Metal-Free Electrophilic Phosphination/Cyclization of Alkynes

Article abstract of DOI:10.1021/jacs.7b02977

A metal-free electrophilic phosphination reaction has been developed. Electrophilic phosphorus species generated in situ from secondary phosphine oxides and Tf₂O smoothly couple with alkynes possessing pendant nucleophiles to afford the corresponding phosphinated cyclization products in good yield. Preliminary NMR studies show that phosphirenium species may be involved as intermediates of the cyclization reactions.

Full text of DOI:10.1021/jacs.7b02977

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Communication
Metal-Free Electrophilic Phosphination/Cyclization of Alkynes
Yuto Unoh, Koji Hirano, and Masahiro Miura
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 17 Apr 2017
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Metal-Free Electrophilic Phosphination/Cyclization of Alkynes
Yuto Unoh, Koji Hirano* and Masahiro Miura*
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Department of Applied Chemistry, Graduate School of Engineering, Osaka University, Suita, Osaka 565ꢀ0871, Japan
Supporting Information Placeholder
tion of nucleophileꢀtethered alkynes. Thus, the formed phosphorus
electrophile may activate such an alkyne to trigger subsequent
cyclization with the pendant nucleophile part.
ABSTRACT: A metalꢀfree electrophilic phosphination reaction
has been developed. Electrophilic phosphorus species generated
in situ from secondary phosphine oxides and Tf2O smoothly couꢀ
ples with alkynes possessing pendant nucleophiles to afford correꢀ
sponding phosphinated cyclization products in good yield. Prelimꢀ
inary NMR studies show that phosphirenium species may be inꢀ
volved as an intermediate of the cyclization reaction.
Figure 1. A Working Hypothesis of This Study
O
R1
R2
R3
P
H
R3
Nu
P(V)
R1
-
+
P
R1
R2
Tf2O
Nu
OTf
P
R2
highly
R1
R2
electrophilic
phosphination
reagent
P
OH
Organophosphorus compounds are now broadly utilized as
building blocks of bioactive molecules, functional materials, and
ligands for transition metals.1 The C(sp2)ꢀP bond formation is one
of the most important and fundamental reactions for the synthesis
of these organophosphorus compounds. The classical synthetic
approaches to form a C(sp2)ꢀP bond are the reaction of halophosꢀ
phine electrophiles with organometallic carbon nucleophiles such
as organolithium and Grignard reagents and the transitionꢀmetal
catalyzed crossꢀcoupling reactions of phosphines with C(sp2)ꢀ
(pseudo)halides.1a,b,2 These methodologies, however, often suffer
from low functional group compatibility and long step preparation
of the coupling precursors. A number of metalꢀpromoted direct Cꢀ
P coupling reactions have recently been reported, while still they
remain underdeveloped.3,4 An alternative way for the formation of
the C(sp2)ꢀP bond is the FriedelꢀCraftsꢀtype electrophilic phosꢀ
phination reaction (phosphaꢀFriedelꢀCrafts: PFC reaction).5 This
process was already known in 1870’s as the reaction of benzene
with PCl3 in the presence of AlCl3.5a However, this kind of transꢀ
formation is usually conducted under harsh conditions in the presꢀ
ence of a stoichiometric amount of Lewis acid such as AlCl3.
Additionally, the reactant halophosphines are toxic and airꢀ and
moistureꢀsensitive, which hampers application in complex molecꢀ
ular synthesis. Therefore PFC reaction has been less utilized in
modern organic synthesis.
P(III)
With the above hypothesis, we commenced optimization of the
electrophilic phosphinative cyclization of alkyne 2a using dipheꢀ
nylphosphine oxide (1a) (Scheme 1). To our delight, treatment of
1a (0.5 mmol) with 2a (0.25 mmol) in the presence of 2,6ꢀlutidine
(0.5 mmol) and Tf2O (0.5 mmol) in DCM (2 mL) at 60 °C for 3 h
in a schlenk tube afforded phosphinative cyclization product 3aa
in 93 % NMR yield (see the Supporting Information (SI) for deꢀ
tailed optimization studies). For an ease of handling, the phosꢀ
phine was isolated as phosphine oxide 4aa (90%) or sulfide 4ab
(84%) after treatment with H2O2 or S8, respectively.
Scheme 1. Electrophilic Phosphination/Cyclization Reac-
tion of 1a with 2a
Recently, metalꢀfree electrophilic Cꢀheteroatom bond forming
reactions have attracted attention as environmentallyꢀfriendly and
unique alternatives to the metalꢀmediated processes.6 The metalꢀ
free CꢀB,7 CꢀN,8 CꢀSi9, and CꢀS10 bond formations have been
achieved. Herein, we report a metalꢀfree electrophilic phosphinaꢀ
tion of alkynes. Compared to the above successful bond forming
processes, there are a few reports of the metalꢀfree intermolecular
electrophilic CꢀP bond forming reaction.11 A working hypothesis
is depicted in Figure 1. Secondary phosphine oxides are basically
stable and readily available phosphorus(V) compounds. It is
known that they are in equilibrium with P(III) forms (hydroxyꢀ
phosphines) in a solution.1a,12 We envisioned that if this hydroxyl
group could be replaced with TfO group upon treatment with
Tf2O, a highly electrophilic phosphorus species would be generatꢀ
ed and utilized for PFC reactions under metalꢀfree conditions.13
As a design of the reaction, we selected an electrophilic cyclizaꢀ
Under the conditions in Scheme 1, we next examined the scope
of alkynes. Representative products are summarized in Table 2. In
some cases, better results were obtained in toluene. In addition to
propargyl amide 2a, simple methyleneꢀtethered arylalkynes posꢀ
sessing both electronꢀdonating and withdrawingꢀgroups at orthoꢀ
(2cꢀ2f) or paraꢀpositions (2g and 2h) smoothly reacted with 1a to
afford corresponding coupling products 4acꢀ4ah. Furthermore,
this methodology was applied to synthesize 1,1ꢀbinaphthyl type
phosphines,14 MOP analogues 4ai and 4aj were formed in synꢀ
thetically useful yields. In addition, not only benzene ring, but
also thiophene (4ak), and conjugated enyne (4al) could be emꢀ
ployed without any difficulties.
Table 1. Scope of Alkynes 2a
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a
Reaction conditions: 1) 1 (0.5 mmol), 2a or 2c (0.25 mmol),
Tf2O (0.5 mmol), 2,6ꢀlutidine (0.5 mmol) in DCM or PhMe (2
mL) at 60 °C under N2 for 3 h; 2) H2O2 or S8 workup. Isolated
yields are shown based on the amount of 2. b Reaction time for 12
h. c Reaction was conducted without 2,6ꢀlutidine.
We also explored nucleophiles other than the aromatic ring
(Table 3). When, tosylamides 6aꢀc were employed under identical
conditions, the corresponding nitrogen heterocycles dihydroꢀ
pyrrole 7aa, tetrahydropyridine 7ab, and indole 7ac were formed.
The successful formation of fiveꢀmembered ring (7aa and 7ac)
was a sharp contrast to the case of arene nucleophile (5at in Table
1), while exclusive 6ꢀendoꢀdig product 7ab was observed in the
reaction of 6b. Furthermore, an alkene could also be employed as
the nucleophile. Thus, the reaction of 1a with 6d afforded 7ad in
an acceptable yield. It was somehow surprising that phenyl 2ꢀ
(phenylethynyl)benzoate 6e underwent the phosphinative cyclizaꢀ
tion to form isocoumarin scaffold 7ae in 59% yield, in which the
ester oxygen atom served as the nucleophile.
a
Reaction conditions: 1) 1a (0.5 mmol), 2 (0.25 mmol), Tf2O
(0.5 mmol), 2,6ꢀlutidine (0.5 mmol) in DCM or PhMe (2 mL) at
60 °C under N2 for 3 h; 2) H2O2 or S8 workup. Isolated yields are
shown based on the amount of 2. b Reaction for 12 h.
As a linker of substrate, ether (4am), thioether (4an), ester
(4ao), arene (4ap), or alkene (4aq) was also viable. The reaction
of 2ꢀnaphthyl ether 2r formed 4ar selectively cyclized at the C1
position, which may be dominated by electronic effect. Interestꢀ
ingly, the reaction of 1,8ꢀdiphenyloctaꢀ3,5ꢀdiyne (2s) selectively
formed 1:1 coupling product 4as. It should be noted that when the
alkyne has a shorter or longer methylene linker (2t, 2u), the cyꢀ
clization did not occur and hydrophosphinylated product 5at or
5au was instead obtained (see below for the detailed pathway to
5at and 5au). Additionally, attempts to apply terminal alkynes
and dialkyl alkynes such as 4ꢀphenylꢀ1ꢀbutyne and 1ꢀphenylꢀ4ꢀ
cyclopropylꢀ3ꢀbutyne remained unsuccessful.
Table 3. Variation of Pendant Nucleophilesa
We subsequently investigated scope of phosphine oxides 1
(Table 2). 4,4’ꢀDisubstituted diphenylphosphine oxides 1b-d reꢀ
acted with 2a or 2c to afford the corresponding coupling products
4ba, 4ca, and 4dc. The present system was tolerated with stericalꢀ
ly demanding 1e, 1f, and 1g (4ec, 4fc, 4gc). In the case of subꢀ
strates possessing electronꢀdonating groups 1b and 1h (and 2j in
Table 1 as well), longer reaction time (12 h) was required for
completion (4ba, 4hc). The hydrophosphinylated products correꢀ
sponding to 5 in Table 1 were formed when the reaction was
quenched in 3 h. This result may imply participation of a phosꢀ
phirenium intermediate (vide infra). Pleasingly, the electrophilic
phosphination was also compatible with phosphinate esters 1i and
1j albeit in moderate yields (4ic, 4jc). In the case of 4jc, addition
of 2,6ꢀlutidine gave a complicated mixture while the reason is
unclear at present. Unfortunately, the present methodology was
not applicable to dialkylphosphine oxides (e.g. dicyclohexylꢀ and
diisopropyl phosphine oxides) and phosphites (e.g. dipheꢀ
nylphosphite, not shown).
a
Reaction conditions: 1) 1 (0.5 mmol), 6 (0.25 mmol), Tf2O
(0.5 mmol), 2,6ꢀlutidine (0.5 mmol) in DCM or PhMe (2 mL) at
60 °C under N2 for 3 h; 2) H2O2 work up. Isolated yields are
shown based on the amount of 6.
Table 2. Scope of Phosphine Oxides 1a
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A Buchwaldꢀtype biarylphosphines were also accessible by usꢀ
To obtain the mechanistic information, we next attempted the
reaction of alkyne without the pendant nucleophile. Treatment of
1a with simple diphenylacetylene (6g) under the standard condiꢀ
tions afforded hydrophosphinylated product 16 in a high yield
(Scheme 5). Interestingly, the product was exclusively obtained in
the phosphine oxide form even without any oxidative workup.
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4
ing the present methodology (Scheme 2). For example, the reacꢀ
tion of 1a with homoallylalkyne 6f generated dihydrobenzene
scaffold 7af along with its double bond isomers. While inseparaꢀ
ble, the mixture was subsequently treated with DDQ at room temꢀ
perature to give single biarylphosphine oxide 8 in 77% yield.
5
6
Scheme 2. Synthesis of Biarylphosphine Oxide 8
Scheme 5. Metal-free Hydrophosphinylation of 6g
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This intriguing result prompted us to carry out in situ 31P{1H}
NMR studies on the reaction in Scheme 5. The phosphine oxide
1a was treated with 6g in CDCl3 under the standard conditions
and the resulting reaction mixture was monitored by 31P{1H}
NMR (Scheme 6, see the SI for details). After 2 h, the signal of 1a
(δ 21.4 ppm) disappeared and two singlet signals (δ ꢀ108.9 and
42.2 ppm) were observed. The signal at δ 42.2 is corresponding to
Ph2P(O)Cl, which could be formed from the phosphenium species
Ph2P+ through Cl abstraction from CDCl3 and oxidation. On the
other hand, the distinctive upshifted signal at δ ꢀ108.9 is assigned
to phosphirenium species 17.18,19 The reaction mixture was then
quenched by D2O and NaHCO3 at room temperature. The viꢀ
nylphosphine oxide 16 and the starting 1a were mainly observed
in the crude mixture. Furthermore, 1H and 2D NMR analyses
showed a 90% deuterium incorporation at the βꢀpositon of 16. It
was previously documented that Ph2PCl underwent [2+1] cyꢀ
cloaddition with diphenylacetylene 6g in the presence of AlCl3 to
form a tetraphenylphosphirenium cation, which was immediately
hydrolyzed upon treatment with H2O to form the same hydroꢀ
phosphinylated product 16.19a
We further demonstrated the utility of this transformation in the
ligand synthesis (Scheme 3). The present PFCꢀtype reaction could
be conducted on a gram scale; 4ac was obtained in 87% yield
(1.07 g, 3 mmol scale). The DDQꢀpromoted dehydrogenative
aromatization of 4ac provided biarylphosphine oxide 9 quantitaꢀ
tively. In addition, 4ac and 9 were reduced with HSiCl3 to the
corresponding phosphines 10 and 11, respectively in excellent
yields. Furthermore, 9 could be transformed to polyarylphosphine
oxide 12 by a Pdꢀcatalyzed CꢀH arylation.15 Isoquinolineꢀ
containing biarylphosphine oxide 13 was also synthesized by
KOHꢀpromoted dehydrosulfination of 4aa.
Scheme 3. Synthetic Applications
Scheme 6. In Situ 31P{1H} NMR Study of The Reaction of
1a with 6g
The present system finds an application in the construction of a
phosphole framework, which considerably attracted attention in
the area of materials chemistry.16 Upon treatment of 1k and 2c
with Tf2O in toluene followed by aqueous workup, secondary
phosphine oxide 14 was selectively formed probably via a preꢀ
formed phenoxyphosphine (Scheme 4). The crude 14 was directly
subjected to silverꢀmediated oxidative radical cyclization condiꢀ
tions,17 leading to benzo[b]phosphole 15 in 66% yield based on
the amount of 2c.
Scheme 7. Proposed Mechanism
Scheme 4. Benzo[b]phosphole Synthesis by Sequential
Double Annulation
Based on the preliminary mechanistic studies, we propose a
tentative reaction mechanism for the present phosphinative cyꢀ
clization reaction in Scheme 7. The electrophilic phosphorus speꢀ
cies A20 generated from 1a and Tf2O undergoes the [2+1] cyꢀ
cloaddition with alkyne 2 to form the phosphirenium cation B.
The phosphirenium B may readily undergo ringꢀopening hydrolyꢀ
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Wang, L. J. Org. Chem. 2014, 79, 10629. (d) Min, M.; Kang, D.; Jung, S.;
Hong, S. Adv. Synth. Catal., 2016, 358, 1296.
sis to form the corresponding hydrophosphinylated product C
upon aqueous workup. If the alkyne 2 has a pendant aryl moiety
as a nucleophile at the appropriate position, the arylative ringꢀ
opening of the phosphirenium may occur to form the phosphinaꢀ
tive cyclization product D. The longer reaction periods with MeOꢀ
substituted substrates (4aj, 4ba, 4hc) were also consistent with the
mechanism; its electronꢀdonating nature may stabilize the phosꢀ
phirenium B and delay the subsequent ringꢀopening event.
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(4) For examples of Pꢀcentered radical involved reactions: (a) Kagaꢀ
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In summary, we have developed the metalꢀfree electrophilic
phosphinative cyclization reaction of alkynes. The electrophilic
phosphination reagent generated in situ from secondary diaꢀ
rylphosphine oxides with the Tf2O/2,6ꢀlutidine system smoothly
undergoes the tandem coupling reaction with alkynes to form
various phosphine derivatives. The 31P NMR mechanistic studies
suggested the intermediacy of phosphirenium species in the reacꢀ
tion medium. Further application of the newly developed metalꢀ
free strategy is under investigation in our group.
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ASSOCIATED CONTENT
Supporting Information
The supporting information is available free of charge via the
Internet at http://pubs.acs.org.
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Procedures and characterization data
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Xꢀray crystallographic data for 4ar and 7ae
AUTHOR INFORMATION
Corresponding Author
*k_hirano@chem.eng.osakaꢀu.ac.jp
*miura@chem.eng.osakaꢀu.ac.jp
ORCID
Yuto Unoh: 0000ꢀ0002ꢀ5200ꢀ7349
Koji Hirano: 0000ꢀ0001ꢀ9752ꢀ1985
Masahiro Miura: 0000ꢀ0001ꢀ8288ꢀ6439
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by JSPS KAKENHI Grant Nos.
14J00760 (GrantꢀinꢀAid for JSPS Research Fellow) to Y.U.,
15K13696 (GrantꢀinꢀAid for Exploratory Research), and
15H05485 (GrantꢀinꢀAid for Young Scientists (A)) to K.H. and
24225002 (GrantꢀinꢀAid for Scientific Research (S)) to M.M.
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(18) (a) Mathey, F. Chem. Rev. 1990, 90, 997. (b) Kühl, O. Phosphoꢀ
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(a)
Beletskaya, I. P.;
Kazankova, M. A.
Russ. J. Org. Chem. 2002, 38, 1391. (b) Schwan, A. L. Chem. Soc. Rev.
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Organic and Organometallic Chemist; Springer Science & Business Meꢀ
dia: Heidelberg, Germany, 2008.
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(19) (a) Breslow, R.; Deuring, L. Tetrahedron Lett. 1984, 25, 1345. (b)
Marinetti, A.; Mathey, F. J. Am. Chem. Soc. 1985, 107, 4700. (c) Heise, G.
L. U.S. Pat. Appl. Publ. 2000, US 6166260 A (CAN134:71387). Our
preliminary DFT calculation at the B3LYP/6ꢀ31G(d) level of theory sugꢀ
gested the chemical shift of phosphirenium species 17 to be δ ꢀ115 ppm,
which is in good agreement with the experimental value. On the other
hand, the chemical shift of Ph2P(O)Cl was calculated to be δ 60 ppm.
(20) A phosphenium cation is considered to be a reactive electrophilic
phosphorus intermediate, while in our studies the free phosphenium cation
was not observed by 31P NMR analysis. See the SI for detailed discussion.
For reviews on phosphenium species, see: (a) Cowley, A. H.; Kemp, R. A.
Chem. Rev. 1985, 85, 367. (b) Gudat, D. Coord. Chem. Rev. 1997, 163, 71.
(c) Gudat, D. Acc. Chem. Res. 2010, 43, 1307. For the limited successful
observation of free phosphirenium species by 31P NMR, see: (d) Laali, K.
K.; Geissler, B.; Wagner, O.; Hoffmann, J.; Armbrust, R.; Eisfeld, W.;
Regitz, M. J. Am. Chem. Soc. 1994, 116, 9407.
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