A novel synthesis of spiro[2.6]nonadienones by the reaction of magnesium cyclopropylidenes with naphtholates and phenolates

Article abstract of DOI:10.1016/j.tetlet.2008.07.066

The sulfoxide-magnesium exchange reaction of aryl 1-chlorocyclopropyl sulfoxides with i-PrMgCl in THF at low temperature gave magnesium cyclopropylidenes. Treatment of the magnesium cyclopropylidenes with lithium naphtholates or phenolates resulted in the formation of spiro[2.6]nonadienones in up to 82% yield. The structure of the spiro[2.6]nonadienones was found to be dependent on the structure of the naphtholates and phenolates.

Full text of DOI:10.1016/j.tetlet.2008.07.066

Tetrahedron Letters 49 (2008) 5431–5435
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Tetrahedron Letters
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A novel synthesis of spiro[2.6]nonadienones by the reaction of magnesium
cyclopropylidenes with naphtholates and phenolates
*
Tsuyoshi Satoh , Shinobu Nagamoto, Masanobu Yajima, Yukie Yamada, Yuki Ohata, Makoto Tadokoro
Department of Chemistry, Faculty of Science, Tokyo University of Science, Ichigaya-funagawara-machi 12, Shinjuku-ku, Tokyo 162-0826, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The sulfoxide–magnesium exchange reaction of aryl 1-chlorocyclopropyl sulfoxides with i-PrMgCl in THF
at low temperature gave magnesium cyclopropylidenes. Treatment of the magnesium cyclopropylidenes
with lithium naphtholates or phenolates resulted in the formation of spiro[2.6]nonadienones in up to 82%
yield. The structure of the spiro[2.6]nonadienones was found to be dependent on the structure of the
naphtholates and phenolates.
Received 30 June 2008
Revised 9 July 2008
Accepted 10 July 2008
Available online 12 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Magnesium carbenoid
Magnesium cyclopropylidene
Cyclopropylation
Ring-expansion
Spiro[2.6]nonadienone
1. Introduction
of spiro[2.6]nonadienones 4 or 5 from naphthols and phenols
(Scheme 1).
Cyclopropanes are one of the most important and fundamental
compounds in organic and synthetic organic chemistry. Because of
their highly strained nature, cyclopropanes have long been
recognized to be highly versatile compounds in organic synthesis
and innumerable studies on their chemistry, synthesis, and
synthetic uses have been carried out;1 however, new methods for
the synthesis of cyclopropanes are still very much desired.
Recently, we are interested in the use of magnesium cyclopropyl-
idenes in organic synthesis,2 and some new synthetic methods
were reported. Those are as follows: generation and properties of
magnesium cyclopropylidenes,3 synthesis of alkylidenecyclopro-
panes,4 N-cyclopropylation of arylamines,5 and direct ortho-cyclo-
propylation of arylamines.6
In continuation of our investigation for the development of new
synthetic method utilizing the magnesium cyclopropylidenes, we
studied the reaction of the magnesium cyclopropylidenes with
lithium naphtholates and phenolates, and very interesting results
were obtained. Thus, the magnesium cyclopropylidenes 2, derived
from aryl 1-chlorocyclopropyl sulfoxides 1 with i-PrMgCl, were
treated with lithium naphtholates or lithium phenolates 3 to afford
unexpected spiro[2.6]nonadienones 4 or 5 in variable yields. This
reaction offers a new method for a short synthesis of various kinds
2. Results and discussion
Recently, we reported that the reaction of magnesium cyclopro-
pylidenes with N-lithio arylamines resulted in the formation of
ortho-cyclopropylated arylamines.6 In continuation of this chemis-
try, we investigated the reaction of magnesium cyclopropylidene 7,
which was generated from 1-chlorocyclopropyl phenyl sulfoxide 1
(R1 = H, Ar = Ph) with i-PrMgCl at À78 °C, with lithium 1-naphtho-
late 6a, and 2-cyclopropylated 1-naphthol 8a was obtained in 37%
yield (Scheme 2).
Next, the reaction was carried out with lithium 4-methoxy-1-
naphtholate 6b. Very interestingly, this reaction afforded 2-cyclo-
propylated compound 8b (23%) and unexpected ring-expanded
spiro[2.6]nona-5,7-dien-4-one derivative 9b in 47% yield. Further,
the reactions of 6a and 6b with magnesium cyclopropylidene
having gem-dimethyl groups 10 were investigated. Interestingly,
these reactions afforded ring-expanded spiro[2.6]nonadienones
11a (70%)7 and 11b (82%), respectively, as a sole product without
2-cyclopropylated product.
A plausible mechanism of this reaction is as follows (Scheme 3).
Addition reaction of magnesium carbenoid 10 is expected to take
place with naphtholate 6b at the most electron-rich double bond
to afford the highly strained spiro[2.2]pentane intermediate A.
Carbon–carbon bond-cleavage of the cyclopropanolate moiety,
depicted in A, would take place easily because of the ring-strain
* Corresponding author. Tel.: +81 3 5228 8272; fax: +81 3 5261 4631.
E-mail address: tsatoh@rs.kagu.tus.ac.jp (T. Satoh).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.066

5432
T. Satoh et al. / Tetrahedron Letters 49 (2008) 5431–5435
OLi
R2
O
O
R1
i-PrMgCl
3
Cl
S(O)Ar
Cl
MgCl
R1
R1
or
R2
R2
R1
5
1
4
2
Ar= Ph,
p-Tol
Scheme 1.
Cl
MgCl
OLi
R
O
OH
7
THF, -78 ~ -20 ºC
OCH3
R
6a R=H
6b R=OCH3
8a R=H 37%
8b R=OCH3 23%
9b 47%
CH3
H3C
Cl
MgCl
O
H3C
H3C
10
THF, -78 ~ -20 ºC
R
11a R=H 70%
11b R=OCH3 82%
Scheme 2.
to afford the final ring-expanded intermediate B. Protonolysis of B
will give the product 11b. In order to confirm the final intermedi-
ate of this reaction to be B, deuteriolysis of this reaction with
CH3OD was carried out and indeed deuterated product 12 was
obtained with perfect deuterium incorporation.
CH3
H3C
H3C
CH3
O
Cl
MgCl
Li
OLi
10
The reaction of magnesium cyclopropylidene 10 with lithium
2-naphtholate gave spiro[2.6]nona-5,7-dien-4-one 13 in 49% yield
(Scheme 4).8 The structure of 13 was confirmed by X-ray analysis
(Fig. 1).9 The structure of 13 and 11 (see Scheme 2) are quite sim-
ilar; however, the position of the carbonyl group is different. The
same reaction mechanism shown in Scheme 3 can be applied to
this reaction. Quenching of the reaction mixture with CH3OD again
gave mono deuterated compound 14. The deuterium incorporation
was found to be highly stereoselective; only the hydrogen appear-
ing at d 3.70 in the 1H NMR was perfectly replaced by deuterium.
Further reactions of the magnesium cyclopropylidenes with
phenolates and naphtholates were carried out and the results are
summarized in Table 1. The reaction of magnesium cyclopropyl-
idene 7 with lithium phenolate gave only ortho-cyclopropylated
Additon of carbenoid 10 to the
electron-rich double bond
OCH3
OCH3
A
6b
O
O
H3C
H3C
H3C
H3C
CH3OD
Li
D
OCH3
OCH3
B
12
Scheme 3.
CH3
δ 2.63 (d,
J
=15.7 Hz)
δ 2.63 (s)
H3C
H3C
H3C
H3C
H3C
Cl
MgCl
δ 3.70 (d, =15.7 Hz)
J
H
H
D
H
LiO
10
O
O
THF, -78 ~ -20 ºC
49%
13
14
(D content 99%)
Scheme 4.

T. Satoh et al. / Tetrahedron Letters 49 (2008) 5431–5435
5433
phenol 15a in low yield without any ring-expanded product (entry
1). The reaction of magnesium cyclopropylidene 7 with lithium 2-
naphtholate gave ring-expanded product 15b in 37% yield without
1-cyclopropylated 2-naphthol (entry 2).
The reaction of magnesium cyclopropylidene bearing gem-di-
methyl groups 10 with lithium phenolate gave ring-expanded
product, 1,1-dimethylspiro[2.6]nona-6,8-dien-5-one 15c,10 in 22%
yield (entry 3). Quite interestingly, the structure of the product
15c was somewhat different compared with that of the product
from 1-naphthol (11a). The cyclopropane and the carbonyl carbon
adjoin in the structure of 11a; however, a methylene carbon is
present between them in the structure of 15c. All the products
from the reactions of magnesium cyclopropylidene 10 with pheno-
lates have the same structure as shown in entries 3–6 in Table 1.
The structure of the products (15c–f) of the reaction with phe-
nolates cannot be explained by the mechanism shown in Scheme 3.
Another reaction mechanism shown in Scheme 5 is proposed for
the products. We still find it difficult to propose the reason why
Figure 1. Crystal structure of spiro[2.6]nonadienone 13.
Table 1
The reaction of magnesium cyclopropylidenes with lithium phenolates or naphtholates
OLi
Cl
MgCl
R1
R2
+
Product 15
2
3
Entry
1
Magnesium cyclopropylidene
Naphtholate or phenolate
Product 15
OH
Yield (%)
21
OLi
Cl
MgCl
7
15a
LiO
OLi
2
3
7
37
22
O
15b
O
O
CH3
H3C
H3C
H3C
Cl
MgCl
10
15c
15d
OLi
H3C
H3C
4
10
26
OCH3
OCH3
OLi
O
O
H3C
H3C
5
6
10
10
20
Ph
Ph
15e
OLi
H3C
H3C
32
CH3
15f
CH3
(continued on next page)

5434
T. Satoh et al. / Tetrahedron Letters 49 (2008) 5431–5435
Table 1 (continued)
Entry
Magnesium cyclopropylidene
Naphtholate or phenolate
Product 15
Yield (%)
33
O
OLi
H3C
H3C
7
8
9
10
Cl
Cl
15g
H3C CH3
LiO
10
36
64
26
Br
O
Br
15h
H3C CH3
OCH3
LiO
OCH3
10
O
15i
CH3
H3C
H3C
H3C
CH3
H3C
OLi
O
Cl
MgCl
10
H3C
CH3
16a
OCH3
OCH3
15j
a
1-Chloro-2,2,3,3-tetramethylcyclopropyl phenyl sulfoxide was used as the starting material.
the mechanism is different between the reactions with naphtho-
In conclusion, we report for the first time, a novel reaction of
lates and phenolates at present.
magnesium cyclopropylidenes with lithium naphtholates and
phenolates to give ring-expanded spiro[2.6]nonadienones. There
are only a few reports on the reactions of lithium cyclopro-
pylidenes;11 however, no report has appeared for the reaction with
naphtholates and phenolates. The results described in this
Letter are the first example of the reaction of cyclopropylidenes
with naphtholates and phenolates giving ring-expanded
spiro[2.6]nonadienones.
The reaction of magnesium cyclopropylidene 10 with lithium
4-chloro-1-naphtholate gave the expected product 15g; however,
the yield was found to be lower than that of 11a and 11b. This
result implied that an electron-withdrawing group may retard
the carbenoid reaction presented herein. The reactions shown in
entries 8 and 9 gave the desired 1,1-dimethylspiro[2.6]nona-5,7-
dien-4-ones 15h and 15i in variable yields. Finally, fully substi-
tuted magnesium cyclopropylidene 16 was treated with lithium
4-methoxynaphtholate. This reaction gave the desired product
15j; however, the yield was not satisfactory (entry 10). Many un-
known by-products, each as a small amount, were obtained when
the yields of the spiro[2.6]nonadienones were low.
Acknowledgments
This work was supported by a Grant-in-Aid for Scientific
Research No. 19590018 from the Ministry of Education, Culture,
Sports, Science and Technology, Japan, which is gratefully
acknowledged.
CH3
H3C
References and notes
Cl
MgCl
1. Some recent reviews concerning chemistry, synthesis, and synthetic uses of
cyclopropanes: (a) Wong, H. N. C.; Hon, M.-Y.; Tse, C.-W.; Yip, Y.-C.; Tanko, J.;
Hudlick, T. Chem. Rev. 1989, 89, 165; (b) Salaun, J. Chem. Rev. 1989, 89, 1247; (c)
Sonawane, H. R.; Bellur, N. S.; Kulkarni, D.; Ahuja, J. R. Synlett 1993, 875; (d)
Doyle, M. P.; Protopopova, M. N. Tetrahedron 1998, 54, 7919; (e) Donaldson, W.
A. Tetrahedron 2001, 57, 8589; (f) Lebel, H.; Marcoux, J.-F.; Molinaro, C.;
Charette, A. B. Chem. Rev. 2003, 103, 977; (g) Pietruszka, J. Chem. Rev. 2003, 103,
1051; (h) Reissig, H.-U.; Zimmer, R. Chem. Rev. 2003, 103, 1151; (i) Kulinkovich,
O. G. Chem. Rev. 2003, 103, 2597; (j) Halton, B.; Harvey, J. Synlett 2006, 1975.
2. Satoh, T. Chem. Soc. Rev. 2007, 36, 1561.
10
Li
MgCl
O
O
H3C
H3C
C
MgCl
O
O
CH3
3. Satoh, T.; Kurihara, T.; Fujita, K. Tetrahedron 2001, 57, 5369.
4. Satoh, T.; Saito, S. Tetrahedron Lett. 2004, 45, 347.
H3C
H3C
H3C
5. Satoh, T.; Miura, M.; Sakai, K.; Yokoyama, Y. Tetrahedron 2006, 62, 4253.
6. Yamada, Y.; Miura, M.; Satoh, T. Tetrahedron Lett. 2008, 49, 169.
7. Compound 11a: Colorless oil; IR (neat) 1651 (CO), 1594 (C@C) cmÀ1 1H NMR d
;
0.75 (1H, d, J= 4.1 Hz), 1.03 (3H, s), 1.35 (3H, s), 1.67 (1H, d, J= 4.1 Hz), 2.15 (1H,
dd, J = 15.9, 7.9 Hz), 2.87 (1H, ddd, J = 15.9, 5.3, 1.8 Hz), 6.33 (1H, ddd, J = 10.8,
7.9, 5.3 Hz), 6.52 (1H, dd, J = 10.8, 1.7 Hz), 7.18 (1H, d, J = 7.6 Hz), 7.30 (1H, t, J
= 7.6 Hz), 7.45 (1H, t, J = 7.6 Hz), 7.99 (1H, d, J = 7.6 Hz). MS m/z (%) 212 (M+,
D
15c
Scheme 5.

T. Satoh et al. / Tetrahedron Letters 49 (2008) 5431–5435
5435
100), 197 (48), 157 (79), 128 (78). Calcd for C15H16O: M, 212.1201. Found: m/z
212.1202.
Diffraction data were measured on
diffractometer with monochromated Mo K
source apparatus. The data reduction, structure solution and refinement, and
all the necessary computational data processes were performed using APEX
a
Bruker APEX CCD-Detector X-ray
a radiation from a rotating anode
8. To a solution of 2-naphthol (0.9 mmol) in 0.8 mL of dry THF in a flame-dried
flask at À78 °C under argon atmosphere was added n-BuLi (0.9 mmol)
,
dropwise with stirring.
A
solution of 1-chloro-2,2-dimethylcyclopropyl p-
SAINT, and SHELXTL programs. The small platelet crystal of 13 was recrystallized
from hexane. The low resolution from the data collection is the reason for a
fragile and very small thin crystal. Therefore, we have restricted the discussion
to only molecular formationand did not discuss the bond lengths and angles of
13. Crystallographic data excluding structures have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publication
numbers CCDC 683165 for 13. A copy of the data can be obtained free of
charge from CCDC, 12 Union road, Cambridge CB2 1EZ. UK [DIRECT LINE: +44
1223 762910, Fax: +44 (0) 1223-336033 or e-mail: deposit@ccdc.cam.ac.uk.
10. Structure of the product 15c was unambiguously determined from its spectral
tolyl sulfoxide (72.8 mg; 0.3 mmol) in 0.7 mL of dry THF was added to the
reaction mixture dropwise with stirring. Finally, i-PrMgCl (2.0 mol/L in THF;
0.75 mmol) was added to the reaction mixture and the temperature of the
reaction mixture was slowly allowed to warm to À20 °C for 1.5 h. The reaction
mixture was quenched with satd aq NH4Cl and the whole was extracted with
CH2Cl2. The organic layer was dried over MgSO4. After removal of the solvent,
the product was purified by silica gel column chromatography followed by
preparative thin layer chromatography (hexane–1,4-dioxane = 30:1) to give 13
(31.3 mg, 49%) as colorless crystals; mp 39.5–40.5 °C (hexane); IR (KBr) 2951,
2346, 1643 (CO), 1408, 1361, 1314, 1281, 1202, 1099, 831, 801, 748 cmÀ1
;
1H
data. Colorless oil; IR (neat) 1659 (CO), 1626 (C@C) cmÀ1 1H NMR d 0.77 (2H,
;
NMR d 0.68 (1H, d, J = 4.0 Hz), 0.89 (3H, s), 1.08 (3H, s), 1.65 (1H, d, J = 4.0 Hz),
2.63 (1H, d, J = 15.7 Hz), 3.70 (1H, d, J = 15.7 Hz), 6.25 (1H, d, J = 12.6 Hz), 7.07
(1H, d, J = 12.6 Hz), 7.18–7.20 (1H, m), 7.27–7.30 (2H, m), 7.33–7.36 (1H, m).
MS m/z (%) 212 (M+, 76), 197 (20), 157 (100), 141 (33), 128 (67), 115 (38). Calcd
for C15H16O: M, 212.1200. Found: m/z 212.1197.
s), 1.06 (3H, s), 1.19 (3H, s), 2.35 (1H, dt, J = 15.5, 1.3 Hz), 3.04 (1H, d, J
= 15.5 Hz), 6.04–6.13 (3H, m), 6.64 (1H, ddd, J = 12.2, 7.0, 1.0 Hz). MS m/z (%)
162 (M+, 39), 147 (83), 119 (32), 107 (100), 91 (76). Calcd for C11H14O: M,
162.1044. Found: m/z 162.1046.
11. Some recent papers for the chemistry of lithium cyclopropyl carbenoids: (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; (c) Oku, A. J. Synth. Org.
Chem. Jpn. 1990, 48, 710; (d) Creary, X.; Jiang, Z.; Butchko, M.; McLean, K.
Tetrahedron Lett. 1996, 37, 579; (e) Tverezovsky, V. V.; Baird, M. S.; Bolesor, I. G.
Tetrahedron 1997, 53, 14773; (f) Azizoglu, A.; Ozen, R.; Hokelek, T.; Balci, M. J.
Org. Chem. 2004, 69, 1202; (g) Thomas, E.; Kasatkin, A. N.; Whitby, R. J.
Tetrahedron Lett. 2006, 47, 9181.
9. Crystal data for spiro[2.6]nonadienone 13: C15H16O, M = 212.12, monoclinic,
space group P21/c (#14), a = 21.26(3) Å, b = 6.075(8) Å, c = 18.92(2) Å, b =
104.06(2)°, V = 2370(5) Å3, Z = 4, F(000) = 1824, Dcalc = 1.190 g cmÀ3
,
l
r
(Mo
(I),
Ka
) = 0.73 cmÀ1, T = 173 K, radiation = 0.71073 Å, R1 = 0.1406 for I > 2.0
wR2 = 0.3986 for all data (5321 reflections), GOF = 0.981 (294 parameters),
crystal dimensions 0.63 Â 0.09 Â 0.02 mm3. The single crystal of 13, coated
with Fluorinert FC-70 (3M), was mounted using loop method at 173 K.