Synthesis of indoles via alkylidenation of acyl hydrazides

Article abstract of DOI:10.1016/j.tetlet.2009.02.060

Indoles have been synthesised via alkylidenation of acyl phenylhydrazides using phosphoranes and the Petasis reagent, followed by in situ thermal rearrangement of the product enehydrazines. The Petasis reagent provides an essentially neutral equivalent of the [acid-catalysed] Fischer indole synthesis, but with acyl phenylhydrazides as starting substrates. Alkylidene triphenylphosphoranes convert aroyl phenylhydrazides to indoles, but acyl phenylhydrazides derived from aliphatic carboxylic acids undergo a Brunner reaction to form indolin-2-ones.

Full text of DOI:10.1016/j.tetlet.2009.02.060

Tetrahedron Letters 50 (2009) 3290–3293
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Tetrahedron Letters
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Synthesis of indoles via alkylidenation of acyl hydrazides
*
Kevin Hisler, Aurélien G. J. Commeureuc, Sheng-ze Zhou, John A. Murphy
WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, Thomas Graham Building, 295 Cathedral Street, Glasgow G1 1XL, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
Indoles have been synthesised via alkylidenation of acyl phenylhydrazides using phosphoranes and the
Petasis reagent, followed by in situ thermal rearrangement of the product enehydrazines. The Petasis
reagent provides an essentially neutral equivalent of the [acid-catalysed] Fischer indole synthesis, but
with acyl phenylhydrazides as starting substrates. Alkylidene triphenylphosphoranes convert aroyl phen-
ylhydrazides to indoles, but acyl phenylhydrazides derived from aliphatic carboxylic acids undergo a
Brunner reaction to form indolin-2-ones.
Received 10 January 2009
Revised 25 January 2009
Accepted 9 February 2009
Available online 13 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
The indole ring system is a crucial structure in drug discovery,
and has become an essential component in many pharmacologi-
cally active compounds. The extensive number of synthetic routes
to and applications of indoles emphasises the great interest in this
area. While a wide range of methods exist, significant efforts have
been made to provide syntheses under mild reaction conditions,
which tolerate a wide range of functional groups and start from
readily available substrates.1,2
The most commonly used method for the preparation of indoles
remains the Fischer indole synthesis discovered in 1883.3,4 In spite
of extensive studies, important efforts are still focussed on provid-
ing synthetic routes under mild conditions and with good regio-
control on the outcome of the reaction.5,6
This approach to indoles could have significant benefits, since it
would take advantage of the key property of the Wittig reaction in
defining the position of the alkene in enehydrazine 5. As alluded to
above, the major drawback of the normal acid-catalysed Fischer in-
dole synthesis is the reversible tautomerism of the enehydrazine;
where the enehydrazine is derived from a fully enolisable ketone,
this tautomerism leads to mixtures of regioisomers at the enehydr-
azine stage, and therefore ultimately results in a regioisomeric pair
of indoles.
To test the reactivity of acyl hydrazides towards phosphorus
ylides, a range of hydrazides were prepared in straightforward
manner as shown below (Scheme 2) from the corresponding acids
Our current approach to indoles arises from our recently re-
ported alkylidenation of Weinreb amides 17,8 in non-classical Wit-
tig reactions.9,10 The expected initial products, enamines 2, were
not isolated, but instead underwent easy hydrolysis to ketones
and aldehydes 3. These transformations make use of the enhanced
reactivity of the Weinreb amide carbonyl group as an electrophile,
due to the inductive effect of the methoxy oxygen atom.
This reaction extends the scope of the Wittig reaction, and pro-
vides alternative routes to ketones and aldehydes from Weinreb
amides without the use of organometallic reagents.
Success in that study led us to investigate the reactivity of Wit-
tig reagents with acyl hydrazides 4. While expected to be less reac-
tive than the Weinreb amides, the hydrazides 4 still benefit from
the activating inductive effect of an electronegative nitrogen atom
attached to the amide nitrogen. If alkylidenation of acyl hydrazides
could be established, then the expected initial products would be
the enehydrazines 5, which are the normal intermediates in the
Fischer indole synthesis (Scheme 1).
OMe
N
OMe
N
R'
R
R
O
R
Me
Me
PPh3
CH2R'
O
R'
2
3
1, R = Aryl, Alkyl, H
O
N
R
R
H2C PPh3
N
N
Me
N
Me
Me
Me
4
5
Δ
H
R
R
N
N
Me
N
Me
Me
* Corresponding author. Tel.: +44 0 141 548 2389; fax: +44 0 141 548 4246.
E-mail address: john.murphy@strath.ac.uk (J.A. Murphy).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.060

K. Hisler et al. / Tetrahedron Letters 50 (2009) 3290–3293
3291
O
R
R
N
H
N
R
RCO2H
80 ºC
O
NaH, MeI
O
N
CH2R
Me
PhNHNH2
N
PhHN
PhN
Me
Me
H2C PPh3
toluene, Δ
O
N
N
Me
8
6
, R = Me, 87%
, R = Me, 47%
Me
Me
, R= H
, R = Me
RCOCl
NEt3
28
29
, R= H
9, R = Et, 88%
8
9
7, R = Et, 42%
, R = Me
O
R
H
N
R
N
R
PhN
R
H
NaH, MeI
PhN
Me
Me
O
O
O
10
11
12
13
15
16
17
18
, R = Ph, 77%
, R = Ph, 86%
N
N
, R = 2-furyl, 55%
, R = 3-pyridyl
, R = 2-furyl, 91%
N
Me
, R = 3-pyridyl, 54%*
, R = 2-methylpropenyl, 20%*
Me
Me
, R = 2-methylpropenyl
30
32
33
, R = H
, R = H, 76%
14, R = cyclohexyl
19, R = cyclohexyl, 54%*
31,
R = Me
, R = Me, 92%
* = yield over 2 steps
O
Et
H
N
O
H
Me
O
10N HCl
t-BuCO.O.CHO
N
Me
, 20%
+
PhN
Me
Me
N
21
N
40 ºC, 72 h
PhN
Me
9
Me
PhN
Me
22
34
O
N
H2C PPh3
20
, 58%
, 78%
N
Me
Scheme 2.
Me
19
N
or acid chlorides. The synthesis of the formyl derivative 22 used a
different approach; hydrolysis of the N-propionyl hydrazide 9
afforded the dimethylphenylhydrazine 20—this was reacted with
formic pivalic anhydride 21 to afford the desired product 22 in
78% yield.
Me
, 3%
35
Scheme 4.
The reaction of methylenetriphenylphosphorane with the N-
benzoylhydrazide 15 afforded 2-phenylindole 23 in good yield
(78%). This was followed by equally successful reactions to form
the 2-(2-furyl)indole 24 and the 2-(3-pyridyl)indole 25, thereby
showing equal success with electron-rich and electron-poor aroyl
hydrazides. Further studies were undertaken with the benzoyl
hydrazide 15. Attempts to form 2-phenyl-3-alkylindoles were
unsuccessful. Reaction of 15 with n-butylidenetriphenylphospho-
rane and 3-phenylpropyl idenetriphenylphosphorane led simply
to recovery of starting hydrazide 15 in high yield (70% and 96%,
respectively).
The formyl hydrazide 22 provided opportunities to form
3-substituted indoles, and towards this end, this substrate was
reacted with alkylidenetriphenylphosphoranes. Reaction with
n-butylidenetriphenylphosphorane and 3-phenylpropylidenetri-
phenylphosphorane afforded the corresponding 3-alkylindoles 26
(41%) and 27 (46%), respectively (Scheme 3).
(92%) when the N-propionyl hydrazide 9 was reacted. In these
cases, the phosphorane clearly shows its basic character and
deprotonates 8/9 to form the enolate of the hydrazide 28/29. These
undergo a Brunner indolin-2-one synthesis,11,12 in high yield, to af-
ford 30/31 before condensation to the final products. Basicity of
phosphoranes had been observed previously,13–15 but to our
knowledge, this is the first report of indolin-2-one synthesis using
a phosphorane. Our ultimate wish was to find a neutral equivalent
of the Fischer indole synthesis, and these reactions clearly show
that phosphoranes are deficient in this respect.
The reactivity of cyclohexyl hydrazide 19 mirrored that of the
acetyl case 8, and produced the spiroindolin-2-one 34 (20%) as well
as a low yield of indole 35 (3%). Clearly, the reactivity of amides
with ‘enolisable’ acyl hydrazides poses a problem for the Wittig
reagents.
3-Methylbut-3-enoyl hydrazide 18 behaved differently, how-
ever, affording the homologated indolin-2-one 39 (Scheme 5).
We propose that this results from conjugate addition of the phos-
Extending the reactions to the N-acetylhydrazide 8 produced an
unexpected result (Scheme 4). Here, N-methylindolin-2-one 32
was isolated in 76% yield. The analogous product 33 was formed
phorane to the a,b-unsaturated hydrazide 18 to afford 36 followed
by expulsion of triphenylphosphine. The resulting cyclopropane 37
then undergoes either base-induced deprotonation of one of the
gem-dimethyl groups in tandem with ring-opening of the cyclopro-
pane to form the enolate 38, or thermal prototropic formation of
the enol that is equivalent to 38, followed by deprotonation. The
enolate 38 then undergoes a Brunner reaction to the indolin-2-
one product 39.
Our reason for proposing the cyclopropane intermediate 37
stems from isolation of an analogous cyclopropane 41 (42%) in
the reaction of isopropylidenetriphenylphosphorane with Weinreb
amide 40. Product 41 shows that gem-dimethylcyclopropanes can
R'
O
N
R
R'HC PPh3
toluene, Δ
R
N
N
Me
Me
Me
15, R = Ph
23, R = Ph, R' = H, 78%
16, R = 2-furyl
17
24
, R = 2-furyl, R' = H, 77%
, R = 3-pyridyl, R' = H, 78%
25
, R = 3-pyridyl
22
26, R = H, R' = Pr, 41%
, R = H
result from reaction between phosphoranes and
a,b-unsaturated
27, R = H, R' = CH2CH2Ph, 46%
amides, although the gem-dimethyl group results from different
Scheme 3.
reactants in each of the two cases.

3292
K. Hisler et al. / Tetrahedron Letters 50 (2009) 3290–3293
reacted with the Petasis reagent. 1H NMR spectroscopic analysis of
+
PPh3
45 revealed no diminution of the one-proton integral at C-3, and
retention of 85% of deuterons on the methyl group at the 2-posi-
tion in 45. Isotopomers (CHD2, CH2D and CH3) were observed,
probably due to exchange caused by hydrochloric acid (2 M) dur-
ing the work-up. 2D NMR spectroscopic analysis confirmed the ab-
sence of deuteration at C-3. A selectively deuterated product would
not have been available from the conventional Fischer indole syn-
thesis with labelled acetone. Consequently, our method can be
used for regioselective labelling of indole products.
O
Me
Me
O
H2C PPh3
Me
N
N
Me
Me
Δ
toluene,
PhN
Me
Me
PhN
Me
36
18
Typical procedure for the synthesis of indoles: A solution of ti-
trated methyllithium in diethyl ether (1.58 M, 4.4 mL, 6.95 mmol,
4.8 equiv) was added slowly to a suspension of bis(cyclopentadi-
enyl)titanium dichloride (770 mg, 3.09 mmol, 2.2 equiv) in toluene
(5 mL) at ꢀ5 °C over 15 min. The mixture was stirred for 1 h at
ꢀ5 °C, then for 1 h at rt. The mixture was cooled to 0 °C, and
quenched carefully by addition of an ice-cold 6% aqueous ammo-
nium chloride solution (10 mL). The phases were separated, and
the organic phase was washed with water (10 mL), brine (10 mL),
dried over sodium sulfate, filtered, and the solvent was removed
in vacuo, until the solution had been reduced to one-third of the
original volume, and then toluene (5 mL) was added. The solution
of dimethyltitanocene in toluene was transferred via cannula
to a solution of N-(3,3-dimethylacryloyl)-N,N0-dimethyl-N0-phen-
ylhydrazine 18 (256 mg, 1.44 mmol, 1.0 equiv) in toluene (5 mL).
The mixture was then heated at reflux for 72 h. The solvent was re-
moved in vacuo and diethyl ether (25 mL) was added. The mixture
was then filtered through CeliteÒ, which was washed with addi-
tional diethyl ether (25 mL). The organic phase was washed with
hydrochloric acid (2 M, 3 ꢁ 25 mL). The combined aqueous layers
were washed with diethyl ether (2 ꢁ 25 mL), and the combined or-
ganic phase was dried over sodium sulfate, filtered, and the solvent
was removed in vacuo. The crude mixture was finally purified by
column chromatography (hexanes–diethyl ether, 98:2) to afford
1,2-dimethylindole 42 (110 mg, 53%). Mp 53–54 °C, (lit.,18 54–
O
N
Me
Me
PhN
Me
Me
37
+
- H
Me
Me
CH2
H2C
O
Brunner
reaction
O
N
N
N
Me
Me
Me
38
39, 24%
O
O
Me2C PPh3
Ph
Me
Me
N
Ph
N
OMe
Δ
toluene,
OMe
Me Me
40
41, 42%
Scheme 5.
From the outcomes of the reactions of phosphoranes with the
alkyl substrates, it is clear that the phosphoranes act as strong
bases with these ‘enolisable’ hydrazides. In the development of
alkylidenation reactions, titanium-based reagents were developed
at least partly to avoid this base property of phosphoranes, and
accordingly, we examined the Petasis reagent16,17 as a non-basic
equivalent for the preparation of 2-alkylindoles and 2-arylindoles.
The difference of reactivity from the phosphoranes was dramat-
ically illustrated on reacting the acetylhydrazide 8 (Scheme 6). This
now afforded 1,2-dimethylindole 42, in contrast to the outcome
with methylenetriphenylphosphorane. With the titanium reagent,
there was no trace of the indolone product 32 that would arise
from the Brunner reaction. Thus, this appears to be an effectively
neutral equivalent of the Fischer indole synthesis. Scheme 6 repre-
sents the outcomes of initial efforts to afford indoles using the
Petasis reagent. Optimisation of the reaction conditions for the
alkylidenations and further investigation of the scope of this route
for indole preparation are now warranted.
55 °C); [Found: [M]+ (EI+) 145.0886, C10H11
N
requires [M]+,
145.0886];
m
max(KBr)/cmꢀ1 3047 (Ar-H), 2988 (C–H), 1605 (C@C);
dH (400 MHz, DMSO-d6) 2.40 (3H, d, J 0.7, CH3), 3.65 (3H, s, CH3),
6.20 (1H, br s, Ar–H), 6.94–6.98 (1H, m, Ar–H), 7.03–7.08 (1H, m,
Ar–H), 7.34–7.36 (1H, m, Ar–H), 7.41–7.42 (1H, m, Ar–H); dC
(100 MHz, DMSO-d6) 13.3 (CH3), 30.1 (CH3N), 100.0 (CH), 110.0
(CH), 119.7 (CH), 120.0 (CH), 120.9 (CH), 128.4 (C), 131.9 (C),
137.9 (C); m/z (EI+) 145 ([M]+, 100%), 144 ([MꢀH]+, 100).
Acknowledgements
We thank the EPSRC and WestCHEM for funding, and EPSRC Na-
tional Mass Spectrometry Service, Swansea, for mass spectral
analysis.
Supplementary data
We were keen to probe for evidence of proton abstraction in the
acyl group, so the trideuteroacetyl hydrazide 44 was prepared and
Supplementary data (preparation of acyl hydrazides, synthesis
of indoles using the Petasis reagent and its reactions with alkyl-
idene triphenylphosphoranes) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2009.02.060.
O
R
Cp2TiMe2
, Δ
R
N
N
N
Me
Me
toluene
References and notes
Me
1. For reviews of indole syntheses: (a) Joule, J. A.. In Science of Synthesis; Thomas,
E. J., Ed.; Thieme: Stuttgart, 2000; Vol. 10, pp 361–652; (b) Gilchrist, T. L. J. J.
Chem. Soc., Perkin Trans. 1 1999, 2849–2866; (c) Gribble, G. W. J. Chem. Soc.,
Perkin Trans. 1 2000, 1045–1075.
2. More recent syntheses of indoles include: (a) Rutherford, J. L.; Rainka, M. P.;
Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 15168–15169; (b) Kamijo, S.;
Yamamoto, Y. Angew. Chem., Int. Ed. 2002, 41, 3230–3233; (c) Arisawa, M.;
Terada, Y.; Nakagawa, M.; Nishida, A. Angew. Chem., Int. Ed. 2002, 41, 4732–
4734; (d) Smith, A. B.; Kano, N.; Ishiyama, H.; Minikawa, N.; Rainier, J. D.; Hartz,
42
8, R = methyl
9, R = ethyl
, R = methyl, 53%
43, R = ethyl, 47%
23, R = phenyl, 48%
24, R = 2-furyl, 8%
15, R = phenyl
16, R = 2-furyl
17, R = 3-pyridyl
44, R = CD3
25, R = 3-pyridyl, 38%
45, R = CD3, 47%
Scheme 6.

K. Hisler et al. / Tetrahedron Letters 50 (2009) 3290–3293
3293
R. A.; Cho, Y. S.; Cui, H.; Moser, W. H. J. Am. Chem. Soc. 2003, 125, 8228–8237;
8. Hisler, K.; Tripoli, R.; Murphy, J. A. Tetrahedron Lett. 2006, 47, 6293.
9. Murphy, P. J.; Lee, S. E. J. Chem. Soc., Perkin Trans. 1 1999, 3049–3066.
10. Murphy, P. J.; Brennan, J. Chem. Soc. Rev. 1988, 17, 1–30.
(e) Siebeneicher, H.; Bytschkov, I.; Doye, S. Angew. Chem., Int. Ed. 2003, 42,
3042–3044; (f) Shimada, T.; Nakamura, I.; Yamamoto, Y. J. Am. Chem. Soc. 2004,
126, 10546–10547; (g) Willis, M. C.; Brace, G. N.; Holmes, I. P. Angew. Chem., Int.
Ed. 2005, 44, 403–406; (h) Baran, P. S.; Guerrero, C. A.; Ambhaikar, N. B.;
Hafensteiner, B. D. Angew. Chem., Int. Ed. 2005, 44, 606–609; (i) Herzon, S. B.;
Myers, A. G. J. Am. Chem. Soc. 2005, 127, 5342–5344; (j) Dunetz, J. R.; Danheiser,
R. L. J. Am. Chem. Soc. 2005, 127, 5776–5777; (k) Taber, D. F.; Tian, W. J. Am.
Chem. Soc. 2006, 128, 1058–1059; (l) Alex, K.; Tillack, A.; Schwarz, N.; Beller, M.
Angew. Chem., Int. Ed. 2008, 47, 2304–2307; (m) Cui, S. L.; Wang, J.; Wang, Y.-G.
J. Am. Chem. Soc. 2008, 130, 13526–13527.
11. Robinson, B. The Fischer Indole Synthesis; John Wiley
& Sons: Chichester,
1982.
12. (a) Brunner, K. Monatsh. Chem. 1896, 17, 479–549; (b) Brunner, K. Monatsh.
Chem. 1897, 18, 95–122; (c) Moore, R. F.; Plant, S. G. P. J. Chem. Soc. 1951, 3475–
3478; (d) Schwarz, H. Monatsh. Chem. 1903, 24, 568–578; (e) Stanek, J. Chem.
Listy 1943, 37, 161–166; (f) Wenkert, E.; Bhattacharyya, N. K.; Reid, T. L.;
Stevens, T. E. J. Am. Chem. Soc. 1956, 78, 797–801; (g) Endo, Y.; Uchida, T.;
Shudo, K. Tetrahedron Lett. 1997, 38, 2113–2116.
3. Fischer, E.; Jourdan, F. Chem. Ber. 1883, 2241–2245.
4. Fischer, E.; Hess, O. Chem. Ber. 1884, 559–568.
13. Marshall, J. A.; Pike, M. T.; Carroll, R. D. J. Org. Chem. 1966, 31, 2933–2941.
14. Heathcock, C. H.; Ratcliffe, R. J. Am. Chem. Soc. 1971, 93, 1746–1757.
15. Lombardo, L. Tetrahedron Lett. 1982, 23, 4293–4296.
16. Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112, 6392–6394.
17. For the recent use of titanium carbenes in indole synthesis, see: Main, C. A.;
Petersson, H. M.; Rahman, S. S.; Hartley, R. C. Tetrahedron 2008, 64, 901–
914.
5. For leading recent work on the Fischer indole reaction, see: Wagaw, S.; Yang, B.
H.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 10251–10263.
6. (a) Simoneau, C. A.; Ganem, B. Tetrahedron 2005, 61, 11374–11379; (b)
Christoffers, J. Synlett 2006, 318–320; (c) Diedrich, C. L.; Frey, W.; Christoffers, J.
Eur. J. Org. Chem. 2007, 4731–4737.
7. Murphy, J. A.; Commeureuc, A. G. J.; Snaddon, T. N.; McGuire, T. M.; Khan, T. A.;
Hisler, K.; Dewis, M. L.; Carling, R. Org. Lett. 2005, 7, 1427–1429.
18. McDonald, B. G.; Proctor, G. R. J. Chem. Soc., Perkin Trans. 1 1975, 1446–
1450.