Diazophosphonates: Effective Surrogates for Diazoalkanes in Pyrazole Synthesis

Article abstract of DOI:10.1002/chem.202101788

Diazophosphonates, readily prepared from α-ketophosphonates by oxidation of the corresponding hydrazones in batch or in flow, are useful partners in 1,3-dipolar cycloaddition reactions to alkynes to give N-H pyrazoles, including the first intramolecular examples of such a process. The phosphoryl group imbues a number of desirable properties into the diazo 1,3-dipole. The electron-withdrawing nature of the phosphoryl stabilizes the diazo compound making it easier to handle, whilst the ability of the phosphoryl group to migrate readily in a [1,5]-sigmatropic rearrangement enables its transfer from C to N to aromatize the initial cycloadduct, and hence its facile removal from the final pyrazole product. Overall, the diazophosphonate acts as a surrogate for the much less stable diazoalkane in cycloadditions, with the phosphoryl group playing a vital, but traceless, role. The cycloaddition proceeds more readily with alkynes bearing electron-withdrawing groups, and is regiospecific with asymmetrical alkynes. The potential of diazophosphonates for use in bioorthogonal cycloadditions is demonstrated by their facile addition to strained alkynes.

Full text of DOI:10.1002/chem.202101788

Accepted Article
Accepted Article
Title: Diazophosphonates: Effective surrogates for Diazoalkanes in
Pyrazole Synthesis
Authors: Katie Ruffell, Frances R. Smith, Michael T. Green, Simon M.
Nicolle, Martyn Inman, William Lewis, Christopher J. Hayes,
and Christopher John Moody
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To be cited as: Chem. Eur. J. 10.1002/chem.202101788
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01/2020

10.1002/chem.202101788
Chemistry - A European Journal
COMMUNICATION
Diazophosphonates: Effective Surrogates for Diazoalkanes in
Pyrazole Synthesis
Katie Ruffell, Frances R. Smith, Michael T. Green, Simon M. Nicolle, Martyn Inman, William Lewis,
Christopher J. Hayes* and Christopher J. Moody*
[a]
Ms K. Ruffell, Dr F. R. Smith, Mr M. T. Green, Dr S. M. Nicolle, Dr M. Inman, Prof Dr C. J. Hayes*, Prof Dr C.J. Moody*
School of Chemistry
University of Nottingham
University Park, Nottingham NG7 2RD, U.K.
E-mail: chris.hayes@nottingham.ac.uk, c.j.moody@nottingham.ac.uk
Supporting information for this article is given via a link at the end of the document.
Abstract: Diazophosphonates, readily prepared from α-
ketophosphonates by oxidation of the corresponding hydrazones
in batch or in flow, are useful partners in 1,3-dipolar cycloaddition
reactions to alkynes to give N-H pyrazoles, including the first
intramolecular examples of such a process. The phosphoryl
group imbues a number of desirable properties in the diazo 1,3-
dipole. The electron-withdrawing nature of the phosphoryl
stabilizes the diazo compound making it easier to handle, whilst
the ability of the phosphoryl group to migrate readily in a [1,5]-
sigmatropic rearrangement enables its transfer from C to N to
aromatize the initial cycloadduct, and hence its facile removal
from the final pyrazole product. Overall, the diazophosphonate
acts as a surrogate for the much less stable diazoalkane in
cycloadditions, with the phosphoryl group playing a vital, but
traceless, role. The cycloaddition proceeds more readily with
alkynes bearing electron-withdrawing groups, and is regiospecific
with unsymmetrical alkynes. The potential for use of
However, the synthesis of pyrazoles by the reaction of 1,3-
dicarbonyl compounds with hydrazines is not the only method
available.[1,2] In particular, the 1,3-dipolar cycloaddition of
diazo compounds to alkynes,[2,4] first discovered by Buchner
in 1889,[5] is a highly effective route to pyrazoles, since no σ-
bonds are broken in the process. Recently, such efficient
cycloadditions have come to the fore in bioorthogonal
chemistry,[6,7] a term first introduced by Bertozzi in 2003 to
cover chemical reactions that can be conducted in living
systems without disrupting natural processes.[8,9] Although
bioorthogonal cycloadditions are mainly exemplified by the
well known azide-alkyne click chemistry,[10-13] other 1,3-
dipoles including diazo compounds also function, sometimes
at higher rates.[14-20] In continuation of our interest in the
generation and reaction of diazo compounds,[21-27] we now
report that diazophosphonates are particularly suitable 1,3-
dipoles in both intermolecular, and for the first time,
intramolecular cycloaddition reactions with alkynes to give N-
unsubstituted pyrazoles.
diazophosphonates
in
bioorthogonal
cycloadditions
is
demonstrated by their facile addition to strained alkynes.
The cycloaddition of diazo compounds to alkynes to
give pyrazoles is an efficient process, notwithstanding the
safety issues in handling diazo compounds, although these
can be alleviated by their generation in situ and direct
conversion into pyrazoles.[28] However, we reasoned that
diazophosphonates[29] would be a viable alternative given the
useful properties of the phosphoryl group, wherein it would
fulfill three key functions. Firstly its electron-withdrawing
nature stabilizes the diazo compound making it easier to
handle, but more importantly, the little known and unexploited
propensity of the phosphoryl group to migrate readily in
sigmatropic rearrangements facilitates its transfer from C to N
in the initial cycloadduct, that, thirdly, results in its facile
removal from the final pyrazole product (Scheme 1). Hence
overall, the diazophosphonate, RCN2PO(OR)2, acts as a
surrogate for the much less stable diazoalkane, RCHN2 in
cycloadditions.
Nitrogen-containing heterocyclic compounds are of huge
academic, industrial and commercial importance, and play a
major role in Nature and as medicines, agrochemicals, and
materials for electronics. Within this large family of ring
systems, pyrazoles hold a special place in view of their
presence in a wide range of bioactive compounds.[1,2] The first
pyrazole derivative was prepared by Ludwig Knorr in 1883 by
the reaction of phenylhydrazine with ethyl acetoacetate,[3] and
the useful medicinal properties of its N-methyl derivative
(phenazone) were very quickly discovered. In the modern era,
a number of pyrazoles have become best-selling medicines,
including the antiinflammatory agent celecoxib and the
phosphodiesterase 5 inhibitor sildenafil (Figure 1).
CF3
OEt
Pr
O
N
O
N
N
N
S
O
N
N
HN
Me
N
Ph
Me
N
Me
O
Me
N
Me
SO2NH2
celecoxib
phenazone
sildenafil
Figure 1.
1
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10.1002/chem.202101788
Chemistry - A European Journal
COMMUNICATION
H
R
P
EWG
H
EWG
hydrazone 5a was also carried out in flow over polymer
supported TsNIK resin in quantitative yield as previously
described (Scheme 2B).[24] Flow chemistry could also be
applied to the synthesis of ketophosphonate 4a by flowing an
equimolar mixture of phenylacetyl chloride and triethyl
phosphite through a coil reactor at 50 °C (residence time 5
min) directly into a solution of hydrazine hydrate in acetic
acid/ethanol. The resulting hydrazone was oxidized giving
diazophosphonate 6a in 75% overall yield from the acid
chloride (Scheme 2C).
1,3-dipolar
R
N
N
cycloaddition
N
N
(EtO)2OP
EtO
EtO
1
O
[1,5]-sigmatropic
shift of PO(OEt)2
H
EWG
H
EWG
mild hydrolysis
N
N
R
R
N
N
H
PO(OEt)2
3
2
NH2
A.
O
N2
N
O
NH2NH2
P(OEt)3
O
O
TsNIK
O
Scheme 1. Diazophosphonates in pyrazole synthesis (EWG = electron-
withdrawing group)
R
P
R
P
OEt
OEt
R
P
R
Cl
OEt
EtO
EtO
EtO
4
5
6
Diazophosphonates, first prepared in 1967,[30,31] are best
known for use in the Seyferth-Gilbert and Bestmann-Oshira
reagents that convert aldehydes into alkynes.[32-34] In some
cases the resulting alkyne can undergo cycloaddition with the
original diazo compound to give pyrazoles.[35,36] However, the
early work on the addition of diazophosphonates to alkynes is
due to Regitz.[37] The reaction proceeds by 1,3-polar
cycloaddition, which is regiospecific in the case of
unsymmetrical alkynes as shown in Scheme 1, to give an
intermediate 3H-pyrazole 1,[38] that undergoes the so-called
van Alphen-Hüttel rearrangement via 1,5-sigmatropic
migration of the phosphoryl group to give the pyrazole-1-
phosphonate 2. N-Phosphorylpyrazoles are reactive
phosphorylating agents,[39,40] and hence the N-P bond in 2 is
readily cleaved under mild conditions to deliver the parent
a R = CH2Ph; b R = 4-MeOC6H4; c R = c-Hex; d R = BnOCH2
e (S)-N-Boc-pyrrolidin-2-yl; f (S)-N-Cbz-pyrrolidin-2-yl
B.
NH2
N
N2
flow rate
Ph
Ph
PO(OEt)2
PO(OEt)2
0.2 ml/min
PS-TsNIK
residence
5 min
6a
0.1 - 0.2 M in CH2Cl2
Diazo compound (ca. 100%)
solution in CH2Cl2
C.
N2
O
50 °C, coil
reactor
residence
time 5 min
Ph
PO(OEt)2
6a (75% overall)
Ph
Cl
0.5 M in CH2Cl2
TsNIK, THF
KOH (in batch)
NH2
N
work up
P(OEt)3
Ph
PO(OEt)2
0.5 M in CH2Cl2
NH2NH2 (1.05 eq)
EtOH, AcOH
5a
pyrazole heterocycle
phosphoryl group being traceless.[41] The key step in the
formation of pyrazole is the facile sigmatropic
3 (Scheme 1) with the original
3
Scheme 2. A. Preparation of diazophosphonates
6
by oxidation of
hydrazones 5; B. Flow preparation of diazophosphonate 6a; C. Flow
preparation of hydrazone 5a, and its subsequent oxidation to
diazophosphonate 6a.
rearrangement of the phosphoryl group. Although acyl groups
are well known for their high migratory aptitude, for example a
formyl group migrates over 100 times faster than hydrogen in
[1,5]-sigmatropic rearrangements in cyclohexa-2,4-dienes,[42]
and
a carboxylate migrates extremely readily in 3H-
The cycloaddition reactions were initially investigated using
the diazophosphonate 6a with a range of alkynes. The
reaction occurred over prolonged time in dichloromethane at
reflux, and after chromatography gave a mixture of the 1-
pyrazoles,[43] almost nothing is known about the participation
of P=O containing groups in sigmatropic rearrangements.
Nevertheless it is clear from Regitz.[37] and the present work
that such groups have high migratory aptitudes.
phosphorylpyrazole
7,
formed
by
1,5-sigmatropic
Intermolecular cycloadditions. The synthesis of a small range
of diazophosphonates 6 was carried out by oxidation of the
corresponding hydrazones 5 using potassium N-iodo p-
toluenesulfonamide (TsNIK, iodamine-T), a reagent recently
developed in our laboratory.[44] This conveniently prepared
reagent has advantages over the heavy-metal based oxidants
traditionally used for this transformation. Also, when
supported on polystyrene it can be used under flow
conditions and readily recycled.[24,45] The hydrazones 5 can
be accessed from the corresponding ketophosphonates 4,
which are commercially available or obtained by Arbuzov-like
reaction of triethyl phosphite with the corresponding acid
chloride (Scheme 2A). Although, the hydrazones 5 can be
isolated, normally the reaction is run in sequence from acid
rearrangement of initial cycloadduct (Scheme 1), and the NH-
pyrazole 8 in which the phosphoryl had partially hydrolysed,
presumably during chromatography. In all cases (Table 1,
entries 1, 3, 5-8), the N-phosphoryl compound 7 was the
major product, although it was not possible to obtain pure
samples due to the aforementioned facile dephosphorylation.
The reaction proceeded more readily, and in better yield, with
electron-deficient alkynes as anticipated for a LUMOdipolarophile
reaction and exhibited the expected regioselectivity with
unsymmetrical alkynes. Thus trimethylsilyl- and phenyl-
acetylene both exhibited poor reactivity with low conversion to
product even after 48 hours (Table 1, entries 7 and 8),
although both reactions were regioselective. The
diazophosphonate 6a derived from the in-flow oxidation of
hydrazone 5a was directly added to a solution of the alkyne.
Under these conditions, the hydrolysis of the phosphoryl
group was more complete upon work, presumably due to the
presence of potassium hydroxide in the polymer supported
chloride to diazophosphonate
6
without isolation and
purification of intermediates. The two proline-derived
diazophosphonates 6e and 6f were prepared in this manner
although the yield of the Boc-compound 6e was poor The
preparation of diazophosphonate 6a by oxidation of
2
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COMMUNICATION
TsNIK resin used for the hydrazone oxidation, and gave the
NH-pyrazole as the major product (Table 1, entries 2 and 4).
R1
R2
N2
R1
R2
O
R
P
OEt
N
1. toluene, reflux
0.75 - 4 h
2. aq NaOH, MeOH
R
N
H
EtO
R1
R2
R1
R2
N2
O
R1
R2
chromatography
PhCH2
6
8
PhCH2
P
OEt
N
N
CH2Cl2, reflux PhCH2
6 - 48 h
N
N
H
EtO
PO(OEt)2
O
6a
7a-f
8a-f
MeO2C
Ph
CO2Me
CO2Me
Me
N
Ph
N
Ph
N
N
N
N
Table 1. 1,3-Dipolar cycloaddition of diazophosphonate 6a to alkynes.
H
H
H
R1
R2
7/8
8a (79%)
8b (79%)
8c (83%)
7 + 8
7 + 8
Entry
Yield (%)
Ratio
Ph
CO2Me
SiMe3
Ph
1
2
3
4
5
6
7
8
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
COMe
CO2Me
SiMe3
Ph
a
a
b
b
c
d
e
f
83
77:23
0:100
86:14
22:78
78:22
72:28
99:1
Ph
N
Ph
N
Ph
N
N
N
N
79 [a]
85
H
H
H
CO2Me
8d (35%)
8e (16%)
8f (29%)
H
O
MeO2C
Ph
CF3
MeO2C
CO2Me
H
86 [a]
75
NH2
N
N
N
N
H
Ph
N
H
H
N
MeO
H
Ph
H
15
8g (68%)
8h (59%)
8i (71%) a
12
O
O
MeO2C
CO2Me
N
H
CO2Me
H
8
81:19
S
Me
BnO
N
N
N
N
N
H
H
[a] Diazophosphonate generated in flow.
H
MeO
At this juncture, we elected to simplify the process by the
addition of a hydrolysis step. Thus after the cycloaddition, the
solution was evaporated to dryness and redissolved in
methanol with the addition of aqueous sodium hydroxide.
Hydrolysis was rapid and gave the NH-pyrazole 8b in 79%
yield from the reaction of diazophosphonate 6a with methyl
propiolate. Subsequently this method was used in the
cycloadditions of diazophosphonates 6a-6d with alkynes,
including two additional alkynes, carried out in toluene at
reflux to accelerate the reaction, to give pyrazoles 8a-8l
(Scheme 3). Unsymmetrical alkynes were regioselective in
their additions. Again, both trimethylsilylacetylene and
phenylacetylene gave the corresponding pyrazoles 8e and 8f
regioselectively but in low yield, with competing Bamford-
Stevens reaction to diethyl (E)-styrylphosphonate occurring at
the higher temperature. Attempted cycloaddition with 1-
octyne and 3-hexyne failed to produce pyrazole products,
with only the formation of the Bamford-Stevens product being
observed. Interestingly methyl 3-trifluoromethylpropiolate
exhibited opposite regiochemistry in the pyrazole 8h to
methyl propiolate and methyl 3-phenylpropiolate, in accord
with the strongly inductively electron withdrawing nature of
the CF3-group. Such regioselectivity with CF3-substituted
alkynes has been observed previously.[46] The regiochemistry
of pyrazole 8h was unambiguously assigned on the basis of
the 36 Hz J2 (F-C) coupling seen to C-3 (143.0 ppm) in the
13C NMR spectrum. In the case of 3-toluenesulfonylpyrazole
8j, the structure of the product was confirmed by X-ray
crystallography (Figure 2) corroborating the regiochemistry of
the cycloaddition. The yield from the reaction of diazo
compound 6d was poor, and the two proline-derived
diazophosphonates 6e and 6f gave no isolable cycloadducts.
The 1H-pyrazoles synthesized are shown in Scheme 3.
8j (50%)
8k (57%)
8l (9%)
Scheme 3. 1,3-Dipolar cycloaddition of diazophosphonates 6 to alkynes
and structures of resulting 1H-pyrazoles. aReaction carried out in
dichloromethane.
Figure 2. X-ray crystal structure of 5-(4-methoxyphenyl)-3-(4-
toluenesulfonyl)-1H-pyrazole 8j. Deposition number 2082983 contains the
supplementary crystallographic data for this paper. These data are
provided free of charge by the Cambridge Crystallographic Data Centre
(http://www.ccdc.cam.ac.uk/structures).
Although the above cycloadditions to generate pyrazoles are
catalyst-free, they require elevated temperatures in order to
proceed at a reasonable rate. If diazophosphonates were to
be applied in bioorthogonal cycloadditions,[7] the reactions
should be able to take place at room temperature. Based on
an early observation by Wittig that the strained, cyclic alkyne
cyclooctyne reacted violently with phenyl azide to give the
triazole cycloadduct,[47] Bertozzi developed the use such
alkynes in bioothogonal chemistry.[48,49] Subsequently
number of cyclic alkynes have been developed for use in
a
3
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COMMUNICATION
Previous work
strain-promoted cycloadditions and used to label azide-
containing proteins and other biomolecules in live cells.[50,51]
TsHN
N
X
N
HN
X
In
diazophosphonates with strained alkynes, we elected to use
the bicyclo[6.1.0]nonyne derivative developed by
order
to
investigate
the
reaction
of
base
R
H
9
R
Dommerholt et al.[50] The compound is readily prepared, and
is symmetrical ensuring that upon cycloaddition only one
regioisomer is formed. The cycloooctyne exo-9 was then
reacted with the diazophosphonate 6b to give pyrazole 10 in
good yield (Scheme 4). This cycloaddition reaction was
performed at room temperature in less than 5 h and, again,
the phosphoryl group fulfilled its role by undergoing facile
[1,5]-sigmatropic migration to nitrogen, followed by its
cleavage under mild conditions. The endo-cyclic alkyne 9
reacted similarly and gave pyrazole 11 (66%) upon reaction
with diazophosphonate 6c for 5 h at room temperature,
followed by hydrolysis. These results illustrate that
appropriate water-compatible diazophosphonates might be
applicable in bioorthogonal cycloaddition reactions.
X= O, NTs
Refs 48 - 50
YHN
N
N
N
R
Y = Ts; base
Y = H; MnO2
R
X
Ar
X
Ar
X= O, NTs
Refs 51, 52
This work
O
H
N
OEt
OEt
P
1. PhMe, reflux
( )n
N
( )n
N2
R
2. MeOH, aq. NaOH
R
Scheme 5. Intramolecular cycloaddition of diazo compounds to alkynes.
H
N
MeO
The synthesis of the substrates for our proposed
intramolecular cycloaddition reactions was achieved from the
N
N2
O
+
P
1. CH2Cl2, rt, 5 h
OEt
known
terminal
trimethylsilyl
alkynoic
acids
EtO
H
H
MeO
2. aq NaOH, MeOH
rt, 2 h
59%
Me3SiC≡C(CH2)nCO2H, which were in turn readily prepared
from lithium trimethylsilylacetylide and the corresponding
bromoalkanoic acid. The acids were converted into the
hydrazones by a three-step sequence carried out without
isolation of intermediates as shown in the Supporting
information. Thus reaction with oxalyl chloride gave the acid
chloride that was immediately reacted with triethyl phosphite
in an Arbuzov reaction to give the ketophosphonates, readily
H
H
6b
OH
10
OH
exo-9
H
N
N
N2
O
+
P
1. CH2Cl2, rt, 5 h
OEt
EtO
H
H
2. aq NaOH, MeOH
rt, 2 h
66%
H
H
converted
into
the
hydrazones
6c
OH
Me3SiC≡C(CH2)nC(=NNH2)PO(OEt)2, isolated as a mixture of
E/Z-isomers, in good overall yield. Finally, TsNIK oxidation of
the hydrazones gave the desired diazophosphonates 12
isolated as yellow oils in excellent yield (see Supporting
Information). Preliminary studies with diazophosphonate 12b
established that the cycloaddition occurred extremely slowly
in dichloromethane at room temperature, and even after
prolonged heating at reflux, the product pyrazole 13b was
formed in mixture with its N-phosphoryl derivative (ca. 1:4,
11
OH
endo-9
Scheme
bicyclo[6.1.0]nonynes.
4.
Addition
of
diazophosphonates
to
strained
Intramolecular cycloadditions. In the vast panoply of
intramolecular cycloaddition reactions, the addition of diazo
1,3-dipoles to alkynes has only featured rarely. Most
examples employ aryl diazo compounds generated in situ
from the corresponding ortho-substituted benzaldehyde
tosylhydrazones, and give fused pyrazoles or spiro-4H-
pyrazoles according to whether the intermediate diazo
species is mono- or di-substituted (Scheme 5).[52-57] In
contrast, we chose to exploit the electron-withdrawing
properties of the phosphoryl group to enable the first
40%
combined).
Subsequently,
the
intramolecular
cycloadditions of diazophosphonates 12 were effected by
heating in toluene at reflux (2.5 – 48 h), followed by addition
of aqueous sodium hydroxide to achieve complete cleavage
of the phosphoryl group to give the fused pyrazoles 13
(Scheme 6). The cyclopenta- and cyclohexa- derivatives 13a
and 13b were formed in good yield whereas the
cycloheptapyrazole 13c formed much more slowly, and was
isolated in poor yield, presumably reflecting the increased
difficulty in forming 7-membered rings in intramolecular
cycloaddition reactions.
utilization of such diazo compounds in
a
range of
intramolecular 1,3-dipolar cycloadditions to give carbocyclic
fused pyrazoles (Scheme 5).
4
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10.1002/chem.202101788
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COMMUNICATION
O
H
N
highlights the role that diazophosphonates can play as
surrogates for less stable diazoalkanes.
OEt
OEt
P
1. PhMe, reflux
( )n
N
( )n
N2
2. MeOH, aq. NaOH
SiMe3
SiMe3
12a n = 1
12b n = 2
12c n = 3
13a n = 1 (73%)
13b n = 2 (85%)
13c n = 3 (15%)
Experimental Section
For full details of all experimental procedures and copies of 1H and
13C NMR spectra, see the Supporting Information.
N2
H
N
N
OEt
P
1. PhMe, reflux
OEt
O
2. MeOH, aq. NaOH
Acknowledgements
H
14
15 (83%)
We thank the BBSRC Doctoral Training Programme (grant ref
BB/M008770/1), the EPSRC Centre for Doctoral Training in
Sustainable Chemistry (grant ref EP/L015633/1) and the
University of Nottingham for studentships (to F.R.S., M.T.G.
and S.M.N. respectively).
N2
H
N
N
OEt
OEt
P
1. PhMe, reflux
O
2. MeOH, aq. NaOH
CO2Me
CO2Me
16
plus
Keywords: pyrazole • diazophosphonate • dipolar
17 (85%)
N-[PO(OEt)2]-17
cycloaddition • 1,5-sigmatropic rearrangement
Scheme 6. Intramolecular cycloaddition of diazophosphonates to alkynes
to give cycloalkapyrazoles.
[1]
A. Ansari, A. Ali, M. Asif, Shamsuzzaman, New J. Chem. 2017, 41,
16-41.
[2]
[3]
[4]
[5]
[6]
A. W. Brown, Adv. Heterocycl. Chem. 2018, 126, 55-107.
L. Knorr, Chem. Ber. 1883, 16, 2597-2599.
Given that use of trimethylsilylacetylene resulted in very poor
yield in the aforementioned intermolecular cycloadditions
(Table 1, entry 7), we investigated the effect that removal of
this bulky electron-releasing group would have on the
J. S. S. Neto, G. Zeni, Chem. Eur. J. 2020, 26, 8175-8189.
E. Buchner, Chem. Ber. 1889, 22, 842-847.
D. M. Patterson, L. A. Nazarova, J. A. Prescher, ACS Chem. Biol.
2014, 9, 592-605.
[7]
[8]
[9]
M. Vrabel, T. Carrell, in Topics in Chemistry Collection, Vol. 374,
Springer, Switzerland, 2016.
intramolecular
process.
Thus
the
alkynoic
acid
Me3SiC≡C(CH2)4CO2H was treated with methanolic
potassium carbonate to give the desilylated material,
heptynoic acid in near quantitative yield. Conversion into the
diazophosphonate 14 proceeded without incident by way of
the corresponding hydrazone (see Supporting Information).
On heating in toluene, diazophosphonate 14 underwent
intramolecular cycloaddition reaching completion in 1.5 h and
gave tetrahydroindazole 15 in high yield. Finally, we
investigated the effect of introduction of an electron-
withdrawing ester group onto the alkyne dipolarophile in
anticipation that its LUMO-lowering effect would increase the
rate of reaction. In the event, this proved to be the case.
However, attempted preparation of the diazophosphonate 16
by oxidation of the corresponding hydrazone, prepared as
shown in the Supporting Information, gave the expected
diazophosphonate 16 together with the phosphorylated
version of pyrazole 17 (68% combined), the cycloaddition
occurring during attempted isolation and purification of the
diazophosphonate 16 due to the reactive nature of the
electron-deficient dipolarophile. Subjecting the mixture of
diazophosphonate 16 and the phosphorylpyrazole to the
normal conditions gave the pyrazole 17 in excellent yield after
aqueous work-up (Scheme 6).
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6
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COMMUNICATION
Entry for the Table of Contents
Insert graphic for Table of Contents here.
H
EWG
N2
H
EWG
PO(OEt)2
N
cyclo-
addition
N
(EtO)2OP
PO(OEt)2 group
[1,5]-shift
stabilizes diazo compound
facile sigmatropic migration
facile removal from pyrazole
H
EWG
hydrolysis
N
H
EWG
N
N
N
H
PO(OEt)2
Diazophosphonates are excellent 1,3-dipoles in both inter- and intra-molecular cycloaddition reactions with alkynes to give N-H
pyrazoles. The phosphoryl group has three key roles: its electron-withdrawing nature stabilizes the diazo compound, its unexploited
propensity to migrate readily in sigmatropic rearrangements facilitates its transfer from C to N in the initial cycloadduct, and hence its
facile removal from the final pyrazole product.
7
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