Dihydrofurans via an intramolecular alkoxide addition to an allenylphosphine oxide

Full text of DOI:10.1021/jo960559a

J . Org. Chem. 1996, 61, 6031-6032
6031
Sch em e 1
Dih yd r ofu r a n s via a n In tr a m olecu la r
Alk oxid e Ad d ition to a n Allen ylp h osp h in e
Oxid e
Katia Pravia, Ron White, Rami Fodda, and
David F. Maynard*
Department of Chemistry, California State Universitys
San Bernardino, San Bernardino, California 92407
Sch em e 2
Received March 26, 1996
Our research interests involve the development of new
synthetic strategies for the synthesis of heterocyclic ring
systems through the reactions of allenes with tethered
nucleophiles. Allenes have recently become important
in the synthesis of five- and six-member carbocyclic1 and
heterocyclic2 ring systems. However, relatively little
work has been performed on the addition of nucleophiles
to allenyl phosphates.3 In this paper we would like to
report our findings on the intramolecular cyclization of
tethered alkoxides to allenylphosphine oxides to afford
good to excellent yields of 2-alkyl- and 2-aryl-3-(diphe-
nylphosphinoyl)-4,5-dihydrofurans (DHFs). To examine
the potential of the cyclization (Scheme 1), a series of
TBDMS protected allenylphosphine oxides 1 were pre-
pared in two steps from conveniently accessible starting
materials. It was originally envisioned that the depro-
tection of 1 would afford the free alcohols 3. Then, using
methods similar Marshall's furan syntheses, the alcohols
would be cyclized to dihydrofurans 2 using base or Lewis
acid.4 Surprisingly, deprotection with TBAF afforded
directly the DHFs 2 in excellent yields.
Synthesis of the starting allenes began with the
coupling of appropriate aldehydes with the lithium salt
of 1-(tert-butyldimethylsilyloxy)-3-butyne to afford pro-
parglylic alcohols 5a -c (Scheme 2).5 Treatment of the
proparglylic alcohols with chlorodiphenylphosphine af-
forded, after a [2,3]-sigmatropic rearrangement, allenyl
phosphine oxides 1a -c in excellent yields.6 Reaction of
1a -c with tetrabutylammonium fluoride in dry THF at
room temperature for 1 h initiated cyclization to DHFs
2a -c.7
Sch em e 3
afforded, after workup and HPLC purification, dihydro-
furan 2b (36%) and allenol 3b (54%). Reaction condi-
tions, including exclusion of a proton source, concentra-
tion, and temperature effects had nominal effect on
product ratio or overall reaction yield. Cyclization is
clearly hindered by the steric bulk of the t-Bu group in
1b. Attempts to cyclize allenol 3b under a variety of
conditions, such as deprotonation with tert-butoxide,8
potassium hydride,9 or reaction with AgNO3 proved
unproductive, affording only trace amounts of DHFs by
10
1H-NMR analysis.
One mechanistic proposal for the formation of the
DHFs involves deprotection of the silyl ether to afford
alkoxide 7, followed by its conjugate addition to the sp-
hybridized carbon of the allenylphosphine oxide to afford
the phosphorus enolate 8. Tautomerization of enolate 8
afforded only dihydrofuran 2. No exocyclic enol ether 9
was ever observed. Attempts to trap 8 or 9 with
electrophilic methyl iodide proved futile. We therefore
propose that the enolate 8 directly protonates to afford
the dihydrofuran 2. However, a second possible mech-
anism would involve addition of alkoxide 7 in an 5-exo-
dig manifold to afford directly DHF 2.11
When the substituents R were sterically small on the
allenylphosphine oxides, such as 1a (R ) Me) or 1c (R )
Ph), only DHFs 2a (91%) and 2c (84%) were isolated.
1
Neither allenols 3a or 3c were observed in the H-NMR
spectra of the crude material. Cyclization occurred in
less than 1 h and was found not to require an inert
atmosphere or rigorous anhydrous conditions. Inspection
1
of the H NMR spectrum of the crude material showed
the near quantitative conversion of 1a to dihydrofuran
2a with little to no side products. Even deprotection of
allenes 1a and 1c in wet THF failed to afford the
corresponding allenols 3. When 1 M TBAF in THF was
diluted with ∼20% water, protected allenols were quan-
titatively recovered. Deprotection of 1b (R ) t-Bu)
We have developed a short and efficient synthesis of
sterically unhindered 2,3-disubstituted dihydrofurans
using an intramolecular addition reaction of a tethered
alkoxide to an allenylphosphine oxide. Future studies
on this potentially important new synthetic methodology
are currently in progress. Studies to determine the
effects of ring size and electronic and steric effects of both
(1) Gueddari, F. E.; Grimaldi, J . R.; Hatem, J . M. Tetrahedron Lett.
1995, 36, 6685.
(2) (a) Marshall, J . A.; Sehon, C. A. J . Org. Chem. 1994, 59, 7169.
(b) Walkup, R. D.; Kim, S. W. J . Org. Chem. 1994, 59, 3433.
(3) (a) Denmark, S. E.; Marlin, J . E. J . Org. Chem. 1991, 56, 1003.
(b)Harmata, M.; Herron, B. F. Synthesis 1993, 2, 202.
(4) Marshall, J . A.; Sehon, C. A. J . Org. Chem. 1995, 60, 5967.
(5) Midland, M. M.: McLaughlin, J .; Werley, R. T. Org. Synth. 1991,
14.
(6) Okamura, W. H.; Curtin, M. L. J . Org. Chem. 1990, 55, 5278.
(7) Corey, E. J .; Venkateswarlu, A. J . Am. Chem. Soc. 1972, 94,
2250.
(8) Marshall, J . A.; Bartley, G. S. J . Org. Chem. 1994, 59, 7169.
(9) Marshall, J . A.; Bennett, C. E. J . Org. Chem. 1994, 59, 6110.
(10) Kinsman, R.; Lathbury, D.; Vernon, P.; Gallagher, T. J . Chem.
Soc., Chem. Commun. 1987, 243.
(11) Baldwin, J . E. J . Chem. Soc., Chem. Commun. 1976, 734.
S0022-3263(96)00559-2 CCC: $12.00 © 1996 American Chemical Society

6032 J . Org. Chem., Vol. 61, No. 17, 1996
Notes
(54%) of uncyclized allenol 3b 1H-NMR (270 MHz, CDCl3): δ
0.72 (9H, s), 2.46-2.55 (2H, m), 3.82-3.74 (2H, m), 5.10 (1H,
dt, J ∼ 10.9 Hz,1.7 Hz), 7.4-7.6 (6H, m), 7.6-7.8 (4H, m).
2-P h en yl-3-(diph en ylph osph in oyl)-4,5-dih ydr ofu r an (2c).
Following the procedures for the deprotection of 2a , (n-Bu)4NF
(2.8 mL, 1 M in THF, 2.8 mmol) was added dropwise to TBDMS
allene 1c (443 mg, 0.93 mmol) in dry THF (3 mL) to afford after
workup and purification 282 mg (84%) of dihydrofuran 2c. 1H-
NMR (270 MHz, CDCl3): δ 2.62 (2H, t, J ∼ 9.2 Hz), 3.80 (2H,
s), 4.35 (2H, t, J ∼ 9.2 Hz), 7.1-7.2 (5H, m), 7.4-7.5 (6H, m),
7.6-7.8 (4H, m).
1-(ter t-Bu tyld im eth ylsilyloxy)-3-p en tyn -5-ol (5a ). A so-
lution of 4-(tert-butyldimethylsilyloxy)-1-butyne (6.78 g, 36.8
mmol) in dry THF (100 mL) was cooled to -78 °C, and
n-butyllithium (25 mL, 1.55 M , 38.8 mmol) was added dropwise.
The solution was stirred for 5 min at -78 °C, warmed to rt for
20 min, and then recooled to -78 °C. A solution of acetaldehyde
(4a ) (5.00 g, 58.1 mmol) in 100 mL of THF was added dropwise
via cannula. After stirring for 1 h at -78 °C, the reaction was
warmed to rt and quenched with water. The organic layer was
separated and the aqueous layer extracted with ether (3 × 100
mL). The combined organic layers were washed with saturated
NH4Cl, dried over MgSO4, and concentrated. Distillation of the
crude residue (Kugelrohr (165-170 °C, 1 mm) afforded 11.9 g
of the proprogyl alcohol 5a (82%) as a clear oil. 1H-NMR (270
MHz, CDCl3): δ -0.01 (6H, s), 0.82 (9H, s), 1.31 (3H, d, J ∼ 7.4
Hz), 2.32 (2H, dt, J ∼ 1.1 Hz, 7.9 Hz), 3.62 (2H, t, J ∼ 7.9 Hz),
4.39 (1H, tq, J ∼ 1.1 Hz, 7.4 Hz).
allenyl and phosphorus substitutents and mechanism
will be reported in due course.
Exp er im en ta l Section
1-(ter t-Bu tyld im eth ylsilyloxy)-3-(d ip h en ylp h osp h in oyl)-
3,4-h exa d ien e (1a ). To a solution of proparglylic alcohol 5a
(951 mg, 4.16 mmol), dry ethyl ether (20 mL), and DMAP (2.04
g, 16.6 mmol) was added chlorodiphenylphosphine (1.84 g, 8.32
mmol). After stirring for 48 h at rt, the reaction was quenched
with water (20 mL) and the aqueous layer extracted with ether
(3 × 20 mL). The combined organic layers were dried over
MgSO4, filtered, concentrated, and chromatographed (80% EtOAc/
hexane) to afford 1.48 g (86%) of allene 1a . 1H-NMR (270 MHz,
CDCl3): δ -0.01 (6H, s), 0.84 (9H, s), 1.42 (3H, t, J ∼ 6.9 Hz),
2.3-2.3 (2H, m), 3.71 (2H, t, J ∼7 Hz), 5.0 (1H, m), 7.3-7.5 (6H,
m), 7.6-7.7 (4H, m).
1-(t er t -B u t y ld i m e t h y ls i ly lo x y )-6,6-d i m e t h y l-3-(d i -
p h en ylp h osp h in oyl)-3,4-h ep ta d ien e (1b). Using the proce-
dure for the synthesis of 1a , to proparglylic alcohol 5b (400 mg,
1.48 mmol), dry diethyl ether (9 mL), and DMAP (723 mg, 5.92
mmol) was added chlorodiphenylphosphine (651 mg, 2.96 mmol).
Workup and chromatography (80% EtOAc/hexane) afforded 618
mg (92%) of allene 1b. 1H-NMR (270 MHz, CDCl3): δ -0.06
(6H, s), 0.68 (9H, s), 0.81 (9H, s), 2.3-2.5 (2H, m), 3.71 (2H, dt,
J ∼1.7 Hz, 8.6 Hz), 5.0 (1H, dt, J ∼11.1 Hz,1.7 Hz), 7.2-7.5
(6H, m), 7.6-7.8 (4H, m).
1-(ter t-Bu tyldim eth ylsilyloxy)-5-ph en yl-3-(diph en ylph os-
p h in oyl)-3,4-p en ta d ien e (1c). Using the procedure for the
synthesis of 1a , to proparglylic alcohol 5c (643 mg, 1.35 mmol),
dry diethyl ether (10 mL), and DMAP (394 mg, 5.42 mmol) was
added chlorodiphenylphosphine (596 mg, 2.71 mmol). Workup
and chromatography (80% EtOAc/hexane) afforded 5.97 mg
(86%) of allene 1c. 1H-NMR (270 MHz, CDCl3): δ -0.05 (3H,
s), -0.03 (3H, s) 0.82 (9H, s), 2.5-2.6 (2H, m), 3.81 (2H, t, J
∼6.7 Hz), 6.37 (1H, dt, J ∼11.1, Hz, 3.0 Hz,), 7.0-7.4 (11H, m),
7.6-7.7 (4H, m).
1-(ter t-Bu t yld im et h ylsilyloxy)-6,6-d im et h yl-3-h ep t yn -
5-ol (5b). Using the procedure for the preparation of 5a ,
n-butyllithium (25 mL, 1.55 M in hexanes, 38.8 mmol) was added
to 4-(tert-butyldimethylsilyloxy)-1-butyne (6.56 g, 35.6 mmol) in
THF (100 mL), followed by trimethylacetaldehyde (4b) (5.00 g,
58.1 mmol) in THF (100 mL) to afforded after workup and
distillation (165-170 °C, 1 mm), 11.9 g of the proprogyl alcohol
5b (82%) as a clear oil. 1H-NMR (270 MHz, CDCl3): δ 0.05 (6H,
s), 0.88 (9H, s), 0.96 (9H, s), 2.42 (2H, dt, J ∼ 1.8 Hz, 7.1 Hz),
3.70 (2H, t, J ∼ 7.1 Hz), 3.97 (1H, dt, J ∼ 1.8 Hz, 5.9 Hz).
5-(ter t-Bu tyldim eth ylsilyloxy)-1-ph en yl-2-pen tyn -1-ol (5c).
Using the procedure for the preparation of 5a , n-butyllithium
(24 mL, 1.55 M , 37.2 mmol) was added to 4-(tert-butyldimeth-
ylsilyloxy)-1-butyne (6.30 g, 34.2 mmol) in THF (100 mL),
followed by benzaldehyde (4c) (5.00 g, 59.0 mmol) in THF (100
mL) to afforded after workup and distillation (200-210 °C, 1
2-Eth yl-3-(d ip h en ylp h osp h in oyl)-4,5-d ih yd r ofu r a n (2a ).
A solution of (n-Bu)4NF (3.5 mL, 1 M in THF, 3.5 mmol) was
added dropwise to the TBDMS allene 5a (391 mg, 94 mmol) in
dry THF (3.5 mL) under a nitrogen atmosphere. The mixture
was stirred for 1 h at rt, quenched with brine (3 mL), and
extracted with ether (3 × 3 mL). The combined organic layers
were washed with saturatated NaHCO3 (5 × 10 mL), dried over
MgSO4, filtered, concentrated, and chromatographed (80% EtOAC/
hexanes) to afford 257 mg (91%) of dihydrofuran 2a . 1H-NMR
(270 MHz): (CDCl3): δ 2.94 (3H, t, J ∼ 7.5 Hz), 2.33 (2H, q, J
∼7.5 Hz), 2.62 (2H, t, J ∼ 9.4 Hz), 4.36 (2H, t, J ∼ 9.4 Hz), 7.5-
7.6 (6H, m), 7.6-7.8 (4H, m). 13C-NMR (67.95 MHz): (CDCl3)
δ 11.6, 21.3, 33.4 (d, J ∼ 10 Hz), 70.1 (d, J ∼ 10 Hz), 95.3 (d, J
∼ 123 Hz), 128.4, 128.6, 131.4, 131.5, 131.6, 131.7, 132.8, 134.3,
173.4 (d, J ∼ 20 Hz). IR: (CCl4) ν 3058, 2973, 2939, 2898, 1623,
1438, 1365, 1199,1118, 1064, 721, 698 cm-1. HRMS (70 ev EI):
298.1122 calcd for C18H19O2P, 298.1114). LRMS; m/z 298(74,
M+), 283(11), 269(11), 241(7), 227(3), 201(34), 183(14), 173(4),
155(8), 141(10), 129(21), 115(14), 91(10), 84(base), 77(54).
2-(2,2-Dim eth ylp r op yl)-3-(d ip h en ylp h osp h in oyl)-4,5-d i-
h yd r ofu r a n (2b). Following the procedures for the deprotection
of 2a , (n-Bu)4NF (3.2 mL, 1 M in THF, 3.2 mmol) was added
dropwise to TBDMS allene 1b (473 mg, 1.04 mmol) to afford
after workup and purification, 134 mg (36%) of dihydrofuran
1
mm), 11.4 g of the proprogyl alcohol 5c (85%) as a clear oil. H-
NMR (270 MHz, CDCl3): δ 0.08 (6H, s), 0.91 (9H, s), 2.50 (2H,
dt, J ∼ 1.8 Hz, 7.1 Hz), 3.76 (2H, t, J ∼ 7.0 Hz), 5.40 (1H, s)
7.3-7.6 (5H, m).
Ack n ow led gm en t. We gratefully acknowledge the
support of the Research Corporation Cottrell Grant
Program (CC3959). The NMR spectrometer used in this
study was funded through a NSF-ILI Grant (DUE-
9452076).
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic data
(1H-NMR, 13C-NMR, IR, HRMS, and LRMS) for all new
compounds (11 pages). This material is contained in libraries
on microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered form the ACS: see
any current masthead page.
1
2b H-NMR (270 MHz): (CDCl3): δ 0.92 (9H, CH3, s), 2.46 (2H,
CH2, s), 2.60 (2H, H3, t, J ∼ 9.2 Hz), 4.35 (2H, H3, t, J ∼ 9.2
Hz), 7.4-7.5 (6H, ArH, m), 7.6-7.8 (4H, ArH, m), and 191 mg
J O960559A