Carbon Nucleophiles with Alkenes and Alkynes

3.2 Carbon Nucleophiles with Alkenes and Alkynes LOUIS s. HEGEDUS Colorado State University, Fort Collins, CO, USA 3.2.1

INTRODUCTION

571

3.2.2 ALKYLATION OF MONOALKENES

571

3.2.3 ALKYLATION OF ALKADIENES

580

3.2.4 ALKYLATION OF ALKYNES

582

3.2.5 REFERENCES

583

3.2.1 INTRODUCTION The same transition metal systems which activate alkenes, alkadienes and alkynes to undergo nucleophilic attack by heteroatom nucleophiles also promote the reaction of carbon nucleophiles with these unsaturated compounds, and most of the chemistry in Scheme 1 in Section 3.1.2 of this volume is also applicable in these systems. However two additional problems which seriously limit the synthetic utility of these reactions are encountered with carbon nucleophiles. Most carbanions are strong reducing agents, while many electrophilic metals such as palladium(II) are readily reduced. Thus, oxidative coupling of the carbanion, with concomitant reduction of the metal, is often encountered when carbon nucleophiles are studied. In addition, catalytic cycles invariably require reoxidation of the metal used to activate the alkene [usually palladium(II)]. Since carbanions are more readily oxidized than are the metals used, catalysis of alkene, diene and alkyne alkylation has rarely been achieved. Thus, virtually all of the reactions discussed below require stoichiometric quantities of the transition metal, and are practical only when the ease of the transformation or the value of the product overcomes the inherent cost of using large amounts of often expensive transition metals.

3.2.2 ALKYLATION OF MONOALKENES Terminal monoalkenes were alkylated by stabilized carbanions (pKa ~ 10-18) in the presence of 1 equiv. of palladium chloride and 2 equiv. of triethylamine, at low temperatures (Scheme 1).1 The resulting unstable
571

572

Polar Additions to Alkenes and Alkynes

RI

']

+

PdCI2(MeCNh

-78°C

THF

70-90%

path b, >-20 °C

70-90%

-PdH

pathc, I

~eOH

Rl"(R

2

50-80%

C02Me R 1 =H, Me, Et, NHAc, Ph, BuD; R2 =NaC(Me)(C02Et)2' NaCH(C02Me)2' LiCHPh(OMe), LiCH(Ph)(C02Et), NaC(NHAc)(C02Et)2 42%

Scheme 1

stituted alkene terminus) is consistent with attack by the nucleophile without prior coordination (see below). Because it requires stoichiometric amounts of expensive palladium(II) salts, this process has found little use in the synthesis of more complex organic compounds. Two exceptions are seen in equation (1)3 and Scheme 2. 4

o

i, 1 equiv. PdCI 2(MeCNh

ii, 2 equiv. Et3N

o

Q--R

(1)

55-78% Ac I

R-= Me02C~C02Me, Me02C~C02Me, Me02C~C02Me, -o~Nyo NHCHO

NHAc

Me

'L-.J

The above system failed entirely when nonstabilized carbanions such as ketone or ester enolates or Grignard reagents were used as carbon nucleophiles, leading to reductive coupling of the anions rather than alkylation of the alkene. However, the fortuitous observation that the addition of HMPA to the reaction mixture prior to addition of the carbanion prevented this side reaction 1 extended the range of useful carbanions substantially to include ketone and ester enolates, oxazoline anions, protected cyanohydrin anions, nitrile-stabilized anions 5 and even phenyllithium (Scheme 3).5 With these nonstabilized carbanions, attack occurred almost exclusively at the less-substituted terminus of the alkene, regioselectivity opposite that observed with stabilized carbanions. This regioselectivity

Carbon Nucleophiles with Alkenes and Alkynes

o

+

0

~O/'-..Ph

+

573 i, 2 equiv. NEt3 ii,CO,MeOH

Scheme 2

'1

R1

+ PdClz + Et 3N + HMPA -

~-elimination

60-80%

o

A -

Ph~CN

-

""'CN,

~CN

Scheme 3

is that commonly observed in the insertion of alkenes into metal-carbon a-bonds (Chapter 4.3, Volume 4), and implies a change in mechanism wherein direct alkylation of the metal followed by insertion of the alkene occurred rather than external nucleophilic attack of the carbanion on the metal-bound alkene. Again, the requirement of stoichiometric quantities of palladium salts has limited the synthetic applications of this chemistry. In contrast, the closely related palladium acetate-promoted intramolecular alkylation of alkenes by trimethylsilyl enol ethers (Scheme 4)6,7 has been used to synthesize a large number of bridged carbocyclic systems (Table 1). In principle, this process should be capable of being made catalytic in palladium(II), since silyl enol ethers are stable to a range of oxidants used to carry the PdQ ~ PdII redox chemistry required for catalysis. In practice, catalytically efficient conditions have not yet been developed, and the reaction is usually carried out using a full equivalent of palladium(II) acetate. This chemistry has been used in the synthesis of quadrone (equation 2). 8 With the more electrophilic palladium(II) trifluoroacetate, methyl enol ethers underwent this cyclization process (equation 3).9 Chelating alkenes such as allylic 10 and homoallylic 11 amines and sulfides underwent alkylation by a range of stabilized carbanions to produce stable a-alkylpalladium(II) complexes. In these cases the regioselectivity was strictly governed by the inherent stability of a five (versus four or six) membered chelate a-alkylpalladium complex, with allylic systems (Scheme 5) being alkylated at the more sub-

574

Polar Additions to Alkenes and Alkynes

1 equiv. Pd(OAch MeCN

""

"",,,"';YPd

0

-PdH

"""'" "",

80%

Scheme 4

i, Pd(OAch --~.

ii,KOH 58%

~

Quadrone

(2)

1 equiv. Pd(TFAh

(3) 8 cases, ::::50% yield

600/0

stituted position and homoallylic systems at the less substituted terminus (Scheme 6). Reduction of these complexes produced the saturated hydrocarbons, while treatment with conjugated enones resulted in insertion of the alkene.

~L

R'C CI

+

/

L

81-94%

R Y = CN, C02Me, COMe

Sf

Pd ......

2

Ly L

o L = NMez, SCHMez; r

0

= -CH(COzEth, -CH(COPhh,M O M e ' Scheme 5

00

Ph~

0 , aCOzEt

cJ:o j

OSiR3

"'OSiMe3

#

~

"'OSiMe3

#

~

ct::

P'

53%

68%

98%

67%

72%

Table 1

O?

~

\\\\\\\\\\\~._------

a

\\\\\\\\ \\\~0-1

x~

U',,"" 'OSiMe3

#

'OSiMe3

OSiMe3

~OSiR3 C02Et

~

~

#

P'

46%

42%

65%

85%

60%

Palladium(II) Acetate Assisted Cyclization of Trimethylsilylenol Ethers

\\\\\\\~

C02Et

Mo

o

~.

~

U-: U

\\\\

a

o

\\\\\\\\ \\\~-0-1

~

Ul

Ul

~

~

~

~

~

~

~

;:s

~

~

~

§:

~

~

~

~

=:

~

~

~

~

;:s

~ ti~

576

Polar Additions to Alkenes and Alkynes

L = NMe2, SCHMe2;

00

R-= E t O V O E t '

00

00

00

Ph~Ph ' ~OMe' Ph~

•

Scheme 6

In contrast to the above stoichiometric palladium-assisted reactions, palladium(II) chloride efficiently catalyzed a variety of Cope rearrangements (Scheme 7 and Table 2).12 The mechanism of this process is not known, but is likely to involve 'cyclization-induced catalysis' as noted in Section 3.1.2.3 of this volume. This rearrangement has several important features. Successful catalysis required that C-2 or C-5 of the diene had an alkyl substituent present, perhaps to stabilize the developing positive charge at these positions during rearrangement. Alkyl substituents at both C-2 and C-5 suppressed the rearrangement, reflecting the steric inhibition of placing the bulky metal at a sterically hindered tertiary position. With chiral, optically active dienes, complete 1,4-transfer of chirality was observed, as was the case in the related palladium-catalyzed allylic transposition of allyl acetates discussed above (Section 3.1.2.3, this volume).

25°C, 24 h 87%

Ph

Ph~

+

~

Ph

93:7

Scheme 7

Cationic cyclopentadienyliron dicarbonyl (Fp) complexes of alkenes are generally reactive toward a wide range of nucleophiles, including carbanions, producing very stable cr-alkyliron complexes (Scheme 8).13,14 Again, attack at the more substituted alkene terminus predominated. These cr-alkyliron complexes required chemical removal of the iron to free the organic fragment, making catalytic processes impossible. As a consequence little use of these simpler systems in synthesis has resulted. However, a number of synthetically useful transformations involving alkoxyalkenes have been developed. a-Methylene lactones were produced by the reaction of cyclohexanone enolate with the Fp-a-ethoxyacrylate complex (Scheme 9)15 while ethoxyethylene was converted to the corresponding ')'-lactones (Scheme 10).16 Dimethoxyethylene-Fp complexes provided routes to efficiently dialkylate ethylene (Scheme 11).17 Using this methodology, a variety of furans were synthesized (Scheme 12).18 This chemistry was noteworthy in two respects. Firstly, all transformations were highly stereoselective, permitting the facile synthesis of complex molecules having multiple stereogenic centers. Secondly, the oxidative cleavage of the cr-alkyliron complexes led to nucleophilic displacement of the oxidized iron fragment, rather than the normal insertion of CO to form acyl complexes. Thus furans, rather than the expected lactones, were formed.

Table 2

RC R~

(3R)-(5E)

Ph~

86%

90%

(2Z)-(5R)

Me02C,§'

R = C02Et, COMe, CN, C02H

64-94%

Palladium(II)-catalyzed Cope Rearrangements

'~H (2E)-(58)

7:3

k

P

+

~

-...J -...J

Ul

~

~ ;:s

).

~

~

~

~ ;:s

~

§:

~

t.oo.2

~

~

=:

~

~

~

~

;:s

~

~

~

(J

578

Polar Additions to Alkenes and Alkynes +

+

Nuc-

o

0

0

0

~OMe' MeO~OMe'

6, 6 OLi

OLi

R = H, Me, Ph, CHO, CH 20Me

Scheme 8

6 OLi

+

[

~C02Et I

Fp

]

0X102Et

+ 81%

if1~2Et

H-

Fp

OEt

0 0

0 i,HBF4

OEt

~

Fp

= L- selectride, cis

~=

BH4 , trans

ii,Cl72%

Scheme 9

6 OLi

0

+ +

[

OEt

~

I

Fp

]

90%

HO

OEt

~ = = =

Fp

L-selectride

OEt

~Fp

0 HO Ce IV

0 Fp

63%

""H

OEt

Scheme 10

Cationic iron-alkene complexes also participate in an unusual 'cycloaddition' process, wherein electron-deficient alkenes are attacked by nucleophilic
579

Carbon Nucleophiles with Alkenes and Alkynes MeO \

I

OMe

o

+

Fp

1

Nuc 1

Nuc

HBF4

1

=Me2CuLi, BU2CuLi,

RO

~Nucl

RO

d

\

1

60-90%

OR

Fp

+

+

OR

Nuc 1

Fp

Q

! 1

Fp

i,Nuc 2 ii,NaI

i,Nuc 2 ii,NaI

::::30%

OLi

Nuc 2 = Me2CuLi, PhMgBr

Nuc 2

Nuc 1

Nuc 1

\==:=J

::::300/0

Nucl~

Nuc

2

Scheme 11

OLi

EtO

OEt

"==d

+

F1+ p

6

-78°C, THF 96%

rY 0

QE

i, L-selectride

~~pii,ceIV H :: OEt

1 diastereomer

i, L-selectride

o

Co)-FP+

H

('+-0\

~"'''OEt

H OLi

-78°C THF

1

6

DEt

55%

(X) 60% i, L-selectride ii,Ce lv

96%, 1 diastereomer 55%

Scheme 12

This chemistry has been used to synthesize cyclopentanoid derivatives used in the synthesis of sarkomycin and brefeldin A.22 Azulene derivatives were also synthesized using this chemistry (Scheme 14).23

580

Polar Additions to Alkenes and Alkynes

F~ p

+

_ _..... F

flR3

P~

70--90%

R

2

1R

R 1 = C02Et, C02Me, CN

R2 =CN, C02Me, C02Et

:0

~

<, ....../ ..' +/ '-""

Scheme 13

~~~'

~\

ru / ~

F~ p '--/

+

/

Fe(CO)3

Fe(CO)3

75%

-

(\ +

Fp

ii,Ce IV 48%

Scheme 14

3.2.3 ALKYLATION OF ALKADIENES 1,3-Dienes fonn very stable complexes with a variety of metal carbonyls, particularly Fe(CO)5, and the neutral 'T)4-diene metal carbonyl complexes are quite resistant to normal reactions of dienes (e.g. hydrogenation, Diels-Alder). However, they are subject to nucleophilic attack by a variety of nonstabilized carbanions. Treatment of'T)4-cyclohexadiene iron tricarbonyl with nonstabilized carbanions, followed by protonolysis of the resulting complex, produced isomeric mixtures of alkylated cyclohexenes (Scheme 15).24 With acyclic dienes, this alkylation was shown to be reversible, with kinetic alkylation occurring at an internal position of the complexed dienes but rearranging to the terminal position under thermodynamic conditions (Scheme 16).25 By trapping the kinetic product with an electrophile, overall 'carbo-

o

6+6+0 R

Fe(CO)!

48-80%

Scheme 15

R

R

581

Carbon Nucleophiles with Alkenes and Alkynes

acylation' was achieved (Schemes 17 and 18).26,27 With cyclic dienes, alkylation occurred from the face opposite the metal, and acylation from the same face as the metal to produce exclusively trans product. As expected, cationic diene complexes (as well as cationic dienyl complexes, see Chapter 3.4, of this

X~-Fe(COh ~

X

+

~

R-

=H, Me, OMe; R- =Ph2CH-,

Y

:X :x: +

+

R major (25°C)

major (-78°C)

CN

X\

Scheme 16

o

R",,~

Fe(CO)(

70-90%

• R,

'"

Fe(CO)3

y

~CN

CN E+ = CF3C02H, Mel, MeOTf, O 2; E ' = H, Me, OH, OEt

Scheme 17

(-Fe(COh +

R- ---- [R ue(COh] - ____

[R~O ] y

57-85% ~CN

CN

Scheme 18

volume) are considerably more reactive toward nucleophiles than are the corresponding neutral complexes. Using this feature, very efficient processes for stereocontrolled alkylation of cyclohexadiene (Scheme 19)28 and cycloheptadiene (Scheme 20)29 have been developed. They share many common features. A range of carbanions attacked, always from the face opposite the metal, producing a neutral ,.,,3allylmolybdenum complex. Further functionalization of the cyclohexadiene system was not studied. However in the cycloheptadiene series the initially formed ,.,,3-allyl complex was reconverted into a cationic diene complex, which could be alkylated again. Both alkyl groups entered from the face opposite the metal, giving cis-l,2- and -1,4-dialkyl systems in high yield and with high diastereoselectivity. The potential for further functionalization of the resulting ,.,,3- allyl systems is high, but has yet to be extensively explored.

582

Polar Additions to Alkenes and Alkynes

RIII'G~MO(COhCP 2---

80-90%

R'",O 11111

I

major

single diastereoisomer (S)

Scheme 19

major

C02Me

R~ = -Me, -CN,p-MeOC6H4-, - (

minor

S02Ph ,-(,

C02Me

C02Me

Scheme 20

3.2.4 ALKYLATION OF ALKYNES Although alkynes are highly reactive toward a wide range of transition metals, few instances of metalcatalyzed reactions of carbanions with alkynes are known. The most extensively developed system involves cationic iron complexes of internal alkynes. These complexes underwent alkylation by a range of carbanions to produce stable
@R I

I

OC"I

'-III

Fe C

L

C

+

Nuc-

@RceIVyOR ,.PerNUC -RO Nuc

-78°C 70-90%

OC

I

#

I

L

I

R

R'

Scheme 21

ROH

60-90%

,

R

Carbon Nucleophiles with Alkenes and Alkynes

583

trans, and also regioselective, with the nucleophile adding away from ester groups on the alkyne, and on the alkyne carbon bearing a phenyl group. Oxidation promoted CO insertion with retention of alkene geometry (in most cases) producing acyliron complexes which upon further oxidation cleaved to give a,f3unsaturated esters. At present, the process is stepwise, and the metal complex must be destroyed to free the organic ligand. More efficient systems await development.

3.2.5 REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30.

L. S. Hegedus, R. E. Williams, M. A. McGuire and T. Hayashi, J. Am. Chem. Soc., 1980,102,4973. L. S. Hegedus and W. H. Darlington, J. Am. Chem. Soc., 1980,102,4980. L. V. Dunkerton and A. J. Sermo, J. Org. Chem., 1982,47,2814. G. M. Wieber, L. S. Hegedus, B. Akermark and A. Kramer, J. Org. Chem., 1989,54,4649; J. Montgomery, G. M. Wieber and L. S. Hegedus, J. Am. Chem. Soc., 1990,112,6255. L. S. Hegedus and M. A. McGuire, Organometallics, 1982,1, 1175. A. S. Kende, B. Roth and P. J. Sanfillippo, J. Am. Chem. Soc., 1982, 104, 1784. A. S. Kende and D. J. Wustrow, Tetrahedron Lett., 1985,26, 5411. A. S. Kende, B. Roth, P. J. Sanfillippo and T. J. Blacklock, J. Am. Chem. Soc., 1982,104,5808. A. S. Kende, R. A. Battista and S. B. Sandoval, Tetrahedron Lett., 1984,25, 1341. R. A. Holton and R. A. Kjonaas, J. Am. Chem. Soc., 1977,99,4177. R. A. Holton and R. A. Kjonaas, J. Organomet. Chem., 1977, 142, C15. L. E. Overman, Angew. Chem., Int. Ed. Engl., 1984,23,579. P. Lennon, M. Madhavarso, A. Rosan and M. Rosenblum, J. Organomet. Chem., 1976, 108, 93. P. Lennon, A. Rosan and M. Rosenblum, J. Am. Chem. Soc., 1977,99,8426. T. C. Chang and M. Rosenblum, Tetrahedron Lett., 1983,24,695; Isr. J. Chem., 1984,24,99. T. C. Chang, T. S. Coolbaugh, B. M. Foxman, M. Rosenblum, N. Simms and C. Stockmann, Organometallics, 1987, 6, 2394. M. Marsi and M. Rosenblum, J. Am. Chem. Soc., 1984,106,7264. M. Rosenblum, B. M. Foxman and M. M. Turnbull, Heterocycles, 1987,25,419. T. S. Abraham, R. Baker, C. M. Exon and V. B. Rao, J. Chem. Soc., Perkin Trans. 1,1982,285. R. Baker, C. M. Exon, V. B. Rao and R. W. Turner, J. Chem. Soc., Perkin Trans. 1,1982,295. T. S. Abraham, R. Baker, C. M. Exon, V. B. Rao and R. W. Turner, J. Chem. Soc., Perkin Trans. 1, 1982, 301. R. Baker, R. B. Keen, M. D. Morris and R. W. Turner,J. Chem. Soc., Chem. Commun., 1984,987. N. Genco, D. F. Marten, S. Raghu and M. Rosenblum, J. Am. Chem. Soc., 1976,98, 848. M. F. Semmelhack and J. W. Herndon, Organometallics, 1983,2,363. M. F. Semmelhack and H. T. M. Lee, J. Am. Chem. Soc., 1984,106,2715. M. F. Semmelhack, J. W. Herndon and J. P. Springer, J. Am. Chem. Soc., 1983,105,2497. M. F. Semmelhack, J. W. Herndon and J. K. Lin, Organometallics, 1983,2, 1885. A. J. Pearson, M. N. I. Khand, J. C. Clardy, and He. Chung-heng, J. Am. Chem. Soc., 1985,107,2748. A. J. Pearson and M. N. I. Khand, J. Org. Chem., 1985,50,5276. D. L. Reger, S. A. Klaeren and L. Lebioda, Organometallics, 1986,5, 1072; J. Am. Chem. Soc., 1986, 108, 1940; for a review see D. L. Reger, Ace. Chem. Res., 1988, 21, 279.