Palladium(0)-catalyzed cyclopropanation of benzyl bromides via C(sp 3)-H bond activation

Article abstract of DOI:10.1039/c3cc49231a

A novel and highly efficient Pd(0)-catalyzed domino reaction to prepare cyclopropane derivatives has been established. The process involves a Heck-type coupling reaction and a C(sp³)-H bond activation. Preliminary DFT calculations suggest that a four-membered palladacycle intermediate is involved. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c3cc49231a

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Palladium(0)-catalyzed cyclopropanation of benzyl bromides via C(sp3)-
H bond activation
Jiangang Mao,a,b Weiliang Bao,*a
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
molecules via C(sp3)−H bond activation has not been reported.
A novel and highly efficient Pd(0)-catalyzed domino reaction
to prepare cyclopropane derivatives has been established. The
process involves a Heck-type coupling and a C(sp3)–H bond
activation. Preliminary DFT calculations suggest that a four-
10 membered palladacycle intermediate is involved.
Herein, we report the first example of intermolecular C(sp3)−H
activation cyclopropanation catalyzed by Pd(0) (Scheme 1).
40
Norbornene11 and Cyclopropane-fused norbornene skeleton12
present in many natural products and pharmaceuticals and exhibit
biological activity. Cyclopropane-fused dicyclopentadienes are
also used as high energetic materials.13 Cyclopropane-fused
norbornene and dicyclopentadiene were useful precursors of
Due to the smallest bonding angle and corresponding unique
properties, synthesis and transformations of cyclopropanes have
attracted tremendous interest of chemists.1 The cyclopropane
subunit is also found in many natural products and unnatural
15 pharmaceuticals, so studies on their synthetic stratagies were
further propelled.2 A general method for the synthesis of
cyclopropane derivative is the addition of carbenes to alkenes.3
The Simmons–Smith reaction is also an important method for
converting carbon-carbon double bonds to cyclopropane rings.4
20 Michael-initiated ring closure (MIRC)5 and intramolecular
cycloisomerization of designed highly-unsaturated molecules6 are
delicate strategies to install a cyclopropane unit. Transition metal
catalyzed transformations may become the most efficient and
powerful methodology to construct structurally diverse small ring
25 compounds. A few examples for making cyclopropanes via C−H
or C–C bond activation have been reported.7,8,9,10
45 cycloisomerization in organic synthesis.14
Based on our interesting in the cyclopropane-fused norbornene
derivatives and envisioning for Pd(0)-catalyzed cyclopropanation
of norbornenes via C(sp3)−H bond activation,15 benzyl bromide
1a and endo-N-(p-tolyl) norbornenesuccinimide 2a were
50 employed as model substrates to perform the reaction. The
desired product 3aa was obtained when the reaction was
catalyzed by Pd(OAc)2/PPh3. So the reaction parameters were
investigated and the results are summarized in table 1.
Firstly, the metal catalyst and the ligand were screened in the
55 [2+1] cycloadditions. Pd(OAc)2 was better than PdCl2 and
Pd(PPh3)4 (Table 1, entries 4, 9 and 10, 91% yield compared with
64% and 72%). Pd(dppf)Cl2 did not give the desired product,
possibly because of steric effect from the sterically encumbered
ligand. The effect of the ligand was also important. In contrast to
60 PPh3 (entry 4, 91% yield), BINAP was not effective in this
reaction, and TMOPP resulted in a lower yield of 3aa (entry 13,
53%). The base also had a significant effect on the yield of the
reaction product. t-BuOK, Cs2CO3, and K3PO4 gave the low to
good yield respectively (Table 1, entries 1, 2 and 6, 31%-76%).
65 NaNH2 and DBU were not effective. The use of KOH as a base
provided a complex mixture. Compared to K2CO3, CH3ONa was
the best in promoting this reaction (Table 1, entries 3 and 4). The
effects of solvent and temperature were also investigated. The
reaction could be conducted successfully in toluene (Table 1,
70 entry 4). Other polar aprotic solvents, such as CH3NO2 and
dioxane only gave low or moderate yields (Table 1, entries 14
and 15), while DMF resulted in a failure reaction (Table 1, entry
16). Reduced reactivity and conversion were observed when the
reaction was performed at 90 °C (entry 17, 51%). For the model
75 reaction, the best yield was obtained when the reaction was
catalyzed by Pd(OAc)2/PPh3 and CH3ONa was employed as base
in toluene (Table 1, entry 4, 91%).
cyclopropanation of C(sp)
ref 8,
R2
R2
R3
[Pd]/ligand
R1
R1
+
R3
cyclopropanation of C(sp2)
ref 9,
R3
R4
R3 [Rh]/ligand
R4
R1
BHR2
+
R1
This work, cyclopropanation of C(sp3)
H
R2
R3
R2
R3
Pd(OAc)2/PPh3
Br
R1
+
R1
base, toluene
100 oC, 12 h
1
2
3
Scheme 1. Strategies for the formation of cyclopropanes.
Buono and co-workers reported Pd-catalyzed cyclopropanation
30 of terminal alkynes with norbornene derivatives via C(sp)−H
bond activation (Scheme 1).8 Lautens and Murakami reported
rhodium-catalyzed tandem vinylcyclopropanation of vinylboronic
compounds to strained alkenes.9 However, cyclopropanation via
C(sp3)−H bond activation remains underdeveloped, with only one
35 example of Rh(1)-catalyzed intramolecular cyclopropanation
reported by Sato.10 Intermolecular cyclopropanation of simple
With the optimized reaction conditions in hand, the substrate
scope was examined using varieties of benzyl bromides 1 and
80 norbornene derivatives 2, as shown in Table 2. In general, benzyl
This journal is © The Royal Society of Chemistry [year]
[journal], [year], [vol], 00–00 | 1

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Page 2 of 4
bromides
bearing
electron-donating
groups
provided
eliminate to carbene under this reaction condition.
Table 2. Substrate scope of Pd(0)-catalyzed cyclopropanation.
corresponding cyclopropane products in higher yields than those
containing electron-withdrawing groups (except for 3da). The
benzyl bromides substituted by methyl or methoxy group
afforded product 3 in good to excellent yields (Table 2, 3ba-3da,
3bb, 3bc-3cc, 3ic, 3bd-3cd, 3id). Benzyl bromides bearing
electron-withdrawing groups (fluoro and chloro) also provided
products 3 in good to high yields (Table 2, 3ea-3ha, 3eb-3gb, 3gc,
3ed-3gd). The ortho-methyl and chloro benzyl bromides could
10 not give pure products because of their steric hindrance. The
structure of 3aa is further unambiguously elucidated by X-ray
crystallography (see the SI, Figure 1). On the basis of the
chemical shifts and coupling constants (J) of all the products as
well as the NOESY analysis of 3aa, 3ea and 3ic, it can be
15 ascertained that the stereochemistry of all the compounds is the
same with that of 3aa. In addition, they are all the sole
diastereomers obtained in each case.
View Article Online
DOI: 10.1039/C3CC49231A
H
R2
R1
R2
R3
Pd(OAc)2/PPh3
Br
5
R1
+
base, toluene
100 oC, 12 h
R3
H
1
2
3
O
O
H
H
H
O
H
H
H
N
N
H
H
H
H
O
O
O
a
3aa,
91%
3bb,
3ic,
93%
90%
O
H
H
H
H
H
H
N
F
N
H
H
H
H
95%
H
H
82%
H
H
H
O
O
O
O
90%b
H
3ba,
3eb,
H
3ad,
3bd,
3cd,
3ed,
3fd,
H
N
Cl
N
H
H
H
93%b
H
H
77%
H
H
O
O
O
3fb,
3ca,
93%
O
Cl
H
H
H
H
H
Table 1. Optimization of reaction conditions a
O
N
N
H
91%b
O
O
H
3gb,
H
H
H
H
H
74%
H
H
H
O
O
H
H
3da,
82%
[Pd]/ligand
Br
O
H
H
N
+
N
H
H
base, solvent
100 oC, 12 h
F
F
N
H
2a
O
O
1a
3aa
H
86%b
H
H
H
H
H
86%
O
89%a
3ac,
3bc,
3cc,
3gc,
3ea,
O
entry
[Pd]
ligand
base
solvent
yield(%)
H
H
H
H
Cl
N
Cl
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
-
BINAP
TMOPPd
PPh3
PPh3
PPh3
PPh3
Cs2CO3
K3PO4
K2CO3
CH3ONa
NaNH2
t-BuOK
DBU
KOH
CH3ONa
CH3ONa
CH3ONa
CH3ONa
CH3ONa
CH3ONa
CH3ONa
CH3ONa
CH3ONa
CH3ONa
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH3NO2
Dioxane
DMF
54
76
80
H
H
92%a
H
92%b
H
O
H
H
3fa,
83%
H
Cl
O
Cl
H
H
H
91
NRb
31
N
H
90%a
H
H
91%b
H
78%
H
H
H
O
O
3gd,
3id,
3ga,
H
NRb
Cl
O
H
H
c
-
N
9
64
72
H
H
86%a
H
H
H
O
10
11
12
12
13
14
15
16
Pd(PPh3)4
Pd(dppf)Cl2
-
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
b
3ha,
94%
85%
c
-
45 Reaction conditions unless otherwise noted: 1 (0.55 mmol), 2 (0.5 mmol),
NRb
NRb
53
Pd(OAc)2 (0.05 mmol), PPh3 (0.11 mmol), CH3ONa (1.5 mmol), toluene
a
(2.0 mL), 100 °C, 12 h in sealed tube. Isolated yields. 1 (0.5 mmol), 2
(0.5 mmol), K2CO3 (0.25 mmol), toluene (3.0 mL), 120 °C, 12 h. b 1 (0.5
34
mmol), 2 (0.5 mmol), K2CO3 (0.25 mmol), toluene (3.0 mL), 100 °C, 12 h.
56
NRb
17
toluene
51e
a
20 Reaction conditions unless otherwise noted: 1a (0.55 mmol), 2a (0.5
mmol), catalyst (0.05 mmol), ligand (0.11 mmol), base (1.5 mmol),
b
solvent (2.0 mL), 100 °C, 12 h in sealed tube. Isolated yields. No
c
d
f
reaction. No product.
TMOPP=tris(4-methoxylphenyl)phosphine.
90°C.
25
Substituted norbornene substrates were also examined.
Norbornene itself afforded the expected corresponding
benzylcyclopropane products (Table 2, 3ac-3cc, 3gc, 3ic) in good
to excellent yields (90%-93%) in the presence of 0.5 equiv
30 K2CO3 and 3.0mL toluene at 120°C. Functionalized norbornenes
afforded the corresponding products in good to excellent yields
(Table 2, 3aa-3ha, 3bb, 3fb-3gb, 77%-96%) in the presence of
1.5 equiv CH3ONa and 2.0mL toluene at 100°C.
Dicyclopentadiene afforded the desired products (Table 2, 3ad-
35 3gd, 3id) with good to excellent yields in the presence of 0.5
equiv K2CO3 and 3.0 mL toluene at 100°C.
In order to better understand the reaction mechanism, the blank
test without Pd(OAc)2/PPh3 was performed (Table 1, entry 12)
and no reaction occurred. So the reaction should not proceed
40 through carbene intermediate. Benzyl bromide could not
50 Scheme 2. Plausible reaction mechanism and DFT calculations
on deprotonation process for TS1a and TS1b.
Based on the above results and earlier precedents,10,16
a
putative mechanism was proposed (Scheme 2). The oxidative
2
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Charette, Chem. Eur. J., 2012, 18, 14784; (d) J. S. Alford and H. M.
L. Davies, Org. Lett., 2012, 14, 6020; (e) A. Biswas, S. D. Sarkar, L.
addition of palladium(0) species to benzyl bromides generated a
benzylpalladium(II) species II. Subsequent Heck-type
carbopalladation at the exo-face of the norbornene gave
norbornenylpalladium complex III, which undergowent C(sp3)-H
bond activation on the methylene of benzyl and generated a
palladacycle IV. DFT calculations on the deprotonation process
showed that the TS1a was more stable than TS1b with a
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more details). The optimized geometry of TS1a exhibited a much
10 stronger interaction between OMe and H than TS1b. Therefore,
the complex III prefered TS1a route to TS1b and palladacycle
IV was formed. Reductive elimination of IV afforded the desired
cyclopropane compound 3 and regenerated Pd(0) I.
In conclusion, a novel and highly efficient Pd(0)-catalyzed
15 domino cyclopropanation reaction has been established. The
process involves a Heck-type coupling and a C(sp3)–H bond
activation. Benzyl bromide is coupled with norbornenes via
Pd(0)-catalyzed [2+1] cycloaddition reaction and a series of
cyclopropane-fused tricyclo-compounds were synthesized. DFT
20 calculations suggest that a four-membered palladacycle transition
state is involved. Application of this Pd(0)-catalyzed
cycloaddition reaction via C(sp3)–H Bond activation to other
biologically significant compounds is currently underway.
Tebben and A. Studer, Chem. Commun., 2012, 48, 5190; (f) V. N. G.
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Acknowledgements
25 Financial support from the Natural Science Foundation of China
(No. 21072168) is greatly acknowledged. We thank gratefully Dr
Shuo-Qing Zhang and Dr Bing-Feng Shi for DFT calculations.
95
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Notes and references
a Department of Chemistry, Zhejiang University, 148 Tianmushan road,
30 Hangzhou, 310028, Zhejiang, China. E-mail: wlbao@zju.edu.cn
b School of Metallurgy and Chemical Engineering, Jiangxi University of
Science and Technology, 86 Hongqi Avenue, Ganzhou, 341000, Jiangxi,
China.
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† Electronic Supplementary Information (ESI) available: [Experimental
35 procedure, characterization data, H and 13C NMR spectra of compounds
1
3.]. See DOI: 10.1039/b000000x/.
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This journal is © The Royal Society of Chemistry [year]
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TOC
H
View Article Online
DOI: 10.1039/C3CC49231A
H
H
R2
R3
R2 Pd(OAc)2/PPh3
R1
Br
R1
R3
+
base, toluene
100 oC, 12 h
1
2
3
A novel Pd(0)-catalyzed domino cyclopropanation reaction was
established. The process involves a Heck-type coupling and a
C(sp3)–H activation.
4
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