Organic Letters
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Table 2). The ferrocene group was tested and proved to be
compatible, and the desired product 3ra was obtained in a 41%
yield (entry 18, Table 2).
Table 3. Phosphine Oxide Scope for Stereo- And
Regioselective cis-Hydrophosphorylation
a
In view of the vinyl group of the 1,3-enynes, different alkyl
groups on the α- or β-position were tested, and all were
compatible under the current reaction conditions. 3sa and 3ta,
with cyclopropyl groups or hydrogen atoms at the α-position,
respectively, were obtained in 65% and 58% yields (entries 19
and 20, Table 2). The gem-dimethyl groups at the terminal
position also successfully gave the desired product 3ua,
although the yield was low (34% yield, entry 21, Table 2).
To evaluate the synthetic utility of the stereo- and
regioselective cis-hydrophosphorylation protocol, the reaction
was scaled up to 6.0 mmol 1a and 2a under the standard
reaction conditions, affording 1.67 g of 3aa in a 74% isolated
yield (entry 1, Table 2).
The phosphine oxide scope for the present stereo- and
regioselective cis-hydrophosphorylation reaction was tested
next, and various phosphine oxides (2b−2p) were subjected to
the reaction conditions. Both the same and different aryl
group-derived phosphine oxides were tested, and all could be
used. Different aryl group-derived phosphine oxides were
tested next. All the reactions were successful, and the
corresponding products 3ab−3af and 3kg−3kn were obtained
in moderate to good yields (40−80%, entries 1−13, Table 3).
Different alkyl groups such as n-butyl- and benzyl-derived
phenyl phosphine oxides were successfully subjected to the
reaction conditions, and 3ko and 3kp were obtained in 45%
and 40% yields, respectively (entries 14 and 15, Table 3).
To identify the role of the alkene in cis-hydrophosphor-
ylation, the reaction of prop-1-yn-1-ylbenzene 4 with 2a under
standard reaction conditions was carried out, and the reaction
gave an inseparable mixture of products 5 and 6 in a 53%
combined yield. The 31P NMR analysis indicated that 5 and 6
were in a 2:1 ratio (Scheme 2). The above results
demonstrated that the alkene motif of the 1,3-enynes was
crucial for excellent stereo- and regioselectivities (see the
a
1a or 1j (0.3 mmol), 2 (0.2 mmol), NiCl2(PPh3)2 (0.02 mmol), L-1
(0.024 mmol), Cs2CO3 (0.4 mmol), and MeOH (2.0 mL); for details,
b
crystal diffraction analysis.21 Different ligands were tested next,
and a more sterically hindered ligand gave the product in a
lower yield; when 2,9-dimethyl-1,10-phenanthroline L-2 was
used, 3a was detected in a 36% NMR yield (entry 2, Table 1).
When L-3 or L-4 was used, no reaction was observed (entry 3,
Table 1). Different solvents, such as THF, MeCN, and toluene,
were tested next, and no better results were obtained (entries
4−6, respectively, Table 1). Various NiII complexes, such as
NiBr2(PPh3)2, NiCl2DME, NiCl2(PMe3)2, and NiCl2, were
tested and failed to furnish 3aa (entry 7, Table 1). The
background reactions were carried out carefully, and 3aa was
not observed when the reactions were performed in the
absence of visible light, without the base or ligand, or under air
conditions (entries 8−10, respectively, Table 1).
Under the above standard reaction conditions, different 1,3-
enynes were tested. Terminal phenyl groups with different
substituents at the o-, p-, and m-positions were tested and
shown to be compatible, yielding the corresponding products
3aa−3oa in moderate to good yields (48−95%, entries 1−15,
Table 2). The complex substrate was tested next, and the
natural amino acid-derived product 3ja was obtained in a 58%
yield (entry 10, Table 2). Heteroaromatic groups such as 3-
thienyl and 3-pyridyl gave the corresponding products 3pa and
3qa in 35% and 48% yields, respectively (entries 16 and 17,
Scheme 2. Hydrophosphorylation of the Internal Alkyne
Preliminary mechanistic studies were carried out next, and
the results are listed in Scheme 3. The deuteration experiment
of 1k and d-2a (80% percent deuteration ratio) in d4-MeOH
successfully gave d-3ka in a 51% yield at a 70% deuteration
ratio (Scheme 3a). Switching the solvent from d4-MeOH to
MeOH led to the formation of 3ka without deuteration (see
Radical survey and radical initiation experiments were next
performed. When 1.0 equiv of TEMPO (2,2,6,6-tetramethyl-1-
piperidinyloxy) was used as the additive, 3aa was not observed,
and diphenylphosphinic chloride 7 and its ester-derived 8 were
detected by high-resolution mass spectrometry (HRMS)
analysis (Scheme 3b). When BHT (2,6-di-tert-butyl-4-methyl-
phenol) 4 was used as the additive, 3aa was isolated in a 24%
yield; products 7, 8, and 9, the cross-coupling products of BTH
2983
Org. Lett. 2021, 23, 2981−2987