Use of the bifunctional reagent (Z)-4-iodo-1-(tributylstannyl)but-1-ene: A new cyclohexenone annulation method

Article abstract of DOI:10.1055/s-1998-1707

A new cyclohexenone annulation method, based on the use of the bifunctional reagent (Z)-4-iodo-1-(tributylstannyl)but-l-ene (6) and exemplified by conversion of the substrate 8 into the annulated products 13 and 18 and of the starting materials 19-23 into the products 34-38, respectively, is described.

Full text of DOI:10.1055/s-1998-1707

516
LETTERS
SYNLETT
Use of the Bifunctional Reagent (Z)-4-Iodo-1-(tributylstannyl)but-1-ene: A New
Cyclohexenone Annulation Method
Edward Piers*, Serge L. Boulet
Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia, Canada V6T 1Z1
Fax 604-822-2847; Bitnet epier@unixg.ubc.ca
Received 23 January 1998
Abstract: A new cyclohexenone annulation method, based on the use of
the bifunctional reagent (Z)-4-iodo-1-(tributylstannyl)but-1-ene (6) and
exemplified by conversion of the substrate 8 into the annulated products
13 and 18 and of the starting materials 19–23 into the products 34–38,
respectively, is described.
without full characterization of the intermediates 9 and 10, proceeded in
92% overall yield.
Functionalized six-membered carbocyclic rings are very common
structural features of many classes of natural products and, over the
years, a number of methods have been developed for the conversion of
ketones into annulated cyclohexenones, as indicated by the generalized
1-6
transformation of 1 into 2 (Scheme 1). Although the best known of
1-6
these methods is probably the Robinson annulation, other protocols
1-5
have also been devised. We report herein a new six-membered ring
annulation method that is based on the theoretical combination of the
7
two acceptor–donor synthons 3 and 4, followed by oxidative con-
version of the resultant tertiary allylic alcohol 5 into the corresponding
enone 2. Clearly, the ketone 1 correlates with the synthon 3, while we
have employed (Z)-4-iodo-1-(tributylstannyl)but-1-ene (6) as the
synthetic equivalent of the synthon 4.
Scheme 2
Slow addition of a solution of intermediate 11 in THF to a solution of
16
butyllithium (2.5 equivalents) in cold THF, followed by a reaction
time of one hour and workup with aqueous NaHCO , produced an
3
excellent yield of the alkenol 12, which proved to be a mixture of two
epimers in a ratio of approximately 1:1. Treatment of this material with
17
18
pyridinium chlorochromate (PCC) on alumina effected the required
19
rearrangement–oxidation sequence and provided the enone ketal 13
(89%). Thus, the overall yield of the annulation product 13 from the
hydrazone 8 was over 75%.
The enone 18, related in structure to 13 but possessing an angular
methyl group, was also readily prepared via this methodology (Scheme
Scheme 1
8
The iodide 6 was readily prepared by treatment of the corresponding
9
10
alcohol 7 with Ph P•I in the presence of imidazole (Equation 1).
3
2
Equation 1
The new annulation method is illustrated by the preparation of the enone
11
12
ketal 13 (Scheme 2). The dimethylhydrazone 8 is readily obtained
from the corresponding, commercially available ketal ketone. Treatment
of 8 with lithium diisopropylamide (LDA) in tetrahydrofuran (THF),
followed by addition of hexamethylphosphoramide (HMPA) and the
13
bifunctional reagent 6, afforded the alkylated product 9. Iodo-
14
destannylation of the latter (crude) material afforded 10, which, upon
15
treatment with buffered acetic acid in THF–water, provided the keto
iodide 11. The conversion of 8 into 11, which was accomplished
Scheme 3

May 1998
SYNLETT
517
3). Hydrolysis (NaOAc, HOAc, H O, THF) of the hydrazone 9 gave the
2
ketone 14 (>90% yield). Sequential treatment of the latter material with
potassium tert-butoxide (THF, 60 °C) and excess MeI (THF, -78°C)
20
produced, as the major product (70% yield), the mono-alkylated
compound 15, which was transformed smoothly into the corresponding
iodide 16. Butyllithium–mediated cyclization of 16 provided a single,
21
crystalline (mp 89-91 °C) allylic alcohol 17, which, upon reaction
with PCC on alumina, afforded the enone 18 in 76% overall yield from
the keto stannane 15.
Additional examples of the new annulation method are summarized in
the Table. The hydrazones 19–23 were converted into the corresponding
iodo ketones 24–28 via three-step protocols very similar to that outlined
in Scheme 2 for the transformation of 8 into 11. Thus, in each case, the
starting material was alkylated with the iodide 6, the crude product was
immediately subjected to iododestannylation, and the resultant
hydrazone–iodide was hydrolyzed to the required iodo ketone. The
intermediate products (corresponding to 9 and 10 in Scheme 2) were
used as crude materials and were not fully characterized. The yields of
24–28 given in the Table represent overall yields from the hydrazones
19–23, respectively. It should be noted that the iodo ketone derived
from the hydrazone 21 consisted of a mixture of epimers with respect to
the stereochemical orientation of the newly introduced side chain.
Equilibration (NaOMe, MeOH, room temperature) of this material
provided 26.
Butyllithium–mediated cyclization of each of the iodo ketones 24-28
was accomplished as outlined earlier for the conversion 11→12
(Scheme 2). The bicyclo[5.4.0]undecenol 33 (cyclization of 28) was
22
obtained as a mixture of diastereomers, while each of the allylic
alcohols 29-32 proved to be a single (racemic) substance. Although the
relative configuration of the carbinol stereogenic center in each of 29-32
was not definitively established, molecular modelling suggests that the
newly formed ring fusion in 29 and 30 should be cis, while that in 31
23
and 32 is likely to be trans.
Although the conversions 11→12, 16→17, and 26→31 were very clean
and produced no detectible byproducts, the allylic alcohols 29, 30, 32,
and 33 were accompanied by minor amounts (~8%, 17%, 14%, and 6%,
respectively) of the corresponding uncyclized materials in which the
iodine in the starting material had been replaced by a hydrogen.
Fortunately, these substances were readily separated from the required
alcohols by means of silica gel chromatography.
(217 mg, 0.574 mmol) in dry THF (2 mL). The reaction mixture was
stirred at -78 °C for 1 h and then was treated with saturated aqueous
Oxidation of the tertiary allylic alcohols 29–33 with PCC on alumina
provided the corresponding cyclohexenones 34–38 in moderate to
excellent yields. The volatility of 34 probably accounts for the lower
yield in this case. The reaction involving substrate 32 produced a
number of minor byproducts. Since the tertiary hydroxyl group in 32 is
also both allylic and benzylic, it is likely that this material is quite
susceptible to conversion into a carbocation. The observed occurrence
of minor processes in competition with the desired oxidation reaction is,
therefore, not unexpected.
NaHCO (15 mL). The mixture was warmed to room temperature,
3
diluted with diethyl ether (15 mL) and water (15 mL), and the layers
were separated. The aqueous layer was extracted three times with
diethyl ether. The combined organic extracts were washed with brine,
1
dried (MgSO ), and concentrated. The H NMR spectrum of the crude
4
oil indicated a 1:1 mixture of epimeric alcohols 12, as determined by the
integration of the vinyl signals for each diastereomer. Flash
chromatography (10 g TLC–grade silica gel, 1:1.5 petroleum ether–
diethyl ether) of this material afforded, after concentration of the
appropriate fractions and removal of traces of solvent (vacuum pump),
the allylic alcohols 12 (140 mg, 96%), as a viscous semi-solid.
Subjection of a sample of this material to flash chromatography (TLC–
grade silica gel, 1:1.5 petroleum ether–diethyl ether) led to the isolation
In summary, a new cyclohexenone annulation method has been
developed. The efficacy of the method has been demonstrated by the
annulation of substrates containing five- (19, 20), six- (8, 21, 22), and
seven-membered rings (23). This protocol should find useful
applications in the synthesis of structurally complex molecules.
of a small amount of each diastereomer. The compound that eluted first
1
was an off-white solid that exhibited mp 123-125 °C; H NMR (CDCl ,
3
Experimental Section
400 MHz): δ 0.91 (s, 3H), 0.98 (s, 3H), 1.15-1.21 (m, 1H), 1.37-1.70 (m,
6H), 1.75 (ddd, 1H, J = 13.5, 13.5, 4.4 Hz), 1.88-1.93 (dm, 1H, J for d =
9.7 Hz), 2.03-2.11 (m, 2H), 2.16-2.24 (dm, 1H, J for d = 13.5 Hz), 3.42-
3.58 (m, 4H), 5.66 (br d, 1H, J = 9.8 Hz), 5.73 (ddd, 1H, J = 9.8, 3.1, 3.1
Preparation of the ketal alcohols 12: To a cold (-78 °C), stirred
solution of BuLi (1.4 mmol) in dry THF (28 mL, argon atmosphere) was
added dropwise, via a Teflon cannula, a solution of the keto iodide 11
®

518
LETTERS
SYNLETT
13
Hz); C NMR (CDCl , 75.3 MHz): δ 22.5, 22.7, 23.7, 25.7, 26.9, 30.0,
(4) Larock, R. C. Comprehensive Organic Transformations; VCH
3
34.0, 34.6, 37.8, 66.9, 69.8 (2 carbons), 98.0, 130.1, 133.0. Exact Mass
Publishers: New York, 1989; pp. 668-672.
calcd. for C
H O : 252.1726; found: 252.1724. Anal. calcd.: C 71.39,
15 24 3
(5) Jung, M. E. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 4,
Semmelhack, M. E., Ed.; pp. 6-10.
H 9.59; found: C 71.47, H 9.61 (determined on the 1:1 mixture of the
alcohols 12).
The compound that eluted second was an off-white solid that exhibited
(6) March, J. Advanced Organic Chemistry, 4th ed.; Wiley: New
1
mp 94-95 °C; H NMR (CDCl , 400 MHz): δ 0.92 (s, 3H), 0.98 (s, 3H),
3
York, 1992; pp. 943-944.
1.15-1.27 (m, 1H), 1.32 (ddd, 1H, J = 13.3, 13.3, 4.1 Hz), 1.40-1.57 (m,
2H), 1.63-1.79 (m, 2H), 1.88-2.08 (m, 5H), 2.12-2.20 (dm, 1H, J for d =
(7) Seebach, D. Angew. Chem. Int. Ed. Engl. 1979, 18, 239.
(8) All new, fully characterized compounds reported herein exhibit
spectra in accord with structural assignments and gave satisfactory
elemental analyses and high resolution mass spectrometric
molecular mass determinations.
13.3 Hz), 3.43-3.53 (m, 4H), 5.52 (dd, 1H, J = 10.1, 1.1 Hz), 5.83 (ddd,
13
1H, J = 10.1, 2.9, 2.9 Hz); C NMR (CDCl , 75.3 MHz): δ 21.6, 22.5,
3
22.6, 22.7, 28.5, 30.0, 33.4, 34.6, 37.2, 68.8, 69.7, 70.1, 97.5, 130.9,
131.3. Exact Mass calcd. for C
H O : 252.1726; found: 252.1717.
15 24 3
(9) Barbero, A.; Cuadrado, P.; Fleming, I.; González, A. M.; Pulido,
Preparation of the annulation product 13: To a stirred solution of the
allylic alcohol 12 (105 mg, 0.42 mmol, 1:1 mixture of epimers) in dry
CH Cl (4.0 mL, argon atmosphere) at room temperature was added
F. J.; Rubio, R. J. Chem. Soc. Perkin Trans 1 1993, 1657.
(10) Millar, J. G.; Underhill, E. W. J. Org. Chem. 1986, 51, 4726.
(11) Piers, E.; Friesen, R. W. Can. J. Chem. 1992, 70, 1204.
2
2
PCC on basic alumina (1.06 g, 21.5 wt. % PCC, 1.04 mmol) and the
dark brown mixture was stirred at room temperature for 3.5 h. Dry
diethyl ether (20 mL) was added, the mixture was stirred under an
atmosphere of argon for 1 h, and then was filtered through a column of
(12) Corey, E. J.; Enders, D. Chem. Ber. 1978, 111, 1337; Bergbreiter,
D. E.; Momongan, M. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991;
Vol. 2, Heathcock, C. H., Ed.; pp. 503-525.
®
Florisil (~10 g). The column was eluted with diethyl ether and then
with ethyl acetate until no uv active product could be detected in the
eluate. The combined eluate was concentrated under reduced pressure.
The crude product was purified by flash chromatography (10 g TLC–
grade silica gel, 2.3:1 petroleum ether–diethyl ether). The oil thus
obtained was distilled (bulb-to-bulb, 175-185 °C/0.15 Torr) to afford the
(13) Attempts to alkylate ketone enolates with the iodide 6 resulted
primarily in elimination of HI from the homoallylic electrophile.
This problem was circumvented by the use of the dimethyl-
hydrazone derivatives.
1
enone 13 (92 mg, 89%) as a colourless, viscous oil that displayed H
(14) Piers, E.; Coish, P. D. Synthesis 1995, 47, and citations therein.
(15) Corey, E. J.; Pearce, H. L. J. Am. Chem. Soc. 1979, 101, 5841.
NMR (CDCl , 400 MHz): δ 0.94 (s, 3H), 1.00 (s, 3H), 1.24 (dd, 1H, J =
3
12.9, 12.9 Hz), 1.40-1.50 (m, 1H), 1.56-1.68 (m, 1H), 2.03-2.11 (m,
(16) Piers, E.; Cook, K. L.; Rogers, C. Tetrahedron Lett. 1994, 35,
13
1H), 2.23-2.63 (m, 7H), 3.46-3.58 (m, 4H), 5.83 (s, 1H); C NMR
8573.
(CDCl , 75.3 MHz): δ 22.4, 22.6, 29.0, 30.1, 30.8, 30.9, 33.8, 36.5,
3
(17) Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 2647.
(18) Cheng, Y.-S.; Liu, W.-L.; Chen, S. Synthesis 1980, 223.
(19) Dauben, W. G.; Michno, D. M. J. Org. Chem. 1977, 42, 682.
39.5, 70.1 (2 carbons), 96.8, 124.6, 164.9, 199.5. Exact Mass calcd. for
C
H O : 250.1569; found: 250.1563. Anal. calcd.: C 71.97, H 8.86;
15 22 3
found: C 71.83, H 9.01.
(20) Cf. Piers, E.; Friesen, R. W.; Keay, B. A. Tetrahedron 1991, 47,
Acknowledgements. We are grateful to the Natural Sciences and
Engineering Research Council of Canada for financial support and for a
postgraduate scholarship (to S. L. B.).
4555.
(21) On the basis of examination of molecular models, it seems likely
that cyclization of the organolithium intermediate derived from 16
would occur via attack on the carbonyl carbon from the side
opposite to the adjacent methyl group. Thus, although the relative
configuration of 17 was not rigorously established, one would
predict a cis ring fusion.
References and Notes
(1) Jung, M. E. Tetrahedron 1976, 32, 3.
(2) Gawley, R. E. Synthesis 1976, 777.
(22) These isomers, produced in a ratio of approximately 2.5:1, were
chromatographically separated and individually characterized.
(3) Waring, A. J. In Comprehensive Organic Chemistry; Barton, D.
H. R., Ollis, W. D., Eds.; Pergamon Press: Oxford, 1979; Vol. 1,
Stoddart, J. F., Ed.; pp. 1049-1056.
(23) This issue will be discussed in detail in a full account of this work.