Phosphonylation of 2-amino- and 2-amido-3-bromopyridines and 2-amino-3-chloroquinoxalines with triethyl phosphite

Article abstract of DOI:10.1002/ejoc.200900698

The Tavs reaction of 2-amino- and 2-acylamido-3-bromopyr-idines 1 and 2 with triethyl phosphite in the presence of palladium, acetate or chloride allows the synthesis of 2-aminoand 2-acylamidopyridine-3-phosphonates 3 and 4. A second ring nitrogen atom ca

Full text of DOI:10.1002/ejoc.200900698

FULL PAPER
DOI: 10.1002/ejoc.200900698
Phosphonylation of 2-Amino- and 2-Amido-3-bromopyridines and
2-Amino-3-chloroquinoxalines with Triethyl Phosphite
M. Shaker S. Adam,[a] Markus K. Kindermann,[a] Martin Köckerling,[b] and
Joachim W. Heinicke*[a]
Keywords: Cross-coupling / Palladium / Nitrogen heterocycles / Phosphorus / Phosphonylation
The Tavs reaction of 2-amino- and 2-acylamido-3-bromopyr-
idines 1 and 2 with triethyl phosphite in the presence of pal-
ladium acetate or chloride allows the synthesis of 2-amino-
and 2-acylamidopyridine-3-phosphonates 3 and 4. A second
ring nitrogen atom causes strong activation and leads to ex-
cellent yields in the phosphonylation of 2-amino-3-chloro-
quinoxalines. 2,3-Dichloroquinoxaline does not need a cata-
lyst and undergoes double phosphonylation with sodium di-
ethyl phosphite under Michaelis–Becker conditions. The re-
sults show an activating influence of pyridine nitrogen (–M)
and deactivating influence of the amino group (+M). The re-
activity of 1 and 2 in the Tavs coupling is compared with that
of the 3-NH-2-bromopyridine position isomers and 2-bromo-
anilines and discussed in terms of the opposite effects of pyr-
idine and amino(amido) nitrogen and different position of the
N atoms towards the reaction site. The advantage of the Tavs
reaction is the easy optimization because neither auxiliary
ligands are required nor a base to trap the halide or a solvent.
Triethyl phosphite itself acts as ligand and forms Pd0{P-
(OEt)3}n in the initial phase of the reaction. The structures
of the products and the expected intramolecular N–H···O=P
hydrogen bridging bonds were proven by solution NMR and
by X-ray crystal structure analysis of single crystalline 3c.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
years P–C cross coupling reactions using dialkyl phosphite
were preferred. Despite donor atoms tend to block the cata-
lyst metal, under suitable conditions also some heteroaryl
phosphonates became accessible.[8–12] Additional NH-func-
tional groups in the heteroarylhalides increase, however, the
probability to deactivate the catalyst, and to the best of our
knowledge only a very recent paper describes the Hirao-
type coupling of a limited variety of NH-functional bromo-
pyridines, 2-bromo-5-amino- and several amino-3-bromo-
pyridines. Thorough optimization experiments with varia-
tion of the ligand (Pd/ligand ratio usually 10:30 mol-%),
base, solvent and reaction time (24–72 h) led to very good
yield with 2-amino-3-bromo-4-methylpyridine whereas the
yields in the coupling of the closely related 4-amino-3-bro-
mopyridine remained zero or low, even after long reaction
time.[12] This shows that the position of the substituents in
NH-functionally substituted heteroaryl halides plays a cru-
cial role in transition metal catalysis or its blockage by co-
ordination of heteroatom(s) and that even small changes
may require new time consuming optimizations.
Introduction
Phosphonic acid derivatives are of broad interest particu-
larly with regard to the large number of biologically active
compounds containing such P–O functional groups.[1] The
access to phosphonylated azaheterocycles and their impor-
tance in synthetic, agrochemical and medicinal chemistry
has very recently been reviewed.[2] Whereas aliphatic repre-
sentatives are easily available by alkylation of di- or trialkyl
phosphite, well known as Michaelis–Becker or Arbuzov re-
actions,[3] the direct arylation of phosphites requires either
activation by strongly electron-withdrawing groups such as
in dinitroarenes or pyridine N-oxides,[4] or activation by UV
light, known for aryl iodides.[5] Another route to these ma-
terials is transition metal catalysis, introduced by Tavs,[6]
using trialkyl phosphite, and by Hirao et al.,[7] using dialkyl
phosphite in the presence of an auxiliary ligand and a base
in a suitable solvent, respectively. Tavs reactions usually
need higher reaction temperatures. Therefore, to avoid ther-
mal decomposition or competing side reactions, in the last
The Tavs procedure is more easy to perform, does neither
need auxiliary ligands (triethyl phosphite itself acts as li-
gand[13]) nor a base or solvent, and for thermally suffi-
ciently stable aromatic compounds this reaction is thus an
advantageous alternative. Optimization is reduced to
screening for suitable transition metal precursors. For appli-
cation to NH-functionally substituted aryl or heteroaryl ha-
lides the transition metal must tolerate the heteroatoms,
[a] Institut für Biochemie, Ernst-Moritz-Arndt-Universität Greifs-
wald,
Felix-Hausdorff-Str. 4, 17489 Greifswald, Germany
Fax: +49-3834-864377
E-mail: heinicke@uni-greifswald.de
[b] Anorganische Chemie-Festkörperchemie, Universität Rostock,
Albert-Einstein-Str. 3a, 18059 Rostock, Germany
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900698.
Eur. J. Org. Chem. 2009, 4655–4665
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4655

M. S. S. Adam, M. K. Kindermann, M. Köckerling, J. W. Heinicke
FULL PAPER
also its position relative to the reaction centre must be taken 30–40%, and after 40 min all 3a was decomposed. The 31P
into account. We used the Tavs reaction to synthesize o- NMR spectrum after 10 min reaction time displayed signals
amino(amido)benzenephosphonates as starting materials for 3a, (EtO)2PHO and (EtO)3PO. The signal for the latter
for benzo-fused P=C–N heterocycles[14–16] and recently is increasing with the reaction time. After heating for longer
demonstrated the applicability also to 3-amino- and 3- times further signals were observed in the phosphate region,
amido-2-phosphonopyridines, likewise used as building indicating P–C bond cleavage in connection with formation
blocks for heterocycles.[17,18] Whereas N-secondary o-anil- of highly viscous condensation products.
ido phosphonates were obtained in high yields from triethyl
phosphite and o-bromoanilides in the presence of anhy-
drous nickel bromide,[15] the cross coupling with N-basic o-
bromoanilines and 3-amino- or 3-amido-2-bromopyridines
requires palladium catalysts that are more tolerant towards
other functional groups.[16] For the 3-NH-functional 2-bro-
mopyridines the yields were only low to moderate, although
for this position the C–halogen bond should be activated
by the adjacent pyridine N-atom.[18] In the isomers with
Scheme 1. Synthesis of 2-acylamidopyridine-3-phosphonates 3a–f
(a R = tBu, b R = 2-furyl, c R = 2-thienyl, d R = Ph, e R = 4-
ClC6H4, f R = 1-naphthyl, X = OAc or Cl).
bromine in 3- and the amino or amido group in 2-position
the C–Br bond will not be activated by the pyridine nitro-
gen, but the ring N-atom is more remote to the catalyst
metal and catalyst blockage less probable. This prompted
us to explore if this makes these compounds comparable to
2-bromoanilides or -anilines, allows the use of Ni catalysts
for the coupling of N-acyl-bromopyridines or leads to im-
proved yields with Pd catalysts. To additionally get evidence
whether the electron-withdrawing power of pyridine-type
nitrogen (σ2-N) atoms has indeed an impact on the Tavs
coupling or not, to open a route to the still unknown 2-
aminoquinoxaline-3-phosphonates, and to more generally
show if the Tavs protocol is suitable for the phosphonyl-
ation of NH-functionally substituted N-heteroaryl halides,
we included 2-amino-3-chloroquinoxalines into this investi-
gation.
The primary amino-bromopyridine 1a is more suscepti-
ble to side reactions than the acylamides 2 and provides the
2-aminopyridine-3-phosphonate 4a under the above condi-
tions only in low yield (19%). Prolonged heating of 1a with
P(OEt)3/PdCl2 (10 mol-%) did not lead to improved forma-
tion of 4a but to yellowish and finally brown (after 35–
40 min) condensation products with high viscosity and low
content of 4a. To access 4a, the Hirao coupling is clearly
more suitable.[12] Because the yields in the Pd-catalyzed
Tavs coupling of N-secondary o-bromoanilines improved
strongly with bulkier N-substituents,[16] some N-alkyl- and
N-aryl-2-amino-3-bromopyridines 1b–f were prepared and
subjected to this P–C coupling protocol (Scheme 2). The N-
(phenylamino)pyridine-3-phosphonate 4d was obtained in
good and the primary N-alkyl derivatives 4b and 4c in mod-
erate yields, similar to comparably N-substituted 2-anilino-
phosphonates.[16] As shown for the anilinophosphonates,
the outcome can further be improved by more bulky N-
alkyl groups. An additional nitrogen atom in the N-substit-
uent, however, lowers the yields as demonstrated for the N-
2. Results and Discussion
2.1. Synthesis of 2-Amino- and 2-Amidopyridine-3-
phosphonates
The 2-amino-3-bromopyridine 1a and various 2-acyl-
amido-3-bromopyridines 2a–f, obtained from 1a and the re-
spective acyl chlorides, were used in this study. Attempts
aiming at cross coupling of various 2-acylamido-3-bromo-
pyridines 2 with triethyl phosphite in the presence of anhy-
drous NiBr2 failed, even for conditions with high tempera-
tures and long reaction time (200 or 225 °C/15 to 60 min).
The coupling requires the presence of palladium acetate or
palladium chloride (8–12 mol-%) under harsh conditions
(heating for 10 min at 170 °C bath temperature). The acyl-
amidopyridine-3-phosphonates 3a–f (Scheme 1) are then
obtained in moderate yields, highest for the pivaloyl com-
pound 3a with the bulky +I tert-butyl group (NMR scale
70%, preparative scale 40%) and for the π-excess heteroaryl
derivatives 3b and 3c, clearly lower for the benzamides 3d
and 3e, and lowest for the naphthoylamido-pyridinephos-
phonate 3f. Prolonged heating of 2a with P(OEt)3/PdCl2
(10 mol-%) also resulted in lower yields. After 10 min at
(heteroarylamino)pyridinephosphonates
(Table 1).
4e
and
4f
Scheme 2. Synthesis of 2-aminopyridine-3-phosphonates 4a–f (a R
= H, RЈ = Me; b R = CH2-2Ј-furyl, RЈ = Me; c R = Et, RЈ = Me;
d R = Ph, RЈ = Me; e R = 2-pyridyl, RЈ = H; f R = 3-quinolyl, RЈ
1
170 °C, 70% of 3a was detected (by H NMR integration)
in the crude product, after further 10 min at 180 °C only = H; X = OAc or Cl).
4656
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 4655–4665

Phosphonylation of o-Amino N-Heterocyclic Halides
Table 1. Pd-catalyzed phosphonylation of 2-amino- or 2-amido- achieved by an equimolar ratio of the reactants. In this case
substituted 3-bromopyridines and 3-chloroquinoxalines with
unconverted dichloroquinoxaline was recovered, showing
that monophosphonylation causes increased reactivity of
P(OEt)3.[a]
the remaining C–Cl bond. The amino groups in 2-amino-
3-chloroquinoxaline 5a[19] and 2-(tert-butylamino)-3-chlo-
roquinoxaline 5b[20] accomplish the contrary. Attempts to
couple the 2-amino-3-chloroquinoxalines 5a and 5b simply
by heating with sodium diethyl phosphite (Michealis–
Becker protocol) or with triethyl phosphite (Arbuzov proto-
col) failed, even in the presence of anhydrous NiCl2 or
NiBr2 (5–100 mol-%) under forced conditions (120–225 °C
up to 20 min). Furthermore, heating with diethyl phosphite
in the presence of excess base (Et3N or iPr2NH or NaOtBu)
and catalytic amounts of Pd(OAc)2 in toluene (Hirao proto-
col) or N-methylpyrrolidone (180–225 °C) did not lead to
phosphonylation. However, heating of 5a or 5b with triethyl
phosphite in the presence of palladium acetate as catalyst
provided the 2-aminoquinoxaline-3-phosphonates 7a and
7b in excellent yields (Scheme 3).
Scheme 3. Synthesis of 6 and substituted 2-aminoquinoxaline-3-
phosphonates 7a,b (a R = H, b R = tBu).
2.3. Remarks on Mechanistic Aspects
The easy reaction of 2,3-dichloroquinoxaline with
amines and sodium diethyl phosphite is due to the pro-
motion of nucleophilic substitution by electron deficiency.
Replacement of the first chlorine by a phosphono group
causes enhanced activation, replacement of chlorine by the
electron-donating amino group decreases the reactivity, so
that a catalyst becomes necessary, like as for the 2-amino-
3-bromopyridines. The much higher yield in the coupling
of 5a compared to 1a reflects the activation of the C–halo-
gen bond by the electron withdrawing effect of σ2-N atoms,
although the diminished nucleophilic reactivity of the
amino group certainly also contributes to the excellent cou-
[a] Conditions: 1.2 equiv. of P(OEt)3 were used; heating usually
10 min at 170 °C, in the case of 7a 2.5 h/180 °C, 7b 1 h/160 °C;
yields refer to isolated products. [b] NMR yield at optimal reaction
time.
2.2. Synthesis of Quinoxaline-2,3-diphosphonates and 2-
Aminoquinoxaline-3-phosphonates
Due to its strong electron deficiency, 2,3-dichloroquinox- pling results by lower tendency to side reactions. In 1a the
aline is more reactive towards nucleophiles than bromo- –M effect of the pyridine nitrogen on the 3-position is low
and in particular chloropyridines. This allows for phos- and the reactivity rather controlled by the +M effect of the
phonylation without a transition metal catalyst. Heating 2-amino group. That the reactivity of 1 and 2 in the Tavs
with sodium diethyl phosphite leads to a double Michaelis– coupling is comparable with that of the position isomeric
Becker reaction with formation of quinoxaline-2,3-diphos- 3-amino- and 3-amido-2-bromopyridines may be attributed
phonate 6. Selective mono-phosphonylation could not be to the contrary effects of adjacent pyridine and amino/
Eur. J. Org. Chem. 2009, 4655–4665
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4657

M. S. S. Adam, M. K. Kindermann, M. Köckerling, J. W. Heinicke
FULL PAPER
amido nitrogen atoms (–M vs. +M effect by o and oЈ posi- [RC6H4PdII{PO(ORЈ)2}(bipy)] species, related to the as-
tion) and the proximity of both N-atoms to the reaction sumed second intermediate, have recently been reported
site in the latter.
and were shown to eliminate arylphosphonates.[21] (EtO)2-
A proposal for a possible mechanism for the Pd-cata- PHO and (EtO)3PO are formed in connection with the re-
lyzed Tavs coupling of amino- and amido pyridine bro- duction of PdCl2 to the initial Pd0 catalyst.
mides with triethyl phosphite, apart from a distinct initia-
tion similar to that for P–C coupling with diethyl phos-
phite,[8,21,22] is depicted in Scheme 4.
2.4. Structural Aspects
Evidence for the structures of 1–7 is given by conclusive
NMR and mass spectroscopic data, for 3c additionally by
crystal structure analysis. The characteristic 31P resonances
of 3a–f and 4a–f appear only marginally below those of 2-
acylanilido-[15] and 2-anilinophosphonates[16] (δ = 16.5–20.4
vs. 18.3–22.6 ppm) and indicate thus close electronic simi-
larity. The isomeric 3-acylamido- and 3-aminopyridine-2-
phosphonates (δ = 11.3–12.3; 14.5 ppm)[18] absorb at mark-
edly higher field, halfway to 2-aminoquinoxaline-3-phos-
phonates 7a,b, which by further electron release resonate in
Scheme 4. Proposed mechanism for the Pd-catalyzed aryl phos-
phonylation with P(OEt)3.
Because the behavior of Pd(OAc)2 and PdCl2 in the Tavs
coupling was similar but for the Hirao-type coupling dif-
ferent,[22] a NMR experiment was performed to shed light
on the reason. We observed that PdCl2 on heating with tri-
ethyl phosphite is reduced to give a [Pd0{P(OEt)3}n] species,
[23]
similarly as reported for NiCl2
or for Pd(OAc)2 with
Figure 1. Molecular structure of 3c in the crystal with one disor-
dered ethyl group (78:22%). Selected bond lengths (Å) and angles
(°): C2–P1 1.790(2), P1–O4 1.468(1), P1–O2 1.559(1), P1–O3
1.566(2), C1–N1 1.330(2), C1–N2 1.398(2), C5–N1 1.343(2), N2–
C7 1.362(2), C1–C2 1.413(2), C2–C3 1.392(2); C3–C2–P1 118.5(1),
C1–C2–P1 123.9(1), C2–C1–N2 118.4(1), N1–C1–N2 118.9(1), O4–
phosphanes.[24] Evidence is provided by 31P NMR spectra
(in CDCl3 at 25 °C) of the crude product mixture formed
by refluxing excess triethyl phosphite with PdCl2 (10 min).
Broadened signals for a dynamic system of the Pd(P-
(OEt)3)4 complex[25] and P(OEt)3 (δ31P 156.8 and P1–O2 115.56(9), O4–P1–O3 114.1(1), O2–P1–O3 102.2(1), O4–
P1–C2 113.46(7), O2–P1–C2 103.05(7), O3–P1–C2 107.22(8);
N2···O 42.743(2).
136.4 ppm) with a small downfield phosphorus coordina-
tion chemical shift (∆δ = 20.4 ppm) were observed along
with signals for (EtO)2PHO and a smaller amount of
(EtO)3PO. The amount of the Pd0 complex did not signifi-
cantly increase if heating was prolonged (to 20 min). The
31P coordination chemical shift is similar to the known
value for Pd0(P(OMe)3)4/P(OMe)3 (∆δ
= )
21 ppm[26]
whereas PdCl2(P(OEt)3)2 displays an upfield shift (δ = 92.0,
∆δ = –46 ppm[27]). On addition of 1a or 2a the Pd0 complex
is no longer detectable by 31P NMR spectroscopy. Rapid
insertion of Pd0 into the C–Br bond, the typical oxidative
addition step in Pd-catalyzed cross couplings,[8] is assumed
to form an intermediate complex [pyPdII{P(OEt)3}2Br].
Subsequent elimination of EtBr (evaporates from the mix-
ture) converts the triethyl phosphite to a diethyl phos-
phonate ligand (cf. Arbuzov reactions[2]) and generates in-
termediates [pyPdII{PO(OEt)2}L2] as discussed for the Hi-
rao coupling.[8,21,22] These undergo reductive elimination to
afford the product with regeneration of Pd0, here stabilized
Figure 2. Molecular structure of 1a in the crystal, showing the for-
mation of hydrogen bridged dimers. Selected bond lengths (Å) and
angles (°): C1–Br1 1.903(2), C2–N2 1.349(2), C2–N1 1.361(2), C3–
N2 1.339(2), C1–C2 1.405(2), C1–C5 1.369(3); C5–C1–Br1
120.4(1), C2–C1–Br1 119.2(1), C1–C2–N1 122.9(2), N1–C2–N2
by
triethyl
phosphite
as
ligand
(Scheme 4). 117.4(2).
4658
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 4655–4665

Phosphonylation of o-Amino N-Heterocyclic Halides
pyridine (1a), 2,3-dibromopyridine, triethyl phosphite and catalyst
reagents were used as received from commercial suppliers. 1c and
1d were prepared from 1a by Pd-catalyzed N-alkylation[28] with
ethyl bromide or N-arylation with iodobenzene.[29] 1e was synthe-
sized by Pd-catalyzed monoarylation of 2,3-dibromopyridine with
2-aminopyridine.[30] The acylation of 1a to 2a–f was carried out in
analogy to the syntheses of the respective 2-amido-3-bromo iso-
mers.[31] NMR spectra were measured at 25 °C on a multinuclear
FT-NMR spectrometer Bruker ARX300 or AVANCE300 at 300.1
(1H), 75.5 (13C), and 121.5 (31P) MHz. The 1H, 13C and 31P chemi-
the range of δ = 9.4–9.8 ppm. The electronic effects are also
reflected in the 13C chemical shifts, which are strongly influ-
enced by changes of the π-electron density. The most char-
1
acteristic feature in the solution H NMR spectra of 3 and
4 compared to 1 and 2 is the large downfield shift of the
NH signals (∆δ = 1.9–2.8 ppm). This indicates strong intra-
molecular hydrogen bonds to the phosphono group, con-
firmed by single-crystal X-ray structure analysis of 3c (Fig-
ure 1). The π-systems of the amido group and pyridine ring
are nearly coplanar. The small interplanar angle (3.1°) al- cal shifts δ are given in ppm relative to Me4Si and H3PO4 (85%),
respectively, as external standards. The assignments made corre-
spond to position numbers in the pyridine or quinoxaline ring and
in the N-substituents (denoted by additional Ј or i, o, m, p for
phenyl). Coupling constants refer to JHH in 1H and JPC in 13C
NMR unless denoted otherwise. Splitting pattern for larger and
smaller coupling constant are given in the same order as the J val-
ues. τ (in compound 6) denotes a three or five line X signal (13C)
coupling with two chemically equivalent phosphorus nuclei (ABX
type by different 12C/13C surrounding of the 31P nuclei), |J+JЈ| the
distance of line 1 to 3 or 2 to 4. Mass spectra were measured on a
single-focusing sector-field mass spectrometer AMD40, high-reso-
lution mass spectra on a double-focussing sector field mass spec-
trometer MAT 95 (Fa. Finnigan) with EI (70 eV) or ESI. PFK
were used as references. Elemental analyses were carried out with
lows stabilization by extended delocalization. In the absence
of the phosphono group 2-aminopyridines prefer intermo-
lecular N–H···N hydrogen bonds between the amino group
and the pyridine nitrogen atom, forming pairs of molecules,
as seen in the structure of 1a (Figure 2). Both compounds,
3c and 1a, crystallize monoclinic in the space group P21/n.
All bond lengths and angles are observed within the ex-
pected ranges.
Conclusions
The basic pyridine nitrogen in 2 prevents nickel-catalyzed
Tavs phosphonylation, which is highly efficient for the elec- a CHNS-932 analyzer from LECO using standard conditions. IR
spectra were recorded as KBr pellets, or using capillaries with nujol
tronically related o-bromoanilides (see comparison of the
phosphorus resonance of the products). Phosphonylation
of 2-amino or 2-acylamido-3-bromopyridines 1 and 2 with
on a Nicolet® Magna550.
3-Bromo-2-[(furan-2-ylmethyl)amino]-5-methylpyridine (1b): A solu-
triethyl phosphite can, however, be achieved in the presence tion of 2b (see below; 1.0 g, 3.56 mmol) in diethyl ether (30 mL)
was added dropwise at 0 °C to LiAlH4 tablets (0.41 g, 10.80 mmol)
stirred in diethyl ether (30 mL). Stirring was continued for 2 d.
Then degassed water was added dropwise at 5–10 °C until the evol-
ution of hydrogen ceased. Solids were filtered off and washed with
diethyl ether. The filtrate was dried by Na2SO4, the solvent was
removed in vacuo, and the remaining pale yellow viscous liquid
was purified by column chromatography using silica gel and ethyl
acetate/n-hexane (10:90%) to give 0.64 g (67%) of a white powder,
of palladium acetate or chloride by short heating at high
temperature (170 °C). N-Alkyl, N-aryl or N-acyl groups im-
prove the yield, suitable substituents strongly. The coupling
results are comparable to those of 3-amino/3-amido-2-
bromo-position isomers despite in 1 and 2 the reaction site,
the 3-C–Br bond, lacks activation by the –M effect of the
pyridine nitrogen. That the reactivity of the two isomeric o-
amino-bromopyridines is levelled out may be attributed to
compensation of the –M-activating effect (in 2- and 4-posi-
1
3
m.p. 48 °C. H NMR (CDCl3): δ = 2.18 (s, 3 H, 5-Me), 4.48 (d, J
3
= 3.3 Hz, 2 H, NCH2), 4.80 (very br. s, 1 H, NH), 6.22 (dd, J =
4
3
4
tion) by the deactivating effect of the 3-amino group (+M 3.2, J = 0.7 Hz, 1 H, 3Ј-H), 6.31 (dd, J = 3.2, J = 1.9 Hz, 1 H,
4Ј-H), 6.40 (d, 3J = 8.4 Hz, 1 H, 4-H), 7.27 (dd, 3J = 8.4, 4J =
in 2- and 4-position) in the 3-NH-2-Br isomer and the prox-
imity of both nitrogen atoms to the reaction site at C-2.
2.0 Hz, 1 H, 4-H), 7.35 (dd, 3J = 3.2, J = 0.7 Hz, 1 H, 5Ј-H), 7.93
4
(s, 1 H, 6-H) ppm. 13C{1H} NMR (CDCl3): δ = 17.39 (5-Me), 39.63
The activation of the phosphonylation by the –M effect of
(NCH2), 106.81, 107.09, 110.32, 122.23 (CH-4Ј, Cq-3, Cq-5), 138.76
σ2-nitrogen was shown for dichloroquinoxaline, which cou-
(Cq-4), 141.89 (CH-5Ј), 147.07 (CH-6), 152.72 (Cq-2Ј), 156.28 (Cq-
ples even without a transition metal catalyst, and for 2-
2) ppm. Mass calcd. for C11H11BrN2O: 266.01, 268.00 (100, 97
amino-3-chloroquinoxaline which gives high yields using
the Tavs protocol with palladium catalysts more tolerant
towards functional groups. In conclusion, the above results
outline that amino or amido substituted electron-deficient
N-heteroaryl bromides with sufficient activation by one or
better more σ2N atoms are able to undergo Pd-catalyzed
phosphonylation simply by heating with triethyl phosphite
in the presence of a PdII salt which at about 170 °C forms
Pd0{P(OEt)3}n as the active catalysts.
rel.%). MS (EI 70 eV, 140 °C): m/z (%) = 268 (5) [M+], 266 (7)
[M+], 188 (32), 159 (44), 81 (100). C11H11BrN2O (267.12): calcd. C
49.46, H 4.15, N 10.49; found C 49.24, H 4.36, N 10.26.
3-Bromo-2-(ethylamino)-5-methylpyridine (1c): Was prepared in
analogy to (3-bromopyridin-2-yl)ethylamine[28] from 1a (4.0 g,
21.4 mmol), added to a suspension of NaH (0.62 g, 25.7 mmol) in
THF (20 mL) at –20 °C and heated at 40 °C for 30 min, by reaction
with ethyl bromide (2.4 mL, 3.51 g, 32.2 mmol) (room temperature,
2 h 50 °C) and extraction with CH2Cl2; yield 4.31 g (94%) of 1c.
3
1H NMR (CDCl3: δ = 1.25 (t, J = 7.2 Hz, 3 H, CH3), 2.14 (s, 3
3
3
H, 5-Me), 3.45 (qd, J = 7.2, JNH = 5.5, 2 H, CH2), 4.78 (br. s, 1
4
4
H, NH), 7.43 (d, J = 1.9 Hz, 1 H, 4-H), 7.87 (br. d, J ≈ 2 Hz, 1
H, 6-H) ppm. 13C{1H} NMR (CDCl3): δ = 14.00 (Me), 16.79 (Me-
5), 36.53 (NCH2), 105.09 (Cq-3), 122.00 (Cq-5), 140.11 (CH-4),
146.13 (CH-6), 152.72 (Cq-2) ppm. Mass calcd. for C8H11BrN2:
214.01, 216.01 (100, 97 rel.%). MS (EI 70 eV, 20 °C): m/z (%) =
Experimental Section
General: Reactions with moisture- or air-sensitive compounds were
conducted in dried and deoxygenated solvents under an argon at-
mosphere using Schlenk techniques. 2-Amino-3-bromo-5-methyl-
Eur. J. Org. Chem. 2009, 4655–4665
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4659

M. S. S. Adam, M. K. Kindermann, M. Köckerling, J. W. Heinicke
FULL PAPER
217 (4) [M + 1+], 216 (38) [M+], 215 (13), 214 (42) [M+], 201 (97),
199 (100), 92 (43), 44 (89). C8H11BrN2 (215.09): calcd. C 44.67, H
5.15, N 13.05; found C 44.25, H 5.32, N 13.24.
2), 147.66 (CH-6), 176.02 (CO) ppm. MS (EI 70 eV, 300 °C): m/z
(%) = 271 (3.5), 269 (4) [M – 1+], 228 (4), 226 (4), 190 (88) [M –
Br+], 187 (43), 185 (48), 57 (100). C11H15BrN2O (271.15): calcd. C
48.72, H 5.58, N 10.33; found C 48.79, H 5.72, N 9.92.
(3-Bromo-5-methylpyridin-2-yl)aniline (1d): This compound was
prepared in analogy to (3-bromopyridine-2-yl)aniline[29] from a
mixture of 1a (4.2 g, 22.5 mmol), iodobenzene (3.09 mL,
27.0 mmol), tBuONa (2.99 g, 31.2 mmol), Pd2(dba)3 [dba = dibenz-
ylideneacetone] (1.06 g, 1.16 mmol) and DPPF [1,1Ј-bis(diphenyl-
phosphanyl)ferrocene] (1.25 g, 2.26 mmol) in toluene (50 mL) at
100 °C for 20 h. After cooling, the reaction mixture was diluted
with Et2O and filtered through a Celite pad. The solvent was re-
moved in vacuo, and the product was purified by column
chromatography using silica gel (25% ethyl acetate/75% n-hexane)
N-(3-Bromo-5-methylpyridin-2-yl)-2-furoylamide (2b): Reaction of
2-furoyl chloride (2.43 mL, 24.1 mmol) with 1a (4.5 g, 24.1 mmol)
and pyridine (24 mL) gave 4.8 g (71%) of 2b, m.p. 93 °C. 1H NMR
(CDCl3): δ = 2.33 (s, 3 H, 5-Me), 6.57 (d, 3J = 3.5, 1.7 Hz, 1 H,
3
4
3
4Ј-H), 7.31 (d, J = 3.5, J = 0.7 Hz, 1 H, 3Ј-H), 7.55 (br. d, J =
4
4
1.6, J = 0.6 Hz, 1 H, 5Ј-H), 7.76 (d, J = 1.3 Hz, 1 H, 4-H), 8.29
(br. d, 4J = 1.1 Hz, 1 H, 6-H), 8.75 (very br. s, 1 H, NH) ppm.
13C{1H} NMR (CDCl3, 298 K): δ = 17.42 (s, 5-Me), 112.17 (3-
Cq), 112.59 (4Ј-CH), 116.09 (3Ј-CH), 131.77 (5-Cq), 141.82 (4-CH),
144.60 (5Ј-CH), 145.65 (2Ј-Cq), 147.42 (2-Cq), 147.49 (6-CH),
155.19 (Cq, CO) ppm. MS (EI 70 eV, 345 °C): m/z (%) = 282 (1)
[M+], 280 (1) [M+], 254 (54), 252 (55), 228 (11), 226 (13), 201 (8)
[M – Br+], 95 (100), 51 (9). C11H9BrN2O2 (281.11): calcd. C 47.00,
H 3.23, N 9.97; found C 47.31, H 3.65, N 9.81.
1
to give 3.80 g (64%) of 1d as pale yellow oil. H NMR (CDCl3): δ
= 2.23 (s, 3 H, 5-Me), 6.64 (br. s, 1 H, NH), 7.02 (tm, 1 H, p-H),
7.26–7.36 (m, 5 H, m-H, o-H, 4-H), 8.02 (br., 1 H, 6-H) ppm.
13C{1H} NMR (CDCl3): δ = 17.50 (Me-5), 108.24 (Cq-3), 119.76
(2 CH-o), 122.38 (CH-p), 124.09 (Cq-5), 129.25 (2 CH-m), 138.75
(CH-4), 140.80 (Cq-i), 147.62 (CH-6), 153.76 (Cq-2) ppm. Mass
calcd. for C12H11BrN2: 262.01, 264.01 (100, 97 rel.%). MS (EI,
200 °C): m/z (%) = 265 (5) [M + 1+], 264 (49) [M+], 263 (100) [M –
1+ and M + 1+ (79Br)], 262 (53) [M+], 261 (91) [M – 1+], 182 (20),
181 (17), 77 (25), 51 (17). C12H11BrN2 (263.13): calcd. C 54.77, H
4.21, N 10.25; found C 54.63, H 4.53, N 10.53.
N-(3-Bromo-5-methylpyridin-2-yl)-2-thenoylamide (2c): Reaction of
2-thiophenylacetyl chloride (2.80 mL, 25.7 mmol) with 1a (4.8 g,
25.7 mmol) and pyridine (24 mL) gave 5.3 g (70%) of 2c, m.p.
1
3
115 °C. H NMR (CDCl3): δ = 2.33 (s, 3 H, 5-Me), 7.14 (d, J =
3
4
5.0, 3.7 Hz, 1 H, 4Ј-H), 7.57 (d, J = 5.0, J = 1.1 Hz, 1 H, 3Ј-H),
3
4
4
4
7.70 (dd, J = 3.7, J = 1.1 Hz, 1 H, 5Ј-H), 7.76 (d, J = 2.0, J =
0.6 Hz, 1 H, 4-H), 8.26 (br. s, 1 H, 6-H), 8.39 (very br. s, 1 H, NH)
ppm. 13C{1H} NMR (CDCl3): δ = 17.51 (s, 5-Me), 112.94 (3-Cq),
127.88 (4Ј-CH), 129.44, 131.48 (5Ј-CH, 3Ј-CH), 132.08 (5-Cq),
138.59 (2Ј-Cq), 141.94 (4-CH), 146.05 (2-Cq), 147.64 (br., 6-CH),
159.33 (Cq, CO) ppm. MS (EI 70 eV, 345 °C): m/z (%) = 298 (2),
296 (2) [M+], 270 (2.5), 268 (2.5), 218 (5), 217 (40) [M – Br+], 111
(5), 110 (100), 45 (25), 44 (26). C11H9BrN2OS (297.17): calcd. C
44.46, H 3.05, N 9.43; found C 43.93, H 2.90, N 9.09.
3-[(3-Bromopyridin-2-yl)amino]quinoline (1f): Pd2(dba)3 (0.29 g,
0.32 mmol, 2 mol-%) was mixed with XANTPHOS (0.41 g,
0.71 mmol, 4.4 mol-%) in DME (5 mL) for 15 min at room tem-
perature. After the change of the colour of the solution red to yel-
low, a solution of 2,3-dibromopyridine (3.8 g, 16.0 mmol), 3-ami-
noquinoline (2.78 g, 19.3 mmol) and Cs2CO3 (20.9 g, 64.2 mmol)
in DME (50 mL) was added. The reaction mixture was refluxed for
2 h. After cooling the solvent was removed in vacuo, and the prod-
uct was extracted with CHCl3 and purified by column chromatog-
raphy using silica gel (35% ethyl acetate/65% n-hexane) to yield
3.5 g (73%) of white crystals of 1f. 1H NMR (CDCl3): δ = 6.75
(dd, 3J = 7.8, 4.8 Hz, 1 H, 5-H), 7.25 (br., 1 H, NH, superimposed
by solvent), 7.52 (td, 3J = 8.1, 6.9, 4J = 1.3 Hz, 1 H, 6Ј-H), 7.59
(td, J = 8.4, 6.9, J = 1.6 Hz, 1 H, 7Ј-H), 7.81 (dd, J = 7.8, J =
1.6 Hz, 1 H, 4-H), 7.81 (d superimposed, 3J = 8 Hz, 1 H, 5Ј-H),
8.05 (br. d, 3J = 8.3 Hz, 1 H, 8Ј-H), 8.25 (dd, 3J = 4.8, 4J = 1.6 Hz,
1 H, 6-H), 8.83, 8.90 (2d, 4J = 2.4 Hz, 2 H, 2Ј-H, 4Ј-H) ppm. Mass
calcd. for C14H10BrN3: 299.01, 301.00 (100, 97 rel.%). MS (EI,
345 °C): m/z (%) = 301 (34) [M+], 300 (74) [M – 1+], 299 (39) [M+],
298 (57) [M – 1+], 188 (41), 159 (57), 81 (100), 57 (98), 55 (54), 43
(72). C14H10BrN3 (300.15): calcd. C 56.02, H 3.36, N 14.00; found
C 55.83, H 3.58, N 14.35.
N-(3-Bromo-5-methylpyridin-2-yl)benzamide (2d): Reaction of ben-
zoyl chloride (2.82 mL, 24.1 mmol) with 1a (4.5 g, 24.1 mmol) and
pyridine (24 mL) provided 5.2 g (84%) of 2d, m.p. 135 °C. 1H
NMR (CDCl3): δ = 2.35 (s, 3 H, 5-Me), 7.46–7.60 (m, 3 H, m-CH,
3
4
3
4
4
p-CH), 7.78 (d, J = 1.2 Hz, 1 H, 4-H), 7.96 (dm, ΣJ = 9.6 Hz, 2
H, o-CH), 8.30 (br. s, 1 H, 6-H), 8.43 (very br. s, 1 H, NH) ppm.
13C{1H} NMR (CDCl3, 298 K): δ = 17.52 (s, 5-Me), 112.85 (3-Cq),
127.50, 128.83 (2 o-CH, 2 m-CH), 132.00 (i-Cq), 132.27 (p-CH),
134.26 (5-Cq), 141.90 (4-CH), 146.36 (2-Cq), 147.69 (6-CH), 165.10
(Cq, CO) ppm. MS (EI 70 eV, 250 °C): m/z (%) = 292 (4) [M+], 290
(4) [M+], 291 (2), 289 (2), 264 (6), 263 (16), 262 (6), 261 (16), 211
(46) [M – Br+], 106 (8), 105 (100), 77 (60), 51 (14). C13H11BrN2O
(291.14): calcd. C 53.63, H 3.81, N 9.62; found C 53.28, H 4.19, N
9.42.
General Procedure for 2a–f: cf. ref.[31]; the acyl chloride was added
dropwise to a solution of 1a and pyridine or triethylamine in THF
at –10 °C. The reaction mixture was stirred at –10 °C for 1 h and
at room temperature overnight, was washed several times with
water, and the product was extracted by ethyl acetate. The product
solution was dried with solid MgSO4. Ethyl acetate was removed
in vacuo, and the residue was purified by column chromatography
using silica gel (20–30% ethyl acetate and 80–70% n-hexane).
N-(3-Bromo-5-methylpyridin-2-yl)-2-chlorobenzamide (2e): Reaction
of 2-chlorobenzoyl chloride (4.15 mL, 32.7 mmol) with 1a (6.0 g,
32.1 mmol) and pyridine (34 mL) provided 6.1 g (58%) colourless
solid 2e, m.p. 54–59 °C, slightly contaminated by the N-bis(chloro-
1
benzoylation) product 2eЈ. 2e H NMR (CDCl3 7.25): δ = 2.33 (s,
3 H, 5-Me), 7.24–7.26 (m, 1 H, aryl-H), 7.35–7.47 (m, 2 H, aryl-
H), 7.72–7.84 (m, 2 H, aryl-H), 8.26 (d, 4J = 1.6 Hz, 1 H, 6-H),
8.48 (br., 1 H, NH) ppm. 13C{1H} NMR (CDCl3): δ = 17.68 (5-
Me), 119.77 (Cq-3), 127.25, 130.33, 130.79 (very br.), 131.87 (CH),
132.26 (Cq-2Ј), 134.77 (Cq-5), 135.59 (Cq-1), 141.90 (br) (CH-4),
145.9 (very br., Cq), 147.6 (very br.) (CH-6), 168.46 (Cq, CO) ppm.
Mass calcd. for C13H10BrClN2O: 323.97, 325.96 (100, 97 rel.%).
MS (EI 70 eV, 130 °C): m/z (%) = 328 (0.6), 326 (2.6) [M+], 324 (2)
[M+], 310 (2.7), 308 (2), 292 (1.6), 290 (1.4), 139 (100)
N-(3-Bromo-5-methylpyridin-2-yl)pivaloylamide (2a): Reaction of
pivaloyl chloride (3.21 mL, 25.7 mmol) with 1a (4.0 g, 21.4 mmol)
and triethylamine (4.61 mL, 32.1 mmol) in THF (20 mL) provided
1
4.80 g (83%) of 2a, m.p. 156 °C. H NMR (CDCl3): δ = 1.36 (s, 9
H, CMe3), 2.31 (s, 3 H, 5-CH3), 7.72 (d, 4J = 1.8 Hz, 1 H, 4-H),
4
7.90 (very br. s, 1 H, NH), 8.25 (d, J = 1.8 Hz, 1 H, 6-H) ppm.
13C{1H} NMR (CDCl3): δ = 17.46 (Me-5), 27.51 (CMe3), 40.02
(CMe3), 112.95 (Cq-3), 131.70 (Cq-5), 141.63 (CH-4), 146.25 (Cq- [ClC6H4CO+]. (impurity by 2eЈ: 13C{1H} NMR (CDCl3): δ = 17.55
4660
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 4655–4665

Phosphonylation of o-Amino N-Heterocyclic Halides
3
(5-Me), 126.48, 129.23, 131.67, 142.76, 148.62 (CH) ppm, Cq sig-
solid 3b, m.p. 109 °C. 1H NMR (CDCl3): δ = 1.35 (t, J = 7.1, Hz,
2
3
3
nals at noise level. MS: m/z = 430, 428 [2cЈ – Cl+]).
6 H, CH3), 2.35 (s, 3 H, 5-Me), 4.11 (m, J = 10.1, J = 7.1, JPH
= 8.1 Hz, 2 HA, OCH2), 4.22 (m, 2J = 10.1, 3J = 7.1, JPH
=
3
(3-Bromo-5-methylpyridin-2-yl)-1-naphthoylamide (2f): Reaction of
1-naphthoyl chloride (3.29 mL, 21.4 mmol) with 1a (4.0 g,
21.4 mmol) and pyridine (24 mL) provided 4.9 g (67%) of 2f, m.p.
128 °C. 1H NMR (CDCl3): δ = 2.04 (s, 3 H, 5-CH3), 7.52–7.64 (m,
3
14.2 Hz, 2 HB, OCH2), 6.54 (dd, J = 3.5, 1.7 Hz, 1 H, 4Ј-H), 7.30
(dd, 3J = 3.6, 4J = 0.6 Hz, 1 H, 3Ј-H), 7.59 (dd, 3J = 1.7, 4J =
3
4
4
0.7 Hz, 1 H, 5Ј-H), 7.78 (ddd, JPH = 14.8, J = 2.5, J = 0.5 Hz,
4
5
1 H, 4-H), 8.54 (d, J = 2.5, J = 1.3 Hz, 1 H, 6-H), 10.98 (br. s, 1
3
4
3 H, naph), 7.91 (dd, J = 7.1, J = 1.1 Hz, 1 H, naph), 7.93–7.98
(m, 1 H, naph), 8.05 (d, 3J = 8.6 Hz, 1 H, naph), 8.07 (d, J = 1 Hz,
1 H, 4-H), 8.33 (d, 4J = 1.1 Hz, 1 H, 6-H), 8.42–8.49 (m, 1 H,
naph) ppm. 13C{1H} NMR (CDCl3): δ = 17.49 (Me-5), 113.89 (Cq-
3), 125.87 (CH), 126.47 (CH), 127.08 (CH), 127.57 (CH), 128.15
(CH), 129.47 (CH), 131.60 (Cq-5), 132.24 (CH), 135.25 (Cq, naph),
144.14 (CH-4), 147.74 (CH-6), 148.95 (Cq-2), 150.82, 170.57,
171.39 (2 Cq and CO) ppm. MS (EI 70 eV, 150 °C): m/z (%) = 342
(7) [M+], 341 (2), 340 (7) [M+], 314 (8), 312 (9), 156 (15), 155 (100),
77 (12). C17H13BrN2O (341.20): calcd. C 59.84, H 3.84, N 8.21;
found C 59.64, H 3.86, N 7.80.
3
H, NH) ppm. 13C{1H} NMR (CDCl3): δ = 16.24 (d, J = 6.6 Hz,
2
1
CH3), 17.78 (5-Me), 63.07 (d, J = 5.4 Hz, OCH2), 110.79 (d, JPC
= 182.4 Hz, Cq-3), 112.26 (CH-4Ј), 115.74 (CH-3Ј), 128.37 (d, J =
3
10.0 Hz, Cq-5), 142.26 (d, 2J = 5.4 Hz, CH-4), 145.06 (CH-5Ј),
148.06 (Cq-2Ј), 151.26 (d, 2J = 9.4 Hz, Cq-2), 153.25 (CH-6), 155.34
(CO) ppm. 31P{1H} NMR (CDCl3): δ = 17.37 ppm. MS (EI 70 eV,
345 °C): m/z (%) = 338 (8) [M+], 311 (15), 310 (100), 284 (18), 282
(18), 254 (30), 236 (21), 95 (69). C15H19N2O5P (338.30): calcd. C
53.26, H 5.66, N 8.28; found C 52.93, H 5.87, N 8.15.
Diethyl [5-Methyl-2-(2-thenoylamino)pyridin-3-yl]phosphonate (3c):
Reaction of 2c (5.0 g, 16.8 mmol) with P(OEt)3 (3.5 mL,
20.18 mmol, 1.2 equiv.) in the presence of Pd(OAc)2 (0.45 g,
2.0 mmol, 8.4 mol-%) and purification by column chromatography
with ethyl acetate/n-hexane (65:35%) gave 2.4 g (40%) of pale yel-
low solid 3c, m.p. 94 °C. Single crystals suitable for crystal structure
determination were grown by slow evaporation of a CHCl3 solution
(crystal data in Table 2, selected bond lengths and angles in Fig-
ure 1). 1H NMR (CDCl3): δ = 1.35 (t, 3J = 7.1, Hz, 6 H, CH3),
General Procedure for Diethyl 2-Acylamido- and 2-Amino-3-pyr-
idinephosphonates 3 and 4: A mixture of solid 1 or 2 and palladium
acetate or chloride was placed into a distillation apparatus and
heated at 170 °C. Then triethyl phosphite was added slowly, and
heating was continued for a total reaction time of 10 min unless
indicated otherwise. The resulting product was purified by column
chromatography on silica gel using ethyl acetate/n-hexane.
Diethyl [5-Methyl-2-(pivaloylamino)pyridin-3-yl]phosphonate (3a):
Reaction of 2a (4.8 g, 17.7 mmol) with P(OEt)3 (3.7 mL,
21.3 mmol, 1.2 equiv.) in the presence of Pd(OAc)2 (0.47 g,
2.09 mmol, 12 mol-%) and purification by column chromatography
with ethyl acetate/n-hexane (85:15%) or by distillation at
10–6 mbar/100–105 °C (bath temperature) gave 2.32 g (40%) of 3a
as pale yellow oil. 1H NMR (CDCl3): δ = 1.34 (s, 9 H, CMe3), 1.34
2
3
3
2.35 (s, 3 H, 5-Me), 4.12 (m, J = 10.1, J = 7.1, JPH = 8.0 Hz, 2
HA, OCH2), 4.21 (m, 2J = 10.1, 3J = 7.1, JPH = 14.8 Hz, 2 HB,
3
3
3
OCH2), 7.12 (dd, J = 5.0, 3.8 Hz, 1 H, 4Ј-H), 7.56 (dd, J = 5.0,
4J = 1.0 Hz, 1 H, 3Ј-H), 7.72 (dd, JPH = 14.7, J = 2.4 Hz, 1 H,
3
4
3
4
4-H), 7.85 (dd, J = 3.8, J = 1.0 Hz, 1 H, 5Ј-H), 8.53 (unresolved
dd, 1 H, 6-H), 11.20 (br. s, 1 H, NH) ppm. 13C{1H} NMR (CDCl3):
δ = 16.26 (d, 3J = 6.5 Hz, CH3), 17.78 (5-Me), 63.11 (d, 2J = 5.6 Hz,
3
2
(t, J = 7.0 Hz, 6 H, CH3), 2.33 (s, 3 H, 5-Me), 4.06 (m, J = 10.1,
1
OCH2), 109.92 (d, JPC = 181.7 Hz, Cq-3), 127.91 (CH-4Ј), 128.08
3J = 7.1, JPH = 8.2 Hz, 2 HA, OCH2), 4.14 (m, 2J = 12.0, 3J =
3
(d, 3J = 10.0 Hz, Cq-5), 128.90 (CH-3Ј), 131.57 (CH-5Ј), 140.35
7.1, JPH = 14.6 Hz, 2 HB, OCH2), 7.73 (dd, JPH = 14.6, 4J =
3
3
2
2
(Cq-2Ј), 141.99 (d, J = 5.1 Hz, CH-4), 151.72 (d, J = 9.8 Hz, Cq-
2), 153.42 (CH-6), 158.93 (CO) ppm. 31P{1H} NMR (CDCl3): δ =
18.09 ppm. MS (EI 70 eV, 345 °C): m/z (%) = 354 (16) [M+], 323
(13), 246 (15), 186 (15), 110 (100), 95 (28). C15H19N2O4PS (354.36):
calcd. C 50.84, H 5.40, N 7.91; found C 50.71, H 5.72, N 7.62.
2.3 Hz, 1 H, 4-H), 8.50 (d, 4J = 2.3, JPH = 1.5 Hz, 1 H, 6-H),
5
10.13 (br. s, 1 H, NH) ppm. 13C{1H} NMR (CDCl3): δ = 16.27 (d,
3J = 6.4 Hz, CH3), 17.73 (s, 5-Me), 27.40 (CMe3), 40.28 (CMe3),
62.93 (d, 2J = 5.6 Hz, OCH2), 110.88 (d, 1J = 182.8 Hz, Cq-3),
128.08 (d, 3J = 10.3 Hz, Cq-5), 142.12 (d, 2J = 5.5 Hz, CH-4),
151.77 (d, 2J = 9.5 Hz, Cq-2), 153.11 (s, CH-6), 176.42 (s, CO) ppm.
31P{1H} NMR (CDCl3): δ = 17.70 ppm. MS (EI 70 eV, 150 °C):
m/z (%) = 328 (8) [M+], 272 (13), 271 (100) [M – CMe3+], 243 (23),
215 (51), 163 (32), 107 (25), 57 (26). C15H25N2O4P (328.34): calcd.
C 54.57, H 7.67, N 8.53; found C 54.31, H 7.74, N 8.41.
Diethyl (2-Benzoylamino-5-methylpyridin-3-yl)phosphonate (3d):
Reaction of 2d (4.5 g, 15.5 mmol) with P(OEt)3 (3.3 mL,
19.0 mmol, 1.2 equiv.) in the presence of Pd(OAc)2 (0.43 g,
1.92 mmol, 12 mol-%) and purification by column chromatography
with ethyl acetate/n-hexane (65:35%) gave 1.7 g (32%) of pale yel-
low solid 3d, m.p. 86 °C. 1H NMR (CDCl3): δ = 1.34 (t, 3J =
7.1 Hz, 6 H, CH3), 2.36 (s, 3 H, 5-Me), 4.10 (m, 2J = 10.1, 3J =
7.1, 3JPH = 8.1 Hz, 2 HA, OCH2), 4.20 (m, 2J = 10.1, 3J = 7.1, 3JPH
= 14.8 Hz, 2 HB, OCH2), 7.46–7.57 (m, 3 H, m- and p-H), 7.75
Screening Test: 2a (1.2 g, 4.4 mmol) was heated with P(OEt)3
(0.95 mL, 5.5 mmol, 1.2 equiv.) in the presence of PdCl2 (80 mg,
10 mol-%). After 10 min at 170 °C the crude yield of 3a was about
1
70% based on H NMR integration of NH and aryl CH-4 signals.
3
4
3
4
The 31P NMR signal intensity ratio (not quantitatively) was
48:25:27% for 3a: (EtO)2PHO/(EtO)3PO for large signals, others
were small. Heating further 10 min at 180 °C led to a drop of the
31P signal of 3a by ca. 50% relative to the signal of (EtO)2PHO in
favor of the signal for (EtO)3PO and to new 31P NMR signals in
the phosphate region (δ = 0.7, 1.5, 3.6 ppm), indicating P–C bond
cleavage. Also the yield by 1H NMR integration became lower. This
trend continued on further heating; after 40 min almost all 3a was
decomposed.
(dd, JPH = 14.6, J = 2.4 Hz, 1 H, 4-H), 8.11 (td, J = 7.7–8.2, J
4
5
= 1.4–1.9 Hz, 2 H, o-H), 8.57 (d, J = 2.4, JPH = 1.4 Hz, 1 H, 6-
H), 11.14 (br. s, 1 H, NH) ppm. 13C{1H} NMR (CDCl3): δ = 16.26
(d, 3J = 6.6 Hz, CH3), 17.81 (5-Me), 62.83 (d, 2J = 5.4 Hz, OCH2),
110.52 (d, JPC = 183.0 Hz, Cq-3), 127.63 (2 CH-o or CH-m),
128.24 (d, J = 10.5 Hz, Cq-5), 128.73 (2 CH-o or CH-m), 131.99
(CH-p), 134.59 (Cq-i), 142.04 (d, J = 5.3 Hz, CH-4), 151.93 (d, J
= 9.2 Hz, Cq-2), 153.38 (CH-6), 164.41 (CO) ppm. 31P{1H} NMR
(CDCl3): δ = 17.89 ppm. MS (EI 70 eV, 345 °C): m/z (%) = 349 (3)
[M + 1+], 348 (27) [M+], 347 (14), 320 (22), 319 (100), 291 (13),
240 (11), 211 (11), 105 (95), 77 (72). C17H21N2O4P (348.33): calcd.
C 58.62, H 6.08, N 8.04; found C 58.68, H 6.28, N 7.87.
1
3
2
2
Diethyl [2-(2-Furoylamino)-5-methylpyridin-3-yl]phosphonate (3b):
Reaction of 2b (5.4 g, 19.2 mmol) with P(OEt)3 (4.0 mL,
23.1 mmol, 1.2 equiv.) in the presence of Pd(OAc)2 (0.43 g,
1.92 mmol, 10 mol-%) and purification by column chromatography
with ethyl acetate/n-hexane (60:40%) gave 2.73 g (42%) of white
Diethyl [2-(2-Chlorobenzoylamino)-5-methylpyridin-3-yl]phosphon-
ate (3e): Reaction of 2e (5.69 g, 17.5 mmol) with P(OEt)3 (3.61 mL,
Eur. J. Org. Chem. 2009, 4655–4665
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4661

M. S. S. Adam, M. K. Kindermann, M. Köckerling, J. W. Heinicke
FULL PAPER
21.0 mmol, 1.2 equiv.) in the presence of Pd(OAc)2 (0.37 g, After 10 min at 170 °C the crude yield of 4a was about 14% based
2.10 mmol, 12 mol-%) and purification by column chromatography
with ethyl acetate/n-hexane (65:35%) gave 2.4 g (36%) of pale yel-
low solid 3e, m.p. 109 °C. 1H NMR (CDCl3): δ = 1.32 (t, 3J =
on 1H NMR integration of NH and aryl CH-4 signals. The 31P
NMR signal intensity ratio (not quantitatively) was 31:42:27% for
4a: (EtO)2PHO/(EtO)3PO for large signals except of unreacted
7.1 Hz, 6 H, CH3), 2.36 (s, 3 H, 5-Me), 4.11 (m, 2J = 10.1, 3J = P(OEt)3, and other small signals. Heating for further 10 min at
7.0, 3JPH = 8.2 Hz, 2 HA, OCH2), 4.20 (m, 2J = 10.1, 3J = 7.1, 3JPH 180 °C led to a drop of the 31P signal of 4a relative to those of
= 14.3 Hz, 2 HB, OCH2), 7.31–7.46 (m, 3 H, 3Ј-, 4Ј- and 5Ј-H), (EtO)2PHO and (EtO)3PO (rel. intensity 12:37:31%), and to
7.66 (dd, 3J = 6.7, J = 2.6, J = 1.4 Hz, 1 H, 6Ј-H), 7.78 (dd, 3JPH
= 14.7, 4J = 2.6 Hz, 1 H, 4-H), 8.52 (unresolved dd, 1 H, 6-H),
10.55 (br. s, 1 H, NH) ppm. 13C{1H} NMR (CDCl3): δ = 16.24 (d,
3J = 6.5 Hz, CH3), 17.79 (5-Me), 63.04 (d, 2J = 5.4 Hz, OCH2),
stronger signals for EtP(O)(OEt)2 and an unknown with δ =
3.2 ppm (5 and 15% rel. intensity). Proton signal integration gave
similar yield as after 10 min whereas longer heating led to a de-
crease.
4
4
1
3
111.02 (d, JPC = 182.6 Hz, Cq-3), 127.06 (CH-5Ј), 128.77 (d, J =
10.0 Hz, Cq-5), 129.19 (CH-6Ј), 130.38 (CH-3Ј), 131.03 (Cq-2Ј),
131.99 (CH-4Ј), 136.11 (Cq-i), 142.25 (d, 2J = 5.4 Hz, CH-4), 151.15
Diethyl
{2-[(Furan-2-ylmethyl)amino]-5-methylpyridin-3-yl}phos-
phonate (4b): Triethyl phosphite (0.31 mL, 1.80 mmol) was added
to a mixture of solid 1b (0.40 g, 1.50 mmol) and palladium acetate
(34 mg, 0.15 mmol, 10 mol-%) at 180 °C in a distillation apparatus,
and heating was continued for 15–20 min. The product was purified
by column chromatography on silica gel using ethyl acetate/n-hex-
ane (30:70%) yielding 0.22 g (45%) of yellow oil. 1H NMR
2
4
(d, J = 9.4 Hz, Cq-2), 153.19 (d, J = 0.9 Hz, CH-6), 164.57 (CO)
ppm. 31P{1H} NMR (CDCl3): δ = 16.57 ppm. MS (EI 70 eV,
140 °C): m/z (%) = 383 (2.4), 354 (18), 349 (21), 348 (100) [M+],
319 (23), 292 (23), 139 (41), 111 (29). HRMS (ESI): m/z calcd. for
C17H20ClN2O4P 382.09, [M + H+]: 383.09217; found 383.09220.
3
(CDCl3): δ = 1.24 (t, J = 7.1, Hz, 6 H, CH3), 2.12 (s, 3 H, 5-Me),
Diethyl
[5-Methyl-2-(1-naphthoylamino)pyridin-3-yl]phosphonate
3
4.00 (m, 4 H, OCH2), 4.59 (d, J = 5.5 Hz, 2 H, NCH2), 6.15 (d,
(3f): Reaction of 2f (5.0 g, 14.65 mmol) with P(OEt)3 (3.15 mL,
18.2 mmol, 1.2 equiv.) in the presence of Pd(OAc)2 (0.39 g,
1.74 mmol, 8.4 mol-%) and purification by column chromatog-
raphy with ethyl acetate/n-hexane (55:45%) gave 1.2 g (21%) of
3
3
3J = 2.7 Hz, 1 H, 3Ј-H), 6.23 (dd, J = 3.2, J = 1.8 Hz, 1 H, 4Ј-
3
4
H), 6.92 (br. s, NH), 7.27 (dd, J = 1.8, J = 0.8 Hz, 1 H, 5Ј-H),
7.49 (dd, JPH = 15.4, 4J = 2.3 Hz, 1 H, 4-H), 8.05 (t, 4J = 2.2,
3
5JPH = 2.0 Hz, 1 H, 6-H) ppm. 31P{1H} NMR (CDCl3): δ =
19.02 ppm. MS (EI 70 eV, 100 °C): m/z (%) = 325 (100) [M+].
HRMS (EI): m/z calcd. for C15H21N2O4P 324.13, [M + H+]:
325.13117; found 325.13123.
1
pale yellow solid 3f, m.p. 110 °C. H NMR (CDCl3): δ = 1.30 (t,
2
3
3J = 7.1 Hz, 6 H, CH3), 2.38 (s, 3 H, 5-Me), 4.10 (m, J = 10.1, J
3
2
3
= 7.1, JPH = 8.1 Hz, 2 HA, OCH2), 4.18 (m, J = 10.1, J = 7.2,
3JPH = 15.1 Hz, 2 HB, OCH2), 7.49–7.60 (m, 3 H, aryl-H), 7.81
3
4
Diethyl (2-Ethylamino-5-methylpyridin-3-yl)phosphonate (4c): Reac-
tion of 1c (4.81 g, 22.4 mmol) with triethyl phosphite (5.39 mL,
26.8 mmol, 1.2 equiv.) in the presence of PdCl2 (0.40 g, 2.24 mmol,
10 mol-%) and purification by column chromatography with ethyl
acetate/n-hexane (10:90%) gave 2.68 g (44%) of 4c as pale yellow
(dd, JPH = 14.7, J = 2.0 Hz, 1 H, 4-H), 7.86–8.01 (m, 3 H, aryl-
H), 8.61 (unresolved dd, 1 H, 6-H), 8.64 (dd, 3J = 7.4, 4J = 1.8 Hz,
1 H, 8Ј-H), 10.66 (br. s, 1 H, NH) ppm. 13C{1H} NMR (CDCl3):
δ = 16.19 (d, 3J = 6.6 Hz, CH3), 17.79 (s, 5-Me), 63.00 (d, 2J =
1
5.4 Hz, OCH2), 111.20 (d, JPC = 182.7 Hz, Cq-3), 124.77 (CH),
1
3
oil. H NMR (CDCl3): δ = 1.24 (t, J = 7.2 Hz, 3 H, CH3), 1.34
125.40 (CH), 125.81 (CH), 126.38 (CH), 127.12 (CH), 128.25 (CH),
128.62 (d, 3J = 10.6 Hz, Cq-5), 130.52 (Cq), 131.41 (CH), 133.84
(Cq), 133.91 (Cq), 142.30 (d, 2J = 5.4 Hz, CH-4), 151.57 (d, 2J =
9.6 Hz, Cq-2), 153.26 (CH-6), 166.68 (CO) ppm. 31P{1H} NMR
(CDCl3): δ = 17.27 ppm. MS (EI 70 eV, 345 °C): m/z (%) = 398
(18) [M+], 370 (14), 369 (42), 171 (61), 155 (84), 148 (71), 127 (100),
91 (80), 84 (43), 72 (51), 57 (84). HRMS (ESI): m/z calcd. for
C21H23N2O4P 398.14, [M + H+]: 399.14681; found 399.14682.
3
3
(t, J = 7.1 Hz, 6 H, CH3), 2.17 (s, 3 H, 5-Me), 3.44 (qd, J = 7.2,
2
3
3
5.3 Hz, 2 H, CH2), 4.05 (m, J = 10.1, JPH = 8.0, J = 7.1 Hz, 2
HA, OCH2), 4.14 (m, JPH = 14.6, 2J = 10.1, 3J = 7.1 Hz, 2 HB,
3
3
4
OCH2), 6.65 (br. s, 1 H, NH), 7.51 (dd, JPH = 15.6, J = 2.3 Hz,
1 H, 4-H), 8.09 (br. d, J = 2.0 Hz, 1 H, 6-H) ppm. 13C{H} NMR
4
3
(CDCl3): δ = 14.67 (s, CH3), 16.10 (d, J = 6.5 Hz, CH3), 16.99 (s,
2
5-Me), 35.93 (s, NCH2), 62.05 (d, J = 5.1 Hz, OCH2), 102.92 (d,
1JPC = 184.9 Hz, Cq-3), 119.43 (d, J = 11.0 Hz, Cq-5), 142.65 (d,
3
Diethyl (2-Amino-5-methylpyridin-3-yl)phosphonate (4a): Reaction
of 1a (5.0 g, 26.7 mmol) with P(OEt)3 (5.5 mL, 31.7 mmol) in the
presence of Pd(OAc)2 (0.60 g, 2.67 mmol, 10 mol-%) and distil-
lation at 10–6 mbar/120–123 °C (bath temperature) provided the
product contaminated by 4c in 80:20 mol-% ratio (based on 1H
NMR integration). Column chromatography with ethyl acetate/n-
hexane (75:25%) gave 1.2 g (19%) of pure white solid 4a, m.p. 69–
71 °C. 1H NMR (CDCl3): δ = 1.34 (t, 3J = 7.0 Hz, 6 H, CH3), 2.20
2J = 6.3 Hz, CH-4), 152.74 (d, J = 1.0 Hz, CH-6), 157.72 (d, 2J =
4
11.1 Hz, Cq-2) ppm. 31P{H} NMR (CDCl3): δ = 20.43 ppm. MS
(EI 70 eV, 25 °C): m/z (%) = 274 (10), 273 (64) [M+], 259 (14), 258
(100), 229 (41), 202 (46), 183 (38), 93 (27). HRMS (ESI): m/z calcd.
for C12H21N2O3P: 272.13, [M + H]+: 273.13625; found 273.13625.
Diethyl [5-Methyl-2-(phenylamino)pyridin-3-yl]phosphonate (4d):
Reaction of 1d (8.60 g, 32.7 mmol) with P(OEt)3 (6.80 mL,
39.2 mmol) in the presence of Pd(OAc)2 (0.88 g, 3.92 mmol,
8.3 mol-%) and purification by column chromatography with ethyl
acetate/n-hexane (10:90%) gave 6.3 g (60%) of white solid 4d, m.p.
5
2
3
3
(d, J = 0.5 Hz, 3 H, 5-Me), 4.05 (m, J = 10.1, J = 7.1, JPH
=
8.1 Hz, 2 HA, OCH2), 4.16 (m, 2J = 10.2, 3J = 7.1, 3JPH = 14.4 Hz,
2 HB, OCH2), 5.65 (br. s, 2 H, NH), 7.57 (dd, JPH = 15.1, 4J =
3
2.3 Hz, 1 H, 4-H), 8.04 (dd, 4J = 2.3, JPH = 1.9 Hz, 1 H, 6-H)
5
1
3
4
60 °C. H NMR (CDCl3): δ = 1.35 (td, J = 7.1, JPH = 0.5 Hz, 6
ppm. 13C{1H} NMR (CDCl3): δ = 16.21 (d, 3J = 6.4 Hz, CH3),
5
2
H, CH3), 2.23 (d, JPH = 0.5 Hz, 3 H, 5-Me), 4.08 (m, J = 10.2,
17.16 (5-Me), 62.23 (d, 2J = 5.2 Hz, OCH2), 103.37 (d, JPC
=
1
3J = 7.0, JPH = 8.2 Hz, 2 HA, OCH2), 4.19 (m, 2J = 10.1, 3J =
3
185.8 Hz, Cq-3), 121.74 (d, 3J = 10.6 Hz, Cq-5), 142.77 (d, 2J =
6.3 Hz, CH-4), 153.09 (CH-6), 158.29 (d, 2J = 10.5 Hz, Cq-2) ppm.
31P{1H} NMR (CDCl3): δ = 19.70 ppm. MS (EI 70 eV, 100 °C):
m/z (%) = 245 (7), 244 (68) [M+], 216 (12), 188 (18), 171 (22), 135
(19), 107 (100), 80 (14), 53 (16). C10H17N2O3P (244.23): calcd. C
49.18, H 7.02, N 11.47; found C 49.50, H 6.90, N 11.40.
3
3
4
7.1, JPH = 14.2 Hz, 2 HB, OCH2), 6.98 (tt, J = 7.4, J = 1.1 Hz,
3
3
1 H, p-H), 7.30 (tm, J = 8.5, 7.4 Hz, 2 H, m-H), 7.62 (dd, JPH
=
15.5, 4J = 2.3 Hz, 1 H, 4-H), 7.62–7.67 (superimposed dd, 3J = 8.5,
4J = 1.1 Hz, 2 H, o-H), 8.20 (d, J = 2.2, JPH = 2 Hz, 1 H, 6-H),
9.20 (br. s, 1 H, NH) ppm. 13C{1H} NMR (CDCl3): δ = 16.19 (d,
3J = 6.6 Hz, CH3), 17.28 (5-Me), 62.49 (d, 2J = 5.1 Hz, OCH2),
4
5
1
Screening Test: 1a (1.0 g, 5.3 mmol) was heated with P(OEt)3
(1.1 mL, 1.2 equiv.) in the presence of PdCl2 (94 mg, 10 mol-%).
105.17 (d, JPC = 182.7 Hz, Cq-3), 119.65 (2 CH-o), 121.87 (CH-
p), 122.40 (d, J = 10.5 Hz, Cq-5), 128.66 (2 CH-m), 140.35 (Cq-i),
3
4662
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 4655–4665

Phosphonylation of o-Amino N-Heterocyclic Halides
142.64 (d, 2J = 6.4 Hz, CH-4), 152.32 (CH-6), 155.21 (d, 2J = (td, J = 8.3, 6.8, J = 1.4 Hz, 1 H, 7-H), 7.69 (dd br, J = 8.3, J
3
4
3
4
5
3
4
5
9.7 Hz, Cq-2) ppm. 31P{1H} NMR (CDCl3): δ = 19.70 ppm. IR
= 1.5, J = 0.5 Hz, 1 H, 8-H), 7.86 (ddd, J = 8.2, J = 1.3, J =
(KBr): ν = 3429–3308 (very br.) (H O, NH), 1240 (very strong, 0.5 Hz, 1 H, 5-H) ppm. 13C{1H} NMR (CDCl3): δ = 125.41 (CH-
˜
2
P=O) cm–1. MS (EI 70 eV, 270 °C): m/z (%) = 321 (10), 320 (100) 6), 126.06 (CH-8), 128.10 (CH-5), 130.63 (CH-7), 137.05, 137.33
[M+], 319 (84), 291 (18), 263 (19), 245 (68), 183 (26), 131 (10), 77 (Cq-4a, Cq-3), 140.31 (Cq-8a), 148.71 (Cq-2) ppm. MS (EI 70 eV,
(28). C16H21N2O3P (320.32): calcd. C 59.99, H 6.61, N 8.75; found
C 60.13, H 6.80, N 8.61.
165 °C): m/z (%) = 181 (30) [M+(37Cl)], 179 (100) [M+(35Cl)], 144
(84), 117 (23), 102 (8), 90 (26), 44 (81).
N-(3-Bromoquinoxalin-2-yl)-tert-butylamine (5b): 1H NMR
(CDCl3): δ = 1.57 (s, 9 H, CMe3), 5.49 (br. s, 1 H, NH), 7.36 (td,
Diethyl [2-(Pyridin-2-ylamino)pyridin-3-yl]phosphonate (4e): Reac-
tion of 1e (0.61 g, 2.44 mmol) with triethyl phosphite (0.43 mL,
2.48 mmol) in the presence of Pd(OAc)2 (55 mg, 0.245 mmol,
10 mol-%) and purification by column chromatography with ethyl
acetate/n-hexane (25:75%) gave 0.27 g (36%) 4e as pale yellow oil.
4
3
4
3J = 8.3, 7.0, J = 1.5 Hz, 1 H, 6-H), 7.55 (td, J = 8.4, 7.0, J =
3
4
5
1.5 Hz, 1 H, 7-H), 7.70 (ddd, J = 8.3, J = 1.3, J = 0.3 Hz, 1 H,
8-H), 7.76 (ddd, J = 8.4, 4J = 1.3, J = 0.3 Hz, 1 H, 5-H) ppm.
13C{1H} NMR (CDCl3): δ = 29.0 (CMe3), 52.9 (CMe3), 125.7 (CH-
6), 127.2 (CH-8), 129.0 (CH-5), 130.7 (CH-7), 137.4, 139.1 (Cq-4a,
Cq-3), 142.2 (Cq-8a), 148.3 (Cq-2) ppm.
3
5
3
1H NMR (CDCl3): δ = 1.28 (t, J = 7.1 Hz, 6 H, CH3), 4.06 (m,
3
3
3
2J = 10.1, JPH = 8.5, J = 7.1 Hz, 2 HA, OCH2), 4.16 (m, JPH
=
14.3, 2J = 10.2, 3J = 7.1 Hz, 2 HB, OCH2), 6.79 (ddd, 3J = 7.5, 4.9,
4JPH = 2.2 Hz, 1 H, 5-H), 6.83 (ddd, J = 7.2, 4.9, J = 1.0 Hz, 1
3
4
Diethyl (3-Aminoquinoxalin-2-yl)phosphonate (7a): Triethyl phos-
phite (1.86 mL, 10.7 mmol) was added to a mixture of solid 5a
(1.3 g, 7.24 mmol) and Pd(OAc)2 (90 mg, 0.40 mmol, 5.5 mol-%).
The reaction mixture was refluxed for almost 2.5 h at 180 °C. The
resulting crude product was distilled at 160 °C (bath)/10–6 mbar to
H, 5Ј-H), 7.58 (ddd, 3J = 8.6, 7.2, 4J = 1.9 Hz, 1 H, 4Ј-H), 7.85
3
3
4
3
(ddd, JPH = 15.2, J = 7.5, J = 2.0 Hz, 1 H, 4-H), 8.24 (ddd, J
= 4.9, 4J = 1.9, JPH = 0.7 Hz, 1 H, 6Ј-H), 8.32 (br. d, 3J = 8.6 Hz,
5
4J ≈ 5J, small, 1 H, 3Ј-H), 8.35 (dt, 3J = 4.9, 4J = 2.0, 5JPH ≈ 2.5 Hz,
1 H, 6-H), 9.71 (br. s, 1 H, NH) ppm. 13C{1H} NMR (CDCl3): δ
= 16.26 (d, 3J = 6.3 Hz, CH3), 62.73 (d, 2J = 5.2 Hz, OCH2), 107.46
(d, 1JPC = 183.1 Hz, Cq-3), 113.14 (CH-3Ј), 114.69 (d, 3J = 10.5 Hz,
CH-5), 117.51 (CH-5Ј), 137.58 (CH-4Ј), 142.82 (d, 2J = 5.9 Hz,
CH-4), 148.22 (CH-6Ј), 151.98 (CH-6), 153.21 (Cq-2Ј), 155.62 (d,
2J = 9.6 Hz, Cq-2) ppm. 31P{1H} NMR (CDCl3): δ = 18.12 ppm.
MS (EI 70 eV, 345 °C): m/z (%) = 308 (0.6), 307 (8) [M+], 234 (10),
199 (13), 171 (100), 78 (10). HRMS (ESI): m/z calcd. for
C14H18N3O3P: 307.10, [M + H]+: 308.11600; found 308.11585.
1
give 1.81 g (89%) yellow solid 7a, m.p. 57 °C. H NMR (CDCl3):
δ = 1.39 (dd, 3J = 6.9, 4J = 0.6 Hz, 6 H, CH3), 4.28 (m, 4 H,
3
4
OCH2), 6.54 (br. s, 2 H, NH), 7.43 (td, J = 8.3, 6.0, J = 2.4 Hz,
3
4
1 H, 7-H), 7.61–7.70 (m, 2 H, 5-H, 6-H), 7.97 (dp, J = 8.2, J =
1.4, J ≈ JPH = 0.7 Hz, 1 H, 8-H) ppm. 13C{H} NMR (CDCl3): δ
= 16.20 (d, 3J = 6.3 Hz, CH3), 63.91 (d, 2J = 6.0 Hz, OCH2), 125.18
(s, CH-7), 125.73 (d, 5J = 2.5 Hz, CH-5), 129.83 (d, 4J = 1.2 Hz,
CH-8), 132.48 (s, CH-6), 136.59 (d, 1J = 218.1 Hz, Cq-2), 137.33
5
5
3
4
(d, J = 19.8 Hz, Cq-8a), 142.46 (d, J = 2.3 Hz, Cq-4a), 153.59 (d,
Diethyl [2-(Quinolin-3-ylamino)pyridin-3-yl]phosphonate (4f): Reac-
tion of 1f (5.50 g, 18.3 mmol) with triethyl phosphite (3.79 mL,
21.9 mmol) in the presence of Pd(OAc)2 (0.49 g, 2.18 mmol,
8.4 mol-%) and purification by column chromatography with ethyl
acetate/n-hexane (30:70%) gave 1.38 g (21%) yellow solid 4f, m.p.
94 °C. 1H NMR (CDCl3): δ = 1.30 (t, 3J = 7.1 Hz, 6 H, CH3), 4.04
(m, 2J = 10.1, 3JPH = 8.1, 3J = 7.1 Hz, 2 HA, OCH2), 4.12 (m, 3JPH
2J = 28.2 Hz, Cq-3) ppm. 31P{H} NMR (CDCl3): δ = 9.37 ppm.
IR (KBr): ν = 1231 (P=O), 1030 (C–O) cm–1. MS (EI 70 eV,
˜
300 °C): m/z (%) = 282 (5) [M+], 281 (55), 280 (1), 237 (21), 208
(33), 145 (90). C12H16N3O3P (281.25): calcd. C 51.25, H 5.73, N
14.94; found C 51.12, H 5.90, N 14.45.
Diethyl [3-(tert-Butylamino)quinoxalin-2-yl]phosphonate (7b): Tri-
ethyl phosphite (1.86 mL, 10.7 mmol) was added to a mixture of
solid 5b (1.30 g, 5.52 mmol) and palladium acetate (90 mg,
0.4 mmol, 7.2 mol-%). The reaction mixture was refluxed for al-
most 1 h at 160 °C (bath). Then the resulting crude product was
distilled at 65–75 °C/10–6 mbar to give 1.40 g (75%) yellow oily 7b.
1H (with and without coupling to 31P) and CH-COSY NMR
2
3
3
= 14.2, J = 10.2, J = 7.1 Hz, 2 HB, OCH2), 6.78 (ddd, J = 7.5,
4
3
4
4.9, JPH = 2.2 Hz, 1 H, 5-H), 7.42 (td, J = 7.8, 7.1, J = 1.3 Hz,
1 H, 6Ј-H), 7.48 (td, 3J = 8.3, 7.1, 4J = 1.5 Hz, 1 H, 7Ј-H), 7.72
3
4
3
3
(dd, J = 7.8, J = 1.4 Hz, 1 H, 5Ј-H), 7.76 (ddd, JPH = 15.2, J
= 7.5, 4J = 2.0 Hz, 1 H, 4-H), 7.96 (d, 3J = 8.3 Hz, 1 H, 8Ј-H),
8.38 (dt, J = 4.9, J = 2.0, JPH = 2.4 Hz, 1 H, 6-H), 8.78 (d, J
3
4
5
4
3
4
4
(CDCl3): δ = 1.37 (dd, J = 7.1, JPH = 0.4 Hz, 6 H, CH3), 1.56 (s,
= 2.5 Hz, 1 H, 4Ј-H), 8.88 (d, J = 2.6 Hz, 1 H, 2Ј-H), 9.85 (br. s,
9 H, CMe3), 4.23 (m, 2J = 10.1, JPH = 8.0, 3J = 7.0 Hz, 2 H,
3
1 H, NH) ppm. 13C{1H} NMR (CDCl3): δ = 16.28 (d, 3J = 6.5 Hz,
2
3
3
2
1
OCHA), 4.30 (m, J = 10.1, JPH = 7.9, J = 7.1 Hz, 2 H, OCHB),
CH3), 62.83 (d, J = 5.4 Hz, OCH2), 106.36 (d, JPC = 183.3 Hz,
Cq-3), 114.48 (d, 3J = 10.3 Hz, CH-5), 121.81 (CH-4Ј), 126.74 (CH-
5Ј), 127.00 (CH-7Ј), 127.34 (CH-6Ј), 128.64 (Cq-4aЈ), 128.87 (CH-
8Ј), 133.85 (Cq-3aЈ), 142.31 (d, 2J = 5.4 Hz, CH-4), 144.09 (Cq-8aЈ),
145.79 (CH-2Ј), 152.35 (CH-6), 156.85 (d, 2J = 10.6 Hz, Cq-2) ppm.
31P{1H} NMR (CDCl3): δ = 19.02 ppm. MS (EI 70 eV, 345 °C):
m/z (%) = 359 (23), 358 (100) [M + 1+], 357 (95) [M+], 329 (38),
300 (42), 282 (81), 221 (20), 220 (55), 219 (24), 149 (20). HRMS
(ESI): m/z calcd. for C18H20N3O3P 357.13, [M + H]: 358.13146;
found 358.13150.
3
4
3
7.31 (td, J = 8.3, 6.7, J = 1.6 Hz, 1 H, 7-H), 7.57 (tdd, J = 8.2,
6.7, 4J = 1.4, JPH = 0.4 Hz, 1 H, 6-H), 7.64 (ddd, J = 8.4, J =
3
4
5
3
1.6, J = 0.6 Hz, 1 H, 5-H), 7.74 (br. s, 1 H, NH), 7.86 (dp, J =
8.3, 4J = 1.4, 5J = 0.6, JPH = 0.7 Hz, 1 H, 8-H) ppm. 13C{H}
5
3
NMR and CH COSY NMR (CDCl3): δ = 16.21 (d, J = 6.3 Hz,
CH3), 28.47 (s, CMe3), 51.79 (s, CMe3), 63.83 (d, 2J = 6.2 Hz,
OCH2), 123.97 (s, CH-7), 126.57 (d, 5J = 2.6 Hz, CH-5), 129.61 (d,
4J = 1.4 Hz, CH-8), 131.74 (s, CH-6), 135.80 (d, J = 19.8 Hz, Cq-
3
8a), 137.61 (d, 1J = 213.6 Hz, Cq-2), 142.74 (d, 4J = 2.3 Hz, Cq-
4a), 152.87 (d, J = 27.6 Hz, Cq-3) ppm. 31P{H} NMR (CDCl3): δ
2
Quinoxaline Derivatives 5–7: 2,3-Dichloroquinoxaline,[32] 3-chloro-
quinoxalin-2-amine (5a)[19] and N-(3-bromoquinoxalin-2-yl)-tert-
butylamine (5b)[20] were synthesized according to known pro-
cedures, 5a slightly modified, using a reaction temperature of 80 °C
instead of 140 °C, yield 67%, m.p. 137–139 °C. NMR spectroscopic
data of 5a (not given in ref.[19]) and corrected NMR spectroscopic
data of 5b are presented.
= 9.82 ppm. IR (KBr): ν = 1230 (m, P=O), 1052 cm–1. MS (EI
˜
70 eV, 65 °C): m/z (%) = 338 (1) [M+], 337 (20), 323 (15), 322 (100),
294 (8), 248 (17), 184 (87), 145 (41). C16H24N3O3P (337.35): calcd.
C 56.96, H 7.17, N 12.46; found C 56.82, H 7.26, N 12.84.
Diethyl Quinoxaline-2,3-diphosphonate (6): Under argon, sodium
pellets (1.0 g, 43.5 mmol) were added with stirring to a solution of
diethyl phosphite (6.03 mL, 46.8 mmol) in dry diethyl ether
(50 mL) at room temperature. Hydrogen slowly evolved. After the
1
3-Chloroquinoxalin-2-amine (5a): H NMR (CDCl3): δ = 5.53 (br.
3
4
s, 2 H, NH2), 7.47 (td, J = 8.3, 6.8, J = 1.7 Hz, 1 H, 6-H), 7.63
Eur. J. Org. Chem. 2009, 4655–4665
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4663

M. S. S. Adam, M. K. Kindermann, M. Köckerling, J. W. Heinicke
FULL PAPER
Table 2. Crystal and structure refinement data of 1a and 3c.
1a
3c
Empirical formula
Formula weight
Temperature
C6H7BrN2
187.05
293(2) K
0.71073 Å
C15H19N2O4PS
354.35
293(2) K
Wavelength
0.71073 Å
Crystal system
Space group
Unit cell dimensions
monoclinic
P21/n
monoclinic
P21/n
a = 6.199(3) Å
b = 10.582(4) Å
c = 11.218(4) Å
β = 102.68(2)°
717.9(5) Å3
4
a = 10.7353(2) Å
b = 9.6415(2) Å
c = 16.7093(4) Å
β = 92.084(1)°
1728.34(6) Å3
4
Volume
Z
Density (calculated)
Absorption coefficient
F(000)
1.731 g/cm3
5.634 mm–1
368
1.362 g/cm3
0.300 mm–1
744
Crystal size
θ range data collection
Index ranges
0.58ϫ0.32ϫ0.32 mm
3.47–36.07°
–9 Յ h Յ 10,
–17 Յ k Յ 17
–18 Յ l Յ 18
17363
0.43ϫ0.35ϫ0.32 mm
2.22–36.33°
–15 Յ h Յ 17
–14 Յ k Յ 16
–20 Յ l Յ 27
27227
Reflections collected
Independent reflections
Absorption correction
Refinement method
Data/restraints/parameters
Goodness-of-fit on F[a]
Final R indices, [IϾ2σ(I)][a]
Extinction coefficient
3378 [R(int) = 0.0304]
multiscan (SADABS)
8355 [R(int) = 0.0245]
multiscan (SADABS)
full-matrix least-squares on F2
full-matrix least-squares on F2
8355/0/228
3378/0/82
1.005
R1 = 0.0341, wR2 = 0.0808
1.105
R1 = 0.0622, wR2 = 0.1943
0.009(3)
–
Largest diff. peak and hole
0.410 and –0.491 eÅ–3
0.661 and –0.530 eÅ–3
[a] R1 = Σ||Fo| – |Fc||/Σ|Fo|.
sodium was fully consumed (several hours) a solution of 2,3-dichlo-
roquinoxaline (2.2 g, 11.05 mmol) in diethyl ether (50 mL) was
added slowly (over 1 h), and then the mixture was stirred for 2 d
at room temperature. The white precipitate was removed by fil-
tration, and then the solvent was evaporated in vacuo. The crude
product was washed with water, extracted with chloroform and the
extract dried by MgSO4. The solvent was removed in vacuo and
the residue heated under high vacuum at 180 °C (bath) for almost
1 h to remove the excess amount of HP(O)(OEt)2 yielding 3.20 g
(73%) of spectroscopically pure 6, m.p. 67–70 °C. 1H NMR
were done using Bruker–Nonius Software.[33] The structure was
solved via Direct Methods and refined by full-matrix least-square
methods on F2 using the SHELX-97 program package.[34] All
atoms (except hydrogen) were treated anisotropically. Crystal data,
data collection and refinement parameters are given in Table 2. One
ethyl group of 3c is disordered on two locations (solid and open
lines in Figure 1) with little change in the bond lengths [O3–C14A
1.45(5) and O3–C14B 1.43(1) Å]. The C14A–C15A part is occupied
by 78% and the C14B, C15B part by the remaining 22%.
For selected bond lengths and angles of 1a and 3c see Figures 1
and 2.
3
(CDCl3): δ = 1.46 (d, J = 7.1 Hz, 12 H, CH3), 4.37–4.50 (m, 8 H,
OCH2), 7.92 (mAAЈBBЈ, 2 H, 6- and 7-H), 8.22 (mAAЈBBЈ, 2 H, 5-
and 8-H) ppm. 13C{H} NMR (CDCl3): δ = 16.33 (τ, |3J + 6J| =
5.9 Hz, CH3), 63.95 (τ,|2J ≈ 5J| = 5 Hz, OCH2), 129.85 (s, CH-6,
CH-7), 132.39 (s, CH-5, CH-8), 140.70 (τABX, 5 lines, |3J + 4J| =
CCDC-706484 (for 1a) and -706483 (for 3c) contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge from the Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
1
2
17.0 Hz, Cq-4a and –8a), 150.00 (dd, J = 226.3, J = 29.8 Hz, Cq-
2, Cq-3) ppm. 31P{H} NMR (CDCl3): δ = 7.38 ppm; small impurity
by an unknown compound containing three P atoms: δ = 1.86,
4.07, 17.32 (A, B, C); JPP(AB) = 1.6–1.9, JPP(AC) = 16.2, JPP(BC)
Supporting Information (see also the footnote on the first page of
this article): 1H and/or 13C NMR spectra of the compounds 2e, 3e,
3f, 4b, 4c, 4e, and 4f (Figures S1–S9).
= 13.6 Hz. IR (KBr): ν = (PO) = 1263 cm–1. MS (EI 70 eV, 250 °C):
˜
m/z (%) = 403 (3) [M+], 402 (14), 358 (5), 266 (31), 222 (26), 193
(41), 130 (100), 102 (42). C16H24N2O6P2 (402.32): calcd. C 47.77,
H 6.01, N 6.96; found C 47.51, H 6.37, N 6.83.
Acknowledgments
Crystal Structure Analysis: Crystals were glued on the tip of thin
glass fibers. X-ray intensity data were collected at room tempera-
ture using a Bruker–Nonius Apex X8-diffractometer equipped with
a CCD-detector. Graphite monochromated Mo-Kα radiation (λ =
0.71073 Å) was employed. First unit cell dimensions were obtained
from the reflections, which were taken from a total of 36 frames,
measured in three different crystal directions. Data collection and
reduction including corrections for Lorentz and polarization effects
Financial support from the Deutsche Forschungsgemeinschaft
(DFG) and a fellowship (to M. S. S. A.) from the Deutsche Akade-
mische Auslandsdienst (DAAD) is gratefully acknowledged. We
thank B. Niaz for detecting the formation of [Pd0{P(OEt)3}4], B.
Witt and W. Heiden for measuring numerous NMR and mass spec-
tra, Dr. H. Frauendorf and G. Sommer-Udvarnoki (Georg-August-
Universität Göttingen, Institut für Organische und Biomolekulare
Chemie) for HRMS measurements.
4664
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 4655–4665

Phosphonylation of o-Amino N-Heterocyclic Halides
[15] a) R. K. Bansal, N. Gupta, J. Heinicke, G. N. Nikonov, F. Sag-
uitova, D. C. Sharma, Synthesis 1999, 264–269; b) J. Heinicke,
N. Gupta, A. Surana, N. Peulecke, B. Witt, K. Steinhauser,
R. K. Bansal, P. G. Jones, Tetrahedron 2001, 57, 9963–9972.
[16] a) B. R. Aluri, Ph. D. Thesis, Greifswald, 2008; b) B. R. Aluri,
M. K. Kindermann, P. G. Jones, I. Dix, J. Heinicke, Inorg.
Chem. 2008, 47, 6900–6912.
[17] M. S. S. Adam, Ph. D. Thesis, Greifswald, 2008.
[18] M. S. S. Adam, O. Kühl, M. K. Kindermann, J. Heinicke, P. G.
Jones, Tetrahedron 2008, 64, 7960–7967.
[19] W. Deuschel, G. Riedel (Badische Anilin- & Soda-Fabrik A.-
G.), 1962, DE 1135471 (30. Aug. 1962, appl. 19. June 1960).
[20] O. Kühl, P. Lönnecke, J. Heinicke, New J. Chem. 2002, 29, 771–
777.
[1]
[2]
[3]
a) P. Savignac, B. Iorga, Modern Phosphonate Chemistry, CRC
Press, 2003; b) Aminophosphonic and Aminophosphinic Acids
(Eds.: V. P. Kuhkar, H. R. Hudson), Wiley, Chichester, 2000.
a) S. Van der Jeught, C. V. Stevens, Chem. Rev. 2009, 109,
2672–2702; b) K. Moonen, I. Laureyn, C. V. Stevens, Chem.
Rev. 2004, 104, 6177–6216.
a) D. E. C. Corbridge, Phosphorus 2000: Chemistry, Biochemis-
try and Technology, Elsevier, Amsterdam, 2000, chapter 6, pp.
297–454; b) K. H. Worms, M. Schmidt-Dunker, Organic Phos-
phorus Compounds (Eds.: G. M. Kosolapoff, L. Maier), Wiley,
New York, 1976; c) K. Sasse, Methoden der organischen Chemie
(Ed.: E. Müller), Thieme, Stuttgart, 1963.
[4]
[5]
[21] M. C. Kohler, R. A. Stockland Jr., N. P. Rath, Organometallics
2006, 25, 5746–5756.
[22] M. Kaleck, J. Stawinski, Organometallics 2007, 26, 5840–5847.
[23] T. M. Balthazor, R. C. Grabiak, J. Org. Chem. 1980, 45, 5425–
5426.
[24] a) C. Amatore, A. Jutand, A. Thuilliez, Organometallics 2001,
20, 3241–3249; b) C. Amatore, E. Carre, A. Jutand, M. A.
M’Barki, Organometallics 1995, 14, 1818–1826.
[25] a) M. Meier, F. Basolo, R. G. Pearson, Inorg. Chem. 1969, 8,
795–801; b) M. Meier, F. Basolo, Inorg. Synth. 1990, 28, 104–
107.
[26] C. Crocker, R. J. Goodfellow, J. Chem. Res. (S) 1979, 378–379.
[27] A. G. Troitskaya, G. A. Levshina, T. V. Zykova, L. F. Gogolyu-
khina, Zh. Obshch. Khim. 1976, 46, 1235–1237.
[28] I.-C. Grig-Alexa, A.-L. Finaru, L. Ivan, P. Caubère, G. Guil-
laumet, Synthesis 2006, 619–628.
[29] T. Iwaki, A. Yasuhara, T. Sakamoto, J. Chem. Soc. Perkin
Trans. 1 1999, 1505–1510.
[30] K. T. J. Loones, B. U. W. Maes, C. Meyers, J. Deruytter, J. Org.
Chem. 2006, 71, 260–264.
[31] E. Garnier, S. Blanchard, I. Rodriguez, C. Jarry, J. Leger, P.
Caubere, G. Guillaumet, Synthesis 2003, 13, 2033–2040.
[32] C. A. Obafemi, W. Pfleiderer, Helv. Chim. Acta 1994, 77, 1549–
1556.
a) L. Achremowicz, Synthesis 1975, 653–654; b) T. Kato, N.
Katagiri, A. Wagai, Chem. Pharm. Bull. 1981, 29, 1069–1075;
c) A. A. Russell, R. L. Meline, E. N. Duesler, R. T. Paine, Inorg.
Chim. Acta 1995, 231, 1–5; d) D. Redmore, J. Org. Chem. 1970,
35, 4114–4117.
a) A. Boumekouez, E. About-Jaudet, N. C. P. Savignac, J. Or-
ganomet. Chem. 1992, 440, 297–301; b) J. F. Bunnett, X. Cre-
ary, J. Org. Chem. 1974, 39, 3612–3614.
[6]
[7]
P. Tavs, Chem. Ber. 1970, 103, 2428–2436.
a) T. Hirao, T. Masunaga, Y. Yamada, Y. Ohshiro, T. Agawa,
Bull. Chem. Soc. Jpn. 1982, 55, 909–913; b) T. Hirao, T. Masun-
aga, Y. Ohshiro, T. Agawa, Synthesis 1981, 56–57.
[8] J. F. Hartwig, in: Handbook of Organopalladium Chemistry for
Organic Synthesis, vol. 1 (Eds.: E.-I. Negishi, A. de Meijere),
Wiley Interscience, New York, 2002, pp. 1051–1096.
[9] a) D. Gelman, L. Jiang, S. L. Buchwald, Org. Lett. 2003, 5,
2315–2318; b) A. Osuka, N. Ohmasa, Y. Yoshida, H. Suzuki,
Synthesis 1983, 69–71.
[10] a) K. Bravo-Altamirano, Z. Huang, J.-L. Montchamp, Tetrahe-
dron 2005, 61, 6315–6329; b) Y. Belabassi, S. Alzghari, J.-L.
Montchamp, J. Organomet. Chem. 2008, 693, 3171–3178.
[11] a) L. J. Gooßen, M. K. Dezfuli, Synlett 2005, 3, 445–448; b) J.
Park, P. Ho Lee, Bull. Korean Chem. Soc. 1997, 18, 1130–1132.
[12] A. Bessmertnykh, C. M. Douaihy, S. Muniappan, R. Guilard,
Synthesis 2008, 1575–1579.
[33] SADABS, Bruker AXS Inc., Madison, WI (USA), 2003.
[34] SHELXS-97 and SHELXL-97, programs for the solution and
refinement of crystal structures: G. M. Sheldrick, University of
Göttingen, Germany, 1997.
[13] T. M. Balthazor, J. A. Miles, B. R. Stults, J. Org. Chem. 1978,
43, 4538–4540.
[14] R. K. Bansal, J. Heinicke, Chem. Rev. 2001, 101, 3549–3578.
Received: June 22, 2009
Published Online: August 10, 2009
Eur. J. Org. Chem. 2009, 4655–4665
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4665