Palladium-catalyzed cyclopropanation of electron-deficient olefins with aryldiazocarbonyl compounds

Article abstract of DOI:10.1016/j.tetlet.2008.09.024

A concise and efficient protocol for the preparation of cyclopropanes from various aryldiazocarbonyl compounds and electron-deficient olefins catalyzed by Pd(OAc)₂ is reported.

Full text of DOI:10.1016/j.tetlet.2008.09.024

Tetrahedron Letters 49 (2008) 6781–6783
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Tetrahedron Letters
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Palladium-catalyzed cyclopropanation of electron-deficient
olefins with aryldiazocarbonyl compounds
*
Shufeng Chen, Jian Ma, Jianbo Wang
Beijing National Laboratory of Molecular Sciences (BNLMS), and Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education,
College of Chemistry, Peking University, Beijing 100871, China
The State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 July 2008
Revised 1 September 2008
Accepted 9 September 2008
Available online 11 September 2008
A concise and efficient protocol for the preparation of cyclopropanes from various aryldiazocarbonyl
compounds and electron-deficient olefins catalyzed by Pd(OAc)2 is reported.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Diazo compounds
Cyclopropanation
Pd-catalyzed reaction
Electron-deficient olefin
The cyclopropane units have received considerable attention
because of their common structural motifs in biologically active
natural and unnatural compounds and of their importance as
valuable synthetic intermediates.1,2 Among the various methods
available for the preparation of cyclopropanes, transition metal-
catalyzed cyclopropanation of olefins with diazo reagents has
attracted great interest for its high efficiency and high regio-, dia-
stereo-, and enantioselectivity.2 It is well documented that the
Cu(I) and Rh(II) are generally efficient catalysts for the synthesis
N2
Pd(OAc)2
PhCH3, 80 oC
CO2Me
OMe
+
Ph
O
86%
1a
2a
Ph
MeO2C
CO2Me
3a
cis:trans > 95:5
Scheme 1. Pd(OAc)2-catalyzed cyclopropanation of methyl phenyldiazoacetate 1a
with methyl acrylate 2a.
of cyclopropane derivatives from olefins and a-diazocarbonyl com-
pounds. However, because of the electrophilic nature of the metal
carbene intermediates in the catalytic cycle, the alkenes used in
this type of reactions are generally electron-rich olefins.2 Cyclo-
propanations of electron-deficient olefins, such as a,b-unsaturated
carbonyl compounds, remain to be a challenging problem. Among
our knowledge the corresponding reaction with aryldiazoacetates
is unknown.2a,9 On the other hand, the general synthetic routes
to 1-arylcyclopropane-1,2-dicarboxylate derivatives involve the
reaction of
a-bromophenylacetates with acrylic esters under
several previous efforts toward transition metal-catalyzed cyclo-
strong basic conditions,10 or the reaction of ammonium ylides in
basic two-phase systems.11 Considering the fact that cyclopro-
panes containing two or more electron-withdrawing groups are
valuable synthetic intermediates for various applications,12 and
there are only limited methods available for their preparation,
we believe the Pd-catalyzed reaction shown in Scheme 1 will be
highly attractive. In this Letter, we wish to report the results of a
detailed study on the reaction of electron-deficient olefins with
aryldiazocarbonyl compounds catalyzed by Pd(II) complex.
propanation of electron-deficient olefins with diazo reagents,3–7
a
notable example is the Co(II)-based asymmetric catalytic system
recently reported by Zhang and co-workers.7
During our recent research in palladium-catalyzed reaction of
diazo compounds,8 we found that Pd(OAc)2 could catalyze cyclo-
propanation of methyl acrylate with methyl phenyldiazoacetate
1a in high yield and stereoselectivity (Scheme 1).
Although palladium salts are already found as catalysts in cyclo-
propanation of electron-deficient olefins with diazomethane, to
At the outset of this investigation, various transition metal com-
plexes were examined as the catalysts in the reaction of methyl
phenyldiazoacetate 1a with methyl acrylate 2a. For comparison,
we first examined Rh2(OAc)4, Cu(CH3CN)4PF6, and AgSbF6 as the
* Corresponding author. Tel.: +86 10 6275 7248; fax: +86 10 6275 1708.
E-mail address: wangjb@pku.edu.cn (J. Wang).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.024

6782
S. Chen et al. / Tetrahedron Letters 49 (2008) 6781–6783
Table 1
on the aromatic ring could be tolerated, and the reaction gave
moderate to good yields and selectivities of the products 3a–k. It
was found that substrates with phenyl ring bearing electron-
donating group generally gave slightly lower yields with high
selectivity (Table 2, entries 2 and 3), while substrates with elec-
tron-withdrawing substituent on the phenyl ring, such as halogen
and nitro, gave good yields with moderate selectivities (entries 4–
9). To our delight, when the less reactive diazo compound 1j was
subjected to this reaction, the cyclopropanation product 3j was ob-
tained in moderate yield and with high selectivity (entry 10).
Moreover, it was noted that the ester moiety of the diazo com-
pounds did not affect the reaction (entry 11). The cis configuration
of product was determined by NOE experiment with 3d.
Transition metal-catalyzed cyclopropanation of methyl phenyldiazoacetate 1a with
methyl acrylate 2a
Entry
Cat. (mol %)
t (h)
Yielda (%)
cis:transb
1
2
3
4
5
6
7
Rh2(OAc)4 (0.5)
Cu(CH3CN)4PF6 (10)
AgSbF6 (10)
Pd(OAc)2 (5)
Pd(PPh3)4 (5)
PdCl2 (5)
24
24
24
0.5
0.5
0.5
3
0
0
0
86
72
71
67
—
—
—
>95:5
>95:5
84:16
>95:5
Pd(OAc)2 (1)
a
Yield of isolated product after chromatography.
b
Ratio was determined by 1H NMR (300 MHz) of the crude product.
Next, we examined the scope of electron-deficient olefin sub-
strates, as shown in Table 3. The ester moiety of the acrylate did
not affect the reaction, and cyclopropanation proceeded smoothly
to give the products with high yields and selectivities (Table 3, en-
tries 1 and 2). However, when the substituted methyl acrylate was
catalysts. These transition metal complexes have been proven to be
the efficient catalysts for cyclopropanation of electron-rich olefins
by diazo compounds. However, in the reaction with 2a, no ex-
pected product 3a could be observed under the similar conditions
(Table 1, entries 1–3). The following experiment showed that
Pd(OAc)2 could give the highest yield in this reaction, generating
the cyclopropane 3a with very high diastereoselectivity (entry 4).
Next we screened the commonly available palladium salts in this
cyclopropanation, Pd(PPh3)4 gave the moderate yield of 3a under
the same condition (entry 5), while PdCl2 could only afford 3a with
moderate yield and selectivity (entry 6). Finally, when we de-
creased the catalyst loading of Pd(OAc)2 from 5 mol % to 1 mol %,
the yield diminished and the reaction took longer (entry 7).
Having established the optimal reaction conditions, we next
examined the scope of the reaction with an assortment of methyl
acrylate 2a and aryldiazocarbonyl compounds 1a–k, and the
corresponding results are listed in Table 2.13 Various substitutions
applied as substrate, we found that a-substituted methyl acrylate
was suitable for this reaction, while b-substituted methyl acrylate
could only give the lowest yield of cyclopropanation product (en-
tries 3 and 4). With acrylaldehyde, only 15% yield product could
be obtained even ligand was added to improve the reaction (entry
5). It was noted that acrylamide 2f and acrylonitrile 2g could react
with methyl phenyldiazoacetate 1a when 1,10-phenanthrolin li-
gand was added, albeit with essentially no selectivities (entries 6
and 7).
In the previous report on the Pd-catalyzed cyclopropanation
with diazo substrates, Pd carbene generation followed by [2+2]
cyclization and reductive elimination has been suggested to be
the possible mechanism. However, in the present investigation,
the following observation led us to consider an alternative reaction
pathway for the cyclopropanations.
Table 2
When the reaction of methyl phenyldiazoacetate 1a with acry-
lonitrile 2g was carried out at room temperature with Pd(OAc)2/
1,10-phenanthrolin as the catalyst, it proceeded very slowly. After
10 days, the pyrazole derivative 5 was isolated in 57% yield. Careful
inspection of the reaction process indicated that cyclic azo product
4 was initially formed. Compound 4 was converted to 5 during the
column chromatographic separation with silica gel. Compound 4
could be converted to cyclopropane product 3q when it was heated
(Scheme 2).2a
Pd(OAc)2-catalyzed reaction of aryldiazo compounds 1a–k with methyl acrylate 2a
N2
Pd(OAc)2
R2
(5 mol%)
PhCH3, 80 oC
CO2Me
CO2Me
+
R1
CO2Me
CO2Me
1a-k
2a
R2
R1
3a-k
Entry
1a–k, R1, R2
t (h)
Yielda (%)
cis:transb
1
2
3
4
5
6
7
8
1a, H, H
0.5
0.5
1
1
1
2
0.5
1
3a, 86
3b, 70
3c, 48
3d, 81
3e, 72
3f, 73
3g, 72
2h, 83
>95:5
>95:5
>95:5
91:9
88:12
83:17
89:11
85:15
Table 3
1b, Me, H
1c, OMe, H
1d, Cl, H
1e, Br, H
1f, NO2, H
1g, H, Cl
1h, Cl, Cl
Pd(OAc)2-catalyzed cyclopropanation of methyl phenyldiazoacetate 1a with electron-
deficient olefin 2a–g
R1
R2
N2
Pd(OAc)2
(5 mol%)
PhCH3, 80 oC
R2
OMe
Ph
MeO2C
R1
EWG
Ph
+
EWG
O
3q
2a-g
1a
N2
9
1i,
1j,
3
3i, 73
84:16
CO2Me
Entry
2a–g, R1, R2, EWG
t (h)
Yielda (%)
cis:transb
1
2
3
2a, H, H, CO2Me
2b, H, H, CO2Bu
2c, Me, H, CO2Me
2d, H, Ph, CO2Me
2e, H, H, CHO
0.5
1
4
12
12
12
8
3,ª 86
3l, 79
3m, 63
3n, 30
3,° 15
3p, 58
3q, 73
>95:5
>95:5
>95:5
89:11
>95:5
50:50
50:50
N2
4c
5c
6d
7e
10
11
1
3j, 51
>95:5
>92:8
O
2f, H, H, C(O)NEt2
2g, H, H, CN
N
H
N2
a
Yield of isolated product after chromatography.
b
c
Ratio was determined by 1H NMR (300 MHz) of the crude product.
10 mol % dppf ligand was added.
O
Ph
1k,
1.5
3k, 75
Ph
d
e
O
Ph
10 mol % 1,10-phenanthrolin ligand was added.
6 mol % 1,10-phenanthrolin ligand was added, chlorobenzene was used as
a
Yield of isolated product after chromatography.
b
Ratio was determined by 1H NMR (300 MHz) of the crude product.
solvent.

S. Chen et al. / Tetrahedron Letters 49 (2008) 6781–6783
6783
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L:
N
N
OMe
O
3q
Scheme 2. Pd(OAc)2-catalyzed reaction of methyl phenyldiazoacetate 1a with
acrylonitrile 2g.
In conclusion, we have developed a concise and efficient proto-
col for the preparation of cyclopropanes from various aryldiazocar-
bonyl compounds with electron-deficient olefins catalyzed by
Pd(OAc)2. This catalytic methodology is highly attractive and pro-
vides a valuable choice for the organic synthesis.
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Acknowledgments
13. General procedure for the cyclopropanation of aryldiazo compounds 1a–k with
olefins 2a–g catalyzed by Pd(OAc)2: To a solution of Pd(OAc)2 (0.025 mmol) with
olefins 2a–g (2.5 mmol) in anhydrous toluene (1 mL) at 80 °C under N2 was
added dropwise a solution of individual diazo compounds 1a–g (0.5 mmol) in
anhydrous toluene (2 mL). The progress of the reaction was monitored by TLC.
After completion of the reaction, solvent was removed by evaporation, and the
residue was purified by column chromatography over silica gel to give the
cyclopropane products 3a–q. Representative spectroscopic data: 3d: A colorless
The project is generously supported by Natural Science Founda-
tion of China (Nos. 20572002, 20521202, 20772003) and the Min-
istry of Education of China (Cheung Kong Scholars Program).
oil; IR (neat) 1725, 1258, 1162, 1093 cmÀ1 1H NMR (300 MHz, CDCl3) d 1.90
;
References and notes
(dd, J = 4.5, 8.4 Hz, 1H), 1.98 (dd, J = 4.5, 6.6 Hz, 1H), 2.76 (dd, J = 6.6, 8.4 Hz,
1H), 3.48 (s, 3H), 3.65 (s, 3H), 7.20 (d, J = 6.6 Hz, 2H), 7.28 (d, J = 6.6 Hz, 2H); 13C
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