Methods for the synthesis of 5,6,7,8-tetrahydro-1,8-naphthyridine fragments for αvβ3 integrin antagonists

Article abstract of DOI:10.1021/jo0486950

The preparation of 3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propan-1- amine 2a and 3-[(7R)-7-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl]propan-1- amine 2b, key intermediates in the synthesis of α_vβ ₃ antagonists, is described. The syntheses rely on the efficient double Sonogashira reactions of 2,5-dibromopyridine 3 with acetylenic alcohols 4a/4b and protected propargylamines 10a-e followed by Chichibabin cyclizations of 3,3′-pyridine-2,5-diyldipropan-1-amines 9a/9b.

Full text of DOI:10.1021/jo0486950

Methods for the Synthesis of 5,6,7,8-Tetrahydro-1,8-naphthyridine
Fragments for rVâ3 Integrin Antagonists
Frederick W. Hartner,* Yi Hsiao, Kan K. Eng, Nelo R. Rivera, Michael Palucki, Lushi Tan,
Nobuyoshi Yasuda, David L. Hughes, Steven Weissman,* Daniel Zewge, Tony King,
Dave Tschaen, and R. P. Volante
Department of Process Research, Merck Research Laboratories, Rahway, New Jersey 07065
fred_hartner@merck.com; steven_weissman@merck.com
Received July 28, 2004
The preparation of 3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propan-1-amine 2a and 3-[(7R)-7-
methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl]propan-1-amine 2b, key intermediates in the
synthesis of RVâ3 antagonists, is described. The syntheses rely on the efficient double Sonogashira
reactions of 2,5-dibromopyridine 3 with acetylenic alcohols 4a/4b and protected propargylamines
10a-e followed by Chichibabin cyclizations of 3,3′-pyridine-2,5-diyldipropan-1-amines 9a/9b.
The development of efficacious therapies for the treat-
ment of osteoporosis remains an active field of research.
In the US alone, 10 million individuals have already been
diagnosed with the disease, and the estimated direct cost
for hospital and nursing home care in 2001 was $17
billion. Osteoporosis results from an imbalance between
the natural processes of bone resorption and bone forma-
tion. An initial step in bone resorption is the binding of
osteoclast cells to bone surfaces, which is thought to be
mediated by the cell surface glycoprotein, RVâ3 integrin.
A novel approach to interrupting this mechanism is
minimizing osteoclast activity by introducing Rvâ3 inte-
grin antagonists.1 The binding of Rvâ3 to the receptor
occurs through recognition of the Arg-Gly-Asp (“RGD”)
peptide sequence. Accordingly, recent efforts to develop
drug therapies have centered on small molecule (non-
peptide) mimetics of RGD.2 Reports from these labora-
tories3 and others4 have described a series of novel
compounds designed to bind to Rvâ3 and thus act as
antagonists. A common structural component of these
compounds is the 5,6,7,8-tetrahydro-1,8-naphthyridine
skeleton that functions as a guanidine mimic. Herein,
we describe two synthetic methods for 3-(5,6,7,8-tetrahy-
dro-1,8-naphthyridin-2-yl)propan-1-amine (2a) and 3-[(7R)-
7-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl]propan-
1-amine (2b), structural components of drug candidates
in this class.
(1) Rodan, S. B.; Rodan, G. A. J. Endocrinol. 1997, 154, S47.
(2) (a) Engleman, V. W.; Nickols, G. A.; Ross, F. P.; Horton, M. A.;
Griggs, D. W.; Settle, S. L.; Ruminski, R. G.; Teitelbaum S. L. J. Clin.
Invest. 1997, 99, 2284. (b) For
a review, see: Duggan, M. E.;
Hutchinson, J. H. Exp. Opin. Ther. Pat. 2000, 10, 1367.
A practical synthesis of 1a, in which tetrahydronaph-
thyridine 2a serves as a key intermediate, was recently
described.5 Two methods for the preparation of 2a via
the Friedla¨nder reaction were discussed. Although a
scalable synthesis was developed, it required cryogenic
conditions and an expensive Rh catalyst. A synthesis of
2a via a double Suzuki-Miyaura reaction of 2,5-dibro-
mopyridine 3 with the borane derived from 9-BBN
addition to phthalimide-protected allylamine was previ-
ously reported by some of us in a communication.6 The
phthaloyl groups were subsequently removed by treat-
(3) (a) Askew, B. C.; Coleman, P. J.; Duggan, M. E.; Halczenko, W.;
Hutchinson, J. H.; Meissner, R. S.; Patane, M. A.; Wang, J. U.S. Patent
6017926, 2000. (b) Hutchinson, J. H.; Halczenko, W.; Brashear, K. M.;
Breslin, M. J.; Coleman, P. J.; Duong, L. T.; Fernandez-Metzler, C.;
Gentile, M. A.; Fisher, J. E.; Hartman, G. D.; Huff, J. R.; Kimmel, D.
B.; Leu, C.-T.; Meissner, R. S.; Merkle, K.; Nagy, R.; Pennypacker, B.;
Perkins, J. J.; Prueksaritanont, T.; Rodan, G. A.; Varga, S. L.;
Wesolowski, G. A.; Zartman, A. E.; Rodan, S. B.; Duggan, M. E. J.
Med. Chem. 2003, 46, 4790. (c) Breslin, M. J.; Duggan, M. E.;
Halczenko, W.; Hartman, G. D.; Duong, L. T.; Fernandez-Metzler, C.;
Gentile, M. A.; Kimmel, D. B.; Leu, C.-T.; Merkle, K. Bioorg. Med.
Chem. Lett. 2004, 14, 4515.
(4) Miller, W. H.; Manley, P. J.; Cousins, R. D.; Erhard, K. F.;
Heerding, D. A.; Kwon, C.; Ross, S. T.; Samanen, J. M.; Takata, D. T.;
Uzinskas, I. N.; Yuan, C. C. K.; Haltiwanger, R. C.; Gress, C. J.; Lark,
M. W.; Hwang, S.-M.; James, I. E.; Rieman, D. J.; Willette, R. N.; Yue,
T.-L.; Azzarano, L. M.; Salyers, K. L.; Smith, B. R.; Ward, K. W.;
Johanson, K. O.; Huffman, W. F. Bioorg. Med. Chem. Lett. 2003, 13,
1483.
(5) Yasuda, N.; Hsiao, Y.; Jenson, M. S.; Rivera, N. R.; Yang, C.;
Wells, K. M.; Yau, J.; Palucki, M.; Tan, L.; Dormer, P. G.; Volante, R.
P.; Hughes, D. L.; Reider, P. J. J. Org. Chem. 2004, 69, 1959.
10.1021/jo0486950 CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/13/2004
J. Org. Chem. 2004, 69, 8723-8730
8723

Hartner et al.
SCHEME 1. Synthetic Route to
ment with hydrazine, and the resultant diamine was
converted to 2a with a Chichibabin cyclization. Though
this synthesis of 2a was shorter than those employing
the Friedla¨nder reaction, it still suffered from high
catalyst loading for the double Suzuki-Miyaura reaction
(10 mol %), the use of expensive (9-BBN) or hazardous
(hydrazine) reagents, and low productivity because of the
poor solubility of 9-BBN and large protecting groups. A
double Sonogashira7 reaction of 3 with propynyl and
chiral butynyl derivatives could provide a solution to
these problems. Indeed, the ability of 3 to undergo double
Sonogashira reactions is known.8 Presented in this paper
are efficient syntheses of 2a and 2b and results from a
study of the double Sonogashira reaction of 2,5-dibro-
mopyridine with acetylenic alcohols and protected acety-
lenic amines.
3,3′-Pyridine-2,5-diyldipropan-1-amines (9a/9b)
Using Propargyl Alcoholsa
Results and Discussion
Sonogashira Coupling of 2,5-Dibromopyridine 3
with Acetylenic Alcohols. Initially, we investigated
acetylenic alcohols as coupling partners in the Sonogash-
ira reaction with 3, as propargyl alcohol 4a is com-
mercially available and inexpensive, while (S)-3-butyn-
2-ol (4b) is readily prepared by Noyori’s Ru-catalyzed
asymmetric transfer hydrogenation (ATH).9 The reaction
of 1.0 equiv of 4a with 3 under standard Sonogashira
conditions proceeded at room temperature in MeCN to
give 3-(5-bromopyridin-2-yl)prop-2-yn-1-ol 5 in 75% yield
with 98:2 mono/bis selectivity (Scheme 1). Under the
same conditions, coupling at the 5-position with a second
equivalent of 4a proceeded slowly, but at 70 °C, conver-
sion to disubstituted pyridine 6a was rapid, and the
product could be isolated in 80% yield. Coupling of
monosubstituted pyridine 5 with (S)-3-butyn-2-ol at 65
°C for 20 h afforded mixed product 6b in 89% assay yield.
Although a recent report indicated that the 2-(3-
halopropyl) derivatives of both 1,8-naphthyridine and the
5,6,7,8-tetrahydro analogue are very prone to intra-
molecular cyclization to the cyclic ammonium deriva-
tives,5 under Mitsunobu conditions (PPh3/DIAD) with
phthalimide in THF the reactions of both bis-alkyndiols
6a and 6b gave bis-phthalimides 7a and 7b in 85% and
70% yield, respectively. The successful outcome of this
reaction was likely due to the presence of the triple bonds,
which structurally resisted intramolecular cyclization.
Hydrogenation of 7a and 7b at 3 atm H2 using 5% Pd/C
in DMF at 45 °C gave the saturated derivatives 8a and
8b in 90% isolated yield. Interestingly, reversing the
latter two steps whereby 6 was hydrogenated first
followed by the Mitsunobu reaction gave 8 in poor yield.
Finally, amine deprotection was achieved using hydra-
zine in EtOH at 60 °C for 2 h to provide 9b in 85% yield.
a Reagents: (a) PdCl2(PPh3)2, CuI, MeCN, rt, 75%; (b) PdCl2-
(PPh3)2, CuI, MeCN, 70 °C, 6a 80%, 6b 89%; (c) phthalimide,
DIAD, PPh3, THF, 7a 85%, 7b 70%; (d) H2, 5% Pd/C, DMF, 90%;
(e) H2NNH2, EtOH, 85%.
reaction. To overcome these issues, we explored the
Sonogashira coupling using acetylenic amine derivatives.
Selection of N-Protecting Group. Notwithstanding
reports that 1,1-dimethyl-2-propynylamine10 and pro-
pargylamine11 are viable coupling partners in Sonogash-
ira reactions, some difficulty was encountered during an
initial investigation of this chemistry. Attempts to couple
propargylamine with 3 afforded at best a 4:1 ratio of
mono-Sonogashira product (substitution at the 2-position)
to starting material.6 However, communications of suc-
cessful reactions with protected propargylamines, includ-
ing N-tosylpropargylamine,12 N-Boc-propargylamine 10d,13
N-methoxycarbonylpropargylamine,14 and N-trifluoro-
acetylpropargylamine,11 as well as a report on the Sono-
gashira reaction of 38 suggested that this approach with
the appropriate reagent should be achievable. Indeed,
modification of propargylamine by protection of the
amino functionality with acyl groups, including acetyl,
Boc, and Cbz, afforded reagents that cross-coupled with
3 under Sonogashira conditions (vide infra) (Scheme 2).
Initially, the Cbz-protected propargylamine 10c was
selected for further study since the Cbz group could be
removed from the product concurrently with the hydro-
genation of the triple bonds. However, during the course
of this work, we learned that propargylamine is unavail-
able in bulk quantities because of safety issues. It is also
tedious to prepare.15 Because the Cbz, acetyl, and Boc
propargylamine derivatives are prepared from propar-
Although the double Sonogashira approach with acety-
lenic alcohols was successful, it still suffered from some
of the problems of the Suzuki-Miyaura route, as well
as, poor atom economy associated with the Mitsunobu
(10) Mladenova, M.; Alami, M.; Linstrumelle, G. Synth. Commun.
1995, 25, 1401.
(6) Palucki, M.; Hughes, D. L.; Yasuda, N.; Yang, C.; Reider, P. J.
Tetrahedron Lett. 2001, 42, 6811.
(11) Hobbs, F. W., Jr. J. Org. Chem. 1989, 54, 3420.
(12) Arnautu, A.; Collot, V.; Ros, J. C.; Alayrac, C.; Witulski, B.;
Rault, S. Tetrahedron Lett. 2002, 43, 2695.
(7) Sonogashira, K.; Tohda, Y.; Hagihara, H. Tetrahedron Lett. 1975,
16, 4467.
(8) Tilley, J. W.; Zawoiski, S. J. Org. Chem. 1988, 53, 386.
(9) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1997, 119, 8738.
(13) Lindel, T.; Hochgurtel, M. J. Org. Chem. 2000, 65, 2806.
(14) Dakin, L. A.; Langille, N. F.; Panek, J. S. J. Org. Chem. 2002,
67, 6812.
8724 J. Org. Chem., Vol. 69, No. 25, 2004

5,6,7,8-Tetrahydro-1,8-naphthyridine Fragments for RVâ3 Integrins
SCHEME 2. Synthetic Route to 3,3′-Pyridine-
2,5-diyldipropan-1-amines Using Protected
Propargylaminesa
ployed with amines containing R-protons as solvent.
Several variables were explored with 10c or 10e using
the relative amounts of bis- vs monosubstituted products
as a guide for an optimized set of conditions (Table 1).
The reaction proceeded in amine solvents such as diiso-
propylamine (DIPA), triethylamine (TEA), diisopropyl-
ethylamine (DIEA), and dibenzylamine, but no reaction
was observed with collidine. DIPA was the solvent of
choice as the product readily crystallized in high yield
during the course of the reaction. The Sonogashira
reaction proceeded stepwise. Substitution at the 2-posi-
tion occurred at room temperature, while reaction at the
5-position required temperatures >50 °C.20 At >50 °C the
reaction was faster, but impurity levels also increased.
The optimum balance between reaction rate and the
generation of impurities was found between 65 and 70
°C. PdCl2(PPh3)2, which is air stable and readily avail-
able, was employed in this reaction at an optimized level
of 1 mol %. Coupling at the 2-position of 3 was indepen-
dent of the CuI/Pd ratio and could be accomplished
without CuI. The second coupling proceeded sluggishly
at the usual ratio of >1 reported in the literature.
Experiments revealed an optimum CuI/Pd ratio of 0.25.
Several cocatalysts, including Co(acac)2, FeCl3, and ZnCl2,
were compared to the commonly employed CuI21 in
reactions with 10e, and the latter produced the best
results. Using these optimized conditions of 1 mol %
PdCl2(PPh3)2, 0.25 mol % CuI, at 65-70 °C in DIPA, a
double Sonogashira reaction of 10c was successfully
demonstrated on a 1 kg scale.
a Reagents: (a) PdCl2(PPh3)2, CuI, DIPA; (b) H2, 5% Pd/Al2O3,
MeOH; (c) 6 N HCl; (d) NaNH2, toluene.
SCHEME 3. Synthesis of N-Formylpropargyl-
aminea
a Reagents: (a) reflux, CH3CN; (b) K2CO3, MeOH (87%, two
steps).
The above conditions for the Sonogashira coupling were
not further optimized for 10a. The reaction proceeded to
a 2-substituted intermediate in 1-2 h and to the product
in 5-10 h. The disubstituted product 11a was isolated
in 79% yield. Several minor impurities were generated
in the Sonogashira reaction, including oxazole 16 and the
homocoupling product of 10a. An independent experi-
ment showed that 16 did not form from the product.
gylamine, the need arose for an alternative protecting
group. The N-formyl protecting group could overcome this
shortcoming. Although the literature preparation16 of 10a
also begins with propargylamine, a more attractive route
would involve amidation of activated propargyl deriva-
tives with sodium diformylamide 13 (Scheme 3). Alky-
lations of 13 with a variety of electrophiles were reported,
although propargyl derivatives were not studied.17
The literature procedure for preparing 13 was modified
to include the use of a solvent, 1,2-dimethoxyethane, to
facilitate mixing and isolation.17 Propargylimide 15 was
prepared by alkylation of 13 with propargyl mesylate
14b18 in refluxing MeCN. A Sonogashira reaction of 3
with 15 gave a complex mixture due to the instability of
the imide toward loss of one formyl group. Alternatively,
15 was solvolyzed to 10a using MeOH and K2CO3. The
product 10a could also be obtained by alkylation of 13
with propargyl bromide 14a or propargyl benzene-
sulfonate 14c, but high levels of bromoallene were
observed when 14a was used.19
To further explore the reactivity of these protected
propargylamine reagents with 3, a series of cross-
coupling reactions was performed using reported proce-
dures that were successful with analogous substrates. For
example, the reaction of 5-bromo-2-[2-(trimethylsilyl)-
ethynyl]pyridine with 4-pentyn-2-ol with 1 mol % PdCl2-
(PPh3)2 and CuI in a 3:1 mixture of triethylamine and
dichloromethane at room temperature afforded the di-
Sonogashira Coupling of 2,5-Dibromopyridine 3
with N-Protected Propargylamines. The double So-
nogashira reaction proceeded well when the standard
Sonogashira catalysts, PdCl2(PPh3)2 and CuI, were em-
(19) Neat N-formylpropargylamine (10a) is a crystalline solid.
Although it was not stable when it was heated to >170 °C as neat, its
solutions were safe. Thus, a nonisolation procedure was developed in
which the reaction solvent, acetonitrile, was switched to DIPA, and
the DIPA solution was used directly without further purification in
the Sonogashira coupling. Thermal characterization of 10a showed an
exotherm of 5.3 cal/g that initiated at 170 °C followed immediately by
a large decomposition exotherm of 311 cal/g that initiated at 215 °C.
The heat release of the second exotherm was rapid and approached
the shock sensitivity potential range.
(15) (a) Beil. 4, IV, 1135. (b) Koziara, A.; Zwierzak, A. Synthesis
1992, 1063.
(16) Dumont, J.-L.; Chodkiewicz, W.; Cadiot, P. Bull. Soc. Chim.
Fr. 1967, 588.
(20) Chambers, R. D.; Hall, C. W.; Hutchinson, J.; Millar, R. W. J.
Chem. Soc., Perkin Trans. 1 1998, 1705.
(17) Han, Y.; Hu, H. Synthesis 1990, 122.
(18) Masuyama, Y.; Watabe, A.; Ito, A.; Kurusu, Y. J. Chem. Soc.,
Chem. Commun. 2000, 2009.
(21) Campbell, I. B. In Organocopper Reagents; Taylor, R. J. K., Ed.;
IRL Press: Oxford, 1994; pp 217-235.
J. Org. Chem, Vol. 69, No. 25, 2004 8725

Hartner et al.
TABLE 1. Effect of Conditions on Double Sonogashira Reaction of 3a
entry
substrate
solvent
collidine
dibenzylamine
DIEA
TEA
DIPA
DIPA
DIPA
DIPA
DIPA
DIPA
DIPA
DIPA
DIPA
DIPA
DIPA
DIPA
DIPA
cocatalyst
T (°C)
time, h
% mono
% bis
1
2
10c
10c
10c
10c
10c
10c
10c
10c
10c
10c
10c
10c
10e
10e
10e
10e
10e
CuI, 1 mol %
CuI, 1 mol %
CuI, 1 mol %
CuI, 1 mol %
CuI, 1 mol %
CuI, 1 mol %
CuI, 1 mol %
CuI, 1 mol %
none
50
50
50
50
50
21
65
85
65
65
65
65
85
85
85
85
85
2.5
2.5
2.5
2.5
2.5
2.5
1.5
2
0
72
63
63
62
58
76
4
35
66
61
58
4
0
13
31
29
31
2
23
85
1
34
39
38
96
63
15
31
66
3
4
5
6
7
8
9
1.5
1.5
1.5
1.5
3
10
12
13
16
17
18
19
20
CuI, 0.1%
CuI, 0.25%
CuI, 0.5%
CuI, 0.25%
Co(acac)2, 2 mol %
FeCl3, 1 mol %
ZnCl2, 2 mol %
Ni(acac)2, 1 mol %
3
22
56
48
18
3
3
3
a Percent mono and bis were determined by HPLC area percent.
SCHEME 4. Synthesis of Diyne 11b.
substituted product.8 However, under the same condi-
tions, reaction of 3 with less reactive alkyne 10a gave
predominantly the 2-substituted product and only 5% of
the desired disubstituted compound, even at 70 °C. The
use of pyrrolidine and piperidine as solvents with PdCl2-
(PPh3)2 or PdCl2(PhCN)2 as catalysts had been shown to
greatly improve the reactivity of alkynes with iodoben-
zene and vinyl chloride substrates.22 In contrast, reac-
tions of 3 with 10a in pyrrolidine using PdCl2(PPh3)2 or
in piperidine using PdCl2(PhCN)2 produced 2-pyrrolidi-
nyl-5-bromopyridine and 2-piperidinyl-5-bromopyridine
as the major products, respectively, and only traces of
the desired 2-substituted acetylenic product.23 Difficulty
in coupling N-propargylalanine with 3-bromopyridine
was overcome using Pd/C, PPh3, CuI, and K2CO3 in DME/
water.24 A reaction of 10a with 3 under the same
conditions produced mainly the 2-substituted product,
however. The same result was found using PdCl2(PhCN)2,
P(t-Bu)3, CuI, and DIPA in dioxane, although this
procedure had been effective for the coupling of 4-bro-
moanisole with alkyl and aryl alkynes.25 The results of
these cross-coupling experiments suggested that the
reactivity of these propargylamine reagents lay between
the reactivity of most alkyl or aryl alkynes and the
reactivity of alkynes that are conjugated to electron-
withdrawing groups, which are poor coupling partners.21
Applying our methodology to the synthesis of 2b began
with the preparation of the alkyne piece. Thus, the
product of the ATH reaction, (S)-4-trimethylsilyl-3-butyn-
2-ol 18 (98% ee), was converted into the corresponding
a Reagents/conditions: (a) MsCl/TEA/DCM/rt (94%); (b) (i) 13/
DMF, 65 °C; (ii) MeOH/cat K2CO3/rt (58%); (c) PdCl2(PPh3)2/CuI/
DIPA/MeCN 18h/rt (77%); (d) PdCl2(PPh3)2/CuI/DIPA/DMF 60
°C/5 h (77%).
mesylate 19 under standard conditions (MsCl/TEA) in
94% yield. The crude product was reacted with 13 in
DMF at 62 °C for 6 h, followed by MeOH/K2CO3, which
solvolyzed one of the formyl groups to give 20 as a low
melting solid in 58% overall yield. The requisite bro-
mopyridine 21 was prepared by coupling 3 with 10a in
MeCN at room temperature (vida supra) to give 21 in
77% yield. The Sonogashira coupling of alkyne 20 with
aryl bromide 21 proceeded under standard conditions to
give diyne 11b in 77% assay yield (Scheme 4). Chiral SFC
assay indicated 98% ee.
Preparation of Diamines 9a/9b. Conversion of the
Sonogashira product 11a to diamine 9a was accomplished
by hydrogenation at 40 psi H2 in MeOH using 5% Pd/
Al2O3 to give 12a, followed by hydrolysis of the formyl
groups with 6 N HCl at 90 °C. Diamine 9a was obtained
as an oil in 88% yield over the two steps. Similarly, diyne
(22) (a) Alami, M.; Ferri, F.; Linstrumelle, G. Tetrahedron Lett. 1993,
34, 6403. (b) Alami, M.; Crousse, B.; Ferri, F. J. Organomet. Chem.
2001, 624, 114.
(23) DIPA did not react with 3 even in the absence of an alkyne.
(24) (a) Lopez-Deber, M. P.; Castedo, L.; Granja, J. R. Org. Lett.
2001, 3, 2823. (b) Bleicher, L.; Cosford, N. D. P. Synlett 1995, 1115.
(25) Hundertmark, T.; Littke, A. F.; Buchwald, S. L.; Fu, G. C. Org.
Lett. 2000, 2, 1729.
8726 J. Org. Chem., Vol. 69, No. 25, 2004

5,6,7,8-Tetrahydro-1,8-naphthyridine Fragments for RVâ3 Integrins
min. The crystallized product was filtered and washed with
11b was hydrogenated to 12b in THF/MeOH (90% yield)
and deprotected with HONH2‚HCl to give diamine 9b in
94% yield.
toluene and hexane. The product was dried at reduced pres-
1
sure at 50 °C to afford 65.4 g (77%). Mp: 128.3-129.6 °C. H
NMR (CDCl3): δ 8.62 (d, J ) 2.0, 1H), 7.79 (dd, J ) 8.3, 2.0,
1H), 7.31 (d, J ) 8.3, 1H), 4.52 (d, J ) 6.1, 2H), 3.43 (t, J )
6.1, 1H). 13C NMR (CDCl3): δ 150.9, 141.0, 139.0, 128.0, 120.3,
89.4, 83.4, 51.0.
Chichibabin Cyclization. The Chichibabin cycliza-
tion of diamines 9a/9b to target compounds 2a/2b was
accomplished in 90%/69% assay yield, respectively, using
4-5 equiv of NaNH2 in toluene at 90 °C, conditions that
had been optimized for these substrates.6 As published
studies on the Chichibabin reaction in aprotic solvents
were confined to intermolecular examples, we investi-
gated whether the intramolecular cyclization could pro-
vide additional mechanistic details. There is extensive
literature on the mechanism of the Chichibabin reaction,
but only limited work has been done on heterogeneous
systems because of the difficulty in studying the trans-
formation.26 The reaction is regarded to proceed by an
addition-elimination pathway, but σ-adduct intermedi-
ates have not been observed.27 We investigated the
reaction using FT-IR and NMR, which revealed a clean
transformation of 9a to 2a with no evidence for an
intermediate. This observation suggested that oxidation
(re-aromatization) occurred during the reaction, not after
the quench, which corresponds to the intermolecular
examples reported previously.
Summary. In summary, an efficient synthesis of
3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propan-1-
amine 2a and 3-[(7R)-7-methyl-5,6,7,8-tetrahydro-1,8-
naphthyridin-2-yl]propan-1-amine 2b was accomplished
via a double Sonogashira coupling and a Chichibabin
cyclization reaction. Conditions were discovered for the
coupling of 2,5-dibromopyridine with N-protected prop-
argylamines that provided the double-substituted product
in significantly better yield compared to successful
literature procedures for other reaction partners.28
3,3′-(2,5-Pyridinediyl)bis-2-propyn-1-ol (6a). A mixture
of 3 (23.7 g, 100 mmol), 4a (14.0 g, 250 mmol), PdCl2(PPh3)2
(1.4 g, 2.0 mmol), and CuI (0.22 g, 1.2 mmol) in DIPA (300
mL) was heated at 70 °C overnight. The mixture was cooled
to rt, and the solvent was removed at reduced pressure. The
residue was dissolved in THF (300 mL), and the solution was
filtered through a pad of silica gel (160 g). The silica gel pad
was washed with THF. The solution was concentrated to 300
mL at reduced pressure, and the remaining THF was gradu-
ally removed while maintaining the volume with toluene. The
mixture was stirred in toluene for 1 h at rt, and the precipi-
tated product was filtered and washed with toluene. The crude
product was suspended in EtOAc (50 mL), and the slurry was
stirred overnight at rt. The slurry was cooled at 0 °C for 1 h
and filtered. The product was washed with cold EtOAc. The
product was dried at reduced pressure at 40 °C overnight to
1
give 15.0 g (80%) of a tan solid. H NMR (DMSO-d6): δ 8.58
(d, J ) 2.4, 1H), 7.83 (dd, J ) 8.0, 2.4, 1H), 7.49 (d, J ) 8.0,
1H), 5.44 (t, J ) 6.0, 1H), 5.42 (t, J ) 6.0, 1H), 4.34 (d, J )
6.4, 4H). 13C NMR (DMSO-d6): δ 151.8, 141.2, 138.8, 126.4,
118.7, 94.8, 91.3, 83.1, 80.2, 49.4, 49.3. HRMS (ESI): calcd
for C11H9NO2 188.0712, found 188.0712.
(2R)-4-[6-(3-Hydroxyprop-1-yn-1-yl)pyridin-3-yl]but-3-
yn-2-ol (6b). A solution of 5 (25.0 g, 118 mmol), powdered K2-
CO3 (32 g, 231 mmol), and MeCN (250 mL) was prepared.
PdCl2(PPh3)2 (1.2 g, 1.7 mmol) was added, the solution was
aged at rt for 30 min, and 4b (84 mL of 2.1 M solution in
MeOH, 176 mmol) and CuI (224 mg, 1.2 mmol) were added.
The reaction was warmed to 65 °C, aged for 17 h, and filtered
through a neutral alumina plug (62 g). The alumina plug was
washed with MeCN and THF. Assay of the combined filtrates
indicated 18.2 g of 6b was present (77% yield). A sample was
removed, chromatographed over neutral alumina (eluting with
THF), and recrystallized from IPAc-toluene to provide an
analytically pure sample. Mp:. 102.7-103.8 °C. 1H NMR
(DMSO-d6): δ 8.55 (J ) 1.8, 1H), 7.80 (dd, J ) 8.1, 1.8, 1H),
7.47 (d, J ) 8.1, 1H), 5.54 (d, J ) 5.4, 1H), 5.43 (t, J ) 6.0,
1H), 4.62 (m, 1H), 4.33 (d, J ) 6.0, 2H), 1.38 (d, J ) 6.6, 3H).
13C NMR (DMSO-d6): δ 152.2, 141.5, 139.2, 126.9, 119.1, 98.7,
91.7, 83.5, 79.2, 57.1, 49.7, 24.7. HRMS (ESI): calcd for C12H11-
NO2 202.0868, found 202.0865. Anal. Calcd for C12H11NO2: C,
71.63; H, 5.51; N, 6.87. Found: C, 71.92; H, 5.47; N, 6.88.
Experimental Section
General Methods. All reactions were carried out under an
atmosphere of N2 (unless otherwise noted), and solvents and
reagents were dried where appropriate over molecular sieves
prior to use. Other solvents and reagents were used as
1
received. H and 13C NMR spectra were collected at 400 and
101 MHz, respectively. Coupling constants (J) are reported in
Hz. Melting points are uncorrected.
3-(5-Bromopyridin-2-yl)prop-2-yn-1-ol (5).8 A mixture of
3 (94.8 g, 400 mmol), 4a (22.4 g, 400 mmol), DIPA (115 mL),
PdCl2(PPh3)2 (2.8 g, 4.0 mmol), and CuI (0.8 g, 4.4 mmol) in
CH3CN (1 L) was prepared at 13-15 °C and allowed to warm
slowly to rt and to stir overnight. Water (200 mL) was added,
and the reaction mixture was concentrated at reduced pressure
to e300 mL. The mixture was further diluted with water (300
mL) and aged for 1 h at rt. The crystallized solid was filtered,
and the cake was washed with water. The solid was dried at
reduced pressure at 40 °C. The brown solid was dissolved in
THF (800 mL), and the solution was passed through a pad of
silica gel (130 g). The silica pad was further washed with THF
(800 mL). The solution was concentrated at reduced pressure
to 300 mL, and toluene (300 mL) was slowly added. The
mixture was concentrated by half at 50 °C at reduced pressure.
The mixture was allowed to cool to rt and was stirred for 30
2,2′-[Pyridine-2,5-diylbis(prop-1-yne-1,3-diyl)]bis(1H-
isoindole-1,3(2H)-dione) (7a). DIAD (2.43 g, 12 mmol) was
added slowly to a mixture of 6a (0.94 g, 5 mmol), PPh3 (3.3 g,
12.5 mmol), and phthalimide (1.84 g, 12.5 mmol) in THF (30
mL) while maintaining the temperature below 40 °C. The
reaction was complete within 30 min. The volume was reduced
by 66%, and MTBE (10 mL) was slowly added. The THF/
MTBE mixture was filtered after 1 h, and the collected product
was washed with THF/MTBE (1:2). The product was dried at
reduced pressure at 40 °C to give 2.0 g (90% yield) of a beige
1
solid. H NMR (CF3CO2H-d): δ 8.73 (s, 1H), 8.52 (d, J ) 8.4,
1H), 8.02 (d, J ) 8.4, 1H), 8.01-7.95 (m, 4H), 7.92-7.85 (m,
4H), 4.94 (s, 2H), 4.87 (s, 2H). 13C NMR (CF3CO2H-d): δ 172.4,
172.1, 151.5, 146.9 (2C), 138.2, 138.1, 136.1, 133.1, 133.0,
126.8, 126.7, 126.0, 100.6, 95.4, 77.4, 75.4, 29.8 (2C).
2-(3-{5-[(3S)-3-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)-
but-1-yn-1-yl]pyridin-2-yl}prop-2-yn-1-yl)-1H-isoindole-
1,3(2H)-dione (7b). The solution of diol 6b from above (10.6
assay g, 52 mmol) was solvent switched into THF (200 mL)
and was treated with PPh3 (34.3 g, 131 mmol) and phthalimide
(19.3 g, 131 mmol). The solution was stirred at rt for 30 min,
and DIAD (24.7 mL, 126 mmol) was slowly added as a solution
in THF (50 mL) at 22-48 °C. The reaction mixture was aged
(26) McGill, C. K.; Rappa, A. Adv. Heterocycl. Chem. 1988, 44, 1.
(27) Breuker, J.; van der Plas, H. C. Recl. Trav. Chim. Pays-Bas
1983, 102, 367.
(28) During the preparation of our manuscript, a paper describing
a synthesis of Boc- and phthaloyl-protected aminopropargyl derivatives
of similar bromopyridines was published: Russo, O.; Alami, M.; Brion,
J.-D.; Sicsic, S.; Berque-Bestel, I. Tetrahedron Lett. 2004, 45, 7069.
J. Org. Chem, Vol. 69, No. 25, 2004 8727

Hartner et al.
for 3 h at rt, concentrated at reduced pressure, and solvent
switched into MeCN (200 mL). The resulting slurry was stirred
at rt for 2 h, and the solids were isolated by filtration to provide
13.2 g (55%) of 7b after drying at reduced pressure at 40 °C.
stituted intermediate was g96%. HPLC conditions: Zorbax
SB-C8 4.6 × 250, 1 mL/min, 210 nm, 30 °C, gradient A ) 0.1%
H3PO4, B ) CH3CN, t ) 0, B ) 10%, t ) 10, B ) 85%, t ) 15,
B ) 85%. Retention times of 11a, the 2-substituted intermedi-
ate, and 3 were 6.3, 8.2, and 11.2 min, respectively. The
mixture was cooled to 20-22 °C and filtered, and the cake was
washed with DIPA and dried. The dried cake was slurried in
water (32 L), and the mixture was cooled with an ice bath to
0-5 °C. The slurry was filtered, and the cake was washed with
cold H2O. The cake was dried to afford 1.187 kg of solid (84.3
wt % purity, 79.1% yield). The product was assayed by HPLC.
HPLC conditions: Zorbax SB-C8 4.6 × 250, 1 mL/min, 210
nm, 30 °C, A ) 0.1% H3PO4, B ) CH3CN, t ) 0, B ) 20%, t )
10, B ) 20%, t ) 15, B ) 85%. Retention times for 11a and
the 2-substituted intermediate were 5.8 and 15 min, respec-
tively. The product was recrystallized from 10% aq CH3CN.
Mp: 178.1-179.1 °C. The compound exists as a 92:8 mixture
1
Mp: >230 °C dec. H NMR (CDCl3): δ 8.57 (d, J ) 2.1, 1H),
7.92-7.83 (m, 4H), 7.78-7.71 (m, 4H), 7.74 (dd, J ) 8.1, 2.1,
1H), 7.33 (d, J ) 8.1, 1H), 5.43 (q, J ) 7.2, 1H), 4.71 (s, 2H),
1.79 (d, J ) 7.2, 3H). 13C NMR (CDCl3): δ 166.8, 166.8, 152.4,
141.2, 138.8, 134.1 (2C), 131.9, 131.8, 126.3, 123.5, 123.4,
119.0, 91.7, 84.4, 82.0, 79.4, 37.5, 27.6, 20.0. HRMS (ESI):
calcd for C28H17N3O4:460.1297, found 460.1290. Anal. Calcd
for C28H17N3O4: C, 73.20; H, 3.73; N, 9.15. Found: C, 72.93;
H, 3.70; N, 9.08.
2,2′-[Pyridine-2,5-diylbis(propane-3,1-diyl)]bis(1H-isoin-
dole-1,3(2H)-dione) (8a). Compound 7a (256 mg, 0.58 mmol)
was dissolved in a mixture of TFA (7 mL) and MeOH (3 mL)
and hydrogenated at 40 psi with 5% Pd/C (25 mg) at rt for 18
h. The reaction mixture was filtered through a plug of Solka
Floc, the filtrate was concentrated at reduced pressure, and
the residue was neutralized with aq KHCO3. The solution was
extracted with EtOAc and dried over sodium sulfate. The
filtrate was concentrated at reduced pressure to give an off-
white solid (285 mg, 100% yield). Mp: 155-156 °C. 1H NMR:
(CDCl3): δ 8.30 (d, J ) 2.0, 1H), 7.82 (m, 4H), 7.70 (m, 4H),
7.41 (dd, J ) 8.0, 0.4), 7.06 (d, J ) 8.0, 1H), 3.74 (m, 4H), 2.78
(apparent t, 2H), 2.61 (apparent t, 2H), 2.10 (m, 2H), 1.98 (m,
2H). 13C NMR (CDCl3): δ 168.2 (2C), 158.4, 149.1, 136.0, 133.8,
133.8, 133.5, 132.1, 131.9, 123.1, 123.0, 122.3, 37.6, 37.5, 35.0,
29.8, 29.5, 28.2.
2-(3-{5-[(3S)-3-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)-
butyl]pyridin-2-yl}propyl)-1H-isoindole-1,3(2H)-dione (8b).
Compound 7b (18.0 g, 39 mmol) was dissolved in DMF (375
mL) and hydrogenated at 40 psi with 5% Pd/C (1.3 g) at 40 °C
for 18 h. The reaction mixture was filtered through a plug of
Solka Floc, and the filtrate was concentrated at reduced
pressure to an oil. The oil was dissolved in a mixture of IPAc
(75 mL) and MTBE (100 mL), and the solution was washed
with water. The organic layer was dried over sodium sulfate,
and the volatiles were removed at reduced pressure to give
16.6 g of 8b as an orange solid (91% yield). Mp: 117-119 °C.
1H NMR (CDCl3): δ 8.24 (s, 1H), 7.83-7.77 (m, 4H), 7.71-
7.67 (m, 4H), 7.35 (dd, J ) 8.0, 2, 1H), 7.01 (d, J ) 8.0, 1H),
4.37 (m, 1H), 3.73 (m, 2H), 2.72 (apparent t, 2H), 2.61-2.40
(m, 3H), 2.04 (m, 2H), 1.95 (m, 1H), 1.48 (d, J ) 6.9, 3H). 13C
NMR (CDCl3): δ 168.3, 168.2, 158.2, 149.0, 136.0, 133.8, 133.7,
133.6, 132.0, 131.7, 123.0 (2C), 122.2, 47.1, 37.6, 35.0, 34.5,
29.9, 28.2, 18.8. HRMS (ESI): calcd for C28H25N3O4 468.1923,
found 468.1937. Anal. Calcd for C28H25N3O4: C, 71.93; H, 5.39;
N, 8.99. Found: C, 71.67; H, 5.27; N, 5.85.
1
of rotamers; only the major is reported. H NMR (DMSO-d6):
δ 8.56-8.58 (m, 3H), 8.10 (s, 2H), 7.82 (dd, J ) 8.1, 2.1, 1H),
7.47 (d, J ) 8.1, 1H), 4.19 (d, J ) 5.6, 4H). 13C NMR (DMSO-
d6): δ 161.0, 161.0, 152.0, 141.0, 139.0, 126.6, 118.6, 91.8, 88.3,
81.1, 78.3, 27.3, 27.1. Anal. Calcd for C13H11N3O2: C, 64.72;
H, 4.60; N, 17.42. Found: C, 64.32; H, 4.51; N, 17.20.
Diphenyl [Pyridine-2,5-diylbis(prop-1-yne-1,3-diyl)]-
1
biscarbamate (11c). Mp: 156-158 °C. H NMR (CDCl3): δ
8.65 (br s, 1H), 7.63 (d, J ) 7.6, 1H), 7.32-7.37 (m, 11H), 5.16
(s, 2H), 5.15 (s, 2H), 5.09 (broad s, 2H), 4.24-4.28 (m, 4H).
13C NMR (CDCl3): δ 156.1, 152.7, 141.7, 138.9, 136.40, 136.37,
128.69, 128.67, 128.5, 128.4, 126.5, 119.3, 90.5, 87.3, 82.6, 80.0,
67.32, 67.28, 31.8, 31.7. Anal. Calcd. for C27H23N3O4: C, 71.51;
H, 5.11; N, 9.27. Found: C, 71.78; H, 5.23; N, 9.18.
Di-tert-butyl[Pyridine-2,5-diylbis(prop-1-yne-1,3-diyl)]-
biscarbamate (11d). The preparation of 11d followed the
procedure described above for 11a. At the end of the reaction,
the mixture was diluted with EtOAc, and the precipitates were
filtered and washed with EtOAc. The filtrate and washings
were combined, concentrated under reduced pressure, and
purified by silica gel column chromatography (hexanes/MTBE).
The fractions containing 11d were combined and concentrated
under reduced pressure to give crystalline product. Mp:
123.0-124.5 °C. 1H NMR (CDCl3): δ 8.55 (d, J ) 2.0, 1H),
7.61 (dd, J ) 8.0, 2.0, 1H), 7.31 (d, J ) 8.0, 1H), 4.96 (br s,
2H), 4.24-4.05 (m, 4H), 1.45 (s, 9H), 1.44 (s, 9H). 13C NMR
(CDCl3): δ 155.3, 152.4, 141.5, 138.7, 126.2, 119.1, 90.8, 87.6,
82.1, 80.1, 79.4, 31.0, 28.3. Anal. Calcd for C21H27N3O4: C,
65.44; H, 7.06; N, 10.90. Found: C, 65.37; H, 7.05; N, 10.77.
N,N′-[Pyridine-2,5-diylbis(prop-1-yne-1,3-diyl)]diacet-
amide (11e). Mp: 188.8-189.8 °C. 1H NMR (DMSO-d6): δ
8.55 (dd, J ) 2.4, 0.8, 1H), 8.44-8.36 (m, 2H), 7.82 (dd, J )
8.0, 2.4, 1H), 7.47 (dd, J ) 8.0, 0.8, 1H), 4.131 (d, J ) 5.6,
2H), 4.127 (d, J ) 5.6, 2H), 1.85 (s, 3H), 1.84 (s, 3H). 13C NMR
(DMSO-d6): δ 169.0, 169.0, 152.0, 141.1, 139.0, 126.6, 118.6,
92.3, 88.9, 80.9, 78.1, 28.6, 28.4, 22.3. Anal. Calcd for
C15H15N3O2: C, 66.90; H, 5.61; N, 15.60. Found: C, 66.77; H,
5.52; N, 15.38.
[Pyridine-2,5-diylbis(propane-3,1-diyl)]diformamide
(12a). A stirred autoclave was charged with a slurry of 11a
(693 g, 2.87 mol) in MeOH (9 L), a slurry of 5% Pd/Al2O3 (21
g) in MeOH (1 L), and a final wash of MeOH (4 L). The mixture
was cooled to 10 °C and hydrogenated at 40 psi of H2. The
temperature rose to 24 °C over 1 h and was maintained at
that temperature for 17 h. The reaction was assayed by 1H
NMR (DMSO-d6), which showed about 5% of an olefinic
intermediate remaining (olefinic protons at 5.7 and 6.5 ppm).
An additional charge of 5% Pd/Al2O3 (14 g) was made, and the
hydrogenation was continued for 7 h. Analysis showed no
olefinic intermediate. The reaction mixture was removed from
the autoclave and filtered through a pad of Solka Floc. HPLC
analysis of the filtrate showed a total of 638 g (89%). A sample
was isolated by concentration at reduced pressure and was
chromatographed on silica gel (EtOAc/MeOH) to afford crys-
tals. Mp: 85.7-87.1 °C. HPLC conditions: Zorbax SB-C8 4.6
(2S)-4-[6-(3-Aminopropyl)pyridin-3-yl]butan-2-amine
(9b) (from 8b). A mixture of 8b (16.6 g, 35.5 mol), hydrazine
hydrate (10.2 mL, 328 mmol), and ethanol (400 mL) was
heated at 65 °C for 4 h. The mixture was filtered, and the cake
was washed with toluene. The filtrate was concentrated,
solvent switched into toluene, and azeotropically dried. A
1
sample of 9b was removed for purification/identification. H
NMR (CDCl3): δ 8.34 (d, J ) 2.3, 1H), 7.40 (dd, J ) 8.0, 2.3,
1H), 7.06 (d, J ) 8.0, 1H), 2.95-2.87 (m, 1H), 2.80-2.76 (m,
2H), 2.74-2.71 (m, 2H), 2.69-2.54 (m, 2H), 1.88-1.81 (m, 2H),
1.68-1.55 (m, 2 H), 1.34 (br s, 4H), 1.10 (d, J ) 6.2, 3H). 13C
NMR (CDCl3): δ 159.2, 149.1, 136.2, 134.6, 122.3, 46.4, 41.8,
41.5, 35.1, 33.9, 29.5, 24.1. HRMS (ESI): calcd for C12H21N3
208.1814, found 208.1813.
Representative Procedure of the Sonogashira Reac-
tion. [Pyridine-2,5-diylbis(prop-1-yne-1,3-diyl)]diforma-
mide (11a). A mixture of 3 (1.242 kg, 5.243 mol), PdCl2(PPh3)2
(36.8 g, 52.4 mmol), CuI (2.49 g, 13.1 mmol), and DIPA (27 L)
was stirred at ambient temperature for 1 h. A DIPA solution
of 10a (6.127 kg of solution containing 1.089 kg of 10a, 13.11
mol) was added, and the mixture was heated at 70 °C for 5 h.
The reaction was monitored by HPLC and was considered
complete when the ratio of disubstituted product to monosub-
8728 J. Org. Chem., Vol. 69, No. 25, 2004

5,6,7,8-Tetrahydro-1,8-naphthyridine Fragments for RVâ3 Integrins
× 250, 1 mL/min, 210 nm, 30 °C, gradient A ) 0.15% H3PO4,
5 mM heptanesulfonic acid, B ) CH3CN, t ) 0, B ) 10%, t )
10, B ) 30%, t ) 18, B ) 30%, t ) 18.1, B ) 10%. The retention
time of 12a was 5.8 min, and that of 11a was 7.7 min. 1H NMR
(DMSO-d6): δ 8.32 (d, J ) 2.0, 1H), 8.01-8.04 (m, 4H), 7.53
(dd, J ) 8.0, 2.0, 1H), 7.17 (d, J ) 8.0, 1H), 3.09 (quintet, J )
6.8, 4H), 2.69 (t, J ) 7.6, 2H), 2.56 (t, J ) 7.6, 2H), 1.78
(quintet, J ) 7.2, 2H), 1.69 (quintet, J ) 7.6, 2H). 13C NMR
(DMSO-d6): δ 161.1, 161.0, 158.4, 148.8, 136.4, 134.2, 122.4,
48.6, 36.9, 36.6, 34.3, 30.5, 29.1. Anal. Calcd. for C13H19N3O2:
C, 62.63; H, 7.68; N, 16.85. Found: C, 62.60; H, 7.66; N, 16.85.
major rotamer δ 161.4, 78.9, 71.3, 27.4; minor rotamer δ 164.7,
78.7, 72.8, 31.2.
((3R)-3-{[Dihydroxy(methyl)-λ4-sulfanyl]oxy}but-1-yn-
1-yl)(trimethyl)silane (19). Compound 18 (5.73 g, 40 mmol)
was dissolved in CH2Cl2 (50 mL) and triethylamine (6.7 mL,
48 mmol), and the solution was cooled to -10 °C. Methane-
sulfonyl chloride (3.5 mL, 45 mmol) was added slowly over 15
min, and the resulting solution was warmed to 22 °C and aged
for 1 h. Water (25 mL) was added, followed by sufficient aq
HCl to lower the pH to 3.0. The layers were separated, and
the organic layer was dried over sodium sulfate. The volatiles
were removed at reduced pressure to provide 8.35 g (94% yield)
of 19 as an oil. 1H NMR: δ 5.26 (q, J ) 6.7, 1H), 3.12 (s, 3H),
1.64 (d, J ) 6.7, 3H), 0.20 (s, 9H). 13C NMR: δ 101.2, 93.6,
68.5, 57.9, 39.0, 22.4, -0.6.
[(1S)-1-Methylprop-2-yn-1-yl]formamide (20). To a solu-
tion of 19 (8.35 g, 37.6 mmol) in DMF (50 mL) was added 13
(4.1 g, 43.3 mmol). The solution was heated to 62 °C for 6 h
and cooled to 22 °C. The reaction mixture was partitioned
between EtOAc and water. The layers were separated, and
the aqueous layer was back extracted with EtOAc. The
combined organic layers were washed with water and dried
over Na2SO4. The volatiles were removed at reduced pressure,
and the residue was dissolved in MeOH (11 mL). K2CO3 (193
mg) was added, and the solution was stirred at 22 °C for 1 h.
The solution was filtered, and the volatiles were removed at
reduced pressure. The residue was dissolved in EtOAc/hexanes
(4/1 v/v) and passed through a plug of neutral alumina eluting
with the diluent. Evaporation of the filtrate provided 20 (2.1
g, 58%) as an orange solid. Mp: 59.3-60.7 °C. The compound
exists as rotamers: 87:13 ratio. 1H NMR: major rotamer
(CDCl3) δ 8.12 (s, 1H), 6.07 (br, 1H), 4.88 (m 1H), 1.50 (d, J )
7.0, 1H), 1.44 (d, J ) 7.0). 13C NMR: major rotamer δ 159.9,
83.5, 70.5, 35.5, 22.0. Anal. Calcd for C5H7NO: C, 61.84; H,
7.27; N, 14.42. Found: C, 61.85; H, 7.50; N, 14.39.
[3-(5-Bromopyridin-2-yl)prop-2-yn-1-yl]formamide (21).
To a mixture of 3 (8.3 g, 35 mmol) and MeCN (85 mL) were
added DIPA (16 mL, 116 mmol), 10a (3.1 g, 37 mmol), PdCl2-
(PPh3)2 (245 mg, 0.35 mmol), and CuI (31 mg, 0.16 mmol), and
the solution was stirred at 22 °C for 18 h. The solids were
removed by filtration, and the volatiles were removed at
reduced pressure. The residue was dissolved in EtOAc, and
the solution was washed with water. The organic layer was
dried over sodium sulfate, and the volatiles were removed at
reduced pressure. The residue was combined with 75 mL of
95:5 MeCN/EtOAc. The slurry was heated to reflux and slowly
cooled to 20 °C during which time the product crystallized.
Isolation by filtration provided 6.5 g (77% yield) of 21. Mp:
153.5-155 °C. The compound exists as rotamers: 91:9 ratio.
1H NMR: δ 8.62 (d, J ) 2.4, 1H), 8.23 (s, 1H), 7.79 (dd, J )
8.4, 2.4, 1H), 7.30 (d, J ) 8.4, 1H), 6.23 (br s, 1H), 4.35 (dd, J
) 5.6, 0.7, 2H). 13C NMR: δ 160.5, 151.1, 140.7, 138.9, 128.0,
120.4, 85.7, 81.9, 28.3. HRMS: calcd for C9H7BrN2O + 1
238.9820, found 238.9821. Anal. Calcd for C9H7BrN2O: C,
45.22; H, 2.95; N, 11.72. Found: C, 45.23; H, 2.75; N, 11.44.
(3-{5-[(3S)-3-(Formylamino)but-1-yn-1-yl]pyridin-2-yl}-
prop-2-yn-1-yl)formamide (11b). To a mixture of 21 (1.97
g, 8.2 mmol) and DMF (12 mL) at rt was added a 0.84 M DIPA
solution of alkyne 20 (14.2 mL, 11.9 mmol), followed by PdCl2-
(PPh3)2 (125 mg, 0.18 mmol). The mixture was stirred at 25
°C for 20 min, CuI (16 mg, 0.08 mmol) was added, and the
mixture was heated to 60 °C. The solution was aged at 60 °C
for 5 h and cooled to rt, and the DIPA was evaporated at
reduced pressure. The residue was passed through a plug of
neutral alumina eluting with 4:1 EtOAc/:MeOH. Assay of the
filtrate revealed that 1.60 g of product was present (77% yield).
The eluant was evaporated at reduced pressure (<35 °C), the
DMF-rich residue was treated with toluene (20 mL), and the
resulting slurry was aged at rt for 17 h. The solids were
collected by filtration and washed with toluene. Drying at
reduced pressure at 45 °C provided 11b (850 mg, 41% isolated
yield) as an off-white solid. A second crop provided an
3,3′-Pyridine-2,5-diyldipropan-1-amine (9a). The MeOH
solution of 12a (638 g, 2.56 mol) was concentrated to wet solids,
and 6 N HCl (5.15 L) was slowly added. The solution was
heated to 90 °C for 1 h and cooled to 15 °C. The pH was
adjusted to 12.7 with 50% NaOH (1.9 L) while maintaining
the temperature at e31 °C. The solution was extracted with
2-BuOH, and the extracts were combined. The 2-BuOH solu-
tion was concentrated, toluene was added, and the mixture
was concentrated again. This was repeated until the mole
percent of 2-BuOH vs product was e1%. The progress of the
solvent switch was monitored by 1H NMR (DMSO-d6). Signals
for 2-BuOH at 0.83 and 1.05 ppm were integrated vs signals
for the amine product at 1.63 and 1.70 ppm. The solvent switch
was done at a temperature of about 70 °C. The final toluene
solution was cooled to 20 °C, and Solka Floc was added. The
mixture was stirred for 10 min and filtered, and the cake was
washed with toluene. The weight of the final toluene solution
was 8.02 kg, and it contained 489 g (98.8%) of 9a by HPLC
assay. HPLC conditions: Zorbax SB-C8 4.6 × 250, 1 mL/min,
210 nm, 30 °C, gradient A ) 0.15% H3PO4, 5 mM heptane-
sulfonic acid, B ) CH3CN, t ) 0, B ) 10%, t ) 10, B ) 30%,
t ) 18, B ) 30%, t ) 18.1, B ) 10%. The retention time of 12a
was 5.8 min and that of 9a was 9.4 min. 1H NMR (DMSO-d6):
δ 8.29 (d, J ) 2.0, 1H), 7.49 (dd, J ) 8.0, 2.0, 1H), 7.13 (d, J
) 8.0, 1H), 2.68 (t, J ) 7.6, 2H), 2.55 (t, J ) 7.6, 2H), 2.52 (m,
4H), 1.69 (m, 2H), 1.60 (m, 2H), 1.3 (br s, 4H). 13C NMR
(DMSO-d6): δ 159.0, 148.7, 136.0, 134.5, 122.0, 41.3, 41.0, 34.9,
34.5, 33.5, 29.1. HRMS (ESI): calcd for C11H19N3 + 1 194.1657,
found 194.1658.
Sodium Diformylamide (13).17 To a solution of NaOMe
in MeOH (25.4 wt %, 3.619 kg, 17.02 mol) were added
formamide (1765 g, 39.18 mol) and 1,2-dimethoxyethane
(DME) (2.0 L). The mixture was heated to begin distillation
of volatiles. Approximately 2 L of volatiles was collected, and
then additional DME (8.8 L) was added at a rate such that
the volume of the mixture remained constant. A total of 13.6
L of distillate was collected by the end of the addition (6 h).
The mixture was cooled to 20-25 °C and was filtered. The cake
was washed with DME and dried to afford 1.595 kg (98.6%)
of an off-white solid. 1H NMR (DMSO-d6): δ 8.96 (s). 13C NMR
(DMSO-d6): δ 180.6.
Prop-2-yn-1-ylformamide (10a).16 To a solution of 14b
(89.5 wt % in toluene, 15.00 g, 100.1 mmol) were added CH3-
CN (73 mL) and 13 (11.42 g, 120.1 mmol), and the mixture
was heated to reflux for 12 h. The mixture was cooled to 18-
22 °C, MeOH (7.85 mL) and K2CO3 (2.70 g) were added, and
the mixture was stirred for 4 h. The mixture was concentrated
at reduced pressure to 47 mL. DIPA (50 mL) was added, and
the mixture was reconcentrated a total of three times. The
mixture was filtered, and the cake was washed with DIPA.
The filtrate and washes were combined to give a light colored
solution. The total weight was 37.72 g, which contained 7.25
g of N-formylpropargylamine (87.1% yield). The amount of
N-formylpropargylamine in the solution was determined by
concentrating an aliquot to an oil, seeding, and drying the
resulting crystals. Thus, 6.56 g of solution gave 1.26 g of
crystals. 1H NMR (CDCl3): major rotamer δ 8.13 (s, 1H), 6.94
(br, 1H), 4.02 (ddd, J ) 5.6, 2.6, 0.8, 2H), 2.23 (t, J ) 2.6, 1H);
minor rotamer δ 8.09 (d, J ) 12.1, 1H), 6.51 (br, 1H), 3.97
(dd, J ) 6.0, 2.6, 2H), 2.34 (t, J ) 2.6, 1H). 13C NMR (CDCl3):
J. Org. Chem, Vol. 69, No. 25, 2004 8729

Hartner et al.
additional 325 mg for a total of 1.175 g (57% isolated yield).
for 9a above. The retention time of 2a was 9.8 min. The
mixture was cooled to 5 °C, and a 4.4 M aqueous solution of
NaCl (1 L) was added at such a rate as to maintain the
temperature e10 °C. When the addition was complete, the
mixture was allowed to warm to 18-22 °C and was stirred
for 18 h. The layers were separated, and the aqueous phase
was extracted with toluene. Water was added to the aqueous
phase, and it was further extracted with toluene. The toluene
extracts were combined to give 6.1 kg of solution containing
207 g of 2a (90% yield).
3-[(7R)-7-Methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-
2-yl]propan-1-amine (2b) (from 9b). The dry toluene solu-
tion of 9b prepared from 8b above (110 mL, 35.5 mmol) was
treated with NaNH2 (6.2 g, 110 mmol) and was heated to 90
°C for 17 h. The reaction mixture was cooled to 30 °C and
treated with a solution of citric acid (8 g) in THF (100 mL).
After being stirred for 10 min, the slurry was filtered, and the
solids were washed with THF. The volatiles were evaporated
at reduced pressure to give 5.0 g of crude 2b (69% overall from
8b) as a brown oil. 2b free base: Mp: < 22 °C. 1H NMR
(CDCl3): δ 7.03 (d, J ) 7.2, 1 H), 6.32 (d, J ) 7.2, 1H), 4.61
(br s, 1H), 3.48 (m, 1H), 2.73-2.61 (overlapping m, 4H), 2.54
(overlapping m, 2H), 1.87 (m, 1H), 1.76 (m, 2H), 1.49 (m, 1H),
1.19 (d, J ) 6.4, 3H), 1.15 (v br s, 2H). 13C NMR (CDCl3): δ
157.9, 155.6, 136.3, 112.6, 111.2, 47.0, 41.8, 35.1, 33.9, 29.4,
25.5, 22.3. 2b bis HCl salt: 13C NMR (MeOH-d4) δ 152.6, 147.4,
142.8, 121.2, 112.1, 49.0, 39.8, 30.4, 28.2, 27.6, 25.0, 21.5.
HRMS (ESI): calcd for C28H25N3O4 206.1657, found 206.1658.
Anal. Calcd for C12H21Cl2N3 (bis HCl salt): C, 51.80; H, 7.61;
N, 15.10. Found: C, 51.78; H, 7.54; N, 14.84.
1
Mp: 161-162 °C dec. H NMR: δ 8.62 (1H), 8.23 (1H), 8.18
(1H), 7.65 (d, J ) 8.1, 1H), 7.35 (d, J ) 8.1, 1H), 6.41 (br, 1H),
6.30 (?), 5.15 (m, 1H), 4.36 (d, J ) 5.3, 2H), 1.49 (d, J ) 6.5,
3H). 13C NMR (CDCl3): δ 160.7, 159.9, 152.2, 141.2, 138.8,
126.3, 119.1, 94.1, 86.6, 82.3, 78.7, 36.2, 28.3, 22.0. HRMS
(ESI): calcd for C14H13N3O2 + 1 256.1086, found 256.1083.
Anal. Calcd for C14H13N3O2: C, 65.87; H, 5.13; N, 16.46.
Found: C, 65.56; H, 4.80; N, 16.37. Chiral SFC assay:
Chiralpak AD-H, 250 mm × 4.6 mm, 4% MeOH/CO2 for 4 min,
2%/min to 40% MeOH/CO2, hold for 3 min, 1.5 mL/min, 200
bar, 35 °C, 215 nm. The retention time of 11b was 19.2 min,
and that of its enantiomer was 20.3 min.
(3-{5-[(3S)-3-(Formylamino)butyl]pyridin-2-yl}propyl)-
formamide (12b). 11b (800 mg, 3.1 mmol) was dissolved in
1/1 THF/MeOH (20 mL) at 25 °C. The solution was combined
with 5% Pd/Al2O3 (100 mg) and hydrogenated at 40 psi for 18
h. The catalyst was removed by filtration, and the filtrate was
evaporated at reduced pressure to give an oil, which upon
trituration with MTBE provided 12b as an off-white solid (755
mg, 90%). Mp: 61-63.5 °C. 1H NMR (CDCl3): δ 8.34 (1H),
8.16 (2H), 7.48 (dd, J ) 8.0, 2.3, 1H), 7.11 (d, J ) 8.0, 1H),
6.49 (br, 1H), 5.74 (d, J ) 5.5, 1H), 4.12 (dq, J ) , 1H), 3.33
(m, 2H), 2.64 (m, 2H), 1.96 (m, 2H), 1.77 (m, 2H), 1.21 (d, J )
6.8, 3H). 13C NMR (CDCl3): major rotamer δ 161.4, 160.7,
158.4, 148.7, 136.8, 134.4, 122.7, 43.6, 38.7, 37.5, 34.7, 29.0,
28.8, 20.9. HRMS (ESI): calcd for C14H21N3O2 + 1 264.1712,
found 264.1712.
(2S)-4-[6-(3-Aminopropyl)pyridin-3-yl]butan-2-amine
(9b) (from 12b). Compound 12b (87 mg, 0.33 mmol) was
dissolved in a mixture of methanol (2.5 mL) and water (0.25
mL), and hydroxylamine hydrochloride (100 mg, 1.4 mmol) was
added. The solution was heated at 70 °C for 20 h. Assay of the
reaction mixture showed 64 mg of 9b present (94% yield).
3-(5,6,7,8-Tetrahydro-1,8-naphthyridin-2-yl)propan-1-
amine (2a).6 To a solution of 9a (233 g, 1.21 mol) in toluene
(4 L) was added NaNH2 (255 g, 90 wt %, 5.88 mol), and the
mixture was heated to 90 °C for 7 h. The reaction was
monitored by HPLC and was considered complete when the
ratio of 2a to 9a was >99:1. HPLC conditions were as described
Acknowledgment. We thank Dr. T. T. Lam for the
thermal characterization of N-formylpropargylamine
and Mr. R. Reamer for NMR support.
1
Supporting Information Available: Copies of H NMR
spectra of 6a, 7a, 8a, 9a, 12b, and 19 and a copy of the 13C
NMR spectrum of 9a. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO0486950
8730 J. Org. Chem., Vol. 69, No. 25, 2004