Cyclobutenediones as precursors to quinones and cyclopentenones

T~~~rul,edr,,n Vol 45, No Prmted III Great Bntam

004&4020/89 $3.00 + .OO :cj 1989 Pcrgamon Press plc

10. pp. 3053 to 3060, 1989

Cyclobutenediones

as Precursors

to Quinones

and Cyclopentenones

by Lanny S. Liebeskindl Department of Chemistry, Emory University Atlanta, Georgia 30322 (Rrceired in Belgium 30 Augusf 1988) Introduction For many years, cyclobutenediones

1 and benzocyclobutenediones

2 were studied as theoreti-

cally interesting molecules without any obvious potential for use in the intentional design of complex organic molecules.2 Within the last 10 years this situation has begun to change. A variety of simple, yet powerful, methods have been developed that allow the conversion of cyclobutenediones benzocyclobutenediones

and

into highly functionalized quinones and cyclopentenone derivatives (Scheme

1). This article will highlight the synthetic potential of some of these recent reactions, and demonstrate that substituted cyclobutenediones

R’

are readily available starting materials.

’

I ML, Rx

0 A

cat. Pd+2

1. A

2. “0”

/\\

Z = CH&I, N&H, 0, S, NR

Discussion Although Staab and Ipaktschi showed that benzocyclobutenedione

and maleic anhydride upon

irradiation would undergo a Diels-Alder reaction to afford the adduct 3 in good yield (eq. 1). attempts by these workers and others to extend this chemistry to other oletinic and acetylenic substrates led to very low yields of Diels-Alder adducts or gave alternative products.3 This interesting reaction is presumed to proceed via a bisketene 4 generated by photolysis of the benzocyclobutenedione. 3053

3054

L. S. LIEBESKIND

ml

+4

A-

&

(eq. 1) OH

o

The concept of quinone synthesis by the [4 + 21 reaction of a bisketene with an alkyne would represent a very powerful synthetic entry to substituted quinones, if a general and high-yielding metbod could be found to join the reactants or their synthetic equivalents (eq. 2). The reaction of transition metal complexes of general structure 5 with alkynes by an insertion-elimination studied in our laboratories as a synthetic equivalent of the bisketene+lkyne

sequence was

approach to quinone syn-

thesis (eq. 3).4 Although a variety of different metallic species were investigated, cobalt complexes proved most useful for the synthesis of quinones. These compounds were readily available by the reaction of the low-valent cobalt reagent, CICo(PPh3)3, with either benzocyclobutenediones butenediones to form phfhaloylcobalt

4 and 5). Subsequent treatment of the bistriphenylphosphine

species with one equivalent of dimethyl-

glyoxime (dmg) in pyridine provided a high yield route to the dimethylglyoxime From the phrhafoylcobalt

or cyclo-

and maleoylcobalt complexes such as 6 and 7, respectively (eqn!

complex 8, naphthoquinones

variants 8 and 9.

such as those shown in Table I were prepared

in high isolated yields simply by heating to 8O’C in the presence of an alkyne and a mild Lewis acid such as CoCl2*6H2O. Similar reactions in the benzoquinone series were explored by investigating the reaction of maleoylcobalt complex 9 with unsymmetrical alkynes, and this chemistry demonstrated the high benzoquinone regioselectivity obtainable on reaction of an unsyrnmenical aIkyne with an unsymmetrical maleoylcobah complex (Table 2). In order to maximize the regioselecdvity in the benzo quinone synthesis most reactions were performed at room temperature in dichloroethane.

Effective re-

action rates were only achieved at room temperature in the presence of a strong Lewis acid such as SnC4 or Zn(OS@CF&

+

Q-

R4

(eq. 0

2)

Cyclobutenediones

CICO(PP4)~ 84%

Table 1. Alkynes.

Synthesis

3055

as precursors

Me

(es. 5)

of Some Naphthoquinones

From

Phthaloylcobalt

Complex

8 and

0 R’RR2 dichloroethane I 80°C CoCI,*6H,O

Table

R’

R2

n-BU

H

Et

Et

86

Me

C@Et

99

Et

OEt

85

Me

t-Bu

12

Me

CHzN(COMe)Ph

70

Me

CHzCH=CMe2

94

2.

quinones

Regioselective

Synthesis

From Maleoylcobalt

isolated

of Some Unsymmetrically

Complex

yield

87

Substituted

Benzo-

9 and Alkynes.

RkR2 Me dichloroethane

/ rt

SnCll

2 R1

R2

n-Bu

H

SnCl&-t

65

10: 1

Me

COlEt

SnCl‘$Al

62

20

Et0

Me

notle&o”c

81

14: 1

(Z)-MeOCRCH

H

none/n

50

20

CH2SiMe2-t-Bu

Me

SnCldrt

51

20

(CH2)2N(Bn)COC@Et

H

SnCl&t

65

7:l

Lewis

acidltemp

isolated

yield

ratio of regioisome

:1 :1 :1

With the development of a method of benxoquinone synthesis from metal complexes of general structure 5, the need for a simple and efftcient mute to substituted cyclobutenediones,

the organic

precursors to maleoyhnetal complexes, became apparent. Our studies of cyclobutenedione

synthesis

culminated recently in a very simple preparation of generally substituted cyclobutenediones

starting

from commercially available squaric acid.5 The synthetic sequences and results ate depicted in Tables 3 and 4. Basically, substituted cyclobutenediones

are available by treating diisopropylsquarate

10, a

crystalline ester of squaric acid, with organolithium nucleophiles followed by processing with acid. Addition of one organolithium

nucleophile generates the 1,2-adducts 11 and acid treatment provides a

route to the sernisquaric acid derivatives 12 shown in Table 3. Standard acid catalyzed hydrolysis and

L. S. LIEBESKIND

3056 reesterification

allows the isopropyl group of 12 to be replaced with other alkoxy substitutents.

Differentially disubstituted cyclobutenediones

are available by the sequential addition of two different

organolithium reagents to diisopmpylsquarate

as shown in Table 4. Addition of either LiAl(O+Bu)3E

or MeLi fo diisopropylsquarate

gives an isolable Qadduct

that is protected as the t-butyldimethylsilyl

ether 13 in Table 4. A second organolithium reagent can be added and after treatment of the intermediate double adducts 14 with acid, the disubstituted cyclobutenediones 15 arc isolated. Table 3.

Addition

i-Pr

I i-Pr x

of Organolithium

Reagents

to Diisopropyl

1) RLi I -78=C I THP

i-Pr

2) Hz0 quench,

i-Pr

-78%

12N HCl CH,Cl,

14

0 i-Pr

R

I.I

z

!Liel!lllm

B

Yidlufm

a

H

a9

65

b

hk

97

92

C

n-Bu

80

88

d

t-Bu

a3

95

e

Ph

93

89

f

2-thienyl

98

96

g h

CkCPh

84

98

CkCBu

82

i

c=cl-Ms

j Table

squarate.

4-(C&jC’CTMS) 4.

Synthesis

88

of Differentially

i-Pr

93 90

3,4-Disubstituted-3-Cyclobutene-1,2-diones. H

i-Pr

I

i-Pr

88

70 (22% CXH)

i-Pr

%

g:

-

TBDMS

B

RZ

I

R’

L5

U

IL2

comDound

Ii1

a

H

ivk

81

88

b

H

n-Bu

80

94

C

H

t-Bu

a5

90

d

H

2-thienyl

96

90

e

hk

M?

96

f

M

n-Bu

91 ___

g h

kk

t-Bu

___

96

Mc

Ph

___

78

Yisldldm

The ready availability of numerous cyclobutenediones other synthetic applications of these highly functional&d

79

opened the way for the development of

starting materials. During the course of a

study of the reactions of 2,3dimethyl-4-hydroxy-4-phenylcyclobut-2-enone, of PhLi to 3,4-dimethylcyclobut-3-ene-1,2dione,

!lieldl.5czd

prepared by the addition

a simple synthesis of ring-fused quinones was

uncovered.6 After heating to 160°C in xylene and exposing to air, the 4-hydroxy+phenylcyclobutenone was converted into 2.3~dimethyl-l&naphthoquinone out to be very general, 4-hydroxycyclobutenones

in 87% yield (eq. 6). This reaction turned

bearing an unsaturated substiment af the 4-position rearranged on heating followed by oxidation to give ring-fused quinones. Some typical examples are

Cyclobutenediones

as precursors

3057

shown in equations 7 - 10. The reaction is presumed to proceed via a vinylketene intermediate (Scheme 2).

87%

yield

(es. 10)

‘SOZPh

regioisomer

62% ratio:

13

:1

regioisomer

86% ratio:

heat OH

1. tautomerize

2. oxidize OH

13 : 1

3058

L. S.

LIEBESKIND

During the course of his study of unsaturated ketenes, Moore explored the thermolysis of 4alkynyl-4-hydroxycyclobutenones

and discovered a novel rearrangement leading to either benzoquin-

ones or alkylidene cyclopentenediones

(eq. 1 1).7 ‘Ihe outcome of the reaction was dependent on the

alkyne substitutent R. An alternative and more general route to alkylidene cyclopentenediones achieved when the 4-alkynyla-hydroxycyclobutenones

was

were exposed to a catalytic amount of Pd(+2)

(eq. 12).s This palladium induced ring expansion provides a general route to alkylidene cyclopentenediones and related molecules with exceptional control over the stereochemisny of the newly formed exocyclic double bond The reaction is presumed to proceed via a vinylpalladium intermediate 16 that either suffers protonation or undergoes reaction with substrates added to the reaction mixture. Representative examples are shown in equations 13 - 15. 0

heat

R

::*

t

zvIeiMe;

IvIvII?JRMes

3

(eq.

11)

ii 0

45% / 12

(es.

13)

(eq.

14)

(es.

15)

:1

Pd(OCOCF,) BU

/,,Br

s

73% I >20

My+

: 1 0

BU

Pd(OCOCF,),

”

NBS 77% I 13 : 1

r

It also proved feasible to perform the palladium catalyzed rearrangement with benzo analogs of the cyclobutenones.

Benzocyclobutenedione

hydroxybenzocyclobutenone

in 83% yield

reacted with 1-lithiol-hexyne

to give 2-(1-hexynyl)-2-

Upon treatment with 5% Pd(OCOCF3)2 in metbylene

chloride at rt, the anticipated rearran gement to the 5-membered ring occurred and provided the alkylidene indandione in what appeared to be a high yield (eq. 16). However, the alkyldene indanedione was not stable to chromatography

nor to distillation. The instability of the alkylidene indanedione was

circumvented by preparing a monoketal of bcnzocyclobutenedione.

Reaction with lithioalkynes pro

vided the alkyne adducts and treatment with catalytic Pd(OCOCW2

in methylene chloride at R induced

the ring expansion and gave monoketals of alkylidene indandiones in high yield and with excellent exocyclic double bond stereoselectivity (Table 5).

Cyclobutenediones Equation

3059

as precursors 16

unstable

Table

5.

butenone

Palladium

Catalyzed

Ring Expansion

to chromatography

of Z-Alkynyl-Z-hydroxybenzocyclo-

Monoketals. cat. Pd(OCOCF,),

LiCECR

yield

R

yield

conditions 12h

isomer

91

ratio

36:l

n-CqHg

92

2.5% Pd(OCOCF3)2,

n-C&13

81

2.5% Pd(OCOCF3)2,24h

51

26:l

c-C6Hl I SiMe3

91

2.5% Pd(OCOCF3)2,

IOh

75

>20: 1

84

2.5% Pd(OCOCF3)2,

12h

56

2O:l

Ph

92

2.5% Pd(OCOCF3)2,

12h

89

2O:l

CHzOCH3

90

2.5% Pd(OCOCF3)2,

12h

84

>20: 1

CH(OTBDMS)CHs

9-l

5.0% Pd(OCOCF$z

10h

66

18:l

(CH2)20TEJDMS

74

5.0% Pd(OCOCF3)2,

12h

75

22:l

The mild conditions of the palladium induced ring expansion of alkynylcyclobutenol

deriva.

tives has allowed a number of highly functionalized compounds to be prepared. Two of the more elaborate transformations

we have conducted to date are shown in equations 17 and 18. Equation

17

Equation

18

H BDMS

Conclusions Although fairly strained and reactive, a variety of cyclobutenediones

and benzocyclobutene-

diones can easily be prepared and manipulated and thus are valuable starting materials for the synthesis of highly functionalized organics such as quinones and cyclopentenones. routes to variously substituted cyclobutenediones

With reasonable preparative

now established, additional uses of these reactive

small ring compounds in synthesis can be anticipated.

3060

L. S.

LIEBESKIND

Acknowledgments This investigation was supported by Grants No. CA 40157 and CA44404 awarded by the National Cancer Institute, DHHS. The dedication and ski&d assistance of the coworkers listed in the references is gratefully acknowledged.

1

2

3

Camille and Henry Dreyfus Teacher Scholar, 19861991. (a) West, R. “Oxocarbons”; Academic Press: New York, 1980; (b) Schmidt, A. H.; Reid, W. &Q&&

1978, 1; (c) Knorr, H.; Ried, W. &.l&&

&a&&s

1978, 869.

(a) Staab, H. A.; Ipaktschi, J. m&, Lowe, L&g.&&

1977,42,

1968,101,

1978, 649; (d) Schmidt, Ried, W.

1457-1472; (b) Jung, M. E.; J. A.

2371.

(a) Liebeskind, L. S.; Baysdon, S. L.; South, M. S.; Blount, J. F. J.., 1980,202,

C73; (b) Liebeskind, L. S.; Baysdon, S. L.; South, M. S. J.

,%x.,1980,

102.7397;

(c) Baysdon. S. L.; Liebeskind, L. S. m.

771; (d) South, M. S.; Liebeskind, L. S. J.., Liebeskind,

1982, I,

1984, J&4181;

(e)

L. S.; Leeds, J. P.; Baysdon, S. L.; Iyer, S. L Am. Cbem..,

6451; (t) Liebeskind, L. S.; Jewel], C. F., Jr. J.., Jewell, C. F., Jr.; Liebeskind, L. S.; Williamson,

1984, 106,

1985,285,305; M. J..,

(g)

1985,107,6715;

(h) Liebeskind, L. .S.; Baysdon, S. L.; South, M. S.; Iyer, S.; Leeds, J. P. Tetrahedron

.

n,

.

1985.41.5839;

R.; Goedken, V. m, Chem., 5

(i) Liebeskind, L. S.; Baysdon, S. L.; Chidambamm, 1986,5,

1086; (i) Iyer, S.; Liebeskind, L. S. 3.

1987, JO9, 2759.

Liebeskind,

L. S.; Fengl, R. W.; Wirtz, K. R.; Shawe, T. T. L-w,

2482. A similar synthetic approach to substituted cyclobutencdiones

1988.53, was simultaneously

disclosed by Moore and coworkers: Reed, M. W.; Pollan, D. J.; Perri, S. T.; Foland, L. D.; Moore, H. W. L&&JJ,L, 6

1988,53,

2477-2482.

Liebeskind, L. S.; Iyer, S.; Jewell, C. F., Jr., J.., was simultaneously

1986,51,

3065. This reaction

discovered and subsequently developed by H. Moore and coworkers of

the University of California at Irvine: (a) Perri, S. T.; Foland, L. D.; Decker, 0. H. W.; Moore, H. W. L & h

m.,

1987,52,

28,4507-4510

QIQIL, 1986,51, 3491-3492;

3067-3068; (b) Moore, H. W.; Reed, M. W. L

(c) Peni, S, T.; Moore, H. W. w

(c) Moore, H. W.; Peni, S. T. LQrg.m,

related chemistry see: Moore, H. W.; Decker, 0. H. W. m&x,, 7

u.,

1988,53,996-1003.

1987, For

1986,86,821-830.

(a) Karlsson, J. 0.; Nguyen, N. V.; Foland, L. D.; Moore, H. W. LAm,~Ss&, 1985,107, m,

3392; (b) Perri, S. T.; Foland, L. D.; Decker, 0. H. W.; Moore, H. W. L&g.

1986.51,

3067; (c) Decker, 0. H. W.; Moore, H. W. L&S&m_,

1987.52,

1174. 8

(a) Liebeskind, L. S.; Mitchell, D. M.; Foster, B. S. ,I. Am. Chem. Seq. 1987, 109, 7908; (b) Liebeskind, L. S.; Chidambaram, a,

1988, 60, 2734.

R.; Mitchell, D. M.; Foster, B. S. &ZJJXI

Applied