Efficient synthesis of optically active 2,3-allenols via the simple CuBr-mediated reaction of optically active propargylic alcohols with paraformaldehyde

Article abstract of DOI:10.1055/s-2002-33656

Enantiomerically enriched 2,3-allenols were prepared by the CuBr-mediated homologation of the relatively easily available optically active terminal propargylic alcohols with paraformaldehyde in the presence of diisopropylamine.

Full text of DOI:10.1055/s-2002-33656

SHORT PAPER
1643
Efficient Synthesis of Optically Active 2,3-Allenols via the Simple
CuBr-Mediated Reaction of Optically Active Propargylic Alcohols
with Paraformaldehyde
Synthesis of
O
h
ptically Acti
e
ve 2,3-Alle
n
nols gming Ma,* Hairong Hou, Shimin Zhao, Guangwei Wang
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin
Lu, Shanghai 200032, P. R. China
Fax +86(21)64166128; E-mail: masm@pub.sioc.ac.cn
Received 16 April 2002; revised 3 June 2002
1) LiNH2/NH3
2) RX
LiAlH4
Abstract: Enantiomerically enriched 2,3-allenols were prepared by
the CuBr-mediated homologation of the relatively easily available
optically active terminal propargylic alcohols with paraformalde-
hyde in the presence of diisopropylamine.
R
OH
OH
THF, reflux
R
R
Ti(O-i-Pr)4, tartrate, 4A MS
*
OH
*
TBHP, CH2Cl2,
-20 °C, 3.5-5 h
Key words: propargylic alcohols, 2,3-allenols, copper
O
OH
R
R
n-BuLi
PPh3, CCl4
reflux, 2 h
2,3-Allenols are an important class of functionalized al-
lenes, which can be used as the starting materials for the
synthesis of oxiranes,1 2,5-dihydrofurans,2 -methyle-
nelactone,3 - or -amino alcohols,4 and , -unsaturated
ketones.5 For the synthesis of oxygen-containing hetero-
cycles, it should be possible to transfer the chirality of the
optically active 2,3-allenols into the corresponding final
products. Thus, the syntheses of optically active 2,3-alle-
nols are of current interest. In this paper, we wish to report
a facile synthesis of terminally unsubstituted 2,3-allenols
with the chirality at the carbon atom connected to the hy-
droxyl group.
*
*
*
OH
O
Cl
THF, -35 °C
Scheme 1
HO
n-C8H17
MgBr
CrO3, H2SO4
n-C8H17CHO
acetone, 0 °C
BINOL, LiAlH4, MeOH
O
HO
n-C8H17
n-C8H17
THF, -100→-78 °C
Scheme 2
These optically active 2,3-allenols are usually prepared
via the reaction of optically active 1,2-allenylboron re-
agents with aldehydes6 or the (S)-BINOL(2,2 -dihydroxy-
1,1 -binaphthyl)-Ti(IV)-catalyzed reaction of propargyl-
ictin with aldehydes.7 Recently, we have prepared the op-
tically active 2,3-allenols via the SN2-type reduction of
optically active 1-OTHP-alk-2-yn-4- ols with LiAlH4.1a
In this study, (R)- or (S)-undecyn-3-ols were also prepared
by the catalytic enantioselective reduction of 1-trimethyl-
silylundec-1-yn-3-one
followed
by
desilylation
(Scheme 3).8e
Using these above synthesized optically active propargyl-
ic alcohols as the starting materials, the results of CuBr-
mediated reaction of optically active terminally unsubsti-
tuted propargylic alcohols with paraformaldehyde were
summarized in Table 1.
Since optically active propargylic alcohols are relatively
easily available by several approaches,8 we reasoned that
the optically active 2,3-allenols with the chiral centers
connected to the hydroxyl group can be synthesized via
the CuBr-mediated reaction of optically active terminal
propargylic alcohols with paraformaldehyde in the pres-
ence of diisopropylamine.9
From the results listed in Tables 1 and 2, it is obvious that
the reaction afforded 2,3-allenols in moderate yields and
the enantiopurity of the chiral center remained essentially
unchanged. Due to the synthetic importance of (S)- or (R)-
2,3-allenols, this route will show its utility in organic syn-
thesis.
The optically active propargylic alcohols used in this
study were prepared via the treatment of corresponding
optically active chloromethylepoxide with BuLi in THF
(Scheme 1)10 or the enantioselective reduction of 1-ethy-
nyl ketones (Scheme 2).8a
All reactions were carried out under argon unless otherwise noted.
All solvents were distilled prior to use. 1,4-Dioxane was distilled
from sodium ketyl. 1H NMR spectra were recorded in CDCl3 on a
Varian 300 MHz spectrometer. IR spectra were obtained using a
Perkin-Elmer 983 instrument. Mass spectra were obtained using a
HP 5989A mass spectrometer. GC spectra were obtained using a
Perkin-Elmer Autosystem XL Gas Chromatograph instrument(RT-
DEXcst, 30 meter, 0.25 m ID, 0.25 m DF).
Synthesis 2002, No. 12, Print: 06 09 2002.
Art Id.1437-210X,E;2002,0,12,1643,1645,ftx,en;F02802SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1644
S. Ma et al.
SHORT PAPER
3.0 mmol; purity: 97% ee; GC conditions: carrier N2; 8.0 psi; injec-
tor 250 °C; detector (FID, H2, 0.218 MPa) 250 °C; oven tempera-
ture 120 °C (20 min), 1 °C min–1 to 140 °C (20 min); t1 (S) 10.877
min, t2 (R) 11.257 min], and 1,4-dioxane (4.0 mL). The mixture was
heated at 120 °C for 2 h. After cooling, the mixture was evaporated
and the crude product was submitted to chromatography on silica
gel (petroleum ether–EtOAc, 10:1) to afford 242 mg (64%) of (R)-
2a11 with 97% ee [GC conditions: carrier N2; 6.8 psi; injector
250 °C; detector (FID, H2, 0.218 MPa) 250 °C; oven temperature
100 °C (10 min), 1 °C min–1 to 120 °C, 2 °C min–1 to 180 °C; t1 (S)
28.867 min, t2 (R) 29.428 min].
O
OH
n-C8H17
2 mol% (S,S)-complex
TMS
TMS
n-C8H17
i-PrOH
100%
Ts
N
Ru
K2CO3
Ph
Ph
MeOH/H2O (15:1)
OH
N
H
n-C8H17
(S,S)-complex
yield : 99%
ee : 98%
OH
O
2 mol% (R,R)-complex
IR (neat): 3360, 1957, 842 cm–1.
TMS
TMS
n-C8H17
n-C8H17
1H NMR (CDCl3): = 5.23 (q, J = 6.5 Hz, 1 H), 4.86–4.83 (m, 2 H),
4.18–4.16 (m, 1 H), 1.57–1.53 (m, 2 H), 1.39–1.18 (m, 4 H), 0.89 (t,
J = 6.9 Hz, 3 H).
MS: m/z (%) = 126 (M+, 21.21), 87 (8.03), 69 (61.57), 57 (30.82),
43 (100.00), 41 (39.90).
i-PrOH
97%
Ts
K2CO3
MeOH/H2O (15:1)
Ph
N
Ru
N
OH
Ph
H
n-C8H17
(R,R)-complex
(S)-Octa-1,2-dien-4-ol [(S)-2a)]
yield : 99%
ee : 98%
The typical procedure given above was followed starting from CuBr
(96 mg, 0.67 mmol), paraformaldehyde (98 mg, 3.3 mmol), i-Pr2NH
(0.35 mL, 250 mg, 2.5 mmol), (S)-hept-1-yn-3-ol (221 mg, 2.0
mmol, 80% ee), and 1,4-dioxane (3.5 mL) to afford 196 mg (79%,
80% ee) of (S)-2a.11
Scheme 3
(R)-1,2-Undeca-1,2-dien-4-ol [(R)-2b]
(R)-Octa-1,2-dien-4-ol [(R)-2a]; Typical Procedure
The typical procedure given above was followed starting from CuBr
(94 mg, 0.66 mmol), paraformaldehyde (96 mg, 3.2 mmol), i-Pr2NH
(242 mg, 2.4 mmol, 0.34 mL), (R)-dec-1-yn-3-ol [308 mg, 2.0
In a reaction flask containing CuBr (142 mg, 0.99 mmol) and
paraformaldehyde (144 mg, 4.8 mmol) were added subsequently i-
Pr2NH (0.51 mL, 364 mg, 3.6 mmol), (R)-hept-1-yn-3-ol [336 mg,
Table 1 Homologation of (S)-Propargylic Alcohols (S)-1 to (S)-2,3-Allenols (S)-2
Entry
(S)-1
ee of (S)-1
Yield of
ee of (S)-2 (%)
[ ]D20 (MeOH)
(%)
(S)-2 (%)
1
2
3
4
Bu [(S)-1a]
80
92
96
96
79 [(S)-2a]
79 [(S)-2b]
72 [(S)-2c]
77 [(S)-2d]
80
92
95
96
–17.8 (c, 1.00)
–16.5 (c, 0.95)
–19.6 (c, 0.95)
–130.6 (c, 0.95)
C7H15 [(S)-1b]
C8H17 [(S)-1c]
Ph [(S)-1d]
Table 2 Homologation of (R)-Propargylic Alcohols to (R)-2,3-Allenols
Entry
(R)-1
ee of (R)-1 (%)
Yield of
ee of (R)-2 (%)
[ ]D20 (MeOH)
(R)-2 (%)
1
2
3
4
5
Bu [(R)-1a]
97
89
94
96
98
64 [(R)-2a]
70 [(R)-2b]
69 [(R)-2c]
69 [(R)-2d]
71 [(R)-2c]
97
89
97
97
98
+22.8 (c, 1.05)
+18.9 (c, 0.95)
+15.3 (c, 1.05)
+121.4 (c, 1.10)
+20.3 (c, 1.30)
C7H15 [(R)-1b]
C8H17 [(R)-1c]
Ph [(R)-1d]
C8H17 [(R)-1c]
Synthesis 2002, No. 12, 1643–1645 ISSN 0039-7881 © Thieme Stuttgart · New York

SHORT PAPER
Synthesis of Optically Active 2,3-Allenols
1645
mmol; purity: 89% ee; GC conditions: carrier N2; 8.0 psi; injector
250 °C; detector (FID, H2, 0.218 MPa) 250 °C; oven temperature
130 °C (10 min), 1 °C min–1 to 180 °C (10 min); t1 (S) 23.815 min,
t2 (R) 24.292 min], and 1,4-dioxane (3.0 mL) to afford 234 mg
(70%) of (R)-2b12 with 89% ee [GC conditions: carrier N2, 6.8 psi;
injector 250 °C; detector (FID, H2, 0.218 MPa) 250 °C; oven tem-
perature 100 °C (10 min), 1 °C min–1 to 120 °C, 2 °C min–1 to
180 °C; t1 (S) 52.345 min, t2 (R) 52.863 min].
1H NMR (CDCl3): = 7.36–7.20 (m, 5 H), 5.39 (q, J = 6.5 Hz, 1 H),
5.23–5.22 (m, 1 H), 4.90–4.85 (m, 2 H), 2.10 (s, 1 H).
MS: m/z (%) = 145 (M+ – 1, 4.09), 129 (100.00).
(S)-1-Phenylbuta-2,3-dien-1-ol [(S)-2d]
The typical procedure given above was followed starting from CuBr
(94 mg, 0.66 mmol), paraformaldehyde (96 mg, 3.2 mmol), i-
Pr2NH (242 mg, 2.4 mmol, 0.34 mL), (S)-1-phenylprop-2-yn-1-ol
(96% ee, 264 mg, 2.0 mmol), and 1,4-dioxane (3.0 mL), the reaction
afforded 225 mg (77 mg, 96% ee) of (S)-2d.14
IR (neat): 3345, 1957, 842 cm–1.
1H NMR (CDCl3): = 5.24 (q, J = 6.5 Hz, 1 H), 4.87–4.84 (m, 2 H),
4.18–4.16 (m, 1 H), 1.70–1.53 (m, 2 H), 1.39–1.18 (m, 10 H), 0.89
(t, J = 6.9 Hz, 3 H).
Acknowledgements
MS: m/z (%) = 169 (M+ + 1, 0.43), 109 (10.33), 95 (20.11), 81
Financial support from the Major State Basic Research Develop-
ment Program (Grant No. 2000077500), National Natural Science
Foundation of China, Chinese Academy of Sciences, and Shanghai
Municipal Committee of Science and Technology are greatly appre-
ciated. Shengming Ma is the recipient of 1999 Qiu Shi Award for
Young Scientific Workers issued by Hong Kong Qiu Shi Foundati-
on of Science and Technology (1999–2003).
(15.96), 69 (100.00).
(S)-Undeca-1,2-dien-4-ol [(S)-2b]
The typical procedure given above was followed starting from CuBr
(142 mg, 0.99 mmol), paraformaldehyde (144 mg, 4.8 mmol), i-
Pr2NH (0.51 mL, 364 mg, 3.6 mmol), (S)-dec-1-yn-3-ol (462 mg,
3.0 mmol, 92% ee) and 1,4-dioxane (3.5 mL) to afford 395 mg
(79%, 92% ee) of (S)-2b.12
References
(R)-Dodeca-1,2-dien-4-ol [(R)-2c]
The typical procedure given above was followed starting from CuBr
(94 mg, 0.66 mmol), paraformaldehyde (96 mg, 3.2 mmol), i-Pr2NH
(0.34 mL, 242 mg, 2.4 mmol), (R)-undec-1-yn-3-ol [331 mg, 2.0
mmol; purity: 94% ee; GC conditions: carrier N2; 8.0 psi; injector
250 °C; detector (FID, H2, 0.218 MPa) 250 °C; oven temperature
140 °C, t1 (S) 30.770 min, t2 (R) 31.232 min], and 1,4-dioxane (3.0
mL) to afford 248 mg (69%) of (R)-2c13 with 97% ee [GC condi-
tions: carrier N2; 8.0 psi; injector 250 °C; detector (FID, H2, 0.218
MPa) 250 °C; oven temperature 140 °C; t1 (S) 44.560 min, t2 (R)
45.055 min].
(1) (a) Ma, S.; Zhao, S. J. Am. Chem. Soc. 1999, 121, 7943.
(b) Kang, S.-K.; Yamaguchi, T.; Pyun, S.-J.; Lee, Y.-T.;
Baik, T.-G. Tetrahedron Lett. 1998, 39, 2127.
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112, 878.
When the same experiment was carried out with (R)-undec-1-yn-3-
ol of 98% ee (332 mg, 2.0 mmol) (R)-2c13 of 98% ee was obtained;
yield: 256 mg (71%).
IR (neat): 3344, 1957, 842 cm–1.
1H NMR (CDCl3): = 5.18 (q, J = 6.5 Hz, 1 H), 4.80–4.77 (m, 2 H),
4.11–4.10 (m, 1 H), 1.54–1.44 (m, 2 H), 1.38–1.21 (m, 12 H), 0.81
(t, J = 6.7 Hz, 3 H).
(7) Yu, C.-M.; Yoon, S.-K.; Baek, K.; Lee, J.-Y. Angew. Chem.
Int. Ed. 1998, 37, 2392.
(8) For some typical methods, see: (a) Noyori, R.; Tomino, I.;
Yamada, M.; Nishizawa, M. J. Am. Chem. Soc. 1984, 106,
6717. (b) Frantz, D. E.; Fässler, R.; Carreira, E. M. J. Am.
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A. J. Am. Chem. Soc. 1994, 116, 3151. (d) Lütjens, H.;
Nowotny, S.; Knochel, P. Tetrahedron: Asymmetry 1995, 6,
2675. (e) Matsumura, K.; Hashiguchi, S.; Ikariya, T.;
Noyori, R. J. Am. Chem. Soc. 1997, 119, 8738. (f) He, Q.;
Ma, S. Chin. J. Org. chem. 2002, 22, 375.
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Soc., Chem. Commun. 1979, 859. (b) Crabbé, P.; Nassim,
B.; Robert-Lopes, M.-T. Org. Synth. 1985, 63, 203.
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Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987,
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MS: m/z (%) = 183 (M+ + 1, 0.21), 109 (6.07), 95 (10.76), 69
(100.00), 57 (19.14).
(S)-Dodeca-1,2-dien-4-ol [(S)-2c]
The typical procedure given above was followed starting from CuBr
(94 mg, 0.66 mmol), paraformaldehyde (96 mg, 3.2 mmol), i-Pr2NH
(0.34 mL, 242 mg, 2.4 mmol), (S)-undec-1-yn-3-ol (336 mg, 2.0
mmol, 96% ee) and 1,4-dioxane (3.0 mL) afforded 262 mg (72%,
95% ee) of (S)-2c.13
(R)-1-Phenylbuta-2,3-dien-1-ol [(R)-2d]
The typical procedure given above was followed starting from CuBr
(94 mg, 0.66 mmol), paraformaldehyde (96 mg, 3.2 mmol), i-Pr2NH
(0.34 mL, 242 mg, 2.4 mmol), (R)-1-phenylprop-2-yn-1-ol [264
mg, 2.0 mmol; purity: 97% ee; GC conditions: carrier N2; 6.4 psi;
injector 250 °C; detector (FID, H2, 0.218 MPa) 250 °C; oven tem-
perature 130 °C (2 min), 1 °C min–1 to 180 °C (20 min); t1 (S):
31.365 min, t2 (R): 31.753 min], and 1,4-dioxane (3.0 mL) to afford
182 mg (69%) of (R)-2d14 with 97% ee [GC conditions: carrier N2;
8.0 psi; injector 250 °C; detector (FID, H2, 0.218 MPa) 250 °C;
oven temperature 140 °C; t1 (S) 41.060 min, t2 (R) 41.372 min].
IR (neat): 3361, 1956, 850, 700 cm–1.
Synthesis 2002, No. 12, 1643–1645 ISSN 0039-7881 © Thieme Stuttgart · New York