Organic Letters
Letter
showed that base was a key reaction parameter, so different bases
such as K2CO3, Cs2CO3, CsOAc, C2H5ONa, and CH3ONa were
reviewed first. It affected both product yields and product
categories. When 2.0 and 3.0 equiv of Cs2CO3 was used as base
and 0.2 mL of CH3OH was added, the desired product 3aa was
isolated, respectively, in 31% and 78% yields (see Table SI1,
entries 2 and 3). When K2CO3 was employed as base, the
reaction gave 4aa as product but not 3aa (92% yield, Table SI1,
entry 1).13a Even if 4.0 or 6.0 equiv of CsOAc was used as base,
4aa was still the main product (72% and 75% yield, Table SI1,
entries 4 and 5). C2H5ONa afforded 85% yield product 3aa. The
[2 + 1] cycloaddition afforded methylcyclopropane 3aa with the
best yield in the presence of 3.0 equiv of CH3ONa (96% yield,
entry 10).
Scheme 2. Substrate Scope of Pd-Catalyzed
Methylcyclopropanation of Norbornenes with (Z)-Vinyl
a
Bromides
After CH3ONa was identified as the best base, other reaction
parameters were optimized using it. Several Pd precatalysts were
screened (Table SI1, entries 10−13). Using Pd(dppf)Cl2 as the
precatalyst, 3aa was obtained in 83% yield (Table SI1, entry 13),
while PdCl2 and Pd(PPh3)4 delivered the desired products in
52% and 74% yields, respectively (Table SI1, entries 11 and 12).
Then the ligands dppe, BINAP, TMOPP, and TCHP were
screened and afforded 3aa in 74%, 70%, 91%, and 68% yields,
respectively (Table SI1, entries 6−9). The effects of solvent and
additive were also investigated. The reaction could be conducted
successfully in methanol (63% yield, Table SI1, entry 18). Other
solvents, such as CH3CN, dioxane, DMSO, and DMF, were also
suitable for the reaction but only afforded 3aa in low or moderate
yields (43%−66% yield, Table SI1, entries 14−17). Subse-
quently, additives such as C2H5OH, PhCH2OH, and Cl-
(CH2)2OH were also surveyed; methylcyclopropane 3aa was
obtained in 42%, 61%, and 72% yields, respectively, in the
presence of Cs2CO3 due to the different pKa and steric hindrance
of the alcohols (Table SI1, entries 21−23). The loading of 1.0
mL of CH3OH reduced the yield of 3aa to 75% (Table SI1, entry
20). When the reaction was carried out in the absence of
CH3OH, the result was not ideal and only afforded a trace of the
desired product (Table SI1, entry 19). The best reaction
temperature is at 110 °C (96% yield, Table SI1, entry 10). The
yields decreased to 91% and 66%, respectively, when the
reactions were carried out at 120 and 90 °C (Table SI1, entries 24
and 25). The best yield of methylcyclopropane 3aa was obtained
when the model reaction was catalyzed by Pd(OAc)2/PPh3, 3.0
equiv of CH3ONa was employed as base, and 0.2 mL of CH3OH
was used as the additive in toluene (96% yield, Table SI1, entry
10).
With the optimized reaction conditions in hand, some
representative substrates were employed to investigate the
scope and generality of the [2 + 1] cycloaddition domino
reaction, as shown in Scheme 2. (Z)-2-Bromovinylarenes bearing
electron-donating (3-Me, 4-Me, and 4-MeO) groups on the
benzene core afforded the corresponding methylcyclopropane
derivatives 3 in excellent yields (Scheme 2, 3aa, 3ca−da, 3db,
3ac, 3cc−dc, 3ad, 3cd−dd), while (Z)-2-bromovinylarenes
bear-ing electron-withdrawing groups (2-Cl, 3-Cl, 4-Cl, and 4-F)
on the benzene ring provided products 3 in good to high yields
(Scheme 2, 3ea−ha, 3fb, 3hb, 3hc, 3hd). The para-substituted
vinylarenes provided methylcyclopropane products 3ca, 3ea,
3cc, and 3cd in higher yield (Scheme 2, 95%, 89%, 85% and 83%
yield) owing to much smaller steric hindrance compared with the
corresponding meta-substituted vinylarenes (3da, 3fa, 3dc, and
3dd; 91%, 82%, 82%, and 81% yield). The reaction scope was
further extended to aliphatic (Z)-1-bromoalkenes 1i successfully,
a
Reaction conditions unless otherwise noted: 1 (0.55 mmol), 2 (0.5
mmol), Pd(OAc)2 (0.05 mmol), PPh3 (0.11 mmol), CH3ONa (1.5
mmol), toluene (2.0 mL), CH3OH (0.2 mL), 110 °C, 12 h in sealed
tube. Isolated yields are shown. CH3ONa (1.0 mmol). Reaction
conditions: 1 (0.5 mmol), 2 (0.6 mmol), Pd(OAc)2 (0.05 mmol),
PPh3 (0.11 mmol), CH3ONa (2.0 mmol), toluene (2.0 mL).
b
c
and afforded methylcyclopropanation products 3ia and 3ib in
71% and 76% yields, respectively.
After the scope of the (Z)-2-bromovinylarenes was screened,
another coupling partner, norbornene derivatives, was inves-
tigated. endo-N-Isobutylnorbornenesuccinimide 2b was coupled
smoothly with (Z)-vinyl bromides to give corresponding
products 3db, 3fb, and 3hb−ib in good to high yields under
the optimized reaction conditions. Norbornene itself 2c also
provided the desired methylcyclopropanes with good yields in
the presence of 4.0 equiv of CH3ONa (Scheme 2, 3ac, 3cc−dc,
3hc). Functionalized norbornene derivatives such as (1R,4S)-
1,4-dihydro-1,4-methanonaphthalene-5,8-diyl diacetate success-
fully produced the corresponding methylcyclopropanes in good
to excellent yields (Scheme 2, 3ad, 3cd, 3dd, 3hd). Cyclohexene
was also employed as alkene to carry out the [2 + 1]
cycloaddition reaction, however, the reaction did not proceed
smoothly. The structure of products was further confirmed
unambiguously by X-ray crystallography of 3da (see the SI,
Figure S1). The formed methylcyclopropane subunit took the
exo-face of norbornane.
Subsequently, (E)-2-bromovinylarene substrates (E)-1 were
investigated, and the corresponding methylcyclopropane prod-
3679
Org. Lett. 2015, 17, 3678−3681