Insertion of Arynes into P-O Bonds: One-Step Simultaneous Construction of C-P and C-O Bonds

Article abstract of DOI:10.1021/acs.orglett.6b03283

The insertion of arynes into P-O bonds for the preparation of o-hydroxy-substituted arylphosphine oxides, -phosphinates, and -phosphonates is described. This novel reaction leads to the simultaneous formation of C-P and C-O bonds in one step with good yie

Full text of DOI:10.1021/acs.orglett.6b03283

Letter
pubs.acs.org/OrgLett
Insertion of Arynes into P−O Bonds: One-Step Simultaneous
Construction of C−P and C−O Bonds
Na Qi,† Ning Zhang,† Srinivasa Rao Allu, Jiangsheng Gao, Jian Guo,* and Yun He*
School of Pharmaceutical Sciences and Innovative Drug Research Centre, Chongqing University, 55 Daxuecheng South Road,
Shapingba, Chongqing 401331, P. R. China
S
* Supporting Information
ABSTRACT: The insertion of arynes into P−O bonds for the
preparation of o-hydroxy-substituted arylphosphine oxides,
-phosphinates, and -phosphonates is described. This novel
reaction leads to the simultaneous formation of C−P and C−
O bonds in one step with good yields and regioselectivities
under mild and transition-metal-free conditions. The easy
follow-up transformations of the resulting o-hydroxyl group
extend these reactions to the facile construction of other ortho-
substituted arylphosphorus compounds.
rganophosphorus compounds have a broad spectrum of
applications. In particular, arylphosphorus compounds
involving the insertion of arynes into P−O bonds of
organophosphorus acids to access various o-hydroxy-substituted
arylphosphorus compounds (Scheme 1b). To the best of our
knowledge, the insertion of arynes into P−O bonds has not
been explored. Moreover, the newly formed phenolic hydroxyl
group in these reactions could be directly modified or
transformed into other useful functional groups.
To verify our hypothesis, we initially examined the reaction
with diphenylphosphinic acid 1a and β-trimethylsilyl triflate 2a
(Table 1). The reaction with 3.0 equiv of 2a and 5.0 equiv of
CsF in CH3CN was attempted first (Table 1, entry 1). The
expected insertion of aryne into the P−O bond indeed
occurred. However, it was compound 4a instead of the desired
O
are extremely useful in organic synthesis,1 material chemistry,2
and medicinal chemistry.3 Although alkylphosphorus com-
pounds could be synthesized easily via the classical Arbuzov
reaction,4 the synthesis of arylphosphorus compounds poses a
major challenge, and the existing methods often require
expensive transition metals and harsh reaction conditions,
such as Pd/Cu/Ni-catalyzed Arbuzov5 or Hirao reactions.5a,6
Therefore, the development of new methods for the
preparation of arylphosphorus compounds is of importance.
In particular, a step-economic difunctionalization reaction that
enables simultaneous introduction of phosphorus-containing
and other functional groups into one single aryl framework is
practically desired.
a
Table 1. Optimization of Reaction Conditions
Arynes are highly reactive intermediates and have been
widely used in organic synthesis.7 The insertion of arynes into σ
bonds (Scheme 1a) is one of the most common reaction mode
Scheme 1. Aryne σ-Insertion Reactions
b
yield (%)
entry
2a (equiv)
F− (equiv)
solvent
3a
4a
c
1
2
3
4
5
6
3.0
1.3
1.3
1.3
1.5
1.5
CsF (5.0)
CsF (2.6)
CH3CN
CH3CN
THF
0
12
38
35
57
65
42
11
9
d
KF (2.6)
TBAF (2.6)
TBAT (2.5)
TBAT (2.5)
THF
THF
0
e
THF
71
0
a
All reactions were carried out on a 0.2 mmol scale in 8.0 mL of
b
c
solvent at 25 °C unless otherwise specified. Isolated yields. CH3CN
(4.0 mL). 2.0 equiv of 18-crown-6 ether as an additive. The reaction
of arynes, which enables two functional groups to be
introduced simultaneously at the ortho positions of the aromatic
rings.8 Some insertion involving σ-bonds linking a variety of
atoms (C−C,8b,9 C−O,10 C−N,11 C−P,12 P−H,13 P−N,14 P−
Sn,15 etc.) has been reported. As a continuation of our interest
in the aryne field,16 we envisioned a novel transformation
d
e
was conducted at 60 °C.
Received: November 1, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03283
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
3a that was obtained in 65% yield. This could be explained by
the further reaction of 3a with another equivalent of benzyne
generated in situ. To optimize the formation of 3a, the effects
of solvent, fluoride source, temperature, and stoichiometry were
carefully studied (entries 2−6). Considering the basicity of
fluoride source and enhanced nucleophilicity of the phenolic
hydroxyl group under basic conditions, TBAT (tetrabutylam-
monium difluorotriphenylsilicate) with weaker basicity17 was
chosen as the fluoride source to suppress the further reaction of
3a. Under the optimized conditions, 3a was obtained in 71%
yield (entry 6). The same reaction on a larger scale (1a, 600
mg, 2.75 mmol) also provided 3a in a similar yield.
Table 2. Scope of Aryne Precursor Substrates
To understand the scope of the novel transformation, a wide
range of β-trimethylsilyl triflates 2b−j were then examined with
diphenylphosphinic acid 1a, and the results are summarized in
Table 2. All of the reactions for aryne precursors with electron-
donating groups led to the formation of the desired products in
good yields of 77−86% (Table 2, entries 1−5, 8, and 10), which
were slightly higher than the yield for unsubstituted benzyne
precursor 2a. The positions and amounts of electron-donating
groups did not affect yields significantly, and even the steric
hindrance of 3- and/or 6-substituted groups had no influence
on yields (entries 1, 2, and 5). Lower yields were observed in
the reactions with 4,5-difluorobenzyne precursor 2g bearing
strong electron-withdrawing groups (entry 6) and naphthalyne
precursor 2h (entry 7). It was noteworthy that the reactions
with asymmetric 3-methoxy- or 3,5-dimethoxybenzyne pre-
cursors (entries 1 and 2) exhibited excellent regioselectivity at
the meta position, which was consistent with the reported
selectivity.18 The structure of 3b was unequivocally confirmed
by single-crystal X-ray analysis (Figure 1).19 Under the
conditions of CsF in CH3CN, excess benzyne precursors
could lead to further reaction of the resulting phenol with
benzyne, as indicated by the formation of compounds 4i and 4j
(entries 9 and 11). This could be utilized to transform phenolic
hydroxyl groups to expand its potential applications.
In order to further gauge the scope and generality of the
reaction, a series of organophosphorus acids 1b−n were reacted
with β-trimethylsilyl triflate 2a under the optimized reaction
conditions (Table 3). For the phosphinic acids bearing aryl
groups, para electron-donating groups on aryl groups did not
influence the yields apparently (Table 3, entries 1 and 2).
However, para or ortho strong electron-withdrawing groups on
aryl groups reduced the yields greatly, which might result from
the reduced nucleophilicity of the phosphinic acids (entries 3−
5). For phosphinic acid 1f, in the presence of K2CO3, the
phenolate anion formed in situ could continue to undergo a
nucleophilic aromatic substitution to give 4o along with the
departure of fluoride ion. This provides a novel route to
synthesize benzofused phosphacycles in a cascade fashion
(entry 6), which usually possess unique physical properties and
draw much attention.20 For the phosphinic acids bearing alkyl
or alkenyl groups, all reactions could lead to the desired
products in good yields (entries 7−12). The insertion of arynes
into P−O bonds of phosphonate 1m (entry 14) and phosphate
1n (entry 16) was also explored, which provided the desired
products in good yields under the same conditions as for
phosphinic acids. For different kinds of organophosphorus
acids, an excess of benzyne precursor 2a could lead to further
reaction of the resulting phenol, for example, the formation of
4u (entry 13), 4v (entry 15), and 4w (entry 17).
a
1a (0.2 mmol), 2 (0.3 mmol), TBAT (0.5 mmol), THF (8.0 mL), 60
b
c
°C, 6 h. Isolated yields. 1a (0.2 mmol), 2i (0.6 mmol), KF (1.6
mmol), 18-crown-6 (0.8 mmol), dioxane (4.0 mL), 60 °C, 8 h. 1a
(0.2 mmol), 2j (0.6 mmol), CsF (1.0 mmol), CH3CN (4.0 mL), 60
°C, 8 h.
d
Figure 1. Crystal structure of 3b.
Based on our experimental results and related literatures,10,14
the proposed mechanism for the transformation is shown in
B
DOI: 10.1021/acs.orglett.6b03283
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 3. Scope of Organophosphorus Acid Substrates
Scheme 2. Proposed Mechanism for the Insertion of
Benzyne into P−O Bond
Scheme 2. Theoretically, two pathways could possibly lead to
the desired product 3a. In pathway A, benzyne 5 generated in
situ reacts with the PO bond in 1a through concerted [2 + 2]
cycloaddition to form intermediate 7 in one step, which could
rearrange to 3a. In pathway B, the oxygen anion attacks
benzyne 5 to form aryl anion intermediate 6, which undergoes
an anionic Fries rearrangement through 7 to produce 3a.
Although it was reported that PN and PS bonds could
react with arynes through a similar process to pathway A,21 we
found the PO bond in triphenylphosphine oxide 9 did not
react with benzyne under the optimized conditions, which
supported pathway B for our reaction to some extent.
Moreover, considering the stronger nucleophilicity of the
oxygen anion than the oxygen atom of PO bond, pathway B
might be a plausible process.
To illustrate the synthetic utility of this novel transformation,
the follow-up chemistries on 3a were investigated (Scheme 3).
Considering the importance of ortho-substituted arylphospho-
rus compounds, we transformed phenol 3a into triflate 10,
which could be easily employed for various transition-metal-
catalyzed coupling reactions. For example, the respective
transformations of triflate 10 into olefin 12 and biphenyl 15
a
Scheme 3. Follow-up Chemistry
a
1 (0.2 mmol), 2a (0.3 mmol), TBAT (0.5 mmol), THF (8.0 mL), 60
b
c
°C, 6 h. Isolated yields. 1f (0.2 mmol), 2a (0.3 mmol), TBAT (0.5
mmol), K2CO3 (0.6 mmol), THF (8.0 mL), 60 °C, 24 h. 1l, 1m or
d
1n (0.2 mmol), 2a (0.6 mmol), CsF (1.0 mmol), CH3CN (4.0 mL),
60 °C, 8 h.
a
Yields were not optimized.
C
DOI: 10.1021/acs.orglett.6b03283
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(5) (a) Demmer, C. S.; Krogsgaard-Larsen, N.; Bunch, L. Chem. Rev.
2011, 111, 7981. (b) Ballester, J.; Gatignol, J.; Schmidt, G.; Alayrac,
C.; Gaumont, A. C.; Taillefer, M. ChemCatChem 2014, 6, 1549.
(6) (a) Hirao, T.; Masunaga, T.; Ohshiro, Y.; Agawa, T. Synthesis
1981, 1981, 56. (b) Jablonkai, E.; Keglevich, G. Curr. Org. Synth. 2014,
11, 429.
(7) For reviews, see: (a) Tadross, P. M.; Stoltz, B. M. Chem. Rev.
2012, 112, 3550. (b) Gampe, C. M.; Carreira, E. M. Angew. Chem., Int.
Ed. 2012, 51, 3766.
by Stille and Suzuki couplings could lead to alternative routes
to tertiary phosphine 1322 and a series of phosphine−oxazoline
derivatives,23 which are examples of useful ancillary ligands in
homogeneous catalysis. Other transformations involved the
methylation of phenolic hydroxyl group leading to compound
16 and subsequent nucleophilic aromatic substitution to
produce chiral aminophosphine ligands24 or easy modification
to access kinds of functionalized compounds.25
In summary, a novel strategy for the simultaneous
construction of C−P and C−O bonds to synthesize o-
hydroxy-substituted arylphosphorus compounds was devel-
oped. This scalable transformation proceeded via the insertion
of arynes into P−O bonds under mild and transition-metal-free
conditions. The resulting products, as well as a series of follow-
up chemistries, provided novel synthetic routes for ortho-
substituted arylphosphorus compounds.
(8) (a) Pena, D.; Perez, D.; Guitian, E. Angew. Chem., Int. Ed. 2006,
45, 3579. (b) Yoshida, H.; Takaki, K. Synlett 2012, 23, 1725.
(9) Rao, B.; Tang, J.; Zeng, X. Org. Lett. 2016, 18, 1678.
(10) (a) Dubrovskiy, A. V.; Larock, R. C. Org. Lett. 2010, 12, 3117.
(b) Dubrovskiy, A. V.; Larock, R. C. Tetrahedron 2013, 69, 2789.
(11) (a) Rao, B.; Zeng, X. Org. Lett. 2014, 16, 314. (b) Wright, A.;
Haley, C. K.; Lapointe, G.; Stoltz, B. M. Org. Lett. 2016, 18, 2793.
(12) (a) Dhokale, R. A.; Mhaske, S. B. Org. Lett. 2013, 15, 2218.
(b) Yoshida, S.; Hosoya, T. Chem. Lett. 2013, 42, 583. (c) Rem
́
ond, E.;
Tessier, A.; Leroux, F. R.; Bayardon, J.; Juge, S. Org. Lett. 2010, 12,
́
ASSOCIATED CONTENT
1568. (d) Yoshida, H.; Watanabe, M.; Ohshita, J.; Kunai, A. Chem. Lett.
2005, 34, 1538. (e) Zbiral, E. Tetrahedron Lett. 1964, 5, 1649.
(f) Griffin, C.; Castellucci, N. J. Org. Chem. 1961, 26, 629.
(13) (a) Yang, G.-Q.; Shen, C.-R.; Quan, M.; Zhang, W.-B.
Tetrahedron 2016, 72, 333. (b) Chen, Q.; Yan, X.-X.; Du, Z.-Y.;
Zhang, K.; Wen, C.-X. J. Org. Chem. 2016, 81, 276.
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03283.
(14) Shen, C.-R.; Yang, G.-Q.; Zhang, W.-B. Org. Lett. 2013, 15,
5722.
Experimental procedures and spectral data for all new
compounds (PDF)
(15) Li, Y.; Chakrabarty, S.; Muck-Lichtenfeld, C.; Studer, A. Angew.
̈
Chem., Int. Ed. 2016, 55, 802.
(16) (a) Guo, J.; Kiran, I. N. C.; Reddy, R. S.; Gao, J.-S.; Tang, M.-
Q.; Liu, Y.-Y.; He, Y. Org. Lett. 2016, 18, 2499. (b) Reddy, R. S.;
Lagishetti, C.; Kiran, I. N. C.; You, H.-Y.; He, Y. Org. Lett. 2016, 18,
3818. (c) Reddy, R. S.; Lagishetti, C.; Chen, S.; Kiran, I. N. C.; He, Y.
Org. Lett. 2016, 18, 4546. (d) Guo, J.; Kiran, I. N. C.; Gao, J.-S.;
Reddy, R. S.; He, Y. Tetrahedron Lett. 2016, 57, 3481.
(17) Pilcher, A. S.; Ammon, H. L.; DeShong, P. J. Am. Chem. Soc.
1995, 117, 5166.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: jian.guo@cqu.edu.cn.
*E-mail: yun.he@cqu.edu.cn.
ORCID
Yun He: 0000-0002-5322-7300
Author Contributions
†N.Q. and N.Z. contributed equally.
(18) (a) Liu, Z.-J.; Larock, R. C. J. Org. Chem. 2006, 71, 3198.
(b) Tadross, P. M.; Gilmore, C. D.; Bugga, P.; Virgil, S. C.; Stoltz, B.
M. Org. Lett. 2010, 12, 1224.
(19) CCDC no. for 3b: 1510951.
(20) (a) Baba, K.; Tobisu, M.; Chatani, N. Org. Lett. 2015, 17, 70.
(b) Chen, H.; Delaunay, W.; Li, J.; Wang, Z.-Y.; Bouit, P.-A.;
Tondelier, D.; Hissler, M. Org. Lett. 2013, 15, 330. (c) Baumgartner,
Notes
The authors declare no competing financial interest.
T. Acc. Chem. Res. 2014, 47, 1613.
(21) Lopez-Leonardo, C.; Raja, R.; Lop
́
ACKNOWLEDGMENTS
́
ez-Ortiz, F.; del Aguila-
■
́
San
́
chez, M. A.; Alajarin, M. Eur. J. Org. Chem. 2014, 2014, 1084.
We are grateful for financial support from the National Natural
Science Foundation of China (Nos. 21572027 and 21372267),
the Postdoctoral Science Foundation of China
(2014M562285), and the Chongqing Postdoctoral Research
Grant (Xm2014030).
(22) (a) Williams, D. B. G.; Shaw, M. L. Tetrahedron 2007, 63, 1624.
(b) Lexer, C.; Burtscher, D.; Perner, B.; Tzur, E.; Lemcoff, N. G.;
Slugovc, C. J. Organomet. Chem. 2011, 696, 2466.
(23) (a) Mikami, K.; Aikawa, K.; Korenaga, T. Org. Lett. 2001, 3, 243.
(b) Liu, Y.-Y.; Yang, G.-Q.; Yao, D.-M.; Tian, F.-T.; Zhang, W.-B. Sci.
China: Chem. 2011, 54, 87.
(24) (a) Tanaka, Y.; Mino, T.; Akita, K.; Sakamoto, M.; Fujita, T. J.
Org. Chem. 2004, 69, 6679. (b) Mino, T.; Tanaka, Y.; Sakamoto, M.;
Fujita, T. Tetrahedron: Asymmetry 2001, 12, 2435.
(25) (a) Varnek, A. A.; Morosi, G.; Gamba, A. J. Phys. Org. Chem.
1992, 5, 109. (b) Liu, J.-Y.; Liu, S.-R.; Li, B.-X.; Li, Y.-G.; Li, Y.-S.
REFERENCES
■
(1) (a) Grushin, V. V. Chem. Rev. 2004, 104, 1629. (b) Inoue, A.;
Shinokubo, H.; Oshima, K. J. Am. Chem. Soc. 2003, 125, 1484. (c) Xu,
G.-Q.; Fu, W.-Z.; Liu, G.-D.; Senanayake, C. H.; Tang, W.-J. J. Am.
Chem. Soc. 2014, 136, 570.
(2) (a) Taylor, C. M.; Watson, A. J. Curr. Org. Chem. 2004, 8, 623.
(b) Gagnon, K. J.; Perry, H. P.; Clearfield, A. Chem. Rev. 2012, 112,
1034. (c) Mou, L.-Y.; Singh, G.; Nicholson, J. W. Chem. Commun.
2000, 2000, 345.
Organometallics 2011, 30, 4052. (c) Mamat, C.; Kockerling, M.
̈
Synthesis 2015, 47, 387.
(3) (a) Tsukada, T.; Takahashi, M.; Takemoto, T.; Kanno, O.;
Yamane, T.; Kawamura, S.; Nishi, T. Bioorg. Med. Chem. Lett. 2009, 19,
5909. (b) Sawa, M.; Kiyoi, T.; Kurokawa, K.; Kumihara, H.; Yama
moto, M.; Miyasaka, T.; Ito, Y.; Hirayama, R.; Inoue, T.; Kirii, Y.;
Nishiwaki, E.; Ohmoto, H.; Maeda, Y.; Ishibushi, E.; Inoue, Y.;
Yoshino, K.; Kondo, H. J. Med. Chem. 2002, 45, 919.
(4) Bhattacharya, A. K.; Thyagarajan, G. Chem. Rev. 1981, 81, 415.
D
DOI: 10.1021/acs.orglett.6b03283
Org. Lett. XXXX, XXX, XXX−XXX