Cycloaddition of aromatic α,β-unsaturated aldehydes and ketones with epoxides: One-step approach to synthesize seven-membered oxacycles catalyzed by Lewis acid

Article abstract of DOI:10.1021/jo101669t

A novel intermolecular [4 + 3] cycloaddition method to construct 1,4-dioxide seven-membered oxacycles was developed. This one-step method was carried out in the presence of catalytic amount of (C₂H ₅)₂OBF₃ under

Full text of DOI:10.1021/jo101669t

pubs.acs.org/joc
these skeletons in natural products, as well as functionalized
[4þ3] Cycloaddition of Aromatic r,β-Unsaturated
Aldehydes and Ketones with Epoxides: One-Step
Approach to Synthesize Seven-Membered Oxacycles
Catalyzed by Lewis Acid
organic molecules, such as, marcfortine,1 paraherquamide,2
and some other compounds.3 Unfortunately, unlike methods
for the synthesis of five- and six-membered oxacycles, which are
known and widely applied, the synthesis of seven-membered
oxacycles, especially 1,4-dioxide seven-membered oxacycles,
has evolved a smaller array of methods because of the unusual
molecular architecture, entropy reasons, ring strain, and the
transannular interaction of such compounds.4 Traditional
synthesis of these seven-membered oxacycles are reported
usually by intramolecular ring closure reactions,5 with intricate
procedures, complicated byproducts, extreme conditions, and
low yields. Therefore, the development of efficient methodol-
ogies that enables simple and more concise approaches to
generate this kind of oxacycles remains a preeminent challenge
in modern organic chemistry. The [4 þ 3] cycloaddition reac-
tion is a powerful approach to construct both seven-membered
carbocycles6 and seven-membered nitrogen-containing
heterocycles;7 however, seven-membered oxacycles are rarely
synthesized by [4 þ 3] cycloaddition method. Herein, we would
like to report a novel method to synthesize seven-membered
oxacycles via intermolecular [4 þ 3] cycloaddition. To the best
of our knowledge, it is the first time to report the synthesis of
1,4-dioxide seven-membered oxacycles from epoxides and R,β-
unsaturated carbonyls by intermolecular reaction.
Yu-Qiang Zhou,† Nai-Xing Wang,*,† Shu-Bao Zhou,†,‡
Zhong Huang,† and Linghua Cao‡
†Technical Institute of Physics and Chemistry, Chinese
Academy of Sciences, Beijing, China, 100190, and
‡College of Chemistry and Chemical Engineering,
Xinjiang University, Urumqi, China, 830046
nxwang@mail.ipc.ac.cn
Received February 4, 2010
A novel intermolecular [4 þ 3] cycloaddition method to
construct 1,4-dioxide seven-membered oxacycles was devel-
oped. This one-step method was carried out in the presence
of catalytic amount of (C2H5)2OBF3 under mild conditions.
Seven-membered oxacycles and some natural compounds
could be easily synthesized via this protocol. Control
experiments were carried out and possible mechanism for
the reaction was proposed. Asymmetric reactions were
proceeded and 3e was obtained with moderate ee value.
(4) (a) Entrena, A.; Gallo, M. A.; Espinosa, A.; Jaime, C.; Campos, J.;
Dominguez, J. F. J. Org. Chem. 1989, 54, 6034–6039. (b) Espinosa, A.;
Entrena, A.; Gallo, M. A.; Campos, J.; Domhguez, J. F.; Camacho, E.;
Garrido, R. J. Org. Chem. 1990, 55, 6018–6023. (c) Ullapu, P. R.; Min, S. J.;
Chavre, S. N.; Choo, H.; Lee, J. K.; Pae, A. N.; Kim, Y.; Chang, M. H.; Cho,
Y. S. Angew. Chem., Int. Ed. 2009, 48, 2196–2200. (d) Illuminati, G.;
Mandolini, L. Acc. Chem. Res. 1981, 14, 95–102. (e) Mandolini, L. Adv.
Phys. Org. Chem. 1986, 22, 1–111. (f) Kreiter, C. G.; Lehr, K.; Leyendecker,
M.; Sheldrik, W. S.; Exner, R. Chem. Ber. 1991, 124, 3–12.
(5) For traditional synthesis of 1,4-dioxide seven-membered oxacycles,
see: (a) Wilckens, K.; Uhlemann, M.; Czekelius, C. Chem.;Eur. J. 2009, 15,
13323–13326. (b) Chambers, R. D.; Lindley, A. A.; Philpot, P. D. J. Chem.
~
Soc., Perkin I 1979, 214–219. (d) Sierra, M. A.; Amo, J. C.; Mancheno, M. J.;
Gomez-Gallego, M. J. Am. Chem. Soc. 2001, 123, 851–861. (e) Sierra, M. A.;
ꢀ
Search for new methodologies for the selective synthesis
of 1,4-dioxide seven-membered oxacycles continues to be of
great interest for organic chemists because of the presence of
~
Mancheno, M. J.; Saez, E.; Amo, J. C. J. Am. Chem. Soc. 1998, 120, 6812–
6813. (f) Bottini, A. T.; Corson, F. P.; Bottner, E. F. J. Org. Chem. 1965, 31,
ꢀ
€
586–587. (g) Ozaki, S.; Matsui, E.; Yoshinaga, H.; Kitagawa, S. Tetrahedron
Lett. 2000, 41, 2621–2624. (h) Wei, H. X.; Schlosser, M. Chem.;Eur. J. 1998,
4, 1738–1743. (i) Dmitrieva, L. L.; Nikitina, L. P.; Albanov, A. I.; Nedolya,
N. A. Russ. J. Org. Chem. 2005, 41, 1430–1444. (j) Chatterjee, A. K.; Morgan,
J. P.; Scholl, M.; Grubbs, R. H. J. Am. Chem. Soc. 2000, 122, 3783–3784.
(1) For selected examples, see: (a) Kuo, M. S.; Yurek, D. A.; Mizsak,
S. A.; Cialdella, J. I.; Baczynskyj, L.; Marshall, V. P. J. Am. Chem. Soc. 1999,
121, 1763–1767. (b) Trost, B. M.; Cramer, N.; Bernsmann, H. J. Am. Chem.
Soc. 2007, 129, 3086–3087. (c) Lee, B. H.; Kornis, G. I.; Cialdella, J. I.;
Clothier, M. F.; Marshall, V. P.; Martin, D. G.; McNally, P. L.; Mizsak,
S. A.; Whaley, H. A.; Wiley, V. H. J. Nat. Prod. 1997, 60, 1139–1142. (d) Lee,
B. H.; Clothier, M. F. J. Org. Chem. 1997, 62, 1863–1867.
€
(k) Bottini, A. T.; Corson, F. P.; Bottner, E. F. J. Org. Chem. 1965, 30, 2988–
2994. (l) Bottini, A. T.; Maroski, J. G. J. Org. Chem. 1973, 38, 1455–1462.
(m) Yamanaka, H.; Shimamura, T.; Teramura, K. Chem. Lett. 1972, 921–922.
(n) Wei, H. X.; Schlosser, M. Chem.;Eur. J. 1998, 4, 1738–1743. (o) Bottini,
€
A. T.; Corson, F. P.; Bottner, E. F. J. Org. Chem. 1966, 31, 389–391.
(2) For selected examples, see: (a) Stocking, E. M.; Sanz-Cervera, J. F.;
Williams, R. M. Angew. Chem., Int. Ed. 1999, 38, 786–789. (b) Williams,
R. M.; Cao, J.; Tsujishima, H. Angew. Chem., Int. Ed. 2000, 39, 2540–2544.
(c) Stocking, E. M.; Sanz-Cervera, J. F.; Williams, R. M. Angew. Chem., Int.
Ed. 2001, 40, 1296–1298. (d) Lee, B. H.; Clothier, M. F.; Johnson, S. S.
(6) For [4 þ 3] cycloaddition to construct seven-membered carbocycles, see:
(a) Ivanova, O. A.; Budynina, E. M.; Grishin, Y. K.; Trushkov, I. V.; Verteletskii,
P. V. Angew. Chem., Int. Ed. 2008, 47, 1107–1110. (b) Trost, B. M.; MacPherson,
ꢀ
ꢀ
D. T. J. Am. Chem. Soc. 1987, 109, 3483–3484. (c) Prie, G.;Prveost, N.; Twin, H.;
Fernandes, S. A.; Hayes, J. F.; Shipman, M. Angew. Chem., Int. Ed. 2004, 43,
6517–6519. (d) Davies, H. M. L.; Dai, X. J. Am. Chem. Soc. 2004, 126, 2692–
ꢀ
Bioorg. Med. Chem. Lett. 2001, 11, 553–554. (e) Lopez-Gresa, M. P.;
Gonzalez, M. C.; Ciavatta, L.; Ayala, I.; Moya, P.; Primo, J. J. Agric. Food
ꢀ
ꢀ ꢀ ꢁ
2693. (e) Gulıas, M.; Duran, J.; Lopez, F.; Castedo, L.; Mascarenas, J. L. J. Am.
´
Chem. 2006, 54, 2921–2925. (f) Stocking, E. M.; Williams, R. M.; Sanz-
Cervera, J. F. J. Am. Chem. Soc. 2000, 122, 9089–9098. (g) Williams, R. M.;
Cao, J. H.; Tsujishima, H.; Cox, R. J. J. Am. Chem. Soc. 2003, 125, 12172–
Chem. Soc. 2007, 29, 11026–11027. (f) Rameshkumar, C.; Hsung, R. P. Angew.
Chem., Int. Ed. 2004, 43, 615–618.
(7) For [4 þ 3] cycloaddition to construct seven-membered nitrogen-
ꢀ
12178. (h) Domingo, L. R.; Zaragoza, R. J.; Williams, R. M. J. Org. Chem.
containing heterocycles, see: (a) Trost, B. M.; Marrs, C. M. J. Am. Chem.
ꢀ
Soc. 1993, 115, 6636–6645. (b) Barluenga, J.; Tomas, M.; Ballestros, A.;
2003, 68, 2895–2902.
(3) For selected examples, see: (a) Conejo-Garcı
ꢀ~
a, A.; Nuneza, M. C.;
guez-Serrano, F.; Aranega, A.; Gallo, M. A.; Espinosa,
´
ꢀ
´
Santamarıa, J.; Lopez-Ortiz, F. J. Chem. Soc., Chem. Commun. 1994, 3, 321–
322. (c) Shintani, R.; Murakami, M.; Hayashi, T. J. Am. Chem. Soc. 2007,
129, 12356–12357. (d) Lautens, M.; Klute, W.; Tam, W. Chem. Rev. 1996, 96,
49–92.
ꢀ
Marchal, J. A.; Rodrı
´
A.; Campos, J. M. Eur. J. Med. Chem. 2008, 43, 1742–1748. (b) Fall, Y.;
ꢀ
Vidal, B.; Alonso, D.; Gomez, G. Tetrahedron Lett. 2003, 44, 4467–4469.
DOI: 10.1021/jo101669t Published on Web 12/30/2010
r
J. Org. Chem. 2011, 76, 669–672 669
2010 American Chemical Society

Zhou et al.
JOCNote
TABLE 1. Optimized Conditions for [4 þ 3] Cycloaddition
TABLE 2. Expansion of [4 þ 3] Cycloaddition of r,β-Unsaturated
Carbonyls with Epoxides under Optimized Conditionsa
of Cinnamaldehyde with Isobutylene Oxidea
entry
solvent
catalysts
SmI2
CuBr2
ZnCl2
AlCl3
SnCl2
SnCl4
FeCl3
(C2H5)2OBF3
(C2H5)2OBF3
(C2H5)2OBF3
(C2H5)2OBF3
(C2H5)2OBF3
(C2H5)2OBF3
(C2H5)2OBF3
(C2H5)2OBF3
(C2H5)2OBF3
time (h)
yield (%)b
entry
R1
Ph
2-furyl
R2
R3
R4
Me
Me
M e
Me
Me
R5 product yield (%)b ratioc
1
2
3
4
5
6
7
8
THF
72
72
72
72
72
72
72
8
8
8
8
8
trace
9
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3OH
toluene
THF
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
H
3a
3b
3c
3d
3e
3f
67
69
42
40
65
68
73
66
58
69
62
15
32
41
45
55
63
NRc
45
42
50
67
65
62
65
4-MePh Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-ClPh
Me
Me
Me
Me
Me
H
Me Me
H
H
-(CH2)4-
Me Me
Me Me
5:3
5:2
5:3
CH2Cl H
Ph
3g
3h
3i
3j
3k
9
H
H
H
H
10
11
12
13
14
15d
16e
10 2-furyl
11 Ph
1:1
3:2
Et2O
H
CHCl3
CHCl3
CHCl3
CHCl3
8
16
8
aUnless otherwise specified, reaction were carried out in CHCl3 with
1 mmol of 1 and 1 mmol of 2 in the presence of 5 mol % of (C2H5)2OBF3
for 2-8 h. For a detail, see Supporting Information. All the epoxides
used are nonoptically pure. b3f, 3g, 3h could be isolated as an isomer, 3j
and 3k are isolated as the mixture of the isomers. Yields are calculated by
the combination of all the isolated products. The absolute configuration
was not determined. cDetermined by 1H NMR.
8
aReaction conditions: 1a (0.5mmol), 2a (0.5mmol), Lewisacid(5mol%),
solvent (2 mL), room temperature. Isolated yields. NR = no reactions.
b
c
dReaction was performed at 60 °C. e(C2H5)2OBF3 (20 mol %).
Initially, this work was inspired by the original synthesis
of 1,3-oxazolidines from imines and epoxides reported by
Ishii.8 It was very interesting that the product was not a five-
membered ring compound like Ishii reported8 when we used
cinnamaldehyde as a standard substrate to react with epoxide.
Accordingtodataof1HNMR, 13CNMR, IR, andHRMSand
the literature,4a,b,5h,i we are sure that the product is a seven-
membered heterocycle.
phosphoric acid and hydrochloric acid, could also be used in
this reaction yet with low efficience and failed to give products
with yields highter than 10%.
An examination of substrates scope revealed that (C2H5)2-
OBF3 could tolerate a range of substrates (Table 2). First,
several aromatic R,β-unsaturated carbonyls were chosen to
react with isobutylene oxide. As can be seen from Table 2,
carbonyls with small substituents delivered the products with
good yields (Table 2, entries 1, 2, and 5). Lower yields were
obtained when these carbonyls bearing bulky hindrance
(Table 2, entries 3 and 4). Three different epoxides generated
from oxirane were also employed and provided the corre-
sponding cycloaddition adducts efficiently (Table 2, entries
6, 7, and 8). Delightedly, the adduct with the highest yield of
73% was achieved by benzylideneacetone with (() 2-(chloro-
methyl)-oxirane (Table 2, entry 7). Even the cyclohexene oxide
can provide a 58% yield product (Table 2, entry 9). Unlike 3f,
3g, and 3h could be successfully separated from the isomers,
both 3j and 3k were isolated only as mixture of isomers in
different ratio (Table 2, entries 10 and 11).9 Interestingly, 3i is a
pure compound that is quite different from 3f, 3g, 3h, 3j, and3k,
perhaps the aliphatic six-membered ring, as an important
factor, is responsible for this. In general, substituents on
epoxides have no significant effect on the reactions, while
substituents on the aromatic R,β-unsaturated aldehydes and
aromatic R,β-unsaturated ketones do have great influence on
the reactions.
With this unexpected detection, our starting point for cata-
lyst screening was carried out. On the basis of the reaction of
cinnamicaldehyde 1a with isobutylene oxide 2a, some Lewis
acids were tried as catalysts. An initial experiment, using Ishii’s
conditions (SmI2), was tried, unfortunately, only trace of the
target compounds could be obtained (Table 1, entry 2). The use
of CuBr2 gave an isolated yield of 9% (Table 1, entry 2). A little
bit higher yield was obtained when we changed the catalyst to
ZnCl2 (Table 1, entry 3). Although AlCl3 led to a sudden color
change, it gave the product in only a 32% yield (Table 1, entry 4).
On the contrary, SnCl2 could afford a moderate yield of
41% (Table 1, entry 5), and SnCl4 could afford a higher yield
of 45% (Table 1, entry 6). It seems that FeCl3 is an appropriate
catalyst with a higher yield of 55%, but long reaction time is
needed (Table 1, entry 7). To our delight, (C2H5)2OBF3 gave
the highest yield of 63% in a short time (Table 1, entry 8). Thus,
(C2H5)2OBF3 is the suitable Lewis acid with moderate acidity
neither strong as AlCl3 nor weak as CuBr2 and could sharply
short the reaction time. The solvents were subsequently ex-
plored (Table 1, entries 8-13). And we found that CHCl3 was
the most efficient one among the various solvents. Whether
employing higher catalyst loadings or raising the reaction
temperature did not lead to any improvement for the reaction,
we could conclude that the amount of catalyst and reaction
temperature had no significant effect on this reaction (Table 1,
entries 14, 15, and 16). Protonic acids, such as sulfuric acid,
When aromatic R,β-unsaturated acids and aromatic R,β-
unsaturated esters were used as substrates to react with
epoxides, no seven-membered oxacycles could be obtained,
indicating that this reaction was not applicable to these
substrates. This is probably because of the instability of the
seven-membered oxacycles generated from the aromatic R,β-
unsaturated acids and aromatic R,β-unsaturated esters.
(8) Nishitani, T.; Shiraishi, H.; Sakaguchi, S.; Ishii, Y. Tetrahedron Lett.
2000, 41, 3389–3393.
(9) For details of the spectroscopic data, see Supporting Information.
670 J. Org. Chem. Vol. 76, No. 2, 2011

Zhou et al.
JOCNote
SCHEME 1. Plausible Mechanism
TABLE 3. Asymmetric Synthesis of 3e Catalyzed by 4 and 5a
temperature
(°C)
yield
(%)b
ee
entry
catalysts
solvent
(%)c
1
2
3
4
5
6
7
4
5
DCM
DCM
DCM
toluene
toluene
toluene
toluene
rt
rt
rt
rt
rt
rt
0
16
NRd
55
53
47
23.0
5, Ti(OiPr)4 (1:1)
5, Ti(OiPr)4 (1:1)
5, Ti(OiPr)4 (2:1)
5, Ti(OiPr)4 (1:2)
5, Ti(OiPr)4 (1:1)
27.3
43.5
42.0
14.0
43.0
It is worth mentioning that aliphatic R,β-unsaturated
aldehyde and aliphatic R,β-unsaturated ketones were also
used as substrates to examine the [4 þ 3] cycloaddition.
Unfortunately, neither of them could provide corresponding
seven-membered oxacycles. Probably because of the higher
reactivity of these enolizable aldehydes.
35
5
aUnless otherwise specified, reactions were performed on a 1 mmol
scale in 2.5 mL solvent in the presence of 5% catalyst at room tem-
perature for 4 h. bIsolated yield. cDetermined by chiral HPLC analysis.
The absolute configuration was not determined. dNR = no reaction.
To understand the reaction, control experiments were
carried out. Addition of benzylideneacetone to a CHCl3
solution containing (C2H5)2OBF3 led to the system with an
immediate color change from light yellow to brown, then 2,3-
dimethyoxirane was subsequently added and 1,4-dioxepine
derivative 3f was obtained successfully. But when 2,3-
dimethyoxirane was first added to the CHCl3 solution contain-
ing (C2H5)2OBF3 and then benzylideneacetone was added, no
product was detected. This suggests that the reaction is initiated
by BF3 and R,β-unsaturate carbonyl but not by epoxide. A
possible mechanism is proposed as following (Scheme 1). R,β-
Unsaturate carbonyl A reacts with BF3 to give a reactive
intermediate B, which could be stabilized by both phenyl and
the double bound. Then B immediately reacts with epoxide C,
which not only gets 1,4-dioxepine D but also releases the BF3 at
the same time.
It is well-known that the asymmetric reactions attract
more and more attention. As part of the examination to this
system, we tried to find suitable chiral catalyst to enhance the
enantioselectivity and diastereoselectivity, 4 and 5 were used
as catalysts. Unfortunately, the use of 4 only gave 3e in 16%
yield and 23% ee (Table 3, entry 1). When we changed the
catalyst to 5, no product could be obtained (Table 3, entry 2).
Moderate yield 3e with 27.3% ee was obtained when 5% 5
and 5% Ti(OiPr)4 were employed (Table 3, entry 3). It is
delightedly that 53% yield and 43.5% ee 3e could be provided in
the present of 5% 5 and 5% Ti(OiPr)4 when changing the
solvent from DCM to toluene (Table 3, entry 4). This is the
best result which has been achieved by our group until now,
because both changing the ratio of 5 and Ti(OiPr)4 (Table 3,
entries 5 and 6) and lowering the temperature failed to afford
higher ee (Table 3, entry 7). Studies on the diastereo- and
enantioselectivity are proceeding in our group.
methodologies for the synthesis of seven-membered oxacycles.
Also, the reaction could be a useful method for the preparation
of a great number of natural compounds. Preliminary explora-
tion of the asymmetric synthesis of these seven-membered
oxacycles was carried out and product with moderate ee value
was obtained. Futher studies are currently under investigation
and will be presented in a due time.
Experimental Section
General Procedure. To a solution of (C2H5)2OBF3 (0.05 mmol)
in CHCl3 (2.5mL), R,β-unsaturated carbonyl (1.0 mmol) was added.
The mixture was cooled in an ice bath. Then epoxide (1 mmol) was
added dropwise and the resulting mixture was stirred for 2-8 h
at room temperature. The reactions were monitored by TLC (1: 5
ethyl acetate: petroleum ether). After evaporation of the solvents,
the residue was purified by silica gel column chromatography (1: 40
ethyl acetate: petroleum ether).
2-Dimethyl-5-phenyl-3,5-dihydro-2H-1,4-dioxepine (3a): pale
yellow oil; Rf = 0.58 (1:5 ethyl acetate/petroleum ether); 67%
yield; 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J=7.32 Hz, 2H),
7.33 (m, 2H), 7.27 (d, J = 9.16 Hz, 1H), 6.77 (d, J = 15.96 Hz,
1H), 6.18 (dd, J=9.60, 6.36 Hz, 1H), 5.53 (d, J=6.36 Hz, 1H),
3.78 (d, J=7.76, H1), 3.69 (d, J=7.80, H2), 1.39 (s, 3H), 1.37 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 136.0, 134.9, 128.6 (2C),
128.4, 127.1(2C), 126.2, 103.6, 79.2, 76.3, 26.8, 25.2; IR (KBr)
3030, 1722,1675, 1495, 1163, 1141, 961, 890, 748 cm-1; HRMS
(ESIþ) calcd for C13H16O2, 204.1150; Found 204.1151.
5-(Furan-2-yl)-2,2-dimethyl-3,5-dihydro-2H-1,4-dioxepine (3b):
pale yellow oil; Rf=0.62 (1:5 ethyl acetate/petroleum ether); 69%
yield; 1H NMR (400 MHz, CDCl3) δ 7.36 (d, J=1.28 Hz, 1H),
6.56 (d, J=15.88 Hz, 1H), 6.36 (dd, J=2.64, 1.76 Hz, 1H), 6.31
(d, J = 3.28, 1H), 6.11 (dd, J = 9.72, 6.16 Hz, 1H), 5.49 (d, J =
6.08, Hz 1H), 3.75 (d, J=7.76 Hz, H1), 3.67 (d, J=7.76 Hz, H2),
1.36 (s, 3H), 1.34 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 151.9,
142.7, 124.7, 122.4, 111.5, 109.7, 103.2, 79.2, 76.2, 26.8, 25.2; IR
In summary, we have developed a novel intermolecular
[4þ 3] cycloaddition of R,β-unsaturated carbonyls with epoxides.
This one-step reaction is carried out by using (C2H5)2OBF3 as
catalyst under mild conditions and gives 1,4-dioxide deriva-
tives with satisfactory yields in a short time. It enriches the
(KBr) 2924, 1722, 1463,1258, 1138, 1064, 1013, 955, 733 cm-1
;
HRMS (ESIþ) calcd for C11H14O3, 194.0943; Found 194.0903.
2,2,7-Trimethyl-5-phenyl-3,5-dihydro-2H-1,4-dioxepine (3e):
pale yellow oil; Rf = 0.60 (1:5 ethyl acetate/petroleum ether);
J. Org. Chem. Vol. 76, No. 2, 2011 671

Zhou et al.
JOCNote
65% yield; 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J=7.36 Hz,
2H), 7.34-7.30 (m, 2H), 7.25 (d, J=6.56, 1H) 6.72 (d, J=15.96
Hz, 1H), 6.21 (d, J = 15.96 Hz, 1H), 3.78 (d, J = 8.08 Hz, H1),
3.69 (d, J=8.08 Hz, H2), 1.56 (s, 3H), 1.36 (s, 3H), 1.35 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 136.5, 131.5, 129.3, 128.7 (2C),
127.9, 126.8 (2C), 108.3, 79.7, 75.3, 27.6, 27.1, 26.1; IR (KBr)
3060, 1722, 1458, 1369, 1222, 1173, 1099, 1047, 961, 890, 748,
692 cm-1; HRMS (ESIþ) calcd for C14H18O2, 218.1307; Found
218.1250.
2,3,7-Trimethyl-5-phenyl-3,5-dihydro-2H-1,4-dioxepine (3f1):
white oil; Rf = 0.68 (1:5 ethyl acetate/petroleum ether); 68%
yield; 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J=7.36 Hz, 2H),
7.34-7.30 (m, 2H), 6.71 (d, J=15.92 Hz, 1H), 6.17 (d, J=15.92
Hz, 2H), 4.24 (m, 1H), 4.23 (m, 1H), 1.58 (s, 3H), 1.21 (d, J =
4.52 Hz,3H), 1.18 (d, J = 4.48 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 136.4, 130.8, 129.3, 128.6 (2C), 127.8, 126.8 (2C),
106.1, 73.9 (2C), 27.2, 15.5 (2C); HRMS (ESIþ) calcd for
C14H18O2, 218.1307; Found 218.1273.
(m, Ha), 3.52 (m, Hb), 1.59 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
136.0, 130.1, 129.3, 128.7(2C), 128.2, 126.9(2C), 109.2, 75.7, 67.4,
44.8, 26.1; HRMS (ESIþ) calcd for C13H15ClO2, 238.0761; Found
238.0771.
4-Methyl-2-phenyl-5a,6,7,8,9,9a-hexahydro-2H-benzo[b][1,4]-
dioxepine(3i): Pale yellow oil; Rf = 0.61 (1:5 ethyl acetate/petro-
leum ether); 58% yield; 1H NMR (400 MHz, CDCl3) δ7.41-7.43
(m, 2H), 7.34-7.30 (m, 2H) 7.26-7.24 (m, 1H), 6.76 (d, J=15.92
Hz, 1H), 6.27 (d, J=15.96 Hz, 1H), 3.35-3.38 (m,1H), 3.34-3.30
(m, 1H), 2.16-2.15 (m, 2H), 1.83-1.80 (m, 2H), 1.59 (s, 3H),
1.51-1.46 (m, 2H), 1.30-1.26 (m, 2H); 3C NMR (100 MHz,
CDCl3) δ 136.5, 130.9, 129.1, 128.6(2C), 127.9,126.9(2C), 107.3,
80.7, 80.2, 29.0, 28.8, 26.3, 23.8(2C); HRMS (ESIþ) calcd for
C16H20O2, 244.1463; Found, 244.1462.
Acknowledgment. We thank the National 973 Program
(NO. 2010CB732202) Foundation for financial support.
2-(Chloromethyl)-7-methyl-5-phenyl-3,5-dihydro-2H-1,4-dioxepine
(3g1): pale yellow oil; Rf=0.68 (1:5 ethyl acetate/petroleum ether);
73% yield; 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 1.52 Hz,
2H), 7.35 (m, 2H), 7.27 (m, 1H), 6.70 (d, J=15.96 Hz, 1H), 6.12 (d,
J=15.92 Hz, 1H), 4.34 (m, 1H), 4.05 (m, H1), 3.95 (m, H2), 3.62
Supporting Information Available: General experimental
method, 1H NMR, 13C NMR, and MS data for 3a-3i, IR
spectra data for 3a, 3b, and 3e, and copies of 1H and 13C NMR
spectra for the all the new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
672 J. Org. Chem. Vol. 76, No. 2, 2011