Tandem Meinwald rearrangement-Fischer indolisation: A one-pot conversion of epoxides into indoles

Article abstract of DOI:10.1055/s-0028-1087476

A tandem Sc(OTf)3-mediated Meinwald epoxide rearrangement-Fischer indole synthesis is reported. Optimisation and scope and limitation studies are described. In addition, preliminary investigations to develop a telescoped epoxidation-Meinwald rearrangement

Full text of DOI:10.1055/s-0028-1087476

LETTER
59
Tandem Meinwald Rearrangement–Fischer Indolisation:
A One-Pot Conversion of Epoxides into Indoles
One-Pot
C
a
onversion o
m
f
E
poxide
s
into Ind
e
oles s R. Donald, Richard J. K. Taylor*
Department of Chemistry, University of York, Heslington, York, YO10 5DD, UK
Fax +44(1904)434523; E-mail: rjkt1@york.ac.uk
Received 6 October 2008
Table 1 Preliminary Studies on the Conversion of Styrene Oxide
(1a) into 3-Phenylindole (4a)a
Abstract: A tandem Sc(OTf)3-mediated Meinwald epoxide re-
arrangement–Fischer indole synthesis is reported. Optimisation and
scope and limitation studies are described. In addition, preliminary
investigations to develop a telescoped epoxidation–Meinwald re-
arrangement–Fischer indole sequence are outlined.
Ph
PhNHNH2
(3a)
O
catalyst
(see below)
Ph
N
Key words: aldehydes, epoxides, indoles, rearrangements, tandem
reactions
H
4a
1a
Entry
Catalyst
BF3·OEt2
Zn(OTf)2
Yield (%)
1
2
3
4
5
6
16
As part of our continuing interest in the design and devel-
opment of tandem processes leading to heterocyclic sys-
tems,1 we now report initial studies towards an epoxide
rearrangement–indole forming sequence. The Meinwald
rearrangement of epoxides to aldehydes and ketones2 has
received significant attention in recent years with effort
focused on the discovery of systems which are both cata-
lytic in Lewis acid and selective in the formation of either
aldehydes3a–c or ketones.3a,4 Whilst the Meinwald rear-
rangement has been widely exploited in natural product
synthesis,5 there have been fewer reports of tandem pro-
cesses in which the resulting aldehyde is trapped in situ.6
Such a process would be particularly valuable when the
intermediate carbonyl compound is inaccessible or diffi-
cult to handle.
21
CuOTf·C6H6
AgOTf
25
36
Bi(OTf)3
Sc(OTf)3
36
51 (57)b
a Epoxide (0.9 mmol), hydrazine (0.9 mmol), Lewis acid (0.5 equiv),
THF (2 mL), Ace pressure tube, 100 °C (oil bath), 1 h.
b Yield in the presence of 3 Å MS.
tween styrene oxide (1a) and phenylhydrazine (3a) to give
3-phenylindole (4a, Table 1). Styrene oxide (1a) was cho-
sen as its rearrangement to phenyl acetaldehyde (2a) is
well documented.9 The Fischer indole synthesis of indole
4a from phenyl acetaldehyde (2a) and phenylhydrazine
(3a) is also known.10
Given the prevalence of the indole structure in biological-
ly active molecules,7 we decided to investigate the possi-
bility of combining the Meinwald rearrangement and
the Fischer indole synthesis8 into a tandem process
(Scheme 1). Such a procedure seemed potentially viable
given that both the Meinwald rearrangement and Fischer
indole synthesis are mediated by mineral or Lewis acids.
The first trial experiment used THF as solvent with boron
trifluoride diethyl etherate as Lewis acid and we were de-
lighted to obtain the desired indole 4a, albeit in low yield
(Table 1, entry 1). Several other Lewis acidic metal
halides (e.g., ZnCl2, ZrCl4, SnCl2·2H2O, and MgBr2) were
evaluated but were found to be poor catalysts for the reac-
tion as were lithium tetrafluoroborate and copper(II)
tetrafluoroborate. Protic acids were also investigated, but
were unsuccessful. Metal triflates, however, were much
more efficient (entries 2–6) with commercial Sc(OTf)3 by
far the best (51%, entry 6).
R1
Fischer
indole synthesis
Meinwald
rearrangement
R1
R1
N
R2
CHO
R3
O
1
2
4
N(R2)NH2
R3
3
Scheme 1
Further optimisation of the scandium(III) triflate process
was then carried out. It was established that a minimum
loading of 50 mol% of scandium(III) triflate was required
to achieve the optimum reaction efficiency (with a molar
equivalent the yield was essentially unchanged at 52%).
In terms of hydrazine 3a, an equimolar amount was opti-
mal; the use of an excess (1.5 equiv) led to a reduction in
the yield of indole 4a to 25%. Then, following a report by
In order to explore the viability of the tandem sequence
shown in Scheme 1, we first investigated the reaction be-
SYNLETT 2009, No. 1, pp 0059–0062
x
x.
x
x.
2
0
0
8
Advanced online publication: 12.12.2008
DOI: 10.1055/s-0028-1087476; Art ID: D35308ST
© Georg Thieme Verlag Stuttgart · New York

60
J. R. Donald, R. J. K. Taylor
LETTER
Table 2 Scope and Limitations of the Tandem Sequence
Entry Reactants
Products (yield, %)a,b
Kobayashi’s group that the addition of dehydrating agents
increased the yield of Yb(OTf)3-catalysed Pictet–
Spengler reactions,11 we found that the addition of 3 Å
molecular sieves gave a small increase in yield of indole
4a to 57%. In the final set of optimisation experiments, the
reaction solvent was investigated; ethereal and chlorinat-
ed solvents are commonly used for the Meinwald rear-
rangement, whereas the Fischer indole synthesis is usually
conducted in alcoholic solution or neat acid. For the tan-
dem Meinwald rearrangement–Fischer indole sequence
several solvent types were examined but none offered an
improvement in yield over THF.
Ph
O
1
1a
Ph
N
R
3a PhN(H)NH2
3b PhN(Me)NH2
4a R = H (57)
4b R = Me (85)
C6H4(4-Cl)
O
2
1b
4-ClC6H4
N
R
Having established a robust practical procedure for the
tandem Meinwald epoxide rearrangement–Fischer indole
synthesis using styrene oxide and phenylhydrazine, we
went on to explore the scope and limitations of the process
in terms of both epoxide and hydrazine substrate
(Table 2). First, the reactions of styrene oxide (1a) with
phenylhydrazine (3a) and 1-methyl-1-phenylhydrazine
(3b) were compared (entry 1). As can be seen, the reaction
with 3b to produce the N-methylindole (4b) proceeded in
excellent yield (85%), presumably reflecting the more ef-
ficient trapping of the intermediate phenylacetaldehyde
(2a, which is known to readily undergo aldol condensa-
tion and also to trimerise) by the more nucleophilic hydra-
zine.12 For this reason, the reactions of both
phenylhydrazine (3a) and 1-methyl-1-phenylhydrazine
(3b) were explored with the substrates 1b–g (entries 2–7).
3a
3b
5a R = H (52)
5b R = Me (81)
O
O
3
1c
O
N
R
3a
3b
6a R = H (21)
6b R = Me (31)
Ph
O
4
5
1d
Ph
N
R
3a
3b
7a R = H (10)
7b R = Me (13)c
Initially, epoxides which rearrange to intermediate alde-
hydes were investigated. As can be seen from Table 2, in
addition to styrene oxide, two other aryl epoxides also un-
derwent the tandem Meinwald epoxide rearrangement–
Fischer indole synthesis. 4-Chlorostyrene oxide (1b) gave
the indoles 5a and 5b13 in moderate to high yields via the
unstable intermediate 4-chlorophenylacetaldehyde (entry
2). Benzofuranyl epoxide (1c) gave the novel bishetero-
cycles 6a and 6b, albeit in low yields (entry 3);14 to the
best of our knowledge, this is the first example of the
Meinwald rearrangement of a heteroaryl-substituted ep-
oxide.
O
1e
N
H
3a
3b
8a R = H (0)
8b R = Me (0)
O
6
7
1f
N
R
3a
3b
9a R = H (56)
9b R = Me (63)
Moving on from aryl epoxides, the vinyl and alkyl vari-
ants 1d and 1e were studied (entries 4 and 5). With ep-
oxide 1d, the expected indole products 7a and 7b were
isolated in low yields only, possibly due to the sensitivity
of the highly unstable g,d-unsaturated aldehyde interme-
diate. In the case of iso-propyloxirane (1e) no trace of in-
dole formation was observed and this was the case with
other aliphatic epoxides also, indicating a current limita-
tion of the tandem process.
O
1g
N
R
3a
3b
10a R = H (36)
10b R = Me (70)c,d
Cl
O
Cl
Ph
8
1a
Ph
N
H
Epoxides which rearrange to aryl ketones were studied
next and these performed well in the tandem Meinwald
epoxide rearrangement–Fischer indole sequence. Thus,
acenaphthylene oxide (1f) gave the highly coloured penta-
3c
3,5-Cl2C6H3N(H)NH2 11 (61)e
a Unless stated otherwise all reactions were conducted with epoxide
(1.0 equiv), hydrazine (1.0 equiv), Sc(OTf)3 (0.5 equiv), 3 Å MS,
cyclic indoles 9a and 9b in 56% and 63% yield, respec- THF, Ace pressure tube, 100 °C, 1 h.
b All yields refer to isolated material after flash column chromatography.
tively (entry 6). With indene oxide (1g) and phenylhydra-
zine (3a), indole 10a was obtained in 36% yield; though
moderate, this yield reflects the propensity of the Mein-
wald rearrangement product, 2-indanone, to undergo
c Sc(OTf)3 was added at 0 °C to minimise the exotherm.
d The product was found to be unstable to SiO2 and was therefore pu-
rified on Florisil® (200 mesh).
e The reaction required heating at 150 °C for 3 h to reach completion.
Synlett 2009, No. 1, 59–62 © Thieme Stuttgart · New York

LETTER
One-Pot Conversion of Epoxides into Indoles
61
(i) UHP, MeReO3 (6 mol%)
THF, r.t., 24 h (then MnO2)
aldol self-condensation (for example, under the condi-
tions employed by Sainsbury et al. the Fischer synthesis of
indole 10a from 2-indanone proceded in only 8%
yield).15a The isolation of N-methylindole 10b from in-
dene oxide (1g) and hydrazine 3b in 70% yield is also
noteworthy as the Fischer method for the synthesis of in-
dole 10b directly from 2-indanone afforded 10b in only
59% yield.15b
(ii) 3b, Sc(OTf)3, 3 Å MS
THF, heat, 1 h
13
33%
(i) MTBD, THF
r.t., 18 h
OH
N
Me
10b
(ii) 3b, Sc(OTf)3, 3 Å MS
THF, heat, 1 h
64%
The final example in Table 2 (entry 8) illustrates that by
replacing phenylhydrazine (3a) with arylhydrazines such
as 3c, aryl-substituted indoles such as the novel doubly
chlorinated example 11 can be prepared.
Br
14
Scheme 3
This reaction required more vigorous conditions (150 °C
for 3 h), presumably as a consequence of the additional
steric and electronic perturbations of the [3,3]-sigmatrop-
ic rearrangement.
sis) into a one-pot process and avoid the need to directly
handle epoxides. Further optimisation is required but the
potential of these telescoped procedures has been clearly
established.
In all of the examples in Table 2, the use of 1-methyl-1-
phenylhydrazine (3b) resulted in higher, often significant-
ly higher, yields. However, the demethylation of N-meth-
ylindoles is not well precedented. We therefore carried
out the tandem rearrangement on styrene oxide 1a using
1-benzyl-1-phenylhydrazine (3d, Scheme 2). This pro-
cess gave the N-benzylated indole 12 in good yield. De-
benzylation to produce 3-phenylindole (4a) was then
carried out using a published procedure, involving treat-
ment with KOt-Bu and oxygen.16 Although unoptimised,
the sequence in Scheme 2 illustrates the potential of the
Meinwald epoxide rearrangement–Fischer indole meth-
odology to directly generate indoles with a removable N-
protecting group.
In summary, we have developed a tandem Meinwald re-
arrangement–Fischer indole sequence for the direct con-
version of epoxides into indoles thereby avoiding the need
to handle the intermediate carbonyl compounds. The pro-
cess has been shown to be compatible with a range of sub-
stituted aryl epoxides and phenylhydrazines allowing for
the formation of indoles functionalised at nitrogen, on the
aryl substituent, and on the indole carbocycle. Finally,
preliminary experiments indicate that the sequence can be
further telescoped with epoxide formation to achieve a
one-pot preparation of indoles directly from an alkene or
bromohydrin. The development of other tandem process-
es in combination with the Meinwald rearrangement is un-
der way and will be reported in due course.
In principle it should be possible to further extend this
novel tandem process by the in situ generation of the ep-
oxide prior to the Meinwald rearrangement–Fischer in-
dole sequence. Scheme 3 illustrates two preliminary
experiments which confirm the viability of such an ap-
proach.
Representative Experimental Procedure
Preparation of 3-(4¢-Chloro-phenyl)-1-methylindole (5b)
1-Methyl-1-phenylhydrazine (3b, 103 mL, 0.88 mmol, 1.0 equiv)
and powdered Sc(OTf)3 (216 mg, 0.44 mmol, 0.5 equiv) were added
to a mixture of 2-(4-chlorophenyl) oxirane (1b, 106 mL, 0.88 mmol,
1.0 equiv) and activated 3 Å MS (150 mg) in anhyd THF (2 mL) in
an Ace pressure tube under argon. The resulting mixture was heated
to 100 °C over 10 min and maintained at this temperature for 1 h.
The cooled reaction mixture was then diluted with sat. aq NaHCO3
(10 mL), extracted with EtOAc (3 × 10 mL), and the combined
organic layers were dried (MgSO4), filtered, and concentrated in
vacuo. The crude material was pre-adsorbed on to SiO2 and purified
by silica flash column chromatography eluting with PE–acetone
(50:1) to afford indole 5b (171 mg, 0.71 mmol, 81%) as a pale yel-
low solid, which was recrystallised from PE to afford pale yellow
plates mp 95–96 °C (lit.13 mp 96.6–97 °C); which gave fully consis-
tent 1H NMR, 13C NMR, and IR data.
Thus, indene oxide (1g) was formed by the methyltrioxo-
rhenium-catalysed17 urea–hydrogen peroxide (UHP) ep-
oxidation of indene 13 (MnO2 was subsequently added to
quench excess UHP). Then, in the same ‘pot’, 1-methyl-
1-phenylhydrazine (3b) and scandium triflate were added
to effect the Meinwald rearrangement–Fischer indole se-
quence giving tetracyclic indole 10b. The same product
was prepared by starting with the readily available bromo-
hydrin (14) which was treated with 7-methyl-1,5,7-triaza-
bicyclo[4.4.0]dec-5-ene (MTBD) to generate indene
oxide (1g) in situ, with further elaboration giving indole
10b. These procedures combine three steps (epoxide for-
mation–Meinwald rearrangement–Fischer indole synthe-
Ph
Ph
KOt-Bu, O2
DMSO, r.t., 1.5 h
Sc(OTf)3
THF, heat, 1 h
O
+
Ph
65%
88%
N
N
N(Bn)NH2
Bn
H
4a
1a
3d
12
Scheme 2
Synlett 2009, No. 1, 59–62 © Thieme Stuttgart · New York

62
J. R. Donald, R. J. K. Taylor
LETTER
(12) (a) Anderson, A. M.; Blazek, J. M.; Garg, P.; Payne, B. J.;
Mohan, R. S. Tetrahedron Lett. 2000, 41, 1527.
Acknowledgment
We thank the University of York for studentship support, and Dr.
T. Dransfield (University of York) for assistance with mass spectro-
metry.
(b) Johnson, A. P.; Luke, R. W. A.; Singh, G.; Boa, A. N.
J. Chem. Soc., Perkin Trans. 1 1996, 907.
(13) Blades, C. E.; Wilds, A. L. J. Org. Chem. 1956, 21, 1013.
(14) All novel compounds were fully characterized.
3-(2¢-Benzofuranyl) indole (6a)
References and Notes
Pale orange microcrystals; mp 162–163 °C (heptane);
Rf = 0.27 (PE–Et2O, 4:1). 1H NMR (400 MHz, CDCl3):
d = 8.33 (br s, 1 H), 8.05–8.00 (m, 1 H), 7.71 (d, J = 2.5 Hz,
1 H), 7.57–7.52 (m, 1 H), 7.49–7.45 (m, 1 H), 7.44–7.39 (m,
1 H), 7.29–7.24 (m, 2 H), 7.23–7.16 (m, 2 H), 6.91 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 154.0, 152.9, 136.6,
129.9, 124.6, 123.3, 123.12, 123.08, 122.8, 121.1, 120.4,
120.3, 111.7, 110.8, 108.8, 99.7. IR (neat): nmax = 3399,
2918, 2850, 1623, 1453, 1427, 1358, 1249, 1100 cm–1. MS
(EI+): m/z (%) = 233 (97) [M+], 135 (38), 97 (37), 95 (50), 93
(37), 91 (52), 83 (37), 81 (63), 79 (50), 71 (51), 69 (71), 67
(100), 57 (73), 55 (91), 43 (48), 41 (52). HRMS (EI+): m/z
calcd for C16H11NO: 233.0841; Found: 233.0842 [M+] (0.4
ppm error).
(1) For recent examples, see: (a) Taylor, R. J. K.; Reid, M.;
Foot, J. S.; Raw, S. A. Acc. Chem. Res. 2005, 38, 851; and
references cited therein. (b) Robinson, R. S.; Taylor, R. J. K.
Synlett 2005, 1003. (c) Cayley, A. N.; Cox, R. J.; Ménard-
Moyon, C.; Schmidt, J. P.; Taylor, R. J. K. Tetrahedron Lett.
2007, 48, 6556. (d) Donald, J. R.; Edwards, M. G.; Taylor,
R. J. K. Tetrahedron Lett. 2007, 48, 5201.
(2) (a) Meinwald, J.; Labana, S. S.; Chadha, M. S. J. Am. Chem.
Soc. 1963, 85, 582. (b) For a review, see: Rickborn, B. In
Comprehensive Organic Synthesis, Vol. 3; Trost, B. M.;
Fleming, I.; Pattenden, G., Eds.; Pergamon: Oxford, 1991,
733.
(3) For recent examples, see: (a) Maruoka, K.; Murase, N.;
Bureau, R.; Ooi, T.; Yamamoto, H. Tetrahedron 1994, 50,
3663. (b) Suda, K.; Kikkawa, T.; Nakajima, S.; Takanami,
T. J. Am. Chem. Soc. 2004, 126, 9554. (c) Procopio, A.;
Dalpozzo, R.; De Nino, A.; Nardi, M.; Sindona, G.;
Tagarelli, A. Synlett 2004, 2633.
(4) For recent examples, see: (a) Takanami, T.; Hirabe, R.;
Ueno, M.; Hino, F.; Suda, K. Chem. Lett. 1996, 1031.
(b) Kulasegaram, S.; Kulawiec, R. J. J. Org. Chem. 1997, 62,
6547.
(5) For recent examples, see: (a) Srikrishna, A.; Satyanarayana,
G.; Prasad, K. R. Synth. Commun. 2007, 37, 1511.
(b) Wilson, M. S.; Woo, J. C. S.; Dake, G. R. J. Org. Chem.
2006, 71, 4237. (c) Vital, P.; Tanner, D. Org. Biomol. Chem.
2006, 4, 4292. (d) For a review, see: Silva, L. F. Jr.
Tetrahedron 2002, 58, 9137; and references cited therein.
(6) For recent examples, see: (a) Wang, L.; Maddess, M. L.;
Lautens, M. J. Org. Chem. 2007, 72, 1822. (b) Nokami, J.;
Maruoka, K.; Souda, T.; Tanaka, N. Tetrahedron 2007, 63,
9016. (c) Albert, B. J.; Koide, K. J. Org. Chem. 2008, 73,
1093.
(7) D’Ischia, M.; Napolitano, A.; Pezzella, A. In
Comprehensive Heterocyclic Chemistry III; Katritzky,
A. R.; Ramsden, C. A.; Scriven, E. F. V.; Taylor, R. J. K.,
Eds.; Elsevier: Oxford, 2008, Chap. 3.04; and references
therein.
1-Methyl-3-(2¢-benzofuranyl) indole (6b)
Colourless microcrystals; mp 109–110 °C (i-PrOH);
Rf = 0.44 (PE–Et2O, 7:3). 1H NMR (400 MHz, CDCl3):
d = 8.06 (dd, J = 8.0, 1.0 Hz, 1 H), 7.62 (s, 1 H), 7.60–7.57
(m, 1 H), 7.54–7.49 (m, 1 H), 7.40 (dd, J = 7.5, 1.5 Hz, 1 H),
7.35 (app. td, J = 7.5, 1.5 Hz, 1 H), 7.31 (app. td, J = 7.5, 1.5
Hz, 1 H), 7.27–7.22 (m, 2 H), 6.91 (d, J = 0.5 Hz, 1 H) 3.85
(s, 3 H). 13C NMR (100 MHz, CDCl3): d = 154.0, 153.1,
137.5, 130.0, 127.7, 125.1, 123.1, 122.8, 122.6, 120.7,
120.5, 120.1, 110.7, 109.9, 107.0, 99.1, 33.2. IR (neat):
n
max = 3053, 2924, 2853, 1624, 1609, 1468, 1452, 1371,
1254, 1203, 1156, 1088, 1014 cm–1. MS (EI+): m/z (%) = 247
(100) [M+], 232 (26). HRMS (EI+): m/z calcd for C17H13NO:
247.0997; found: 247.0987 [M+] (4.0 ppm error). Anal.
Calcd for C17H13NO: C, 82.57; H, 5.30; N, 5.66. Found: C,
82.39; H, 5.36; N, 5.57.
4,6-Dichloro-3-phenylindole (11)
Orange oil; Rf = 0.16 (PE–Et2O, 4:1). 1H NMR (400 MHz,
CDCl3): d = 8.30 (br s, 1 H), 7.50 (dd, J = 8.0, 1.5 Hz, 2 H),
7.42–7.36 (m, 3 H), 7.34 (d, J = 2.0 Hz, 1 H), 7.19 (d, J = 2.5
Hz, 1 H), 7.15 (d, J = 2.0 Hz, 1 H). 13C NMR (100 MHz,
CDCl3): d = 137.5, 134.5, 131.0, 128.1, 127.6, 127.2, 126.9,
124.9, 122.3, 121.9, 119.5, 110.1. IR (neat): nmax = 3417,
3079, 2921, 2851, 1601, 1546, 1474, 1423, 1393, 1188,
1129, 1105, 1076 cm–1. MS (EI+): m/z (%) = 263 (64)
[37Cl35ClM+], 261 (100) [35Cl35ClM+], 199 (25). HRMS
(EI+): m/z calcd for C14H9NCl2: 261.0112; found: 261.0108
[M+] (1.5 ppm error)].
(8) For recent reviews, see: (a) Hughes, D. L. Org. Prep.
Proced. Int. 1993, 25, 607. (b) Robinson, B. The Fischer
Indole Synthesis; Wiley: Chichester, 1982.
(15) (a) Brown, D. W.; Graupner, P. R.; Sainsbury, M.; Shertzer,
H. G. Tetrahedron 1991, 47, 4383. (b) Armit, J. W.;
Robinson, R. J. Chem. Soc. Trans. 1922, 121, 827.
(16) Sanz, R.; Castroviejo, M. P.; Guilarte, V.; Pérez, A.;
Fañanás, F. J. J. Org. Chem. 2007, 72, 5113.
(17) Herrmann, W. A.; Fischer, R. W.; Marz, D. W. Angew.
Chem., Int. Ed. Engl. 1991, 30, 1638.
(9) See, for example: Robinson, M. W. C.; Pillinger, K. S.;
Graham, A. E. Tetrahedron Lett. 2006, 47, 5919; and
references therein.
(10) Rodríguez, J. G.; Lafuente, A.; García-Almaraz, P.
J. Heterocycl. Chem. 2000, 37, 1281.
(11) Manabe, K.; Nobutou, D.; Kobayashi, S. Bioorg. Med.
Chem. 2005, 13, 5154.
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