Synthesis of 1H-1,3-benzazaphospholes: Substituent influence and mechanistical aspects

Article abstract of DOI:10.1016/S0040-4020(01)01019-5

Various substituted carboxylic acid 2-chloro- and 2-bromoanilides 1a-j react with triethylphosphite in the presence of anhydrous NiCl₂ or NiBr₂ to give o-acylamido-benzenephosphonic acid esters 2a-g and 2j. Yields depend strongly on the substituents. 2-Fluoro-4,6-dibromoacetanilide 1g reacts only at 6-position, indicating an o-directed process. Based on substituent effects, we infer a mechanism via Ni(0) intermediates that insert into the carbon-halogen bond. The N-tertiary 2-bromoformanilide 4 does not undergo phosphonylation to 5 in the presence of the Ni-catalyst but reacts in the presence of Pd-catalysts. The subsequent reduction of the N-secondary o-acylamido-benzenephosphonic acid esters 2 with excess LiAlH₄ is coupled with an intramolecular cyclisation to the 1H-1,3-benzazaphospholes 6 whereas the N-tertiary derivative 5 does not undergo cyclisation upon reduction. NMR data and the crystal structure of 6d are reported.

Full text of DOI:10.1016/S0040-4020(01)01019-5

TETRAHEDRON
Pergamon
Tetrahedron 57 72001) 9963±9972
Synthesis of 1H-1,3-benzazaphospholes: substituent in¯uence and
mechanistical aspects
Joachim Heinicke,a,p Nidhi Gupta,a Anushka Surana,a,² Normen Peulecke,a Brigitte Witt,a
b
c
Kinga Steinhauser,a Raj K.Bansal and Peter G.Jones
a
È È
Institut fur Chemie und Biochemie, Ernst±Moritz±Arndt Universitat Greifswald, Soldmannstrasse 16, D-17487 Greifswald, Germany
bDepartment of Chemistry, University of Rajasthan, Jaipur 302 004, India
È È
Institut fur Anorganische und Analytische Chemie, Technische Universitat Braunschweig, D-38023 Braunschweig, Germany
c
Received 26 July 2001; revised 19 September 2001; accepted 19 October 2001
AbstractÐVarious substituted carboxylic acid 2-chloro- and 2-bromoanilides 1a±j react with triethylphosphite in the presence of
anhydrous NiCl2 or NiBr2 to give o-acylamido-benzenephosphonic acid esters 2a±g and 2j.Yields depend strongly on the substituents.
2-Fluoro-4,6-dibromoacetanilide 1g reacts only at 6-position, indicating an o-directed process.Based on substituent effects, we infer a
mechanism via Ni70) intermediates that insert into the carbon±halogen bond.The N-tertiary 2-bromoformanilide 4 does not undergo
phosphonylation to 5 in the presence of the Ni-catalyst but reacts in the presence of Pd-catalysts.The subsequent reduction of the
N-secondary o-acylamido-benzenephosphonic acid esters 2 with excess LiAlH4 is coupled with an intramolecular cyclisation to the 1H-
1,3-benzazaphospholes 6 whereas the N-tertiary derivative 5 does not undergo cyclisation upon reduction.NMR data and the crystal structure
of 6d are reported. q 2001 Elsevier Science Ltd.All rights reserved.
1. Introduction
2. Results and discussion
2.1. P±C-coupling reaction
Stressing the nitrogen±phosphorus analogy and the closer
diagonal relationship of low-coordinated carbon and phos-
phorus,1 1H-1,3-benzazaphospholes2±5 are close relatives of
the well known benzimidazoles6 and indoles.7 Whereas the
latter display a varied and well-established chemistry,
comparably little is known of the chemical behaviour of
the low-coordinated phosphorus analogues.Apart from the
relatively recent discovery of PvC compounds and their
absence in nature, the laborious synthesis of benzazaphos-
pholes2±4 may be a major reason.1 H-1,3-benzazaphos-
pholes are thermally very stable and easy to handle.They
have an interesting reactivity essentially intermediate
between that of the two classical heterocycles and addition-
ally display a coordination chemistry at the low-coordinated
phosphorus atom that has scarcely been investigated.We
have studied alternative synthetic routes5 to these
compounds and their reactivity towards organometallic
reagents and electrophiles.8±11 We report here in more detail
on the new three-step synthesis of benzazaphospholes,
together with its mechanisms and limitations.
The key steps in the novel synthesis of 2-methyl-, 2-t-butyl-
and 2-phenyl-1H-1,3-benzazaphosphole presented recently5
are the P±C coupling and the ring closure reaction.The
former is accomplished by a nickel catalysed arylation of
phosphite 7phosphonylation of aryl halide), often referred to
as Tavs' reaction,12±14 which usually is strongly disfavoured
by o-substituents and prevented by OH or NH2 groups in
p-position.12 This is in agreement with our observation that
2-bromoaniline gives only phosphorous acid derivatives
HP7O)7OEt)2, HP7O)7OEt)7NHC6H4Br) and a diamide,
identi®ed by typical chemical shifts of d31P 7.6, 4.6, 2.7
and large 1J7PH) coupling constants.However, N-secondary
o-bromoanilides of acetic, pivalic, and benzoic acid were
found to couple with triethylphosphite in the presence of
anhydrous NiBr2 in excellent yields,5 comparable to the
reaction of 2-bromoacetanilide with methylphosphonous
acid ethyl ester.13 Problems in utilising this coupling
reaction for N-tertiary o-bromoanilides inspired us to
explore its scope and mechanism.We synthesised various
o-haloanilides 1a±j and studied their coupling reactions
with triethyl phosphite.Most of the anilides were easily
accessible from carboxylic acids, or their acyl chlorides,
and the respective anilines by standard procedures.The
coupling attempts showed a more sophisticated chemical
Keywords: anilides; phosphorus heterocycles; catalytic phosphonylation;
cyclisation.
p
Corresponding author.Tel:. 149-3834-864-337; fax: 149-3834-864-
3197; e-mail: heinicke@mail.uni-greifswald.de
Deceased.
²
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd.All rights reserved.
PII: S0040-4020701)01019-5

9964
J. Heinicke et al. / Tetrahedron 57 72001) 9963±9972
phosphonylation of 1g indicates therefore a supporting
o-directed process that will be discussed later.More serious
problems arise with o-bromoanilides of formic, picolinic or
oxalic acid, which seem not to bene®t from the above-
mentioned support.The nickel catalysed coupling reaction
of 2-bromoformanilide 1h with P7OEt)3 failed completely.
Heating to 1908C in the presence of NiBr2 led to vigorous
evolution of a gas and formation of an insoluble brown
polymer along with a mixture of phosphorus compounds.
Studies of the NiCl2-catalysed reaction of picolinic acid
o-bromoanilide 1i with P7OEt)3 in the temperature range
180±2008C displayed strong 31P signals at d 20.5, 0.4,
7.8 and 34.0 but only small 31P signals at d 18, the typical
region for the P±Caryl coupling products.Oxalic acid bis7 o-
bromoanilide) 1j reacts with excess P7OEt)3 in the presence
of NiCl2 to give the monosubstitution product 2j in rather
low yield.The disubstitution product constitutes only a
minor component in the crude product and was not isolated
in pure form.
Scheme 1.
behaviour of 1a±g 7Scheme 1) than was expected from prior
results.
o-Chloroacetanilide 1a and o-chlorobenzanilide 1b were
found to couple in moderate yields 7about 50%) with triethyl
phosphite in presence of NiCl2 to give 2a and 2b, respec-
tively.Although this conversion is signi®cantly lower than
with o-bromoacetanilide 781%),5 and about three times as
much of the catalyst is needed to suppress the competing
formation of phosphorus acid derivatives 7d31P 20.7 to
21), it is remarkable considering the generally much
lower reactivity of chlorobenzene derivatives. o-Bromo-
anilides display a varied reactivity.The NiCl -catalysed
2
The N-tertiary o-bromoformanilide 4 behaves differently
from the NH±CHO derivative 1h.Heating 4 with P7OEt)3
in the presence of NiBr2 did not lead to a polymer, nor was
any P±C coupling observed.Attempts with other transition
metal compounds showed that palladium acetate may be
used as catalyst for the coupling of 4 with P7OEt)3
7Scheme 2), but the yield of the N-tertiary 2-formamido-
benzenephosphonic acid ester 5 was much lower than in
the above-mentioned reactions, 35±40% when excess
triethyl phosphite and a stream of argon or nitrogen was
used to remove EtBr, thus reducing the amount of the
Arbuzov-product EtPO7OEt)2.It should be mentioned that
the competing Arbuzov reaction is not observed in the
Ni-catalysed coupling reactions with reactive N-secondary
o-bromoanilides such as 1c±e.
coupling reaction of the ring-alkylated 2-bromo-4-methyl-
anilides 1c±e with P7OEt)3 gives 2c±e in good yields,
comparable with the non-methylated 2-bromoanilides.5
Electron-withdrawing substituents, i.e. bromine or ¯uorine
in 4-/6-position of the 2-bromoacetanilides, cause lower
yields of the coupling products 2f and 2g and increase the
amount of the Arbuzov product EtPO7OEt)2 7d31P 34.1)
formed with EtBr, of PO7OEt)3 7d31P 20.8 to 20.5) and
of by-products with phosphorus signals in the region of d31P
15.As seen from the P±F± and F±H coupling pattern, the
latter are related to the substitution products, judging from
1
the integral ratios in the H NMR spectrum of 2f probably
the monoesters, formed by partial O-dealkylation.Crude 2g
contains a further weak signal in this region 7d31P 15.4) and
also a signal 7d31P 2.7) for a small amount of another P±C
coupling product 3g that distils together with 2g and gives
1
rise to H NMR signals consistent with a cyclic structure.
The aryl protons of 2g and of 3g exhibit the same splitting,
3
3
typical J7PH) and J7FH) coupling constants 714.0, 15.1;
9.3, 9.3 Hz), aryl/ethyl/tBu integral ratios of 2:4:6:9 and
2:2:3:9, and no NH or OH signal for 3g.However, no
evidence was obtained for a product formed by replacement
of the 4-bromo substituent by phosphorus, which should
3
Scheme 2.
easily be recognised by large J7PH) couplings to both
aryl hydrogens.This means that the NiCl -catalysed phos-
2
phonylation of 2-¯uoro-4,6-dibromoacetanilide 1g proceeds
regioselectively at the bromine in o-position of the amide
group 76-position), although this is sterically hindered
compared to the 4-position.To be sure that the phosphonyl-
ation of the above NH-species is possible in the 4-position,
we checked the reaction of 4-bromoacetanilide with P7OEt)3
in presence of NiBr2 under equal conditions and found in
the crude product according to the NMR spectra a high
conversion to 4-acetamido-benzenephosphonic acid diethyl
ester 7d31P 19.1). The observed regioselectivity in the
Since in the above experiments the NH-amide function is
essential for the nickel-catalysed, but not for the Pd-cata-
lysed coupling reaction, different mechanisms might be
possible and could involve a Ni7II) catalyst.It is known
that o-chloroanilines or -phenols react with triphenyl-
phosphine in presence of anhydrous nickel chloride at
comparable elevated temperature by polarisation of the
C±Br bond and nucleophilic attack of the phosphine to
give phosphonium tetrachloroniccolate.15 The above
observed substitution by triethylphosphite, the necessity

J. Heinicke et al. / Tetrahedron 57 72001) 9963±9972
9965
Scheme 3.
Scheme 4.
for the NH function and the o-direction can be accounted for
by deprotonation and formation of a catalytic amount of an
amidate nickel complex supporting the activation of the
C±Br bond, as illustrated in Scheme 3.This should allow
the attack of triethyl phosphite as in the above mentioned
coupling with Ph3P or in the usual Arbuzov reactions and
lead to formation of an intermediate phosphonium niccolate
complex [arP7OEt)3]1 [Br2NiL]2 that eliminates EtBr.The
transfer of the nickel7II) to unreacted o-bromoanilide might
be accomplished by a combined proton-transfer and
complex formation equilibrium in which uncomplexed 2
seems to be favoured.As the NH and C vO stretching
yields of the coupling products in reactions with 4,6-
di¯uoro- or 4-bromo-6-¯uoro-substituted 2-bromoacet- or
-pivalanilides may be due to a lower rate of the P±C
coupling in relation to the competing Arbuzov and other
side reactions.Since the intermediate arylnickel7II)bromide
complex can be stabilised by intramolecular coordination of
the amide±oxygen, forming a six-membered chelate ring,
the lack of the usual steric hindrance and preference of
o-substitution can also be explained.The low reactivity of
the N-methyl-o-bromoformamide may be attributed to steric
hindrance of a coplanar orientation of the benzene ring and
the amido group necessary to support the o-substitution as
proposed above.The catalytic cycle would be closed by the
liberation of EtBr and a phosphite-stabilised Ni70) species
7Scheme 4).The mechanism assuming Ni70) is preferred by
us since it explains better the in¯uence of the substituents.
vibrations in 2f 7nˆ3682 w, 3619 w, 3431 m, sharp, 3346
Å
m br, 1694 s cm21, cˆ0.06±0.015 m in CHCl ; nˆ3423 s,
Å
3
3346 s NH in KBr) are independent of the concentration,
stabilisation by an intramolecular hydrogen bond can be
proposed.
The lack of coupling in the case of the 2-picolinic acid
derivative 1i could be understood within both models by
formation of an alternative ®ve-membered chelate complex,
which is more stable than an amidate intermediate.
Disubstitution of the oxalic acid bis7o-bromoanilide) 1j
may similarly be prevented by interactions of nickel at the
catalytic centre with the phosphonodiester group in the
monosubstitution product 2j.
Since it is known that NiX2 and triethylphosphite form
Ni[P7OEt)3]4 along with some PO7OEt)3 and that Ni70)
14
inserts into C±I or C±Br bonds16 a mechanism via nickel70)
has also to be considered.In contrast to the above path,
formation of an intermediate arylnickel7II)bromide complex
should promote a nucleophilic attack of the carbanion at the
polar P±O bond of triethylphosphite and thus be in¯uenced
by electronic substituent effects in the opposite fashion to
the situation described above.Electron withdrawal by
¯uorine or bromine in m,m0-position should reduce the
negative charge and lower the activity of the anion, whereas
the polarisation of the C±Br bond should be enhanced and
attack by nucleophiles favoured.This should allow a
distinction between the two conceivable mechanisms.
2.2. Reductive cyclisation of 2-acylamidobenzene-
phosphonic acid ester
The reduction of the 2-acylamidophosphonates with
2 equiv.of LiAlH 4, suf®cient to reduce both the phos-
phonodiester and the amido group, led to a mixture of
products containing small amounts of benzazaphospholes.
Whereas utilisation of a smaller amount of LiAlH4 did not
result in a selective reduction of either of the two groups,
excess LiAlH4 gave rise to formation of 1H-1,3-benzaza-
phospholes 6a±f in reasonable yields 7Scheme 5).The
N-secondary 2-phosphinoanilines 7, of interest as starting
materials for N-substituted 1,3-benzazaphospholes,4,10 are
observed as by-products but have not been isolated in
pure form.
A control experiment showed that 2-bromobenzanilide
couples with triethylphosphite if heated to 2008C in
presence of catalytic amounts of Ni71,5-COD)2.The selec-
tivity is high, as indicated by the 31P NMR spectrum of the
crude mixture, and PO7OEt)3 could not be detected, but the
yield of the coupling product is considerably lower than
upon catalysis with NiX2.This may be attributed to thermal
decomposition of the Ni70) species and permanent genera-
tion of small amounts of the Ni70) catalyst when P7OEt)3 is
added to the mixture of o-haloanilide and NiX2 at high
temperature.The substituent effects are also consistent
with the second mechanistic proposal.The much lower
The formation of 1H-1,3-benzazaphospholes can be under-
stood in terms of a reduction of the phosphonodiester group
in the ®rst step and subsequent preferred cyclisation,

9966
J. Heinicke et al. / Tetrahedron 57 72001) 9963±9972
2.3. Properties of 1H-1,3-benzazaphospholes and
structural aspects
As reported earlier, 1H-1,3-benzazaphospholes are
thermally stable and in most cases not very sensitive
towards hydrolysis.They are relatively stable towards air
oxidation in the solid state, but are oxidised in solution.
Puri®cation of 2-methyl- and 2-aryl-1,3-benzazaphospholes
can be accomplished by extracting the basic or acidic
impurities from ethereal solutions with dilute 710%)
sulphuric acid or dilute aqueous sodium hydroxide
solutions.Only 2- t-butyl-1,3-benzazaphospholes add water
during such a procedure forming P-secondary phosphine
oxides.This shows that the t-butyl group does not
provide steric protection but rather activates the PvC
bond.An X-ray structure investigation of 6d 7Fig.1,
Scheme 5.
initiated by intramolecular attack of the nucleophilic
phosphido group on the electrophilic amidate carbon.
Metalation at phosphorus and of the amido group increases
the reactivity by formation of phosphide and amidate
structures, the latter with increased weight of C±N double
bond character as compared to amides.As observed in
earlier investigations on the reactivity of arsino-substituted
amines and anilines towards carbonic acid derivatives,
cyclisation under mild conditions could be achieved only
with iminoacyl compounds whilst amides formed with acyl
chlorides did not undergo ring closure.17 The resulting
metalated 1,3-benzazaphospholides 6MI are stable under
the reaction conditions in presence of excess LiAlH4.The
formation of a delocalised, p-excess aromatic system with
increased electron density at the phosphorus atom prevents
the attack of the reducing agent at the PvC bond.
Hydrolysis liberates the NH-compounds.In view of the
stability of 6MI the formation of 7 is attributable to com-
peting reduction of the amido group, either of 2 or of the
intermediate primary phosphine or phosphide.
Figure 1. Crystal structure of 6d.Ellipsoids represent 50% probability
Ê
levels.Selected bond lengths 7A ) and angles 78): P±C2 1.7278712), P±C3
1.7820712), N±C2 1.3562715), N±C1 1.3836715), C1±C3 1.4007716); C2±
P±C3 89.4776), P±C2±N 112.9579), P±C3±C1 111.0978), C2±N±C1
114.86710), N±C1±C3 111.61710), P±C2±C9 126.9979), N±C2±C9
119.88711).
Table 1. Crystal data and structure re®nement of 6d
Empirical formula
Formula weight
Temperature
C12H16NP
205.23
13372) K
0.71073 A
Orthorhombic
P212121
The reduction of the N-methyl-2-formamido benzene-
phosphonic acid ester 5 with LiAlH4 did not result in the
corresponding N-methyl-1,3-benzazaphosphole but gave a
small amount of 2-phosphino-N,N-dimethylaniline 8.
When the reduction was carried out in presence of
potassium t-butoxide to activate the amide group by inter-
molecularly mediated polarisation of the CvO bond,
the formyl group was cleaved instead of undergoing
Ê
Wavelength
Crystal system
Space group
Unit cell dimensions
Ê
Ê
aˆ5.995776) A
bˆ8.869978) A
Ê
cˆ21.3567718) A
Ê 3
Volume
Z
Density 7calculated)
Absorption coef®cient
F7000)
Crystal size
Theta range for data collection
Index ranges
1135.78718) A
4
1.200 mg m23
0.203 mm21
440
cyclisation affording 2-phosphino-N-methylaniline
7Scheme 6).
9
0.37£0.23£0.16 mm3
1.91±30.038
28#h#8, 212#k#12,
230#l#30
16446
Re¯ections collected
Independent re¯ections
Completeness to thetaˆ30.008
Absorption correction
Maximum and minimum
transmission
3321 [R7int)ˆ0.0328]
99.8%
Semi-empirical from equivalents
0.962 and 0.810
Re®nement method
Full-matrix least-squares on F2
3321/0/135
1.043
Data/restraints/parameters
Goodness-of-®t on F2
Final R indices [I.2sigma7I)]
R indices 7all data)
R1ˆ0.0323, wR2ˆ0.0853
R1ˆ0.0351, wR2ˆ0.0869
Ê 23
Largest diff.peak and hole
03. 86 and 20.171 e A
Scheme 6.

J. Heinicke et al. / Tetrahedron 57 72001) 9963±9972
9967
Table 1), crystallised after high-vacuum distillation from
toluene, shows the planar benzazaphosphole ring system
with the t-butyl group hindering access to the nitrogen rather
than the phosphorus atom, which is of importance in sub-
stitution reactions.9 The angle N±C2±C9 corresponds
closely to ideal sp2 geometry, whereas the angle P±C2±
C9 is signi®cantly larger at 126.9979)8.This is certainly
attributable in part to the size of phosphorus and the
constraints of the ®ve-membered ring, but also to an addi-
tional effect of the t-butyl group.In comparison with the
values determined for the unsubstituted 1H-1,3-benzaza-
phosphole [1.80777), 1.69579), 115.777)]18 the distances
P±C3 [1.7820712) A] and P±C2 [1.7278712) A] are slightly
shorter and longer, respectively, and the P±C±N angle
[112.9579)8] is reduced, suggesting that the phosphorus
atom is repelled slightly towards C3 by the methyl groups
of the 2-t-butyl substituent [cf.torsion angle C12±C9±C2±
P 17.972)8].The resulting better bond equalisation in 6d
should enhance the aromatic stabilisation and does not
explain the increased sensitivity towards hydrolysis.Thus,
the electronic effect of the t-butyl group has to be
considered.
P±C coupling, and that donor functions at the acyl group,
possibly enabling the formation of chelate complexes with
Ni7II), suppress this reaction.Based upon these observations
two models for a possible mechanism were discussed.The
substituent effects on the yields account rather for catalysis
by Ni70) and intermediate carbanionic aryl±NiBr
complexes reacting with the polar P±O bond than an intra-
molecular, Ni-amidate-supported polarisation of the C±Br
bond and nucleophilic attack of phosphite.The reduction of
the resulting o-amidobenzenephosphonic acid diesters with
excess LiAlH4 again depends on the nature of the amide
group.Whereas the N-tertiary N-methyl-formamidobenze-
nephosphonic diethyl ester furnishes either 2-phosphino-
N,N-dimethylaniline or, in presence of KOtBu, 2-phos-
phino-N-methylaniline, NH-derivatives form benzaza-
phospholes.This is explained by primary reduction of the
phosphonodiester group and rapid ring closure by intra-
molecular attack of the o-phosphido group at the amidate
carbon.Thus, only a minor part of the amidate group can be
reduced giving rise to small amounts of by-products, the
respective N-secondary 2-phosphinoanilines.The in¯uence
of substituents on some properties of 1H-1,3-benzazaphos-
pholes is discussed.
Ê
Ê
The 1I effect of the t-butyl group results in an increased
s-electron density at C-2, which in turn repels p-electron
density, in part towards phosphorus.The resulting increased
polarity of the PvC bond facilitates the acid-catalysed
addition of water.The effect on the NMR spectra resembles
that of lithiation at C2,10 though to a much smaller extent.
The C2 signal is strongly deshielded and the P±C coupling
is signi®cantly increased 71JPCˆ57.5 Hz versus 51.5 and
51.3 Hz in 6c and 6e), whereas the phosphorus resonance
is shifted to higher ®eld 7d31Pˆ63.5 versus 71.8 in 6c and
74.4 in 6e).The in¯uence of the 5-methyl group in 6c±e on
the d31P values is low.Substituents at the benzene ring may
have some in¯uence, however, as seen by the signi®cant
down®eld shift of the phosphorus resonance in 5,7-
di¯uoro-2-methyl-1,3-benzazaphosphole 6f 7d31P 80.5)
and four-bond couplings with the ¯uorine nuclei
74JPFˆ15.9, 8.3 Hz). The carbon atoms C2 and C3 are
in¯uenced similarly but to a smaller degree.The strongest
changes are restricted to the residual carbon nuclei of the
benzene ring.As the polarity of the P±C bonds is not much
changed, the in¯uence of the substituents at the benzene ring
on the reactivity, such as the stability towards hydrolysis or
alcoholysis, is low.Reactivity studies concerning the
lithiation of the NH function and substitution or complex
formation of the resulting ambident benzazaphospholides,8,9
formation of transition metal carbonyl benzazaphosphole10 or
cyclopentadienylnickel±benzazaphospholide complexes,11
or cycloaddition reactions with o-choranil will all be
reported separately.
4. Experimental
4.1. General considerations
All reactions were conducted under an atmosphere of dry
argon using Schlenk techniques.Ether, THF and hydro-
carbons were dried and deoxygenated by re¯uxing and
distilling from sodium/benzophenone ketyl before use.
The bromoanilines and the acetanilides 1a and 1c were
commercially available 7Lancaster) and used as purchased.
The other anilides were prepared by a standard procedure, if
known 71b,19 1e,20 1f,21), mps agree. 422 was obtained as
reported earlier.NMR spectra were measured on a multi-
nuclear FT-NMR spectrometer Bruker Model ARX300 at
300.1 71H), 75.5 713C), and 121.5 731P) MHz.The 1H, 13C
and 31P chemical shifts are d values relative to Me4Si and
H3PO4 785%), respectively.Assignment numbers are
identical with the position number according to the nomen-
clature unless indicated otherwise; for phenyl substituents
the indices i, o, m, p are used.Coupling constants refer to
H±H 71H NMR) or P±C couplings 713C NMR) unless stated
otherwise.IR spectra were recorded on a Perkin±Elmer
Model system 2000 and mass spectra on a single-focussing
mass spectrometer AMD40 7Intectra).Elemental analyses
were carried out with an elemental analyzer LECO Model
CHNS-932 with standard combustion conditions and
handling of the samples at air.Melting points were deter-
mined in sealed capillaries under argon and are uncorrected.
3. Conclusions
4.2. 2-Bromoanilides; general procedure
The in¯uence of substituents on the NiX2-catalysed 7XˆCl,
Br) coupling of 2-haloanilides of carboxylic acids with
triethyl phosphite and on the reduction of the coupling
products with LiAlH4 was studied.Apart from effects on
the yields it was found that the P±C coupling reaction
takes place selectively in o-position of the amide group,
that the NH function is essential for the NiX2-catalysed
The acid chloride was added dropwise at 0±58C with stir-
ring to a solution of the respective 2-haloaniline and a slight
excess of triethylamine in ether.After 2 d at room tempera-
ture, unless indicated otherwise, the precipitate was sepa-
rated, thoroughly washed with ether and treated with water
to remove Et3N´HCl.The remaining anilide 7if less soluble
in ether) was dried in vacuum.The ®ltrate was washed with

9968
J. Heinicke et al. / Tetrahedron 57 72001) 9963±9972
3
4
cold 10% aqueous sulphuric acid, cold 10% aqueous sodium
hydroxide solution, and water and was dried with sodium
sulphate.The solvent was removed in vacuo and the residue
was recrystallised from ethanol.
7CDCl3): d 7.01 7td, J<7.9, 7.5 Hz, Jˆ1.6 Hz, 1H, H-4),
3
4
7.38 7td, J<8.6, 8.4 Hz, Jˆ1.5 Hz, 1H, H-5), 7.50 7ddd,
3
3
4
J5 4 ˆ7.6 Hz, J5 6 ˆ4.8 Hz, Jˆ1.2 Hz, 1H, H-50), 7.60
0
0
0 0
4
3
3
7dd, Jˆ8.0 Hz, Jˆ1.5 Hz, 1H, H-3), 7.92 7td, Jˆ7.8,
7.6 Hz, Jˆ1.7 Hz, 1H, H-40), 8.30 7ddd, 3Jˆ7.8 Hz,
4
4.2.1. 2-Bromo-4-methyl-420,20-dimethyl)propionanilide
41d). The reaction of pivaloyl chloride 712.5 mL,
102 mmol), 2-bromo-4-methylaniline 718.94 g, 101 mmol)
and Et3N 714.5 mL, 104 mmol) in ether 7250 mL) furnished
4/5J<2.0, 1.0 Hz, 1H, H-30), 8.64 7dd, 3Jˆ8.3 Hz,
4Jˆ1.6 Hz, 1H, H-6), 8.68 7ddd, J6 5 ˆ4.8 Hz, 4/5J<1.5,
0.8 Hz, 1H, H-60), 10.71 7s br, 1H, NH). 13C NMR
7CDCl3): d 113.9 7C-2), 121.4 7C-6), 122.5, 125.1 7C-4),
126.6, 128.4 7C-5), 132.5 7C-3), 135.9 7C-1), 137.6 7C-50),
148.3 7C-60), 149.7 7C-20), 162.3 7CvO).Anal.calcd for
C12H9BrN2O 7277.12): C, 52.01; H, 3.27; N, 10.11. Found:
C, 51.97; H, 3.41; N, 10.11.
3
0
0
26 g 794%) of 1d, isolated from the ®ltrate, mp 698C
1
7EtOH).IR 7KBr): n 3423, 3309, 1657 cm21. H NMR
Å
7CDCl3): d 1.34 7s, 9H, Me), 2.29 7s, 1H, Me), 7.11 7dd,
4
4
3Jˆ8.4 Hz, Jˆ1.8 Hz, 1H, H-5), 7.35 7d, Jˆ1.8 Hz, 1H,
H-3), 7.91 7br, 1H, NH), 8.23 7d, 3Jˆ8.4 Hz, 1H, H-6). 13
C
4.2.6. Oxalic acid bis42-bromoanilide) 41j). The reaction
of oxalyl chloride 70.87 mL, 10.0 mmol), 2-bromoaniline
73.45 g, 20.0 mmol) and triethylamine 72.8 mL, 20.0 mL)
gave 2.5 g 763%) of the dianilide 1j, mp 2108C.It is
NMR 7CDCl3): d 20.5 7s, 4-Me), 27.6 7s, Me), 40.1 7CMe3),
113.5 7C-2), 121.5 7C-6), 129.0 7C-5), 132.3 7C-3), 133.3
7C-4), 134.9 7C-1), 176.5 7CO). Anal. calcd for C12H16NOBr
7270.17): C, 53.35; H, 5.97; N, 5.18. Found: C, 53.29; H,
6.21; N, 5.35.
insoluble in CHCl , C H and CH OH.IR 7KBr): n 3434,
Å
3
6
6
3
3328, 3307, 1703, 1678, 1521 cm21.Anal.calcd for
C14H10Br2N2O2 7398.05): C, 42.24; H, 2.53; N, 7.04.
Found: C, 42.42; H, 2.73; N, 7.10.
4.2.2. 2-Bromo-4-methyl-benzanilide 41e).20 The reaction
of benzoic acid chloride 713.62 mL, 117 mmol), 2-bromo-4-
methylaniline 721.81 g, 117 mmol) and Et3N 716.34 mL) in
ether 7300 mL) gave a total of 23.8 g 779%) of 1e, thereof
4.3. Phosphonylation of 2-bromoanilides; general
procedure
16.7 g 7mp 1488C) isolated from the precipitate.IR 7KBr): n
Å
1
3415, 3254, 1649 cm21. H NMR 7CDCl3): d 2.33 7s, 3H,
3
4
Me), 7.18 7dd, Jˆ8.4 Hz, Jˆ1.8 Hz, 1H, H-5), 7.40 7dd,
4Jˆ1.8 Hz, 5Jˆ0.6 Hz, 1H, H-3), 7.48±7.61 7m, 3H, 2H-m,
H-p), 7.93 7dm, 2H, H-o), 8.38 7s br, NH), 8.40 7d,
3Jˆ8.4 Hz, 1H, H-6). 13C NMR 7CDCl3): d 20.56 74-Me),
113.6 7C-2), 121.6 7C-6), 127.1 and 128.9 72 C-o,m), 129.1
7C-5), 132.1, 132.5 7C-3, C-p), 133.2 7C-4), 134.7 7C-i),
135.4 7C-1), 165.1 7CO).
The corresponding 2-haloanilide and 0.2 g of anhydrous
NiCl2 or NiBr2 were placed in a distillation device and
heated to 180±1908C while excess triethyl phosphite was
added dropwise 710±20 min).Heating was continued for a
while to complete the reaction.EtCl or EtBr and a small
amount of triethyl phosphite distilled off.The residue was
fractionally distilled in vacuum.
4.2.3. 2-Bromo-4,6-di¯uoro-acetanilide 41f).21 The
reaction of acetyl chloride 722.4 mL, 316 mmol), 2-
bromo-4,6-di¯uoroaniline 732.85 g, 158 mmol) and Et3N
744.2 mL, 316 mmol) in Et2O 7250 mL), work up after
3 d, gave a total of 23.7 g 760%) of 1f, mp 1578C, isolated
4.3.1. 2-Acetamido-benzenephosphonic acid diethylester
42a). Triethyl phosphite 716.14 mL, 94 mmol) was added
within 5 min to a mixture of 2-chloro-acetanilide 713.3 g,
78.4 mmol) and anhydrous NiCl2 70.2 g) at 1808C and heat-
ing continued at 2058C for 15 min.Only little conversion
7but main product d31P 20) took place.To complete the
reaction more NiCl2 71 g) was added and the mixture heated
to 2158C for 30 min).Distillation furnished 11 g 746%) of a
colourless oil, bp 120±1258C/4£1022 Torr, identi®ed as 2a;
analytical data as described earlier.5
from the precipitate and from the ®ltrate.IR 7KBr): n 3432,
Å
3240, 3194, 1670, 850, 833 cm21. 1H NMR 7CDCl3): d 2.20
7s, 3H, Me), 6.87 7m br, 3JFHˆ8 Hz, 2H, H-5, NH), 7.16 7d
3
br, JFHˆ7 Hz, 1H, H-3).
4.2.4. 2,4-Dibromo-6-¯uoro-420,20-dimethyl)propionani-
lide 41g). Excess pivaloyl chloride 78.2 mL, 66.9 mmol)
was added to 2,4-dibromo-6-¯uoroaniline 712.0 g,
44.6 mmol) and Et3N 79.86 mL, 71.2 mmol) in ether
790 mL).Control by NMR indicated a very slow conversion
at ambient temperature 74 d 25%, 7 d 50%, 13 d 66%, 20 d
75%; re¯ux for further 4 d 78%).Work-up gave 116. g
4.3.2. 2-Benzamido-benzenephosphonic acid diethylester
42b). Triethyl phosphite 713.7 mL, 79.8 mmol) was added to
a mixture of 2-chloro-benzanilide 715.4 g, 66.5 mmol) and
anhydrous NiBr2 70.2 g) at 1808C and heated to 2058C for
15 min.Since there was no conversion, NiCl 71 g) and
2
NiCl2dioxane 70.3 g) was added and heating repeated
730 min 2158C) until no more P7OEt)3 distilled off.Vacuum
distillation was accompanied by partial decomposition and
gave 11 g 745%) of an yellow oil, bp 140±1458C/
1.5£1023 Torr, analytical data as described earlier.5
774%) of 1g, mp 1448C 7EtOH).IR 7KBr): n 3433, 3291,
Å
1
1658, 909, 852 cm21. H NMR 7CDCl3): d 1.35 7s, 9H,
3
CMe3), 6.95 7s br, 1H, NH), 7.29 7dd, JFH<8.9 Hz,
4J<2.1 Hz, 1H, H-5), 7.56 7dd, JFH<1.7 Hz, 1H, H-3).
5
Anal.calcd for C 11H12Br2 FNO 7353.03): C 37.42, H 3.43,
N 3.97. Found: C 37.38, H 3.71, N 4.25.
4.3.3. 2-Acetamido-5-methylbenzenephosphonic acid
diethylester 42c). Triethyl phosphite 729.54 mL,
172.3 mmol) was added to a mixture of 1c 7Lancaster)
732.75 g, 143.6 mmol) and NiCl2 70.2 g) at 180±1908C.
Heating to 1908C was continued for 15 min and the residue
was distilled in vacuum to give 34.7 g 785%) of colourless
4.2.5. 2-Picolinic acid 2-bromoanilide 41i). A mixture of
2-bromoaniline 75.13 g, 29.8 mmol) and picolinic acid
73.67 g, 29.8 mmol) was heated for 2 d to 2008C.The result-
ing solid was crystallised from ethanol to give 3.5 g 742%)
of needle-shaped crystals, mp 128±1298C. 1H NMR
1
oily 2c, bp 123±1288C/5£1024 Torr. H NMR 7CDCl3): d

J. Heinicke et al. / Tetrahedron 57 72001) 9963±9972
9969
3
2.19 7s, 3H, 5-Me), 1.34 7t, Jˆ7.1 Hz, 6H, Me), 4.10 7m,
ratio 80:20%).The increased content of the impurity after
distillation and the integral ratio of CH3C7O) to OCH2
protons indicate partial loss of O-ethyl groups by thermal
elimination and formation of the monoethyl ester.The
mixture was used for the synthesis of 6f without further
puri®cation.
3
4H, OCH2), 7.34 7dd, superimposed with H-6, J<8 Hz,
4JHHˆ2 Hz, 1H, H-4), 7.35 7d br, JPH<14.4 Hz, 1H, H-6),
3
8.47 7t, 3J<8 Hz, 4JPH<7 Hz, 1H, H-3), 10.48 7br, 1H, NH).
31P NMR 7CDCl3): d 20.3. Anal. calcd for C13H20NO4NP
7285.50): C, 54.69; H, 7.06; N, 4.91. Found: C, 54.27; H,
7.30; N, 4.85.
4.3.7. 5-Bromo-2-420,20-dimethylpropionamido)-3-¯uoro-
benzenephosphonic acid diethyl ester 42g). Triethyl phos-
phite 73.8 mL, 22.0 mmol) was added to 1g 75.04 g,
14.3 mmol) and NiBr2 70.2 g) at 1808C, heating at 2008C
continued for 20 min.The residue exhibits 31P NMR signals
at d31P 20.5, 2.8 7d, JPFˆ13.1 Hz,), 14.2 7d, JPFˆ10.4 Hz,
strong), 15.1 and 15.4 7small) and 33.9. Repeated distilla-
tion gave 4.23 g of a viscous oil with bp 1218C/1022 Torr
which became solid at room temperature.It is 2g, contami-
nated by monoester 3g 716 mol% based upon the 1H integral
ratio); corrected yield: 2g 62%, 3g 12%.7The mixture can
4.3.4. 2-420,20-Dimethylpropionamido)-5-methyl-benzene-
phosphonic acid diethyl ester 42d). Triethyl phosphite
721.1 mL, 0.123 mol) was added to 1d 727.7 g, 0.10 mol)
and NiCl2 70.1 g) at 180±1958C.Heating was continued
for 20 min, then the residue was distilled in vacuum yielding
26.23 g 780%) of viscous oily 2d, bp 139±1418C/
3.8£1024 Torr.IR 7KBr): n 3430, 3293, 3259, 1688 cm21
.
Å
1H NMR 7CDCl3): d 1.33 7s, 9H, CMe3), 1.33 7t, 3Jˆ7.2 Hz,
6H, Me), 2.33 7s, 5-Me), 4.11 7m, 4 H, OCH2), 7.34 7d,
3Jˆ8.5 Hz, 1H, H-4), 7.39 7dd, JPHˆ14.9 Hz, Jˆ1.6 Hz,
3
4
3
4
1H, H-6), 8.50 7dd, Jˆ8.4 Hz, JPHˆ7.0 Hz, 1H, H-3),
10.41 7br s, 1H, NH). 13C NMR 7CDCl3): d 16.0 7d,
3Jˆ6.6 Hz, Me), 20.4 7s, 5-Me), 27.3 7CMe3), 39.8
7CMe3), 62.2 7d, 2Jˆ4.8 Hz, OCH2), 113.6 7d,
be used to prepare 6g.) IR: in KBr n 3423, 3346, 1694, 1666,
Å
Å
1257, 1117; in CHCl3 70.06, 0.03, 0.015 mol L21) n 3682,
3619, 3431, 3346, 1694 cm21. 2g: 1H NMR 7CDCl3): d 1.33
7td, 3Jˆ7.0 Hz, 4JPHˆ0.5 Hz, 6H, Me), 1.34 7s, 9H, CMe3),
3
3
1Jˆ179.5 Hz, C-1), 120.9 7d, Jˆ12.0 Hz, C-3), 131.9 7d,
4.04±4.20 7m, 4H, OCH2), 7.48 7dd, JFHˆ9.3 Hz, 4Jˆ
2
3
3Jˆ14.4 Hz, C-5), 132.2 7d, Jˆ6.2 Hz, C-6), 134.4 7d,
2.2 Hz, 1H, H-4), 7.62 7ddd, JPHˆ14.0 Hz, 4Jˆ2.2 Hz,
4Jˆ2.1 Hz, C-4), 140.3 7d, 2Jˆ7.0 Hz, C-2), 177.2 7s,
CO). 31P NMR 7CDCl3): d 20.1. MS 7EI, 70 eV): m/z
7%)ˆ328 735), 327 750) [M1], 271 725), 270 7100), 242
754), 214 792), 170 742).Anal.calcd for C 16H26PO2N
7327.36): C, 58.70; H, 8.01; N, 4.28. Found: C, 58.48; H,
8.10; N, 4.54.
5JFHˆ1.1 Hz, 1H, H-6), 8.58 7br, 1H, NH). 13C NMR
3
7CDCl3): d 16.2 7d, Jˆ6.5 Hz, Me), 27.4 7CMe3), 39.3
7CMe3), 63.1 7d, 2Jˆ5.6 Hz, OCH2), 118.7 7dd, 4Jˆ
2
8.5 Hz, JFCˆ22.4 Hz, C-4), 124.3 7dd, 3Jˆ24.0 Hz,
1
3
3JFCˆ2.5 Hz, C-5), 125.2 7dd, Jˆ182.0 Hz, JFCˆ1.7 Hz,
C-1), 128.1 7dd, 2Jˆ6.5 Hz, 2JFCˆ13.7 Hz, C-2), 130.6 7dd,
2Jˆ7.2 Hz, JFCˆ3.7 Hz, C-6), 157.0 7dd, 3Jˆ20.0 Hz,
4
4.3.5. 2-Benzamido-5-methyl-benzenephosphonic acid
diethyl ester 42e). Triethyl phosphite 711.74 mL,
68.5 mmol) was added to 1e 716.685 g, 57.5 mmol) and
NiCl2 70.1 g) at 165±1908C and heating continued for
15 min at 1908C.Distillation of the residue in a short-path
high-vacuum device furnished 10.96 g 755%) of syrupy 2e,
boiling range 180±2058C/3.5£1024 Torr 7partially over-
heated). 1H NMR 7CDCl3): d 1.33 7td, 3Jˆ7.1 Hz,
4JPHˆ0.5 Hz, 6H, Me), 2.36 7s, 3H, 5-Me), 4.00±4.30 7m,
4H, 2 OCH2), 7.38±7.55 7m, 5H, H-m/p, H-4, H-6), 8.08-
1JFCˆ260.3 Hz, C-3), 177.2 7s, CO). 31P NMR 7CDCl3): d
14.2 7d, JPFˆ10.6 Hz). 3g: 1H NMR: d 1.35 7s, 9H, CMe3),
3
4
1.38 7td, Jˆ7.0 Hz, JPHˆ0.5 Hz, 3H, Me), 4.15±4.30 7m,
3
4
2H, OCH2), 7.54 7dd, JFH4ˆ9.3 Hz, Jˆ2.1 Hz, 1H, H-4),
3
5
7.74 7ddd, JPHˆ15.1 Hz, Jˆ2.1 Hz, JFHˆ1.3 Hz, 1H, H-
6). 31P NMR: d 2.8 7d, JPFˆ13.1 Hz). 2g13g: MS 7EI,
70 eV, 2058C): m/z 7%)ˆ411 738)/409 735) [M1], 365
725)/363 726) [M0 ], 364 784)/362 784) [M0211], 340
1
758)/338 756), 339 752), 337 737), 314 737)/311 735), 312
767) 310 762).Anal.calcd for C 15H22BrFNO4P 7410.21)/
C13H16BrFNO3P 7364.15) 784/16 mol%): C, 43.75; H,
5.25; N, 3.48. Found C, 43.51; H, 5.31; N, 3.71.
3
4
8.14 7m, 2H, H-o), 8.73 7dd, Jˆ8.1 Hz, JPHˆ7.3 Hz, 1H,
H-3), 11.38 7br, 1H, NH). 13C NMR 7CDCl3): d 15.9 7d,
3Jˆ6.7 Hz, Me), 20.4 7s, 5-Me), 62.4 7d, 2Jˆ4.9 Hz,
OCH2), 113.5 7d, 1Jˆ179.4 Hz, C-1), 120.7 7d,
3Jˆ12.4 Hz, C-3), 126.8 and 128.0 72C-o/m), 130.8 7C-p,
uncertain), 132.5 7d, 2Jˆ6.0 Hz, C-6), 132.6 7d, 3Jˆ
4.3.8. Oxalic acid 2-4diethoxyphosphono)anilide 2-
bromoanilide 42j). Excess triethyl phosphite 715.65 mL,
91.1 mmol) was added to 1j 715.2 g, 38.2 mmol) and 0.2 g
NiCl2 at 190±2008C.Heating was continued for 15 min at
200±2158C.After cooling to room temperature, the crude
solid 7d31P 18.5 and 18.2 st, 7.8 w) was extracted several
times with ether.On concentration and cooling of the ether
fraction 5.2 g 730%) of pale yellow 2j were collected, mp
117±1198C.7Extraction of the residue with ethanol and
removal of the solvent gave further 2 g of a pale green
4
14.0 Hz, C-5), 134.5 7C-i, uncertain), 134.6 7d, Jˆ2.0 Hz,
2
C-4), 140.2 7d, Jˆ7.1 Hz, C-2), 167.3 7s, CO). 31P NMR
7CDCl3): d 20.5. Anal. calcd for C18H22NO4P 7347.35): C,
62.24; H, 6.38; N, 4.03. Found: C, 61.72; H, 6.17; N, 3.95.
4.3.6. 2-Acetamido-3,5-di¯uorobenzenephosphonic acid
diethylester 42f). Triethyl phosphite 710.95 mL,
63.9 mmol) was added to 1f 713.74 g, 54.9 mmol) and
NiCl2 70.2 g) at 1708C and heating continued for 30 min at
1908C. 31P NMR control of the residue displays compounds
with d31P -0.8, 7.7, 13.8 7main product), 15.2 and 33.9
[EtPO7OEt)2].Distillation gave 73. g 744%) of a viscous
liquid fraction, bp 129±1318C/2.6£1023 Torr, identi®ed
by NMR as 2f contaminated by a second P±C coupling
product: 31P NMR 7CDCl3) dˆ13.7 7t, JPF<10, 9 Hz, 2f),
15.2 7dd, JPFˆ12.1, 9.2 Hz, impurity; estimated intensity
1
solid, mp 78±838C, consisting mainly of 2j.) H NMR
3
7CDCl3): d 1.34 7t, Jˆ7.0 Hz, 6H, Me), 4.12, 4.25 7m,
2JHHˆ10.0 Hz, 3JPHBˆ7.9 Hz, 3JPHA<8.6 Hz, 3JHH
ˆ
7.1 Hz, 4H, POCHAHB), 7.05 7td, 3Jˆ8, 7.6 Hz,
4J<1.5 Hz, 1H, 4-H0), 7.26 7tdd superimposed, J<7.5 Hz,
3
JPH<3.1 Hz, 4J<1 Hz, 4-H), 7.36 7td, 3Jˆ8.1, 7.5 Hz,
3
4J<1 Hz, 1H, 5-H0), 7.62 7t br, J<7.8 Hz, 1H, 5-H), 7.60
7dd, 3Jˆ8.1 Hz, 4J<1.5 Hz, 1H, 3-H0), 7.74 7ddd,
3
4
3JPHˆ14.3 Hz, Jˆ7.6 Hz, Jˆ1.4 Hz, 1H, 3-H), 8.60 7dd,

9970
J. Heinicke et al. / Tetrahedron 57 72001) 9963±9972
4
3Jˆ8.2 Hz, Jˆ1.2 Hz, 1H, 6-H0), 8.70 7dd, 3J<7.6 Hz,
7100) [M1], 162 779), 161 710), 148 719), 131 77), 121 76),
77 77).Anal.calcd for C H10NP 7163.16): C, 66.25; H, 6.17;
N, 8.58. Found: C, 65.90; H, 6.10; N, 8.50.
4JPH<6.8 Hz, 1H, 6-H), 9.98 7s, 1H, NH0), 12.20 7s, 1H,
9
NH). 13C NMR 7CDCl3): d 15.2 7d, Jˆ6.2 Hz, Me), 61.8
3
7d, 2Jˆ5.2 Hz, OCH2), 112.8 7C-20), 115.2 7d, 1Jˆ180.9 Hz,
3
C-2), 119.8 7d, Jˆ10.9 Hz, C-6), 120.2 7C-60), 123.6 7d,
4.4.2. 2-t-Butyl-5-methyl-1H-1,3-benzazaphosphole 46d).
A solution of 2d 725.50 g, 0.077 mol) in ether 720 mL) was
added dropwise at 0±58C to LiAlH4 tablets 77.36 g,
0.193 mol) stirred in ether 7250 mL). Stirring was continued
for 2 d at 208C, then the mixture was cooled to 0±58C, and
hydrolysed with degassed water until the hydrogen evolu-
tion ceased.Na 2SO4 was added, the mixture was ®ltered and
the solid thoroughly washed with ether.Removal of the
solvent gave a viscous oil which was distilled at 90±958C/
0.5£1024 Torr.Crystallisation from dry pentane furnished
7.2 g 746%) 6d as colourless solid, mp 97±998C.IR 7Nujol):
3Jˆ13.1 Hz, C-4), 125.1 7C-40), 127.5 7C-50), 131.5 7C-30),
132.2 7d, 2Jˆ6.3 Hz, C-3), 133.0 7C-10), 133.6 7C-5), 139.3
7C-1), 156.4 and 157.1 7CvO). 31P NMR 7CDCl3): d 18.3.
Anal.calcd for C 18H20BrN2O5P 7455.24): C, 47.49; H, 4.43;
N, 6.15. Found: C, 47.25; H, 4.55; N, 6.03.
4.3.9. 2-4N-Methyl)formamido-benzenephosphonic acid
diethyl ester 45). Triethyl phosphite 714.9 mL,
86.7 mmol) was added to 422 716.15 g, 75.4 mmol) and
0.1 g PdCl2 heated at 1708C.Heating up to 190 8C was
continued for 1 h.The resulting yellow-brown solution
was distilled in vacuum to give 8.84 g 743%) colourless
1
4
n 3375 cm21. H NMR 7CDCl3): d 1.49 7d, JPHˆ1.2 Hz,
Å
9H, CMe3), 2.17 7s, 5-Me), 7.10 7dm, 3Jˆ8.3 Hz, 4Jˆ
1
5
3
oily 5, bp 125±1288C/0.01 Torr. H NMR 7CDCl3): d 1.36
0.9 Hz, JPHˆ0.5 Hz, 1H, H-6), 7.43 7d br, Jˆ8.3 Hz, 1H,
H-7), 7.76 7m, 3JPHˆ3.5 Hz, Jˆ1.8, 0.9 Hz, 1H, H-4), 9.24
7br, 1H, NH). 13C NMR 7CDCl3): d 21.2 75-Me), 31.4 7d,
3
7t, Jˆ7.1 Hz, 6H, Me), 3.27 7s, 3H, NMe), 4.19 7m, 4H,
OCH2), 7.31 7ddd, 3Jˆ7.8 Hz, 3JPHˆ5.9 Hz, 4Jˆ1.1 Hz, 1H,
H-3), 7.51 7tdd, 3Jˆ7.6 Hz, JPHˆ3.4 Hz, 4Jˆ1 Hz, 1H,
4
3Jˆ9.1 Hz, CMe3), 35.8 7d, Jˆ13.3 Hz, CMe3), 112.8 7s,
2
H-5), 7.66 7tdd, 3Jˆ7.7 Hz, JPHˆ1.6 Hz, JPHˆ1.3 Hz,
4
5
4
2
C-7), 126.0 7d, Jˆ2.1 Hz, C-6), 128.0 7d, Jˆ21.1 Hz,
1H, H-4), 8.04 7ddd, 3Jˆ7.7 Hz, JPHˆ14.7 Hz, 4Jˆ
3
3
1
C-4), 129.3 7d, Jˆ11.6 Hz, C-5), 140.5 7d, Jˆ40.9 Hz,
1.6 Hz, 1H, H-6), 8.13 7s, CHO). 13C NMR 7CDCl3): d
2
1
C-3a), 140.6 7d, Jˆ5.8 Hz, C-7a), 189.8 7d, Jˆ57.5 Hz,
C-2). 31P NMR 7CDCl3): d 63.5. MS 7EI, 70 eV): m/z
7%)ˆ206 742), 205 7100) [M1], 191 756), 190 745), 177
723), 162 736), 158 763), 150 750), 149 757), 148 735).
Anal.calcd for C 12H16PN 7205.24): C, 70.23; H, 7.86; N,
6.82. Found: C, 69.87; H, 8.00; N, 6.70.
16.0 7d, 3Jˆ6.4 Hz, Me), 33.7 7s, NMe), 62.3 7d,
2Jˆ6.1 Hz, OCH2), 127.9 7d, Jˆ187.9 Hz, C-1), 128.1 7d,
1
3Jˆ15.1 Hz, C-3), 129.6 7d, Jˆ10.6 Hz, C-5), 133.7 7d,
3
4Jˆ2.3 Hz, C-4), 134.5 7d, 2Jˆ8.3 Hz, C-6), 143.8 7d,
2Jˆ4.5 Hz, C-2), 162.6 7s, CO). 31P NMR 7CDCl3): d
15.9. 7Low intensity set of signals for less populated rotamer
not indicated.) MS 7EI, 70 eV): m/z 7%)ˆ271 76) [M1], 258
717), 248 7100), 223 758), 205 749), 194 762), 173 776), 153
731), 134 737), 106 747), 77 743), 65 719), 47 719), 29 731).
Anal.calcd for C 12H18NO4P 7271.25): C, 53.14; H, 6.69; N,
5.15. Found: C, 52.87; H, 6.66; N, 5.50.
4.4.3. 2-Phenyl-5-methyl-1H-1,3-benzazaphosphole 46e).
2e 710.43 g, 30 mmol) was added in small portions at 0±58C
to LiAlH4 tablets 73 g, 79 mmol) stirred in ether 7250 mL).
After stirring for 2 d at 208C the mixture was hydrolysed. 7e
7d31P 2152.3) and smaller amounts of other side products
were removed as described for 6c.46. 1 g 768%) of yellow
6e was crystallised from toluene, mp 175±1778C. 1H NMR
4.4. Reduction of 2-amidobenzenephosphonic acid esters
with LiAlH4
3
7CDCl3): d 2.44 7s, 5-Me), 7.15 7dm, Jˆ8.4 Hz, J<1.1,
0.5 Hz, 1H, H-6), 7.30-7.44 7m, 3H, H-m/p), 7.48 7d br,
3Jˆ8.4 Hz, 1H, H-7), 7.74±7.78 7m, 2H, H-o), 7.81 7m,
3JPHˆ3.9 Hz, J<1.5, 0.7 Hz, 1H, H-4), 9.45 7br, 1H, NH).
13C NMR 7CDCl3): d 21.2 75-Me), 113.2 7s, C-7), 125.2 7d,
Reduction of 2a and 2b was described earlier.5
4.4.1. 2,5-Dimethyl-1H-1,3-benzazaphosphole 46c). LiAlH4
tablets 74.0 g, 105.4 mmol) were stirred in ether 7ca.
300 mL) for 20 min, and 2c 713.79 g, 48.0 mmol) was
added dropwise at 15±208C.The mixture was allowed to
stir for 1 d.Then, degassed water was added dropwise until
the evolution of hydrogen ceased.Solids were ®ltered off
and washed with ether.The slightly yellow ®ltrate was
extracted with air-free cold 10% aqueous H2SO4 to remove
contamination by 2-phosphinoanilines.The ether layer was
then washed with water, dried over Na2SO4, and ®ltered.
White crystals were obtained from the concentrated solution
and were recrystallised from toluene, yield 4.01 g 751%),
4
3Jˆ12.6 Hz, C-o), 127.0 7d, Jˆ3.1 Hz, C-6), 128.2 7d,
2Jˆ21.1 Hz, C-4), 128.8 7d, 5Jˆ3.0 Hz, C-p), 129.1 7s,
3
2
C-m), 129.8 7d, Jˆ12.9 Hz, C-5), 135.1 7d, Jˆ15.3 Hz,
2
1
C-i), 141.2 7d, Jˆ7.0 Hz, C-7a), 141.9 7d, Jˆ41.0 Hz,
1
C-3a), 174.1 7d, Jˆ51.3 Hz, C-2); CH-COSY supported
assignment. 31P NMR 7CDCl3): d 74.4. MS 7EI, 70 eV):
m/z 7%)ˆ226 799), 225 7100) [M1], 224 780), 211 710),
197 774), 183 719), 148 731), 121 741), 107 728), 91 799),
77 757).Anal.calcd for C 14H12NP 7225.23): C, 74.66; H,
5.37; N, 6.22: Found: C, 74.57; H, 5.57; N, 6.16.
1
4.4.4. 5,7-Di¯uoro-2-methyl-1H-1,3-benzazaphosphole
46f). A solution of crude 2f 77.34 g, 23.9 mmol) in ether
720 mL) was added dropwise to four tablets of LiAlH4
7ca.4 g, 105 mmol) stirred in ether 7100 mL) at ca.5 8C.
The mixture was stirred for a further 2 d at 208C and
hydrolysed.Minor amounts of 7f 7d31P 2136) and traces
of two other PH compounds were removed as described for
6c yielding 1.22 g 728%) of 6f as colourless crystals, mp
mp 125±1278C. H NMR 7CDCl3): d 2.41 7s, 3H, 5-Me),
2.70 7d, JPHˆ12.1 Hz, 3H, Me), 7.08 7dm, 3Jˆ8.3 Hz,
3
5
3
4J<1.6 Hz, JPH<0.5 Hz, 1H, H-6), 7.36 7d, Jˆ8.3 Hz,
3
4
1H, H-7), 7.72 7dm, JPHˆ3.6 Hz, J<1.6 Hz, 1H, H-4),
9.00 7br, 1H, NH). 13C NMR 7CDCl3): d 17.6 7d,
2Jˆ22.4 Hz, 2-Me), 21.2 7s, 5-Me), 112.6 7s, C-7), 125.9
3
3
7d, Jˆ2.2 Hz C-6), 127.8 7d, Jˆ20.1 Hz, C-4), 129.5 7d,
2Jˆ10.6 Hz, C-5), 140.6 7d, Jˆ5.7 Hz, C-7a), 141.4 7d,
2
1
3
1Jˆ41.7 Hz, C-3a), 173.3 7d, Jˆ51.5 Hz, C-2). 31P NMR
1
1058C. H NMR 7CDCl3): d 2.79 7d, JPHˆ12.3 Hz, 3H,
4
Me), 6.82 7ddd, JFHˆ11.0, 8.9 Hz, Jˆ2.3 Hz, 1H, H-6),
7CDCl3): d 71.8. MS 7EI, 70 eV): m/z 7%)ˆ164 711), 163

J. Heinicke et al. / Tetrahedron 57 72001) 9963±9972
9971
4
3
3
7.40 7ddd, JFHˆ8.4 Hz, JPHˆ3.0 Hz, Jˆ2.3 Hz, 1H, H-4),
7.21 7tm, Jˆ8.2, 7.3 Hz, 1H, H-5), 7.51 7ddd, Jˆ7.4 Hz,
9.13 7br, 1H, NH). 13C NMR 7CDCl3): d 17.6 7d,
2Jˆ22.6 Hz, 2-Me), 149.5 7dd, JFCˆ250.7, 12.9 Hz, C-7),
3JPHˆ12.6 Hz, Jˆ1.5 Hz, 1H, H-3). 13C NMR 7C6D6): d
4
1
31.0 7Me), 110.1 7br, C-6), 111.3 7d, Jˆ10.8 Hz, Cq-2),
3
3
108.2 7dt, Jˆ4.1 Hz, JFCˆ22.1 Hz, C-6), 99.4 7ddd, Jˆ
117.4 7d, 3Jˆ12.1 Hz, C-4), 132.4 7s, C-5), 139.2 7d,
2Jˆ34.2 Hz, C-3), 152.5 7s, Cq-1). 31P NMR 7C6D6): d
2155.1.
2
20.1 Hz, JFCˆ30.0, 1.5 Hz, C-4), 156.9 7ddd, Jˆ8.9 Hz,
JFCˆ241.7, 12.4 Hz, C-5), 127.6 7dd, 2Jˆ4.3 Hz, JFCˆ
1
9.9 Hz, C-7a), 144.5 7ddd, Jˆ46.6 Hz, JFCˆ8.5, 1.6 Hz,
C-3a), 175.5 7dd, 1Jˆ54.5 Hz, JFCˆ1.4 Hz, C-2). 31P
NMR 7CDCl3): d 80.5 7dd, JPFˆ15.9, 8.3 Hz). MS 7EI,
70 eV): m/z 7%)ˆ186 723), 185 7100) [M1], 184 794), 183
715), 157 711), 153 719), 143 718), 142 727), 139 712), 134
724), 75 718), 69 724).Anal.calcd for C 8H6F2NP 7185.11):
C, 51.91; H, 3.27; N, 7.57. Found: C, 52.4; H, 3.88; N, 7.52.
4.5. Crystal-structure analysis of 6d
A yellow tablet was mounted in inert oil on a glass ®ber and
transferred to the cold gas stream of a Bruker SMART 1000
CCD diffractometer.The structure was solved by direct
methods and re®ned using the program SHELXL-97
È
7G.M. Sheldrick, University of Gottingen).Hydrogen
4.4.5. 5-Bromo-2-t-butyl-7-¯uoro-1H-1,3-benzazaphos-
phole 46g). A solution of 2g and 3g 76.48 g, ca.
15.8 mmol) in ether 730 mL) was added dropwise at
0±58C to LiAlH4 tablets 71.44 g, 37.9 mmol) stirred in
ether 770 mL).Stirring was continued for 4 d at 20 8C.
Then the mixture was hydrolysed with degassed water at
0±58C, ®ltered and the ®ltrate was dried with Na2SO4.
Removal of the solvent gave viscous oily 6g, slightly
contaminated by primary 7mainly d31P 2141.7) and second-
ary phosphines and a small amount of another 1H-1,3-
atoms were re®ned either freely 7NH), as rigid methyl
groups, or using a riding model.The compound crystallises
in a chiral space group; the absolute structure for the crystal
investigated was determined by the Flack parameter of
20.0277).
Complete crystallographic data 7excluding structure
factors) have been deposited at the Cambridge Crystallo-
graphic Data Centre under the number CCDC 164270,
and may be obtained free of charge from the Director
7deposit@ccdc.cam.ac.uk).
4
benzazaphosphole with d731P) 72.6, JPFˆ7.9 Hz. Distilla-
tion furnished 1.8 g 740%) of a colourless oil, bp 85±908C/
2£1022 Torr which was crystallised from pentane 7258C),
mp 63±658C.It is easily soluble in common organic
solvents.IR 7KBr):
n .
3403, 3349 cm21 1H NMR
Acknowledgements
Å
4
7CDCl3): d 1.51 7d, JPHˆ1.2 Hz, 9H, CMe3), 7.15 7dd,
4
3
3JFHˆ10.3 Hz, Jˆ1.6 Hz, 1H, H-6), 7.86 7t, JPHˆ2.5 Hz,
We thank the Deutsche Forschungsgemeinschaft 7N.G,.
A.S). and the Deutsche Akademische Austauschdienst
7K.S). for grants and the Fonds der Chemischen Industrie
for ®nancial support.
Jˆ1.6 Hz, 1H, H-4), 9.18 7br, 1H, NH). 13C NMR 7C6D6): d
3
2
31.6 7d, Jˆ9.2 Hz, CMe3), 36.4 7d, Jˆ13.0 Hz, CMe3),
113.5 7dd, 4Jˆ1.5 Hz, JFCˆ20 Hz, C-6), 113.6 7dd,
2
3
3Jˆ10.6 Hz, JFCˆ6.9 Hz, C-5), 127.5 7dd, 2Jˆ22.2 Hz,
4JFCˆ3.8 Hz, C-4), 130.8 7dd, Jˆ4.5 Hz, JPFˆ10.7 Hz,
2
2
1
3
C-7a), 146.5 7d, Jˆ47.9 Hz, JPFˆ1.3 Hz, C-3a), 150.9
References
1
7dd, JFCˆ251.7 Hz, 3Jˆ1.5 Hz, C-7), 192.5 7dd, 1Jˆ
4
61.4 Hz, JFCˆ1.5 Hz, C-2). 31P NMR 7CDCl3): d 72.6 7d,
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721), 274 7100), 273 724), 272 7100), 233 721), 231 721), 193
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5
79.47 g,
5. Bansal, R. K.; Gupta, N.; Heinicke, J.; Nikonov, G. N.;
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