Stereoselective SN2-Substitutions Using Polyfunctional Lithium Arylcuprates Prepared by an Iodine-Copper Exchange

Article abstract of DOI:10.1021/ol0362865

(Equation presented) Polyfunctional mixed lithium arylcuprates of the type (FG-Ar)(PhMe₂CCH₂)CuLi obtained via iodine- or bromine-copper exchange with (PhMe₂CCH₂)₂CuLi react with cyclic 2-iodoallylic acetates with high S_N2 selectivity. The addition of ZnBr₂ changes this selectivity and allows the performance of highly regioselective and enantioselective anti S _N2′ substitutions using open-chain allylic pentafluorobenzoates.

Full text of DOI:10.1021/ol0362865

ORGANIC
LETTERS
2004
Vol. 6, No. 4
529-531
Stereoselective SN2-Substitutions Using
Polyfunctional Lithium Arylcuprates
Prepared by an Iodine−Copper
Exchange
M. Isabel Calaza, Xiaoyin Yang, Darunee Soorukram, and Paul Knochel*
Department Chemie, Ludwig-Maximilians-UniVersita¨t, Butenandtstrasse 5-13,
81377, Mu¨nchen, Germany
paul.knochel@cup.uni-muenchen.de
Received November 24, 2003
ABSTRACT
Polyfunctional mixed lithium arylcuprates of the type (FG-Ar)(PhMe2CCH )CuLi obtained via iodine− or bromine−copper exchange with
2
(PhMe2CCH ) CuLi react with cyclic 2-iodoallylic acetates with high SN2 selectivity. The addition of ZnBr2 changes this selectivity and allows
2 2
the performance of highly regioselective and enantioselective anti SN2′ substitutions using open-chain allylic pentafluorobenzoates.
The use of highly functionalized organometallics consider-
ably enhances the synthetic potential of these reagents.1
Recently, we have reported an efficient preparation of
polyfunctional lithium arylcuprates2 of the type (FG-Ar)-
(Neophyl)CuLi 1 (Neophyl ) PhMe2CCH2) from function-
alized aryl iodides 2 via an iodine-copper exchange reaction3
using the bulky lithium cuprate (Neophyl)2CuLi 3. The
Neophyl moiety present in the mixed cuprates of type 1 plays
the role of a nontransferable group.4 Lithium diorgano-
cuprates are powerful nucleophiles and have been extensively
used for performing allylic substitutions.5 Recently, we have
shown that chiral 2-iodoallylic alcohol derivatives of type 4
are highly reactive electrophiles that undergo anti SN2′
substitution reactions with a range of zinc-copper reagents
(RCu(CN)ZnI), providing chiral products with high enantio-
selectivity.6 We have also reported that aryl zinc-copper
reagents react with open-chain allylic pentafluorobenzoates
providing only the anti SN2′ products allowing an enantio-
selective synthesis of (+)-ibuprofen.7 Herein, we wish to
report that in the absence of zinc salts, polyfunctionalized
aromatic lithium cuprates of type 1 obtained via an iodine-
copper exchange undergo a highly stereoselective SN2
substitution with the allylic acetates 4 leading to chiral
products of type 5 (Scheme 1 and Table 1).
(1) (a) Knochel, P.; Millot, N.; Rodriguez, A. L.; Tucker, C. E. Org.
React. 2001, 58, 417. (b) 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.
(2) (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.
(3) (a) Corey, E. J.; Posner, G. H. J. Am. Chem. Soc. 1968, 90, 5615.
(b) Kondo, Y.; Matsudaira, T.; Sato, J.; Murata, N.; Sakamoto, T. Angew.
Chem., Int. Ed. Engl. 1996, 35, 736.
(5) (a) Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135. (b) Tseng,
C. C.; Paisley, S. D.; Goering, H. L. J. Org. Chem. 1986, 51, 2884. (c)
Underiner, T. L.; Goering, H. L. J. Org. Chem. 1988, 53, 1140. (d) Krause,
N.; Gerold, A. Angew. Chem., Int. Ed. Engl. 1997, 36, 186. (e) Krause N.;
Hoffmann-Roder, A.; Canisius, J. Synthesis 2002, 1759. (f) Hoffmann-Roder,
A.; Krause N. Angew. Chem., Int. Ed. 2002, 41, 2933.
(4) (a) Jones, P.; Reddy, C. K.; Knochel, P. Tetrahedron 1998, 54, 1471.
(b) Bertz, S. H.; Eriksson, M.; Miao, G.; Snyder, J. P. J. Am. Chem. Soc.
1996, 118, 10906.
(6) Calaza, M. I.; Hupe, E.; Knochel, P. Org. Lett. 2003, 5, 1059.
(7) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986. (b)
Wallbaum, S.; Martens, J. Tetrahedron: Asymmetry 1992, 3, 1475.
10.1021/ol0362865 CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/16/2004

Scheme 1. Stereoselective SN2 Substitution of Polyfunctional
Table 1. Reactions of Polyfunctional Copper Organometallics
of Type 1 with Various Electrophiles
Lithium Arylcuprates with Cyclic 2-Iodoallylic Acetates
The new polyfunctional arylcopper reagents 1 were pre-
pared by the reaction of aryl iodides 2 with (PhMe2CCH2)2-
CuLi (1.1 equiv) at -78 °C. The reaction mixture was
warmed to 0 °C, which leads to a complete exchange reaction
within 0.5 h. In the case of the p-cyanophenylcopper reagent
1c, the precursor was the corresponding bromide (4-bromo-
benzonitrile). The Br/Cu exchange reaction was performed
at room temperature for 0.5 h. The acetates 4a,b were added
at -40 °C, and the reaction mixture was stirred at -20 °C
for 12 h leading to the products 5a-j in 50-89% yields
and excellent enantioselectivities (89-98% ee); see Table
1. (R)-2-Iodo-2-cyclopentenyl acetate 4a (96% ee)7 reacts
with arylcuprates bearing both electron-withdrawing and
donating groups (entries 1 and 2 of Table 1) leading to the
cyclopentenyl iodides 5a,b in 50-71% yields and 92-96%
ee. (R)-2-Iodo-2-cyclohexenyl acetate 4b undergoes the SN2
substitution with better yields (66-89%; entries 3-9) and
an excellent transfer of the stereochemical information. A
broad range of functional groups can be present in the
arylcuprate (CO2Et, CN, CF3, MeO, COCH3). Remarkably,
reactive halogenides such as an iodide (entry 6) or a bromide
(entry 7) are compatible with the substitution reaction. The
resulting chiral dihalogenated products 5f-g (94-96% ee)
are versatile building blocks in which the two halogen-
carbon bonds can be differentiated in future transformations.
Interestingly, the presence of a keto group in the copper
reagent 1g is possible (entry 9). The desired product 5i is
obtained in 67% yield and 89% ee, showing ca. 5%
racemization (enantiomer ratio from 99:1 to 95:5). This is
may be due to a competitive enolization of the keto group
by (Neophyl)2CuLi leading to a new copper bearing an
enolate ligand and displaying another chemoselectivity.
The SN2 nature of the substitution was established by
preparing (S)-3-phenylcyclohexene by our method ((i) sub-
stitution of (R)-4b with Ph(Neophyl)CuLi, (ii) n-BuLi, -78
°C, then H2O) and measuring its [RD] (-147.2° (c 0.795,
benzene, 25 °C). The literature8 indicates that for (R)-3-
phenylcyclohexene, [RD] ) +149.7°, benzene, 29 °C.
Furthermore, we have prepared 1-d-2-iodo-2-cyclohexenyl
acetate 4c9 and treated it with the mixed lithium cuprate 1b
a Isolated yield of analytically pure product. b Enantiomeric excess was
determined by HPLC-analysis and chiral-GC. In each case, the racemic
product was prepared for calibration.
under our standard conditions. We have observed only the
formation of the product 5k having the deuterium atom at
the allylic position 6 (Scheme 2), clearly indicating the
occurrence of an SN2 substitution.
We have also examined substitution reactions using
2-methyl-2-cyclohexenyl acetate instead of the iodo-substi-
Scheme 2. Stereoselective SN2 Substitution of 1b with
1-d-2-Iodo-2-cyclohexenyl Acetate
(8) Berti, G.; Macchia, B.; Macchia, F.; Monti, L. J. Org. Chem. 1968,
33, 4045.
530
Org. Lett., Vol. 6, No. 4, 2004

tuted allylic acetate 4b. We have observed in this case
sluggish reactions with loss of stereochemical information.
The use of 2-iodo-substituted allylic acetates is therefore
essential. Furthermore, we have shown that the iodine in
position 2 can be replaced by various groups using cross-
coupling reactions (Scheme 3).
zinc salts, which strongly favor the occurrence of SN2′
substitutions. We have found that in the absence of zinc salts,
the mixed arylcuprate of type 1 reacts nonregioselectively.
However, the addition of zinc bromide (1.0 equiv) allows
the performance of a highly stereoselective anti SN2′
substitution as has been observed with zinc-copper reagents
prepared from organozinc reagents. Thus, reaction of the
lithium cuprate 1b with a THF solution of ZnBr2 followed
by addition of the chiral cis-allylic pentafluorobenzoate 7
(97% ee)14 furnishes, in THF/ether (3:1), only the SN2′
product 8 (85%; 95% ee); Scheme 4.
Scheme 3. Cross-coupling Reactions of Compounds of Type
5 in Position 2
Scheme 4. Stereoselective Anti SN2′ Substitution of
Arylcuprates 1 with Chiral Open-Chain Allylic
Pentafluorobenzoates 7
In summary, we have demonstrated14 that the new poly-
functional mixed lithium arylcuprates of type 1 react with
high stereoselectivity and excellent yields with chiral 2-iodo-
cycloalkenyl acetates of type 4, affording the SN2 substitution
products. The addition of zinc bromide dramatically changes
this behavior and, with an open-chain allylic pentafluoro-
benzoate, provides only the anti SN2′-substitution product.
We are currently exploring the generality of these allylic
reactions as well as their application in natural product
synthesis.
Thus, the treatment of cyclohexenyl iodide 5c (95% ee)
with 1-hexyne in the presence of a catalytic amount of PdCl2-
(PPh3)2 (5 mol %), CuI (5 mol %), and Et3N (25 °C, 25 h)
provides the expected enyne 6a in 70% yield.10 Similarly,
the reaction of 5c with 4-carbophenoxyphenylzinc iodide
prepared from phenyl 4-iodobenzoate via an iodine-
magnesium exchange reaction11 furnishes, in the presence
of Pd(dba)2 (3.5 mol %) and dppf (3.5 mol %) (THF, 25 °C,
16 h), the expected Negishi cross-coupling12 product 6b in
75% yield. Finally, the performance of the cross-coupling
reaction with BuZnI prepared by the desired insertion of zinc
dust in butyl iodide leads,1a under the same conditions, to
the expected product 6c in 69% yield (Scheme 3). These
cross-coupling reactions indicate that the carbon-iodine bond
can be readily transformed to Csp2-Csp3, Csp2-Csp2, and
Csp2-Csp bonds.
Acknowledgment. We thank the Fonds der Chemischen
Industrie for financial support. M.I.C. thanks the European
Community (Marie Curie Fellowship of the program “Im-
proving Human Research Potential and the Socio-economic
Knowledge Base” Contract HPM-FCT-2000-01024) for a
fellowship. We thank Boehringer-Ingelheim (Vienna) and
Chemetall GmbH (Frankfurt) for the generous financial
support and gifts of chemicals.
Finally, we examined the nucleophilic substitution of the
functionalized arylcuprates of type 1 with chiral open-chain
allylic pentafluorobenzoates13 in the presence of zinc salts.
We have indicated above the importance of the presence of
Supporting Information Available: Experimental pro-
cedures and analytical data. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL0362865
(9) 1-d-2-Iodo-2-cyclohexenyl acetate 4c was prepared in two steps from
2-iodo-2-cyclohexen-1-one: reduction with NaBD4 and CeCl3‚7H2O in
methanol (25 °C, 3 h; 76%) followed by an acylation with Ac2O in pyridine
(83%).
(10) (a) Qing, F.-L.; Gao, W.-Z. Tetrahedron Lett. 2000, 41, 7727. (b)
Marshall, J. A.; Pinney, K. G. J. Org. Chem. 1993, 58, 7180.
(11) (a) Klement, I.; Rottla¨nder, M.; Tucker, C. E.; Majid, T. N.; Knochel,
P.; Venegas, P.; Cahiez, G. Tetrahedron 1996, 52, 7201. (b) Staubitz, A.;
Dohle, W.; Knochel, P. Synthesis 2003, 233.
(12) (a) Negishi, E. Acc. Chem. Res. 1982, 15, 340. (b) Negishi, E.;
Matsushita, M.; Kobayashi, M.; Rand, C. L. Tetrahedron Lett. 1983, 24,
3822. (c) Negishi, E.; Owczarczyk, Z. Tetrahedron Lett. 1991, 32, 6683.
(13) Harrington-Frost, N.; Leuser, H.; Calaza, M. I.; Knochel, P. Org.
Lett. 2003, 5, 2111.
(14) Typical Procedure: Preparation of 5c. A dry and argon-flushed
25 mL flask, equipped with a magnetic stirrer and a septum, was charged
with a solution of Nphyl2CuLi (1.1 mmol, 1.1 equiv). Ethyl 4-iodobenzoate
(276 mg, 1.0 mmol) was added at -78 °C, and the resulting mixture was
kept stirring at 0 °C for 30 min. Then, the reaction was cooled to -40 °C,
and (R)-2-iodo-cyclohex-2-enyl acetate (266 mg, 1.0 mmol) was added.
The resulting mixture was allowed to warm to -20 °C and stirred overnight.
The reaction was quenched with saturated aqueous NH4Cl solution, and
the mixture was poured into water (25 mL). The aqueous phase was
extracted with diethyl ether (3 × 30 mL). The organic fractions were washed
with brine, dried over MgSO4, and concentrated in vacuo. Purification by
flash chromatography (SiO2, n-pentane/diethyl ether ) 10:1) yielded 274
mg (77% yield) of 5c as a colorless oil.
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