 3 mmol), Et3N (0.42 mL, 304 mg, 3 mmol), HOBt (1-
hydroxybenzotriazole) (811 mg, 6 mmol) and EDCI (1-[3-
(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride) (598
mg, 3.1 mmol) at 0 °C. The reaction mixture was stirred for 1 h at
0 °C and was allowed to warm to room temperature and stirred
overnight. The reaction mixture was concentrated under reduced
pressure, and the residue was diluted with CH2Cl2. The organic phase
was washed with saturated aqueous NaHCO3 solution, 2 M aqueous
citric acid, saturated aqueous NaHCO3 and water, dried (Na2SO4),
and evaporated in vacuo. The residue was purified by column
chromatography over silica gel eluting with hexane−ether (1:3) to give
8a (718 mg, 89%).
8a: pale yellow oil; 1H NMR (400 MHz, CDCl3) (2 rotamers, ratio
1.2:1) δ (ppm) 1.31 (t, J = 7.1, 3H × 0.55, major rotamer) 1.320 (t, J =
7.1 Hz, 3H × 0.45, minor rotamer), 1.323 (t, J = 7.1 Hz, 3H × 0.45),
1.33 (t, J = 7.1 Hz, 3H × 0.55), 2.98 (s, 3H × 0.55), 3.00 (s, 3H ×
0.45), 3.95 (ddd, J = 5.1, 1.6, 1.6 Hz, 2H × 0.55), 4.04 (ddd, J = 6.0,
1.4, 1.4, 2H × 0.45), 4.26−4.37 (m, 4H), 5.19−5.29 (m, 2H),
Diethyl 2-(trans-4-(bromomethyl)-1-methyl-2-oxopyrroli-
din-3-yl)malonate (9b). (Table 2, entry 8, 0.5 mmol scale, 121 mg,
1
69%); pale yellow oil: H NMR (400 MHz, CDCl3) δ (ppm) 1.26
H
dx.doi.org/10.1021/jo401106m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
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(t, J = 7.1 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H), 2.88 (s, 3H), 2.87−2.98
(m, 2H), 3.26 (dd, J = 9.9, 5.4 Hz, 1H), 3.45 (dd, J = 10.3, 7.3 Hz,
1H), 3.57 (dd, J = 9.9, 8.9 Hz, 1H), 3.61 (dd, J = 10.3, 3.8 Hz, 1H),
4.05 (d, J = 4.0 Hz, 1H), 4.15−4.29 (m, 4H); 13C NMR (100.6 MHz,
CDCl3) δ (ppm) 14.08 (q), 14.12 (q), 29.9 (q), 35.9 (d), 37.0 (t),
46.2 (d), 51.3 (d), 52.9 (t), 61.9 (t), 62.0 (t), 167.9 (s), 168.7 (s),
and δ 36.5 (C-4), 47.5 (CH2Cl), between δ 4.26 (CH(CO2Et)2) and δ
45.1 (C-3), 36.5 (C-4), and between δ 3.20, 3.37 (CH2Cl) and δ 48.8
(C-5), 45.1 (C-3), 36.5 (C-4); IR (neat) 2983, 1733, 1694, 1645,
1491, 1450, 1373, 1274, 1176, 1176, 1031 cm−1; MS (EI) m/z 333
(M+, 26), 331 (M+, 72), 282 (100), 190 (96%); HRMS M+ 331.1188,
333.1154 (calcd for C15H22ClNO5 331.1187, 333.1157).
1
172.2 (s); H NMR (400 MHz, C6D6) δ (ppm) 0.857 (t, J = 7.1 Hz,
Diethyl 2-(trans-1-allyl-4-(bromomethyl)-2-oxopyrrolidin-3-
yl)malonate (9e). (Table 2, entry 14, 0.5 mmol scale, 128 mg, 71%);
3H), 0.910 (t, J = 7.1 Hz, 3H), 2.45 (d, J = 0.7 Hz, 3H), 2.61 (dd, J =
9.9, 5.9 Hz, 1H), 2.74 (dd, J = 7.3, 4.7 Hz, 1H), 2.86 (ddddd, J = 9.2,
8.2, 7.3, 5.9, 3.8 Hz, 1H), 2.99 (dd, J = 10.1, 8.2 Hz, 1H), 3.02 (dd, J =
9.9, 9.2 Hz, 1H), 3.28 (dd, J = 10.1, 3.8 Hz, 1H), 3.80−3.97 (m, 4H),
4.22 (d, J = 4.7 Hz, 1H); Selected NOEs are between δ 2.74 (H-3) and
δ 2.99, 3.28 (CH2Br) and between δ 2.86 (H-4) and δ 4.22
(CH(CO2Et)2); 13C NMR (100.6 MHz, C6D6) δ (ppm) 13.8 (q), 13.9
(q), 29.3 (q), 36.4 (d), 36.9 (t), 46.4 (d), 51.7 (d), 52.4 (t), 61.5 (t),
61.6 (t), 168.1 (s), 168.7 (s), 171.5 (s); Selected HMBC correlations
are between δ 2.74 (H-3) and δ 51.7 (CH(CO2Et)2), 36.4 (C-4),
between δ 2.61, 3.02 (H-5) and δ 36.9 (CH2Br), between δ 4.22
(CH(CO2Et)2) and δ 46.4 (C-3), 36.4 (C-4), and between δ 2.99,
3.28 (CH2Br) and δ 52.4 (C-5), 46.4 (C-3); IR (neat) 2984, 2940,
1734, 1698, 1502, 1446, 1373, 1270, 1178, 1035 cm−1; MS (EI) m/z
351 (M+, 70), 349 (M+, 70), 306 (36), 304 (28), 270 (51), 256
(100%); HRMS M+ 349.0516, 351.0496 (calcd for C13H20BrNO5
349.0525, 351.0504).
1
pale yellow oil: H NMR (400 MHz, CDCl3) δ (ppm) 1.27 (t, J =
7.1 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H), 2.92−2.99 (m, 2H), 3.22 (dd, J =
9.8, 5.7 Hz, 1H), 3.46 (dd, J = 10.3, 7.0 Hz, 1H), 3.55 (dd, J = 9.8, 9.4
Hz, 1H), 3.61 (dd, J = 10.3, 3.7 Hz, 1H), 3.90 (dddd, J = 15.2, 6.0, 1.2,
1.2 Hz, 1H), 3.94 (dddd, J = 15.2, 6.0, 1.4, 1.4 Hz, 1H), 4.07 (d, J = 3.8
Hz, 1H), 4.14−4.30 (m, 4H), 5.22 (dddd, J = 10.1, 1.3, 1.3, 1.3 Hz,
1H), 5.25 (dddd, J = 17.2, 1.5, 1.5, 1.5 Hz, 1H), 5.73 (dddd, J = 17.2,
10.1, 6.0, 6.0 Hz, 1H); 13C NMR (100.6 MHz, CDCl3) δ (ppm) 14.05
(q), 14.08 (q), 35.8 (d), 37.0 (t), 45.5 (t), 46.3 (d), 50.2 (t), 51.2 (d),
61.8 (t), 62.0 (t), 118.4 (t), 131.9 (d), 167.8 (s), 168.6 (s), 171.9 (s);
1H NMR (400 MHz, C6D6) δ (ppm) 0.862 (t, J = 7.1 Hz, 3H), 0.901
(t, J = 7.1 Hz, 3H), 2.74 (dd, J = 9.6, 6.0 Hz, 1H), 2.83 (dd, J = 7.7, 4.4
Hz, 1H), 2.93 (ddddd, J = 8.7, 7.7, 7.7, 6.0, 3.7 Hz, 1H), 3.04 (dd, J =
10.2, 7.7 Hz, 1H), 3.18 (dd, J = 9.6, 8.7 Hz, 1H), 3.24 (dd, J = 10.2, 3.7
Hz, 1H), 3.60 (dd, J = 15.4, 6.0 Hz, 1H), 3.80 (dddd, J = 15.4, 5.7, 1.6,
1.6 Hz, 1H), 3.80−3.96 (m, 4H), 4.27 (d, J = 4.4 Hz, 1H), 4.96 (dddd,
J = 10.3, 1.4, 1.4, 1.4 Hz, 1H), 5.00 (dddd, J = 17.2, 1.6, 1.6, 1.6 Hz,
1H), 5.54 (dddd, J = 17.2, 10.3, 6.0, 5.7 Hz, 1H); Selected NOEs are
between δ 2.83 (H-3) and δ 3.04, 3.24 (CH2Br) and between δ 2.93
(H-4) and δ 4.27 (CH(CO2Et)2), 3.18 (H-5b); 13C NMR (100.6
MHz, C6D6) δ (ppm) 13.85 (q), 13.87 (q), 36.3 (d), 36.9 (t), 45.3 (t),
46.4 (d), 49.9 (t), 51.5 (d), 61.5 (t), 61.6 (t), 117.5 (t), 132.6 (d),
168.1 (s), 168.8 (s), 171.4 (s); Selected HMBC correlations are
between δ 2.83 (H-3) and δ 51.5 (CH(CO2Et)2), 36.3 (C-4), 36.9
(CH2Br), between δ 2.74, 3.18 (H-5a,b) and δ 36.3 (C-4), between δ
4.27 (CH(CO2Et)2) and δ 46.4 (C-3), 36.3 (C-4), and between δ
3.04, 3.24 (CH2Br) and δ 49.9 (C-5), 46.4 (C-3); IR (neat) 2981,
1734, 1696, 1645, 1491, 1448, 1374, 1265, 1033 cm−1; MS (EI) m/z
377 (M+, 53), 375 (M+, 53), 332 (41), 330 (38), 296 (56), 282
(100%); HRMS M+ 375.0689, 377.0665 (calcd for C15H22BrNO5
375.0681, 377.0661). Anal. Calcd for C15H22BrNO5: C, 47.88; H, 5.89;
N, 3.72. Found: C, 48.14; H, 6.00; N, 3.74.
Diethyl 2-(trans-1-allyl-4-(iodomethyl)-2-oxopyrrolidin-3-
yl)malonate (9f). (Table 2, entry 16, 0.5 mmol scale, 164 mg,
77%); pale yellow oil: 1H NMR (400 MHz, CDCl3) δ (ppm) 1.27 (t,
J = 7.1 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H), 2.71 (ddddd, J = 8.8, 7.9, 7.5,
6.0, 3.7 Hz, 1H), 2.84 (dd, J = 7.5, 4.2 Hz, 1H), 3.08 (dd, J = 9.9, 6.0
Hz, 1H), 3.24 (dd, J = 10.1, 7.9 Hz, 1H), 3.42 (dd, J = 10.1, 3.7 Hz,
1H), 3.53 (dd, J = 9.9, 8.8 Hz, 1H), 3.89 (dd, J = 15.2, 6.0 Hz, 1H),
3.94 (dddd, J = 15.2, 4.5, 1.4, 1.4 Hz, 1H), 4.05 (d, J = 4.2 Hz, 1H),
4.14−4.31 (m, 4H), 5.22 (dddd, J = 10.1, 1.3, 1.3, 1.3 Hz, 1H), 5.25
(dddd, J = 17.2, 1.4, 1.4, 1.4 Hz, 1H), 5.73 (dddd, J = 17.2, 10.1, 6.0,
6.0 Hz, 1H); Selected NOEs are between δ 2.84 (H-3) and δ 3.24,
3.42 (CH2I), between δ 2.71 (H-4) and δ 4.05 (CH(CO2Et)2), 3.53
(H-5b), and between δ 3.08 (H-5a) and δ 3.24, 3.42 (CH2I); 13C
NMR (100.6 MHz, CDCl3) δ (ppm) 11.8 (t), 14.07 (q), 14.12 (q),
35.7 (d), 45.5 (t), 48.4 (d), 51.0 (d), 52.4 (t), 61.8 (t), 62.0 (t), 118.5
(t), 131.9 (d), 167.9 (s), 168.6 (s), 172.1 (s); Selected HMBC
correlations are between δ 2.84 (H-3) and δ 51.0 (CH(CO2Et)2), 35.7
(C-4), 11.8 (CH2I), between δ 3.08, 3.53 (H-5a,b) and δ 35.7 (C-4),
between δ 4.05 (CH(CO2Et)2) and δ 35.7 (C-4), and between δ 3.24,
3.42 (CH2I) and δ 52.4 (C-5); IR (neat) 2982, 1731, 1694, 1645,
1489, 1447, 1372, 1270, 1178, 1159, 1033 cm−1; MS (EI) m/z 423
(M+, 21), 378 (23), 296 (100%); HRMS M+ 423.0548 (calcd for
C15H22INO5 423.0543).
Diethyl 2-(trans-4-(iodomethyl)-1-methyl-2-oxopyrrolidin-3-
yl)malonate (9c). (Table 2, entry 11, 0.5 mmol scale, 145 mg, 73%);
1
colorless oil: H NMR (400 MHz, CDCl3) δ (ppm) 1.26 (t, J = 7.1
Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H), 2.71 (ddddd, J = 8.8, 8.1, 7.2, 5.8, 3.7
Hz, 1H), 2.79 (dd, J = 7.2, 4.4 Hz, 1H), 2.84 (d, J = 0.7 Hz, 3H), 3.12
(dd, J = 9.8, 5.8 Hz, 1H), 3.22 (dd, J = 10.1, 8.1 Hz, 1H), 3.43 (dd, J =
10.1, 3.7 Hz, 1H), 3.55 (dd, J = 9.8, 8.8 Hz, 1H), 4.03 (d, J = 4.4 Hz,
1H), 4.13−4.31 (m, 4H); Selected NOEs are between δ 2.79 (H-3)
and δ 3.22, 3.43 (CH2I) and between δ 2.71 (H-4) and δ 4.03
(CH(CO2Et)2), 3.55 (H-5b); 13C NMR (100.6 MHz, CDCl3) δ
(ppm) 11.7 (t), 14.07 (q), 14.13 (q), 29.9 (q), 35.9 (d), 48.3 (d), 51.1
(d), 55.1 (t), 61.8 (t), 62.0 (t), 167.9 (s), 168.6 (s), 172.4 (s); Selected
HMBC correlations are between δ 2.79 (H-3) and δ 51.13 (CH(CO2Et)2),
35.9 (C-4), 11.7 (CH2I), between δ 3.12, 3.55 (H-5a,b) and δ 35.9 (C-
4), 11.7 (CH2I), between δ 4.03 (CH(CO2Et)2) and δ 48.3 (C-3),
35.9 (C-4), and between δ 3.22, 3.43 (CH2I) and δ 55.1 (C-5), 35.9
(C-4), 48.3 (C-3); IR (neat) 2980, 2935, 1730, 1694, 1499, 1443,
1372, 1300, 1267, 1176, 1032 cm−1; MS (EI) m/z 397 (M+, 10), 352
(59), 306 (56), 270 (100%); HRMS M+ 397.0381 (calcd for
C13H20INO5 397.0386).
Diethyl 2-(trans-1-allyl-4-(chloromethyl)-2-oxopyrrolidin-3-
yl)malonate (9d). (Table 2, entry 13, 0.5 mmol scale, 143 mg,
86%); colorless oil: 1H NMR (400 MHz, CDCl3) δ (ppm) 1.26 (t, J =
7.1 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H), 2.92−2.94 (m, 2H), 3.25 (dd, J =
9.8, 5.6 Hz, 1H), 3.55 (dd, J = 9.8, 9.6 Hz, 1H), 3.59 (dd, J = 11.2, 6.6
Hz, 1H), 3.72 (dd, J = 11.2, 3.7 Hz, 1H), 3.90 (dddd, J = 15.2, 6.0, 1.5,
1.5 Hz, 1H), 3.93 (dddd, J = 15.2, 6.0, 1.5, 1.5 Hz, 1H), 4.07 (d, J = 3.8
Hz, 1H), 4.14−4.30 (m, 4H), 5.22 (dddd, J = 10.3, 1.5, 1.5, 1.5 Hz,
1H), 5.24 (dddd, J = 17.0, 1.5, 1.5, 1.5 Hz, 1H), 5.73 (dddd, J = 17.0,
10.3, 6.0, 6.0 Hz, 1H); 13C NMR (100.6 MHz, CDCl3) δ (ppm) 14.0
(q), 14.1 (q), 36.0 (d), 45.0 (d), 45.3 (t), 47.5 (t), 49.1 (t), 51.3 (d),
61.8 (t), 61.9 (t), 118.3 (t), 131.9 (d), 167.9 (s), 168.6 (s), 171.9 (s);
1H NMR (400 MHz, C6D6) δ (ppm) 0.869 (t, J = 7.1 Hz, 3H), 0.907
(t, J = 7.1 Hz, 3H), 2.79 (dd, J = 9.5, 5.7 Hz, 1H), 2.86 (dd, J = 7.4, 4.3
Hz, 1H), 2.91 (ddddd, J = 9.0, 7.6, 7.4, 5.7, 3.8 Hz, 1H), 3.19 (dd, J =
9.5, 9.0 Hz, 1H), 3.20 (dd, J = 11.0, 7.6 Hz, 1H), 3.37 (dd, J = 11.0, 3.8
Hz, 1H), 3.61 (dd, J = 15.3, 6.1 Hz, 1H), 3.81 (dddd, J = 15.3, 5.7, 1.6,
1.6 Hz, 1H), 3.80−3.97 (m, 4H), 4.26 (d, J = 4.3 Hz, 1H), 4.96 (dddd,
J = 10.2, 1.4, 1.4, 1.4 Hz, 1H), 5.02 (dddd, J = 17.2, 1.6, 1.6, 1.6 Hz,
1H), 5.54 (dddd, J = 17.2, 10.2, 5.8, 5.8 Hz, 1H); Selected NOEs are
between δ 2.86 (H-3) and δ 3.20, 3.37 (CH2Cl) and between δ 2.91
(H-4) and δ 4.26 (CH(CO2Et)2); 13C NMR (100.6 MHz, C6D6) δ
(ppm) 13.9 (q × 2), 36.5 (d), 45.1 (d), 45.3 (t), 47.5 (t), 48.8 (t), 51.6
(d), 61.5 (t), 61.6 (t), 117.5 (t), 132.6 (d), 168.1 (s), 168.8 (s), 171.4
(s); Selected HMBC correlations are between δ 2.86 (H-3) and δ 51.6
(CH(CO2Et)2), 36.5 (C-4), 47.5 (CH2Cl), between δ 2.79, 3.19 (H-5)
Diethyl 2-(trans-4-(chloromethyl)-1-propyl-2-oxopyrrolidin-
3-yl)malonate (9g). (Table 2, entry 18, 0.5 mmol scale, 163 mg,
98%); pale yellow oil: 1H NMR (400 MHz, CDCl3) δ (ppm) 0.908 (t,
J = 7.4 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H), 1.30 (t, J = 7.1 Hz, 3H), 1.57
(qt, J = 7.4, 7.4 Hz, 2H), 2.91−2.98 (m, 2H), 3.21- 3.32 (m, 3H),
3.55−3.61 (m, 2H), 3.72 (dd, J = 11.0, 3.7 Hz, 1H), 4.07 (d, J = 4.0
Hz, 1H), 4.13−4.29 (m, 4H); 13C NMR (100.6 MHz, CDCl3) δ
I
dx.doi.org/10.1021/jo401106m | J. Org. Chem. XXXX, XXX, XXX−XXX

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(ppm) 11.3 (q), 14.08 (q), 14.10 (q), 20.3 (t), 36.1 (d), 44.5 (t), 45.2
(d), 47.7 (t), 49.4 (t), 51.3 (d), 61.8 (t), 62.0 (t), 168.0 (s), 168.7 (s),
172.0 (s); H NMR (400 MHz, C6D6) δ (ppm) 0.744 (t, J = 7.3 Hz,
Transformation of 2a to 10. A solution of compound 2a (158
mg, 0.54 mmol), Bu3SnH (313 mg, 290 μL, 1.08 mmol), and AIBN
(17.4 mg, 0.108 mmol) in benzene (3.3 mL) was heated at reflux for 3
h and cooled to room temperature. The reaction mixture was
concentrated under reduced presure. The residue was purified by
column chromatography over silica gel with hexane−ether as the
eluent to give 10 (137 mg, 98%).
1
3H), 0.869 (t, J = 7.1 Hz, 3H), 0.904 (t, J = 7.1 Hz, 3H), 1.26 (qt, J =
7.3, 7.3 Hz, 2H), 2.76 (dd, J = 9.5, 5.9 Hz, 1H), 2.84 (dd, J = 7.3, 4.4
Hz, 1H), 2.92 (m, 1H), 3.02 (dt, J = 13.7, 6.9 Hz, 1H), 3.08−3.23 (m,
3H), 3.41 (dd, J = 11.1, 3.9 Hz, 1H), 3.80−3.97 (m, 4H), 4.27 (dd, J =
4.4, 1.8 Hz, 1H); Selected NOEs are between δ 2.84 (H-3) and δ
3.08−3.23 (overlapped), 3.41 (CH2Cl) and between δ 2.92 (H-4) and
δ 4.27 (CH(CO2Et)2); 13C NMR (100.6 MHz, C6D6) δ (ppm) 11.3
(q), 13.9 (q × 2), 20.5 (t), 36.6 (d), 44.3 (t), 45.3 (d), 47.7 (t), 49.1
(t), 51.6 (d), 61.4 (t), 61.6 (t), 168.1 (s), 168.8 (s), 171.5 (s); Selected
HMBC correlations are between δ 2.84 (H-3) and δ 51.6 (CH(CO2Et)2),
36.6 (C-4), 47.7 (CH2Cl), between δ 2.76 (H-5a) and δ 36.6 (C-4),
47.7 (CH2Cl), between δ 4.27 (CH(CO2Et)2) and δ 45.3 (C-3), 36.6
(C-4), and between δ 3.41 (CHHCl) and δ 49.1 (C-5), 45.3 (C-3),
36.6 (C-4); IR (neat) 2970, 1734, 1694, 1493, 1456, 1373, 1274, 1373,
1274, 1178, 1033 cm−1; MS (EI) m/z 335 (M+, 32), 333 (M+, 91), 305
(53), 284 (100%); HRMS M+ 333.1344 (calcd for C15H24ClNO5
333.1343).
10: colorless oil; 1H NMR (400 MHz, CDCl3) δ (ppm) 1.14 (d, J =
6.4 Hz, 3H), 1.29 (t, J = 7.1 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H), 2.73−
2.84 (m, 2H), 3.80 (dd, J = 8.9, 8.9 Hz, 1H), 3.90 (d, J = 4.6 Hz, 1H),
4.20−4.30 (m, 2H), 4.48 (dd, J = 8.9, 7.8 Hz, 1H); 13C NMR (100.6
MHz, CDCl3) δ (ppm) 14.0 (q), 14.1 (q), 17.4 (q), 33.2 (d), 46.5 (d),
50.6 (d), 62.03 (t), 62.04 (t), 73.1 (t), 167.4 (s), 167.7 (s), 176.6 (s);
Selected HMBC correlations are between δ 3.80, 4.48 (H-5) and δ
33.2 (C-4), between δ 4.48 (CH(CO2Et)2) and δ 46.5 (C-3), 33.2 (C-4),
and between δ 1.14 (CH3) and δ 73.1 (C-5), 46.5 (C-3), 33.2 (C-4); IR
(neat) 2983, 1777, 1736, 1466, 1391, 1372, 1252, 1176, 1024 cm−1;
MS (CI) m/z 259 ([M + 1]+); HRMS [M + 1]+ 259.1183 (calcd for
C12H19O6 259.1182) . Anal. Calcd for C12H18O6: C, 55.81; H, 7.02.
Found: C, 55.91; H, 7.15.
1
Diethyl 2-(trans-4-(bromomethyl)-1-propyl-2-oxopyrrolidin-
11: (0.2 mmol scale, 34 mg, 60%); colorless oil; H NMR (400
3-yl)malonate (9h). (Table 2, entry 20, 0.5 mmol scale, 167 mg,
MHz, CDCl3) δ (ppm) 1.13 (d, J = 6.8 Hz, 3H), 1.26 (t, J = 7.1 Hz,
3H), 1.29 (t, J = 7.1 Hz, 3H), 2.54 (ddqd, J = 8.5, 7.9, 6.8, 6.5 Hz, 1H),
2.68 (ddq, J = 7.9, 5.0, 0.7 Hz, 1H), 2.85 (d, J = 0.7 Hz, 3H), 2.93 (dd,
J = 9.4, 6.5 Hz, 1H), 3.50 (dd, J = 9.4, 8.5 Hz, 1H), 3.90 (d, J = 5.0 Hz,
1H), 4.13−4.29 (m, 4H); Selected NOEs are between δ 2.68 (H-3)
and δ 1.13 (CH3), between δ 2.54 (H-4) and δ 3.90 (CH(CO2Et)2),
3.50 (H-5b), and between 2.93 (H-5a) and 1.13 (CH3); 13C NMR
(100.6 MHz, CDCl3) δ (ppm) 14.05 (q), 14.10 (q), 19.9 (q), 29.5 (d),
29.8 (q), 49.3 (d), 51.4 (d), 55.6 (t), 61.5 (t), 61.6 (t), 168.1 (s), 168.6
(s), 173.3 (s); Selected HMBC correlations are between δ 2.68 (H-3)
and δ 51.4 (CH(CO2Et)2), 29.5 (C-4), 19.9 (CH3), between δ 2.54
(H-4) and δ 55.6 (C-5), 51.4 (CH(CO2Et)2), 49.3 (C-3), 19.9 (CH3),
between δ 2.93, 3.50 (H-5a,b) and δ 29.5 (C-4), 19.9 (CH3), between
δ 3.90 (CH(CO2Et)2) and δ 49.3 (C-3), 29.5 (C-4), and between δ
1.13 (CH3) and δ 55.6 (C-5), 49.3 (C-3), 29.5 (C-4); IR (neat) 2980,
1733, 1696, 1501, 1444, 1372, 1270, 1157, 1032 cm−1; MS (EI) m/z
271 (M+, 31), 226 (18), 152 (64), 124 (100%); HRMS M+ 271.1416
(calcd for C13H21NO5 271.1420). Anal. Calcd for C13H21NO5: C,
57.55; H, 7.80; N, 5.16. Found: C, 57.37; H, 7.83; N, 5.07.
1
88%); colorless oil: H NMR (400 MHz, CDCl3) δ (ppm) 0.910 (t,
J = 7.3 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H), 1.57
(qt, J = 7.3, 7.3 Hz, 2H), 2.89−2.98 (m, 2H), 3.21−3.32 (m, 3H), 3.45
(dd, J = 10.3, 7.1 Hz, 1H), 3.58 (dd, J = 9.5, 9.5 Hz, 1H), 3.61 (dd, J =
10.3, 3.5 Hz, 1H), 4.06 (d, J = 4.0 Hz, 1H), 4.13−4.30 (m, 4H); 13C
NMR (100.6 MHz, CDCl3) δ (ppm) 11.3 (q), 14.07 (q), 14.10 (q),
20.4 (t), 35.9 (d), 37.1 (t), 44.5 (t), 46.5 (d), 50.6 (t), 51.2 (d), 61.8
1
(t), 61.9 (t), 167.9 (s), 168.7 (s), 172.0 (s); H NMR (400 MHz,
C6D6) δ (ppm) 0.745 (t, J = 7.3 Hz, 3H), 0.864 (t, J = 7.1 Hz, 3H),
0.900 (t, J = 7.1 Hz, 3H), 1.27 (qt, J = 7.3, 7.3 Hz, 2H), 2.71 (dd, J =
9.6, 6.0 Hz, 1H), 2.81 (dd, J = 7.5, 2.9 Hz, 1H), 2.94 (ddddd, J = 8.6,
7.9, 7.5, 6.0, 3.7 Hz, 1H), 2.98−3.12 (m, 2H), 3.04 (dd, J = 10.1, 7.9
Hz, 1H), 3.14 (dd, J = 9.6, 8.6 Hz, 1H), 3.29 (dd, J = 10.1, 3.7 Hz,
1H), 3.80−4.00 (m, 4H), 4.28 (d, J = 4.4 Hz, 1H); Selected NOEs are
between δ 2.81 (H-3) and δ 3.04, 3.29 (CH2Br) and between δ 2.94
(H-4) and δ 4.28 (CH(CO2Et)2), and between δ 2.71 (H-5a) and δ
3.29 (CHHBr); 13C NMR (100.6 MHz, C6D6) δ (ppm) 11.3 (q),
13.86 (q), 13.87 (q), 20.5 (t), 36.4 (d), 37.1 (t), 44.3 (t), 46.6 (d),
50.3 (t), 51.5 (d), 61.5 (t), 61.6 (t), 168.1 (s), 168.8 (s), 171.5 (s);
Selected HMBC correlations are between δ 2.81 (H-3) and δ 51.5
(CH(CO2Et)2), 36.4 (C-4), 37.1 (CH2Br), between δ 2.71 (H-5a) and
δ 37.1 (CH2Br), between δ 4.28 (CH(CO2Et)2) and δ 46.6 (C-3),
36.4 (C-4), and between δ 3.04, 3.29 (CH2Br) and δ 50.3 (C-5); IR
(neat) 2966, 2935, 1732, 1694, 1490, 1453, 1372, 1267, 1176, 1035 cm−1;
MS (EI) m/z 380 ([M + 1]+, 15), 378 ([M + 1]+, 16), 85 (84), 83
(100%); HRMS M+ 377.0838, 379.0823 (calcd for C15H24BrNO5
377.0838, 379.0817).
Diethyl 2-(t-4-(chloromethyl)-c-5-methyl-2-oxotetrahydro-
furan-r-3-yl)malonate (13). A 1.3:1 (13:7a) mixture (eq 7, 1
equiv of AlCl3, 0.5 mmol scale, 80 mg, combined yield 52%); colorless
1
oil: H NMR (400 MHz, CDCl3) δ (ppm) peaks for 13, 1.27−1.34
(m, 6H), 1.53 (d, J = 6.2 Hz, 3H), 2.81 (ddt, J = 10.1, 8.2, 4.2 Hz, 1H),
3.29 (dd, J = 10.1, 4.0 Hz, 1H), 3.69 (d, J = 4.2 Hz, 2H), 4.07 (d, J =
4.0 Hz, 1H); Selected NOEs are between δ 3.29 (H-3) and δ 3.69
(CH2Cl), between δ 2.81 (H-4) and δ 4.07 (CH(CO2Et)2), 1.53
(CH3), and between δ 4.52 (H-5) and δ 3.69 (CH2Cl); 13C NMR
(100.6 MHz, CDCl3) δ (ppm) peaks for 13, 13.98 (q), 14.02 (q), 20.1
(q), 42.5 (d), 43.9 (t), 46.4 (d), 50.4 (d), 62.2 (t), 62.3 (t), 77.5 (d),
167.3 (s), 168.0 (s), 174.8 (s); Selected HMBC correlations are
between δ 3.29 (H-3) and δ 50.4 (CH(CO2Et)2), 46.4 (C-4), between
δ 4.52 (H-5) and δ 43.9 (CH2Cl), between δ 3.69 (CH2Cl) and δ 77.5
(C-5), and between δ 1.53 (CH3) and δ 77.5 (C-5), 46.4 (C-4); IR
(neat) 2984, 1779−1732, 1466, 1446, 1373, 1197, 1097, 1031 cm−1;
MS (CI) m/z 309 ([M + H]+, 49%), 307 ([M + H]+, 100%); HRMS
M+ 307.0941, 309.0924 (calcd for C13H20ClO6 307.0948, 309.0919).
Diethyl 2-(trans-4-(2-chloropropan-2-yl)-2-oxotetrahydro-
furan-3-yl)malonate (15). (eq 8, TiCl4, 0.5 mmol scale, 27 mg,
Diethyl 2-(trans-4-(iodomethyl)-1-propyl-2-oxopyrrolidin-3-
yl)malonate (9i). (Table 2, entry 22, 0.5 mmol scale, 184 mg, 87%);
1
colorless oil: H NMR (400 MHz, CDCl3) δ (ppm) 0.913 (t, J = 7.4
Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H), 1.57 (qt, J =
7.4, 7.4 Hz, 2H), 2.70 (ddddd, J = 8.6, 8.1, 7.3, 5.9, 3.6 Hz, 1H), 2.82
(dd, J = 7.3, 4.2 Hz, 1H), 3.11 (dd, J = 9.9, 5.9 Hz, 1H), 3.23 (dd, J =
10.0, 8.1 Hz, 1H), 3.23−3.32 (m, 2H), 3.43 (dd, J = 10.0, 3.6 Hz, 1H),
3.56 (dd, J = 9.9, 8.6 Hz, 1H), 4.05 (d, J = 4.2 Hz, 1H), 4.13−4.30 (m,
4H); Selected NOEs are between δ 2.82 (H-3) and δ 3.23, 3.43
(CH2I), between δ 2.70 (H-4) and δ 4.05 (CH(CO2Et)2), 3.56
(H-5b), and between δ 3.11 (H-5a) and δ 3.23, 3.43 (CH2I); 13C
NMR (100.6 MHz, CDCl3) δ (ppm) 11.3 (q), 11.9 (t), 14.09 (q),
14.13 (q), 20.4 (t), 35.8 (d), 44.6 (t), 48.6 (d), 51.1 (d), 52.9 (t), 61.8
(t), 62.0 (t), 167.9 (s), 168.7 (s), 172.2 (s); Selected HMBC
correlations are between δ 2.82 (H-3) and δ 51.1 (CH(CO2Et)2), 35.8
(C-4), 11.9 (CH2I), between δ 3.11, 3.56 (H-5a,b) and δ 35.8 (C-4),
11.9 (CH2I), between δ 4.05 (CH(CO2Et)2) and δ 48.6 (C-3), 35.8
(C-4), and between δ 3.23, 3.43 (CH2I) and δ 52.9 (C-5); IR (neat)
2965, 2934, 1732, 1694, 1489, 1450, 1372, 1269, 1177, 1158, 1033
cm−1; MS (EI) m/z 426 ([M + 1]+); HRMS M+ 425.0706 (calcd for
C15H24INO5 425.0699).
1
isolated yield 17%); pale yellow oil: H NMR (400 MHz, CDCl3) δ
(ppm) 1.29 (t, J = 7.1 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H), 1.54 (s, 3H),
1.56 (s, 3H), 2.78 (ddd, J = 8.8, 5.7, 4.6 Hz, 1H), 3.18 (dd, J = 5.7, 4.1
Hz, 1H), 4.00 (d, J = 4.1 Hz, 1H), 4.15−4.33 (m, 4H), 4.47 (dd, J =
9.3, 4.6 Hz, 1H), 4.57 (dd, J = 9.3, 8.8 Hz, 1H); Selected NOEs are
between δ 3.18 (H-3) and δ 1.54, 1.56 (C(CH3)2Cl) and between δ
2.78 (H-4) and δ 4.00 (CH(CO2Et)2), 4.57 (H-5b); 13C NMR (100.6
MHz, CDCl3) δ (ppm) 14.0 (q), 29.9 (q), 30.2 (q), 42.1 (d), 49.4 (d),
52.9 (d), 62.3 (t), 62.4 (t), 69.1 (t), 70.6 (s), 167.4 (s), 167.8 (s),
176.2 (s); Selected HMBC correlations are between δ 3.18 (H-3) and
J
dx.doi.org/10.1021/jo401106m | J. Org. Chem. XXXX, XXX, XXX−XXX

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Article
δ 70.6 (C(CH3)2Cl), 52.9 (CH(CO2Et)2), 49.4 (C-4) and between δ
4.47, 4.57 (H-5a,5b) and δ 70.6 (C(CH3)2Cl), 176.2 (C-2); IR (neat)
2984, 1778, 1735, 1467, 1393, 1374, 1182, 1034 cm−1; MS (EI) m/z
322 (M+, 2.7), 320 (M+, 7.5), 285 (100), 275 (41), 243 (74%); HRMS
M+ 320.1027, 322.1005 (calcd for C14H21ClO6 320.1027, 322.0997).
Diethyl 2-(trans-4-(propen-2-yl)-2-oxotetrahydrofuran-3-yl)-
malonate (16). (eq 9, AlCl3, 0.5 mmol scale, 27 mg, isolated yield
19%); pale yellow oil: 1H NMR (400 MHz, CDCl3) δ (ppm) 1.276 (t,
J = 7.1 Hz, 3H), 1.280 (t, J = 7.1 Hz, 3H), 1.75 (dd, J = 1.5, 0.7 Hz,
3H), 3.25 (dd, J = 10.8, 5.5 Hz, 1H), 3.50 (ddd, J = 10.8, 9.3, 8.9 Hz,
1H), 3.84 (d, J = 5.5 Hz, 1H), 4.00 (dd, J = 9.3, 9.3 Hz, 1H), 4.14−
4.25 (m, 4H), 4.46 (dd, J = 8.9, 8.9 Hz, 1H), 4.89 (qd, J = 0.7, 0.7 Hz,
1H), 4.91 (qd, J = 1.5, 1.5 Hz, 1H); Selected NOEs are between δ 3.25
(H-3) and δ 4.89 (CHH), 1.75 (C(CH3)CH2), between δ 3.50
(H-4) and δ 3.84 (CH(CO2Et)2), 4.46 (H-5b), and between δ 4.00
(H-5a) and δ 1.75 (C(CH3)CH2); 13C NMR (100.6 MHz, CDCl3)
δ (ppm) 14.0 (q), 14.1 (q), 18.6 (q), 42.1 (d), 45.9 (d), 50.4 (d), 61.9
(t), 62.0 (t), 70.0 (t), 115.1 (t), 140.5 (s), 167.3 (s), 167.4 (s), 176.0
(s); Selected HMBC correlations are between δ 3.25 (H-3) and δ 50.4
(CH(CO2Et)2), 45.9 (C-4), between δ 3.50 (H-4) and δ 42.1 (C-3),
and between δ 4.00, 4.46 (H-5a,5b) and δ 45.9 (C-4); IR (neat) 2982,
1779, 1734, 1647, 1372, 1263, 1163, 1032 cm−1; MS (EI) m/z 285
([M + 1]+, 54), 239 (37), 85 (98), 83 (100%); HRMS M+ 284.1259
(calcd for C14H20O6 284.1260).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Ministry of Education,
Culture, Sports, Science, and Technology (MEXT), Japan. This
work was partly supported by Nanotechnology Platform
Program of MEXT, Japan. We thank Mr. M. Takebayashi
(Kinki University Technical College) for experimental help. We
also thank Prof. S. Umetani (Kyoto University) for elemental
analyses.
REFERENCES
■
(1) For reviews of tetrahydrofurans, see: (a) Keay, B. A.; Hopkins, J.
M.; Dibble, P. W. In Comprehensive Heterocyclic Chemistry III;
Katritzky, A. R., Ramsden, C. A., Scriven, E. F. V., Taylor, R. J. K.,
Eds.; Elsevier: Amsterdam, 2008; Vol. 3, p 571. (b) Lorente, A.;
́
Lamariano-Merketegi, J.; Albericio, F.; Alvarez, M. Chem. Rev. 2013,
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(3) For recent examples of tetrahydrofuran syntheses, see:
(a) Hanessian, S.; Hou, Y.; Bayrakdarian, M.; Tintelnot-Blomley, M.
J. Org. Chem. 2005, 70, 6735. (b) Chavre, S. N.; Choo, H.; Cha, J. H.;
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J. Org. Lett. 2012, 14, 5632. (f) Evans, P. A.; Inglesby, P. A. J. Am.
Chem. Soc. 2012, 134, 3635.
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Goddard, W. A., III; Toste, F. D. J. Am. Chem. Soc. 2011, 133, 5500.
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J. I. Org. Lett. 2010, 12, 5334. (e) Schomaker, J. M.; Bhattacharjee, S.;
Yan, J.; Borhan, B. J. Am. Chem. Soc. 2007, 129, 1996. (f) Agbodjan, A.
A.; Cooley, B. E.; Copley, R. C. B.; Corfield, J. A.; Flanagan, R. C.;
Glover, B. N.; Guidetti, R.; Haigh, D.; Howes, P. D.; Jackson, M. M.;
Matsuoka, R. T.; Medhurst, K. J.; Millar, A.; Sharp, M. J.; Slater, M. J.;
Toczko, J. F.; Xie, S. J. Org. Chem. 2008, 73, 3094. (g) Yu, J.-D.; Ding,
W.; Lian, G.-Y.; Song, K.-S.; Zhang, D.-W.; Gao, X.; Yang, D. J. Org.
Chem. 2010, 75, 3232.
(5) Snider, B. B.; Roush, D. M. J. Org. Chem. 1979, 44, 4229.
(6) Yamazaki, S.; Yamada, K.; Yamabe, S.; Yamamoto, K. J. Org.
Chem. 2002, 67, 2889.
(7) (a) Karras, M.; Snider, B. B. J. Am. Chem. Soc. 1980, 102, 7951.
(b) Tietze, L. F.; Beifuss, U.; Ruther, M.; Ruhlmann, A.; Antel, J.;
Sheldrick, G. M. Angew. Chem., Int. Ed. Engl. 1988, 27, 1186.
(c) Tietze, L. F.; Beifuß, U. Synthesis 1988, 359. (d) Tietze, L. F.;
Steinmetz, A. Angew. Chem., Int. Ed. Engl. 1996, 35, 651.
(8) (a) Tietze, L. F.; Ruther, M. Chem. Ber. 1990, 123, 1387.
(b) Tietze, L. F.; Schunke, C. Eur. J. Org. Chem. 1998, 2089.
(9) (a) Snider, B. B. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Heathcock, C. H., Eds.; Pergamon Press: Oxford, U.K.,
1991; Vol. 2, p 527. (b) Olier, C.; Kaafarani, M.; Gastaldi, S.; Bertrand,
M. P. Tetrahedron 2010, 66, 413. (c) Miles, R. B.; Davis, C. E.; Coates,
R. M. J. Org. Chem. 2006, 71, 1493. (d) Miranda, P. O.; Carballo, R.
Diethyl 2-(t-5-chloro-5-methyl-2-oxo-2H-tetrahydropyran-r-
3-yl)malonate (19). (eq 10, 0.5 mmol scale, 108 mg, 70%); colorless
1
oil: H NMR (400 MHz, CDCl3) δ (ppm) 1.29 (t, J = 7.1 Hz, 3H),
1.31 (t, J = 7.1 Hz, 3H), 1.67 (s, 3H), 2.20 (ddd, J = 13.9, 7.1, 3.1 Hz,
1H), 2.34 (dd, J = 13.9, 11.7 Hz, 1H), 3.45 (ddd, J = 11.7, 7.1, 4.6 Hz,
1H), 4.19 (d, J = 4.6 Hz, 1H), 4.17−4.29 (m, 4H), 4.33 (dd, J = 12.1
Hz, 1H); Selected NOEs are between δ 3.45 (H-3) and δ 2.20 (H-4a),
between δ 2.34 (H-4b) and δ 4.43 (H-6b), 1.67 (CH3), and between δ
4.43 (H-6b) and δ 1.67 (CH3); 13C NMR (100.6 MHz, CDCl3) δ
(ppm) 14.0 (q), 14.1 (q), 28.3 (q), 37.6 (d), 38.5 (t), 52.3 (d), 62.08
(t), 62.13 (t), 63.9 (s), 77.5 (t), 167.8 (s), 168.2 (s), 169.6 (s);
Selected HMBC correlations are between δ 3.45 (H-3) and δ 169.6
(C-2), 38.5 (C-4), between δ 2.20, 2.34 (H-4a,4b) and δ 169.6 (C-2),
37.6 (C-3), and between δ 4.33, 4.43 (H-6a,6b) and δ 169.6 (C-2),
63.9 (C-5); IR (neat) 2983, 1738, 1464, 1448, 1373, 1332, 1274, 1213,
1179, 1032 cm−1; MS (EI) m/z 308 (M+, 0.6%), 306 (M+, 1.4), 271
(100%); HRMS M+ 306.0871, 308.0851 (calcd for C13H19ClO6
306.0870, 308.0841).
́
ez, A. Z.; Benitez, D.; Tkatchouk, E.;
́
,
20: Compound 20 is unstable to column chromatography (SiO2)
and contains a small amount of starting material 18 (eq 11, 0.5 mmol
1
scale, 64 mg, isolated yield 42%); colorless oil; H NMR (400 MHz,
CDCl3) δ (ppm) 1.26 (t, J = 7.1 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H),
1.78 (narrow multiplet, 3H), 4.10 (d, J = 10.4 Hz, 1H), 4.17−4.31 (m,
4H), 4.61 (d, J = 13.0 Hz, 1H), 4.64 (d, J = 13.0 Hz, 1H), 4.84 (d, J =
10.4 Hz, 1H), 4.98 (m, 1H), 5.05 (m, 1H); 13C NMR (100.6 MHz,
CDCl3) δ (ppm) 14.0 (q), 14.1 (q), 19.4 (q), 52.7 (d), 56.3 (d), 62.4
(t), 62.5 (t), 69.6 (t), 114.1 (t), 139.0 (s), 165.6 (s), 166.0 (s), 167.5
(s); IR (neat) 2984, 1748, 1659, 1447, 1370, 1306, 1258, 1164, 1028
cm−1; MS (EI) m/z 309 ([M + 1]+, 25), 307 ([M + 1]+, 100%);
HRMS M+ 306.0872, 308.0846 (calcd for C13H19ClO6 M+ 306.0870,
308.0841).
̈
ASSOCIATED CONTENT
■
S
* Supporting Information
̈
The additional proposed reaction mechanism for the model
compounds, Cartesian coordinates of the optimized geometries,
1H and 13C NMR spectral data, and 2D NOESY spectra. This
information is available free of charge via the Internet at http://
pubs.acs.org.
́
M.; Martín, V. S.; Padron, J. I. Org. Lett. 2009, 11, 357. (e) Chavre, S.
N.; Choo, H.; Lee, J. K.; Pae, A. N.; Kim, Y.; Cho, Y. S. J. Org. Chem.
2008, 73, 7467. (f) Jacolot, M.; Jean, M.; Levoin, N.; van de Weghe, P.
Org. Lett. 2012, 14, 58. (g) Overman, L. E.; Velthuisen, E. J. J. Org.
Chem. 2006, 71, 1581.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yamazaks@nara-edu.ac.jp.
K
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Article
(10) (a) Yamazaki, S.; Takebayashi, M. J. Org. Chem. 2011, 76, 6432.
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(11) Formation of 3 presumably arises from participation of
adventitious water in situ.
(12) Use of 1 or 2 equiv of SnCl4 or ZnBr2 gave the starting material,
and BCl3 gave a complex mixture at room temperature.
(13) Snider and Roush assigned the stereochemistry using coupling
constants J3,4 by comparison with the reported data (9−12 Hz for 3,4-
trans; 5.0−9.0 Hz for 3,4-cis). Savastianoff, D.; Pfau, M. Bull. Soc.
Chem. Fr. 1967, 4162. 3,4-trans coupling constants J3,4 determined by
NOESY for 2-oxotetrahydrofurans in this work range from 5.7 to 10.8
Hz (2a (8.4 Hz), 2b (8.6 Hz), 7a (8.0 Hz), 7b (8.1 Hz, 8 Hz in ref 5),
13 (10.1 Hz), 15 (5.7 Hz), and 16 (10.8 Hz)).
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(23) Snider, B. B.; Roush, D. M.; Killinger, T. A. J. Am. Chem. Soc.
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(14) Chemical shifts of H-3 and H-4 for Cl- and Br-adducts
9a,b,d,e,g,h are overlapped in CDCl3. They are separated in C6D6.
(15) The 3,4-trans coupling constants J3,4 (7.3−7.9 Hz) determined
by NOESY for 2-oxopyrrolidines in this work (9a (7.5 Hz), 9b (7.3
Hz), 9c (7.2 Hz), 9d (7.7 Hz), 9f (7.5 Hz), 9g (7.3 Hz), 9h (7.5 Hz),
9i (7.3 Hz), and 11 (7.9 Hz)) are in agreement with the reported data
(Jtrans = 6−8 Hz) for some 2-oxopyrrolidines. (a) Yang, D.; Lian, G.-Y.;
Yang, H.-F.; Yu, J.-D.; Zhang, D.-W.; Gao, X. J. Org. Chem. 2009, 74,
8610. (b) Yang, D.; Yan, Y.-L.; Law, K.-L.; Zhu, N.-Y. Tetrahedron
2003, 59, 10465.
(16) Calculations of 1:1 complex of the substrate and AlCl3 were also
examined. Although the concerted formations of both 3,4-cis and trans-
tetrahydrofuran rings by intramolecular Cl− attack were calculated,
they have higher activation energies (ΔG‡) than the systems of the
substrate and Al2Cl6.
(17) Lewis acid-promoted ene reactions leading to trans-3,4
stereochemistry preferably have been reported (refs 7b−d).
(18) Yamazaki, S.; Ohmitsu, K.; Ohi, K.; Otsubo, T.; Moriyama, K.
Org. Lett. 2005, 7, 759.
(19) (a) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1972, 11, 129.
(b) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1972, 11, 131. (c) Reetz,
M. T. Tetrahedron 1972, 29, 2189. (d) Reetz, M. T. Adv. Organomet.
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Chem. 1977, 16, 33. (e) Fernandez, I.; Cossío, F. P.; Sierra, M. A.
Chem. Rev. 2009, 109, 6687. (f) Davis, R. L.; Leverett, C. A.; Romo,
D.; Tantillo, D. J. J. Org. Chem. 2011, 76, 7167.
(20) Concerted dyotropic TS of B3′ to D3′ could also be calculated.
However, the path has high activation energy (ΔG‡ = 61.39 kcal/mol)
(Supporting Information).
(21) A referee suggested another reaction mechanism shown below.
The mechanism involves formation of a cyclopropane intermediate G3
from B3, via cyclization of the enolate F3, along with AlCl3 and H+
transfers. The mechanism will also be examined in the further study.
For the related cyclopropane opening, see: (a) Stork, G.; Gregson, M.
J. Am. Chem. Soc. 1969, 91, 2373. (b) Stork, G.; Marx, M. J. Am. Chem.
Soc. 1969, 91, 2371.
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dx.doi.org/10.1021/jo401106m | J. Org. Chem. XXXX, XXX, XXX−XXX