Divergent intramolecular reactions between phosphines and alkynes

Article abstract of DOI:10.1016/j.cclet.2019.05.053

A divergent intramolecular reaction of phosphine tethered alkyne in protic solvent was developed. This provided a novel and simple access to a large variety of (Z)-alkenylphosphine oxides and phospholane oxides. Our preliminary studies suggested that these divergent reactions are closely related to the reaction condition and molecular structure. A possible mechanism of C-P bond cleavage of a pentacoordinated hydroxyphosphorane intermediate was proposed.

Full text of DOI:10.1016/j.cclet.2019.05.053

Accepted Manuscript
Title: Divergent intramolecular reactions between phosphines
and alkynes
Authors: Yanying Song, Lili Wang, Zheng Duan, Franc¸ois
Mathey
PII:
DOI:
Reference:
S1001-8417(19)30310-9
https://doi.org/10.1016/j.cclet.2019.05.053
CCLET 5021
To appear in:
Chinese Chemical Letters
Accepted date:
27 May 2019
Please cite this article as: Song Y, Wang L, Duan Z, Mathey F, Divergent
intramolecular reactions between phosphines and alkynes, Chinese Chemical Letters
(2019), https://doi.org/10.1016/j.cclet.2019.05.053
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Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Communication
Divergent intramolecular reactions between phosphines and alkynes
Yanying Song#, Lili Wang#, Zheng Duan, François Mathey
College of Chemistry and Molecular Engineering, International Phosphorus Laboratory, International Joint Research Laboratory for Functional
Organophosphorus Materials of Henan Province, Zhengzhou University, Zhengzhou 450001, China
Graphical Abstract
The unexpected divergent reactions of phosphine tethered alkyne in protic solvent with the presence of base were reported. This
provided facile syntheses of (Z)-alkenylphosphine oxides and phospholane oxides.
ARTICLE INFO
ABSTRACT
Article history:
A divergent intramolecular reaction of phosphine tethered alkyne in protic solvent was developed.
This provided a novel and simple access to a large variety of (Z)-alkenylphosphine oxides and
phospholane oxides. Our preliminary studies suggested that these divergent reactions are closely
related to the reaction condition and molecular structure. A possible mechanism of C-P bond
cleavage of a pentacoordinated hydroxyphosphorane intermediate was proposed.
Received 29 April 2019
Received in revised form 18 May 2019
Accepted 22 May 2019
Available online
Keywords:
C-P Bond Cleavage
Phosphine
Alkyne
Alkenylphosphine
Phospholane
The carbon-carbon triple bond appears to be extremely versatile
due to its ability to undergo a wide variety of transformations for
applications in medical chemistry, agrochemistry, and material
chemistry [1]. There are numerous publications dealing with the
synthetic applications of the C≡C bond [2].
Very recently, much attention has been paid to the synthesis of
various important organophosphorus derivatives through
phosphination or phosphorylation of carbon-carbon triple bond [3-
5]. Among these useful transformations, the generation of active
phosphorus species via selective C-P cleavage is a challenging
topic. Transition-metal-catalyzed C-P bond cleavage plays an
important role in the synthetic applications of diverse
organophosphorus moieties [6]. Herein, we would like to report a
rare example of the synthesis of Z-alkenylphosphine oxides and
phospholane oxides via C−P bond cleavage in protic solvent.
During our explorations of the reaction with phosphine tethered
alkyne [4], we tried to synthesize a terminal alkyne 2 from 1a by
removing the trimethylsilyl (TMS) group. Interestingly, after 1a
was stirred with K2CO3 (1 equiv.) at room temperature in a mixture
of MeOH/DCM, an (Z)-alkenylphosphine oxide 3a was isolated,
while the desired terminal alkyne 2 was not detected (Table 1,
entry 1). Similar result was observed with Cs2CO3 (entry 2).
Absence of base resulted in no conversion of 1a (entry 3).
Increasing the amount of K2CO3 (entry 4) or the reaction
———
 Corresponding author.
E-mail address: duanzheng@zzu.edu.cn
# These two authors contributed equally to this work.

temperature (entry 5) did not improve the yield of the reaction. We
were pleased to observe the transformation of 1a even with a
catalytic amount of K2CO3 (5 mol%, entry 7). When the mixture
of H2O/DMSO was used as solvent, the conversion of 1a
proceeded very slowly in the presence of a catalytic amount of
K2CO3. Surprisingly, phospholane oxide 4a was obtained as major
product and only trace amount of 3a was observed (entry 8). Such
phospholane could potentially be used as ligand [7] and
organocatalyst [8] in organic synthesis, which is difficult to obtain
by other methods [9]. The reaction efficiency could be increased
at elevated temperature (entry 9). Higher amount of base did not
improve the reaction efficiency (entry 10). The yield of 4a could
be further improved by using KOTMS as the catalyst. (See more
details in the Supporting information.)
the TMS group was replaced by a phenyl group. However, an
alkyne reduced product 5i was obtained, which is in accordance
with the reported results [10]. When n-butyl substituted 1h was
used, phospholane oxide 4h was isolated as major product and a
trace amount of unknown mixture of organophosphorus
compounds was also observed. These results indicated the
presence of TMS group is crucial to the formation of (Z)-
alkenylphosphine oxides.
Table 1
Optimizations of the reaction conditions.a
Scheme 1. The reaction of phosphine tethered alkyne in the presence
of K2CO3. Reaction conditions: 1 (2 mmol), K2CO3 (2 mmol) in DCM
(4 mL) and MeOH (4 mL), N2, room temperature, 6-9 h, isolated yield.
Entry
Base
(equiv.)
Solvent
T
Time Yield (%)
(h)
(oC)
To be noticed, when the control reaction of 1a was performed
in the deuterated solvent, d4-methanol/DCM, poly-deuterated
product 3aD (D≥95%) was furnished (Scheme 2).
3a
4a
1
2
3
4
5
6
7
K2CO3 (1)
Cs2CO3 (1)
-
MeOH/DCM
MeOH/DCM
MeOH/DCM
MeOH/DCM
MeOH/DCM
25
25
8
7
69
-
-
-
63
-
25
25
50
25
25
6
8
6
9
8
K2CO3 (2)
K2CO3 (1)
68
-
-
-
-
63
64
60
Scheme 2. Deuterated experiment.
K2CO3 (0.5) MeOH/DCM
After screening the scope of (Z)-alkenylphosphine oxide, we
moved our attention to the KOTMS catalyzed reaction of
phosphine tethered alkynes 1 (Table 2). It is noteworthy that the
complexity may arise with the TMS substituted alkynes (R'' =
TMS), since the selectivity of the reactions are highly reliable on
the substituents on phosphorus and the electronic effect of the aryl
anchor. The diphenylphosphine derivative 1a gave the cyclized
product 4a as major product (entry 1), while (Z)-alkenylphosphine
oxide 3c was obtained selectively in the case of the dialkyl
substituted phosphine 1c (entry 2). When R'' is TMS, the product
will be either 3 or 4 (entries 1-5). The effect of R on anchored aryl
group is elusive. When R is neutral H or Me, the formation of
cyclized product 4 was favored (entries 1, 3). When R is electron-
K2CO3
(0.05)
MeOH/DCM
H2O/DMSO
H2O/DMSO
8
9
K2CO3
(0.05)
25
70
38
8
trace
trace
46
53
K2CO3
(0.05)
10
11
K2CO3 (1)
H2O/DMSO
H2O/DMSO
70
70
8
6
trace
trace
49
58
KOTMS
(0.05)
a Reaction conditions: 1a (1mmol) in DCM (2 mL)/ MeOH (2 mL) or DMSO
(4 mL) / H2O (0.3 mL) under N2 atmosphere.
donating
OMe
or
electron-withdrawing
CF3,
(Z)-
Encouraged by these unexpected results, we decided to
investigate the synthetic applications of these base-promoted
transformations of phosphine tethered alkynes in protic solvent.
Our initial studies focused on the K2CO3 promoted transformation
of phosphine tethered alkynes 1 in the mixture of MeOH/DCM.
The reaction proved to be robust and versatile and allowed the
synthesis of a broad range of (Z)-alkenylphosphine oxides 3
(Scheme 1). Both aryl-(3a, b) and alkyl-(3c) substituted phophine
oxides were well tolerated. Next, products with various substituted
anchors were synthesized in modest to good yields, indicating that
the reactions are essentially independent of the electronic
properties of the anchors (3d, e: electron-donating Me and OMe;
3f: electron-withdrawing CF3). When the reaction was performed
with a pyridine derivative 1g, 3g was isolated in 67% yield. To
demonstrate the synthetic value of our newly developed reaction,
alkenylphosphine oxides were isolated as major products (entries
4, 5). When R'' is aryl or alkyl group, the reactions gave 4 and/or
5 (entries 6-11). When R'' is electron neutral or rich aryl group, the
formation of cyclized product 4 was preferred (entries 6, 7). The
structure of 4k was unambiguously established by X-ray
crystallographic analysis (Fig. 1) (CCDC 1892220). The
formation of 5 was preferred with electron deficient derivatives
(entries 8, 9). The structure of 5m (CCDC 1892217) was
confirmed by X-ray analysis (Fig. 1). The reaction of n-butyl
substituted (R'' = n-Bu) 1h gave cyclized 4h, but the reaction of
bulky alkyl substituted (R'' = t-Bu) 1n provided 5n.
Table 2
The reaction of phosphine tethered alkyne with a catalytic amount of
KOTMS.a

Yield (%)b
Entry Substrate
R
R'
R'
3
4
5
Scheme 4. Control and deuterated experiments.
1
2
1a
1c
1d
1e
1f
H
H
Ph
Cy
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
TMS
TMS
TMS
TMS
TMS
trace
3c (41)
4a (58)
-
-
-
-
-
On the basis of the literatures [11] and control experiments, a
plausible reaction mechanism is proposed and outlined in Fig. 2.
The reaction starts with an intramolecular nucleophilic attack of
the alkynyl group by phosphine to form zwiterionic 8 [10].
Subsequently, hydrolysis of 8 by the protic solvent to generate
pentacoordinated hydroxyphosphorane 9, followed by the
decomposion of 9 to give the tertiary phosphine oxide 3 or 5. Upon
the removal of the hydroxyl proton from 9, a concerted aryl
migration process gives 11 [12], which provides phospholane
oxide 4 after hydrolysis.
-
3
Me
OMe
CF3
H
3d (11) 4d (43)
4
3e (67)
trace
trace
5
3f (64)
p-MeO-
C6H4
6
1j
-
-
-
-
-
-
4j (64)
4k (56)
trace
trace
7
1k
1l
H
p-Tol
5k (23)
5l (58)
8
H
p-F-C6H4
p-CF3-
C6H4
5m
(75)
9
1m
1h
1n
H
trace
10
11
H
n-Bu
t-Bu
4h (61)
trace
trace
H
5n (69)
a
Reaction conditions: 1 (1 mmol), KOTMS (5 mol %) in H2O (0.3 mL) and
o
DMSO (2 mL), N2, 70 C, 6-8 h.
b Isolated yield.
Fig. 2. The proposed mechanism.
In summary, a divergent reaction of phosphine tethered alkyne
in protic solvent has been realized. Our preliminary studies suggest
that these divergent reactions are closely related to the reaction
condition and molecular structure. In the presence of K2CO3, the
TMS substituted alkynes were converted into (Z)-
alkenylphosphine oxides in the mixture of MeOH and DCM. The
reaction pathways in the mixture of H2O and DMSO with a
catalytic amount of KOTMS are complicated. The divergences are
dependent on the electronic nature of aryl anchor, the substituents
on alkyne and phosphine: When TMS substituted alkynes were
used, the alkylphosphines gave (Z)-alkenylphosphine oxides
selectively. Arylphophines with electron neutral anchors produced
phospholane oxides as major products, which are difficult to
access by other methods. Arylphophines with electron-rich or
deficient anchor preferred the formation of (Z)-alkenylphosphine
oxides. When aryl substituted alkynes were used, the electron-rich
aryl substituents favored the formation of phospholane oxides
while the electron-deficient ones favored the alkenylphosphine
oxide products. Placement of primary alkyl group on the end of
alkyne allows for the selective formation of phospholane oxide.
But the bulky alkyl substituted alkyne gives the alkenylphosphine
oxide. Further efforts on the understanding the rules governing the
selective transformations of phosphine tethered alkynes as well as
the synthetic applications of these transformations are underway
in our laboratory.
Fig. 1. The crystal structures of 4k and 5m.
Scheme 3. Synthesis of phosphahexacycle 7 (CCDC 1892219)
The KOTMS catalyzed cascaded phosphination, aryl migration
and protonation were used to synthesize
phosphahexacycle 7 (Scheme 3).
To understand the reaction mechanism, the control and
deuterium-labeling experiments were performed (Scheme 4).
Partial deuterated product 4aD' was obtained in D2O/DMSO. The
deuterated product 4aD (D ≥ 95 %) was isolated when reaction
was performed in D2O/DMSO-d6. These results indicated the
importance of both H2O and DMSO in this tandem process.
a new fused
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