Free radical ring expansion and spirocyclization of 1,3-diketone derivatives

Article abstract of DOI:10.1016/j.tetlet.2008.10.038

Free radical-promoted three-carbon ring expansions of 1,3-diketones to form corresponding nine-membered 1,6-diketones and associated spirocyclization reactions are described.

Full text of DOI:10.1016/j.tetlet.2008.10.038

Tetrahedron Letters 49 (2008) 7311–7314
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Tetrahedron Letters
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Free radical ring expansion and spirocyclization of 1,3-diketone derivatives
a
b,
Wei Xu a, Jian-Ping Zou a, , Xue-Jun Mu , Wei Zhang
*
*
a Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry and Chemical Engineering, Suzhou University, 199 Renai Street, Suzhou, Jiangsu 215123, China
b Department of Chemistry, University of Massachusetts Boston,100 Morrissey Boulevard, Boston, MA 02125, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Free radical-promoted three-carbon ring expansions of 1,3-diketones to form corresponding nine-
membered 1,6-diketones and associated spirocyclization reactions are described.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 20 September 2008
Accepted 8 October 2008
Available online 14 October 2008
1. Introduction
radicals, chain extension compounds 2 were the major products,
and the ring expansion compounds 3 were the minor ones (Scheme
Free radical cyclizations to form five- and six-membered cyclic
compounds are important synthetic methods for the preparation of
biologically active natural products and pharmaceutical chemi-
cals.1 Free radical ring expansions2 of five- and six-membered rings
further extend the utility of radical chemistry to access medium
and large cyclic compounds. The Dowd-Beckwith reaction of cyclic
b-ketoesters3 and ring expansion of fused-cyclobutanones4,5 are
two well-known systems, which are both good for one- and
three-carbon ring expansions (Scheme 1).6 The ring expansions
are accomplished through the b-scission of an alkoxy radical7 gen-
erated by carbon radical addition to the carbonyl. The ester group
and the strained ring are critical for the ring expansion of these two
systems.8
2).9 Reported in this Letter are the new results obtained from a sim-
ilar system but involving reactions of three-carbon chain radicals.
The synthesis of radical precursors is shown in Scheme 3. Read-
ily prepared 2-benzoyl-3,4-dihydro-2H-naphthalen-1-ones 4 were
R
O
O
2, major (46-68%)
O
O
I
Bu3SnH
AIBN
+
O
O
Recently, we designed a unique 1,3-diketone system 1 which has
neither ester group nor strained ring, but contains a cyclic keto
group and an acyclic keto group. This system can be used to test
the competitive ring expansion versus chain extension reactions.
Our previous work shows that for the reactions of single-carbon
C6H6, 80 0C
R
1
R
3, minor (10-26%)
Scheme 2.
CO2R
CO2R
CO2R
O
O
O
Br
.
O
O
Bu3SnH
AIBN
H
H
H
H
R
O
O
I(CH2)3I
I
5a-d
6a-d
+
Br
O
.
O
O
H
R
H
I
O
O
4a-d
Scheme 1.
R
* Corresponding authors. Tel./fax: +86 512 65112371 (J.-P.Z.); tel.: +1 617 287
6147; fax: +1 617 287 6030 (W.Z.).
E-mail addresses: wuyanhong@pub.sz.jsinfo.net (J.-P. Zou), wei2.zhang@umb.
edu (W. Zhang).
Scheme 3.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.038

7312
W. Xu et al. / Tetrahedron Letters 49 (2008) 7311–7314
used for alkylations with 1,3-diiodopropane to form 2-benzoyl-2-
(3-iodopropyl)-3,4-dihydro-2H-naphthalen-1-ones 5. We found
that in addition to the desired C-alkylation products 5, the O-alkyl-
ated compounds 6 were generated as the major products (Table 1).
Since the cyclic keto is preferred to exist in enol form that leads to
O-alkylation as the major product. We were able to separate the
reaction mixtures and got enough C-alkylated compounds to study
ring expansion versus chain extension reactions.
Free radical reaction of 5a was carried out under general free
radical reaction conditions using tri-n-butyltin hydride, a catalytic
amount of AIBN, and reflux benzene as a solvent. From the reaction
mixture, two compounds were isolated and characterized to be 2-
benzoyl-2-propyl-3,4-dihydro-2H-naphthalen-1-one 8a and three-
carbon ring expansion product 7a, respectively. Compound 8a was
a direct reduction product and in a minor amount. The ring-expan-
sion product 7a was the major product and in 68% yield (Scheme 4,
Table 2, entry 1). It was surprised to find that no chain extension
product 9a in reaction mixture. We then carried out similar reac-
tions on other substrates 5b–d with the variation of R substitution.
Similar ring expansion products 7b–d were obtained in 69–72%
yields together with a small amount of direct reduction products
8b–d (Table 2, entries 2–4).
O
O
R
5
I
O
O
Bu3SnH
AIBN
Bu3SnH
R
R
path 1
O
O
CH3
8 (minor)
.
R
O
.
path 2
10
path 3
O
11
O
O
O
.
.
R
13
R
O
12
R
O
Bu3SnH
.
O
Table 1
O
C- and O-alkylations of 1,3-diketones 4a–d
14
Product (yield %)a,b
R
Total yieldb (%)
Bu3SnH
Entry
R
R
O
1
2
3
4
5a(21) + 6a(40)
5b(28) + 6b(48)
5c(16) + 6c(52)
5d(15) + 6d(59)
H
61
76
68
74
O
CH3
OCH3
Cl
7 (major)
O
9 (not observed)
a
All products were characterized by 1H NMR, 13C NMR and HRMS.
Isolated yield.
b
Scheme 5.
Based on the results described above, radical transformation
mechanisms for the reaction of 5 were proposed (Scheme 5). Alkyl
radical 10 is generated by the reaction of 5 with tri-n-butyltin hy-
dride and AIBN. This radical has following three potential path-
ways: (1) formation of 8 via direct reduction; (2) three-carbon
ring expansion via radicals 11 and 12 to form product 7; and (3)
chain-extension via radicals 13 and 14 to form compound 9. Since
only compounds 7 and 8 were isolated from the reaction mixtures,
the third pathway seems to be not so competitive to the first two
pathways. The formation of a new nine-membered ring as the ma-
jor product makes it to be a synthetically useful ring-expansion
reaction. This result is different from that obtained from the reac-
tion of one-carbon chain radical shown in Scheme 2, where the
chain extension product was the major one. Different results sug-
gest that for one-carbon ring expansion, carbon radical attacking
of the rigid cyclic keto has more steric hindrance than attacking
the acyclic keto, and leads to chain extension product as the major
one. In the case of three-carbon ring expansion, the long chain is
kinetically more favorable to attack the cyclic keto than the flexible
acyclic keto, and leads to ring expansion product as the major one.
For the purpose of study on ring-expansion reactions, the yields
of C-alkylation reaction for compounds 5 should be optimized. But
on the other hand, the O-alkylated compounds 6 may be synthet-
ically useful for formation of tetrahydrofuran which is spiro to the
naphthalen-1-one skeleton. Indeed, under the general free radical
reaction conditions using tri-n-butyltin hydride and AIBN, com-
pounds 6 led to the formation of tetrahydrofuran through the con-
O
R
O
+
7a-d (major)
O
O
O
O
Bu3SnH
AIBN
C6H6, 80 0
C
R
R
CH3
+
I
8a-d (minor)
5a-d
R
O
O
9a-d (not observed)
Scheme 4.
Table 2
Reaction of 2-aroyl-2-(3-iodopropyl)-3,4-dihydro-2H-naphthalen-1-ones 5a–d
Entry
Product (yield %)a
R
Total yieldb (%)
1
2
3
4
7a(68) + 8a(8)
7b(69) + 8b(8)
7c(72) + 8c(12)
7d(70) + 8d(15)
H
76
77
84
85
CH3
OCH3
Cl
jugate addition to the
a,b-unsaturated ketone group. The spiro
products 16 were the only compounds isolated from the reaction
mixture (Scheme 6, Table 3), no direct reduction products were
observed.
All products were characterized by 1H NMR, 13C NMR, and HRMS.
Isolated yield.
a
b

W. Xu et al. / Tetrahedron Letters 49 (2008) 7311–7314
7313
and dry benzene (22 mL) were added to a 50 mL three-necked
flask. The mixture was refluxed for 0.5 h under the nitrogen atmo-
sphere.7 After the reaction was completed (monitored by TLC), the
solvent was removed, and the residue was dissolved in dichloro-
methane (25 mL), washed with 10% aqueous potassium fluoride,
dried over MgSO4, and concentrated. The residue was then dis-
solved in acetonitrile (25 mL), washed with petroleum ether, and
concentrated to afford the crude product, which was purified by
silica gel chromatography eluted with petroleum ether/ethyl ace-
tate (15:1) to afford major three-carbon ring expansion product
7a in 68% yield, and minor reduced product 8a in 10% yield.
Compound 7a: 1H NMR (CDCl3, 400 MHz): d 1.63–1.68 (m, 1H),
1.83–1.89 (m, 1H), 1.91–2.00 (m, 2H, CH2), 2.03–2.11 (m, 1H),
2.29–2.36 (m, 1H), 2.52–2.59 (m, 1H), 3.05–3.10 (m, 4H, 2CH2),
7.26–8.06 (m, 9H, C6H5, C6H4). 13C NMR (CDCl3, 100 MHz): d
200.6, 200.5, 144.4, 137.4, 133.6, 133.4, 132.9, 129.1, 129.0,
128.4, 127.8, 127.0, 47.9, 39.1, 29.5, 28.9, 28.6, 22.1. HRMS: m/z
calcd for C20H20O2 292.1463; found 292.1460 (M+). Compound 8a:
1H NMR (CDCl3, 400 MHz): d 0.92–0.95 (t, 3H, CH3, J = 7.2 Hz),
1.32–1.44 (m, 1H), 1.94–2.01 (m, 1H), 2.04–2.11 (m, 1H), 2.15–
2.22 (m, 1H), 2.83–2.89 (m, 1H), 2.97–3.04 (m, 1H), 3.07–3.31
(m, 1H), 7.20–7.90 (m, 9H, C6H4, C6H5). 13C NMR (CDCl3,
100 MHz): d 199.8, 198.9, 143.3, 136.9, 134.0, 132.9, 132.6, 129.5,
129.2, 128.6, 128.4, 127.2, 62.8, 36.5, 31.7, 26.1, 18.3, 15.0. HRMS:
m/z calcd for C20H20O2 292.1463; found 292.1460(M+).
Bu3SnH
AIBN
O
O
I
O
O
.
C6H6, 80 °C
R
R
6a-d
15a-d
Bu3SnH
O
O
R
16a-d
Scheme 6.
Table 3
Cyclization of O-alkylated compounds 6
Entry
Product (yield %)a,b
R
Total yieldb (%)
1
2
3
4
16a
16b
16c
16d
H
55
64
75
64
CH3
OCH3
Cl
All products were characterized by 1H NMR, 13C NMR and HRMS.
Isolated yield.
a
b
4. Typical procedure for preparation of 16a
In conclusion, six-membered 2-aroylbenzocyclohexanones 5
can be converted to nine-membered 5-aroylbenzocyclononanones
7 in 68–72% yields via the three-carbon ring expansion process. On
the other hand, using O-alkylated compounds 6 as radical precur-
sors, tetrahydrofuran spiro-benzocyclohexanones 16 can be syn-
thesized in 55–75% yields.
Compound 6a (83 mg, 0.20 mmol), AIBN (10 mg, 0.06 mmol),
tri-n-butyltin hydride (116 mg, 0.40 mmol), and dry benzene
(22 mL) were added to a 50 mL three-necked flask, and the mixture
was refluxed for 0.5 h under the nitrogen atmosphere. After the
reaction was completed (monitored by TLC), the solvent was re-
moved, the residue was dissolved in dichloromethane (25 mL),
washed with 10% aqueous potassium fluoride, dried over MgSO4,
and concentrated. The residue was then dissolved in acetonitrile
(25 mL), washed with petroleum ether, and concentrated to afford
the crude product, which was purified by silica gel chromatogra-
phy eluted with petroleum ether/ethyl acetate (15:1) to give 16a
in 55% yield. Compound 16a: 1H NMR (CDCl3, 400 MHz): d 2.05–
1.63 (m, 4H, 2CH2), 2.73–2.22 (m, 2H, CH2), 2.93–2.91 (m, 2H,
CH2), 3.98–3.43 (dd, 1H, CH, J1 = 14.4 Hz, J2 = 7.2 Hz), 4.05–4.00
(m, 2H, CH2), 8.13–7.08 (m, 9H, C6H4, C6H5). 13C NMR (CDCl3,
100 MHz): d 204.3, 145.4, 138.3, 135.5, 133.3, 129.6, 128.8, 128.7,
127.3, 126.7, 125.7, 86.7, 70.2, 51.0, 36.3, 28.5, 26.6, 24.9. HRMS:
m/z calcd for C20H20O2 292.1463; found 292.1472 (M+).
2. Typical procedure for alkylation
Preparation of C-alkylated product 5a and O-alkylated product
6a. 2-Benzoyl-3,4-dihydro-2H-naphthalen-1-one 4a (1.25 g,
5 mmol), anhydrous potassium carbonate (1.38 g, 10 mmol), tetra-
butylammonium bromide (0.64 g, 2 mmol), and dry toluene
(15 mL) were added to a 50 mL three-necked flask, and the mixture
was refluxed for 1 h under the nitrogen atmosphere.7 Then, the
mixture was cooled to 40 °C, 1,3-diiodopropane (1.47 g, 5.5 mmol)
was added, stirred at 40 °C for 2 h and refluxed for another 2 h.
After the reaction was completed (monitored by TLC), the resultant
was cooled to room temperature, filtered, and washed with diethyl
ether. The filtrate was concentrated, and the residue was purified
by chromatography on silica gel eluted with petroleum ether/ethyl
acetate (20:1) to afford 5a in 21% and 6a in 40% yields, respec-
tively.7 Compound 5a: 1H NMR (CDCl3, 400 MHz): d 1.80–1.96 (m,
2H, CH2), 2.05–2.17 (m, 2H, CH2), 2.21–2.29 (m, 1H), 2.82–2.89
(m, 1H), 3.05–3.08 (m, 2H, CH2), 3.16–3.23 (m, 2H, CH2), 7.22–
8.01 (m, 9H, C6H4, C6H5). 13C NMR (CDCl3, 100 MHz): d 198.5,
198.4, 143.1, 136.3, 134.3, 132.9, 132.5, 129.4, 129.3, 128.7,
128.5, 127.4, 62.1, 35.1, 31.9, 29.0, 25.9, 7.1. Compound 6a: 1H
NMR (CDCl3, 400 MHz): d 1.77–1.84 (m, 2H, CH2), 2.65–2.69 (m,
2H, CH2), 2.87–2.91 (m, 4H, 2 Â CH2), 3.67–3.70 (m, 2H, CH2),
7.22–7.89 (m, 9H, C6H4, C6H5). 13C NMR (CDCl3, 100 MHz): d
198.0, 155.4, 139.1, 138.8, 132.9, 131.0, 129.7, 129.5, 128.6,
128.1, 127.0, 123.9, 121.6, 73.3, 33.9, 28.3, 25.6, 2.4.
Acknowledgment
J.P.Z. thanks the financial support from National Natural Science
Foundation of China (No. 20772088).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.10.038.
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