6-(2-Haloethyl)-2,2-dimethyl-4H-1,3-dioxins: versatile haloethyl vinyl ketone equivalents for carbocycle construction

Article abstract of DOI:10.1016/j.tetlet.2006.05.171

6-(2-Iodoethyl)-2,2-dimethyl-4H-1,3-dioxin has been prepared in five steps from ethyl acetoacetate. A variety of enolates were then alkylated with this iodide. The resulting 6-alkyl-4H-1,3-dioxins were either subjected to further transformations and/or he

Full text of DOI:10.1016/j.tetlet.2006.05.171

Tetrahedron Letters 47 (2006) 5437–5439
6-(2-Haloethyl)-2,2-dimethyl-4H-1,3-dioxins: versatile
haloethyl vinyl ketone equivalents for carbocycle construction
Thomas J. Greshock and Raymond L. Funk*
Department of Chemistry, The Pennsylvania State University, University Park, PA 16802, United States
Received 17 May 2006; revised 19 May 2006; accepted 30 May 2006
Abstract—6-(2-Iodoethyl)-2,2-dimethyl-4H-1,3-dioxin has been prepared in five steps from ethyl acetoacetate. A variety of enolates
were then alkylated with this iodide. The resulting 6-alkyl-4H-1,3-dioxins were either subjected to further transformations and/or
heated (or subjected to a Lewis acid) to effect facile retrocycloaddition reactions. The resulting enones were found to smoothly par-
ticipate in conjugate addition or olefin metathesis reactions to provide various carbocyclic ring systems. Collectively, these examples
document the synthetic equivalency of dioxin 2 with iodoethyl vinyl ketone and, moreover, delineate a strategy for accomplishing
the sequential reactions with nucleophiles at the b0, followed by the b electrophilic sites.
Ó 2006 Elsevier Ltd. All rights reserved.
O
O
The discovery of more convenient and efficient strategies
for hetero- and carbocyclic ring construction is an ongo-
ing endeavor. For years, sequential reactions of doubly
nucleophilic compounds with bis electrophiles have been
a cornerstone method in achieving this goal.1 Haloalkyl
vinyl ketones represent a potentially valuable class of bis
electrophiles that could be employed in this general
strategy. However, only a few examples of this type of
cyclization have been reported,2 probably because of a
lack of selectivity between the b enone and halocarbon
electrophilic sites, and sensitivity of these compounds
to basic reaction conditions conspire to render most
strategies problematic. To circumvent these inherent
problems, we recently reported the use of 6-bromo-
methyl-4H-1,3-dioxin (1)3 as a bromomethyl vinyl
ketone equivalent (Fig. 1), which permitted its unambig-
uous initial alkylation (including the use of highly basic
Nu1
Nu Cm
O
O
O
1.
2
Cn
Nu1
Nu2 Cm
Cn
Nu1
Nu2 Cm
Cn
X
Cn
X
2.
Δ
Nu
-CH2O
O
O
O
O
Br
I
2
1
Figure 1.
The synthesis of iodide 2 (Scheme 1) commenced with
cyclization of the known b-ketoester 34 to the acetonide
4 upon treatment with 2-methoxypropene and pyridi-
nium tosylate in THF. The acetonide is formed rela-
tively quickly in this reaction (1–2 h); however, a large
amount of the exocyclic conjugated ester is initially
produced. Allowing the reaction to stir for an extended
`
nucleophiles) on the halocarbon electrophilic site vis-a-
vis the b enone carbon. Following a mild thermal
retrocycloaddition reaction of the 1,3-dioxin, the second
nucleophilic site could then be activated to undergo a
conjugate addition into the newly derived enone to fur-
nish a variety of hetero- and carbocyclic compounds.
We now wish to report the preparation and utility of
the homologous reagent, 6-(2-iodoethyl)-2,2-dimethyl-
4H-1,3-dioxin (2), as a haloethyl vinyl ketone equivalent
for the construction of carbocyclic ring systems.
OMe
OH
O
O
1. LAH
99%
O
O
O
O
O
2. PPh3, I2
imidazole
71%
PPTS
16h, rt
OEt
R
OEt
85%
2
5
R = I
3
4
or
CBr4, PPh3
Et3N, CH2Cl2
R = Br
80%
*
Corresponding author. Tel.: +1 814 865 2057; fax: +1 814 863
8403; e-mail: rlf@chem.psu.edu
Scheme 1.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.171

5438
T. J. Greshock, R. L. Funk / Tetrahedron Letters 47 (2006) 5437–5439
period of time produces almost exclusively the desired
endocyclic isomer 4. Next, reduction of the ester moiety
with LiAlH4, followed by Mitsunobu reaction (PPh3, I2,
imidazole) of the resultant alcohol successfully produced
iodoethyl dioxin 2 in good yield. It should be noted that
this compound is not nearly as stable as bromomethyl
dioxin 1,3 and it was found to readily polymerize if left
on the benchtop for an extended period of time. It can,
however, be stored in the freezer (ꢀ50 °C) for several
months with no noticeable decomposition. The analo-
gous bromide 5 was also prepared from the correspond-
ing alcohol (CBr4, PPh3, Et3N) in an attempt to obtain a
more stable alkylating agent. However, bromide 5
seemed to decompose just as readily at room tempera-
ture as the iodide. Thus, once prepared, the haloethyl
dioxins 2 and 5 were immediately stored in the freezer
until ready for use.
O
O
O
O
2 equiv
LDA;
Tf2O
O
O
OH
O
OTf O
i
-Pr2NEt
2
O
O
O
CH2Cl2
-78 oC, 15 min
THF
rt
59%
90%
11
10
9
Pd2(dba)2
LiCl, NMP
73%
O
SnBu3
O
O
O
Mes
N
N
Mes
Ph
Cl
Ru
110 o
C
O
O
O
Cl
P(Cy)3
toluene
O
O
O
CH2Cl2
reflux, 16 h
1 h
61% 2 steps
14
Scheme 3.
13
12
We first examined the alkylation reactions of iodide 2
with b-ketoester Weiler dianions.5 Indeed, the dianion
of ethyl acetoacetate (6) can be smoothly alkylated with
iodide 2 to afford dioxin 7 (Scheme 2). Thermolysis of
dioxin 7 effected a clean retrocycloaddition reaction to
produce the desired enone, which was subsequently
found to undergo a facile 8-endo conjugate addition
reaction when subjected to conditions (0.2 equiv of
Cs2CO3, CH3CN)6 we had previously employed for
the related 7-endo ring closures of acyclic b-ketoesters.3
To the best of our knowledge, this is the first example of
an endo-Michael addition of an endocyclic enolate lead-
ing to an eight-membered ring.
O
O
O
O
OMe
O
O
NaHMDS
PhNTf2
NaH;
O
OMe
OMe
2
O
O
TfO
THF
DMF
rt, 4 h
o
-78 C - rt
16
15
81%
17
86%
Pd2(dba)2
LiCl, NMP
82%
SnBu3
O
Mes
N
N
Mes
O
Cl
O
O
O
O
Ru
O
Ph
P(Cy)3
Cl
ZnCl2
C, 3 h
OMe
OMe
In addition to the Michael addition reaction illustrated
in Scheme 2, we have also found retrocycloaddition
products to be useful substrates in olefin metathesis
reactions (Scheme 3). To that end, iodide 2 was alkyl-
ated with the dianion prepared from b-ketoester 9.
Alkylation product 10, which preferred to exist in its
OMe
0
CH2Cl2
˚
CH2Cl2
reflux, 16 h
72% 2 steps
18
19
20
Scheme 4.
enol form, was easily sulfonylated with Tf O and Hu-
¨
2
a Lewis acid. In this case, a competing thermally in-
duced intramolecular cycloaddition reaction of enone
19 warranted the use of ZnCl2 as a mild alternative in
the retrocycloaddition reaction of dioxin 18.
nigs base to provide enol triflate 11. Stille coupling with
tributylvinyltin, followed by thermolysis of the resultant
dienoate 12, effected a facile retrocycloaddition (110 °C,
1 h) to give rise to the desired enone 13. Finally, enone
13 underwent an olefin metathesis reaction to give the
bicyclic dienone 14 in good yield using Grubb’s second
generation catalyst.7
In addition to using the haloethyl dioxins as electro-
philes in nucleophilic displacement reactions, we also
examined their utility as nucleophiles in conjugate addi-
tion reactions (Scheme 5). We were pleased to find that
the 2-thienylcyanocuprate reagent8 of bromodioxin 5
could be prepared and used in a conjugate addition with
the a,b-unsaturated ketoester 21. The retrocycloaddition
product derived from dioxin 22 was found to be unsta-
ble and could not be isolated. However, upon heating
dioxin 22 in the presence of Cs2CO3, the b-ketoester
In a similar application, we have also been able to pre-
pare tetrahydroazulenone 20 through olefin metathesis
of its enone precursor 19 (Scheme 4). In this sequence,
iodide 2 was successfully alkylated with the less reactive
enolate of methyl cyclopentanone-2-carboxylate (15). In
addition, we also found that retrocycloadducts could be
obtained through treatment of the requisite dioxin with
O
2 equiv
LDA;
O
O
O
O
O
O
O
5
-BuLi;
1. 110 o
toluene, 1 h
C
Cs2CO3
CH3CN
O
O
O
t
O
2
O
O
O
O
110 oC, 1.5 h
O
74%
Li
CuCN
ether, -78 o
O
THF
rt
2. Cs2CO3
CH3CN
rt, 16 h
74%
EtO
EtO
O
S
O
EtO
O
C
68%
22
23
21
Scheme 5.
8
7
6
51%
Scheme 2.

T. J. Greshock, R. L. Funk / Tetrahedron Letters 47 (2006) 5437–5439
5439
chloride, followed by hydrogenation (Pd(OH)2, H2) of the
benzyl group, see: Moyer, M. P.; Feldman, P. L.; Rapo-
port, H. J. Org. Chem. 1985, 50, 5223.
anion effectively trapped the enone intermediate, thus
producing hydroazulene 23 in good yield. The cis-stereo-
chemistry was assigned based on similar Michael
addition reactions reported by Deslongchamps,6 in
which b-ketoesters were transformed to cis-hydro-
azulenes.
5. Weiler, L.; Huckin, S. N. Can. J. Chem. 1974, 52, 2157.
´
6. Berthiaume, G.; Lavallee, J.-F.; Deslongchamps, P. Tetra-
hedron Lett. 1986, 27, 5451.
7. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett.
1999, 1, 953.
In conclusion, we have prepared 6-haloethyl-4H-1,3-
dioxins and used them as haloethyl vinyl ketone equiva-
lents for the construction of a variety of carbocyclic ring
systems. The homoallylic halide moiety of iododioxin 29
is sufficiently reactive to allow for facile substitution by
a variety of nucleophiles. The 1,3-dioxin ring is quite
robust and permits, if necessary, further multistep trans-
formations of the alkylation products. The potentially
sensitive enone moiety can then be released under mild,
thermal or Lewis acid mediated conditions, and
smoothly participates in a variety of ring closure reac-
tions forming carbocyclic ring systems.
8. Lipshutz, B. H.; Koerner, M.; Parker, D. A. Tetrahedron
Lett. 1987, 28, 945.
9. Preparation of dioxin 2:
(2,2-Dimethyl-6H-[1,3]dioxin-4-yl)acetic acid ethyl ester
(4). To a solution of alcohol 34 (5.16 g, 32.2 mmol) in THF
(105 mL) at 0 °C was added 2-methoxypropene (9.26 mL,
96.7 mmol), followed by pyridinium p-toluenesulfonate
(2.43 g, 9.67 mmol). The resulting mixture was warmed to
rt and stirred for 16 h. To the resulting solution was added
solid Na2CO3 (10 g). The mixture was stirred at rt for 1 h,
filtered, and concentrated. Purification by silica gel chro-
matography (ethyl acetate–hexanes, 1:4) provided dioxin 4
as a colorless oil (5.48 g, 85%); 1H NMR (200 MHz,
CDCl3): d 1.25 (t, J = 7.5 Hz, 3H), 1.47 (s, 6H), 3.03 (s,
2H), 4.17 (q, J = 7.5 Hz, 2H), 4.20 (m, 2H), 4.78 (m, 1H).
2-(2,2-Dimethyl-6H-[1,3]dioxin-4-yl)ethanol. To a solution
of LiAlH4 (1.06 g, 28.0 mmol) in ether (215 mL) at 0 °C was
added ester 4 (4.32 g, 21.6 mmol) in ether (15 mL) dropwise
over 10 min. The mixture was stirred at 0 °C for 20 min.
The resulting solution was quenched successively with H2O
(1.1 mL), 10% NaOH (1.7 mL), and H2O (3.3 mL). The
resulting mixture was filtered, washed with ether, and
concentrated. Purification by silica gel chromatography
(ethyl acetate–hexane, 2:3) provided the alcohol as a
colorless oil (3.40 g, 99%); 1H NMR (200 MHz, CDCl3):
d 1.43 (s, 6H), 2.28 (t, J = 6.2 Hz, 2H), 3.75 (m, 2H), 4.19
(m, 2H), 4.71 (t, J = 2.7 Hz, 1H); 13C NMR (50 MHz,
CDCl3): d 24.0, 37.1, 58.9, 59.6, 95.4, 98.6, 148.4. HRMS
(MH+) calcd for C8H14O3 158.0937, found 158.0934.
6-(2-Iodoethyl)-2,2-dimethyl-4H-1,3-dioxin (2). To a solu-
tion of the above alcohol (611 mg, 3.86 mmol) in THF
(38 mL) at 0 °C was added imidazole (605 mg, 8.89 mmol),
PPh3 (1.11 g, 4.25 mmol), and iodine (1.08 g, 4.25 mmol).
The resulting solution was stirred at 0 °C for 1 h. The
mixture was quenched with 10% aqueous Na2S2O3 and
extracted with ether. The combined extracts were dried
(Na2SO4) and concentrated. Purification by silica gel
chromatography (ethyl acetate–hexane, 1:19) afforded
iodide 2 as a colorless oil (734 mg, 71%); 1H NMR
(300 MHz, CDCl3): d 1.43 (s, 6H), 2.53 (t, J = 7.1 Hz,
2H), 3.22 (t, J = 7.1 Hz, 2H), 4.13 (m, 2H), 4.66 (t,
J = 2.6 Hz, 1H); 13C NMR (75 MHz, CDCl3): d 2.3, 24.3,
38.1, 58.9, 95.9, 98.8, 148.8. HRMS (MH+) calcd for
C8H13IO2 267.9955, found 267.9944.
Acknowledgment
We appreciate the financial support provided by the
National Institutes of Health (GM28553).
References and notes
1. For several examples of bis electrophiles in organic
synthesis, see (a) Matsumoto, T.; Masu, H.; Yamaguchi,
K.; Takeda, K. Org. Lett. 2004, 6, 4367; (b) Wasserman, H.
H.; Parr, J. Acc. Chem. Res. 2004, 37, 687; (c) Balskus, E.
P.; Mendez-Andino, J.; Arbit, R. M.; Paquette, L. A. J.
Org. Chem. 2001, 66, 6695; (d) Hussenether, T.; Troschuetz,
R. J. Heterocycl. Chem. 2004, 41, 857; (e) Bennett, G. B.;
Simpson, W. R. J.; Mason, R. B.; Strohschein, R. J.;
Mansukhani, R. J. Org. Chem. 1977, 42, 221; (f) Jones, R.
C. F.; Patel, P. Tetrahedron 1998, 54, 6191.
2. For a few examples of halomethyl vinyl ketones used as bis
electrophiles in ring construction sequences, see: (a) How-
ard, A. S.; Katz, R. B.; Michael, J. P. Tetrahedron Lett.
1983, 24, 829; (b) Frontier, A. J.; Danishefsky, S. J.;
Koppel, G. A.; Meng, D. Tetrahedron 1998, 54, 12721; (c)
Westerlund, A.; Gras, J.-L.; Carlson, R. Tetrahedron 2001,
57, 5879.
3. Greshock, T. J.; Funk, R. L. J. Am. Chem. Soc. 2002, 124,
754.
4. Prepared in two steps from ethyl acetoacetate by alkylation
of its dianion (2 equiv LDA, THF) with benzyloxymethyl-