Synthesis of spiro[26]nonadienones and spiro[3.6]decadienones by the reaction of cyclopropyl- and cyclobutylmagnesium carbenoids with lithium phenolates and naphtholates

Article abstract of DOI:10.1055/s-0031-1291011

Treatment of 1-chlorocyclopropyl p-tolyl sulfoxides and 1-chlorocyclobutyl p-tolyl sulfoxides with a Grignard reagent at low temperature afforded cyclopropylmagnesium carbenoids and cyclobutylmagnesium carbenoids, respectively, via a sulfoxide-magnesium e

Full text of DOI:10.1055/s-0031-1291011

PAPER
▌2091
paper
Synthesis of Spiro[2.6]nonadienones and Spiro[3.6]decadienones by the
Reaction of Cyclopropyl- and Cyclobutylmagnesium Carbenoids with Lithium
Phenolates and Naphtholates
Reaction of Magnesium Carbenoids with Lithium Naphtholates
Tsuyoshi Satoh,* Tsutomu Kimura, Yuki Sasaki, Shinobu Nagamoto
Graduate School of Chemical Sciences and Technology, Tokyo University of Science, Ichigaya-funagawara-machi 12, Shinjuku-ku, Tokyo
162-0826, Japan
Fax +81(3)52614631; E-mail: tsatoh@rs.kagu.tus.ac.jp
Received: 08.03.2012; Accepted after revision: 12.04.2012
synthetic methods with small-ring magnesium carben-
Abstract: Treatment of 1-chlorocyclopropyl p-tolyl sulfoxides and
oids, we found that the reaction of cyclopropylmagnesium
1-chlorocyclobutyl p-tolyl sulfoxides with a Grignard reagent at
carbenoids with lithium phenolates and naphtholates re-
sulted in the formation of spiro[2.6]nonadienones in vari-
low temperature afforded cyclopropylmagnesium carbenoids and
cyclobutylmagnesium carbenoids, respectively, via a sulfoxide–
magnesium exchange reaction. The reaction of these magnesium able yields.4
carbenoids with lithium phenolates afforded spiro[2.6]nona-6,8-
In this paper, we report in detail the reactions of small-
dien-5-ones and spiro[3.6]deca-7,9-dien-6-ones, respectively; how-
ever, the yields were rather low. Reaction of the cyclopropylmagne-
sium carbenoids with lithium 1-naphtholates gave spiro[2.6]nona-
5,7-dien-4-ones in moderate to good yields; however, reaction of
the cyclobutylmagnesium carbenoids with lithium 1-naphtholates
did not give the desired products. Reaction of the cyclopropyl- and
cyclobutylmagnesium carbenoids with lithium 2-naphtholates gave
spiro[2.6]nona-5,7-dien-4-ones and spiro[3.6]deca-7,9-dien-6-
ones, respectively, in moderate to good yields. These unprecedented
reactions provide a procedure for the synthesis of spiro[2.6]nona-
5,7-dien-4-ones and spiro[3.6]deca-7,9-dien-6-ones from 1-naph-
ring magnesium carbenoids, cyclopropylmagnesium car-
benoids 2a and cyclobutylmagnesium carbenoids 2b,
which are derived from aryl 1-chlorocyclopropyl sulfox-
ides 1a and 1-chlorocyclobutyl p-tolyl sulfoxides 1b, re-
spectively, with a Grignard reagent via a sulfoxide–
magnesium exchange reaction,5 with lithium phenolates
3, lithium 1-naphtholates 5, and lithium 2-naphtholates 7
(Scheme 1). Thus, the reaction of magnesium carbenoids
2a and 2b with lithium phenolates 3 afforded spi-
thols and 2-naphthols with a one-carbon ring expansion of the phe- ro[2.6]nona-6,8-dien-5-ones 4 (n = 1) and spiro[3.6]deca-
nol ring.
7,9-dien-6-ones 4 (n = 2), respectively, in rather low
yields. The reaction of magnesium carbenoids 2a with
lithium 1-naphtholates 5 gave spiro[2.6]nona-5,7-dien-4-
ones 6 (n = 1), in moderate to good yields; however, the
reaction of 2b with lithium 1-naphtholates 5 did not give
the expected products. The reaction of magnesium car-
benoids 2a and 2b with lithium 2-naphtholates 7 gave spi-
ro[2.6]nona-5,7-dien-4-ones 8a and spiro[3.6]deca-7,9-
dien-6-ones 8b, respectively, in moderate to good yields.
The mechanism of these reactions is also discussed.
Key words: magnesium carbenoids, lithium phenolates, lithium
naphtholates, ring expansion, spirocyclic compounds, dienones
Carbenes and carbenoids are undoubtedly one of the most
important sets of highly reactive carbon species and have
long been studied for their chemistry, synthesis, and syn-
thetic uses in the territory of organic and synthetic organic
chemistry.1 Carbenes and carbenoids show a variety of re-
actions, such as addition into a carbon–carbon double
bond to give cyclopropanes, dimerization to give olefins,
ylide formation, rearrangement, carbon–hydrogen inser-
tion, carbon–carbon insertion, and so on.
As noted above, we reported the first example for the di-
rect cyclopropylation of arylamines at the 2-position by
the reaction of cyclopropylmagnesium carbenoids with N-
lithio arylamines.2d,i As an extension of this chemistry, it
was expected that the reaction of cyclopropylmagnesium
carbenoids with lithium phenolate would result in the for-
mation of 2-cyclopropylphenols in a similar manner. At
first, 1-chlorocyclopropyl phenyl sulfoxide (1aa)2i was
treated with isopropylmagnesium chloride (2.5 equiv) in
tetrahydrofuran at –78 °C, followed by 5 equivalents of
lithium phenolate (Scheme 2).6,7 This reaction gave a rath-
er complex mixture; however, we obtained the expected
2-cyclopropylphenol (9) as an isolable product in 21%
yield.
Small-ring carbenes and carbenoids, cyclopropylidenes
and cyclobutylidenes, are highly reactive carbon species
and have been recognized as being too reactive to control.
Recently, we have investigated the chemistry of more sta-
ble small-ring carbenoid species, cyclopropylmagnesium
carbenoids2 and cyclobutylmagnesium carbenoids,3 and
many new reactions have been described.2,3
In 2008, we reported the first example for the direct cyclo-
propylation of arylamines at the 2-position by the reaction
of cyclopropylmagnesium carbenoids with N-lithio aryl-
amines.2d,i In continuation of our efforts to develop new
Next, cyclopropylmagnesium carbenoid 2ab bearing
gem-methyl groups, derived from 1ab2i with isopropyl-
magnesium chloride, was reacted with 3 equivalents of
lithium phenolate at –78 to –20 °C. This reaction again
gave a rather complex mixture; however, we obtained an
SYNTHESIS 2012, 44, 2091–2101
Advanced online publication: 14.05.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
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DOI: 10.1055/s-0031-1291011; Art ID: SS-2012-F0243-OP
© Georg Thieme Verlag Stuttgart · New York

2092
T. Satoh et al.
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OLi
A plausible mechanism for this reaction is proposed as
follows (Scheme 3). Thus, the substitution reaction of cy-
clopropylmagnesium carbenoid 2ab with lithium 4-meth-
ylphenolate would take place at the 2-position of the
phenolate to give cyclopropylmagnesium chloride inter-
mediate A. Conjugate addition of the carbanion to the
straight dienone moiety affords highly strained spi-
ro[2.2]pentane alkoxide B. The negative charge on the ox-
ygen atom would move to the carbon next to the carbonyl
group with cleavage of the highly strained carbon–carbon
bond to afford the product 10b. When this reaction was
quenched with methanol-d (MeOD), indeed, the hydrogen
on the carbon at the 4-position of 10b was replaced by
deuterium.
Cl
R1
( )n
S(O)Ar
O
R3
1a: n = 1
1b: n = 2
R3
3
Ar = Ph, p-Tol
R2MgCl
Cl
R1
( )n
OLi
4
R3
O
R1
( )n
5
R1
( )n
MgCl
R3
2a: n = 1
2b: n = 2
6
R1
LiO
R3
O
Cl
MgCl
Li
R3
8a
7
MgCl
O
O
2ab
R1
O
A
R3
8b
MgCl
O
O
(D) H
(MeOD)
Scheme 1 General scheme for this work
unanticipated product in low yield, without the expected
2-cyclopropylated phenol. The product showed C11H14O
as a molecular formula, and the IR spectrum of the prod-
uct suggested the presence of a conjugated carbonyl group
10b
B
Scheme 3 A plausible mechanism for the reaction of cyclopropyl-
magnesium carbenoid 2ab with lithium 4-methylphenolate giving
spiro[2.6]nona-6,8-dien-5-one 10b
1
(1659 cm–1), while the H NMR spectrum indicated four
olefinic protons. From this evidence, the structure of the
product was determined to be one-carbon ring-expanded
1,1-dimethylspiro[2.6]nona-6,8-dien-5-one (10a). As we
recognized that this is an unprecedented reaction, an in-
vestigation for obtaining better yields was carried out;
however, all efforts were fruitless. The reactions of 2ab
with lithium 4-methylphenolate, lithium 4-phenylpheno-
late, and lithium 4-methoxyphenolate were carried out as
shown in Scheme 2. The 1,1-dimethylspiro[2.6]nona-6,8-
dien-5-ones 10b–d were obtained in up to 32% yield.
Recently, we have been investigating the chemistry and
synthetic uses of cyclobutylmagnesium carbenoids.3 As a
development of the above-described reaction, we carried
out the reaction of lithium phenolates with cyclobutyl-
magnesium carbenoids 2b, and the results are summarized
in Table 1. Thus, 1-chlorocyclobutyl p-tolyl sulfoxide
(1ba)3c was treated with ethylmagnesium chloride in the
presence of 3 equivalents of lithium phenolate in tetrahy-
OLi
OH
(5 equiv)
i-PrMgCl (2.5 equiv)
Cl
Cl
MgCl
S(O)Ph
THF, –78 °C
–78 to 0 °C, 21%
1aa
2aa
9
O
(3 equiv)
R
LiO
i-PrMgCl (2.5 equiv)
Cl
S(O)Tol
Cl
MgCl
–78 to –20 °C
THF, –78 °C
1ab
2ab
R
10a R = H, 22%
10b R = Me, 32%
10c R = Ph, 20%
10d R = OMe, 26%
Scheme 2 Reaction of cyclopropylmagnesium carbenoids 2aa and 2ab with lithium phenolates
Synthesis 2012, 44, 2091–2101
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Reaction of Magnesium Carbenoids with Lithium Naphtholates
2093
drofuran at –78 °C, and the mixture was allowed to slowly 2b with lithium 1-naphtholates, and the results are sum-
warm to 0 °C (entry 1). This reaction gave a rather com- marized in Scheme 4. Thus, the reaction of cyclopropyl-
plex mixture of products from which spiro[3.6]deca-7,9- magnesium carbenoid 2aa with lithium 1-naphtholate
dien-6-one (11a) was obtained as a major product in 30% (5a) gave the anticipated 2-cyclopropyl-1-naphthol (12a)
yield. The expected 2-cyclobutylphenol was not observed in 37% yield, without ring-expanded product. On the oth-
at all. The structure of 11a was proved to be as shown in er hand, the reaction of lithium 4-methoxy-1-naphtholate
Table 1 from spectroscopic data. By comparison of the (5b) with carbenoid 2aa afforded 2-cyclopropylated prod-
structure of 11a with that of 10a, it is expected that the re- uct 12b (23%) and one-carbon ring-expanded spi-
actions of lithium phenolate with both cyclopropylmagne- ro[2.6]nona-5,7-dien-4-one 13 (47%) as the major
sium carbenoids and cyclobutylmagnesium carbenoids product.
are governed by the same mechanism.
Cl
OH
O
OLi
Table 1 Reaction of Cyclobutylmagnesium Carbenoids 2b with
Lithium Phenolates
MgCl
2aa
EtMgCl
THF
–78 to –20 °C
R1
Cl
(2.5 equiv)
R1
R1
Cl
R1
S(O)Tol
R
R
OMe
THF, –78 °C
MgCl
5a R = H
5b R = OMe
5c R = Cl
12a R = H, 37%
12b R = OMe, 23%
13 47%
1ba: R1 = H
2b
1bb: R1 = CH2O(CH2)3Ph
1bc: R1 = CH2OEt
O
O
Cl
R2
(3 equiv)
MgCl
LiO
2ab
R1
R1
THF, –78 to –20 °C
THF, –78 to 0 °C
R2
R
11
14a R = H, 70%
14b R = OMe, 82%
14c R = Cl, 33%
Entry Sulfoxide 2b
R1
R2
Yield (%)
of 11
Cl
MgCl
1
2
3
4
5
6
7
8
1ba
1ba
1ba
1ba
1bb
1bc
1bb
1bc
2ba
2ba
2ba
2ba
2bb
2bc
2bb
2bc
H
H
H
H
H
11a: 30
11b: 33
11c: 32
11d: 37
11e: 24
11f: 16
11g: 35
11h: 22
Me
Ph
O
2ac
5b
OMe
THF, –78 to –20 °C
26%
CH2O(CH2)3Ph Ph
CH2OEt Ph
CH2O(CH2)3Ph OMe
CH2OEt OMe
OMe
15
Ph(CH2)3OH2C
Ph(CH2)3OH2C
Cl
MgCl
Cl
MgCl
,
2bb
2ba
complex mixture
5a, 5b
The reaction of magnesium carbenoid 2ba with lithium 4-
methylphenolate, lithium 4-phenylphenolate, and lithium
4-methoxyphenolate gave the corresponding spi-
ro[3.6]deca-7,9-dien-6-ones 11b–d in 32 to 37% yield
(Table 1, entries 2–4). The reactions of cyclobutylmagne-
sium carbenoids 2bb and 2bc bearing substituents at the
3-position with lithium 4-phenylphenolate and lithium 4-
methoxyphenolate gave the expected spiro[3.6]deca-7,9-
dien-6-ones 11e to 11h in somewhat lower yields (Table
1, entries 5–8).
Scheme 4 Reaction of cyclopropylmagnesium carbenoids 2aa, 2ab,
and 2ac with lithium 1-naphtholates 5
The reaction of cyclopropylmagnesium carbenoid 2ab
bearing gem-methyl groups with lithium 1-naphtholate
(5a) gave 1,1-dimethylspiro[2.6]nona-5,7-dien-4-one 14a
in a relatively good yield of 70%. When this reaction was
carried out with lithium 4-methoxy-1-naphtholate (5b),
14b was obtained in 82% yield; however, the reaction of
carbenoid 2ab with lithium 4-chloro-1-naphtholate (5c)
gave the expected product 14c in only 33% yield (Scheme
4). The reaction of fully substituted cyclopropylmagne-
sium carbenoid 2ac with lithium 4-methoxy-1-naphtho-
late (5b) gave the desired product 15; however, the yield
was not satisfactory. The reaction of lithium 1-naphtho-
lates 5a and 5b with cyclobutylmagnesium carbenoids
2ba and 2bb was carried out. Unfortunately, these reac-
tions gave only complex mixtures.
As described above, we found that the reaction of cyclo-
propylmagnesium carbenoids and cyclobutylmagnesium
carbenoids with lithium phenolates gave the unprecedent-
ed spiro[2.6]nona-6,8-dien-5-ones 10 and spiro[3.6]deca-
7,9-dien-6-ones 11, respectively; however, the yields
proved to be low and they are not promising from the
standpoint of synthetic organic chemistry.
Next, we investigated the reaction of cyclopropylmagne-
sium carbenoids 2a and cyclobutylmagnesium carbenoids
© Georg Thieme Verlag Stuttgart · New York
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2094
T. Satoh et al.
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The structure of the products 13, 14, and 15 from the re- diate E, which on protonation would give the product 14b.
action of cyclopropylmagnesium carbenoids 2a with lith- When this reaction was quenched with MeOD, the hydro-
ium 1-naphtholates 5 is complementary to that from the gen on the carbon at the 9-position of 14b was replaced by
reaction with lithium phenolates. As described above, the deuterium (D content: 99%). This result provides strong
reaction of cyclopropylmagnesium carbenoid 2ab with evidence for the support of the presented mechanism. The
lithium phenolates gives spiro[2.6]nona-6,8-dien-5-ones presence of intermediate E was further confirmed by trap-
10, in which the cyclopropane ring is placed at the β-posi- ping experiments using allyl iodide and iodomethane. Spi-
tion to the carbonyl group (see Scheme 2). On the other ro[2.6]nona-5,7-dien-4-ones bearing allyl and methyl
hand, the cyclopropane ring is placed at the α-position to groups at the 9-position (14d and 14e, see experimental
the carbonyl group in the products 13, 14, and 15 of the re- section) were obtained in 30% and 12% yield, respective-
action of carbenoids 2a with lithium 1-naphtholates 5. ly.
These results imply that the two reactions must be gov-
erned by different mechanisms.
The reaction of cyclopropylmagnesium carbenoids and
cyclobutylmagnesium carbenoids with lithium 2-naph-
A plausible mechanism for the reaction of cyclopropyl- tholates was investigated next. At first, cyclopropylmag-
magnesium carbenoid 2ab with lithium 4-methoxy-1- nesium carbenoid 2aa was treated with 3 equivalents of
naphtholate giving 14b is shown in Scheme 5. Thus, the lithium 2-naphtholate (7a) at –78 °C and the temperature
substitution reaction of cyclopropylmagnesium carbenoid of the reaction mixture was allowed to slowly warm to
2ab with lithium 1-naphtholate 5b would take place at the –20 °C (Scheme 6). This reaction gave spiro[2.6]nona-
2-position of the naphtholate to give cyclopropylmagne- 5,7-dien-4-one 16 in 37% yield as an isolable major prod-
sium chloride intermediate C. In the case of the reaction uct. The reaction of cyclopropylmagnesium carbenoid
of 2ab with lithium 4-methylphenolate, as shown in 2ab bearing gem-methyl groups with 2-naphtholate 7a
Scheme 3, conjugate addition of the straight dienone in- gave the expected product 17 in a better yield of 49%. The
termediate A with the carbanion proceeded to give inter- structure of 17 was confirmed by X-ray analysis, which
mediate B; however, as one of the double bonds of the was reported as a preliminary letter of the present study.2f
straight dienone moiety of intermediate C is a component The reaction of carbenoid 2ab with other lithium 2-naph-
of the aromatic ring, conjugate addition of the magnesium tholates 7b and 7c under the same conditions gave the
carbanion is thought to be difficult. Intramolecular 1,2-ad- corresponding spiro[2.6]nona-5,7-dien-4-ones 19 in
dition of the carbanion to the ketone group would take somewhat variable yields.
place to afford the highly strained spiro[2.2]pentane alk-
oxide D, instead of the conjugate addition. The negative
charge on the oxygen atom would move to the carbon next
to the cyclopropane ring, concomitant with cleavage of
As shown in Scheme 6, product 17 has two benzylic hy-
drogens at the 9-position, which appear at δ = 2.63 and
1
3.70 ppm in its H NMR spectrum. When this reaction
was quenched with MeOD, the hydrogen observed at 3.70
ppm was completely replaced by deuterium to give 18.
the highly strained carbon–carbon bond to afford interme-
Based on this result, the mechanism of the reaction of 2ab
with 7a is proposed as shown in Scheme 6. Thus, similar
Cl
Li
MgCl
to the reaction of 2ab with 5b (shown in Scheme 5), the
reaction of 2ab with lithium 2-naphtholate (7a) would
give cyclopropylmagnesium chloride intermediate F. In-
tramolecular 1,2-addition of the cyclopropylmagnesium
chloride to the ketone group gives the highly strained spi-
ro[2.2]pentane alkoxide G. The negative charge on the
oxygen atom would move to the benzylic carbon, con-
comitant with cleavage of the highly strained carbon–car-
bon bond to afford intermediate H, which on protonation
would give product 17. It is noteworthy that the chiral car-
bon center bearing the magnesium chloride is formed in a
stereospecific manner; however, the mechanism of this
selectivity is not clearly explained at the present stage.
MgCl
O
O
2ab
OMe
OMe
5b
C
MgCl
O
O
ClMg
OMe
OMe
D
E
Finally, the reaction of cyclobutylmagnesium carbenoids
2ba, 2bb, and 2bc, as well as 2bd, with lithium 2-naph-
tholates was investigated. 1-Chloro-3,3-dimethylcyclobu-
tyl p-tolyl sulfoxide (1bd), the precursor of
cyclobutylmagnesium carbenoid 2bd, was synthesized
from known compound 208 as shown in Scheme 7. Thus,
hydrogenolysis, followed by tosylation, of benzyl ether 20
gave tosylate 21 in high overall yield. Tosylate 21 was
treated with potassium p-toluenethiolate to afford sulfide
22 in 73% yield. The sulfur group was oxidized to the
O
(MeOD)
(D) H
OMe
14b
Scheme 5 A plausible mechanism for the reaction of cyclopropyl-
magnesium carbenoid 2ab with lithium 4-methoxy-1-naphtholate
(5b) giving spiro[2.6]nona-5,7-dien-4-one 14b
Synthesis 2012, 44, 2091–2101
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Reaction of Magnesium Carbenoids with Lithium Naphtholates
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Cl
MgCl
LiO
2aa
O
THF, –78 to –20 °C
37%
7a
16
δ 2.63 (d, J = 15.8 Hz)
δ 3.70 (d, J = 15.8 Hz)
δ 2.62
H
H
D
Cl
H
MgCl
LiO
2ab
O
O
THF, –78 to –20 °C
49%
18 (D content 99%)
7a
17
Cl
R1
R2
MgCl
LiO
R1
R2
2ab
O
THF, –78 to –20 °C
7b R1 = OMe, R2 = H
19a R1 = OMe, R2 = H 64%
19b R1 = H, R2 = Br 36%
7c R1 = H, R2 = Br
MgCl
H
ClMg
O
2ab
ClMg-O
O
17
7a
G
F
H
Scheme 6 Reaction of cyclopropylmagnesium carbenoids 2aa and 2ab with lithium 2-naphtholates 7, and a proposed reaction mechanism
sulfoxide group with m-chloroperoxybenzoic acid, and 13C HMBC spectra (see experimental section). In contrast
the ethyl ester groups were reduced to hydroxymethyl to these results, the reaction of cyclobutylmagnesium car-
groups with sodium borohydride in tetrahydrofuran– benoids bearing substituents at the 3-position, 2bb and
methanol,9 to give 23. The hydroxymethyl groups in 23 2bc, with lithium 2-naphtholates gave spiro[3.6]deca-7,9-
were reduced to methyl groups in two steps2i to give 24. dien-6-ones 25c–f in good yields (Table 2, entries 3–6).
Finally, sulfoxide 24 was chlorinated with N-chlorosuc-
cinimide in tetrahydrofuran to afford 1bd in good overall
yield.
These results implied that gem-disubstituents at the 3-po-
sition play some essential role in the reaction. In order to
make it clear that the effect belongs to the presence of a
The results for the reaction of cyclobutylmagnesium car- substituent itself, rather than the presence of the oxygen
benoids 2ba to 2bd, generated from 1-chlorocyclobutyl p- atom in the substituent, we synthesized 1-chloro-3,3-di-
tolyl sulfoxides 1ba to 1bd, with lithium 2-naphtholate methylcyclobutyl p-tolyl sulfoxide (1bd) as described
and lithium 7-methoxy-2-naphtholate are summarized in above. Thus, treatment of cyclobutylmagnesium carben-
Table 2. As shown in entries 1 and 2, the reaction of cy- oid 2bd with lithium 2-naphtholate afforded the expected
clobutylmagnesium carbenoid 2ba bearing no R substitu- product 25g in 69% yield (Table 2, entry 7). The reaction
ent with lithium 2-naphtholates gave mixtures of with lithium 7-methoxy-2-naphtholate also gave the de-
spiro[3.6]deca-7,9-dien-6-ones 25a and 25b and spi- sired product 25h in 65% yield (Table 2, entry 8). On the
ro[3.6]deca-6,8-dien-5-ones 26a and 26b (Figure 1). The basis of the regiochemical outcome, the reaction appears
structures of 25a and 25b were determined from their 1H– to proceed via a mechanism similar to that of the lithium
1) H2, Pd/C
EtOOC
EtOOC
EtOOC
EtOOC
EtOAc–MeOH, 90%
EtOOC
EtOOC
TolSH, t-BuOK
OTs
STol
OBn
2) TsCl, Et3N, DMAP
CHCl3, 0 °C, 99%
t-BuOH, reflux, 73%
20
21
22
1) MsCl, Et3N, THF
–78 to –10 °C, 83%
HOH2C
S(O)Tol
HOH2C
Cl
1) MCPBA, CHCl3, 99%
NCS
THF
S(O)Tol
2) NaBH4, THF–MeOH
reflux, 88%
2) NaBH4, DMI
100 °C, 89%
S(O)Tol
0 °C to r.t., 89%
23
24
1bd
Scheme 7 Synthesis of 1-chloro-3,3-dimethylcyclobutyl p-tolyl sulfoxide (1bd) from benzyl ether 20
© Georg Thieme Verlag Stuttgart · New York
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2096
T. Satoh et al.
PAPER
phenolates. Although the real reason for the effect of the
substituents at the 3-position is unclear at present, this
finding is quite important for the uses of the procedure de-
scribed in this paper.
Table 2 Reaction of Cyclobutylmagnesium Carbenoids 2b with
Lithium 2-Naphtholates
EtMgCl
R1
Cl
R1
R1
Cl
(2.5 equiv)
R1
S(O)Tol
THF, –78 °C
MgCl
1ba: R1 = H
2b
R
1bb: R1 = CH2O(CH2)3Ph
1bc: R1 = CH2OEt
1bd: R1 = Me
O
R1
R1
LiO
R2
26a R = H
26b R = OMe
(3 equiv)
R2
Figure 1
O
THF, –78 to 0 °C
25
In order to elucidate the regioselectivity observed in the
reaction of magnesium carbenoids 2a and 2b with lithium
1- and 2-naphtholates, geometry optimization and molec-
ular orbital calculation of four model compounds, 1-naph-
tholate anion (I), 2-naphtholate anion (II), 2-
methylnaphthalen-1(2H)-one (III), and 1-methylnaphtha-
len-2(1H)-one (IV), were performed at the B3LYP/6-
311++G(d,p) level with Gaussian software.10 Selected
molecular orbitals of model compounds I–IV are shown
in Figure 2.11 The HOMO of 1-naphtholate anion is main-
ly localized on the carbon atoms at the 2- and 4-positions
of the naphthol ring, and the reaction at the 2-position
would be sterically favorable in comparison with that at
the 4-position. 2-Naphtholate anion has a large HOMO
coefficient on the carbon atom at the 1-position. There-
fore, it is expected that the reaction of magnesium carben-
oids with 1-naphtholate anion takes place preferentially at
the 2-position to give the intermediate C in Scheme 5 and
the reaction with 2-naphtholate anion would proceed ex-
clusively at the 1-position to give the intermediate F in
Entry Sulfoxide 2b
R1
R2
H
Yield (%)
of 25
1
2
3
4
5
6
7
8
1ba
1ba
1bb
1bc
1bb
1bc
1bd
1bd
2ba
2ba
2bb
2bc
2bb
2bc
2bd
2bd
H
H
25a: 37a
25b: 31b
25c: 69
25d: 70
25e: 69
25f: 60
25g: 69
25h: 65
OMe
H
CH2O(CH2)3Ph
CH2OEt
CH2O(CH2)3Ph
CH2OEt
Me
H
OMe
OMe
H
Me
OMe
a Compound 26a was obtained in 24% yield.
b Compound 26b was obtained in 18% yield.
Figure 2 (a) Chemical structures of model compounds I–IV, (b) HOMO of 1-naphtholate anion (I), (c) HOMO of 2-naphtholate anion (II), (d)
LUMO of 2-methylnaphthalen-1(2H)-one (III), (e) LUMO of 1-methylnaphthalen-2(1H)-one (IV).
Synthesis 2012, 44, 2091–2101
© Georg Thieme Verlag Stuttgart · New York

PAPER
Reaction of Magnesium Carbenoids with Lithium Naphtholates
2097
1H NMR (400 MHz): δ = 0.63–0.66 (m, 2 H), 0.96–0.99 (m, 2 H),
1.81 (tt, J = 5.3, 8.3 Hz, 1 H), 5.47 (s, 1 H), 6.82–6.87 (m, 2 H),
7.06–7.15 (m, 2 H).
Scheme 6. In the model compounds III and IV, the coef-
ficients of the LUMO on the carbonyl carbon atoms are
larger than those on the carbon atoms at the δ-position.
These results suggest that internal cycloalkylmagnesium
MS (EI): m/z (%) = 134 (100) [M]+, 119 (41), 91 (37), 77 (21).
chlorides would attack the carbonyl carbon atoms (1,2-ad- HRMS (EI): m/z [M]+ calcd for C9H10O: 134.0732; found:
134.0726.
dition) rather than the carbon atoms at the δ-position;
however, the reaction of cyclobutylmagnesium carben-
1,1-Dimethylspiro[2.6]nona-6,8-dien-5-one (10a); Typical Pro-
oids 2b with lithium 2-naphtholates afforded spi-
ro[3.6]deca-7,9-dien-6-ones 25 (Table 2). Although the
precise origin of the regioselectivity remains obscure, it is
attributable to steric repulsion between the substituents at
the 3-position of the cyclobutyl ring and the hydrogen
atom at the 8-position of the naphthalen-2(1H)-one ring.
cedure
The reactions of magnesium carbenoids with lithium phenolates
and lithium naphtholates (except the reaction of 2aa with lithium
phenolate) were carried out according to the following procedure. A
1.65 M soln of BuLi in hexane (0.545 mL, 0.90 mmol) was added
dropwise to a soln of phenol (84.7 mg, 0.90 mmol) in THF (0.8 mL)
at –78 °C, and the mixture was stirred at that temperature for 10
min. A soln of sulfoxide 1ab (72.6 mg, 0.30 mmol) in THF (0.7 mL)
was added to the resulting solution at –78 °C. A 2.0 M soln of i-
PrMgCl in THF (0.375 mL, 0.75 mmol) was then added to the mix-
ture at –78 °C, and the mixture was allowed to warm to –20 °C over
1.5 h. The reaction was quenched with sat. aq NH4Cl (1.5 mL), and
the mixture was extracted with CHCl3 (3 × 7 mL). The organic layer
was dried over MgSO4 and concentrated under reduced pressure.
The residue was purified by column chromatography on silica gel
[Rf = 0.4 (hexane–1,4-dioxane, 10:1)] to give 10a as a yellow oil;
yield: 10.7 mg (0.066 mmol, 22%).
In conclusion, we have outlined a novel reaction of cyclo-
propylmagnesium carbenoids and cyclobutylmagnesium
carbenoids with lithium phenolates, lithium 1-naphtho-
lates, and lithium 2-naphtholates giving ring-expanded
spiro[2.6]nonadienones and spiro[3.6]decadienones. Al-
though there are a few reports on the reactions of lithium
cyclopropylidenes,1j,12 there is no previous report on the
reaction with phenolates and naphtholates. The results de-
scribed in this paper are unprecedented for the reactions of
cyclopropylmagnesium carbenoids and cyclobutylmagne-
sium carbenoids, and we believe that they will contribute
very much to the chemistry of carbenes and carbenoids.
IR (neat): 2947, 1659 (C=O), 1626, 1573, 1113, 718 cm–1.
1H NMR (500 MHz): δ = 0.77 (s, 2 H), 1.06 (s, 3 H), 1.19 (s, 3 H),
2.35 (d, J = 15.5 Hz, 1 H), 3.04 (d, J = 15.5 Hz, 1 H), 6.04–6.13 (m,
3 H), 6.64 (ddd, J = 0.7, 7.2, 12.3 Hz, 1 H).
MS (EI): m/z (%) = 162 (39) [M]+, 147 (83), 119 (32), 107 (100), 91
(76).
HRMS (EI): m/z [M]+ calcd for C11H14O: 162.1045; found:
162.1046.
Melting points were measured on a Yanaco MP-S3 apparatus and
are uncorrected. NMR spectra were measured in CDCl3 solution
with Jeol JNM-LA 300, Jeol JNM-LA 500, Bruker DPX 400, and
Bruker AV 600 spectrometers. Assignments in 13C NMR spectra
were made using DEPT 90 and 135 experiments. Electron-impact
(EI) mass spectra were obtained at 70 eV by direct insertion with a
Hitachi M-80B mass spectrometer. IR spectra were recorded on a
Perkin–Elmer Spectrum One FTIR instrument. Silica gel 60 N
(Kanto Chemical) containing 0.5% fluorescence reagent 254 and a
quartz column were used for column chromatography, and the prod-
ucts having UV absorption were detected by UV irradiation. In ex-
periments requiring anhydrous solvents and reagents, THF was
distilled from sodium diphenyl ketyl. Et3N was distilled from CaH2.
All reactions involving air- or water-sensitive compounds were rou-
tinely conducted in glassware which had been flame-dried under a
positive pressure of argon. Sulfoxides 1aa,2b 1ab,2i 1-chloro-
2,2,3,3-tetramethylcyclopropyl p-tolyl sulfoxide (1ac),2i 1ba,3c
1bb,3c and 1bc3c were prepared according to the procedures de-
scribed in the literature.
1,1,8-Trimethylspiro[2.6]nona-6,8-dien-5-one (10b)
Yield: 16.9 mg (32%); yellow oil.
IR (neat): 2983, 2945, 1662 (C=O), 1637, 1575, 1455, 1417, 1378,
771 cm–1.
1H NMR (400 MHz): δ = 0.63 (d, J = 4.5 Hz, 1 H), 0.66 (d, J = 4.5
Hz, 1 H), 1.02 (s, 3 H), 1.16 (s, 3 H), 1.93 (d, J = 1.5 Hz, 3 H), 2.33
(d, J = 16.1 Hz, 1 H), 3.00 (d, J = 16.1 Hz, 1 H), 5.88 (s, 1 H), 6.06
(d, J = 12.5 Hz, 1 H), 6.52 (d, J = 12.5 Hz, 1 H).
MS (EI): m/z (%) = 176 (48) [M]+, 161 (75), 121 (100), 105 (50), 91
(70).
HRMS (EI): m/z [M]+ calcd for C12H16O: 176.1201; found:
176.1204.
4-Deuterio-1,1,8-trimethylspiro[2.6]nona-6,8-dien-5-one (10b′)
1H NMR (500 MHz): δ = 0.62–0.66 (m, 2 H), 1.02 (s, 3 H), 1.16 (s,
3 H), 1.93 (s, 3 H), 2.31 (br s, 0.4 H), 2.99 (br s, 0.4 H), 5.87 (s, 1
H), 6.06 (d, J = 12.5 Hz, 1 H), 6.52 (d, J = 12.5 Hz, 1 H).
2-Cyclopropylphenol (9)13
A soln of sulfoxide 1aa (60.0 mg, 0.30 mmol) in THF (0.8 mL) was
added dropwise to a 2.0 M soln of i-PrMgCl in THF (0.375 mL,
0.75 mmol) at –78 °C, and the mixture was stirred at that tempera-
ture for 10 min. A soln of lithium phenolate, prepared in situ from
1.65 M BuLi in hexane (0.91 mL, 1.5 mmol) and phenol (141 mg,
1.50 mmol) in THF (0.7 mL) at –78 °C, was added via a cannula to
the resulting solution at –78 °C, and the mixture was allowed to
warm to 0 °C over 1.5 h. The reaction was quenched with sat. aq
NH4Cl (1.5 mL), and the mixture was extracted with CHCl3 (3 × 7
mL). The organic layer was dried over MgSO4 and concentrated un-
der reduced pressure. The residue was purified by column chroma-
tography on silica gel [Rf = 0.3 (hexane–1,4-dioxane, 10:1)] to give
9 as a yellow oil; yield: 8.5 mg (0.063 mmol, 21%).
1,1-Dimethyl-8-phenylspiro[2.6]nona-6,8-dien-5-one (10c)
Yield: 14.3 mg (20%); yellow oil.
IR (neat): 2947, 1721, 1660 (C=O), 1601, 1495, 1448, 1418, 1378,
1293, 1269, 1113, 765, 749, 699 cm–1.
1H NMR (500 MHz): δ = 0.80 (d, J = 4.7 Hz, 1 H), 0.81 (d, J = 4.7
Hz, 1 H), 1.12 (s, 3 H), 1.23 (s, 3 H), 2.41–2.45 (m, 1 H), 3.15 (d,
J = 16.3 Hz, 1 H), 6.23–6.26 (m, 1 H), 6.34 (s, 1 H), 6.95 (dd,
J = 1.2, 12.5 Hz, 1 H), 7.29–7.38 (m, 5 H).
MS (EI): m/z (%) = 238 (100) [M]+, 223 (44), 183 (84), 165 (36),
155 (55), 115 (36).
HRMS (EI): m/z [M]+ calcd for C17H18O: 238.1358; found:
238.1359.
IR (neat): 3401 (OH), 3003, 2926, 1754, 1493, 1452, 1214, 1193,
752 cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2091–2101

2098
T. Satoh et al.
PAPER
8-Methoxy-1,1-dimethylspiro[2.6]nona-6,8-dien-5-one (10d)
13C NMR (126 MHz): δ = 20.4 (CH2), 28.8 (CH2), 36.6 (C), 55.2
(CH3), 97.3 (CH), 126.6 (CH), 128.4 (CH), 128.7 (CH), 131.3 (CH),
134.3 (C), 138.5 (C), 155.4 (C), 206.2 (C=O).
Yield: 15.0 mg (26%); yellow oil.
IR (neat): 2945, 1662 (C=O), 1633, 1594, 1453, 1413, 1269, 1211,
1156 cm–1.
MS (EI): m/z (%) = 214 (100) [M]+, 199 (68), 183 (27), 171 (20),
1H NMR (400 MHz): δ = 0.58 (d, J = 4.5 Hz, 1 H), 0.66 (d, J = 4.5
Hz, 1 H), 1.05 (s, 3 H), 1.16 (s, 3 H), 2.38 (d, J = 16.3 Hz, 1 H), 3.03
(d, J = 16.3 Hz, 1 H), 3.54 (s, 3 H), 5.14 (s, 1 H), 6.09 (d, J = 12.8
Hz, 1 H), 6.55 (d, J = 12.8 Hz, 1 H).
13C NMR (126 MHz): δ = 20.0 (C), 22.9 (CH3), 23.1 (C), 23.9
(CH3), 30.1 (CH2), 49.1 (CH2), 54.7 (CH3), 114.1 (CH), 130.2 (CH),
137.9 (CH), 154.0 (C), 199.4 (C).
MS (EI): m/z (%) = 192 (100) [M]+, 177 (92), 137 (59), 117 (42), 91
(45).
HRMS (EI): m/z [M]+ calcd for C12H16O2: 192.1150; found:
192.1154.
153 (12), 143 (13), 128 (17), 115 (26).
HRMS (EI): m/z [M]+ calcd for C14H14O2: 214.0994; found:
214.0995.
2′,2′-Dimethylspiro[benzo[7]annulene-6,1′-cyclopropan]-
5(7H)-one (14a)
Yield: 44.6 mg (70%); yellow oil.
IR (neat): 3031, 2950, 1651 (C=O), 1594, 1442, 1376, 1353, 1309,
1244, 1111, 794 cm–1.
1H NMR (500 MHz): δ = 0.75 (d, J = 4.1 Hz, 1 H), 1.03 (s, 3 H),
1.35 (s, 3 H), 1.67 (d, J = 4.1 Hz, 1 H), 2.15 (dd, J = 7.9, 15.9 Hz, 1
H), 2.87 (ddd, J = 1.7, 5.3, 15.9 Hz, 1 H), 6.33 (ddd, J = 5.3, 7.9,
10.8 Hz, 1 H), 6.52 (dd, J = 1.7, 10.8 Hz, 1 H), 7.18 (d, J = 7.6 Hz,
1 H), 7.30 (t, J = 7.6 Hz, 1 H), 7.45 (t, J = 7.6 Hz, 1 H), 7.99 (d,
J = 7.6 Hz, 1 H).
MS (EI): m/z (%) = 212 (100) [M]+, 197 (48), 179 (21), 169 (21),
157 (79), 129 (41), 128 (78), 115 (38), 102 (11), 89 (7).
HRMS (EI): m/z [M]+ calcd for C15H16O: 212.1201; found:
212.1202.
Spiro[3.6]deca-7,9-dien-6-one (11a)
EtMgCl (2.5 equiv) was used; yield: 18.3 mg (30%); pale yellow
oil.
IR (neat): 2936, 1658 (C=O), 1630, 1581, 1418, 1303, 706 cm–1.
1H NMR (300 MHz): δ = 1.95–2.08 (m, 6 H), 2.89 (s, 2 H), 5.87
(dd, J = 7.3, 11.2 Hz, 1 H), 6.01 (d, J = 12.2 Hz, 1 H), 6.52 (dd,
J = 7.3, 12.2 Hz, 1 H), 6.57 (d, J = 11.2 Hz, 1 H).
MS (EI): m/z (%) = 148 (3) [M]+, 120 (40), 105 (14), 91 (100), 79
(14).
HRMS (EI): m/z [M]+ calcd for C10H12O: 148.0888; found:
148.0889.
9-Methoxy-2′,2′-dimethylspiro[benzo[7]annulene-6,1′-cyclo-
propan]-5(7H)-one (14b)
Yield: 59.6 mg (82%); yellow oil.
IR (neat): 3067, 2991, 2949, 2873, 1652 (C=O), 1596, 1464, 1360,
1267, 1238, 1209, 1137, 1110, 985, 768 cm–1.
2-Cyclopropyl-1-naphthol (12a)
1H NMR (500 MHz): δ = 0.84 (d, J = 4.0 Hz, 1 H), 1.19 (s, 3 H),
1.34 (s, 3 H), 1.67 (d, J = 4.0 Hz, 1 H), 2.38 (d, J = 7.6 Hz, 2 H),
3.69 (s, 3 H), 5.24 (t, J = 7.6 Hz, 1 H), 7.36 (dt, J = 1.4, 7.6 Hz, 1
H), 7.47 (dt, J = 1.4, 7.6 Hz, 1 H), 7.57 (dd, J = 1.4, 7.6 Hz, 1 H),
7.60 (dd, J = 1.4, 7.6 Hz, 1 H).
13C NMR (126 MHz): δ = 19.8 (CH3), 23.4 (CH3), 26.7 (CH2),
30.78 (CH2 or C), 30.83 (CH2 or C), 46.8 (C), 55.1 (CH3), 98.1
(CH), 126.1 (Ar), 127.9 (Ar), 128.3 (Ar), 130.7 (Ar), 133.6 (C),
139.6 (C), 155.0 (C), 204.0 (C=O).
Yield: 20.4 mg (37%); colorless oil.
IR (neat): 3547 (OH), 3057, 1574, 1509, 1386, 1351, 1267, 1239,
1060, 808, 746 cm–1.
1H NMR (500 MHz): δ = 0.71–0.74 (m, 2 H), 1.05–1.08 (m, 2 H),
1.92 (tt, J = 5.3, 8.2 Hz, 1 H), 6.06 (s, 1 H), 7.26 (d, J = 8.4 Hz, 1
H), 7.35 (d, J = 8.4 Hz, 1 H), 7.42–7.48 (m, 2 H), 7.75 (dd, J = 1.8,
7.2 Hz, 1 H), 8.20 (d, J = 7.7 Hz, 1 H).
MS (EI): m/z (%) = 184 (100) [M]+, 169 (19), 155 (14), 141 (28),
128 (25), 115 (18).
MS (EI): m/z (%) = 242 (100) [M]+, 227 (63), 211 (26), 187 (17),
HRMS (EI): m/z [M]+ calcd for C13H12O: 184.0888; found:
184.0893.
158 (13), 128 (17), 115 (26), 102 (7), 89 (5).
HRMS (EI): m/z [M]+ calcd for C16H18O2: 242.1307; found:
242.1307.
2-Cyclopropyl-4-methoxy-1-naphthol (12b)
Yield: 14.8 mg (23%); yellow oil.
7-Deuterio-9-methoxy-2′,2′-dimethylspiro[benzo[7]annulene-
6,1′-cyclopropan]-5(7H)-one (14b′)
IR (neat): 3552 (OH), 3003, 1598, 1459, 1389, 1283, 1223, 1128,
1097, 766 cm–1.
1H NMR (500 MHz): δ = 0.73 (br s, 2 H), 1.05 (br s, 2 H), 1.95 (br
s, 1 H), 3.95 (br s, 3 H), 5.68 (s, 1 H), 6.60 (br s, 1 H), 7.44–7.49 (m,
2 H), 8.13–8.17 (m, 2 H).
MS (EI): m/z (%) = 214 (100) [M]+, 199 (68), 183 (23), 154 (14),
141 (15), 128 (20), 115 (22).
1H NMR (500 MHz): δ = 0.84 (d, J = 3.9 Hz, 1 H), 1.19 (s, 3 H),
1.34 (s, 3 H), 1.67 (d, J = 3.9 Hz, 1 H), 2.37–2.39 (m, 1 H), 3.68 (s,
3 H), 5.23 (t, J = 7.4 Hz, 1 H), 7.36 (dt, J = 1.4, 7.6 Hz, 1 H), 7.47
(dt, J = 1.4, 7.6 Hz, 1 H), 7.56 (dd, J = 1.4, 7.6 Hz, 1 H), 7.60 (dd,
J = 1.4, 7.6 Hz, 1 H).
9-Chloro-2′,2′-dimethylspiro[benzo[7]annulene-6,1′-cyclopro-
pan]-5(7H)-one (14c)
Yield: 24.4 mg (33%); yellow oil.
HRMS (EI): m/z [M]+ calcd for C14H14O2: 214.0994; found:
214.0992.
IR (neat): 3065, 2991, 2928, 2873, 1661 (C=O), 1594, 1468, 1351,
1196, 1105, 975, 764 cm–1.
9-Methoxyspiro[benzo[7]annulene-6,1′-cyclopropan]-5(7H)-
one (13)
Yield: 30.2 mg (47%); yellow oil.
1H NMR (500 MHz): δ = 0.88 (d, J = 4.1 Hz, 1 H), 1.21 (s, 3 H),
1.35 (s, 3 H), 1.73 (d, J = 4.1 Hz, 1 H), 2.43 (d, J = 7.8 Hz, 2 H),
6.50 (t, J = 7.8 Hz, 1 H), 7.39 (dt, J = 1.2, 7.8 Hz, 1 H), 7.52 (dt,
J = 1.2, 7.8 Hz, 1 H), 7.58 (dd, J = 1.2, 7.8 Hz, 1 H), 7.69 (dd,
J = 1.2, 7.8 Hz, 1 H).
MS (EI): m/z (%) = 246 (24) [M]+, 211 (100), 191 (25), 165 (12),
141 (23), 127 (14), 115 (14).
IR (neat): 3002, 2939, 2905, 1652 (C=O), 1596, 1439, 1355, 1237,
1211, 1135, 1099, 983, 769 cm–1.
1H NMR (500 MHz): δ = 0.93 (q, J = 3.5 Hz, 2 H), 1.40 (q, J = 3.5
Hz, 2 H), 2.20 (d, J = 7.4 Hz, 2 H), 3.70 (s, 3 H), 5.24 (t, J = 7.4 Hz,
1 H), 7.38 (t, J = 7.4 Hz, 1 H), 7.51 (t, J = 7.4 Hz, 1 H), 7.62 (d,
J = 7.4 Hz, 1 H), 7.63 (d, J = 7.4 Hz, 1 H).
HRMS (EI): m/z [M]+ calcd for C15H15ClO: 246.0811; found:
246.0814.
Synthesis 2012, 44, 2091–2101
© Georg Thieme Verlag Stuttgart · New York

PAPER
Reaction of Magnesium Carbenoids with Lithium Naphtholates
2099
7-Allyl-9-methoxy-2′,2′-dimethylspiro[benzo[7]annulene-6,1′-
cyclopropan]-5(7H)-one (14d)
13C NMR (126 MHz): δ = 19.3 (CH2), 32.4 (C), 39.0 (CH2), 127.0
(CH), 129.1 (CH), 129.6 (CH), 130.67 (CH), 130.75 (CH), 134.3
(C), 139.2 (C), 140.5 (CH), 202.0 (C=O).
A 2.0 M soln of i-PrMgCl in THF (0.375 mL, 0.75 mmol) was add-
ed to a soln of sulfoxide 1ab (72.8 mg, 0.30 mmol) and lithium 4-
methoxy-1-naphtholate (0.90 mmol) in THF–hexane (3:1, 2.0 mL)
at –78 °C, and the mixture was allowed to warm to –20 °C over 1.5
h. Allyl iodide (252 mg, 1.50 mmol) was added dropwise to the re-
action mixture at –20 °C, and the mixture was allowed to warm to
0 °C over 1 h. The reaction was quenched with sat. aq NH4Cl (1.5
mL), and the mixture was extracted with CHCl3 (3 × 7 mL). The or-
ganic layer was dried over MgSO4 and concentrated under reduced
pressure. The residue was purified by column chromatography on
silica gel [Rf = 0.4 (hexane–1,4-dioxane, 10:1)] and preparative
thin-layer chromatography (hexane–1,4-dioxane, 30:1) to give 14d
as a yellow oil; yield: 25.4 mg (0.090 mmol, 30%).
Anal. Calcd for C13H12O: C, 84.75; H, 6.57. Found: C, 84.58; H,
6.64.
2′,2′-Dimethylspiro[benzo[7]annulene-6,1′-cyclopropan]-
7(5H)-one (17)
Yield: 31.2 mg (49%); colorless crystals; mp 39.5–40.5 °C (hex-
ane).
IR (KBr): 2951, 1643 (C=O), 1408, 1361, 1314, 1281, 1099, 831,
801, 748 cm–1.
1H NMR (500 MHz): δ = 0.68 (d, J = 4.0 Hz, 1 H), 0.89 (s, 3 H),
1.08 (s, 3 H), 1.65 (d, J = 4.0 Hz, 1 H), 2.63 (d, J = 15.8 Hz, 1 H),
3.70 (d, J = 15.8 Hz, 1 H), 6.25 (d, J = 12.7 Hz, 1 H), 7.07 (d,
J = 12.7 Hz, 1 H), 7.18–7.20 (m, 1 H), 7.27–7.30 (m, 2 H), 7.34–
7.36 (m, 1 H).
13C NMR (126 MHz): δ = 20.1 (CH3), 23.8 (CH3), 28.3 (CH2), 28.9
(C), 37.4 (CH2), 39.1 (C), 126.8 (CH), 129.5 (CH), 130.2 (CH),
130.8 (CH), 132.0 (CH), 133.7 (C), 140.5 (C), 141.1 (CH), 199.9
(C=O).
MS (EI): m/z (%) = 212 (76) [M]+, 197 (20), 169 (17), 157 (100),
141 (33), 128 (67), 115 (39), 102 (8), 89 (9), 77 (11).
HRMS (EI): m/z [M]+ calcd for C15H16O: 212.1201; found:
212.1197.
IR (neat): 2947, 1650 (C=O), 1593, 1365, 1212, 986, 766 cm–1.
1H NMR (500 MHz): δ = 0.69 (d, J = 4.1 Hz, 1 H), 0.98 (s, 3 H),
1.39 (s, 3 H), 1.76 (d, J = 4.1 Hz, 1 H), 2.19–2.21 (m, 3 H), 3.71 (s,
3 H), 4.83 (d, J = 17.2 Hz, 1 H), 4.89 (d, J = 10.1 Hz, 1 H), 5.52 (d,
J = 8.0 Hz, 1 H), 5.70–5.78 (m, 1 H), 7.36 (t, J = 7.6 Hz, 1 H), 7.52
(t, J = 7.6 Hz, 1 H), 7.86 (d, J = 7.6 Hz, 1 H), 8.11 (d, J = 7.6 Hz, 1
H).
MS (EI): m/z (%) = 282 (0.1) [M]+, 242 (18), 241 (100).
HRMS (EI): m/z [M]+ calcd for C19H22O2: 282.1620; found:
282.1614.
9-Methoxy-2′,2′,7-trimethylspiro[benzo[7]annulene-6,1′-cyclo-
propan]-5(7H)-one (14e)
5-Deuterio-2′,2′-dimethylspiro[benzo[7]annulene-6,1′-cyclo-
propan]-7(5H)-one (18)
Yield: 9.2 mg (12%); yellow oil.
1H NMR (500 MHz): δ = 0.68 (d, J = 4.0 Hz, 1 H), 0.89 (s, 3 H),
1.09 (s, 3 H), 1.65 (d, J = 4.0 Hz, 1 H), 2.62 (t, J = 1.9 Hz, 1 H), 6.25
(d, J = 12.7 Hz, 1 H), 7.07 (d, J = 12.7 Hz, 1 H), 7.18–7.20 (m, 1 H),
7.27–7.30 (m, 2 H), 7.34–7.36 (m, 1 H).
IR (neat): 2927, 1651 (C=O), 1596, 1460, 1388, 1365, 1218, 1100,
987, 765 cm–1.
1H NMR (300 MHz): δ = 0.63 (d, J = 4.1 Hz, 1 H), 0.97 (s, 3 H),
1.07 (d, J = 7.4 Hz, 3 H), 1.39 (s, 3 H), 1.67 (d, J = 4.1 Hz, 1 H),
2.21–2.32 (m, 1 H), 3.70 (s, 3 H), 5.55 (d, J = 9.4 Hz, 1 H), 7.35 (dt,
J = 1.3, 8.0 Hz, 1 H), 7.51 (dt, J = 1.5, 8.0 Hz, 1 H), 7.86 (dd,
J = 1.3, 8.0 Hz, 1 H), 8.09 (dd, J = 1.5, 8.0 Hz, 1 H).
MS (EI): m/z (%) = 256 (18) [M]+, 241 (100), 225 (17), 211 (18),
186 (17).
3-Methoxy-2′,2′-dimethylspiro[benzo[7]annulene-6,1′-cyclo-
propan]-7(5H)-one (19a)
Yield: 46.5 mg (64%); yellow oil.
IR (neat): 3066, 2991, 2950, 2838, 1635 (C=O), 1603, 1564, 1505,
1456, 1433, 1334, 1286, 1251, 1107, 1037, 839, 817, 734 cm–1.
1H NMR (500 MHz): δ = 0.63 (d, J = 4.1 Hz, 1 H), 0.89 (s, 3 H),
1.10 (s, 3 H), 1.65 (d, J = 4.1 Hz, 1 H), 2.57 (d, J = 15.8 Hz, 1 H),
3.68 (d, J = 15.8 Hz, 1 H), 3.83 (s, 3 H), 6.14 (d, J = 12.7 Hz, 1 H),
6.71 (d, J = 2.6 Hz, 1 H), 6.80 (dd, J = 2.6, 8.5 Hz, 1 H), 7.02 (d,
J = 12.7 Hz, 1 H), 7.29 (d, J = 8.5 Hz, 1 H).
HRMS (EI): m/z [M]+ calcd for C17H20O2: 256.1463; found:
256.1461.
9-Methoxy-2′,2′,3′,3′-tetramethylspiro[benzo[7]annulene-6,1′-
cyclopropan]-5(7H)-one (15)
Yield: 21.1 mg (26%); yellow oil.
MS (EI): m/z (%) = 242 (94) [M]+, 227 (18), 199 (12), 187 (100),
158 (24), 144 (13), 128 (17), 115 (29), 102 (7), 89 (6), 77 (8), 63 (5).
HRMS (EI): m/z [M]+ calcd for C16H18O2: 242.1307; found:
IR (neat): 3017, 2938, 2835, 1646 (C=O), 1594, 1463, 1375, 1361,
1283, 1201, 1101, 979, 768 cm–1.
1H NMR (500 MHz): δ = 1.26 (s, 6 H), 1.32 (s, 6 H), 2.40 (d, J = 7.7
Hz, 2 H), 3.68 (s, 3 H), 5.12 (t, J = 7.7 Hz, 1 H), 7.31–7.34 (m, 1 H),
7.40–7.43 (m, 2 H), 7.52 (d, J = 7.7 Hz, 1 H).
242.1309.
2-Bromo-2′,2′-dimethylspiro[benzo[7]annulene-6,1′-cyclopro-
pan]-7(5H)-one (19b)
Yield: 31.4 mg (36%); yellow oil.
MS (EI): m/z (%) = 270 (52) [M]+, 239 (3), 227 (14), 213 (15), 199
(13), 186 (100), 165 (5), 152 (5), 141 (4), 128 (6), 115 (9).
HRMS (EI): m/z [M]+ calcd for C18H22O2: 270.1620; found:
IR (neat): 3024, 2991, 2951, 2872, 1646 (C=O), 1587, 1559, 1485,
1455, 1376, 1360, 1105, 891, 834, 732 cm–1.
270.1618.
1H NMR (500 MHz): δ = 0.69 (d, J = 4.1 Hz, 1 H), 0.89 (s, 3 H),
1.09 (s, 3 H), 1.65 (d, J = 4.1 Hz, 1 H), 2.61 (d, J = 15.8 Hz, 1 H),
3.62 (d, J = 15.8 Hz, 1 H), 6.28 (d, J = 12.7 Hz, 1 H), 6.97 (d,
J = 12.7 Hz, 1 H), 7.08 (d, J = 8.1 Hz, 1 H), 7.40 (dd, J = 1.8, 8.1
Hz, 1 H), 7.49 (d, J = 1.8 Hz, 1 H).
MS (EI): m/z (%) = 290 (77) [M]+, 275 (12), 235 (100), 208 (23),
196 (24), 181 (22), 168 (22), 152 (24), 141 (21), 139 (17), 128 (47),
115 (28).
Spiro[benzo[7]annulene-6,1′-cyclopropan]-7(5H)-one (16)
Yield: 20.4 mg (37%); colorless crystals; mp 45.0–46.0 °C (hex-
ane).
IR (KBr): 3005, 1649 (C=O), 1570, 1404, 1363, 1204, 1115, 1097,
820, 748 cm–1.
1H NMR (500 MHz): δ = 0.85 (d, J = 3.4 Hz, 2 H), 1.29 (br s, 2 H),
2.93 (br s, 2 H), 6.29 (d, J = 12.5 Hz, 1 H), 7.12–7.15 (m, 2 H),
7.29–7.35 (m, 3 H).
HRMS (EI): m/z [M]+ calcd for C15H15BrO: 290.0306; found:
290.0305.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2091–2101

2100
T. Satoh et al.
PAPER
Spiro[benzo[7]annulene-5,1′-cyclobutan]-7(6H)-one (25a)
Acknowledgment
A combination of NMR techniques including H–13C HSQC, H–
13C HMBC, and DEPT 90 and 135 were applied to elucidate the
structures of regioisomers 25a and 26a. In the 1H–13C HMBC spec-
trum of 26a, correlation between the resonances associated with 1H
at the 2′-position (δH 1.76) and 13C of the carbonyl group (δC 203.1)
was observed. In addition, 1H at the 8-position (δH 6.11) correlated
with secondary 13C (δC 53.9) in the 1H–13C HMBC spectrum of 25a,
and that of 26a (δH 6.13) correlated with quaternary 13C (δC 51.0).
The structure of 25a was further confirmed by deuteration experi-
ments (see 25a′).
1
1
This work was supported by a Grant-in-Aid for Scientific Research
No. 19590018 and 22590021 from the Ministry of Education, Cul-
ture, Sports, Science and Technology, Japan, and a TUS Grant for
Research Promotion from the Tokyo University of Science, which
are gratefully acknowledged. High-performance computing resour-
ces were provided by the Tokyo University of Science. We also
thank Mr. Masaya Watanabe for outstanding research assistance.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
EtMgCl (2.5 equiv) was used; yield: 22.0 mg (37%); pale yellow
oil.
m
tgioSrantnugIifoop
r
itmnatr
IR (neat): 2979, 2939, 1658 (C=O), 1617, 1311, 1279 cm–1.
References
1H NMR (600 MHz): δ = 1.82–1.85 (m, 1 H), 1.98–2.08 (m, 1 H),
2.21 (br s, 4 H), 3.05 (s, 2 H), 6.11 (d, J = 12.3 Hz, 1 H), 7.11 (d,
J = 12.3 Hz, 1 H), 7.28 (dt, J = 1.4, 7.4 Hz, 1 H), 7.32 (dd, J = 1.4,
7.4 Hz, 1 H), 7.38 (dt, J = 1.4, 7.4 Hz, 1 H), 7.43 (d, J = 7.4 Hz, 1
H).
(1) For some monographs and reviews on the chemistry of
carbenes and carbenoids, see: (a) Kirmse, W. Carbene
Chemistry; Academic: New York, 1971. (b) Dorwald, F. Z.
Metal Carbenes in Organic Synthesis; Wiley-VCH:
Weinheim, 1999. (c) Carbene Chemistry; Bertrand, G., Ed.;
Marcel Dekker: New York, 2002. (d) Kobrich, G. Angew.
Chem., Int. Ed. Engl. 1972, 11, 473. (e) Stang, P. J. Chem.
Rev. 1978, 78, 383. (f) Burke, S. D.; Grieco, P. A. Org.
React. 1979, 26, 361. (g) Schaefer, H. F. III Acc. Chem. Res.
1979, 12, 288. (h) Wynberg, H.; Meijer, E. W. Org. React.
1982, 29, 1. (i) Taylor, K. G. Tetrahedron 1982, 38, 2751.
(j) Oku, A. J. Synth. Org. Chem., Jpn. 1990, 48, 710.
(k) Adams, J.; Spero, D. M. Tetrahedron 1991, 47, 1765.
(l) Padwa, A.; Weingarten, M. D. Chem. Rev. 1996, 96, 223.
(m) Zaragoza, F. Tetrahedron 1997, 53, 3425. (n) Kirmse,
W. Angew. Chem., Int. Ed. Engl. 1997, 36, 1164. (o) Braun,
M. Angew. Chem. Int. Ed. 1998, 37, 430. (p) Bourissou, D.;
Guerret, O.; Gabbai, F. P.; Bertrand, G. Chem. Rev. 2000,
100, 39. (q) Boche, G.; Lohrenz, J. C. W. Chem. Rev. 2001,
101, 697. (r) Mehta, G.; Muthusamy, S. Tetrahedron 2002,
58, 9477. (s) Muller, P. Acc. Chem. Res. 2004, 37, 243.
(t) Knorr, R. Chem. Rev. 2004, 104, 3795. (u) Zhang, Z.;
Wang, J. Tetrahedron 2008, 64, 6577.
13C NMR (126 MHz): δ = 15.7 (CH2), 31.4 (CH2), 41.8 (C), 53.9
(CH2), 124.6 (CH), 126.6 (CH), 129.2 (CH), 130.0 (CH), 132.8 (C),
133.1 (CH), 143.3 (CH), 147.8 (C), 200.9 (C=O).
MS (EI): m/z (%) = 198 (18) [M]+, 170 (33), 142 (100), 128 (21),
115 (27).
HRMS (EI): m/z [M]+ calcd for C14H14O: 198.1045; found:
198.1042.
Spiro[benzo[7]annulene-6,1′-cyclobutan]-7(5H)-one (26a)
Yield: 14.3 mg (24%); yellow oil.
IR (neat): 2985, 2936, 1652 (C=O), 1617, 1318, 1204, 1099, 839,
748 cm–1.
1H NMR (600 MHz): δ = 1.74–1.78 (m, 2 H), 1.83–1.94 (m, 2 H),
2.30–2.34 (m, 2 H), 3.19 (s, 2 H), 6.13 (d, J = 12.6 Hz, 1 H), 7.01
(d, J = 12.6 Hz, 1 H), 7.29–7.30 (m, 2 H), 7.31–7.33 (m, 2 H).
13C NMR (126 MHz): δ = 14.9 (CH2), 28.9 (CH2), 41.3 (CH2), 51.0
(C), 127.1 (CH), 128.1 (CH), 129.8 (CH), 130.9 (CH), 131.9 (CH),
133.7 (C), 138.9 (C), 141.3 (CH), 203.1 (C=O).
(2) For papers from our laboratories on the chemistry and
synthetic uses of cyclopropylmagnesium carbenoids, see:
(a) Satoh, T.; Kurihara, T.; Fujita, K. Tetrahedron 2001, 57,
5369. (b) Satoh, T.; Saito, S. Tetrahedron Lett. 2004, 45,
347. (c) Satoh, T.; Miura, M.; Sakai, K.; Yokoyama, Y.
Tetrahedron 2006, 62, 4253. (d) Yamada, Y.; Miura, M.;
Satoh, T. Tetrahedron Lett. 2008, 49, 169. (e) Miyagawa, T.;
Tatenuma, T.; Tadokoro, M.; Satoh, T. Tetrahedron 2008,
64, 5279. (f) Satoh, T.; Nagamoto, S.; Yajima, M.; Yamada,
Y.; Ohata, Y.; Tadokoro, M. Tetrahedron Lett. 2008, 49,
5431. (g) Satoh, T.; Noguchi, T.; Miyagawa, T. Tetrahedron
Lett. 2008, 49, 5689. (h) Yajima, M.; Nonaka, R.;
MS (EI): m/z (%) = 198 (25) [M]+, 170 (11), 157 (70), 141 (100),
128 (24), 115 (46), 102 (4), 89 (7).
HRMS (EI): m/z [M]+ calcd for C14H14O: 198.1045; found:
198.1046.
6,6-Dideuteriospiro[benzo[7]annulene-5,1′-cyclobutan]-7(6H)-
one (25a′)
A soln of 25a (61.3 mg, 0.309 mmol) in THF (1.2 mL) was added
to a soln of K2CO3 (0.8 mg, 0.006 mmol) in D2O (0.6 mL) and
MeOD (1.2 mL) at r.t., and the mixture was stirred at that tempera-
ture for 36 h. The reaction mixture was extracted with CHCl3
(3 × 15 mL). The organic layer was dried over MgSO4 and concen-
trated under reduced pressure. The residue was purified by column
chromatography on silica gel [Rf = 0.3 (hexane–EtOAc, 15:1)] to
give 25a′ as a pale yellow oil; yield: 59.4 mg (0.297 mmol, 96%; D
content: 96%).
Yamashita, H.; Satoh, T. Tetrahedron Lett. 2009, 50, 4754.
(i) Yamada, Y.; Mizuno, M.; Nagamoto, S.; Satoh, T.
Tetrahedron 2009, 65, 10025. (j) Satoh, T.; Ikeda, S.;
Miyagawa, T.; Noguchi, T. Tetrahedron Lett. 2010, 51,
1955. (k) Momochi, H.; Noguchi, T.; Miyagawa, T.; Ogawa,
N.; Tadokoro, M.; Satoh, T. Tetrahedron Lett. 2011, 52,
3016. (l) Satoh, T.; Kashiwamura, G.; Nagamoto, S.; Sasaki,
Y.; Sugiyama, S. Tetrahedron Lett. 2011, 52, 4468.
(m) Satoh, T.; Tsuru, T.; Ikeda, S.; Miyagawa, T.; Momochi,
H.; Kimura, T. Tetrahedron 2012, 68, 1071.
1H NMR (300 MHz): δ = 1.75–1.88 (m, 1 H), 1.97–2.11 (m, 1 H),
2.21 (br s, 4 H), 6.11 (d, J = 12.4 Hz, 1 H), 7.11 (d, J = 12.4 Hz, 1
H), 7.25–7.44 (m, 4 H).
Calculation
Density functional theory (DFT) calculations were performed with
Gaussian 03 software,10 and the geometries were fully optimized in
the gas phase without any symmetry constraints at the B3LYP/6-
311++G(d,p) level. Frequency calculations at the same level were
performed to determine if the structures corresponded to energy
minima (no imaginary frequencies). The Jmol program11 was used
to draw the molecular structures and molecular orbitals.
(3) For papers from our laboratories on the chemistry and
synthetic uses of cyclobutylmagnesium carbenoids, see:
(a) Nakaya, N.; Sugiyama, S.; Satoh, T. Tetrahedron Lett.
2009, 50, 4212. (b) Satoh, T.; Kasuya, T.; Miyagawa, T.;
Nakaya, N. Synlett 2010, 286. (c) Satoh, T.; Kasuya, T.;
Ishigaki, M.; Inumaru, M.; Miyagawa, T.; Nakaya, N.;
Synthesis 2012, 44, 2091–2101
© Georg Thieme Verlag Stuttgart · New York

PAPER
Sugiyama, S. Synthesis 2011, 397. (d) Ishigaki, M.;
Inumaru, M.; Satoh, T. Tetrahedron Lett. 2011, 52, 5563.
(4) Preliminary results of this investigation were reported as a
Letter; see ref. 2f.
(5) (a) Satoh, T. Chem. Soc. Rev. 2007, 36, 1561. (b) Satoh, T.
In The Chemistry of Organomagnesium Compounds;
Rappoport, Z.; Marek, I., Eds.; John Wiley & Sons:
Chichester, 2008, 717–769. (c) Satoh, T. Yakugaku Zasshi
2009, 129, 1013. (d) Satoh, T. Heterocycles 2012, 85, 1.
(6) Hoffmann, R. W.; Hölzer, B.; Knopff, O.; Harms, K. Angew.
Chem. Int. Ed. 2000, 39, 3072.
(7) Excess lithium phenolates and naphtholates were used
throughout the study. Otherwise, the desired ring-expanded
products were obtained in very low yields. The major
byproducts in the reactions were 1-chlorocycloalkanes,
which were formed by protonation of unreacted magnesium
carbenoids 2, and ethyl- or isopropyl-substituted
cycloalkanes; see ref. 3c.
(8) Michejda, C. J.; Comnick, R. W. J. Org. Chem. 1975, 40,
1046.
(9) Soai, K.; Oyamada, H.; Takase, M.; Ookawa, A. Bull. Chem.
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Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.;
Reaction of Magnesium Carbenoids with Lithium Naphtholates
2101
Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.;
Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.;
Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
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(11) Jmol: an open-source Java viewer for chemical structures in
3D. http://www.jmol.org/.
(12) For some papers on the chemistry of lithium
cyclopropylidenes, see: (a) Oku, A.; Harada, T. J. Synth.
Org. Chem., Jpn. 1986, 44, 736. (b) Harada, T.; Yamaura,
Y.; Oku, A. Bull. Chem. Soc. Jpn. 1987, 60, 1715.
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2091–2101