Organic Letters
Letter
examples of the Pd-catalyzed directed C−H alkynylation of
the targeted 5da was isolated in a synthetically useful yield.
The linear cis-allylic alcohols were also amenable, and the
corresponding C−H alkynylated products 5ea−ga were
obtained albeit with variable stereospecificity (cis/trans =
1.5:1−9:1). Moreover, the conceivably more challenging trans-
15
unconjugated internal alkenes. Namely, a treatment of 1a
with TIPS-substituted alkynyl bromide 4a in the presence of
Pd(OAc) catalyst and AgBF /NaOAc additives in heated 1,2-
2
4
dichloroethane (DCE; 90 °C) afforded the conjugated enyne
16
5aa in 73% isolated yield (Scheme 3). Both additives were
allylic alcohol formed the desired product 5fa.
The phenanthroline auxiliary in the products could be easily
removed and manipulated (Scheme 4). The Brønsted acid
Scheme 3. Products of Phenanthroline-Directed, Pd-
17
catalyzed substitution of 3aj with H O proceeded smoothly
2
a
Alcohols 1 with Alkynyl Bromides 4
to deliver the corresponding free dienyl alcohol 3aj-OH and 2-
18
phenanthrolinone in 89 and 95% yields, respectively. The
latter was easily recycled via conversion back into the diecting
1
0a
group precursor.
The etherification with the alcohol
nucleophile was also feasible (3aj-OMe). Moreover, the
dienylamines 6aa-Pr-Cy were obtained by the quaternary-
driven nucleophilic amination with primary amines. On the
other hand, the formed 1,3-diene moiety was a reactive
enophile, and Diels−Alder reaction with the triazoledione was
possible to afford the cycloadduct 7aj in a good yield. The C−
H alkynylated product 5ba was also readily and regioselectively
converted to the free alcohol 5ba-OH along with phenan-
throlinone under the aforementioned acid-mediated condi-
tions. The cleavage of the TIPS moiety with TBAF (5ba-OH
to 8) was followed by the Cu-catalyzed azide−alkyne
cycloaddition to afford the functionalized triazole 9 in a
good overall yield. Additionally, the direct desilylative
Sonogashira coupling of 5aa could also be performed to
form the aryl-conjugated enyne 10, which overcomes the
16
limitation of alkynyl bromides in the C−H alkynylation.
Our proposed reaction mechanism for the phenanthroline-
directed Pd-catalyzed alkenylation of 1b with 2a is shown in
Scheme 5a. The initial coordination of phenanthroline moiety
of 1b to PdX (X = OAc, OCOCMe Ph, or TFA) is followed
2
2
by C−H cleavage to form the 6-membered palladacycle
intermediate 1b-PdX. Subsequent ligand exchange on Pd
between the alkene 2a and X occurs to afford an alkene-
coordinated cationic Pd species 11. The C−H alkenylated
product 3ba is formed by successive insertion and β-H
elimination. The liberation of HX and reoxidation with AgTFA
a
−
Conditions: 1 (0.20 mmol), 4 (0.40 mmol), Pd(OAc)2 (0.020
mmol), AgBF (0.20 mmol), NaOAc (0.20 mmol), DCE (2.0 mL), 90
4
b
c
°
C, 16 h. On a 0.10 mmol scale. With the corresponding alkynyl
chloride instead of 4a. At 110 °C. With AgPF instead of AgBF .
d e
6
4
f
g
On a 2.0 mmol scale. At 100 °C.
regenerate the starting PdX to complete the catalytic cycle.
2
The deuterium incorporation experiments and KIE studies
critical: AgBF could abstract Br derived from 4a to enable the
with the deuterated 1b suggest the irreversible and rate-
4
19
catalytic turnover of Pd, whereas NaOAc greatly improved the
mass balance of the reaction. As seen in the alkenylation, the
phenanthroline bidentate auxiliary was necessary for the
limiting C−H cleavage. Given the better reactivity of 1a and
1a-bpy than 1a-Py observed in Scheme 1 and our previous Cu-
catalyzed phenanthroline-directed C−H amination of phenol-
11
10a
acceptable conversion. Several other bulky alkynyl bromides
were successfully coupled with 1a. For example, the reaction
with TBS- and tert-butyl-substituted alkynyl bromides 4b and
c provided 5ab and 5ac, respectively, in good yields. The Pd
s, the chelating nature of phenanthroline (and bipyridine)
4
moiety accelerates the otherwise challenging C−H cleavage
step. Additionally, the positive effects of acid additive can
support the operation of acetate-ligand-promoted concerted
4
20
catalysis was also tolerated with the protected propargylic
alcohol derivatives that bear the cyclohexyl as well as the
heterocyclic pyran and piperidine rings (5ad−af). At higher
reaction temperature (110 °C), the corresponding alkynyl
chloride was also available for use (5aa). As a general trend,
AgPF showed better performance than AgBF when the alkyl-
metalation-deprotonation mechanism. The exact role of BQ
is not clear at this stage, but it can coordinate to Pd(0) to
21
avoid the formation of catalytically inactive Pd black.
All attempts to detect and isolate the key palladacycle
intermediate 1b-PdX from 1b and Pd(OAc)2 remained
unsuccessful, but we were pleased to prepare the correspond-
ing acetate complex 1b-PdOAc from the alkenyl iodide 1b-I
and Pd (dba) (Scheme 5b). Oxidative addition of 1b-I to the
6
4
substituted alkynyl bromides were employed. The scope of
allylic alcohols 1 was also evaluated. The 4,4-dimethylcyclo-
hexenol 1b smoothly reacted with 4a to form the
corresponding conjugated enyne 5ba in 79% yield; the
structure of which was determined by the single X-ray
crystallographic analysis (CCDC 2022024). The reaction was
scalable and easily conducted on a 2.0 mmol scale. The
reactivity of cyclopentenol derivative was somewhat lower, but
2
3
Pd proceeded smoothly in DCE at 50 °C, and complete
consumption of 1b-I and formation of 1b-PdI were assigned
by APCI-HRMS. Subsequent addition of AgOAc at room
temperature promoted I/OAc ligand exchange to give the
targeted 1b-PdOAc as a bench-stable white solid in 48%
1
13
overall yield. The structure was confirmed by H/ C NMR,
C
Org. Lett. XXXX, XXX, XXX−XXX
Hirano, Koji
