An autoxidative approach to 1,2,3,4-tetrahydroisoquinolin-1-one and tetrahydro-β-carbolin-1-one

Article abstract of DOI:10.1016/S0040-4039(01)00482-8

Treatment of N-benzyl 1,2,3,4-tetrahydroisoquinoline-1-carboxylate with sodium hydride in N,N-dimethylformamide gives the corresponding N-benzyl 1,2,3,4-tetrahydroisoquinolin-1-one in quantitative yield. The N-benzyl 1,2,3,4-tetrahydro-β-carbolin-1-one is prepared in a similar fashion. The N-deprotection occurred concomitantly with the oxidative decarboxylation when the nitrogen was benzyloxycarbonylated.

Full text of DOI:10.1016/S0040-4039(01)00482-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3427–3430
An autoxidative approach to 1,2,3,4-tetrahydroisoquinolin-1-one
and tetrahydro-b-carbolin-1-one
Miche`le Bois-Choussy, Michae¨l De Paolis and Jieping Zhu*
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette, France
Received 22 March 2001; accepted 23 March 2001
Abstract—Treatment of N-benzyl 1,2,3,4-tetrahydroisoquinoline-1-carboxylate with sodium hydride in N,N-dimethylformamide
gives the corresponding N-benzyl 1,2,3,4-tetrahydroisoquinolin-1-one in quantitative yield. The N-benzyl 1,2,3,4-tetrahydro-b-car-
bolin-1-one is prepared in a similar fashion. The N-deprotection occurred concomitantly with the oxidative decarboxylation when
the nitrogen was benzyloxycarbonylated. © 2001 Elsevier Science Ltd. All rights reserved.
1,2,3,4-Tetrahydroisoquinolin-1-one is a structural unit
found in a number of complex natural products such as
the Narcissus alkaloids narciclasine (1) and pancratis-
tatin (2) (Fig. 1).1 It is conventionally prepared by the
Bischler–Napieralski reaction from the corresponding
N-carbamate.2 However, such conversion usually
requires drastic conditions and yields are generally only
moderate at best. To overcome this drawback, a
modified procedure using a reagent combination (Tf2O–
DMAP) has been developed and applied to the total
synthesis of Amaryllidaceae alkaloids.3 Nevertheless,
the yield still remains moderate when applied to the
synthesis of complex molecules.4 Alternatively, an
intramolecular Friedel–Crafts reaction of isocyanate5
taking advantage of the facile 6-exo-dig mode of
cyclization,6 as well as the condensation of lithiated
phthalides,7 homophthalic anhydrides8 and lithiated
N,N-diethyl-ortho-toluamides9 with imines10 followed
by ring closure, have been developed for the same
purpose. In a series of papers dealing with the chem-
istry of mu¨nchnones, Kawase and co-workers described
a synthesis of 1,2,3,4-tetrahydroisoquinolin-1-one by
simple treatment of the N-acyl tetrahydroisoquinoline-
In connection with our ongoing project, we had the
occasion to investigate the hydroxymethylation of
methyl 1,2,3,4-tetrahydroisoquinoline-1-carboxylate (3)
and found, accidentally, a simple yet high yield synthe-
sis of the title compound (Scheme 1). Thus, treatment
of 3a with sodium hydride (NaH) in N,N-dimethylfor-
mamide (DMF) followed by addition of paraformalde-
hyde gave, instead of the aldol product, the
OH
OH
HO
H
OH
OH
OH
OH
O
O
O
O
H
H
NH
NH
OH
O
OH
O
1 narciclasine
2 pancratistatin
Figure 1.
MeO
MeO
MeO
MeO
a
NBn
NBn
1-carboxylic acid with DCC in dichloromethane.11
A
O
COOR
mechanism involving a formal cycloaddition of oxygen
and the mu¨nchnone intermediate followed by fragmen-
tation has been advanced. This same transformation
(activation of an acid as a mixed anhydride instead of
DCC), with a different mechanistic view, has previously
been reported from the group of Debaert.12
3a R = Me
3b R = Et
4
6
NBn
O
a
NBn
N
H
COOMe
N
H
5
* Corresponding author. Fax: 33 1 69 07 72 47; e-mail: zhu@
icsn.cnrs-gif.fr
Scheme 1. (a) NaH, DMF, room temperature.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00482-8

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M. Bois-Choussy et al. / Tetrahedron Letters 42 (2001) 3427–3430
corresponding N-benzyl tetrahydroisoquinolin-1-one 4
in a quantitative yield. The reaction course was not
modified whether the reaction was run at −5°C or at
room temperature. Subsequent studies showed that the
presence of formaldehyde was not required and that the
reaction proceeded smoothly by simply adding a DMF
solution of 3a into the suspension of NaH in the same
solvent. The transformation took place readily in
dimethyl sulfoxide (DMSO), but not in tetra-
hydrofurane (THF). The oxidative process dominated
even in the presence of a large excess of gaseous
formaldehyde. The reaction was accelerated in air-bub-
bled DMF under an aerobic atmosphere, indicating the
role of oxygen in the present process. Nevertheless, the
amount of oxygen dissolved in the solvent is sufficient
to complete the oxidation. Analytic grade DMF can be
used as received from the commercial sources. How-
ever, the reaction was slowed down significantly when a
freshly redistilled DMF was used. The ethyl ester 3b
was similarly converted to 4 in quantitative yield.
MeO
MeO
7 R = COOBn
8 R = COOtBu
9 R = COMe
10 R = H
N
R
EtOOC
MeO
MeO
NaH
DMF
7 R = COOBn
8 R = COOtBu
+
NH
O
11
MeO
MeO
NHR
MeO
+
OH
NR
MeO
O
O
12 R = COOBn
13 R = COOtBu
14 R = COOBn
15 R = COOtBu
Scheme 2.
The procedure applied with equal efficiency to the
tetrahydro-b-carboline. Thus, treatment of methyl Nb-
mediate 19 followed by fragmentation then afforded the
observed compound 4.16
benzyl-1,2,3,4-tetrahydrocarboline-1-carboxylate
(5)
under identical conditions provided the corresponding
Nb-benzyl-1,2,3,4-tetrahydro-b-carbolin-1-one (6) in
higher than 85% isolated yield. Protection of the indole
nitrogen was not required.
The effect of the N-protective group on the reaction
outcome was intriguing and was indicative of the com-
plex reaction manifolds. The most direct yet logical
mechanism that accounts for the results from the reac-
tion of 7 and 8 would involve the formation of imide 14
and 15, which could then be hydrolyzed to the tetra-
hydroisoquinolinone 11 and the amino acids 12 and 13
(route a, Scheme 4). In the case of the N-Boc tetra-
hydroisoquinoline 8, the formation of amino acid 13 as
the major product indicated that pathway a may be
operating. Indeed, when imide 15 (R=OtBu) was re-
submitted to the identical reaction conditions (NaH,
DMF, then H2O), a mixture of the amino acid 13 and
To examine the influence of the N-protecting group on
the outcome of the reaction, compounds 7, 8 and 9, 10
were synthesized. When the N-Cbz protected derivative
7 was treated with NaH in DMF, oxidation with
concomitant removal of the N-benzyloxy carbonyl
function occurred to give the tetrahydroisoquinolin-1-
one (11) and the ring opened amino acid 12 in 80 and
10% isolated yields, respectively. An analytically pure
11 can be obtained by a simple acid–base extraction.
Thus, depending on the choice of N-protecting group,
it is possible to synthesize directly either the N-alkyl-
ated (4) or the N-unprotected 1,2,3,4-tetrahydro-
isoquinolin-1-one (11) at will.13 The reaction of the
N-Boc derivative 8 produced, under identical condi-
tions, three compounds 11, 13 and 15 in 10, 50 and 30%
yields, respectively.14 Surprisingly, when the N-acetyl-
ated derivative (9) was subjected to the same reaction
conditions, a complex mixture was obtained from
which the corresponding tetrahydroisoquinolinone 11
was isolated in less than 10% yield. On the other hand,
no oxidation product was isolable from the complex
reaction mixture of the N-unprotected derivative 10.
Since Kawase’s method works only with N-acylated
tetrahydroisoquinoline-1-carboxylic acid, a different
reaction mechanism should thus be envisaged (Scheme
2).
MeO
MeO
MeO
MeO
NaH
NBn
NBn
COOMe
NaO
16
OMe
3
MeO
MeO
O2
O2
NBn
COOMe
17
MeO
NBn
O
MeO
MeOOC
O
18
MeO
MeO
While no detailed mechanistic study was performed, a
working hypothesis is depicted in Scheme 3 for the
formation of compound 4 from 3. Enolization followed
by single electron transfer (SET) with oxygen gave the
stabilized capto-dative radical 1715 and the superoxide
radical anion that may combine to produce the
hydroperoxide anion 18. Formation of the spiro inter-
4
+ CO2
NBn
O
O
O
19
Scheme 3.

M. Bois-Choussy et al. / Tetrahedron Letters 42 (2001) 3427–3430
3429
Acknowledgements
MeO
MeO
N
O
R
We thank CNRS for financial support. A doctoral
fellowship from the MENRT to M.D. is gratefully
acknowledged.
O
EtOOC
O
O
20
a
b
MeO
MeO
References
MeO
MeO
N
O
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NCOOR
O
O
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21
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13 R = tBu
Scheme 4.
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The failure to isolate the imide 14 from 7 prompted us
to follow the reaction course by 1H NMR using
DMSO-d6 as a solvent. It was observed that the forma-
tion of tetrahydroisoquinolin-1-one 11 was accompa-
nied by the concomitant formation of ethanol and
benzyl alcohol. The imide intermediate 14 (R=Bn) was
undetectable even at the very early stage of the reac-
tion.18 This observation led us to suppose that an
alternative reaction path such as the one involving
participation of the N-carbamoyl carbonyl function
may be operating (Scheme 4, route b). The diminished
steric hindrance of the N-Cbz function may compete
favorably with the ester group in intercepting the per-
oxide anion, leading to the intermediate 21 (Scheme 4).
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13. To a flask containing sodium hydride (15.0 mg, 60% in
In summary, we have developed an operationally
simple yet efficient synthesis of 1,2,3,4-tetra-
hydroisoquinolin-1-one and 1,2,3,4-tetrahydro-b-carbo-
lin-1-one by an autoxidative process. Since the starting
material can be prepared in high yield by the classic
Pictet–Spengler reaction,19 its combination with the
present methodology constitutes an attractive alterna-
tive to the Bischler–Napieralski reaction for the synthe-
sis of tetrahydroisoquinolinone and should find
applications in complex product syntheses.
paraffin, 0.4 mmol) washed twice with pentane was added
a
solution of ethyl N-benzyl-1,2,3,4-tetrahydroiso-
quinoline-1-carboxylate (3b, 71 mg, 0.2 mmol) in DMF (6
mL) at room temperature. After being stirred at the same
temperature for 30 min, the reaction mixture was
quenched by the addition of an aqueous HCl solution
and extracted with EtOAc. The combined organic
extracts were washed with brine, dried (Na2SO4) and

3430
M. Bois-Choussy et al. / Tetrahedron Letters 42 (2001) 3427–3430
evaporated to afford analytically pure quinolinone 4 in a
DMF seems to be beneficial to the present reaction.
Nevertheless treatment of 7 with sodium hydroxide in
quantitative yield. Mp 52–54°C; IR (CHCl3) w 1638, 1604,
1510, 1480, 1280 cm−1; 1H NMR (CDCl3, 250 MHz) l 2.87
(t, J=6.0 Hz, 2H), 3.48 (t, J=6.0 Hz, 2H), 3.91 (s, 3H),
3.94 (s, 3H), 4.78 (s, 2H), 6.62 (s, 2H), 7.33 (m, 5H), 7.67
(s, 1H); 13C NMR (CDCl3, 62.5 MHz) l 27.7, 29.7, 45.7,
50.5, 56.1, 109.4, 110.8, 121.9, 127.4, 128.0, 128.7, 131.8,
137.6, 148.0, 151.9, 164.7; MS (EI) m/z 297. Following the
same procedure, the N-Cbz derivative 7 was transformed
into tetrahydroisoquinolinone 11 in an 80% yield. Mp
171–175°C, lit:2 169–171°C; IR (CHCl3) l 1659, 1606,
1513, 1481, 1339, 1276 cm−1; 1H NMR (CDCl3, 250 MHz)
l 2.93 (m, 2H), 3.53 (m, 2H), 3.93 (s, 6H), 6.0 (br s, 1H),
6.67 (s, 1H), 7.57 (s, 1H); 13C NMR (CDCl3, 62.5 MHz)
l 28.2, 40.7, 56.2, 56.3, 109.7, 110.3, 121.5, 132.7, 148.2,
152.2, 166.5; MS (ES) m/z 208 (M+1).
DMF produced only
a
trace amount of tetra-
hydroisoquinolinone.
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1
18. The H NMR spectra of starting material, N-alkoxycar-
bonyl quinolinone and N-unprotected quinolinone are
easily distinguishable. DMSO-d6, containing
a trace
amount of water, was used as received.
14. More reproducible results were obtained using non-dis-
tilled analytically pure DMF. A trace amount of water in
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.
.