Insertion of arynes into arylphosphoryl amide bonds: One-step simultaneous construction of C-N and C-P bonds

Article abstract of DOI:10.1021/ol402748u

The insertion of arynes into arylphosphoryl amide bonds to synchronously construct C-P and C-N bonds is described. Arynes generated in situ from o-triflate arylsilanes under fluoride-promoted conditions insert into relatively inert P-N bonds, producing o-

Full text of DOI:10.1021/ol402748u

ORGANIC
LETTERS
2013
Vol. 15, No. 22
5722–5725
Insertion of Arynes into Arylphosphoryl
Amide Bonds: One-Step Simultaneous
Construction of CÀN and CÀP Bonds
Chaoren Shen, Guoqiang Yang, and Wanbin Zhang*
School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University,
800 Dongchuan Road, Shanghai 200240, P. R. China
wanbin@sjtu.edu.cn
Received September 23, 2013
ABSTRACT
The insertion of arynes into arylphosphoryl amide bonds to synchronously construct CÀP and CÀN bonds is described. Arynes generated in situ from
o-triflate arylsilanes under fluoride-promoted conditions insert into relatively inert PÀN bonds, producing o-amine-substituted arylphosphine oxides.
This process provides a simple pathway for the preparation of precursors for a number of bidentate aminophosphine ligands.
Arylphosphines and their derivatives are widely used in
organic synthesis,1 polymers,2 and functional materials.3
Particularly in organic synthesis, arylphosphines with
bulky ortho-substituted groups such as Buchwald-type
ligands play important roles in organometallic catalysis.4
Their preparation usually requires transition-metal, moisture-
sensitive reagents and oxygen-free conditions.5 The transition-
metal-catalyzed CÀP cross-coupling reaction is one of the
most important methods to prepare arylphosphines and
their derivatives.6 Because of its intrinsic properties, it is not
applicable to the preparation of arylphosphines with bulky
ortho-substituted functional groups. As a continuation of our
research interests concerning the construction of sp2 CÀP
bonds,6b,d we intended to develop a simple method to prepare
arylphosphine oxides with bulky ortho-substituted groups.
As a useful and highly reactive intermediate in orga-
nic synthesis, the aryne group generated in situ from 2--
(trimethylsilyl)aryl trifluoromethanesulfonate under fluoride-
promoted conditions7 has been used in numerous reactions
for the construction of various bonds.8 Due to its prominent
character for the simultaneous construction of two different
bonds in one reaction, insertion of arynes into certain bonds is
(1) Grushin, V. V. Chem. Rev. 2004, 104, 1629.
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G.; Fang, M.; Zhao, Y. Org. Lett. 2011, 13, 2110. (b) Yang, G.; Shen, C.;
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G.-J.; Li, Y.; Gao, L.-X.; Han, F.-S. Chem.;Eur. J. 2012, 18, 9622. (i)
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2000, 65, 5334. (b) Baillie, C.; Chen, W.; Xiao, J. Tetrahedron Lett. 2001,
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r
10.1021/ol402748u
Published on Web 11/04/2013
2013 American Chemical Society

a powerful strategy that can be used to synthesize a number of
different structures.9 To the best of our knowledge, aryne
insertion into PÀN bonds remains unexplored. To date, there
are only a handful of reported examples concerning the pre-
paration of arylphosphines and aryl quaternary phospho-
nium salts via nucleophilic addition of phosphines on
arynes.10 Recently, the P-arylation of aryne with nucleophilic
trialkyl phosphates was also reported.11 These methods are
not suitable for the synthesis of arylphosphines with bulky
ortho-substituted functional groups. On the other hand,
bidentate arylphosphine amine ligands have been widely
applied in transition-metal-catalyzed reactions.5f,12 Develop-
ing efficient pathways to prepare them has become a sig-
nificant issue. Our study has forcused on the direct
preparation of o-aniline-substituted arylphosphine oxides
via the cleavage of an arylphosphoryl amide bond and aryne
insertion (Scheme 1). The reaction involving the simultaneous
construction of CÀP and CÀN bonds can produce various
o-aniline-substituted arylphosphine oxides, some of which
are versatile intermediates for the preparation of bidentate
aminophosphine ligands.13 The general approach to these
bidentate aminophosphine ligands usually requires a transi-
tion metal, ligand, and anhydrous oxygen-free conditions.13
To some extent, their preparation can be simplified by the
methodology developed in this work.
(8) For reviews on the use of arynes in organic synthesis, see: (a)
Kessar, S. V. In Comprehensive Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon: New York, 1991; Vol. 4, pp 483À515. (b) Chen, Y.;
Larock, R. C. In Modern Arylation Methods; Ackermann, L., Ed.; Wiley-
VCH: New York, 2009; Chapter 12, pp 401À473. (c) Wenk, H. H.;
Winkler, M.; Sander, W. Angew. Chem., Int. Ed. 2003, 42, 502. (d)
Pellissier, H.; Santelli, M. Tetrahedron 2003, 59, 701. (e) Tadross, P. M.;
Stoltz, B. M. Chem. Rev. 2012, 112, 3550. (f) Bhunia, A.; Yetra, S. R.;
Biju, A. T. Chem. Soc. Rev. 2012, 41, 3140. (g) Bhojgude, S. S.; Biju, A. T.
Angew. Chem., Int. Ed. 2012, 51, 1520. (h) Dubrovskiy, A. V.; Markina,
N. A.; Larock, R. C. Org. Biomol. Chem. 2013, 11, 191. (i) Wu, C.; Shi, F.
Asian J. Org. Chem. 2013, 2, 116.
Scheme 1. Insertion of Benzyne into the Arylphosphoryl Amide
Bond
(9) For related reviews regarding aryne insertion reaction, see: (a)
Yoshida, H.; Ohshita, J.; Kunai, A. Bull. Chem. Soc. Jpn. 2010, 83, 199.
(b) Yoshida, H.; Takaki, K. Synlett 2012, 23, 1725. For selected recent
examples of insertion of arynes into CÀC bonds: (c) Allan, K. M.; Hong,
B. D.; Stoltz, B. M. Org. Biomol. Chem. 2009, 7, 4960. (d) Yoshida, H.;
Ito, Y.; Yoshikawa, Y.; Ohshita, J.; Takaki, K. Chem. Commun. 2011,
47, 8664. (e) Okuma, K.; Itoyama, R.; Sou, A.; Nagahora, N.; Shioj, K.
Chem. Commun. 2012, 48, 11145. For selected recent examples of
insertion of arynes into carbonÀheteroatom bonds, see: (f) Yoshida,
H.; Okada, K.; Kawashima, S.; Tanino, K.; Ohshita, J. Chem. Commun.
2010, 46, 1763. (g) Pintori, D. G.; Greaney, M. F. Org. Lett. 2010, 12,
168. (h) Biswas, K.; Greaney, M. F. Org. Lett. 2011, 13, 4946. (i)
Laczkowski, K. Z.; Garcia, D.; Pena, D.; Cobas, A.; Perez, D.; Guitian,
E. Org. Lett. 2011, 13, 960. (j) Dubrovskiy, A. V.; Larock, R. C. Org.
Lett. 2010, 12, 3117. (k) Dubrovskiy, A. V.; Larock, R. C. Tetrahedron
2013, 69, 2789. (l) Goetz, A. E.; Garg, N. K. Nature Chem. 2013, 5, 54.
For selected recent examples of insertion of arynes into various hetero-
atomÀheteroatom bonds, see: (m) Liu, Z.; Larock, R. C. J. Am. Chem.
Soc. 2005, 127, 13112. (n) Yoshida, H.; Okada, K.; Kawashima, S.;
Tanino, K.; Ohshita, J. Chem. Commun. 2010, 46, 1763. (o) Alajarin, M.;
Lopez-Leonardo, C.; Raja, R.; Orenes, R.-A. Org. Lett. 2011, 13, 5668.
(p) Hoye, T. R.; Baire, B.; Niu, D.; Willoughby, P. H.; Woods, B. P.
Our studies began with the reaction of N-phenyl diphe-
nylphosphinic amide 2a with benzyne generated in situ
from 2-(trimethylsilyl)phenyl triflate 1a under fluoride-
promoted condititons. To identify the optimal conditions
for the formation of the reaction product 3a, we investi-
gated the effect of fluoride salts, aprotic solvents, reaction
temperature, and time on the reaction yield. Considering
that the addition of base can accelerate the deprotonation
of N-phenyl diphenylphosphinic amide 2a, which would
enhance the nucleophilicity of the arylphosphoryl amide,
several kinds of bases were also employed as the reaction
additive (detailed results in Table S1 of Supporing
Information). Based on these results, we found that the
use of 2.0 equiv of KF along with 2.0 equiv of 18-crown-6
and 2.0 equiv of Cs2CO3 in THF provided the optimal
conditions for this reaction (Scheme 2). The reaction time
is 8 h and reaction temperature is 80 °C. The desired
product was obtained in 44% yield, with the remainder of
the recovered material being unreacted 2a. It was suggested
that the low yield resulted from some side reactions that
consumed very reactive benzyne.
~
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Nature 2012, 490, 208. (q) Rodrıguez-Lojo, D.; Cobas, A.; Pena, D.;
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Perez, D.; Guitian, E. Org. Lett. 2012, 14, 1363. (r) Hendrick, C. E.;
McDonald, S. L.; Wang, Q. Org. Lett. 2013, 15, 3444. (s) Yoshida, H.;
Yoshida, R.; Takaki, K. Angew. Chem., Int. Ed. 2013, 52, 8629. (t) Baire,
B.; Niu, D.; Willoughby, P. H; Woods, B. P; Hoye, T. R. Nat. Protoc.
2013, 8, 501.
(10) For nucleophilic addition of phosphines on arynes to synthesize
aryl quaternary phosphonium salts, see: (a) Wittig, G.; Benz, E. Chem.
Ber. 1959, 92, 1999. (b) Zbiral, E. Tetrahedron Lett. 1964, 25, 1649. (c)
Wittig, G.; Maturza, H. Liebigs Ann. Chem. 1970, 732, 97. (d) Wittig, G.;
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Leroux, F. R.; Bayardon, J.; Juge, S. Org. Lett. 2010, 12, 1568. For
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K.; Yanagisawa, A.; Imamoto, T. Org. Lett. 2010, 12, 4400. (g)
Bayardon, J.; Laureano, H.; Diemer, V.; Dutartre, M.; Das, U.;
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Rousselin, Y.; Henry, J.-C.; Colobert, F.; Leroux, F. R.; Juge, S.
J. Org. Chem. 2012, 77, 5759. (h) Diemer, V.; Berthelot, A.; Bayardon,
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Yoshida, S.; Hosoya, T. Chem. Lett. 2013, 42, 583.
Scheme 2. Reaction of N-Phenyl Diphenylphosphinic Amide 2a
with Benzyne
(12) For some selected recent applications of bidentate arylpho-
sphine amine in transition-metal-catalyzed reactions, see: (a) Hesp,
K. D.; Stradiotto, M. J. Am. Chem. Soc. 2010, 132, 18026. (b) Lundgren,
R. J.; Peters, B. D.; Alsabeh, P. G.; Stradiotto, M. Angew. Chem., Int.
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Stradiotto, M. Chem.;Eur. J. 2013, 19, 2131.
Org. Lett., Vol. 15, No. 22, 2013
5723

Table 1. Scope of Diphenylphosphinic Amide Substratesa
Table 2. Scope of 2-(Trimethylsilyl)aryl Triflate Substratesa
a Unless otherwise stated, the reaction was conducted on a 0.10 mmol
scale (0.10 mmol of 1a, 0.12 mmol of 2, 0.20 mmol of KF, 0.20 mmol of
18-crown-6 and 0.20 mmol of Cs2CO3) with 3.0 mL of THF in a sealed
tube with a Teflon plug valve. Reaction time was 8 h. b Isolated yield.
c Xylyl = 3,5-dimethylphenyl.
a Unless otherwise stated, reaction was conducted on a 0.10 mmol
scale (0.10 mmol of 1, 0.12 mmol of 2, 0.20 mmol of KF, 0.20 mmol of 18-
crown-6, and 0.20 mmol of Cs2CO3) with 3.0 mL of THF in a sealed tube
with a Teflon plug valve. Reaction time was 8 h. b Isolated yield. NR =
no reaction, no consumption of N-(4-chlorophenyl)diphenylphosphinic
amide. ND = trace, not detected.
The scope of the reaction was next investigated by
subjecting various N-aryl diphenylphosphinic amides to
the optimized reaction conditions (Table 1). Compared
with the result obtained for the reaction between 1a and 2a
(Scheme 1), reactions of N-aryl diphenylphosphinic amides
with para-substituted electron-netrual or electron-rich groups
showed similar results with respect to yield (Table 1, entries 1
and 2). However, when the para-substituted group on the aryl
ring was switched to an electron-deficient group such as
fluoride, chloride, or trifluoromethyl substituent, a significant
increase in yield occurred (entries 3À8). This may be attrib-
uted to the enhanced acidity of the N-aryl diphenylpho-
sphinic amide.9m The introduction of electron-deficient
groups at the aryl ring’s meta-position also promoted an
increase in yield (entries 9À11). The ortho-substituted electron-
withdrawing group influences the yield of product via steric
hinrance (entry 12) because it hinders the nucleophilic attack of
the amide to the benzyne.9g,m Using the same protocol, we also
examined the reaction between 2-(trimethylsilyl)phenyl triflate
and N-butyl diphenylphosphinic amide. Only a trace
amount of product was observed.
After we discovered that N-aryl diphenylphosphinic
amides with electron-deficient groups provided better
results for the reaction, we further explored the scope of
2-(trimethylsilyl)aryl triflate substrates with N-aryl diphe-
nylphosphinic amides possessing para- or meta-substituted
electron-deficient groups (Table 2). Yield obtained from
the reaction of the symmetrically electron-neutral sub-
stituted aryne precursor, 4,5-dimethyl-2-(trimethylsilyl)-
phenyl triflate, with N-aryl diphenylphosphinic amides
and N-aryl di(p-tolyl)phosphinic amide with para- or
meta-substituted electron-deficient groups (entries 2À6)
gave higher yields than reactions involoving simple N-
phenyl diphenylphosphinic amide (entry 1). For the sym-
metrically substituted electron-deficient aryne precursor,
6-(trimethylsilyl)benzo[d][1,3]dioxol-5-yl triflate, a similar
phenomenon was also observed between the reaction with
N-aryl diphenylphosphinic amides possessing para- or
meta-substituted electron-deficient groups (entries 8À12)
and the reaction with the simple N-phenyl diphenylphosphinic
(13) (a) Liang, L.-C.; Lee, W.-Y.; Hung, C.-H. Inorg. Chem. 2003, 42,
5471. (b) Liang, L.-C.; Huang, M.-H.; Hung, C.-H. Inorg. Chem. 2004,
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5724
Org. Lett., Vol. 15, No. 22, 2013

Scheme 3. Scale-up of the Reaction
Scheme 5. Proposed Mechanism for the Reaction
Scheme 4. Derivation of Reaction Products
anion intermediate 6, formed after N-arylation of the
arylphosphoryl amide, undergoes a formal anionic Fries
rearrangement14 to the anion 8 via a four-membered ring
intermediate 7. The product 3a is then formed by the
protonation of 8. The low/moderate yield of this reaction
is probably due to the steric hindrance during the forma-
tion of 7 from 6.
In summary, a simple and easily operated method to
directly synthesize ortho aniline-substituted arylphosphine
oxides has been developed via insertion of in situ generated
arynes into the PÀN bonds of arylphosphoryl amides. The
product can be converted to ortho-amine-substituted ar-
ylphosphines which provide a new approach to accessing
arylphosphines with a bulky ortho-substituted group.
amide (entry 7). For the unsymmetrically substituted aryne
precursor, 1-(trimethylsilyl)naphthalen-2-yl triflate, the de-
sired product 3z was not obtained (entry 13). This may be
due to the steric hindrance of the bulky diphenylphos-
phinic group. Although both of the substrates were completely
consumed in the reaction between 4,5-difluoro-2-(trimethyl-
silyl)phenyl triflate and substrate N-(4-chlorophenyl) diphe-
nylphosphinic amide, no desired product 3aa was detected
(entry 14). We surmised that this outcome was related to
the reactivity of the highly electron-deficient 4,5-difluoro-
benzyne which probably triggered some undesired side
reactions.
Acknowledgment. We thank Prof. Tsuneo Imamoto,
Chiba University, and Dr. Masashi Sugiya, Nippon Che-
mical Industrial Co., Ltd., for helpful discussions and Dr.
Nicholas Butt, Shanghai Jiao Tong University, for his help
with corrections. We also give our thanks to the reviewers
for their helpful suggestions. This work was partially
supported by the National Natural Science Foundation of
China (Nos. 21172143 and 21232004), Shanghai Jiao Tong
University (SJTU), and Nippon Chemical Industrial Co., Ltd.
We also thank the Instrumental Analysis Center of SJTU.
The scale-up of the reaction between aryne precusor 1a
and N-(4-chlorophenyl)diphenylphosphinic amide was
alsoattempted. Whenweincreased the scale ofthe reaction
from 0.10 to 1.5 mmol, the yield only slightly decreased
(Scheme 3). Arylphosphine 4 and 5 could be easily ob-
tained in high yield via the reduction of product 3a and 3e,
respectively (Scheme 4). The compound 4 is a bidentate
aminophosphine ligand13aÀc and the intermediate of some
versatile chiral ligands.13d
Supporting Information Available. General experimen-
tal procedure and characterization details. This material
is available free of charge via the Internet at http://pubs.
acs.org.
Based on previous reports,9g,j,k,m we propose the follow-
ing mechanism for the formation of 3 (Scheme 5), The aryl
(14) Slana, G. B. C. A.; de Azevedo, M. S.; Lopes, R. S. C.; Lopes,
C. C.; Cardoso, J. N. Beilstein J. Org. Chem. 2006, 2, 1.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 22, 2013
5725