Ruthenium-catalysed isomerisation of allylhydrazines: A new entry to the Fischer indole synthesis

Article abstract of DOI:10.1055/s-2006-967949

The synthesis of non-symmetrically substituted allyl phenylhydrazines and their isomerisation to the corresponding enehydrazines is reported. The isomerisation is triggered by a combination of Grubbs' first-generation catalyst and LiBEt₃H. Indo

Full text of DOI:10.1055/s-2006-967949

LETTER
443
Ruthenium-Catalysed Isomerisation of Allylhydrazines: A New Entry to the
Fischer Indole Synthesis
R
uthenium-Ca
i
talysed
m
Isomerisation of
A
o
llylhydrazine
n
s
D. Nielsen,a Thomas Ruhland,b Lars K. Rasmussen*a,b
a
Faculty of Pharmaceutical Sciences, University of Copenhagen, 2 Universitetsparken, 2100 Copenhagen, Denmark
b
Department of Medicinal Chemistry, H. Lundbeck A/S, 9 Ottiliavej, 2500 Valby, Denmark
Fax +45(36)438237; E-mail: lars@kemiker.dk
Received 14 July 2006
be efficient catalysts. In particular, the combination of a
ruthenium catalyst and a hydride donor has proven useful
for the isomerisation. The process is believed to take place
through an addition–elimination sequence of an in situ
Abstract: The synthesis of non-symmetrically substituted allyl
phenylhydrazines and their isomerisation to the corresponding ene-
hydrazines is reported. The isomerisation is triggered by a combina-
tion of Grubbs’ first-generation catalyst and LiBEt3H. Indoles are
formed directly from the enehydrazines by the Fischer indole syn- generated ruthenium hydride species.14,17 Most often
thesis under the reaction conditions.
isomerisation has been used for deprotection of allyl-pro-
tected alcohols and amines. In addition, the combination
of ring-closing metathesis and double bond isomerisation
has recently been used in the formation of heterocyclic
compounds, such as cyclic enol ethers, indoles, and 1,2-
dihydroquinolines.17–21
Key words: indoles, reduction, regioselectivity, hydrazines, transi-
tion metals
Indoles are an important structural motif found in many
bioactive molecules.1–3 As a consequence of the impor-
tance of the indole structure, a great number of methods
for synthesising indoles have been developed. The Fischer
indole synthesis, discovered by Herman Emil Fischer in
1883, is probably still the most used method among the
vast number of indole synthesis strategies.4–7 The reaction
is initiated by condensation of an aldehyde or ketone with
a phenylhydrazine to yield a phenylhydrazone. An ene-
hydrazine is then formed by isomerisation of the phenyl-
hydrazone, this isomerisation can be catalysed by a
variety of reagents, including acids. The intermediate
enehydrazine then undergoes a cascade of reactions,
including a [3,3]-sigmatropic rearrangement, leading to
the indole.8,9
PCy3
Cl
Cl
Ph
Ru
PCy3
1
Figure 1 Grubbs’ first-generation catalyst
In this paper we demonstrate that a combination of
Grubbs’ first-generation catalyst 1 (Figure 1) and lithium
triethylborohydride catalytically isomerises allyl phenyl-
hydrazines of type 2 to phenyl enehydrazines of type 3
(Scheme 1). To the best of our knowledge, this particular
type of isomerisation has not previously been reported.
The intermediate phenyl enehydrazines 3 were not iso-
lated but their formation was indirectly proven by the
formation of the corresponding indoles.22,23 In addition,
we demonstrate a convenient and high yielding synthesis
of non-symmetric tetrasubstituted phenylhydrazines and
phenylhydrazides via chemoselective reduction.
We envisioned that a catalytic isomerisation of allyl
phenylhydrazines to phenyl enehydrazines would trigger
the rearrangement to the corresponding indoles.
Isomerisation reactions of allyl ethers and allyl amines
yielding the corresponding enol ethers and enamines, re-
spectively, have been described.10 Among the different
methods, transition metals, like palladium,11 iridium,12
rhodium,13 and ruthenium complexes,14–16 have proven to
In order to prove the isomerisation concept, four tetra-
substituted allyl phenylhydrazines 6a–d and one tetrasub-
stituted allyl phenylhydrazide 8 were synthesised as
rearrangement
isomerisation
N
N
EtNH2
+
N
R
N
R
N
R
2
3
Scheme 1
shown in Scheme 2.
SYNLETT 2007, No. 3, pp 0443–0446
Advanced online publication: 07.02.2007
1
5.
0
2.
2
0
0
7
DOI: 10.1055/s-2006-967949; Art ID: G23306ST
© Georg Thieme Verlag Stuttgart · New York

444
S. D. Nielsen et al.
LETTER
R1
R1
Br
BH3·THF
H
N
N
K2CO3, DMF, 50 °C
N
N
THF, 5 °C
R1
6a (84%)
5a (72%)
5b (78%)
5c (82%)
5d (73%)
R2
R2
6b (73%)
6c (89%)
6d (73%)
N
O
N
R2
R1
R2
Br
BH3·NMe3
H
Me
Ph
Me
Ph
4a
4b
4c
4d
H
H
N
N
O
HCl, toluene, 50 °C
Cs2CO3, DMF, 50 °C
N
N
7 (91%)
8 (85%)
Me
Me
O
Scheme 2 Isolated yields obtained after purification by flash chromatography are given in brackets
The acylated arylhydrazones 4a–d were synthesised in with Grubbs’ first-generation catalyst 1 (5 mol%) and
two steps from commercially available hydrochloride lithium triethylborohydride (20 mol%) at 100 °C in tolu-
salts of phenylhydrazine and 4-methylphenylhydrazine by ene furnished indoles 9a–d in moderate yields (56–62%).
previously described methods.24,25
Unfortunately, no conversion of hydrazide 8 into the
We found that both the C=N bond and the C=O bond of corresponding N-acylated indole was observed under the
4a–d were reduced using borane tetrahydrofuran complex conditions employed for 6a–d. Deactivation of Grubbs’
in tetrahydrofuran at 5 °C, providing the trisubstituted first-generation catalyst by acylated allylamines has pre-
hydrazines 5a–d in good yields (72–82%). In a mixture of viously been described.27 The authors propose a rutheni-
toluene, diethyl ether and HCl at 50 °C, the C=N bond is um chelate as the reason for the lack of catalytic activity.
selectively reduced by borane trimethylamine complex to In our case a similar explanation might be the reason for
hydrazide 7 in 91% yield.26
the lack of conversion in the reaction of 8 (Scheme 3).
Subsequent allylation of 5a–d with allyl bromide and po- In summary, we have demonstrated that the combination
tassium carbonate in DMF provided the tetrasubstituted of Grubbs’ first-generation catalyst and lithium triethyl-
hydrazines 6a–d in good yields (73–89%). Hydrazide 7 borohydride is able to catalyse the isomerisation of N-
was converted into hydrazide 8 in 85% yield using allyl allyl-N¢-arylhydrazines to aryl enehydrazines. This was
bromide and cesium carbonate in DMF.
proven by rearrangement of the generated aryl enehydra-
zines to N-alkyl-substituted 3-methyl indoles.28 To the
best of our knowledge this is the first example of a catal-
ysed isomerisation of allyl phenylhydrazines to enehydra-
zines using transition metal catalysis. In addition we
reported a high-yielding procedure for the synthesis of
unsymmetrically tetrasubstituted phenylhydrazines as
well as the corresponding hydrazides.
Isomerisation was tested using a combination of Grubbs’
first-generation catalyst 1 and a hydride source. It was
found that sodium borohydride and lithium triethylboro-
hydride both were suitable additives for the isomerisation.
Lithium triethylborohydride was chosen for the experi-
ments due to the solubility in THF and hence the easier
handling and dosing. Treatment of the hydrazines 6a–d
R2 Yield, %
R1
H
R1
R1
1 (5 mol%)
LiBEt3H (20 mol%)
9a
9b
Me
Ph
56
62
N
N
H
N
toluene, 100 °C, 12 h
9c Me Me
9d Me Ph
62
58
R2
R2
6a–d
1 (5 mol%)
LiBEt3H (20 mol%)
no reaction
N
O
toluene, 100 °C, 12 h
N
8
Scheme 3 Isolated yields obtained after purification by flash chromatography
Synlett 2007, No. 3, 443–446 © Thieme Stuttgart · New York

LETTER
Ruthenium-Catalysed Isomerisation of Allylhydrazines
with 2 M aq KOH (130 mL). CAUTION: Hydrogen
445
References and Notes
generation. After the gas evolution has ended the reaction
mixture was extracted with EtOAc (4 × 50 mL) and the
combined organic phases were dried over MgSO4,
concentrated in vacuo and purified by flash chromatography
(2% Et2O in heptane).
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3575.
(13) Krompiec, S.; Pigulla, M.; Krompiec, M.; Baj, S.; Mrowiec-
Bialon, J.; Kasperczyk, J. Tetrahedron Lett. 2004, 45, 5257.
(14) Schmidt, B. Eur. J. Org. Chem. 2004, 1865.
(15) Cadot, C.; Dalko, P. I.; Cossy, J. Tetrahedron Lett. 2002, 43,
1839.
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Lett. 2001, 3, 3781.
(17) Schmidt, B. J. Org. Chem. 2004, 69, 7672.
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Tetrahedron Lett. 2003, 44, 6483.
(20) Arisawa, M.; Terada, Y.; Nakagawa, M.; Nishida, A. Angew.
Chem. Int. Ed. 2002, 41, 4732.
(21) Arisawa, M.; Terada, Y.; Takahashi, K.; Nakagawa, M.;
Nishida, A. J. Org. Chem. 2006, 71, 4255.
(22) Hughes, D. L.; Zhao, D. J. Org. Chem. 1993, 58, 228.
(23) Przheval’skii, N. M.; Kostromina, L. Y.; Grandberg, I. I.
Chem. Heterocycl. Compd. 1989, 24, 709.
(24) Yamamoto, H. J. Org. Chem. 1967, 32, 3693.
(25) Maguire, A. R.; Plunkett, S. J.; Papot, S.; Clynes, M.;
O’Connor, R.; Touhey, S. Bioorg. Med. Chem. 2001, 9, 745.
(26) Perdicchia, D.; Licandro, E.; Maiorana, S.; Boldoli, C.;
Giannini, C. Tetrahedron 2003, 59, 7733.
N,N¢-(Diethyl)phenylhydrazine (5a):29 yield 72% from 4a;
yellow oil. 1H NMR: d = 6.70–7.20 (m, 5 H), 3.46 (q, 2 H,
J = 7.1 Hz), 3.40 (1 H, s), 2.90 (q, 2 H, J = 7.2 Hz), 1.13 (t,
3 H, J = 7.1 Hz), 1.10 (t, 3 H, J = 7.2 Hz). 13C NMR: d =
150.3, 129.5, 117.9, 113.5, 45.9, 43.0, 13.5, 11.2.
N¢-Allyl-N,N¢-(dialkyl)arylhydrazines (6) – General
Procedure.
To a mixture of a N,N¢-(dialkyl)arylhydrazine (5a–d, 11
mmol) and K2CO3 (5.3 g, 38 mmol) in DMF (15 mL) was
added allyl bromide (2.8 mL, 33 mmol). The mixture was
stirred overnight at 50 °C. Then, H2O (40 mL) was added
and the reaction mixture was extracted with EtOAc (4 × 50
mL). The combined organic phases were washed with brine
(2 × 30 mL), dried over MgSO4, concentrated in vacuo and
purified by flash chromatography (heptane).
N¢-Allyl-N,N¢-(diethyl)phenylhydrazine (6a): yield 84%
from 5a; yellow oil. 1H NMR: d = 7.19 (dd, 2 H, J1 = 8.8 Hz,
J2 = 7.2 Hz), 6.99 (d, 2 H, J = 8.8 Hz), 6.65 (t, 1 H, J = 7.2
Hz), 5.80–5.90 (ddt, 1 H, J1 = 17.2 Hz, J2 = 10.3 Hz, J3 = 6.3
Hz), 5.15 (dd, 1 H, J1 = 17.2 Hz, J2 = 1.8 Hz), 5.02 (dd, 1 H,
J1 = 10.3 Hz, J2 = 1.3 Hz), 3.32 (d, 2 H, J = 6.3 Hz), 3.30 (q,
2 H, J = 7.1 Hz), 2.73 (q, 2 H, J = 7.1 Hz), 1.22 (t, 3 H,
J = 7.1 Hz), 1.01 (t, 3 H, J = 7.1 Hz). 13C NMR: d = 149.1,
134.7, 127.7, 115.7, 115.2, 110.9, 56.5, 45.9, 35.1, 13.2,
11.7. HRMS: m/z calcd for C13H20N2: 204.1626; found:
204.1631.
N¢-Ethyl-N-phenylacetohydrazide (7).
To a solution of acetaldehyde N-acetylphenylhydrazone (4a,
3.0 g, 17 mmol) and BH3·NMe3 (1.6 g, 26 mmol) in toluene
(40 mL), was slowly added a solution of HCl in Et2O
(approximately 4.5 M, 3 mL) and the reaction was stirred
overnight at 50 °C. To the reaction was added Na2CO3 (aq
sat., 50 mL) and phases were separated. The aqueous phase
was extracted with EtOAc (3 × 30 mL). The combined
organic phased were washed with brine, dried over MgSO4,
and concentrated in vacuo. Purification by flash
(27) Theeraladanon, C.; Arisawa, M.; Nishida, A.; Nakagawa, M.
Tetrahedron 2004, 60, 3017.
(28) General.
chromatography (heptane–Et2O, 3:1) yielded 2.67 g (91%)
of 7 as a colourless solid, mp 65–68 °C. The 1H NMR
spectrum shows double signals due to the existence of two
conformers. 1H NMR: d = 7.30–7.40 (m, 5 H), 5.81 (br s, 1
H) [4.18 (br s, 1 H)], 2.86 (br q, 2 H, J = 7.1 Hz) [2.74 (br s,
2 H)], 1.96 (s, 3 H) [2.37 (br s, 3 H)], 1.06 (t, 3 H, J = 7.1
Hz). 13C NMR: d = 168.4, 141.6, 129.3, 127.8, 127.3, 44.3,
21.8, 12.8. Anal. Calcd for C10H14N2O: C, 67.39; H, 7.92; N,
15.72. Found: C, 67.60; H, 7.92; N, 15.70.
All reactions were carried out in oven-dried glassware under
argon or nitrogen atmosphere. Chemicals and solvents were
obtained from commercial suppliers and used as received
unless otherwise noted. Toluene and THF were dried with
sodium. DMF was dried over molecular sieves (4 Å) prior to
use. 1H NMR and 1H-decoupled/13C NMR spectra were
recorded at 500.13 MHz and 125.67 MHz, respectively, on a
Bruker Avance DRX 500 instrument using deuterated
CHCl3 (99.8%). Chemical shifts for 1H NMR are reported in
N¢-Allyl-N¢-ethyl-N-phenylacetohydrazide (8).
To a mixture of N¢-ethyl-N-phenylacetohydrazide (7, 2.10 g,
11.8 mmol) and Cs2CO3 (16 g, 50 mmol) in DMF (20 mL)
was added allyl bromide (4.1 mL, 47 mmol) at r.t., the
reaction was then stirred overnight at 50 °C. Then, H2O (30
mL) was added and the mixture was extracted with EtOAc
(4 × 50 mL). The combined organic phases were dried over
MgSO4, concentrated in vacuo and purified by flash
chromatography (heptane–Et2O, 4:1) to yield 2.15 g (84%)
of 8 as a colorless oil. 1H NMR: d = 7.10–7.40 (m, 5 H), 5.93
(m, 1 H), 5.21 (br d, 2 H, J = 14.1 Hz), 3.38 (dd, 1 H,
J1 = 14.1 Hz, J2 = 5.9 Hz), 3.20 (dd, 1 H, J1 = 14.1 Hz,
J2 = 6.2 Hz), 2.72 (m, 1 H), 2.57 (m, 1 H), 2.36 (s, 3 H) [1.84
(s, 3 H)], 1.21 (br t, 3 H, J = 7.0 Hz). 13C NMR: d = 176.0,
135.8, 135.7, 131.2, 130.3, 129.6, 119.8, 60.25, 55.3, 49.0,
23.1, 13.9. HRMS: m/z calcd for C13H18N2O: 218.1419;
found: 218.1417.
ppm with TMS as internal reference. Chemical shifts for 13
NMR are reported in ppm relative to chemical shifts of
C
CHCl3. Elemental analyses were performed at the University
of Vienna, Department of Physical Chemistry (Vienna,
Austria), with a Perkin-Elmer 2.400 CHN elemental
analyzer and at the University of Copenhagen with a CE
Elantech-Thermoquest Flash EA 1112. HRMS were
performed on a Jeol JMS-HX/HX110A MS instrument at the
University of Copenhagen.
N,N¢-(Dialkyl)arylhydrazines (5) – General Procedure.
To a solution of acylated hydrazone28,29 (4a–d, 23 mmol) in
THF (40 mL) at 0 °C was added dropwise BH3·THF, 1 M in
THF, (50 mL, 50 mmol) over 15 min. The reaction mixture
was left at 5 °C overnight and subsequently treated carefully
Synlett 2007, No. 3, 443–446 © Thieme Stuttgart · New York

446
S. D. Nielsen et al.
LETTER
General Procedure for the Conversion of Allyl
Arylhydrazines 6 into Indoles 9.
in vacuo and the purified by flash chromatography (heptane–
toluene, 4:1).
To a solution of N¢-allyl-N,N¢-dialkylarylhydrazine (6a–d,
1.0 mmol) and bis(tricyclohexylphosphine) benzylidine
ruthenium(IV) dichloride (42 mg, 49 mmol) in toluene (4
mL) was added LiBHEt3 1 M in THF (100 mL, 100 mmol).
The reaction was stirred for 16 h at 100 °C. Then, H2O (20
mL) and EtOAc (20 mL) were added to the reaction, phases
were separated and the aqueous phase was extracted with
EtOAc (3 × 30 mL). The combined organic phases were
washed with brine (30 mL), dried over MgSO4, concentrated
N-Ethyl-3-methylindole (9a):30 yield 56% from 6a; colorless
oil. 1H NMR: d = 7.10–7.60 (m, 4 H), 6.86 (s, 1 H), 4.08 (q,
2 H, J = 7.3 Hz), 2.32 (s, 3 H), 1.40 (t, 3 H, J = 7.3 Hz). 13
C
NMR: d = 136.4, 129.2, 125.1, 121.7, 119.4, 118.8, 110.6,
109.4, 41.0, 15.9, 10.0.
(29) Buchwald, S. L.; Wagaw, S.; Geis, O. WO A2 9943643,
1997.
(30) Galons, H.; Girardeau, J. F.; Farnoux, C. C.; Miocque, M. J.
Heterocycl. Chem. 1981, 18, 561.
Synlett 2007, No. 3, 443–446 © Thieme Stuttgart · New York