Conjugate addition of organocopper reagents in dichloromethane to α,β-unsaturated esters

Article abstract of DOI:10.1016/j.tetlet.2007.08.105

Organocopper reagents in conjunction with Lewis acid activators provide greater stability than traditional cuprate reagents while maintaining the reactivity needed for conjugate addition reactions in dichloromethane. Whereas cuprates engage in cross-coupl

Full text of DOI:10.1016/j.tetlet.2007.08.105

Tetrahedron Letters 48 (2007) 7887–7889
Conjugate addition of organocopper reagents in
dichloromethane to a,b-unsaturated esters
Jingyue Yang and Gregory B. Dudley*
Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306-4390, USA
Received 7 August 2007; revised 23 August 2007; accepted 29 August 2007
Available online 1 September 2007
Abstract—Organocopper reagents in conjunction with Lewis acid activators provide greater stability than traditional cuprate
reagents while maintaining the reactivity needed for conjugate addition reactions in dichloromethane. Whereas cuprates engage
in cross-coupling pathways, organocopper nucleophiles are more selective for conjugate addition. The utility of organocopper
reagents in dichloromethane for the conjugate addition to a,b-unsaturated esters is expanded upon herein.
Ó 2007 Elsevier Ltd. All rights reserved.
In the course of studies directed toward the chemical
synthesis of roseophilin,1 we confronted the issue of a
difficult conjugate addition of an isopropyl substituent
to an a-alkyl-b-pyrrolyl-a,b-unsaturated ester (Eq. 1).
Despite the wealth of information on organocuprate
conjugate additions,2 we could not find clear precedent
to guide our investigation.
copper reagents solubilized in dichloromethane in con-
junction with trimethylsilyl iodide (Eq. 2).8 Previous
reports mention ester enoates only briefly, but we found
the Nilsson–Olsson protocol to have significant utility
with respect to conjugate addition reactions of carban-
ionic nucleophiles to a,b-unsaturated esters (Table 1).
R
R–Li, CuI, Me2S
CO2Me
Aryl
CO2Me
Aryl
TMSCl, NaI, CH2Cl2
CO2Me
CO2Me
R'
R'
R'
R'
R"
R"
RN
RN
ð2Þ
1
2
ð1Þ
Entries 1–5 depict a series of addition reactions invol-
ving methyl cinnamate (3, Table 1).9 One significant
advantage of organocopper over cuprate species is that
organocopper reagents are more robust, thereby permit-
ting reactions to be conducted at higher temperatures
and for prolonged times without decomposition. Such
conditions are useful for addition of less stable carban-
ionic nucleophiles (entries 3 and 4), addition to less elec-
trophilic alkenes (entries 6 and 7), and/or combinations
thereof (entry 12). For example, to achieve the conjugate
addition of sec-butylcopper (entry 4), the reaction
mixture was stirred without external cooling for 3 h;
analogous conditions for the conjugate addition of
sec-butylcuprate have not been reported.4
Our particular goal represents an extreme case in the
scope of conjugate addition reactions3 for at least two
reasons: (a) pyrrolyl ester 1 is less electrophilic than
typical enoates, due to conjugation with the electron-
rich pyrrole; (b) isopropylcuprate is more hindered
and less stable than other alkyl- or arylcuprate
reagents.4 Indeed, we have yet to satisfy our ambitions
relating to the desired addition (Eq. 1), and we have
taken recourse to alternative tactics.5 Nonetheless, in
the process of screening a wide range of reaction condi-
tions and completing careful optimization of model
conjugate addition reactions, we made relevant observa-
tions regarding the rather unconventional protocol of
Nilsson and Olsson,6,7 which features stable organo-
The fidelity of mono-organocopper reagents for conju-
gate addition provides further advantages: conjugate
addition to iodo-enoate 11 occurs more efficiently with
phenylcopper than diphenylcuprate, which is more
*
Corresponding author. Tel.: +1 850 644 2333; fax: +1 850 644
8281; e-mail: gdudley@chem.fsu.edu
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.08.105

7888
J. Yang, G. B. Dudley / Tetrahedron Letters 48 (2007) 7887–7889
Table 1. Conjugate addition of organocopper reagents to a,b-unsaturated esters according to Eq. 2
Entry
1
a,b-Unsaturated ester
Conjugate addition product
R
Yield %a
95
R
CO2Me
CO2Me
Me
3
4a
2
3
4
5
3
3
3
3
4b
4c
4d
4e
n-Bu
i-Pr
s-Bu
Ph
88
74
73
>95
R
CO2Et
O
CO2Et
6
O
i-Pr
46
5
6
R
CO2Me
CO2Me
7
8
Ph
Ph
55
TsN
7
8
TsN
R
CO2Me
67b
CO2Me
10
9
R
CO2Me
CO2Me
9
i-Pr
61
11
12a
I
I
10
11
11
11
12b
12b
Ph
Ph
94
<64c,d
R
CO2Et
CO2Et
12
13
i-Pr
80
EtO
13
14
EtO
R
CO2Et
Ph
>95
C7H15
CO2Et
C7H15
15
16
O
R
O
CH2Ph
O
CH2Ph
O
14
Ph
N
Ph
N
Me
86e
O
O
17
18
a Isolated yield of material judged to be >95% pure by 1H NMR analysis, unless otherwise indicated. See Supplementary data for details.
b Incomplete reaction; adjusted yield based on recovered starting material was 95%.
c Diphenylcuprate (2:1 Ph–Li: CuI) employed.
d Desired product recovered alongside unidentifiable impurities.
e Conjugate addition product 18 obtained in an approximately 1:1 ratio of diastereomers.
likely to engage in cross-coupling side reactions (entries
10 and 11, Table 1). Our efforts focused on b-aryl-eno-
ates, although alkenoate substrates are suitable (entry
13 and Ref. 6). Diastereoselection in the addition of
methylcopper to chiral cinnamic imide 1710 was negligi-
ble under the current conditions (entry 14).
organocopper conjugate addition reactions. Aromatic
hydrocarbons are less effective at solvating cuprate
reagents, and Lewis-basic ethereal solvents are known
to dampen the reactivity of cuprates,11 likely through
interactions with the metal centers.
In summary, observations on conjugate addition reac-
tions to a,b-unsaturated carbonyl compounds are
reported. Robust organocopper compounds withstand
Dichloromethane, along with dimethyl sulfide as a
cosolvent, provides an excellent medium for these

J. Yang, G. B. Dudley / Tetrahedron Letters 48 (2007) 7887–7889
7889
1992, 41, 135–631; (f) Yamamoto, Y. Angew. Chem., Int.
Ed. Engl. 1986, 25, 947–1038.
3. Perlmutter, P. Conjugate Addition Reactions in Organic
Synthesis; Pergammon: Oxford, 1992.
4. Alkylcuprates, particularly secondary alkylcuprates, that
possess b-hydrogens are susceptible to b-hydride elimina-
tion and other disproportionation pathways that are not
available to aryl- or vinylcuprates.
5. Yang, J.; Katukojvala, S.; Dudley, G. B., unpublished
results to be disclosed at a future date.
higher temperatures and longer reaction times than cup-
rate reagents, and organocopper reagents provide better
selectivity for conjugate addition over competing cross-
coupling pathways than that provided by cuprates. The
mixture of trimethylsilyl chloride and sodium iodide
promotes reactivity. This protocol and our observations
are likely to be of use for other problems in chemical
synthesis.
6. Bergdahl, M.; Lindstedt, E.-L.; Nilsson, M.; Olsson, T.
Tetrahedron 1988, 44, 2055–2062.
Acknowledgments
7. Related work: (a) Johnson, C. R.; Marren, T. J. Tetra-
hedron Lett. 1987, 28, 27–30; (b) Bergdahl, M.; Lindstedt,
E.-L.; Nilsson, M.; Olsson, T. Tetrahedron 1989, 45, 535–
543; (c) Bergdahl, M.; Eriksson, M.; Nilsson, M.; Olsson,
T. J. Org. Chem. 1993, 58, 7238–7244; (d) Eriksson, M.;
Nilsson, M.; Olsson, T. Synlett 1994, 271–272; (e) Berg-
dahl, M.; Iliefski, T.; Nilsson, M.; Olsson, T. Tetrahedron
Lett. 1995, 36, 3227–3230; (f) Eriksson, M.; Hjelmenc-
rantz, A.; Nilsson, M.; Olsson, T. Tetrahedron 1995, 51,
12631–12644; (g) Eriksson, M.; Johansson, A.; Nilsson,
M.; Olsson, T. J. Am. Chem. Soc. 1996, 118, 10904–10905.
8. Note that we used a combination of Me3SiCl and NaI in
lieu of Me3SiI.
This research was supported by the James and Ester
King Biomedical Research Program, Florida Depart-
ment of Health, an award from Research Corporation,
and by the FSU Department of Chemistry and Bio-
chemistry. We thank Dr. Umesh Goli for providing
the mass spectrometry data, and the Krafft Lab for
the use of their FT-IR instrument.
Supplementary data
9. Active organocopper reagents were prepared at ꢀ78 °C by
mixing 1.1 equiv of CuI, 2.0 equiv of NaI, and dimethyl
sulfide (0.6 mL/mmol of CuI) in CH2Cl2 and then adding
the appropriate organolithium reagent (1.0 equiv) and
2.0 equiv of Me3SiCl. The active organocopper reagents
were then typically employed in fivefold excess with
respect to the unsaturated ester or imide, which was
added as a solution in dry CH2Cl2 at ꢀ78 °C. The reaction
mixtures were allowed to warm, typically to room
temperature, and monitored for consumption of the
activated alkene. Standard aqueous workup and purifica-
tion techniques were employed to isolate the pure conju-
gate addition products. See Supplementary data for
complete details and characterization data.
Experimental procedures, characterization data, and
copies of NMR spectra are provided. Supplementary
data associated with this article can be found, in the on-
line version, at doi:10.1016/j.tetlet.2007.08.105.
References and notes
1. (a) Salamone, S. G.; Dudley, G. B. Org. Lett. 2005, 7,
4443–4445; For a review of the chemistry and biology of
roseophilin and related compounds, see: (b) Furstner, A.
¨
Angew. Chem., Int. Ed. 2003, 42, 3582–3603.
10. Dambacher, J.; Anness, R.; Pollock, P.; Bergdahl, M.
Tetrahedron 2004, 60, 2097–2110.
11. (a) Bertz, S. H.; Miao, G.; Rossiter, B. E.; Snyder, J. P. J.
Am. Chem. Soc. 1995, 117, 11023–11024; (b) House, H. O.;
Respess, W. L.; Whitesides, G. M. J. Org. Chem. 1966, 31,
3128–3141.
2. (a) Woodward, S. Angew. Chem., Int. Ed. 2005, 44, 5560–
5562; (b) Modern Organocopper Chemistry; Krause, N.,
Ed.; Wiley-VCH: Weinheim, 2002; (c) Nakamura, E.;
Mori, S. Angew. Chem., Int. Ed. 2000, 39, 3750–3771; (d)
Krause, N.; Gerold, A. Angew. Chem., Int. Ed. 1997, 36,
186–204; (e) Lipshutz, B. H.; Sengupta, S. Org. React.