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Cuprates as Selective Metalating Reagents for Aromatic Halides.

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[7] a) P. J. Stang. D. H. Cao. S. Saito. A M. Arif, J. Am. Chem. Soc. 1995, 117,
6273; b) C. M. Drain, J:M. Lehn. J Chem. Soc. Chem. Commun. 1994, 2313;
c) P. J. Stang, J. A. Whiteford, Organometal1ic.s 1994, 13. 3776; d) P. J. Stang.
A m . Chem. SOC.1994, 116, 4981; e) M. Fujita, Y. J. Kwon, S.
D. H. Cao, .
Washizu, K. Ogura, ibid. 1994, 116, 1151; f ) H. Rauter, E. C. Hillgeris, A.
Erxleben, B. Lippert, rhid 1994, lf6.616, g) M. Fujita, S. Nagao, M. Iida, K.
Ogura, [hid. 1993, lfS, 1574; h) M. Fujita, J. Yazdki. K. Ogura, ihid. 1990, f12,
[XI a) P. J. Stang, K. Chen, J Am. Cheni. Sac. 1995, l f 7 , 1667; b) P. J. Stang, K.
Chen, A.M. Arif. ;bid 1995, / f 7 , 8793.
[9] a) C. A. Hunter, Angew. Chem. 1995, 107, 1181; Angew. Chem. Int. Ed. Engl.
1995, 34. 1079; b) D . S. Lawrence, T. Jiang, M. Levett, Chem. Rev. 1995, 95,
[lo] P. J. Stang, B Olenyuk, A. M. Arif. Organometallics 1995. 14,5281. For another example of restricted rotation, see also J. M. Brown, J. J. Ptrez-Torrente,
N. W. Alcock, Ibid. 1995, 14. 1195.
[ I f ] a) U. Burkett, N. L. Allinger, Molecular Mechanics, American Chemical Society, Washington, D. C., 1982; b) T. Clark, Computational Chemistry, Wiley.
New York, 1985
[12] The R,S,S configuration around each metal center was assigned by using the
standard Canh-Ingold-Prelog conventions for the assignment of atropoisomeric chirality and treating the trans-P-M-N' as one pair of substituents about
the Pt -N axis: V. Prelog, G. Helmchen, Angew. C k m . 1982, 94, 614; Angew.
Chem.. Int. Ed. Engl 1982, 21, 567. Note that the first letter ( R ) refers to the
configuration of the binap ligand.
[13] a) F. Cozzi, J. S. Siege], Pure Appl. Chem. 1995,67,683; b)C. A. Hunter, Chem.
Soc. Res. 1994. 23. 101
[14] The bistriflate complex 9 was prepared in analogy to the synthesis of complex
2 by the reaction of [Pt(S-(-)-BINAP)CI,] with AgOTf.
Since the first preparation of [LiCuMe,]['] a number of
Gilman-type reagents of the general formula [LiCuR,] have
been used in organic syntheses, and recently higher order, mixed
cuprates [Li,Cu(CN)R,J have been reported to show high reactivity toward a variety of organic substrates.[61During our recent studies on arene and heteroarene chemistry,[" we became
interested in developing methods for preparing mixed arylcuprates with functional groups from haloarenes by halogencopper exchange. The halogen -metal exchange reaction is one
of the most useful processes for the preparation of metalated
arenes such as the lithium[81and magnesium[g1compounds.
However, use of other organometallic compounds other than
organolithiums and organomagnesiums for the halogen -metal
exchange reaction seems to be rather limited. Although the possibility of halogen-copper exchange has been suggested in the
coupling reaction of aryl halides with cuprates," the reactions
of organocopper intermediates with electrophiles are still unexplored from the viewpoint of synthetic chemistry.
Cuprate 2a was prepared by reaction of iodobenzene (la)
with [Li,Cu(CN)Me,] in T H F at -40°C for 2.5 h (Table 1).
Table 1. Formation of cuprates 2a-c by halogen-metal exchange and addition to
benzdldehyde. RT = room temperature.
Cuprates as Selective Metalating Reagents for
Aromatic Halides
Yoshinori Kondo, Tetsuji Matsudaira, J u n k o Sato,
N a o k o Murata, and Takao Sakamoto*
Ate complexes such as cuprates have been used as versatile
reagents for selective carbon-carbon bond forming reactions;
however, little attention has been paid to halogen -metal exchange reactions using ate complexes.['] With the aim of developing a new facile method for the preparation of arylcuprates,
we investigated the halogen-copper exchange reaction of aromatic halides using cuprates. [Li,Cu(CN)Me,] was found to be
an excellent metalating reagent. We describe here the application of this metalating method for the asymmetric synthesis of
precursors of the CC-l065/duocarmycin pharmacophore with
high enantiomeric purity.
Organocopper complexes are the organotransition metal
reagents most widely used as soft nucleophiles in organic synthesis.['] Organocopper and organocuprate reagents are employed for carbon -carbon bond formation owing to their characteristic reactivities in conjugate additions to or,D-unsaturated
carbonyl compounds, in substitution reactions, and in carbometalations of carbon -carbon triple bonds. Although these
reagents tolerate a wide range of electrophilic functional groups,
the formation of functionalized organocopper reagents is not
promising, because transmetalation of organolithium or
Grignard reagents is typically required. Functionalized
organocopper reagents have been prepared by transmetalation
of functionalized organozinc compounds[3]and by direct oxidative addition of active copper to organic halides.C4I
[*I Prof. Dr. T. Sakamoto, Prof. Dr. Y Kondo, T. Matsudaira, J. Sato, N. Murdta
Department of Heterocyclic Chemistry
Faculty of Pharmaceutical Sciences, Tohoku University
Aobayama, Aoba-ku, Sendai 980-77 (Japan)
Fax: Int. code +(22)217-6864
e-mail . j23396(a
Verlagsgrsellschqft mbH, 0.69451 Weinheim, 1996
- 40
- 40
- 20
- 78
Yield [ O h ]
Subsequent reaction with benzaldehyde at - 78 "C gave benzhydrol 3a in 89% yield. Yields were moderate when Et,O
was employed as solvent. Other mixed cuprates such as
[LiCuMe,], [Li,CuMe,(SCN)], [Li,Cu(C=CPh)(CN)Me], and
[Li,Cu(C,H,S)(CN)Me] (C,H3S = thienyl) were found to be
less reactive than [Li,Cu(CN)Me,], and benzhydrol3a was obtained in 12-32 YOyield under otherwise identical reaction conditions. The halogen-copper exchange reaction of p-iodoanisole (lb) with [Li,Cu(CN)Me,] seemed to be slower than the
reaction of iodobenzene. Satisfactory results were obtained
when the metalation was conducted at -20 "C. A p-methoxycarbonyl group (lc) was tolerated in the halogen -copper exchange reaction, and the intermediary copper reagent 2c reacted
with benzaldehyde to give the alcohol 3c. For better yields the
metalation was conducted at - 78 "C.
The high reactivity of the cuprates formed in this halogencopper exchange reaction in 1,2-addition reactions encouraged
us to investigate other classical reactions for carbon-carbon
bond formation. The conjugate addition of the phenylcuprate
2a to 2-cyclohexenone afforded 3-phenylcyclohexanone (4) in
61 YOyield without additional reagents (Scheme 1). The reaction
of 2a with 1,2-epoxycyclohexane gave trans-2-phenylcyclohexanol (5)in 53 740 yield in the absence of additives.
0570-0833/96/3507-0736$ 15.00+ ,2510
Angew. Cliem. Ini. Ed. Engl. 1996, 35, No. 7
THF or EtaO
c: &
The halogen-copper exchange reaction of aryl halides with
[Li,Cu(CN)Me,] is a new method for the preparation of functionalized arylcuprates. To determine the structure of the arylcopper intermediate, arylcuprate 6, which was obtained by halogen -copper exchange reaction of methyl p-iodobenzoate (lc),
was hydrolyzed and oxidized with oxygen (Scheme 2). The hy-
c=, R'O
Scheme 3. Retrosynthetic analysis of the spirocyclic pharmacophore of CC-1065
and 3and the duocarmycins leading back to 3-hydroxymethyl-2,3-dihydroindole
ed in the asymmetric synthesis of 3-hydroxymethyl-2,3-dihydroindoles and 3-hydroxy-I ,2,3,4-tetrahydroquinolines.
If these
precursors are available in enantiomerically pure form, asymmetric synthesis of the pharmacophore should be straightforward.
The intramolecular ring opening of epoxyorganometallic
compounds is of interest in particular with regard to the regioselectivity of subsequent cyclizations.r'61We investigated the synthesis of a precursor of the CC-I065/duocarmycin pharmacophore by intramolecular ring opening of epoxyarylmetal ate
complexes. The chiral epoxide 9 was chosen as a substrate and
the regioselectivity of the cyclization was investigated. When 9
was treated with nBuLi at -9O"C, the 5-exo cyclization
10 was formed in 43% yield without loss of enantiomeric purity (Table 2, Entry 1). At higher temperature the
Table 2. Synthesis of the precursors 10 and 11 of the CC-1065~duocarmycinpharmacophore.
[LizCu(CN)Mez] t
(2 equiv)
61 %
Scheme 1. 3,4-Addition and epoxide opening with cuprate Za, which is formed from
- 7 a ~
aq. NH CI
8 76%
Scheme 2. Hydrolysis and oxidation of cuprate 6, which is formed from lc.
drolysis of 6 in aqueous NH,Cl at -40 "C gave methyl benzoate
(7) in 85% yield; formation of methyl p-methylbenzoate (8)
was not observed. In the halogen-copper exchange process
Me1 is probably produced and may be scavenged by another
equivalent of [Li,Cu(CN)Me,]. The resulting [LiCu(CN)Me] is
less reactive to electrophiles than [Li,CuAr(CN)Me] is. Oxidation of 6 by bubbling oxygen through the reaction mixture at
- 78 "C gave coupling product 8 in 76 % yield. These results
suggest the arylcopper intermediate is a mixed higher order
species." '1
Our interest next focused on the application of the method to
the synthesis of biologically active molecules. CC-1065[' and
duocarmycins A['2b1and SA['2"' are potent antitumour antibiotics, and they have been synthetic targets for many synthetic
chemists in connection with the mechanism of their biological
activity.[13*14] They contain a common spirocyclic subunit, and
and 3-hydroxy-I ,2,3,4-tetrahydroquinolines are considered to be key precursors for the
synthesis of the spirocyclic pharmacophore (Scheme 3).
In connection with our recent studies on the synthesis of
CC-I065/duocarmycin pharmacophores["I we became interestAngew. Chrm. In!. Ed. EngI. 1996, 35, N o . 7
T ["Cl
- 50
- 78
- 78
- 78
Yield [%I (ee [%] [a])
43 (93)
40 (91)
12 (90)
6 (78)
57 (91)
15 (91)
62 (90)
73 (92)
[a] The enantiomeric excesses were determined with a Chlralcel OD-H column
yield of the product decreased dramatically (Entry 2 ) . The reaction of 9 with lithium trim@thylzincateat - 50 "C gave the 5-exo
product 10 in 40 % yield and the 6-endo product 11 in 57 % yield.
Reaction with the zincate obtained from three equivalents of
MeLi and [Zn(SCN)2][181
furnished the 5-exo product 10 as the
main product together with the 6-end0 product 11 (Entry 3).1'61
The reactions of 9 with cuprates (Entries 4,5) showed reverse
regioselectivity, and the 6-end0 product 11 was obtained exclusively when [ L ~ , C U ( C N ) M ~ , ] was
~ ' ~ ] used as the metalating
reagent. In general, enantiomeric purity was unchanged after
the ring opening; the only exception was the 5-ex0 product 10
in the reaction of 9 with [Li,Cu(CN)Me,].
We do not yet have enough experimental data for discussing
the origin of this diverse selectivity in the cyclization which
Verlagsgesellschafi mbH, 0-69451 Weinheim, 1996
0570-0833/9613507-0737$15.00+ .ZSj0
depends on the metalating reagent. However, the coordination
of the oxygen atoms of the epoxide and sulfonyl groups to the
metals of the ate complex is considered to be important in determining the direction of cyclization.
We have described a new method for the synthesis of enantiomerically pure 3-hydroxmethyl-2,3-dihydroindole
and 3-hydroxyl-l,2,3,4-tetrahydroquinoline.The reagents of choice for
the regioselective ring closure are [Li,ZnMe,(SCN),] for the
5-exo cyclization and [Li,Cu(CN)Me,] for the 6-end0 cyclization.
2305-2307; c) J. Org. Chem. 1983, 48, 546-550; d) B. H. Lipshutz, R. S.
Wilhelm, J. A. Kozlowski, D. Parker, ibid. 1984,49,3928-3938;e) B.H. Lipshutz, R. s. Wilhelm, J. A. Kozlowski, ibid. 1984,49,3938-3942; f) Tetrahedron, 1984,40,5005-5038; g) B. H. Lipshutz, Synthesis. 1987,325-341.
[7]a) T. Sakamoto, Y. Kondo, N. Murata, H. Yamanaka, Tetrahedron Lett. 1992,
33,5373-5374;b) Tetrahedron, 1993,49,9713-9720;
c) T. Sakamoto, Y Kondo, N. Takazawa, H. Yamanaka, Heterocycles 1993,36,941-942;d) Telrahedron L e t t 1993,34, 5955-5956.
[8] a) B. J. Wakefield. The Chemistry of Organolilhium Compounds, Pergamon,
Oxford, 1974;b) Organolithium Method, Academic Press, London, 1988.
[9]a) C. Tamborski, G. J. Moore, J Organomet. Chem. 1971,26, 153-156; b)
H. H. Parddies, M. Gorbing, Angew. Chem. 1969,81, 293;Angew. Chem. Inl.
Ed. Engl. 1969,8, 279.
[lo] a) H. 0. House, D. G. Koepsell, W. J. Campbell, J. Org. Chem. 1972,37,1003Experimental Procedure
1011; b) G. M. Whitesides, W. F. Fischer, Jr., J. S. SanFilippo, Jr., R. W.
Bashe, H. 0. House, J. Am. Chem. SOC.1969,91,4871-4882; c) E Babdri, L.
General procedure for halogen -copper exchange reaction followed by reaction
DiNunno, S. Florio, G. Marchese, F. Naso, J. Organomet. Chem. 1979,166,
with an electrophile: MeLi (1.04 M solution in Et,O; 3.84 mL, 4 mmol) was added
to a suspension of dry CuCN (179mg, 2 mmol) in T HF or Et,O (5 mL) at -78 "C,
[Ill Although the structure of [Li,Cu(CN)R,] is still uncertain and is a controverand the mixture was stirred at -40 "C for 30 min. Then an aryl iodide (1 mmol) in
sial issue, the synthetic potential of these organocopper species should be disTHF or Et,O (1 mL) was added and the reaction mixture stirred at -40 "C for 1 h.
tinguished from that of the Gilman-type lower order cuprates. For recent
The mixture was cooled to -78°C before an electrophile (2mmol or excess) was
discussion on the structure ofcyanocuprates see a) J. P. Snyder, D. P. Spangler,
added. The mixture was gradually warmed to room temperature over 12 h. The
J. R. Behling, J. Org. Chem. 1994, 59. 2665-2667; b) B. H. Lipshutz, E. L.
reaction mixture was quenched with aqueous NH,CI (2mL) and the solvent reEllsworth, T. J. Siahaan, J. Am. Chem. Soc. 1988, 110, 4834-4835;c) S.H.
moved in vacuo. The residue was diluted with H,O (30 mL), and the mixture was
Bertz, ibid. 1990, 112, 4031-4032; d) B. H. Lipshutz, S. Sharma, E. L.
extracted with CHCI, (3 x 30 mL). The combined organic layers were dried over
Ellsworth, &id. 1990,112,4032-4034.
anhydrous MgSO,. After purification by silica gel column chromatography, the
[12]a) C. G. Chidester, W. C. Krueger, S. A. Mizsak, D. J. Duchamp, D. G. Marcrude material was recrystallized or distilled under reduced pressure.
tin, J. Am. Chem. SOC.1981, 103, 7629; b) I. Takahashi, K. Takahashi, M.
Reaction of 8 with [Li,Cu(CN)Me,]: Under Ar atomosphere. MeLi (1.03M solution
Ichimura, M. Morimoto, K. Asano, I. Kawamoto, F. Tomita, H. Nakano, J.
in Et,O, 1.46mL, 1.5 mmol) was added to the mixture of 90% CuCN (74.6mg,
Anribiot. 1988, 41, 1915; c) M. Ichimura, T. Ogawa, K. Takahashi, E.
0.75mmol) and dry TH F (3mL) at - 78 "C. The mixture was warmed to -40 "C
Kobayashi, 1. Kawamoto, T. Yasuzawa, I. Takahashi, H. Nakano, ibid. 1990,
and stirred for 30 min. The mixture was cooled to 78 "C and a solution of 9
43, 1037.
(223mg, 0.50 mmol) in dry THF (5 mL) was added dropwise. The mixture was
[I31 CC-1065 synthesis: a) D. L. Boger, R. S. Coleman, J. Am. Chem. Soc. 1988,
allowed to warm to room temperature and was stirred for 12 h. After evaporation
110,1321-1323;b) ibid. 1988,110.4796-4807;c) R. C. Kelly, I. Gehhard, N.
of the solvent, the residue was diluted with H,O (30mL) and was extracted with
Wicnienski, P. A. Aristoff, P. D. Johnson, D. G. Martin, ibid. 1987,109,6837CH,CI, (3x 50 mL). The combined extracts were dried over MgSO, and the solvent
was removed under reduced pressure. The residue was purified by silica gel column
[14]Duocarmycin synthesis: a) D. L. Boger, K. Machiya, J Am. Chem. Soc. 1992,
chromatography (EtOAc/hexane (l/l)) to give a viscous oil (10:9.5mg. 6%,
114,10056-10058;b)D. L.Boger, K. Machiya, D. L. Hertog. P. A. Kitos, D.
78% ee)andacolorlesssolid(ll:98.1 mg,62%,90% ee). 10:viscousoil;'HNMR
Holmes, ;bid. 1993, 115. 9025-9036;c) H. Muratake, I. Abe, M. Natsume,
(300MHz,CDC13,TMS):6 =1.87-2.06(br.s, lH),3.20-3.32(m,2H),3.47-3.56
Telrahedron Lett. 1994,35, 2573-2576.
(m,lH),3.81(s,3H),3.88(dd,lH,J=4.6,ll.OHz),3.97(dd,1H.J=8.8, [I51 T. Sakamoto, Y Kondo, M. Uchiyama, H. Yamanaka, J. Chem. Soc. ferkin
11.0 Hz), 6.53(dd, 1H, J = 2.2, 8.1 Hz), 7.00 (d, 1H, J = 8.1 Hz), 7.26 (d, 1 H,
Trans. 1 1993, 1941 -1942.
J = 2 . 2 H ~ ) , 7 . 4 4 ( d d , 2 H , J = 7 . 3 , 7 . 3 H z ) , 7 . 5 5 ( t , l H ,J = 7 , 3 H z ) , 7 , 8 2 ( d , 2 H ,
[16]a) W. E. Parham, C. K. Bradsher, Arc. Chem. Res. 1982,15, 300-305;b) C. K.
J=7.3 Hz); MS: mjz: 319 [ M ' ] . 11: m.p. 113T; ' HNMR (300MHz, CDCI,,
Brasher, D. C. Reames, J. Org. Chem. 1978,43, 3800-3802; c) L.A. Last,
d) M. P. Cook, Jr., I. N.
E. R. Fretz, R. M. Coates, ibid. 1982,47,3211-3219;
J = 4.6,15.9Hz),3.57-3.68 (m, 1 H), 3.78(s, 3 H), 3.98~-4.07
(m, 2H), 6.67(d, 1 H,
Houpis, Tetrahedron Lett. 1985,26,3643-3646; e) J. H. Babler, W. E. Bauta,
J = 8.4 Hz), 6.93(d,l H , J = 8.4 Hz), 7.30(s,1 H), 7.41-7.47(m,2H), 7.55 (t. 1 H,
ibid. 1984.25,4323-4324; f) I. R. Hardcastle, P. Quale, E. L. M. Ward, ibid.
= - 50.0(c = 3.09,
1994,35, 1747-1748; g) K. L. Dhawan, B. D. Gowland, T. Durst, J. Org.
Chem. 1980,45,924-926; h) R. D. Rieke, D. E. Stack. B. T. Dawson, T:C.
Wu, ibid. 1993,58, 2483-2491.
Received: August 7, 1995 [Z8288 IE]
[17] J. E. Baldwin, J. Chem. SOC.Chem. Commun. 1976,734-736.
German version: Angew. Chem. 1996,108, 818-820
[18]We are currently studying the nature of organozinc compounds derived from
[Zn(SCN),] and organolithiums; the difference in the reactivity of [LiZnMe,]
Keywords: asymmetric syntheses cuprates
copper comand [Li,ZnMe,(SCN),] was observed. Details of these new organozinc derivatives will be reported elsewhere soon.
pounds * metalations
[19]The formula [Li,Cu(CN)Me,]indicates amixture ofCuCN (1 equiv) and MeLi
(3equiv); however, the reactivity described in the present study suggests that
[l] Lithium trimethylzincate can be used to metalate aromatic halides having
[Li,Cu(CN)Me,] is not a mixture of [Li,Cu(CN)Me,] and and MeLi.
electrophilic functional groups: Y. Kondo, N. Takazawa, C. Yamazaki, T.
Sakamoto, J. Org. Chem. 1994,59. 4717-4718.
[2] a) G. H. Posner, Org. React. 1972, 19,1-113; b) ibid. 1975,22, 253-400;c)
B. H. Lipshutz. S. Sengupta, ibid. 1992, 41, 135-631; d) Comprehensive
Organometallic Chemistry, Vol. 2 (Eds.: G. Wilkinson, F. G. A. Stone, E. W.
Abel), Pergamon, Oxford, 1982;e) G. Van Koten. J. G. Noltes in ref. [2d], pp.
709-763; e) W Cwruther in ref. [2d], pp. 685-722.
[3]a) L.Zhu, R. M. Wehmeyer. R. D. Rieke, J. Org. Chem. 1991,56,144-1453;
b) L.Zhu, R. D. Rieke, Tetrahedron Lett. 1991,32,2865-2866;
c) P. Knochel,
S. A. Rao, 1 Am. Chem. Soc. 1990,112,6146-6148;d) P. Knochel, ibid. 1990,
112,7431-7433; e) S.A. Rao, P. Knochel, ibid. 1991. 113,5735-5741; f) P.
Wipf, Synthesis 1993,537-557;g) P. Knochel, R. D. Singer, Chem. Rev. 1993,
[4]a) G. W. Ebert, R. D. Rieke, J Org. Chem. 1984.49.5281 -5282; h) ibid. 1988,
53, 4482-4488; c) R. D. Rieke, R. M. Wehmeyer, T.-C. Wu, G. W. Ebert.
Tetrahedron 1989,45, 443--454;
d) R. D.Rieke, B. T. Dawson, D. E. Stack,
D. E. Stinn. Synth. Commun. 1990, 20, 2711-2721; e) G. W. Ehert, J. W.
Cheasty, S. S. Tehrani, E. Aouad, Organometallics 1992, fi, 1560-1564; f)
R. D. Rieke, D. E. Stack, B. T. Dawson, T.-C. Wu, J. Org. Chem. 1993,58,
2483-2491; g) G. W. Ebert, D. R. Pfennig, S. D. Suchan, T. A. Donovan, Jr.,
Tetrahedron Lett. 1993,34, 2279-2282.
[5] H. Gilman, R. G. Jones, L. A. Woods, J. Org. Chem. 1952,17, 1630-1634.
[6] a) B. H. Lipshutz, R. S. Wilhelm, D. M. Floyd, J. Am. Chem. SOC.1981,103,
7672-7674;b) B. H.Lipshutz, J. A. Kozlowski, R. S. Wilhelm, ibid. 1982,104,
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