Aminomethylation of lithiated nicotinamide: access to new pyridolactams

Article abstract of DOI:10.1016/j.tetlet.2007.11.109

New 2,3-dihydropyrrolopyridinones were conveniently prepared by trapping lithiated pyridine carboxamides with highly reactive formimines. In this Letter, we report that a wide range of N-functionalised compounds can be synthesised in one step by this process, allowing the presence of ethers, acetals or ester moieties.

Full text of DOI:10.1016/j.tetlet.2007.11.109

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 437–440
Aminomethylation of lithiated nicotinamide: access to new
pyridolactams
*
Emilie Prieur, Rabah Azzouz, Geoffrey Deguest, Corinne Fruit
*
Laurent Bischoff , Francis Marsais
Laboratoire de Chimie Organique Fine et H e´ t e´ rocyclique, UMR CNRS 6014 IRCOF-INSA Rouen, Universit e´ de Rouen,
BP08 76131 Mont-Saint-Aignan Cedex, France
Received 23 October 2007; accepted 20 November 2007
Available online 23 November 2007
Abstract
New 2,3-dihydropyrrolopyridinones were conveniently prepared by trapping lithiated pyridine carboxamides with highly reactive
formimines. In this Letter, we report that a wide range of N-functionalised compounds can be synthesised in one step by this process,
allowing the presence of ethers, acetals or ester moieties.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Pyridine; Metalation; Formimine; Lactam; Aminomethylation
1
. Introduction
derived synthons, taking advantage of the p-deficient
character of the heterocycle, which allows intramolecular
nucleophilic addition of a benzylic carbanion followed by
oxidative rearomatisation. We recently disclosed that the
condensation of a Mannich equivalent with a tertiary
amide derived from nicotinic acid or its isomers could also
The synthesis of isoindolinones is widely reported in the
1
literature, whereas their aza-analogue derivatives such as
2
As depicted in Scheme 1, formation of the C–C bond of
the lactam can be achieved via five different methodologies.
Couture and co-workers were the first to describe a
process based on aromatic nucleophilic substitution with
phosphonic enolates, as an efficient way to obtain azaiso-
indolinones especially in benzenic series. Then, his group
developed a further strategy accomplished by a two steps
sequence involving the quenching with DMF of a dilithia-
,3-dihydropyrrolopyridinones are much less described.
6
efficiently lead to this structure. The aminomethylated
2
intermediate, bearing both electrophilic and nucleophilic
centres, is a versatile intermediate for the synthesis of
pyrrolopyiridinones. These five methods open the way to
different structures covering a wide range of potential
targets.
In the course of using nicotinic acid derivatives as build-
ing blocks, we worked out a straightforward synthesis of
N-functionalised 2,3-dihydropyrrolopyridinones as precur-
sors for new heterocyclic compounds by modulating the
alkyl group of substituted formimines. N-Alkyl formimines
3
ted isonicotinamide derivative. This relevant approach
involved the C–C bond formation before the C–N intra-
molecular bond. Substituted 3-(arylmethylene)-pyrrolopy-
ridinones were efficiently synthesised by Cossy and
co-workers using Pd(0)-catalysed Heck–Suzuki–Miyaura
7
constitute a family of imines, which are extremely reactive
4
5
domino reactions. Clayden’s group obtained pyridine-
despite the absence of electron-withdrawing groups on the
nitrogen atom. Our conceptual strategy for the synthesis of
N-functionalised 2,3-dihydropyrrolopyridinones is detailed
in Scheme 2 and consists in the reaction of a lithiated
pyridine carboxamide with in situ generated formimines.
*
Corresponding authors. Tel./fax: +33 2 35522962.
E-mail addresses: corinne.fruit@insa-rouen.fr (C. Fruit), laurent.
bischoff@insa-rouen.fr (L. Bischoff).
0
040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.109

438
E. Prieur et al. / Tetrahedron Letters 49 (2008) 437–440
Li
O
Me
N
(
EtO) OP
N
2
Cl
N
O
Ref 4
R
Br
N
Ref 2
Ph
Li
X
tBu
N
N
O
Ref 5
O
N
N
Ref 3
Ref 6
Li
N
OLi
Li
O
O
PMB
NMe
+
NR'2
N
Me N
N
2
Scheme 1. C–C bond formation in pyridolactam syntheses.
R
R
N
Li
N
O
Li
O
N
RNH
CN
N
O
N
N
N
Scheme 2. Synthesis of pyrrolopyiridinones using the tandem aminomethylation–cyclization reaction.
Precedence for this approach was provided in 1984 by
Overman who showed that unstable formimines were
formed in situ by reacting organolithiums or Grignard
reagents with secondary N-cyanomethylamines. These
formimines allowed further lactamisation of esters and
Table 1
Preparation of cyanomethylamines
K CO , MeCN, reflux
2
3
R-NH2
ClCH CN
R-NH-CH
2
-CN
2
Entry
R
Yield (%)
8
synthesis of azetidinones.
1
2
3
4
5
6
7
8
(CH
2
2
2
2
2
2
2
)
)
)
)
)
)
)
3
2
2
3
2
3
4
CH
CH=CH
2
3
81
90
65
63
(CH
(CH
(CH
(CH
(CH
(CH
CH(OEt)
CH(OEt)
COOMe
OTBDMS
OTBDMS
2
2
. Results and discussion
2
a
92
Due to their high propensity for trimerisation, N-alkyl
b
88
95
b
formimines require in situ generation through elimination
of cyanide ion starting from cyanomethylamines. Despite
the toxicity of the released cyanide ions, cyanomethylam-
ines are useful compounds for this reaction. In particular,
their preparation is very easy and does not give rise to poly-
alkylated compounds. As listed in Table 1, we first pre-
pared some cyanomethylamines by N-alkylation with
chloroacetonitrile.
c
p-Me(C
6
H
4
)
95
Me
c
9
98
COOMe
10
N(CH2)5
35
a
Prepared from the hydrochloride salt, with an additional equivalent of
K CO .
2
3
b
Yields obtained over two steps: alkylation of 3-aminopropanol then
protection with TBDMSCl/imidazole.
This reaction was conducted in refluxing acetonitrile for
c
Reaction was conducted in the presence of 1 equiv NaI.
3
h in the presence of potassium carbonate and gave good
9
yields of pure products after distillation, except in the case
of piperidine hydrazine (entry 10). In the case of aromatic
amines, the reaction was slow but accelerated by the addi-
tion of sodium iodide providing N-arylcyanomethylamines
in very good yields (entries 8 and 9).
Given the easy access to these N-substituted cyanometh-
ylamines, aminomethylation of lithiated N-piperidylnicoti-
namide and further cyclization were explored. The results
of performing this tandem reaction are displayed in Table
(LiTMP, 3 equiv) and immediately treated with 1 equiv of
cyanomethylamine derivative. After 7 h at À78°C, the reac-
tion was quenched with aqueous NH Cl. This reaction
4
took place with moderate to good yields. We were pleased
to notice that the presence of functional groups such as
masked aldehydes (entries 3 and 4) or protected alcohols
(entries 5 and 6) did not interfere with the reaction condi-
tions. To our surprise, subjecting the methyl ester deriva-
tive to this reaction conditions results in cyclisation
(entry 7). The modest yield is presumably due to a possible
2
. The ortho-lithiated nicotinamide was generated at
À78 °C in THF with lithium 2,2,6,6-tetramethylpiperidine

E. Prieur et al. / Tetrahedron Letters 49 (2008) 437–440
439
Table 2
cyclic compounds, since further C–C bond formations
can be envisaged between the lactamic methylene and elec-
trophilic moieties branched on the starting cyanomethyl-
amines. The synthesis of new heterocyclic compounds is
currently under investigation.
New N-functionalised 2,3-dihydropyrrolopyridinones
Entry
Product
Yield (%)
n-Bu
N
N
4
2
1
O
4. Experimental
N
N
The following procedure for the synthesis of 2-(3,3-dieth-
oxypropyl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (Table 2,
entry 3), is illustrative:
2
3
4
5
6
53
53
69
52
67
O
To a stirred solution of n-butyllithium (1.6 M, 2.96 mL,
CH(OEt)2
CH(OEt)
4.74 mmol) in anhydrous THF (50 mL) was added drop-
N
N
N
wise 2,2,6,6-tetramethylpiperidine (0.81 mL, 4.74 mmol)
O
O
O
at À10 °C. The solution was allowed to stir at 0 °C for
3
0 min then cooled to À78 °C. Piperidine nicotinamide
N
N
N
2
(302 mg, 1.59 mmol) in anhydrous THF (5 mL) was added
in 5 min immediately followed by dropwise addition of 3,3-
diethoxypropylaminoacetonitrile (297 mg, 1.59 mmol) in
anhydrous THF (5 mL). The reaction was kept at this tem-
perature for 7 h and was quenched with aqueous ammo-
nium chloride (10%) and extracted with diethyl ether
OTBDMS
OTBDMS
(
3 Â 40 mL). The combined organic layers were dried over
MgSO , filtered and concentrated in vacuo. The product
4
was purified by flash chromatography through SiO2
(
dichloromethane/isopropanol/triethylamine: 20:1:0.2, R =
f
0.63) to give the pyridolactam (219 mg, 53%) as a yellow
N
N
liquid.
O
O
1
H NMR (CDCl , 300 MHz): 1.15 (t, J = 7.0 Hz, 6H),
3
2
4
.00 (dt, J = 5.4 Hz, 5.7 Hz, 2H), 3.49 (m, 2H), 3.67 (m,
H), 4.45 (s, 2H), 4.57 (t, J = 5.7 Hz, 1H), 7.42 (dd, J =
N
N
COOMe
0.8 Hz, 5.1 Hz, 1H), 8.74 (d, J = 5.1 Hz, 1H), 9.08 (d,
7
8
28
25
13
J = 0.8 Hz, 1H); C NMR (CDCl , 75 MHz): 15.4, 32.6,
3
3
1
8.7, 50.1, 62.1, 101.5, 118.2, 129.1, 146.0, 149.8, 151.3,
66.9; IC(+)-MS (MH+) m/z = 265, 219, 191; Anal. Calcd
for C H N O : C, 64.26; H, 8.63; N, 9.99. Found: C,
1
4
20
2
3
N
N
64.09; H, 8.47; N, 10.12.
O
Acknowledgement
N
Geoffrey Deguest is grateful to the MNESR for a Grant.
N-deprotection via b-elimination of methyl acrylate. In
addition, the reactivity of a hydrazine-derived compound
References and notes
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entry 8) was examined, the tandem reaction leading in this
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place but further lactamisation was sluggish, due to low-
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2
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