Room temperature alkynylation of H-phosphi(na)tes and secondary phosphine oxides with ethynylbenziodoxolone (EBX) reagents

Article abstract of DOI:10.1039/c4cc06851c

Highly efficient protocols for the alkynylation of H-phosphi(na)tes and secondary phosphine oxides with silyl, aryl and alkyl ethynyl-benziodoxolone (EBX) reagents are reported. Alkynyl phosphorus compounds were obtained in 69-93% yield without the need for a transition metal catalyst at room temperature under open flask conditions.

Full text of DOI:10.1039/c4cc06851c

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Room temperature alkynylation of H-phosphi(na)tes
and secondary phosphine oxides with ethynyl-
benziodoxolone (EBX) reagents†
Cite this: Chem. Commun., 2014,
50, 12923
Received 30th August 2014,
Accepted 9th September 2014
C. Chun Chen and Jerome Waser*
DOI: 10.1039/c4cc06851c
www.rsc.org/chemcomm
Highly efficient protocols for the alkynylation of H-phosphi(na)tes
and secondary phosphine oxides with silyl, aryl and alkyl ethynyl-
benziodoxolone (EBX) reagents are reported. Alkynyl phosphorus
compounds were obtained in 69–93% yield without the need for a
transition metal catalyst at room temperature under open flask
conditions.
Phosphorus-based functional groups are important in biology,
medicine and synthetic chemistry.1 Synthetic phosphorus deriva-
tives display a broad range of bioactivities, including drugs like the
blood-pressure lowering fosinopril 12a and the antiviral cidofovir 22b
and the nerve poison sarin 3 (Fig. 1, A). Furthermore, ligands such
as BINAP 4 based on phosphorus play a privileged role in modern
organic and organometallic chemistry. Phosphonium salts and
phosphonic esters are also important building blocks to access
alkenes via Wittig or Horner–Wadsworth–Emmons (HWE) reac-
tions. The development of general methods for the synthesis of
organophosphorus compounds is consequently an important goal
in organic chemistry.
In this context, alkynyl phosphorus derivatives constitute an
important class of building blocks because of the versatile reactivity
of the triple bond (Fig. 1, B).3 Hydration of the alkyne leads to
b-ketophosphonates, which are used in the HWE reaction.4 The
addition of other nucleophiles has been also intensively investi-
gated.3b The use of alkynyl phosphorus in [3+2], [4+2] and [2+2+2]
cycloadditions5 gives access to important phosphorus cyclic com-
pounds, including versatile chiral ligands for metal catalysis3b,5f–h
or amino acids analogues for studies in chemical biology.5a
To date, four different approaches have been developed for
the synthesis of alkynyl phosphorus compounds, including: (1)
reaction of electrophilic alkynes or their precursors with nucleo-
philic phosphorus(III) reagents involving Michaelis–Arbuzov and
Michaelis–Becker reactions,4a,6 (2) reaction of nucleophilic alkynes
Fig. 1 Important phosphorus-containing bioactive molecules (A) and
alkynyl phosphorus derivatives as important building blocks (B).
with electrophilic phosphorus,7 (3) b-elimination of heteroatom-
substituted vinylphosphonates,8 and (4) metal-mediated reaction
of H-phosphites with 1,1-dibromo alkenes, terminal acetylenes,
propiolic acid derivatives, copper acetylides or bromo alkynes.9
In addition, metal-catalyzed method to access alkynyl phos-
phines have also been reported.10 Despite these different alter-
natives, there are currently no general access to alkynyl phosphorus
compounds under mild conditions in absence of transition metals.
Most works focus on only one class of phosphorus compounds,
especially phosphonates.
´ ´
Laboratory of Catalysis and Organic Synthesis, Ecole Polytechnique Federale de
Lausanne, EPFL SB ISIC LCSO, BCH 4306, 1015 Lausanne (CH), Switzerland.
E-mail: jerome.waser@epfl.ch; Web: http://lcso.epfl.ch; Fax: +41 21 693 97 00
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4cc06851c
In this context, alkynyl iodonium salts have been long
known as electrophilic alkynylation reagents,11 but their use
for the synthesis of alkynyl phosphorus compounds has been
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 12923--12926 | 12923

View Article Online
Communication
ChemComm
Scheme 1 Our approach towards phosphorus alkynylation.
limited to phosphites6b and phosphonates salts.12 Our group
has discovered and exploited the properties of cyclic alkynyl
benziodoxolone reagents, such as TIPS-ethynyl-benziodoxolone
(TIPS-EBX, 6a) for the alkynylation of nucleophiles.13 This class of
reagents, first synthesized by Ochiai and Zhdankin,14 has then later
also been exploited by others.15 Herein, we would like to report the
successful alkynylation of H-phosphites, H-phosphinates and secondary
phosphine oxides at room temperature in open flask and a short
reaction time (o5 minutes) using EBX reagents (Scheme 1).
To start our studies, we selected 1,1,3,3-tetramethyl guanidine
(TMG) for the preparation of alkyne 7a from diethyl phosphinate
5a with TIPS-EBX 6a, as it has been the base of choice in the case of
thiol nucleophiles.13h To our delight, 53% isolated yield of 7a was
obtained (Table 1, entry 1). Other amine bases such as 4-dimethyl-
aminopyridine (4-DMAP), 1,4-diazabicyclo[2,2,2]octane (DABCO)
and triazabicyclodecene (TBD) led to lower yields (entries 2–4).
In contrast, the use of 1,8-diazabicycloundec-7-ene (DBU) gave
product 7a in 82% isolated yield (entry 5). A fast examination of
base and reagent loading showed that 1.5 equivalents of DBU and
1.1 equivalents of TIPS-EBX 6a were optimal (entries 6–8). Other
solvents gave lower yields when compared to THF (entries 9–13).
Alkynyl phosphite 7a was already formed within 3 min in 90%
isolated yield (entry 14). The formation of 7a was not observed in
the absence of DBU (entry 15).
Scheme 2 Scope of the alkynylation of phosphites and phosphinates.
Reaction conditions: 0.15–0.29 mmol of H-phosphite or H-phosphinate 5
(1.0 equiv.), 1.5 equiv. of DBU and 1.2 equiv. of R-EBX 6, 0.1 M in THF at
23 1C. Isolated yield after purification on column chromatography is given.
2.5 equiv. of DBU was used in the case of 7i.
Table 1 Optimization of the alkynylation of phosphite 8a
With optimum conditions in hand the scope of H-phosphites
and H-phosphinates was examined (Scheme 2).16 Dimethyl and
dibenzyl phosphites 6b and 6c gave the desired product 7b and 7c
in 85% and 89% yield respectively. H-(R)-BINOL phosphite deriva-
tive 7d was obtained in 86% yield. In addition, alkynes 7e and 7f
were obtained from the corresponding phosphinates in 76% and
87% yield respectively. More complex (R)-phenyl menthoxy and
phenyl AZT H-phosphinates were also suitable substrates to deliver
the products 7g (71%) and 7h (70%) as a mixture of diastereo-
isomers. However, phenylphosphinic acid 6i could not be converted
into alkyne 7i. Substituted ethynyl-benziodoxolones (R-EBXs), such
as Ph-EBX 6b,13f tBu-EBX 6c,13f and nHex-EBX 6d15g could also be
used in this direct alkynylation successfully to give products 7j–l.
Notably, an 1,5-C–H insertion product resulting from a carbene
intermediate was not observed in the alkynylation of 5a with
nHex-EBX 6d, in contrast to what had been observed when
ketoesters were used as nucleophiles with alkynyliodonium salts.17
We then turned our attention to the alkynylation of secondary
phosphine oxides (SPO) (Scheme 3).16 The alkynylation of this
class of substrates has been much less studied in the past. Indeed,
to the best of our knowledge, only the alkynylation of diphenyl
Entry Equiv. 6a Base (equiv.) Solvent Time (min) Yielda (%)
1
2
3
4
5
6
7
8
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
TMG (2.0)
4-DMAP (2.0) THF
THF
90
90
90
90
90
90
90
90
90
55 (53)b
0
30
DABCO (2.0)
TBD (2.0)
DBU (2.0)
DBU (1.5)
DBU (1.2)
DBU (1.5)
DBU (1.1)
DBU (1.5)
DBU (1.5)
DBU (1.5)
DBU (1.5)
DBU (1.5)
DBU (0)
THF
THF
THF
THF
THF
THF
THF
i-PrOH 90
TBME
MeCN
0
85 (82)b
84
50
89 (88)b
9
45
5
22
61
10
11
12
13
14
15
90
90
CH2Cl2 90
THF
THF
23
3
92 (90)b
3 or 90
0
a
0.05 mmol 5a was used. The yield is obtained from 1H-NMR with
b
1,3,5-trimethoxybenzene as internal reference. Isolated yield after
purification on column chromatography.
12924 | Chem. Commun., 2014, 50, 12923--12926
This journal is ©The Royal Society of Chemistry 2014

View Article Online
ChemComm
Communication
had been observed in the case of aliphatic alkynes could be
rationalized by a fast 1,2-shift of the phosphorus atom. Never-
theless, an alternative mechanism involving nucleophilic attack of
phosphi(na)te/phosphine oxide onto the iodine atom of benz-
iodoxolone, followed by C–P bond formation to give the alkyne
product cannot be excluded at this stage. A single electron transfer
(SET) from phosphi(na)te/phosphine oxide to the ethynyl-
benziodoxolone, could also be proposed as a first step in the
reaction. Recombination on the iodine to give an I–P bond
followed by reductive elimination or direct alkynylation of the
phosphorus atom would then lead to the observed product.
However, when TEMPO was added to the reaction mixture
under the standard reaction conditions (Table 1, entry 14),
alkyne 7a was still obtained in 85% yield. This result suggests
that long-living radical intermediates are probably not involved.
It is also important to notice that SET pathways often require
further activation of the hypervalent iodine reagent by a Lewis
or Brønsted acid to facilitate electron transfer, and the devel-
oped method proceeded under basic conditions.18
In conclusion, we have described very simple and general
protocols for the alkynylation of H-phosphites, -phosphinates,
and secondary phosphine oxides using ethynyl-benziodoxolone
reagents in good to excellent yield. The developed alkynylation
method proceeded at room temperature in a few minutes and
did not require the use of transition metals. It could be applied
to the synthesis of silyl, alkyl and aryl substituted alkynes and
was efficient for a broad range of different substituents on
phosphorus. Further extension of the scope, application of the
obtained building blocks in synthesis, and more detailed
investigation of the reaction mechanism are currently ongoing
in our laboratory and the results will be reported in due course.
EPFL, F. Hoffmann-La Roche Ltd and ERC (Starting Grant
iTools4MC, number 334840) are acknowledged for financial support.
Scheme 3 Scope of the H-phosphine oxides. Reaction conditions: 0.15–
0.29 mmol of H-phosphine oxide 8 (1.0 equiv.), 1.5 equiv. of TMG and
1.5 equiv. of R-EBX 6, 0.1 M in THF at 23 1C. Isolated yield after purification
on column chromatography is given.
phosphine oxide 8a has been reported.6d,9e, f Initially, the condi- We also thank Dr P. A. Donets and Prof. N. Cramer from the
tions used in alkynylation of H-phosphites and H-phosphinates Laboratory of Asymmetric Catalysis and Synthesis at EPFL for dona-
using DBU as a base (Table 1, entry 14) were tested for the tion of starting materials 5d, 8e, 8f and 8g. Dr C. C. Chen dedicates
alkynylation of diphenyl phosphine oxide 8a, but only 60% this article to Prof. V. K. Aggarwal FRS at University of Bristol.
isolated yield of 9a was obtained. TMG, which had been the
Notes and references
1 (a) F. H. Westheimer, Science, 1987, 235, 1173; (b) C. S. Demmer,
second best base in the case of phosphites, gave better results
and the alkynylation product 9a was isolated in 91% yield. This
protocol could also be used in the synthesis of di-(4-tolyl)
phosphinite 9b (89%), di-(4-fluorophenyl) phosphinite 9c (93%),
di-(n-butyl) phosphinite 9d (86%), and phenyl-t-butyl phosphinite
9e (87%). Significantly, cyclic phosphinite 9f can be made in 89%
yield. However, bulky substituted phosphinite, such as 9g and 9h
could not be synthesized. We further investigated the synthesis of
ethynyl phosphinite bearing aryl or alkyl groups on the alkyne.
Phenylethynyl phosphine 9i and t-butylethynyl phosphine 9j were
obtained in 72% and 87% yield respectively. n-Hexyl ethynyl
phosphine 9k could also be obtained in 85% yield.
Several plausible mechanisms could be envisaged for the direct
alkynylation reaction. For the reaction of alkynyliodonium salts with
carbon nucleophiles, conjugate addition onto the b-carbon of ethynyl-
benziodoxolone, followed by an a-elimination of the aryliodide and
1,2-shift rearrangement to deliver the alkyne has been most often
proposed.17 The fact that no products resulting from C–H insertion
N. Krogsgaard-Larsen and L. Bunch, Chem. Rev., 2011, 111, 7981;
(c) J. L. Montchamp, Acc. Chem. Res., 2013, 47, 77; (d) D. E. C.
Corbridge, Phosphorus: Chemistry, Biochemistry and Technology, CRC
Press, 6th edn, 2013.
2 (a) P. Tatti, M. Pahor, R. P. Byington, P. Di Mauro, R. Guarisco,
G. Strollo and F. Strollo, Diabetes Care, 1998, 21, 597; (b) U. Eriksson,
L. W. Peterson, B. A. Kashemirov, J. M. Hilfinger, J. C. Drach, K. Z.
Borysko, J. M. Breitenbach, J. S. Kim, S. Mitchell, P. Kijek and
C. E. McKenna, Mol. Pharmaceutics, 2008, 5, 598.
3 For reviews, see: (a) B. Iorga, F. Eymery, D. Carmichael and P. Savignac,
Eur. J. Org. Chem., 2000, 3103; (b) A. Kondoh, H. Yorimitsu and
K. Oshima, Chem. – Asian J., 2010, 5, 398.
4 (a) G. Sturz, C. Charrier and H. Normant, Bull. Soc. Chim. Fr., 1966,
1707; (b) E. J. Corey and S. C. Virgil, J. Am. Chem. Soc., 1990,
112, 6429; (c) X. Li, G. Hu, P. Luo, G. Tang, Y. Gao, P. Xu and
Y. Zhao, Adv. Synth. Catal., 2012, 354, 2427; (d) L. Y. Xie, R. Yuan,
R. J. Wang, Z. H. Peng, J. N. Xiang and W. M. He, Eur. J. Org. Chem.,
2014, 2668.
5 Selected examples: [3+2]: (a) J. M. Kee, B. Villani, L. R. Carpenter and
T. W. Muir, J. Am. Chem. Soc., 2010, 132, 14327; [4+2]: (b) D. Seyferth
and J. Paetsch, J. Org. Chem., 1969, 34, 1483; (c) B. O. Ashburn and
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 12923--12926 | 12925

View Article Online
Communication
ChemComm
R. G. Carter, Angew. Chem., Int. Ed., 2006, 45, 6737; (d) B. O.
Ashburn, R. G. Carter and L. N. Zakharov, J. Am. Chem. Soc., 2007,
129, 9109; [2+2+2]: (e) M. Schelper, O. Buisine, S. Kozhushkov,
C. Aubert, A. de Meijere and M. Malacria, Eur. J. Org. Chem., 2005,
3000; ( f ) G. Nishida, K. Noguchi, M. Hirano and K. Tanaka, Angew.
Chem., Int. Ed., 2007, 46, 3951; (g) G. Nishida, S. Ogaki, Y. Yusa,
T. Yokozawa, K. Noguchi and K. Tanaka, Org. Lett., 2008, 10, 2849;
(h) N. Sakiyama, D. Hojo, K. Noguchi and K. Tanaka, Chem. – Eur. J.,
2011, 17, 1428.
Angew. Chem., Int. Ed., 2010, 49, 7304; (c) D. Fernandez Gonzalez,
J. P. Brand and J. Waser, Chem.
– Eur. J., 2010, 16, 9457;
(d) S. Nicolai, S. Erard, D. Fernandez Gonzalez and J. Waser, Org.
Lett., 2010, 12, 384; (e) S. Nicolai, C. Piemontesi and J. Waser, Angew.
Chem., Int. Ed., 2011, 50, 4680; ( f ) J. P. Brand, C. Chevalley,
R. Scopelliti and J. Waser, Chem. – Eur. J., 2012, 18, 5655;
´
´
`
(g) D. Fernandez Gonzalez, J. P. Brand, R. Mondiere and J. Waser,
Adv. Synth. Catal., 2013, 355, 1631; (h) R. Frei and J. Waser, J. Am.
Chem. Soc., 2013, 135, 9620; (i) Y. Li, J. P. Brand and J. Waser, Angew.
Chem., Int. Ed., 2013, 52, 6743. For a review see: ( j) J. P. Brand,
D. Fernandez Gonzalez, S. Nicolai and J. Waser, Chem. Commun.,
2011, 47, 102.
6 (a) B. I. Ionin and A. A. Petrov, J. Gen. Chem. USSR (Engl. Transl.),
1962, 32, 2355; (b) J. S. Lodaya and G. F. Koser, J. Org. Chem., 1990,
55, 1513; (c) Y. Yatsumonji, A. Ogata, A. Tsubouchi and T. Takeda,
Tetrahedron Lett., 2008, 49, 2265; (d) Y. Wang, J. Gan, L. Liu, 14 (a) M. Ochiai, Y. Masaki and M. Shiro, J. Org. Chem., 1991, 56, 5511;
H. Yuan, Y. Gao, Y. Liu and Y. Zhao, J. Org. Chem., 2014, 79, 3678,
For a review on electrophilic alkynylation, see: (e) J. P. Brand and
J. Waser, Chem. Soc. Rev., 2012, 41, 4165.
7 (a) A. M. Aguiar and M. S. Chattha, J. Org. Chem., 1971, 36, 2719;
(b) A. J. Rudinskas and T. L. Hullar, J. Med. Chem., 1976, 19, 1367.
8 (a) H. I. Jacobson, M. J. Griffin, S. Preis and E. V. Jensen, J. Am. Chem.
Soc., 1957, 79, 2608; (b) J. E. Hong, C. W. Lee, Y. Kwon and D. Y. Oh,
Synth. Commun., 1996, 26, 1563.
9 From 1,1-dibromo alkenes: (a) M. Lera and C. J. Hayes, Org. Lett.,
2000, 2, 3873. From terminal alkynes: (b) Y. Gao, G. Wang, L. Chen,
P. Xu, Y. Zhao, Y. Zhou and L. B. Han, J. Am. Chem. Soc., 2009,
131, 7956; (c) Z. B. Qu, X. L. Chen, J. W. Yuan, L. B. Qu, X. Li,
F. J. Wang, X. L. Ding and Y. F. Zhao, Can. J. Chem., 2012, 90, 747.
From propiolic acid derivatives: (d) J. Hu, N. Zhao, B. Yang, G. Wang,
L. N. Guo, Y. M. Liang and S. D. Yang, Chem. – Eur. J., 2011, 17, 5516;
(e) X. Li, F. Yang, Y. Wu and Y. Wu, Org. Lett., 2014, 16, 992. From
(b) V. V. Zhdankin, C. J. Kuehl, A. P. Krasutsky, J. T. Bolz and
A. J. Simonsen, J. Org. Chem., 1996, 61, 6547.
15 (a) Y. Ohta, Y. Tokimizu, S. Oishi, N. Fujii and H. Ohno, Org. Lett.,
2010, 12, 3963; (b) X. Liu, Z. Wang, X. Cheng and C. Li, J. Am. Chem.
Soc., 2012, 134, 14330; (c) Z. Wang, X. Li and Y. Huang, Angew.
Chem., Int. Ed., 2013, 52, 14219; (d) T. Aubineau and J. Cossy, Chem.
Commun., 2013, 49, 3303; (e) M. Kamlar, P. Putaj and J. Vesel´y,
Tetrahedron Lett., 2013, 54, 2097; ( f ) A. Nierth and M. A. Marletta,
Angew. Chem., Int. Ed., 2014, 53, 2611; (g) H. Huang, G. Zhang,
L. Gong, S. Zhang and Y. Chen, J. Am. Chem. Soc., 2014, 136, 2280;
(h) C. Feng and T. P. Loh, Angew. Chem., Int. Ed., 2014, 53, 2722;
(i) F. Xie, Z. Qi, S. Yu and X. Li, J. Am. Chem. Soc., 2014, 136, 4780;
( j) K. D. Collins, F. Lied and F. Glorius, Chem. Commun., 2014,
50, 4459; (k) L. F. Silva Jr, A. Utaka and L. Calvalcanti, Chem.
Commun., 2014, 50, 3810; (l) P. Finkbeiner, N. M. Weckenmann
and B. J. Nachtsheim, Org. Lett., 2014, 16, 1326.
copper acetylides: ( f ) K. Jouvin, J. Heimburger and G. Evano, Chem. 16 Preparation of non-commercially available H-phosphi(na)tes and
Sci., 2012, 3, 756; (g) C. Theunissen, M. Lecomte, K. Jouvin,
A. Laouiti, C. Guissart, J. Heimburger, E. Loire and G. Evano,
Synthesis, 2014, 1157. From bromoalkynes: O. Berger, C. Petit,
E. L. Deal and J. L. Montchamp, Adv. Synth. Catal., 2013, 355, 1361.
10 Selected examples: (a) I. P. Beletskaya, V. V. Afanasiev, M. A. Kazankova
and I. V. Efimova, Org. Lett., 2003, 5, 4309; (b) E. Bernoud, C. Alayrac,
O. Delacroix and A. C. Gaumont, Chem. Commun., 2011, 47, 3239;
(c) K. Jouvin, R. Veillard, C. Theunissen, C. Alayrac, A. C. Gaumont and
secondary phosphine oxides: (a) X. B. Sun, J. X. Kang and Y. F. Zhao,
Chem. Commun., 2002, 2414; (b) K. Afarinkia and H. W. Yu, Tetra-
hedron Lett., 2003, 44, 781; (c) C. A. Busacca, J. C. Lorenz,
N. Grinberg, N. Haddad, M. Hrapchak, B. Latli, H. Lee, P. Sabila,
A. Saha, M. Sarvestani, S. Shen, R. Varsolona, X. Wei and C. H.
Senanayake, Org. Lett., 2005, 7, 4277; (d) P. Fourgeaud, C. Midrier,
J. P. Vors, J. N. Volle, J. L. Pirat and D. Virieux, Tetrahedron, 2010,
66, 758. For detail, see the ESI.†.
G. Evano, Org. Lett., 2013, 15, 4592. For a review, see: (d) E. Bernoud, 17 (a) M. Ochiai, M. Kunishima, Y. Nagao, K. Fuji, M. Shiro and
R. Veillard, C. Alayrac and A. C. Gaumont, Molecules, 2012, 17, 14573.
11 V. V. Zhdankin and P. J. Stang, Tetrahedron, 1998, 54, 10927.
12 J. L. Zhang and Z. C. Chen, Synth. Commun., 1998, 28, 175.
E. Fujita, J. Am. Chem. Soc., 1986, 108, 8281; (b) M. Ochiai, T. Ito,
Y. Takaoka, Y. Masaki, M. Kunishima, S. Tani and Y. Nagao, J. Chem.
Soc., Chem. Commun., 1990, 118.
13 Selected examples: (a) J. P. Brand, J. Charpentier and J. Waser, 18 T. Dohi, M. Ito, N. Yamaoka, K. Morimoto, H. Fujioka and Y. Kita,
Angew. Chem., Int. Ed., 2009, 48, 9346; (b) J. P. Brand and J. Waser, Tetrahedron, 2009, 65, 10797.
12926 | Chem. Commun., 2014, 50, 12923--12926
This journal is ©The Royal Society of Chemistry 2014