GMEWUE

Volume 27 . Number 9
September 1988
Pages 1113-1 226

International Edition in English

Transition Metals in the Synthesis and Functionaiization of Indoles New Synthetic

Methods (72)
By Louis S. Hegedus*

The use of transition-metal complexes as reagents for the synthesis of complex organic
compounds has been under development for at least several decades, and many extraordi-
nary organic transformations of profound potential have been realized. However, adoption
of this chemistry by the practicing synthetic organic chemist has been inordinately slow,
and only now are transition-metal reagents beginning to achieve their rightful place in the
arsenal of organic synthesis. Several factors contributed to the initial reluctance of synthetic
organic chemists to use organometallic reagents. Lacking education and experience in the
ways of elements having d electrons, synthetic chemists viewed organometallic processes as
something mysterious and unpredictable, and not to be discussed in polite society. Orga-
nometallic chemists did not help matters by advertising their latest advances as useful syn-
thetic methodology, but restricting their studies to very simple organic systems lacking any
serious functionality (e.g., the methyl, ethyl, butyl, futile syndrome). Happily, things have
changed. Organometallic chemists have turned their attention to more complex systems,
and more recently trained organic chemists have benefited from exposure to the application
of transition metals. This combination has set the stage for major advances in the use of
transition metals in the synthesis of complex organic compounds. This review deals with
one aspect of this area, the use of transition metals in the synthesis of indoles.

1. Introduction 0

The indole nucleus 1 is common to a large number and

a wide variety of biologically active natural and unnatural
compounds,[]and the synthesis and functionalization of
indoles has been the object of research for over one
hundred years, beginning with synthetic studies of indole-
based dyesf2]Among the many more recent synthetic tar- 1 2
gets have been the pharmacologically active ergot alka-
0
loids 2,l3]the antitumor agents ellipticine 3[41and mitomy-

+
II

indole
cin C 4,ls1
alkaloids
and the
such
considerably
as vincristine
more
andcomplex
vinblastine.161
dimeric
/ /
H2N I I
NH
[*] Prof L. S . Hegedus 0
Department of Chemistry, Colorado State University
Fon Collins, CO 80523 (USA) 3 L

Angew. Chem. Int. Ed. Engl. 27 (1988) 1113-1126 0 VCH Verlagsgesellschaji mbH. 0-6940 Weinheim, 1988 0570-0833/88/0909-1113 !$ 02.50/0 I 113
 Until very recently, indole syntheses relied primarily on
well-established methods such as the Fischer indole syn-
thesis, the Madelung cyclization of N-acyl-o-toluidines, the
reductive cyclization of o-nitrobenzyl ketones, the Batcho-
Leimgruber synthesis of indoles from o-nitrotoluenes and
dimethylformamide acetal, and the Gassman synthesis of
indoles from N-halo aniline~.~ All of these approaches in-
volve classic organic synthetic methodology and display
typical organic reactivity patterns and selectivities. Simi-
larly, functionalization of existing indole ring systems re-
lied heavily on well-established electrophilic substitution
reactions, typical reactions for 71-electron-rich systems.[]
With the advent and continuing refinement of transi-
tion-metal-assisted organic synthetic methodology,[91 a
number of new and potentially quite versatile methods for
both the synthesis and the functionalization of indoles
have been developed. This new methodology is the subject
of this review.
Virtually all organic functional groups will coordinate to
some transition metal, producing either stable complexes
or unstable, but reactive, organometallic intermediates.
This complexation is usually quite specific, permitting the
activation of a single functional group in the presence of
other quite similar ones, thereby reducing the need for pro-
tecting groups. Once complexed, the reactivity of the or-
ganic functional group is governed by the chemistry of the
metal, and the normal reactivity patterns of the functional
group are often dramatically altered. Since most transition
metals also have associated with them ancillary specta-
tor ligands which d o not participate directly in reactions
at the coordinated functional group but d o affect the over-
all reactivity of the system, it is often possible to fine-
tune the reactivity of the complexed species. These fea-
tures, exemplified by the transition-metal-assisted indole
syntheses presented below, permit the use of unconven-
tional starting materials with unusual reactivity patterns to
produce complex organic compounds with a high degree
of efficiency and selectivity.
2. Palladium Complexes in the Synthesis of Indoles
Palladium complexes have been used in the synthesis of
organic compounds for over twenty years, starting with the
commercially important Wacker process for the oxidation
of ethylene to acetaldehyde.o1 A number of palladium
complexes are commercially available and can be used as
catalysts or catalyst precursors without further processing.
Hence, a wide variety of palladium-assisted organic reac-
tions has been developed and applied to the synthesis of
complex organic molecules, including indoles. Palladium
exists in two stable oxidation states-Pd and Pdo-and,
as usual, the chemistry of these differs substantially with
regard to both substrate specificity and type of reaction
promoted.
2.1. Palladium(1r) Complex Chemistry
Palladium(ri) salts are moderate to strong electrophiles,
depending on the counterion. Commercially available salts
are Pd(OAc),, Pd(CF3C02)2,and [PdCI2],. The former two
1114
are relatively soluble in organic solvents, but [PdCl,], is a
chloro-bridged polymer which is quite insoluble. It does
form soluble solvates with nitriles or ate complexes with
lithium or sodium chloride, and it is in these soluble forms
that it is normally used in organic synthesis.
RCN
- PdCI,(RCN),
M = Na. LI L i n R = Me.Ph
Palladium(tr) complexes are electrophiles, and they
complex and activate 71-electron-rich organic compounds.
Arenes are directly metalated by Pd(OAc), or
Pd(CF,C02)2, forming a-arylpalladium(r~)complexes in a
typical electrophilic aromatic substitution. Arenes can be
coupled to give biphenyls by treatment with Pd(OAc)2 in
acetic acid, in a process that probably involves two succes-
sive substitutions followed by a reductive elimination. Un-
fortunately, this process has not yet been developed into
an efficient catalytic one (Ar = aryl).
ArH ArPdOAc ArPdAr Ar-Ar
HOAc ArH
+ - + - + - +
Pd(OAc), H@ H@ Pdo
Olefins rapidly and reversibly complex to PdC12, form-
ing relatively stable but reactive 71-olefin complexes. Once
complexed, the olefin becomes generally reactive toward
nucleophilic attack-a reversal of normal olefin reactivity-
forming a carbon-nucleophile bond and a palladium(r1)-
carbon o bond (Scheme I). Nucleophiles ranging from Cl
to Ph react, spanning a range of in basicity. Most
nucleophiles attack at the more-substituted olefin position.
The o-alkylpalladium(tl) complex is generally not stable
and can only be isolated in unusual cases. However, it is
highly reactive and undergoes transformations typical of
a-alkylpalladium(1r) species, regardless of the method of
formation. Thus p-hydride elimination ensues at tempera-
tures above about OC, giving the formal product of nu-
cleophilic substitution. Hydrogenolysis ( > -2OC, 1 atm
H,) produces the formal product of nucleophilic addition.
Transmetalation from a main-group organometallic- Sn,
Hg, Cu, TI-produces a dialkylpalladium(rr) complex
which can undergo reductive elimination resulting in over-
all difunctionalization of the olefin. Difunctionalization of
the olefin also results from insertion of carbon monoxide
or olefins. The regiochemistry of olefin insertion is gov-
erned by steric rather than electronic factors, and alkyla-
tion at the less-substituted olefin terminus usually predom-
inates in intermolecular insertion processes. Note that all
of these processes produce Pdo in the final step, while Pd
is required for the olefin-activation step. Reoxidation of
Pd to Pd is thus required for catalytic processes. Oxi-
dants such as CuCI2/O2, benzoquinone, and K2SZ08are
most commonly used for this purpose, the choice of oxi-
dants being dictated by the reactant and product compati-
bility. All of these processes have been used in the synthe-
sis and functionalization of indoles and will be discussed
below.
Angew. Chem. In1 Ed. Engl 27 11988) 1113-1126
 "1

PdCI,(RCN),

Pdo + HCI +

Pdo + HCI + Rq:R- 0

ROH
+ Pdo + MCI

Scheme I . Reactions of nucleophiles with palladiurn(l1) complexes. Nuc = CI, OH, AcO, R2N (from R2NH),
HC(CO*R),, Ph; Z = H, R, Ph, CN, C02Me, OR, NHAc; L = RCN (not always drawn).

2.1.1. Coupling of Arenes by Palladation

Although the coupling of arenes by direct palladation is

not an efficient process, it has been used in several cases to
synthesize functionalized indole ring systems. The early
studies involved the coupling of substituted diphenylam-
ines. Although one to two equivalents of palladium(1r) ace-
okR. '
R' = H. CI. Me; R2 = H.
Pd(OAc),
HoAc

Me, CI
-% RZ

5,6-40%
R'

tate were required, reasonable yields of carbazoles were

obtained.'"] Ellipticine 3 was made by this Al-
though the yield of the coupling was low, the directness of
the approach made it competitive with other synthetic
routes.

0
, AcOH/lO% CF3COOH
H H
Me
3,25%

Indole itself undergoes direct palladation at the 2- and

3-positions. This has been used to make fused-ring indole 7 30%
I

systems-e.g., 5:l3I 6, and 7[141-as well as to introduce

olefinic side chains at the 3-position (cf. 8) or at the 2-
position in 3-methylind0le.~'~-'~~ Carbonylation at the 3-
position has also been achieved by this method, carbon
l e q Pd(OAC1,
monoxide being inserted rather than an olefin.[IE1Unfortu- R R
nately, all of these processes require virtually stoichiomet-
R = CH,CO. S02Ph, PhCH,. H 8,40-70%
ric amounts of Pd(OAc), even when suitable reoxidants
are present, and efficient catalysis has not yet been X = CN, C0,Me. Ph
achieved in these systems.
Finally, in a remarkable reaction, Pd(OAc)2 catalyzed a
single-electron-transfer process which combined 4,N,N-tri-
methylaniline with tetrahydrofuran to produce dihydro- 5
H3C.N,CH3
indole 9."91Iodobenzene served as the reoxidant. This

6
z 10% Pd(0Ac)dPhl
unusual process was not general.
Although direct aromatic palladation remains a catalyti- Ph,P/Et,N/AcOH)
I
cally inefficient process, palladium(I1) is an efficient cata- I
+

50C. 83h CH3

lyst for the olefination and alkylation of thallated indoles, CH3 9 ,70%

Angew. Chem. In?. Ed. Engl. 27(1988) 1113-1126 1115

via a transmetalation-insertion-elimination process
(Scheme 1). Thus, indole-3-carbaldehyde underwent thal-
lation primarily at the 4-position (-, 10). In the presence of
a Pd(OAc), as catalyst, transmetalation to palladium, fol-
lowed by olefin insertion or reductive elimination, ensued
producing 4-alkylated indoles in modest yield (R = C02Me,
H). Thallium(rrr) probably serves as the reoxidant for pal-
ladium(0). This is a synthetically important reaction for er-
got alkaloid synthesis, since ergots require substitution in
the normally unreactive 4-position of the indole ring sys-
tem (TFA = trifluoroacetyl; cat. = catalytic amount).
thought to involve coordination of the olefin to Pd" fol-
lowed by intramolecular amination. As expected, attack
occurred at the more-substituted position of the olefin,
forming the indole ring and an unstable o-alkylpalladium
complex. P-Hydrogen elimination followed by olefin rear-
rangement produced the indole. When P-hydrogen elimi-
nation was suppressed, either by blocking with an alkyl
group, or by careful control of conditions, insertion of CO
or an olefin ensued, leading to more complex indoles such

C02Me
I
H PdCI,(MeCN), - [ a P dR' - C l ]

R 0
11, ~ 7 0 % 12 ,60-90%

as 11 and 12.[251When the olefin was also incorporated

I into the starting aniline, pyrroloindoles such as 13 were
i ArB(OH), - CH0[221 formed e f f i ~ i e n t l y . [ ~This
~ , ~process
~' was used in the syn-

Pd(OAc), cat.

2.1.2. Palladium(II)-Catabzed Amination of Olefins

Palladium( 11) chloride catalyzes the amination of olefins

(cf. Scheme 1). When the amine and the olefin are in the
same molecule, cyclization to give nitrogen heterocycles
occurs. o-Allylanilines were efficiently converted into 2-
60%

R = H,Me
0
PdCI,(MeCN),

II
I
- CI

methylindoles using palladium(I1) catalysis and benzoqui-

~ , ~ ~ ' 2). The process was
none as r e ~ x i d a n t ' ~ (Scheme

RK thesis of pyrroloindolequinones such as 14 and 15,which

are related to mitomycin C 4.[,']
R' = H, Me, Ac
+ i
-
PdC12(CH3CN), Pdo

1- 10%
t -HCI
- N W vNQ
8% PdCI,(MeCN),

+
NHV
2.1 THF/DMF -
65OC. 2 h
R' 0
4 R 14,15%

/ R = 5-Me,5-COzMe. 6-Me0.
5-Me0, 5,6-(MeO),
0
+
0

R
NHR'

--I p-elim

20%

Indoles such as 16 were also produced in a stoichiomet-

15 ,25%

ric reaction involving most of the processes described in

Scheme I, including transmetalation, insertion, elimina-
Scheme 2. Palladium(~l)-wtalyzedcyclization of allylanilines to 2-methyl-
indoles. tion, and amination of olefins."*]

1116 Angew. Chem. Int. Ed. Engl. 27/1988) I113-I126

 Ph

PhC = CCu 10% PdCI,(MeCN),

L c
NH MeCN
MeCN
I 1
RAO
60-80%

Pd-CI

Ph mph + PdCI,

L
0 1

[!iC1] NHAc
1%,67-90%

must be somewhat different from that observed with ole-

--
Ac
16,45%
Palladium-assisted amination of olefins was also used to
N-alkylate indole with olefins, giving N-alkylindoles upon
reduction, N-vinylindoles upon &elimination, and 3-( l-in-
do1yl)propionic esters upon ~arbonylation."~~ This was a
stoichiometric process since conditions to carry out the
Pdo to Pd" redox chemistry in the presence of indole anion
could not be found. The strongly electrophilic
Pd(CH,CN),( BF4)2 promoted a Ritter-like reaction be-
tween N-allyl-3-methylindole and nitriles, giving pyrazi-
no[l,2-a]indoles such as 17 .1301 While interesting, this pro-
cess was neither efficient nor general.
fins, since the e-vinylpalladium(II) intermediate cannot
undergo P-hydride elimination, and protolytic cleavage of
the Pd-C bond is assumed. Acetylenedicarboxylates were
annelated to anilines to give indoIe-2,3-dicarboxylic acids
in an electron-transfer process requiring stoichiometric
amounts of palladium.[321
2.1.3. Palladium(u)-Catalyzed (and Other Metal-Catalyzed)
Reaction of Azirines
Thermolysis of phenylazirines 19 at temperatures above
170C produced indoles, presumably via a nitrene inter-
mediate. Palladium(i1) chloride catalyzed this process, per-
mitting it to ensue at 30C.[331Rhodium(I), palladium(o),
Ph

/ \q R
- H
l9 \ f :loo%
,
/
\ ~~
R = H,Me.Ph

PdCI,(PhCN), cat., 3 0 C

b L L,Pd. CO
\
phase transfer,

6"
I6-20% \\

R
20

R = H, p-Me PhH, 52.95%

p-OMe. p-Br

and cobalt(o) complexes catalyzed a puzzling dimerization

11
of azirines 20 to produce indoles in variable yield^.[^^-^^]

CO,Me
2.2. Palladium(o) (and Nickel(0)) Complex Chemistry
R = Me, 34%. Et, 47%; Ph. 35%

While palladium(i1) salts are electrophilic reagents

In contrast to alkenes, alkyne aminations assisted by
palladium(1r) are much less common, primarily because of
facile alkyne oligomerization reactions which occur. How-
ever, o-alkynylated anilides were successfully cyclized to
indoles such as 18 by PdC12(MeCN)2.[3'JThe mechanism
which react with olefins and arenes, palladium(0) com-
plexes are strong nucleophiles and are most reactive
toward organic halides. The two most common, commer-
cially available complexes for palladium(0) catalysis are
Pd(PPh3), and Pd(dba), (dba = dibenzylideneacetone),

Angew. Chem. Inr. Ed. Engl. 27(1988) 1113-1126 1117

 which is converted into Pd(PPh3), when treated with tri- sis in the syntheses and functionalizations discussed be-
phenyl phosphane. Both of these have been extensively low.
used as catalysts in organic synthesis. However, it is fre-
quently more convenient to generate palladium(0) catalysts
2.2.1. PaIladium(0)-Catalyzed Alkynylation of Bromoanilines
in situ, by reducing palladium(r1) catalyst precursors. Thus,
treatment of Pd(PPh,)2C12 with diisobutylaluminum hy- o-Alkynylanilines such as 21, made by palladium(0)-ca-
dride or with CO or triethylamine (see below) will generate talyzed coupling of alkynes with o-haloaniline precur-
the catalytically active Pdo species PdL,. Perhaps the sors,140,411
are readily cyclized to indoles. (Note that a Pd
most extensively used palladium(0) catalyst precursor, complex is the precatalyst which is reduced to Pdo by
however, is palladium(I1) acetate, which is readily reduced triethylamine.) In a related process, hydroboration of
in situ by a range of compounds including carbon monox-
ide, olefins, phosphanes, and tertiary aliphatic amines RCECH
such as triethyl- or tri-n-b~tylamine.~~] This causes some
bPdCI, cat.
confusion in the literature, since palladium(0) catalysis is
involved but palladium(I1) acetate appears in all the equa- E1,N. 100C 21
tions. Invariably, some reducing agent is present in these
systems, and palladium(0) catalysis is indeed involved. 1) NaOEt
The typical reaction of Pdo complexes is the oxidative
2) H,O
addition of organic halides, wherein the Pdo complex is
formally oxidized to a o-alkylpalladium(II) halide complex R = H, Bu, Ph

and the oxidizing agent (RX) adds to the metal (Scheme 65-93/0
3). This reaction is limited to halides lacking fl hydrogens,
ethoxyacetylene gave a vinylborane, 22, which under-
went Pdo-catalyzed oxidative addition/transmetalation to
produce an indole precursor.[421
R

I
RX + Pdo
ox.
odd.
II
R-Pd-X - co
0
(1
R-C-Pd-X
II 22 NHR 61-97%

HPdXA nx
i p y

I ROH
R = H.n~C,n,,

R = H,CH3C0
R
60-99%

t 2.2.2. Palladium(0)-Catalyzed Cyclization of 2-Halogenated

R+y N-AIIyl-, N- Yinyl-, or N-Arylanilines to Indoles

Scheme 3. Palladium@-catalyzed reactions of organic halides o-Bromoanilines are easily N-allylated, producing sub-
strates ideally suited for a Pdo-catalyzed oxidative addi-
tion/olefin insertion approach to the indole ring system.
since 0-hydride elimination (cf. Scheme 1) prevents the As a consequence, this route has been extensively develop-
further use of these complexes. The most common sub- ed. Both a ~ t i v a t e d ~and
~ . ~simple
01efins~~
inserted effi-
strates are aryl, vinyl, benzyl, and ally1 halides. The order
of halide reactivity is I>Br>Cl, and iodides will often
react in the absence of phosphane ligands while bromides
require a phosphane. Chlorides generally are not useful.
This oxidative addition produces a G-alkylpalladium(rr)
complex which undergoes all the reactions described in
Scheme 1 for a-alkylpalladium(II) species produced by nu- ~~ ~

A R X Y Z 24, Yield 19/01

cleophilic attack on olefins. The most extensively used
reactions are transmetalation from main-group organome- 1/20= PhCHz BI Ph H
50-73
tallics, and insertion of CO or olefins. These reactions are C02Me
summarized in Scheme 3. These processes all re-form Pd, Br C0,Me H
H Ac 73
which can reenter the catalytic cycle directly, in contrast to
Pd-catalyzed reactions, which require an additional oxi- n H I H 5-Me 1
dant. This feature, in conjunction with recent advances 5,6-(Me0)2
50-87
5-C02Me
which permit very high catalyst and very mild
condition^,'^^] accounts for the extensive use of Pdo cataly-
H I

1118 Angew. Chem. Int. Ed. Engl. 27(1988) 1113-1126

ciently. The insertion product 23 of simple olefins gave
good yields of indoles 24 with catalytic amounts of palla-
dium. This cyclization was even effective with highly sub-
stituted arenes and was used to synthesize indolequinones
via 25 and 26.1461Carbazoles were produced in low yields
from 3-anilinocyclohexenones such as 27 (R = H, Et)l4']
30.89%
OAc
3% Pd(OAc),
* used to cyclize N-allyl-2-haloanilines to indoles, although

VN-/ OAc
Ac
Et,N, CH3CN
P(oTol)3,80'C
the yields obtained are somewhat l o ~ e r . [ ~ ~ - ' ~ ~
The regioselectivity of intramolecular olefin insertion
processes warrants comment. As noted in Section 2.1, the
OAc regioselectivity in the intermolecular insertion process is
strongly governed by steric rather than electronic factors,
and alkylation at the less-substituted terminus of the olefin
predominates regardless of the electronic nature of the ole-
OAc
fin substituents. In intramolecular processes, the effects of
developing ring strain may well override those of olefin
substituents, making the site of alkylation (e.g., ring size)
and in good yield from diphenylamines such as 28[48Juti- difficult to predict.
lizing similar oxidative addition/insertion chemistry. Mi-
2.2.3. Palladium(0)-Catalyzed Functionalization of Indoles

a;/&
/
R

21
0
Pd(OAc), cat.

P h p , NaHCO,. -a
DMF

36%
R
0
Palladium(0) catalysis has also been used extensively to
functionalize indoles. Chloropyrazines 31 coupled to the
2-position of indole in the presence of Pd(o), probably by

3% Pd(OAc),

Et3N. CH,CN, 150%

H
C02H C02H
20 73%

tomycin analogues (cf. 29) were prepared very efficiently

by the same p r o c e s ~ , [although
~ ~ * ~ ~the
~ last cyclization also
R', R3 = Me, Et.,Pr. Ph. H , R2 = H, Ph
occurred in the absence of a Pd catalyst. Carbazoles such

an oxidative addition/insertion process.'6o1The 3-amino-

0 0
COpEt
ethyl side chains of indoles were elaborated by a PdO-
Pd(OAc), cat.
catalyzed carbonylation, for example with ring closure to
give 32.I6lJ

H
Pd(OAc), cal
+
CO. Ph,P
0

as 30 were also produced by an intramolecular amination

of an aryl halide.[51-531This process required 1.2 equival-
ents of Pdo complex (L = Ph,P) and its mechanism is not
yet understood.
In contrast to nickel(I1) salts, which differ dramatically
from palladium(1r) salts in their chemistry, nickel(o) com-
plexes closely resemble palladium(0) complexes in their
reaction chemistry. Thus nickel(0) complexes can also be
Palladium(0)-catalyzed reactions of haloindoles are
among the most synthetically useful processes and have
been extensively developed for application in the synthesis
of 3,4-disubstituted indole ring systems including ergot al-
kaloids (see Section 2.2.4). Introduction of functionality at
the 4-position of indole using conventional electrophilic
indole chemistry is difficult, since the 1-, 2-, and 3-posi-

Angew. Chem. In[. Ed. Engl. 27(1988) 1113-1126 1119

&
' NO,
Br,. hv

(PhC0)202
&Or

NO,
1) Ph,P

2) CH,O(g) & NO2

good yield by Pd"-catalyzed cyclization of the appropriate
N-tosyl-o-vinylaniline, or, more recently, by the DMF-ace-
tal/reduction/tosylation approach. Compound 33 reacted
in typical aryl halide fashion in the Pdo-catalyzed oxida-
79% overall yield
tive addition/insertion process to produce 4-alkylated in-
doles 35 in excellent yield. Direct electrophilic mercura-
tion at the 3-position produced 34, which was readily iod-
inated to give 4-bromo-3-iodoindole 36. The same Pdo-ca-
talyzed process permitted facile alkylation of the 3-posi-
NHTS LiCL, quinone HCIO(LiC1 tion as well (cf. 37). Complete discrimination between the
80% Ts Ts
33.80% 34,99% bromide, which requires a phosphane to react, and the io-
dide, which reacts in the absence of a phosphane, was pos-
Et,N. P(oToL13 Li,PdCI, sible by appropriate choice of conditions. The mercurioin-
cat
dole 34 also underwent a facile Pd"-catalyzed transmetal-
Br J ation/insertion process to give the 3-allyl-4-bromoindole.
I Cyclization to tricyclic compound 38 was catalyzed by
35 Ts
palladium(0). Although 38 had the tricyclic ring system
Y = CO,Me, 86%; found in ergot alkaloids, rearrangement of the indole to
Ph, 74%; 36.90% Ts
NPhth. 74% the more stable naphthalene made this specific compound
'N'
C(Me);OH. 97% of little synthetic interest. 7-Substituted indoles were avail-

1
Pd(OAc), cat Ts
Et,N. b
1 Pd(OAc), cat able by a related route involving thallation/iodination of

ey
y

/Et,N. PtoTolI, the 7-position of an indole followed by Pdo-catalyzed oxi-

dative additiodolefin i n ~ e r t i o n . [ ~ ~ . ~ ~ ~

Ts 37 2.2.4. Palladium Catalysis in the Synthesis of Ergot

Y = CO,Me.81%
Alkaloids
NPhth, 77%

38,50% After many years of development, palladium catalysis is

Scheme 4. Palladium(0)-catalyzed synthesis of 3- and 4-substituted indoles.
NPhth (cf. 35 a n d 37)= phthalylimido, Py = pyridine.
tions are considerably more reactive. Scheme 4 shows one
approach to the introduction of functionality at the 3- and
4-positions of indoles.'621The key compound in all these
transformations is 4-bromo-N-tosylindole 33, prepared in
finding its way into mainstream Organic synthesis'
Its utility is evident from the ergot syntheses discussed be-
low, as are its limitations. When properly applied, howev-
er, palladium catalysis can result in very short and efficient
synthetic approaches to complex organic compounds. A
fine example of this is seen in Scheme 5 , wherein Pdo-cata-
lyzed functionalization of the 4-position of the indole nu-
cleus provided the key intermediate 39 for the synthesis of

1) TI(TFA),
P
Pd(OAc), cat _c
R
DMF. Et,N

40, 83%
1) CH,NO, &la,R = H; 36% overall yield

2) NaBH,
L l b , R = OMe, 20% overall yield

81%

hNH
H O W

&
Pd(OAc), cat.
42,20% overall yield 43,17% overall yield
Bu,NEr. DMF H
92% OH

wnc; &NH \ \

Scheme 5 . Palladium-catalyzed \ \
synthesis of clavine alkaloids,
which belong to the ergot alka-
/ NH
loids. The yields of 39 and 40 44,68% ; 31% o v e r a l l yield 45 4 6 , 3% overall yield
refer to R = H, OMe. 80%

1120 Angew. Chem. I n f . Ed. Engl. 27 (1988) 1113-1126

a number of ergot alkaloids such as (+.)-6,7-secoagroclav-
ine 41a (via 40),'651(-+)-l-rnethoxy-6,7-secoagroclavine
41b,[661(-t )-norchanoclavine I 42, (-t)-chanoclavine I
43,i6'1 (f)-aurantioclavine 44,l6*I(+)-isochanoclavine 45,
and (f)-agroclavine 46.i671 These all rely on the formyl-
directed thallation of indole-3-carbaldehyde, followed by Ts
Ts
iodination with iodine to give the iodide 39 and Pdo-cata- 36 LAWcat./NaOH
Iyzed introduction of the appropriate side chain at the 4- B@ OEq3 (0.70%)
position. The remaining steps involve conventional organic
chemistry.
An even more extensive use of palladium catalysis is
1) BBr3 SMe,
seen in the total synthesis of the methyl ester of ( + ) - N - +
2) E10H/NaHC03 Pd(OAc), cat
acetylclavicipitic acid 49,'691which involves as key steps Et,N. P(oTol1,
Pd"-catalyzed formation of the indole ring, Pdo-catalyzed Ts
96%
introduction of both C-ring side-chain precursors, and 93% Ts
Pd"-catalyzed formation of the seven-membered ring
(Scheme 6). This twelve-step synthesis in 18% overall yield
from commercially available starting materials is quite effi- Ik
-
c

cient. TsOH, A
2hv4 1 DME/MeOH/H,O 23% overall yield

H
56%

Pd(OAc), cat.. Et3N Scheme 7. Palladium-catalyzed synthesis of (5)-aurantioclavinc 44

c

OH
NHAc Ts
36
17,60%

OH

\
&C02Me

/ N
TS
PdCI,(MeCN), cat

or TsOH/A
L
& ' \
/ N
TS
NaBH4/Na2C03
Me
hv , -2O"C
-
4 2.1 MeOH/DME/H,O

83% 10,95%

@ + @/

19a
10 h

205h
N
H

61%

37%
0%

37%
/ N

19b
H

Scheme 6. Palladium-catalyzed synthesis of the methyl ester of (k)-N-acetyl-

clavicipitic acid, 49. Only the isomer shown here is formed from compound
VNH

a- /

53
NTs

56

Scheme 8. Palladium-catalyzed synthesis of tetracyclic ergot alkaloids such

41. as 54. The reaction of 51 was carried out without solvent.

A related approach was used in the total synthesis of

In this case, oxida-
7).i701
( f)-aurantioclavine 44 (Scheme
tive addition to Nio followed by transmetalation from Zr'"
proved more reliable than Pdo-catalyzed oxidative addi-
tiodtransmetalation from boron for introduction of the
enol ether at the 3-position. Pdo-catalyzed introduction of
the 4-alkyl group, followed by acid-catalyzed condensa-
tion/cyclization and photolytic reductive decarbonylation,
completed the synthesis of compound 44.
A potential approach to tetracyclic ergot alkaloids in-
volving extensive palladium catalysis is shown in Scheme
8.[7'1 Acylation of the 3-mercurioindole 34 by acryloyl
chloride using Pdo-catalyzed oxidative additiodtransme-
talation to give 50, followed by Pdo-catalyzed cyclization,
produced tricyclic intermediate 51, which was prevented
from rearranging to the naphthalene (cf. 38 in Scheme 4)
by the position of the carbonyl group. Cycloaddition of 51
to an azadiene produced the proper ergot alkaloid skele-
ton, 52, in a highly oxidized state. Reduction and removal
of heteroatoms are required to produce the proper ergot
ring system.
2.3. x-Allylpalladium Complexes in the Synthesis and
Funttionalization of Indoles
n-Allylpalladium(ii) complexes can be prepared by pro-
ton abstraction from olefin palladium(r1) complexes, by in-

Angon. Chem. Int. Ed. Engl. 27(1988) 1113-1126 I121

sertion of dienes into o-alkylpalladium(rI) complexes, or
by oxidative addition of allylic substrates to palladium(0)
complexes. They are yellow, air-stable crystalline solids,
quite stable to a variety of reactive species. In the presence
of good donor ligands (usually phosphanes), however,
these complexes become generally reactive toward nucleo-
philes such as amines or stabilized carbanions, resulting in
allylation of these nucleophiles and production of Pdo spe-
cies (Scheme 9). This forms the basis of a very useful Pdo-

e.JH

N
+
PdCI,

+
RPdX
/
I
7mx+
x = a.OAc. OPh. NO,, /o,
'II,

Pdo
R

1) 1 eq PdClZ(MeCN),

AgBF,, EI3N
2) NaBH4
--
more commonly used to elaborate existing indole ring sys-
tems. The isoquinuclidine ring of ibogamine 57[761and
cantharanthine 58I''l were synthesized by a Pdo-catalyzed

A *M&
ti

57

allylic a m i n a t i ~ n . [ ~Alkylation
45%
~

R = Et
N
H
L4Pd

~ - ~ ~ I at the indole 2-position

was accomplished using palladium(rr) activation.'781Other
indole alkaloid syntheses have used Pdo-catalyzed aliylic
alkylation to elaborate nonindolic heterocyclic rings such
as 59 and 60.r781
0
58
H
45%

COzMe
/
R

Y
NU@ = R ~ N OO<
,
X
Scheme 9. Synthesis and reactions of n-allylpalladium(ii) complexes
Pd(diphos),

catalyzed allylic activation process which has been exten- I SPh

SPh 59
sively developed for use in organic synthesis. Some of
these applications involve indoles and are presented be-
low.
Formation of the indole ring via x-allylpalladium(rI) in-
termediates-e.g., 55[721and 56'731-is relatively uncom-
ROC0

a NOz

[fl-
Pdocat.-

Et,N.THF \ \

N
HgoAc LtPdCI, >
]p
( H

D -o NHAc NHAc
60,75-80%

55
3. Other Transition Metals in the Synthesis and
Functionalization of Indoles

3.1. Copper(1)-Catalyzed Cyclization and Condensation

Ac

74% Although palladium is by far the most extensively used

transition metal for the synthesis and functionalization of
indoles, many others have found at least limited use in this

93%
61

70%

N DMF. A

mon. These two examples involve diene insertion into o-

d H R H

62 80.90%
arylpalladium(1r) species. x-Allylpalladium(r~)chemistry is

1122 Angew. Chem. lnt. Ed. Engl. 27(1988) 1113-1126

regard. For instance, copper(1) salts have long been known
to catalyze the reactions of nucleophiles with aromatic hal-
ides (e.g., the Hurtley reaction). With appropriate sub-
strates, indoles can be formed. Thus o-haloaryl enamines,
such as 61, R = Me, OMe, HJ8] and 62JS2]cyclized to in-
doles in the presence of copper(1) iodide in excellent yield.
Under similar conditions enoiates condensed with u-io-
doaniline to produce i n d o l e ~ . [ ~
o-Haloacetamides
~] (e.g.
63[841)also cyclized to indole derivatives under these con-
ditions. Copper(1) oxide catalyzed the cyclization of
o-isocyanophenylacetones to in dole^.[^^^^^^
RZ
derivatives such as 65 were reductively cyclized to 8-car-
bolines by NaBH, and copper(rr), iron(III), or chrom-
ium(rr1) halides.[] Dihydroisoindoles 66 were produced
in excellent yield by the KHFe(CO),-promoted reductive
amination of ~-dialdehydes.[~]Finally, o-nitrostyrenes
such as 67 were reductively cyclized to indoles by metal
carbonyls, in a process which must involve olefin activa-
tion by the metal, as well as nitro group reduction.[931
3.3. Ruthenium(r1)- or Palladium-Catalyzed Oxidative
Cyclization

RP N t
63
R = Me, OMe. H,
iBr A c 7
Cul. DMF

m
R
Ac
53.75%
Ruthenium(i1) chloride-catalyzed oxidation of alcohols
has been used to form indoles in modest yield, although
the conditions are somewhat s e v e ~ e . [ ~2,6-Dimethyl-
-~~~
phenyl isocyanide was converted into 7-methylindole 68 in
-OCH,O-
R2 = Me,

3.2. Reductive Cyclizations using Low-Valent

R RuCI,L,
Transition-Metal Compounds or
180T R H
A number of indole syntheses use low-valent transition
30-60%
metals to reduce aromatic nitro groups to amines, which
can then cyclize with electrophilic groups in the ortho posi-
tion to form indoles. These typically involve o-nitroaryl en-
amines (cf. 64) and reducing agents such as iron(o),[881ti-
t a n i u m ( ~ ~chloride,891
~) or nickel boride.[l Tryptamine
RUH, (diphos), cat. -
N 140%
Ill
C

Y = NH,,NOp
68 70%
M = Fe/HOAc/stlica gel, TICI,, Ni,B/NH,NH,

a process which must have involved C-H activation by the

- ruthenium (four catalytic cycles per [R~H,(diphos)~]).[~~

Palladium on carbon catalyzed oxidative cyclization to
H CUCI, 69 .191
FeCI, 70-85%
65 CrCI, n
pdc * \ OMe
I I
8

69,20-40%
66
R = Me.PhCH,,Ar.w

3.4. Cobalt-Catalyzed Cyclotrimerization Reactions

The cobalt(1)-catalyzed cyclotrimerization of alkynes

and cocyclotrimerization of alkynes and alkenes have been
67 extensively developed for use in organic synthesis.[991The
30-70% synthesis of compounds 7O[Oo1 and 71Ol exemplify the
R = H, Me,
use of the latter in the synthesis of indoles. Cobalt(r) com-
plexes also catalyzed the addition of alkynes to diazenes to
produce N-aminoindoles 72.1021

Angew. Chem. Inr. Ed. Engl. 27(1988) 1113-1126 1123

 duce functionality at normally unreactive positions of the
indole ring system.
This chemistry allowed 5-chlorodihydroindoles to be
converted into 5-methoxydihydroindoles by nucleophilic
substitution of chloride by m e t h o ~ i d e , [ ' and
~ ~ ] complexed

i
"CPCO" + R p J
R
indoles (73) were alkylated in the 4- and 7-positions (ma-
jor and minor product, respectively) by car bani on^."^^. 'OS1

R
R

R'

R' = H. Me, PhCH,, R,Si, C0,tBu

R = H. Me, AcNH(CH,),, Me,SiO(CH,),,

COC,H,
-

R' = Me,Si

E
x&
Y

-
1) BuLi

2) Eo hE k R

E
P h C E CPh

L,COCI R = Me, R,Si, E = Me$, C 0 2 E t y i

+ c

NH
Lithiation of complexed indoles (74) occurred at the 4-PO-
sition when the N-substituent was large, but at the 2-, 4-,
and 7-positions when it was small.~'06.'071

3.6. Miscellaneous Indole Syntheses

3.5. Arenechromium Tricarbonyl Complexes in Indole
Chemistry The copper-catalyzed decomposition of aryl azides to
produce nitrenes has been used to synthesize a number of
Arenes readily form q6 complexes with chromium hexa- pyrroloindolequinones (such as 75)."08] The site of inser-
carbonyl usually by simply heating the two together. Once
complexed to the chromium tricarbonyl fragment, the ar- 0
ene becomes reactive toward nucleophilic attack and
toward ring lithiation, the effect of the Cr(C0)3 fragment
being comparable to having introduced a nitro group.
Thus, direct nucleophilic aromatic substitution and lithia-
15 ,48%
tion becomes feasible. This feature has been used to intro-

0 0

-6
OX.
Pd(OAc),

11.51-77%

-c
E
R4
1) E@ 16

2) ox. R' = H. Me, El, R2 = /Pr, H

R3 = Et, Me, R4 = H, PhCH,. Ts

1124 Angew. Chem. In[. Ed. Engl. 27(1988) 1113-1126

tion of carbenes generated by transition-metal-catalyzed
decomposition of a-diazoesters such as 76 depended
strongly on the catalyst (cf. 77 and 78).O9]Aryl isocyan-
ides combined with carbene complexes (M = Cr, Mo, W)
to produce indoles, via ketenimine complexes 79.o.1
i 1 ArNC
4. Outlook
Although most of the fundamental organometallic reac-
tion chemistry utilized in the synthesis of indoles has been
known for at least a decade, only recently have these fun-
damental processes been applied to complex multifunc-
tional organic substrates with the serious intent of accom-
plishing the total synthesis of a natural product. This ex-
tension to more complex systems has vividly brought into
focus both the power and the Limitations of organometafiic
chemistry in the synthesis of complex organic compounds.
A decade ago only inorganic and organometallic chem-
ists ventured into the transition series to find useful or-
ganic transformations. Today, transition metals are com-
mon in synthetic organic chemistry, and new transition-
metal-catalyzed transformations of organic substrates are
readily adopted by synthetic chemists. This is expected to
continue.
Our research in the area of palladium catalysis in the syn-
thesis and functionaiization of indoles was supported by the
National Science Foundation and the National Institutes of
General Medical Sciences of the Public Health Service,
whom we gratefully acknowledge.
Received: November 23, 1987 [A 687 IE]
German version: Angew. Chem. 100 (1988) 1147
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