Room temperature, copper-catalyzed amination of bromonaphthyridines with aqueous ammonia

Article abstract of DOI:10.1021/jo100476x

(Figure Presented) Room temperature, copper-catalyzed amination of amido-bromo-1,8-naphthyridines is reported. Use of Cu₂O and aqueous ammonia at ambient temperature affords amination products in 10-87% yield. Bromonaphthyridines are prepared in 15-65% yield via treatment of amidonaphthyridinones with phosphorus tribromide. This methodology provides an alternative route to functional, nonsymmetric 2,7-diamido-1,8-naphthyridines.

Full text of DOI:10.1021/jo100476x

pubs.acs.org/joc
QHBM systems exhibiting high-affinity and high-fidelity.5 The
Room Temperature, Copper-Catalyzed Amination of
Bromonaphthyridines with Aqueous Ammonia
weak self-dimerization of the 2,7-diamido-1,8-naphthyridine
(DAN) unit, i.e., Kdimer > 10 M-1, and its high affinity for
QHBMs, such as UG, DeUG, and UPy, makes this unit
particularly valuable.2b,3-6 Indeed, the DAN motif has been
employed in molecular recognition and self-assembly studies,7
and has found applications in supramolecular polymer
chemistry.8,9 These and future advances depend on the avail-
ability of preparations that allow access to functional derivatives
of DAN. Such functional groups should allow the covalent
attachment of DAN to other molecules, macromolecules, sur-
faces, and nanostructures.
Cyrus A. Anderson, Phillip G. Taylor, Mary A. Zeller,† and
Steven C. Zimmerman*
Department of Chemistry, University of Illinois at
Urbana-Champaign, 600 S. Mathews Avenue, Urbana,
Illinois 61801. †Current address: Department of Chemistry,
Purdue University, 560 Oval Drive, West Lafayette, IN 47907
sczimmer@illinois.edu
Functional DAN units have typically incorporated the
reactive functionality in one or both amide side chains. The
naphthyridine ring system can also be functionalized;10 how-
ever, these methods involve either lengthy syntheses or have
not yet been shown to allow attachment to other materials.
The syntheses of nonsymmetric diamidonaphthyridines 1 have
typically involved selective hydrolysis of one amide of diami-
donaphthyridine 2 (Figure 1a).3,6a Compound 2 is prepared via
acylation of 2,7-diaminonaphthyridine, which is in turn obtai-
ned through high-pressure ammonolysis of a chloronaphthyr-
idine precursor.11 The hazardous ammonolysis conditions, or
use of ammonia surrogates,12 combined with the circuitous syn-
thetic sequence have prompted investigations into alternative
routes.3,13 A straightforward approach has been reported by
Sijbesma and Meijer14 wherein chloronaphthyridines 3 undergo
palladium-catalyzed amidation (Figure 1b). Multiple nonsym-
metric diamidonaphthyridines were successfully obtained
in 50-90% yield. Given recent advancements in C-N bond
Received March 15, 2010
Room temperature, copper-catalyzed amination of ami-
do-bromo-1,8-naphthyridines is reported. Use of Cu2O
and aqueous ammonia at ambient temperature affords ami-
nation products in 10-87% yield. Bromonaphthyridines are
prepared in 15-65% yield via treatment of amidonaphthyr-
idinones with phosphorus tribromide. This methodology
provides an alternative route to functional, nonsymmetric
2,7-diamido-1,8-naphthyridines.
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60, 2063. (b) Ong, H. C.; Zimmerman, S. C. Org. Lett. 2006, 8, 1589.
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2009, 11, 61.
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4848 J. Org. Chem. 2010, 75, 4848–4851
Published on Web 06/15/2010
DOI: 10.1021/jo100476x
r
2010 American Chemical Society

Anderson et al.
JOCNote
TABLE 1. Bromination of Amidonaphthyridinones
FIGURE 1. Conventional synthetic routes to nonsymmetric dia-
mido-naphthyridines via (a) hydrolysis and acylation of symmetric
diamidonaphthyridines or (b) Buchwald-Hartwig amidation.
forming reactions,15 we explored a copper-catalyzed amina-
tion toward the synthesis of diamidonaphthyridines. Herein
we describe methodology featuring mild amination of bro-
monaphthyridines followed by acylation. This approach
may be useful in cases where palladium catalysis cannot be
used or where the amide needed in Figure 1b is not readily
available.
a20 equiv of PBr3. b30 equiv of PBr3. c65 equiv of PBr3.
chlorides required activated substrates or microwave condi-
tions. Syntheses of anilines via CuI salts and ammonium
chloride or aqueous ammonia have been reported; however,
supporting ligands and base additives are necessary.20c,d
Mechanistic aspects of these and related copper-mediated
transformations have yet to be resolved.21
Syntheses of (hetero)aryl amines are often accomplished
via the Ullmann reaction, wherein use of high temperatures
and stoichiometric amounts of copper reagents are frequen-
tly required. Recent examples demonstrate that various
secondary and tertiary (hetero)aryl amines can be prepared
under milder conditions.15 Obtaining primary (hetero)aryl
amines, however, has proven difficult. Palladium-mediated
syntheses are typically achieved via coupling of (hetero)aryl
halides with ammonia surrogates.16 Hartwig,17 Buchwald,18
and Beller19 have recently demonstrated palladium-catalyzed
coupling of (hetero)aryl halides with anhydrous ammonia.
Elevated pressures and strong bases are often required to
obtain these amines. Reports of copper-mediated syntheses
have also been rare.20 For example, Lang20a and Gaillard20b
reported the preparation of aminopyridines by heating
halopyridines, Cu2O, and anhydrous ammonia. Bromides,
iodides, and chlorides were successfully converted to the
corresponding amines; however, yields appear to be quite
substrate dependent. More recently, Wolf20e reported ami-
nation of activated and unactivated aryl iodides and bro-
mides by heating the substrate, Cu2O, and concentrated
aqueous ammonia (NH4OHaq) in NMP. Conversion of aryl
Initial attempts to aminate 3 (R1 = Me)11 with 10 mol %
of Cu2O and 10 equiv of NH4OHaq at 90 °C in ethylene glycol
were unsuccessful, giving exclusively the product of amide
hydrolysis. Attention was thus turned to the study of bro-
monaphthyridines. Heating 7-amino-1,8-naphthyridin-2(1H)-
one22 in POBr3/PBr5 resulted in low conversion and decom-
position of the starting material. PBr3 was similarly ineffec-
tive; use of cosolvents such as pyridine or chloroform gave no
improvement. Fortunately, heating alkyl amidonaphthyri-
dinones 4-7 to 110 °C in PBr3 gave acceptable yields of the
corresponding bromides 8-11 after 6-24 h (Table 1). Reac-
tions performed at lower temperatures or for shorter dura-
tion gave incomplete conversion. Substrates 12 and 13 gave
incomplete conversion to bromides 14 and 15, respectively,
upon prolonged heating and were hard to purify.
With bromides 8-11 in hand, the copper-mediated ami-
nation was evaluated (Table 2). The method of Lang20a was
used with the modification that NH4OHaq was used in place
of anhydrous ammonia. The HPLC analysis of reaction
mixtures obtained from heating bromide 8, 10 mol %
Cu2O, and 10 equiv of NH4OHaq in ethylene glycol at
90 °C for 12 h indicated a 3:2 mixture of product 16 and
2,7-diaminonaphthyridine.11 The latter resulted from amide
cleavage of 16. Some solvolysis products were detected by
LC/MS. Conditions were sought to suppress the side reac-
tions. Increasing catalyst loading to 30 mol % and heating to
90 °C allowed consumption of 8 within 1 h. HPLC analysis
(15) (a) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400.
(b) Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2009, 48, 6954.
(16) (a) Grasa, G. A.; Viciu, M. S.; Huang, J. K.; Nolan, S. P. J. Org.
Chem. 2001, 66, 7729. (b) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.;
Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653.
ꢀ
(c) Barluenga, J.; Aznar, F.; Valdes, C. Angew. Chem., Int. Ed. 2004, 43,
343. (d) Lee, D.-Y.; Hartwig, J. F. Org. Lett. 2005, 7, 1169.
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15, 4528.
(20) (a) Lang, F.; Zewge, D.; Houpis, I. N.; Volante, R. P. Tetrahedron
Lett. 2001, 42, 3251. (b) Gaillard, S.; Elmkaddem, M. K.; Fischmeister, C.;
Thomas, C. M.; Renaud, J.-L. Tetrahedron Lett. 2008, 49, 3471. (c) Kim, J.;
Chang, S. Chem. Commun. 2008, 3052. (d) Xia, N.; Taillefer, M. Angew.
Chem., Int. Ed. 2009, 48, 337. (e) Xu, H.; Wolf, C. Chem. Commun. 2009,
3035. (f) Wang, D.; Cai, Q.; Ding, K. Adv. Synth. Catal. 2009, 351, 1722.
(g) Wu, X.-F.; Darcel, C. Eur. J. Org. Chem. 2009, 4753.
(21) (a) Huffman, L. M.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 9196.
(b) Tye, J. W.; Weng, Z.; Giri, R.; Hartwig, J. F. Angew. Chem., Int. Ed. 2010,
49, 2185. (c) Jones, G. O.; Liu, P.; Houk, K. N.; Buchwald, S. L. J. Am. Chem.
Soc. 2010, 132, 6205.
(22) Newkome, G. R.; Garbis, S. J.; Majestic, V. K.; Fronczek, F. R.;
Chiari, G. J. Org. Chem. 1981, 46, 833.
J. Org. Chem. Vol. 75, No. 14, 2010 4849

Anderson et al.
JOCNote
TABLE 2. Copper-Catalyzed Amination of Bromonaphthyridines
entrya
Cu source
mol % cat.b
time (h)
tempc (°C)
solventd
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13e
14
15
16
17
18
Cu2O
Cu2O
Cu2O
Cu0
10
30
30
10
10
10
10
10
10
5
12
1
90
90
45
45
45
45
45
45
45
45
45
rt
rt
rt
rt
rt
rt
rt
EG
EG
EG
EG
EG
EG
EG
EG
EG
EG
EG
EG
EG
THF
34
74
73
7
0
0
0
0
2
7
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
CuO
CuCl2
Cu(OAc)2
CuI
CuBr
Cu2O
0
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
30
30
30
30
30
30
30
10
65
5
glyme
i-PrOH
EtOH
1:1 (v:v) glyme:EG
8
17
37
87
a570 μmol of 8, 10 equiv of NH4OHaq. bvs bromide. crt = 25 ( 3 °C. dEG = ethylene glycol. e570 μmol of 9.
TABLE 3. Room Temperature, Copper-Catalyzed Amination of
Bromonaphthyridines with Aqueous Ammonia
substrate is important to the outcome. A short survey of
solvents revealed that reactions performed at room tempera-
ture in 1:1 mixtures of ethylene glycol and glyme afforded 16
in yields as high as 87%. LC/MS indicated that hydrolysis
and solvolysis products accounted for the remaining UV-
active species (260 nm). Note that secondary or tertiary
amines, resulting from amination of 8 with 16, were not
detected throughout the course of these investigations.
Applying the conditions optimized for 8 to 9-11, 14, and 15
afforded the corresponding aminonaphthyridines 17-21 in
10-65% yield (Table 3). No attempt was made to optimize
thesereactionyields, whichappear tocorrelate withhydrolytic
stability of the amide. Bromides featuring alkyl amides gave
the highest yields while yields for aryl and benzyl substrates
were significantly lower. Indeed, amination of 15 and 11 gave
25% and up to 60% yield of 2-amino-7-bromonaphthyridine,
respectively, resulting from amide hydrolysis. In the caseof11,
the desired product 19 could be neither isolated nor detected
by LC/MS. Although >10 wt % CuI is used as precatalyst,
ICP-MSanalysisforCuindicatessamplesof16 and17 contain
e0.1 wt % Cu upon purification by column chromatography.
Conditions for the preparation of functional, nonsym-
metric diamidonaphthyridines were sought. Coupling of 16
and 21 with various carboxylic acids was carried out with
N-(3-dimethylaminopropyl)-N0-ethylcarbodiimide hydrochlor-
ide (EDC) and 4-(dimethylamino)pyridine (DMAP) in CH2Cl2.
The desired diamidonaphthyridines 22-27 were readily
obtained in 60-95% yield (Table 4). Through this metho-
dology, mono- and heterobifunctional diamidonaphthyri-
dines amenable to copper-catalyzed azide-alkyne cyclo-
addition (CuAAC),23 and those bearing polymerizable vinyl
moieties, or atom-transfer radical polymerization24 initiat-
ors can be prepared without protecting group chemisry.
a1 mmol of bromide, 10 equiv of NH4OHaq, 25 ( 3 °C, 24 h. bEG =
ethylene glycol.
indicated a 19:1 ratio of 16 and its hydrolysis product, with
16 isolated in 73% yield. Changing the conditions to 45 °C
for 24 h gave an improved ratio without a loss in yield.
A brief survey of other copper reagents indicated that Cu0
and other CuI-based salts were competent, although Cu2O
was the most effective. Reactions performed with 30 mol %
catalyst at room temperature (25 °C) gave incomplete con-
version after 24 h; however, reaction of 9 under otherwise
identical conditions (Table 2, entry 13) gave the correspond-
ing product 17 in 65% yield, suggesting that solubility of the
(23) Meldal, M.; Tornøe, C. W. Chem. Rev. 2008, 108, 2952.
(24) Matyjaszewski, K.; Xia, J. Chem. Rev. 2001, 101, 2921.
4850 J. Org. Chem. Vol. 75, No. 14, 2010

Anderson et al.
JOCNote
TABLE 4. Nonsymmetric Diamidonaphthyridines via Carbodiimide
Coupling of Aminonaphthyridines with Functional Carboxylic Acids
cm-1) 3168 (NH), 1691 (CdO); UV λmax (CHCl3) 340 nm; ESI-
HRMS calcd for [C16H20BrN3O H]þ 350.0868, found 350.0866.
3
Anal. Calcd for C16H20BrN3O: C, 54.87; H, 5.76; N, 12.00.
Found: C, 55.22; H, 5.81; N, 11.82. ICP-MS: 0.003 wt % Cu.
Procedure for Cu-Catalyzed Amination of 2-Bromonaphthyr-
idines. A thick-walled high-pressure tube with cap was charged
with bromonaphthyridine (1 equiv), Cu2O (0.3 equiv), and
0.15 M in either 1:1 (v:v) ethylene glycol:glyme or ethylene
glycol (see the Supporting Information for details). To the slurry
was added NH4OHaq (10 equiv). The tube was capped and
the reaction was stirred at room temperature (25 ( 3 °C) for
24 h. The vessel was carefully opened, diluted with water and
CH2Cl2, and stirred, open to air, for 1 h. The crude reaction
mixture was extracted with organic solvent, washed with water
and brine, dried over Na2SO4, filtered, and dried in vacuo. Cha-
racterization data for 16: mp 192-193 °C; 1H NMR (500 MHz;
CDCl3) δ 8.26 (br s, 1H), 8.05 (br s, 1H), 7.97 (d, J = 8.1 Hz,
1H), 7.83 (d, J = 8.5 Hz, 1H), 6.68 (br s, 1H), 4.91 (br s, 2H),
2.21-2.16 (m, 1H), 1.77-1.70 (m, 2H), 1.64-1.58 (m, 2H),
1.35-1.30 (m, 4H), 0.97 (t, J = 7.4 Hz, 3H), 0.88 (t, J = 7.0 Hz,
3H); 13C NMR (126 MHz; CDCl3) δ 175.5, 160.2, 155.5, 153.3,
139.0, 138.0, 115.4, 111.0, 110.7, 51.2, 32.7, 30.0, 26.3, 23.0, 14.2,
12.2; IR (Nujol, cm-1) 3423, 3289, 3102 (NH), 1697 (CdO); UV
a350 μmol of amine, 0.25 equiv of DMAP, 2 equiv of acid, 2 equiv of
EDC. b45 °C.
λ
max (CHCl3) 352 nm; ESI-HRMS calcd for [C16H22N4O H]þ
3
287.1872, found 287.1867. Anal. Calcd for C16H22N4O: C,
67.11; H, 7.74; N, 19.56. Found: C, 66.92; H, 7.80; N, 19.18.
ICP-MS: 0.09 wt % Cu.
In summary, we have disclosed a route to nonsymmetric 2,7-
diamido-1,8-naphthyridines that relies on copper-mediated
amination of bromonaphthyridines, which are prepared from
the corresponding naphthyridinones via treatment with PBr3.
The amination can be performed in ethylene glycol/aqueous
ammonia solution at room temperature, in the presence of
Cu2O, and is effective for preparation of alkyl 2,7-diamino-
naphthyridine monoamides. This approach may offer an
alternative to that reported by Sijbesma and Meijer14 in cases
where the substrate prevents the use of palladium catalysis or
where the required primary amide is not readily available. In
the present case, the synthesis of “clickable” and polymeriz-
able diamidonaphthyridines without use of protecting group
chemistry may make this an appealing route to functional
materials.
Procedure for Acylation of 7-Amido-2-aminonaphthyridines. A
round-bottomed flask equipped with a stir bar was charged with
aminonaphthyridine (1 equiv), DMAP (0.25 equiv), carboxylic
acid (2-3 equiv), and 0.16 M CH2Cl2 and was cooled to 0 °C via
an ice-water bath. N-(3-Dimethylaminopropyl)-N0-ethylcar-
bodiimide hydrochloride (EDC) (2-3 equiv) was added, the
vessel was capped with a rubber septum, and the reaction was
warmed to room temperature over several hours and kept there
for 12-24 h. The solution was diluted with CH2Cl2 and washed
with water, saturated aqueous NaHCO3, and brine. The com-
bined organic portions were dried over Na2SO4, filtered, and
were dried in vacuo. Characterization data for 24: mp 115-
116 °C; 1H NMR (400 MHz; CDCl3) δ 8.48 (d, J = 8.8 Hz, 1H),
8.44 (d, J = 8.8 Hz, 1H), 8.23 (br s, 1H), 8.21 (br s, 1H), 8.14 (d,
J = 8.4 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 2.46 (t, J = 7.5 Hz,
2H), 2.26-2.21 (m, 1H), 2.18 (td, J = 7.0, 2.7 Hz, 2H), 1.94 (t,
J = 2.6 Hz, 1H), 1.79-1.68 (m, 4H), 1.65-1.49 (m, 4H),
1.44-1.30 (m, 12H), 0.98 (t, J = 7.4 Hz, 3H), 0.88 (t, J = 7.0
Hz, 3H); 13C NMR (101 MHz; CDCl3) δ 175.5, 172.4, 153.9,
153.9, 153.8, 139.2, 118.5, 113.7, 113.5, 84.9, 68.3, 51.2, 38.2,
32.6, 29.9, 29.3, 29.2, 29.0, 28.8, 28.6, 26.2, 25.4, 22.9, 18.5, 14.1,
12.2; IR (CCl4, cm-1) 1698 (CdO); UV λmax (CHCl3) 347 nm;
Experimental Section
Procedure for Bromination of 7-Amidonaphthyridinones. A
three-necked round-bottomed flask, equipped with a stir bar,
reflux condenser, and thermometer, containing a slurry of 1
equiv of amidonaphthyridinone in 20 equiv of PBr3 was heated
in a 110 °C oil bath for 6-72 h under a nitrogen atmosphere.
The mixture was cooled to 0 °C then diluted with CH2Cl2, and
the slurry was poured carefully over crushed ice/water. The
mixture was extracted with organic solvent, dried over Na2SO4,
filtered through Celite, and dried in vacuo. Characterization
data for 8: mp 130-131 °C; 1H NMR (500 MHz; CDCl3) δ 8.62
(d, J = 8.9 Hz, 1H), 8.37 (s, 1H), 8.19 (d, J = 8.9 Hz, 1H), 7.96
(d, J = 8.4 Hz, 1H), 7.54 (d, J = 8.3 Hz, 1H), 2.30-2.21 (m, 1H),
1.78-1.69 (m, 2H), 1.63-1.53 (m, 2H), 1.33-1.31 (m, 4H), 0.97
(t, J = 7.4 Hz, 3H), 0.87 (t, J = 7.0 Hz, 3H); 13C NMR (126
MHz; CDCl3) δ 175.7, 154.8, 154.2, 145.7, 139.5, 138.3, 125.7,
119.5, 115.7, 51.2, 32.5, 29.9, 26.2, 22.9, 14.1, 12.1; IR (Nujol,
ESI-HRMS calcd for [C27H38N4O2 H]þ 451.3073, found
3
451.3084. Anal. Calcd for C27H38N4O2: C, 71.97; H, 8.50; N,
12.43. Found: C, 71.89; H, 8.66; N, 12.19.
Acknowledgment. This work was supported by the NSF
(CHE-1012212) and the University of Illinois Department of
Chemistry through an R. Carr Fellowship (C.A.A.) and H.
Snyder Scholarhip (M.A.Z.).
Supporting Information Available: Detailed experimental
procedures and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 14, 2010 4851