REVIEW 7

CuCl(OH).TMEDA: A Novel, Efficient Catalyst for Aerobic Oxidative Coupling Reactions.

anics g r O s Acro m o r f w Ne
Shashi Bhushan1 and Kuppuswamy Vijayakumaran2 1 Gerchem Labs (India) Pvt. Ltd., Hyderabad 700 001, India. (e-mail: gerchem@hd2.dot.net.in) 2 Chimique Laboratories (India) Ltd., Alathur 603 110 (TN) India. (e-mail: kvjkum@eth.net)

Catalysts for organic synthesis

CuCl(OH).TMEDA: A NOVEL, EFFICIENT CATALYST FOR AEROBIC OXIDATIVE COUPLING REACTIONS.

Shashi Bhushan1 and Kuppuswamy Vijayakumaran2

1) Gerchem Labs (India) Pvt. Ltd., Hyderabad 700 001, India. (e-mail: gerchem@hd2.dot.net.in) 2) Chimique Laboratories (India) Ltd., Alathur 603 110 (TN) India. (e-mail: kvjkum@eth.net)

INTRODUCTION C-C bond formation lies at the heart of organic chemistry and in this context biaryl coupling occupies a prominent place, particularly with important applications to natural products synthesis. Oxidative phenolic coupling is an area that has been actively pursued with synthetic and biosynthetic implications. Transition metal ions such as Fe(III) are well known to catalyze aerobic oxidative biaryl coupling. There is continued interest in this field one of the objectives being the discovery of efficient catalytic systems which will perform under mild conditions, avoiding (or minimizing) the formation of unwanted side products such as quinones. In 1994, Noji et al1 introduced a copper-derived complex viz. CuCl(OH).TMEDA2 as catalyst for oxidative coupling of beta-naphthols1,3 based on the previously reported ability of Cu(I)-amine complexes to catalyze the oxidative coupling of acetylenes and active methine compounds (Glaser-Hay coupling). NOVEL Cu-BASED CATALYST FOR AEROBIC COUPLING CuCl(OH).TMEDA is a stable, free flowing solid, soluble in chlorinated solvents, ethanol, diethylether, methanol and THF. It is sparingly soluble in acetone, benzene, toluene and other non-polar solvents. The reactions are usually carried out in dichloromethane or chloroform under aerobic conditions (air or oxygen). The catalyst is formulated as CuCl(OH).TMEDA and in some references a dimeric structure 1 is also depicted.4
H3C N Cu N H3C CH3 O H H3C CH3 H O Cu N CH3 H3C N 2 Cl CH3 ++

-2This article presents selected applications of CuCl(OH).TMEDA in biaryl coupling reactions and inter alia some recent reports on Glaser-Hay acetylenic coupling with particular reference to diyne-bridged chiral binaphthol oligomers, macrocycles and porphyrins.

I BIARYL COUPLING REACTIONS

I.1 SYNTHESIS OF BINAPHTHOLS In recent years, axially chiral binaphthalene derivatives have emerged as important ligands and chirality inducers in organic synthesis. Nakajima and coworkers observed that in the presence of CuCl(OH).TMEDA with oxygen or air as the oxidant, 2-naphthol 2 is transformed to 1,1'-bi-2-naphthol ("BINOL") 3 (Scheme I).1,3 A wide variety of substrates undergo oxidative coupling in excellent yields (Table I). It is noteworthy that the reaction requires as little as 1% (mol) of the catalyst.
R2 R2

CuCl(OH).TMEDA (1 mol%) O2 , CH2Cl2

R1 R1

OH OH

R1

OH

R2

2 (a-e)
SCHEME- I

3 (a-e)

Table I. Synthesis of BINOLS 3 using CuCl(OH).TMEDA1 Substrate (naphthol)

2a 2b 2c 2d

R1 H H OCH3 H

R2 H CH3 H COOCH3

Oxidant

Time (h) 8.5 1 1.5 96

Temp. (oC) 0 RT RT RT

Yield (%) 90 92 96 99

O2 O2 O2 O2

-3Nakajima and coworkers also compared the efficacy of CuCl(OH).TMEDA with classical Glaser-Hay coupling catalysts derived from Cu(I) and Cu(II) salts (in conjunction with TMEDA) in the oxidative coupling of 2-naphthol. They found CuCl(OH).TMEDA to be much superior, enabling an efficient catalytic oxidative coupling of 2-naphthols which could be applied to a large-scale synthesis of binaphthols.3 Not surprisingly, 2-methoxynaphthalene itself did not undergo oxidative coupling under these conditions. Ng et al5,6 took advantage of CuCl(OH).TMEDA to synthesize 4,4'-dibromo-1,1'-bi-2-naphthol 5 through the oxidative coupling of 4-bromo-2-naphthol 4 in 90% yield (Scheme II). The 4,4'-dibromo-1,1'-bi-2naphthol 5 thus prepared was resolved, converted to chiral oligo-1,1'-bi-2-naphthalene molecules through Glaser-Hay acetylenic coupling (see further, II.2.).
Br Br

CuCl(OH)-TMEDA (10 mol %)

OH

OH OH

O2, CH2Cl2, 25oC, 4 h

Br

4
SCHEME-II

I.2 SYNTHESIS OF "CYCLO-BINOLS" Lipshutz et al7,8 developed a modular approach to tethered non-racemic cyclo-BINOLS 7 by the use of CuCl(OH).TMEDA on chiral 6 to give 7 in 90-95% isolated yield. The level of chiral induction due to the chiral acetal auxiliary in the crucial biaryl coupling-cyclization step is quite high, attaining a diastereomeric excess (de) of 90% (Scheme III).

R1 O O O O OH OH R1
6 7 (R1=H)
CuCl(OH).TMEDA (8 mol%) O2, CH2Cl2

R1 O O O O
R

OH OH R1

[12:1 R,R,R : R,R,S ] SCHEME- III

-4In this intramolecular biaryl coupling, use of concentrations greater than 0.001M led to increasing amounts of polymeric materials. Syringe pump addition, however, allowed for a final working concentration of 0.01M. Noteworthy is the comment by the authors that salts of other metal ions commonly used in this kind of coupling process, such as Fe(III), are required in stoichiometric amounts, besides leading to inferior yields in the biaryl coupling step.7 The cyclo-BINOL 7 (useful as a chiral ligand) was obtained as a separable diastereomeric mixture.

I.3 SYNTHESIS OF BINOL-6,6'-DIPHOSPHONIC ACIDS

Villemin and coworkers9 synthesized binol-6,6'-diphosphonic acids through two different routes both of which involved catalysis by CuCl(OH).TMEDA in the biaryl coupling of suitably functionalized betanaphthols. Thus, these authors extended the Cu-catalyzed biaryl coupling methodology of Nakajima and Koga1,3 to 6-bromo-2-naphthol 8 which on oxidative coupling gave the key intermediate, viz. 6,6'-dobromo-1,1'binaphthalene-2,2'-diol 9 in 80% yield (Scheme IV). Dibromo-BINOL 9 was then converted to 6,6'diphosphono-BINOL 11 in a four step sequence.9
Br Br

CuCl(OH).TMEDA (1 mol%)
OH

OH OH

air, CH2Cl2, 24 h
Br

8
SCHEME-IV

Villemin and coworkers9 commented that bromination of binol itself depends on the purity of the substrate. Where binol is prepared by oxidative coupling of beta-naphthol using iron(III) chloride in stoichiometric amount, several recrystallizations are needed to remove all the iron salts before the bromination step. Indeed, traces of iron(III) chloride catalyze the bromination reaction and thus induce the formation of unwanted byproducts. In this instance, use of just 1% CuCl(OH).TMEDA serves admirably to obtain the desired 6,6'-dibromo-binol in excellent yields. As an alternative route to 11, these authors tried the oxidative coupling of dialkyl 6hydroxynaphthylphosphonate 10 using 5% CuCl(OH).TMEDA to give 11 (Scheme V).9 In spite of the use of dioxygen instead of air, they could not realize yields higher than 25% (R=C2H5) and 60% [R=CH(CH3)2]. They explained these relatively lower yields based on mechanistic considerations of the oxidative coupling reaction. Besides, they also surmised that the reactivity of the Cu-complex might be reduced due to complexation with the phosphonate substituent.

-5O O (RO)2P (RO)2P

CuCl(OH).TMEDA (5 mol%)
OH

OH OH

air, CH2Cl2, 4 days

(RO)2P O

10
SCHEME-V

11

I.4 HETEROARYL COUPLING

Of late arylboronic acids have become important biaryl coupling partners (eg. Suzuki reaction). In an interesting variant, Collman and Zhong have shown the ability of CuCl(OH).TMEDA to catalyze the cross-coupling reaction of arylboronic acids 12 with imidazoles 13 leading to N-arylimidazole derivatives 14 in a mild, efficient, high yielding (69-98%) process (Scheme VI).10 In this N-arylation reaction the addition of a small amount of 4 A molecular sieves powder resulted in moderate yield improvement. Benzimidazole was also shown to react with arylboronic acids yielding the corresponding N-arylbenzimidazoles. The authors speculated on the mechanism, implicating a Cu(III) species.

[Cu(OH).TMEDA]2Cl2
B(OH)2 R1 NH R2 N N N R2

O2, CH2Cl2, RT, overnight

R1

12

13

14

SCHEME-VI

This catalytic coupling process of for preparing N-arylimidazoles10 is a considerable improvement over previous reports which used p-tolyllead triacetate and catalytic Cu(OAc)2 at 90oC, or arylboronic acids and more than equimolar quantities of Cu(OAc)2 and a tertiary amine (triethylamine or pyridine).

-6-

I.5 SYNTHESIS OF 5,5'-BI(1H-NAPHTHO[2,3-c]PYRAN)-10,10'-DIOLS

A Japanese patent describes the synthesis a range of diversely substituted 5,5'-bi(1H-naphtho[2,3c]pyran)-10,10'-diol derivatives 17 having N-methyl-D-aspartic acid antagonist activity. The crucial step is the biaryl coupling catalyzed by the Cu-amine complex in high yields. Interestingly, coupling of pyranonaphthol 15 initially leads to the 10,10'-dione derivative 16 which is subsequently aromatized by base-catalyzed enolization giving the 10,10'-diol 17 (Scheme VII).11

CH3O

OH O

CH3O

O O

"Cu(II).TMEDA complexHCl" O2, CH2Cl2, 1.5 h, 95.2%

CH3O

CH3O OR

CH3

CH3 OR OR

(R = -CH2OCH3)
CH3O

CH3 O CH3O O

16 1) 2 N aq. NaOH 2) 1 N aq HCl

CH3O OH O CH3O OR OR CH3O O CH3O OH CH3 CH3

17 SCHEME-VII

-7-

I.6 ASYMMETRIC SYNTHESIS OF BINOL DERIVATIVES

Nakajima et al developed an asymmetric version of their elegant Cu-diamine catalyzed binaphthol coupling by replacing TMEDA with L-proline derived diamines.3,12 They investigated the asymmetric aerobic oxidation of esters of 3-hydroxy-2-naphthoic acid with 10 % (mol) of the chiral catalyst prepared in situ from a chiral diamine and cuprous chloride in refluxing dichloromethane and reported ee (enantiomeric excess) up to 73% in the coupling reaction. A review (in Japanese) has appeared on the aerobic oxidative coupling of 2-naphthol derivatives catalyzed by CuCl(OH).TMEDA including asymmetric coupling reactions using L-proline derived diamine.13

I.7 OXIDATIVE COUPLING WITHOUT SOLVENT

Nakajima and coworkers also investigated the aerobic oxidative coupling of 2-naphthol derivatives without solvent.14 Thus, a mixture of 2-naphthol and CuCl(OH).TMEDA (5 mol %) was finely ground into a powder with a mortar and pestle, and heated at 50oC for 2 hours. According to the authors the mixture apparently remained as a powder without being liquefied. Washing the mixture with aqueous ammonia and water reportedly afforded practically pure BINOL in quantitative yield. Thus, several substituted binaphthols were obtained in high yields, the process being amenable for scaling up to 50 g level.

II GLASER-HAY ACETYLENIC COUPLING REACTIONS

II.1 SYNTHESIS OF DI- AND OLIGOACETYLENES
Coupling of terminal acetylenes is an important reaction in aliphatic chemistry for the extension of linear scaffolds. In this context, CuCl.TMEDA has been used for the synthesis of oligoacetylene moieties (Scheme VIII).15 Yields are in the range of 70-75% in the synthesis of 1,4bis(trimethylsilyl)buta-1,3-diyne 18, from trimethylsilylacetylene 17. We may note that diyne 18 is a convenient source of butadiyne, a useful, but explosive chemical. 18 is also a versatile intermediate offering, for example, the possibility of selective replacement of one of the TMS (trimethylsilyl) groups with electrophiles to give TMS-butadiynyl ketone 19 (Scheme VIII).
(CH3)3Si

CuCl.TMEDA, O2
C CH

(CH3)3Si

Si(CH3)3

acetone, 25-30 C, 2.5 h 17 18 RCOCl, AlCl3

R C O C C C C Si(CH3)3

19

SCHEME-VIII

-8-

II.2 CHIRAL BINAPHTHALENE OLIGOMERS

Starting from binaphthyl-acetylene 19 (prepared from the optically resolved 4,4'-dibromo-1,1'-bi-2naphthol derivative, discussed earlier, I.1), Chow and coworkers5,6 prepared several oligo-1,1'-bi-2naphthalene molecules through the crucial Cu-catalyzed acetylenic coupling reaction in chloroform (0.05M). It is noteworthy that oxidative coupling led to a mixture of oligomers rather than polymeric material (Scheme IX). The lower oligomers 21, 22 and 23 were separated by column chromatography as yellow fluorescent solids. The authors comment that higher oligomers were perhaps formed, but could not be isolated due to poor solubility. The chiroptical properties and redox behaviour of the isolated oligomes were studied.

CuCl.TMEDA (10 mol%)

H H OCH3 H H OCH3

CH3O

O2, CHCl3, 25oC, 1h

CH3O

(R)-(+)-20 n=2, (R,R)-(+)-21 (20%) n=3, (R,R,R)-(+)-22 (30%) n=4, (R,R,R,R)-(+)-23 (10%) SCHEME-IX

II.3 MACROCYCLIC RECEPTORS

In yet another example of acetylenic coupling demonstrated by Diederich and coworkers, the buta-1,3diynediyl-linked macrotricyclic cyclophane ()-25 (precursor to a synthetic steroid binding receptor) was synthesized using CuCl.TMEDA in a critical ring closure reaction in a remarkable 42% yield (Scheme X)16,17. It is interesting to note that Glaser-Hay macrocylization of cyclophane 24 furnished a single chiral (racemic) D2-symmetric macrotricyclic product which was established by chiral HPLC.

-9-

(CH2)4

EtN

OCH3

CH3O

NEt

(CH2)4

24

CH2Cl2, CuCl.TMEDA air, 20oC, 16 h

C2H5N O O NC2H5

(CH2)4 CH3O O O O OCH3 CH3O O OCH3

(CH2)4 (CH2)4 O

O C2H5N NC2H5

25 SCHEME-X

-10-

II.4 PORPHYRIN SYNTHESIS

Anderson's group has reported extensively on acetylene-bridged porphyrin oligomers and polymers constructed through Glaser-Hay coupling. Thus, butadiyne-linked porphyrin dimers were prepared through sequential Glaser-Hay coupling.18 Glaser-Hay coupling of a meso-diethynyl zinc porphyrin was reported to give the first soluble conjugated porphyrin polymer, extremely soluble in chlorinated solvents in the presence of coordinating ligands such as pyridine.19 Anderson et al prepared a series of conjugated porphyrin oligomers by adopting a stepwise approach from a silyl-protected monomer using just two reactions: (i) protodesilylation with tetra-nbutylammonium fluoride and (ii) Glaser-Hay coupling with CuCl.TMEDA in CH2Cl2 under air.20 Wilson and Anderson21 recently reported the synthesis of a conjugated tetrapyridylporphyrin dimer 27 in 91% yield using Glaser-Hay coupling methodology (Scheme VII).

N R C C N Zn

N C C H N

CuCl.TMEDA

N R C C N Zn

N C C N

CH2Cl2 , O2

N
26 [R = Si(n-C6H13)]

N
27

SCHEME-XI

Recently, Maya et al reported the synthesis of exclusively linearly conjugated phthalocyanine dimers through homo-coupling reaction of the ethynyl precursors under Glaser-Hay conditions in the presence of molecular sieves.22

-11-

SUMMARY
CuCl(OH).TMEDA is an efficient catalyst for achieving oxidative biaryl coupling reactions. The salient features are: ! ! ! ! The reagent is fairly stable, easily handled and soluble in common organic solvents. The reaction conditions are mild and many functional groups are tolerated. The requirement of catalyst can be as low as 1% (mol) and yields are generally high. The reaction is amenable for scale-up.

CONCLUSION
CuCl(OH).TMEDA is a useful addition to the existing choice of reagents which effect catalytic oxidative coupling reactions. There is ample scope for enlarging the utility domain of this reagent.

REFERENCES AND NOTES

1 Noji, M.; Nakajima, M ; Koga K., Tetrahedron Lett., 35, 7983 (1994). 2 TMEDA = N,N,N',N'-Tetramethylethylenediamine 3 Nakajima, M.; Miyoshi, I.; Kanayama, K ; Hashimoto, S.; Noji, M.; Koga K., J. Org. Chem., 64, 2264 (1999). 4 This may explain the two different CAS registry numbers found in the literature, viz. [30698-64-7] for di--hydroxo-bis[(N,N,N',N'-)(tetramethylethylenediamine)copper(II)] chloride and [160492-47-7] for chloro(hydroxyl)(tetramethylethylenediamine)copper (II) both of which apparently refer to the same material. We may also note here that the copper is generally formulated as Cu(I) while in some publications it is mentioned as Cu(II). 5 Ng, M-K.; Chow, H-F.; Chan, T-L.; Mak, T.C.W., Tetrahedron Lett., 37, 2979 (1996). 6 Chow,H-F.; Ng, M-K, Tetrahedron: Asymmetry, 7, 2251 (1996). 7 Lipshutz, B.H.; James, B., Vance, S.; I. Carrico, Tetrahedron Lett., 38, 753 (1997) 8 Lipshutz, B.H.; Young-Jun Shin, Y-J., Tetrahedron Lett., 39, 7017 (1998). 9 Jaffres, P-A.; Bar, N.;Villemin, D., J. Chem. Soc., Perkin Trans. 1, 2083 (1998). 10 Collman, J.P.; Zhong, M., Org. Lett., 2, 1233 (2000). 11 Doi, S.; Nakanishi, S.; Tatsuta, K., Jpn. Kokai Tokkyo Koho JP 11 180,972 [99 180,972] (Cl, C07D311/92), 6 Jul 1999. Appl. 1997/352,991, 22 Dec 1997; 18 pp; Chemical Abstracts, 131: 73557v (1999). 12 Nakajima, M.; Kanayama, K.; Miyoshi, I.; Hashimoto, S., Tetrahedron Lett., 36, 9519 (1995) 13 Nakajima, M., Yakugaku Zasshi, 120, 68 (2000) ; Chemical Abstracts, 132: 194141j (2000). 14 Nakajima, M.; Hashimoto, S.; Noji, M.; Koga, K., Chem. Pharm. Bull, 46, 1814 (1998). 15 Jones G.E.; Kendrick D.A.; Holmes A.B., Organic Synthesis, 65, 52 (1987). 16 Peterson B.R.; Mordasini-Denti T.; Diederich F., Chem. Biol., 2, 139 (1995). 17 Furer A.; Marti T.; Diederich F.; Kunzer H.; Brehm M., Helv. Chim. Acta, 82, 1843 (1999).

-12-

18 Anderson H.L.; Inorg. Chem., 33, 972 (1994). 19 Anderson H.L.; Martin S.J.; Bradley D.D.C., Angew. Chem. Int. Ed. Engl., 33, 655 (1994). 20 Taylor P.N.; Huuskonen J.; Rumbles G.; Aplin R.T.; Williams E.; Anderson H.L., Chem. Commun., 909 (1998). 21 Wilson G.S.; Anderson H.L., Chem. Commun., 1539 (1999). 22 Maya E.M.; Vazquez P.; Torres T.; Gobbi L.; Diederich F.; Pyo S,; Echegoyen L., J. Org. Chem., 65, 823 (2000).

ACKNOWLEDGEMENT
The authors thank Prof. K.K. Balasubramanian (Department of Chemistry, Indian Institute of Technology, Madras) for useful suggestions and constant encouragement.

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Di-Micron-hydroxo-bis-[N,N,N',N'-tetramethyl-ethylenediamine)copper(II)]chloride

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