Regioselective addition of n-alkyllithiums to α,α′- disubstituted-1,8-naphthyridines: Synthesis of 6-amino-3-pyridinol analogs of α-tocopherol

Article abstract of DOI:10.1055/s-2005-865308

n-Alkyllithiums were added to α,α′-disubstituted-1,8- naphthyridines in non-polar solvents such as Et₂O-hexane mixtures. In polar solvents such as THF, alkyllithium acts as a base rather than a nucleophile. Regioselective addition was achieved for substrates capable of five-membered cyclic chelation of the (alkyl)lithium reagent. Substrates with a TBS-protected alcohol as the co-chelating moiety afforded the best combination of yield and regioselectivity. This methodology was successfully employed in the preparation of two 6-amino-3-pyridinol analogs of pentamethyl-chromanol (PMC), an a-tocopherol derivative with its isoprenoid side chain truncated to a methyl group. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-865308

PAPER
1397
Regioselective Addition of n-Alkyllithiums to a,a¢-Disubstituted-1,8-
Naphthyridines: Synthesis of 6-Amino-3-Pyridinol Analogs of a-Tocopherol
ridine gyu Nam, Maikel Wijtmans, Derek A. Pratt,* Ned A. Porter*a
a
a,1
b,2
A
T
lkyllithium
A
d
a
dition to
1
e
,8-Naphthy
-
a
Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235, USA
Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA
E-mail: dpratt@uiuc.edu; E-mail: n.porter@vanderbilt.edu
b
Received 15 February 2005
This manuscript is dedicated to Bernd and Anne Giese for their many contributions to the organic and bioorganic communities.
naphthyridine moiety) and similar side chain substitution
Abstract: n-Alkyllithiums were added to a,a¢-disubstituted-1,8-
as a-tocopherol or its structural analog 2,2,5,7,8-penta-
naphthyridines in non-polar solvents such as Et O–hexane mix-
tures. In polar solvents such as THF, alkyllithium acts as a base rath-
2
methyl-6-chromanol (PMC) wherein the isoprenoid side
8
er than a nucleophile. Regioselective addition was achieved for chain has been truncated to a methyl group. Since it has
substrates capable of five-membered cyclic chelation of the been reported that the isoprenoid side chain of a-toco-
(
alkyl)lithium reagent. Substrates with a TBS-protected alcohol as
pherol also plays an important role in its biological activ-
ity, this protocol could lead to novel antioxidants with
therapeutic potential.
the co-chelating moiety afforded the best combination of yield and
regioselectivity. This methodology was successfully employed in
the preparation of two 6-amino-3-pyridinol analogs of pentamethyl-
9
chromanol (PMC), an a-tocopherol derivative with its isoprenoid Alkyllithium addition to the C(7)-position of 4 was envi-
side chain truncated to a methyl group.
sioned as a promising route to 3 (Scheme 1). The trimeth-
Key words: 1,8-naphthyridine, alkyllithium, chelation, solvent ef- ylated 1,8-naphthyridine 4 is readily obtained by the
fects, a-tocopherol
Skraup reaction of 2,4-dimethyl-6-aminopyridine and
1
0
crotonaldehyde. In addition to installing the desired 2,4-
dimethyl substitution on the left ring, the asymmetry of 4
may provide some preference for addition at the more
electron-poor C(7)- over the undesired C(2)-position.
1
,8-Naphthyridines (1, Figure 1) are important scaffolds3
in many compounds with pharmacological applications.
They are also known to be good bidentate ligands in orga-
nometallic complexes. The dihydro- and tetrahydro
forms have also shown pharmacological application as
high affinity ligands of the b -adreno and a b -
vitronectin receptors, respectively. Recently we demon-
strated that this moiety can also serve as the key skeleton
in novel radical-trapping 3-pyridinol antioxidants, such as
4
HO
R-Li
R
R
5
7
3
V 3
N
N
N
N
N
N
6
H
H
3
4
Scheme 1 Retrosynthesis of desired 3-pyridinols with a quaternary
center adjacent the 6-amino group from a substituted 1,8-naphthyri-
dine
2
(Figure 1). For example, in model studies, we found that
the tetrahydronaphthyridine 2 is almost 30 times more ef-
fective at inhibiting lipid peroxidation than a-tocopherol,
the most potent form of vitamin E and nature’s most pow-
Some precedent can be found in the literature regarding
nucleophilic addition to the C(7)-position of 1,8-naphthy-
ridines when no alkyl substituents are present. For exam-
7
erful lipophilic antioxidant.
4
11
12
13
ple, MeLi, PhLi and KCN are readily added to the
unsubstituted C(7)-position of 1,8-naphthyridines
(Scheme 2). However, additions generating a quaternary
center at C(2)/C(7), such as that which we desire at the
C(7)-position in Scheme 1, have yet to be described.
Herein we report on the addition of n-alkyllithiums to 1,8-
naphthyridines such as 4 that hold alkyl substitution at the
C(7)-position, thereby generating a quaternary center in
high yield and good regioselectivity. We also present the
synthesis of two 3-pyridinol analogs of PMC.
HO
HO
R
2
7
N
1
N
8
N
N
O
1
2
α-Tocopherol (R = C16H33)
PMC (R = Me)
Figure 1
Inspired by this finding, we have endeavored to synthe-
size new 3-pyridinols such as 3, which exhibit both the
key structure of 2 (2,4-dimethyl-3-hydroxy-tetrahydro
The results of our initial explorations utilizing n-BuLi as
model alkyllithium reagent in additions to the 2,7-disub-
stituted naphthyridine 4 are presented in Table 1. The data
reveal that both solvent polarity and reaction temperature
play important roles in the yield of the two regioisomeric
addition products 5a and 5b. In THF (entry 1), only a
SYNTHESIS 2005, No. 9, pp 1397–1404
x
x
.
x
x
.2
0
0
5
Advanced online publication: 18.04.2005
DOI: 10.1055/s-2005-865308; Art ID: C00905SS
Georg Thieme Verlag Stuttgart · New York
©

1
398
T.-g. Nam et al.
PAPER
1
terated starting material (d -4) almost quantitatively by H
1
. R'-Li/Et2O or PhMe
2
(
A)
NMR (Scheme 3A). The preference for lithiation of 2,4-
dimethylpyridine is consistent with this kinetically fa-
vored deprotonation (Scheme 3B). Thus, it appears that
two competing reaction pathways which depend heavily
on solvent polarity exist. This solvent dependence can be
2
. rearomatization
R
N
N
N
N
R
N
N
R'
(
(
R = Me, R' = Me : 84%)
R = H, R' = Ph : 65%)
1
4
+
–
KCN, BnEt3N Cl , BzCl
CH2Cl2–H2O
(B)
N
N
CN
15
rationalized on the basis of a chelation effect. 1,8-Naph-
thyridines are known as good bidentate ligands (Figure 2,
Bz
(
27%)
11
A) and alkyllithium coordination to the bidentate naph-
thyridine moiety would be expected to dramatically in-
crease the electrophilicity of the C(2) and C(7) positions,
activating them towards n-BuLi addition (Figure 2, B). In
more polar solvents, this chelation is interrupted, reducing
the rate of nucleophilic addition and allowing deprotona-
tion to compete. This explanation is supported by the ob-
servation that addition of LiBr to the reaction mixtures
leads to an increase in yield (entries 1 and 3).
Scheme 2 Nucleophilic addition to 1,8-naphthyridines
small amount of the products (5a + 5b = 12%) was ob-
tained. The yield was even lower in more polar solvents,
such as DMPU [1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-
pyrimidinone] (entry 2). Decreasing the polarity of the
solvent afforded a significant increase in the yield; 62%
when Et O was used (entry 3). Addition of hexanes to the
2
solution afforded a maximum yield of 87% for a 2:1 ratio The marginal observed regioselectivity of the additions
of hexanes–Et O (entry 4). Higher amounts of hexanes can also be rationalized on the basis of this coordination
2
caused solubility problems with 4 leading to lower yields. chemistry. By virtue of the electron-donating effect of the
Solubility also becomes an issue at lower reaction temper- C(4¢)-methyl group, the slightly more electron-rich left
atures. At –78 °C, 4 precipitated, leading to a poor yield ring should more strongly coordinate n-BuLi, leading to a
(
26%, entry 5). Although the starting material was soluble preference for left ring attack (5a > 5b, Table 1).
at –43 °C, the yields obtained at 0 °C could not be
matched (entries 6 and 7).
4
i. n-BuLi, THF, 0 °C
ii. D2O
The poor yields (and recovered starting material) that
were obtained when THF and DMPU were employed as
solvents prompted us to investigate whether preferential
deprotonation could account for our observations. Indeed,
(
A)
2
7
D
D
N
N
N
N
4
d2-4
i. n-BuLi, THF, –50 °C
ii. PhCHO
treatment of 4 with n-BuLi followed by D O gave di-deu-
2
OH
(86%) (B)
N
Ph
N
Table 1 Effect of Solvent Polarity and Reaction Temperature on n-
BuLi Addition to 4a
Scheme 3 Kinetically favored deprotonation by n-BuLi
n-BuLi
solvent, temp,
N
N
N
N
N
N
1 h
2
7
8
N
Hg Hg
N
N
N
(
X
)n
+
n-Bu
4
n-Bu
Li
Li
N
N
N
N
R
H
H
R
A
B
C (n = 1 or 2)
5a
5b
Figure 2 Chelation in naphthyridine chemistry
Entry Solvent
Temp (°C) Yield (%)b 5a:5bb
1
2
3
4
5
6
7
THF
0
12 (25)
< 3
1:0.9
n/a
These initial studies led us to the hypothesis that alkyllith-
iums may be added regioselectively to the C(7) position if
the interaction between the reagent and the naphthyridine
ring system could be biased to the right ring nitrogen, N8.
DMPU
0
Et O
0
62 (71)
87
1:0.9
1:0.9
1:0.9
1:0.9
1:0.9
2
In order to induce this complexation, the C(7)-CH group
3
Et O–hexanes(1:2)
0
2
of 4 was modified to (CH ) -X (Figure 2, C) such that the
2
n
Et O–hexanes(1:2)
–78
–43
–43
26
alkyllithium could form a cyclic chelate with N and an-
2
8
other coordinating moiety, X.
Et O
50
2
Naphthyridines with X = OH, OMOM and OTBS as part
of either five-membered (9–12) or six-membered (13–15)
cyclic chelates were investigated (Scheme 4). The prepa-
ration of each of these compounds began from the dimeth-
ylnaphthyridine 6, which was synthesized by the Skraup
reaction of 2,4-dimethyl-6-aminopyridine and acrolein
Et O–hexanes(1:2)
74
2
a
n-BuLi (4.5 equiv) was used.
Determined by H NMR on crude reaction mixtures. Values in pa-
b
1
rentheses are the yields in presence of LiBr (1 equiv).
Synthesis 2005, No. 9, 1397–1404 © Thieme Stuttgart · New York

PAPER
generated in situ from glycerol).10 A vinyl group was
Alkyllithium Addition to 1,8-Naphthyridine
1399
(
j
i
added regioselectively to the unsubstituted C(7)-position
of 6, which was followed by re-aromatization with the
OTBS
2
OH
2
OMOM
N
N
N
N
N
N
mild oxidant MnO to give 7 in 72% yield. Carrying on to
2
2
1
5
13
14
obtain the five-membered cyclic chelating agents, treat-
ment of 7 with OsO followed by NaIO gave aldehyde 8
4
4
h
in 84% yield. There were two pathways for generating the
alcohol function. First, 8 was treated with hexylmagne-
sium bromide to give secondary alcohol 9. This alcohol
was further modified to give MOM-protected 10 by a
b
c
O
7
2
N
N
N
N
N
N
1
6
H
LiBr-mediated alkoxy-exchange reaction. Secondly, 8
6
7
8
was simply reduced by NaBH to alcohol 11, which was
d
4
a
subsequently protected with a TBS group to give 12. Sub-
strates for six-membered chelation were obtained by
oxymercuration–demercuration of 7 to yield the anti-
f
Hex
OR
1
7
N
N
Markovnikov alcohol 13, which was subsequently con-
verted into the MOM- and TBS-protected compounds 14
and 15 under the same conditions as for 10 and 12, respec-
tively.
N
N
N
NH2
OR
0 (R = MOM)
9
1
(R = H)
g
11 (R = H)
12 (R = TBS)
e
Scheme 4 Synthesis of substrates for five- and six-membered cyclic
SO , H BO , glycerol,
NO PhSO Na, H O, FeSO , 150 °C, 4 h, 75%; (b) (i) CH =CHMgBr,
Et O, 0 °C, 1 h; (ii) MnO , CH Cl , r.t., overnight, 72% for two steps;
c) (i) OsO , K Fe(CN) , K CO , DABCO, t-BuOH–H O, r.t., 40 min,
Table 2 summarizes the results of MeLi addition to the chelation. Reagents and conditions: (a) H
,8-naphthyridines where either five-membered (9, 10
2
4
3
3
1
2
3
2
4
2
2
2
2
2
and 12) or six-membered (14 and 15) cyclic chelation is
possible. In general, five-membered chelation gave higher
regioselectivity than six-membered chelation. The hexyl
(
9
4 3 6 2 3 2
0%; (ii) NaIO , 1,4-dioxane–H O, r.t., 45 min, 93%; (d) NaBH ,
4 2 4
MeOH, r.t., 1 h, quant.; (e) TBSCl, 4-DMAP, Et N, CH Cl , r.t., over-
3
2
2
side chain in 9 provided adequate solubility for the alco- night, 93%; (f) C H MgBr, THF, –78 °C, 1 h, 42%; (g) (MeO) CH ,
6
13
2
2
hol to be useful (entry 1), but it required 12 equivalents of LiBr, CH
SO
H, r.t., 2 h, 31% (h) Hg(O
CCF
)
, NaOH, NaBH
,
3
3
2
3
2
4
THF–H O, r.t., 3 h, 70%; (i) (MeO) CH , LiBr, CH SO H, r.t., 2 h,
MeLi instead of the 4 equivalents used for all other sub-
strates. Nevertheless, the desired regioisomer was ob-
tained in five-fold excess. In contrast, the five- and six-
2
2
2
3
3
4
3%; (j) TBSCl, 4-DMAP, imidazole, CH Cl , r.t., 8 h, 100%
2 2
membered chelates derived from alcohols 11 and 13, re- increasing structural similarity to 2. Finally, 21a and 21b
spectively, yielded only trace product (not shown). were obtained using a lithiation/oxidation sequence re-
MOM-protected 10 provided a higher yield (72%, entry cently reported by us.7
2
), but lower regioselectivity (1:1.5). The low solubility of
the MOM-protected 14 lead to a very poor yield from this
substrate. The TBS-protected compounds 12 and 15 af- Table 2 Chelation-Directed MeLi Additiona
forded the highest yields (entries 3 and 5), presumably due
to their improved solubility. However, regioselectivity
was significantly different between them. While 12 gave
MeLi
+
Et2O–hexanesb
N
N
X
N
N
X
N
N
X
good regioselectivity (5.2:1, entry 3) through five-mem-
bered cyclic chelation, 15 (entry 6) showed practically no
regioselectivity. The six-membered chelate would appear
to be too large and flexible to afford a preference for MeLi
addition to the proximal ring nitrogen. Again, addition of
LiBr to the reaction mixture was found to improve the
yield of addition product (entry 4).
0
°C, 45 min
H
H
A
B
Entry
Chelation
Substrate
Yield (%)c Ratio (A:B)c
1
Five-membered
Six-membered
9
10
12
12
14
15
50
72
80
95
< 5
93
1:5
2
1:1.5
1:5.2
1:5.2
n/a
We demonstrate here the synthetic potential of our meth-
odology by preparing 21a and 21b, the simplest examples
of 3 containing a quaternary center at C(7) (Scheme 5).
3
4d
Thus, MeLi was added to 12 and the desired regioisomer 5e
1
6 was isolated in 63% yield following column chroma-
6
1:0.9
tography. The dihydronaphthyridine was subsequently
hydrogenated to afford the tetrahydro derivative 17, from
which the TBS group was removed with TBAF to give 18
a
X = co-chelation group. MeLi (4 equiv) [except for entry 1 (12
equiv)].
b
1
8
Et O–hexanes = 1:1.5–2.
Determined by H NMR on crude reaction mixtures.
MeLi–LiBr complex (4 equiv) was added.
Performed in Et O because of its low solubility in Et O–hexanes sys-
2
in 98% yield. The alcohol function of 18 was reductively
c
d
e
1
cleaved in 78% yield via the corresponding iodide. The
2
,2-dimethyl derivative 19 was subsequently brominated
2
2
to give 20a, which could be used to reductively aminate tem.
formaldehyde to afford the N-methyl analog 20b thereby
Synthesis 2005, No. 9, 1397–1404 © Thieme Stuttgart · New York

1
400
T.-g. Nam et al.
PAPER
M in hexane, 720 mL, 1.8 mmol) at 0 °C and the reaction mixture
turned deep brown instantly. After stirring for 1 h at 0 °C, the reac-
tion mixture was quenched with water, neutralized with sat. aq
a
b
d
12
OR
N
N
N
N
NH Cl (pH 6) and extracted with EtOAc (3 × 5 mL). The combined
4
H
H
OTBS
organic layer was washed with water (3 × 5 mL) and brine, dried
1
7 (R = TBS)
16
c
over anhyd MgSO and concentrated. The residue was purified by
4
1
8 (R = H)
column chromatography on silica gel (MeOH–CHCl , 5:95) to give
3
5
a (41 mg, 44%) and 5b (36 mg, 38%).
Br
HO
e
g
Compound 5a
N
N
N
N
R
N
N
R
1
H NMR (300 MHz, CDCl ): d = 0.81 (t-like, 3 H), 1.42–1.20 (m, 6
H), 1.22 (s, 3 H), 2.07 (s, 3 H), 2.18 (s, 3 H), 4.46 (br s, 1 H), 5.26
3
H
19
20a (R = H)
21a (R = H)
(
dd, J = 10.1, 2.1 Hz, 1 H), 6.09 (s, 1 H), 6.34 (d, J = 10.2 Hz, 1 H).
f
20b (R = Me)
21b (R = Me)
1
3
C NMR (75 MHz, CDCl ): d = 14.5, 18.0, 23.4, 24.2, 26.9, 31.8,
3
Scheme 5 Synthesis of 6-amino-3-pyridinol analogs of PMC.
45.0, 56.8, 110.1, 114.8, 119.8, 129.3, 142.4, 154.9, 155.4.
Reagents and conditions: (a) MeLi, Et O–hexanes (1:2), 0 °C, 1 h,
HRMS: m/z [M + H]+ calcd for C H N : 231.1856; found:
2
1
5
22
2
6
9
3%; (b) Pd/C, MeOH, r.t., overnight, 86%; (c) TBAF, THF, r.t., 1 h,
8%; (d) (i) Ph P, imidazole, I , CH Cl , r.t., 1.5 h; (ii) Zn, AcOH, 70
2
31.1848.
3
2
2
2
°
C, 1 h, 78% for two steps; (e) 1,3-dibromo-5,5-dimethylhydantoin,
Compound 5b
CH Cl , –78 °C, 40 min, 75%; (f) HCHO (aq), NaBH CN, AcOH,
MeOH, r.t., 3 h, 95%; (g) n-BuLi (for 21a) or t-BuLi (for 21b), THF,
–
3
1
2
2
3
H NMR (300 MHz, CDCl ): d = 0.80 (t-like, 3 H), 1.18–1.44 (m, 6
H), 1.20 (s, 3 H), 1.86 (d, J = 1.5 Hz, 3 H), 2.23 (s, 3 H), 4.48 (br s,
3
78 °C, 30 min, DMPU followed by o-nitro-m-xylene, –78 °C, 2.5 h,
7% for 21a, 48% for 21b
1
H), 5.07 (s, 1 H), 6.25 (dd, J = 7.4, 0.3 Hz, 1 H), 6.99 (d, J = 7.5
Hz, 1 H).
1
3
C NMR (75 MHz, CDCl ): d = 14.5, 18.3, 23.4, 24.4, 26.8, 31.9,
3
4
5.3, 56.5, 112.0, 113.4, 127.0, 128.2, 130.8, 155.1, 155.9.
The two 3-pyridinols 21a and 21b are the most complex
in the series of antioxidants that we have prepared to date.
These compounds are expected to be upwards of 30-fold
more reactive towards peroxidation chain-carrying perox-
yl radicals than PMC, the structural analog on which their
design was based. Studies of their radical-trapping activi-
ties are underway and will be reported in due course. We
are currently working towards a 3-pyridinol analog of a-
tocopherol with its C16 isoprenoid side chain intact using
the regioselective alkylation strategy described here.
HRMS: m/z [M + H]+ calcd for C H N : 231.1856; found:
15 22
2
2
31.1834.
2
,4-Dimethyl-1,8-naphthyridine (6)
10
Compound 6 was prepared according to the literature procedure.
1
H NMR (300 MHz, CDCl ): d = 2.27 (d, J = 0.7 Hz, 3 H), 2.75 (s,
3
3
1
H), 7.28 (s, 1 H), 7.43 (dd, J = 8.3, 4.2 Hz, 1 H), 8.31 (dd, J = 8.3,
.9 Hz, 1 H), 9.05 (dd, J = 4.2, 1.9 Hz, 1 H).
1
3
C NMR (75 MHz, CDCl ): d = 18.3, 25.9, 114.9, 121.3, 123.9,
3
1
33.4, 145.7, 153.2, 156.3, 163.0.
2
,4-Dimethyl-7-vinyl-1,8-naphthyridine (7)
Unless noted otherwise, materials were purchased from commercial
suppliers and used as received. Air- and/or moisture-sensitive reac-
To a solution of naphthyridine 6 (1.22 g, 7.7 mmol) in Et O (75 mL)
was added vinylmagnesium bromide (1.0 M in THF, 23.1 mL, 23.1
mmol) at 0 °C. The reaction mixture was stirred for 1 h, quenched
2
tions were carried out under an inert gas atmosphere. THF, Et O and
2
CH Cl2 were dried using a Solvent Purification System from
2
with sat. aq NH Cl, neutralized with 1 N HCl (pH 6) and extracted
Solvtek. Reaction progress was monitored by TLC using silica gel
F254 plates. Flash column chromatography was performed using sil-
ica gel 60 (230–400 mesh) with the indicated solvents. For 21a, the
4
with EtOAc (3 × 30 mL). The combined organic layer was washed
with water (3 × 15 mL) and brine, dried over anhyd MgSO and con-
4
centrated in vacuo. The residue was dissolved in CH Cl (70 mL)
silica gel was pre-treated with Et N. NMR spectra were taken on ei-
2
2
3
and MnO (activated, <5 m, 85% assay, 6.7 g, 77 mmol) was added
slowly and the reaction mixture stirred overnight. MnO was fil-
tered over Celite and the filtrate was concentrated under reduced
pressure. The resulting brown oil was purified by column chroma-
tography on silica gel (CHCl then MeOH–CHCl , 1:40) to yield the
ther a 300 MHz or 400 MHz Bruker DRX spectrometer. Chemical
shifts (d) are expressed in ppm using the indicated deuterated sol-
vent as internal standard and coupling constants (J) are given in Hz.
GC–MS spectra were obtained with a Hewlett-Packard 5890 series
II gas chromatograph and 5971 mass selective detector. HRMS
spectra were recorded in the positive ion mode using the electro-
spray technique and were obtained at the Ohio State University.
2
2
3
3
product as a light brown oil (1.02 g, 72% from 6).
1
H NMR (300 MHz, CDCl ): d = 2.68 (d, J = 0.9 Hz. 3 H), 2.76 (s,
3
3
H), 5.70 (dd, J = 10.8, 0.9 Hz, 1 H), 6.51 (dd, J = 17.6, 0.9 Hz, 1
2
,4,7-Trimethyl-1,8-naphthyridine (4)
H), 7.07 (dd, J = 17.4, 10.8 Hz, 1 H), 7.18 (d, J = 0.6 Hz, 1 H), 7.59
(d, J = 8.7 Hz, 1 H), 8.29 (d, J = 8.4 Hz, 1 H).
1
0
Compound 4 was prepared according to the literature procedure.
1
13
H NMR (300 MHz, CDCl ): d = 2.63 (d, J = 0.9 Hz, 3 H), 2.72 (s,
C NMR (75 MHz, CDCl ): d = 18.4, 25.9, 119.1, 120.4, 121.4,
3
3
3
H), 2.77 (s, 3 H), 7.13 (d, J = 0.9 Hz, 1 H), 7.30 (d, J = 8.7 Hz, 1
123.5, 133.7, 137.8, 145.4, 156.2, 158.7, 163.2.
H), 8.18 (d, J = 8.4 Hz, 1 H).
1
+
HRMS: m/z [M + Na] calcd for C H N Na: 207.0893; found:
207.0900.
1
2
12
2
3
C NMR (75 MHz, CDCl ): d = 18.3, 25.8, 25.8, 119.0, 121.9,
3
1
23.0, 133.2, 145.4, 156.0, 162.4, 162.6.
5
,7-Dimethyl-1,8-naphthyridine-2-carbaldehyde (8)
n-BuLi Addition to Compound 4 (Table 1, Entry 4); Typical
Procedure
To a solution of vinyl naphthyridine 7 (4.08 g, 22.2 mmol), potassi-
um ferricyanide [K Fe(CN) , 21.9 g, 66.6 mmol], K CO (9.19 g,
66.6 mmol) and 1,4-diazacyclo[2.2.2]octane (DABCO, 622 mg,
5.55 mmol) in t-BuOH (150 mL) and water (150 mL) was added os-
3
6
2
3
To a solution of naphthyridine 4 (70 mg, 0.4 mmol) in Et O (4 mL)
2
was added hexanes (8 mL) followed by slow addition of n-BuLi (2.5
Synthesis 2005, No. 9, 1397–1404 © Thieme Stuttgart · New York

PAPER
Alkyllithium Addition to 1,8-Naphthyridine
1401
1
mium tetroxide (OsO , 4% in water, 2.82 g, 0.44 mmol). The brown
H NMR (300 MHz, CDCl ): d = 0.78 (t, J = 6.6 Hz, 3 H), 1.13–1.48
4
3
slurry was stirred for 40 min at r.t. NaHSO (60% assay, 17.7 g) in
(m, 8 H), 1.83 (q, J = 7.5 Hz, 2 H), 2.60 (d, J = 0.3 Hz, 3 H), 2.68
(s, 3 H), 3.30 (s, 3 H), 4.33 (dd, J = 7.5, 6.3 Hz, 2 H), 4.85 (t, J = 6.3
Hz, 1 H), 7.13 (d, J = 0.9 Hz, 1 H), 7.57 (d, J = 8.4 Hz, 1 H), 8.26
(d, J = 8.7 Hz, 1 H).
3
water (70 mL) was added and the mixture was stirred for 10 min.
The reaction mixture was diluted with water (50 mL) and extracted
with CHCl (3 × 40 mL). The combined organic layer was washed
3
with brine, dried over anhyd MgSO and concentrated to give crude
13
4
C NMR (75 MHz, CDCl ): d = 14.4, 18.4, 23.0, 25.9, 29.5, 32.1,
3
diol (4.37 g, ca 90%).
3
7.1, 39.6, 56.2, 81.3, 96.1, 118.5, 120.2, 123.6, 134.0, 145.5,
1
H NMR (300 MHz, CD OD): d = 2.72 (s, 3 H), 2.73 (d, J = 0.9 Hz,
155.6, 163.0, 166.5.
GC–MS (EI): m/z = 316 [M]+.
3
3
H), 3.86 (dd, J = 11.3, 6.3 Hz, 1 H), 4.0 (dd, J = 11.3, 4.2 Hz, 1
H), 4.96 (dd, J = 6.2, 4.2 Hz, 1 H), 7.37 (d, J = 0.6 Hz, 1 H), 7.81
(
1
d, J = 8.4 Hz, 1 H), 8.55 (d, J = 8.4 Hz, 1 H).
(
5,7-Dimethyl-1,8-naphthyridin-2-yl)methanol (11)
3
C NMR (75 MHz, CD OD): d = 18.4, 25.3, 68.0, 76.7, 120.8,
To a solution of aldehyde 8 (250 mg, 1.34 mmol) in MeOH (10 mL),
was added NaBH (25 mg, 0.67 mmol) at r.t. After stirring for 1 h,
3
1
21.8, 125.0, 135.9, 148.9, 155.9, 164.3, 166.9.
4
+
water was added and the mixture was extracted with CHCl (3 × 15
3
HRMS: m/z [M + Na] calcd for C H N O Na: 241.0947; found:
2
1
2
14
2
2
mL). The combined organic layer was washed with water (10 mL)
41.0932.
The crude diol (3.77 g, 17.2 mmol) was dissolved in 1,4-dioxane
130 mL) and water (130 mL). Sodium periodate (NaIO , 3.80 g,
7.7 mmol) was added at r.t. The reaction mixture was stirred at the
same temperature for 45 min. Water (150 mL) was added and the
mixture was extracted with CHCl (5 × 40 mL). The combined or-
ganic layer was washed with brine, dried over anhyd MgSO and
concentrated under reduced pressure. The residue was purified by
column chromatography on silica gel (MeOH–CHCl , 1:20) to give
and the aq layer was back-extracted with CHCl (8 mL). The com-
3
bined organic layer was washed with brine, dried over anhyd
(
4
MgSO and concentrated in vacuo to give alcohol 11 (256 mg,
4
1
1
00%), which was sufficiently pure to be used directly without pu-
rification.
3
1
H NMR (300 MHz, CDCl ): d = 2.59 (d, J = 0.6 Hz, 3 H), 2.67 (s,
3
4
3
H), 4.51 (br s, 1 H), 4.88 (s, 2 H), 7.13 (s, 1 H), 7.28 (d, J = 8.4
Hz, 1 H), 8.21 (d, J = 8.4 Hz, 1 H).
3
1
3
8
(3.44 g, 93%).
C NMR (75 MHz, CDCl ): d = 18.5, 25.8, 64.6, 118.5, 120.4,
3
1
123.8, 134.2, 146.1, 155.1, 162.9, 163.1.
H NMR (300 MHz, CDCl ): d = 2.67 (s, 3 H), 2.74 (s, 3 H), 7.27
d, J = 0.9 Hz, 1 H), 8.00 (d, J = 8.4 Hz, 1 H), 8.43 (dd, J = 8.4, 0.6
3
+
(
HRMS: m/z [M + Na] calcd for C H N ONa: 211.0842; found:
1
1
12
2
Hz, 1 H), 10.2 (d, J = 0.9 Hz, 1 H).
211.0843.
1
3
C NMR (75 MHz, CDCl ): d = 18.5, 26.0, 117.4, 124.0, 125.8,
3
7
-[(tert-Butyldimethylsilyloxy)methyl]-2,4-dimethyl-1,8-naph-
1
35.2, 145.9, 154.5, 155.9, 164.7, 194.4.
thyridine (12)
+
HRMS: m/z [M + Na] calcd for C H N ONa: 209.0690; found:
1
1
10
2
A mixture of alcohol 11 (640 mg, 3.44 mmol), tert-butyldimethyl-
silyl chloride (1.03 g, 6.88 mmol), Et N (1.18 mL, 8.6 mmol) and
2
09.0680.
3
4
-dimethylaminopyridine (83 mg, 0.69 mmol) in CH Cl (33 mL)
2 2
1
-(5,7-Dimethyl-1,8-naphthyridin-2-yl)heptan-1-ol (9)
was stirred overnight at r.t. The reaction mixture was diluted with
CHCl (20 mL), washed with water (3 × 10 mL) and brine, dried
over anhyd MgSO and concentrated under reduced pressure. The
residue was purified by column chromatography on silica gel
(EtOAc–hexanes, 2:1) to give 12 (970 mg, 93%).
To a solution of aldehyde 8 (755 mg, 4.1 mmol) in THF (80 mL)
was added n-hexylmagnesium bromide (2.0 M in Et O, 2.2 mL, 4.3
mmol) at –78 °C. The reaction mixture was stirred at the same tem-
perature for 1 h. After quenching with sat. aq NH Cl, THF was re-
moved under reduced pressure. Water was added and the mixture
was extracted with EtOAc (4 × 15 mL). The combined organic layer
was washed with water (2 × 20 mL) and brine, dried over anhyd
MgSO and concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel (MeOH–CHCl3,
3
2
4
4
1
H NMR (300 MHz, CDCl ): d = 0.00 (s, 6 H), 0.84 (s, 9 H), 2.52
s, 3 H), 2.59 (s, 3 H), 4.90 (s, 2 H), 7.02 (s, 1 H), 7.61 (d, J = 8.4
3
(
Hz, 1 H), 8.20 (d, J = 8.7 Hz, 1 H).
4
1
3
C NMR (75 MHz, CDCl ): d = –4.94, 18.4, 18.7, 25.9, 26.3, 67.0,
3
1
:9) to give a yellow oil (457 mg, 42%).
118.4, 120.0, 123.3, 133.9, 145.6, 155.4, 162.9, 165.3.
1
+
H NMR (300 MHz, CDCl ): d = 0.78 (t-like, 3 H), 1.17–1.47 (m, 8
HRMS: m/z [M + Na] calcd for C H N OSi: 325.1687; found:
325.1698.
3
17 26
2
H), 1.81–1.92 (m, 1 H), 1.63–1.75 (m, 1 H), 2.62 (d, J = 0.6 Hz, 3
H), 2.65 (s, 3 H), 4.87 (m, 1 H), 5.57 (s, 1 H), 7.16 (s, 1 H), 7.32 (d,
J = 8.4 Hz, 1 H), 8.3 (d, J = 8.4 Hz, 1 H).
2-(5,7-Dimethyl-1,8-naphthyridin-2-yl)ethanol (13)
1
3
To a solution of vinyl naphthyridine 7 (746 mg, 4.05 mmol) in a
C NMR (75 MHz, CDCl ): d = 14.5, 18.5, 23.0, 25.6, 25.9, 29.7,
3
THF–H O mixture (4:1, 20 mL) was added mercury(II) trifluoroac-
2
3
1
2.1, 38.9, 73.3, 118.8, 120.4, 123.8, 134.2, 146.0, 155.0, 163.2,
66.1.
etate (1.73 g, 4.05 mmol). After stirring at r.t. for 1.5 h, 3 M NaOH
(
4.1 mL) was added. After 3 min, NaBH (0.5 M in 3 M NaOH, 4.1
4
GC–MS (EI): m/z = 172 [M]+.
mL) was added. The resulting dark green slurry was stirred at r.t. for
1
1
h. Extraction was performed with water (50 mL) and CHCl (3 ×
3
7
-[1-(Methoxymethoxy)heptyl]-2,4-dimethyl-1,8-naphthyri-
5 mL). The combined organic layer was washed with brine, dried
dine (10)
over anhyd MgSO and concentrated under reduced pressure. The
4
To a mixture of alcohol 9 (457 mg, 1.68 mmol), LiBr (73 mg, 1.68
mmol) and 2,2-dimethoxymethane (30 mL) was added methane-
sulfonic acid (110 mL, 1.68 mmol). After stirring for 2 h at r.t., the
reaction mixture was quenched with sat. aq Na CO and extracted
residue was purified by column chromatography on silica gel
(
MeOH–CHCl , 1:9) to give a pale yellow solid (576 mg, 70%).
3
1
H NMR (300 MHz, CDCl ): d = 2.58 (d, J = 0.9 Hz, 3 H), 2.68 (s,
3
2
3
3
H), 3.23 (t, J = 5.7 Hz, 2 H), 4.22 (t, J = 5.4 Hz, 2 H), 4.54 (s, 1
with CH Cl (3 × 15 mL). The combined organic layer was washed
2
2
H), 7.09 (d, J = 0.6 Hz, 1 H), 7.30 (d, J = 8.4 Hz, 1 H), 8.12 (d, J =
with water (2 × 10 mL) and brine, dried over anhyd MgSO and con-
4
8
.4 Hz, 1 H).
centrated under reduced pressure. The residue was purified by col-
1
3
umn chromatography on silica gel (EtOAc–hexanes, 3:1) to give 10
C NMR (75 MHz, CDCl ): d = 18.3, 25.8, 41.1, 61.5, 119.5, 122.3,
3
(
165 mg, 31%).
123.3, 133.4, 145.7, 155.5, 162.7, 164.4.
Synthesis 2005, No. 9, 1397–1404 © Thieme Stuttgart · New York

1
402
T.-g. Nam et al.
PAPER
+
HRMS: m/z [M + Na] calcd for C H N ONa: 225.0998; found:
matography on silica gel (EtOAc–hexanes, 1:3) to give a colorless
1
2
14
2
2
25.0991.
oil (1.05 g, 86%).
1
H NMR (300 MHz, CDCl ): d = 0.02 (d, J = 0.9 Hz, 6 H), 0.86 (s,
3
7
-[2-(Methoxymethoxy)ethyl]-2,4-dimethyl-1,8-naphthyridine
9
3
H), 1.15 (s, 3 H), 1.48–1.58 (m, 1 H), 1.70–1.79 (m, 1 H), 2.07 (s,
(
14)
H), 2.24 (s, 3 H), 2.55 (d, J = 6.9 Hz, 2 H), 3.39 (dd, J = 34.8, 9.3
The same procedure was applied as for compound 10 (43%).
Hz, 2 H), 4.79 (s, 1 H), 6.23 (s, 1 H).
1
H NMR (400 MHz, CDCl ): d = 2.43 (s, 3 H), 2.51 (s, 3 H), 3.08
s, 3 H), 3.06–3.10 (overlapped, 2 H), 3.87 (t, J = 6.8 Hz, 2 H), 4.40
s, 2 H), 6.94 (s, 1 H), 7.17 (d, J = 8.4 Hz, 1 H), 8.00 (d, J = 8.4 Hz,
13
3
C NMR (75 MHz, CDCl ): d = –5.03, 18.7, 19.0, 20.3, 24.1, 24.4,
3
(
(
1
1
2
6.3, 29.4, 53.2, 70.6, 110.7, 114.6, 146.0, 154.3, 155.0.
+
HRMS: m/z [M + H] calcd for C H N OSi: 321.2357; found:
H).
18 32
2
3
21.2346.
3
C NMR (100 MHz, CDCl ): d = 18.4, 25.9, 39.7, 55.6, 67.3, 96.9,
3
1
19.6, 122.1, 123.3, 133.4, 145.5, 156.1, 162.8, 163.2.
(
2,5,7-Trimethyl-1,2,3,4-tetrahydro-1,8-naphthyridin-2-
+
HRMS: m/z [M + Na] calcd for C H N O Na: 269.1260; found:
yl)methanol (18)
1
4
18
2
2
2
69.1271.
To a solution of 17 (1.05 g, 3.27 mmol) in THF (20 mL) was added
n-tetrabutylammonium fluoride (TBAF, 1.0 M in THF, 3.43 mL,
3.43 mmol) at 0 °C. The reaction mixture was stirred for 1.5 h at the
same temperature. The solvent was removed under reduced pres-
sure. The residue was purified by column chromatography on silica
7
-[2-(tert-Butyldimethylsilyloxy)ethyl]-2,4-dimethyl-1,8-naph-
thyridine (15)
A solution of alcohol 13 (45 mg, 0.22 mmol), imidazole (24 mg,
0
.35 mmol), DMAP (5.4 mg, 0.04 mmol) and TBSCl (50 mg, 0.33
gel (10% MeOH in CHCl ) to give the product (664 mg, 98%).
3
mmol) in CH Cl (10 mL) was stirred overnight at r.t. The reaction
1
2
2
H NMR (300 MHz, DMSO-d ): d = 1.09 (s, 3 H), 1.42–1.51(m, 1
6
mixture was diluted with CH Cl (10 mL), washed with water (3 ×
2
2
H), 1.68–1.76 (m, 1 H), 2.04 (s, 3 H), 2.14 (s, 3 H), 2.50 (t, J = 6.3
Hz, 2 H), 3.23 (dd, J = 27.6, 10.5 Hz, 2 H), 4.78 (s, 1 H), 5.79 (s, 1
H), 6.19 (s, 1 H).
8
mL) and brine, dried over anhyd MgSO and concentrated under
4
reduced pressure. The residue was purified by column chromatog-
raphy on silica gel (EtOAc–hexanes, 3:2) to give the product (70
mg, 100%).
1
3
C NMR (75 MHz, DMSO-d ): d = 18.5, 19.7, 23.6, 24.3, 29.0,
6
5
2.7, 68.1, 110.1, 113.4, 145.0, 153.0, 155.1.
1
H NMR (300 MHz, CDCl ): d = 0.0 (s, 6 H), 0.88 (s, 9 H), 2.68 (d,
3
HRMS: m/z [M + H]+ calcd for C H N O: 207.1492; found:
2
J = 0.3 Hz, 3 H), 2.76 (s, 3 H), 3.25 (t, J = 6.6 Hz, 2 H), 4.15 (t, J =
12 18
2
07.1493
6
.6 Hz, 2 H), 7.19 (s, 1 H), 7.42 (d, J = 8.4 Hz, 1 H), 8.23 (d, J = 8.4
Hz, 1 H).
2
,2,5,7-Tetramethyl-1,2,3,4-tetrahydro-1,8-naphthyridine (19)
1
3
C NMR (75 MHz, CDCl ): d = –4.98, 18.4, 18.6, 25.9, 26.3, 42.9,
3
To a solution of triphenylphosphine (1.04 g, 3.98 mmol), imidazole
6
3.2, 119.5, 122.7, 123.2, 132.9, 145.5, 156.2, 162.7, 163.8.
(
483 mg, 7.1 mmol) and alcohol 18 (586 mg, 2.84 mmol) in CH Cl
2
2
+
HRMS: m/z [M + Na] calcd for C H N ONa: 225.0998; found:
(20 mL) was added I (1.01 g, 3.98 mmol) at 0 °C. After 10 min, the
1
2
14
2
2
2
25.1001.
ice bath was removed and the reaction mixture was stirred for 1.5 h
at r.t. Na SO (4.5 g, 35.7 mmol) in water (20 mL) was added and
2
3
MeLi Additions to Compounds 9–15 (Table 2, entry 3); Typical
Procedure
the mixture was stirred for 30 min. The mixture was extracted with
CHCl (3 × 10 mL). The combined organic layers were washed with
3
2
-[(tert-Butyldimethylsilyloxy)methyl]-2,5,7-trimethyl-1,2-di-
water (3 × 15 mL) and brine and dried over anhyd MgSO . After
4
hydro-1,8-naphthyridine (16)
evaporation of solvent, the residue (which still contained triphe-
nylphosphine oxide) was dissolved in glacial AcOH (2 mL). Zinc
dust (activated, 428 mg, 3.93 mmol) was added at r.t. in one portion
and the mixture was stirred at 70 °C for 1 h. After cooling down to
r.t., the zinc metal was filtered through a pad of Celite. The filtrate
was neutralized with sat. aq NaHCO and extracted with CHCl .
To a solution of 12 (1.85 g, 6.12 mmol) in a mixture of Et O (50
2
mL) and hexanes (80 mL), was added MeLi (1.6 M in Et O, 15.3
2
mL, 24.5 mmol) at 0 °C. The reaction mixture was stirred for 45 min
after which it was quenched with sat. aq NH Cl and neutralized with
4
1
N HCl. The mixture was extracted with EtOAc (3 × 15 mL). The
3
3
combined organic layer was washed with water (3 × 10 mL) and
brine, dried over anhyd MgSO and concentrated under reduced
The organic layer was dried over anhyd MgSO and purified by col-
4
umn chromatography on silica gel (EtOAc–CHCl , 1:1 then
4
3
pressure. The residue was purified by column chromatography on
MeOH–CHCl , 1:20). A pale yellow solid (424 mg, 78%) was ob-
3
silica gel (EtOAc–hexanes, 1:3) to give a yellow oil (1.23 g, 63%).
tained.
1
1
H NMR (300 MHz, CDCl ): d = 0.01 (d, J = 3.0 Hz, 6 H), 0.85 (s,
H NMR (300 MHz, CDCl ): d = 1.14 (s, 6 H), 1.62 (t, J = 6.6 Hz,
3
3
9
9
1
H), 1.23 (s, 3 H), 2.11 (s, 3 H), 2.23 (s, 3 H), 3.48 (dd, J = 60.5,
.6 Hz, 2 H), 4.82 (s, 1 H), 5.31 (dd, J = 10.1, 2.1 Hz, 1 H), 6.15 (s,
H), 6.44 (d, J = 9.9 Hz, 1 H).
2 H), 2.05 (s, 3 H), 2.21 (s, 3 H), 2.53 (t, J = 6.6 Hz, 2 H), 4.52 (s, 1
H), 6.20 (s, 1 H).
13
C NMR (75 MHz, CDCl ): d = 19.0, 20.9, 24.1, 29.5, 34.4, 49.6,
3
1
3
C NMR (75 MHz, CDCl ): d = –5.03, 18.0, 18.7, 24.3, 26.3, 26.9,
110.4, 114.6, 146.2, 154.1, 155.1.
HRMS: m/z [M + H]+ calcd for C H N : 191.1543; found:
191.1540.
3
5
7.5, 71.4, 110.5, 115.1, 121.3, 126.5, 142.4, 154.9, 155.9.
1
2
18
2
+
HRMS: m/z [M + H] calcd for C H N OSi: 319.2200; found:
1
8
30
2
3
19.2208.
6
-Bromo-2,2,5,7-tetramethyl-1,2,3,4-tetrahydro-1,8-naphthyri-
2
-[(tert-Butyldimethylsilyloxy)methyl]-2,5,7-trimethyl-1,2,3,4-
dine (20a)
tetrahydro-1,8-naphthyridine (17)
To a solution of 16 (1.21 g, 3.80 mmol) in MeOH (150 mL) was
added palladium (10 wt% on charcoal, dry type, 182 mg). The reac-
tion mixture was stirred overnight at r.t. under a H atmosphere. The
catalyst was removed over Celite and the filtrate was concentrated
under reduced pressure. The residue was purified by column chro-
To a solution of 19 (400 mg, 2.10 mmol) in CH Cl (10 mL) was
2
2
added 1,3-dibromo-5,5-dimethylhydantoin (330 mg, 1.16 mmol) at
–78 °C. After stirring for 40 min, the reaction mixture was quenched
with sat. aq Na CO and the mixture was extracted with CHCl (3 ×
2
2
3
3
15 mL). The combined organic layers were washed with water (3 ×
15 mL) and brine and dried over anhyd MgSO . After concentra-
4
Synthesis 2005, No. 9, 1397–1404 © Thieme Stuttgart · New York

PAPER
Alkyllithium Addition to 1,8-Naphthyridine
1403
tion, the residue was purified by column chromatography on silica
fied by column chromatography on silica gel (EtOAc–hexanes, 1:3)
gel (EtOAc–hexanes, 1:5) to give the product (425 mg, 75%).
to give a brown thick oil (102 mg, 37%).
1
1
H NMR (300 MHz, CDCl ): d = 1.14 (s, 6 H), 1.63 (t, J = 6.6 Hz,
H NMR (300 MHz, DMSO-d ): d = 1.14 (s, 6 H), 1.70 (t, J = 6.9
3
6
2
H), 2.21 (s, 3 H), 2.39 (s, 3 H), 2.60 (t, J = 6.6 Hz, 2 H), 4.49 (s, 1
Hz, 2 H), 2.00 (s, 3 H), 2.20 (s, 3 H), 2.53 (t, J = 6.9 Hz, 2 H), 2.87
H).
(s, 3 H), 7.44 (s, 1 H).
1
3
13
C NMR (75 MHz, CDCl ): d = 19.5, 22.4, 25.8, 29.3, 34.4, 49.5,
C NMR (75 MHz, DMSO-d ): d = 12.1, 20.0, 21.1, 25.4, 28.9,
3
6
1
11.8, 112.5, 145.4, 153.1, 153.7.
35.9, 52.5,, 113.3, 133.6, 140.4, 140.5, 149.5.
+
HRMS: m/z [M + H]+ calcd for C H N O: 221.1648; found:
HRMS: m/z [M + H] calcd for C H BrN : 269.0648; found:
1
2
17
2
13 20
2
2
69.0643.
221.1660.
6
-Bromo-1,2,2,5,7-pentamethyl-1,2,3,4-tetrahydro-1,8-naph-
Acknowledgment
thyridine (20b)
To a solution of 20a (349 mg, 1.30 mmol) in MeOH (15 mL) was
added formaldehyde (37% in water, 5.3 g, 65 mmol) and AcOH
This work was supported by the U.S. National Institutes of Health
and National Science Foundation through grants to NAP.
(
3.72 mL, 65 mmol). At r.t., sodium cyanoborohydride (817 mg, 13
mmol) was added portionwise. After stirring for 3 h, the reaction
mixture was neutralized with sat. aq Na CO and extracted with
2
3
References
EtOAc (3 × 15 mL). The combined organic layers were washed with
water (3 × 15 mL) and brine and dried over anhyd MgSO . After
(1) Current address: Department of Pharmacochemistry, Vrije
Universiteit Amsterdam, Amsterdam, The Netherlands.
(2) Current address: Department of Chemistry, Queen’s
University, Kingston, Ontario, Canada.
4
concentration, the residue was purified by column chromatography
on silica gel (EtOAc–hexanes, 1:6) to give 20b (351 mg, 95%).
1
H NMR (300 MHz, CDCl ): d = 1.16 (s, 6 H), 1.69 (t, J = 6.6 Hz,
3
(
3) (a) Badawneh, M.; Manera, C.; Mori, C.; Saccomanni, G.;
Ferrarini, P. L. Farmaco 2002, 57, 631. (b) Leonard, J. T.;
Gangadhar, R.; Gnanasam, S. K.; Ramachandran, S.;
Saravanan, M.; Sridhar, S. K. Biol. Pharm. Bull. 2002, 25,
798. (c) Misbahi, H.; Brouant, P.; Hever, A.; Molnar, A. M.;
Wolfard, K.; Spengler, G.; Mefetah, H.; Molnar, J.; Barbe, J.
Anticancer Res. 2002, 22, 2097.
2
H), 2.18 (s, 3 H), 2.42 (s, 3 H), 2.57 (t, J = 6.6 Hz, 2 H), 2.97 (s, 3
H).
1
3
C NMR (75 MHz, CDCl ): d = 19.5, 22.4, 26.2, 26.3, 29.2, 36.2,
3
5
3.5, 111.1, 114.5, 143.6, 152.2, 154.4.
+
HRMS: m/z [M + H] calcd for C H BrN : 283.0804; found:
1
3
19
2
2
83.0814.
(
4) (a) Tomon, T.; Ooyama, D.; Wada, T.; Shiren, K.; Tanaka,
K. Chem. Commun. 2001, 1100. (b) He, C.; DuBois, J. L.;
Hedman, B.; Hodgson, K. O.; Lippard, S. J. Angew. Chem.
Int. Ed. 2001, 40, 1484. (c) He, C.; Lippard, S. J.
2
,4,7,8-Tetramethyl-5,6,7,8-tetrahydro-1,8-naphthyridin-3-ol
(
21a)
At –78 °C, t-BuLi (1.5 M in pentane, 2.73 mL, 4.10 mmol) was add-
ed to a solution of 20a (344 mg, 1.28 mmol) in anhyd THF (8 mL).
The formation of the metalated adduct was monitored by TLC. Af-
ter 45 min, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
Tetrahedron 2000, 56, 8245.
(
5) (a) Ferrarini, P. L.; Mori, C.; Badawneh, M.; Calderone, V.;
Greco, R.; Manera, C.; Martinelli, A.; Nieri, P.; Saccomanni,
G. Eur. J. Med. Chem. 2000, 35, 815. (b) Saccomanni, G.;
Badawneh, M.; Adinolfi, B.; Calderone, V.; Cavallini, T.;
Ferrarini, P. L.; Greco, R.; Manera, C.; Testai, L. Bioorg.
Med. Chem. 2003, 11, 4921.
(
DMPU, 304 mL, 2.56 mmol) was added at the same temperature.
After 10 min, anhyd 2-nitro-m-xylene (1.22 mL, 8.96 mmol) was
added in one portion. The color changed immediately from yellow
to dark brown. After stirring for 3 h at –78 °C, the reaction mixture
(
6) (a) Duggan M. E., Duong L. T., Fisher J. E., Hamill T. G.,
Hoffman W. F., Huff J. R., Ihle N. C., Leu C. T., Nagy R.
M., Perkins J. J., Rodan S. B., Wesolowski G., Whitman D.
B., Zartman A. E., Rodan G. A., Hartman G. D.; J. Med.
Chem.; 2000, 43: 3736. (b) Meissner R. S., Perkins J. J.,
Duong L. T., Hartman G. D., Hoffman W. F., Huff J. R., Ihle
N. C., Leu C. T., Nagy R. M., Naylor-Olsen A., Rodan G. A.,
Rodan S. B., Whitman D. B., Wesolowski G. A., Duggan M.
E.; Bioorg. Med. Chem. Lett.; 2002, 12: 25.
was quenched and neutralized with sat. aq NH Cl. The mixture was
4
extracted with CHCl (4 × 15 mL). The combined organic layer was
3
dried over anhyd MgSO and concentrated. The residue was puri-
4
fied by column chromatography on silica gel (CHCl then MeOH–
3
CHCl , 1:20) to give orange solid (126 mg, 48%).
3
1
H NMR (300 MHz, DMSO-d ): d = 1.09 (s, 6 H), 1.55 (t, J = 6.9
6
Hz, 2 H), 2.00 (s, 3 H), 2.24 (s, 3 H), 2.51 (overlapped t, J = 6.9 Hz,
2
H), 5.34 (s, 1 H), 7.39 (s, 1 H).
1
3
C NMR (75 MHz, DMSO-d ): d = 12.0, 19.4, 21.3, 28.6, 34.4,
(7) (a) Wijtmans, M.; Pratt, D. A.; Valgimigli, L.; DiLabio, G.
6
4
8.4, 110.9, 134.3, 140.8, 141.5, 149.4.
A.; Pedulli, G. F.; Porter, N. A. Angew. Chem. Int. Ed. 2003,
4
2, 4370. (b) Wijtmans, M.; Pratt, D. A.; Brinkhorst, J.;
HRMS: m/z [M + H]+ calcd for C H N O: 207.1492; found:
1
2
18
2
Swerza, R.; Valgimigli, L.; Pedulli, G. F.; Porter, N. A. J.
Org. Chem. 2004, 69, 9215.
2
07.1495.
(
(
8) Burton, G. W.; Ingold, K. U. J. Am. Chem. Soc. 1981, 103,
2
,4,7,7,8-Pentamethyl-5,6,7,8-tetrahydro-1,8-naphthyridin-3-ol
6472.
(
21b)
9) (a) Traber, M. G.; Ramakrishnan, R.; Kayden, H. J. Proc.
Natl. Acad. Sci., U.S.A. 1994, 91, 10005. (b) Traber, M. G.
Free Radical Biol. Med. 1994, 16, 229.
At –78 °C, n-BuLi (2.5 M in hexane, 1.1 mL, 2.73 mmol) was added
to a solution of 20b (350 mg, 1.24 mmol) in anhyd THF (6 mL). The
formation of the metalated adduct was monitored by TLC. After 30
min, DMPU (648 mL, 5.46 mmol) was added at the same tempera-
ture. After 10 min, anhyd 2-nitro-m-xylene (844 mL, 6.20 mmol)
was added in one portion. The color changed immediately from yel-
low to brown. After 3 h of stirring, the reaction mixture was
quenched and neutralized with sat. aq NH Cl. The mixture was ex-
tracted with CHCl (4 × 15 mL). The combined organic layers were
dried over anhyd MgSO and concentrated. The residue was puri-
(
10) Hamada, Y.; Takeuchi, I.; Sato, M. Yakugaku Zasshi 1974,
94, 1328.
(
11) Newkome, G. R.; Theriot, K. J.; Majestic, V. K.; Spruell, P.
A.; Baker, G. R. J. Org. Chem. 1990, 55, 2838; and
references therein.
4
(
12) Dietrichbuchecker, C. O.; Marnot, P. A.; Sauvage, J. P.
3
Tetrahedron. Lett. 1982, 23, 5291.
4
Synthesis 2005, No. 9, 1397–1404 © Thieme Stuttgart · New York

1
404
T.-g. Nam et al.
PAPER
(
(
(
13) Bhattacharjee, D.; Popp, F. D. J. Heterocycl. Chem. 1980,
7, 1211.
14) Evans, D. A.; Cee, V. J.; Smith, T. E.; Santiago, K. J. Org.
Lett. 1999, 1, 87.
15) Mansour, T. S.; Wong, T. C.; Kaiser, E. M. J. Chem. Soc.,
Perkin Trans. 2 1985, 2045.
Markovnikov adduct with NaBH . Then, the cyclopropane
4
1
ring opens in such a way that anti-Markovnikov alcohol is
produced. Similar cyclopropane intermediates have been
proposed in a conjugated diene system: Brown, H. C.;
Geoghegan, P. J.; Lynch, G. J.; Kurek, J. T. J. Org. Chem.
1972, 37, 1941.
(
(
16) Fuji, K.; Nakano, S.; Fujita, E. Synthesis 1975, 276.
17) We speculate that a cyclopropane intermediate is formed by
radical cyclization upon treatment of the initial
(18) Deprotection of TBS group in 16 resulted in unidentified by-
product up to 50%.
Synthesis 2005, No. 9, 1397–1404 © Thieme Stuttgart · New York