Synthesis of α-aryl-diazophosphonates via palladium-catalyzed cross-coupling of aryl iodides with diethyl diazomethylphosphonate

Article abstract of DOI:10.1016/j.tetlet.2014.10.048

An efficient procedure for the Pd-catalyzed arylation of diethyl α-diazomethylphosphonate with aryl iodides is described. It can serve as a pathway for the generation of arylated diazophosphonates, which are typically difficult to access. The significance of this methodology was demonstrated via further synthetic transformations of newly synthesized diazo compounds in cyclopropanation, epoxidation, N-H and O-H insertion reactions.

Full text of DOI:10.1016/j.tetlet.2014.10.048

Tetrahedron Letters 55 (2014) 6791–6794
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of
a-aryl-diazophosphonates via palladium-catalyzed
cross-coupling of aryl iodides with diethyl diazomethylphosphonate
⇑
Mikhail D. Kosobokov, Igor D. Titanyuk , Irina P. Beletskaya
Department of Chemistry, Moscow State University, Leninskie Gory 1-3, Moscow 119991, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient procedure for the Pd-catalyzed arylation of diethyl
a-diazomethylphosphonate with aryl
Received 25 June 2014
Revised 19 September 2014
Accepted 8 October 2014
Available online 17 October 2014
iodides is described. It can serve as a pathway for the generation of arylated diazophosphonates, which
are typically difficult to access. The significance of this methodology was demonstrated via further syn-
thetic transformations of newly synthesized diazo compounds in cyclopropanation, epoxidation, N–H
and O–H insertion reactions.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Diazo compounds
Phosphonates
Cross-coupling
Palladium catalysis
Phosphorylated compounds
N2
P(O)(OEt)2
Transition-metal-catalyzed transformations of
a-diazo com-
N2
pounds have become a standard method in organic synthesis. They
are traditionally used for carbene generation in reactions such as
X–H insertion (X = C, N, O, S), cyclopropanation, cycloaddition to
nitriles and carbonyl compounds, and amongst other reactions.1,2
H
1
P(O)(OEt)2
Cat., base
+
MeO2C
I
3a
Despite the fact that
a-diazophosphonates have received less
MeO2C
attention in organic synthesis than diazocarboxylates, they are
widely used for the preparation of different derivatives of phos-
phonic acids, such as cyclopropanes,3 aziridines,4 phosphonoke-
2a
Scheme 1.
tones,5 aminophosphonates,6 and ,b-unsaturated phosphonates.7
a
It is known that the diazocarbonyl species has considerable
Despite the fact, that Pd(PPh3)4 gave a slightly better yield than
PdCl2(PPh3)2 [45% vs 36% (entries 2 and 3)], the latter was chosen
for further exploration because this palladium complex is regarded
as being much cheaper and easy to handle.
nucleophilicity and the hydrogen at the -position can be success-
a
fully substituted with an electrophile using the Arndt–Eistert reac-
tion.8 Moreover, ethyl diazoacetate has been utilized for the
Pd(PPh3)4-catalyzed cross-coupling with vinyl- and aryl iodides
with retention of the diazo function.9 Having in mind this proce-
dure, we have modified it in order to explore more readily avail-
able and inexpensive palladium catalysts, and have applied it for
the synthesis of diazophosphonates.
The reaction was more favored in acetonitrile than in the other
tested solvents. DBU appeared to be the best base for this coupling,
whereas other bases such as triethylamine, pyridine, and inorganic
bases were found to be ineffective (entries 8–11). It was found that
one equivalent of DBU was insufficient for complete conversion.
The use of two equivalents of DBU relative to ArI increased the
yield of 3a two-fold (entry 12). Formic acid was used as a reducing
agent to generate a Pd(0) species and its amount appeared to be
highly important for product yield. When 10 mol % of HCO2H was
used, 3a was formed in only 65% yield, whereas the application
of 70 mol % resulted in a significant increase in the amount of prod-
uct (entry 14). Finally it was found that the most favorable temper-
ature was 45 °C; under these conditions the isolated yield of 3a
reached 95%. Other temperatures resulted in reduced yields of 3a.
The coupling of methyl 4-iodobenzoate (2a) with diethyl dia-
zomethylphosphonate (1) was selected as
a model reaction
(Scheme 1, Table 1).
Screening of catalytic systems, solvents, and bases revealed that
application of the zero-valent palladium catalyst Pd2(dba)3 led to
rapid decomposition of the diazo compound (Table 1, entry 1).
⇑
Corresponding author. Tel./fax: +7 495 9392221.
E-mail address: i-titan@yandex.ru (I.D. Titanyuk).
http://dx.doi.org/10.1016/j.tetlet.2014.10.048
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

6792
M. D. Kosobokov et al. / Tetrahedron Letters 55 (2014) 6791–6794
Table 1
Table 2
Yield of the hydroarylation product 2a produced via Scheme 1a
Cross-coupling of aryl iodides with 1 via Scheme 2a
Entry Catalyst (mol %)
Additive
(mol%)
Base
Solvent
Yield
(%)
Entry
ArI
Product
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
p-MeO2C-C6H4I
m-MeO2C-C6H4I
p-O2N-C6H4I
m-O2N-C6H4I
o-O2N-C6H4I
PhI
3a
3b
3c
3d
3e
3f
1
2
0.5
2
1.5
5
7
95
75
94
76
70
60
66
25
1
2
Pd2(dba)3 (5)
Pd(PPh3)4 (5)
PPh3 (10)
—
DBU
DBU
DBU
DBU
DBU
DBU
DBU
Et3N
CH3CN
CH3CN
CH3CN
Benzene 25
Acetone
DMF
0
45
36
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Pd(PPh3)2Cl2 (10) HCO2H (10)
Pd(PPh3)2Cl2 (10) HCO2H (10)
Pd(PPh3)2Cl2 (10) HCO2H (10)
Pd(PPh3)2Cl2 (10) HCO2H (10)
Pd(PPh3)2Cl2 (10) HCO2H (10)
Pd(PPh3)2Cl2 (10) HCO2H (10)
Pd(PPh3)2Cl2 (10) HCO2H (10)
Pd(PPh3)2Cl2 (10) HCO2H (10)
Pd(PPh3)2Cl2 (10) HCO2H (10)
Pd(PPh3)2Cl2 (10) HCO2H (10)
Pd(PPh3)2Cl2 (10) HCO2H (10)
Pd(PPh3)2Cl2 (10) HCO2H (70)
Pd(PPh3)2Cl2 (10) HCO2H (140)
0
10
30
5
m-Me-C6H4I
p-MeO-C6H4I
3g
3h
CH2Cl2
CH3CN
12
a
Reaction conditions: aryl iodide (1 mmol),
HCO2H (1.5 mmol), Pd catalyst (0.05 mmol), 80 °C.
1
(1.5 mmol), base (2.5 mmol),
Pyridine CH3CN
0
K2CO3
Cs2CO3
DBUb
DBUb
DBUb
DBUb
DBUb,c
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Trace
Trace
65
73
86
15
95
b
Isolated yield.
PPh3
Ar Pd
I
H-CP(O)(OEt)2
N2
Pd(PPh3)2Cl2
(10)
HCO2H (70)
Ar-I
PPh3
A
Bold indicates the best reaction conditions.
Reaction conditions: 2a (1 mmol); 1 (1.5 mmol); base (1 mmol), Pd catalyst,
40 °C.
Ph3P
Ar Pd
PPh3
HCO2H
H
a
Pd(PPh3)2
PdCl2(PPh3)2
CP(O)(OEt)2
B
reduction
N2 I-
+
b
c
2 mmol of DBU used.
Reaction at 45 °C.
ArCP(O)(OEt)2
N2
base
- HI
PPh3
Ar Pd
PPh3
CP(O)(OEt)2
N2
Various aryl iodides were subjected to three-component aryla-
C
tion under the optimized reaction conditions10 (Scheme 2). The
scope of the method was examined by varying the substituents
on the iodides (Table 2). A significant influence from the electronic
effects was observed. In the case of aryl iodides containing elec-
tron-withdrawing groups, the reaction proceeded smoothly giving
high yields (up to 95%) (Table 2, entries 1–5). Good yields were also
obtained in the cases with unsubstituted phenyl or arenes contain-
ing weak electron-donating groups (entries 6 and 7), however, the
p-MeO-substituted substrate gave an unsatisfactory yield (entry 8).
The reaction was not affected significantly by steric hindrance from
the substituents on the benzene ring, as confirmed by the produc-
tion of diazophosphonate 3e. Aryl bromides and aryl chlorides
were ineffective in the presented cross-coupling.
The proposed mechanism for the hydroarylation is presented in
Scheme 3. The palladium dichloride complex can be easily reduced
by formic acid resulting in a Pd(0) species. The catalytic cycle starts
with oxidative addition to form arylpalladium iodide complex A.
Then coordination of diazo compound to this complex generates
the complex B. Base-assisted removal of HI affords the intermedi-
ate C. Finally, reductive elimination provides the aryl-diazoacetate
product with simultaneous regeneration of the Pd(0) species.
The arylation of diazomethylphosphonate reported in this work
represents a simple method for the preparation of a wide range of
new diazophosphonates, which possess high synthetic potential in
phosphorus-organic chemistry. Their synthetic utility was
demonstrated via the preparation of a new family of phospho-
nate-containing substances starting from diazo compound 3c
(Scheme 4).
Scheme 3.
We found that 0.5 mol % of Rh2(OAc)4 catalyzed the cycloaddi-
tion of 3c to styrene smoothly in DCE at 60 °C to furnish
cyclopropane 4 in 78% yield after two hours. Compound 4 was iso-
lated as a mixture of Z/E isomers (dr 3:97 Z/E), as determined by 1H
and 31P NMR spectroscopy. The structure of product 4 was further
confirmed by elemental analysis and from spectral data. The
assignment of the relative configuration of 4 was deduced from
the 1H–31P HOESY spectrum (Fig. 1).
NOE correlations were found for the phosphorus signal at
24.5 ppm and the two cis-configured protons of the cyclopropane
ring of 4-major (Fig. 2) at 2.8 ppm (CHAr) and 1.8 ppm (CH2, Hcis),
respectively. This fact evidenced the proximity of these protons
to the P atom indicating the anti configuration of the molecule
(Fig. 1).
Addition of 3c to 3,5-dimethoxybenzaldehyde afforded epoxide
5 in 82% yield under the same reaction conditions as described
above. The epoxide is a somewhat unusual product of this transfor-
mation. It is well known that 1,3-dioxolanes are typically furnished
as the main products resulting from the reaction of two molecules
of an aldehyde with one fragment of a diazo compound under
metal catalysis.11
A single diastereomer of epoxide 5 was detected by 31P NMR
spectroscopy and isolated by column chromatography. 1H–1H
NOE correlations were found between the doublet of the epoxide
proton (4.0 ppm) and signals A at 7.7 ppm and 8.2 ppm corre-
sponding to the 4-nitrophenyl moiety (Fig. 3). Additionally, multi-
plet signals due to the OCH2 protons of the diethoxyphosphoryl
group (3.7–3.8 ppm, signal B) correlated with the signals at
6.8 ppm and 6.9 ppm corresponding to the aromatic protons in
the 3,5-dimethoxyphenyl fragment (Fig. 3) The spatial proximity
of these groups indicated the syn configuration of 5.
N2
N2
H
P(O)(OEt)2
1
PdCl2(PPh3)2, DBU
HCO2H, CH3CN
P(O)(OEt)2
3a-h
+
R
I
R
Both OH- and NH-insertion reactions of metal carbenoid inter-
mediates derived from their corresponding diazo compounds have
found widespread use in the synthesis of biologically active
compounds, including the construction of bicyclic b-lactams,
2a-h
Scheme 2.

M. D. Kosobokov et al. / Tetrahedron Letters 55 (2014) 6791–6794
6793
OEt
O
OEt
O
O
O
P
O
O
P
OEt
N
OEt
N
O
MeOH
styrene
6
4
OEt
78%
O
93%
O
P
OEt
N
O
N2
OEt
O
3c
O
O
P
O
OEt
N
Cbz-NH2
O
OEt
O
O
P
O
O
OEt
N
O
O
HN Cbz
7
79%
5
O
82%
Scheme 4.
transformations under rhodium-catalyzed conditions. It was found
that heating 3c with methanol or benzyl carbamate in DCE in the
O
P
EtO
EtO
H
presence of Rh2(OAc)4 afforded
a-methoxyphosphonate 6 and
H
H
aminophosphonate derivative 7, respectively, in high yields.
In conclusion, we have reported an efficient procedure for the
Pd-catalyzed arylation of diethyl a-diazomethylphosphonate with
O2N
Figure 1. 1H–31P HOESY correlations of compound 4.
aryl iodides. The described reaction can serve as a pathway for the
generation of difficult to access arylated diazophosphonates. The
significance of this methodology was demonstrated via further
synthetic transformations of the newly synthesized diazo com-
pounds 3c in cyclopropanation, epoxidation, and N–H and O–H
insertion reactions.
amino and
a-hydroxy acids, peptides, depsipeptides, etc. We
examined the reactivity of diazophosphonate 3c in such
Figure 2. 1H–31P HOESY spectrum of compound 4.

6794
M. D. Kosobokov et al. / Tetrahedron Letters 55 (2014) 6791–6794
B
MeO
OMe
O
P
H
CH3CH2
CH3CH2
O
O
O
H
H
A
H
O2N
Figure 3. 1H–1H NOESY spectrum of compound 5.
3. Azzi, S.; Charette, A. B.; Fiset, D.; Gritsch, P. J.; Lindsay, V. N. G. J. Am. Chem. Soc.
Acknowledgements
2013, 135, 1463–1470.
4. Che, C.; Reddy, A. R.; Zhou, C.; Che, C.; Reddy, A. R.; Zhou, C. Org. Lett. 2014, 16,
1048–1051.
This work was supported by a Grant-in-Aid of the Russian Foun-
dation for Basic Research and NFFD of Ukraine (No. 14-03-90404).
The authors thank Dr. R. A. Novikov for his contribution in registra-
tion of NMR spectra.
5. Dayoub, W.; Doutheau, A.; Diab, Y. Tetrahedron Lett. 2001, 42, 8455–8457.
6. (a) Blake, A. J.; Lewis, W.; Moody, C. J.; Shi, B.; Campbell, I. B.; Judkins, B. D. J.
Org. Chem. 2010, 75, 152–161; (b) Wang, J.-C.; Xu, Z.-J.; Che, C.-M.; Zhou, C.-Y.;
Wei, J.; Guo, Z.; Low, K.-H. Angew. Chem., Int. Ed. 2012, 51, 11376–11380.
7. Charette, A. B.; Davi, M.; Lebel, H.; Roy, M.-N.; Zeghida, W. Synthesis 2011,
2275–2280.
8. (a) Pace, V.; Verniest, G.; Sinisterra, J.-V.; Alcantara, A. R.; De Kimpe, N. J. Org.
Chem. 2010, 75, 5760–5763; (b) Ellerbrock, P.; Koschker, P.; Malhotra, S.; Trost,
B. M. J. Am. Chem. Soc. 2012, 134, 2075–2084.
9. Peng, C.; Cheng, J.; Wang, J. J. Am. Chem. Soc. 2007, 129, 8708.
10. Typical procedure for the Pd-catalyzed cross-coupling: To a mixture of aryl iodide
2a–h (1 mmol) and PdCl2(PPh3)2 (36 mg, 0.05 mmol) in a Schlenk flask under
an argon atmosphere DBU (304 mg, 2 mmol) and formic acid (32 mg,
0.7 mmol) in CH3CN (10 mL) were added. The mixture was stirred and
heated at 45 °C, then compound 1 (267 mg, 1.5 mmol) in CH3CN (2 mL) was
added in small portions over 10–20 min. The mixture was stirred at the same
temperature until compound 2 had been consumed (monitored by TLC, the
total heating time is indicated in Table 2). The solvent was evaporated in vacuo.
Purification of the mixture by column chromatography (EtOAc/hexane, 1:1 v/v)
gave pure product 3a–h.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.10.
048.
References and notes
1. (a) Doyle, M. P.; Forbes, D. C. Chem. Rev. 1998, 98, 911–936; (b) Zhang, Zh.;
Wang, J. Tetrahedron 2008, 64, 6577–6605; (c) Doyle, M. P.; Duffy, R.; Ratnikov,
M.; Zhou, L. Chem. Rev. 2010, 110, 704–724; (d) Zhang, Y.; Wang, J. Eur. J. Org.
Chem. 2011, 1015–1026.
2. (a) Hou, Z.; Wang, J.; He, P.; Wang, J.; Qin, B.; Liu, X.; Lin, L.; Feng, X. Angew.
Chem., Int. Ed. 2010, 49, 4763–4766; (b) Hyster, T. K.; Ruhl, K. E.; Rovis, T. J. Am.
Chem. Soc. 2013, 135, 5364–5367.
11. (a) DeAngelis, A.; Fox, J. M.; Panne, P.; Yap, G. P. A. J. Org. Chem. 2008, 73, 1435–
1439; (b) Li, Z.-C.; Zhang, J.; Hu, W.-H.; Chen, Z.-Y.; Yu, X.-Q. Synlett 2005,
1711–1715.