A phosphine-mediated stereocontrolled synthesis of Z-enediynes by a vicinal dialkynylation of ethynylphosphonium salts

Article abstract of DOI:10.1039/c4cc03415e

Z-Enediynes are prepared by a vicinal dialkynylation of triaryl(arylethynyl)phosphonium cations. The method, which proceeds under mild transition metal-free conditions, can be conducted on multigram scale as a one-pot, phosphine-mediated synthetic cycle giving enediyne products with excellent control of configuration.

Full text of DOI:10.1039/c4cc03415e

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A phosphine-mediated stereocontrolled synthesis
of Z-enediynes by a vicinal dialkynylation of
ethynylphosphonium salts†
Cite this: Chem. Commun., 2014,
50, 9302
Received 6th May 2014,
Accepted 20th June 2014
Kyle D. Reichl and Alexander T. Radosevich*
DOI: 10.1039/c4cc03415e
www.rsc.org/chemcomm
Z-Enediynes are prepared by a vicinal dialkynylation of triaryl(aryl-
ethynyl)phosphonium cations. The method, which proceeds under
mild transition metal-free conditions, can be conducted on multigram
scale as a one-pot, phosphine-mediated synthetic cycle giving
enediyne products with excellent control of configuration.
Ethynyl onium cations of the p-block elements (1, Fig. 1a) are
versatile electrophilic reagents in organic synthesis exhibiting
multifaceted reactivity. For instance, reactions with nucleophiles
leading to bond formation at Ca illustrate the synthetic equivalency
of these species with alkynyl cations.1 Alternatively, addition to the
Cb position may generate ylidic intermediates, which have been
shown to undergo a range of subsequent chemistries as a function
of the nucleofugality of the p-block moiety.2
Within this latter framework, reactions leading to vicinal
difunctionalization of ethynyl onium compounds by introduction of
either one or two heteroatomic substituents are well-known Fig. 1 (a) Typical reactivity of ethynyl onium reagents. (b) Z-Enediynes by
(Fig. 1a),3 having been featured in several complex target syntheses.4
dicarbofunctionalization of triaryl(arylethynyl)phosphonium salts.
By contrast, reactions resulting in vicinal dicarbofunctionalization
of the LnE+–CaRCb moiety are significantly less common.5 We
report here an intermolecular reaction of ethynylphosphonium
Triaryl(ethynyl)phosphonium salts are readily prepared under
cations with acetylene derivatives that results in two C–C bond mild conditions by reaction of neutral triarylphosphines with
forming events across the CRC ethynyl onium unit (Fig. 1b). 1-haloalkynes;7 specifically, treatment of 1-bromo-2-phenylacetylene
This transformation results in a mild and stereoselective pre- with tris(p-anisyl)phosphine (P(p-An)3) in toluene affords the
paration of Z-enediynes (Z-1,2-diethynylethenes), a valuable corresponding ethynylphosphonium salt 3 in good yield.
class of p-conjugated hydrocarbons with significant biomedical Further reaction of this salt with lithium phenylacetylide in
and electronic materials applications,6 by three-component THF produces a small amount of 1,4-diphenylbutadiyne, corre-
coupling of acetylene derivatives. In addition to the preparative sponding to alkynyl transfer at Ca.8 In addition, a second
utility of this reaction, the findings described below suggest a unsaturated hydrocarbon was also isolated in trace amounts;
broader role for ethynylphosphonium salts as ditopic electro- mass spectral analysis suggested this to be a species containing
philic reagents for conjunctive transformations.
two addend alkynyl units in addition to the phosphonium-
derived ethynyl fragment. X-ray diffraction of a monocrystalline
sample showed this species to be a Z-enediyne 4a,‡ corresponding to
a functionalization at both Ca and Cb of the ethynylphosphonium
cation. With alteration of the reaction conditions, 4a could be made
the major reaction product; deliberate addition of two equiva-
lents of phenylacetylene significantly increased the yield. Highest
yields (ca. 80%) of Z-enediyne 4a were obtained upon use of
Department of Chemistry, The Pennsylvania State University, University Park,
PA 16802, USA. E-mail: radosevich@psu.edu
† Electronic supplementary information (ESI) available: Synthetic procedures,
spectral data, crystallographic data. CCDC 1000559–1000563. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/c4cc03415e
9302 | Chem. Commun., 2014, 50, 9302--9305
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Table 1 Z-Enediynes by dicarbofunctionalization of triaryl(arylethynyl)-
phosphonium salts
Fig. 2 One-pot, phosphine-mediated synthetic cycle for the multigram
preparation of Z-enediyne 4g. (a) PhMe, 45 1C, 72 h; (b) 1.1 equiv.
Li–CRC–Ar, 2.0 equiv. H–CRC–Ar, PhMe/THF, rt, 1 h.
Entry
PR3
Equiv. MCCPh
Equiv. HCCPh
Yielda (%)
1
2
3
4
5
6
7
P( p-An)3
P( p-An)3
P( p-An)3
P( p-An)3
P( p-An)3
PPh(o-An)2
PPh(o-An)2
1.0 (M = Li)
0.0
2.0
1.0
2.0
2.0
2.0
2.0
Trace
21
30
49
52
83
80
0.9 (M = MgBr)
1.3 (M = MgBr)
1.3 (M = MgBr)
1.7 (M = MgBr)
1.5 (M = Li)
(entries 4 and 5) (aryl)acetylenes undergo smooth reaction. Halogen
substituents (entries 6 and 7) are well-tolerated, permitting subse-
quent functionalization by a range of synthetic methods. Steric
1.1 (M = Li)
a
Yields are for isolated material. ca. 7–10% of 1,4-diphenyl-1,3- parameters, however, have a significant impact on the reaction
butadiyne is also isolated. See ESI for details.
outcome as evidenced in the case of the o-tolyl derivative (entry 3),
where a significant quantity of 1,4-di-o-tolyl-1,3-butadiyne is isolated
lithium phenylacetylide as nucleophilic reagent and bis(o-anisyl)-
phenylphosphine (PPh(o-An)2) as the phosphine substituent
(entries 6 and 7).9 Under these conditions, we detect minor amounts
(7–10%) of the direct Ca alkynylation product, but we do not observe
any of the E configurational isomer of 4a. The trivalent phosphorus
by-product can be easily recovered and recycled (Table 1).
Treatment of a variety of alkynylphosphonium salts (prepared
from the corresponding 1-bromoalkynes)10 with 1.1 equiv. of
lithio(aryl)acetylide and 2.0 equiv. of protio(aryl)acetylene in THF
provides the corresponding enediyne in good yield as a single (Z)
configurational isomer (Table 2). In each of these reactions,
free triarylphosphine PPh(o-An)2 can be reisolated with good
mass recovery. Both electron-rich (entries 2 and 3) and -deficient
at the expense of the desired enediyne 4c. This result is consistent
with steric blocking of the b-carbon of the ethynylphosphonium salt
that consequently favors direct a-alkynylation. Attempts to prepare
differentially aryl-substituted and aliphatic-substituted enediynes
have been unsuccessful to date (see ESI† for full details).
The reaction is scalable to multigram batch without signifi-
cant decrease in yield, and can furthermore be conducted as a
one-pot transformation without isolation of the intermediate
alkynylphosphonium salt (Fig. 2). Specifically, treatment of
10 mmol of bromoalkyne 5 with bis(o-anisyl)phenylphosphine
in toluene results in the formation of heterogeneous suspen-
sion of the corresponding ethynylphosphonium intermediate
3g, to which lithium acetylide/protioacetylene can directly be
added at ambient temperature to afford 3.80 g of Z-enediyne 4g
(70% yield from 5). Bis(o-anisyl)phenylphosphine can also be
recovered via chromatography, resulting in a closed synthetic
cycle with respect to the phosphine promoter.
Table 2 Z-Enediynes by dicarbofunctionalization of triaryl(arylethynyl)-
phosphonium saltsa
A mechanistic proposal consistent with the observed Z-selective
enediyne synthesis is offered in Fig. 3. The sequence is initiated by
b-addition of the lithioacetylide reagent11 to the ethynylphos-
phonium cation12 to give a vinylidene phosphorane13 intermediate 6,
which by virtue of its bent geometry14 may exist as either E or Z
configurational isomers. In contrast to vinylidene ylides of more
electronegative elements, the poor nucleofugality of the triaryl-
phosphine moiety implicates vinylidene phosphorane 6 as a
persistent intermediate in solution, assuring equilibration of
the geometrical isomers to the less hindered Z configuration.15
Protonation of Z–6 by protioacetylene then fixes the alkene configu-
ration by installation of the vinylic C–H substituent in vinylphos-
phonium intermediate 7. This provenance for the vinylic hydrogen
is secured by a deuterium isotope labeling experiment in which the
use of D–CRC–Ph (95% D) as a component in the dialkynylation
reaction results in enediyne 4a-d with 93% deuterium incorpora-
Entry Phosphonium Ar
Product Yieldb,c (%)
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
3g
3h
3i
C6H5–
4a
4b
4c
4d
4e
4f
80
71
46d
69
68
78
79
64
78
56
4-MeC6H4–
2-MeC6H4–
3-CF3C6H4–
4-CF3C6H4–
4-ClC6H2–
4-BrC6H4–
b-Naphthyl–
4-(Vinyl)C6H4–
4g
4h
4i
10
3j
4-(tBuCRC)C6H4– 4j
a
Conditions: 1.0 equiv. [(o-An)2PhP–CRC–Ar]Br, 1.1 equiv. Li–CRC–Ar, tion at the vinylic position (Fig. 4a).
b
2.0 equiv. H–CRC–Ar, THF, rt, 0.5 h. Yields of isolated Z-enediyne
following silica gel chromatography. In all cases, mass recovery of
PPh(o-An)2 4 75%. See ESI for full details. 1,4-Di-o-tolyl-1,3-butadiyne
also isolated in 37%.
We therefore posit vinylphosphonium 7 as the penultimate
intermediate en route to enediyne product. In accord with this
notion, subjection of an independently prepared vinylphosphonium
c
d
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of 10 is converted into enediyne product Z-4a (E/Z ratio 4 : 96),
although we cannot rigorously exclude the possibility that an
E - Z isomerization event (for instance, via Ca deprotonation/
reprotonation or reversible Michael-type b-addition to 10) pre-
cedes a stereospecific C–C ligand coupling.18 The mechanistic
relationship between ligand coupling at phosphorus and vinylic
addition/elimination has been previously noted by Trippett.19
Further efforts to delineate between these mechanistic variants
are being pursued.
In summary, the described dialkynylation of ethynylphos-
phonium salts illustrates the capacity of these ditopic electrophilic
reagents to behave as vicinal acceptors of carbon-based nucleo-
philes. The reaction permits the synthesis of Z-enediynes with
excellent configurational control starting from easily accessible
and nonconfigurationally predefined components. In view of the
fact that the reaction can be conducted as a closed synthetic cycle
with respect to phosphine promoter, the further development of
P-catalytic variants of this transition metal-free enediyne synthesis
may be envisioned and is the focus of ongoing investigation.
We thank the Pennsylvania State University for financial
support. Eric Miller and Shi Liu (Pennsylvania State University
Chemistry) are acknowledged for initial studies.
Fig. 3 Mechanistic proposal.
Z-10 leads stereospecifically and nearly quantitatively to product
Z-4a (Fig. 4b). Two scenarios to describe the mechanistic course
for this conversion may be envisioned. In the first, attack of
acetylide anion directly at phosphorus could give a phosphorane
intermediate (8), which may evolve via Csp–Csp2 ligand coupling
to deliver the observed products (Fig. 3).16 Alternatively, vinylic
substitution by an addition/elimination sequence via 9 could
account for the observed reactivity.17 The latter of these two
possibilities is suggested by the finding that 48: 52 E/Z mixture
Notes and references
‡ Crystal structural data have been deposited with the Cambridge
Crystallographic Data Centre. See ESI† for details.
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