Free radical ring expansion and chain extension of 1,3-diketones

Article abstract of DOI:10.1016/j.tetlet.2005.05.036

Free radical-promoted one carbon ring expansion and chain extension of 1,3-diketones including 1,3-diarylpropane-1,3-diones and 2-aroyl-3,4-dihydro-2H- naphalen-1-one to generate corresponding 1,4-diketones are described.

Full text of DOI:10.1016/j.tetlet.2005.05.036

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4727–4729
Free radical ring expansion and chain extension of 1,3-diketones
Xue-Jun Mu,a Jian-Ping Zou,a,* Zhi-Tao Wanga and Wei Zhangb,*
aKey Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry and Chemical Engineering, Suzhou University,
1 Shizi Street, Suzhou, Jiangsu 215006, China
bFluorous Technologies, Inc., University of Pittsburgh Applied Research Center, 970 William Pitt Way, Pittsburgh, PA 15238, USA
Received 17 April 2005; revised 9 May 2005; accepted 11 May 2005
Available online 31 May 2005
Abstract—Free radical-promoted one carbon ring expansion and chain extension of 1,3-diketones including 1,3-diarylpropane-1,3-
diones and 2-aroyl-3,4-dihydro-2H-naphalen-1-one to generate corresponding 1,4-diketones are described.
Ó 2005 Elsevier Ltd. All rights reserved.
Reactions to increase the chain length or ring size of a
molecule with existing functional groups have general
interest in organic synthesis.1 Over the years, numerous
ring expansion reactions have been developed.2 Among
them, the Dowd–Beckwith reaction of cyclic b-keto es-
ters3 and ring expansion of fused-cyclobutanones4,5 are
two well-known free radical reaction systems (Scheme
1). These reactions start with an alkyl radical cyclization
to a carbonyl followed by a b-scission of the alkoxy rad-
ical to produce the desired product. The ester group and
the strained-ring system are critical for the ring expan-
sion process.6 In this communication, we report exam-
ples of chain extension and ring expansion reactions of
the 1,3-diketone system. A keto group of the 1,3-diketone
plays a similar role as the ester group in the ring expan-
sion of b-keto esters. Our method converts readily avail-
able 1,3-diketones to synthetically useful cyclic and
acyclic 1,4-diketones. To our knowledge, such reactions
have never been reported in the literature.
The one carbon chain extension of 2-(iodomethyl)-2-
methyl-1,3-diphenyl-propane-1,3-dione 3a was first at-
tempted. This compound was prepared by methylation
of 1,3-diphenylpropane-1,3-dione 1a followed by
iodomethylation of 2a (Scheme 2). The free radical reac-
tion of 3a was promoted by Bu3SnH with a catalytic
amount of 2,20-azobis(2-methylpropionitrile) (AIBN)
as an initiator to give one carbon chain extension
product 4a in 76% yield. This method was then extended
to other 2-(iodomethyl)-2-methyl-1,3-diarylpropane-1,3-
diones with different substitution groups on the benzene
rings (Table 1). We found these substitution groups
have significant affect on the yield of iodomethyl-
ation reactions. 2-Methyl-1,3-bis(p-methoxyphenyl) and
CO2R
CO2R
CO2R
.
.
O
.
O
.
O
O
O
O
O
O
CH2I2
R2
CH3I
1
R
R2
R1
.
1a-e
2a-e
O
.
O
O
O
R2
O
Scheme 1. Ring expansion of a b-keto ester radical and a cyclobuta-
none radical.
Bu3SnH
AIBN
R2
R1
I
R1
O
Keywords: 1,3-Diketones; 1,4-Diketones; Chain extension; Ring expan-
sion; Radical reaction; Tributyltin hydride.
3a-e
4a-c
*
Scheme 2. Chain extension of 2-(iodomethyl)-2-methyl-1,3-diarylpro-
pane-1,3-diones 3.
Corresponding authors. Tel.: +1 412 826 3062; fax: +1 412 826 3053
(W.Z.); e-mail: w.zhang@fluorous.com
0040-4039/$ - see front matter Ó 2005Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.05.036

4728
X.-J. Mu et al. / Tetrahedron Letters 46 (2005) 4727–4729
Table 1. Yields for iodomethylation products 3 and chain extension
products 4
Table 2. Yields for alkylation products 6 and radical reaction products
7 and 8
Entry
Producta
R1
R2
Yield (%)b
Entry
Producta
R
Yield (%)b
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
4a
4b
4cc
H
H
5
49
2
1
6a
6b
6c
6d
6e
7a
7b
7c
7d
7e
8a
8b
8c
8d
8e
H
5
3
p-CH3
p-CH3
p-CH3O
p-Cl
p-CH3
H
2
p-CH3
p-CH3O
p-Cl
58
5
42
3
9
p-CH3O
p-Cl
H
Trace
Trace
76
4
62
56
68c
52
46
55
51
26c
18
23
13
10
5
p-Br
H
H
6
p-CH3
p-CH3
p-CH3
H
64
62
7
p-CH3
p-CH3O
p-Cl
8
9
a All products were characterized by NMR and MS.
b Isolated yield after column chromatography.
c 4c is a mixture of 4c-1 and 4c-2 (1:1).
10
11
12
13
14
15
p-Br
H
p-CH3
p-CH3O
p-Cl
Me
O
O
p-Br
a All products were characterized by NMR and MS.
b Isolated yield after column chromatography.
c Analyzed by HPLC.
O
O
Me
4c-1
4c-2
2-methyl-1,3-bis(p-chlorophenyl)propane-1,3-diketones
(2d and 2e) were difficult to be iodomethylated. Iodo-
methylations of 2b and 2c, however, afforded desired
products 3b and 3c in good yield. They were taken to
radical reactions to produce corresponding products
4b and 4c. Since compound 3c is an unsymmetric1,3-
dione, a mixture of 4c-1 and 4c-2 was produced in a
ratio of 1:1 (Table 1, entry 8). No regioselectivity was
found for the chain extension reaction of 3c. These
two compounds were difficult to be isolated by
chromatography.
.
O
Ar
O
O
.
Ar
O
O
O
10a
11a
Ar
.
O
.
O
O
O
.
9
Ar
Ar
We next explored radical reactions of a different kind of
1,3-diketones 6. This system contains both cyclic and
acyclic keto groups. Five radical precursors 6a–e were
prepared by iodomethylation of 2-aroyl-3,4-dihydro-
2H-naphalen-1-ones of 5a–e (Scheme 3). Results listed
in Table 2 show that radical reaction of 6 gave two prod-
ucts; chain extension product 7 and ring expansion
product 8, compound 7 was the major product.7 The
mixture was separated by flash chromatography and
the structure of each product was characterized by IR,
NMR, and HRMS analyses.
10b
11b
Scheme 4. Free radical ring expansion and chain extension of a
2-aroyl-3,4-dihydronaphalen-1(2H)-one radical.
tions of initial alkyl radical 9 to two different carbonyl
groups generate cyclopropylalkoxy radicals 10a and
10b. Selective b-scissions of spirocyclopropylalkoxy rad-
ical 10a and fused-cyclopropylalkoxy radical 10b pro-
duce chain-extended radical 11a and ring-expanded
radical 11b, respectively. Since the chain-extension was
found to be the major process, it suggests that cycliza-
tion of alkyl radical 9 to the acyclic carbonyl is superior
to the cyclic carbonyl. This is probably due to the differ-
ence of stereo hindrance associated with these two cycli-
zation processes.
A mechanism to explain two competitive radical reac-
tion processes is outlined in Scheme 4. 3-Exo cycliza-
O
O
O
O
O
CH2I2
Bu3SnH
AIBN
I
In summary, we have explored the one carbon ring
expansion and chain extension of two different kinds
of 1,3-diketones. For 1,3-diarylpropane-1,3-dione sys-
tem, the chain extension reaction has high yield. It is
good for symmetric 1,3-diketones. Reactions of 2-
aroyl-3,4-dihydro-2H-naphalen-1-one system produce
R
R
6a-e
5a-e
O
R
O
+
R
O
a mixture of chain-extension and ring-expansion
products. The chain extension is the major process.
8a-e
7a-e
General procedures for alkylation:8 Preparation of 3a—
2-Methyl-1,3-diphenylpropane-1,3-dione 2a (1.19 g,
Scheme 3. Ring expansion and chain extension of 2-aroyl-3,4-dihydro-
2H-naphalen-1-ones 6.

X.-J. Mu et al. / Tetrahedron Letters 46 (2005) 4727–4729
4729
5mmol), anhydrous potassium carbonate (1.38 g, 10
References and notes
mmol), tetrabutylammonium bromide (0.64 g, 2 mmol)
and dry toluene (15mL) were added to 50 mL three-
necked flask and the mixture was refluxed for 5h under
the nitrogen atmosphere. The mixture was then cooled
to 40 °C, diiodomethane (1.47 g, 5.5 mmol) was added,
stirred at 40 °C for 2 h and refluxed for another 2 h.
The mixture was cooled to room temperature, filtered,
and washed with diethyl ether. After removal of the sol-
vent, the residue was purified by chromatography on sil-
ica gel eluted with petroleum ether/ethyl acetate (20:1) to
afford 3a in 52% yield, mp 88–90 °C, IR (KBr)m 1677
(C@O), 1654 (C@O). 1H NMR (CDCl3) d 7.86–7.34
(m, 10H, 2C6H5), 3.86 (s, 2H, CH2), 1.76 (s, 3H, CH3).
13C NMR (CDCl3) d 198.0, 136.1, 133.9, 129.6, 129.3,
63.4, 24.7, 14.2. HRMS calcd for C17H15O2I 378.0117;
found 378.0118 (M+).
1. Reviews on ring expansion reactions: (a) Ramona, H.;
Charles, K. Z. Tetrahedron 2001, 57, 8793; (b) Kantorowski,
E. J.; Kurth, M. J. Tetrahedron 2000, 56, 4317; (c) Yet, L.
Tetrahedron 1999, 55, 9349; (d) Hesse, M. Ring Enlargement
in Organic Chemistry; VCH: Weinheim, 1991; (e) Gutsche,
C. D.; Redmore, D. Carbocyclic Ring Expansion Reactions;
Academic Press: New York, 1968.
2. Reviews on free radical ring expansion reactions: (a) Zhang,
W. In Radical in Organic Synthesis; Renaud, P., Sibi, M. P.,
Eds.; Wiley-VCH: Weinheim, 2001; Vol. 2, pp 234–245; (b)
Dowd, P.; Zhang, W. Chem. Rev. 1993, 93, 209.
3. (a) Dowd, P.; Choi, S.-C. J. Am. Chem. Soc. 1987, 109,
3493; (b) Dowd, P.; Choi, S.-C. Tetrahedron 1989, 45, 77;
(c) Beckwith, A. L. J.; OÕShea, D. M.; Gerba, S.;
Westwood, S. W. J. Chem. Soc., Chem. Commun. 1987,
666; (d) Beckwith, A. L. J.; OÕShea, D. M.; Westwood, S.
W. J. Am. Chem. Soc. 1988, 110, 2565; (e) Baldwin, J. E.;
Adlington, R. M.; Robertson, J. Tetrahedron 1989, 45, 909;
(f) Bowman, W. R.; Westlake, P. J. Tetrahedron 1992, 48,
4027.
4. (a) Zhang, W. Curr. Org. Chem. 2002, 6, 1015; (b) Dowd,
P.; Zhang, W. J. Am. Chem. Soc. 1991, 113, 9875; (c)
Dowd, P.; Zhang, W. J. Org. Chem. 1992, 57, 7163; (d)
Zhang, W.; Hua, Y.; Geib, S. J.; Hoge, G.; Dowd, P.
Tetrahedron 1994, 50, 12579; (e) Zhang, W.; Dowd, P.
Tetrahedron Lett. 1992, 33, 3285; (f) Zhang, W.; Collins,
M.; Mahmood, K.; Dowd, P. Tetrahedron Lett. 1995, 36,
2729; (g) Zhang, W.; Dowd, P. Tetrahedron Lett. 1992, 33,
7307.
General procedures for free radical one-carbon chain
extension: Preparation of 4a—Compound 3a (76 mg,
0.20 mmol), AIBN (10 mg, 0.06 mmol), tributyltin hy-
dride (116 mg, 0.40 mmol) and dry benzene (22 mL) were
added to a 50 mL three-necked flask. The mixture was re-
fluxed for 0.5h under the nitrogen atmosphere. The sol-
vent was removed, the residue was dissolved in
dichloromethane (25mL), washed with 10% aqueous
potassium fluoride, dried over MgSO4, and concen-
trated. The residue was then dissolved in acetonitrile
(25mL), washed with petroleum ether, and concen-
trated. The crude product was purified by silica gel chro-
matography eluted with petroleum ether/ethyl acetate
(15:1) to afford 4a in yield 76%, mp 96-98 °C. IR (KBr)
5. (a) Oh, H.-S.; Cha, J. K. Tetrahedron: Asymmetry 2003, 14,
2911; (b) Oh, H.-S.; Lee, H. I.; Cha, J. K. Org Lett. 2002, 4,
3707.
6. (a) Wilsey, S.; Dowd, P.; Houk, K. N. J. Org. Chem. 1999,
64, 8801; (b) Ardura, D.; Sordo, T. L. Tetrahedron Lett.
2004, 45, 8691.
1
m 1678 (C@O). H NMR (CDCl3) d 8.07–7.45(m, 10H,
2C6H5), 4.20 (m, 1H, CH), 3.75(dd, 1H, J1 = 8.60 Hz,
J2 = 18.00 Hz), 3.14 (dd, 1H, J1 = 4.80 Hz, J2 = 18.00
Hz), 1.29 (d, 3H, CH3, J = 6.80 Hz); 13C NMR (CDCl3)
d 203.8, 198.9, 137.3, 136.7, 133.6, 133.4, 129.2, 129.1,
129.0, 128.6, 42.8, 36.8, 18.4. HRMS calcd for
C17H16O2 252.1150; found 252.1144 (M+).
1
7. Analytical data for 7a: mp 80–82 °C. H NMR (CDCl3) d
8.05–7.25 (m, 9H, C6H4 and C6H5), 3.89–3.84 (m, 1H, CH),
3.61–3.15(m, 2H, CH 2), 3.02–2.96 (m, 2H, CH2), 2.32–1.97
(m, 2H, CH2). 13C NMR (CDCl3) d 199.5, 199.0, 144.6,
137.4, 133.9, 133.6 132.7, 129.3, 129.1, 128.6, 127.9, 127.1,
44.7, 39.5, 30.0, 29.9. HRMS (M+) calcd for C18H16O2
264.1150; found 264.1130 (M+). Analytical data for 8a: mp
68–70 °C. 1H NMR (CDCl3): d 7.91–7.25(m, 9H, C 6H4 and
C6H5), 3.88–3.81 (m, 1H, CH), 3.26–3.16 (m, 2H, CH2),
2.96–2.92 (m, 2H, CH2), 2.29–2.09 (m, 2H, CH2). 13C NMR
(CDCl3): d 203.4, 201.4, 142.0, 138.6, 135.9 133.9, 133.0
130.4, 129.4, 129.3, 129.0, 127.5, 43.4, 40.4, 31.9, 29.8;
HRMS calcd for C18H16O2 264.1150; found 264.1148 (M+).
8. Choudhary, A.; Baumstark, A. L. Synthesis 1989, 688.
Acknowledgments
We thank the Key Laboratory of Organic Synthesis of
Jiangsu Province and Suzhou Scientific Committee for
financial supports (JSK016 and SG 0219).