Synthesis of β-substituted α-iodo cycloalkanones by the CuI-mediated conjugate addition of Grignard reagents to α-iodo cycloalkenones

Article abstract of DOI:10.1016/S0040-4039(00)02016-5

CuI-mediated conjugate addition of Grignard reagents to α-iodo cycloalkenones afforded β-substituted α-iodo cycloalkanones in good to excellent yields.

Full text of DOI:10.1016/S0040-4039(00)02016-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 683–685
Synthesis of b-substituted a-iodo cycloalkanones by the
CuI-mediated conjugate addition of Grignard reagents to a-iodo
cycloalkenones
Chin-Kang Sha,* Chen-Tso Tseng and Wen-Sheng Chang
Department of Chemistry, National Tsing Hua University, Hsinchu 300, Taiwan, ROC
Received 12 November 2000; accepted 13 November 2000
Abstract—CuI-mediated conjugate addition of Grignard reagents to a-iodo cycloalkenones afforded b-substituted a-iodo
cycloalkanones in good to excellent yields. © 2001 Elsevier Science Ltd. All rights reserved.
b-Substituted a-iodo ketones 3 are versatile intermedi-
ates in organic synthesis. Although various methods to
prepare a-iodo ketones from olefins,1 epoxides,2
ketones,3 enol esters4 and silyl enol ethers4,5 have been
reported, with a few exceptions3,4b these methods have
serious limitations, such as use of toxic reagents or the
difficult purification of silyl enol ethers. Moreover,
these methods are generally not adaptable for the
regioselective synthesis of b-substituted a-iodo ketones.
During work on a-carbonyl radical cyclization, we dis-
covered a facile method for the preparation of b-substi-
tuted a-iodo ketones.6 We applied that method in total
synthesis of several natural products, e.g. (+)-modhep-
hene,6 (−)-dendrobine,7 (−)-5-oxosilphiperfol-6-ene,8
dimethyl gloiosiphone A9 and (−)-paniculatine,10 but we
later found that our method sometimes afforded b-sub-
stituted a-iodo ketones in only moderate yield, pre-
sumably due to the hydrolysis of TMS-enol-ether
intermediates. Therefore, we became interested in devel-
oping a more efficient method to prepare b-substituted
a-iodo ketones. We envisaged that conjugate addition
of a Grignard reagent to a-iodo enone 1 would afford
compound 3 (Scheme 1) directly, and thus could serve
as an alternative entry to b-substituted a-iodo ketones.
To our knowledge the conjugate addition of a Grignard
reagent to a-iodo enones has not been explored, proba-
bly because the vinyl iodide moiety in a-iodo enones is
known to react readily with organometallic reagents.11
In the related work, Normant and co-workers reported
the conjugate addition of lithium dimethylcuprate to
a-chloro or a-fluoro enones.12 Vandewalle et al. per-
formed 1,4-addition of a Grignard reagent to 4,4-
dimethyl-2-bromocyclopentenone in a total synthesis of
quadrone.13 Paquette and Klemeyer described conju-
gate addition of allyllithium to an a-bromo enone.14 In
a alkylated cubane synthesis, Tsanaktsidis and co-
workers preformed conjugate addition of methyl Grig-
nard to a bicyclic a-bromo enone.15
Here we report results on conjugate addition of Grig-
nard reagents to a-iodo cycloalkenones, which provides
a new entry to b-substituted a-iodo cycloalkanones.
Treatment of a-iodo cycloalkenones 4–10 with a mix-
Scheme 1.
Keywords: a-iodo ketone; a-iodo enone; Grignard reagents; conjugate addition; a-carbonyl radical.
* Corresponding author. Fax: 886-3-5725870; e-mail: cksha@mx.nthu.edu.tw
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02016-5

684
C.-K. Sha et al. / Tetrahedron Letters 42 (2001) 683–685
ture of a Grignard reagent (RMgCl or RMgBr) and
CuI at 0°C, followed by quenching with saturated
NH4Cl and extraction with Et2O, gave b-substituted
a-iodo cycloalkanones 11–17 in good to excellent
yields;16 the results are summarized in Table 1. This
reaction succeeds presumably because of formation of
enolate 2, shown in Scheme 1, which can prevent
further reaction of the Grignard reagent with the iodo
group. The starting materials, a-iodo enones 4–6 are
readily available on iodination of the corresponding
cycloalkenones according to conventional methods.17
b-Substituted a-iodo enones 7–10 were prepared
according to our methods.18 Various Grignard reagents
such as alkyl, vinyl, and phenyl Grignard can be used.
Use of CuI is necessary. Without its addition, both 1,2-
and 1,4-addition products are obtained. b,b-Disubsti-
tuted a-iodocycloalkanones 14–17 can also be prepared
in good yield. Products 11a–b, 12a–e and 13 are formed
Table 1. Conjugate addition of Grignard reagents to a-iodo cycloalkenones

C.-K. Sha et al. / Tetrahedron Letters 42 (2001) 683–685
685
as mixtures of cis and trans isomers. Compounds 16
and 17 are obtained as a mixture of two diastereomers.
10. Sha, C.-K.; Lee, F.-K.; Chang, C.-J. J. Am. Chem. Soc.
1999, 121, 9875.
11. (a) Corey, E. J.; Posner, G. H. J. Am. Chem. Soc. 1967,
89, 3911. (b) Corey, E. J.; Katzenellenbogen, J. A.;
Gilman, N. W.; Roman, S. A.; Erickson, B. W. J. Am.
Chem. Soc. 1968, 90, 5618.
In summary, we have developed a new method to
prepare b-substituted a-iodo cycloalkanones via conju-
gate addition of a Grignard reagent to a-iodocy-
cloalkenones. This method is also useful for synthesis of
b,b-disubstituted a-iodocycloalkanones. Application of
this method for the preparation of a-iodo ketone inter-
mediates in total synthesis of natural products is cur-
rently under investigation in our laboratory.
12. Chuit, C.; Sauvetre, R.; Masure, D.; Normant, J. F.
Tetrahedron 1979, 35, 2645.
13. Vandewalle, M.; Dewanckele, J. M.; Zutterman, F. Tet-
rahedron 1983, 39, 3235.
14. Klemeyer, H. J.; Paquette, L. A. J. Org. Chem. 1994, 59,
7924.
15. Lowe, D. A.; Moorhouse, C. J.; Walter, J. M.; Tsanakt-
sidis, J. Aust. J. Chem. 1994, 47, 1647.
Acknowledgements
16. A representative procedure for conjugate addition: To a
solution of CuI (385 mg, 2.02 mmol) in dry THF (3 mL)
was added MeMgBr (2.7 M in Et2O, 0.75 mL, 2.02
mmol) at 0°C. The mixture was stirred at the same
temperature for 10 min. A solution of 5 (150 mg, 0.68
mmol) in dry THF (3 mL) was then added. The reaction
mixture was stirred at 0°C for 1 h and then quenched
with saturated NH4Cl (5 mL). The aqueous layer was
extracted with Et2O (5 mL×3). The combined organic
layers were washed with saturated NaHCO3 (10 mL) and
brine (10 mL), and then dried over MgSO4. Filtration,
concentration and silica gel column chromatography
(EtOAc–hexane, 1:15) gave 12a as a colorless oil (127 mg,
79%): 1H NMR (400 MHz, CDCl3): l 4.50–4.49 (dd,
J=2.0, 2.0 Hz, 0.38 H), 4.40–4.38 (dd, J=7.0, 0.8 Hz,
0.62 H), 3.36–3.28 (m, 0.38 H), 3.05–2.98 (m, 0.62 H),
2.34–1.48 (m, 6 H), 1.17–1.15 (d, J=7.2 Hz, 1.86 H),
1.01–0.99 (d, J=6.0 Hz, 1.14 H); 13C NMR (100 MHz,
CDCl3) l 205.3, 203.9, 45.2, 42.0, 41.9, 37.1, 37.0, 34.1,
29.8, 28.8, 24.9, 23.0, 22.7, 21.8; IR (neat): 2961, 1712,
1218 cm−1; MS (EI): m/z 238 (M+, 100), 111 (23);
HRMS: m/z calcd for C7H11IO: 237.9855, found
237.9859.
We thank the National Science Council of the Republic
of China for financial support.
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