Application of the Sonogashira coupling reaction to the stereoselective synthesis of chiral 1,3-dienol ethers

Article abstract of DOI:10.1055/s-1998-1976

Sonogashira couplings of 2-iodo enol ethers or ynol ethers provide enynes which undergo semihydrogenation to afford 4-alkyl-1,3-dienol ethers. (1Z, 3E), (1E, 3Z) and (1Z, 3Z)-4-alkyl-1,3-dienol ethers are accessible using this strategy.

Full text of DOI:10.1055/s-1998-1976

December 1998
SYNLETT
1387
Application of the Sonogashira Coupling Reaction to the Stereoselective Synthesis of
Chiral 1,3-Dienol Ethers
Patrick H. Dussault*, Darby G. Sloss, and David J. Symonsbergen
Department of Chemistry, University of Nebraska-Lincoln, Lincoln, Nebraska 68588-0304, USA
FAX (402) 472-9402 internet: dussault@unlinfo.unl.edu
Received 13 October 1998
Abstract: Sonogashira couplings of 2-iodo enol ethers or ynol ethers
ii
RO
RO
i
RO
ROH
provide enynes which undergo semihydrogenation to afford 4-alkyl-1,3-
dienol ethers. (1Z, 3E), (1E, 3Z) and (1Z, 3Z)-4-alkyl-1,3-dienol ethers
are accessible using this strategy.
I
1
2
a, R =
b, R =
Ph
iii
X
As part of a synthetic program targeting peroxide-containing natural
products, we required a stereoselective preparation of chiral dienol
ethers as substrates for stereoselective addition of singlet oxygen (eq. 1)
3: X = SnBu3
4: X = I
iv
i. KH, THF, cat. imidazole, ROH, 0 °C; trichloroethene, -40 °C;
n-BuLi, -78 °C; MeOH, -40 °C ii. ethynol ether, Cp2ZrHCl, THF
then I2 iii. Et3B, HSnBu3; iv. THF, NIS
Ph
O
Ph
O
Ph
Scheme 1
(1)
R
OH
O
O
v
RO
R
RO
RO
5
6
Bu
Bu
1
1
Equation 1
vi
RO
Bu
However, a review of the literature revealed surprisingly few general
methods for synthesis of alkyl dienol ethers.
(Stephens-Castro) coupling reaction is
vii
vii
RO
RO
1-3
The Sonogashira
I
a
convenient Pd(0)/Cu(I)
2
4
7
8
mediated process which has been used for the formation of numerous
4
enynes. Herein we report the application of the Sonogashira coupling
RO
I
RO
towards the stereoselective synthesis of (1Z, 3E), (1E, 3Z) and (1Z, 3Z)-
4-alkyl-1,3-dienol ethers. As illustrated in eq. 2, our strategy relies upon
a Sonogashira coupling followed by selective reduction of the alkyne
for formation of the diene functionality.
Bu
v. i-PrNH2, (E)-1-iodohexene, Pd(Ph3)4, CuI vi. i-PrNH2,
(Z)-1-iodohexene, Pd(Ph3)4, CuI vii. i-PrNH2, hexyne, Pd(Ph3)4, CuI
Scheme 2
Bu
Bu
13-15
16
Yamanaka
and Suginome have described the palladium catalyzed
RO
(2)
RO
H
coupling of aryl and heteroaryl halides with (Z)-1-ethoxy-2-
stannylethene or (E)-tris(2-ethoxyethenyl)borane; however, attempts to
perform a direct synthesis of the dienol ether through Stille coupling
between stannylenol ether 3 and iodohexene were unsuccessful under a
variety of conditions (eq. 3), as were attempts to perform Suzuki
RO
Equation 2
17
couplings via the corresponding enol boronate.
Alkynol ethers 1a and 1b were readily synthesized from L-menthol and
(R,S)-trans-2-phenylcyclohexanol using the method of Greene
5
(Scheme 1). Alternatively, these alkynol ethers could be converted to
Bu
6
various Pd(0)
(E)-2-iodo enol ethers
2
by hydrozirconation-iodination.
RO
Bu
(3)
+
SnBu3
I
X
RO
Hydrostannylation of the alkynyl ethers selectively produced
3
(Z)-tributylstannyl enol ethers 3 which underwent iodination to produce
7
the (Z)-2-iodo enol ethers 4 (Scheme 1).
Equation 3
8,9
Coupling of 1 with (Z)- or (E)-1-iodohexene furnished enynol ethers
10
5 and 6 in a stereospecific fashion (Table 1). Coupling of the (E)- and
In summary, we have demonstrated that the use of the Sonagashira
coupling permits rapid access to three of the four possible geometric
isomers of dienol ethers. Application of this methodology for peroxide
synthesis will be described in due course.
(Z)-iodo enol ethers 2 and 4 with 1-hexyne furnished enynol ethers 7
and 8 (Scheme 2 and Table 1).
11
Semihydrogenation
of the enynes with P-2 Nickel selectively
introduced a (Z)-alkene (Table 1). The dienol ethers were susceptible to
overreduction to enol ethers under the semihydrogenation conditions,
but overreduction could be minimized with careful monitoring of
reaction progress. Attempted hydride reduction of the alkyne to the (E)-
Acknowledgments: This work was supported by a grant from the NIH
(GM 45571).
12
alkene was unsuccessful, thus limiting the scope of this strategy to the
preparation of dienol ethers containing at least one (Z)-olefin.

1388
LETTERS
SYNLETT
Notes and References
31.0, 31.1, 32.5, 33.8, 39.8, 49.0, 89.4, 95.6, 109.3, 126.5, 127.5,
128.3, 140.6, 142.5; FT-IR (neat) 698, 754, 940, 995, 1253, 1449,
(1) Luengo, J. I.; Koreeda, M. Tetrahedron Lett. 1984, 25, 4881.
(2) McDougal, P. G.; Rico, J. G. J. Org. Chem. 1987, 52, 4817.
-1
2245, 2858, 2930, 3028 cm ; HRMS calcd for C
282.1984, found 282.1973.
H O (M+)
20 26
(3) Nicolaou, K. C.; Shi, G.-Q.; Gunzner, J. L.; Gärtner, P.; Zang, Y. J.
Am. Chem. Soc. 1997, 119, 5467.
(11) To an oven dried 3-neck flask topped with a 3-way stopcock and a
hydrogen balloon was added nickel (II) acetate (482 mg, 1.94
mmol) and 7 mL of absolute ethanol. Following two vacuum/
repressurization cycles (nitrogen), the flask was evacuated and
charged with hydrogen. Sodium borohydride (73 mg, 1.9 mmol)
dissolved in 5 mL of absolute ethanol was added. After stirring for
20 minutes, ethylenediamine (0.52 mL, 7.7 mmol) and a solution
of the enynol ether (570 mg, 2.02 mmol, 5b) in ethanol (3 mL)
was added and the reaction was stirred at RT for 1 h. The
hydrogen was released and the reaction mixutre was diluted with
(4) Sonogashira, K. In Comprehensive Organic Synthesis; B. M.
Trost, Ed.; Pergamon Press: New York, 1991; Vol. 3; pp 521.
(5) Greene, A. E. J. Org. Chem. 1987, 2919.
(6) Lipshutz, B. H.; Keil, R.; Ellsworth, E. L. Tetrahedron Lett. 1990,
31, 7257.
(7) Chen, S. M.; Schaub, R. E.; Grudzinskas, C. V. J. Org. Chem.
1978, 43, 3450.
(8) Brown, H. C.; Blue, C. D.; Nelson, D. J.; Bhat, N. G. J. Org.
Chem. 1989, 54, 6064.
hexane and extracted with NaHCO (10% aq.). The combined
3
organics were dried over Na SO , evaporated and purified by
2
4
(9) Polt, R.; Peterson, M. Synth. Comm. 1992, 22, 477.
flash chromatography (100% pentane, Et N pretreated) to afford a
3
(10) To tetrakis(triphenylphosphine) palladium (100 mg, 0.086 mmol)
colorless oil (396 mg, 69%). When necessary, overreduced enol
dissolved in i-PrNH (12 mL) was added (E)-1-iodo-1-hexene
2
ether and dienol ether could be separated using HPLC (100%
(362 mg, 1.73 mmol), (R,S)-trans-2-phenylcyclohexanol ethynyl
ether 1b (449 mg, 2.24 mmol), and copper (I) iodide (33 mg, 0.17
1
pentane): R 0.87 (95% hexane-EtOAc); H NMR (360 MHz,
f
CDCl ) δ 0.87 (t, J= 7 Hz, 3H), 1.60-1.24 (m, 8H), 1.74-1.79 (m,
3
mmol) dissolved in i-PrNH (5 mL). The resulting orange solution
2
1H), 1.85-2.01 (m, 3H), 2.13-2.19 (m, 1H), 2.66 (app dt, J= 4, 11
Hz, 1H), 3.63 (dt, J= 4, 10 Hz, 1H), 4.77 (dd, J= 6, 11 Hz, 1H),
was stirred in the dark for 5 h. The reaction was diluted with
hexane and thoroughly washed with NaHCO (sat. aq.). The
3
5.37 (dt, J= 7, 15.5 Hz, 1H), 5.62 (d, J= 6 Hz, 1H), 6.08 (dd, J=
aqueous layers were combined and extracted with hexane. The
13
11, 15.5 Hz, 1H), 7.15-7.33 (m, 5H); C NMR (75 MHz, CDCl )
3
combined organic layers were dried over Na SO , concentrated,
2
4
δ 13.9, 22.2, 24.9, 25.8, 31.7, 32.5, 32.8, 33.4, 50.4, 84.5, 106.6,
and purified by chromatography (100% hexane, no Et N
3
123.1, 126.2, 127.7, 128.1, 130.2, 143.4, 143.6; FT-IR (neat) 698,
pretreatment of silica) to afford 5b as an oil (375 mg, 77%): R
1
f
754, 970, 1075, 1108, 1448, 1615, 1656, 2856, 2927, 3029 cm- ;
1
0.66 (95% hexane-EtOAc); H NMR (500 MHz, CDCl ) δ 0.95 (t,
3
HRMS calcd for C
H O (M+) 284.2140, found 284.2142.
20 28
J= 9 Hz, 3H), 1.33-1.51 (m, 6H), 1.58 (dq, J= 3, 13 Hz, 1H), 1.68
(dq, J= 4, 12.5 Hz, 1H), 1.79-1.82 (m, 1H), 1.97-2.00 (m, 2H),
2.10 (dq, J= 1, 7 Hz, 2H), 2.46-2.49 (m, 1H), 2.81 (app dt, J= 4, 11
Hz, 1H), 4.15 (dt, J= 4.5, 11 Hz, 1H), 5.44 (dt, J= 1.5, 15.5 Hz,
(12) Denmark, S. E.; Thorarensen, A. J. Am. Chem. Soc. 1997, 119,
125.
(13) Sakamoto, T.; Kondo, Y.; Yasuhara, A.; Yamanaka, H.
Heterocycles 1990, 31, 219.
1H), 5.92 (dt, J= 7, 15.5 Hz, 1H), 7.35-7.38 (m, 2H), 7.26-7.31
13
(m, 3H); C NMR (125 MHz, CDCl ) δ 13.8, 22.0, 24.6, 25.5,
3
Table 1
Dienol Ether
Entry
Alkyne
Iodide
Bu
Ene-yne
Yielda (%)
94
Yielda (%)
82b
Bu
RaO
RaO
1
1a
RaO
RaO
Bu
5a
I
I
9a
52
69
Bu
Bu
57
77
2
3
4
1a
1b
6a
Bu
Bu
10a
Bu
RbO
RbO
Bu
Bu
5b
7a
I
9b
RaO
ORa
Bu
Bu
2a
4a
100
63
53
RaO
RaO
11a
99c
5
Bu
Bu
10a
8a
Bu
Ph
a Isolated yields. All new compounds were characterized by 1H and 13C-NMR,
and by HRMS or elemental analysis. b Contains 12% over-reduced enol ether
that is separable by HPLC. c Without chromatographic purification.
Ra =
Rb =

December 1998
SYNLETT
1389
(14) Sakamoto, T.; Kondo, Y.; Yasuhara, A.; Yamanaka, H.
(17) Farina, V.; Krishnamurthy, V.; Scott, W. J. Organic Reactions
1997, 50, 1. (MeCN) PdCl , (PPh ) Pd(OAc) , (PPh ) PdCl ,
Tetrahedron 1991, 1877.
2
2
3 2
2
3 2
2
and Pd dba /P(2-furyl) catalysts in THF or DMF, with or without
(15) Sakamoto, T.; Satoh, C.; Kondo, Y.; Yamanaka, H. Chem. Pharm.
Bull. 1993, 41, 81.
2
2
3
CuI cocatalyst, at 25-65°C for 2-117 h were utilized for the
attempted Stille couplings. Attempted Suzuki couplings of the
9-BBN borane, catechol boronate, or boronic acid derives of the
(16) Miyaura, N.; Maeda, K.; Suginome, H.; Suziki, A. J. Org. Chem.
1982, 2117.
alkynol ether with (E)-1-iodohexne using Pd(PPh ) and K PO at
3 4
3
4
65 °C in THF were unsuccessful.