The enantioselective synthesis of (R)- and (S)-3-amino-3,4-dihydro-1H-[1,8] naphthyridin-2-one

Article abstract of DOI:10.1016/j.tetasy.2010.06.023

A number of approaches to the enantioselective synthesis of (R)- and (S)-3-amino-3,4-dihydro-1H-[1,8]naphthyridin-2-one were studied. A novel one-pot asymmetric reduction/lactamization provided the desired products in high yield and enantiomeric excess.

Full text of DOI:10.1016/j.tetasy.2010.06.023

Tetrahedron: Asymmetry 21 (2010) 2072–2075
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Tetrahedron: Asymmetry
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The enantioselective synthesis of (R)- and
(S)-3-amino-3,4-dihydro-1H-[1,8]naphthyridin-2-one
*
Allyn T. Londregan , David Bernhardson, James Bradow, Teresa M. Makowski, Gregory Storer,
Joseph Warmus, Ceshea Wooten, Xiaojing Yang
Worldwide Medicinal Chemistry, Pfizer Inc., Groton, CT 06340, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 May 2010
Accepted 17 June 2010
A number of approaches to the enantioselective synthesis of (R)- and (S)-3-amino-3,4-dihydro-1H-
[1,8]naphthyridin-2-one were studied. A novel one-pot asymmetric reduction/lactamization provided
the desired products in high yield and enantiomeric excess.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
3-Amino-3,4-dihydro-1H-[1,8]naphthyridin-2-ones have emerged
as common building blocks in putative chemotherapeutics and
molecules with biological activity.1a,b During the course of our stud-
ies, we required the enantioselective synthesis of 3-amino-3,4-
dihydro-1H-[1,8]naphthyridin-2-one 1 (Fig. 1). Despite a number
of racemic syntheses for this moiety in the literature,1 no enantio-
selective syntheses have been reported. There is a single report of
access to enantiomerically pure material via chiral HPLC resolu-
tion,2 but this method is suboptimal due to the intrinsic yield lim-
itations.3 We investigated several different approaches to this
problem. A novel one-pot asymmetric reduction/lactamization ulti-
mately provided the desired products in high yield and enantio-
meric excess. Our results indicate that the methodology is
scalable and reproducible. Herein we report a robust method for
the preparation of optically active 3-amino-dihydronapthyridinon-
Our initial approach to the synthesis of enantiopure 1 employed
methodology developed by our co-workers for the synthesis of chi-
ral quinolinones (Scheme 1).4 We reasoned that asymmetric alkyl-
ation of 2 with 3-(bromomethyl)-2-nitropyridine 4 would proceed
in an analogous fashion to that with 3. Repeated attempts gave
only a 35% yield of 6 (99% ee),5 in comparison with a 92% yield
of 5 (93% ee). This discrepancy may in part be attributed to the
decomposition of 4 under the reaction conditions. The subsequent
lactamization afforded a low yield (35%) of (R)-1. These results,
combined with the challenging6 synthesis of 4, prompted us to ex-
plore suitable replacements.
When 3-(bromomethyl)-2-aminopyridine 9 was used in the
place of 4, none of compound 11 was obtained (Scheme 2). How-
ever, when the asymmetric alkylation was attempted with 2-
chloro-3-chloromethyl-pyridine 10, clean conversion to 12 was ob-
served in good yield (75%, 92% ee). With compound 12 in hand,
several approaches were investigated to introduce the requisite
amino functionality onto the chloropyridine. Attempts at the direct
nucleophilic displacement of 12, with ammonia and 4-methoxy-
benzylamine to give 13 and 14, respectively, resulted in rapid
decomposition. Buchwald coupling7 of 4-methoxybenzylamine
with 12 was equally unsuccessful, as was sodium azide displace-
ment of 12 to yield 15.
The asymmetric hydrogenation of olefins with ruthenium and
rhodium catalysts is well known.8 Many of these catalysts are com-
mercially available and can safely be used on a large scale.9 We
sought to apply such a reduction in our system, thus avoiding
the aforementioned alkylation chemistry and allowing for a more
robust approach to (R)-1 (Scheme 3). Using a high pressure hydro-
genation apparatus,10 we initiated a catalyst screen with enone 18,
which was synthesized in one step (86% yield) from 16 via a Horn-
er–Wadsworth–Emmons olefination.1d Upon hydrogenation with a
selection of commercially available rhodium and ruthenium cata-
es via
a
one-pot asymmetric hydrogenation/lactamization
sequence.
N
N
N
NH
NH
NH
H2N
H2N
H2N
O
O
O
1
(R)-1
(S)-1
Figure 1. (R)- and (S)-3-amino-3,4-dihydro-1H-[1,8]naphthyridin-2-one.
* Corresponding author. Tel.: +1 860 715 6150; fax: +1 860 686 0001.
E-mail address: allyn.t.londregan@pfizer.com (A.T. Londregan).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.06.023

A. T. Londregan et al. / Tetrahedron: Asymmetry 21 (2010) 2072–2075
2073
O2N
X
O2N
X
Ph
8, CsOH
+
Ph
N
COOtBu
Ph
CH2Cl2, -30ºC
Br
Ph
N
COOtBu
3 X = C
5 X = C (92%)
6 X = N (35%)
2
4
X = N
H2, Pd/C
O
N+
X
2M HCl
MeOH
8 =
NH
N
Br-
H2N
O
7 X = C (65%)
(R)-1·2HCl X = N (35%)
Scheme 1. First approach to (R)-1.
N
X
Table 1
X
Y
N
Asymmetric hydrogenation catalyst screen
2
8, CsOH
+
Entry
Catalyst
%ee5 19
Yield 19 (%)
Ph
CH2Cl2, -30ºC
1
Ru((R)-BINAP)OAc2
Ru((R)-BINAP)OAc2
Ru((R)-xylyl-BINAP)Cl2
Rh(COD)((R,R)-EtDuPhos)SO3CF3
Rh(COD)(TCFP)BF4
98
92
82
80
76
97
2a
3
n/db
n/d
n/d
n/d
Ph
N
COOtBu
4
5
9 X = NH2, Y = Br
10 X = Cl, Y = Cl
11 X = NH2 (0%)
12 X = Cl (75%)
a
Ethanol used as solvent.
Not determined.
b
NH4OH
or
Z
N
PMB-NH2, 80ºC
or
PMB-NH2, Pd(OAc)2,
Cs2CO3, DME, 100ºC
or
sults in our screen (97% yield, 98% ee) were obtained with 3 mol %
Ru((R)-BINAP)OAc2,11 at 70 °C and 150 psi of hydrogen for 36 h.
When these conditions were applied in a gram-scale reactor, as de-
scribed in Section 4, we achieved an identical yield and enantio-
meric excess of 19 (97% yield, 98% ee), when compared to the
trial run. Upon treatment of 19 with 4 M HCl, (R)-1 was obtained
as the dihydrochloride salt in 97% yield and 98% ee.12
Ph
12
X
+
Ph
N
COOtBu
13 Z = NH2
14 Z = NHPMB
15 Z = N3
NaN3, 70ºC
By simply switching the chirality of the ruthenium catalyst to
Ru((S)-BINAP)OAc2 under the identical reaction conditions, we
were able to obtain (S)-1 in similar yield and enantiomeric excess
(97%, 97% ee for the reduction/lactamization and 96%, 97% ee for
the deprotection). When the reduction/lactamization procedure
was repeated in the presence of catalytic HCl, in order to affect a
simultaneous removal of the N-Boc-protecting group, the yield
and enantiomeric excess of the reaction were significantly reduced.
Scheme 2. Additional approaches to the synthesis of (R)-1.
lysts, we were able to obtain 19, the result of tandem reduction/
lactamization sequence. As shown in Table 1, the choice of catalyst
appeared to have a significant impact on the observed enantio-
meric excess, with results ranging from 76% to 99% ee. The best re-
O
O
DBU
BocHN
BocHN
H
+
OMe
N
MeO
THF
-78ºC to 25ºC
86%
N
NH2
PO(OMe)2
NH2
O
16
17
18
Conditions
in
Table 1
N
4M HCl
(R)-1·2HCl
MeOH
97%
NH
H2, 150 psi
trifluoroethanol, 70ºC
BocHN
O
19
Scheme 3. Synthesis of (R)-1 via asymmetric hydrogenation.

2074
A. T. Londregan et al. / Tetrahedron: Asymmetry 21 (2010) 2072–2075
were evacuated to afford (R)-1 as a white solid (15 mg, 97%, 98%
3. Conclusion
ee). Mp: >250 °C 1H NMR (400 MHz, DMSO-d6) 11.14 (s, 1H), 10.3
(br s, 1H), 8.75 (br s, 3H), 8.18 (d, J = 5.1 Hz, 1H), 7.73 (d,
J = 7.4 Hz, 1H), 7.05 (dd, J = 7.42, 4.88 Hz, 1H), 4.31 (m, 1H), 3.21–
3.34 (m, 1H), 3.01–3.19 (m, 1H); 13C NMR (100 MHz, DMSO-d6):
d 172.8, 144.3, 144.1, 137.5, 132.1, 118.1, 63.2, 32.4; IR (cmꢀ1):
2853, 1732, 1628, 1508, 1236; MS m/z = 164.1 [M+H]+;
In conclusion, we investigated several enantioselective synthe-
ses of 3-amino-3,4-dihydro-1H-[1,8]naphthyridin-2-ones, result-
ing in a highly selective, scalable, and robust one-pot asymmetric
hydrogenation/lactamization sequence.
½
a 2D0
ꢂ
¼ þ50:1 (c 1.25 mg/mL, CH3OH).
4. Experimental
4.5. (S)-3-Amino-3,4-dihydro-1H-[1,8]naphthyridin-2-one 2HCl
(S)-1ꢃ2HCl
4.1. (Z)-Methyl 3-(2-aminopyridin-3-yl)-2-(tert-butoxycarbonyl)-
acrylate 18
Prepared by the same procedure as (R)-1. White solid (14.8 mg,
To ꢀ78 °C solution of ( )-Boc-alpha-phosphonoglycine tri-
methyl ester 17 (12.8 g, 43.0 mmol) in THF (100 mL) was added
DBU (6.73 mL, 45.0 mmol) dropwise. After stirring for 20 min at
96%, 97% ee). ½a 2D0
¼ ꢀ48:7 (c 1.15 mg/mL, CH3OH).
ꢂ
4.6. (R)-tert-Butyl 2-(diphenylmethyleneamino)-3-(2-nitropyri-
din-3-yl)propanoate 6
ꢀ78 °C,
a
solution of 2-aminonicotinaldehyde 16 (5.00 g,
40.9 mmol) in THF (20 mL) was added. The reaction was warmed
to room temperature and stirred for 18 h. The reaction was evacu-
ated to half-volume and poured into ethyl acetate (200 mL). The
organics were washed with water (1 ꢁ 100 mL), brine (1 ꢁ
100 mL), dried (Na2SO4), and evacuated. The resulting solids were
triturated with 50:50 diethyl ether/ethyl acetate and vacuum fil-
tered to yield 18 (E/Z determined by NOE) as an analytically pure
yellow solid (10.3 g, 86%). Mp: 163 °C; 1H NMR (400 MHz,
MeOD-d4): d 7.91 (dd, J = 5.1, 1.8 Hz, 1H), 7.69 (s, 1H), 7.14 (dd,
J = 7.6, 1.8 Hz, 1H), 6.67 (dd, J = 7.6, 5.1 Hz, 1H), 3.83 (s, 3H), 1.40
(s, 9H); 13C NMR (100 MHz, DMSO-d6): d 169.7, 158.2, 149.5,
137.2, 127.6, 113.1, 112.9, 79.7, 52.7, 39.6, 28.6; IR (cmꢀ1): 3367,
3210, 2978, 1706, 1449, 1261; MS m/z = 294.3 [M+H]+.
To a round-bottomed flask at 0 °C were added diphenylmethyl-
ene glycine t-butyl ester (377 mg, 1.28 mmol), catalyst 8 (61 mg,
0.13 mmol), 3-(bromomethyl)-2-nitropyridine (252 mg, 1.16 mmol),
and DCM (10 mL). The mixture was cooled to ꢀ30 °C. Next, CsOH
(383 mg, 2.56 mmol) was added and the reaction mixture was stir-
red at ꢀ30 °C for 18 h. The reaction was quenched with water
(25 mL) and the mixture was diluted with DCM (50 mL). The layers
were separated. The aqueous was extracted with DCM (25 mL) one
more time. The organics were dried (Na2SO4) and evacuated. The
crude material was purified by column chromatography (0–35%
EtOAc/heptanes) to afford the desired product (174 mg, 35%, 99%
ee) as a colorless oil. 1H NMR (400 MHz, CDCl3-d): d 8.39 (dd,
J = 4.6, 1.7 Hz, 1H), 7.88 (s, 1H), 7.56 (d, J = 7.4 Hz, 2H), 7.28–7.44
(m, 7H), 6.67 (m, 2H), 4.31 (m, 1H), 3.50 (m, 1H), 3.34 (br s, 1H),
1.41 (s, 9H); 13C NMR (100 MHz, CDCl3-d): d 171.4, 168.3, 156.2,
144.6, 139.8, 139.0, 133.6, 131.1, 129.0, 128.2(2), 81.3, 70.2, 33.6,
28.7; IR (cmꢀ1): 1740, 1680, 1560; MS m/z 432.3 (M+1).
4.2. (R)-tert-Butyl 2-oxo-1,2,3,4-tetrahydro-1,8-naphthyridin-3-
ylcarbamate 19
Compound 18 (1.50 g, 5.11 mmol) and Ru((R)-BINAP)OAc2
(122 mg, 0.03 equiv) were added to the pressure vessel10 which
was then purged with nitrogen (four times). Nitrogen-flushed tri-
fluoroethanol (15 mL) was added and the reactor was purged with
additional nitrogen (four times) and then hydrogen gas (four
times). The reactor was heated to 70 °C and then pressurized to
150 psi with hydrogen. After 36 h, the reactor was cooled to ambi-
ent temperature and purged with nitrogen (four times). The dark
brown solution was concentrated to approximately 5 mL/g and
stirred overnight, resulting in the precipitation of off-white solids.
These were filtered and slurried in ethanol (3 mL/g). After filtration
and air-drying, 19 was obtained as a white solid. (1.30 g, 97%, 98%
ee). Mp: 191–196 °C; 1H NMR (400 MHz, CDCl3-d): d 9.33 (br s,
1H), 8.27 (d, J = 5.1 Hz, 1H), 7.54 (d, J = 7.3 Hz, 1H), 6.99 (dd,
J = 7.3, 5.1 Hz, 1H), 5.66 (br s, 1H), 4.38 (m, 1H), 3.54 (m, 1H),
2.80–2.85 (t, J = 15.2, 1H), 1.48 (s, 9H); 13C NMR (100 MHz,
CDCl3-d): d 172.5, 156.9, 144.0 (2), 137.0, 132.4, 119.1, 79.5, 65.8,
30.6, 28.5; IR (cmꢀ1): 1677, 1522, 1390, 1168; MS m/z = 264.0
½
a 2D0
ꢂ
¼ þ182:6 (c 10.3 mg/mL, CH3OH).
4.7. (R)-tert-Butyl 3-(2-chloropyridin-3-yl)-2-(diphenylmethyle-
neamino)propanoate 12
To a round-bottommed flask were added 2-chloro-3-(chloro-
methyl)pyridine (1.00 g, 6.17 mmol), catalyst 8 (324 mg, 0.62
mmol), diphenylmethylene glycine t-butyl ester (2.19 g,
7.40 mmol), and DCM (50 mL). The mixture was cooled to
ꢀ30 °C. CsOH (2.09 g, 12.3 mmol) was added and the reaction mix-
ture was stirred at ꢀ30 °C for 18 h. The reaction mixture was
warmed to room temperature and water (25 mL) was added. The
layers were separated. The aqueous was extracted with DCM
(25 mL) once more. The organics were dried (Na2SO4) and evacu-
ated. The crude was purified by column chromatography (10–
30% EtOAc/heptanes) to afford the desired product (1.96 g, 75%,
99% ee) as a colorless oil. 1H NMR (400 MHz, CDCl3-d): d 8.21
(dd, J = 4.9, 2.0 Hz, 1H), 7.56 (d, J = 7.4 Hz, 3H), 7.26–7.38 (m, 6H),
7.07 (dd, J = 7.5, 4.8 Hz, 1H), 6.66 (m, 2H), 4.33 (m, 1H), 3.41 (m,
1H), 3.17 (br s, 1H), 1.42 (s, 9H); 13C NMR (100 MHz, CDCl3-d): d
171.3, 169.2, 147.0, 146.3, 139.9, 138.0, 137.2, 131.1, 129.8,
128.7, 121.3, 82.3, 71.6, 33.5, 28.6. IR (cmꢀ1): 1735; 1540; MS m/
[M+H]+; ½a 2D0
¼ þ27:0 (c 1.50 mg/mL, CH3OH).
ꢂ
4.3. (S)-tert-Butyl 2-oxo-1,2,3,4-tetrahydro-1,8-naphthyridin-3-
ylcarbamate
Prepared by the same procedure as 19. White solid (305 mg,
z 421.2 (M+1). ½a D20
¼ þ240:9 (c 12.7 mg/mL, CH3OH).
ꢂ
97%, 97% ee). ½a 2D0
¼ ꢀ26:2 (c 1.95 mg/mL, CH3OH).
ꢂ
4.8. (R)-3-Amino-3,4-dihydro-1H-[1,8]naphthyridin-2-one 2HCl
(R)-1ꢃ2HCl
4.4. (R)-3-Amino-3,4-dihydro-1H-[1,8]naphthyridin-2-one 2HCl
(R)-1ꢃ2HCl
4.8.1. Preparation found in Scheme 1
To a solution of 19 (25 mg, 0.10 mmol) in MeOH (3 mL) was
To a Parr shaker bottle were added 6 (821 mg, 1.91 mmol), 3 mL
of MeOH, 10 mL of 2 N HCl, and 10% Pd/C (80 mg). The reaction was
placed on the Parr shaker for 18 h at room temperature under
added a solution of HCl (4 M in 1,4-dioxane, 500
lL). The reaction
mixture was stirred at room temperature for 2 h. The volatiles

A. T. Londregan et al. / Tetrahedron: Asymmetry 21 (2010) 2072–2075
2075
3. Chiral column type and size limits material throughput. Resolution of desired
enantiomer results in 50% material loss.
4. (a) Hulin, B.; Lopaze, M. G. Tetrahedron: Asymmetry 2004, 15, 1957–1958; (b)
Corey, E. J.; Xu, F.; Noe, M. J. Am. Chem. Soc. 1997, 119, 12414–12415.
35 psi of H2. After a nitrogen purge, the solution was filtered
through Celite and the filtrate was concentrated. The residue was
dissolved in MeOH and precipitated by the dropwise addition of
diethyl ether. The reaction mixture was allowed to stand for one
hour, at which time white solids crystallized from the solution.
The solid was vacuum filtered to afford the desired product
(134 mg, 35%). Further crystallization attempts failed to yield addi-
tional material. For characterization see (R)-1ꢃ2HCl above.
5. Determined on
a Chiralpak AD Column, 5% IPO/heptanes with 0.1% DEA,
210 nm, 1 mL/ min flow rate and compared to a racemic standard.
6. Limited commercial availability of suitable nitropyridine precursors. The
peroxide oxidation of amino-pyridine precursors was not amenable to scale.
7. The coupling of 12 with 4-methoxy-benzylamine was performed in parallel
format varying catalyst, temperature, base, and solvent. No product was
obtained.
8. (a) Tungler, A.; Sipos, E.; Hada, V. Curr. Org. Chem. 2006, 10, 1569–1583; (b) Cui,
X.; Burgess, K. Chem. Rev. 2005, 105, 3272–3296; (c) Gallagher, T.; Szeto, P.;
Bower, J. F. Chem. Commun. 2005, 5793–5795; (d) Knowles, W. S.; Sabacky, M. J.
Chem. Commun. 1968, L1445.
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