Stereoselective functionalization of β-iodo-α,β-unsaturated ketones via an iodine-copper exchange reaction

Article abstract of DOI:10.1021/ol060540m

β-Iodo-α,β-unsaturated carbonyl compounds undergo a stereoselective iodine-copper exchange reaction with (Nphyl)₂CuLi, providing the corresponding alkenyl cuprates with retention of the double bond configuration. No competitive addition/elimina

Full text of DOI:10.1021/ol060540m

ORGANIC
LETTERS
2006
Vol. 8, No. 9
1941-1943
Stereoselective Functionalization of
-Iodo- -Unsaturated Ketones via an
Iodine Copper Exchange Reaction
â
r,â
−
Xiaoyin Yang and Paul Knochel*
Department Chemie und Biochemie, Ludwig-Maximilians-UniVersita¨t Mu¨nchen,
Butenandtstr. 5-13, Haus F, 81377 Mu¨nchen, Germany
paul.knochel@cup.uni-muenchen.de
Received March 4, 2006
ABSTRACT
â
-Iodo-r,â-unsaturated carbonyl compounds undergo a stereoselective iodine−copper exchange reaction with (Nphyl)2CuLi, providing the
corresponding alkenyl cuprates with retention of the double bond configuration. No competitive addition/elimination was observed, and the
resulting cuprates were successfully functionalized with various electrophiles.
The preparation of functionalized organometallics is an
important synthetic task since these reagents are key
intermediates for the preparation of polyfunctional mol-
ecules.1 In recent years, it was found that the iodine-
magnesium exchange reaction is an excellent method for the
preparation of various aryl, heteroaryl, and alkenyl Grignard
reagents that bear ester, nitrile, amino, or nitro groups.2
However, more sensitive functionalities, such as ketones, are
usually not compatible with the presence of a C-Mg bond.
To overcome these problems, we have developed an iodine-
copper exchange reaction,3 which allows a practical prepara-
tion of functionalized aryl and heteroaryl copper reagents in
the presence of a keto group.4 Herein, we wish to report a
new application of this exchange reaction for performing a
stereoselective metalation of R,â-unsaturated carbonyl com-
pounds of type 1.5 The preparation of â-keto alkenylcopper
(3) For previous preparation of functionalized copper reagents, see: (a)
Corey, E. J.; Posner, G. H. J. Am. Chem. Soc. 1968, 90, 5615. (b) Kondo,
Y.; Matsudaira, T.; Sato, J.; Muraka, N.; Sakamoto, T. Angew. Chem. 1996,
108, 818; Angew. Chem., Int. Ed. Engl. 1996, 35, 736. (c) Ebert, G. W.;
Rieke, R. D. J. Org. Chem. 1984, 49, 5281. (d) Rieke, R. D.; Wehmeyer,
R. H.; Wu, T. C.; Ebert, G. W. Tetrahedron 1989, 45, 443. (e) Ebert, G.
W.; Cheasty, J. W.; Tehrani, S. S.; Aouad, E. Organometallics 1992, 11,
1560. (f) Ebert, G. W.; Pfennig, D. R.; Suchan, S. D.; Donovan, T. A.
Tetrahedron Lett. 1993, 34, 2279. (g) Posner, G. H.; Harrison, W.;
Wettlaufer, D. G. J. Org. Chem. 1985, 50, 5041. (h) Posner, G. H.; Whitten,
C. E.; McFarland, P. J. Am. Chem. Soc. 1972, 94, 5106.
(4) (a) Piazza, C.; Knochel, P. Angew. Chem., Int. Ed. 2002, 41, 3263.
(b) Yang, X.; Rotter, T.; Piazza, C.; Knochel, P. Org. Lett. 2003, 5, 1229.
(c) Yang, X.; Knochel, P. Synlett 2004, 81. (d) Yang, X.; Althammer, A.;
Knochel, P. Org. Lett. 2004, 6, 1665. (e) Yang, X.; Knochel, P. Synlett
2004, 2303. (f) Calaza, M. I.; Yang, X.; Soorukram, D.; Knochel, P. Org.
Lett. 2004, 6, 529.
(1) (a) Knochel, P., Ed. Handbook of Functionalized Organometallics;
Wiley-VCH: Weinheim, Germany, 2005. (b) d’Augustin, M.; Palais, L.;
Alexakis, A. Angew. Chem., Int. Ed. 2005, 44, 1376. (c) Naasz, R.; Arnold,
L. A.; Pineschi, M.; Keller, E.; Feringa, B. L. J. Am. Chem. Soc. 1999,
121, 1104. (d) Marek, I.; Normant, J.-F. Chem. ReV. 1996, 96, 3241.
(e) Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135. (f) Knochel,
P.; Millot, N.; Rodriguez, A. L.; Tucker, C. E. Org. React. 2001, 58,
417.
(2) (a) Sapountzis, I.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43, 897.
(b) Kneisel, F. F.; Dochnahl, M.; Knochel, P. Angew. Chem., Int. Ed. 2004,
43, 1017. (c) 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. (d) Staubitz, A.; Dohle, W.; Knochel, P. Synthesis 2003,
233. (e) Thibonnet, J.; Knochel, P. Tetrahedron Lett. 2000, 41, 3319.
(f) Rottla¨nder, M.; Boymond, L.; Cahiez, G.; Knochel, P. J. Org. Chem.
1999, 64, 1080. (g) Ren, H.; Krasovskiy, A.; Knochel, P. Org. Lett. 2004,
6, 4215.
(5) (a) Taniguchi, M.; Kobayashi, S.; Nakagawa, M.; Hino, T.; Kishi,
Y. Tetrahedron Lett. 1986, 27, 4763. (b) Coperet, C.; Sugihara, T.;
Wu, G.; Shimoyama, I.; Negishi, E. J. Am. Chem. Soc. 1995, 117,
3422. (c) Zhang, Y.; O’Connor, B.; Negishi, E. J. Org. Chem. 1988, 53,
5588.
10.1021/ol060540m CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/01/2006

Scheme 1. Functionalization of â-Iodo-R,â-Unsaturated
Carbonyl Compounds via an Iodine-Copper Exchange
Table 1. Functionalization of â-Iodo-R,â-Unsaturated Carbonyl
Compounds via an Iodine-Copper Exchange
derivatives is a challenging task since â-substituted R,â-
unsaturated carbonyl compounds usually react with organo-
metallics via an addition/elimination pathway.6
Thus, the â-iodo-R,â-unsaturated ketones of type 1 reacted
with (Nphyl)2CuLi (2) in THF at -100 °C for 15 min lead-
ing to the functionalized alkenylcoppers 3, which were
quenched with various electrophiles providing highly func-
tionalized enones of type 4 in moderate to good yields
(Scheme 1).7 The reactions occurred stereoselectively
with retention of the double bond configuration (>99%).
The phenyl-substituted alkenyl cuprate 3a reacted with
various aromatic and heteroaromatic acid chlorides lead-
ing to diketones 4a-c in moderate to good yields (78-83%,
entries 1-3 of Table 1). The reaction of the cuprate 3a
with 3-iodo-2-cyclohexenone provided the addition-elimi-
nation product 4d in 71% yield (entry 4). In a similar way,
the bisalkyl-substituted alkenyl cuprate 3b was readily
acylated with 2-thiophenecarbonyl chloride and 4-fluoro-
benzoyl chloride, giving the diketones 4e,f in 75-78% yields
(entries 5 and 6). The carbocupration of ethyl propiolate
with 3b stereoselectively led to the dienone 4g in 80% yield
(entry 7). Furthermore, the allylation of cuprate 3b pro-
ceeds smoothly with ethyl(2-bromomethyl)acrylate, pro-
viding the polyfunctional compound 4h in 90% yield (entry
8). Even a change of the substituent R1 in the â-iodo-
R,â-unsaturated ketones of type 1 from phenyl in 1a or
alkyl group in 1b to the electron-donating trimethylsilyl
group in 1c did not affect the exchange reaction rate. The
corresponding cuprate 3c readily underwent acylation with
benzoyl chloride and 2-thiophenecarbonyl chloride, providing
the diketones 4i and 4j in 76-84% yields (entries 9 and 10).
However, acylation with ethyl oxalyl chloride led after an
(6) (a) Krause, N., Ed. Modern Organocopper Chemistry; Wiley-VCH:
Weinheim, Germany, 2002. (b) Taylor, R. J. K., Ed. Organocopper
Reagents; IRL Press: Oxford, 1994.
(7) Typical Procedure for the Synthesis of the Enone 4a. A dry and
argon flushed 25 mL flask, equipped with a magnetic stirrer and a septum,
was charged with CuCN (86 mg, 0.96 mmol) and dry THF (5 mL). A
solution of neophyllithium (1.3 M Et2O, 1.5 mL, 1.92 mmol) was added at
-78 °C. The resulting reaction mixture was stirred at room temperature
for 10 min, and then Et2O was removed carefully under vacuum. The
remaining solution was cooled to -100 °C and cannulated into a solution
of 1a (262 mg, 0.8 mmol) in dry THF (2 mL). After 5 min, benzoyl chloride
(280 mg, 2.0 mmol) was added and the mixture stirred at room temperature
for 30 min. The reaction was quenched with saturated aqueous NH4Cl
solution (5 mL) and poured into water (10 mL). The aqueous phase was
extracted with Et2O (3 × 10 mL), and the combined organic fractions were
washed with brine (10 mL), dried over Na2SO4, and concentrated in vacuo.
The residue was purified by flash chromatography, yielding 4a (203 mg,
83%) as a colorless oil.
a Yield of analytically pure product. b Diastereomeric ratio ) 8:1.
Org. Lett., Vol. 8, No. 9, 2006
1942

Scheme 2. Influence of the Double Bond Configuration of
Enone 1 on the Reaction Outcome
Scheme 3. Synthesis of Pyridazines of Type 5
intramolecular aldol reaction to the five-membered enone
4k in 72% yield in a 8:1 mixture of diastereoisomers (entry
11). Finally, the allylation of the cuprate 3c with ethyl(2-
bromomethyl)acrylate furnished ketone 4l in 89% yield (entry
12).
The cis-configuration between the iodine and the carbonyl
group in the â-iodo-unsaturated carbonyl derivatives of type
1 is crucial for the success of the exchange reaction, probably
due to a chelation effect.8 With the enone trans-1a under
our standard reaction conditions, no iodine-copper exchange
was observed in the reaction with (Nphyl)2CuLi (2). The
only reaction observed here was an addition-elimination
(Scheme 2).
The iodine-copper exchange reaction provides function-
alized organocopper intermediates 3 and gives after acylation
a simple access to diketones. These diketones are versatile
building blocks for the synthesis of pyridazines. The treat-
ment of the diketones 4b, 4f, and 4i with NH2NH2‚H2O in
refluxing EtOH for 15 min affords the pyridazines of type 5
in excellent yields (Scheme 3).9
copper exchange reaction under mild conditions and react
with various electrophiles in good yields with retention of
configuration. Further transformations of the products to
pyridazines are described. Further extension of this method
is currently underway in our laboratory.
Acknowledgment. We thank the Fonds der Chemischen
Industrie for financial support. We thank Chemetall GmbH,
Degussa AG, and BASF AG for the generous gifts of
chemicals.
In conclusion, we have shown that â-iodo-R,â-unsaturated
carbonyl compounds undergo a stereoselective iodine-
Supporting Information Available: Experimental pro-
cedures and analytical data. This material is available free
of charge via the Internet at http://pubs.acs.org.
(8) Snieckus, V. Chem. ReV. 1990, 90, 879.
(9) Haddadin, M. J.; Agha, B. J.; Tabri, R. F. J. Org. Chem. 1979, 44,
494.
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