Organic Syntheses, Vol. 79, pp. 27-34
Submitted by Frank E. McDonald and Brian H. White
1.
Checked by Peter B. Ranslow and Louis S. Hegedus.
1. Procedure
Caution: All manipulations should be conducted in a well-ventilated fume
hood.
A. 1-Phenyl-3-butyn-1-ol
(1) (Note
1). A
1000-mL, oven-dried,
three-necked, round-bottomed flask is equipped with a
magnetic
stir bar and
pressure-equalizing addition funnel,
fitted with a
rubber septum, and placed under an
argon
atmosphere. The flask is charged with
lithium
acetylide-ethylenediamine complex (50 g, 543 mmol)
(Note
2), which is dissolved in
anhydrous
dimethyl sulfoxide (360 mL) (Note
3) with stirring. The flask is placed in a
room temperature
water bath (Note
4), the addition funnel is charged
with
styrene oxide (42.0 mL,
368 mmol) (Note
5), and
styrene
oxide is added dropwise over a period of approximately 5 min.
The reaction mixture is stirred for 2 hr and quenched by pouring slowly into 600 mL
of ice water in a
4-L beaker (Note
6).
The contents are transferred to a
2-L separatory funnel, and
the mixture is extracted with
diethyl ether
(6 × 350 mL). The combined organic extracts are
washed once with water and decanted with evaporation of solvents by rotary evaporation.
The crude product is purified by vacuum distillation. Any remaining traces of solvent
and water distill over first, followed by the product (88-89°C, 1.0 mm) to provide
1-phenyl-3-butyn-1-ol (1,
43.98 g, 82% yield) as a colorless oil.
B. 2-Phenyl-2,3-dihydrofuran
(2). A
500-mL, oven-dried Airfree® reaction
flask (Note
7) containing a
magnetic stir
bar is charged with
molybdenum hexacarbonyl
(Mo(CO)6, 3.21 g, 12.2 mmol) (Note
8) and fitted with a
rubber septum, with
an
argon atmosphere introduced via the side-arm.
Triethylamine (Et3N, 220
mL, 1.58 mol) (Note
9) is
added, followed by
diethyl ether (Et2O,
180 mL) (Note
10), and the mixture
is stirred for 10-15 min, until the
molybdenum
hexacarbonyl has dissolved. The solution is placed in a
Rayonet
Photochemical Reactor Chamber (Notes
11,
12,
13)
equipped with
350-nm ultraviolet lamps. The septum is removed
under positive argon pressure, and a
reflux condenser bearing a rubber
septum that has been previously flushed with
argon
is quickly fitted onto the Schlenk tube. The solution is irradiated for 1 hr under
argon while the photochemical reactor interior is cooled with
the built-in cooling fan. The light is turned off and the reaction mixture is allowed
to cool to room temperature while maintaining an inert atmosphere to afford a yellow
solution of
triethylamine-molybdenum pentacarbonyl.
The condenser is removed and a septum is quickly refitted while under a positive flow
of argon. A solution of
1-phenyl-3-butyn-1-ol
(1, 13.50 g, 92.3 mmol) in
diethyl ether (40 mL)
is injected into the solution, and the mixture is stirred at room temperature under
a slow
argon stream for 72 hr; the solution slowly turns dark
red over this period. The solvent is then removed by rotary evaporation, leaving a
dark red liquid and a precipitate of
molybdenum-containing by-products,
which are removed by sublimation by heating under vacuum (35°C, 0.5 mm) The remaining
liquid is vacuum distilled through a short-path distillation column (45-47°C,
0.5 mm) to give
2-phenyl-2,3-dihydrofuran
(2, 10.3 g, 76% yield) as a clear liquid (Notes
14,
15).
2. Notes
1. This preparation was previously described by Brandsma.
2 Substrate
1 can be prepared
in enantiomerically pure form beginning with chiral, non-racemic
styrene
oxide, available as either antipode from Aldrich Chemical Company,
Inc., or by kinetic resolution of racemic
styrene
oxide.
3
2.
Lithium acetylide-ethylenediamine
complex was purchased from the Aldrich Chemical Company, Inc.,
and used as received.
3.
Anhydrous dimethyl sulfoxide
was purchased from the Aldrich Chemical Company, Inc.,
and used as received in a Sure/Seal bottle.
4. This reaction is somewhat exothermic, and the water bath serves
as a heat sink to maintain the reaction temperature under 25°C.
5.
Styrene oxide was
purchased from the Aldrich Chemical Company, Inc.,
and used without purification.
Caution! Styrene
oxide is listed as a cancer suspect agent.
6. The quench should be done by pouring the reaction mixture
very
slowly into ice water, as the quench is rather violent on occasions when unreacted
lithium acetylide is present.
7. This glass flask is Kjeldahl-shaped, with a ground glass 24/40
top joint and side-arm fitted with a 2-mm ground glass stopcock, and was purchased
from Chemglass (part number AF-0520-08), 3861 North Mill Road, Vineland, NJ 08360,
phone 1-800-843-1794.
8.
Molybdenum hexacarbonyl
was purchased from Aldrich Chemical Company, Inc.,
and used without further purification.
9.
Triethylamine was
purchased from Fisher Scientific Company, and purified
immediately before use by distillation from
calcium
hydride under an inert atmosphere.
10.
Diethyl ether was
purchased from Mallinckrodt Baker, Inc., and purified
immediately before use by distillation from
sodium/
benzophenone under inert atmosphere.
11. The model used was a
RPR-100 reactor purchased
from the Southern New England Ultraviolet Company, Branford, CT.
12. The photochemical step could also be accomplished by adding Mo(CO)
6,
Et
3N and Et
2O to a
photochemical immersion well,
and irradiating under an inert atmosphere with a
Hanovia medium pressure
450W mercury vapor lamp for 20-30 min. Commercially available immersion
wells generally require > 800 mL of solvent in order to work effectively (so that
the solvent is level with the lamp), and the submitters have found that the more concentrated
solution reported here (ca. 450 mL) is more effective.
14.
2-Phenyl-2,3-dihydrofuran
(2) tends to turn pale yellow after cooling and exposure to air,
but no significant decomposition is revealed by NMR.
15. Characterization data for compound
2: IR (neat) cm
−1: 3053, 2923,
2858, 1620, 1493, 1451, 1136,
1051, 930, 782, 697;
1H NMR (400 MHz,
CDCl
3) δ: 2.59-2.66 (m, 1 H), 3.06-3.13 (m, 1
H), 4.97 (q, 1 H, J = 2.8), 5.53 (dd, 1 H, J = 2, 8.4),
6.47 (q, 1 H, J = 2), 7.28-7.38 (m, 5 H);
13C NMR (100 MHz, CDCl
3)
δ: 38.1, 82.5, 99.3, 125.8,
127.8, 128.7, 143.2, 145.5;
MS (70 eV, EI) 146, 117,
105, 91, 77, 57, 43;
HRMS (EI) calcd for C
10H
10O
146.0732; found 146.0742. Anal. Calcd for C
10H
10O:
C, 82.16; H, 6.90. Found: C, 82.07; H, 6.88.
Waste Disposal Information
All toxic materials were disposed of in accordance with "Prudent Practices in the
Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
The single-step transformation of alkynyl alcohols to endocyclic enol ethers was
unknown until the submitters' discovery that trialkylamine-molybdenum pentacarbonyl
reagents catalyzed the cycloisomerization of
1-phenyl-3-butyn-1-ol
(1) into
2-phenyl-2,3-dihydrofuran
(2).
4 Cycloisomerization of alkynol
1 to dihydrofuran
2 was previously accomplished by multistep synthesis,
including hydroboration/oxidation of the alkyne of
1 followed by hemiacetal
acylation and thermal elimination.
5
A two-step preparation of
2 involving the stoichiometric reaction of
1
with
chromium pentacarbonyl-diethyl ether
complex and subsequent thermal reaction with
dimethylaminopyridine
was reported after their initial communications.
6
The title compound
2 has also been prepared by pyrolysis of
1-phenyl-2-vinyloxirane
at 450°C and 15 mm.
7 Palladium-catalyzed
Heck reactions of
2,3-dihydrofuran
with
iodobenzene or
phenyl triflate provide compound
2
along with the 2,5-dihydro regioisomer, although regioselectivity can be enhanced
for either isomer depending on the choice of ligands and additives.
8 An enantioselective Heck synthesis
of title compound
2 has also been reported.
9
The
molybdenum-catalyzed
cyclization procedure works well for a variety of homoprogargylic alcohols to afford
the cycloisomeric 2,3-dihydrofuran compounds, as shown in Table I. The transformation
was originally discovered with the reagent arising from reaction of
molydbenum
hexacarbonyl and
trimethylamine
oxide,
4a but catalyst
turnover and product isolation yields are significantly improved with the current
procedure, which involves photolysis of
molybdenum
hexacarbonyl in the presence of excess
triethylamine
prior to addition of the alkynyl alcohol substrate.
4b Chiral non-racemic alkynyl alcohol substrates undergo cycloisomerization
without racemization at stereogenic centers (entries 2, 4-7).
10,11 The method is compatible with
ester, amide, and silyl ether functional groups, and five-membered ring products are
generally produced in good yields. The submitters have observed that good leaving
groups at the propargylic position tend to provide furan products by a cyclization/elimination
process (entries 11-13).
4,11
The
molybdenum-catalyzed
alkynol cycloisomerization is the key transformation in short, stereoselective syntheses
of the anti-AIDS drug d4T,
10 the antibiotic cordycepin,
10 and puromycin aminonucleoside.
11
Reaction in the presence of
tributyltin triflate
affords the corresponding 5-tributylstannyl-2,3-dihydrofuran products (entries 8-10).
12 Tungsten carbonyl-catalysis
has recently been demonstrated for the efficient cycloisomerization of bishomopropargylic
alcohols to the corresponding six-membered ring dihydropyran products (entry 7).
13 Analogous cycloisomerization
reactions of terminal alkynes tethered to
nitrogen,
14 carbon,
15
and sulfur
16 17
nucleophiles have also been developed.
Table I
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
2-Phenyl-2,3-dihydrofuran: Furan, 2,3-dihydro-2-phenyl-
(8,9); (33732-62-6)
1-Phenyl-3-butyn-1-ol: Benzenemethanol, α-2-propynyl-
(9); (1743-36-8)
Lithium acetylide-ethylenediamine complex: Ethylenediamine,
compd. with lithium acetylide (Li(HC2)) (1:1) (8);
1,2-Ethanediamine, compd. with lithium acetylide (Li(HC2))
(1:1) (9); (6867-30-7)
Dimethyl sulfoxide: Methyl sulfoxide
(8); Methane, sulfinylbis- (9); (67-68-5)
Styrene oxide: Benzene, (epoxyethyl)-
(8); Oxirane, phenyl- (9); (96-09-3)
Molybdenum hexacarbonyl: Molybdenum carbonyl
(8); Molybdenum carbonyl,(OC-6-11) (9); (13939-06-5)
Triethylamine (8); Ethanamine, N,N-diethyl-
(9); (121-44-8)
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