.
Angewandte
Communications
À
Table 1: Selected experiments in the optimization of the C C coupling of
propargyl chlorides 1a–e to alcohol 2d.[a]
Entry 1, R
Catalyst, ligand (mol%)
iPrOH
Yield [%]
(mol%)
(ee [%])
1
1a
[Ir(cod)2]OTf (5), biphep
–
0 (rac)
H
(6)
2
1b
TMS
1c
TBS
1c
TBS
1d
TIPS
1e
Me2PhSi (6)
[Ir(cod)2]OTf (5), biphep
(6)
[Ir(cod)2]OTf (5), biphep
(6)
[Ir(cod)2]OTf (5), biphep
(6)
[Ir(cod)2]OTf (5), biphep
(6)
[Ir(cod)2]OTf (5), biphep
–
17 (rac)
18 (rac)
40 (rac)
trace (rac)
26 (rac)
62 (rac)
65 (91)
72 (93)
57 (77)
60 (87)
3
–
4
500
–
À
Scheme 2. Carbonyl propargylation through C C bond forming transfer
hydrogenation. cod=1,5-cyclooctadiene, DM-segphos=5,5’Àbis-
[di(3,5-xylyl)phosphino]-4,4’-bi-1,3-benzodioxole, segphos=5,5’-bis(di-
phenylphosphino)-4,4’-bi-1,3-benzodioxole, TIPS=triisopropylsilyl.
5
6
–
7
1e
[Ir(cod)2]OTf (5), biphep
500
however, the reaction involving TMS-substituted propargyl
chloride 1b delivered the homopropargylic alcohol 4d
(R=TMS) in 17% yield (Table 1, entries 1 and 2). Based on
this result, other silyl-substituted propargyl chlorides were
tested. Although, no significant improvement in yield was
observed when the TBS-substituted propargyl chloride 1c
was used (Table 1, entry 3), the alcohol 2d was fully converted
into piperonal 3d. This observation suggested that an
exogenous hydride source might increase conversion of the
transient aldehyde into the desired product. Indeed, upon
addition of isopropanol to the reaction mixture, product 4d
(R = TBS) was obtained in 40% yield upon isolation (Table 1,
entry 4). The use of the TIPS-substituted chloride 1d in the
absence of isopropanol gave only trace amounts of 4d (R =
TIPS), suggesting that the steric demand of the silyl group
may influence the equilibrium between the allenyliridium and
propargyliridium species to favor the latter. This led us to
explore the smaller and more electron deficient Me2PhSi-
substituted propargyl chloride 1e, which performed better
than chlorides 1a–1d in the absence of isopropanol (Table 1,
entry 6). Furthermore, upon addition of isopropanol, the
Me2PhSi-substituted propargyl chloride 1e delivered 4d
(R=PhMe2Si) in 62% yield upon isolation (Table 1,
entry 7). At this stage, the chiral catalyst modified by (R)-
segphos[15] was evaluated. Gratifyingly, the homopropargylic
alcohol 4d (R = PhMe2Si) was formed in 65% yield and
91% ee upon isolation (Table 1, entry 8). Extending the
reaction time led to product decomposition, which included
alkyne reduction. It was found that the use of 3-hexyne as an
additive improved conversion and enantioselectivity, allowing
4d (R = PhMe2Si) to be obtained in 72% yield and 93% ee
upon isolation (Table 1, entry 9). Finally, the use of other
chiral ligands, for example (R)-binap and (R)-Cl,MeO-
biphep, did not lead to improved selectivity or enhanced
yield (Table 1, entries 10 and 11).
Me2PhSi (6)
1e
Me2PhSi (5)
1e
Me2PhSi (5)
1e
Me2PhSi
1e
8
[Ir(cod){(R)-segphos}]OTf 500
9[b]
10
11
[Ir(cod){(R)-segphos}]OTf 500
[Ir(cod){(R)-binap}]OTf (5) 500
[Ir(cod){(R)-Cl,MeO-biphe- 500
Me2PhSi p]}OTf (5)
[a] Yields of isolated material. The ee values were determined by chiral
stationary phase HPLC analysis. See the Supporting Information for
details. [b] 3-Hexyne (200 mol%), 28 h. binap=2,2’-bis(diphenylphos-
phino)-1,1’-binaphthyl, biphep=2,2’-bis(diphenylphosphino)-1,1’-
biphenyl, rac=racemic, TBS=tert-butyldimethylsilyl.
entries 5–7). Whereas electron-neutral and electron-rich
benzylic alcohols couple efficiently with chloride 1e
(Table 2, entries 1–7, 10, and 11), lower yields and enantio-
selectivities were observed for electron-deficient benzylic
alcohols 2h and 2i. To address this issue, the Ph2MeSi-
substituted propargyl chloride 1 f was used, which improved
the yield and enantiomeric excess of isolated homopropar-
gylic alcohol 4h (Table 2, entry 8). For alcohol 2i, which
incorporates a p-carbomethoxy substituent, the use of o-
TolMe2Si-substituted propargyl chloride 1g was necessary to
improve enantioselectivity (62% yield, 87% ee, Table 2,
entry 9). Finally, in a reaction with chloride 1e, heteroaryl
methanols 2j and 2k were converted into homopropargylic
alcohols 4j and 4k, albeit in modest yield (Table 2, entries 10
and 11). Under identical conditions aryl aldehydes are
converted into an identical set of homopropargylic alcohols
4a–4k with similar yields and ee values upon isolation
(Table 2, entries 1–11).
In the presence of tetrabutylammonium fluoride (TBAF)
in THF, propargylation products 4d, 4g, and 4h were
converted into the corresponding terminal alkynes 5d, 5g,
and 5h (Scheme 3). Homopropargylic compound 5h is
a known compound of established absolute stereochemistry.
The absolute stereochemical assignments of adducts 4a–4k
Under these optimized reaction conditions, propargyl
chlorides 1e–1g were coupled with benzylic alcohols 2a–2k
to form homopropargyl alcohols 4a–4k in good yields with
high levels of enantioselectivity (Table 2). Notably, o-, m-, and
p-substituted benzyl alcohols are tolerated (Table 2,
2
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!
Woo, Sang Kook
