Rhodium(I)-catalyzed Pauson-Khand-type [3 + 2 + 1] cycloaddition reaction of ene-vinylidenecyclopropanes and CO: A highly regio- and stereoselective synthetic approach for the preparation of aza- and oxa-bicyclic compounds

Article abstract of DOI:10.1021/om3004288

In this paper, a novel Rh(I)-catalyzed Pauson-Khand-type [3 + 2 + 1] cycloaddition reaction of ene-vinylidenecyclopropanes (Ene-VDCPs) and carbon monoxide (CO) has been developed to furnish a series of aza- and oxa-bicyclic compounds in moderate to good yields in a highly regio- and diastereoselective manner, which provides an alternative and efficient synthetic approach for the access of bicyclic cyclohexanone frameworks. The substrate scope and limitations and a plausible mechanism are discussed.

Full text of DOI:10.1021/om3004288

Article
pubs.acs.org/Organometallics
Rhodium(I)-Catalyzed Pauson−Khand-type [3 + 2 + 1] Cycloaddition
Reaction of Ene-Vinylidenecyclopropanes and CO: A Highly Regio-
and Stereoselective Synthetic Approach for the Preparation of Aza-
and Oxa-Bicyclic Compounds
Bei-Li Lu, Yin Wei, and Min Shi*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Lingling Road, Shanghai 200032, People's Republic of China
S
* Supporting Information
ABSTRACT: In this paper, a novel Rh(I)-catalyzed Pauson−
Khand-type [3 + 2 + 1] cycloaddition reaction of ene-
vinylidenecyclopropanes (Ene-VDCPs) and carbon monoxide
(CO) has been developed to furnish a series of aza- and oxa-
bicyclic compounds in moderate to good yields in a highly
regio- and diastereoselective manner, which provides an
alternative and efficient synthetic approach for the access of
bicyclic cyclohexanone frameworks. The substrate scope and
limitations and a plausible mechanism are discussed.
attempted to develop a practical Pauson−Khand-type reaction
using functionalized VDCPs as the substrates. It can be
envisioned that the control of regio- and stereoselectivity in this
reaction might be difficult because different potential reaction
sites, including allene, alkene, and cyclopropane, existed in the
starting materials. Herein, we wish to report a highly regio- and
diastereoselective Rh(I)-catalyzed intramolecular Pauson−
Khand-type [3 + 2 + 1] cycloaddition reaction of Ene-
VDCPs and CO to give aza- or oxa-bicyclic cyclohexanone
derivatives.
INTRODUCTION
■
Since the first paper reported by Khand and Pauson and their
co-workers in 1971, the Pauson−Khand reaction has become a
powerful synthetic tool in organic chemistry and other related
areas.1 Recently, a metal-catalyzed Pauson−Khand reaction for
the coupling of enynes with carbon monoxide (CO) has been
developed as an efficient protocol to afford bicyclic frameworks,
which are important structural motifs in many biologically
active compounds.2 Among the employed metal catalysts,
rhodium complexes3 have achieved remarkable progress and
have attained great popularity thus far, probably due to their
mild conditions, low catalyst loadings, and good control of
stereoselectivities. Moreover, dienes,4 allenes,5 heteroalkenes,6
and the recently reported cyclopropanes7 and cyclopropenes8
could be also used as alkene sources to produce Pauson−
Khand-type reaction products in the presence of an alkyne.
However, employing novel substrates and further optimizing
the catalysts and reaction conditions for Pauson−Khand-type
reactions are still highly desirable, enabling the discovery of
unprecedented reaction modes.
Vinylidenecyclopropanes (VDCPs) bearing an allene moiety
connected with a highly strained cyclopropane have been
fascinating building blocks in organic synthesis and have
attracted much interest from organic chemists. In the past few
years, the chemistry of VDCPs has been extensively studied due
to their unique structural and electronic properties.9,10
Recently, we reported a rhodium(I)-catalyzed intramolecular
cycloaddition of yne- and ene-vinylidenecyclopropanes (Yne-
and Ene-VDCPs) to provide functionalized polycyclic com-
pounds containing cyclobutene or azacyclooctene moieties in a
highly regio- and diastereoselective manner.10l In view of the
significant biological properties of the cyclic units, we
RESULTS AND DISCUSSION
■
Initially, the Ene-VDCP 1a was used as a model substrate to
examine the Pauson−Khand-type [3 + 2 + 1] cycloaddition
reaction with a rhodium(I) catalyst under a carbon monoxide
atmosphere, and the results are summarized in Table 1. As a
first try, no reaction happened by using RhCl(CO)(PPh3)2 as
the catalyst (Table 1, entry 1). However, when 5 mol % of
[Rh(CO)2Cl]2 was used as the catalyst, the Pauson−Khand-
type [3 + 2 + 1] cycloaddition product 2a was obtained in 56%
yield with an 11.0:1.0 ratio of the diastereoselectivity (Table 1,
entry 2). An X-ray diffraction study of the major diastereomer
of 2a was carried out, and its configuration has been
unambiguously determined as cis. The related CIF data are
presented in the Supporting Information, and an ORTEP
drawing is shown in Figure 1.11 Then we screened a variety of
rhodium complexes in 1,2-dichloroethane (DCE) and found
that the yield of 2a was quite sensitive to the rhodium complex
employed. In the case of IPrRh(cod)Cl (IPr = 1,3-bis(2,6-
Received: May 17, 2012
Published: June 8, 2012
© 2012 American Chemical Society
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Table 1. Optimization of the Reaction Conditions for Rh(I)-Catalyzed Pauson−Khand-Type [3 + 2 + 1] Cycloaddition
Reactions of Ene-VDCP 1a
a
b
entry
cat.
additive (amt (mol %))
solvent
T (°C)
t (h)
yield (%) (cis:trans)
1
RhCl(CO)(PPh3)2
[Rh(CO)2Cl]2
IPrRh(cod)Cl
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
THF
dioxane
DMF
CH2CI2
CHCI3
DCE
DCE
DCE
DCE
DCE
DCE
80
80
80
80
80
80
80
80
80
70
80
80
35
50
60
80
80
80
80
80
24
5
c
2
56 (11.1:1.0)
45 (10.0:1.0)
62 (11.1:1.0)
76 (12.5:1.0)
68 (9.1:1.0)
71 (8.3:1.0)
d
3
5
4
Rh(cod)2SbF6
[Rh(cod)Cl]2
5
5
5
6
[Rh(cod)Cl]2/dppp
[Rh(cod)Cl]2/dppf
[Rh(cod)Cl]2/DPEPhos
[Rh(cod)Cl]2/PPh3
[Rh(cod)Cl]2
5
7
5
8
24
24
24
5
9
e
10
11
12
13
14
15
16
trace
[Rh(cod)Cl]2
20 (4.7:1.0)
complex
[Rh(cod)Cl]2
24
12
24
12
5
f
[Rh(cod)Cl]2
31 (11.8:1.0)
[Rh(cod)Cl]2
23 (6.3:1.0)
59 (11.8:1.0)
75 (11.8:1.0)
72 (4.4:1.0)
76 (11.8:1.0)
64 (11.1:1.0)
59 (12.5:1.0)
[Rh(cod)Cl]2
[Rh(cod)Cl]2
NMO (1.0)
g
17
[Rh(cod)Cl]2
5
h
18
[Rh(cod)Cl]2
5
i
19
[Rh(cod)Cl]2
5
j
20
[Rh(cod)Cl]2
5
a
All reactions were carried out using 1a (0.1 mmol) in the presence of catalyst (5 mol %) in various solvents (1.0 mL), for entries 6−9, using 10 mol
% ligands. Abbreviations: dppp = 1,3-bis(diphenylphosphino)propane, dppf = 1,1′-bis(diphenylphosphino)ferrocene, DPEPhos = bis[(2-
b
c
d
diphenylphosphino)phenyl] ether, NMO = 4-methylmorpholine N-oxide. Isolated yield. 84% of 1a was recovered. 54% azacyclooctene derivative
was obtained, and 29% of 1a was recovered. 86% of 1a was recovered. 22% of 1a was recovered. CO (5.0 atm). Using 10 mol % catalyst. The
reaction was carried out in 2.0 mL of DCE. The reaction was carried out in 0.5 mL of DCE.
e
f
g
h
i
j
kinds of products such as the azacyclooctene derivatives
reported by our group previously10l were observed. The
reaction for the formation of azacyclooctene derivatives was
carried out in toluene/acetonitrile (2/1) in the presence of
[RhCl(CO)2]2 and CO, suggesting that the coordinative
acetonitrile solvent can significantly affect the reaction
outcome. Other catalyst systems, such as [Rh(cod)Cl]2/
diphosphine ligand (dppp or dppf), produced 2a in reduced
yields (Table 1, entries 6 and 7). [Rh(cod)Cl]2/DPEPhos did
not catalyze this Pauson−Khand-type [3 + 2 + 1] cycloaddition
reaction, and the azacyclooctene derivative10l was formed in
54% yield and 29% of 1a was recovered (Table 1, entry 8).
[Rh(cod)Cl]2/PPh3 was also not an efficient catalyst system
(Table 1, entry 9). We next attempted to optimize the reaction
conditions by using [Rh(cod)Cl]2 as the catalyst in various
solvents. Among the examined solvents, DCE was found to be
the optimal solvent and other solvents such as tetrahydrofuran
(THF), dioxane, DMF, CH2Cl2, and CHCl3 were not suitable
for this reaction, suggesting the strong solvent effect on this
Figure 1. ORTEP drawing of cis-2a.
reaction (Table 1, entries 10−14). Reducing the reaction
temperature to 60 °C diminished the yield of 2a (Table 1, entry
15). 4-Methylmorpholine N-oxide (NMO), which can lead to
dissociation of CO from the metal center and allow
coordination of the olefin to accelerate the reaction rate,12
has been also used as an additive in this Pauson−Khand-type [3
+ 2 + 1] cycloaddition reaction, affording 2a in 75% yield with
11.8:1.0 diastereoselectivity (cis:trans) (Table 1, entry 16).
Furthermore, carrying out the reaction under a higher pressure
diisopropylphenyl)imidazol-2-ylidene) and a cationic rhodium
complex such as Rh(cod)2SbF6, adduct 2a was afforded in 45%
and 62% yields as cis and trans isomeric mixtures, respectively
(Table 1, entries 3 and 4). However, when [Rh(cod)Cl]2 was
used as the catalyst, the reaction afforded 2a in 76% yield
exclusively with a higher diastereoselectivity (cis:trans =
12.5:1.0) in DCE at 80 °C (Table 1, entry 5), and no other
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of CO was less efficient for the production of 2a (Table 1, entry
17). Increasing the employed amount of catalyst [Rh(cod)Cl]2
to 10 mol % did not improve the yield of 2a (Table 1, entry
18). We also examined the impact of the concentration of the
reaction mixtures on the reaction outcomes and found that the
yields of 2a became lower either by increasing or decreasing the
concentration of the substrates (Table 1, entries 19 and 20).
Therefore, the best reaction conditions have been identified as
to carry out the reaction in 1.0 mL of DCE at 80 °C using 0.1
mmol of substrate 1a in the presence of 5 mol % [Rh(cod)Cl]2
and under 1.0 atm CO atmosphere.
group at the internal position of the alkene moiety, this Rh(I)-
catalyzed Pauson−Khand-type [3 + 2 + 1] cycloaddition
reaction could also proceed smoothly to give the desired
products 2j,k in moderate yields and excellent cis diaster-
eoselectivities (Table 2, entries 9 and 10). The structure of 2k
was unambiguously determined by an X-ray diffraction study.
Its CIF data are presented in the Supporting Information, and
an ORTEP drawing is shown in Figure 2.13 Furthermore, the
Having these optimal reaction conditions in hand, we next
examined the generality of this highly regio- and diastereose-
lective intramolecular reaction of Ene-VDCPs 1, and the results
are summarized in Table 2. In the cases of Ene-VDCPs 1b−e
Table 2. Rh(I)-Catalyzed Pauson−Khand-Type [3 + 2 + 1]
Cycloaddition Reaction of Ene-VDCPs 1 under the Optimal
Conditions
b
product, yield (%)
a
entry
1
1; R1, R1
1b;
R2
H
R3
H
X
(cis:trans)
NTs
2b, 73 (16.7:1.0)
−(CH2)5−
1c;
−(CH2)4−
1d;
−(CH2)6−
2
3
4
H
H
H
H
H
H
NTs
NTs
NTs
2c, 46 (16.7:1.0)
2d, 50 (9.5:1.0)
2e, 55 (11.8:1.0)
Figure 2. ORTEP drawing of cis-2k.
oxygen-tethered Ene-VDCP 1l could be also successfully
applied in this reaction under the optimal reaction conditions,
furnishing the corresponding oxa-bicyclic adduct 2l in 45%
yield and excellent diastereoselectivity (Table 2, entry 11).
However, this reaction was not suitable for substrates 1m,n (R2
= C6H5 or R3 = C6H5). The large phenyl group may affect the
coordination of the metal catalyst with the alkene moiety and
further affect the cyclometalation process, giving complex
product mixtures. Meanwhile, the electronic effect of the
phenyl group may also have some influence on this process
(Table 2, entries 12 and 13).
Moreover, when a methyl group was introduced at the
terminal position of the alkene substituent, this Pauson−
Khand-type [3 + 2 + 1] cycloaddition reaction for substrate 1o
proceeded efficiently to give the desired product 2o in 52%
yield with high diastereoselectivity (Scheme 1, eq 1). The
structure of the major diastereomer 2o was also characterized
by an X-ray diffraction study. Its CIF data are presented in the
Supporting Information, and an ORTEP drawing is shown in
Figure 3.14 Extending the length of the tethered alkene moiety,
we found that the expected 6,6-fused azabicyclic derivative 2p
could be produced in 46% yield with a 16.7:1.0 diastereose-
lectivity (Scheme 1, eq 2). On the basis of the X-ray diffraction
study, the major diastereomer of 2p was identified as having a
trans onfiguration (Figure 4),15 which is different from the case
for the 5,6-fused azabicyclic derivatives (the major diastereomer
is cis).
1e; C4H9/
C4H9
5
6
7
1f; CH3/CH3
1g; CH3/CH3
H
H
H
H
H
H
NBs
NNs
NBs
2f, 64 (15.4:1.0)
2g, 54 (6.9:1.0)
2h, 69 (>20.0:1.0)
1h;
−(CH2)5−
8
1i;
H
H
NNs
2i, 48 (12.5:1.0)
−(CH2)5−
9
1j, CH3/CH3
H
H
CH3
CH3
NTs
NBs
2j, 63 (>20.0:1.0)
2k, 57 (>20.0:1.0)
10
1k;
−(CH2)5−
1l; CH3/CH3
11
12
H
H
H
O
2l, 45 (>20.0:1.0)
1m; CH3/
CH3
C6H5
NTs
complex
13
1n; CH3/
CH3
H
C6H5
NTs
complex
a
All reactions were carried out using 1 (0.2 mmol) in the presence of
[Rh(cod)CI]2 (5 mol %) in DCE (2.0 mL) under a CO atmosphere
(1.0 atm) at 80 °C for 5 h. Abbreviations: Ts = 4-toluenesulfonyl, Bs =
b
4-bromobenzenesulfonyl, Ns = 4-nitrobenzenesulfonyl. Isolated yield.
(R2 = H, R3 = H, X = NTs), regardless of whether R1 is a cyclic
substituent (−(CH2)5− = cyclohexyl, −(CH2)4− = cyclopentyl,
−(CH2)6− = cycloheptyl) or a noncyclic substituent (C4H9 =
butyl), these Rh(I)-catalyzed reactions proceeded smoothly to
give the desired products 2b−e in moderate to good yields
(46−73%) with high diastereoselectivities ((9.5−16.7):1.0)
(Table 2, entries 1−4). Changing the substituent at the
nitrogen atom from Ts to Bs and Ns (Bs = 4-
bromobenzenesulfonyl, Ns = 4-nitrobenzenesulfonyl) produced
the corresponding bicyclic cyclohexanone derivatives 2f−i in
48−69% yields with (6.9−20.0):1.0 diastereoselectivities
(Table 2, entries 5−8). As for substrates 1j,k bearing a methyl
Further transformations of product 2a are shown in Scheme
2. As can be seen from Scheme 2, the corresponding epoxy
product 3a could be obtained in 72% yield with 15.4:1.0
diastereoselectivity upon subjecting 2a to a conventional O3
oxidation procedure (Scheme 2, eq 1).16 Moreover, the
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Scheme 1. Rh(I)-Catalyzed Pauson−Khand-Type [3 + 2 + 1]
Cycloaddition Reactions of Ene-VDCPs 1o,p
Scheme 2. Transformations of Products 2a,h
corresponding alcohol derivative 4a in high yield and
stereoselectivity (Scheme 2, eq 2). When the Bs substituent
was introduced at the nitrogen atom, in addition to the
reduction of the carbonyl group, the bromine atom also
underwent hydrogenolysis to the to give the corresponding
product 4h smoothly (Scheme 2, eq 3).17 The structures of the
major diastereomers 3a and 4h were confirmed by X-ray
diffraction studies, and their CIF data are presented in the
Supporting Information.18,19
On the basis of the above results, a plausible mechanism for
the formation of azabicyclic cyclohexanone derivatives 2 is
outlined in Scheme 3. The selective coordination of the internal
double bonds of the allene and alkene moieties in substrate 1a
to the rhodium(I) complex gives intermediate A. Insertion of
the rhodium(I) center into the distal C−C bond of
cyclopropane produces the (π-allyl)(σ-alkyl)RhIII intermediate
B.7a,e,8 Subsequent isomerization of intermediate B affords the
rhodacyclobutane intermediate C,20 which undergoes insertion
of CO and the intramolecular CC bond to give intermediate
D or D′. Then product 2a could be obtained from intermediate
D or D′ via reductive elimination along with the regeneration of
the rhodium(I) catalyst (Scheme 3).
Figure 3. ORTEP drawing of the major diastereomer 2o.
In summary, we have developed an efficient Rh(I)-catalyzed
Pauson−Khand-type [3 + 2 + 1] cycloaddition reaction of Ene-
VDCPs 1 under a CO atmosphere to produce the
corresponding 5,6-fused or 6,6-fused bicyclic cyclohexanone
derivatives in moderate to good yields with high diastereose-
lectivities. Our findings in this paper offer an easy one-pot
process to construct complex bicyclic structures, which are
important building blocks in organic synthesis. The scope and
limitations of this reaction have been carefully examined, and
the possible reaction mechanism has been discussed. Further
applications of this practical rhodium-catalyzed Pauson−
Khand-type [3 + 2 + 1] cycloaddition reaction and more
detailed mechanistic investigations are under way in our
laboratory.
Figure 4. ORTEP drawing of trans-2p.
EXPERIMENTAL SECTION
General Methods. Melting points were obtained with a
■
1
carbonyl group in product 2a could be easily reduced by
treatment with Red-Al reagent in toluene, thus giving the
Yanagimoto micro melting point apparatus and are uncorrected. H
and 13C NMR spectra were recorded for solutions in CDCl3 with
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Scheme 3. Plausible Mechanism for the Formation of 2a
tetramethylsilane (TMS) as internal standard; J values are in Hz. Mass
and HRMS spectra were recorded by the EI, ESI, or MALDI method.
Organic solvents used were dried by standard methods when
necessary. Commercially obtained reagents were used without further
purification. All reactions were monitored by TLC with Huanghai
GF254 silica gel coated plates. Flash column chromatography was
carried out using 300−400 mesh silica gel at increased pressure. All
reactions were performed under 1.0 atm of carbon monoxide using
standard Schlenk techniques. The substrates 1a−d,f−j,o are all known
compounds, and the detailed spectroscopic data are included in the
previous literature.10l
8.7 Hz, 2H, Ar), 7.71 (d, J = 8.7 Hz, 2H, Ar). 13C NMR (CDCl3, 100
MHz, TMS): δ 19.2, 19.9, 24.0, 25.9, 26.0, 27.3, 27.4, 29.2, 32.0, 32.3,
47.0, 53.1, 89.6, 106.1, 113.5, 127.1, 128.6, 132.1, 139.5, 140.3, 182.2.
IR (CH2Cl2): ν 2925, 2854, 2007, 1716, 1575, 1471, 1447, 1388, 1343,
1260, 1161, 1098, 1068, 1010, 917, 798, 776, 735 cm−1. MS (ESI): m/
z 464 (M+ + 1). HRMS (ESI): calcd for C23H30BrNO2S 463.1181,
found 463.1178.
N-Cinnamyl-N-((2,2-dimethyl-3-(2-methylprop-1-enylidene)-
cyclopropyl)methyl)-4-tolylsulfonamide (1m). Yield: 136 mg, 54% of
a yellow oil. 1H NMR (CDCl3, 400 MHz, TMS): δ 1.19 (s, 3H, CH3),
1.20 (s, 3H, CH3), 1.68 (t, J = 6.8 Hz, 1H, CH), 1.73 (s, 6H, 2CH3),
2.39 (s, 3H, CH3), 3.15 (dd, J1 = 6.8 Hz, J2 = 14.4 Hz, 1H, CH), 3.65
(dd, J1 = 6.8 Hz, J2 = 14.4 Hz, 1H, CH), 3.98−4.10 (m, 2H, CH2),
5.93−6.01 (m, 1H, CH), 6.45 (d, J = 15.6 Hz, 1H, CH), 7.21−7.29
(m, 7H, Ar), 7.73 (d, J = 8.4 Hz, 2H, Ar). 13C NMR (CDCl3, 100
MHz, TMS): δ 19.3, 21.2, 21.3, 21.5, 23.9, 25.9, 29.5, 46.7, 49.0, 89.7,
98.6, 124.4, 126.2, 127.1, 127.6, 128.4, 129.5, 133.0, 136.3, 137.4,
143.0, 185.3. IR (CH2Cl2): ν 2963, 2924, 2855, 2010, 1729, 1598,
1495, 1448, 1341, 1261, 1159, 1093, 1019, 969, 923, 800, 742, 695,
657 cm−1. MS (ESI): m/z 422 (M+ + 1). HRMS (ESI): calcd for
C26H31NNaO2S 444.196 77, found 444.197 74.
Typical Procedure for the Preparation of the Ene-Vinyl-
idenecyclopropanes 1e,k,m,n. N-Allyl-N-((3-(2-butylhex-1-enyli-
dene)-2,2-dimethylcyclopropyl)methyl)-4-tolylsulfonamide (1e).
Under an argon atmosphere, triphenylphosphine (165 mg, 0.63
mmol) and N-allyl-4-methylbenzenesulfonamide (139 mg, 0.66 mmol)
were added into a Schlenk tube. Then, 5.0 mL of tetrahydrofuran
(THF) was added and the reaction mixture was cooled to 0 °C. (3-(2-
Butylhex-1-enylidene)-2,2-dimethylcyclopropyl)methanol (142 mg,
0.6 mmol),21 which was dissolved in THF (1.0 mL), was added into
the above Schlenk tube. Then diisopropyl azodicarboxylate (DIAD;
0.12 mL, 0.63 mmol) was added dropwise at 0 °C and the mixture
warmed to room temperature naturally. On completion of the
reaction, the solvent was removed under reduced pressure and the
residue was purified by flash column chromatography. Yield: 147 mg,
57% of a yellow oil. 1H NMR (CDCl3, 400 MHz, TMS): δ 0.85−0.89
(m, 6H, 3CH3), 1.18 (s, 3H, CH3), 1.20 (s, 3H, CH3), 1.27−1.40 (m,
8H, 4CH2), 1.63 (t, J = 6.8 Hz, 1H, CH), 1.93−2.01 (m, 4H, 2CH2),
2.41 (s, 3H, CH3), 3.16 (dd, J1 = 6.8 Hz, J2 = 14.4 Hz, 1H, CH), 3.52
(dd, J1 = 6.8 Hz, J2 = 14.4 Hz, 1H, CH), 3.87 (d, J = 6.0 Hz, 2H, CH2),
5.11 (dd, J1 = 1.6 Hz, J2 = 10.4 Hz, 1H, CH), 5.18 (dd, J1 = 1.6 Hz, J2
= 17.2 Hz, 1H, CH), 5.61−5.71 (m, 1H, CH), 7.28 (d, J = 8.8 Hz, 2H,
Ar), 7.71 (d, J = 8.8 Hz, 2H, Ar). 13C NMR (CDCl3, 100 MHz, TMS):
δ 13.9, 19.2, 21.4, 22.3, 23.9, 25.8, 29.5, 29.7, 29.9, 32.8, 32.9, 46.8,
49.6, 92.1, 108.3, 117.8, 127.1, 129.5, 133.3, 137.3, 143.0, 184.2. IR
(CH2Cl2): ν 2957, 2924, 2871, 2858, 2005, 1599, 1455, 1345, 1260,
1159, 1091, 1017, 927, 799, 758, 660 cm−1. MS (ESI): m/z 430 (M+ +
1). HRMS (ESI): calcd for C26H40NO2S 430.277 43, found 430.276
42.
N-((2,2-Dimethyl-3-(2-methylprop-1-enylidene)cyclopropyl)-
methyl)-4-methyl-N-(2-phenylallyl)benzenesulfonamide (1n). Yield:
1
134 mg, 53% of a yellow oil. H NMR (CDCl3, 400 MHz, TMS): δ
1.09 (s, 3H, CH3), 1.12 (s, 3H, CH3), 1.56 (t, J = 6.8 Hz, 1H, CH),
1.60 (s, 3H, CH3), 1.68 (s, 3H, CH3), 2.42 (s, 3H, CH3), 3.12 (dd, J1 =
6.8 Hz, J2 = 14.8 Hz, 1H, CH), 3.60 (dd, J1 = 6.8 Hz, J2 = 14.8 Hz, 1H,
CH), 4.27 (s, 2H, CH2), 5.29 (s, 1H, CH), 5.46 (s, 1H, CH), 7.28−
7.33 (m, 5H, Ar), 7.37−7.39 (m, 2H, Ar), 7.68 (d, J = 8.4 Hz, 2H, Ar).
13C NMR (CDCl3, 75 MHz, TMS): δ 19.1, 21.16, 21.24, 21.4, 23.8,
25.7, 29.0, 47.2, 50.5, 89.6, 98.5, 114.5, 126.0, 127.1, 127.7, 128.2,
129.5, 137.0, 138.7, 142.5, 143.0, 185.2. IR (CH2Cl2): ν 2962, 2923,
2860, 2009, 1598, 1495, 1446, 1342, 1306, 1261, 1159, 1119, 1094,
1018, 931, 912, 803, 749, 707, 659 cm−1. MS (ESI): m/z 422 (M+ +
1). HRMS (ESI): calcd for C26H31NNaO2S 444.196 77, found
444.198 08.
Synthesis of the Vinylidenecyclopropane Derivative 2-
(Allyloxymethyl)-1,1-dimethyl-3-(2-methylprop-1-enylidene)-
cyclopropane (1l). Under an argon atmosphere, sodium hydride (36
mg, 0.9 mmol) and (2,2-dimethyl-3-(2-methylprop-1-enylidene)-
cyclopropyl)methanol (91 mg, 0.6 mmol)21 in THF (2.0 mL) were
added into a Schlenk tube. After 20 min, allyl bromide (104 μL, 1.2
mmol) was added into the above Schlenk tube and the reaction
mixture was warmed to 50 °C. On completion of the reaction the
mixture was quenched by addition of water. The reaction solution was
diluted with ether (10.0 mL × 3), and the organic layers were dried
4 - B r o m o - N - ( ( 3 - ( c y c l o h e x y l i d e n e m e t h y l e n e ) - 2 , 2 -
dimethylcyclopropyl)methyl)-N-(2-methylallyl)benzenesulfonamide
(1k). Yield: 139 mg, 50% of a yellow oil. 1H NMR (CDCl3, 300 MHz,
TMS): δ 1.14 (s, 3H, CH3), 1.17 (s, 3H, CH3), 1.53−1.59 (m, 7H,
7CH), 1.69 (s, 3H, CH3), 2.10−2.14 (m, 4H, 4CH), 3.09 (dd, J1 = 7.2
Hz, J2 = 14.4 Hz, 1H, CH), 3.61 (dd, J1 = 6.0 Hz, J2 = 14.4 Hz, 1H,
CH), 3.78 (s, 2H, 2CH), 4.88 (d, J = 9.3 Hz, 2H, 2CH), 7.63 (d, J =
4605
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Organometallics
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over anhydrous Na2SO4. The solvent was removed under reduced
pressure and the residue was purified by a flash column
chromatography. Yield: 70 mg, 61% of a yellow oil. 1H NMR
(CDCl3, 400 MHz, TMS): δ 1.24 (s, 3H, CH3), 1.28 (s, 3H, CH3),
1.73 (s, 3H, CH3), 1.75 (s, 3H, CH3), 1.82 (dd, J1 = 5.2 Hz, J2 = 8.8
Hz, 1H, CH), 3.42 (dd, J1 = 8.8 Hz, J2 = 10.4 Hz, 1H, CH), 3.67 (dd,
J1 = 5.2 Hz, J2 = 10.4 Hz, 1H, CH), 3.94−4.04 (m, 2H, 2CH), 5.16−
5.19 (m, 1H, CH), 5.25−5.30 (m, 1H, CH), 5.87−5.96 (m, 1H, CH).
13C NMR (CDCl3, 100 MHz, TMS): δ 19.1, 21.2, 21.6, 24.4, 26.1,
30.7, 69.3, 71.3, 89.2, 97.9, 116.7, 135.0, 185.4. IR (CH2Cl2): ν 2956,
2922, 2853, 1739, 1460, 1377, 1260, 1162, 1090, 1016, 863, 796, 700,
663 cm−1. MS (%) (EI): m/z 192 (M+, 32), 77 (100), 91 (74), 135
(71), 105 (47), 115 (46), 41 (43), 43 (35), 119 (33); HRMS (EI):
calcd for C13H20O 192.1514, found 192.1529.
(CDCl3, 75 MHz, TMS): δ 19.7, 21.4, 21.8, 26.1, 27.0, 27.5, 29.9, 31.9,
34.6, 39.6, 40.5, 51.9, 53.3, 127.2, 127.9, 129.6, 129.8, 131.8, 132.1,
143.6, 154.4, 202.0. IR (CH2Cl2): ν 2926, 2855, 1682, 1597, 1473,
1448, 1347, 1165, 1096, 1039, 982, 840, 817, 739, 708, 665 cm−1. MS
(ESI): m/z 414 (M+ + 1). HRMS (ESI): calcd for C24H31NNaO3S
436.191 69, found 436.190 60.
6-Cyclopentylidene-7-(propan-2-ylidene)-2-tosylhexahydro-1H-
isoindol-5(6H)-one (2c). Yield: 37 mg, 46% of a white solid. Mp:
1
117−118 °C. (cis-2c) H NMR (CDCl3, 400 MHz, TMS): δ 1.50 (s,
3H, CH3), 1.58−1.65 (m, 4H, 4CH), 1.74 (s, 3H, CH3), 1.79−1.85
(m, 1H, CH), 1.97−2.06 (m, 1H, CH), 2.11−2.21 (m, 4H, 4CH), 2.42
(s, 3H, CH3), 2.44−2.48 (m, 1H, CH), 2.76−2.83 (m, 2H, 2CH), 3.54
(t, J = 8.8 Hz, 1H, CH), 3.61−3.74 (m, 2H, 2CH), 7.29 (d, J = 8.4 Hz,
2H, Ar) (7.33 (d, J = 8.4 Hz, 2H, Ar, trans-2c)), 7.59 (d, J = 8.4 Hz,
2H, Ar) (7.74 (d, J = 8.4 Hz, 2H, Ar, trans-2c)). (cis-2c) 13C NMR
(CDCl3, 100 MHz, TMS): δ 19.8, 21.4, 22.3, 24.8, 26.0, 33.3, 34.4,
35.0, 39.5, 40.6, 52.4, 53.2, 127.96, 128.02, 128.8, 129.4, 131.2, 131.5,
143.6, 163.7, 200.3. IR (CH2Cl2): ν 2955, 2925, 2856, 1684, 1600,
1473, 1452, 1347, 1184, 1164, 1095, 1035, 983, 817, 735, 710, 666
cm−1. MS (ESI): m/z 400 (M+ + 1). HRMS (MALDI): calcd for
C23H30NO3S 400.1932, found 400.1941.
Synthesis of the Vinylidenecyclopropane Derivative N-(But-
3 - e n y l ) - N - ( ( 3 - ( c y c l o h e x y l i d e n e m e t h y l e n e ) - 2 , 2 -
dimethylcyclopropyl)methyl)-4-tolylsulfonamide (1p). Under
an argon atmosphere, triphenylphosphine (165 mg, 0.63 mmol) and
N-(but-3-en-1-yl)-4-methylbenzenesulfonamide (149 mg, 0.66 mmol)
were added into a Schlenk tube. Then, 5.0 mL of THF was added and
the reaction mixture was cooled to 0 °C. (3-(Cyclohexylidene-
methylene)-2,2-dimethylcyclopropyl)methanol (115 mg, 0.6 mmol),21
which was dissolved in THF (1.0 mL), was added into the above
Schlenk tube. Then DIAD (0.12 mL, 0.63 mmol) was added dropwise
at 0 °C and the mixture was warmed to room temperature naturally.
On reaction completion, the solvent was removed under reduced
pressure and the residue was purified by flash column chromatography.
6-Cycloheptylidene-7-(propan-2-ylidene)-2-tosylhexahydro-1H-
isoindol-5(6H)-one (2d). Yield: 43 mg, 50% of a white solid. Mp:
1
128−130 °C. (cis-2d) H NMR (CDCl3, 300 MHz, TMS): δ 1.29−
1.47 (m, 7H, 7CH), 1.51 (s, 3H, CH3), 1.54−1.58 (m, 1H, CH), 1.74
(s, 3H, CH3), 1.77−1.82 (m, 1H, CH), 2.10−2.19 (m, 2H, 2CH), 2.31
(t, J = 9.9 Hz, 1H, CH), 2.38−2.46 (m, 6H, 6CH), 2.53−2.62 (m, 1H,
CH), 2.68−2.78 (m, 1H, CH), 3.57 (t, J = 8.1 Hz, 1H, CH), 3.62−
3.76 (m, 2H, 2CH), 7.30 (d, J = 8.1 Hz, 2H, Ar), 7.63 (d, J = 8.1 Hz,
2H, Ar) (7.73 (d, J = 8.1 Hz, 2H, Ar, trans-2d)). (cis-2d) 13C NMR
(CDCl3, 100 MHz, TMS): δ 19.8, 21.5, 22.3, 26.0, 27.3, 28.9, 30.5,
32.6, 33.9, 34.9, 40.0, 41.1, 51.7, 53.3, 128.0, 128.1, 129.6, 131.3, 131.8,
132.0, 143.6, 158.6, 201.4. IR (CH2Cl2): ν 2960, 2924, 2854, 1725,
1680, 1596, 1531, 1452, 1347, 1260, 1164, 1094, 1017, 982, 859, 799,
708, 663 cm−1. MS (ESI): m/z 428 (M+ + 1). HRMS (ESI): calcd for
C25H34NO3S 428.225 39, found 428.224 48.
1
Yield: 113 mg, 47% of a yellow oil. H NMR (CDCl3, 300 MHz,
TMS): δ 1.17 (s, 3H, CH3), 1.21 (s, 3H, CH3), 1.53−1.60 (m, 7H,
7CH), 2.10−2.16 (m, 4H, 2CH2), 2.27−2.36 (m, 2H, CH2), 2.42 (s,
3H, CH3), 2.99 (dd, J1 = 7.8 Hz, J2 = 14.4 Hz, 1H, CH), 3.19−3.31
(m, 2H, CH2), 3.69 (dd, J1 = 5.7 Hz, J2 = 14.4 Hz, 1H, CH), 4.99−
5.07 (m, 2H, CH2), 5.64−5.78 (m, 1H, CH), 7.29 (d, J = 7.8 Hz, 2H,
Ar), 7.71 (d, J = 7.8 Hz, 2H, Ar). 13C NMR (CDCl3, 75 MHz, TMS):
δ 19.3, 21.4, 23.7, 26.00, 26.03, 27.2, 27.4, 29.5, 32.0, 32.3, 33.2, 46.6,
47.6, 89.8, 106.1, 116.7, 127.0, 129.6, 134.9, 137.2, 142.9, 182.1. IR
(CH2Cl2): ν 2956, 2924, 2854, 2008, 1728, 1448, 1343, 1260, 1159,
1091, 1018, 918, 800, 746, 658 cm−1. MS (ESI): m/z 400 (M+ + 1).
HRMS (ESI): calcd for C24H33NNaO2S 422.212 42, found 422.214 35.
Typical Procedure for the Preparation of 6,7-Bis(propan-2-
ylidene)-2-tosylhexahydro-1H-isoindol-5(6H)-one (2a). Under
an argon atmosphere, [Rh(cod)Cl]2 (5.0 mg, 0.01 mmol) was added
into a Schlenk tube. Then the atmosphere was pumped off and a
balloon filled with CO was connected to the reaction flask. A solution
of substrate 1a (69 mg, 0.2 mmol) in 1,2-dichloroethane (DCE; 2.0
mL) was added into the Schlenk tube. The reaction mixture was
stirred at 80 °C for 5 h. Then, the solvent was removed under reduced
pressure and the residue was purified by flash column chromatography.
6-(Nonan-5-ylidene)-7-(propan-2-ylidene)-2-tosylhexahydro-1H-
isoindol-5(6H)-one (2e). Yield: 50 mg, 55% of a white solid. Mp:
1
114−116 °C. (cis-2e) H NMR (CDCl3, 300 MHz, TMS): δ 0.89−
0.95 (m, 6H, 6CH), 1.06−1.21 (m, 2H, 2CH), 1.25−1.40 (m, 6H,
6CH), 1.48 (s, 3H, CH3), 1.68−1.89 (m, 6H, CH3+3CH), 2.08−2.17
(m, 2H, 2CH), 2.30−2.38 (m, 2H, 2CH), 2.43 (s, 3H, CH3), 2.48−
2.56 (m, 1H, CH), 2.62−2.70 (m, 1H, CH), 3.54 (t, J = 8.4 Hz, 1H,
CH), 3.59−3.71 (m, 2H, 2CH), 7.30 (d, J = 7.8 Hz, 2H, Ar) (7.34 (d,
J = 7.8 Hz, 2H, Ar, trans-2e)), 7.64 (d, J = 7.8 Hz, 2H, Ar) (7.73 (d, J
= 7.8 Hz, 2H, Ar, trans-2e)). (cis-2e) 13C NMR (CDCl3, 100 MHz,
TMS): δ 13.75, 13.84, 19.8, 21.5, 22.0, 23.2, 23.5, 28.5, 31.2, 31.4, 33.9,
35.0, 40.0, 41.2, 51.7, 53.3, 127.80, 127.84, 129.6, 131.3, 132.2, 132.3,
143.5, 156.4, 201.1. IR (CH2Cl2): ν 2956, 2928, 2858, 1683, 1585,
1458, 1347, 1163, 1095, 1038, 981, 816, 735, 709, 664 cm−1. MS
(ESI): m/z 458 (M+ + 1). HRMS (MALDI): calcd for C27H40NO3S
458.2734, found 458.2723.
1
Yield: 57 mg, 76% of a white solid. Mp: 138−140 °C. (cis-2a) H
NMR (CDCl3, 300 MHz, TMS): δ 1.40 (s, 3H, CH3), 1.44 (s, 3H,
CH3), 1.73 (s, 3H, CH3), 1.77 (s, 3H, CH3), 2.17−2.27 (m, 2H,
2CH), 2.33−2.41 (m, 2H, 2CH), 2.45 (s, 3H, CH3), 2.71−2.82 (m,
1H, CH), 3.53 (t, J = 8.4 Hz, 1H, CH), 3.64−3.75 (m, 2H, 2CH), 7.32
(d, J = 7.8 Hz, 2H, Ar), 7.62 (d, J = 7.8 Hz, 2H, Ar) (7.74 (d, J = 7.8
Hz, 2H, Ar, trans-2a)). (cis-2a) 13C NMR (CDCl3, 100 MHz, TMS): δ
19.7, 21.3, 21.4, 21.7, 23.7, 34.5, 39.7, 40.5, 52.0, 53.3, 127.9, 128.1,
129.4, 131.2, 131.8, 131.9, 143.6, 148.5, 201.4. IR (CH2Cl2): ν 2982,
2923, 2854, 1684, 1598, 1439, 1368, 1344, 1254, 1185, 1162, 1094,
1032, 982, 832, 817, 735, 709, 682, 662, 611 cm−1. MS (ESI): m/z 374
(M+ + 1). HRMS (MALDI): calcd for C21H28NO3S 374.1797, found
374.1784.
2-(4-Bromophenylsulfonyl)-6,7-bis(propan-2-ylidene)hexahydro-
1H-isoindol-5(6H)-one (2f). Yield: 56 mg, 64% of a white solid. Mp:
1
173−174 °C. (cis-2f) H NMR (CDCl3, 300 MHz, TMS): δ 1.44 (s,
3H, CH3), 1.45 (s, 3H, CH3), 1.74 (s, 3H, CH3), 1.86 (s, 3H, CH3)
(1.90 (s, 3H, CH3, trans-2f)), 2.19−2.31 (m, 2H, 2CH), 2.37−2.49
(m, 2H, 2CH), 2.73−2.83 (m, 1H, CH), 3.53 (t, J = 8.1 Hz, 1H, CH),
3.64−3.76 (m, 2H, 2CH), 7.60 (d, J = 8.4 Hz, 2H, Ar), 7.68 (d, J = 8.4
Hz, 2H, Ar). (cis-2f) 13C NMR (CDCl3, 100 MHz, TMS): δ 19.7,
21.4, 21.8, 23.8, 34.5, 39.8, 40.5, 52.2, 53.3, 127.8, 128.0, 129.4, 131.7,
132.1, 132.2, 133.3, 148.7, 201.1. IR (CH2Cl2): ν 2983, 2923, 2852,
1684, 1600, 1574, 1471, 1439, 1348, 1255, 1167, 1093, 1068, 1034,
1009, 982, 822, 737, 706, 619 cm−1. MS (ESI): m/z 438 (M+ + 1).
HRMS (MALDI): calcd for C20H25NO3SBr 438.0739, found
438.0733.
6-Cyclohexylidene-7-(propan-2-ylidene)-2-tosylhexahydro-1H-
isoindol-5(6H)-one (2b). Yield: 60 mg, 73% of a white solid. Mp:
1
134−135 °C. (cis-2b) H NMR (CDCl3, 300 MHz, TMS): δ 0.89−
0.99 (m, 1H, CH), 1.07−1.17 (m, 1H, CH), 1.36−1.45 (m, 5H, CH3
+ 2CH), 1.50−1.59 (m, 2H, 2CH), 1.73 (s, 3H, CH3), 1.77−1.80 (m,
2H, 2CH), 2.18−2.34 (m, 2H, 2CH), 2.38−2.48 (m, 6H, CH3
+
2-(4-Nitrophenylsulfonyl)-6,7-bis(propan-2-ylidene)hexahydro-
3CH), 2.64−2.79 (m, 2H, 2CH), 3.58 (t, J = 8.1 Hz, 1H, CH), 3.65−
3.76 (m, 2H, 2CH), 7.31 (d, J = 8.1 Hz, 2H, Ar), 7.65 (d, J = 8.1 Hz,
2H, Ar) (7.74 (d, J = 8.1 Hz, 2H, Ar, trans-2b)). (cis-2b) 13C NMR
1H-isoindol-5(6H)-one (2g). Yield: 44 mg, 54% of a yellow solid. Mp:
1
158−159 °C. (cis-2g) H NMR (CDCl3, 300 MHz, TMS): δ 1.47 (s,
3H, CH3), 1.48 (s, 3H, CH3), 1.75 (s, 3H, CH3), 1.85 (s, 3H, CH3)
4606
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Organometallics
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(1.89 (s, 3H, CH3, trans-2g)), 2.24 (dd, J1 = 3.0 Hz, J2 = 16.8 Hz, 1H,
CH), 2.43−2.50 (m, 2H, 2CH), 2.58−2.66 (m, 1H, CH), 2.73−2.85
(m, 1H, CH) (2.91−2.97 (m, 1H, CH, trans-2g)), 3.54 (t, J = 9.3 Hz,
1H, CH), 3.64−3.74 (m, 2H, 2CH), 7.95 (d, J = 8.7 Hz, 2H, Ar) (8.04
(d, J = 8.7 Hz, 2H, Ar, trans-2g)), 8.38 (d, J = 8.7 Hz, 2H, Ar). (cis-2g)
13C NMR (CDCl3, 100 MHz, TMS): δ 19.8, 21.4, 21.8, 23.8, 34.7,
40.0, 40.6, 52.4, 53.1, 124.0, 127.5, 128.9, 131.9, 132.6, 140.8, 148.3,
150.1, 200.8. IR (CH2Cl2): ν 2025, 2855, 1685, 1603, 1530, 1472,
1441, 1349, 1309, 1255, 1168, 1095, 1037, 1013, 982, 857, 822, 736,
688, 664, 621 cm−1. MS (ESI): m/z 405 (M+ + 1). HRMS (MALDI):
calcd for C20H25N2O5S 405.1475, found 405.1479.
(M+ + 1). HRMS (ESI): calcd for C24H30BrNO3S 491.1130, found
491.1147.
6,7-Bis(propan-2-ylidene)hexahydroisobenzofuran-5(1H)-one
(2l). Yield: 20 mg, 45% of a yellow oil. (cis-2l) 1H NMR (CDCl3, 400
MHz, TMS): δ 1.53 (s, 3H, CH3), 1.72 (s, 3H, CH3), 1.80 (s, 3H,
CH3), 2.19 (s, 3H, CH3), 2.29 (dd, J1 = 2.0 Hz, J2 = 16.4 Hz, 1H, CH),
2.55 (dd, J1 = 6.0 Hz, J2 = 16.4 Hz, 1H, CH), 2.64−2.73 (m, 1H, CH),
3.16 (t, J = 9.2 Hz, 1H, CH), 3.29 (dd, J1 = 6.8 Hz, J2 = 9.2 Hz, 1H,
CH), 3.65−3.72 (m, 1H, CH), 3.96 (t, J = 8.0 Hz, 1H, CH), 4.08 (t, J
= 8.0 Hz, 1H, CH). (cis-2l) 13C NMR (CDCl3, 100 MHz, TMS): δ
19.8, 21.99, 22.02, 24.3, 35.8, 40.3, 41.2, 72.2, 73.2, 128.6, 131.1, 132.3,
148.9, 202.0. IR (CH2Cl2): ν 2963, 2924, 2855, 1683, 1599, 1437,
1415, 1369, 1327, 1252, 1198, 1190, 1162, 1096, 1062, 1048, 1019,
981, 932, 830, 745, 693, 672 cm−1. MS (%) (EI): m/z 220 (M+, 21),
175 (100), 133 (50), 91 (47), 105 (37), 147 (36), 77 (36), 134 (30),
119 (30); HRMS (EI): calcd for C14H20O2 220.1463, found 220.1466.
4-Methyl-6,7-bis(propan-2-ylidene)-2-tosylhexahydro-1H-isoin-
dol-5(6H)-one (2o). Yield: 40 mg, 52% of a white solid. Mp: 135−137
2-(4-Bromophenylsulfonyl)-6-cyclohexylidene-7-(propan-2-
ylidene)hexahydro-1H-isoind-ol-5(6H)-one (2h). Yield: 66 mg, 69%
1
of a white solid. Mp: 155−156 °C. (cis-2h) H NMR (CDCl3, 300
MHz, TMS): δ 0.88−1.12 (m, 2H, 2CH), 1.46 (s, 3H, CH3), 1.50−
1.60 (m, 4H, 4CH), 1.74 (s, 3H, CH3), 1.79−1.86 (m, 2H, 2CH),
2.21−2.37 (m, 2H, 2CH), 2.40−2.49 (m, 3H, 3CH), 2.69−2.80 (m,
2H, 2CH), 3.58 (t, J = 8.4 Hz, 1H, CH), 3.66−3.78 (m, 2H, 2CH),
7.63 (d, J = 8.7 Hz, 2H, Ar), 7.67 (d, J = 8.7 Hz, 2H, Ar). (cis-2h) 13C
NMR (CDCl3, 100 MHz, TMS): δ 19.8, 21.9, 26.0, 27.2, 27.8, 30.0,
32.0, 34.6, 39.6, 40.4, 52.0, 53.3, 127.1, 128.0, 129.4, 129.7, 132.3,
132.4, 133.9, 154.7, 201.8. IR (CH2Cl2): ν 2927, 2854, 1682, 1595,
1574, 1471, 1448, 1388, 1351, 1266, 1248, 1169, 1095, 1068, 1041,
1009, 982, 820, 738, 706, 613 cm−1. MS (ESI): m/z 478 (M+ + 1).
HRMS (ESI): calcd for C23H28BrNNaO3S 500.086 55, found 500.086
89.
1
°C. (major diastereomer 2o) H NMR (CDCl3, 300 MHz, TMS): δ
1.05 (d, J = 7.2 Hz, 3H, CH3), 1.42 (s, 3H, CH3), 1.46 (s, 3H, CH3),
1.71 (s, 3H, CH3), 1.75 (s, 3H, CH3), 2.09−2.18 (m, 1H, CH), 2.33−
2.41 (m, 1H, CH), 2.44 (s, 3H, CH3), 2.62−2.72 (m, 2H, 2CH), 3.45
(dd, J1 = 7.2 Hz, J2 = 9.6 Hz, 1H, CH), 3.50−3.64 (m, 2H, 2CH), 7.32
(d, J = 8.1 Hz, 2H, Ar), 7.66 (d, J = 8.1 Hz, 2H, Ar). (major
diastereomer 2o) 13C NMR (CDCl3, 100 MHz, TMS): δ 16.9, 19.7,
21.0, 21.4, 21.7, 22.7, 39.2, 43.1, 45.3, 51.4, 53.3, 127.1, 127.8, 129.5,
131.7, 132.1, 132.6, 143.6, 144.3, 204.8. IR (CH2Cl2): ν 2975, 2926,
2872, 2855, 1682, 1599, 1473, 1448, 1371, 1344, 1163, 1093, 1030,
982, 966, 836, 816, 735, 708, 662, 609 cm−1. MS (ESI): m/z 388 (M+
+ 1). HRMS (MALDI): calcd for C22H30NO3S 388.1948, found
388.1941.
6-Cyclohexylidene-2-(4-nitrophenylsulfonyl)-7-(propan-2-
ylidene)hexahydro-1H-isoindol-5(6H)-one (2i). Yield: 43 mg, 48% of
a yellow solid. Mp: 138−140 °C. (cis-2i) 1H NMR (CDCl3, 300 MHz,
TMS): δ 0.83−0.96 (m, 1H, CH), 1.00−1.10 (m, 1H, CH), 1.35−1.45
(m, 1H, CH), 1.47 (s, 3H, CH3), 1.53−1.65 (m, 3H, 3CH), 1.74 (s,
3H, CH3), 1.82−1.87 (m, 2H, 2CH), 2.23−2.32 (m, 2H, 2CH), 2.43−
2.51 (m, 1H, CH), 2.56−2.65 (m, 2H, 2CH), 2.73−2.85 (m, 2H,
2CH), 3.60 (t, J = 9.0 Hz, 1H, CH), 3.68−3.77 (m, 2H, 2CH), 7.98
(d, J = 8.7 Hz, 2H, Ar) (8.05 (d, J = 8.7 Hz, 2H, Ar, trans-2i)), 8.38 (d,
J = 8.7 Hz, 2H, Ar). (cis-2i) 13C NMR (CDCl3, 100 MHz, TMS): δ
19.8, 21.9, 26.0, 27.3, 27.7, 30.1, 32.0, 34.8, 39.9, 40.5, 52.2, 53.2,
124.3, 127.0, 128.9, 129.9, 132.8, 141.4, 150.1, 154.3, 201.5. IR
(CH2Cl2): ν 2927, 2855, 1681, 1601, 1530, 1474, 1447, 1401, 1350,
1312, 1265, 1168, 1095, 1043, 1012, 982, 857, 819, 735, 688, 614
cm−1. MS (ESI): m/z 445 (M+ + 1). HRMS (ESI): calcd for
C23H28N2NaO5S 467.161 11, found 467.162 07.
3a-Methyl-6,7-bis(propan-2-ylidene)-2-tosylhexahydro-1H-isoin-
dol-5(6H)-one (2j). Yield: 49 mg, 63% of a white solid. Mp: 138−139
°C. (cis-2j) 1H NMR (CDCl3, 400 MHz, TMS): δ 1.18 (s, 3H, CH3),
1.42 (s, 3H, CH3), 1.45 (s, 3H, CH3), 1.72 (s, 3H, CH3), 1.77 (s, 3H,
CH3), 2.17 (d, J = 16.0 Hz, 1H, CH), 2.25 (d, J = 16.0 Hz, 1H, CH),
2.44 (s, 3H, CH3), 2.46−2.50 (m, 2H, CH2), 3.08 (d, J = 9.2 Hz, 1H,
CH), 3.21 (t, J = 8.4 Hz, 1H, CH), 3.67 (t, J = 9.2 Hz, 1H, CH), 7.32
(d, J = 8.0 Hz, 2H, Ar), 7.62 (d, J = 8.0 Hz, 2H, Ar). (cis-2j) 13C NMR
(CDCl3, 100 MHz, TMS): δ 19.8, 21.2, 21.4, 21.9, 23.6, 28.0, 41.7,
47.6, 49.0, 51.6, 59.1, 127.8, 127.9, 129.4, 131.3, 131.4, 132.0, 143.6,
147.6, 201.1. IR (CH2Cl2): ν 2956, 2926, 2855, 1686, 1599, 1454,
1349, 1166, 1093, 1032, 845, 817, 738, 664 cm−1. MS (ESI): m/z 388
(M+ + 1). HRMS (MALDI): calcd for C22H30NO3S 388.1938, found
388.1941.
2-(4-Bromophenylsulfonyl)-6-cyclohexylidene-3a-methyl-7-
(propan-2-ylidene)hexahydro-1H-isoindol-5(6H)-one (2k). Yield: 56
mg, 57% of a white solid. Mp: 150−151 °C. (cis-2k) 1H NMR
(CDCl3, 300 MHz, TMS): δ 0.96−1.13 (m, 2H, 2CH), 1.17 (s, 3H,
CH3), 1.48 (s, 3H, CH3), 1.54−1.66 (m, 4H, 4CH), 1.73 (s, 3H,
CH3), 1.80−1.84 (m, 2H, 2CH), 2.24 (d, 2H, J = 4.2 Hz, 2CH), 2.27−
2.33 (m, 1H, CH), 2.59 (t, J = 8.1 Hz, 1H, CH), 2.66−2.75 (m, 2H,
2CH), 3.14 (d, J = 9.6 Hz, 1H, CH), 3.23 (t, J = 8.1 Hz, 1H, CH), 3.69
(t, J = 9.6 Hz, 1H, CH), 7.64 (d, J = 8.4 Hz, 2H, Ar), 7.68 (d, J = 8.4
Hz, 2H, Ar). (cis-2k) 13C NMR (CDCl3, 100 MHz, TMS): δ 19.8,
21.9, 26.0, 27.2, 27.8, 30.0, 32.0, 34.6, 39.6, 40.4, 52.0, 53.3, 127.1,
128.0, 129.4, 129.7, 132.3, 132.4, 133.9, 154.7, 201.8. IR (CH2Cl2): ν
2955, 2924, 2853, 1683, 1595, 1574, 1471, 1449, 1388, 1351, 1260,
1168, 1090, 1067, 1036, 1009, 823, 805, 738 cm−1. MS (ESI): m/z 493
7-Cyclohexylidene-8-(propan-2-ylidene)-2-tosyloctahydroisoqui-
nolin-6(7H)-one (2p). Yield: 39 mg, 46% of a white solid. Mp: 176−
1
177 °C. (trans-2p) H NMR (CDCl3, 300 MHz, TMS): δ 1.15−1.39
(m, 3H, 3CH), 1.42−1.59 (m, 6H, 3CH + CH3), 1.64−1.75 (m, 3H,
3CH), 1.82 (s, 3H, CH3), 1.88−1.92 (m, 1H, CH), 2.00−2.10 (m, 3H,
3CH), 2.18−2.36 (m, 2H, 2CH), 2.39−2.49 (m, 5H, CH3 + 2CH),
2.70−2.77 (m, 1H, CH), 3.91−4.02 (m, 2H, 2CH), 7.31 (d, J = 7.8
Hz, 2H, Ar), 7.66 (d, J = 7.8 Hz, 2H, Ar) (7.74 (d, J = 8.4 Hz, 2H, Ar,
cis-2p)). (trans-2p) 13C NMR (CDCl3, 100 MHz, TMS): δ 20.2, 21.5,
22.2, 26.2, 27.6, 28.3, 29.9, 30.0, 31.8, 36.8, 44.6, 44.9, 46.2, 49.8,
124.9, 127.4, 129.6, 131.8, 134.0, 135.3, 143.4, 148.8, 203.8. IR
(CH2Cl2): ν 2922, 2851, 1689, 1611, 1448, 1344, 1307, 1186, 1162,
1104, 1091, 1025, 990, 950, 841, 729 cm−1. MS (ESI): m/z 428 (M+ +
1). HRMS (ESI): calcd for C25H33NNaO3S 450.207 34, found
450.207 46.
Typical Procedure for the Synthesis of 3,3-Dimethyl-5-
(propan-2-ylidene)-2-tosylhexahydrospiro[isoindole-4,2-oxir-
an]-6(5H)-one (3a). The compound 2a (0.1 mmol, 37 mg, 1.0 equiv)
was dissolved in dichloromethane and methanol (v/v, 5.0 mL/1.0
mL). The solution was cooled to −78 °C, and O3 was directed into the
solution until it turned deep blue. The resulting solution was then
bubbled with argon to remove the excess O3. Dimethyl sulfide (0.5
mmol, 5.0 equiv) was added, and the solution was warmed to room
temperature and stirred for 3 h. The residue was washed successively
with water and brine. The combined organic layers were dried over
anhydrous Na2SO4 and filtered. Then, the solvent was removed under
reduced pressure and the residue was purified by flash column
chromatography. Yield: 28 mg, 72% of a white solid. Mp: 159−161 °C.
1
(major diastereomer 3a) H NMR (CDCl3, 400 MHz, TMS): δ 1.21
(s, 3H, CH3), 1.41 (s, 3H, CH3), 1.54 (s, 3H, CH3), 1.69 (s, 3H,
CH3), 2.23 (t, J = 9.6 Hz, 1H, CH), 2.33 (d, J = 15.6 Hz, 1H, CH),
2.46 (s, 3H, CH3), 2.67−2.70 (m, 2H, 2CH), 2.83−2.90 (m, 2H,
2CH), 3.50 (t, J = 9.6 Hz, 1H, CH), 3.62 (t, J = 11.6 Hz, 1H, CH),
7.36 (d, J = 8.4 Hz, 2H, Ar), 7.65 (d, J = 8.4 Hz, 2H, Ar). (major
diastereomer 3a) 13C NMR (CDCl3, 100 MHz, TMS): δ 20.1, 20.8,
21.5, 22.9, 24.6, 34.8, 40.4, 43.8, 49.2, 53.0, 64.3, 67.6, 128.1, 129.2,
129.6, 131.1, 144.0, 147.2, 201.1. IR (CH2Cl2): ν 3001, 2964, 2927,
2877, 2851, 1693, 1626, 1598, 1444, 1377, 1345, 1165, 1093, 1039,
4607
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Organometallics
Article
983, 832, 818, 736, 711, 665, 611 cm−1. MS (ESI): m/z 390 (M+ + 1).
HRMS (ESI): calcd for C21H27NNaO4S 412.155 30, found 412.156 50.
Typical Procedure for the Synthesis of 6,7-Bis(propan-2-
ylidene)-2-tosyloctahydro-1H-isoindol-5-ol (4a). Under an argon
atmosphere, a solution of compound 2a (0.1 mmol, 37 mg, 1.0 equiv)
in toluene (2.0 mL) was added into the Schlenk tube. Then Red-Al
(39 μL, 0.2 mmol, 2.0 equiv) was added into the above Schlenk tube
and the reaction mixture was stirred for 2 h at room temperature. On
reaction completion the reaction was quenched by addition of water.
The reaction solution was diluted with ether (10.0 mL × 3), and the
organic layers were dried over anhydrous Na2SO4. The solvent was
removed under reduced pressure, and the residue was purified by flash
column chromatography. Yield: 34 mg, 91% of a white solid. Mp:
REFERENCES
■
(1) Selected references are as follows; see the parts on Pauson−
Khand reactions: (a) Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts,
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1
167−169 °C. (major diastereomer 4a) H NMR (CDCl3, 300 MHz,
TMS): δ 1.41−1.47 (m, 4H, CH + CH3), 1.50 (s, 3H, CH3), 1.61−
1.69 (m, 4H, CH + CH3), 1.86 (s, 3H, CH3), 2.09 (d, J = 6.9 Hz, 1H,
OH), 2.41−2.53 (m, 4H, CH3 + CH), 2.90 (t, J = 8.4 Hz, 1H, CH),
3.15 (t, J = 8.4 Hz, 2H, 2CH), 3.35−3.45 (m, 2H, 2CH), 4.37−4.41
(m, 1H, CH), 7.33 (d, J = 8.1 Hz, 2H, Ar), 7.69 (d, J = 8.1 Hz, 2H,
Ar). (major diastereomer 4a) 13C NMR (CDCl3, 100 MHz, TMS): δ
19.6, 20.0, 21.5, 22.1, 23.1, 35.9, 37.4, 40.2, 50.8, 54.1, 70.7, 128.0,
128.5, 129.4, 130.3, 132.1, 132.30, 132.32, 143.6. IR (CH2Cl2): ν 3521,
2955, 2922, 2854, 1598, 1448, 1369, 1341, 1305, 1261, 1159, 1089,
1042, 1007, 949, 804, 734, 708 cm−1. MS (ESI): m/z 398 (M+ + Na).
HRMS (ESI): calcd for C21H29NO3S 375.1868, found 375.1871.
6-Cyclohexylidene-2-(phenylsulfonyl)-7-(propan-2-ylidene)-
octahydro-1H-isoindol-5-ol (4h). Yield: 36 mg, 89% of a white solid.
(2) For selected reviews on the construction of complex molecules or
natural compounds by Pauson−Khand reactions, please see:
(a) Habermann, J. Curr. Org. Chem. 2010, 14, 1139−1152. (b) Alcaide,
B.; Almendros, P. Eur. J. Org. Chem. 2004, 3377−3383. (c) Blanco-
́ ́
Urgoiti, J.; Anorbe, L.; Perez-Serrano, L.; Domínguez, G.; Perez-
̃
1
Mp: 129−131 °C. (major diastereomer 4h) H NMR (CDCl3, 400
Castells, J. Chem. Soc. Rev. 2004, 33, 32−42. For selected recent
reports on the construction of natural compounds using Pauson−
Khand reactions as a crucial step, please see: (d) Nakayama, A.;
Kogure, N.; Kitajima, M.; Takayama, H. Angew. Chem., Int. Ed. 2011,
50, 8025−8028. (e) Farwick, A.; Engelhart, J. U.; Tverskoy, O.; Welter,
MHz, TMS): δ 1.17−1.34 (m, 2H, 2CH), 1.40−1.52 (m, 5H, CH3 +
2CH), 1.58−1.60 (m, 1H, CH), 1.62−1.75 (m, 7H, CH3 + 4CH),
1.92−2.04 (m, 2H, 2CH), 2.18 (d, J = 6.8 Hz, 1H, OH), 2.53−2.60
(m, 1H, CH), 2.78−2.82 (m, 1H, CH), 2.89 (dd, J1 = 6.8 Hz, J2 = 9.2
Hz, 1H, CH), 3.15−3.24 (m, 2H, 2CH), 3.43 (dd, J1 = 2.8 Hz, J2 = 9.6
Hz, 1H, CH), 3.51 (dd, J1 = 9.2 Hz, J2 = 16.4 Hz, 1H, CH), 4.45−4.49
(m, 1H, CH), 7.52−7.56 (m, 2H, Ar), 7.60−7.64 (m, 1H, Ar), 7.82 (d,
J = 8.0 Hz, 2H, Ar). (major diastereomer 4h) 13C NMR (CDCl3, 100
MHz, TMS): δ 19.6, 22.1, 26.7, 27.9, 28.5, 30.4, 32.7, 35.0, 36.9, 39.7,
51.8, 54.2, 69.6, 128.0, 128.4, 128.7, 129.8, 132.7, 134.7, 141.2. IR
(CH2Cl2): ν 3518, 2955, 2924, 2853, 1998, 1602, 1507, 1459, 1260,
1223, 1157, 1093, 1013, 911, 836, 800, 750, 721 cm−1. MS (ESI): m/z
424 (M+ + Na). HRMS (ESI): calcd for C23H31NO3S 401.2025, found
401.2021.
́
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ASSOCIATED CONTENT
■
S
* Supporting Information
Figures giving compound characterization data and figures
giving ORTEP drawings and CIF files giving X-ray crystal data
of cis-2a (CCDC 865612), cis-2k (CCDC 868900), major
diastereomer 2o (CCDC 826605), trans-2p (CCDC 867084),
major diastereomer 3a (CCDC 858045), and major diaster-
eomer 4h (CCDC 874178). This material is available free of
charge via the Internet at http://pubs.acs.org.
(4) For selected recent reports on the Pauson−Khand-type reactions
of dienes, please see: (a) Iwasawa, N.; Ooi, I.; Inaba, K.; Takaya, J.
Angew. Chem., Int. Ed. 2010, 49, 7534−7537. (b) Croatt, M. P.;
Wender, P. A. Eur. J. Org. Chem. 2010, 19−32. (c) Wender, P. A.;
Croatt, M. P.; Deschamps, N. M. Angew. Chem., Int. Ed. 2006, 45,
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N. M.; Williams, T. J. Angew. Chem., Int. Ed. 2004, 43, 3076−3079.
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of allenes, please see: (a) Grillet, F.; Huang, C.; Brummond, K. M.
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Matsui, Y.; Mukai, C. Beilstein J. Org. Chem. 2011, 7, 404−409.
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1220. (f) Alcaide, B.; Almendros, P. Eur. J. Org. Chem. 2004, 3377−
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Lett. 2002, 4, 1755−1758. (h) Brummond, K. M.; Chen, H.; Fisher, K.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: Mshi@mail.sioc.ac.cn. Fax: 86-21-64166128.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Shanghai Municipal Committee of Science and
Technology (11JC1402600), National Basic Research Program
of China ((973)-2009CB825300), and the National Natural
Science Foundation of China (21072206, 20472096, 20872162,
20672127, 21121062 and 20732008) for financial support.
(6) For selected recent reports on the Pauson−Khand-type reactions
of heteroalkenes, please see: (a) Saito, T.; Furukawa, N.; Otani, T. Org.
4608
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wR2 = 0.1220.
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with the CCDC as file 858045: empirical formula C21H27NO4S,
formula weight 389.50, crystal color colorless, crystal dimensions 0.258
× 0.137 × 0.069 mm, crystal system monoclinic, lattice parameters a =
19.2333(13) Å, b = 8.4368(6) Å, c = 12.4042(8) Å, α = 90°, β =
96.411(2)°, and γ = 90°, V = 2000.2(2) Å3, space group P21/c, Z = 4,
Dcalcd = 1.293 g/cm3, F000 = 832, final R indices (I > 2σ(I)) R1 =
0.0541 and wR2 = 0.1354.
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W.; Pindi, S.; Shi, M.; Li, G.-G. Org. Lett. 2010, 12, 64−67. (j) Lu, B.-
L.; Wei, Y.; Shi, M. Chem. Eur. J. 2010, 16, 10975−10979. (k) Lu, B.-
L.; Shi, M. Eur. J. Org. Chem. 2011, 243−248. (l) Lu, B.-L.; Shi, M.
Angew. Chem., Int. Ed. 2011, 50, 12027−12031.
(19) The crystal data of major diastereomer 4h have been deposited
with the CCDC as file 874178: empirical formula C23H31NO3S,
formula weight 401.55, crystal color colorless, crystal dimensions 0.231
× 0.207 × 0.115 mm, crystal system orthorhombic, lattice parameters
a = 14.689(3) Å, b = 9.005(2) Å, c = 32.942(8) Å, α = 90°, β = 90°,
and γ = 90°, V = 4357.3(17) Å3, space group Pbca; Z = 8, Dcalcd
=
1.224 g/cm3, F000 = 1728, final R indices (I > 2σ(I)) R1 = 0.0493 and
wR2 = 0.1180.
(20) (a) Alcock, N. W.; Brown, J. M.; Conneely, J. A.; Stofko, J. J. J.
Chem. Soc., Chem. Commun. 1975, 234−235. (b) Matsuda, T.; Tsuboi,
T.; Murakami, M. J. Am. Chem. Soc. 2007, 129, 12596−12597.
(c) Walczak, M. A. A.; Wipf, P. J. Am. Chem. Soc. 2008, 130, 6924−
6925. (d) Evans, P. A.; Inglesby, P. A. J. Am. Chem. Soc. 2008, 130,
12838−12839. (e) Zhang, Y.; Chen, Z.; Xiao, Y.; Zhang, J. Chem. Eur.
J. 2009, 15, 5208−5211. (f) Wang, T.; Wang, C.-H.; Zhang, J. Chem.
Commun. 2011, 47, 5578−5580.
(11) The crystal data of cis-2a have been deposited with the CCDC
as file 865612: empirical formula C21H27NO3S, formula weight 373.50,
crystal color colorless, crystal dimensions 0.30 × 0.25 × 0.20 mm,
crystal system triclinic; lattice parameters a = 8.5624(12) Å, b =
8.6068(12) Å, c = 13.3479(19) Å, α = 91.113(2)°, β = 98.047(2)°, and
(21) (a) Mills, W.; Murray, H.; Raphael, A. J. Chem. Soc., Perkin
Trans. 1 1973, 133−137. (b) Sheu, J.-H.; Yen, C.-F.; Chan, Y.-L.;
Chung, J.-F. J. Org. Chem. 1990, 55, 5232−5233.
γ = 95.389(2)°, V = 969.2(2) Å3, space group P1, Z = 2; Dcalcd = 1.280
̅
g/cm3, F000 = 400, final R indices (I > 2σ(I)) R1 = 0.0428 and wR2 =
0.1305.
(12) (a) Brown, C. K.; Wilkinson, G. J. Chem. Soc. A 1970, 2753−
2764. (b) Shambayati, S.; Crowe, W. E.; Schreiber, S. L. Tetrahedron
Lett. 1990, 31, 5289−5292. (c) Jeong, N.; Chung, Y. K.; Lee, B. Y.;
Lee, S. H.; Yoo, S.-E. Synlett 1991, 204−206. (d) VanRooy, A.;
deBruijin, J. N. H. K.; Roobeek, F.; Kamer, P. C. J.; van Leeuwen, P. J.
Organomet. Chem. 1996, 507, 69−73.
(13) The crystal data of cis-2k have been deposited with the CCDC
as file 868900: empirical formula C24H30BrNO3S, formula weight
492.46, crystal color colorless, crystal dimensions 0.248 × 0.156 ×
0.123 mm, crystal system triclinic, lattice parameters a = 12.2812(12)
Å, b = 13.3467(14) Å, c = 15.9608(17) Å, α = 77.980(2)°, β =
74.061(2)°, and γ = 89.870(3)°, V = 2456.3(4) Å3, space group P1, Z
̅
= 4, Dcalcd = 1.332 g/cm3, F000 = 1024, final R indices (I > 2σ(I)) R1 =
0.0674 and wR2 = 0.1832.
(14) The crystal data of major diastereomer 2o have been deposited
with the CCDC as file 826605: empirical formula C22H29NO3S,
formula weight 387.52, crystal color colorless, crystal dimensions 0.353
× 0.268 × 0.043 mm, crystal system orthorhombic, lattice type
primitive, lattice parameters a = 9.1187(7) Å, b = 20.3918(15) Å, c =
23.2981(18) Å, α = 90°, β = 90°, and γ = 90°, V = 4330.5(6) Å3, space
group Pbca; Z = 8, Dcalcd = 1.189 g/cm, F000 = 1664, final R indices (I >
2σ(I)) R1 = 0.0567 and wR2 = 0.1290.
(15) The crystal data of trans-2p have been deposited with the
CCDC as file 867084: empirical formula C25H33NO3S, formula seight
427.58, crystal color colorless, crystal dimensions 0.321 × 0.165 ×
0.112 mm, crystal system orthorhombic, lattice parameters a =
4609
dx.doi.org/10.1021/om3004288 | Organometallics 2012, 31, 4601−4609