Grignard reagent/CuI/LiCl-mediated stereoselective cascade addition/cyclization of diynes: A novel pathway for the construction of 1-methyleneindene derivatives

Article abstract of DOI:10.1002/chem.201302191

Diynes containing a cyclopropane group smoothly undergo a novel intramolecular and stereoselective cascade addition/cyclization reaction to produce the corresponding 1-methyleneindene derivatives in moderate to good yields. This interesting transformation is mediated by Grignard reagent/CuI with LiCl as an additive under mild conditions. The obtained product can easily be further functionalized through cyclopropyl ring opening. A plausible reaction mechanism has also been presented on the basis of deuterium labeling and control experiments. Diyne cyclization: Diynes containing a cyclopropane group undergo a novel intramolecular and stereoselective cascade addition/cyclization reaction to produce the corresponding 1-methyleneindene derivatives (see scheme). The transformation proceeds under mild conditions and is promoted by a combination of Grignard reagent Copyright

Full text of DOI:10.1002/chem.201302191

DOI: 10.1002/chem.201302191
Grignard Reagent/CuI/LiCl-Mediated Stereoselective Cascade Addition/
Cyclization of Diynes: A Novel Pathway for the Construction of
1-Methyleneindene Derivatives
De-Yao Li, Yin Wei, and Min Shi*[a]
Abstract: Diynes containing a cyclopropane group smoothly undergo a novel in-
tramolecular and stereoselective cascade addition/cyclization reaction to produce
the corresponding 1-methyleneindene derivatives in moderate to good yields. This
interesting transformation is mediated by Grignard reagent/CuI with LiCl as an
additive under mild conditions. The obtained product can easily be further func-
tionalized through cyclopropyl ring opening. A plausible reaction mechanism has
also been presented on the basis of deuterium labeling and control experiments.
Keywords: alkenes · alkynes · car-
bocycles · cyclization · Grignard re-
action · small ring systems
Introduction
stereoselectively. Herein, we wish to report an effective and
highly stereoselective synthetic method for the construction
of the 1-methyleneindene skeleton. CuI, Grignard reagents
and LiCl were employed as the catalytic system and diynes
containing a cyclopropane group were used as substrates.
The indene skeleton, including 1-methyleneindene, has been
recognized as a privileged fragment that exists in many nat-
ural products as well as drug candidates, and such com-
pounds often have extraordinary biological properties in
therapeutic use.[1] Additionally, several applications in the
field of material science have also been discovered in recent
years.[2] Many synthetic methodologies have been developed
to access indene substructures.[3] Moreover, because func-
tionalized indenes can be conveniently obtained from 1-
methyleneindene, efficient synthetic approaches to the 1-
methyleneindene skeleton has also attracted much attention.
Inter/intramolecular strategies have been used with various
substrates in the presence of metal catalysts, as well as other
nonmetal processes (Figure 1).[4]
Recently, organocopper-mediated cyclization has been
used, often with the participation of other metal salts such
as Mg or Li, through the formation of ate-complexes to im-
prove the reaction efficiency and chemoselectivity.[5,6] Con-
sidering that 1-methyleneindene derivatives have extensive
applications and potential value in medicinal and material
chemistry, we attempted to explore a new synthetic method
with which to construct this kind of pivotal structural motif
Results and Discussion
During our ongoing investigation into the preparation of
functionalized vinylidenecyclopropanes (VDCPs),[7] we
found that using diyne 1aa as substrate (0.5 mmol, Ms=
methanesulfonyl) in the presence of MeMgBr (2.5 mmol,
1.8 mL, 1.4m in tetrahydrofuran (THF)/toluene=1:3) with
CuI (2.5 mmol) and LiCl (2.5 mmol) as the additives,[8]
indene derivative 2aa was obtained in 27% yield, and 2aa’
was obtained in 12% yield in THF at ꢀ408C within 12 h
(Table 1, entry 1). Considering the importance of this indene
structure, we decided to optimize the reaction conditions;
the results are summarized in Table 1. As can be seen from
Table 1, compound 2aa’ was always formed in low yields,
but was not observed when 2aa was obtained in high yields.
We assume that 2aa’ was generated as an intermediate
during the reaction. Use of LiCl as additive revealed that in-
clusion of this salt could dramatically increase the yield of
2aa,[9] giving the desired product in 27% yield with 56%
conversion at ꢀ408C (Table 1, entries 1 and 2). Carrying out
the reaction at ꢀ20 or 08C gave 2aa in 55% yield (67%
conversion) and 81% yield (>99% conversion), respective-
ly (Table 1, entries 3 and 6). Further increasing the reaction
temperature to 258C (room temperature) afforded 2aa in
lower yield (Table 1, entry 10). Investigation of other CuI or
CuII salts such as CuCl, CuCN, CuBr, CuCl2, and CuBr2 in
this reaction at ꢀ20, 0, or 258C, revealed that 1) no signifi-
cant improvement was observed; 2) the inclusion of CuII
salts impaired the reaction outcome; and 3) the inclusion of
CuI gave the best result for the production of 2aa (Table 1,
[a] D.-Y. Li, Dr. Y. Wei, Prof. Dr. M. Shi
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Ling-Ling Lu
Shanghai, 200032 (P. R. China)
Fax : (+86)21-64166128
E-mail: Mshi@mail.sioc.ac.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201302191. It contains spectro-
scopic charts of the compounds shown in Tables 1–3, X-ray crystal
data of 2af, 2c, and 2g as well as detailed descriptions of experimen-
tal procedures.
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FULL PAPER
tained in higher yield (56%;
Table 1, entries 16 and 17). Re-
ducing the CuI loading de-
creased the yield of 2aa
(Table 1, entries 12–14). Exami-
nation of other OR functional
groups indicated that when R
was an acyl or a tosyl group
(1ab and 1ac), 2aa was formed
in lower yield; when OR was
a free hydroxyl group (R=H;
1ad), no reaction occurred
under the standard conditions
(Table 1, entries 18–20). Thus,
we established that by using
MeMgBr (5.0 equiv) combined
with CuI (5.0 equiv) and LiCl
(5.0 equiv) as the additives and
carrying out the reaction at 08C
in THF within 12 h, 2aa could
Figure 1. Synthetic approach to the production of 1-methyleneindene derivatives.
be obtained in the best yield
(Table 1, entry 6).
Table 1. Optimization of reaction conditions for the Grignard reagent/
Having established the optimized reaction conditions, we
next examined the use of various Grignard reagents to
extend the reaction scope; the results are presented in
Table 2. The reactions proceeded smoothly in the presence
CuI/LiCl-mediated cascade addition/cyclization reaction of diynes 1.[a]
Table 2. Substrate scope of the intramolecular cascade addition/cycliza-
tion reaction of diyne 1a with Grignard reagents.[a]
1
R
CuX
Additive T [8C] Conv. [%][b] Yield [%][c]
2aa 2aa’
1
2
3
4
5
6
7
8
1aa Ms CuI
1aa Ms CuI
1aa Ms CuI
1aa Ms CuCl
1aa Ms CuCN LiCl
1aa Ms CuI
1aa Ms CuCl
LiCl
–
LiCl
LiCl
ꢀ40
ꢀ40
ꢀ20
ꢀ20
ꢀ20
0
0
0
0
25
25
0
0
0
0
0
0
0
56
46
67
78
73
>99
>99
>99
>99
>99
>99
57
66
91
90
96
>99
26
91
27
6
12
13
–
–
14
–
–
5
–
–
–
10
–
–
5
12
–
–
–
–
55
57
31
81
79
37
44
47
45
8
21
40
10
14
56
8
Entry RMgX
Yield [%][b]
Entry RMgX
Yield [%][b]
LiCl
LiCl
1aa Ms CuCN LiCl
1
2
3
MeMgBr
EtMgBr
4
iPrMgCl
BnMgCl
PhMgBr
9
10
11
1aa Ms CuBr
1aa Ms CuI
1aa Ms CuCl
LiCl
LiCl
LiCl
LiCl
LiCl
LiCl
12[d] 1aa Ms CuI
13[e] 1aa Ms CuI
14[f] 1aa Ms CuI
5
15
16
1aa Ms CuCl2 LiCl
1aa Ms CuBr2 LiCl
17[g] 1aa Ms CuBr2 LiCl
nBuMgBr
6[c]
18
19
20
1ab Ac CuI
1ac Ts CuI
LiCl
LiCl
LiCl
0
0
43
–
1ad
H
CuI
–
[a] Reaction conditions: Diyne 1a (0.5 mmol), CuI (2.5 mmol), LiCl
(2.5 mmol), THF, 08C, 12 h. [b] Isolated yield. [c] The structure of prod-
uct 2af was confirmed by X-ray diffraction analysis.
[a] Diyne substrate 1 (0.5 mmol) and the reagents were added to a reac-
tion tube under argon, then the reaction was carried out in THF for 12 h.
[b] Conversion was determined on the basis of recovered starting materi-
als. [c] Isolated yield. [d] CuI (0.5 equiv.) was added. [e] CuI (1 equiv.)
was added. [f] CuI (3 equiv.) was added. [g] MeMgBr (10 equiv.) was
added.
of alkyl or aryl Grignard reagents to give the corresponding
products 2aa–ae and 2af in 29–81% yields (Table 2, en-
tries 1–6). By using iPrMgCl to initiate the reaction, indene
derivative 2ad, bearing a terminal olefin, was formed, pre-
sumably due to the steric bulk of the isopropyl Grignard re-
agent. When BnMgCl was employed in this reaction, a simi-
lar result was obtained, perhaps due to the electronic nature
entries 4–5, 7–9, 11 and 15–16). Because it was considered
that CuII salts are probably first reduced to CuI with the
Grignard reagent by SET, we then increased the amount of
MeMgBr employed to 10 equiv and found that 2aa was ob-
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M. Shi et al.
and steric effects of the benzyl group (Table 2, entry 4). Fur-
thermore, the E-configuration and exocyclic alkene struc-
ture of 2af was unambiguously determined by X-ray crystal-
lographic analysis, the ORTEP drawing of which is shown in
Figure 2 (the CIF data are presented in the Supporting In-
formation). The NOESY-1D and NOESY-2D spectra of 2aa
revealed that the indene derivatives derived from alkyl
Grignard reagents also had E-configuration (see the Sup-
porting Information for the details).
Figure 2. ORTEP drawing of 2af.
Under the optimized conditions, the substrate scope was
then examined; the results are summarized in Table 3. The
reaction conditions were suitable for a variety of diyne sub-
strates 1b–j and 1q with a range of functional groups on the
terminal alkyne (Table 3, entries 1–9 and 16) and substrates
1j–p, bearing either an electron-withdrawing or an electron-
donating group on the aromatic ring (Table 3, entries 10–
15), affording the desired indene derivatives in 70–99%
yield. It is noteworthy that this cascade addition and cycliza-
tion process is stereospecific. For diyne substrates 1b–j,
having substitution on the terminal alkyne, the correspond-
ing indene products were formed with Z-configuration
(Table 3, entries 1-9); whereas for diyne substrates 1j–p,
with no substitution on the terminal alkyne, the correspond-
ing indene products were formed with E-configuration
(Table 3, entries 10–15). The structures of 2c and 2g were
determined by X-ray crystallographic analysis; their
ORTEP drawings are shown in Figure 3 (the related CIF
data are presented in the Supporting Information). In the
case of diyne substrate 1q, the desired indene product 2q,
having two substituents on the terminal alkene, was ob-
tained in 82% yield (Table 3, entry 16). It should also be
noted that when MeMgBr (4.0 equiv), CuI (4.0 equiv), and
LiCl (4.0 equiv) were used in this reaction, the yield of the
desired indene product 2 decreased (Table 3, entry 6).
Figure 3. ORTEP drawings of 2c and g.
(phenylethynyl)cyclopropyl methanesulfonate as substrate,
the corresponding vinylidenecyclopropane could be isolated
in 92% yield under the standard conditions, which is consis-
tent with previous reports [Scheme 1, Eq. (1)].[8] Another
control experiment using S10b as the substrate also gave the
corresponding vinylidenecyclopropane 2l’ in 24% yield
under the standard conditions, presumably due to the spe-
cial electronic properties of the fluorine atom and the steric
bulk of TIPS, suggesting that this novel cascade addition/
cyclization reaction might proceed through a vinylidenecy-
clopropane-like intermediate [Scheme 1, Eq. (2); see the
Supporting Information for details]. To verify the possibility
of cross-coupling between vinyl and alkyl Grignard reagents,
we also conducted a coupling reaction between (E)-styryl-
magnesium bromide and MeMgBr under the standard con-
ditions. However, the corresponding homo-coupling product
was identified in 20% yield rather than the cross-coupling
To explore a plausible reaction mechanism, several con-
trol experiments and isotope labeling experiments were car-
ried out. As shown in Scheme 1, we found that by using 1-
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Cascade Addition/Cyclization of Diynes
FULL PAPER
Table 3. Substrate scope of the intramoleculor cycloaddition reactions of diynes 1 substituted on the terminal
(2.5 equiv)
and
EtMgBr
alkyne or on the aromatic ring.[a]
(2.5 equiv) as reagents under
the standard conditions to gain
more insights into the coupling
process, we found that the
cross-over product was indeed
formed (GC-MS analysis), sug-
gesting that the cross-coupling
process should exist in this par-
ticular case during the reaction
[Scheme 1, Eq. (4); see the Sup-
porting Information for details
and product ratios]. To investi-
gate whether carbomagnesia-
tion or carbocupration was in-
volved during the reaction,
Entry
1
1
Yield [%][b]
Entry
9
1
Yield [%][b]
2[c]
10
11
a
a
control experiment using
combination of MeLi
(5.0 equiv), CuI (5.0 equiv), and
LiCl (5.0 equiv) without the use
of Grignard reagent, was con-
ducted [Scheme 1, Eq. (5)].
Under these conditions the de-
sired product 2aa was produced
in 56% yield, suggesting that
methyl copper species is in-
volved in the above reaction
system.
3
4
5
12
13
To gain more mechanistic in-
sights into the reaction, we con-
ducted isotope labeling experi-
ments to further examine the
active intermediates in this re-
action. First, by using D2O to
quench the reaction after 2 h,
deuterated product [D]-2aa’ (D
content > 99%) was obtained
in 17% yield with E-configura-
tion, along product 2aa in 42%
yield (Scheme 2, see the Sup-
porting Information for details).
Second, substrate [D]-1aa was
prepared and the reaction was
conducted under the optimized
conditions, affording [D]-2aa in
80% yield without deuterium
loss. This finding excludes the
possibility of methyl copper
species adding to the methylene
group of 2aa’ with subsequent
elimination of a copper hydride
species to form 2aa. A second
isotope labeling experiment,
similar to the first, was carried
6[d]
14
15
16
7
8
[a] Reaction conditions: Diyne 1 (0.5 mmol), CuI (2.5 mmol), LiCl (2.5 mmol), THF, MeMgBr (2.5 mmol),
08C, 12 h. [b] Isolated yield. [c] The structure was confirmed by X-ray diffraction analysis. [d] The structure of
product 2g was confirmed by X-ray diffraction analysis. [e] Isolated yield with CuI (2.0 mmol), LiCl
(2.0 mmol) and MeMgBr (2.0 mmol) under the standard conditions.
product [Scheme 1, Eq. (3); see the Supporting Information
for details]. Furthermore, when cross-over experiments
were conducted with 1a as substrate and MeMgBr
out by using 1g as the substrate under the standard condi-
tions, producing [D]-2g in 86% yield (D content=88%)
(Scheme 2, see the Supporting Information for details). We
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M. Shi et al.
also attempted to trap the gen-
erated active species in situ by
inclusion of another electro-
phile such as iodine during the
quenching process. Under these
conditions, the iodinated prod-
uct 3a was indeed obtained in
74% yield (Scheme 2, see the
Supporting Information for de-
tails). Together, these results
implied that a vinyl Grignard
type intermediate was generat-
ed during the reaction. In addi-
tion, on the basis of TLC analy-
sis, we observed that during the
reaction, 2aa’ could be trans-
formed into 2aa.
The control and deuterium
labeling experiments described
above, as well as previous re-
ports,[8] allowed a plausible re-
action mechanism for the for-
mation of
2 to be outlined
(Scheme 3) with 1 as a reaction
model and MeMgBr as the re-
actant. Initial reaction of ethy-
nylcyclopropyl methanesulfo-
nate 1 with MeCu·MgBrI·LiCl,
generated in situ, gives vinyli-
denecyclopropane (VDCP) in-
termediate A, which undergoes
addition with the active copper
species (MeCu) generated in
situ, to give intermediate B.
Subsequent intramolecular syn-
carbocupration takes place to
generate the corresponding
vinyl copper species. When R1
is not a hydrogen atom, subse-
quent addition of vinyl copper
to the alkyne moiety gives the
corresponding indene derivative
Scheme 1. Control and crossover experiments.
2
with Z-configuration after
quenching (work-up). When
R1 =H, a similar intramolecular
syn-carbocupration takes place
to generate the corresponding
vinyl copper species. In this
case, the cross-coupling reac-
tion with MeCu might take
place to give the desired indene
derivative 2 with E-configura-
tion. For the copper species
generated in situ from sterically
bulky Grignard reagent, the
cross-coupling reaction might
take place with more difficulty,
Scheme 2. Isotope/iodine labeling experiments.
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Cascade Addition/Cyclization of Diynes
FULL PAPER
Experimental Section
General procedure for the synthesis of 2: To a flame-dried, argon-purged
Schlenk tube, was added LiCl (2.5 mmol), which was heated vigorously,
evacuated to dry, and purged with argon three times. CuI (2.5 mmol) was
then added into the reaction vessel under argon. The reaction tube was
set in an ice-water bath and THF (2 mL) was added to generate a white
suspension. Grignard reagent (2.5 mmol) was added and the reaction
mixture was stirred for 10 min, then 1-[(2-ethynylphenyl)ethynyl]cyclo-
propyl methanesulfonate (0.5 mmol) dissolved in THF (5 mL) was
added. The reaction was allowed to proceed at 08C for 12 h, then
quenched by the addition of water (2 mL) and the reaction mixture was
extracted with petroleum ether. The organic phase was concentrated
under reduced pressure and the residue was purified by silica gel flash
column chromatography with petroleum ether as eluent.
1
Compound 2aa: Yield: 84 mg (80%); yellow-green oil; H NMR (CDCl3,
400 MHz, TMS): d=0.67–0.88 (m, 4H; CH2), 1.35 (s, 3H; CH3), 2.24 (s,
3H; CH3), 2.35 (d, J=7.6 Hz, 3H; CH3), 6.64 (q, J=7.6 Hz, 1H; CH),
7.11–7.22 (m, 3H; Ar), 7.45 ppm (d, J=7.6 Hz, 1H; Ar); 13C NMR
(CDCl3, 100 MHz, TMS): d=11.5, 13.8, 15.9, 25.3, 29.7, 117.60, 117.63,
124.6, 124.8, 126.5, 137.5, 139.1, 139.3, 139.7, 142.1 ppm; IR (CH2Cl2): n˜ =
2993, 2951, 2923, 2855, 1640, 1463, 1422, 1477, 1350, 1109, 1046, 1020,
964, 931, 876, 833, 812, 759, 708 cmꢀ1; MS (%): m/z: 210 (19.55) [M]+,
195 (70.84), 180 (30.71), 179 (16.59), 178 (15.52), 166 (15.74), 165 (50.06),
Scheme 3. A plausible reaction mechanism for the formation of 2.
thus only affording the terminal alkene indene derivative.[10]
When R1 ¼ H, the steric bulk of the exocyclic alkene can
prevent cross coupling with MeCu under the standard condi-
tions.
Further transformation of indene derivative 2 could be re-
alized through a cyclopropane ring-open reaction upon
treatment with BiCl3 at 1008C in toluene.[11] The newly gen-
erated double bond could be used for further application
(Scheme 4).
43 (100.00); HRMS (EI): m/z calcd for C16H18
: 210.1409; found:
210.1413.
Compound 2aa’: Reacted for 3 h then worked up. Yield: 44 mg (42%);
yellow-green oil; 1H NMR (CDCl3, 400 MHz, TMS): d=0.67–0.73 (m,
4H; CH2), 1.29 (s, 3H; CH3), 2.19 (s, 3H; CH3), 5.90 (s, 1H; =CH2), 5.94
(s, 1H; =CH2), 7.12–7.16 (m, 2H; Ar), 7.22–7.26 (m, 1H; Ar), 7.49–
7.51 ppm (m, 1H; Ar); 13C NMR (CDCl3, 100 MHz, TMS): d=10.9, 12.4,
12.8, 26.0, 109.6, 117.9, 118.9, 125.0, 127.9, 135.9, 139.1, 139.9, 143.9,
146.5 ppm; IR (CH2Cl2): n˜ =3075, 2995, 2951, 2858, 1605, 1460, 1421,
1387, 1281, 1258, 1108, 933, 898, 761, 730 cmꢀ1; MS (%): m/z: 196 (54.72)
[M]+, 182 (15.65), 181 (100.00), 179 (14.17), 167 (17.51), 166 (54.49), 165
(67.22), 152 (15.58); HRMS (EI): m/z calcd for C15H16: 196.1252; found:
196.1253.
Acknowledgements
We thank the Shanghai Municipal Committee of Science and Technology
(11JC1402600), the National Basic Research Program of China ACHTUNGTRENNUNG(973)-
2009CB825300, and the National Natural Science Foundation of China
for financial support (21102166, 21072206, 20472096, 20872162, 20672127,
21121062, and 20732008).
Scheme 4. Further transformation of 2g.
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Conclusion
We have developed a novel Grignard reagent/CuI/LiCl
mediated stereoselective cascade addition/cyclization reac-
tion of diynes containing a cyclopropane group that could
be used to synthesize a 1-methyleneindene skeleton with
a stereospecific exocylic olefin. The strained cyclopropane
ring can be used for further transformation through ring
opening. A plausible reaction mechanism for the formation
of these 1-methyleneindene derivatives has been proposed
on the basis of control experiments, deuterium labeling ex-
periments, and previous reports. Further investigations on
the mechanistic detail and the application of this novel syn-
thetic method are in progress.
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Received: June 8, 2013
Published online: October 7, 2013
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