Rapid generation of molecular complexity: Synthesis of α- hydroxyallenes using functionalized grignard reagents

Article abstract of DOI:10.1055/s-2007-970768

The use of functionalized aryl-Grignard reagents in the copper-mediated S_N2′ substitution of propargylic oxiranes leads to structurally complex α-hydroxyallenes, usually with high yield and diastereoselectivity. Further transformations, such as gold-catalyzed cycloisomerization to 2,5-dihydrofurans and palladium-catalyzed coupling reactions, demonstrate the high potential of these compounds for the rapid generation of molecular complexity. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-970768

LETTER
737
Rapid Generation of Molecular Complexity: Synthesis of a-Hydroxyallenes
Using Functionalized Grignard Reagents
S
ynthesis of Func
a
tionalized
r
a
-Hydro
l
xyallenes Deutsch, Anja Hoffmann-Röder,1 Axel Domke, Norbert Krause*
University of Dortmund, Organic Chemistry II, Otto-Hahn-Straße 6, 44227 Dortmund, Germany
Fax +49(231)7553884; E-mail: norbert.krause@uni-dortmund.de
Received 4 January 2007
i-PrMgX
Abstract: The use of functionalized aryl-Grignard reagents in the
FG
FG
copper-mediated SN2¢ substitution of propargylic oxiranes leads to
–40 °C, r.t.
structurally complex a-hydroxyallenes, usually with high yield and
I
MgX
FG = Br, CO2Me, OMe, CN, etc.
diastereoselectivity. Further transformations, such as gold-cata-
lyzed cycloisomerization to 2,5-dihydrofurans and palladium-cata-
lyzed coupling reactions, demonstrate the high potential of these
compounds for the rapid generation of molecular complexity.
Equation 1 Synthesis of functionalized Grignard reagents by
halogen–metal exchange
Key words: allenes, chirality transfer, functionalized Grignard
reagents, organocopper reagents, SN2¢ substitution
We began our study with the model substrates 17 bearing
a silyl or benzyl ether protecting group,3,4 as well as the 4-
trifluoromethylphenyl group, a well-known pharmaco-
phore8 (Table 1).
Allenes in general and a-hydroxyallenes in particular are
versatile building blocks for advanced organic synthesis
because of the high reactivity inherent to their axially
chiral backbone.2 They are usually prepared by SN2¢ sub-
stitution of propargylic electrophiles (esters, halides, ox-
iranes, sulfonates, etc.) with organocopper compounds.2,3
Although the use of various organometallic precursors,
which are transmetalated to the corresponding cuprates, is
highly developed and well established, the scope of these
nucleophiles was mostly limited to alkyl or simple aryl
compounds. In our ongoing research dedicated to the syn-
thesis and transformation of a-hydroxyallenes3 and other
functionalized allenes,4 we became interested in the rapid
formation of highly functionalized target molecules by
using functionalized organometallic reagents.
Knochel and co-workers5 have developed efficient proto-
cols for the generation of arylmagnesium reagents bearing
various functional groups which undergo trapping reac-
tions with reactive electrophiles (including allylations) af-
ter transmetalation to copper. The key step is the halogen–
magnesium exchange of an aryl bromide or iodide with
isopropylmagnesium chloride or other Grignard reagents
(Equation 1) which shows a high tolerance towards func-
tional groups like halides, nitriles, esters and even nitro
groups.5,6 Aromatic iodides bearing electron-donating
groups, like anisole derivatives, undergo the halogen–
metal exchange as well, but higher temperatures and long-
er reaction times are required.5 Thus, the application of
these nucleophiles in the copper-mediated SN2¢ substitu-
tion of propargylic oxiranes would open up a rapid access
to highly complex a-hydroxyallenes bearing several func-
tionalities for further transformations.
We were pleased to find that treatment of propargyl
oxiranes 1 with various functionalized aryl cuprates con-
sistently led to the exclusive formation of the desired
SN2¢-substitution products 2a–j which were mostly
obtained with good to excellent chemical yield. Besides
halides and methoxy groups, esters, nitro groups and even
nitriles (which sometimes cause problems in copper-
mediated reactions9) are tolerated. All reactions were
performed in the presence of one equivalent of tri-n-bu-
tylphosphine or triethylphosphite in order to prevent the
known2,3,10 copper-promoted epimerization of the allene,
so that the a-hydroxyallenes 2 were formed with high anti
diastereoselectivity in most cases. Lower stereoselec-
tivities were observed for the 2- and 3-methoxyphenyl
cuprate (entries 6 and 7); in the latter case, use of tri-
ethylphosphite as additive gave a much higher diastereo-
selectivity, but a decreased chemical yield, compared to
tri-n-butylphosphine (entry 8).
The dependence of allene epimerization on the nature of
the cuprate and the additive is even more pronounced in
the SN2¢ substitution of the bicyclic epoxide 3 (Table 2).
Here, the electron-deficient ester-substituted cuprate gave
a dismal diastereoselectivity in the presence of n-Bu3P,
but a diastereomerically pure a-hydroxyallene with
(EtO)3P (entries 1 and 2). In striking contrast, the sub-
stitution of the electron-rich anisol-derived cuprate hardly
showed any dependence on the additive (entries 3–5);
the highest diastereoselectivity (but the lowest chemi-
cal yield) was observed in the absence of an additive
(entry 5).
Gratifyingly, the method is not restricted to terminal
propargylic oxiranes. For steric and electronic reasons,
the substrates 5 and 7 bearing an internal triple bond are
expected to be less reactive towards nucleophiles than
terminal alkynes; nevertheless, the reactivity of the
SYNLETT 2007, No. 5, pp 0737–0740
Advanced online publication: 08.03.2007
DOI: 10.1055/s-2007-970768; Art ID: G00507ST
© Georg Thieme Verlag Stuttgart · New York
1
6.
0
3.
2
0
0
7

738
C. Deutsch et al.
LETTER
Table 1 Synthesis of the Functionalized a-Hydroxyallenes 2
1. i-PrMgX, THF, temp.
FG
Me
FG
2. CuCN, additive
•
OR
3.
Me
O
OH
I
H
2
1
OR
Entry
1
R
FG
Temp (°C)
–40
–40
–40
–20
–78
r.t.
Additive
n-Bu3P
n-Bu3P
n-Bu3P
n-Bu3P
n-Bu3P
n-Bu3P
n-Bu3P
(EtO)3P
n-Bu3P
n-Bu3P
n-Bu3P
Yield of 2 (%)
2a (68)
2b (99)
2c (77)
2d (85)
2e (62)
2f (52)
dr
TBS
TBS
TBS
TBS
TBS
TBS
TBS
TBS
TBS
Bn
4-F
2-F
4-Br
94:6
85:15
>95:5
15:85
10:90
75:25
75:25
>95:5
>95:5
>95:5
97:3
2
3
4a
5a
6
4-CO2Me
4-CN
2-OMe
3-OMe
3-OMe
4-OMe
2-NO2
7
r.t.
2g (77)
2g (44)
2h (71)
2i (59)
8
r.t.
9
r.t.
10b
11
–90
–40
4-CF3C6H4
4-CO2Me
2j (66)
a The trans-oxirane was used instead of the cis-isomer.
b PhMgBr was used for the halogen–magnesium exchange.
smooth gold-catalyzed cycloisomerization3,4 to the 2,5-di-
hydrofuran 9 (72% yield) which was then subjected to a
Sonogashira coupling with trimethylsilylacetylene in
THF solution,11 affording the functionalized heterocycle
10 in a highly stereoselective fashion. The reverse order of
events gave the same product via allene 11 with a slightly
lower chemical yield.
Table 2 Synthesis of the Functionalized a-Hydroxyallenes 4
1. i-PrMgCl, THF, temp.
FG
FG
2. CuCN, additive
•
3.
OH
I
H
O
4
3
In conclusion, we have expanded the scope of the copper-
promoted SN2¢ substitution of propargylic oxiranes by us-
ing functionalized Grignard reagents formed by halogen–
magnesium exchange.12 We were able to obtain highly
functionalized a-hydroxyallenes with high yield and
excellent center-to-axis chirality transfer in most cases.
The method can be applied to terminal and internal
alkynes with similar efficiency. The utility of the products
for further transformations was demonstrated in the gold-
catalyzed cycloisomerization to 2,5-dihydrofurans, as
well as in the palladium-catalyzed Sonogashira coupling,
thereby taking advantage of the functionality introduced
with the Grignard reagent.
Entry FG
T (°C) Additive
Yield of 4 (%) dr
1
2
3
4
5
6
4-CO2Me
–20
–20
r.t.
n-Bu3P
(EtO)3P
n-Bu3P
(EtO)3P
–
4a (77)
4a (85)
4b (75)
4b (75)
4b (41)
4c (85)
60:40
4-CO2Me
4-OMe
4-OMe
4-OMe
3-OMe
>95:5
85:15
88:12
91:9
r.t.
r.t.
r.t.
n-Bu3P
85:15
functionalized aryl cuprate obtained from methyl 4-iodo-
benzoate is sufficient to convert these electrophiles into
the highly functionalized tetrasubstituted allenes 6 and 8
with good chemical yield and high anti diastereoselec-
tivity (Scheme 1).
Acknowledgment
Continuous support of our work by the Deutsche Forschungs-
gemeinschaft, the Fonds der Chemischen Industrie, and the
European Community is gratefully acknowledged. We thank Prof.
Dr. P. Knochel (LMU München) for fruitful discussions.
The functionalized a-hydroxyallenes described in this pa-
per are highly useful synthetic intermediates (Scheme 2).
For example, the bromo-substituted allene 2c underwent a
Synlett 2007, No. 5, 737–740 © Thieme Stuttgart · New York

LETTER
Synthesis of Functionalized a-Hydroxyallenes
739
1. i-PrMgCl, THF, –40 °C
2. CuCN, n-Bu3P
MeO2C
Me
MeO2C
•
OMe
3.
Me
O
OH
I
Me
OMe
6
Me
5
67% (dr = 85:15)
1. i-PrMgCl, THF, –40 °C
2. CuCN, n-Bu3P
MeO2C
MeO2C
•
3.
n-C5H11
OH
I
n-C5H11
O
8
7
64% (dr > 95:5)
Scheme 1 Synthesis of the functionalized a-hydroxyallenes 6 and 8
Br
Br
Me
AuCl3
•
OTBS
Me
(1 mol%)
THF
O
OH
H
OTBS
9
2c
72%
(Ph3P)2PdCl2 (2 mol%)
CuI (4 mol%)
(Ph3P)2PdCl2 (2 mol%)
CuI (4 mol%)
Me3SiC CH, Et3N
Me3SiC CH, Et3N
99%
Me
92%
Me3Si
Me3Si
AuCl3
•
OTBS
Me
O
(1 mol%)
THF
OH
H
OTBS
50%
10
11
Scheme 2 Gold- and palladium-catalyzed transformations of a-hydroxyallene 2c
(4) (a) Morita, N.; Krause, N. Org. Lett. 2004, 6, 4121.
References and Notes
(b) Morita, N.; Krause, N. Angew. Chem. Int. Ed. 2006, 45,
1897; Angew. Chem. 2006, 118, 1930. (c) Morita, N.;
Krause, N. Eur. J. Org. Chem. 2006, 4634. (d) Gockel, B.;
Krause, N. Org. Lett. 2006, 8, 4485.
(1) New address: Institute of Organic Chemistry, University of
Mainz, Duesbergweg 10–14, 55128 Mainz, Germany.
(2) (a) Schuster, H. F.; Coppola, G. M. Allenes in Organic
Synthesis; Wiley: New York, 1984. (b) Modern Allene
Chemistry; Krause, N.; Hashmi, A. S. K., Eds.; Wiley-VCH:
Weinheim, 2004. (c) Zimmer, R.; Dinesh, C. U.; Nandanan,
E.; Khan, F. A. Chem. Rev. 2000, 100, 3067. (d) Marshall,
J. A. Chem. Rev. 2000, 100, 3163. (e) Hoffmann-Röder, A.;
Krause, N. Angew. Chem. Int. Ed. 2002, 41, 2933; Angew.
Chem. 2002, 114, 3057. (f) Hoffmann-Röder, A.; Krause,
N. Angew. Chem. Int. Ed. 2004, 43, 1196; Angew. Chem.
2004, 116, 1216. (g) Krause, N.; Hoffmann-Röder, A.
Tetrahedron 2004, 60, 11671. (h) Ma, S. Chem. Rev. 2005,
105, 2829.
(5) (a) Handbook of Functionalized Organometallics; Knochel,
P., Ed.; Wiley-VCH: Weinheim, 2005. (b) Boudier, A.;
Bromm, L. A.; Lotz, M.; Knochel, P. Angew. Chem. Int. Ed.
2000, 39, 4414; Angew. Chem. 2000, 112, 4584.
(c) Knochel, P. In Modern Organocopper Chemistry;
Krause, N., Ed.; Wiley-VCH: Weinheim, 2002, 45–78.
(d) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F.
F.; Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew.
Chem. Int. Ed. 2003, 42, 4302; Angew. Chem. 2003, 115,
4438.
(6) (a) Sapountzis, I.; Knochel, P. Angew. Chem. Int. Ed. 2002,
41, 1610; Angew. Chem. 2002, 114, 1680. (b) Sapountzis,
I.; Dube, H.; Lewis, R.; Gommermann, N.; Knochel, P. J.
Org. Chem. 2005, 70, 2445. (c) Krasovsky, A.; Straub, B.
F.; Knochel, P. Angew. Chem. Int. Ed. 2006, 45, 159; Angew.
Chem. 2006, 118, 165.
(3) (a) Krause, N.; Morita, N. In Comprehensive
Organometallic Chemistry III, Vol. 9; Crabtree, R. H.;
Mingos, D. M. P., Eds.; Elsevier: Oxford, 2006, 501–586.
(b) Hoffmann-Röder, A.; Krause, N. Org. Lett. 2001, 3,
2537. (c) Krause, N.; Hoffmann-Röder, A.; Canisius, J.
Synthesis 2002, 1759. (d) Ma, S. Acc. Chem. Res. 2003, 36,
701. (e) Kar, A.; Argade, N. P. Synthesis 2005, 2995.
Synlett 2007, No. 5, 737–740 © Thieme Stuttgart · New York

740
C. Deutsch et al.
LETTER
(7) Substrates 1a,b and 3 have been synthesized previously:
(a) Marshall, J. A.; DuBay, W. J. J. Org. Chem. 1993, 58,
3435. (b) Marshall, J. A.; Blough, B. E. J. Org. Chem. 1991,
55, 2225. (c) Alexakis, A.; Marek, I.; Mangeney, P.;
Normant, J. F. Tetrahedron 1991, 47, 1677.
(8) Miko, T.; Ligeneau, X.; Pertz, H. H.; Ganellin, C. R.;
Arrang, J.-M.; Schwartz, J.-C.; Schunack, W.; Stark, H. J.
Med. Chem. 2003, 46, 1523.
(9) (a) Lipshutz, B. H.; Noson, K.; Chrisman, W.; Lower, A. J.
Am. Chem. Soc. 2003, 125, 8779. (b) Chen, J.-X.; Daeuble,
J. F.; Brestensky, D. M.; Stryker, J. M. Tetrahedron 2000,
56, 2153.
of a 2% H2O2 solution, filtration through a pad of Celite®,
evaporation of the solvent and column chromatography
(SiO2, EtOAc–cyclohexane = 10:1) furnished 287 mg (68%)
of 2a as a yellow oil (dr = 94:6 according to NMR analysis).
1H NMR (500 MHz, C6D6): d = 7.14–7.09 (m, 2 H), 6.87–
6.83 (m, 2 H), 6.10 (m, 1 H), 4.21 (m, 1 H), 3.73 (dd,
2JHH = 10.0 Hz, 3JHH = 4.0 Hz, 1 H), 3.66 (dd, 2JHH = 10.0
Hz, 3JHH = 4.0 Hz, 1 H), 2.41 (br s, 1 H), 1.88 (m, 3 H), 0.95
(s, 9 H), 0.04 and 0.03 (2 s, 6 H) ppm. 13C NMR (125 MHz,
C6D6): d = 202.0, 163.4 (d, 1JCF = 241 Hz), 132.3, 128.7 (d,
3JCF = 10 Hz), 115.9 (d, 2JCF = 21 Hz), 105.2, 95.6, 72.8,
66.2, 26.0, 18.4, 15.3, –5.3 ppm.
(10) Claesson, A.; Olsson, L. I. J. Chem. Soc., Chem. Commun.
1979, 524.
(11) Thorand, S.; Krause, N. J. Org. Chem. 1998, 63, 8551.
(12) Representative Procedure and Spectroscopic Data –
Synthesis of 1-(tert-Butyldimethylsilyloxy)-5-(4-fluoro-
phenyl)-3-methylpenta-3,4-dien-2-ol (2a).
Spectroscopic Data of 2-(4-Methoxycarbonylphenyl-
ethenylidene)cyclohexan-1-ol (4a).
1H NMR (400 MHz, C6D6): d = 8.18 (d, 3JHH = 8.2 Hz, 2 H),
7.26 (d, 3JHH = 8.2 Hz, 2 H), 6.13 (s, 1 H), 4.04 (m, 2 H), 3.49
(s, 3 H), 2.43 (m, 1 H), 1.99 (m, 3 H), 1.65 (m, 1 H), 1.56 (m,
1 H), 1.44 (m, 1 H), 1.36 (m, 1 H) ppm. 13C NMR (100 MHz,
C6D6): d = 199.1, 166.6, 140.7, 130.5, 127.0, 112.3, 97.0,
69.2, 51.6, 36.3, 29.3, 27.0, 23.3 ppm.
To a stirred solution of 4-fluoroiodobenzene (706 mg, 3.2
mmol) in anhyd THF (15 mL) was added i-PrMgCl (2.1 mL,
3.4 mmol; 1.7 M in Et2O) at –40 °C. After 1 h at this
temperature, the Grignard reagent was added via cannula to
a cold (–30 °C), freshly prepared solution of copper(I)
cyanide (142 mg, 1.6 mmol) and tri-n-butylphosphine (322
mg, 1.6 mmol) in anhyd THF (20 mL). The resulting cuprate
solution was stirred for 30 min at –30 °C, followed by
addition of cis-1-(tert-butyldimethylsilyloxy)-2,3-epoxy-3-
methylpent-4-yne (1, 300 mg, 1.3 mmol) in anhyd THF (3
mL). After stirring for 16 h under warming to r.t., quenching
with 3 mL of a sat. NH4Cl solution, washing with 3 × 10 mL
Spectroscopic Data of cis-2-(tert-Butyldimethylsilyloxy-
methyl)-3-methyl-5-(4-trimethylsilylethynylphenyl)-2,5-
dihydrofuran (10).
1H NMR (400 MHz, C6D6): d = 7.43 (d, 3JHH = 8.3 Hz, 2 H),
7.21 (d, 3JHH = 8.3 Hz, 2 H), 5.58 (br s, 1 H), 5.21 (s, 1 H),
4.68 (br s, 1 H), 3.79 (dd, 2JHH = 10.0 Hz, 3JHH = 4.0 Hz, 1
H), 3.66 (dd, 2JHH = 10.0 Hz, 3JHH = 4.0 Hz, 1 H), 1.62 (s, 3
H), 0.95 (s, 9 H), 0.10 (s, 9 H), 0.05 (s, 6 H) ppm. 13C NMR
(100 MHz, C6D6): d = 142.2, 137.6, 131.4, 129.0, 125.7,
121.5, 88.7, 86.1, 65.1, 25.9, 18.3, 12.4, –0.8, –5.5 ppm.
Synlett 2007, No. 5, 737–740 © Thieme Stuttgart · New York

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