A facile synthesis of the 3-amino-5,6,7,8-tetrahydro[1,6]naphthyridine system and some alkylated and polycyclic homologues

Article abstract of DOI:10.1081/SCC-100103271

A facile, two step synthesis of the 3-amino-5,6,7,8-tetrahydro[1,6]naphthyridine system 1 and its more substituted homologues 2-5 via the condensation of mono- and bicyclic-4-piperidinones 11a-c, 12-14 with 3,5-dinitro-1-methyl-2-pyridone 6 in the presenc

Full text of DOI:10.1081/SCC-100103271

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A FACILE SYNTHESIS OF
THE 3-AMINO-5,6,7,8-
TETRAHYDRO[1,6]NAPHTHYRIDINE
SYSTEM AND SOME
ALKYLATED AND POLYCYCLIC
HOMOLOGUES
John D. Harling, Frank P. Harrington & Mervyn
Thompson
Version of record first published: 16 Aug 2006
To cite this article: John D. Harling, Frank P. Harrington & Mervyn
Thompson (2001): A FACILE SYNTHESIS OF THE 3-AMINO-5,6,7,8-
TETRAHYDRO[1,6]NAPHTHYRIDINE SYSTEM AND SOME ALKYLATED AND POLYCYCLIC
HOMOLOGUES, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 31:5, 787-797
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SYNTHETIC COMMUNICATIONS, 31(5), 787–797 (2001)
A FACILE SYNTHESIS OF THE
3-AMINO-5,6,7,8-
TETRAHYDRO[1,6]NAPHTHYRIDINE
SYSTEM AND SOME ALKYLATED AND
POLYCYCLIC HOMOLOGUES
John D. Harling, Frank P. Harrington,*
and Mervyn Thompson
SmithKline Beecham Pharmaceuticals, New Frontiers
Science Park, Third Avenue, Harlow,
Essex CM19 5AW, UK
ABSTRACT
A facile, two step synthesis of the 3-amino-5,6,7,8-tetra-
hydro[1,6]naphthyridine system 1 and its more substituted
homologues 2–5 via the condensation of mono- and bicyclic-
4-piperidinones 11a–c, 12–14 with 3,5-dinitro-1-methyl-2-
pyridone 6 in the presence of ammonia is described.
During the course of our research on potential anticonvulsants1
we required the synthesis of 3-amino-6-methyl-5,6,7,8-tetrahydro[1,6]-
naphthyridine 1d, hopefully utilising methodology that would also allow
for the rapid synthesis of a number of homologues 2b–5b. Although
much is known about the synthesis and chemistry of the fully aromatic
1,6-naphthyridine system,2,3 much less is known4–11 about the correspond-
ing, partially reduced system 1. The 8,8-disubstituted 2 and tricyclic systems
3–5 have not previously been reported. (The only reported synthesis of
* Corresponding author.
787
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

788
HARLING, HARRINGTON, AND THOMPSON
3-amino-6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridine 1d promising any
degree of versatility was published by Marcelis and Van der Plas.11
The authors described the condensation of enamines with 5-nitropyr-
imidine to give fused nitropyridines, of which 1a and 1b are illustrated
examples. However, the yield of 1a was a disappointing 16% and the utility
of the reaction was not exhaustively investigated.)
Furthermore, apart from this one exception, the published syntheses
of 5,6,7,8-tetrahydro[1,6]naphthyridines containing a nitrogen functionality
at C(3) are highly convoluted, universally low yielding and not amenable to
the rapid synthesis of analogues containing further substituents in the par-
tially saturated ring. Moreover, 3-nitropyridines are notoriously difficult
molecules to synthesize by simple nitration.12 Tohda et al.13–15 later
described the condensation of 3,5-dinitro-1-methyl-2-pyridone 6 with
cyclic ketones 7 and ammonia to give 3-nitro-5,6,7,8-tetrahydroquinolines
8 as shown in Scheme 1.
Subsequently, Takada et al.16 demonstrated that pyranones 9 would
also participate in the reaction giving rise to 3-nitro-7,8-dihydro-5H-
pyrano[4,3-b]pyridine containing a second heterocyclic ring 10.
No literature reports have appeared to date, however, describing the
use of 4-piperidinones 11a–c, 12–15 in this reaction, which would be
expected to give 3-nitro-5,6,7,8-tetrahydro[1,6]naphthyridines 1a–c, 2a–5a.
We now wish to report the results of our work in this area and to describe
the preparation of a number of hitherto, unknown and rather inaccessible

3-AMINO-5,6,7,8-TETRAHYDRO[1,6]NAPHTHYRIDINE
789
Scheme 1.
3-nitro- and 3-aminoheterocycles 1–5, which are readily available using this
chemistry.
The condensation of a small range of N(1)-substituted-4-piperidinones
11a–c with dinitropyridone 6 demonstrated that the bulk of the substituent
at N(1) has no detrimental effect on the outcome of the reaction. Indeed, the
smaller N-methyl-4-piperidinone 11a gave the bicycle 1a in 59% yield,
whereas, the bulkier N-benzyl 11b and N t-butoxycarbonyl 11c 4-piperidi-
nones gave naphthyridines 1b and 1c in 93% and 84% yields respectively.

790
HARLING, HARRINGTON, AND THOMPSON
Substitution at the C3 position of the 4-piperidinone ring, as in 12, also had
little or no effect, the bicycle 2a being isolated in 57% yield. The azabicyclic
ketones 13 and 14a also participated in the reaction, giving 3a and 4a in
52% and 50% yields respectively; 14b, however, only gave bicycle 5a in a
disappointing 40% yield. Interestingly, we were unable to find any trace of
product when the tetramethyl-4-piperidinone 15 was used in the reaction
and the azepan-4-one 16 only gave trace amounts of the expected bicyclic
products 17 and 18.17
Catalytic reduction of the nitro derivatives was facile and no evidence
of 5,6 cleavage was ever seen. In the case of the N-benzyl derivative 1b, the
nitro group was smoothly reduced to the amine 1e with tin(II) chloride and
conc. hydrochloric acid in hot ethanol, although the corresponding, par-
tially reduced hydroxylamine 1g was also obtained in 9% yield.
In conclusion, we have demonstrated a rapid and versatile method by
which to access the 3-amino-5,6,7,8-tetrahydro[1,6]naphthyridine system.
This methodology was also shown to be applicable to the assembly of
more substituted or polycyclic homologues.
EXPERIMENTAL
Chromatography refers to flash chromatography through Merck Silica
Gel 60 (less than 0.063 mm) and the solvent is stated. Infra red spectra were
recorded for dichloromethane solutions on a Perkin–Elmer 1600 FTIR.
1H NMR spectra were obtained using a Brucker AC250 and the solvent is
stated. Accurate mass measurements were recorded by Analytical Sciences,
SB, on a Jeol JMS DX303/DA 5000 at 70 eV. Melting points were taken on
a Galen III Kofler hotstage and are uncorrected.
6-Methyl-3-nitro-5,6,7,8-tetrahydro[1,6]naphthyridine 1a
Pyridone 618 (5.97 g, 30 mmol) was treated with a solution of ammonia
in methanol (1.22 M, 300 ml, 366 mmol) followed by 11a (3.73 g, 33 mmol)
and the resulting mixture heated at an oil bath temperature of 60ꢀC for 5 h.
The mixture was allowed to stand at ambient temperature for 72 h before
being evaporated to dryness under reduced pressure. The residual orange/
red solid was digested with dichloromethane (2ꢁ100 ml) and the dichloro-
methane extracts combined and evaporated to dryness under reduced press-
ure. The red residue was subjected to chromatography, eluting with ethyl
acetate, and the title compound (3.14 g, 59%) isolated as a red solid;
ꢀmax=cmꢂ1 (CH2Cl2) 1530 and 1351; ꢁH (CDCl3) 2.53 (3H, s, NMe), 2.85

3-AMINO-5,6,7,8-TETRAHYDRO[1,6]NAPHTHYRIDINE
791
(2H, t, J ¼ 6 Hz, 8-CH2), 3.18 (2H, t, J ¼ 6 Hz, 7-CH2), 3.69 (2H, s, 5-CH2),
8.14 (1H, d, J ¼ 2 Hz, 4-H), 9.23 (1H, s, J ¼ 2 Hz, 2-H); Found: 193.0832.
C9H11N3O2 requires: 193.0851.
3-Amino-6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridine 1d
A solution of 1a (2.72 g, 1.41 mmol) in methanol (100 ml) was hydro-
genated over 10% palladium on charcoal (1.0 g). The catalyst was removed
by filtration through Celite and the combined filtrate and washings evapo-
rated to dryness under reduced pressure. The residue was triturated under
diethyl ether and the product (1.89 g, 83%) collected by filtration, washed
with diethyl ether and dried under reduced pressure. Recrystallization from
dichloromethane – 60–80ꢀ petroleum ether gave the title compound as white
crystals, mp. 153–154ꢀC; ꢀmax=cmꢂ1 (CH2Cl2) 3377; ꢁH(CDCl3) 2.46 (3H, s,
NMe), 2.75 (2H, t, J ¼ 6 Hz, 8-CH2), 2.95 (2H, t, J ¼ 6 Hz, 7-CH2), 3.50
(2H, s, 5-CH2), 3.56 (2H, brs, exchangeable, NH2), 6.65 (1H, d, J ¼ 2 Hz,
4-H), 7.92 (1H, d, J ¼ 2 Hz, 2-H). Found: 163.1106. C9H13N3 requires:
163.1106.
6-Benzyl-3-nitro-5,6,7,8-tetrahydro[1,6]naphthyridine 1b
6 (1.99 g, 10 mmol) was added to methanolic ammonia (1.1 M, 100 ml,
110 mmol) and the resulting mixture treated with 11b (2.27 g, 12 mmol). The
mixture was heated in an oil bath at 60ꢀC for 5 h. Evaporation to dryness
under reduced pressure gave a red solid, which was triturated under
dichloromethane and the insolubles removed by filtration. The filtrate and
washings were combined and evaporated to dryness under reduced pressure.
The residue was triturated under ethyl acetate and the insolubles again
removed by filtration. The filtrate and washings were combined, evaporated
to dryness under reduced pressure then chromatographed, eluting with 50%
ethyl acetate in 60–80ꢀ petroleum ether, to give the title compound (2.5 g,
93%). A sample was recrystallized from ethyl acetate – 60–80ꢀ petroleum
ether as a pale orange, microcrystalline solid, mp. 108ꢀC; ꢀmax=cmꢂ1 (CH2Cl2)
1523 and 1351; ꢁH(CDCl3) 3.03 (2H, t, J ¼ 6 Hz, 8-CH2), 3.28 (2H, t,
J ¼ 6 Hz, 7-CH2), 3.83 and 3.87 (2s, each 2H, 5-CH2 and NCH2Ph), 7.38–
7.49 (5H, m, C6H5), 8.21 (1H, d, J ¼ 2 Hz, 4-H), 9.33 (1H, d, J ¼ 2 Hz, 2-H);
Found: C, 66.75, H, 5.48, N, 15.61%. C15H15N3O2 requires: C, 66.84, H,
5.56, N, 15.60%.

792
HARLING, HARRINGTON, AND THOMPSON
3-Amino-6-benzyl-5,6,7,8-tetrahydro[1,6]naphthyridine 1e and
6-Benzyl-3-hydroxyamino-5,6,7,8-tetrahydro[1,6]naphthyridine 1g
1b (790 mg, 2.93 mmol) was dissolved in ethanol (100 ml) and the
resulting solution heated to 50ꢀC and treated with a solution of tin(II)
chloride dihydrate (2.65 g, 11.73 mmol) in conc. hydrochloric acid (10 ml).
After 10 min, the reaction mixture was concentrated to low volume under
reduced pressure, basified to pH 10 with 2 Maq. sodium hydroxide solution
and extracted with dichloromethane (2ꢁ50 ml). The extracts were com-
bined, washed with water, saturated brine, dried and evaporated to dryness
under reduced pressure. The residue was purified by chromatography, elut-
ing with ethanol in ethyl acetate (0 to 20% ethanol gradient), to give 1g
(143 mg, 19%) as a yellow foam; ꢁH [(CD3)2SO] 2.72–2.76 (4H, brm,
(CH2)2), 3.52 and 3.66 (each 2H, 2brs, 5-CH2 and NCH2Ph), 6.85 (1H,
brs, 4-H), 7.27–7.37 (5H, m, C6H5), 7.94 (1H, brs, 2-H), 8.34 and 8.42
(each 1H, 2brs, exchangeable, NH and OH ); Found: 256.1450.
C15H18N3O requires: 256.1431.
Furhter elution gave 1e (275 mg, 39%) as a white powder; ꢁH
[(CD3)2SO] 2.51 (4H, br, 7 and 8 CH2’s), 3.25 and 3.45 (each 2H, 2brs,
5-CH2 and NCH2Ph), 4.84 (2H, brs, exchangeable, NH2), 6.37 (1H, brs,
4-H), 7.11–7.22 (5H, m, C6H5), 7.56 (1H, brs, 2-H); Found: 240.1501.
C5H18N3 requires: 240.1584.
6-t-Butoxycarbonyl-3-nitro-5,6,7,8-tetrahydro[1,6]naphthyridine 1c
11c (l0.14 g, 50.9 mmol) and 6 (9.12 g. 45.8 mmol) were suspended in
methanol (250 ml) and the resulting mixture treated with 0.88 aq. ammonia
solution (20 ml). The resulting mixture was heated at 70ꢀC for 5 h then left to
stand at ambient temperature for 18 h. Volatiles were removed under
reduced pressure and the residue was partitioned between dichloromethane
and water. The phases were separated and the organic phase washed with
water (ꢁ2), saturated brine, dried and evaporated to dryness under reduced
pressure. The residue was purified by chromatography, eluting with 50%
ethyl acetate in 60–80ꢀ petroleum ether, to give 1c (10.75 g, 84%) as a fawn
powder. 1c was recrystallized as white needles from ethanol-water, mp.
143–144ꢀC; ꢀmax=cmꢂ1 (CH2C12) 1692, 1529 and 1353; ꢁH(CDCl3) 1.51 (9H,
s, CMe3), 3.12 (2H, t, J ¼ 6 Hz, 8-CH2), 3.81 (2H, t, J ¼ 6 Hz, 7-CH2), 4.72
(2H, s, 5-CH2), 8.23 (1H, d, J ¼ 2 Hz, 4-H), 9.25 (1H, d, J ¼ 2 Hz, 2-H);
Found: 279.1224. C13H17N3O4 requires: 279.1900.

3-AMINO-5,6,7,8-TETRAHYDRO[1,6]NAPHTHYRIDINE
793
3-Amino-6-t-butoxycarbonyl-5,6,7,8-tetrahydro[1,6]naphthyridine 1f
1c (1.62 g, 5.80 mmol) was dissolved in methanol (50 ml) and the mix-
ture hydrogenated at STP over 10% palladium on carbon (200 mg) until
hydrogen uptake ceased. Catalyst was removed by filtration through Celite,
the filter bed washed well with methanol and the filtrate and washings
combined and evaporated to dryness under reduced pressure. The residue
was crystallized from dichloromethane – 60–80ꢀ petroleum ether to give 1f
as brown, microcrystalline plates (1.22 g, 84%), mp. 117–119ꢀC; ꢀmax=cmꢂ1
(CH2Cl2) 1684, 1422 and 1250; ꢁH(CDCl3) 1.49 (9H, s, CMe3), 2.88 (2H, t,
J ¼ 6 Hz, 8-CH2), 3.64 (2H, br, exchangeable, NH2), 3.71 (2H, t, J ¼ 6 Hz,
7-CH2), 4.50 (2H, s, 5-CH2), 6.73 (1H, d, J ¼ 2 Hz, 4-H), 7.94 (1H, d,
J ¼ 2 Hz, 2-H); Found: 249.1476. C13H19N3O2 requires: 249.1477.
3-Nitro-6,8,8-trimethyl-5,6,7,8-tetrahydro[1,6]naphthyridine 2a
1219 (1.69 g, 12 mmol) and 6 (l.99 g, 10 mmol) were mixed together in
methanol (50 ml) containing 0.88 aq. ammonia solutions. The resulting mix-
ture was heated at 70ꢀC for 5 h. After cooling to room temperature, the
volatiles were removed under reduced pressure. The residue was digested
with dichloromethane (2ꢁ50 ml) and the combined extracts were evaporated
to dryness under reduced pressure. Chromatography of the residue, eluting
with 50% ethyl acetate in 60–80ꢀ petroleum ether, gave the title compound
as a yellow oil, which crystallized on standing (1.26 g, 57%). Recrystal-
lization from acetone-water gave 2a as yellow needles, mp. 54–56ꢀC;
ꢀmax=cmꢂ1 (CH2Cl2) 1525 and 1349; ꢁH (CDCl3) 1.38 (6H, s, CMe2), 2.47
(3H, s, NMe), 2.55 (2H, s, 7-CH2), 3.64 (2H, s, 5-CH2), 8.09 (1H, d,
J ¼ 3 Hz, 4-H), 9.25(1H, d, J ¼ 3 Hz, 2-H); Found: 221.1164. C11H15N3O2
requires: 221.1164.
3-Amino-6,8,8-trimethyl-5,6,7,8-tetrahydro[1,6]naphthyridine 2b
2a (1.0 g, 4.5 mmol) was dissolved in methanol (30 ml) and hydroge-
nated at STP over 10% palladium on charcoal (100 mg) until hydrogen
uptake had ceased. Catalyst was removed by filtration through Celite and
the combined filtrate and washings evaporated to dryness under reduced
pressure to give 2b as a white powder (864 mg, 100%). Recrystallization
from dichloromethane – 60–80ꢀ petroleum ether gave white needles,
mp. 121–122ꢀC; ꢁH(CDCl3) 1.31 (6H, s, CMe2), 2.41 (3H, s, NMe), 2.46
(2H, s, 7-CH2), 3.45 (2H, s, 5-CH2), 3.43 (2H, brs, NH2, exchangeable),

794
HARLING, HARRINGTON, AND THOMPSON
6.61 (1H, d, J ¼ 3 Hz, 4-H), 7.97 (1H, d, J ¼ 3 Hz, 2-H); Found: 191.1420.
C11H17N3 requires: 191.1422.
5-Nitro-3,9-diazatricyclo[7.3.1.02,7]trideca-2,4,6-triene 3a
13 (1.93 g, 12 mmol)20 and 6 (1.99 g, 10 mmol) were mixed together in
methanolic ammonia (2 M, 100 ml, 200 mmol) and the resulting mixture
heated at 60ꢀC for 5 h. Evaporation to dryness under reduced pressure
followed by chromatography, eluting with methanol in dichloromethane
gradient, gave the product (1.13 g, 52%). A sample was recrystallized
from 60–80ꢀ petroleum ether as yellow plates, mp. 125–127ꢀC, ꢀmax=cmꢂ1
(CH2Cl2) 1528 and 1348; ꢁH(CDCl3)21 1.14–1.20 and 1.31–1.34 (each 1H,
2m, 11-CH2), 1.94–1.96 and 2.01–2.06 (each 1H, 2m, 12-CH2), 3.07–3.16
(4H, m, 1-H, 10-CH2 and 13-H), 3.34 (1H, d, J ¼ 12 Hz, 13-H), 3.95 and 4.43
(each 1H, 2d, J ¼ 18 Hz, 8-CH2), 8.17 (1H, d, J ¼ 2 Hz, 6-H), 8.24 (1H, d,
J ¼ 2 Hz, 4-H). Found: 219.1006. C11H13N3O2 requires: 219.1008.
5-Amino-3,9-diazatricyclo[7.3.1.02,7]trideca-2,4,6-triene 3b
3a (1.1 g, 5 mmol) was dissolved in methanol (50 ml) and hydrogenated
at STP over 10% palladium on charcoal (100 mg) until hydrogen uptake
ceased. The catalyst was removed by filtration and the filtrate and washings
evaporated to dryness under reduced pressure. Trituration under diethyl
ether gave 3b (795 mg, 84%). Recrystallization from dichloromethane
gave off-white, microcrystalline colonies, mp. 181–182ꢀC; ꢁH (CD3OD)
1.00–1.40 (2H, m, 11-CH2), 1.60–1.90 (2H, m, 12-CH2), 2.60–3.25 (5H, m,
10-CH2, 13-CH2 and CH), 3.68 and 4.10 (2H, ABq, J ¼ 18 Hz, 8-CH2), 6.74
(1H, br, 6-H), 7.71 (1H, d, J ¼ 2 HZ, 4-H); Found: 189.1265. C11H15N3
requires: 189.1266.
12-Methyl-4-nitro-6,12-diazatricyclo[7.2.1.02,7]dodeca-2,4,6-
triene 4a
14a (1.67 g, 12 mmol) and 6 (l.99 g, 10 mmol) were mixed together in
methanol (100 ml). 0.88 aq. Ammonia solution (10 ml) was added and the
resulting mixture heated at 60ꢀC for 5 h then left at ambient temperature for
18 h. The volatiles were removed by evaporation to dryness under reduced
pressure and the residue digested with dichloromethane (2ꢁ50 ml).
Filtration and evaporation of the filtration to dryness under reduced

3-AMINO-5,6,7,8-TETRAHYDRO[1,6]NAPHTHYRIDINE
795
pressure gave a red semi-solid residue, which was purified by chromatogra-
phy, eluting with dichloromethane then 2% methanol in dichloromethane.
The appropriate fractions were combined and evaporated to dryness under
reduced pressue. Extraction of the residue with hot 60–80ꢀ petroleum ether
gave, after evaporation, 4a (1.1 g, 50%). Recrystallization from 60–80ꢀ
petroleum ether gave chunky, yellow needles, mp. 93–94ꢀC; ꢀmax=cmꢂ1
(CH2Cl2) 1526 and 1348; ꢁH (CD3OD) 1.78–2.62 (7H, 3m, 10-CH2, 11-
CH2 and NMe), 2.92 (1H, d, J ¼ 19 Hz, 8-H), 3.49 and 3.56 (1H, dd, J ¼
19 and 5 Hz, 8-H), 3.75–3.80 (1H, m, 9-H), 4.32 (1H, d, J ¼ 6 Hz, 1-H), 8.48
(1H, d, J ¼ 2 Hz, 3-H), 9.31 (1H, d, J ¼ 2 Hz, 5-H); Found: 219.1017.
C11H13N3O2 requires: 219.1008.
4-Amino-12-methyl-6,12-diazatricyclo[7. 2.1.02,7]dodeca-
2,4,6-triene 4b
4a (1.1 g, 5 mmol) was dissolved in methanol (50 ml) and hydrogenated
at STP over 10% palladium on carbon (100 mg) until hydrogen uptake
ceased. The catalyst was removed by filtration through Celite, the filter
bed washed well with methanol and the filtrate and washings combined.
Evaporation to dryness under reduced pressure, followed by trituration
under diethyl ether and collection by filtration, gave 4b (795 mg, 84%) as
a grey powder; ꢀmax=cmꢂ1 (CH2Cl2) 3628 and 3420; ꢁH (CD3OD) 1.73–2.55
(7H, 3m, 10-CH2, 11-CH2 and NMe), 2.63 (1H, d, J ¼ 17 Hz, 8-H), 3.29 and
3.36 (1H, dd, J ¼ 17 and 5 Hz, 8-H), 3.66–3.71 (1H, m, 9-H), 3.99 (1H, d,
J ¼ 6 Hz, 1-H), 6.95 (1H, d, J ¼ 3 Hz, 3-H), 7.95 (1H, d, J ¼ 3 Hz, 5-H);
Found: 181.1273. C11H15N3 requires: 181.1266.
12-t-Butoxycarbonyl-4-nitro-6,12-diazatricyclo[7.2.1.02,7]dodeca-
2,4,6-triene 5a
14b (5.0 g, 22.2 mmol) and 6 (4.42 g, 22.2 mmol) were mixed together in
methanol (100 ml) containing 0.88 aq. ammonia solution (25 ml) and the
resulting mixture heated at 70ꢀC for 5 h. The volatiles were removed
under reduced pressure and the residue was partitioned between dichloro-
methane and water. The organic phase was washed with water (2ꢁ50 ml),
saturated brine, dried and evaporated to dryness under reduced pressure.
Chromatography, eluting with 25% ethyl acetate in 60–80ꢀ petroleum ether,
gave the product as a yellow oil, which crystallized on standing (2.73 g,
40%). Recrystallization from ethyl acetate – 60–80ꢀ petroleum ether gave
5a as needles, mp. 97–100ꢀC; ꢀmax=cmꢂ1 (CH2Cl2) 1690, 1528, 1349 and 1274;

796
HARLING, HARRINGTON, AND THOMPSON
ꢁH (CDCl3) 1.42 and 1.50 (each 9H, 2s, CMe3, rotamers), 1.60–2.45 (4H, 3m,
10-CH2 and 11-CH2), 2.89 (1H, d, J ¼ 18 Hz, 8-H), 3.40–3.60 (1H, brm, 8-H,
rotamers), 4.65 (1H, brm, 9-H, rotamers), 5.08 (1H, brm, 1-H), 8.18 (1H, d,
J ¼ 2 Hz, 3-H), 9.24 (1H, d, J ¼ 2 Hz, 5-H); Found: 305.1380. C15H19N3O4
requires: 305.1376.
4-Amino-12-t-butoxycarbonyl-6,12-diazatricyclo
[7.2.1.02,7]dodeca-2,4,6-triene 5b
5a (2.66 g, 8.7 mmol) was dissolved in methanol (50 ml) and hydro-
genated at STP over 10% palladium on charcoal (300 mg) until hydrogen
uptake had ceased. The catalyst was removed by filtration through Celite
and the combined filtrate and washings were evaporated to dryness under
reduced pressure to give a white solid (2.18 g, 91%). A small sample of 5b
was recrystallized from dichloromethane – 60–80ꢀ petroleum ether as a
white, microcrystalline solid, mp. 141–142ꢀC; ꢁH (CDCl3)22 1.42 and 1.50
(2s, each 9H, CMe3, rotamers). 1.60–2.40 (4H, 3m, 10-CH2 and 11-CH2),
2.62 (1H, d, J ¼ 17 Hz, 8-H), 3.20–3.45 (1H, brm, 8-H, rotamers), 4.40–4.65
(1H, brm, 9-H, rotamers), 4.70–4.90 (1H, brm, 1-H, rotamers), 6.70 (1H,
brd, 3-H, rotamers), 7.92 (1H, d, J ¼ 2 Hz, 5-H); Found: 275.1635.
C15H21N3O2 requires: 275.1634.
ACKNOWLEDGMENT
The authors would like to acknowledge Miss Helen Eley, for her
excellent practical skills and Drs. J. P. Heer and M. S. Hadley, for useful
discussions and help in the preparation of this manuscript.
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17. Both 16 and 17 were isolated in single figure yields and possessed
1
satisfactory H NMR, infra red and mass spectral data.
18. The authors would like to point out that preparation of 613 proceeds
with a large exotherm and recommend great care be taken when adding
1-methyl-2-pyridone to fuming nitric acid.
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1
21. 400 MHz H NMR COSY experiments were performed on 3a to con-
firm the structure.
1
22. Further NMR studies at 400 MHz, i.e. COSY, NOESY, TOCSY and
variable temperature, we used to confirm the structure of 5b. The
rotamers coalesced at 353ꢀK.
Received in the U.K. February 10, 2000