Environmentally friendly TPDS-mediated free radical ring expansion of α-haloalkyl cyclic β-keto esters

Article abstract of DOI:10.1016/S0040-4020(02)00241-7

Reactivities of tetraphenyldisilane (TPDS), tris(trimethylsilyl)silane, and tributyltin hydride in the radical ring expansion of α-haloalkyl cyclic β-keto esters were examined. Among these reagents, TPDS was found most effective for the preparation of medium-sized cyclic compounds in terms of yields and ring-expansion/reduction selectivity.

Full text of DOI:10.1016/S0040-4020(02)00241-7

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 3171±3175
Environmentally friendly TPDS-mediated free radical ring
expansion of a-haloalkyl cyclic b-keto esters
Masaaki Sugia and Hideo Togoa,b,p
aDepartment of Chemistry, Graduate School of Science and Technology, Chiba University, Yayoi-cho 1-33,
Inage-ku, Chiba 263-8522, Japan
bDepartment of Chemistry, Faculty of Science, Chiba University, Yayoi-cho 1-33, Inage-ku, Chiba 263-8522, Japan
Received 4 February 2002; accepted 1 March 2002
AbstractÐReactivities oftetraphenyldisilane (TPDS), tris(trimethylsilyl)silane, and tributyltin hydride in the radical ring expansion of
a-haloalkyl cyclic b-keto esters were examined. Among these reagents, TPDS was found most effective for the preparation of medium-sized
cyclic compounds in terms ofyields and ring-expansion/reduction selectivity. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
alkenones.10 These methods are ef®cient for the construction
ofmedium-sized cyclic compounds and the reaction is very
attractive and important, since these types ofring expansion
are speci®c radical reactions and may be applicable to a
wide range ofufnctional groups ofvarious ring size.
However, highly toxic tin species are required for the
preparation ofthese ring-expanded compounds. Therefore,
use ofradical reactions with organotin reagents cannot be
considered in the chemical and pharmaceutical industries,
even ifresults ofthe radical reactions for organic synthesis
are excellent and effective. Very recently, treatment of
a-halomethyl b-keto esters with SmI2 in THF in the
Recently, free radical reactions have become important in
organic synthesis, since functional group conversion of
organic compounds under mild reaction conditions is criti-
cal for the preparation of natural products and biologically
active compounds.1 Tributyltin hydride2 and tris(trimethyl-
silyl)silane3 are well-known reagents for these radical reac-
tions, though the former reagent is highly toxic and the
complete removal ofthe tin species rfom the reaction
products is dif®cult, while the latter one is a less stable oil
under aerobic conditions for storage. Radical cyclization
reactions in 5-exo-trig and 6-exo-trig manner are a most
powerful and versatile method for the construction of ®ve-
and six-membered cyclic systems.4 However, the direct
construction ofa medium-sized ring skeleton by radical
cyclization is normally not so useful because of poor yields
ofthe cyclization products. 5 Thus, the construction ofthese
compounds have been carried out by using non-radical
methods extensively.6 On the other hand, since their
pioneering work on intramolecular alkyl radical addition
to a carbonyl group with tributyltin hydride,7 Beckwith8
and Dowd9 have reported a interesting free-radical ring
expansion of a-halomethyl- and a-halopropyl cyclic
b-keto esters to one-carbon and three-carbon ring-expanded
cyclic keto esters, respectively, in 3-exo-trig and 5-exo-trig
manner and subsequent b-cleavage in re¯uxing benzene
solutions oftributyltin hydride in the presence ofAIBN.
Baldwin has also reported a radical ring expansion of
a-(haloalkyl) b-stannylcyclohexanone with tributyltin
hydride to form the corresponding ring expanded cyclo-
presence ofan activator such as MeOH, HMPA, NiI
2
was reported to give the corresponding one-carbon ring-
expanded products in good yields.11 However, this reagent
cannot be used for the three-carbon ring expansion reactions
and one-carbon extension ofacyclic a-halomethyl b-keto
esters. As a part ofour study on the synthetic application of
1,1,2,2-tetraphenyldisilane (TPDS) to organic synthesis as a
radical reagent,12 we report herein TPDS-mediated radical
ring expansion of b-haloalkyl cyclic b-keto esters to form
ring-expanded cyclic keto esters through the radical cycli-
zation ofthe initially formed carbon radicals to the carbonyl
group in exo-trig manner, followed by b-cleavage ofthe
Keywords: 1,1,2,2-tetraphenyldisilane; medium-sized cyclic ketones; ring
expansion.
p
Corresponding author. Fax: 181-43-290-2874;
e-mail: togo@scichem.schiba-u.ac.jp
Scheme 1.
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00241-7

3172
M. Sugi, H. Togo / Tetrahedron 58 (2002) 3171±3175
Table 1. Ring expansion ofcyclic b-keto ester 1a-i with various radical
reagents
Table 3. Reactivities ofTPDS, (TMS) 3SiH, and Bu3SnH in ring expansion
ofcyclic b-keto esters 1a
Entry
Reagent (equiv.)
Solvent
Yields (%)
Entry
m, 1a
1 (i)
Reagenta
Yields (%)
2a-i
3a-i
2a
3a
1
2
3
4
5
6
7
8
9
H3PO2 (5.0)
PhSiH3 (1.2)
EtOHa
ca. 20
3c
ca. 30
0
1
2
3
Ph4Si2H2
(TMS)3SiH
Bu3SnH
66
64
65
Trace
Trace
Trace
Toluneb
Toluneb
Tolunea
Tolunea
Tolunea
Tolunea,e
AcOEta
AcOEtf
Ph2SiH2 (1.2)
Bu3SnH (1.2)
(TMS)3SiH (1.2)
Ph4Si2H2 (1.2)
Ph4Si2H2 (1.2)
Ph4Si2H2 (1.2)
Ph4Si2H2 (1.2)
47d
65
Trace
Trace
Trace
Trace
Trace
Trace
20
4
2 (ii)
Ph4Si2H2
0
86
64
66
5
6
7
3 (iii)
Ph4Si2H2
(TMS)3SiH
Bu3SnH
47
25
25
42
78
61
59
Trace
3g
8
4 (iv)
Ph4Si2H2
5
60
a
Slow addition ofAIBN with a dropping funnel.
b
c
d
e
f
a
Slow addition ofbenzoyl peroxide with a dropping funnel.
Compound 1a-i was recovered in 81% yield.
Compound 1a-i was recovered in 36% yield.
Mg(ClO4)2 was added.
Et3B was used as an initiator, and the reaction was carried out at rt.
Compound 1a-i was recovered in 64% yield.
Substrate/radical reagent/AIBNˆ1/1.2/3±5.
g
2. Results and discussion
Ring expansion ofmethyl 1-bromomethyl-2-oxocyclopen-
tanoate with various radical reagents, such as phosphinic
acid, phenylsilane, diphenylsilane, tributyltin hydride, tris-
(trimethylsilyl)silane, and TPDS, in the presence ofAIBN,
Et3B, or peroxide was carried out, and the results are shown
in Table 1.
resulting bicyclic alkoxy radical intermediate (Scheme 1).
The reactivities were compared with those ofother typical
radical reagents such as tributyltin hydride, tris(trimethyl-
silyl)silane, etc. under the same conditions.
All reactions were carried out by the dropwise addition of
a radical initiator to the re¯uxing solution ofcyclic
bromoalkyl b-keto esters in the presence ofa radical reagent
through a dropping funnel. The results suggest that phenyl-
silane did not work at all (entry 2), and phosphinic acid
showed moderate reactivity, though the ratio ofring-
expanded compound 2a-i to the direct reduction product
3a-i was poor (entry 1).
Table 2. Reactivities ofTPDS, (TMS) 3SiH, and Bu3SnH in ring expansion
ofcyclic b-keto esters 1
Entry
n
R
X 1
Reagenta
Yields (%)
Surprisingly, diphenylsilane gave the ring-expanded
product in moderate yield together with a trace amount of
the direct reduction product (entry 3). However, much
excess amount ofperoxide is required. TPDS, tributyltin
hydride, and tris(trimethylsilyl)silane showed almost the
same reactivity to give the ring-expanded compound 2a-i
in good yields, together with trace amounts ofthe direct
reduction product 3a-i (entries 4±6) and starting material
1a-i (,10%). So, here, there is no difference in the reac-
tivity among TPDS, tributyltin hydride, and tris(trimethyl-
silyl)silane. Moreover, there is no effect of a Lewis acid
such as Mg(ClO4)2 and Yb(OTf)3 on the formation of
ring-expanded ketones (2a-i, entry 7). The reaction initiated
by Et3B at room temperature markedly reduced the forma-
tion ofthe ring-expanded ketone 2a-i and the starting
bromide 1a-i was mainly recovered (entry 9).
2
3
1
2
3
4
5
6
1
Me
Me
Br (1a)
Ph4Si2H2
(TMS)3SiH
Bu3SnH
Ph4Si2H2
(TMS)3SiH
Bu3SnH
66
64
65
64
65
47
Trace
Trace
Trace
Trace
Trace
22
I
7
8
9
2
3
4
8
Et
Br (1b)
Br (1c)
Br (1d)
I (1e)
Ph4Si2H2
(TMS)3SiH
Bu3SnH
67
65
20
Trace
Trace
68
10
11
12
Me
Me
Me
Ph4Si2H2
(TMS)3SiH
Bu3SnH
64
52
24
Trace
18
63
13
14
15
Ph4Si2H2
(TMS)3SiH
Bu3SnH
48
48
39
Trace
21
45
16
17
18
Ph4SiH2
(TMS)3SiH
Bu3SnH
53
54
15
9
28
57
The effect of ring size in the TPDS-mediated ring expansion
was examined and the reactivity was compared with those
oftris(trimethylsilyl)silane and tributyltin hydride as shown
in Table 2. Totally, TPDS gave the ring expansion products
a
Substrate/radical reagent/AIBNˆ1/1.2/3±5.

M. Sugi, H. Togo / Tetrahedron 58 (2002) 3171±3175
3173
Table 4. Reactivities ofTPDS, (TMS) 3SiH, and Bu3SnH in chain extension
ofacyclic b-keto esters 4
4. Experimental
4.1. General
1H NMR spectra were recorded on 400 and 500 MHz spec-
trometers, and 13C NMR spectra were recorded on 100 and
125 MHz spectrometers. Chemical shifts are reported as
ppm down®eld from tetramethylsilane (TMS) in d units.
J-Values are given in Hz. 3-Nitrobenzyl alcohol was used
as the matrix ofmass spectra (FAB). Kieselgel 60 F254 was
used for TLC, Silica Gel 60 (Kanto Kagaku) was used for
column chromatography, and Wakogel B-5F was used for
preparative TLC. Solvents were puri®ed and dried by
standard techniques.
Entry
m, 4
Reagenta
Yields (%)
5
6
1
2
3
1 (i)
Ph4Si2H2
(TMS)3SiH
Bu3SnH
75
76
42
Trace
Trace
36
4.2. General procedure using TPDS with Et3B
4
5
6
3 (iii)
Ph4Si2H2
(TMS)3SiH
Bu3SnH
31
34
7
37
43
71
Et3B in THP (0.6 ml, 1 mol/l) was added into a mixture of
a-haloalkyl b-keto ester (0.5 mmol) and TPDS (0.6 mmol)
in a solvent (10 ml) under aerobic conditions.
a
Substrate/radical reagent/AIBNˆ1/1.2/3±5.
After stirring for 4 h, the same amount of Et3B was added
again and the obtained mixture was stirred overnight at
room temperature. After the reaction, the solvent was
removed and the residue was puri®ed by column chroma-
tography using a mixture ofhexane and ethyl acetate (5:1).
2 in better yields than those obtained with tributyltin
hydride, though it showed almost the same reactivity as
that oftris(trimethylsilyl)silane. The efect ofthe arm size
in the bromoalkyl group was studied as shown in Table 3.
4.3. General procedure using TPDS with AIBN
Again, the same reactivity ofbromomethyl compound 1a-i
was observed in TPDS, tris(trimethylsilyl)silane, and tri-
butyltin hydride (entries 1±3), and these three reagents did
not give the two-carbon ring-expanded product at all with
compound 1a-ii; instead, the direct reduction product was
formed (entry 4). Reaction of 3-bromopropyl b-keto ester
1a-iii with TPDS gave a three-carbon ring-expanded
product in moderate yield, though the same reactions with
tris(trimethylsilyl)silane and tributyltin hydride were not so
effective (entries 5±7). These results come from the fact
that Si±H bond in tris(trimethylsilyl)silane is 5 kcal/mol
stronger than Sn±H bond in tributyltin hydride, and prob-
ably Si±H bond in TPDS is slightly stronger than that in
tris(trimethylsilyl)silane.3
AIBN (1.5±2.5 mmol) in toluene (10±15 ml) was added
dropwise over 8 h using a dropping funnel to a re¯uxing
solution of a-haloalkyl b-keto ester (0.5 mmol) and TPDS
(0.6 mmol) in toluene (10 ml) and the obtained mixture was
stirred overnight at the same temperature. After the reaction,
the solvent was removed and the residue was puri®ed by
column chromatography using a mixture ofhexane and
ethyl acetate (5:1±10:1).
4.4. General procedure using tris(trimethylsilyl)silane
and AIBN
AIBN (1.5 mmol) in toluene (10 ml) was added dropwise
over 8 h using a dropping funnel to a re¯uxing solution of
a-haloalkyl b-keto ester (0.5 mmol) and (TMS)3SiH
(0.6 mmol) in toluene (10 ml) and the obtained mixture
was stirred overnight at the same temperature. The mixture
was puri®ed as described in the general procedure using
TPDS and AIBN.
Chain extension ofacyclic bromoalkyl b-keto esters was
carried out and the reactivity was compared with those of
tris(trimethylsilyl)silane and tributyltin hydride as shown in
Table 4. Here again, TPDS showed almost the same reac-
tivity as those with tris(trimethylsilyl)silane, and tributyltin
hydride showed poor results (entries 4±6).
4.5. General procedure using tributyltin hydride and
AIBN
3. Conclusion
AIBN (1.5 mmol) in toluene (10 ml) was added dropwise
over 8 h using a dropping funnel to a re¯uxing solution
of a-haloalkyl b-keto ester (0.5 mmol) and Bu3SnH
(0.6 mmol) in toluene (10 ml) and the obtained mixture
was stirred overnight at the same temperature. The mixture
was puri®ed as described in the general procedure using
TPDS and AIBN.
TPDS and tris(trimethylsilyl)silane generally showed no
remarkable difference in their good reactivities towards
the radical ring expansion reaction, while the same
reaction with tributyltin hydride gave poor yields ofring-
enlarged products. In view ofits stability (stable crystals
in air), less toxicity, and easy handling, TPDS is a useful
reagent for the preparation of medium-sized ring
compounds through the radical ring expansion of
a-haloalkyl cyclic b-keto esters.
4.5.1. Methyl 3-oxocyclohexanoate 2a-i. Oil; IR (neat)
;
2950, 2870, 1740, 1720 cm21 1H NMR (400 MHz,
CDCl3) dˆ3.71 (3H, s), 2.81 (1H, m), 2.56 (2H, d,

3174
M. Sugi, H. Togo / Tetrahedron 58 (2002) 3171±3175
Jˆ8.2 Hz), 2.44±2.28 (2H, m), 2.16±2.02 (2H, m), 1.90±
1.69 (2H, m); 13C NMR (100 MHz, CDCl3) dˆ209.2 (q),
174.2 (q), 52.1 (p), 43.1 (s), 43.1 (t), 40.2 (s), 27.7 (s), 24.5
(s); MS (EI): m/z 156; HRMS (EI) Found: m/z 156.0789,
Calcd for C8H12O3: Mˆ156.0786.
2980, 2940, 1740, 1720 cm21; 1H NMR (400 MHz, CDCl3)
dˆ4.13 (2H, q, Jˆ7.0 Hz), 2.47±2.35 (5H, m), 1.70±1.30
(4H, m), 1.26 (3H, t, Jˆ7.0 Hz), 1.15 (3H, d, Jˆ7.0 Hz),
1.05 (3H, t, Jˆ7.3 Hz); 13C NMR (100 MHz, CDCl3) dˆ
211.3 (q), 176.6 (q), 60.2 (s), 42.1 (s), 39.4 (t), 35.8 (s), 33.2
(s), 21.5 (s), 17.0 (p), 14.2 (p), 7.8 (p); MS (EI): m/z 185;
HRMS (EI) Found: m/z 200.1412, Calcd for C11H20O3:
Mˆ200.1412.
4.5.2. Ethyl 3-oxocycloheptanoate 2b. Oil; IR (neat) 2980,
2940, 2860, 1740, 1700 cm21; 1H NMR (400 MHz, CDCl3)
dˆ4.15 (2H, q, Jˆ7.2 Hz), 2.81 (1H, dd, Jˆ11.0, 15.6 Hz),
2.73±2.66 (2H, m), 2.58±2.44 (2H, m), 2.10 (1H, m), 1.98±
1.61 (5H, m), 1.26 (3H, t, Jˆ7.2 Hz); 13C NMR (100 MHz,
CDCl3) dˆ212.2 (q), 174.5 (q), 60.8 (s), 45.5 (s), 43.5 (s),
41.2 (t), 33.2 (s), 28.3 (s), 27.9 (s), 14.1 (p); MS (FAB): m/z
185; HRMS (FAB) Found: m/z 185.1160, Calcd for
C10H17O3: M1Hˆ185.1178.
Acknowledgements
We are grateful for the ®nancial support from a Grant-in-
Aid for Developmental Scienti®c Research (13554028)
from the Ministry of Education, Science, Sport and Culture
ofJapan.
4.5.3. Methyl 3-oxocyclooctanoate 2c. Oil; IR (neat) 2940,
1
2860, 1730, 1700 cm21; H NMR (400 MHz, CDCl3) dˆ
3.70 (3H, s), 2.94 (1H, s), 2.94 (1H, m), 2.80 (1H, t, Jˆ
13.2 Hz), 2.42 (2H, m), 2.04±1.63 (8H, m); 13C NMR
(100 MHz, CDCl3) dˆ214.5 (q), 174.8 (q), 51.9 (p), 42.9
(s), 42.8 (s), 42.7 (t), 29.7 (s), 27.2 (s), 24.8 (s) 23.2 (s); MS
(EI): m/z 184; HRMS (EI) Found: m/z 184.1085, Calcd for
C10H16O3: Mˆ184.1099.
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4.5.4. Methyl 3-oxocyclononanoate 2d. Oil; IR (neat)
;
2930, 2870, 1740, 1700 cm21 1H NMR (400 MHz,
CDCl3) dˆ3.66 (3H, s), 3.02 (1H, m), 2.85 (1H, dd, Jˆ
11.3, 13.8 Hz), 2.63 (1H, dd, Jˆ2.7, 13.8 Hz), 2.49 (2H,
m), 1.96±1.32 (10H, m); 13C NMR (100 MHz, CDCl3)
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(t), 29.2 (s), 25.6 (s), 25.5 (s), 24.1 (s), 22.9 (s); MS (EI):
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2930, 2860, 1740, 1710 cm21 1H NMR (400 MHz,
CDCl3) dˆ3.69 (3H, s), 2.98 (1H, m), 2.85 (1H, dd,
Jˆ8.9, 16.9 Hz), 2.74 (1H, dd, Jˆ3.4, 16.9 Hz), 2.55 (1H,
m), 2.35 (1H, m), 1.79±1.11 (18H, m); 13C NMR (100 MHz,
CDCl3) dˆ210.2 (q), 175.7 (q), 51.9 (p), 43.5 (s), 42.5 (s),
39.6 (t), 29.5 (s), 26.2 (s), 26.14 (s), 26.11 (s), 25.5 (s), 24.6
(s), 24.3 (s), 23.8 (s), 23.7 (s); MS (EI): m/z 254; HRMS (EI)
Found: m/z 254.1863, Calcd for C15H26O3: Mˆ254.1882.
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acrylates with Bu3SnH/AIBN gave the corresponding
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4.5.6. Methyl 5-oxocyclooctanoate 2a-iii. Oil; IR (neat)
;
2950, 2860, 1740, 1700 cm21 1H NMR (400 MHz,
CDCl3) dˆ3.64 (3H, s), 2.65±2.26 (4H, m), 2.18±1.92
(5H, m), 1.87±1.50 (4H, m); 13C NMR (100 MHz, CDCl3)
dˆ210.9 (q), 176.7 (q), 51.6 (p), 41.9 (t), 41.8 (s), 29.9 (s),
24.4 (s); MS (FAB): m/z 185; HRMS (FAB) Found: m/z
185.1167, Calcd for C10H17O3: M11ˆ185.1178.
4.5.7. Ethyl 2-methyl 4-oxohexanoate 5-i. Oil; IR (neat)
2980, 2940, 1730, 1720 cm21; 1H NMR (400 MHz, CDCl3)
dˆ4.13 (2H, q, Jˆ7.1 Hz), 2.55±2.37 (3H, m), 2.58±2.44
(2H, m), 1.25 (3H, t, Jˆ7.1 Hz), 1.18 (3H, d, Jˆ7.0 Hz),
1.06 (3H, t, Jˆ7.2 Hz); 13C NMR (100 MHz, CDCl3) dˆ
209.5 (q), 175.9 (q), 60.6 (s), 45.3 (s), 36.1 (s), 34.8 (t), 17.2
(s), 14.2 (s), 7.7 (s); MS (EI): m/z 172; HRMS (EI) Found:
m/z 172.1094, Calcd for C9H16O3: Mˆ172.1098.
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4.5.8. Ethyl 2-methyl 6-oxooctanoate 5-iii. Oil; IR (neat)

M. Sugi, H. Togo / Tetrahedron 58 (2002) 3171±3175
3175
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