Halodiazophosphonates, a new class of diazo compounds for the diastereoselective intermolecular Rh(II) catalyzed cyclopropanation

Article abstract of DOI:10.1021/ol3010276

(Halodiazomethyl)phosphonates 2A-C have been generated by a one-pot procedure via a clean, efficient, and rapid deprotonation/electrophilic halogenation sequence from diethyl diazomethylphosphonate 1 (EDP). Subsequent intermolecular Rh(II)-catalyzed cyclopropanation afforded the corresponding halocyclopropylphosphonates 3-10 in moderate to high yields and high diastereomeric ratios. Catalyst loadings down to 0.1 mol % as well as clean and selective product formation were achieved.

Full text of DOI:10.1021/ol3010276

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Halodiazophosphonates, a New Class
of Diazo Compounds for the
Diastereoselective Intermolecular
Rh(II) Catalyzed Cyclopropanation
Christian Schnaars and Tore Hansen*
Department of Chemistry, University of Oslo, Sem Sælands vei 26, N-0315 Oslo, Norway
tore.hansen@kjemi.uio.no
Received April 19, 2012
ABSTRACT
(Halodiazomethyl)phosphonates 2AÀC have been generated by a one-pot procedure via a clean, efficient, and rapid deprotonation/electrophilic
halogenation sequence from diethyl diazomethylphosphonate 1 (EDP). Subsequent intermolecular Rh(II)-catalyzed cyclopropanation afforded
the corresponding halocyclopropylphosphonates 3À10 in moderate to high yields and high diastereomeric ratios. Catalyst loadings down to
0.1 mol % as well as clean and selective product formation were achieved.
Carbenoid chemistry has become a powerful tool in
organic synthesis.1 Numerous efficient transformations
such as cyclopropanations,2 CÀH insertions,3 cyclo-
additions4 and ylide transformations5 have been devel-
oped, as well as studies on reactivities and mechanisms of
the involved transition-metal carbenoids.6 The precursors
for the carbenoids are in most cases diazo compounds, and
several methods for their generation have been developed.7
Among the frequently used and well-employed donorÀ
acceptor1b,d,6b,8 and acceptorÀacceptor diazo compounds,2c,9
our group recently reported halodiazoacetates10 as a new class
(1) For recent reviews, see: (a) Padwa, A. Chem. Soc. Rev. 2009, 38,
3072. (b) Davies, H. M. L.; Denton, J. R. Chem. Soc. Rev. 2009, 38, 3061. (c)
Zhang, Z.; Wang, J. Tetrahedron 2008, 64, 6577. (d) Davies, H. M. L.; Walji,
A. M. Rhodium (II)-Stabilized Carbenoids Containing Both Donor and
Acceptor Substituents. Modern Rhodium-Catalyzed Organic Reactions;
Evans, P. A., Ed.; Wiley-VCH: Weinheim, 2005; pp 301À340. (e) Lydon,
K. M.; McKervey, M. A. Cyclopropanation and CÀH insertion with Rh.
Comprehensive Asymmetric Catalysis I-III; Springer-Verlag: 1999; Vol. 2, pp
539À580. (f) Ye, T.; McKervey, M. A. Chem. Rev. 1994, 94, 1091.
(2) For reviews on cyclopropanations, see: (a) Pellissier, H. Tetra-
hedron 2008, 64, 7041. (b) Maas, G. Chem. Soc. Rev. 2004, 33, 183. For
selected recent examples, see: (c) Lindsay, V. N. G.; Nicolas, C.;
Charette, A. B. J. Am. Chem. Soc. 2011, 133, 8972. (d) Goto, T.; Takeda,
K.; Anada, M.; Ando, K.; Hashimoto, S. Tetrahedron Lett. 2011, 52,
4200. (e) Doyle, M. P. Angew. Chem., Int. Ed. 2009, 48, 850. (f) Ghanem,
(4) For selected recent examples, see: (a) Wang, X.; Xu, X.; Zavalij,
P. Y.; Doyle, M. P. J. Am. Chem. Soc. 2011, 133, 16402. (b) Lian, Y.;
Davies, H. M. L. J. Am. Chem. Soc. 2010, 132, 440. (c) Lian, Y.; Miller,
L. C.; Born, S.; Sarpong, R.; Davies, H. M. L. J. Am. Chem. Soc. 2010,
132, 12422. (d) Kano, T.; Hashimoto, T.; Maruoka, K. J. Am. Chem.
Soc. 2006, 128, 2174.
€
A.; Gardiner, M. G.; Williamson, R. M.; Muller, P. Chem.;Eur. J.
2010, 16, 3291.
(5) For reviews, see: (a) Padwa, A. Helv. Chim. Acta 2005, 88, 1357.
(b) Padwa, A.; Weingarten, M. D. Chem. Rev. 1996, 96, 223. (c) Padwa,
A.; Hornbuckle, S. F. Chem. Rev. 1991, 91, 263. For selected recent
examples, see: (d) Shimada, N.; Oohara, T.; Krishnamurthi, J.; Nambu,
H.; Hashimoto, S. Org. Lett. 2011, 13, 6284. (e) Li, Z.; Davies, H. M. L.
J. Am. Chem. Soc. 2010, 132, 396.
(6) (a) Herrmann, P.; Bach, T. Chem. Soc. Rev. 2011, 40, 2022. (b)
Davies, H. M. L.; Morton, D. Chem. Soc. Rev. 2011, 40, 1857. (c) Bonge,
H. T.; Hansen, T. Tetrahedron Lett. 2010, 51, 5378. (d) Hansen, J.;
Autschbach, J.; Davies, H. M. L. J. Org. Chem. 2009, 74, 6555. (e)
Davies, H. M. L.; Coleman, M. G.; Ventura, D. L. Org. Lett. 2007, 9,
4971. (f) Clark, J. S.; Dossetter, A. G.; Wong, Y.-S.; Townsend, R. J.;
Whittingham, W. G.; Russell, C. A. J. Org. Chem. 2004, 69, 3886.
(3) For recent reviews on carbenoid CÀH insertions, see: (a) Davies,
H.; Dick, A. Top. Curr. Chem. 2010, 292, 303. (b) Doyle, M. P.; Duffy,
R.; Ratnikov, M.; Zhou, L. Chem. Rev. 2010, 110, 704. (c) Davies,
H. M. L.; Manning, J. R. Nature 2008, 451, 417. For selected recent
examples, see: (d) Doyle, M. P.; Ratnikov, M.; Liu, Y. Org. Biomol.
Chem. 2011, 9, 4007. (e) DeAngelis, A.; Shurtleff, V. W.; Dmitrenko, O.;
Fox, J. M. J. Am. Chem. Soc. 2011, 133, 1650. (f) Gauthier, D.; Dodd,
R. H.; Dauban, P. Tetrahedron 2009, 65, 8542. (g) Gomes, L. F. R.;
Trindade, A. F.; Candeias, N. R.; Gois, P. M. P.; Afonso, C. A. M.
Tetrahedron Lett. 2008, 49, 7372. (h) Wolckenhauer, S. A.; Devlin, A. S.;
Du Bois, J. Org. Lett. 2007, 9, 4363. (i) Davies, H. M. L. Angew. Chem.,
Int. Ed. 2006, 45, 6422.
r
10.1021/ol3010276
XXXX American Chemical Society

of diazo compounds. The analogous halodiazophosphonates
2B and 2C have once been synthesized and reported in 1979
by Regitz et al. via the corresponding silver salts.11 However,
because of their instability they could only be trapped with
PPh3 or methyl vinyl ketone but have never been used in
synthesis to the best of our knowledge.
Initial experiments were performed by adding the base
(5 equiv) to a mixture of the SeyferthÀGilbert14 analogue
diethyl diazomethylphosphonate (EDP) 1 and N-bromo-
succinimide (NBS, 1.3 equiv) in dry dichloromethane at
0 °C and following consumption of 1 by TLC analysis.
Full consumption of EDP 1 within 5 min with NaH as base
was achieved.15 Addition of styrene (3 equiv) and 2 mol %
of Rh2(esp)2,16 which proved to be a reliable and robust
catalyst for the cyclopropanations with halodiazo-
acetates,10b resulted in instant gas evolution and decoloriza-
tion of the deep orange mixture and afforded the correspond-
ing bromo cyclopropylphosphonate 3B in 40% isolated yield
along with products from dimerizations D and overbromina-
tion to diethyl dibromomethylphosphonate (Scheme 1).17
Phosphonates and the corresponding phosphonic acids
and cyclopropyl groups are common structural units in
biologically active molecules,12 making halodiazophospho-
nates interesting targets in addition to the field of diazo
chemistry. Thus, we aimed to extend our knowledge from
our previously reported formation of halodiazoacetates from
ethyl diazoacetate (EDA) via a deprotonation/electrophilic
halogenation procedure toward the diazophosphonates.13
The original procedure involving a silica plug filtration10a,b
proved to be incompatible with the halodiazophosphonates
due to tailing and decomposition on silica and alumina. This
focused our attention toward an efficient one-pot procedure
which minimizes decomposition and side reactions. Careful
choice of compatible reaction conditions with main focus on
noncoordinating, clean, and easy to remove bases was
necessary. Therefore, we focused on inorganic bases.
Scheme 2. One-Pot in situ Synthesis of 3B via General Procedure
A
Scheme 1. Initial Experiment
To minimize dimerizations and increase selectivity, we
considered an in situ generation of the halodiazophosphonates
via dropwise addition of EDP 1. The presence of base,
N-halosuccinimide and substrate in excess as well as a low
concentration of the diazo compound at any time during
the reaction should provide rapid formation of the halo-
diazophosphonates and favor catalytic cyclopropanation.
Thus, dropwise addition of a solution of EDP 1 (0.7
mmol) in drydichloromethane (5 mL) over 2 h toa mixture
of Rh2(esp)2 (2 mol %), NBS (1.2 equiv), NaH (5 equiv),
and styrene (3 equiv) in dry toluene/CH2Cl2 (10 mL/5 mL)
at 0 °C was performed and afforded the cyclopropane 3B
as a 12:1 trans/cis mixture in 82% isolated yield with only
traces of dimerization (Scheme 2, Table 1, entry 2, general
procedure A in the Supporting Information). Thus, a clean
and selective reaction to the halo cyclopropylphosphonate
3B is achieved.
(7) For a recent review on the synthesis of diazo compounds, see:
Maas, G. Angew. Chem., Int. Ed. 2009, 48, 8186 and references cited
therein.
(8) (a) Denton, J. R.; Davies, H. M. L. Org. Lett. 2009, 11, 787. (b)
Davies, H. M. L.; Nikolai, J. Org. Biomol. Chem. 2005, 3, 4176.
(9) (a) Zhu, S.; Perman, J. A.; Zhang, X. P. Angew. Chem., Int. Ed.
2008, 47, 8460. (b) John, J. P.; Novikov, A. V. Org. Lett. 2007, 9, 61.
(10) (a) Bonge, H. T.; Hansen, T. Synthesis 2009, 2009, 91. (b) Bonge,
H. T.; Pintea, B.; Hansen, T. Org. Biomol. Chem. 2008, 6, 3670. (c)
Bonge, H. T.; Hansen, T. Pure Appl. Chem. 2011, 83, 565.
(11) Regitz, M.; Weber, B.; Eckstein, U. Liebigs Ann. Chem 1979,
1002.
(12) (a) Engel, R. Chem. Rev. 1977, 77, 349. (b) Christensen, B. G.;
Leanza, W. J.; Beattie, T. R.; Patchett, A. A.; Arison, B. H.; Ormond,
R. E.; Kuehl, F. A.; Albers-Schonberg, G.; Jardetzky, O. Science 1969,
166, 123. (c) Hercouet, A.; Le Corre, M.; Carboni, B. Tetrahedron Lett.
2000, 41, 197. (d) Erion, M. D.; Walsh, C. T. Biochemistry 1987, 26, 3417.
(e) Reid, J. R.; Marmor, R. S. J. Org. Chem. 1978, 43, 999. (f) Hanessian,
S.; Cantin, L.-D.; Roy, S.; Andreotti, D.; Gomtsyan, A. Tetrahedron
Lett. 1997, 38, 1103. (g) El-Gokha, A.; Maas, G. Tetrahedron 2011, 67,
2849.
The same procedure could be applied to the iodination
with N-iodosuccinimide (NIS), affording the correspond-
ing iodocyclopropylphosphonate 3C in 77% isolated yield
(14) (a) Seyferth, D.; Marmor, R. S. Tetrahedron Lett. 1970, 11, 2493.
(b) Seyferth, D.; Marmor, R. S.; Hilbert, P. J. Org. Chem. 1971, 36, 1379.
(c) Gilbert, J. C.; Weerasooriya, U. J. Org. Chem. 1979, 44, 4997.
(15) Other bases such as Na2CO3, K2CO3, and Cs2CO3 were less
active and gave lower yields of the isolated bromo cyclopropylpho-
sphonate 3B, though further studies on carbonate bases and crown
ethers are in progress.
(13) For selected examples of applications of diazophosphonates,
see: (a) Charette, A. B.; Bouchard, J.-E. Can. J. Chem. 2005, 83, 533. (b)
Ferrand, Y.; Le Maux, P.; Simonneaux, G. Org. Lett. 2004, 6, 3211. (c)
Gois, P. M. P.; Afonso, C. A. M. Eur. J. Org. Chem. 2003, 2003, 3798. (d)
ꢀ
Paul-Roth, C.; De Montigny, F.; Rethore, G.; Simonneaux, G.; Gulea,
(16) Espino, C. G.; Fiori, K. W.; Kim, M.; Du Bois, J. J. Am. Chem.
Soc. 2004, 126, 15378.
(17) Isolation of the halo-EDP 2B was attempted but unsuccessful.
(18) Selectfluor and N-fluoro-o-benzenedisulfonimide (NFSI) as F
sources with different solvents.
M.; Masson, S. J. Mol. Catal A: Chem. 2003, 201, 79. (e) Davies,
H. M. L.; Lee, G. H. Org. Lett. 2004, 6, 2117. For examples of
electrophilic functionalization of diazo compounds, see: (f) Hashimoto,
T.; Kimura, H.; Nakatsu, H.; Maruoka, K. J. Org. Chem. 2011, 76, 6030.
(g) Zhang, Y.; Wang, J. Chem. Commun. 2009, 5350. (h) Zhao, Y.;
Wang, J. Synlett 2005, 2005, 2886. (i) Fink, J.; Regitz, M. Synthesis 1985,
569. (j) Regitz, M. Angew. Chem., Int. Ed. 1975, 14, 222.
(19) Davis, F. A.; Han, W.; Murphy, C. K. J. Org. Chem. 1995, 60,
4730.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 3. Overall Reaction Scheme for Chlorination via Bulk Addition (Procedure B) and Iodination and Bromination via in situ
Generation of Halodiazophosphonates 2B and 2C (General Procedure A)
Table 1. Variation of Halogens To Afford Halocyclopropyl-
phosphonates 3AÀC
Table 2. Screening of Catalysts for the Cyclopropanation to 3Ba
loading
(mol %)
yield of
3Bb (%)
entry
catalyst
dr (trans/cis)c
1a
1b
1c
1d
1e
2
Rh2(esp)2
2
1
82, 78,d 0e
12:1
88f,g
78f,h
74f,i
0f,j
78
73
54
43
40
66
47
0
0.5
0.1
0
Rh2(piv)4
Rh2(oct)4
Rh2(OAc)4
Rh2(TPA)4
Rh2(TFA)4
Rh2(S-PPTL)4
Rh2(S-TBSP)4
CuCl
2
12:1
14:1
14:1
9:1
3
2
entry
X
product
yielda (%)
dr (trans/cis)b
4
2
5
2
1
2
3
4
Clc
Br
I
3A
3B
3C
77
82
77
0
12:1
12:1
16:1
6
2
10:1
14:1
13:1
7
2
8
2
Fd
9
2
a Isolated yields of both diastereomers. b Estimated by 1H NMR
spectra of the crude product mixture. c Bulk addition of NaH (5 equiv) to
a mixture of EDP (1 equiv) and NCS (1.3 equiv) in dry CH2Cl2 at 0 °C,
exchange of CH2Cl2 with toluene (see procedure B in the Supporting
Information). d Selectfluor and NFSI19 as F sources.
10
11
12
13
Cu(OTf)2
Cu(acac)2
RuCl3
5
0
10
10
2
0
0
Ag(OAc)
0
a Conditions: EDP 1 (0.7 mmol, 1 equiv) in 5 mL of dry CH2Cl2 was
added dropwise to NaH (5 equiv), NBS (1.2 equiv), styrene (3 equiv), and
catalyst in toluene/CH2Cl2 (10 mL/5 mL), general procedure A, Scheme 2.
b Isolated yield of both diastereomers after column chromatography.
c Measured by 1H NMR spectra of the crude product mixture. d 1.2
equiv of NaH. e Reaction at room temperature. f Measured by inter-
nal standard from 1H NMR of crude reaction mixture for both
diastereomers. g 3 h addition time. h 4 h addition time. i 5 h addition
time. j Only dimer D could be detected.
(Table 1, entry 3, Scheme 3). However, the analogous
chlorination with N-chlorosuccinimide (NCS) did not give
the desired product 3A, instead the cyclopropanation with
the nonhalogenated EDP 1 occurred. This issue could be
solved via bulk addition of base NaH to a mixture of EDP
1 and NCS in dichloromethane at 0 °C followed by
exchange of solvent with toluene and addition of Rh2(esp)2
and the substrate (Scheme 3). The product 3A was ob-
tained in a good isolated yield of 77% with only traces of
overchlorinated product compared to the initial experi-
ment with NBS (Table 1, entry 1).
is the rate-determining step for the iodination and
bromination.
Dichloromethane was required to provide solubility of
the N-halosuccinimide and was removed in vacuo at 0 °C
after complete addition of EDP 1 to leave the toluene
reaction mixture at room temperature for 30 min. Toluene
provides precipitation of the sodium succinimide to make a
convenient workup by filtration through Celite possible.20
Fluorination was attempted but unsuccessful.18
The halogen transfer from NCS to EDP 1 is slower
compared to NIS and NBS; thus, cyclopropanation of
EDP 1 precedes formation of the chlorinated diazo
compound. This means that the halogen transfer can
be considered as the rate determining step in the case of
the chlorination, whereas the catalytic cyclopropanation
1
(20) A reaction in pure DCM gave slightly lower yields with an H
NMR spectrum of the crude product mixture containing more succini-
mide than with toluene.
Org. Lett., Vol. XX, No. XX, XXXX
C

After having shown the efficiency of Rh2(esp)2 for the
studied system, several Rh(II) as well as other metal based
catalysts were tested (Table 2).
Table 3. Synthesis of Cyclopropylphosphonates 3BÀ10Ba
Besides Rh2(esp)2 with bischelating carboxylates, differ-
ent Rh(II) catalysts with monochelating carboxylates gave
moderate to high yields of 3B with the pivalate and
octanoate catalysts as the most active ones affording
78% and 73% yield (Table 2, entries 2 and 3). This trend
is in accordance with the literature for intermolecular
cyclopropanations with the nonhalogenated diethyl di-
azomethylphosphonate 1.13a High diastereomeric ratios
of >9:1 trans:cis with all catalysts could be obtained in the
studied system. Two chiral Rh(II) catalysts gave medium
yields of 3B; however, enantiomeric excess was below 15%
ee in both cases (Table 2, entries 7 and 8).21 Other transition-
metal-based catalysts did not show any product formation
at all. Cu(acac)2 has been used before for cyclopropanation
with trifluoromethylated diazophosphonates22 but was in-
active in our system (Table 2, entry 11).
yieldb
(%)
dr (trans/
entry
substrate
styrene
product
cis)c
1
2
3
4
5
3B
4B
5B
6B
7B
82
79
81
67
62
12:1
15:1
17:1
13:1
13:1
4-methylstyrene
4-methoxystyrene
4-chlorostyrene
4-trifluoromethyl-
styrene
6
7
8
2-vinylnaphthalene
N-vinylphthalimide
1,1-diphenylethylene
8B
64
64
47
9:1
A reaction at room temperature under otherwise iden-
tical conditions only gave the dimer D of bromo-
EDP, showing the instability of the halodiazophospho-
nates. At lower temperatures, the solubility of NBS in
dichloromethane dropped and the yield of product 3B
decreased.
The catalyst loading for the most active Rh2(esp)2 could
be decreased to 0.1 mol % without significant decrease of
yield. However, adjustment of addition time of EDP 1 was
necessary (Table 2).
A substrate scope mainly focusing on styrene derivatives
was performed. Electron-rich and sterically less hindered
styrene derivatives gave highest yields (Table 3, entries 1À3).
1,1-Disubstituted and electron-deficient double bonds gave
lower yields (entries 5À8), and all products showed high
diastereomeric ratios in favor of the trans isomer.
9B
10:1
10B
a Conditions: EDP 1 (0.7À1.0 mmol, 1 equiv) in 5 mL of dry CH2Cl2
added dropwise to NaH (5 equiv), NBS (1.2 equiv), substrate (3 equiv),
and Rh2(esp)2 (2 mol %) in toluene/CH2Cl2 (10 mL/5 mL), general
procedure A. b Isolated yield of both diastereomers after column chroma-
tography. c Measured by 1H NMR spectra of the crude product mixture.
The X-ray crystal structure of the main isomer of
product 9B also clearly shows the trans configuration of
the phosphonate group and the aryl substituent.24
In conclusion, we developed a convenient, one-pot
procedure for the generation of halodiazophosphonates
and their subsequent diastereoselective intermolecular
cyclopropanation with styrene derivatives with various
Rh(II) catalysts. Moderate to high yields as well as high
diastereomeric ratios were obtained, and low catalyst
loadings of 0.1 mol % could be achieved.
Structure elucidation was performed. The 2D-NOESY
NMR of the major isomer of 3B showed NOE correlations
between the cyclopropyl proton H1 of the CH group with
the POCH2CH3 groups which is only expectedfor the trans
isomer. Additionally, no correlation between the phospho-
nate ester and the aryl protons was detected. Furthermore,
Acknowledgment. Financial support from the Norwe-
gian Research Council (NFR) is greatly acknowledged.
We thank Vitthal N. Yadav (UiO) for the X-ray crystal
structure determination.
the 31P proton-decoupled NMR spectrum showed one 31
P
signal at 20.03 ppm, indicating the presence of only one
diastereomer.23
(21) Enantiomeric excess determined by HPLC: ChiralcelOD-H
column, 1% iPrOH/isohexane. See the Supporting Information.
(22) Titanyuk, I. D.; Beletskaya, I. P.; Peregudov, A. S.; Osipov, S. N.
J. Fluorine Chem. 2007, 128, 723.
Supporting Information Available. Experimental pro-
cedures and full characterization of all products 3À10
including 1H and 13C spectra and X-ray crystal structure
data. This material is available free of charge via the
Internet at http://pubs.acs.org.
(23) 2D-NOESY and 31P NMR spectra for trans-3B are available in
the Supporting Information.
(24) The crystal structure of trans-9B has been deposited at the
Cambridge Crystallographic Data Centre. Deposition no.: CCDC
873532.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX