Isoquinolin-1(2H)-ones and 1,6-naphthyridin-5(6H)-ones by an N-acylation-SNAr sequence

Article abstract of DOI:10.1016/j.tet.2013.12.033

A new synthesis of 2,3-dialkyl-4-carbomethoxyisoquinolin-1(2H)-ones and 6,7-dialkyl-8-carbomethoxy-1,6-naphthyridin-5(6H)-ones is reported. The process involves treatment of a β-enaminoester with 2-fluoro-5-nitrobenzoyl chloride, 2-fluorobenzoyl chloride or 2-chloronicotinoyl chloride followed by heating in the presence of base. The conversion, which proceeds by an N-acylation-S_NAr reaction sequence, affords 50-86% yields when R ¹ is n-alkyl but ≤30% yields when R¹ is α-branched.

Full text of DOI:10.1016/j.tet.2013.12.033

Tetrahedron 70 (2014) 838e844
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Isoquinolin-1(2H)-ones and 1,6-naphthyridin-5(6H)-ones by an
N-acylation-S Ar sequence
N
*
Richard A. Bunce , Baskar Nammalwar, Krishna Kumar Gnanasekaran, Nicholas R. Cain
Department of Chemistry, Oklahoma State University, Stillwater, OK 74078-3071, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 October 2013
Received in revised form 9 December 2013
Accepted 12 December 2013
Available online 18 December 2013
A new synthesis of 2,3-dialkyl-4-carbomethoxyisoquinolin-1(2H)-ones and 6,7-dialkyl-8-carbomethoxy-
1,6-naphthyridin-5(6H)-ones is reported. The process involves treatment of a
b-enaminoester with 2-
fluoro-5-nitrobenzoyl chloride, 2-fluorobenzoyl chloride or 2-chloronicotinoyl chloride followed by
heating in the presence of base. The conversion, which proceeds by an N-acylation-S
N
Ar reaction se-
quence, affords 50e86% yields when R1 is n-alkyl but ꢀ30% yields when R is
1
a-branched.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Isoquinolin-1(2H)-ones
1
,6-Naphthyridin-5(6H)-ones
N-acylation-S Ar sequence
Ar by an N-acyl- -enaminoester
Heteroannulation
N
S
N
b
1. Introduction
piperidineacetate and cyclohexanone to produce 1,2,3,4,4a,5,7,8,9,10-
decahydro-6H-benzo[c]quinolizin-6-one as a possible azasteroid
1
2
Recent efforts in our group have been focused on the de-
velopment of methodology for the efficient synthesis of a variety of
precursor. Later, the Stille group disclosed a related aza-annulation
13
sequence and applied it to the synthesis of several alkaloid targets.
heterocyclic scaffolds. These have included approaches to the syn-
This process involved N-acylation of a conjugated enaminoester
with acryloyl chloride followed by intramolecular Michael addition of
the enamine totheresultingacrylamide. Inthe current study, we have
modified this process to utilize an electron-poor fluoroaromatic
moiety to serve as the acceptor for the second stage of this process.
This has led to an efficient synthesis of 2,3-dialkyl-4-
methoxycarbonylisoquinolin- 1(2H)-ones and 6,7-dialkyl-8-methoxy
carbonyl-1,6-naphthyridin-5(6H)-ones. Based on the medicinal
properties of previously reported derivatives in the isoquinoline se-
ries, this method could lead to new structures worthy of further
development.
1
thesis of 1,2,3,4-tetrahydroquinolines, 1,2,3,9-tetrahydro-4H-car-
bazol-4-ones,2 2,3-dihydro-4(1H)-quinolinones,
4
3
2,3-dihydro-
4
5
(1H)-quinazolinones and 1,4- and 2,3-dihydronaphthyridinones.
The current study was undertaken with the goal of providing an
expeditious route to 2,3-dialkyl-4-methoxycarbonylisoquinolin-
1
5
(2H)-ones and 6,7-dialkyl-8-methoxycarbonyl-1,6-naphthyridin-
(6H)-ones. Several 4-methoxycarbonylisoquinolin-1(2H)-ones
6
have previously been prepared from homophthalic acid and 2-
bromobenzoic acid derivatives. While the syntheses described
7
were reasonably short (2e3 steps), the yields were often quite low
(
35e50%). These compounds are known tohave significant potential
8
9
for the treatment of ulcers, inflammation-based diseases and CNS
disorders.10 In contrast, 6,7-dialkyl-8-methoxycarbonyl-1,6-
naphthyridin-5(6H)-ones have been reported only once in 40e50%
yields by a route that differs from the current work, and to the best
of our knowledge, have not been evaluated for biological activity.
Our synthetic approach isbased upon earlier investigations by two
groups. Horii and co-workers were the first to demonstrate the use of
2. Results and discussion
11
Appropriate cyclization substrates were readily obtained
from commercial sources or by standard synthetic procedures
14
(
Scheme 1). b-Ketoesters 1aeg were converted to b-enami-
noesters 2aeg by p-TsOH-catalyzed condensation with benzyl-
amine in refluxing benzene with DeaneStark removal of water. N-
a
tandem enamination-cyclization procedure between ethyl
Methyl-b-enamino-ester 2h was prepared by a literature pro-
15
cedure. Acids 3 and 6 were converted to acid chlorides 4 and 7,
respectively, using thionyl chloride in boiling benzene, while 2-
fluorobenzoyl chloride (5) was commercially available.
*
Corresponding author. Tel.: þ1 405 744 5952; fax: þ1 405 744 6007; e-mail
address: rab@okstate.edu (R.A. Bunce).
0
040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.12.033

R.A. Bunce et al. / Tetrahedron 70 (2014) 838e844
839
R2
Table 2
O
2
NH
R 'NH
Cyclization results for 6,7-dialkyl-8-methoxycarbonyl-1,6-naphthyridin-5(6H)-ones
2
CO CH3
CO CH
2 3
2
R1
R1
PhH, p-TsOH
1
a-g
2a (R
1
1
= CH , R = CH Ph)
3
2
2
2
b (R = C H , R = CH Ph)
2
5
2
2
1
2
2
c (R = n-C H , R = CH Ph)
3 7 2 2
1
d (R = n-C H15, R2 = CH Ph)
5 2
1
2
2
e
f
(R = n-C H , R = CH Ph)
4 7 2 2
1
(R = CH CH Ph, R = CH Ph)
2 2 2 2
1
2
g (R = i-C H , R = CH Ph)
CH NH
3 7 2 2
3
2
1
a
2h (R
1
= R
2
= CH3)
O
CH OH
3
O
X
X
HO
SOCl2
Cl
Cl
PhH, heat
F
F
3
(X = NO2)
4
5
(X = NO2)
(X = H)
O
O
HO
SOCl2
PhH, heat
Cl
N
Cl
N
6
7
Scheme 1. Synthesis of the reaction substrates.
Our cyclization results are summarized in Tables 1 and 2. The
reactions were performed by stirring enaminoesters 2aeh (2 equiv)
with acid chloride 4 (1 equiv) in purified 1,2-dichloroethane
N
room temperature, while the final S Ar ring closure required
heating. For substrates having a monoactivated aromatic acceptor,
DCE)16 at 23 C for 3 h, followed by addition of triethylamine
ꢁ
(
(
such as 5, reactions were performed similarly in purified 1,4-
1
6
TEA, 2 equiv) and heating at reflux for 12e18 h. Our experiments
dioxane
using
a
pressure tube with 1,8-diazabicyclo[5.4.0]
ꢁ
revealed that N-acylation of the enaminoester proceeded best at
undec-7-ene (DBU) as the base (2 equiv, 130 C, 3 h) for the cycli-
zation. Finally, reactions involving 2-chloronicotinoyl chloride 7
were achieved using the enaminoester (3 equiv, see below) in DCE
Table 1
Cyclization results for 2,3-dialkyl-4-methoxycarbonylisoquinolin-(2H)-ones
ꢁ
with TEA as the base (2, equiv, 130 C, 8 h). The use of anhydrous,
purified solvents was essential, as the enaminoesters were both
water and acid sensitive. Failure to remove these impurities from
DCE and dioxane, resulted in hydrolysis of the enamine to give
N
benzylamine, which readily added to the S Ar acceptor ring, pre-
empting the ring closure. The reaction was facilitated by the use of
excess enamine. While TEA or DBU were found to be the best re-
agents for promoting the final cyclization, the use of these bases (or
elevated temperatures) for the initial acylation had a negative im-
pact on the overall yields. Upon completion, the crude reaction
mixtures were added to aqueous NaCl and subjected to an extrac-
tive work-up. Purification was accomplished by chromatography
followed by recrystallization.
Some further discussion is warranted regarding the use of ex-
cess enaminoester 2 for these transformations. In heterocycliza-
tions involving 4 and 5, 2 equiv of this reactant were necessary,
with the second equivalent neutralizing the HCl produced during
the acylation step. For reactions of 2-chloronicotinoyl chloride (7),
however, it was found that 3 equiv of 2 were required for optimum
conversion rather than two. This stems from the fact that 7 in-
corporates an extra equivalent of HCl due to the basic nitrogen of
the pyridine, and this acid could sabotage the reaction sequence at
several stages. Protonation at nitrogen significantly increases the
17
C2 reactivity of 2-chloropyridines toward nucleophiles, and thus,
attack at this site could compete with the acylation process. Addi-
tionally, the 2-chloropyridinium cation could serve as a proton
18
source [pK
a
w0.48 (H
2
O), 2.96 (acetone)]
to deactivate the
enaminoester nitrogen or protonate the enamide double bond.
Hence, it was important to neutralize this salt in addition to the HCl
produced during enamide formation to decrease the probability of
side reactions. This was most effectively accomplished by addition
of 7 to a cooled solution containing 3 equiv of 2. The alternative use
of bases, such as TEA or DBU during the acylation stage was found
to lower the overall product yields, and inorganic bases were
not explored since reaction of these with HCl would produce
water, which could degrade both reactants. The delocalized

840
R.A. Bunce et al. / Tetrahedron 70 (2014) 838e844
enaminoesters have base properties intermediate between 2-
chloropyridine and TEA, and scavenge the acid without in-
troducing additional contaminants. They are easily prepared from
inexpensive commercial chemicals and do not require purification
prior to reaction. Moreover, in applications where the precursor
ketoester is costly or demands independent synthesis, the required
use of surplus 2 is mitigated by the fact that much of this material
can be recovered, as the ketoester, and recycled.
As expected, cyclizations on aromatic acceptors with two
electron-withdrawing groups or a 2-chloropyridine generally pro-
ceeded in higher yields and under milder conditions.19 Mono-
activated substrates required a stronger base and more robust
thermal conditions. The sequence proved limited with respect to
4. Experimental section
4.1. General methods
All reactionswere rununderdry nitrogeninoven-dried glassware.
Reactions were monitored by thin layer chromatography on silica gel
GF plates (Analtech, No. 21521). Preparative separations were per-
formed by one of the following methods: (1) preparative thin layer
chromatography (PTLC) on 20-cmꢂ20-cm silica gel GF plates (Anal-
tech, No. 02015) or (2) column chromatographyon silicagel (grade 62,
60e200 mesh) containing UV-active phosphor (Sorbent Technolo-
gies, No. UV-05) packed into quartz columns. Band elution for all
chromatographic methods was monitored using a hand-held UV
lamp. Melting points were uncorrected. FTIR spectra were run as thin
the steric environment adjacent to the nucleophilic enamine car-
1
1
13
bon. For example, branching at the
a
carbon of R , as in 2g, reduced
films on NaCl disks. Unless otherwise indicated, H and C NMR
spectra were measured in CDCl using (CH Si as the internal stan-
dard; coupling constants (J) are given in Hertz. Low-resolution mass
the yields from mono- and diactivated substrates and completely
suppressed cyclization for heteroaromatic systems. In these cases,
degradation of the acylated enamine, presumably through elimi-
nation of the halogen from the acceptor ring, competed with cy-
3
3 4
)
spectra (electron impact/direct probe) were obtained at 70 eV.
1
clization. Substrates having straight-chain alkyl groups at R ,
4.2. Representative synthesis of
b-enaminoesters 2
however, cyclized in good to excellent yields for all aromatic ac-
ceptors investigated, making this a viable approach to these highly
A solution of -ketoester 1 (10 mmol) [14] in 50 mL of benzene
b
functionalized heterocycles. Though most of our work was done
was treated with benzylamine (10.5 mmol) and one crystal of p-
TsOH. The solution was refluxed for 8 h with DeaneStark removal of
2
using the N-benzyl-
actions with the N-methyl derivative 2h were equally successful.
Thus, variation of both R and R can be used to introduce sub-
stituent diversity to these systems.
b
-enaminoesters (e.g., R ¼benzyl), two re-
2
H O. The reaction was cooled and concentrated under vacuum to
1
2
give the -enaminoester as a yellow oil. The Z isomer was strongly
b
favored due to intramolecular hydrogen bonding. The product was
1
A possiblemechanism is illustrated inScheme 2 forthereaction of
nearly pure by H NMR, but sensitive toward chromatography. It
2
a with 4. In the initial step, the enaminoester 2a is N-acylated by
acid chloride 4 to give 11. This would be followed by attack of the N-
acyl- -enaminoester on the aromatic acceptor to generate the fused-
was, therefore, used without further purification.
b
4.2.1. Methyl (Z)-3-(benzylamino)-2-butenoate (2a). IR: 3292, 1653,
ꢃ1
1
ring system 12. Rearomatization, with loss of fluoride, would then
1607 cm ; H NMR (300 MHz): d 8.94 (br s, 1H), 7.36e7.19 (com-
give the 2,3-dialkyl-4-methoxycarbonyl-7-nitroisoquinolinium-
plex m, 5H), 4.54 (s, 1H), 4.42 (d, J¼6.6 Hz, 2H), 3.63 (s, 3H), 1.90 (s,
13
1
(4H)-one intermediate 13. In thefinalstep, base (TEAor DBU) would
3H); C NMR (75 MHz):
d
170.8, 161.9, 138.6, 128.7, 127.3, 126.6,
þ
remove the acidic proton from the ester-substituted benzylic carbon
to convert 13 to the final product 8a.
82.7, 49.9, 46.7, 19.3; ms: m/z 114 (M ꢃC
7 7
H ).
4
.2.2. Methyl (Z)-3-(benzylamino)-2-pentenoate (2b). IR: 3287,
ꢃ1
1
1653, 1606 cm ; H NMR (300 MHz): d 8.96 (br s, 1H), 7.38e7.18
) 23 o
(complex m, 5H), 4.57 (s, 1H), 4.43 (d, J¼6.6 Hz, 2H), 3.64 (s, 3H),
1
2
C
13
2
a + 4
8a
2
.23 (q, J¼7.1 Hz, 2H), 1.12 (q, J¼7.1 Hz, 3H); C NMR (75 MHz):
) base, heat
O
d
171.2, 167.0, 138.7, 128.7, 127.3, 126.7, 80.7, 50.0, 46.3, 25.1, 12.1;
þ
O
O
ms: m/z 128 (M ꢃC
7 7
H ).
.
.
NO2
NO
2
NO
2
Ph
N
Ph
N
Ph
N
4
.2.3. Methyl (Z)-3-(benzylamino)-2-hexenoate (2c). IR: 3287, 1655,
ꢃ1
1
1606 cm
;
H NMR (300 MHz): d 8.94 (br s, 1H), 7.37e7.21
F
F
CH
O
2
C
CH
H
:B
CH O C
3
3
O
2
C
(
complex m, 5H), 4.55 (s, 1H), 4.42 (d, J¼6.6 Hz, 2H), 3.63 (s, 3H),
3
2
11
12
13
2.20 (t, J¼7.7 Hz, 2H), 1.55 (sextet, J¼7.7 Hz, 2H), 0.95 (t, J¼7.7 Hz,
13
3
4
H); C NMR (75 MHz):
d
171.1, 165.6,138.7, 128.7, 127.3,126.7, 81.8,
Scheme 2. Possible mechanism to form a 2,3-dialkyl-4-methoxycarbonylisoquinolin-
(2H)-one.
þ
9.9, 46.4, 34.2, 21.2, 13.8; ms: m/z 142 (M ꢃC
7 7
H ).
1
4
.2.4. Methyl (Z)-3-(benzylamino)-2-octenoate (2d). IR: 3285, 1657,
ꢃ1
1
3
. Conclusion
1606 cm ; H NMR (300 MHz):
d 8.94 (br s,1H), 7.38e7.22 (complex
m, 5H), 4.55 (s,1H), 4.42 (d, J¼6.6 Hz, 2H), 3.63 (s, 3H), 2.18 (t, J¼7.1 Hz,
13
In conclusion, we have developed a practical and efficient ap-
proach for the synthesis of 2,3-dialkyl-4-methoxycarbonyliso
quinoline-1(2H)-one and 6,7-dialkyl-8-methoxycarbonyl-1,6-naph-
N
thyridin-5(6H)-ones using a sequential N-acylation-S Ar process.
2H),1.52(quintet, J¼7.1 Hz, 2H),1.30 (m, 4H), 0.87(t, J¼6.6 Hz, 3H);
C
NMR (75 MHz):
d
171.1,165.9,138.7,128.7,127.3,126.7, 81.7, 49.9, 46.4,
þ
32.2, 31.4, 27.7, 22.3, 13.7; ms: m/z 170 (M ꢃC
7 7
H ).
The method involved room temperature N-acylation of readily
available enaminoesters 2aeh with 2-fluoro-5-nitrobenzoyl chlo-
ride, 2-fluorobenzoyl chloride, and 2-chloronicotinoyl chloride fol-
4.2.5. Methyl (Z)-3-(benzylamino)-5-phenyl-2-pentenoate (2e). IR:
ꢃ1
1
3285,1653,1606 cm ; H NMR (300 MHz):
d 8.97 (br s,1H), 7.38e7.20
(complex m, 8H), 7.13 (d, J¼6.6 Hz, 2H), 4.62 (s, 1H), 4.37 (d, J¼6.6 Hz,
13
lowed by heating to promote the final S
N
Ar ring closure. Yields were
2H), 3.64 (s, 3H), 2.81 (t, J¼7.7 Hz, 2H), 2.48 (t, J¼7.7 Hz, 2H); C NMR
generally in the 52e86% range. The reaction proceeded smoothly
for mono- and diactivated aromatic acceptor rings as well as 2-
chloropyridine systems but manifested steric limitations in the
(75 MHz):
d
171.1, 164.8, 140.4, 138.5, 128.8, 128.5, 128.2, 127.4, 126.7,
þ
126.3, 82.0, 50.0, 46.4, 34.5, 34.0; ms: m/z 204 (M ꢃC
7 7
H ).
ring-forming step when
adjacent to the nucleophilic enamine carbon.
a
-branched alkyl groups were positioned
4.2.6. Methyl (Z)-3-(benzylamino)-2,6-heptadienoate (2f). IR: 3286,
ꢃ1
1
1655, 1610 cm ; H NMR (300 MHz):
d 8.95 (br s, 1H), 7.39e7.21

R.A. Bunce et al. / Tetrahedron 70 (2014) 838e844
841
þ
(
complex m, 5H), 5.79 (ddt, J¼17.0, 9.3, 4.9 Hz, 1H), 5.02 (d,
51.4, 18.8; ms: m/z 261 (M ꢃC
7
H
7
). Anal. Calcd for C19
H
16
N
2
O
5
: C,
J¼17.0 Hz, 1H), 5.00 (d, J¼9.3 Hz, 1H), 4.56 (s, 1H), 4.43 (d, J¼6.6 Hz,
64.77; H, 4.55; N, 7.95. Found: C, 64.90; H, 4.58; N, 7.74.
13
2
H), 3.64 (s, 3H), 2.28 (m, 4H); C NMR (75 MHz): d 171.0, 164.8,
1
38.6,136.6,128.8,127.4,126.7,115.6, 82.0, 50.0, 46.5, 32.0, 31.5; ms:
4.5.2. 2-Benzyl-3-ethyl-4-methoxycarbonyl-7-nitroisoquinolin-
þ
m/z 154 (M ꢃC
7
H
7
).
1(2H)-one (8b). Yield: 154 mg (0.42 mmol, 86%) as a tan solid, mp
ꢁ
ꢃ1
1
1
28e130 C; IR: 1730, 1630, 1613, 1523, 1354 cm
(300 MHz):
9.22 (d, J¼2.7 Hz, 1H), 8.28 (dd, J¼9.3, 2.7 Hz, 1H),
7.48e7.30 (complex m, 4H), 7.07 (d, J¼6.0 Hz, 2H), 5.52 (s, 2H), 3.97
;
H NMR
4.2.7. Methyl (Z)-3-(benzylamino)-4-methyl-2-pentenoate (2g). IR:
d
ꢃ1
1
3
281, 1653, 1606 cm
; H NMR (300 MHz): d 9.07 (br s, 1H),
13
7
.38e7.21 (complex m, 5H), 4.61 (s, 1H), 4.45 (d, J¼6.0 Hz, 2H), 3.64
(s, 3H), 2.78 (q, J¼7.7 Hz, 2H), 1.40 (t, J¼7.7 Hz, 3H); C NMR
13
(
(
s, 3H), 2.66 (septet, J¼6.6 Hz, 1H), 1.10 (d, J¼6.6 Hz, 6H); C NMR
(75 MHz): 173.6, 167.0, 155.5, 144.2, 143.5, 134.0, 129.6, 128.5,
d
75 MHz):
d
171.8, 171.6, 138.8, 128.7, 127.2, 126.2, 78.1, 50.0, 46.0,
126.7, 126.3, 125.1, 123.3, 119.4, 118.2, 52.7, 50.7, 25.5, 13.7; ms: m/z
þ
þ
2
8.5, 21.5; ms: m/z 142 (M ꢃC
7
7
H ).
275 (M ꢃC
7 7 18 2 5
H ). Anal. Calcd for C20H N O : C, 65.57; H, 4.92; N,
7
.65. Found: C, 65.68; H, 4.90; N, 7.53.
4
.2.8. Methyl (Z)-3-(methylamino)-2-butenoate (2h). This com-
16
pound was prepared in 84% yield by a literature procedure, mp
6
4.5.3. 2-Benzyl-4-methoxycarbonyl-7-nitro-3-propylisoquinolin-
1(2H)-one (8c). Yield: 152 mg (0.40 mmol, 82%) as a tan solid, mp
ꢁ
16
ꢁ
ꢃ1 1
4e66 C (lit mp 65e67 C). IR 3310, 1652, 1604 cm ; H NMR
ꢁ
ꢃ1
1
(
300 MHz): 8.46 (br s, 1H), 4.47 (s, 1H), 3.61 (s, 3H), 2.91 (d,
d
120e121 C; IR: 1730, 1628, 1614, 1525, 1353 cm
(300 MHz):
9.22 (d, J¼2.7 Hz,1H), 8.27 (dd, J¼9.3, 2.7Hz,1H), 7.45 (d,
J¼9.3 Hz, 1H), 7.44e7.32 (complex m, 3H), 7.07 (d, J¼6.6 Hz, 2H), 5.50
s, 2H), 3.97 (s, 3H), 2.72 (t, J¼7.7 Hz, 2H), 1.80 (sextet, J¼7.7 Hz, 2H),
;
H NMR
13
J¼4.9 Hz, 3H), 1.92 (s, 3H); C NMR (75 MHz):
d
170.9, 162.8, 81.4,
d
þ
4
9.8, 29.5, 19.1; ms: m/z 129 (M ).
(
1
13
.04 (t, J¼7.7 Hz, 3H); C NMR (75 MHz):
d 173.5, 167.1, 154.5, 144.2,
43.5, 134.0, 129.6, 128.5, 126.7, 126.3, 125.1, 123.2, 119.6, 118.3, 52.7,
H ). Anal. Calcd for
7 7
21 20 2 5
H N O : C, 66.32; H, 5.26; N, 7.37. Found: C, 66.52; H, 5.59; N, 7.19.
4
.3. 2-Fluoro-5-nitrobenzoyl chloride (4)
1
5
þ
0.8, 34.0, 23.0, 14.3; ms: m/z 289 (M ꢃC
This compound was prepared by refluxing acid 3 (10 mmol)
C
with thionyl chloride (12 mmol) in benzene for 8 h. Removal of the
solvent gave a tan solid, mp 59e60 C. This material was spec-
troscopically pure and was used without further purification. IR:
1
ꢁ
4
1
.5.4. 2-Benzyl-4-methoxycarbonyl-7-nitro-3-pentylisoquinolin-
(2H)-one (8d). Yield: 148 mg (0.36 mmol, 74%) as a tan solid, mp
ꢃ1
1
793, 1770, 1626, 1538, 1352 cm ; H NMR (300 MHz):
d
9.02 (dd,
ꢁ
ꢃ1
1
1
22e123 C; IR: 1733, 1628, 1613, 1523, 1343 cm
;
H NMR
9.18 (d, J¼2.7 Hz, 1H), 8.26 (dd, J¼9.3, 2.7 Hz, 1H), 7.49
d, J¼9.3 Hz, 1H), 7.41e7.30 (complex m, 3H), 7.08 (d, J¼6.6 Hz, 2H),
.54 (s, 2H), 3.95 (s, 3H), 2.73 (t, J¼7.7 Hz, 2H), 1.77 (quintet,
J¼6.0, 3.0 Hz, 1H), 8.57 (dt, J¼8.8, 3.0 Hz, 1H), 7.44 (t, J¼9.3 Hz, 1H);
(
(
5
300 MHz): d
1
3
C NMR (75 MHz):
43.9, 131.5 (d, J¼11.5 Hz), 129.5, 123.0 (d, J¼9.8 Hz), 118.9 (d,
J¼23.8 Hz).
d
164.2 (d, J¼276.8 Hz), 161.3 (d, J¼4.9 Hz),
1
13
J¼7.7 Hz, 2H), 1.34 (m, 4H), 0.88 (t, J¼6.6 Hz, 3H); C NMR
75 MHz): 173.4, 167.0, 154.7, 144.1, 143.3, 134.0, 129.4, 128.3,
26.5,126.1,125.0,123.0,119.4,118.4, 52.5, 50.7, 31.9, 31.6, 28.9, 21.8,
(
d
1
1
4
.4. 2-Chloronicotinoyl chloride (7)
þ
3.6; ms: m/z 317 (M ꢃC
7 7 24 2 5
H ). Anal. Calcd for C23H N O : C, 67.65;
H, 5.88; N, 6.86. Found: C, 67.91; H, 5.93; N, 6.51.
This compound was prepared by refluxing acid 6 (10 mmol)
with thionyl chloride (12 mmol) in benzene for 8 h. Removal of the
ꢁ
20
ꢁ
1
4. 5. 5. 2-Benzyl-3-(3-butenyl)-4-methoxycarbonyl-7-
nitroisoquinolin-1(2H)-one (8e). Yield: 130 mg (0.33 mmol, 68%) as
solvent gave a tan solid, mp 39e42 C (lit. mp 39e42 C). The H
NMR and 13C NMR spectra matched those reported previously
20
ꢁ
a yellow solid, mp 114e116 C; IR: 1730, 1633, 1614, 1524,
and was used without further purification.
ꢃ1
1
1
344 cm ; H NMR (300 MHz):
d
9.23 (d, J¼2.7 Hz, 1H), 8.29 (dd,
J¼9.3, 2.7 1H), 7.45 (d, J¼9.3 Hz, 1H), 7.44e7.31 (complex m, 3H),
7.07 (d, J¼6.6 Hz, 2H), 5.82 (ddt, J¼17.0, 9.9, 6.6 Hz, 1H), 5.50 (s, 2H),
5.07 (d, J¼17.0 Hz, 1H), 5.06 (d, J¼9.9 Hz, 1H), 3.96 (s, 3H), 2.86 (t,
4
.5. General cyclization procedure for systems with diac-
tivated aromatic acceptor rings
13
J¼7.7 Hz, 2H), 2.50 (q, J¼7.7 Hz, 2H); C NMR (75 MHz):
d 173.4,
A solution of enaminoester 2 (0.98 mmol) in 3 mL of purified
166.9, 153.9, 144.2, 143.5, 135.1, 133.9, 129.5, 128.5, 126.7, 126.2,
16
ꢁ
1
,2-dichloroethane (DCE) was cooled to 10 C and a solution of 5
125.1, 123.2, 119.7, 118.4, 116.7, 52.7, 50.9, 33.0, 31.3; ms: m/z 301
þ
(
100 mg, 0.49 mmol) in 3 mL of DCE was added. The solution was
(M ꢃC
7 7 20 2 5
H ). Anal. Calcd for C22H N O : C, 67.35; H, 5.10; N, 7.14.
ꢁ
ꢁ
stirred at 23 C for 3 h, then cooled to 10 C and TEA (0.98 mmol,
9 mg, 0.136 mL) in 2 mL of DCE was added. The reaction was
Found: C, 67.46; H, 5.12; N, 7.07.
9
heated at reflux until complete (12e18 h). The reaction was
cooled and added to aqueous NaCl. The organic layer was sepa-
rated and the aqueous phase was washed with dichloromethane.
The combined organic extracts were washed with aqueous NaCl,
4.5.6. 2-Benzyl-4-methoxycarbonyl-7-nitro-3-(2-phenylethyl)iso-
quinolin-1(2H)-one (8f). Yield: 175 mg (0.40 mmol, 81%) as a tan
ꢁ
ꢃ1 1
solid, mp 188e189 C; IR: 1729,1628,1613,1522,1343 cm ; H NMR
(300 MHz):
9.28 (d, J¼2.7 Hz, 1H), 8.32 (dd, J¼9.3, 2.7 Hz, 1H), 7.43
(d, J¼9.3 Hz, 1H), 7.42e7.23 (complex m, 6H), 7.12 (d, J¼6.0 Hz, 2H),
d
4
dried (MgSO ), filtered, and concentrated under vacuum. The
13
crude product was purified by PTLC eluted with 1:1 ethyl acetate/
hexanes containing 1% TEA. The following compounds were
prepared:
7.05 (d, J¼6.0 Hz, 2H), 5.40 (s, 2H), 4.00 (s, 3H), 3.05 (s, 4H); C NMR
(75 MHz): 173.6, 167.1, 153.7, 144.2, 143.8, 139.1, 133.9, 129.7, 128.9,
d
128.7, 128.1, 127.1, 126.9, 126.5, 125.1, 123.5, 119.8, 118.2, 52.9, 50.9,
þ
3
5.6, 33.9; ms: m/z 351 (M ꢃC
7 7 22 2 5
H ). Anal. Calcd for C26H N O : C,
4
1
.5.1. 2-Benzyl-4-methoxycarbonyl-3-methyl-7-nitroisoquinolin-
70.59; H, 4.98; N, 6.33. Found: C, 70.66; H, 5.01; N, 6.25.
(2H)-one (8a). Yield: 146 mg (0.42 mmol, 85%) as a tan solid, mp
ꢁ
ꢃ1
1
1
92e194 C; IR: 1733, 1632, 1614, 1523, 1342 cm
300 MHz):
9.13 (d, J¼2.7 Hz, 1H), 8.27 (dd, J¼9.9, 2.7 Hz, 1H),
.44e7.31 (complex m, 4H), 7.07 (d, J¼6.6 Hz, 2H), 5.50 (s, 2H), 3.96
s, 3H), 2.51 (s, 3H); 13C NMR (75 MHz):
173.1, 167.0, 151.2, 144.2,
43.4, 133.6, 129.6, 128.4, 126.7, 125.8, 125.0, 122.9, 119.6, 118.1, 52.7,
;
H NMR
4.5.7. 2-Benzyl-3-isopropyl-4-methoxycarbonyl-7-nitroisoquinolin-
(
7
(
1
d
1(2H)-one (8g). Yield: 56 mg (0.15 mmol, 30%) as a tan solid, mp
ꢁ
ꢃ1
1
170e172 C; IR: 1730, 1625, 1610, 1524, 1344 cm
(300 MHz):
9.22 (d, J¼2.7 Hz, 1H), 8.27 (dd, J¼9.3, 2.7 Hz, 1H),
7.45e7.31 (complex m, 4H), 7.10 (d, J¼6.6 Hz, 2H), 5.52 (s, 2H), 3.96
;
H NMR
d
d

842
R.A. Bunce et al. / Tetrahedron 70 (2014) 838e844
s, 3H), 3.20 (septet, J¼7.1 Hz, 1H), 1.42 (d, J¼7.1 Hz, 6H); 13C NMR
92e93 C; IR: 1727, 1619, 1600 cmꢃ1; 1H NMR (300 MHz):
ꢁ
d
8.47 (d,
(
(
1
75 MHz):
d
174.6, 167.3, 158.1, 144.8, 143.4, 134.3, 129.6, 128.46,
J¼7.7 Hz, 1H), 7.52 (t, J¼7.1 Hz, 1H), 7.41e7.27 (complex m, 5H), 7.07
28.43, 126.6, 125.6, 124.9, 123.0, 118.5, 52.6, 51.6, 31.8, 29.6, 20.6;
(d, J¼6.6 Hz, 2H), 5.44 (s, 2H), 3.96 (s, 3H), 2.69 (t, J¼7.7 Hz, 2H),1.75
þ
13
ms: m/z 289 (M ꢃC
7
H
7
). Anal. Calcd for C21
20
H N
2
O
5
: C, 66.32; H,
(quintet, J¼7.1 Hz, 2H), 1.60 (m, 4H), 0.88 (t, J¼7.1 Hz, 3H); C NMR
5
.26; N, 7.37. Found: C, 66.45; H, 5.30; N, 7.23.
(75 MHz): d 174.6, 168.2, 153.5, 140.8, 135.1, 132.7, 129.3, 128.1, 127.0,
1
26.7, 125.3, 124.1, 118.2, 116.5, 52.5, 50.2, 31.9, 31.8, 29.2, 22.1, 13.8;
þ
4
.5.8. 2,3-Dimethyl-4-methoxycarbonyl-7-nitroisoquinolin-1(2H)-
ms: m/z 272 (M ꢃC
7 7 3
H ). Anal. Calcd for C23H25NO : C, 76.03; H,
one (8h). Yield: 115 mg (0.42 mmol, 85%) as a yellow solid, mp
6.89; N, 3.86. Found: C, 75.97; H, 6.93; N, 3.69.
ꢁ
ꢃ1 1
2
98e300 C (darkens); IR: 1725, 1626, 1611, 1523, 1340 cm
; H
NMR (300 MHz, DMSO-d
6
):
d
8.85 (d, J¼2.7 Hz, 1H), 8.49 (dd, J¼9.3,
4.6.5. 2-Benzyl-3-(3-butenyl)-4-methoxycarbonylisoquinolin-1(2H)-
2
3
.7 Hz, 1H), 8.08 (d, J¼9.3 Hz, 1H), 3.83 (s, 3H), 3.82 (s, 3H), 2.50 (s,
one (9e). Yield: 262 mg (0.76 mmol, 60%) as a white solid, mp
13
ꢁ
ꢃ1 1
H); C NMR (75 MHz, DMSO-d
6
):
d
172.0, 167.0, 151.9, 144.6, 142.8,
106e107 C; IR: 1726, 1618, 1601 cm ; H NMR (300 MHz): d 8.48
þ
126.4, 124.8, 121.4, 119.3, 118.7, 52.3, 35.7, 19.3; ms: m/z 276 (M ).
(dd, J¼6.6, 1.6 Hz, 1H), 7.53 (t, J¼7.1 Hz, 1H), 7.40e7.28 (complex m,
5H), 7.07 (d, J¼6.6 Hz, 2H), 5.82 (ddt, J¼17.0, 10.4, 6.6 Hz, 1H), 5.42
(s, 2H), 5.06 (d, J¼17.0 Hz, 1H), 5.05 (d, J¼10.4 Hz, 1H), 3.96 (s, 3H),
12 2 5
Anal. Calcd for C13H N O : C, 56.52; H, 4.35; N, 10.14. Found: C,
5
6.57; H, 4.35; N, 10.08.
1
3
2
d
.83 (t, J¼6.6 Hz, 2H), 2.49 (q, J¼6.6 Hz, 2H); C NMR (75 MHz):
4
.6. General cyclization procedure for systems with mono-
174.6, 168.1, 152.6, 140.8, 135.7, 135.0, 132.8, 129.4, 128.1, 127.0,
activated aromatic acceptor rings
126.7, 125.3, 124.2, 118.2, 116.5, 116.4, 52.5, 50.3, 33.3, 31.2; ms: m/z
þ
2
56 (M ). Anal. Calcd for C22
H
21NO
3
: C, 76.08; H, 6.05; N, 4.03.
A 15-mL, screw-top, pressure vessel (ChemGlass No. CG-1880-01)
Found: C, 76.01; H, 6.08; N, 3.98.
was charged with enaminoester 2 (2.52 mmol) and 2 mL of purified
,4-dioxane.16 The solution was cooled to 15 C and a solution of 2-
ꢁ
4.6.6. 2-Benzyl-4-methoxycarbonyl-3-(2-phenylethyl)isoquinolin-
1
fluorobenzoyl chloride (6) (200 mg, 1.26 mmol) in 2 mL of dioxane
1(2H)-one (9f). Yield: 365 mg (0.92 mmol, 73%) as a white solid,
ꢁ
ꢁ
ꢃ1 1
was added. The reaction was stirred at 23 C for 3 h, then cooled to
mp 154e156 C; IR: 1724, 1616, 1600 cm
8.48 (dd, J¼6.6, 1.1 Hz, 1H), 7.53 (t, J¼8.2 Hz, 1H), 7.40e7.19
(complex m, 9H), 7.12 (d, J¼6.6 Hz, 2H), 7.06 (d, J¼6.6 Hz, 2H), 5.40
; H NMR (300 MHz):
ꢁ
1
5 C and DBU (2.52 mmol, 383 mg, 0.376 mL) in 1 mL of dioxane was
d
ꢁ
added. The reaction was sealed under nitrogen, and heated to 130 C
13
for 3 h. The reactionwas cooled and concentrated under vacuum. The
residue was dissolved in dichloromethane, washed with water and
(s, 2H), 3.98 (s, 3H), 3.03 (s, 3H); C NMR (75 MHz): d 174.6, 168.2,
152.5, 140.9, 138.5, 135.0, 132.8, 129.4, 128.8, 128.1, 127.0, 126.8,
aqueous NaCl, dried (MgSO
4
), filtered, and concentrated under vac-
126.7, 125.3, 124.2, 118.3, 116.5, 52.6, 50.2, 35.6, 33.9 (one aromatic
þ
uum. The resulting product was purified on a 20 cmꢂ2 cm silica gel
column eluted with increasing concentrations of ethyl acetate in
hexanes. The following compounds were prepared:
C was unresolved); ms: m/z 306 (M ꢃC
7 7
H ). Anal. Calcd for
C H23NO : C, 78.59; H, 5.79; N, 3.53. Found: C, 78.55; H, 5.80; N,
26 3
3.49.
4
.6.1. 2-Benzyl-4-methoxycarbonyl-3-methylisoquinolin-1(2H)-one
4.6.7. 2-Benzyl-3-isopropyl-4-methoxycarbonylisoquinolin-1(2H)-
(
9a). Yield: 220 mg (0.72 mmol, 57%) as a white solid, mp
one (9g). Yield: 126 mg (0.38 mmol, 30%) as a white solid, mp
145e147 C; IR: 1729, 1616, 1602 cm ; H NMR (300 MHz): d 8.43
ꢁ
ꢃ1
1
ꢁ
ꢃ1 1
1
13e115 C; IR: 1727, 1618, 1602 cm ; H NMR (300 MHz):
dd, J¼8.2, 1.6 Hz, 1H), 7.53 (td, J¼7.1, 1.6 Hz, 1H), 7.42e7.24 (com-
plex m, 5H), 7.08 (d, J¼6.6 Hz, 2H), 5.44 (s, 2H), 3.96 (s, 3H), 2.43 (s,
d
8.46
(
(dd, J¼7.7, 1.1 Hz,1H), 7.52 (td, J¼7.7, 1.1 Hz,1H), 7.42e7.23 (complex
m, 5H), 7.10 (d, J¼6.6 Hz, 2H), 5.47 (s, 2H), 3.95 (s, 3H), 3.19 (septet,
13
13
3
1
H); C NMR (75 MHz):
d
174.2, 168.2, 149.8, 140.8, 134.6, 132.7,
J¼6.6 Hz, 1H), 1.40 (d, J¼6.6 Hz, 6H); C NMR (75 MHz):
d 175.6,
29.2, 127.9, 126.7, 126.3, 125.1, 124.0, 118.2, 116.2, 52.4, 50.6, 18.6;
168.5,156.7,141.4,135.5, 132.7,129.3,128.0,126.7,126.1,125.1,123.9,
þ
ms: m/z 216 (M ꢃC
H
7 7
3
). Anal. Calcd for C19H17NO : C, 74.27; H,
116.7, 52.4, 51.0, 31.7, 20.7 (1 aromatic C unresolved); ms: m/z 244
þ
5
.54; N, 4.56. Found: C, 74.19; H, 5.55; N, 4.51.
(M ). Anal. Calcd for C21
H
21NO
3
: C, 75.22; H, 6.27; N, 4.18. Found: C,
75.28; H, 6.24; N, 4.16.
4
.6.2. 2-Benzyl-3-ethyl-4-methoxycarbonylisoquinolin-1(2H)-one
(
9b). Yield: 210 mg (0.66 mmol, 52%) as a white solid, mp
4.6.8. 2,3-Dimethyl-4-methoxycarbonylisoquinolin-1(2H)-one
ꢁ
ꢃ1 1
1
(
7
1
08e109 C; IR: 1727, 1618, 1600 cm ; H NMR (300 MHz):
d, J¼8.2 Hz, 1H), 7.51 (t, J¼7.1 Hz, 1H), 7.40e7.25 (complex m, 5H),
.07 (d, J¼7.1 Hz, 2H), 5.46 (s, 2H), 3.96 (s, 3H), 2.76 (q, J¼7.1 Hz, 2H),
d
8.46
(9h). Yield: 154 mg (0.66 mmol, 53%) as a white solid, mp
ꢁ
ꢃ1 1
156e157 C; IR: 1721, 1610, 1601 cm ; H NMR (300 MHz):
d 8.41
(dd, J¼8.2, 1.6 Hz, 1H), 7.64 (td, J¼8.2, 1.6 Hz, 1H), 7.47 (d, J¼8.8 Hz,
1
3
13
.37 (t, J¼7.1 Hz, 3H); C NMR (75 MHz):
d
174.7, 168.2, 154.3, 140.8,
1H), 7.36 (t, J¼7.1 Hz, 1H), 3.94 (s, 3H), 3.74 (s, 3H), 2.50 (s, 3H);
NMR (75 MHz): 174.2, 168.4, 149.6, 141.1, 132.6, 126.9, 126.3, 124.0,
118.1, 115.3, 52.5, 34.7, 19.4; ms: m/z 231 (M ). Anal. Calcd for
C
1
5
35.1, 132.7, 129.3, 128.0, 126.9, 126.6, 125.2, 124.0, 117.9, 116.5, 52.5,
0.0, 25.3,13.8; ms: m/z 230 (M ꢃC
d
þ
þ
7 7 3
H ). Anal. Calcd for C20H19NO :
C, 74.77; H, 5.92; N, 4.36. Found: C, 74.91; H, 5.94; N, 4.27.
13 3
C H13NO : C, 67.53; H, 5.63; N, 6.06. Found: C, 67.66; H, 5.65; N,
5.99.
4
.6.3. 2-Benzyl-4-methoxycarbonyl-3-propylisoquinolin-1(2H)-one
(
1
(
7
1
d
9c). Yield: 245 mg (0.73 mmol, 58%) as a white solid, mp
4.7. General cyclization procedure for systems with 2-
chloropyridine systems
ꢁ
ꢃ1 1
68e169 C; IR: 1727, 1619, 1600 cm ; H NMR (300 MHz):
d, J¼8.2 Hz, 1H), 7.51 (t, J¼6.6 Hz, 1H), 7.40e7.25 (complex m, 5H),
.07 (d, J¼7.1 Hz, 2H), 5.44 (s, 2H), 3.96 (s, 3H), 2.69 (t, J¼7.7 Hz, 2H),
d 8.46
These reactions were run as above using enaminoester 2
(3.42 mmol) and 7 (200 mg, 1.14 mmol) in purified DCE. The
13
16
.79 (sextet, J¼7.7 Hz, 2H), 1.01 (t, J¼7.1 Hz, 3H); C NMR (75 MHz):
174.6, 168.2, 153.3, 140.8, 135.1, 132.7, 129.3, 128.1, 127.0, 126.7,
cyclization was completed by adding TEA (2.28 mmol, 230 mg,
ꢁ
1
(
25.3, 124.1, 118.2, 116.5, 52.5, 50.2, 33.9, 23.1, 14.3; ms: m/z 244
0.317 mL) and heating at 130 C for 8 h in a pressure tube. In
þ
M ꢃC
7
H
7
). Anal. Calcd for C21
3
H21NO : C, 75.22; H, 6.27; N, 4.18.
each case, work-up and purification by PTLC, eluted with 1:1
ethyl acetate/hexanes containing 1% TEA, afforded the final
product. [Note: DBU (2.28 mmol) was also used in the cyclization
step, but the yields were lower.] The following compounds were
prepared:
Found: C, 75.31; H, 6.30; N, 4.05.
4
.6.4. 2-Benzyl-4-methoxycarbonyl-3-pentylisoquinolin-1(2H)-one
(9d). Yield: 229 mg (0.63 mmol, 50%) as a white solid, mp

R.A. Bunce et al. / Tetrahedron 70 (2014) 838e844
843
þ
4
5
.7.1. 6-Benzyl-8-methoxycarbonyl-7-methyl-1,6-naphthyridin-
120.5, 119.1, 52.6, 47.7, 35.7, 33.8; ms: m/z 307 (M ꢃC
Calcd for C25
5.50; N, 6.97.
7
H
7
). Anal.
(6H)-one (10a). Yield: 246 mg (0.80 mmol, 70%) as a tan solid, mp
22 2 3
H N O : C, 75.38; H, 5.53; N, 7.04. Found: C, 75.41; H,
ꢁ
ꢃ1 1
143e145 C; IR: 1727, 1617, 1600 cm ; H NMR (400 MHz): d 8.76
(
4
dd, J¼8.0, 2.0 Hz, 1H), 8.70 (dd, J¼4.5, 2.0 Hz, 1H), 7.38 (dd, J¼7.8,
.5 Hz, 1H), 7.35e7.24 (complex m, 3H), 7.04 (d, J¼6.6 Hz, 2H), 5.89
4.7.7. 6-Benzyl-7-isopropyl-8-methoxycarbonyl-1,6-naphthyridin-
5(6H)-one (10g). No naphthyridinone product was formed in this
reaction.
1
3
(
br s, 2H), 3.94 (s, 3H), 2.47 (s, 3H); C NMR (100 MHz):
d 174.5,
1
67.7, 152.6, 151.4, 150.4, 136.2, 136.1, 129.0, 127.6, 125.8, 120.8,
þ
120.4,119.1, 52.6, 48.0, 18.7; ms: m/z 217 (M ꢃC
7 7
H ). Anal. Calcd for
C
9
H
18 16
N
2
O
3
: C, 70.13; H, 5.19; N, 9.09. Found: C, 70.18; H, 5.20; N,
4.7.8. 6,7-Dimethyl-8-methoxycarbonyl-1,6-naphthyridin-5(6H)-one
.04.
(10h). Yield: 222 mg (0.96 mmol, 84%) as a tan solid, mp
ꢁ
ꢃ1 1
1
89e191 C; IR: 1727, 1617, 1600 cm ; H NMR (400 MHz):
d 8.71
4
.7.2. 6-Benzyl-7-ethyl-8-methoxycarbonyl-1,6-naphthyridin-5(6H)-
(dd, J¼4.5, 2.1 Hz, 1H), 8.68 (dd, J¼8.0, 2.1 Hz, 1H), 7.33 (dd, J¼7.8,
13
one (10b). Yield: 272 mg (0.84 mmol, 74%) as a tan solid, mp
4.5 Hz, 1H), 3.92 (s, 3H), 3.94 (s, 3H), 2.57 (s, 3H); C NMR
ꢁ
ꢃ1 1
156e158 C; IR: 1727, 1617, 1600 cm ; H NMR (400 MHz):
d
8.74
(100 MHz):
d
174.2, 167.8, 152.1, 151.4, 150.2, 136.0, 120.9, 120.0,
þ
(
4
dd, J¼7.8, 2.0 Hz, 1H), 8.67 (dd, J¼4.5, 2.0 Hz, 1H), 7.35 (dd, J¼8.0,
118.5, 52.5, 32.4, 19.2; ms: m/z 232 (M ). Anal. Calcd for
.5 Hz, 1H), 7.32e7.22 (complex m, 3H), 7.01 (d, J¼6.8 Hz, 2H), 5.79
12 12 2 3
C H N O : C, 62.07; H, 5.17; N, 12.07. Found: C, 62.21; H, 5.21; N,
11.94.
(
br s, 2H), 3.94 (s, 3H), 2.77 (q, J¼7.6 Hz, 2H), 1.34 (t, J¼7.6 Hz, 3H);
1
3
C NMR (100 MHz):
d 174.7, 167.5, 156.0, 152.5, 150.3, 136.6, 136.0,
1
28.9, 127.5, 125.5, 120.8, 120.3, 118.7, 52.5, 47.4, 25.1, 13.8; ms: m/z
Acknowledgements
þ
2
8
31 (M ꢃC
7 7 18 2 3
H ). Anal. Calcd for C19H N O : C, 70.81; H, 5.59; N,
.70. Found: C, 70.88; H, 5.61; N, 8.57.
N.R.C. wishes to thank Oklahoma State University for a Wentz
Project Scholarship to support his undergraduate research. Funding
for the 300 MHz NMR spectrometer of the Oklahoma Statewide
Shared NMR Facility was provided by NSF (BIR-9512269), the
Oklahoma State Regents for Higher Education, the W.M. Keck
Foundation, and Conoco, Inc. Finally, the authors wish to thank the
OSU College of Arts and Sciences for funds to upgrade our de-
partmental FT-IR and GCeMS instruments.
4
5
.7.3. 6-Benzyl-8-methoxycarbonyl-7-propyl-1,6-naphthyridin-
(6H)-one (10c). Yield: 291 mg (0.87 mmol, 76%) as a tan solid, mp
ꢁ
ꢃ1 1
162e163 C; IR: 1727, 1617, 1600 cm ; H NMR (400 MHz): d 8.74
(
4
dd, J¼8.0, 2.0 Hz, 1H), 8.67 (dd, J¼4.5, 2.0 Hz, 1H), 7.35 (dd, J¼7.8,
.5 Hz, 1H), 7.36e7.26 (complex m, 3H), 7.02 (d, J¼6.8 Hz, 2H), 5.87
(
2
br s, 2H), 3.94 (s, 3H), 2.70 (t, J¼8.2 Hz, 2H), 1.74 (sextet, J¼7.4 Hz,
13
H), 1.01 (t, J¼7.2 Hz, 3H); C NMR (100 MHz):
d 174.7, 167.6, 154.9,
152.5, 150.3, 136.7, 136.1, 128.9, 127.6, 125.7, 120.9, 120.3, 118.9, 52.5,
Supplementary data
þ
4
C
8
7.6, 33.7, 23.2, 14.4; ms: m/z 245 (M ꢃC
7 7
H ). Anal. Calcd for
H
20 20
N
2
O
3
: C, 71.43; H, 5.95; N, 8.33. Found: C, 71.39; H, 5.92; N,
Supplementary data (experimental details, 1H- and 13C NMR
spectra, and analytical data for 8aeh, 9aeh and 10aef and 10h) can
be found, in the online version, at http://dx.doi.org/10.1016/
j.tet.2013.12.033.
.29.
4
5
.7.4. 6-Benzyl-8-methoxycarbonyl-7-pentyl-1,6-naphthyridin-
(6H)-one (10d). Yield: 290 mg (0.80 mmol, 70%) as a tan solid, mp
ꢁ
ꢃ1 1
165e166 C; IR: 1728, 1619, 1605 cm ; H NMR (400 MHz): d 8.74
References and notes
(
4
dd, J¼8.0, 4.5 Hz, 1H), 8.67 (dd, J¼4.5, 2.0 Hz, 1H), 7.35 (dd, J¼8.0,
.5 Hz, 1H), 7.33e7.23 (complex m, 3H), 7.02 (d, J¼6.8 Hz, 2H), 5.88
1. (a) Bunce, R. A.; Nago, T. J. Heterocycl. Chem. 2008, 45, 1155e1160; (b) Bunce, R.
(
2
br s, 2H), 3.93 (s, 3H), 2.71 (t, J¼8.2 Hz, 2H), 1.71 (quintet, J¼7.4 Hz,
A.; Lee, E. J. J. Heterocycl. Chem. 2010, 47, 1176e1182; (c) Bunce, R. A.; Scham-
merhorn, J. E. J. Heterocycl. Chem. 2013, 50, 373e380.
13
H),1.38 (m, 4H), 0.89 (t, J¼7.0 Hz, 3H); C NMR (100 MHz):
d 174.6,
2
3
. Bunce, R. A.; Nammalwar, B. J. Heterocycl. Chem. 2009, 46, 172e177.
. (a) Bunce, R. A.; Nago, T. J. Heterocycl. Chem. 2009, 46, 623e628; (b) Bunce, R. A.;
Nammalwar, B. Org. Prep. Proced. Int. 2010, 42, 557e563; (c) Bunce, R. A.;
Nammalwar, B. J. Heterocycl. Chem. 2011, 48, 613e619.
167.6, 155.1, 152.5, 150.3, 136.6, 136.0, 128.9, 127.5, 125.6, 120.8,
120.3, 118.8, 52.4, 47.6, 31.8, 31.6 29.2, 22.0, 13.8; ms: m/z 273
þ
(
M ꢃC
7 7 24 2 3
H ). Anal. Calcd for C22H N O : C, 72.53; H, 6.59; N, 7.69.
4
5
. Bunce, R. A.; Nammalwar, B. J. Heterocycl. Chem. 2011, 48, 991e997.
. (a) Bunce, R. A.; Nammalwar, B. J. Heterocycl. Chem. 2012, 49, 658e663; (b)
Bunce, R. A.; Squires, S. T.; Nammalwar, B. J. Org. Chem. 2013, 78, 2144e2148.
Found: C, 72.61; H, 6.59; N, 7.63.
4
5
.7.5. 6-Benzyl-7-(3-butenyl)-8-methoxycarbonyl-1,6-naphthyridin-
6. (a) Datta, D.; Tirodkar, R. B.; Usgaonker, R. N. Indian J. Chem. B 1980, 19B,
641e643; (b) Nadkarni, D. R.; Usgaonker, R. N. Indian J. Chem. B 1980, 19B,
(6H)-one (10e). Yield: 278 mg (0.80 mmol, 70%) as a tan solid, mp
253e255; (c) Modi, A. R.; Usgaonker, R. N. Indian J. Chem. B 1979, 18B, 304e306;
ꢁ
ꢃ1 1
135e136 C; IR: 1727, 1617, 1600 cm ; H NMR (400 MHz): d 8.75
(d) Mutsenietse, D. K.; Rotberg, Y. T. Chem. Heterocycl. Compd. 1977, 13,
(
7
5
d, J¼7.8 Hz, 1H), 8.69 (d, J¼4.3 Hz, 1H), 7.37 (dd, J¼7.8, 4.5 Hz, 1H),
1187e1189; (e) Schnekenburger, J. Arch. Pharm. 1965, 298, 4e18.
7
. (a) Wang, F.; Liu, H.; Fu, H.; Jiang, Y.; Zhao, Y. Org. Lett. 2009, 11, 2469e2472; (b)
Deady, L. W.; Rodemann, T. J. Heterocycl. Chem. 2001, 38, 1185e1190; (c) Si-
monsen, K. B.; Kehler, J.; Juhl, K.; Khanzhin, N.; Nielsen, S. M. US Pat. US
20090143402, 2009; Chem. Abstr. 2009, 151, 8316. (d) Hurtley, W. R. H. J. Chem.
Soc. 1929, 1870e1873.
.34e7.23 (complex m, 3H), 7.02 (d, J¼6.8 Hz, 2H), 5.89 (br s, 2H),
.81 (ddt, J¼16.8, 10.1, 6.4 Hz, 1H), 5.06 (d, J¼16.6 Hz, 1H), 5.05 (d,
J¼10.3 Hz, 1H), 3.94 (s, 3H), 2.84 (t, J¼8.0 Hz, 2H), 2.44 (q, J¼7.6 Hz,
13
2
1
3
7
H); C NMR (100 MHz): d 174.7, 167.5, 154.3, 152.6, 150.4, 136.6,
8
. Analgesics: Senda, S.; Ohtani, O.; Katho, E.; Miyake, H.; Fujiwara, K. German Pat.
DE 3031574, 1981; Chem. Abstr. 1983, 98, 71955.
36.2, 135.7, 129.0, 127.6, 125.7, 120.9, 120.4, 119.1, 116.3, 52.5, 47.7,
þ
3.3, 31.0; ms: m/z 257 (M ꢃC
7
H
7
). Anal. Calcd for C21
H
20
N
2
O
3
: C,
9. COPD and asthma: Hallam, M.; Martin, B.; Raubo, P.; Robert, B.; St-Gallay, S.;
Willis, P. World Pat. WO 2008122765, 2008; Chem. Abstr. 2008, 149, 471348.
0. NK3 antagonists: (a) See Ref. 7a. (b) Simonsen, K. B.; Juhl, K.; Steiniger-Brach, B.;
Nielsen, S. M. Curr. Opin. Drug Discovery Dev. 2010, 13, 379e388.
11. Jhalani, V. K.; Ghalsasi, L. P.; Acharya, S. P.; Usgaonkar, R. N. Indian J. Chem. B
1989, 28B, 173e174.
2.41; H, 5.75; N, 8.05. Found: C, 72.29; H, 5.77; N, 7.99.
1
4
.7.6. 6-Benzyl-8-methoxycarbonyl-7-(2-phenylethyl)-1,6-
naphthyridin-5(6H)-one (10f). Yield: 327 mg (0.82 mmol, 72%) as
ꢁ
ꢃ1
1
12. Horii, Z.; Morikawa, K.; Tamura, Y.; Ninomiya, I. Chem. Pharm. Bull. 1966, 14,
a tan solid, mp 141e142 C; IR: 1726, 1620, 1601 cm
400 MHz):
8.77 (d, J¼7.8 Hz, 1H), 8.70 (d, J¼4.5 Hz, 1H), 7.39 (dd,
J¼7.8, 4.5 Hz, 1H), 7.34e7.21 (complex m, 6H), 7.12 (d, J¼7.2 Hz, 2H),
.01 (d, J¼7.0 Hz, 2H), 5.87 (br s, 2H), 3.96 (s, 3H), 3.04 (m, 2H), 2.97
m, 2H); 13C NMR (100 MHz):
174.8, 167.6, 154.2, 152.6, 150.4,
39.6, 136.6, 136.2, 129.0, 128.8, 128.1, 127.7, 126.8, 125.7, 121.0,
; H NMR
1
399e1404.
3. (a) Paulvannan, K.; Schwarz, J. B.; Stille, J. R. Tetrahedron Lett. 1993, 34, 215e218;
(b) Paulvannan, K.; Stille, J. R. J. Org. Chem. 1994, 59, 1613e1620.
(
d
1
1
4. Ketoesters 1def were prepared by the method described in: (a) Oikawa, Y.;
Yoshioka, T.; Sugano, K.; Yonemitsu, Y. Organic SynthesesCollect. Vol. No. VII;
Wiley: New York, NY, 1990, Collect. Vol. No. VII, pp 359e361; (b) Oikawa, Y.;
Sugano, K.; Yonemitsu, Y. J. Org. Chem. 1978, 43, 2087e2088.
7
(
1
d

844
R.A. Bunce et al. / Tetrahedron 70 (2014) 838e844
1
5. Anderson, P. C.; Staskun, B. J. Org. Chem. 1965, 30, 3033e3037.
18. Cox, B. G. Acids and Bases: Solvent Effects on AcideBase Strength; Oxford Uni-
versity: Oxford, UK, 2013; p 110.
16. Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory Chemicals, 3rd ed.;
Pergamon: Oxford, UK, 1988; p 145; (1,2-dichloroethane) and 164e165 (1,4-
dioxane). The method cited from Hess, K.; Frahm, H. Chem. Ber. 1938, 71,
19. Bunce, R. A.; Nago, T.; Abuskhuna, S.. J. Heterocycl. Chem. in press.
20. Norman, M. H.; Minick, D. J.; Martin, G. E. J. Heterocycl. Chem. 1993, 30,
771e779.
2
627e2636 was used to purify 1,4-dioxane.
7. Katritzky, A. R.; Ramsden, C. A.; Joule, J. A.; Zhdankin, V. V. Handbook of Het-
erocyclic Chemistry, 3rd ed.; Elsevier: Oxford, UK, 2010; p 273.
1