An expeditious synthesis of 3-(difluoromethoxy)- and 3-(trifluoromethoxy)-5,6,7,8-tetrahydro-1,6-naphthyridines

Article abstract of DOI:10.1016/j.tetlet.2008.08.083

An expeditious and concise synthesis of 3-(difluoromethoxy)-5,6,7,8-tetrahydro-1,6-naphthyridine and 3-(trifluoromethoxy)-5,6,7,8-tetrahydro-1,6-naphthyridines is described. Starting from N-benzyl piperidone, the key intermediates leading to these two bio

Full text of DOI:10.1016/j.tetlet.2008.08.083

Tetrahedron Letters 49 (2008) 6368–6370
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Tetrahedron Letters
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An expeditious synthesis of 3-(difluoromethoxy)- and
3-(trifluoromethoxy)-5,6,7,8-tetrahydro-1,6-naphthyridines
*
Deodialsingh Guiadeen , Shankaran Kothandaraman, Lihu Yang, Sander G. Mills, Malcolm MacCoss
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An expeditious and concise synthesis of 3-(difluoromethoxy)-5,6,7,8-tetrahydro-1,6-naphthyridine
and 3-(trifluoromethoxy)-5,6,7,8-tetrahydro-1,6-naphthyridines is described. Starting from N-benzyl
piperidone, the key intermediates leading to these two biologically desirable synthones were rapidly
assembled by inverse electron demand Diels–Alder (IEDA) reaction utilizing microwave irradiation.
The scope of the microwave methodology developed herein was extended to other ketones.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 18 July 2008
Revised 21 August 2008
Accepted 22 August 2008
Available online 28 August 2008
Keywords:
Difluoromethoxy
Trifluoromethoxy
Microwave
In biologically active molecules, replacement of hydrogen
atom(s) with the more electronegative fluorine atom(s) signifi-
cantly alters their electronic properties. However, because of their
similar atomic radius the spatial properties are conserved.1 The net
result is the design of new entities bestowed with improved met-
abolic stability and increased lipophilicity. Ongoing efforts in a
medicinal chemistry project required us to improve on the meta-
bolic stability of our lead naphthyridine containing compound
while maintaining potency. We reasoned that incorporation of
novel 3-(difluoromethoxy) and 3-(trifluoromethoxy)-5,6,7,8-tetra-
hydro-1,6-naphthyridines 2 and 3 into our lead molecule might
offer us analogs with improved metabolic profiles. Herein, we
report a straightforward synthesis of these important pharmaco-
phores starting from readily available 4-piperidones exemplified
by 1.
Several variations of these reactions are known, but have been
severely underutilized. In recent years because of increased effi-
ciency, there have been burgeoning interests in the reactions that
involve the use of microwave technology.3 We further expanded
on the scope and usefulness of the bis-nitro compound 4, by
extending IEDA to a wider array of ketones, but under microwave
conditions.
The IEDA reaction of 4 and 1 (R1 = Bn), with microwave irra-
diation in the presence of methanolic ammonia was conducted
at 120 °C for 20 min.4 Upon routine workup, 5 was isolated in
78% yield. In general, the reaction was very clean and operation-
ally simple. Encouraged by these findings, a broader range of ke-
tones were then subjected to similar reaction conditions, and the
results from these studies are summarized in Table 1 (entries 2–
8). Briefly, the protecting groups (Boc and Bz) on 1 were well
tolerated under these conditions to afford products 6 and 7 as
were products 8 and 9 in good to excellent yields. The successful
outcomes for entries 6–8 demonstrated that ketones other than
piperidones can also be utilized to afford an even wider array
of products (10–12) with good to excellent yields. The only
low yielding example in this study was entry 7, where the yield
obtained for 11 was 28%. However, as can be seen for entry 8,
protection of the OH afforded the desired product 12 in excellent
yield (89%). Desilylation5 of 12 under standard conditions gave
11. Additional analogs could be synthesized from other ketones,
but a glance at Table 1 reveals the potential for even broader
applications for this microwave-assisted protocol that is beyond
the scope of the present investigation.
OCF2R
R
1 N
HN
N
O
R = H, 2
1
F, 3
Synthesis of the naphthyridines (2 and 3) relied on a facile in-
verse electron demand Diels–Alder (IEDA) reaction between 3,5-
dinitro-N-methyl-pyridone (4) and piperidone (1, R1 = Bn) to afford
5. The preparation of 4, its congener and the relative ease with
which it undergoes such a reaction have been amply documented.2
* Corresponding author. Tel.: +1 732 594 6531; fax: +1 732 594 2210.
E-mail address: deodialsingh_guiadeen@merck.com (D. Guiadeen).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.08.083

D. Guiadeen et al. / Tetrahedron Letters 49 (2008) 6368–6370
6369
diazonium salt afforded the phenol 15. It is important to note that
the N-Bn protecting group remained intact during this transforma-
tion. Because the penultimate step for the synthesis of 2 required
us to utilize the N-Boc instead of the N-Bn intermediate, 15 was
converted to 15a.7 This was easily accomplished by hydrogenolysis
of 15 under acidic conditions (2N HCl) followed by N-Boc protec-
tion to give the product 15a.
Inverse Electron
Demand Diels
Alder Reaction.
Ph
N
O2N
NO2
O
NO2
N
N
1
4
5
The transformation of the N-Bz analog 7 to the phenol 16 fol-
lowing the protocol discussed above for 15, was equally facile
and uneventful. Conversion of phenols 15a and 16 to the 3-difluo-
romethoxy and 3-trifluoromethoxy analogs 2 and 3, respectively, is
shown in Scheme 2. A variation of literature8 procedure that in-
volves alkylation of 15a under basic conditions with bromodifluo-
romethane (CHBrF2) gave 17 in 20% yield. Attempts to improve the
yield under a variety of conditions that involved diverse bases
(both organic and inorganic) and temperatures were futile. By con-
trast, a three-step procedure9 for the transformation of 16–19 pro-
ceeded in much better yields. Thus, in a sequence of reactions that
involved conversion of 16 to the xanthate 18 followed by its reac-
tion with 1,3-dibromo- 5,5-dimethylhydantoin (DBDH) and Py-HF
complex, the product 19 was afforded in 90% yield.
Removal of the N-Boc and N-Bz protecting groups in 17 and 19,
respectively, was affected under acidic conditions to afford 2 and 3
as their HCl salts. The hydrochloride salts of 2 and 3 were carried
forward to make the biologically active molecules. The free amine
derived from 19 was also easily obtained by neutralization of the
salt with Ca(OH)2. The medicinal chemistry aspects related to the
utilization of 2 and 3 will be the subject of communication to be
followed elsewhere.
Table 1
Reaction of various ketones with 4 to afford an array of productsa
Entry Ketones
Product
Product Yieldb,c
ID
(%)
Bn
N
NO2
1
5
78
O
Bn N
N
Boc
N
NO2
2
6
7
97
88
O
Boc N
N
Bz
N
NO2
3
4
Bz N
O
N
N
O
NO2
8
77
N
Cl
Cl
N
NO2
EtOOC
5
6
7
8
9
10
11
12
83
89
28
89
N
O
EtOOC
S
N
N
In summary, a concise synthesis of the heterocyclic synthons 2
and 3 is disclosed. The key to these pharmacologically important
scaffolds involved microwave-assisted inverse electron demand
Diels–Alder reaction between 3, 5-dinitro-N-methylpyridone (4)
NO2
S
O
N
HO
NO2
O
HO
d
a
O
F
BocN
15a / 16
N
2
F
N
TBSO
NO2
17
O
b
TBSO
N
a
b
c
Reactions performed under microwave conditions at 120 °C, 20 min.
Isolated yields.
Products 5–12 have been fully characterized by high field NMR and MS.
F
F
c
O
SMe
O
F
BzN
BzN
S
N
N
19
18
Upon synthesis of the key intermediates 5 and 7, we proceeded
DBDH = 1,3-dibromo-
5,5-dimethylhydantoin
d
to complete the transformations to the desired products 2 and 3 as
shown in Schemes 1 and 2. Thus, a short exposure of the nitro
compound 5 to catalytic hydrogenation afforded the aniline 13.
Diazotization6 of 13 followed by thermal decomposition of the
3
Scheme 2. Reagents and conditions: (a) K2CO3, CHBrF2, DMF, 75 °C; (b) NaH, CS2,
DMF, MeI, À78 °C; (c) DBDH, HF-Py complex, DCM; (d) HCl/EtOAc.
OH
NH2
b
a
RN
RN
N
N
R=Bn
15, R = Bn
15a, R = Boc
13
c,d
NO2
RN
N
OH
5, R = Bn
7, R = Bz
b
NH2
a
RN
N
RN
N
R= Bz
R=Bz, 16
14
Scheme 1. Reagents and conditions: (a) Pd/C, H2, MeOH; (b) NaNO2, H2SO4, 90 °C; (c) Pd/C, H2, EtOH, 2 N HCl; (d) Boc2O, NaHCO3, DCM.

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D. Guiadeen et al. / Tetrahedron Letters 49 (2008) 6368–6370
3. Kappe, C. O.; Stadler, A. Microwaves in Organic and Medicinal Chemistry; Wiley-
VCH Verlag GmbH & Co. KGaA: Weinheim, 2005.
4. In a typical experiment exemplified by entry 1, a mixture of 4 (0.199 g, 1 mmol)
and piperidone(s). We believe that our modified microwave proto-
col for IEDA reactions holds greater promise to the synthesis of
other heterocyclic compounds.
in 4 ml of 2 M methanolic ammonia and 4-piperidone
1 (R = Bn, 0.189 g,
1 mmol) in a 10 ml microwave tube was heated at 120 °C for 20 min in the
Biotage Initiator Microwave. The solvent was evaporated and the crude mixture
was purified by silica column on the Combiflash Companion Instrument, eluting
with ethyl acetate/hexane (0–50%) to afford 5 (0.211 g, 78%). 1H NMR (CD3OD,
500 MHz): d 9.14 (d, J = 2.5 Hz, 1H), 8.30 (d, J = 2.3 Hz, 1H), 7.40–7.28 (m, 5H),
3.76 (s, 4H), 3.10 (t, J = 6.0 Hz, 2H), 2.91 (t, J = 6.0 Hz, 2H). LC–MS [M+H]+
calculated 269.12, found 270.05.
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