Formation of N-substituted 4- and 7-oxo-4,5,6,7-tetrahydroindoles revisited: A mechanistic interpretation and conversion into 4- and 7-oxoindoles

Article abstract of DOI:10.1016/j.tetlet.2012.05.090

An efficient method for the preparation of 4-oxo-4,5,6,7-tetrahydroindoles was successfully applied to the synthesis of N-substituted 7-oxo-4,5,6,7- tetrahydroindoles for the first time. Both isomers where converted into their corresponding 4- and 7-oxoindoles in good yields utilizing a novel aromatization protocol. Based on the impurity profile obtained, however, different mechanisms for the formation of the 4- and 7-oxo-4,5,6,7-tetrahydroindole derivatives are discussed. In addition, the reaction sequences appear to be stereospecific allowing for the direct introduction of a chiral center α to the nitrogen and preparation of enantiomerically enriched products.

Full text of DOI:10.1016/j.tetlet.2012.05.090

Tetrahedron Letters 53 (2012) 4276–4279
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Formation of N-substituted 4- and 7-oxo-4,5,6,7-tetrahydroindoles revisited:
a mechanistic interpretation and conversion into 4- and 7-oxoindoles
⇑
Antonio Garrido Montalban , Sven M. Baum, Justin Cowell, Alexander McKillop
School of Chemical Sciences, University of East Anglia, Norwich NR4 7TJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient method for the preparation of 4-oxo-4,5,6,7-tetrahydroindoles was successfully applied to
the synthesis of N-substituted 7-oxo-4,5,6,7-tetrahydroindoles for the first time. Both isomers where
converted into their corresponding 4- and 7-oxoindoles in good yields utilizing a novel aromatization
protocol. Based on the impurity profile obtained, however, different mechanisms for the formation of
the 4- and 7-oxo-4,5,6,7-tetrahydroindole derivatives are discussed. In addition, the reaction sequences
Received 21 April 2012
Revised 15 May 2012
Accepted 19 May 2012
Available online 1 June 2012
appear to be stereospecific allowing for the direct introduction of a chiral center
preparation of enantiomerically enriched products.
a to the nitrogen and
Keywords:
Indoles
Tetrahydroindoles
Cyclization
Aromatization
Chirality
Ó 2012 Elsevier Ltd. All rights reserved.
Over ten thousand biologically active indole derivatives have
been identified to date. Of those, over 200 are currently marked
as drugs or undergoing clinical trials.1 As such, improved or new
methods for the construction of this heterocyclic system are con-
stantly needed. This is particularly true for the development of safe
and efficient large scale preparations, given the ubiquitous charac-
teristics of indoles among bioactive molecules and natural prod-
Several examples of laborious multistep Haworth type ring
annelations, starting from pyrroles, to give N-unsubstituted
7-oxotetrahydroindoles are known.6 N-Methyl 7-oxo-4,5,6,7-tetra-
hydroindole, on the other hand, was obtained in low yield through
a condensation/cyclization sequence of aminoacetaldehyde di-
methyl acetal with 1,2-cyclohexanedione.7 N-Benzyl 7-
oxotetrahydroindoles have been prepared in modest yields via
reaction of 2,3-epoxy-3-methylcyclohexanones with benzylamine
and cyclization of the resulting enamines with dimethylformamide
dimethyl acetal (dmfdma) to form the pyrrole ring in a similar
manner to the Leimgruber–Batcho3 indole synthesis. In our hands,
however, this procedure resulted in much lower yields than
reported.8 Similar enamines as the ones discussed above, give
N-substituted 7-oxotetrahydroindoles when reacted with nitroole-
fins. Again, this method is limited since it is very substrate depen-
dent and in fact the reaction is reported to only proceed rapidly
and almost quantitatively with the enamine derived from benzyl-
amine.9 In contrast, efficient methods for the synthesis of the 4-oxo
isomer are much more abundant, with the first generally useful
method appearing in 1962.10 This procedure and modifications
thereof11 are based on treatment of 4-oxotetrahydrobenzofuran
derivatives with ammonia or primary amines in, for example, a
sealed vessel at high temperatures. Syntheses involving condensa-
tion/cyclization of aminocarbonyl equivalents to 1,3-cyclohexadi-
ones for the formation of 4-oxo-tetrahydroindoles are also
known.12 More recently, Martinelli and co-workers reported a very
elegant entry into the 4-oxotetrahydroindole core via a novel intra-
molecular 1,3-dipolar cycloaddition approach.13
ucts.2 Although
a
variety of ring-substituted indoles are
accessible through classical methods such as the Fischer, Bischler,
Madelung, Reissert, Nenitzescu and Gassman procedures,3 limita-
tions can arise from difficult to obtain precursors and/or low reac-
tion conversions. As part of our pharmacological compound
evaluation, we were interested in synthesizing N-substituted
7-alkoxyindoles with the possibility of introducing a chiral center
a
to nitrogen. The more recent Bartoli indole synthesis is one of
the most efficient methods available for the preparation of 7-
substituted indoles4 and has been successfully applied for the syn-
thesis of 7-alkoxy derivatives.5 As the above syntheses, however, it
is mainly suitable for the formation of N-unsubstituted indoles
and, to our knowledge, direct methods for the synthesis of
N-substituted 7-alkoxyindoles are rare. A survey of the literature
revealed that 7-oxotetrahydroindoles could serve as precursors
to 7-alkoxyindoles and allow us to directly prepare the compounds
of interest. Thus, herein we report our strategy towards the synthe-
sis of N-substituted 7-oxo-4,5,6,7-tetrahydroindoles, an initial
mechanistic interpretation and successful conversion of the former
into 7-oxoindoles including optically active analogs.
The simplicity of Matsumoto and Watanabe11a modified proce-
dure for the synthesis of N-substituted 4-oxotetrahydroindoles
⇑
Corresponding author. Tel.: +1 858 453 7200; fax: +1 858 453 7210.
E-mail address: amontalban@arenapharm.com (A.G. Montalban).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.090

A. G. Montalban et al. / Tetrahedron Letters 53 (2012) 4276–4279
4277
Table 1
mentioned earlier, however, prompted us to exploit the same strat-
egy for the preparation of N-substituted 7-oxotetrahydroindoles.
Thus, treatment of 1,2-cyclohexadione with chloroacetaldehyde
in the presence of sodium bicarbonate gave 7-oxo-4,5,6,7-tetra-
hydrobenzofuran 1 in 40% yield (Scheme 1). At the time we initi-
ated our studies compound 1 had only been prepared via a
Friedel-Crafts cyclization approach14 but reported later in similar
yield by Seki et al.15 using the same modified Feist–Benary furan
synthesis. Conversion of 1 into 7-oxotetrahydroindoles, however,
was not further investigated. Thus, with the requisite precursor 1
in hand, we embarked onto its conversion into 7-oxotetrahydroin-
doles. Reactions were carried out in a sealed tube at 150 °C for
36 h. The results obtained from treating 1 with, 3 equiv each,
ammonia and a variety of primary amines are summarized in Ta-
ble 1. To our delight, the expected 7-oxotetrahydroindoles 2 were
formed but the yields obtained, were much lower than what Mat-
sumoto and Watanabe11a reported for equivalent reactions of the
4-oxo isomer 3. For comparison, we converted the 4-oxo isomer
3 into the corresponding 4-oxotetrahydroindoles 4 under equiva-
lent conditions and confirmed Matsumoto’s observations
(Scheme 2, Table 1, yields and products in parentheses). While
we believe that the decreased yield of 4c is due to its lower relative
stability, the poor yield of 4g is most likely associated with sterics
(vide infra). Nevertheless, reaction of 4- and 7-oxo-4,5,6,7-tetra-
Formation of 7-oxotetrahydroindoles 2 from reaction of 1 with aqueous ammonia and
primary amines
3 RNH2
1
N
R
O
2
Entry
R
Product
Yield (%)
1
2
3
4
5
6
7
H
Me
2a6 (4a11a
)
)
36 (91)
22 (89)
34 (36)
30 (83)
46 (71)
23 (83)
17 (8)
2b7 (4b11a
2c (4c)
C6H11
Bn
2d8 (4d11a
)
PhCH2 CH2
PhCHCH3
PhCHC4H9
2e (4e22
2f (4f)
)
2g (4g)
All reactions were performed in 20% aq EtOH at 150 °C for 36 h in a sealed tube.
Yields and products in parentheses are those obtained from reactions with 4-
oxotetrahydrobenzofuran 3 after 12 h.
O
O
3
4
3a
5
6
i
2
hydrobenzofuran 1 and 3, respectively, with homochiral
a-methyl-
N
R
O
1
7a
benzylamine (Table 1, entry 6) appeared to proceed
7
25ꢁ
589nm
C
4
3
stereospecifically, since both products, 2f (½
a
ꢀ
ꢂ + 140° at
25ꢁ
589nm
C
6.6 mg/mL in CHCl3) and 4f (½
CHCl3), were found to be optically active (vide infra). Furthermore,
2f obtained from reaction of 1 with homochiral -methylbenzyl-
a
ꢀ
ꢂ ꢃ16° at 6.2 mg/mL in
Scheme 2. Reagent and condition: (i) 3 equiv RNH2, 20% aq EtOH, 150 °C, 12 h.
a
amine was not only shown to be optically active but enantiomeri-
cally pure by comparing the 1H NMR spectra of its (+)- and (ꢃ)-1-
(9-anthryl)-2,2,2-trifluoroethanol (TFAE)16 diastereomeric solvates
with those generated from the racemate. Reaction of 1 and 3 with
methyl 2-amino-2-phenylacetate, however, gave only achiral 2d
and 4d, respectively, from apparent hydrolysis and decarboxyl-
ation. Nontheless, in addition to having established that 7-
oxotetrahydroindoles 2 can be obtained from its corresponding
7-oxotetrahydrobenzofuran precursor 1, the reaction proved to
be stereospecific for both, 1 and 3 with compounds 4f and 2f being
the first reported chiral examples of 4- and 7-oxotetrahydroin-
doles, respectively, utilizing this procedure. Due to the low yields
of 7-oxotetrahydroindoles 2 obtained, however, a range of condi-
tions were tried in an attempt to improve upon the original proce-
dure (20% aq EtOH, 3 equiv of amine, 150 °C, 36 h, sealed tube).17
Decreasing the reaction time to below 24 h and lowering the equi-
valences of the amine to below 3 led to even lower yields with sub-
stantial amounts of unreacted starting material present. No
reaction occurred when the temperature was decreased to below
100 °C, whereas aprotic solvents (e.g., dichloroethane) and Lewis
acids under anhydrous or aqueous conditions (AlCl3 and
CeCl3ꢄ7H2O, respectively) tended to stall the transformation. On
the other hand, similar yields to the original conditions were ob-
tained when the reaction was carried out in protic solvents (MeOH,
EtOH) under anhydrous or aqueous conditions in the presence or
absence of small amounts of HCl. Interestingly, in the case of ben-
zylic amines, small amounts of the corresponding carbonyl deriva-
tives 8 could always be detected along with the product under all
conditions. This was never observed with the 4-oxo isomer 3. All of
these variations, however, ultimately failed to increase the yield of
the desired 7-oxotetrahydroindoles despite the fact that, under the
best conditions, the starting material was completely consumed
and no other UV-active organic soluble products than 2 and 8 (vide
supra) were identifiable from the reaction mixtures. Intrigue by
this outcome, we decided to perform a series of additional experi-
ments in order to better understand the formal oxidation to 8, fate
of the starting material 1 and difference in reactivity between the
4- and 7-oxotetrahydrobenzofurans 3 and 1, respectively. Reac-
tions were carried out according to the most successful anhydrous
conditions identified in a sealed tube, with the exception of using
an inert atmosphere and open vessel. Under these conditions, reac-
tion of 1 with
a-methylbenzylamine did not give the expected
product but a more complex mixture of baseline material and three
closely running components by tlc. After column chromatography
on silica the components were isolated and identified as tetra-
hydrobenzofuran derivative 5, the corresponding imine 7 and, as
before, acetophenone 8 (Scheme 3). With the less sterically hin-
dered benzylamine, on the other hand, the expected (confirmed
after hydrolysis of
6 to 2d (10%) with aq NH4Cl) masked
oxotetrahydroindole derivative 6 along with the corresponding
imine 7 and benzaldehyde 8 were obtained in low yield (Scheme 3).
We reasoned that after initial attack of the amine at the 2-position
of 1, as the first step of an ANRORC (Addition of the Nucleophile,
Ring Opening and Ring Closure) type mechanism, the enamine 9
should be formed (Fig. 1). In the case of 3, conjugate addition of
the amine at the 7a-position would result in formation of the more
reactive for cyclization and stable to tautomerization enamine 14
directly (Fig. 2). Intermediate 14 could, therefore, undergo immedi-
ate ring closure to give the corresponding 4-oxotetrahydroindoles
in high yield. In contrast, enamine 9 would presumably have to
equilibrate first to tautomer 13 (Fig. 1, Path b) before ring closure.
4
3
3a
5
6
i
2
O
1
OH
7a
7
O
O
1
Scheme 1. Reagent and condition: (i) chloroacetaldehyde, H2O, NaHCO3, 0–5 °C ?
rt overnight; aq H2SO4 (40%).

4278
A. G. Montalban et al. / Tetrahedron Letters 53 (2012) 4276–4279
less favorable and the tetrahedral intermediate derived thereof
more sterically hindered than the equivalent step in 14. This may
explain why reaction of 1 with -methylbenzylamine in an open
Y
a
X
vessel resulted in products from competing lower energy pathways
in place of 2f. Thus, enamine 9 could have instead tautomerize
through imine 10 to the more stable (at least when R is benzylic)
imine 11 (Fig. 1, Path a) which, in turn, could then have been for-
mally hydrolyzed to 8. The corresponding carbonyl derivative 8
could then give imine 7 by reacting with excess of the amine.
The determined enantiomeric purity of 2f (vide supra) suggests
that formation of the corresponding imine 10 is essentially irre-
versible (Path a), since no decreased enantiomeric excess or race-
mization is observed under sealed tube conditions. Thus, it
appears that cyclization to oxotetrahydroindole 2f occurs via the
corresponding enamine 13 (Path b) without involvement of the
RNH2
5
6
X = NR, Y = O
1
X = NR, Y = NR
aq. NH4Cl
2d X = O, Y = NBn
+
N
R
O
R
R
7
8
Scheme 3. Reagent and condition: (i) excess RNH2, protic solvent, N2,
D
.
1
RNH2
-RNH2
stereogenic center of the starting homochiral
a-methylbenzyl-
NR
NHR
N
amine which is, therefore, likely to be transferred to the product
unchanged. For the same reasons, we expect the asymmetric
center to remain intact over the sequence of reactions leading to
oxoindoles 17f and 19. Attempts to increase the nucleophilicity
of the amine by making the anion led only to deprotonation of 1
instead, as evidenced from the product (6-methyl-7-
oxotetrahydrobenzofuran) obtained along with starting material
after quenching of the reaction mixture with methyl iodide.
Aromatization of 2 and 4 to 4- and 7-hydroxyindoles, respec-
tively, was not straightforward. While reported methods6a,18 were,
in our hands, not as robust as expected, other dehydrogenation
strategies19 or b-elimination procedures20 failed. We attributed
the limited success, in part, due to the relative instability of the
products under the conditions of formation. On the other hand,
refluxing 4b and iodine in methanol21 gave the corresponding
5-iodo derivative 15b in 33% yield (Scheme 4).
a
R
OH
b
OH
OH
O
O
O
O
10
9
11
hydrolysis
NH2
NHR
8 +
RNH2
OHa
O
7
O
13
12
Figure 1. Proposed mechanism for the formation of 7 and 8 from reaction of 1 with
primary amines.
The yield of 15b could be further optimized to 82% by reacting
4b with LDA (lithium diisopropylamide) and trapping of the result-
ing anion with iodine. Dehydrohalogenation, on the other hand,
was best achieved with DBU (1,8-diazabicyclo[5.4.0]undec-7-ene)
as the base, thus, giving 4-hydroxyindole 17b in 75% yield. Simi-
O
O
NHR
20ꢁ
C
14
larly, 15f and enantiomerically enriched 17f (½
aꢀ
ꢂ ꢃ61.4° at
589nm
6.1 mg/mL in CHCl3) were obtained in 63% (as a separable mixture
of diastereoisomers) and 83%, respectively. Interestingly, refluxing
2f and iodine in methanol gave a mixture of the corresponding 6-
iodo analog 16f (60%) and 3-iodo isomer (10%). The two isomers
could easily be separated by column chromatography on silica
(5% EtOAc in light petroleum ether as eluent). The diastereomeric
Figure 2. Proposed intermediate from reaction of 3 with primary amines according
to an ANRORC type mechanism.
In addition, nucleophilic attack of the enamine moiety onto the ke-
tone (compared to aldehyde) group in 13 is probably kinetically
i
R1
R1
R3
or ii
N
N
R2
R2
4b R1 = 4-O, R2 = Me
15b R1 = 4-O, R2 = Me, R3 = 5-I (33 or 82%)
15f R1 = 4-O, R2 = PhCHCH3, R3 = 5-I (63%)
16f R1 = 7-O, R2 = PhCHCH3, R3 = 6-I (60 or 15%)
4f R1 = 4-O, R2 = PhCHCH3
2f R1 = 7-O, R2 = PhCHCH3
iii
iv
R1
N
N
R2
Ph
NC
O
19 (48% over two steps)
17b R1 = 4-OH, R2 = Me (75%)
17f R1 = 4-OH, R2 = PhCHCH3 (83%)
18f R1 = 7-OH, R2 = PhCHCH3
Scheme 4. Reagents and conditions: (i) MeOH, 2 equiv I2, N2, reflux, 2–4 h; (ii) LDA, THF, N2, then I2, ꢃ40 °C ? rt, 2 h; (iii) DBU (neat), N2, rt, 0.25–1 h; (iv) bromoacetonitrile,
K2CO3, butanone, N2, reflux, 1 h.

A. G. Montalban et al. / Tetrahedron Letters 53 (2012) 4276–4279
4279
2nd ed.; Longman Scientific & Technical: Essex, 1992; pp 223–236; (c) Davies,
D. T. In Aromatic Heterocyclic Chemistry; Davies, S. G., Ed.; Oxford University
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mixture (as confirm by H NMR) of 16f, however, could not be fur-
ther resolved. In contrast, deprotonation of 2f with LDA followed
by iodination gave 16f in much lower yield (15%) along with start-
ing material. Base catalyzed dehydrohalogenation (vide supra) of
the diastereomeric mixture 16f gave, as expected, a single product
(18f) but again in low yield, especially at higher temperatures. We
noticed that both, 16f and in particular 18f decomposed readily.
Thus, 18f was converted into its far more stable optically active
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20ꢁ
C
(½
a
ꢀ
ꢂ +133° at 1.9 mg/mL in CHCl3) alkoxy derivative 19 by
589nm
reacting it with bromoacetonitrile under basic conditions. The best
yields (48% over two steps) of 19 were obtained when both, the
dehydrohalogenation and alkylation steps were telescoped.
In Summary, we have developed a new synthesis of N-substi-
tuted 7-oxo-4,5,6,7-tetrahydroindoles and gained an understand-
ing of why the relative yields are lower when compared to the
corresponding 4-oxo-isomers under the conditions presented. Fur-
thermore, both, 4-, and 7-oxo-4,5,6,7-tetrahydroindoles were suc-
cessfully aromatized to their corresponding 4- and 7-oxoindoles
utilizing a novel protocol. In addition, the reaction sequences
appear to be stereospecific in nature resulting in enantiomerically
enriched N-substituted derivatives of both, 4-, and 7-oxo-4,5,6,7-
tetrahydroindoles and 4-, and 7-oxoindoles. Future work will
involve further optimization by, for example, conducting the
synthesis of 7-oxo-4,5,6,7-tetrahydroindoles under microwave
irradiation as recently demonstrated for the 4-oxo derivatives.22
13. Nayyar, N. K.; Hutchinson, D. R.; Martinelli, M. J. J. Org. Chem. 1997, 62, 982–
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17. General Procedure for the preparation of 4- and 7-oxotetrahydroindoles:
A
solution of 1 or 3 (0.10 g, 0.73 mmol) and the corresponding amine (3 equiv)
in 20% aqueous EtOH (ꢅ2 mL) was heated in a sealed tube at 150 °C for 12 or
36 h, respectively. The reaction mixture was poured into H2O (10 mL) and the
resulting aqueous solution extracted with CH2Cl2 (3 ꢆ 10 mL). The combined
organic extracts were dried (MgSO4), concentrated and the brown residue
subjected to column chromatography (silica) with EtOAc/light petroleum ether
as eluent.
Acknowledgments
We would like to thank Eli Lilly (A.G.M. and J.C.) and the Eras-
mus Scheme (S.M.B.) for generous support of our studies.
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