A new approach to the synthesis of 1-oxaspiro[4.n]alkanes and tetrahydrofurans by the 1,5-CH insertion reaction of magnesium carbenoids

Article abstract of DOI:10.1016/j.tetlet.2012.02.034

1-Alkoxy-1-[2-chloro-2-(p-tolylsulfinyl)ethyl]cycloalkanes were prepared from various cyclic ketones in good overall yields. Treatment of these cycloalkanes bearing a sulfinyl group with i-PrMgCl resulted in the formation of 1-oxaspiro[4.n]alkanes in high to quantitative yields via the 1,5-CH insertion reaction of generated magnesium carbenoid intermediates. When this procedure was commenced with acyclic ketones, multi-substituted tetrahydrofurans were obtained in up to a 96% yield. This procedure provides a new and good way for the synthesis of 1-oxaspiro[4.n]alkanes and tetrahydrofurans with the formation of a carbon-carbon bond between a carbenoid carbon and a non-activated carbon in high yields. The oxygen atom in the magnesium carbenoid intermediates was proved to act very important roles in the 1,5-CH insertion reaction.

Full text of DOI:10.1016/j.tetlet.2012.02.034

Tetrahedron Letters 53 (2012) 2074–2077
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Tetrahedron Letters
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A new approach to the synthesis of 1-oxaspiro[4.n]alkanes and
tetrahydrofurans by the 1,5-CH insertion reaction of magnesium carbenoids
⇑
Tsuyoshi Satoh , Tsukasa Yasoshima, Hitoshi Momochi
Graduate School of Chemical Sciences and Technology, 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:
1-Alkoxy-1-[2-chloro-2-(p-tolylsulfinyl)ethyl]cycloalkanes were prepared from various cyclic ketones in
good overall yields. Treatment of these cycloalkanes bearing a sulfinyl group with i-PrMgCl resulted in
the formation of 1-oxaspiro[4.n]alkanes in high to quantitative yields via the 1,5-CH insertion reaction
of generated magnesium carbenoid intermediates. When this procedure was commenced with acyclic
ketones, multi-substituted tetrahydrofurans were obtained in up to a 96% yield. This procedure provides
a new and good way for the synthesis of 1-oxaspiro[4.n]alkanes and tetrahydrofurans with the formation
of a carbon–carbon bond between a carbenoid carbon and a non-activated carbon in high yields. The oxy-
gen atom in the magnesium carbenoid intermediates was proved to act very important roles in the 1,5-
CH insertion reaction.
Received 13 January 2012
Revised 3 February 2012
Accepted 7 February 2012
Available online 15 February 2012
Keywords:
1-Oxaspiro[4.n]alkane
Magnesium carbenoid
1,5-CH insertion reaction
Cyclization
Ó 2012 Elsevier Ltd. All rights reserved.
CH Activation
Carbenes and carbenoids have long been recognized to be
highly reactive carbon species and are widely used as versatile
intermediates in organic and synthetic organic chemistry.1
Carbon–hydrogen insertion (CH insertion) reaction2 is one of the
most striking reactions of carbenes and carbenoids. This reaction
enables the formation of a carbon–carbon bond between non-acti-
vated carbon and the carbene (or carbenoid) carbons. Recently, for-
ketones, with a Grignard reagent resulted in the formation of
1-oxaspiro[4.n]alkanes in high to quantitative yields via the 1,5-
CH insertion reaction of the generated magnesium carbenoid inter-
mediates. Thus, as shown in Scheme 1, cycloalkanols bearing a
2-(p-tolylthio)ethyl group at the 1-position 2 were synthesized
starting from cyclic ketones 1. The hydroxyl group of 2 was alkyl-
ated and the sulfide group was converted to sulfoxide having chlo-
mation of
a
chemical bond to
a
non-activated carbon
rine atom at the a-position to give 3 in high yields. Finally, 3 was
(functionalization of inert C–H bond; CH activation) has been re-
ceived considerable attention.3 The CH insertion is a kind of the
CH activation.
treated with i-PrMgCl in THF at low temperatures to result in the
formation of 1-oxaspiro[4.n]alkanes 5 in high to quantitative yields
via the 1,5-CH insertion reaction of the generated magnesium
carbenoid intermediates 4. When this procedure was commenced
with acyclic ketones, 2,2-disubstituted tetrahydrofurans 5 were
obtained. In this Letter, we report the preliminary results for the
synthesis of 1-oxaspiro[4.n]alkanes and 2,2-disubstituted tetra-
hydrofurans 5 from cyclic and acyclic ketones 1 by the 1,5-CH
insertion reaction of magnesium carbenoids as the key reaction.
Recently, we have been interested in a study for developing new
synthetic methods using the chemistry of magnesium carbenoids,4
that are generated from 1-chloroalkyl p-tolyl sulfoxides via the
sulfoxide-magnesium exchange reaction. Especially, we are inter-
ested in the CH insertion reactions of magnesium carbenoids. Syn-
thesis, including asymmetric synthesis, of cyclopropanes by 1,3-CH
insertion reaction of the magnesium carbenoids was extensively
studied and reported from our research group.5 Quite recently,
we reported a short synthesis of 3-oxabicyclo[3.1.0]hexanes from
Synthesis of 1-oxaspiro[4.n]alkanes 5 from cyclic ketones
a
,b-unsaturated carbonyl compounds by the 1,5-CH insertion reac-
At first, details of this procedure are reported using 1-chloroal-
kyl p-tolyl sulfoxide bearing a benzyl ether group 9 as a represen-
tative example for the precursor of the magnesium carbenoid
intermediates (Scheme 2). Sulfoxide 9 was synthesized from 1,4-
cyclohexanedione mono ethylene acetal 6. Thus, Horner–Wads-
worth–Emmons reaction followed by epoxidation and reduction
of 6 gave a diol in a high yield. The primary hydroxyl group of
the diol was converted to sulfide 7 in a high yield. The tertiary
hydroxyl group of 7 was benzylated and the sulfide group was
tion of cyclopropylmagnesium carbenoids as the key reaction.6
In continuation of our interest in the CH insertion reaction
of magnesium carbenoids in organic synthesis, we recently
found
that
the
reaction
of
1-alkoxy-1-[2-chloro-2-
(p-tolylsulfinyl)ethyl]cycloalkanes, easily prepared from cyclic
⇑
Corresponding author.
E-mail address: tsatoh@rs.kagu.tus.ac.jp (T. Satoh).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.02.034

T. Satoh et al. / Tetrahedron Letters 53 (2012) 2074–2077
2075
Table 1
Investigation for the reaction of 9 with i-PrMgCl giving 1-oxaspiro[4.5]decane 11
STol
S(O)Tol
R1
R1
1
R1
R1
R1
R1
O
Cl
R
S(O)Tol
Cl
H
i-PrMgCl
(3 equiv)
OH
O
O
O
O
O
O
O
Cl
Ph
+
2
3
O
O
O
conditions
Ph
Ph
MgCl
Cl
9
11
12
Yield (%)
R1
R1
R1
R1
i-PrMgCl (3 equiv)
THF
1,5-CH insertion
Entry
Conditions
O
O
R
Solvent
Temperature (°C)
Time (min)
11
12
R
5
4
1
2
3
4
5
6
7
THF
THF
THF
THF
THF
Toluene
Et2O
À78
60
180
60
60
75
11
29
14
93
90
9
73
48
79
Trace
Trace
Trace
Trace
À78
Scheme 1. General scheme for this work.
À78 to À60
À78 to À40
À78 to À20
À78 to À40
À78 to À40
60
60
oxidized to give sulfoxide 8 in a 97% yield. Finally, sulfoxide 8 was
chlorinated by treatment with LDA followed by p-toluenesulfonyl
chloride7 to afford the desired product 9 in a 93% yield.
38
In expectation of producing 1-oxaspiro[4.5]decane 11 through
the 1,5-CH insertion reaction of magnesium carbenoid intermedi-
ate 10, sulfoxide 9 was treated with 3 equiv of i-PrMgCl in THF at
0 °C for 10 min. Gratifyingly, this reaction afforded the desired 11
in a 74% yield with a trace amount of chloroalkane 12 (Scheme 2).
As this is a new and unprecedented way for the synthesis of 1-
oxaspiro[4.5]decane, we investigated the reaction of 9 with i-
PrMgCl in detail and the results are summarized in Table 1. At first,
sulfoxide 9 was treated with 3 equiv of i-PrMgCl at À78 °C and the
reaction mixture was stirred at the temperature for 60 and
180 min (entries 1 and 2). The starting sulfoxide 9 immediately
disappeared; however, both reactions gave chloroalkane 12 as a
major product with up to 29% of 1-oxaspiro[4.5]decane 11. These
results indicated that the sulfoxide–magnesium exchange reaction
of 9 proceeded instantaneously even at À78 °C; however, the 1,5-
CH insertion reaction must be quite slow at À78 °C. Even at
À60 °C, the 1,5-CH insertion reaction took place quite slowly (entry
3).
Next, the reaction was conducted at À78 °C and the tempera-
ture of the reaction mixture was slowly allowed to warm to
À40 °C for 60 min (entry 4). This treatment gave the desired 11
in a 93% yield with a trace of chloroalkane 12. This result indicates
that the 1,5-CH insertion reaction proceeds at around À40 °C. Fur-
ther warming of the reaction mixture to À20 °C did not give a bet-
ter yield (entry 5). Using toluene and diethyl ether, instead of THF,
as the solvent was found to be inefficient (entries 6 and 7). We
decided that the conditions in entry 4 were the conditions of
choice in this reaction and used them throughout in this study.8
As development of this procedure, methyl ether 13a and ethyl
ether 13b were synthesized and treated with i-PrMgCl under the
conditions described above (Scheme 3). Both reactions gave 1-oxa-
spiro[4.5]decane 14a and 2-methyl-1-oxaspiro[4.5]decane 14b in
high yields. These results show that the 1,5-CH insertion reaction
proceeds efficiently between the magnesium carbenoid carbon
and the hydrogens on the benzyl (9), methyl (13a), and methylene-
carbons (13b).
Further, substrate scope of this procedure was investigated
starting from various sizes of cyclic ketones and the results are
summarized in Table 2. Benzyl ethers 15 were synthesized from
cyclic ketones in the same way as described in Scheme 2.
Gratifyingly, the reaction of 1-chloroalkyl p-tolyl sulfoxides
bearing a benzyl ether 15 gave 1-oxa-2-phenylspiro[4.n]alkanes
16 in good to quantitative yields. Although the real reason is ob-
scure at present, the reaction of 15a bearing a cyclobutane ring
gave 4-oxa-5-phenylspiro[3.4]octane 16a in somewhat a lower
yield (entry 1). All other sulfoxides bearing cyclopentane (15b),
cyclohexane (15c), cyclooctane (15d), and cyclopentadecane rings
(15e) gave high to quantitative yields of 1-oxa-2-phenylspi-
ro[4.n]alkanes 16 (entries 2–5). From these results, it was verified
that the procedure presented in this Letter works well with 15 hav-
ing various ring systems.
1) (EtO)2P(O)CH2CO2Et,
STol
O
O
NaH, THF, r.t.
1) BnBr, NaH, DMF, r.t.
O
O
O
2) mCPBA, CHCl3, 0°C
OH
2) mCPBA, CHCl3, r.t.
3) LiAlH4, THF, r.t.
97% (2 steps)
6
7
4) (TolS)2, n-Bu3P, THF, r.t.
80% (4 steps)
S(O)Tol
S(O)Tol
Cl
i-PrMgCl
(3 equiv)
LDA, TsCl
O
O
O
O
THF, -78°C
93%
THF, 0°C, 10 min
O
O
Ph
Ph
8
9
MgCl
H
O
O
O
O
O
1,5-CH insertion
Cl
OCH2Ph
Cl
+
O
O
OCH2Ph
Ph
12
11
(74%)
10
(trace)
Scheme 2. Synthesis of 1-chloro-3-benzyloxypropyl p-tolyl sulfoxide 9 from 1,4-cyclohexanedione mono ethylene acetal 6 and treatment of 9 with i-PrMgCl.

2076
T. Satoh et al. / Tetrahedron Letters 53 (2012) 2074–2077
S(O)Tol
Cl
benzyloxy group 17, except 17d, were synthesized starting from
i-PrMgCl
(3 equiv)
O
O
O
O
acyclic ketones. Compounds 17a–c were synthesized from acetone,
1,5-diphenylpentan-3-one, and benzophenone respectively,
according to the procedure described in Scheme 2. 1-Chloropropyl
p-tolyl sulfoxides 17d were synthesized from 1,3-propanediol.
Sulfoxides 17 were treated with 3 equiv of i-PrMgCl under the con-
ditions described above and the results are summarized in Table 3.
As shown in Table 3, the reaction of 1-chloro-3,3-disubstituted
alkyl p-tolyl sulfoxides 17a to 17c gave the desired 2,2,5-trisubsti-
tuted tetrahydrofurans 18a to 18c in up to a 96% yield. Quite inter-
estingly, the sulfoxide without substituents at the 3-position 17d
gave isopropylated compound9 19 in quantitative yields instead
of the desired 2-phenyltetrahydrofuran 18d. These results implied
that the substituents at the 3-position played a very important role
for the 1,5-CH insertion reaction. The Thorpe–Ingold effect that
arises from gem-disubstituents seems to facilitate the cyclization
reaction.
Finally, in order to disclose that the oxygen atom in magnesium
carbenoid 4 plays a very important role for the 1,5-CH insertion
reaction, sulfoxides without ether functional groups 20a and 20b
(the substrates corresponding to 9 and 13b) were synthesized
and treated with i-PrMgCl (Scheme 4). Interestingly, the reaction
of 20a only gave olefin 22a (1,2-CH insertion product from the
magnesium carbenoid intermediate) in high yields without the de-
sired 1,5-CH insertion product 21a. The reaction of 20b gave a mix-
ture of the desired spiro[4.5]decane 21b (41%) and olefin 22b. Even
in this case, olefin 22b was the major product (49%). Interaction of
the oxygen atom with magnesium was thought to contribute to
maintaining a favorable distance between the carbenoid center
and C–H bond.6b
THF, -78 to -40°C
O
O
R
R
14a R=H (89%)
14b R=CH3 (94%)
13a R=H
13b R=CH3
Scheme 3. Treatment of methyl ether 13a and ethyl ether 13b with i-PrMgCl giving
1-oxaspiro[4.5]decanes 14.
Table 2
Synthesis of 1-oxaspiro[4.n]alkanes 16 from 15 by treatment with i-PrMgCl by the
1,5-CH insertion as the key reaction
S(O)Tol
i-PrMgCl
(3 equiv)
R1
R1
R1
R1
Cl
THF, -78 to -40°C
O
O
Ph
Ph
16
15
Entry
15
16
R1
Yield (%)
1
2
3
4
5
15a
–(CH2)3–
–(CH2)4–
–(CH2)5–
–(CH2)7–
16a
16b
16c
16d
16e
75
89
91
90
95
15b
15c
15d
15e
–(CH2)14
–
Table 3
Synthesis of 2,2,5-trisubstituted tetrahydrofurans 18 from 17 by treatment with i-
PrMgCl
In conclusion, we have developed a new procedure for a synthe-
sis of 1-oxaspiro[4.n]alkanes and 2,2,5-trisubstituted tetrahydrofu-
rans from cyclic ketones and acyclic ketones with 1,5-CH insertion
of magnesium carbenoid as the key reaction. We believe that the
chemistry presented in this paper will contribute to the synthesis
of multi-substituted tetrahydrofurans including spiro-type and
also to the chemistry of magnesium carbenoids.
S(O)Tol
i-PrMgCl
(3 equiv)
R1
R1
R1
R1
Cl
THF, -78 to -40°C
O
O
Ph
Ph
18
17
Entry
17
18
Yield (%)
R1
Acknowledgments
1
2
3
4
17a
CH3
PhCH2CH2
Ph
H
18a
18b
18c
18d
85
90
96
0a
17b
17c
17d
This work was supported by a Grant-in-Aid for Scientific
Research No. 22590021 from the Ministry of Education, Culture,
Sports, Science and Technology, Japan, and TUS Grant for Research
Promotion from Tokyo University of Science, which are gratefully
acknowledged.
a
Isopropylated product 19 was obtained in 99% yield.
Ph
O
19
References and notes
1. For monographs and reviews on chemistry of carbenes and carbenoids: (a)
Kirmse, W. Carbene Chemistry; Academic: New York, 1971; (b) Dorwald, F. Z.
Metal Carbenes in Organic Synthesis; Wiley-VCH: Weinheim, 1999; (c)Carbene
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Angew. Chem., Int. Ed. Engl. 1972, 11, 473; (e) Stang, P. J. Chem. Rev. 1978, 78, 383;
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Chem. Res. 1979, 12, 288; (h) Wynberg, H.; Meijer, E. W. Org. React. 1982, 29, 1;
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Chem. Jpn. 1986, 44, 736; (k) Oku, A. J. Synth. Org. Chem. Jpn. 1990, 48, 710; (l)
Adams, J.; Spero, D. M. Tetrahedron 1991, 47, 1765; (m) Padwa, A.; Weingarten,
Synthesis of 2,2,5-trisubstituted tetrahydrofurans 18 from
acyclic ketones
The above-mentioned procedure was carried out starting from
acyclic ketones. Thus, 1-chloropropyl p-tolyl sulfoxides bearing a
S(O)Tol
i-PrMgCl
O
O
O
O
(3 equiv)
O
O
Cl
+
THF, -78 to 0°C
R
R
R
20a R=Ph
20b R=CH3
21a R=Ph (0%)
21b R=CH3 (41%)
22a R=Ph (89%)
22b R=CH3 (49%)
Scheme 4. Treatment of sulfoxides bearing an alkane group 20a and 20b with i-PrMgCl.

T. Satoh et al. / Tetrahedron Letters 53 (2012) 2074–2077
2077
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Tetrahedron 1992, 48, 5385; (b) Sulikowski, G. A.; Cha, K. L.; Sulikowski, M. M.
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8. To a solution of i-PrMgCl (2.0 M solution in THF; 0.15 mL; 0.3 mmol) in 1 mL of
THF at À78 °C was added
a solution of 9 (45 mg; 0.1 mmol) in dry THF
dropwise with stirring. Temperature of the reaction mixture was slowly
allowed to warm to À40 °C for 1 h and the reaction was quenched by saturated
aqueous NH4Cl. The whole was extracted with CHCl3, and the product was
purified by silica gel column chromatography to give 11 (26 mg; 93%) as
colorless oil. IR (neat) 2951, 2876, 1602, 1495, 1106, 1032, 735, 701 cmÀ1 1H
;
NMR d 1.65 (2H, m), 1.75 (2H, m), 1.80–2.04 (7H, m), 2.31 (1H, m), 3.95 (4H,
m), 4.97 (1H, m), 7.23 (1H, m), 7.33 (4H, m). MS m/z (%) 274 (M+, 48), 175 (97),
118 (20), 99 (100), 86 (44), 57 (28), 31 (21). Calcd for C17H22O3: M, 274.1569.
Found: m/z 274.1566.
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Ogata, S.; Wakasugi, D. Tetrahedron Lett. 2006, 47, 7249; (c) Ogata, S.; Masaoka,
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