Facile synthesis of methylenecyclobutyl-related compounds via rearrangement of methylenecyclopropylcarbinols in the presence of multifluorosulfonyl fluorides and base

Article abstract of DOI:10.1055/s-2007-990836

Methylenecyclopropylcarbinols treated with multifluorosulfonyl fluorides and triethylamine form the 3-methylenecyclobutyl fluorides and 3-methylenecyclobutyl (2-methylenecyclopropyl)methyl ethers in good to high total yields. A proposed mechanism is based on the obtained results. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-990836

SPECIAL TOPIC
3567
Facile Synthesis of Methylenecyclobutyl-Related Compounds via
Rearrangement of Methylenecyclopropylcarbinols in the Presence of
Multifluorosulfonyl Fluorides and Base
F
acile Synthesis of Me
i
thylene
n
cyclobutyl-
R
g
elated Com
-
pounds Hui Qi,a Li-Xiong Shao,*a Min Shi*b
a
b
Fax +86(21)64166128; E-mail: shaolix@ecust.edu.cn, mshi@mail.sioc.ac.cn
Received 24 August 2007
base, can stabilize the separated charges in the transition
state by forming hydrogen bonds. Silica gel significantly
accelerates the reaction and acts as an effective catalyst
for the transformation. In computational studies, we found
that in the rearrangement of the normal sulfonates 2 to
their isomers 3, the carbon skeleton part and the –OSO2R3
part are a pair of tight ions in the intermediate B, while
product 3 will be easily formed from attack of the
–OSO2R3 part to the carbon skeleton through tight ion pair
B (SiO2, silicic acid, has been omitted in the transition
state A and intermediate B for convenience) (Scheme 2).8
Abstract: Methylenecyclopropylcarbinols treated with multifluo-
rosulfonyl fluorides and triethylamine form the 3-methylenecy-
clobutyl fluorides and 3-methylenecyclobutyl (2-methylenecyclo-
propyl)methyl ethers in good to high total yields. A proposed mech-
anism is based on the obtained results.
Key words: methylenecyclopropylcarbinols, multifluorosulfonyl
fluorides, base, rearrangement, etherification
There has been a mounting interest in the application of
methylenecyclopropane (MCP) derivatives in synthetic
transformations.1 Particular attention has been paid to the
transition-metal-catalyzed reactions of MCPs with vari-
ous reactants in organic synthesis over the past decades
and some excellent reviews are available.2 Recent re-
search has resulted in the renaissance of Lewis acid cata-
lyzed chemistry of MCPs, and some novel reaction
patterns have been found by us and other groups.3–6 Previ-
ous reports revealed that when 2-(hydroxymethyl)-substi-
tuted MCPs (methylenecyclopropylcarbinols) 17 are
treated with sulfonation reagents and triethylamine, they
give the normal sulfonates 2, which can be transformed
into their isomers, the 3-methylenecyclobutyl analogues
3, when a silica gel column is used as a workup step
(Scheme 1).8
δ+
δ−
OSO2R3
OSO2R3
SiO2
R1
R2
R1
R2
+
2
transition state A
R1
–OSO2R3
OSO2R3
R2
R1
R2
3
tight ion pair B
Scheme 2 Brief mechanism extracted from the computational stu-
dies
In the mechanism, it can be seen that if –OSO2R3 is a weak
nucleophile and/or a good leaving group, the carbon skel-
etons in the transition state A and/or in the intermediate B
would be attacked by the relatively stronger nucleophiles
present in the reaction system. This hypothesis encour-
aged us to further utilize other sulfonation reagents to
examine the reaction pattern of methylenecyclopropyl-
carbinols 1. For this purpose, multifluorosulfonyl fluo-
rides 4 were selected as the sulfonation reagent since
RFSO2O– (RF = multifluoro group) is a good leaving
group and also a very weak nucleophilic agent.
OH
+
OSO2R3
Et3N
R3SO2Cl
CH2Cl2, r.t.
R1
R2
R1
R2
2
3
1
silica gel
chromatography
R1
R2
OSO2R3
Scheme 1 Sulfonation of methylenecyclopropylcarbinols 1 and fur-
ther rearrangement of the sulfonate
As a consequence, we found that fluorides 5 and ethers 6,
both of which bearing a 3-methylenecyclobutyl group,
were obtained as the products if methylenecyclopropyl-
carbinols 1 were treated with multifluorosulfonyl fluo-
rides 4 and a base (Scheme 3).
Density functional theory (DFT) studies suggest that sili-
ca gel, which serves as both a Lewis acid and a Lewis
SYNTHESIS 2007, No. 22, pp 3567–3573
x
x.
x
x
.
2
0
0
7
Initial examinations of the reactions of methylenecyclo-
Advanced online publication: 16.10.2007
DOI: 10.1055/s-2007-990836; Art ID: C03907SS
© Georg Thieme Verlag Stuttgart · New York
propylcarbinol 1a (R1 = Ph, R2 = H) with perfluorobu-

3568
M.-H. Qi et al.
SPECIAL TOPIC
Table 2 Reaction of Methylenecyclopropylcarbinols 1 with Fluo-
ride 4a in the Presence of Triethylaminea
OH
R1
R2
base
RFSO2F
+
F
OH
R1
R2
4
5
Et3N
RFSO2F
5 +
6
1
R2
+
R1
R2
+
DCE, r.t.
4a: RF = CF3(CF2)3
R1
R1
R2
O
1
6
Entry Carbinol 1 R1
R2
Yieldb (%)
6c
Scheme 3 Reaction of methylenecyclopropylcarbinols 1 in the
presence of multifluorosulfonyl fluorides 4 and a base
5
1
2
1b
1c
1d
1e
1f
3,4,5-(MeO)3C6H2
4-BrC6H4
4-MeC6H4
4-ClC6H4
2,3-Cl2C6H3
H
H
H
H
H
H
Ph
5b, 23 6b, 30
5c, 51 6c, 29
5d, 27 6d, 47
5e, 56 6e, 31
Table 1 Optimization for the Reaction of Methylenecyclopropyl-
carbinol 1a with Fluoride 4aa
3
OH
H
Ph
4
base
solvent, r.t.
F
+
RFSO2F
5
5f, 30
6f, 8
R1
R2
5a
4a: RF = CF3(CF2)3
6
1g
1h
1i
5a, 41 6g, 24
1a: R1 = Ph, R2 = H
+
H
H
7
H
3-MeC6H4 5h, 32 6h, 38
Ph
O
8
4-MeOC6H4
4-FC6H4
H
H
H
H
5i, 21
5j, 9
6i, 28
Ph
6a
9
1j
–
–
Entry
Base
Solvent
Yieldb (%)
10
1k
5k, 7
5a
6ac
35
18
18
24
49
36
28
41
–
a All reactions were carried out using 1 (0.3 mmol) and 4a (0.6 mmol)
in the presence of Et3N (0.4 mmol) and DCE (1.0 mL) at r.t. for 24 h.
b Isolated yields.
1
2
Et3N
DCE
57
23
2
c Ratio of syn/anti = 1:1, as determined by 1H NMR spectroscopy.
DBU
DCE
3
DABCO
DMAP
DIPEA
Et2NH
pyridine
i-Pr2NH
Et3N
DCE
(Table 1, entry 1). For other bases and solvents screened,
the yield(s) of 5a and/or 6a varied from low to moderate
in all other cases (Table 1, entries 2–12).
4
DCE
27
22
20
–
5
DCE
To survey the generality of this transformation, a variety
of methylenecyclopropylcarbinols 1 was examined with
perfluorobutane-1-sulfonyl fluoride (4a) under the opti-
mized conditions. For most of the substrates 1 examined,
either as the E- or Z-isomers, the reactions proceeded
smoothly to give the corresponding products 5 and/or 6 in
moderate to high total yields (Table 2). For substrates 1j
(R1 = 4-FC6H4, R2 = H) and 1k (R1 = R2 = H), only the
corresponding products 5j and 5k, respectively, were ob-
tained in very low yields (Table 2, entries 9 and 10). To
further determine the structure of products 5, fluoride 5c
was unambiguously confirmed by an X-ray diffraction
analysis (Figure 1).9 For all products 6, mixtures of syn-
and anti-isomers were obtained in a ratio of 1:1 (Table 2).
6
DCE
7
DCE
8
DCE
47
27
41
31
10
9
Et2O
10
11
12
Et3N
benzene
toluene
MeCN
–
Et3N
–
Et3N
–
a All reactions were carried out using 1a (0.3 mmol) and 4a (0.6
mmol) in the presence of the listed base (0.4 mmol) and solvent (1.0
mL) at r.t. for 24 h.
b Isolated yields.
To further examine the generality, we also carried out the
transformation of substrates 1 with another multifluoro-
sulfonyl fluoride 4b under the optimized conditions.
Again, all reactions proceeded smoothly to give the corre-
sponding products 5 and 6 in good to high total yields
(Table 3).
c Ratio of syn/anti = 1:1, as determined by 1H NMR spectroscopy.
tane-1-sulfonyl fluoride (4a) were carefully carried out at
room temperature. We found that the reactions took place
smoothly to give the 3-methylenecyclobutyl fluoride 5a
and the corresponding ether 6a in moderate to high total
yields with various bases and solvents, as shown in The reaction of methylenecyclopropylcarbinol 1a with
Table 1. The combination of triethylamine as the base and trifluoromethanesulfonic anhydride was also carried out
1,2-dichloroethane (DCE) as the solvent is the best choice under the standard conditions. Unfortunately, we found
for this transformation, leading to the formation of prod- that the reaction system became disordered and no major
ucts 5a in 57% yield and 6a in 35% yield, respectively product could be obtained (Scheme 4).
Synthesis 2007, No. 22, 3567–3573 © Thieme Stuttgart · New York

SPECIAL TOPIC
Facile Synthesis of Methylenecyclobutyl-Related Compounds
3569
OH
Et3N
+
(CF3SO2)2O
disordered
DCE, r.t.
R1
R2
1a: R1 = Ph, R2 = H
Scheme 4 Reaction of methylenecyclopropylcarbinol 1a with
(CF3SO2)2O under the standard conditions
methylenecyclopropylcarbinols 1 react with RFSO2F in
the presence of triethylamine to give the normal sul-
fonates 7 and triethylamine hydrofluoride (HEt3N+F–).
The enhanced leaving-group ability of RFSO2O– is well
known10 and the C–O bond will become more polarized
according to this property, which will result in a separate
ion pair as shown as intermediate 8 (maybe it is more rea-
sonable to show 8 as an intermediate with more polariza-
tion in the C–O bond rather than a separated ion pair).
Subsequently, the carbon skeleton part in 8, that is, the
methylenecyclopropylmethyl cation, will quickly rear-
range to the methylenecyclobutyl cation, as shown as in-
termediate 9, which will also be a separated ion pair for
the same reason.10 Nucleophilic attack of 9 by F– from
HEt3N+F– will give product 5, while nucleophilic attack
by substrate 1 will furnish product 6. At the same time, in-
termediate 9 can also be shown as the sulfonate 10, which
will also result in products 5 and 6, if it is attacked by the
appropriate nucleophiles (Scheme 5).
Figure 1 ORTEP drawing of product 5c
Table 3 Reaction of Methylenecyclopropylcarbinols 1 with Fluo-
ride 4b in the Presence of Triethylaminea
OH
Et3N
RFSO2F
5
+ 6
+
DCE, r.t.
R1
R2
4b: RF = ICF2OCF2CF2
1
Entry Carbinol 1R1
R2
Yieldb (%)
5
6c
1
2
3
4
1a
1c
1d
1e
Ph
H
H
H
H
5a, 64
5c, 44
5d, 23
5e, 41
6a, 27
6c, 26
6d, 42
6e, 36
4-BrC6H4
4-MeC6H4
4-ClC6H4
In summary, we have found that methylenecyclopropyl-
carbinols 1 treated with multifluorosulfonyl fluorides 4
can give 3-methylenecyclobutyl fluorides 5 and the corre-
sponding 3-methylenecyclobutyl-related ethers 6 in good
to high total yields. A plausible mechanism has been pro-
posed on the basis of the obtained results, which puts its
emphasis on the rearrangement of methylenecyclopropyl-
methyl multifluorosulfonates to methylenecyclobutyl an-
alogues due to the easy leaving-group ability of RFSO2O–.
Furthermore, the reaction also introduces a new and sim-
a All reactions were carried out using 1 (0.3 mmol) and 4b (0.6 mmol)
in the presence of Et3N (0.4 mmol) and DCE (1.0 mL) at r.t. for 24 h.
b Isolated yields.
c Ratio of syn/anti = 1:1, as determined by 1H NMR spectroscopy.
Based on the results obtained above, a plausible mecha-
nism for this transformation of methylenecyclopropyl-
carbinols
1
is outlined in Scheme 5. Firstly,
OSO2RF
OH
RFSO2F, Et3N
+
HEt3N+F–
R1
R1
R2
R2
7
1
F
+
+
HEt3N+F–
–OSO2RF
–OSO2RF
R1
R2
R1
R2
R1
R2
9
5
8
1
HEt3N+F–
R2
R1
R2
R1
R2
R1
1
O
OSO2RF
6
10
Scheme 5 Plausible mechanism for the formation of 5 and 6
Synthesis 2007, No. 22, 3567–3573 © Thieme Stuttgart · New York

3570
M.-H. Qi et al.
SPECIAL TOPIC
13C NMR (75 MHz, CDCl3) (syn- or anti-isomer): d = 10.1, 13.1,
40.7, 41.1, 70.1, 71.1, 119.1, 122.6, 125.9, 126.1, 126.7, 127.1,
128.4, 128.5, 134.9, 137.6, 137.7.
13C NMR (75 MHz, CDCl3) (anti- or syn-isomer): d = 10.1, 13.1,
40.8, 41.2, 70.2, 71.1, 119.1, 122.6, 125.9, 126.1, 126.7, 127.1,
128.4, 128.5, 134.9, 137.6, 137.7.
ple one-step synthetic method for 3-methylenecyclobutyl
fluorides 5 from methylenecyclopropylcarbinols 1 with
easy manipulation and a simple experimental procedure.
Efforts are underway in our laboratory to elucidate the
mechanistic details and to determine the scope and limita-
tions of the reaction.
MS: m/z (%) = 302 (1) [M+], 143 (62), 128 (100), 115 (35).
HRMS: m/z calcd for C22H22O: 302.1671; found: 302.1674.
1H and 13C NMR spectra were recorded on a Varian Mercury VX-
300 spectrometer for solutions in CDCl3 with tetramethylsilane as
an internal standard. IR spectra were measured on a Perkin–Elmer
983 spectrometer. Mass spectra and HRMS were recorded with a
HP-5989 instrument, a Finnigan MA+ mass spectrometer and a Mi-
cromass GCT mass spectrometer. Satisfactory CHN microanalyses
were obtained with a Carlo–Erba 1106 analyzer. Organic solvents
were dried by standard methods when necessary. Melting points are
uncorrected. All reactions were monitored by TLC using Huanghai
GF254 silica gel coated plates. Flash column chromatography was
carried out using 300–400 mesh silica gel at increased pressure.
5b
Colorless liquid.
IR (CH2Cl2): 2960, 2936, 2839, 1750, 1691, 1581, 1507, 1464,
1417, 1350, 1325, 1238, 1184, 1127, 1071, 1008, 931, 879, 826,
700 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.13–3.37 (m, 4 H), 3.85 (s, 3 H,
MeO), 3.86 (s, 6 H, 2 × MeO), 5.19 (d quin, J = 56.1, 6.0 Hz, 1 H),
6.23 (t, J = 2.1 Hz, 1 H), 6.42 (s, 2 H, Ar).
13C NMR (75 MHz, CDCl3): d = 41.3 (d, JCF = 22.4 Hz), 41.8 (d,
JCF = 22.7 Hz), 56.0, 60.9, 84.3 (d, JCF = 209.9 Hz), 104.1, 123.6 (d,
JCF = 7.4 Hz), 130.9 (d, JCF = 18.4 Hz), 133.1, 153.1.
3-(Arylmethylene)cyclobutyl Fluorides 5 and 3-(Arylmethyl-
ene)cyclobutyl [2-(Arylmethylene)cyclopropyl]methyl Ethers
6; General Procedure
MS: m/z (%) = 252 (80) [M+], 237 (20), 221 (100), 191 (46).
Under an argon atmosphere, a methylenecyclopropylcarbinol 1 (0.3
mmol), a multifluorosulfonyl fluoride 4 (0.6 mmol), Et3N (0.4
mmol) and DCE (1.0 mL) were added successively into a flash-
dried Schlenk tube. The reaction mixture was stirred at r.t. and was
monitored by TLC. The reaction usually was completed within 24
h. Then, the reaction was quenched with H2O (10 mL) and the mix-
ture was extracted with CH2Cl2 (3 × 20 mL). The combined organic
layers were washed with 1.0 M aq HCl (10 mL) and sat. aq NaHCO3
soln (10 mL), and dried (anhyd MgSO4), then the solution was con-
centrated under reduced pressure. Pure products were obtained by
flash column chromatography (PE–EtOAc, 50:1).
HRMS: m/z calcd for C14H17FO3: 252.1162; found: 252.1161.
6b
Colorless liquid.
IR (CH2Cl2): 2939, 2839, 1737, 1687, 1584, 1506, 1463, 1417,
1327, 1237, 1185, 1127, 1005 cm–1.
1H NMR (300 MHz, CDCl3) (syn- or anti-isomer): d = 1.23–1.33
(m, 1 H), 1.72 (t, J = 8.7 Hz, 1 H), 1.86–1.94 (m, 1 H), 2.94–3.34
(m, 5 H), 3.52 (dd, J = 6.3, 10.2 Hz, 1 H), 3.84 (s, 3 H, MeO), 3.85
(s, 9 H, 3 × MeO), 3.89 (s, 6 H, 2 × MeO), 4.22 (quin, J = 6.3 Hz, 1
H), 6.19 (s, 1 H), 6.44 (s, 2 H, Ar), 6.75 (s, 1 H), 6.78 (s, 2 H, Ar).
1H NMR (300 MHz, CDCl3) (anti- or syn-isomer): d = 1.23–1.33
(m, 1 H), 1.73 (t, J = 8.7 Hz, 1 H), 1.86–1.94 (m, 1 H), 2.94–3.34
(m, 5 H), 3.53 (dd, J = 6.3, 10.2 Hz, 1 H), 3.84 (s, 3 H, MeO), 3.85
(s, 9 H, 3 × MeO), 3.89 (s, 6 H, 2 × MeO), 4.22 (quin, J = 6.3 Hz, 1
H), 6.19 (s, 1 H), 6.44 (s, 2 H, Ar), 6.76 (s, 1 H), 6.78 (s, 2 H, Ar).
13C NMR (75 MHz, CDCl3) (syn- or anti-isomer): d = 9.8, 13.1,
40.5, 41.0, 55.9, 56.0, 60.89, 60.91, 70.1, 71.0, 103.6, 104.0, 119.1,
122.6, 125.3, 133.4, 133.5, 134.3, 136.5, 137.3, 153.1, 153.2.
13C NMR (75 MHz, CDCl3) (anti- or syn-isomer): d = 9.8, 13.1,
40.6, 41.1, 55.9, 56.0, 60.89, 60.91, 70.1, 71.0, 103.6, 104.0, 119.1,
122.6, 125.3, 133.4, 133.5, 134.3, 136.5, 137.3, 153.1, 153.2.
5a
Colorless liquid.
IR (CH2Cl2): 2924, 2853, 1789, 1705, 1599, 1496, 1453, 1404,
1353, 1269, 1162, 1023, 742 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.11–3.35 (m, 4 H), 5.17 (d quin,
J = 56.1, 6.0 Hz, 1 H), 6.29 (t, J = 2.4 Hz, 1 H), 7.17–7.23 (m, 3 H,
Ar), 7.31–7.34 (m, 2 H, Ar).
13C NMR (75 MHz, CDCl3): d = 41.4 (d, JCF = 22.4 Hz), 41.9 (d,
JCF = 21.8 Hz), 84.4 (d, JCF = 209.7 Hz), 123.6 (d, JCF = 7.3 Hz),
126.5, 127.1, 128.5, 131.5 (d, JCF = 18.5 Hz), 137.3.
MS: m/z (%) = 162 (8) [M+], 158 (50), 129 (38), 115 (32), 105 (100).
MS: m/z (%) = 482 (40) [M+], 233 (66), 232 (42), 202 (100), 189
HRMS: m/z calcd for C11H11F: 162.0845; found: 162.0836.
(32).
6a
HRMS: m/z calcd for C28H34O7: 482.2305; found: 482.2310.
Colorless liquid.
5c
IR (CH2Cl2): 3083, 3060, 3025, 2924, 2855, 1945, 1736, 1685,
1597, 1495, 1450, 1340, 1259, 1184, 1116, 912, 865, 746 cm–1.
White solid; mp 55–57 °C.
1H NMR (300 MHz, CDCl3) (syn- or anti-isomer): d = 1.25–1.33
(m, 1 H), 1.72 (t, J = 8.7 Hz, 1 H), 1.83–1.93 (m, 1 H), 2.90–3.31
(m, 5 H), 3.54 (dd, J = 6.3, 10.2 Hz, 1 H), 4.21 (quin, J = 6.3 Hz, 1
H), 6.25 (s, 1 H), 6.82 (s, 1 H), 7.14–7.36 (m, 8 H, Ar), 7.53 (d,
J = 7.8 Hz, 2 H, Ar).
1H NMR (300 MHz, CDCl3) (anti- or syn-isomer): d = 1.25–1.33
(m, 1 H), 1.73 (t, J = 8.7 Hz, 1 H), 1.83–1.93 (m, 1 H), 2.90–3.31
(m, 5 H), 3.54 (dd, J = 6.3, 10.2 Hz, 1 H), 4.21 (quin, J = 6.3 Hz, 1
H), 6.25 (s, 1 H), 6.83 (s, 1 H), 7.14–7.36 (m, 8 H, Ar), 7.53 (d,
J = 7.8 Hz, 2 H, Ar).
IR (neat): 2990, 2972, 2954, 2901, 1899, 1756, 1677, 1649, 1487,
1427, 1401, 1358, 1228, 1207, 1173, 1110, 1065, 1019, 1007, 978,
934, 879, 822, 782 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.10–3.32 (m, 4 H), 5.18 (d quin,
J = 55.8, 6.0 Hz, 1 H), 6.23 (t, J = 2.4 Hz, 1 H), 7.04 (d, J = 8.4 Hz,
2 H, Ar), 7.42 (d, J = 8.4 Hz, 2 H, Ar).
13C NMR (75 MHz, CDCl3): d = 41.3 (d, JCF = 22.4 Hz), 41.9 (d,
JCF = 22.4 Hz), 84.2 (d, JCF = 209.9 Hz), 120.1, 122.6 (d, JCF = 7.9
Hz), 128.6, 131.5, 132.6 (d, JCF = 17.9 Hz), 136.1.
MS: m/z (%) = 242 (35), 240 (35) [M+], 196 (29), 194 (29), 161 (90),
146 (31), 141 (63), 115 (100).
Synthesis 2007, No. 22, 3567–3573 © Thieme Stuttgart · New York

SPECIAL TOPIC
Facile Synthesis of Methylenecyclobutyl-Related Compounds
3571
Anal. Calcd for C11H10BrF: C, 54.80; H, 4.18. Found: C, 54.80; H,
4.15.
13C NMR (75 MHz, CDCl3) (anti- or syn-isomer): d = 10.1, 13.1,
21.1, 21.2, 40.7, 41.1, 70.2, 71.2, 119.0, 122.4, 124.7, 126.6, 127.0,
129.1, 129.2, 133.8, 134.89, 134.91, 135.8, 136.8.
6c
MS: m/z (%) = 330 (0.3) [M+], 157 (37), 142 (100), 129 (43).
White solid; mp 104–106 °C.
HRMS: m/z calcd for C24H26O: 330.1984; found: 330.1986.
IR (CH2Cl2): 2922, 2853, 1487, 1400, 1276, 1261, 1184, 1106,
1072, 1007, 875, 820, 764, 750 cm–1.
5e
1H NMR (300 MHz, CDCl3) (syn- or anti-isomer): d = 1.26–1.31
(m, 1 H), 1.69 (t, J = 9.0 Hz, 1 H), 1.82–1.91 (m, 1 H), 2.85–3.31
(m, 5 H), 3.48–3.54 (m, 1 H), 4.20 (quin, J = 6.3 Hz, 1 H), 6.18 (s,
1 H), 6.76 (s, 1 H), 7.05 (d, J = 8.7 Hz, 2 H, Ar), 7.37–7.46 (m, 6 H,
Ar).
1H NMR (300 MHz, CDCl3) (anti- or syn-isomer): d = 1.26–1.31
(m, 1 H), 1.70 (t, J = 9.0 Hz, 1 H), 1.82–1.91 (m, 1 H), 2.85–3.31
(m, 5 H), 3.48–3.54 (m, 1 H), 4.20 (quin, J = 6.3 Hz, 1 H), 6.18 (s,
1 H), 6.77 (s, 1 H), 7.05 (d, J = 8.7 Hz, 2 H, Ar), 7.37–7.46 (m, 6 H,
Ar).
White solid; mp 33–35 °C.
IR (CDCl3): 3029, 2970, 2913, 1902, 1680, 1592, 1492, 1405, 1349,
1226, 1207, 1179, 1091, 1073, 1012, 936, 875, 824 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.11–3.31 (m, 4 H), 5.18 (d quin,
J = 55.8, 6.0 Hz, 1 H), 6.24 (t, J = 2.4 Hz, 1 H), 7.10 (d, J = 8.4 Hz,
2 H, Ar), 7.27 (d, J = 8.4 Hz, 2 H, Ar).
13C NMR (75 MHz, CDCl3): d = 41.3 (d, JCF = 22.4 Hz), 41.9 (d,
JCF = 22.3 Hz), 84.3 (d, JCF = 210.1 Hz), 122.6 (d, JCF = 7.4 Hz),
128.3, 128.6, 132.0, 132.4 (d, JCF = 17.8 Hz), 135.7.
MS: m/z (%) = 196 (36) [M+], 161 (91), 150 (33), 141 (52), 115
(100).
13C NMR (75 MHz, CDCl3) (syn- or anti-isomer): d = 10.0, 13.2,
40.6, 41.1, 70.0, 70.9, 118.2, 119.8, 120.8, 121.7, 126.8, 128.2,
128.6, 131.4, 131.5, 136.0, 136.5.
HRMS: m/z calcd for C11H10ClF: 196.0455; found: 196.0455.
13C NMR (75 MHz, CDCl3) (anti- or syn-isomer): d = 10.0, 13.2,
40.7, 41.2, 70.0, 70.9, 118.2, 119.8, 120.8, 121.7, 126.8, 128.2,
128.6, 131.4, 131.5, 136.0, 136.5.
6e
Yellow solid; mp 84–86 °C.
MS: m/z (%) = 458 (0.5) [M+], 143 (11), 142 (100), 141 (36).
IR (CDCl3): 3032, 2961, 2925, 2854, 1735, 1491, 1403, 1261, 1188,
1090, 1012, 969, 871, 822 cm–1.
Anal. Calcd for C22H20Br2O: C, 57.42; H, 4.38. Found: C, 57.63; H,
4.50.
1H NMR (300 MHz, CDCl3) (syn- or anti-isomer): d = 1.28–1.32
(m, 1 H), 1.70 (t, J = 9.0 Hz, 1 H), 1.84–1.92 (m, 1 H), 2.87–3.32
(m, 5 H), 3.51 (dd, J = 6.3, 10.2 Hz, 1 H), 4.20 (quin, J = 6.3 Hz, 1
H), 6.20 (s, 1 H), 6.78 (s, 1 H), 7.12 (d, J = 8.1 Hz, 2 H, Ar), 7.25–
7.31 (m, 4 H, Ar), 7.45 (d, J = 8.1 Hz, 2 H, Ar).
1H NMR (300 MHz, CDCl3) (anti- or syn-isomer): d = 1.28–1.32
(m, 1 H), 1.71 (t, J = 9.0 Hz, 1 H), 1.84–1.92 (m, 1 H), 2.87–3.32
(m, 5 H), 3.52 (dd, J = 6.3, 10.2 Hz, 1 H), 4.20 (quin, J = 6.3 Hz, 1
H), 6.20 (s, 1 H), 6.78 (s, 1 H), 7.12 (d, J = 8.1 Hz, 2 H, Ar), 7.25–
7.31 (m, 4 H, Ar), 7.45 (d, J = 8.1 Hz, 2 H, Ar).
13C NMR (75 MHz, CDCl3) (syn- or anti-isomer): d = 10.0, 13.2,
40.6, 41.1, 70.1, 70.9, 118.1, 121.6, 126.7, 127.8, 128.2, 128.5,
128.6, 131.7, 132.6, 135.8, 136.11, 136.12.
13C NMR (75 MHz, CDCl3) (anti- or syn-isomer): d = 10.0, 13.2,
40.7, 41.2, 70.1, 71.0, 118.1, 121.6, 126.7, 127.8, 128.3, 128.5,
128.6, 131.7, 132.6, 135.8, 136.11, 136.12.
5d
Colorless liquid.
IR (CH2Cl2): 3023, 2967, 2921, 2857, 1896, 1750, 1730, 1700,
1680, 1610, 1514, 1402, 1349, 1179, 1072, 1019, 936, 875, 817,
764, 750 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.33 (s, 3 H, Me), 3.10–3.34 (m,
4 H), 5.17 (d quin, J = 56.4, 6.0 Hz, 1 H), 6.26 (t, J = 2.4 Hz, 1 H),
7.08 (d, J = 8.7 Hz, 2 H, Ar), 7.13 (d, J = 8.7 Hz, 2 H, Ar).
13C NMR (75 MHz, CDCl3): d = 21.1, 41.4 (d, JCF = 22.2 Hz), 41.9
(d, JCF = 22.7 Hz), 84.5 (d, JCF = 209.9 Hz), 123.5 (d, JCF = 7.6 Hz),
127.0, 129.1, 130.3 (d, JCF = 18.2 Hz), 134.5, 136.2.
MS: m/z (%) = 176 (65) [M+], 161 (100), 156 (32), 141 (39), 130
(37), 129 (57), 128 (40), 115 (75).
HRMS: m/z calcd for C12H13F: 176.1001; found: 176.1001.
MS: m/z (%) = 370 (1) [M+], 177 (23), 142 (100), 141 (56).
HRMS: m/z calcd for C22H20Cl2O: 370.0891; found: 370.0889.
6d
Yellow liquid.
5f
IR (CDCl3): 2962, 2920, 1727, 1512, 1458, 1275, 1261, 1187, 1108,
1031, 967, 871, 815, 750 cm–1.
Colorless liquid.
IR (CH2Cl2): 3020, 2971, 2920, 2853, 1680, 1580, 1557, 1450,
1410, 1351, 1275, 1261, 1224, 1183, 1158, 1096, 1074, 1045, 1020,
970, 940, 888, 863, 798, 781, 765, 750 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.17–3.25 (m, 4 H), 5.18 (d quin,
J = 56.1, 6.0 Hz, 1 H), 6.65 (t, J = 2.4 Hz, 1 H), 7.14–7.18 (m, 2 H,
Ar), 7.29–7.33 (m, 1 H, Ar).
13C NMR (75 MHz, CDCl3): d = 41.2 (d, JCF = 22.7 Hz), 42.0 (d,
JCF = 22.4 Hz), 83.9 (d, JCF = 210.5 Hz), 120.3 (d, JCF = 7.3 Hz),
126.1, 126.9, 128.4, 130.9, 133.4, 135.2 (d, JCF = 18.8 Hz), 137.1.
1H NMR (300 MHz, CDCl3) (syn- or anti-isomer): d = 1.25–1.34
(m, 1 H), 1.69 (t, J = 8.7 Hz, 1 H), 1.82–1.90 (m, 1 H), 2.32 (s, 3 H,
Me), 2.34 (s, 3 H, Me), 2.93–3.29 (m, 5 H), 3.54 (dd, J = 6.3, 9.9
Hz, 1 H), 4.19 (quin, J = 6.3 Hz, 1 H), 6.21 (s, 1 H), 6.78 (s, 1 H),
7.10–7.15 (m, 6 H, Ar), 7.42 (d, J = 8.4 Hz, 2 H, Ar).
1H NMR (300 MHz, CDCl3) (anti- or syn-isomer): d = 1.25–1.34
(m, 1 H), 1.70 (t, J = 8.7 Hz, 1 H), 1.82–1.90 (m, 1 H), 2.32 (s, 3 H,
Me), 2.34 (s, 3 H, Me), 2.93–3.29 (m, 5 H), 3.54 (dd, J = 6.3, 9.9
Hz, 1 H), 4.19 (quin, J = 6.3 Hz, 1 H), 6.21 (s, 1 H), 6.79 (s, 1 H),
7.10–7.15 (m, 6 H, Ar), 7.42 (d, J = 8.4 Hz, 2 H, Ar).
MS: m/z (%) = 230 (33) [M+], 197 (25), 195 (72), 184 (26), 175 (40),
13C NMR (75 MHz, CDCl3) (syn- or anti-isomer): d = 10.1, 13.1,
21.1, 21.2, 40.6, 41.0, 70.2, 71.1, 119.0, 122.4, 124.7, 126.6, 127.0,
129.1, 129.2, 133.8, 134.89, 134.91, 135.8, 136.8.
160 (24), 151 (28), 149 (100).
HRMS: m/z calcd for C11H9Cl2F: 230.0065; found: 230.0065.
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M.-H. Qi et al.
SPECIAL TOPIC
MS: m/z (%) = 330 (2) [M+], 157 (47), 142 (100), 129 (30).
Yellow liquid.
HRMS: m/z calcd for C24H26O: 330.1984; found: 330.1985.
IR (CDCl3): 3082, 3059, 3025, 2964, 2905, 1738, 1597, 1494, 1449,
1340, 1188, 1116, 1076, 1008, 912, 865, 768, 744 cm–1.
5i
Yellow liquid.
1H NMR (300 MHz, CDCl3) (syn- or anti-isomer): d = 1.08–1.12
(m, 1 H), 1.46 (t, J = 9.0 Hz, 1 H), 2.08–2.17 (m, 1 H), 2.87–3.25
(m, 5 H), 3.80 (dd, J = 6.3, 9.9 Hz, 1 H), 4.16 (quin, J = 6.3 Hz, 1
H), 6.23 (s, 1 H), 6.76 (s, 1 H), 7.13–7.35 (m, 8 H, Ar), 7.51 (d,
J = 7.5 Hz, 2 H, Ar).
1H NMR (300 MHz, CDCl3) (anti- or syn-isomer): d = 1.08–1.12
(m, 1 H), 1.46 (t, J = 9.0 Hz, 1 H), 2.08–2.17 (m, 1 H), 2.87–3.25
(m, 5 H), 3.80 (dd, J = 6.3, 9.9 Hz, 1 H), 4.16 (quin, J = 6.3 Hz, 1
H), 6.24 (s, 1 H), 6.77 (s, 1 H), 7.13–7.35 (m, 8 H, Ar), 7.51 (d,
J = 7.5 Hz, 2 H, Ar).
IR (CH2Cl2): 2963, 2913, 2832, 1608, 1512, 1461, 1347, 1297,
1275, 1257, 1175, 1071, 1035, 828, 764, 750 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.09–3.34 (m, 4 H), 3.80 (s, 3 H,
MeO), 5.17 (d quin, J = 55.8, 6.3 Hz, 1 H), 6.23 (t, J = 2.4 Hz, 1 H),
6.86 (d, J = 8.7 Hz, 2 H, Ar), 7.13 (d, J = 8.7 Hz, 2 H, Ar).
13C NMR (75 MHz, CDCl3): d = 41.2 (d, JCF = 22.1 Hz), 41.8 (d,
JCF = 21.8 Hz), 55.3, 84.5 (d, JCF = 209.8 Hz), 113.9, 123.0 (d,
JCF = 7.5 Hz), 128.3, 128.8 (d, JCF = 18.5 Hz), 130.2, 158.2.
MS: m/z (%) = 192 (100) [M+], 177 (49), 172 (45), 146 (50), 131
(35), 103 (34).
13C NMR (75 MHz, CDCl3) (syn- or anti-isomer): d = 7.2, 16.8,
40.5, 41.0, 70.3, 70.5, 120.1, 122.6, 125.70, 125.72, 126.1, 126.7,
127.0, 128.3, 128.5, 134.9, 137.3, 137.6.
HRMS: m/z calcd for C12H13FO: 192.0950; found: 192.0950.
13C NMR (75 MHz, CDCl3) (anti- or syn-isomer): d = 7.2, 16.8,
40.7, 41.1, 70.3, 70.5, 120.1, 122.6, 125.70, 125.72, 126.1, 126.7,
127.0, 128.3, 128.5, 134.9, 137.3, 137.6.
MS: m/z (%) = 302 (0.2) [M+], 143 (43), 128 (100), 115 (45), 91
(27).
6i
White solid; mp 73–75 °C.
IR (CH2Cl2): 2955, 2932, 2852, 2836, 1729, 1607, 1511, 1463,
1442, 1339, 1293, 1248, 1174, 1107, 1034, 870, 828 cm–1.
1H NMR (300 MHz, CDCl3) (syn- or anti-isomer): d = 1.25–1.29
(m, 1 H), 1.68 (t, J = 8.7 Hz, 1 H), 1.81–1.90 (m, 1 H), 2.84–3.29
(m, 5 H), 3.53 (dd, J = 6.3, 10.2 Hz, 1 H), 3.80 (s, 3 H, MeO), 3.81
(s, 3 H, MeO), 4.20 (quin, J = 6.3 Hz, 1 H), 6.19 (s, 1 H), 6.76 (s, 1
H), 6.85 (d, J = 8.1 Hz, 2 H, Ar), 6.88 (d, J = 8.1 Hz, 2 H, Ar), 7.14
(d, J = 8.4 Hz, 2 H, Ar), 7.47 (d, J = 8.4 Hz, 2 H, Ar).
1H NMR (300 MHz, CDCl3) (anti- or syn-isomer): d = 1.25–1.29
(m, 1 H), 1.69 (t, J = 8.7 Hz, 1 H), 1.81–1.90 (m, 1 H), 2.84–3.29
(m, 5 H), 3.54 (dd, J = 6.3, 10.2 Hz, 1 H), 3.80 (s, 3 H, MeO), 3.81
(s, 3 H, MeO), 4.20 (quin, J = 6.3 Hz, 1 H), 6.19 (s, 1 H), 6.77 (s, 1
H), 6.85 (d, J = 8.1 Hz, 2 H, Ar), 6.88 (d, J = 8.1 Hz, 2 H, Ar), 7.14
(d, J = 8.4 Hz, 2 H, Ar), 7.47 (d, J = 8.4 Hz, 2 H, Ar).
13C NMR (75 MHz, CDCl3) (syn- or anti-isomer): d = 10.0, 13.2,
40.4, 41.0, 55.2, 55.3, 70.2, 71.2, 113.8, 113.9, 118.5, 121.9, 123.3,
127.8, 128.2, 130.59, 130.62, 132.4, 157.9, 158.8.
13C NMR (75 MHz, CDCl3) (anti- or syn-isomer): d = 10.0, 13.2,
40.5, 41.1, 55.2, 55.3, 70.2, 71.2, 113.8, 113.9, 118.5, 121.9, 123.3,
127.8, 128.2, 130.59, 130.62, 132.4, 157.9, 158.8.
HRMS: m/z calcd for C22H22O: 302.1671; found: 302.1674.
5h
Colorless liquid.
IR (CH2Cl2): 2960, 2925, 2855, 1736, 1720, 1604, 1490, 1466,
1459, 1350, 1259, 1179, 1073, 1021, 904, 881, 785 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.34 (s, 3 H, Me), 3.12–3.36 (m,
4 H), 5.18 (d quin, J = 56.1, 6.0 Hz, 1 H), 6.26 (t, J = 2.4 Hz, 1 H),
7.00–7.02 (m, 3 H, Ar), 7.19–7.24 (m, 1 H, Ar).
13C NMR (75 MHz, CDCl3): d = 21.5, 41.4 (d, JCF = 22.3 Hz), 41.9
(d, JCF = 22.4 Hz), 84.4 (d, JCF = 209.5 Hz), 123.7 (d, JCF = 7.5 Hz),
124.2, 127.3, 127.9, 128.3, 131.2 (d, JCF = 18.5 Hz), 137.2, 138.0.
MS: m/z (%) = 176 (75) [M+], 161 (100), 156 (32), 146 (25), 141
(39), 130 (32), 129 (49), 128 (39), 115 (71).
HRMS: m/z calcd for C12H13F: 176.1001; found: 176.0999.
6h
Yellow liquid.
MS: m/z (%) = 362 (12) [M+], 173 (68), 158 (100).
IR (CH2Cl2): 3032, 2921, 2857, 1782, 1736, 1604, 1584, 1489,
1459, 1338, 1261, 1187, 1114, 1039, 905, 785 cm–1.
HRMS: m/z calcd for C24H26O3: 362.1882; found: 362.1882.
1H NMR (300 MHz, CDCl3) (syn- or anti-isomer): d = 1.07–1.11
(m, 1 H), 1.45 (t, J = 9.0 Hz, 1 H), 2.08–2.18 (m, 1 H), 2.33 (s, 3 H,
Me), 2.36 (s, 3 H, Me), 2.87–3.26 (m, 5 H), 3.79 (dd, J = 6.3, 9.9
Hz, 1 H), 4.17 (quin, J = 6.3 Hz, 1 H), 6.20 (s, 1 H), 6.73 (s, 1 H),
6.97–7.35 (m, 8 H, Ar).
1H NMR (300 MHz, CDCl3) (anti- or syn-isomer): d = 1.07–1.11
(m, 1 H), 1.46 (t, J = 9.0 Hz, 1 H), 2.08–2.18 (m, 1 H), 2.33 (s, 3 H,
Me), 2.36 (s, 3 H, Me), 2.87–3.26 (m, 5 H), 3.80 (dd, J = 6.3, 9.9
Hz, 1 H), 4.17 (quin, J = 6.3 Hz, 1 H), 6.20 (s, 1 H), 6.73 (s, 1 H),
6.97–7.35 (m, 8 H, Ar).
13C NMR (75 MHz, CDCl3) (syn- or anti-isomer): d = 7.1, 16.8,
21.46, 21.48, 40.6, 41.0, 70.4, 70.6, 120.2, 122.7, 123.8, 124.1,
125.5, 126.9, 127.5, 127.8, 127.9, 128.2, 128.4, 134.7, 137.3, 137.7,
137.9, 138.0.
13C NMR (75 MHz, CDCl3) (anti- or syn-isomer): d = 7.1, 16.8,
21.46, 21.48, 40.8, 41.2, 70.4, 70.6, 120.2, 122.7, 123.9, 124.1,
125.5, 126.9, 127.5, 127.8, 127.9, 128.2, 128.4, 134.7, 137.3, 137.7,
137.9, 138.0.
Acknowledgment
We thank the State Key Project of Basic Research (Project 973)
(No. G2000048007), the Chinese Academy of Sciences (KGCX2-
210-01), the Shanghai Municipal Committee of Science and Tech-
nology, the National Natural Science Foundation of China
(203900502, 20025206 and 20272069) and the Cheung Kong Scho-
lar Program for financial support.
References
(1) For the synthesis of MCPs, see: (a) Brandi, A.; Goti, A.
Chem. Rev. 1998, 98, 589. (b) Houben–Weyl Methods of
Organic Chemistry: Carbocyclic Three-Membered Ring
Compounds, Vols. E17a–c; de Meijere, A., Ed.; Georg
Thieme: Stuttgart, 1996.
(2) For some reviews, see: (a) Nakamura, I.; Yamamoto, Y.
Adv. Synth. Catal. 2002, 344, 111. (b) Brandi, A.; Cicchi,
S.; Cordero, F. M.; Goti, A. Chem. Rev. 2003, 103, 1213.
Synthesis 2007, No. 22, 3567–3573 © Thieme Stuttgart · New York

SPECIAL TOPIC
Facile Synthesis of Methylenecyclobutyl-Related Compounds
3573
(3) For a recent review on the Lewis acid catalyzed ring-opening
reactions of MCPs, see: Shao, L.-X.; Shi, M. Curr. Org.
Chem. 2007, 11, 1135; and references cited therein.
(4) For some selected papers on the Lewis acid catalyzed
cycloaddition reactions of MCPs, see: (a) Shi, M.; Shao,
L.-X.; Xu, B. Org. Lett. 2003, 5, 579. (b) Shao, L.-X.; Shi,
M. Adv. Synth. Catal. 2003, 345, 963. (c) Shi, M.; Xu, B.;
Huang, J.-W. Org. Lett. 2004, 6, 1175. (d) Shao, L.-X.; Xu,
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(e) Huang, J.-W.; Shi, M. Synlett 2004, 2343. (f) Shi, M.;
Xu, B. Tetrahedron Lett. 2003, 44, 3839.
(5) For some selected papers from Kilburn’s group, see:
(a) Peron, G. L. N.; Norton, D.; Kitteringham, J.; Kilburn, J.
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Chem. Commun. 2005, 1637.
(6) For some selected papers from Huang’s group, see:
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G.; Ohta, H.; Hara, K.; Kashimura, S. J. Org. Chem. 1993,
58, 5915. (b) Lautens, M.; Delanghe, P. H. M. J. Org. Chem.
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(8) Shao, L.-X.; Li, Y.-X.; Shi, M. Chem. Eur. J. 2007, 13, 862;
and references cited therein.
(9) The crystal data for 5c has been deposited as CCDC 623472.
These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif. Empirical formula:
C11H10BrF; formula weight: 241.10; crystal color, habit:
colorless, prismatic; crystal system: monoclinic; lattice type:
primitive; lattice parameters: a = 4.539 (3) Å, b = 9.933 (6)
Å, c = 11.135 (7) Å, a = 90°, b = 93.865 (10)°, g = 90°,
V = 500.9 (5) Å3; space group: P2 (1); Z = 2; Dcalcd = 1.599
g/cm3; F000 = 240; diffractometer: Rigaku AFC7R;
residuals: R, Rw: 0.0577, 0.1406.
(10) For some related papers using this property of
multifluorosulfonates, see (a) Ritter, K. Synthesis 1993,
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(h) Högermeier, J.; Reißig, H.-U. Chem. Eur. J. 2007, 13,
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Synthesis 2007, No. 22, 3567–3573 © Thieme Stuttgart · New York