Rhodium- or copper-catalysed CH-insertion of carbenoids into dihydro-aromatic compounds and acyclic 1,4-dienes

Article abstract of DOI:10.1055/s-2006-942512

A straightforward reaction sequence consisting of a cobalt-catalysed Diels-Alder reaction for the generation of dihydroaromatic compounds and a rhodium- or alternatively a copper-catalysed CH-insertion reaction of carbenoids from diazo esters generates highly substituted benzene derivatives. When acyclic 1,4-dienes are synthesised by a cobalt-catalysed 1,4-hydrovinylation reaction, the rhodium-catalysed conversion with diazo esters leads to cyclopropanation rather than CH-insertion products. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-942512

PAPER
3589
Rhodium- or Copper-Catalysed CH-Insertion of Carbenoids into Dihydro-
aromatic Compounds and Acyclic 1,4-Dienes
CH Insertion of
C
a
e
rbenoids in
r
to
D
ihy
h
droaromatic
aCompoundsrd Hilt,* Fabrizio Galbiati
Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein Straße, 35043 Marburg, Germany
Fax +49(6421)2825677; E-mail: Hilt@chemie.uni-marburg.de
Received 6 April 2006
Dedicated to Prof. Dr. Martin Semmelhack on the occasion of his 65th birthday and to Prof. Dr. Paul Knochel on the occasion of his 50th
birthday. Many thanks to both of them for their very useful advice and encouragement.
The rhodium-catalysed carbon–carbon bond formation of
Abstract: A straightforward reaction sequence consisting of a co-
diazo esters with 1,4-cyclohexadiene is reported to be per-
balt-catalysed Diels–Alder reaction for the generation of dihydro-
formed with a large excess of the dihydroaromatic deriv-
aromatic compounds and a rhodium- or alternatively a copper-
ative.3 A more economic process is therefore desirable to
catalysed CH-insertion reaction of carbenoids from diazo esters
generates highly substituted benzene derivatives. When acyclic 1,4- minimise the use of excess reagents.5 Therefore, we per-
dienes are synthesised by a cobalt-catalysed 1,4-hydrovinylation re-
action, the rhodium-catalysed conversion with diazo esters leads to
cyclopropanation rather than CH-insertion products.
formed a series of reactions on two different dihydroaro-
matic compounds 3a and 3b with two diazo ester
derivatives 4a and 4b (Scheme 1) to optimise the reaction
conditions. To determine the regiochemistry of the prod-
Key words: catalysis, cobalt, copper, cyclopropanation, 1,4-diene
ucts a DDQ oxidation to 6 was performed directly after
the CH-insertion reaction. Two dimensional NMR spectra
The selective formation of carbon–carbon bonds using revealed that the new carbon–carbon bond was formed ex-
aryl-, alkenyl- and more recently alkyl halides by means clusively at the less-hindered CH2 group of the dihydro-
of palladium or in general transition-metal catalysis is still aromatic compounds 5. The results of these optimisations
of uttermost importance.1 Additionally, the selective func- are given in Table 1.
tionalisation of a carbon–hydrogen bond by insertion of a
carbenoid has also proved to be a valuable method for the
Table 1 Optimisation of the Rhodium-Catalysed CH-Insertion Re-
action
construction of more complex molecules.2
Inspired by the work of Davies and Müller on the rhodi-
Entry
Ratio 3a,3b/
4a,4b
Rh2(OAc)4 Temp./Addition Yield 6
um-catalysed CH-insertion reaction utilising 1,4-cyclo-
hexadiene,3 we started investigating further modifications
of dihydroaromatic compounds which are easily accessi-
ble by our cobalt-catalysed Diels–Alder reaction of
alkynes with 1,3-dienes.4
(mol%)
2.0
2.0
0.5
2.0
0.5
0.5
4.0
2.0
0.5
0.5
0.5
2.0
1.0
0.5
0.5
time
1
3a/4a, 1:3
3a/4a, 1:2
3a/4a, 1:2
3a/4b, 1:3
3a/4b, 1:2
3a/4b, 1:2
3b/4a, 1:2
3b/4a, 1:2
3b/4a, 1:2
3b/4a, 1:2
3b/4a, 1:2
3b/4b, 1:2
3b/4b, 1:2
3b/4b, 1:2
3b/4b, 1:2
0 °C/60 min
0 °C/5 min
0 °C/60 min
0 °C/60 min
0 °C/60 min
0 °C/60 min
0 °C/30 min
0 °C/30 min
0 °C/60 min
0 °C/120 min
25 °C/60 min
0 °C/30 min
0 °C/45 min
0 °C/45 min
0 °C/60 min
58%
30%
52%
70%
89%
78%
20%
35%
55%
33%
21%
44%
52%
54%
77%
2
3
CoBr2(dppe)
Zn, ZnI2
4
+
R1
5
3a R1 = Ph
3b R1 = SiMe3
R1
1
2
6
R2
CO2R3
7
4a R2 = Me; R3 = Et
4b R2 = Ph; R3 = Me
Rh2(OAc)4
CO2R3
8
N2
4a,b
9
R2
CO2R3
R2
10
11
12
13
14
15
DDQ
R1
R1
6
5
Scheme 1
SYNTHESIS 2006, No. 21, pp 3589–3596
x
x.
x
x
.
2
0
0
6
Advanced online publication: 25.07.2006
DOI: 10.1055/s-2006-942512; Art ID: Z07306SS
© Georg Thieme Verlag Stuttgart · New York

3590
G. Hilt, F. Galbiati
PAPER
The lability of both the diazo ester towards decomposition Hence, the copper-catalysed CH-activation procedure
and the dihydroaromatic compound towards oxidation has was extended to some selected examples of 1,3-dienes
to be taken into account for the optimal reaction condi- previously used in the rhodium-catalysed reaction
tions. Accordingly, for the rhodium-catalysed carbenoid (Scheme 2).
insertion reaction one has to conclude that a low catalyst
loading of 0.5 mol% with a double excess of the diazo es-
R1
CO2R2
R1
CO2R2
R5
ter derivatives added over a period of one hour at 0 °C
gave the best results. Shorter or prolonged addition times
led to lower yields, also a higher catalyst loading was
counterproductive. Nevertheless, the yields for the CH-in-
sertion products of both dihydroaromatic compounds
could be raised to acceptable levels with the more labile
diazo ester 4a, while the yields for both 3a and 3b are
good when diazo ester 4b was employed. Also notewor-
thy, in this context, is the fact that only steric demands are
governing the reaction, while the trimethylsilyl group
does not seem to have an electronic influence to direct the
attack of the rhodium carbenoid towards the CH2 group in
close vicinity.
N2
+
1. A) Rh2(OAc)4 or
B) Cu(hfacac)2
R3
R4
2. DDQ
R6
R3
R4
R5
R6
8
7
Scheme 2
All the experiments were performed with 0.5 mol% of
Rh2(OAc)4 or 1.0 mol% of Cu(hfacac)2, and the crude re-
action product was directly subjected to DDQ oxidation.
The diazo ester was added by means of a syringe pump
over one hour in CH2Cl2 at 0 °C. Unfortunately, diazo es-
ters such as ethyl diazo acetoacetate, ethyl 2-diazo-3-
methyl-butyrate, ethyl 2-diazo-4-phenyl-but-3-enoate or
ethyl 2-diazo-propionate failed to give CH-insertion and
only ethyl 2-diazo-2-phenyl-acetate (4b) gave the desired
CH-insertion products after DDQ oxidation.5
As an alternative approach to the expensive rhodium, cop-
per-catalysed CH-insertion of diazo ester derived car-
benoids was envisaged.6 Therefore, the reaction
conditions had again to be optimised to verify the best
temperature for the conversion as well as the addition time
for the two equivalents of diazo ester 4b. The results of the
optimisation process are summarised in Table 2.
As reported in Table 3, the yields with Cu(hfacac)2 and
Rh2(OAc)4 were comparable, and 1H NMR analysis
showed that the regioselectivity of the copper-catalysed
reactions were the same as for the corresponding Rh(II)-
catalysed reaction. Only the nitrogen- and sulfur-func-
tionalised dienes 7e and 7f failed to react with the copper
catalyst, while for diene 7e the rhodium catalyst led to ac-
ceptable conversion. As already reported by Nozaki,7
strongly coordinating heteroatoms are able to destroy the
catalytic activity of the copper complexes. Such a coordi-
nation mechanism is believed to be applicable to the dihy-
droaromatic vinyl sulfide 7f. Cross-check experiments
with the 1,4-cyclohexadiene 7a and one equivalent of
thioanisole as additive resulted in no conversion. These
results were not surprising because copper catalysts are
highly electrophilic and tend to generate carbenoids that
are too reactive and prone to dimerisation. In addition, the
previously described supporting role of the second rhodi-
um atom in the binuclear complex Rh2(OAc)4 is not avail-
able for single metallic complexes such as Cu(acac)2.
However, due to the enhanced stability provided by the a-
substituents to the carbenoid derived from 4b, the CH-
insertion pathway becomes possible. The sole reaction
with donor/acceptor carbenoid precursors is the main lim-
itation of copper-based catalysts, while rhodium(II) cata-
lysts are catalytically active across the entire spectrum of
carbenoid precursors.
Table 2 Optimisation of the Copper-Catalysed CH-Insertion Reac-
tion of 4b with the Dihydroaromatic Derivative 3a
Entry
Catalyst
Loading Temp./Addition
(mol%) time
Yield
1
2
3
4
5
6
7
8
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(hfacac)2
Cu(hfacac)2
Rh2(OAc)4
1.0
1.0
1.0
1.0
5.0
1.0
1.0
0.5
25 °C/5 min
25 °C/60 min
0 °C/5 min
0 °C/60 min
0 °C/5 min
0 °C/5 min
25 °C/60 min
0 °C/60 min
52%
55%
70%
63%
68%
85%
83%
89%
As expected, exchanging the acetylacetonate ligand
(acac) with the hexafluoroacetylacetonate ligand (hfacac)
increased the electrophilicity and therefore the reactivity
of the metallocarbenoid intermediate. The yield rose from
55% to 83% for the reactions at room temperature
(Table 2, entries 2 and 7) and from 70% to 85% for the re-
actions at 0 °C (Table 2, entries 3 and 6) while higher cat-
alyst loadings showed no effect on the conversion
(Table 2, entries 3 and 5). Interestingly, the rate of the di- The nitrogen-functionalised diene 7d could also be suc-
azo ester addition proved to be not so important, unlike in cessfully converted under standard conditions and the
product could be isolated in 45% yield.8 Unexpectedly,
the dihydroaromatic insertion product 8e could not be ox-
idised by DDQ at room temperature. It also showed a re-
the rhodium-catalysed reactions (Table 2, entries 1–4).
Nonetheless, because of the quick evolution of nitrogen, a
slow addition and an ice-cooling bath are advisable.
Synthesis 2006, No. 21, 3589–3596 © Thieme Stuttgart · New York

PAPER
CH-insertion of Carbenoids into Dihydroaromatic Compounds
3591
Table 3 Selected Examples of the Rhodium- and Copper-Catalysed CH-Insertion/DDQ-Oxidation Reaction Sequence
Entry
1,4-Cyclohexadiene 7
Product 8
Yield(a)
1
2
A 89%
B 83%
Ph
CO2Me
Ph
7a
Ph
8a
3
4
A 44%
B 55%
Ph
CO2Me
7b
7c
8b
5
6
A 60%
B 58%
Ph
CO2Me
8c
7
8
A 62%
B 51%
Ph
CO2Me
MeO
MeO
MeO
MeO
7d
8d
8e
9
10
A 45%
B 0%
O
O
N
Ph
CO2Me
N
O
O
Ph
Ph
7e
11
12
A 0%
B 0%
Ph
CO2Me
PhS
PhS
Ph
7f
Ph
8f
a Method A: Rh2(OAc)4 (0.5 mol%), diazo ester (2.0 equiv), 0 °C, 60 min addition time. Method B: Cu(hfacac)2 (1.0 mol%), diazo ester (2.0
equiv), 0 °C, 60 min addition time.
markable resistance towards air oxidation which allowed
crystals to be obtained for X-ray diffraction (Figure 1).
Attempted DDQ oxidation in refluxing benzene resulted
in decomposition. As is evident from the crystal structure
of 8e, the substituents of the highly substituted dihydroar-
omatic compound are preventing the approach of the
DDQ molecules and the subsequent oxidation of the aro-
matic ring.
In fact 8e is the first derivative generated over the course
of our ongoing programme concerning the cobalt-cata-
lysed generation of dihydroaromatic compounds and its
follow-up chemistry that is highly resistant towards oxid-
ising agents.
When 2-alkoxy-functionalised 1,4-dienes such as 9 are
used in the rhodium-catalysed CH-insertion reaction a dif-
ferent scenario arises.9 Oxidative work-up of the dihy-
Figure 1 Crystal structure of 8e
droaromatic intermediate with DDQ could generate the
alkoxy-functionalised benzene derivative 10 (Scheme 3).
Synthesis 2006, No. 21, 3589–3596 © Thieme Stuttgart · New York

3592
G. Hilt, F. Galbiati
PAPER
Ph
CO2Me
process as an ‘indirect’ CH-insertion reaction to cyclo-
hexenones. To the best of our knowledge, only the dearo-
matisation of anisole derivatives performed with
stoichiometric anisole chromium tricarbonyl or anisole
osmium pentamine complexes allows this type of func-
tionalisation.10
Ph
CO2Me
OMe
N2
4b
1. Rh2(OAc)4
+
2. DDQ
67%
10
OMe
9
"Indirect"
carbene
insertion
Scheme 3
dianion
enolate
Meanwhile, the dihydroaromatic compound 12 generated
by a cobalt-catalysed Diels–Alder reaction from 3-hexyne
and 2-silyloxy-1,3-butadiene can be converted to the CH-
insertion product 13 (Scheme 4).
1,2-addition
O
1,4-addition
Baylis–Hillman
CoBr2(dppe)
Zn, ZnI2
Figure 2 Functionalisation of cyclohexenone
+
OTMS
OTMS
As outlined by Davies, the CH-insertion process could
also be realised in an enantioselective rhodium-catalysed
manner when chiral ligands were used.3a–d Accordingly,
in principle very interesting chiral building blocks could
be envisaged using this methodology.
12
Ph
CO2Me
Rh2(OAc)4 35%
Cu(hfacac)2 33%
N2
4b
Ph
CO2Me
Substrates of type 17 (Scheme 5) were of particular inter-
est because of the presence of an exo-chain double bond
and of a 1,4-dihydroaromatic system in the molecule.
They were synthesised via cobalt(I)-catalysed Diels–Al-
der reaction of 2,3-dimethyl-1,3-butadiene and 3-methyl-
but-3-en-1-yne (16). The isopropenyl moiety and the 1,4-
dihydroaromatic ring are competing targets for the inter-
mediate rhodium carbenoids. Unfortunately, it was not
possible to modulate the reactivity of the carbenoids and
mixtures of cyclopropanation and CH-insertion products
were always obtained. When ethyl diazo propionate was
used, the cyclopropane fraction could be separated (40%
yield) from the cyclopropanation and the CH-insertion
products (22% yield) by column chromatography.
Ph
CO2Me
TBAF
O
OTMS
14
13
partially in CDCl3
CO2Me
Ph
O
15
Scheme 4
Subsequent chromatography of the cyclopropane fraction
allowed the isolation of the two racemic diastereoisomers
As in the case of the methoxy-functionalised dihydroaro-
matic compound 9, the 2-silyloxy-1,3-butadiene allows
also the regioselective CH-insertion of carbenoids with
the bulky TMS ether group. The yields for the rhodium-
and the copper-catalysed processes are comparable. The
mild quantitative TBAF deprotection of the silyl enol
ether then leads to the non-conjugated b,g-unsaturated
enone derivative 14. This material undergoes double-
bond migration to the corresponding conjugated a,b-un-
saturated enone 15 as was observed in the NMR tube upon
standing in CDCl3. Thereby, a third stereocentre is gener-
ated and presumably the trans-configuration of the ethyl
group and the CH-inserted substituent is adapted predom-
inantly. Consequently, by this route the 5-position of a cy-
clohexenone system can be addressed and functionalised.
While all other positions in the cyclohexenone system can
be addressed as outlined in Figure 2, the 5-position can
not be functionalised easily starting directly from the cy-
clohexenone. In this context we would like to refer to this
Me
Me
CoBr2(dppe)
Zn, ZnI2
+
17
16
1. Rh2(OAc)4, 4a
2. DDQ
Me
EtO2C
Me
Me
EtO2C
Me
40%
22%
Me
CO2Et
18
19
Scheme 5
Synthesis 2006, No. 21, 3589–3596 © Thieme Stuttgart · New York

PAPER
CH-insertion of Carbenoids into Dihydroaromatic Compounds
3593
Me
CO2Et
18 which were assigned by NOE analysis, whereas, an at-
tempted separation of the cyclopropanation plus CH-
insertion products 19 by column chromatography fur-
nished only a complex mixture of diastereoisomers. An
exact structure determination by means of two-dimen-
sional NMR techniques was not possible.
+
N2
BuO2C
21
Rh2(OAc)4
CO2Et
Me
An even more complex and non-separable mixture of
products were obtained when ethyl 2-diazo-2-phenyl ace-
tate (4b) was used as the carbenoid precursor.
Me
CO2Et
BuO2C
24
EtO2C
Me
BuO2C
Scheme 7
n-Bu
26
CH-Insertion Reactions with Acyclic 1,4-Dienes
BuO2C
25
When the alkyne in the Diels–Alder reaction is replaced
by a terminal alkene, a cobalt-catalysed 1,4-hydrovinyla-
tion process is observed.11 This process leads with very
high selectivity to linear products of type 21 when elec-
tron-poor alkenes such as n-butyl acrylate (20) are used
(Scheme 6). Whereas, branched products with an exo-
chain double bond, such as 23, are generated from a neu-
tral alkene like 1-hexene (22, Scheme 6).
R1
CO2R2
+
N2
23
Rh2(OAc)4
n-Bu
CO2R2
R1
27: 0%
CoBr2(dppe)
Zn, ZnI2
R1
CO2R2
(1)
+
n-BuO2C
n-BuO2C
n-Bu
21
n-Bu
R2O2C
20
n-Bu
R1
CoBr2(dppe)
Zn, ZnI2
n-Bu
29: 0%
(2)
+
28a: R1 = Me, R2 = Et: 58%
28b: R1 = Ph, R2 = Me: 70%
23
22
Scheme 8
Scheme 6
These results are in accordance with the well documented
tendency of olefins to undergo metal-carbenoid cyclopro-
panation, particularly for mono-substituted or cis-disub-
stituted double bonds. The lack of CH activation, despite
the high number of allylic sites available in both starting
materials, indicates the preference for CH activation to
occur at the double allylic methylene positions of cyclic
1,4-dienes.
A common feature of both hydrovinylation products 21
and 23 is the 1,4-diene subunit, which makes them inter-
esting substrates for rhodium-carbenoid CH-activation
chemistry.
Rhodium-based catalysts are also known to be used in cy-
clopropanation reactions. Therefore an alternative reac-
tion pathway is possible. When the acrylate derivative 21
was tested with ethyl 2-diazo propionate and 0.5 mol% of
Rh2(OAc)4 under standard conditions, no cyclopropana-
tion 24 or 25 nor CH-insertion products 26 were observed
(Scheme 7).
In conclusion, we have presented a facile synthesis of
polyfunctionalised benzene derivatives which were syn-
thesised via cobalt(I)-catalysed Diels–Alder reactions and
rhodium- or copper-catalysed CH-insertion reactions of
carbenoids generated from diazo esters. In most cases the
CH-insertion reactions produced comparable yields for
both catalyst systems. Highly substituted dihydroaromatic
Diels–Alder adducts only react with the rhodium catalyst.
For more complex systems incorporating a cyclic 1,4-di-
ene subunit as well as an exo-chain double bond, the rhod-
ium-catalysed CH-insertion leads to mixtures of products
where the CH-insertion is accompanied with a cyclopro-
panation reaction. If acyclic 1,4-dienes are used, which
were generated by a cobalt-catalysed 1,4-hydrovinylation
reaction, no CH-insertion reaction was obtained and only
cyclopropanations occurred. In these cases only 1,1-di-
substituted alkenes could be converted, while tetrasubsti-
While the cyclopropanation at the tetrasubstituted double
bond was believed to be disfavoured because of the steric
hindrance, the lack of reaction on the other functionalities
was disappointing. The branched hydrovinylation product
23 gave, with excellent chemoselectivity, cyclopropana-
tion at the exo-chain double bond (Scheme 8) with both
diazo esters 4a and 4b in 58% (28a) and 70% (28b) yield
and no CH-insertion product could be observed. As in the
reaction with the acrylate derivative 21, also in this reac-
tion with 23, neither CH-insertion to 29 nor cyclopropana-
tion of the tetrasubstituted double bond to 27 was
observed.
Synthesis 2006, No. 21, 3589–3596 © Thieme Stuttgart · New York

3594
G. Hilt, F. Galbiati
PAPER
(2,3-Diethyl-5-methylphenyl)phenylacetic Acid Methyl Ester
tuted double bonds or acceptor-substituted alkenes were
unreactive under the conditions described.
(8c)
Chromatography (pentane–Et2O, 20:1) gave
(A: 60%; B: 58%).
a colourless oil
All commercial reagents were used without further purification.
The solvents were dried using standard procedures (CH2Cl2/P2O5;
THF/CaH2; Et2O/Na; PE/Na). The silica gel was purchased from
Merck. PE with a bp range 40–60 °C was used. NMR spectra were
recorded on Bruker ARX-300, Bruker ARX-500 and Bruker ARX-
600 NMR spectrometers. MS data were obtained using a Varian-
MAT CH7 and a Finnigan-MAT 95Q mass spectrometer and IR
spectra were recorded on a Bruker IFS 88 interferometer.
IR (film): 2965, 1742, 1609, 1452, 1160, 698 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.41–7.36 (m, 2 H), 7.35–7.29 (m,
3 H), 7.09 (s, 1 H), 7.06 (s, 1 H), 5.42 (s, 1 H), 3.81 (s, 3 H), 2.80–
2.65 (m, 4 H), 2.37 (s, 3 H), 1.32 (t, J = 7.5 Hz, 3 H), 1.21 (t, J = 7.6
Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 173.7, 142.3, 138.9, 136.9, 135.9,
135.2, 128.8, 128.7, 128.3, 127.0, 126.9, 52.9, 52.1, 25.8, 21.3,
21.1, 15.5, 15.1.
Method A; General Procedure
MS (EI): m/z = 296 (M+), 237, 209, 192, 117, 91.
A solution of methyl 2-diazo-phenylacetate (4b; 333 mg, 1.89
mmol, 2.0 equiv) in anhyd CH2Cl2 (2.0 mL) was added over 1 h via
syringe pump to a 0 °C solution of freshly made (4,5-dimethylcy-
clohexa-1,4-dienyl)benzene (7a; 174 mg, 0.94 mmol) and
Rh2(OAc)4 (2.0 mg, 4.7 mmol, 0.5 mol%) in anhyd CH2Cl2 (3.0
mL). After the addition was complete the reaction mixture was
stirred for 1 h at r.t. and then filtered through a short pad of silica gel
(pentane–Et2O, 1:1). The filtrate was concentrated under reduced
pressure to give an oily residue that was dissolved in benzene and
oxidised by DDQ (257 mg, 1.13 mmol, 1.2 equiv) at r.t. After 2 h
the reaction mixture was filtered through a short pad of silica gel
(pentane–Et2O, 1:1), concentrated under reduced pressure and puri-
fied by column chromatography on silica gel (pentane–Et2O, 20:1)
to give 276 mg (89%) of 8a as a colourless oil.
HRMS (EI): m/z calcd for C20H24O2: 296.1776; found: 296.1772.
(2,3-Dimethoxymethyl-5,6-dimethylphenyl)phenylacetic Acid
Methyl Ester (8d)
Chromatography (pentane–Et2O, 20:1) gave
(A: 62%; B: 51%).
a colourless oil
IR (film): 2925, 1736, 1448, 1384, 1197, 1094 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.23–7.09 (m, 4 H), 7.07–6.99 (m,
2 H), 5.59 (s, 1 H), 4.44–4.39 (m, 2 H), 4.35 (d, J = 11.4 Hz, 1 H),
4.22 (d, J = 11.4 Hz, 1 H), 3.61 (s, 3 H), 3.32 (s, 3 H), 3.16 (s, 3 H),
2.19 (s, 3 H), 1.94 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 173.7, 137.6, 137.3, 137.0, 136.5,
135.1, 133.3, 130.5, 128.6, 127.9, 126.4, 72.9, 68.2, 58.1, 57.9,
52.1, 50.8, 20.8, 16.9.
Method B; General Procedure
For the copper-catalysed reaction, identical conditions were applied
with Cu(hfacac)2 (1.0 mol%).
MS (ESI): m/z = 365 (M + Na+).
HRMS (ESI): m/z calcd for C21H26O2Na (M + Na+): 365.1729;
found: 365.1723.
(4,5-Dimethylbiphenyl-3-yl)phenylacetic Acid Methyl Ester
(8a)
[2-(1,3-Dioxo-1,3-dihydroisoindol-2-ylmethyl)-5,6-dimethyl-3-
phenylcyclohexa-2,5-dienyl]phenylacetic Acid Methyl Ester
(8e)
Chromatography (pentane–Et2O, 2:1) gave a white solid (A: 45%;
B: 0%). Crystals suitable for X-ray diffraction were obtained from
CH2Cl2–PE.
Chromatography (pentane–Et2O, 20:1) gave a colourless oil
(A: 89%; B: 83%).
IR (film): 3029, 2949, 1740, 1599, 1473, 1196, 1009, 762, 699 cm–1.
1H NMR (600 MHz, CDCl3): d = 7.60 (d, J = 7.9 Hz, 2 H), 7.49–
7.30 (m, 10 H), 5.41 (s, 1 H), 3.82 (s, 3 H), 2.42 (s, 3 H), 2.28 (m, 3
H).
13C NMR (150 MHz, CDCl3): d = 173.3, 140.9, 138.4, 137.9, 137.6,
137.2, 134.0, 128.9, 128.6, 128.5, 127.9, 127.2, 127.0, 126.9, 124.7,
54.2, 52.3, 21.0, 15.1.
IR (KBr): 3026, 2900, 1715, 1388, 1336, 1168, 725, 704 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.81–7.76 (m, 2 H), 7.70–7.64 (m,
2 H), 7.29–7.18 (m, 7 H), 7.13–7.07 (m, 1 H), 7.04–6.97 (m, 2 H),
4.49 (dd, J = 15.7, 2.0 Hz, 1 H), 4.37 (d, J = 15.7 Hz, 1 H), 4.08 (d,
J = 3.3 Hz, 1 H), 3.63 (s, 3 H), 3.58 (s, 1 H), 2.16 (d, J = 21.6 Hz, 1
H), 1.67 (s, 3 H), 1.61–1.51 (m, 1 H), 1.53 (s, 3 H).
MS (EI): m/z = 330 (M+), 271, 241, 181, 91.
HRMS (EI): m/z calcd for C23H22O2: 330.1620; found: 330.1609.
13C NMR (125 MHz, CDCl3): d = 173.6, 168.2, 141.5, 139.4, 134.8,
133.8, 132.1, 130.9, 130.5, 128.2, 127.7, 127.1, 126.9, 126.6, 126.2,
123.8, 123.1, 53.3, 51.8, 48.0, 40.9, 38.7, 18.4, 18.2.
MS (ESI): m/z = 514 (M + Na+).
HRMS (ESI): m/z calcd for C32H29NO4Na (M + Na+): 514.1995;
(2,3-Diethyl-5,6-dimethylphenyl)phenylacetic Acid Methyl Es-
ter (8b)
Chromatography (pentane–Et2O, 20:1) gave
a colourless oil
(A: 44%; B: 55%).
IR (film): 2965, 1738, 1448, 1196, 1174, 1014, 757 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.27–7.00 (m, 5 H), 6.94 (s, 1 H),
5.38 (s, 1 H), 3.62 (s, 3 H), 2.68–2.51 (m, 3 H), 2.50–2.33 (m, 1 H),
2.16 (s, 3 H), 1.88 (s, 3 H), 1.15 (t, J = 7.5 Hz, 3 H), 0.98 (t, J = 7.6
Hz, 3 H).
found: 514.2000.
(3-Methoxyphenyl)phenylacetic Acid Methyl Ester (10)
Chromatography (pentane–MTBE, 10:1) gave a colourless oil
(67%).
13C NMR (75 MHz, CDCl3): d = 174.1, 139.5, 138.6, 137.3, 135.1,
134.6, 134.0, 129.9, 128.9, 127.9, 126.5, 52.2, 50.9, 26.0, 22.6,
20.6, 17.1, 15.6, 15.0.
IR (film): 2951, 1739, 1599, 1540, 1490, 1235, 1203, 1162, 1038,
1012, 731, 698 cm–1.
1H NMR (600 MHz, CDCl3): d = 7.42–7.36 (m, 4 H), 7.34–7.28 (m,
2 H), 6.99–6.96 (m, 1 H), 6.96–6.94 (m, 1 H), 6.87 (ddd, J = 8.3,
2.5, 0.7 Hz, 1 H), 5.08 (s, 1 H), 3.82 (s, 3 H), 3.79 (s, 3 H).
13C NMR (150 MHz, CDCl3): d = 172.7, 159.7, 139.9, 138.4, 129.5,
128.5, 128.5, 127.2, 120.9, 114.5, 112.4, 56.9, 55.1, 52.2.
MS (EI): m/z = 310 (M+), 251, 223, 161, 117, 91, 77.
HRMS (EI): m/z calcd for C21H26O2: 310.1933; found: 310.1924.
Synthesis 2006, No. 21, 3589–3596 © Thieme Stuttgart · New York

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CH-insertion of Carbenoids into Dihydroaromatic Compounds
3595
MS (ESI): m/z = 257 (M + H+).
HRMS (ESI): m/z calcd for C16H17O3 (M + H+): 257.1178; found:
13C NMR (125 MHz, CDCl3; main signals): d = 174.9, 174.8,
174.2, 140.4, 140.3, 139.3, 139.2, 136.9, 132.2, 129.0, 128.9, 124.7,
124.6, 60.6, 60.5, 41.9, 41.8, 33.9, 33.8, 29.9, 29.8, 24.5, 24.4, 22.5,
22.4, 21.0, 18.9, 18.8, 18.1, 14.8, 14.4, 14.1.
257.1174.
(2,3-Diethyl-5-oxocyclohex-2-enyl)phenylacetic Acid Methyl
Ester (14)
Chromatography (pentane–Et2O, 3:1) gave a yellow oil (35%).
IR (film): 2965, 1734, 1455, 1434, 1197, 1157, 699 cm–1.
MS (ESI): m/z = 369 (M + Na+).
HRMS (ESI): m/z calcd for C21H30O4Na: 369.2042 (M + Na+);
found: 369.2036.
cis- and trans-2-Butyl-2-(2,3-dimethylbut-2-enyl)-1-methyl-
cyclopropanecarboxylic Acid Ethyl Ester (28a)
Chromatography (pentane–Et2O, 40:1) gave a colourless oil (58%);
1:1 mixture.
1H NMR (600 MHz, C6D6): d = 7.29–7.26 (m, 2 H), 7.09–7.05 (m,
2 H), 7.03–6.99 (m, 1 H), 3.54 (d, J = 8.2 Hz, 1 H), 3.20 (s, 3 H),
3.14–3.10 (m, 1 H), 2.56 (dd, J = 16.2, 1.7 Hz, 1 H), 2.36–2.21 (m,
3 H), 1.99–1.82 (m, 3 H), 1.64–1.62 (m, 1 H), 0.90 (t, J = 7.5 Hz, 3
H), 0.71 (t, J = 7.5 Hz, 3 H).
IR (film): 2958, 2063, 1720, 1458, 1311, 1136 cm–1.
13C NMR (150 MHz, C6D6): d = 207.8, 173.3, 136.4, 134.4, 132.9,
1H NMR (300 MHz, CDCl3): d = 4.10 (q, J = 7.1 Hz, 4 H), 2.62 (d,
J = 14.4 Hz, 1 H), 2.44 (d, J = 14.4 Hz, 1 H), 1.90 (d, J = 14.4 Hz,
1 H), 1.77 (d, J = 14.4 Hz, 1 H), 1.68 (s, 3 H), 1.67 (s, 6 H), 1.64 (s,
6 H), 1.57 (s, 3 H), 1.46–0.93 (m, 28 H), 0.85 (t, J = 7.1 Hz, 3 H),
0.79 (t, J = 7.2 Hz, 3 H), 0.54 (d, J = 4.7 Hz, 1 H), 0.47 (d, J = 4.7
Hz, 1 H).
129.8, 128.7, 127.9, 54.5, 51.4, 42.4, 42.3, 25.8, 24.7, 13.8, 12.8.
MS (ESI): m/z = 323 (M + Na+).
HRMS (ESI): m/z calcd for C19H24O3Na: 323.1725; found:
323.1728.
13C NMR (75 MHz, CDCl3): d = 174.9, 174.6, 126.2, 125.9, 125.8,
125.3, 60.4, 60.3, 35.3, 34.2, 31.8, 31.7, 31.5, 31.3, 28.9, 28.4, 27.8,
27.3, 26.4, 23.1, 23.0, 20.7, 20.6, 20.5, 17.4, 17.3, 17.0, 16.9, 14.3,
14.2, 13.9, 13.8.
MS (ESI): m/z = 267 (M + H+).
HRMS (ESI): m/z calcd for C17H31O2 (M + H+): 267.2325; found:
trans-2-(3,4-Dimethylphenyl)-1,2-dimethylcyclopropanecar-
boxylic Acid Ethyl Ester (18)
Chromatography (pentane–Et2O, 30:1) gave a colourless oil (20%).
IR (film): 2979, 1720, 1454, 1289, 1266, 1143, 823, 758 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.10–7.06 (m, 1 H), 7.03–7.00 (m,
1 H), 6.99–6.95 (m, 1 H), 4.22 (q, J = 7.1 Hz, 2 H), 2.27 (s, 3 H),
2.25 (s, 3 H), 1.58 (d, J = 4.8 Hz, 1 H), 1.42 (s, 3 H), 1.32 (t, J = 7.1
Hz, 3 H), 1.11 (d, J = 4.8 Hz, 1 H), 0.95 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 174.4, 140.6, 136.4, 134.6, 130.0,
129.5, 126.1, 60.5, 33.8, 29.9, 24.4, 22.7, 19.8, 19.3, 18.9, 14.4.
267.2319.
cis- and trans-2-Butyl-2-(2,3-dimethylbut-2-enyl)-1-phenyl-
cyclopropanecarboxylic Acid Methyl Ester (28b)
Chromatography (pentane–Et2O, 20:1) gave a colourless oil (70%);
1:1 mixture.
MS (ESI): m/z = 247 (M + H+).
HRMS (ESI): m/z calcd for C16H23O2 (M + H+): 247.1699; found:
IR (film): 2954, 1721, 1447, 1434, 1239, 1196, 700 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.45–7.17 (m, 10 H), 3.61–3.57
(m, 6 H), 2.42 (s, 3 H), 1.76–1.70 (m, 10 H), 1.68 (s, 4 H), 1.63–1.53
(m, 6 H), 1.45–0.92 (m, 12 H), 0.87 (t, J = 7.1 Hz, 2 H), 0.68 (t,
J = 7.2 Hz, 4 H), 0.65–0.55 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 172.9, 172.6, 137.9, 137.7, 131.4,
131.3, 127.6, 126.8, 126.7, 126.1, 125.8, 125.7, 125.6, 51.9, 40.2,
38.6, 37.6, 34.6, 34.3, 34.2, 32.9, 30.6, 29.0, 28.5, 27.7, 23.9, 23.0,
22.8, 20.7, 20.6, 20.5, 20.4, 17.6, 17.2, 13.9, 13.8.
247.1693.
cis-2-(3,4-Dimethylphenyl)-1,2-dimethylcyclopropanecarboxy-
lic Acid Ethyl Ester (18)
Chromatography (pentane–Et2O, 30:1) gave a colourless oil (20%).
IR (film): 2976, 1715, 1451, 1318, 1188, 1135, 822 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.01–6.97 (m, 2 H), 6.96–6.92 (m,
1 H), 3.79–3.71 (m, 1 H), 3.69–3.60 (m, 1 H), 2.21 (s, 3 H), 2.19 (s,
3 H), 2.03 (d, J = 4.7 Hz, 1 H), 1.50 (s, 3 H), 1.43 (s, 3 H), 0.82 (t,
J = 7.1 Hz, 3 H), 0.73 (d, J = 4.7 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 173.6, 141.7, 135.9, 134.3, 129.7,
129.3, 125.7, 60.0, 33.8, 29.9, 25.0, 23.8, 19.7, 19.3, 16.4, 13.7.
MS (ESI): m/z = 337 (M + Na+).
HRMS (ESI): m/z calcd for C21H30O2Na (M + Na+): 337.2144;
found 337.2138.
MS (ESI): m/z = 247 (M + H+).
HRMS (ESI): m/z calcd for C16H23O2 (M + H+): 247.1699; found:
Acknowledgment
We thank Prof. Werner Massa for determination of the X-ray struc-
ture of 8e.
247.1693.
2-[3-(1-Ethoxycarbonylethyl)-4,5-dimethylphenyl]-1,2-dimeth-
ylcyclopropanecarboxylic Acid Ethyl Ester (19)
Chromatography (pentane–Et2O, 10:1) gave a colourless oil (22%);
mixture of diastereoisomers.
References
(1) For reviews see: (a) Campeau, L. C.; Fagnou, K. Chem.
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Reactions; Diederich, F.; Stang, P. J., Eds.; Wiley-VCH:
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Fleming, I.; Pattenden, G., Eds.; Pergamon Press: New
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IR (film): 2980, 1732, 1457, 1368, 1286, 1140, 1079, 1028, 861
cm–1.
1H NMR (500 MHz, CDCl3; main signals): d = 6.95–6.90 (m, 4 H),
4.25–4.05 (m, 8 H), 3.98 (q, J = 7.1 Hz, 2 H), 2.29 (s, 6 H), 2.22 (s,
6 H), 1.55 (d, J = 4.8 Hz, 2 H), 1.45 (d, J = 5.3 Hz, 3 H), 1.44 (d,
J = 5.3 Hz, 3 H), 1.39 (s, 6 H), 1.31 (t, J = 7.1 Hz, 3 H), 1.30 (t,
J = 7.1 Hz, 3 H), 1.21 (t, J = 7.1 Hz, 3 H), 1.17 (t, J = 7.1 Hz, 3 H),
1.08 (t, J = 5.4 Hz, 2 H), 0.91 (s, 6 H).
Synthesis 2006, No. 21, 3589–3596 © Thieme Stuttgart · New York

3596
G. Hilt, F. Galbiati
PAPER
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(f) Arndtsen, B. A.; Bergman, R. G.; Mobley, T. A.;
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Synthesis 2006, No. 21, 3589–3596 © Thieme Stuttgart · New York