A new synthesis of α,α-disubstituted carbonyl compounds from carbonyl compounds with one-carbon homologation

Article abstract of DOI:10.1016/j.tetlet.2004.04.154

Lithium α-sulfinyl carbanions of 1-chloroalkyl p-tolyl sulfoxides were reacted with carbonyl compounds to afford adducts in high to quantitative yields. The adducts were treated with t-BuMgCl or LDA to give magnesium or lithium alkoxides, which were treated with i-PrMgCl or t-BuLi to afford the enolate with one-carbon elongation through β-oxido carbenoids. The enolate intermediates were found to be able to be trapped with electrophiles to give α,α-disubstituted carbonyl compounds in moderate to good yields. As a whole, this procedure offers a new and good method for synthesis of α,α-disubstituted carbonyl compounds from carbonyl compounds with one-carbon homologation in only two synthetic steps.

Full text of DOI:10.1016/j.tetlet.2004.04.154

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4859–4864
A new synthesis of a,a-disubstituted carbonyl compounds from
carbonyl compounds with one-carbon homologation
Tsuyoshi Satoh* and Kohsuke Miyashita
Department of Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
Received 24 March 2004; revised 21 April 2004; accepted 23 April 2004
Available online 18 May 2004
Abstract—Lithium a-sulfinyl carbanions of 1-chloroalkyl p-tolyl sulfoxides were reacted with carbonyl compounds to afford adducts
in high to quantitative yields. The adducts were treated with t-BuMgCl or LDA to give magnesium or lithium alkoxides, which were
treated with i-PrMgCl or t-BuLi to afford the enolate with one-carbon elongation through b-oxido carbenoids. The enolate
intermediates were found to be able to be trapped with electrophiles to give a,a-disubstituted carbonyl compounds in moderate to
good yields. As a whole, this procedure offers a new and good method for synthesis of a,a-disubstituted carbonyl compounds from
carbonyl compounds with one-carbon homologation in only two synthetic steps.
Ó 2004 Elsevier Ltd. All rights reserved.
New development of efficient methods for construction
of organic compounds with more than two carbon–
carbon bond-formations is obviously a most important
challenge in synthetic organic chemistry. Tandem or
cascade reactions, in which several transformations are
operated in a single synthetic step, are examples of one
such methodology and have received much attention
these days.1 Another example is the trapping of the
reactive intermediate in a reaction with several reagents
to get over two carbon–carbon bonds in one flask.
one-carbon homologating agent.3 Cohen and co-work-
ers used bis(phenylthio)methyllithium,4 and we used
lithium a-sulfinyl carbanion of 1-chloroalkyl aryl sulf-
oxides as one-carbon homologating agents.5
All these reactions were expected to proceed via enolates
3. If these enolates 3 could be trapped with electrophiles,
a-substituted carbonyl compounds would be expected to
be produced; however, no such investigations have been
reported.
The rearrangement of b-oxido carbenoids 2, which were
derived from carbonyl compounds 1, is reported to be
a useful reaction for one-carbon homologation of
carbonyl compounds 1 to 4, including one-carbon ring-
expansion of cyclic ketones (Scheme 1).2 Nozaki and
co-workers and Normant and co-workers used di-
chloromethyllithium and dibromomethyllithium as a
Recently, we reinvestigated our homologation of car-
bonyl compounds 1 with 1-chloroalkyl aryl sulfoxides 5
as homologating agents.5 Especially, we focused our
attention on trapping the enolate intermediates 8, which
were derived from the adducts 6 via the rearrangement
of b-oxido carbenoids 7, and it was found that the
intermediates 8 indeed could be trapped with some
R1 OLi
R1
O
H
R1
R2
H
2
R1
OLi
O
R2
R2
:
C
H
R2
H
1
3
4
Scheme 1.
Keywords: Sulfoxide; Sulfoxide–metal exchange; b-oxido carbenoid; Homologation; a,a-Disubstituted carbonyl compound.
* Corresponding author. Tel.: +81-3-5228-8272; fax: +81-3-3235-2214; e-mail: tsatoh@ch.kagu.tus.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.154

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T. Satoh, K. Miyashita / Tetrahedron Letters 45 (2004) 4859–4864
O
R3CHSAr
-
R1
R2
9
O
R1
R2
O
C
-
R1
R1 OH
S(O)Ar
R3
Cl
1) Base
2)
R1
O
E
5
O
R3
:
R3
R2
R2
R2
R-Metal
E
R3
Cl
1
8
7
6
R-Metal = i-PrMgCl, t-BuLi
Scheme 2.
electrophiles to afford the a,a-disubstituted carbonyl
compounds 9 with one-carbon homologation (Scheme
2).
kinds of cyclic ketones and the results are summarized in
Table 1.
As shown in Table 1, the adducts 11 derived from 5-
membered ketone to 15-membered ketone gave the
2-methylcycloalkanones with one-carbon expansion in
52–82% chemical yields. The results for the quenching of
this reaction with CD3OD are quite interesting. In the
cases in entries 1–3 and 6, 2-deuterated cyclic ketones 14
in good to high deuterium incorporation were obtained.
No regioisomer was obtained in these cases. From these
results it was anticipated that when this reaction is
quenched with some electrophiles, 2,2-disubstituted
ketones could be obtained. In contrast to these results,
the reaction shown in entries 4 and 5 did not give sat-
isfactory deuterium incorporation. The results were
found not to be experimental error. We investigated the
proton source for these reactions; however, at this time
the real reason for this low deuterium incorporation is
still obscure.
First, we reinvestigated our homologation of ketones 10
through the adducts 11 with various bases and alkyl-
metals, and the magnesium b-oxido carbenoids 12 were
found to give better yields compared with the former
conditions (LDA and t-BuLi).5 The representative
reaction is as follows (see Table 1). To a solution of the
adduct 11, which was synthesized from ketone 10 and
lithium a-sulfinyl carbanion of 1-chloroethyl p-tolyl
sulfoxide at )70 °C in almost quantitative yield, in THF
at )45 °C was added t-BuMgCl (1.2 equiv) and the
reaction mixture was stirred for 10 min. By this treat-
ment, magnesium alkoxide was formed. To this solution
was added 2 equiv of i-PrMgCl and the temperature of
the reaction mixture was allowed to warm to room
temperature. The sulfoxide–magnesium exchange reac-
tion6 takes place to afford the magnesium carbenoid 12,
which rearranges to the magnesium enolate 13. Finally,
the reaction was quenched by adding excess CD3OD to
give 2-deuterio-2-methylcycloalkanone 14 in good
chemical yield. The study was carried out by using six
In any event, several electrophiles were added to the
enolate intermediates 13 and the results are summarized
in Table 2. We selected three adducts 11, which were
Table 1. Synthesis of 2-deuterio-2-methylcycloalkanones 14 from cycloalkanones 10 with one-carbon homologation
TolS(O)CHCH3
OH
O
S(O)Tol
CH3
1) t-BuMgCl (1.2 eq)
R
R
Cl
Cl
2) i-PrMgCl (2 eq)
n
n
-45 °C ~ r.t.
11
10
R
R
OMgCl
MgCl
CH3
OMgCl
CH3
O
Rearrangement
-MgCl2
CD3OD
R
D
CH3
Cl
n
n
n
14
12
13
Entry
Cyclic ketone 10
14
Yield (%)
D
-content (%)a
1
2
70
75
93
95
O
O
O
O
3
4
5
6
Cyclooctanone
Cyclodecanone
54
52
82
78
97
65
51
88
Cyclododecanone
Cyclopentadecanone
a The deuterium incorporation was measured by 1H NMR.

T. Satoh, K. Miyashita / Tetrahedron Letters 45 (2004) 4859–4864
4861
Table 2. Synthesis of 2-methyl-2-(substituted)cycloalkanones 15 and enol carbonates 16 from cycloalkanones 10 with one-carbon homologation
OH
O
R
R
S(O)Tol
CH3
R
O
OE
1) t-BuMgCl (1.2 eq)
2) i-PrMgCl (2 eq)
-45 °C ~ r.t.
3) Electrophile (2 eq)
R
E
or
Cl
n
n
CH3
CH3
n
n
10
11
15
16
Entry
Cyclic ketone 10
Electrophile
CH3CH2CHO
ClCOOC2H5
CH3CH2CHO
PhCHO
Product
Yield (%)
38
O
1
2
3
4
5
6
15a
16a
O
CH(OH)C2H5
CH3
OCOOC2H5
40
71
40
74
63
CH3
O
O
O
O
O
15b
15c
16b
15d
CH(OH)C2H5
O
CH3
O
O
O
CH(OH)Ph
CH3
OCOOC2H5
O
O
ClCOOC2H5
PhCOCl
CH3
O
O
O
COPh
CH3
O
O
7
8
9
CH3CH2CHO
ClCOOC2H5
PhCOCl
15e
15f
15g
73
33
71
CH(OH)C2H5
10
10 CH3
O
COOC2H5
10 CH3
O
COPh
10 CH3
synthesized from 5, 6, and 15-membered cyclic ketones
and 1-chloroethyl p-tolyl sulfoxide. Propionaldehyde,
benzaldehyde, acetone, ethyl chloroformate, and ben-
zoyl chloride were selected as the representative exam-
ples for the electrophiles. The two aldehydes reacted
with the enolate intermediates to give the adducts 15
(entries 1, 3, 4, and 7); however, the yields were found to
be somewhat variable. The reaction with acetone did not
give any adduct and only 2-methylcycloalkanones (15;
E ¼ H) were obtained. Benzoyl chloride was also found
to be effective in this procedure to give the benzoylated
product in up to 71% yield (entries 6 and 9). The reac-
tion with ethyl chloroformate gave somewhat different
results. In case of the reaction with 11 prepared from
five and six-membered ketones, the products were found
to be the enol carbonates 16a and 16b.7 No expected
ketones having ethoxycarbonyl group at the a-position
was obtained (entries 2 and 5). However, the reaction
with 11 prepared from 15-membered ketone gave the 16-
membered ketone having ethoxycarbonyl group at a-
position 15f,8 though the yield was somewhat low (entry
8).
The results in entries 1 and 2 are quite interesting. If one
treats 2-tetralone with a base followed by some elec-
trophiles, the electrophiles must be substituted on the
carbon between the carbonyl carbon and the phenyl
ring, because the hydrogen on the carbon is more acidic
than the hydrogen on the carbon present on the other
side of the carbonyl carbon. The compounds 15a and
16a in entries 1 and 2 are fairly difficult to synthesize
from 2-tetralone by other reactions.
Encouraged by the results described above, we investi-
gated the reaction with 1-chloroalkyl p-tolyl sulfoxides
having a longer carbon chain other than the methyl
group (Scheme 3). The adduct 17, derived from 1,4-
cyclohexanedione mono-ethylene ketal and 1-chloropropyl

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T. Satoh, K. Miyashita / Tetrahedron Letters 45 (2004) 4859–4864
TolS(O)CHCH2CH3
Cl
O
OH
OH
O
O
O
O
O
O
1) t-BuMgCl (1.2 eq)
+
O
CH2CH3
S(O)Tol
O
C2H5
2) i-PrMgCl (2 eq)
CH3
-45 °C ~ r.t.
O
Cl
19(65%)
17
18 (35%)
1) LDA (1.2 eq)
2) t-BuLi (4 eq)
-75 °C (64%)
Scheme 3.
p-tolyl sulfoxide in quantitative yield, was treated under
the conditions described in Table 2. However, we
obtained the desired product 18 (35%) with an allylic
alcohol 19 (65%) as a main product. We applied our
former conditions (LDA–t-BuLi)5 and the desired
product 18 was obtained in 64% yield.
procedure. However, comparing these results with those
in Table 2, entries 3–6, the yields are somewhat lower. In
these cases, the reaction with ethyl chloroformate gave
the ketones having ethoxycarbonyl group at a-position
(21c and 21f) were obtained without the enol carbon-
ates.9
By using the former conditions,5 the effect of the alkyl
substituents in this procedure was investigated and the
results are summarized in Table 3. The adducts 17
having an ethyl group and the adduct 20 having a 4-
phenylbutyl group as R were used. As shown by the
results in Table 3, entries 1–3, 2,2-disubstituted cyclo-
heptanones having an ethyl group were obtained from
46–64% yields, which indicated the effectiveness of this
Entry 5 in Table 3 shows that the yield of one-carbon
expanded 2,2-disubstituted cycloheptanones having a
4-phenylbutyl group was markedly diminished. These
results could be explained by the steric hindrance of the
4-phenylbutyl group.
Finally, this procedure was extended to aldehydes
(Table 4). The addition reaction of 1-chlorobutyl p-tolyl
Table 3. Synthesis of 2-alkyl-2-(substituted)cycloalkanones 21 from the adduct 17 and 20 with one-carbon homologation
OH
O
E
O
O
O
O
1) LDA (1.2 eq)
R
2) t-BuLi (4 eq)
R
S(O)Tol
3) Electrophile (4 eq)
Cl
21
17 R=CH2CH3
20 R=(CH2)4Ph
Entry
17 and 20
Electrophile
21
R
Yield (%)
O
O
1
2
3
4
5
6
CH3CH2
CH3CH2
CH3CH2
Ph(CH2)4
Ph(CH2)4
Ph(CH2)4
CD3OD
21a
64 (
61
D
¼ 99%)
D
O
CH2CH3
O
O
CH3CH2CHO
ClCOOC2H5
CD3OD
21b
CH(OH)C2H5
CH2CH3
O
O
O
21c
46
COOC2H5
CH2CH3
O
O
O
21d
66 (
13
D
¼ 94%)
D
O
(CH2)4Ph
O
O
CH3CH2CHO
ClCOOC2H5
21e
CH(OH)C2H5
(CH2)4Ph
O
O
O
21f
44
COOC2H5
(CH2)4Ph
O

T. Satoh, K. Miyashita / Tetrahedron Letters 45 (2004) 4859–4864
4863
Table 4. Synthesis of a-substituted ketones 25 and a-substituted aldehydes 26 from the adducts 23 and 24 with one-carbon elongation
TolS(O)CHC3H7
OH
OH
Cl
Cl
Cl
RCHO
22a R=CH3O
H
R
+
C3H7
C3H7
R
H
S(O)Tol
S(O)Tol
-
22b R=
PhCH2CH2
23
24
1) LDA (1.2 eq)
R
COCHC3H7
E
23a, 23b, 24b
2) t-BuLi (4 eq)
3) Electrophile (4 eq)
25
R
C(E)CHO
C3H7
24a
26
Entry
Adduct
Electrophile
Product
Yield (%)
CH3O
CH3O
COCHC3H7
D
1
2
23a
23a
CD3OD
80 (
75a
D
¼ 95%)
COCHC3H7
CH3CH2CHO
CH(OH)C2H5
OCOOC2H5
C=CHC3H7
3
4
5
23a
24a
24a
ClCOOC2H5
CD3OD
67b
76 (
59
CH3O
CH3O
C(D)CHO
C3H7
D
¼ 82%)
CH3O
CHCHO
C3H7
CH3CH2CHO
PhCH2CH2 COCHC3H7
CH(OH)C2H5
6
7
23b
24b
CH3CH2CHO
CH3CH2CHO
54
65
a A mixture of two diastereomers (1:2.3).
b A single isomer.
sulfoxide to p-anisaldehyde 22a and 3-phenylpropanal
22b afforded two adducts 23 and 24 in quantitative
yields.5 In the former study, treatment of 23a and 24a
with LDA followed by t-BuLi gave the ketone 25a
(E ¼ H) and aldehyde 26a (E ¼ H), respectively, in high
stereospecificity.5 On the other hand, the reaction of
both 23b and 24b gave ketone 25b (E ¼ H) in high
stereoselectivity.5
We are continuing to study the scope and limitations of
this procedure and the applications to new synthetic
methods, which will be reported in due course.
Acknowledgements
This work was supported by a Grant-in-Aid for Scien-
tific Research from the Ministry of Education, Culture,
Sports, Science and Technology, Japan, which is grate-
fully acknowledged. We thank Mr. Kei Kobayashi for
his assistance in this study.
We tried to trap the enolate intermediate of the reaction
of 23a, 23b, and 24b with CD3OD, propionaldehyde,
and ethyl chloroformate (Table 4; entries 1–3, 6, and 7).
Quite good results were obtained from the trial and a,a-
disubstituted ketones were produced from 54% to 80%.
Again, the product in this reaction with ethyl chloro-
formate was found to be the enol carbonate (entry 3).10
In contrast to these results, when the reaction of 24a was
quenched with CD3OD and propionaldehyde, only
deuterated aldehyde was obtained in 76% yield (entry 4).
The reaction with propionaldehyde did not give the
desired adduct but protonated aldehyde 26a (E ¼ H)
was obtained in 59% yield (entry 5).
References and notes
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Weingarten, M. D. Chem. Rev. 1996, 96, 223; (e) Grigg, R.
Ed. ‘Cascade Reactions’ Tetrahedron Symposia-in-Print

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1752 cmꢀ1 13C NMR d 153.2 (CO). 16b: Colorless oil;
;
IR (neat) 1750 cmꢀ1
8. Ketone 15f: Colorless oil; IR (neat) 1713, 1741 cmꢀ1
NMR d 173.6 (CO for ester), 207.9 (CO for ketone).
9. The ketones 21c and 21f. 21c: Colorless oil; IR (neat)
1711, 1733 cmꢀ1 13C NMR d 172.1 (CO for ester), 209.6
(CO for ketone). 21f: Colorless oil; IR (neat) 1711,
1732 cmꢀ1 13C NMR 172.2 (CO for ester), 209.5 (CO
for ketone).
10. The enol carbonate in Table 4, entry 3: Colorless oil; IR
(neat) 1760 cmꢀ1 13C NMR d 159.5 (CO).
;
13C NMR d 153.5 (CO).
;
13C
;
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;
;