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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 systemswhich 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 oroxygen).

The catalyst is formulated as CuCl(OH).TMEDA and in some references a dimeric structure 1 is also

depicted.4

1

N

N

H3C CH3

H3C CH3

Cu

O

O

Cu

N

N

CH3H3C

CH3H3C

H

H

++

2 Cl -

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This 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-bridgedchiral 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.

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

Substrate R1 R2 Oxidant Time Temp. Yield

(naphthol) (h) (oC) (%)

2a H H O2 8.5 0 90

2b H CH3 O2 1 RT 92

2c OCH3 H O2 1.5 RT 96

2d H COOCH3 O2 96 RT 99

OH

OHOH

R2

R1

R2

R1

R2

R1

CuCl(OH).TMEDA (1 mol%)

O2 , CH2Cl2

2 (a-e) 3 (a-e)

SCHEME- I

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Nakajima 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 oxidativecoupling 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 underthese conditions.

Ng et al5,6

took advantage of CuCl(OH).TMEDA to synthesize 4,4'-dibromo-1,1'-bi-2-naphthol5 throughthe oxidative coupling of 4-bromo-2-naphthol 4 in 90% yield (Scheme II). The 4,4'-dibromo-1,1'-bi-2-

naphthol 5 thus prepared was resolved, converted to chiral oligo-1,1'-bi-2-naphthalene molecules through

Glaser-Hay acetylenic coupling (see further, II.2.).

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 adiastereomeric excess (de) of 90% (Scheme III).

OH

OHOH

CuCl(OH)-TMEDA (10 mol %)

O2, CH2Cl2, 25oC, 4 h

4 5

SCHEME-II

Br

Br

Br

OH

OH

R1

O

R1

O

O

O

OH

OH

R1

O

R1

O

O

O

CuCl(OH).TMEDA(8 mol%)

O2, CH2Cl2

7 (R1=H)6

SCHEME- III

R

[12:1R,R,R:R,R,S]

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In 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 workingconcentration 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 chiralligand) 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 beta-

naphthols.

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

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 instoichiometric 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 servesadmirably 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 6-

hydroxynaphthylphosphonate 10 using 5% CuCl(OH).TMEDA to give 11 (Scheme V).9

In spite of theuse 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 bereduced due to complexation with the phosphonate substituent.

OH

OHOH

CuCl(OH).TMEDA (1 mol%)

8 9

SCHEME-IV

Br

Br

Br

air, CH2Cl2, 24 h

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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 thecross-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 correspondingN-arylbenzimidazoles. The authors speculated on the mechanism, implicating a Cu(III) species.

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)2and a tertiary amine (triethylamine or pyridine).

B(OH)2

R1 NNH

[Cu(OH).TMEDA]2Cl2

O2, CH2Cl2,

N

R1

N

R2

12 14

R2

SCHEME-VI

RT, overnight

13

OH

OHOH

CuCl(OH).TMEDA (5 mol%)

air, CH2Cl2, 4 days

10 11

SCHEME-V

(RO)2P

O(RO)2P

O

(RO)2P

O

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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[2,3-

c]pyran)-10,10'-diol derivatives17 havingN-methyl-D-aspartic acid antagonist activity. The crucial step

is the biaryl coupling catalyzed by the Cu-amine complex in high yields. Interestingly, coupling ofpyranonaphthol 15 initially leads to the 10,10'-dione derivative 16 which is subsequently aromatized by

base-catalyzed enolization giving the 10,10'-diol17 (Scheme VII).11

OHCH3O

CH3O

O

CH3

OR

OCH3O

CH3O

O

CH3

OR

OCH3O

CH3O

O

CH3

OR

OHCH3O

CH3O

O

CH3

OR

OHCH3O

CH3O

O

CH3

OR

"Cu(II).TMEDA complexHCl"

O2, CH2Cl2, 1.5 h, 95.2%

1) 2 Naq. NaOH

(R = -CH2OCH3)

SCHEME-VII

16

17

2) 1 Naq HCl

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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 asymmetricaerobic 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 themixture 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 glevel.

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 1,4-

bis(trimethylsilyl)buta-1,3-diyne 18, from trimethylsilylacetylene 17. We may note that diyne 18 is aconvenient 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 C CH (CH3)3Si C C Si(CH3)3CC

RCOCl,AlCl3

C C Si(CH3)3CCC

SCHEME-VIII

acetone, 25-30o

C, 2.5 h17 18

19O

CuCl.TMEDA, O2

R

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II.2 CHIRAL BINAPHTHALENE OLIGOMERS

Starting from binaphthyl-acetylene 19 (prepared from the optically resolved 4,4'-dibromo-1,1'-bi-2-

naphthol derivative, discussed earlier, I.1), Chow and coworkers5,6

prepared several oligo-1,1'-bi-2-naphthalene 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 oligomers21,22 and 23 were separated by column chromatography asyellow 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.

II.3 MACROCYCLIC RECEPTORS

In yet another example of acetylenic coupling demonstrated by Diederich and coworkers, the buta-1,3-

diynediyl-linked macrotricyclic cyclophane ()-25(precursor to a synthetic steroid binding receptor) wassynthesized 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 singlechiral (racemic) D2-symmetric macrotricyclic product which was established by chiral HPLC.

OCH3CH3O

H H

CuCl.TMEDA(10 mol%)

O2

, CHCl3

,25oC, 1h

(R)-(+)-20

SCHEME-IX

n=2, (R,R)-(+)-21(20%)

n

n=3, (R,R,R)-(+)-22(30%)

n=4, (R,R,R,R)-(+)-23(10%)

OCH3CH3O

H H

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H

O(CH2)4

(CH2)4

O

C2H5N

24

NC2H5

25

CH2Cl2, CuCl.TMEDA

O

CH3O

O

(CH2)4

OOCH3

(CH2)4

O

air, 20oC, 16 h

SCHEME-X

NC2H5

O

CH3OOCH3

O

O

O

(CH2)4

C2H5N

O

H

OCH3NEt

CH3O

O

EtN

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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 ameso-diethynyl zinc porphyrin was reported to give the first soluble conjugatedporphyrin 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 approachfrom a silyl-protected monomer using just two reactions: (i) protodesilylation with tetra-n-

butylammonium fluoride and (ii) Glaser-Hay coupling with CuCl.TMEDA in CH2Cl2under 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).

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

N

N N

N

N N

Zn C C HCCR

N

N N

N

N N

Zn C CCCR

[R = Si(n-C6H13)]26 27

SCHEME-XI

2

CH2Cl2 , O2

CuCl.TMEDA

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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 oxidativecoupling 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'-Tetramethylethylenediamine3 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] forchloro(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).

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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 ofTechnology, Madras) for useful suggestions and constant encouragement.

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