Preparation of 2,7-diamino-1,8-naphthyridine: A useful building block for supramolecular chemistry

Article abstract of DOI:10.1055/s-2005-868507

A two-step conversion of 2-chloro-7-amido-1,8-naphthyridine to 2,7-diamino-1,8-naphthyridine is described. The process, which involves a nucleophilic aromatic substitution reaction with 4-methoxybenzylamine and subsequent deprotection, can be carried out

Full text of DOI:10.1055/s-2005-868507

LETTER
1435
Preparation of 2,7-Diamino-1,8-naphthyridine: A Useful Building Block for
Supramolecular Chemistry
C
onvenient Syn
a
thesis of 2,
i
7-Diam
h
ino-1,8-naph
o
thyridine Park, Michael F. Mayer, Shoji Nakashima, Steven C. Zimmerman*
Department of Chemistry, University of Illinois, 600 S. Mathews Ave., Urbana, IL 61801, USA
Fax +1(217)2449919; E-mail: sczimmer@uiuc.edu
Received 23 February 2005
PhOH, NH3(g),
170 °C, 20 h
Abstract: A two-step conversion of 2-chloro-7-amido-1,8-naph-
thyridine to 2,7-diamino-1,8-naphthyridine is described. The pro-
cess, which involves a nucleophilic aromatic substitution reaction
with 4-methoxybenzylamine and subsequent deprotection, can be
carried out on a large scale.
20% (ref.7)
94% (ref.9)
Cl
N
N
Cl
H2N
N
N
NH2
NH4OH, 180 °C,
sealed tube, 24 h
Key words: heterocycles, nucleophilic aromatic substitution, su-
2
1
70% (ref.1d
)
pramolecular systems, hydrogen bond, amine protecting group
Scheme 1
2,7-Diamino-1,8-naphthyridine (1) and its analogs have
been shown to be very useful intermediates for the syn-
thesis of molecular building blocks that self-assemble into
a variety of super-structures using their donor-acceptor-
acceptor-donor (DAAD) array of hydrogen-bonding
sites.1–4 These compounds are also reported to possess a
variety of pharmacological effects such as antimycobacte-
rial, antitumor, antiallergic and benzodiazepine receptor
activity.5 Further interest in this class of compounds has
involved the study of their coordination complexes which
show strong luminescence6 and catalytic activity in oxida-
tion reactions.7
1) Ac2O, reflux
80%
O
2) POCl3,
90–95 °C,
1.5 h, 60%
H2N
N
N
OH
H3C
N
N
N
Cl
H
4
3
NH3, EtOH
180 °C, 24 h bomb
74%
steel
1
Scheme 2
occurred in a steel bomb in 74% yield but the scale was
limited.
The logical precursor to 1 is 2,7-dichloro-1,8-naphthyri-
dine (2) whose synthesis was reported by Newkome in
1981.8 Indeed, Collin and Youinou9 and later Reedijk7
treated 2 continuously with ammonia gas in phenol at 170
°C for 20 hours affording a variable yield of 1 (Scheme 1).
We found that treatment of 2 with ammonium hydroxide
in a sealed tube afforded 1 in 70% yield. Although the in-
convenient and costly use of gaseous ammonia was avoid-
ed, the scale of the reaction was limited and since the
original report1d we observed three separate sealed tube
explosions. The palladium-mediated coupling of aromatic
and heteroaromatic chlorides with lithium amides has
proven to be a very useful method.10 It was examined with
2 but the yields were variable, the product was difficult to
separate from by-products, and it was difficult to perform
on a large scale.
We report here a simple alternative method to accomplish
the 3 → 1 conversion that avoids the high pressure condi-
tions and can be carried out on a large scale. As outlined
in Scheme 3, 4-methoxybenzylamine serves as a high
boiling ammonia surrogate, by virtue of ready loss of the
4-methoxybenzyl protecting group upon treatment with
acid. A second equivalent of amine removes the acet-
amide group.
4-MeOC6H4CH2NH2,
pyridine, reflux
3
H2N
N
N
N
83%
H
5
OCH3
concd HCl,
reflux
95%
An alternative starting material is 2-chloro-7-acetamido-
1,8-naphthyridine (3), which can be prepared by acetyla-
tion of amine 4,1d and subsequent reaction with phospho-
rous oxychloride (Scheme 2). The synthesis of 4 from 2,6-
diaminopyridine and DL-malic acid was reported by
Newkome as a precursor to 2.8 The conversion of 3 to 1
1
Scheme 3
On a gram scale the four step 4 → 3 → 5 → 1 transforma-
tion proceeded uneventfully with 1 obtained in an overall
yield of 35%. The process was scaled up to the half kilo-
gram level. In this case the acid neutralization in the sec-
ond step led to partial deacetylation of product 3. It was
found that the mixture could be carried forward without
SYNLETT 2005, No. 9, pp 1435–1436
0
1.
0
6.
2
0
0
5
Advanced online publication: 29.04.2005
DOI: 10.1055/s-2005-868507; Art ID: S02405ST
© Georg Thieme Verlag Stuttgart · New York

1436
T. Park et al.
LETTER
ing precipitation. The majority MeOH was removed in vacuo. The
solid slurry was filtered, washed with Et2O and vacuum-dried to
give 223 g of crude 2-amino-7-chloro-1,8-naphthyridine containing
ca. 12% (determined by 1H NMR) of 3 as a brown solid.
separation to give crude 5, which in turn could be depro-
tected with acid giving ca. 95–98% pure 1 obtained by
precipitation.
The main limitation in the method of preparation of 1 de-
scribed herein is the cost of the 4-methoxybenzylamine,
which must be used in excess. Nonetheless, it represents a
safer alternative to our previously published procedure1d
and one that allows 1 to be prepared readily on multigram
scale. As such, the utility of this already useful building
block in supramolecular chemistry should be increased.
To 186 g of the crude mixture obtained above was added pyridine
(500 mL) and 4-methoxybenzylamine (283 mL, 2.19 mol) under
N2. The mixture was heated to reflux for 72 h and then cooled to r.t.
The majority of the pyridine was removed in vacuo giving a brown
sludge. EtOAc was added to form a slurry that was collected by fil-
tration. The filtered solid and concd HCl (2.5 L) was heated to 90
°C (solution temperature) for 2 h. The mixture was allowed to cool
to r.t. giving partial crystallization of the mixture with sludge. The
mixture was neutralized with aq Na2CO3 and then aq NaOH at 0 °C.
CH2Cl2 (1 L) was added to the neutralized solution and the mixture
was stirred for 30 min, giving a precipitate that was collected with
vacuum filtration, washed with CH2Cl2–H2O, and dried in vacuo to
Typical Experimental Procedures
Gram Scale Preparation of N-(4-Methoxybenzyl)-2,7-diamino-
1,8-naphthyridine (5)
1
To a mixture of 3 (4.0 g, 18 mmol) and commercially available 4-
methoxybenzylamine (7.1 mL, 54 mmol) was added pyridine (70
mL) under N2. The mixture was heated to reflux for 48 h and then
cooled to r.t. The majority pyridine was removed in vacuo giving a
brown mud. The crude material was purified by column chromatog-
raphy (SiO2, gradient from EtOAc to 70:30 EtOAc–MeOH), fol-
lowed by recrystallization from CHCl3–MeOH to give 4.2 g (83%)
of 5 as a pale yellow solid: mp 141–143 °C. 1H NMR (400 MHz,
DMSO-d6): d = 7.98 (2 H, t, J = 5.5 Hz, NH2), 7.79 (2 H, d, J = 8.6
Hz, ArH), 7.67 (2 H, d, J = 8.6 Hz, ArH), 7.35 (H, s, NH), 7.26 (2
H, d, J = 8.6 Hz, ArH), 6.83 (2 H, d, J = 8.6 Hz, ArH), 6.56 (2 H, d,
J = 8.6 Hz, ArH), 6.51 (2 H, d, J = 8.6 Hz, ArH) and 3.68 (3 H, s,
OCH3). 13C NMR (125 MHz, DMSO-d6): d = 160.04, 158.87,
158.65, 153.18, 140.37, 137.40, 132.24, 129.57, 114.32, 109.36,
106.83, 55.70, 44.01. MS (ESI): m/z calcd for C16H17N4O [M+H]+:
281.1402; found: 281.1398 [M+H]+.
yield 142 g (86%) of 1 estimated to be ca. 95–98% pure by H
NMR. Spectral properties were identical to that prepared above.
Acknowledgment
Funding of this work by the NSF (CHE-0212772) is gratefully
acknowledged.
References
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Gram Scale Preparation of 2,7-Diamino-1,8-naphthyridine (1)
A mixture of 5 (4.2 g, 15 mmol) and concd HCl (30 mL) was heated
to reflux for 2 h. The solution was allowed to cool to r.t. giving par-
tial crystallization of the mixture with sludge. The mixture was neu-
tralized with aq Na2CO3 and then aq NaOH at 0 °C. Methylene
chloride (40 mL) was added to the neutralized solution and the mix-
ture was stirred for 30 min, giving a precipitate that was collected
with vacuum filtration, washed with CH2Cl2–H2O, and dried in vac-
uo to yield 2.3 g (95%) of 1 as pale yellow solid: mp 270–273 °C.
1H NMR (400 MHz, DMSO-d6): d = 7.89 (2 H, d, J = 8.7 Hz, ArH),
7.83 (4 H, s, NH2), 7.59 (2 H, d, J = 8.6 Hz, ArH). 13C NMR (125
MHz, DMSO-d6): d = 159.51, 149.84, 140.50, 108.57, 108.19.
MS (ESI): m/z calcd for C8H9N4 [M+H]+: 161.0827; found
161.0808 [M+H]+.
Multigram Scale Preparation of 2,7-Diamino-1,8-naphthyri-
dine (1)
A mixture of 2-acetamido-7-hydroxy-1,8-naphthyridine (571 g, 2.8
mol) and POCl3 (2.6 L) was heated at 90–95 °C for 2 h. The result-
ing solution was cooled to r.t., and excess POCl3 was removed by
high vacuum equipped with a double trap. The flask containing the
crude product was placed in an ice-water bath, and the solution was,
carefully and slowly, made basic (pH = 11) with concd NH4OH and
ice water. The mixture was stirred at 55–60 °C for 5 h. Neutraliza-
tion with 6 M HCl produced a dark brown precipitate, which was
collected by vacuum filtration. The resulting solid was dissolved in
hot EtOH and insoluble material was filtered off. The solvent was
removed from the ethanolic filtrate in vacuo to give 398 g (ca. 64%
based on 4 that is 67% in 1H NMR) of a ca. 2:1 mixture of 3 to 2-
amino-7-chloro-1,8-naphthyridine as brown solid.
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To 273 g (1.2 mol based on 2-acetamido-7-hydroxy-1,8-naphthyri-
dine) of the aforementioned mixture was poured 1 wt% KOH–
MeOH solution and the mixture was stirred at r.t. for 1 h. The mix-
ture was cooled to 0 °C and then taken to pH = 8 with 6 M HCl caus-
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Synlett 2005, No. 9, 1435–1436 © Thieme Stuttgart · New York