An Intramolecular Prins Double Cyclization Catalyzed by Silyl Triflates

Article abstract of DOI:10.1021/jo971337v

Several intramolecular Prins double cyclizations are reported. The 2-alkyl 5-hepten-1,2-diols and their analogues, 9-11, were prepared and oxidized to the aldehydes 6-8 under Swern conditions. Treatment of these α-hydroxy aldehydes with TBSOTf and a hindered base gave the products of an intramolecular Prins double cyclization, namely the 7-(silyloxy)-2-oxabicyclo[2.2.1]heptanes, 17- 19, in 84-92% yield. These compounds were formed as single diastereomers with only the anti silyl ethers being obtained. The cyclizations occur when five-membered rings are being formed and when the initially formed cation is highly stabilized. Other substrates do not cyclize, e.g., when the α-hydroxy aldehydes 20-22, prepared from 26-28, are treated under similar conditions, none of the corresponding cyclization products, 23-25, were obtained.

Full text of DOI:10.1021/jo971337v

9182
J . Org. Chem. 1997, 62, 9182-9187
An In tr a m olecu la r P r in s Dou ble Cycliza tion Ca ta lyzed by Silyl
Tr ifla tes1
Michael E. J ung,*,2 Steve Angelica, and Derin C. D’Amico3
Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095-1569
Received J uly 22, 1997X
Several intramolecular Prins double cyclizations are reported. The 2-alkyl 5-hepten-1,2-diols and
their analogues, 9-11, were prepared and oxidized to the aldehydes 6-8 under Swern conditions.
Treatment of these R-hydroxy aldehydes with TBSOTf and a hindered base gave the products of
an intramolecular Prins double cyclization, namely the 7-(silyloxy)-2-oxabicyclo[2.2.1]heptanes, 17-
19, in 84-92% yield. These compounds were formed as single diastereomers with only the anti
silyl ethers being obtained. The cyclizations occur when five-membered rings are being formed
and when the initially formed cation is highly stabilized. Other substrates do not cyclize, e.g.,
when the R-hydroxy aldehydes 20-22, prepared from 26-28, are treated under similar conditions,
none of the corresponding cyclization products, 23-25, were obtained.
Sch em e 1
In the attempted protection of the R-hydroxy aldehyde
1 as the triethylsilyl ether, in addition to the expected
product 2, which was isolated in 17% yield, we isolated
the double cyclization product 3 in 40% yield as the
primary product.4 We discovered that triethylsilyl tri-
flate in the presence of collidine catalyzed an intramo-
lecular Prins reaction presumably via the silylated
aldehyde 4, which was attacked by the trisubstituted
alkene to produce the tertiary carbocation 5 as an
intermediate which then was trapped by the alcohol in
a second intramolecular cyclization (Scheme 1). We
wanted to investigate the generality and scope of this
novel reaction with related substrates. We also thought
that a more hindered reagent such as tert-butyldimeth-
ylsilyl triflate (TBSOTf) might give a higher yield of 5
by discouraging the competing protection of the alcohol
to give the analogue of 2 and thereby favoring the
production of the analogue of 3.
Sch em e 2
A search of the literature revealed only a few prece-
dents for this kind of tandem reaction. Kiyooka demon-
strated an intermolecular Prins reaction where a car-
bobenzyloxy-protected nitrogen formed the second bond,
in that case resulting in a single ring.5 In attempting
an ene reaction starting from an acetal, Bertrand ob-
served a mixture of products including one in which the
liberated alcohol trapped the generated cation.6 But the
general use of an intramolecular Prins reaction to
prepare 2-oxabicyclo[2.2.1]heptane-7-ol derivatives was
unknown.
As a general method for accessing these δ-olefinic
R-hydroxy aldehydes 6-8, we chose to synthesize the
diols 9-11 (Scheme 2) by a variety of routes and then to
use the Swern oxidation7 to produce the desired sub-
strates. The diol 9 was available in two steps and 74%
overall yield by coupling (benzyloxy)methyl chloride
(BOM-Cl)8 and 6-methyl-5-hepten-2-one (12) in the pres-
ence of samarium diiodide (88% yield) followed by dis-
solving metal reduction of the benzyl group (83% yield).
The diol 10 was prepared by the addition of the Grignard
reagent of the known9 bromide 13 to sodium R-ketobu-
tyrate (14) followed by hydride reduction. Finally the
cinnamyl diol 11 was prepared by addition of the Grig-
nard reagent of the known10 bromide 15 to 1-[(tetrahy-
drofuranyl)oxy]acetone 16 followed by acidic hydrolysis.
Of the various possible oxidation methods, the Swern
oxidation proved to be the most reliable, converting the
diols 9-11 into the desired R-hydroxy aldehydes 6-8 in
X Abstract published in Advance ACS Abstracts, December 1, 1997.
(1) Presented at the 213th National Meeting of the American
Chemical Society, Las Vegas, NV, September 1997.
(2) American Chemical Society Arthur C. Cope Scholar, 1995.
(3) UCLA Department of Chemistry Prize for Excellence in Research
1993-94; UCLA Dissertation Year Fellowship 1994-95. Current
address: Zeneca Pharmaceuticals, Wilmington, DE 19850-5437.
(4) D′Amico, D. C. Ph.D. Dissertation, University of California, Los
Angeles, 1995.
(5) Kiyooka, S., Shiomi, Y., Kira, H., Kaneko, Y.; Tanimori, S. J .
Org. Chem. 1994, 59, 1958.
(6) Bertrand, M., Rousmestant, M-L.; Sylvestre-Panthet, P. J .
Chem. Soc., Chem. Commun. 1979, 529.
(8) Imamoto, T., Takeyama, T.; Yokoyama, M. Tetrahedron Lett.
1984, 25, 3225.
(9) Biernacki, W.; Gdula, A. Synthesis 1979, 37.
(10) McCormick, J . P.; Barton, D. L. J . Org. Chem. 1980, 45, 2566.
(7) Mancuso, A. J .; Swern, D. Synthesis 1981, 165.
S0022-3263(97)01337-6 CCC: $14.00 © 1997 American Chemical Society

Prins Double Cyclization Catalyzed by Silyl Triflates
J . Org. Chem., Vol. 62, No. 26, 1997 9183
Sch em e 3
Sch em e 4
good yields. These compounds proved to be somewhat
unstable, decomposing on attempted chromatography on
silica gel and therefore were generally carried forward
in dichloromethane solution to the next reaction, the key
double cyclization.
22 to give compound 25 would have required the forma-
tion of a six-membered ring from the initial Prins
reaction, a process which is known to be less facile.12
Attempts to use stronger Lewis acids, e.g., various alkyl-
substituted aluminum halides, did not give better results.
Thus, in summary, we have demonstrated a novel
intramolecular Prins double cyclization reaction effective
for a family of related R-hydroxy aldehydes with a
properly spaced and electron-rich double bond. We have
optimized this reaction to afford yields of 84-92% for the
two steps from the corresponding diols including a Swern
oxidation. Further research is currently underway in
this area.
As shown in Scheme 3, treatment of the R-hydroxy
aldehydes 6-8 with tert-butyldimethylsilyl triflate and
the hindered base 2,6-di-tert-butyl-4-methylpyridine
(DBMP) afforded the desired intramolecular Prins prod-
ucts 17-19 in yields of 84-92% over the two steps from
the diols 9-11. Thus this intramolecular Prins double
cyclization works well for systems forming five-membered
rings in the initial step and where the initially formed
cation is highly stabilized, e.g., tertiary or benzylic.
In all cases examined, the products were formed with
high diastereoselectivity, with only the anti silyl ether
being produced. This stereochemistry is presumably due
to the other possible cyclization, which would give the
silyl ether syn to the dimethyl-substituted carbocation,
being subject to severe steric hindrance so that the
observed cyclization is greatly favored (e.g., 4 f 5).
However, not all substrates could be induced to un-
dergo the double cyclization, even those with quite
similar structures. For example (Scheme 4) the olefinic
R-hydroxy aldehydes 20-2211 did not produce any of the
desired materials, 23-25, under these cyclization condi-
tions. We believe that the cyclization of 20 failed because
the disubstituted double bond was not sufficiently electron-
rich. In the case of compound 21, the bulky phenyl group
R to the aldehyde may have created unfavorable steric
hindrance to the cyclization. Finally, the cyclization of
Exp er im en ta l Section
Gen er a l. Thin-layer chromatography (TLC) was performed
using Merck silica gel 60 F254 0.2 mm plates. Visualization
was accomplished using ultraviolet light or the following
stain: anisaldehyde (2 mL), acetic acid (10 mL), and sulfuric
acid (2 mL) in 95% ethanol (85 mL). Flash chromatography
was carried out using ICN Biomedicals silica gel 60 (230-400
mesh). Solvent systems are reported as volume percent
mixtures. Concentration or evaporation of solvent refers to
removal at reduced pressure using a Bu¨chi rotary evaporator
and an aspirator pump. All inorganic solutions are aqueous,
and concentrations are indicated in percent weight, except for
saturated sodium chloride, saturated sodium carbonate, and
saturated ammonium chloride. The following solvents and
reagents were distilled from the indicated agent under argon:
tetrahydrofuran (THF) and diethyl ether from sodium ben-
zophenone ketyl; dichloromethane, acetonitrile, and triethy-
lamine from calcium hydride. Dimethyl sulfoxide (DMSO) was
distilled from calcium hydride under reduced pressure. Oxalyl
chloride was distilled just prior to use. All solvents were stored
over calcium hydride.
(11) The precursors to these substrates were prepared as follows
(see Experimental Section for details). (a) Compound 26: reaction of
5-hepten-2-one neat with TESCN (prepared from TESCl and TMSCN
by the method of Bither, T. A., Knoth, W. H., Lindsey, R. V., J r.;
Sharkey, W. H. J . Am. Chem. Soc. 1958, 80, 4151) and the salt of 18-
crown-6 and KCN as a catalyst. Cf. Corey, E. J ., Crouse, D. N.;
Anderson, J . E. J . Org. Chem. 1975, 40, 2140. The silyl cyanohydrin
was then reduced with DIBAL to give 26. (b) Compound 27: alkylation
of the anion of the triethylsilyl cyanohydrin of benzaldehyde with
5-bromo-2-methyl-2-pentene (13). Reduction afforded 27. (c) Com-
pound 28: addition of the Grignard reagent of 5-bromo-2-methyl-2-
pentene to [(2-ethoxyethoxy)methyl]methyloxirane in the presence of
CuI followed by acidic hydrolysis gave 28.
2,6-Dim eth yl-5-h ep ten e-1,2-d iol (9). To a 100 mL oven-
dried round-bottom flask under argon were added 30 mL of
0.1 M samarium diiodide (3 mmol) in tetrahydrofuran (THF)
(12) (a) Snider, B. B. The Prins and Carbonyl Ene Reaction, Chapter
2.1 in Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon:
Oxford, 1991; Vol. 2, pp 527-561. (b) Santelli, M.; Pons, J .-M. Lewis
Acids and Selectivity in Organic Synthesis; CRC Press: Boca Raton,
FL, 1996; Chapter 2. (c) In this case, the simple ene product was
obtained as the major product.

9184 J . Org. Chem., Vol. 62, No. 26, 1997
J ung et al.
and then 6-methyl-5-hepten-2-one (12) (130 mg, 1.03 mmol)
and benzyl chloromethyl ether (160 mg, 1.02 mmol). The
solution was stirred for 1 h and the dark green color gradually
faded to give a light yellow sediment. At this time 5 mL of
0.1 N HCl was added and the solution stirred for 10 min which
allowed the solids to dissolve and gave a slightly cloudy pale
yellow solution. The organic layer was separated, and the
aqueous phase was extracted with 5 × 10 mL of ether. The
organic phases were combined and washed with 5 mL each of
water and of saturated NaCl and then dried over K2CO3. After
the drying agent was removed by filtration, the solution was
evaporated and the crude product was vacuum distilled in a
Kugelrohr at 200 °C (1 mmHg) to give 242 mg of 6-methyl-1-
(phenylmethoxy)-5-hepten-2-ol as a colorless oil, which was
shown by 1H NMR to be 92.9% pure, implying a yield of
87.9%: 1H NMR (200 MHz, CDCl3) δ 7.40-7.25 (m, 5H), 5.12
(br t, J ) 7.1 Hz, 1H), 4.67 (s, 2H), 3.35 (d, J ) 9 Hz, 1 H),
3.30 (d, J ) 9 Hz, 1H), 2.32 (br s, 1H), 2.04 (q, J ) 7.8 Hz,
2H), 1.69 (s, 3H), 1.61 (s, 3H), 1.58 (m, 2H), 1.19 (s, 3H); 13C
NMR (50 MHz) δ 138.3, 131.5, 128.4, 127.6, 127.0, 125.0, 77.8,
73.5, 72.2, 39.0, 25.7, 23.7, 22.5, 17.6.
) 7.0 Hz, 1H), 2.2-1.5 (m, 6H), 1.59 (s, 3H), 1.52 (s, 3H), 0.85
(t, J ) 7.4 Hz, 3H); 13C NMR (50 MHz) δ 180.9, 132.0, 122.7,
77.4, 38.0, 31.7, 24.9, 21.8, 17.0, 7.1.
In a 25 mL oven-dried round-bottom flask with a reflux
condenser and drying tube was placed 2 mL of 1 M lithium
aluminum hydride (LAH, 2.0 mmol) in ether. Then sodium
2-ethyl-2-hydroxy-6-methyl-5-heptenoate (223 mg, 1.07 mmol)
in 6 mL of ether was added dropwise with stirring which
produced slight gas evolution. The solution was stirred for
15 min, and 5 mL of water was cautiously added to decompose
the excess LAH. Then 5 mL of 10% H2SO4 was added slowly
to clarify the solution. The organic phase was separated, and
the aqueous phase was extracted with 3 × 5 mL of ether. The
organic phases were combined and washed with 5 mL of water.
The solution was then dried over Na2SO4 and filtered, the
solution was evaporated, and the crude product was purified
by column chromatography on silica gel with a gradient
hexanes to 1:5 ethyl acetate/hexanes elution to give 179 mg
of the diol 10 as a colorless oil (97.1% yield): 1H NMR (200
MHz, CDCl3) δ 5.10 (br t, J ) 6.4 Hz, 1H), 3.46 (s, 2 H), 2.03
(br s, 2H), 1.98 (m, 2H), 1.68 (s, 3H), 1.62 (s, 3H), 1.52 (m,
4H), 0.88 (t, J ) 7.5 Hz, 3H); 13C NMR δ 132.0, 124.2, 74.9,
67.6, 35.2, 28.4, 25.7, 22.0, 17.6, 7.8.
A 100 mL oven-dried flask with a septum-capped sidearm
inlet was placed under a dry ice condenser connected to a
drying tube. Dry THF (2.5 mL) was added under argon, and
then 3.8 g of lithium wire cut into short pieces was added.
The dry ice condenser was chilled to -60 °C, and gaseous
ammonia was introduced by needle slowly through the septum
on the side inlet, which gave a dark blue solution with stirring
as the ammonia condensed. Enough ammonia was added to
increase the volume of the solution to 5 mL. Then 6-methyl-
1-(phenylmethoxy)-5-hepten-2-ol (150 mg, 0.60 mmol) in 2.5
mL of THF was added dropwise over 10 min. The solution
was stirred for an additional 2 min, the dry ice condenser was
removed, and 1.5 g of solid ammonium chloride was added with
gentle stirring. The mixture was allowed to warm to room
temperature very gradually to minimize foaming as the
ammonia evaporated. Saturated NaCl and ether (20 mL each)
were added, and the organic layer was separated. The aqueous
phase was extracted with 4 × 10 mL of ether, and the
combined organic phases were dried over K2CO3. After the
drying agent was removed by filtration, Kugelrohr vacuum
distillation at 150 °C (1 mmHg) gave 79 mg of the diol 9, as a
pure colorless oil (83.2% yield): 1H NMR (200 MHz, CDCl3) δ
5.05 (br t, J ) 7.0 Hz, 1H), 3.38 (d, J ) 10.9 Hz, 1H), 3.34 (d,
J ) 10.9 Hz, 1H), 2.29 (br s, 2H), 1.99 (app q, J ) 7.7 Hz, 2H),
1.62 (s, 3H), 1.55 (s, 3H), 1.45 (m, 2H), 1.11 (s, 3H); 13C NMR
(50 MHz) δ 132.0, 124.2, 73.0, 69.8, 38.5, 25.7, 23.2, 22.4, 17.6.
2-Eth yl-6-m eth yl-5-h ep ten e-1,2-d iol (10). A Grignard
reagent was made in the usual manner from 5-bromo-2-
methyl-2-pentene (13)9 (1.47 g., 9.0 mmol) and Mg turnings
(219 mg, 9.0 mmol) in 10 mL of dry THF. In another 50 mL
oven-dried round-bottom flask with a stir bar was added
sodium R-ketobutyrate (14) (744 mg, 6 0.0 mmol) and 10 mL
of dry ether under a dry ice condenser with a drying tube. This
flask was heated to 50 °C (reflux) in an oil bath, and the
Grignard solution was added via a large bore needle over 5
min with stirring.13 The solution was refluxed for 2 h and then
chilled in an ice bath while 10 mL of 2 N HCl was carefully
added with vigorous stirring. Over the next 15 min, the solids
gradually dissolved. The organic phase was separated, the
aqueous phase was extracted with 3 × 10 mL of ether, and
the combined organic phases were dried over MgSO4. The
solution was filtered and evaporated, and the crude product
was purified by column chromatography on silica gel with a
gradient hexane to 1:5 ethyl acetate/hexane elution to give 411
mg of sodium 2-ethyl-2-hydroxy-6-methyl-5-heptenoate, as a
colorless liquid which crystallized under refrigeration (32.9%
yield). Higher yields can be obtained by using a slightly larger
excess of the Grignard reagent.13 The melting point of the
product was determined to be 37-39 °C; however the product
appeared to be somewhat hygroscopic and attempts at further
drying with mild heat and high vacuum resulted in decompo-
sition at about 70 °C: 1H NMR (200 MHz, CDCl3) δ 5.02 (t, J
(E)-2-Meth yl-6-p h en yl-5-h exen e-1,2-d iol (11). A Grig-
nard reagent was made in the usual manner from 4-bromo-
1-phenyl-1-butene (15) (1.71 g, 8.1 mmol) and Mg turnings (364
mg, 15.0 mmol) in 15 mL of dry THF. Then 1-[(tetrahydro-
furan-2-yl)oxy]acetone (16) (1.3 g., 9.0 mmol) in 3 mL of dry
THF was added dropwise with stirring. Stirring was contin-
ued in a 50 °C oil bath for 30 min. Then the flask was
transferred to an ice bath and 8 mL of 2 N HCl was added
carefully, followed by stirring at room temperature for 30 min.
The organic phase was separated, and the aqueous phase was
extracted with 2 × 5 mL of ether. The combined organic
phases were washed with 4 mL of cold water and then dried
over Na2SO4. The drying agent was removed by filtration, and
the solution was evaporated down to a couple of milliliters.
At this time 10 mL of 3:1:1 acetic acid/water/THF was added,
and the solution was stirred overnight. The next day the
solution was poured carefully into 40 mL each of ether and of
saturated Na2CO3 which resulted in considerable bubbling.
Additional saturated Na2CO3 was added to bring the pH of
the solution to 7. The organic phase was separated, and the
organic phase was extracted with 2 × 25 mL of ether. The
combined organic phases were washed with 25 mL of saturated
NaCl and dried over MgSO4. The crude product in solution
was filtered, evaporated, and purified by column chromatog-
raphy on silica gel, eluting with hexanes to a 1:3 ethyl acetate/
hexane gradient to give 925 mg of the diol as a colorless oil
(55.4% yield) which began to crystallize into small white
nodules at room temperature; the process was completed in
the refrigerator overnight. The melting point of the product
was determined to be 65-66 °C: 1H NMR (200 MHz, CDCl3)
δ 7.35-7.07 (m, 5H), 6.35 (d, J ) 15.8 Hz, 1H), 6.15 (dt, J )
15.8, 6.3 Hz, 1H), 3.42 (d, J ) 11.0 Hz, 1H), 3.38 (d, J ) 11.0
Hz, 1H), 2.24 (m, 2H), 2.17 (br s, 2H), 1.58 (m, 2H), 1.14 (s,
3H); 13C NMR (50 MHz) δ 137.6, 130.5, 130.1, 128.5, 127.0,
125.9, 72.9, 69.8, 38.1, 27.4, 23.3.
5-Br om o-2-m eth yl-2-p en ten e (13).9 A Grignard reagent
was made in the usual manner from Mg turnings (2.43 g, 100
mmol), methyl iodide (14.6 g, 103 mmol), and 20 mL of dry
ether in
a 100 mL oven-dried round-bottom flask. The
Grignard solution was cooled in an ice bath, and cyclopropyl
methyl ketone (4.5 g, 53.5 mmol) in 5 mL of ether was added
dropwise over 20 min which produced much foaming. The
reaction flask was removed from the ice bath and stirred for
1 h at room temperature. The flask was then returned to the
ice bath, 30 mL of saturated aqueous ammonium chloride was
added gradually, and the solution was stirred for 15 min. The
almost colorless organic phase was separated, and the aqueous
phase was extracted with 4 × 20 mL of ether. The organic
phases turned orange after the extraction due to the presence
of the small amount of iodine which was used to initiate the
Grignard reaction. The combined organic phases were shaken
with 15 mL of water and a little Na2S2O3 until the color faded.
The organic phase was once again separated and washed with
(13) Christie, E. W.; McKenzie, A.; Ritchie, A. J . Chem. Soc. 1935,
153.

Prins Double Cyclization Catalyzed by Silyl Triflates
J . Org. Chem., Vol. 62, No. 26, 1997 9185
20 mL each of water and saturated aqueous NaCl and then
dried over MgSO4. After filtration the solution was evaporated
down to 5.4 g of a pale yellow oil in a 100 mL round-bottom
flask, a stir bar was added, and the flask was placed in an ice
bath. At this time 11.3 mL of 48% HBr (99.9 mmol) was added
dropwise over 30 min with vigorous stirring, and then the
solution was stirred for an additional 1 h to give a clear organic
layer and whitish aqueous phase. TLC showed the second
reaction to be complete with a new high-Rf spot. Water and
ether (10 mL each) were then added, and the solution was
stirred until the mixture clarified. The light yellow organic
phase was separated, and the aqueous phase was extracted
with 3 × 15 mL of ether. The organic phases were combined
and washed with 10 mL each of water, 2% Na2CO3, water, and
saturated NaCl, and the solution was dried over MgSO4. After
filtration to remove the drying agent, the solution was
evaporated to give 7.44 g of the bromide 139 as a pale yellow
oil which was shown by 1H NMR to contain 26% of residual
ether, implying a yield of 67.3% for the two steps: 1H NMR
(200 MHz, CDCl3) δ 5.06 (br t, J ) 7.1 Hz, 1H), 3.27 (t, J )
7.3 Hz, 2H), 2.49 (dt, J ) 7.3, 7.3 Hz, 2H), 1.65 (s, 3 H), 1.56
(s, 3 H).
butyldimethylsilyl trifluoromethanesulfonate (317 mg, 1.2
mmol) which produced a slight bit of fuming. After the
reaction stirred for 20 min, a TLC showed a new high-Rf spot
predominating. The solution was stirred for a total of 30 min.
At this time 4 mL of 5% Na2CO3 was added, and the stirring
was continued for an additional 10 min. The organic phase
was separated, and the aqueous phase was extracted with 3
× 3 mL of dichloromethane. The organic phases were com-
bined, washed with 2 × 3 mL of water and 3 mL of saturated
NaCl, and then dried over MgSO4 and filtered. The solution
was evaporated, and the crude product was purified by column
chromatography on silica gel with a pentane to 1:10 dichlo-
romethane/pentane gradient. After vacuum evaporation at
room temperature (380 mmHg) to just over the theoretical
weight, the flask was left open to the air for 1 h which allowed
the remainder of the elution solvent to evaporate and gave
241 mg of the ether 17 as a colorless liquid (89.1% yield for
two steps): 1H NMR (200 MHz, CDCl3) δ 3.84 (s, 1H), 1.85-
1.78 (m, 2H), 1.75-1.66 (m, 1H), 1.63-1.56 (m, 1H), 1.38-
1.32 (m, 1H), 1.11 (s, 6H), 1.10 (s, 3H), 0.81 (s, 9H), 0.00 (s,
3H), -0.01 (s, 3H); 13C NMR (50 MHz) δ 84.8, 79.9, 77.4, 50.6,
32.1, 29.7, 26.1, 25.7, 21.9, 18.0, 17.4, -4.8, -5.0.
4-Br om o-1-p h en yl-1-bu ten e (15).10 Cyclopropyl phenyl
ketone (1.46 g, 10 mmol) was added to 20 mL of methanol in
a 100 mL oven-dried round-bottom flask which was cooled in
an ice bath. Sodium borohydride (567 mg, 15 mmol) was then
added carefully in small portions, and the solution was stirred
for 15 min. At this time the solution was acidified to pH 3
with 2 N HCl using Congo Red as an indicator. The organic
phase was separated, and the aqueous phase was extracted
with 3 × 35 mL dichloromethane. The combined organic
phases were dried over MgSO4 and then filtered into a 250
mL round-bottom flask. The resultant solution was vacuum
evaporated at 50 °C (50 mmHg) and then put in ice bath where
2.26 mL of 48% HBr (20 mmol) was added dropwise over 20
min with vigorous stirring. The solution was stirred for an
additional 30 min at 0 °C and then for 15 min at room
temperature. The solution was partitioned with 2 mL of water
and 4 mL of ether, and the organic layer was separated. The
aqueous phase was extracted with 3 × 4 mL of ether, and the
combined organic phases were washed with 2 mL each of
water, 2% Na2CO3, water, and saturated NaCl. The solution
was dried over MgSO4, filtered, and evaporated to give 1.911
g of the bromide 15,10 which was shown by 1H NMR to contain
9% residual ether, implying a yield of 82.4% for the two
steps: 1H NMR (200 MHz, CDCl3) δ 7.45-7.19 (m, 5H), 6.49
(d, J ) 15.8 Hz, 1H), 6.18 (dt, J ) 15.8, 6.8 Hz, 1H), 3.47 (t, J
) 6.8 Hz, 2H), 2.79 (dt, J ) 6.8, 6.4 Hz, 2H).
exo-7-[[(1,1-Dim eth yleth yl)d im eth ylsilyl]oxy]-1,3,3-tr i-
m eth yl-2-oxa bicyclo[2.2.1]h ep ta n e (17). To a 25 mL oven-
dried round-bottom flask under argon was added 1 mL of
dichloromethane dried over CaH2. Freshly distilled oxalyl
chloride (254 mg, 2.0 mmol) was added, and the solution was
chilled to -60 °C. Then dimethyl sulfoxide (DMSO, 312 mg,
4.0 mmol) which had been freshly distilled from CaH2 was
added over 5 min dropwise in 1 mL of dry dichloromethane
with stirring. The resultant clear solution was stirred for an
additional 5 min, and then the diol 9 (158 mg, 1.0 mmol) in 1
mL of dry dichloromethane was added dropwise with stirring.
During this time the solution acquired a white slushy appear-
ance and stirring was continued for an additional 15 min at
-60 °C. Then diisopropylethylamine (DIPEA, 1.03 g, 8.0
mmol) which had been stored over KOH was added dropwise
over 5 min and the reaction flask was removed from the cold
bath and allowed to warm gradually to room temperature with
stirring over 15 min. This was followed by the addition of 4
mL of water and stirring for another 10 min. The organic
phase was separated, and the aqueous phase was extracted
with 4 × 3 mL of dichloromethane. The organic phases were
combined and washed with 6 mL each of 0.1 M HCl, water,
dilute Na2CO3, water, and saturated NaCl, and then the
solution was dried over MgSO4. The crude aldehyde 6 in
solution was filtered directly into a 25 mL oven-dried round-
bottom flask with a stirbar, evaporated to about 3 mL, and
flushed with argon. To this new solution were added 2,6-di-
tert-butyl-4-methylpyridine (308 mg, 1.5 mmol) and tert-
exo-3,3-Dim eth yl-7-[[(1,1-d im eth yleth yl)d im eth ylsily-
l]oxy]-3-eth yl-2-oxa -bicyclo[2.2.1]h ep ta n e (18). To a 25
mL oven-dried round-bottom flask under argon was added 1.5
mL of dichloro-methane dried over CaH2. Freshly distilled
oxalyl chloride (82 mg, 0.65 mmol) was added, and the flask
was cooled to -50 °C. DMSO (100 mg, 1.29 mmol) distilled
from CaH2 in 1 mL of dry dichloromethane was then added
dropwise over 5 min, and the solution was stirred for another
5 min. This was followed by the addition of 2-ethyl-6-methyl-
5-hexene-1,2-diol (10) (74 mg, 0.43 mmol) in 1 mL of dichlo-
romethane dropwise over the next 5 min which caused the
solution to assume a white, slushy appearance. Stirring was
continued at the same temperature for another 15 min. Then
triethylamine (261 mg, 2.58 mmol) was added over 5 min and
the solution was allowed to warm gradually to room temper-
ature with stirring. At this time 4 mL of water was added
and the reaction stirred for 10 min to give very pale yellow
solution. The organic phase was separated, and the aqueous
phase was extracted with 4 × 3 mL of dichloromethane. The
organic phases were combined and washed with 3 mL each of
0.1 M HCl, water, dilute Na2CO3, water, and saturated NaCl.
The crude aldehyde 7 in solution was dried over MgSO4 and
filtered directly into a fresh 25 mL oven-dried round-bottom
flask, and its volume was reduced by rotary evaporation down
to about 2 mL. The flask was flushed with argon, and 2,6-di-
tert-butyl-4-methylpyridine (132 mg, 0.645 mmol) and then
tert-butyldimethylsilyl triflate (165 mg, 0.54 mmol) were
added. The reaction was substantially complete in 10 min by
TLC and was stirred for an additional 1 h. At this time 4 mL
of 5% NaHCO3 was added and the solution was stirred for 10
min. The organic phase was separated, and the aqueous phase
was extracted with 3 × 4 mL of ether. The organic phases
were then combined and washed with 2 × 3 mL of water and
then 3 mL of saturated NaCl, dried over MgSO4, and filtered.
After the solvent was removed on a Rotovap, the crude product
was purified by column chromatography on silica gel with a
pentane to 1:6 dichloromethane/pentane gradient. The prod-
uct was vacuum evaporated at 40 °C (380 mmHg) to just above
theoretical weight. Then the flask was left open and monitored
by weight on a scale while the remainder of solvent was
allowed to evaporate over 1 h which left 103 mg of the ether
18 as a colorless liquid (84.1% yield for two steps): 1H NMR
(200 MHz, CDCl3) δ 4.08 (s, 1H), 1.85-1.45 (m, 7H), 1.19 (s,
6H), 0.91 (t, J ) 7.2 Hz, 3H), 0.89 (s, 9H), 0.08 (s, 3H), 0.07 (s,
3H); 13C NMR (50 MHz) δ 87.9, 77.3, 77.2, 50.3, 30.8, 29.6,
26.1, 25.7, 23.9, 21.4, 17.9, 8.5, -4.7, -5.0.
exo-7-[[(1,1-Dim eth yleth yl)d im eth ylsilyl]oxy]-3-p h en -
yl-2-oxa bicyclo-[2.2.1]h ep ta n e (19). To a 25 mL oven-dried
round-bottom flask under argon was added 1.5 mL of dichlo-
romethane dried over CaH2. Freshly distilled oxalyl chloride
(66 mg, 0.52 mmol) was added, and the flask was cooled to
-50 °C. DMSO (82 mg, 1.05 mmol) distilled from CaH2 in 1
mL of dry dichloromethane was then added dropwise over 5
min, and the solution was stirred for another 5 min. The

9186 J . Org. Chem., Vol. 62, No. 26, 1997
J ung et al.
subsequent addition of 2-methyl-6-phenyl-5-hexene-1,2-diol
(11) (54 mg, 0.26 mmol) in 1 mL of dichloromethane dropwise
over the next 5 min caused the solution to assume a white,
slushy appearance, and stirring was continued at the same
temperature for another 15 min. Finally diisopropylethy-
lamine (271 mg, 2.10 mmol) was added over 5 min and the
solution was allowed to warm gradually to room temperature
with stirring. At this time 4 mL of water was added and the
solution was stirred for 10 min to give very pale yellow
solution. The organic phase was separated, and the aqueous
phase was extracted with 4 × 3 mL of dichloromethane. The
organic phases were combined and washed with 3 mL each of
0.1 M HCl, water, dilute Na2CO3, water, and saturated NaCl.
The solution was dried over MgSO4 and filtered directly into
a fresh 50 mL oven-dried round-bottom flask, and its volume
was reduced by rotary evaporation down to about 5 mL. The
flask was flushed with argon, and 2,6-di-tert-butyl-4-meth-
ylpyridine (108 mg, 0.53 mmol) and then tert-butyldimethyl-
silyl triflate (104 mg, 0.39 mmol) were added. The solution
was stirred for 1.5 h until the starting material disappeared
and a new high-Rf spot predominated on TLC. The reaction
was neutralized with 4 mL 5% of Na2CO3 and stirred for 10
min. The organic phase was separated, and the aqueous phase
was extracted with 3 × 4 mL of ether. The organic phases
were then combined and washed with 2 × 3 mL of water and
then 3 mL of saturated NaCl, dried over MgSO4, and filtered.
After the solvent was removed on a Rotovap, the crude product
was purified by column chromatography on silica gel with a
pentane to 1:5 dichloromethane/pentane gradient. The prod-
uct was vacuum evaporated at 40 °C (380 mmHg) to just above
theoretical weight. Then the flask was left open and monitored
by weight on a scale while the remainder of solvent was
allowed to evaporate over 1 h which left 76 mg of the ether 19
as a colorless liquid (91.7% yield for two steps): 1H NMR (200
MHz, CDCl3) δ 7.40-7.19 (m, 5H), 4.75 (s, 1H), 3.78 (s, 1H),
2.23-2.10 (m, 2H), 1.94-1.50 (m, 3H), 1.39 (s, 3H), 0.92 (s,
9H), 0.00 (s, 3H), -0.03 (s, 3H); 13C NMR (50 MHz) δ 143.4,
128.0, 126.6, 125.2, 84.1, 82.4, 48.7, 33.5, 27.5, 25.6, 17.9, 16.6,
-4.8, -5.0.
(E)-2-Meth yl-2-(tr ieth ylsilyloxy)-5-h ep ten a l (26). (E)-
Methyl 2-acetyl-4-hexenoate (2.0 g, 11.75 mmol) was added
to a 50 mL round-bottom flask with a boiling chip together
with 15 mL of DMSO and 450 mg of water. The solution was
then refluxed for 3 h at 185 °C under a reflux condenser. The
resultant orange brown solution was poured onto ice and
extracted with 3 × 20 mL of pentane. The combined organic
extractions were dried over Na2SO4, filtered, and evaporated.
The crude product was then vacuum distilled in a Kugelrohr
apparatus at 100-140 °C (130 mmHg) which gave 801 mg of
(E)-5-hepten-2-one as a colorless liquid (57.1% yield): 1H NMR
(200 MHz, CDCl3) δ 5.55-5.31 (m, 2H), 2.48 (t, J ) 7.2 Hz,
2H), 2.27 (dt, J ) 6.8, 6.8 Hz, 2H), 2.13 (s, 3H), 1.62 (br s,
3H). (E)-5-Hepten-2-one (224 mg, 2.0 mmol) was added to a
10 mL oven-dried round-bottom flask together with triethyl-
silyl cyanide (333 mg, 2.36 mmol) and 1:1 potassium cyanide/
18-crown-6 salt (33 mg, 0.1 mmol) as a catalyst. The neat
mixture was stirred overnight under argon at 70 °C. The next
day 4 mL of pentane and 2 mL of ice were added and the
mixture was stirred for 5 min. Florisil (240 mg) was then
added to absorb impurities, and the mixture was shaken and
stirred for an additional 5 min. The organic phase was
separated, and the aqueous phase was extracted with 3 × 4
mL of pentane. The organic phases were dried over MgSO4,
and the drying agent was removed by filtration into a 25 mL
oven-dried round-bottom flask. The solution was evaporated
down to about 3 mL and the flask flushed with argon and
chilled to -45 °C whereupon 3 mL of 1 M DIBAL (3 mmol) in
hexanes was added dropwise over 20 min. The flask was then
transferred to an ice bath where it was stirred for 1 h. At
this time, 2 mL each of ether and of saturated ammonium
chloride were added and the solution was stirred for 30 min
until the white precipitate had fully coagulated. Then 4 mL
of 0.75 M H2SO4 was added and the solution was stirred for
an additional hour. The organic phase was separated, and the
aqueous phase was extracted with 2 × 3 mL of ether. The
combined organic phases were then dried over MgSO4 and
filtered, and the solvent was removed in a Rotavap. The crude
product was placed on a 1 × 10 cm silica column, eluting with
pentane alone to give 300 mg of the aldehyde as a colorless
liquid (58.5% yield): 1H NMR (200 MHz, CDCl3) δ 9.48 (s, 1H),
5.42-5.20 (m, 2H), 2.10-1.85 (m, 2H), 1.63-1.48 (m, 2H), 1.55
(d, J ) 6.8 Hz, 3H), 1.20 (s, 3H), 0.89 (t, J ) 8.2 Hz, 9H), 0.54
(q, J ) 7.8 Hz, 6H); 13C NMR (50 MHz, CDCl3) δ 205.0, 130.7,
125.4, 80.1, 39.4, 26.5, 22.9, 17.8, 6.9, 6.6.
6-Me t h yl-2-p h e n yl-2-[(t r ie t h ylsilyl)oxy]-5-h e p t e n a l
(27).14 Powdered potassium cyanide (2.6 g, 40 mmol) was
dried in a 50 mL pear-shaped flask in a Kugelrohr apparatus
at 250 °C (1 mmHg) for 30 min. The apparatus was allowed
to cool to 150 °C, and zinc iodide (47 mg, 0.15 mmol) was
added. The mixture was then heated for an additional hour
at heated for 1 h at 150 °C (1 mmHg). After the flask was
cooled under argon, benzaldehyde (1.06 g, 10 mmol) in 40 mL
of dry acetonitrile was added. Subsequent addition of trieth-
ylsilyl chloride (1.8 g, 12 mmol) caused fuming and turned the
solution yellow. It was then stirred under argon overnight.
The next day the yellow color had faded. The solvent was
removed by evaporation, and the crude product, R-[(triethyl-
silyl)-oxy]phenylacetonitrile, was redissolved in 10 mL of ether.
The ether solution was dried over MgSO4, filtered, and vacuum
evaporated at 50 °C (10 mmHg) to give 2.594 g of a pale yellow
liquid. The crude product was chromatographed on silica gel,
eluting with pentane to give 2.287 g of the cyanohydrin silyl
ether as a colorless liquid (92.4% yield): 1H NMR (200 MHz,
CDCl3) δ 7.67-7.37 (m, 5H), 5.49 (s, 1H), 0.96 (t, J ) 7.8 Hz,
9H), 0.73 (q, J ) 7.4 Hz, 6H). To a solution of lithium
diisopropylamide made in situ from diisopropyl-amine (607 mg,
6.0 mmol) in 5 mL of dry THF and 4.58 mL of 1.2 M
n-butyllithium (5.5 mmol) in hexanes at -70 °C in a 25 mL
oven-dried round-bottom flask was added R-[(triethylsilyl)oxy]-
phenylacetonitrile (1.237 g, 5.0 mmol) in 1 mL of THF dropwise
over 5 min, and then the reaction was stirred for an additional
5 min. Then 5-bromo-2-methyl-2-pentene (13)9 (815 mg, 5.0
mmol) was added and the reaction stirred an additional 10
min at -70 °C.15 The reaction mixture was then allowed to
warm to room temperature as stirring was continued for 1.5
h. At this time 5 mL of water was added and the organic phase
was separated. The aqueous phase was extracted with 2 ×
10 mL of dichloromethane, and the combined organic phases
were dried over Na2SO4, filtered, and evaporated down to a
thin orange syrup. The crude product was purified by column
chromatography on silica gel, eluting with pentane. The
volume of the elution solvent was reduced to 5 mL in a fresh
50 mL oven-dried round-bottom flask which was flushed with
and chilled to -50 °C. To this flask was then added 8.8 mL
of 1 M diisobutylaluminum hydride (DIBAL, 8.8 mmol) in
hexanes dropwise over 20 min. Stirring was continued in an
ice bath for an additional 2 h; then 20 mL of ether and 10 mL
of saturated ammonium chloride were added. After the
mixture stirred for an additional hour, 10 mL of 0.75 M H2-
SO4 was carefully added and the solution was stirred over-
night. The next day the organic layer was separated and the
aqueous phase was extracted with 3 × 10 mL of ether. The
organic phases were combined, dried over MgSO4, and filtered.
After the solvent was removed by evaporation, the crude
product was chromatographed on silica gel, eluting with
pentane to give 560 mg of the aldehyde as a colorless oil (33.8%
yield for the two steps): 1H NMR (200 MHz, CDCl3) δ 9.54 (s,
1H), 7.40-7.24 (m, 5H), 5.0 (br t, J ) 7.0 Hz, 1H), 2.0-1.6 (m,
2H), 1.61 (s, 3H), 1.47 (s, 3H), 1.27 (m, 2H), 0.97 (t, J ) 7.4
Hz, 9H), 0.70 (q, J ) 7.7 Hz, 6H).
2,7-Dim eth yl-6-octen e-1,2-d iol (28).16 A Grignard re-
agent was made in the usual manner from 5-bromo-2-methyl-
2-pentene (13)9 (358 mg, 2.2 mmol) and Mg turnings (73 mg,
3.0 mmol) in 3 mL of dry THF. The grayish yellow solution
was cooled to -30 °C which precipitated a large amount of
(14) Rawal, V. H.; Rao, J . A.; Cava, M. P. Tetrahedron Lett. 1985,
26, 4275.
(15) Albright, J . D. Tetrahedron 1983, 39, 3207.
(16) Huynh, C.; Derguini-Boumechal, F.; Linstrumelle, G. Tetrahe-
dron Lett. 1979, 1503.

Prins Double Cyclization Catalyzed by Silyl Triflates
J . Org. Chem., Vol. 62, No. 26, 1997 9187
thick whitish sediment. To this mixture was added 38 mg of
anhydrous copper(I) iodide, and then 2-[(1-ethoxyethoxy)m-
ethyl]-2-methyloxirane17 (280 mg, 1.75 mmol) was added with
stirring to give a purple-black color. The mixture was trans-
ferred to an ice bath, stirred for 1.5 h, and then poured into 6
mL each of saturated ammonium chloride and ice which
resulted in significant bubbling. After the mixture stirred
overnight at room temperature, the last of the solids finally
dissolved and gave a blue solution. The organic phase was
separated, and the aqueous phase was extracted with 3 × 10
mL of ether. The combined organic phases were evaporated
to remove the ether, and 20 mL of THF was added. This
solution was chilled in an ice bath, 20 mL of 0.5 N HCl was
added, and the mixture was stirred for 1 h and then for 1 h at
room temperature as a new TLC spot with very low Rf
appeared. The solution was extracted with 4 × 10 mL of ether,
and the combined organic phases were washed with 5 mL each
of water and dilute Na2CO3. After the organic phase was dried
over Na2CO3, it was filtered and evaporated at 60 °C (380
mmHg). The crude product was chromatographed on silica
gel, and eluting with a gradient dichloromethane to 1:50
methanol/dichloromethane gave 201 mg of the diol 28 as a pale
yellow oil (66.6% yield for the two steps): 1H NMR (200 MHz,
CDCl3) δ 5.09 (br t, J ) 7.2 Hz, 1H), 3.74 (m, 2H), 1.96 (dt, J
) 6.9, 6.9 Hz, 2H), 1.7 (br s, 2H), 1.67 (s, 3H), 1.58 (s, 3H),
1.44 (m, 4H), 1.15 (s, 3H).
Ack n ow led gm en t. We thank the National Insti-
tutes of Health and the Agricultural Research Division
of the American Cyanamid Company for generous
support.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of 9-11, 17-19, and 26 and 1H NMR spectra of 13,
15, and 27-28 (20 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
(17) Ando, K.; Yamada, T.; Shibuya, M. Heterocycles 1989, 29, 2209.
J O971337V