Methyl ketone oxime esters as nucleophilic coupling partners in Pd-catalyzed C-H alkylation and application in the synthesis of isoquinolines

Article abstract of DOI:10.1021/jo5010586

Methyl ketone oxime esters have been found to be excellent coupling partners for C(sp²)-C(sp³) bond formation via Pd-catalyzed aromatic C-H activation. This transformation forms the basis of an approach to regioselectively synthesize substituted isoquinolines via coupling with aryloxime esters. Our mechanistic studies suggested that the reaction proceeded through Pd(II)-catalyzed aromatic C-H activation, tautomerization, and a 1,3-shift of the palladacycle-ligated methyl ketone oxime ester to enable the C-C bond formation by reductive elimination, and intramolecular condensation of an imido-Pd(II) intermediate to form the heterocycle. The aryloxime group not only was used as a directing group for Pd-catalyzed aromatic C-H activation but also functioned as an internal oxidant to allow the reaction to be redox-neutral. Our study illuminated the scope and limitations of this C-H alkylation process, which may serve as the point of departure for developing other C-H functionalization reactions using oxime esters and potentially other carbonyl derivatives as the nucleophilic coupling partners.

Full text of DOI:10.1021/jo5010586

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Article
Methyl ketone oxime esters as nucleophilic coupling partners in Pd-
catalyzed C-H alkylation and application in the synthesis of isoquinolines
Zhi-Wei Zhang, Aijun Lin, and Jiong Yang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo5010586 • Publication Date (Web): 03 Jul 2014
Downloaded from http://pubs.acs.org on July 11, 2014
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Methyl ketone oxime esters as nucleophilic coupling partners in Pd-catalyzed C-H
alkylation and application in the synthesis of isoquinolines
ZhiꢀWei Zhang,†,‡ Aijun Lin,† and Jiong Yang*,†
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†Department of Chemistry, Texas A&M University, College Station, Texas 77843ꢀ3255, USA
‡State Key Laboratory Breeding BaseꢀHebei Province Key Laboratory of Molecular Chemistry for Drug, College of
Chemical & Pharmaceutical Engineering, Hebei University of Science and Technology, Shijiazhuang, Hebei 050018, P. R.
China
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Email: yang@mail.chem.tamu.edu
ABSTRACT: Methyl ketone oxime esters have been found to be excellent coupling partners for C(sp2)ꢀ
C(sp3) bond formation via Pdꢀcatalyzed aromatic CꢀH activation. This transformation forms the basis of
an approach to regioselectively synthesize substituted isoquinolines via coupling with aryloxime esters.
Our mechanistic studies suggested that the reaction proceeded through Pd(II)ꢀcatalyzed aromatic CꢀH
activation, tautomerization and 1,3ꢀshift of the palladacycleꢀligated methyl ketone oxime ester to enable
the CꢀC bond formation by reductive elimination, and intramolecular condensation of an imidoꢀPd(II)
intermediate to form the heterocycle. The aryloxime group not only was used as a directing group for
Pdꢀcatalyzed aromatic CꢀH activation, it also functioned as an internal oxidant to allow the reaction to
be redoxꢀneutral. Our study illuminated the scope and limitations of this CꢀH alkylation process, which
may serve as the point of departure for developing other CꢀH functionalization reactions using oxime
esters and potentially other carbonyl derivatives as the nucleophilic coupling partners.
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INTRODUCTION
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The development of new synthetic methods to address the need of sustainable growth by the modern
society is an important goal of organic chemist. Since the early days of organic chemistry, the carbonyl
compounds and their derivatives have been among the most frequently used in the development of new
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reactions. This is not only because these compounds are versatile electrophiles for reaction with
nucleophilic reagents in diverse settings, but also because these compounds, in the form of enols,
enamines, or related tautomeric isomers, are excellent nucleophilic reagents for reaction with
electrophilic species, including other carbonyl compounds and derivatives, in a wide range of
transformations. Thus, a large body of chemistry has been developed based on the carbonyl derivatives,
and forms a cornerstone of modern organic chemistry.
During the past two decades, direct CꢀH functionalization has emerged as a powerful strategy for
developing new synthetic methods because of its inherent advantages of bypassing preꢀfunctionalization
of the substrates.2 A commonly used approach to regioselectively functionalize one CꢀH bond over the
others makes use of directing groups to activate neighboring CꢀH bonds toward transition metal
mediated functionalization using other reagents. 3 Despite some reports of carbonyl derivatives as
electrophilic coupling partners in transition metalꢀcatalyzed CꢀH alkylation reactions,4 nucleophilic
carbonyl derivatives (through the forms of enols, enamines, etc.) as the coupling partners in transition
metalꢀcatalyzed CꢀH alkylation have been rare. Indeed, whereas examples exist for intramolecular CꢀH
alkylation using nucleophilic enamines or related compounds as the coupling partners to synthesize Nꢀ
heterocycles,5 the intermolecular CꢀH alkylation using nucleophilic carbonyl derivatives appears to be
unknown. Thus, there is a compelling need of developing new approaches for CꢀH alkylation using
carbonyl derivatives. These new approaches not only would significantly increase the scope of CꢀH
functionalization reactions, but also provide opportunities to further exploit the rich chemistry of
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carbonyl derivatives for efficient transformations. Herein we report methyl ketone oxime esters are
excellent coupling partners for Pdꢀcatalyzed CꢀH alkylation reactions and we demonstrate the utility of
the reaction in the regioselective synthesis of substituted isoquinolines from aryloxime esters (Figure 1,
eq. 1). Isoquinolines are important heterocycles found in natural products,6 pharmaceuticals,7 chiral
ligands,8 and organic materials.9 Recently, significant progresses have been made in the synthesis of
isoquinolines or isoquinolinones using transition metal catalysis,10 particularly via transition metal (Rh,
Ru, Ni, Pd, Mn)ꢀcatalyzed tandem CꢀH activation/annulation of aromatic imines, oximes, azides,
amides, etc. with internal alkynes or equivalents to give 3,4ꢀdisubstituted isoquinolines and
isoquinolinones (Figure 1, eq. 2).11,12,13,14 In contrast, synthetic methods that allow direct access of 3ꢀ
substituted isoquinolines have been rare.15 Our synthesis of isoquinolines via Pdꢀcatalyzed coupling of
oxime esters provides an efficient and operationally simple approach (no external oxidants or any other
additives) to this important structural motif using substrates that are readily prepared from commercial
ketones.16,17
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Figure 1. Isoquinolines and isoquinolinones via tandem CꢀH activation/annulation
RESULTS AND DISCUSSION
We commenced the study using acetophenone oxime acetate (1a-Ac, eq. 3) as the substrate not only
because the oxime is an effective directing group for Pdꢀcatalyzed CꢀH activation,18 but also because the
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NꢀO bond is wellꢀpoised for internal oxidation of the transition metal catalytic center to enable a redox–
neutral process without an external oxidant. The initial reaction was carried out using acetophenone as
the reaction partner with the anticipation that its enol form may react with the palladacycle CꢀH
activation intermediate and eventually lead to the alkylation product. Indeed, a reaction occurred in the
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presence of 10 mol% Pd(OAc)2 in toluene at 120 C to give a product identified as isoquinoline 2a in
15% yield (eq. 3, X = O). Interestingly, a control experiment in the absence of acetophenone showed
that 2a could also be formed by 1a-Ac itself (eq. 3, X = NOAc). Since aryloxime esters could be readily
synthesized from commercial aryl ketones, we explored this selfꢀcoupling reaction as an entry to Pdꢀ
catalyzed CꢀH alkylation using nucleophilic carbonyl derivatives.
In order to improve the efficiency of the reaction, we tested acetophenone oxime benzoate as the
substrate and a slightly improved yield of 2a was obtained (Table 1, entry 2). The yield was also
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improved when the reaction was carried out at 150 C (entry 3). Further improvement of the reaction
efficiency was achieved when acetophenone oxime pivalate was used (60% yield, entry 4). The highest
yield was obtained when the reaction was carried out using acetophenone oxime pivalate (1a) and 10
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mol% of Pd(OAc)2 in toluene at 150 C for 36 h (84% yield, entry 5). Additional experimental
parameters, such as common additives and solvents, were also tested (entries 6ꢀ13), but none gave better
yields.
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Table 1. Screening of reaction conditions for the Pd(II)ꢀcatalyzed selfꢀcoupling of 1 to give 2aa
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entry
R
additive
solvent
T
conv.b/
yieldc (%)
(oC)
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1
Ac
Bz
Bz
Piv
Piv
–
–
–
–
–
toluene
toluene
toluene
toluene
toluene
toluene
120 40/15
120 45/25
150 60/42
150 75/60
150 100/84
150 30/0
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5d
6
Piv AgOAc
7
Piv Cu(OAc)2 toluene
150 –/15
8
Piv NaHCO3
Piv Cs2CO3
Piv BzOH
toluene
toluene
toluene
THF
150 91/29
150 100/41
150 100/42
150 20/<10
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Piv
Piv
Piv
–
–
–
1,4ꢀdioxane 150 50/19
DMF 150 30/<10
a Unless noted, the reactions were carried out using 0.25 mmol of 1a and 0.025 mmol of Pd(OAc)2 under
the indicated reaction conditions for 24 h. Determined by 1H NMR. c Isolated yield. d The reaction was
b
carried out for 36 h.
We explored the scope of the reaction using various substrates and found the reaction to be general with
acetophenone oxime pivalates under the optimized conditions. For example, the reaction of paraꢀmethyl
acetophenone oxime pivalate proceeded smoothly to give isoquinoline 2b in 72% yield (Scheme 1).
paraꢀSubstitution of acetophenone with electronꢀwithdrawing groups, such as ethoxycarbonyl and
trifluoromethyl groups, also gave isoquinolines in good yields (2c in 64% yield and 2d in 59% yield) via
their oxime pivalates. Substitution of the aryl with halogens, which are valuable handles for further
elaboration via conventional Pd(0)ꢀcatalyzed reactions, was tolerated in the formation of the fluoroꢀ
substituted 2e (88% yield), bromoꢀsubstituted 2f (70% yield), and chloroꢀsubstituted 2g–2i (76%, 51%,
and 81% yields) from their corresponding substrates. Although regioꢀisomeric products are possible in
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the latter two cases, only the sterically more accessible isomer was formed using each of these
substrates. The πꢀdonating methoxy group on the aryl was also tolerated and gave the products (i.e. 2jꢀ
2l) in good yields with the same regioselectivity as that of their chloroꢀsubstituted counterparts. Our
attempts of the reaction using the oxime pivalates of other aryl ketones, such as propiophenone,
isopropyl phenyl ketone, and tetralone, failed to give the isoquinoline products. These substrates
remained intact under the optimized reaction conditions and decomposed at higher reaction temperature.
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Scheme 1. Isoquinolines by Pd(OAc)2ꢀcatalyzed selfꢀcoupling of 1a
a Unless noted, the reaction was carried out using 0.25 mmol of 1, 0.025 mmol of Pd(OAc)2, and 3 mL
of toluene in a sealed tube at 150 oC for 36 h. b The reaction was run for 48 h.
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In order to expand the scope of this process, we explored the reaction using two different aryloxime
pivalates. We chose to carry out the reactions using an acetophenone oxime pivalate and another (nonꢀ
acetophenone, i.e. nonꢀself coupling) aryloxime pivalate, with the former used in excess because of its
competing selfꢀcoupling under the reaction conditions. Indeed, using benzophenone oxime pivalate as
the substrate, isoquinoline 4a was obtained in 60% yield upon the Pd(II)ꢀcatalyzed reaction with
acetophenone oxime pivalate (Scheme 2). Similarly, paraꢀchloro and paraꢀfluoroacetophenone oxime
pivalate underwent the reaction with benzophenone oxime pivalate to give the isoquinolines 4b (74%
yield) and 4c (70% yield), respectively. Additional aryloxime pivalates were tested and the reaction was
found to be fairly general. For example, the reaction of propiophenone oxime pivalate and acetophenone
oxime pivalate or its paraꢀmethyl analog gave 4d and 4e in 65% and 51% yield, respectively.
Substitution of the aryl group of acetophenone with electronꢀwithdrawing groups, such as
ethoxylcarbonyl and trifluoromethyl, led to products in somewhat better yields (4f for 71% yield, 4g for
66% yield). The reaction was also found to be compatible with substrates in which the aryl was
substituted with halogens, such as with fluoride, chloride, and bromide (4hꢀ4l). A reduced yield was
observed when the chloride substituent was at the orthoꢀ position (i.e. 4k, 39% yield) when compared
with the same substituent at the paraꢀ (i.e. 4j, 63% yield) or metaꢀ position (i.e. 4l, 71% yield). The
isoquinoline products could also be obtained, even though in lower yields, when the πꢀdonating methoxy
substituent was present at the aryl and, again, orthoꢀmethoxy substitution of the aryl led to reduced yield
(i.e. 4n, 27% yield) compared with those substituted at the paraꢀ or metaꢀ position (i.e. 4m in 34%, 4o in
46% yield). The isopropyl phenyl ketone oxime pivalate also participated in the reaction, but affording
the isoqunoline products (i.e. 4pꢀ4r) in lower yield, likely due to the increased steric hindrance by the
isopropyl group.
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Scheme 2. Isoquinolines by Pd(OAc)2ꢀcatalyzed coupling of two different aryloxime pivalatesa
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a Reaction conditions: 0.375 mmol of 1, 0.125 mmol 3, 0.05 mmol of Pd(OAc)2 and 6 mL of toluene in a
sealed tube at 150 oC for 24 h. b The reaction was run for 48 h.
The isoquinolines could also be obtained by the reaction of aryloxime pivalates and nonꢀaryl methyl
ketone oxime pivalates. For example, methyl pyruvate oxime pivalate reacted with priopiophenone
oxime pivalate and benzophenone oxime pivalate to give the isoquinolines 6a and 6b, respectively, in
useful yields (Scheme 3). When used in excess (3 equiv.), acetophenone oxime pivalate also reacted
with methyl pyruvate oxime pivalate to give 6c in 64% yield. The reaction of benzophenone oxime
pivalate and 5d (R = isopropenyl) afforded 6d in low yield.19 Instead of affording an isoquinoline
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product (i.e. 6e), the reaction of propiophenone oxime pivalate and 2ꢀbutanone oxime pivalate led to
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decomposition of the substrates.
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Scheme 3. Isoquinolines by Pd(OAc)2ꢀcatalyzed coupling of aryloxime pivalates and nonꢀaryl methyl
ketone oxime pivalatesa
a Reaction conditions: 0.125 mmol of 3, 0.125 mmol 5, 0.025 mmol of Pd(OAc)2, 3 mL of toluene, 150
oC in a sealed tube for 12 h. b 0.375 mmol of 3c was used.
To better understand this reaction and verify that the oxime esters instead of their potential hydrolysis
products, i.e. the ketones and oximes, are the true reaction partners for this CꢀH alkylation process, a
mixture of propiophenone oxime pivalate and acetophenone was subjected to the reaction conditions,
but no isoquinoline product was formed (Scheme 4, eq. 4). Neither did acetophenone oxime undergo the
Pd(OAc)2ꢀcatalyzed selfꢀcoupling (Scheme 4, eq. 5). These results show that the CꢀH alkylation process
indeed occurred with acetophenone oxime pivalates as the substrates.
Scheme 4. Some control experiments
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Based on these experimental findings, a plausible mechanism for the CꢀH alkylation of 1a and formation
of isoquinoline 2a is depicted in Scheme 5. An oximeꢀdirected CꢀH activation of 1a with Pd(OAc)2
gives palladacycle A.20 This complex undergoes ligand exchange with another 1a to form B with the
oxime ester Nꢀbound as a Lꢀtype ligand. This is followed by extrusion of the acetate ligand and
tautomerization of the Pdꢀbound oxime ester to its enamine form to give C. The Nꢀbound Pd(II) complex
C is expected to be in equilibrium with its Cꢀbound form, i.e. D, which will undergo reductive
elimination to form the C(sp2)ꢀC(sp3) bond to give E. Oxidative addition of Pd(0) across the NꢀO bond
gives an imidoꢀPd(II) species F, which undergoes intramolecular condensation to give 2a and
concomitantly regenerate the Pd(II) catalyst.
Scheme 5. A proposed reaction mechanism
To test this mechanistic hypothesis, the bisꢀoxime pivalate 8, prepared from the known bisꢀketone 7,21
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was treated with a stoichiometric amount of Pd(PPh3)4 in toluene at 140 C (Scheme 5, eq. 6). Indeed,
isoquinoline 2a was formed in 55% yield in 1.5 h. In contrast, only a trace amount of 2a (<5%) was
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formed under the otherwise identical conditions in the presence of Pd(OAc)2 or in the absence of any
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catalysts. This result is consistent with the hypothesis of E being an intermediate of the reaction.
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To gain further insight towards the mechanism of the reaction, the deuterated acetophenone oxime
pivalates 1a-d5 (with deuterated phenyl) and 1a-d3 (with deuterated methyl) were prepared and their
reactions under the optimized conditions were compared with that of 1a. When the reactions were
quenched at 2.5 h (< 30% of conversion of 1a based on TLC), essentially the same conversion and rate
of product formation were observed using 1a and 1a-d5 (2a:2a-d5=1:1.03, eq. 7). However,
approximately 2ꢀfold less of 2a-d3 (2a:2a-d3=2.03:1, eq. 8) was formed from 1a-d3 during the same
interval. Even though the exact kinetics of the reactions using the deuterated and nonꢀdeuterated 1a’s has
not been determined, these results do suggest that the tautomerization of B but not the Pd(II)ꢀcatalyzed
CꢀH activation of 1a is rate limiting. This conclusion is also consistent with the experimental
observation that only methyl ketone oxime pivalates are competent coupling partners as a more
demanding tautomerization step is expected with other oxime esters.
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Scheme 6. Some mechanistic studies
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CONCLUSION
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In summary, we report methyl ketone oxime esters to be excellent coupling partners in Pd(II)ꢀcatalyzed
aromatic CꢀH alkylation reactions. We demonstrate the utility of these CꢀH alkylation reactions in an
efficient and operationally simple procedure for regioselective synthesis of substituted isoquinolines via
Pd(II)ꢀcatalyzed coupling of readily available aryloxime esters. The oxime group not only served as a
directing group for the Pd(II)ꢀcatalyzed aromatic CꢀH activation, it also functioned as an internal oxidant
to render the reaction redoxꢀneutral without external oxidants. Our study illuminated the scope of this Cꢀ
H alkylation process which, despite some of its limitations, may serve as the point of departure for
developing transformations based on transition metalꢀcatalyzed CꢀH alkylation using other nucleophilic
carbonyl derivatives.
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EXPERIMENTAL SECTION
General Procedure for Synthesis of the Oxime Esters: All Oꢀpivaloyl oxime esters 1, 3 and 5 were
generated from the corresponding ketones according to the following procedure, adapted from the
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literature. A suspension of acetophenone (10 mmol), hydroxylamine hydrochloride (1.74 g, 25 mmol)
and KOAc (2.45 g, 25 mmol) in 30 mL of methanol was heated gently to reflux for 40 min. Following
cooling to rt, the mixture was filtered and the filtrate was evaporated to give a residue, which was
dissolved in 40 mL of anhydrous dichloromethane and cooled to 0 oC. After the addition of Et3N (3.03 g,
30 mmol), a solution of pivaloyl chloride (2.41 g, 20 mmol) in 10 mL of dichloromethane was added
dropwise at 0oC. The mixture was stirred at room temperature for 30 min and quenched with water. The
aqueous layer was extracted with dichloromethane for three times and the combined organic layers were
washed with saturated NaHCO3 and brine, dried over NaSO4. After evaporation of the solvent, the
residue was purified by flash column chromatography to give the oxime ester product.
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1-phenylethan-1-one O-pivaloyl oxime (1a): Isolated as white amorphous solid (1.86 g, 8.5 mmol,
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85% yield); Rf = 0.4 (petroleum ether : EtOAc = 8 : 1); H NMR (300 MHz, CDCl3): δ 7.77–7.74 (2H,
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m), 7.43–7.26 (3H, m), 2.38 (3H, s), 1.34 (9H, s) ppm; C NMR (75 MHz, CDCl3): δ 175.0, 163.1,
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134.9, 130.5, 128.5, 127.0, 38.8, 27.3, 14.3 ppm; HRMS (ESI) m/z calculated for C13H18NO2 [M+H]+
220.1338, found 220.1337.
1-(p-tolyl)ethan-1-one O-pivaloyl oxime (1b): Isolated as white amorphous solid (1.98 g, 8.5 mmol,
85% yield); Rf = 0.4 (petroleum ether : EtOAc = 8 : 1); 1H NMR (300 MHz, CDCl3): δ 7.64 (2H, d, J =
13
8.4 Hz), 7.18 (2H, d, J = 8.4 Hz), 2.35 (3H, s), 2.34 (3H, s), 1.33 (9H, s) ppm; C NMR (75 MHz,
CDCl3): δ 175.1, 163.0, 140.7, 132.0, 129.2, 126.9, 38.8, 27.3, 21.8, 14.2 ppm; HRMS (ESI) m/z
calculated for C14H20NO2 [M+H]+ 234.1494, found 234.1529.
methyl 4-(1-((pivaloyloxy)imino)ethyl)benzoate (1c): Isolated as white amorphous solid (2.35 g, 8.5
mmol, 85% yield); Rf = 0.4 (petroleum ether : EtOAc = 8 : 1); 1H NMR (300 MHz, CDCl3): δ 8.07–8.04
(2H, m), 7.84–7.81 (2H, m), 3.92 (3H, s), 2.39 (3H, s), 1.33 (9H, s) ppm; 13C NMR (75 MHz, CDCl3): δ
174.9, 166.4, 162.1, 139.1, 131.8, 129.7, 127.0, 52.3, 38.8, 27.3, 14.3 ppm; HRMS (ESI) m/z calculated
for C15H20NO4 [M+H]+ 278.1392, found 278.1401.
1-(4-(trifluoromethyl)phenyl)ethan-1-one O-pivaloyl oxime (1d): Isolated as white amorphous solid
(2.44 g, 8.5 mmol, 85% yield); Rf = 0.4 (petroleum ether : EtOAc = 8 : 1); 1H NMR (300 MHz, CDCl3):
δ 7.83 (2H, d, J = 8.1 Hz), 7.59 (2H, d, J = 8.1 Hz), 2.35 (3H, s), 1.29 (9H, s) ppm; 13C NMR (75 MHz,
CDCl3): δ 174.8, 161.7, 138.4, 132.1 (q, J = 32.6 Hz), 127.4, 125.4 (q, J = 3.8 Hz), 123.8 (q, J = 270.8
Hz), 38.8, 27.1, 14.1 ppm; HRMS (ESI) m/z calculated for C14H17NO2F3 [M+H]+ 288.1211, found
288.1223.
1-(4-fluorophenyl)ethan-1-one O-pivaloyl oxime (1e): Isolated as white amorphous solid (2.01 g, 8.5
mmol, 85% yield); Rf = 0.2 (petroleum ether : EtOAc = 8 : 1); 1H NMR (300 MHz, CDCl3): δ 7.80–7.73
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(2H, m), 7.29–7.04 (2H, m), 2.37 (3H, s), 1.34 (9H, s) ppm; 13C NMR (75 MHz, CDCl3): δ 175.0, 165.9,
162.3 (d, J = 38.7 Hz), 131.0 (d, J = 3.3 Hz), 129.1 (d, J = 8.5 Hz), 115.6 (d, J = 21.7 Hz), 38.8, 27.3,
14.3 ppm; HRMS (ESI) m/z calculated for C13H17NO2F [M+H]+ 238.1243, found 238.1228.
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1-(4-bromophenyl)ethan-1-one O-pivaloyl oxime (1f): Isolated as white amorphous solid (2.52 g, 8.5
mmol, 85% yield); Rf = 0.2 (petroleum ether : EtOAc = 8 : 1); 1H NMR (300 MHz, CDCl3): δ 7.61–7.58
(2H, m), 7.49–7.46 (2H, m), 2.31 (3H, s), 1.30 (9H, s) ppm; 13C NMR (75 MHz, CDCl3): δ 174.9, 162.0,
133.8, 131.7, 128.5, 125.0, 38.8, 27.3, 14.1 ppm; HRMS (ESI) m/z calculated for C13H17NO2Br [M+H]+
298.0443, found 298.0430.
1-(4-chlorophenyl)ethan-1-one O-pivaloyl oxime (1g): Isolated as white amorphous solid (2.15 g, 8.5
mmol, 85% yield); Rf = 0.3 (petroleum ether : EtOAc = 8 : 1); 1H NMR (300 MHz, CDCl3): δ 7.68 (2H,
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d, J = 8.7 Hz), 7.34 (2H, d, J = 8.7 Hz), 2.34 (3H, s), 1.32 (9H, s) ppm; C NMR (75 MHz, CDCl3): δ
174.9, 161.9, 136.7, 133.3, 128.8, 128.3, 38.8, 27.3, 14.1 ppm; HRMS (ESI) m/z calculated for
C13H17NO2Cl [M+H]+ 254.0948, found 254.0966.
1-(2-chlorophenyl)ethan-1-one O-pivaloyl oxime (1h): Isolated as colorless oil (2.15 g, 8.5 mmol,
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85% yield); Rf = 0.3 (petroleum ether : EtOAc = 8 : 1); H NMR (300 MHz, CDCl3): δ 7.37–7.19 (4H,
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m), 2.32 (3H, s), 1.29 (9H, s) ppm; C NMR (75 MHz, CDCl3): δ 174.7, 164.5, 135.2, 132.3, 130.7,
130.4, 129.9, 126.9, 38.8, 27.3, 17.7 ppm; HRMS (ESI) m/z calculated for C13H17NO2Cl [M+H]+
254.0948, found 254.0956.
1-(3-chlorophenyl)ethan-1-one O-pivaloyl oxime (1i): Isolated as white amorphous solid (2.15 g, 8.5
mmol, 85% yield); Rf = 0.4 (petroleum ether : EtOAc = 8 : 1); 1H NMR (300 MHz, CDCl3): δ 7.73–7.71
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(1H, m), 7.60–7.57 (1H, m), 7.37–7.26 (2H, m), 2.32 (3H, s), 1.30 (9H, s) ppm; C NMR (75 MHz,
CDCl3): δ 174.8, 161.8, 136.7, 134.6, 130.5, 129.8, 127.0, 125.1, 38.8, 27.2, 14.2 ppm; HRMS (ESI) m/z
calculated for C13H16NaNO2Cl [M+Na]+ 276.0767, found 276.0778.
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1-(4-methoxyphenyl)ethan-1-one O-pivaloyl oxime (1j): Isolated as wolorless oil (2.12 g, 8.5 mmol,
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85% yield); Rf = 0.3 (petroleum ether : EtOAc = 8 : 1); H NMR (300 MHz, CDCl3): δ 7.75–7.71 (2H,
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m), 6.92–6.88 (2H, m), 3.82 (3H, s), 2.34 (3H, s), 1.33 (9H, s) ppm; 13C NMR (75 MHz, CDCl3): δ
175.1, 162.5, 161.5, 128.5, 127.2, 113.8, 55.3, 38.8, 27.3, 14.1 ppm; HRMS (ESI) m/z calculated for
C14H20NO3 [M+H]+ 250.1443, found 250.1455.
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1-(2-methoxyphenyl)ethan-1-one O-pivaloyl oxime (1k): Isolated as yellow oil (2.12 g, 8.5 mmol,
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85% yield); Rf = 0.3 (petroleum ether : EtOAc = 8 : 1); H NMR (300 MHz, CDCl3): δ 7.42–7.34 (2H,
m), 6.98–6.89 (2H, m), 3.83 (3H, s), 2.32 (3H, s), 1.33 (9H, s) ppm; 13C NMR (75 MHz, CDCl3): δ
175.0, 165.4, 157.5, 131.1, 130.0, 125.3, 120.6, 110.9, 55.4, 38.8, 27.3, 17.3 ppm; HRMS (ESI) m/z
calculated for C14H20NO3 [M+H]+ 250.1443, found 250.1442.
1-(3-methoxyphenyl)ethan-1-one O-pivaloyl oxime (1l): Isolated as yellow oil (2.12 g, 8.5 mmol, 85%
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yield); Rf = 0.4 (petroleum ether : EtOAc = 8 : 1); H NMR (300 MHz, CDCl3): δ 7.25–7.17 (3H, m),
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6.90–6.86 (1H, m), 3.72 (3H, s), 2.27 (3H, s), 1.26 (9H, s) ppm; C NMR (75 MHz, CDCl3): δ 174.9,
163.0, 159.6, 136.2, 129.4, 119.5, 116.5, 112.0, 55.2, 38.7, 27.2, 14.3 ppm; HRMS (ESI) m/z calculated
for C14H20NO3 [M+H]+ 250.1443, found 250.1455.
1-(phenyl-d5)ethan-1-one O-pivaloyl oxime (1a-d5): Isolated as white amorphous solid (381 mg, 1.7
mmol, 85% yield); Rf = 0.4 (petroleum ether : EtOAc = 8 : 1); 1H NMR (300 MHz, CDCl3): δ2.39 (3H,
s), 1.34 (9H, s) ppm; 13C NMR (75 MHz, CDCl3): δ 175.1, 163.1, 38.8, 27.3, 14.4 ppm.
(Z)-1-phenylethan-2,2,2-d3-1-one O-pivaloyl oxime (1a-d3): Isolated as white amorphous solid (377
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mg, 1.7 mmol, 85% yield); Rf = 0.4 (petroleum ether : EtOAc = 8 : 1); H NMR (300 MHz, CDCl3): δ
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7.77–7.74 (2H, m), 7.43–7.26 (3H, m), 1.34 (9H, s) ppm; C NMR (75 MHz, CDCl3): δ 175.1, 134.9,
130.5, 128.5, 127.0, 38.8, 27.3 ppm;
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(Z)-1-phenylpropan-1-one O-pivaloyl oxime (3a): Isolated as colorless oil (1.98 g, 8.5 mmol, 85%
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yield); Rf = 0.5 (petroleum ether : EtOAc = 8 : 1); H NMR (300 MHz, CDCl3): δ 7.70–7.67 (2H, m),
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7.36–7.32 (3H, m), 2.77 (2H, q, J = 7.5 Hz), 1.28 (9H, s), 1.14 (3H, t, J = 7.8 Hz) ppm; C NMR (75
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MHz, CDCl3): δ 174.9, 167.8, 133.9, 130.4, 128.5, 127.1, 38.7, 27.2, 21.8, 11.2 ppm; HRMS (ESI) m/z
calculated for C14H20NO2 [M+H]+ 234.1494, found 234.1478.
(Z)-2-methyl-1-phenylpropan-1-one O-pivaloyl oxime (3b): Isolated as colorless oil (2.10 g, 8.5 mmol,
85% yield); Mixture of two isomers (ratio = 1 : 1); Rf = 0.4 (petroleum ether : EtOAc = 8 : 1); 1H NMR
(300 MHz, CDCl3): δ 7.40–7.37 (2H, m), 7.33–7.27 (6H, m), 7.08–7.05 (2H, m), 3.48–3.38 (1H, m),
2.98–2.89 (1H, m), 1.27 (9H, s), 1.17 (6H, d, J = 7.5 Hz), 1.12 (6H, d, J = 6.9 Hz), 0.91 (9H, s), ppm;
13C NMR (75 MHz, CDCl3): δ 175.1, 174.8, 173.8, 173.0, 172.2, 134.1, 133.1, 129.3, 128.6, 128.1,
128.0, 127.9, 126.6, 40.1, 38.6, 38.3, 34.8, 30.0, 27.3, 26.8, 26.4, 19.7, 19.5 ppm; HRMS (ESI) m/z
calculated for C15H22NO2 [M+H]+ 248.1651, found 248.1681.
diphenylmethanone O-pivaloyl oxime (3c): Isolated as white amorphous solid (2.39 g, 8.5 mmol, 85%
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yield); Rf = 0.2 (petroleum ether : EtOAc = 20 : 1); H NMR (300 MHz, CDCl3): δ 7.63–7.60 (2H, m),
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7.46–7.27 (8H, m), 1.08 (9H, s) ppm; C NMR (75 MHz, CDCl3): δ 175.1, 165.6, 134.6, 132.8, 130.9,
129.4, 128.9, 128.5, 128.3, 128.1, 38.5, 26.9 ppm; HRMS (ESI) m/z calculated for C18H20NO2 [M+H]+
282.1494, found 282.1482.
methyl (E)-2-phenyl-2-((pivaloyloxy)imino)acetate (5a): Isolated as colorless oil (1.71 g, 8.5 mmol,
85% yield); Rf = 0.4 (petroleum ether : EtOAc = 8 : 1); 1H NMR (300 MHz, CDCl3): δ 3.86 (3H, s), 2.20
(3H, s), 1.29 (9H, s) ppm; 13C NMR (75 MHz, CDCl3): δ 173.9, 163.6, 156.2, 53.1, 38.8, 27.1, 12.8
ppm; HRMS (ESI) m/z calculated for C9H15NaNO4 [M+Na]+ 224.0899, found 224.0895.
(Z)-2-methyl-1-phenylprop-2-en-1-one O-pivaloyl oxime (5d): Compound 5d was prepared according
to Rovis’s procedure.22b Isolated as colorless oil (1.56 g, 8.5 mmol, 85% yield); Rf = 0.5 (petroleum ether
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: EtOAc = 8 : 1); H NMR (300 MHz, CDCl3): δ 5.51 (1H, s), 5.40 (1H, s), 2.09 (3H, s), 2.01 (3H, s),
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General Procedure for Self-Coupling of Acetophenone Oxime Pivalates: Oxime ester (0.25 mmol),
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Pd(OAc)2 (5.7 mg, 0.025 mmol) and 3 mL of anhydrous toluene were added to a sealed tube under N2.
o
The reaction mixture was heated to 150 C (oil bath) for 36 h. Following cooling to rt, the solvent was
evaporated to give a residue, which was purified by flash column chromatography to afford the
isoquinoline product.
1-methyl-3-phenylisoquinoline (2a): Isolated as yellow oil (23 mg, 0.11 mmol, 84% yield); Rf = 0.4
(petroleum ether : EtOAc = 8 : 1); 1H NMR (300 MHz, CDCl3): δ 8.16–8.11 (3H, m), 7.92 (1H, s), 7.85
(1H, d, J = 8.1 Hz), 7.69–7.64 (1H, m), 7.59–7.37 (4H, m), 3.05 (3H, s) ppm; 13C NMR (75 MHz,
CDCl3): δ 158.5, 150.0, 139.9, 136.8, 130.0, 128.7, 128.3, 127.6, 127.0, 126.7, 126.6, 125.6, 115.2, 22.7
ppm; HRMS (ESI) m/z calculated for C16H14N [M+H]+ 220.1126, found 220.1150.
1,6-dimethyl-3-(p-tolyl)isoquinoline (2b): Isolated as yellow oil (22 mg, 0.09 mmol, 72% yield); Rf = 0.4
(petroleum ether : EtOAc = 8 : 1); 1H NMR (300 MHz, CDCl3): δ 8.04–7.80 (3H, m), 7.80 (1H, s), 7.60
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(1H, s), 7.39–7.25 (3H, m), 3.00 (3H, s), 2.54 (3H, s), 2.42 (3H, s) ppm; C NMR (75 MHz, CDCl3): δ
158.1, 150.1, 140.1, 138.0, 137.2, 137.1, 129.4, 128.7, 126.8, 126.5, 125.5, 124.9, 114.3, 22.6, 21.8,21.2
ppm; HRMS (ESI) m/z calculated for C18H18N [M+H]+ 248.1439, found 248.1430.
methyl 3-(4-(methoxycarbonyl)phenyl)-1-methylisoquinoline-6-carboxylate (2c): Isolated as white
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amorphous solid (27 mg, 0.08 mmol, 64% yield); Rf = 0.2 (petroleum ether : EtOAc = 8 : 1); H NMR
(300 MHz, CDCl3): δ 8.60 (1H, s), 8.23–8.14 (6H, m), 8.06 (1H, s), 4.01 (3H, s), 3.95 (3H, s), 3.06 (3H,
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s) ppm; C NMR (75 MHz, CDCl3): δ 167.0, 166.4, 159.0, 149.5, 143.5, 136.0, 131.4, 130.5, 130.1,
130.0, 128.4, 126.8, 126.7, 126.0, 116.7, 52.5, 52.1, 22.7 ppm; HRMS (ESI) m/z calculated for
C20H18NO4 [M+H]+ 336.1236, found 336.1222.
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1-methyl-6-(trifluoromethyl)-3-(4-(trifluoromethyl)phenyl)isoquinoline (2d): Isolated as yellow oil (26 mg,
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0.07 mmol, 59% yield); Rf = 0.5 (petroleum ether : EtOAc = 8 : 1); H NMR (300 MHz, CDCl3): δ
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8.28–8.18 (4H, m), 8.04 (1H, s), 7.79–7.75 (3H, m), 3.08 (3H, s) ppm; C NMR (75 MHz, CDCl3): δ
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159.2, 149.7, 142.4, 135.8, 132.2, 130.4 (q, J = 198.0 Hz), 129.1 (q, J = 209.8 Hz), 127.2, 126.9, 126.0,
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125.7 (q, J = 3.8 Hz), 125.4 (q, J = 4.5 Hz), 123.0 (q, J = 3.0 Hz), 121.9, 116.1, 22.7 ppm; F NMR
(282 MHz, CDCl3): δ –62.6, –63.1 ppm; HRMS (ESI) m/z calculated for C18H12NF6 [M+H]+ 356.0874,
found 356.0881.
6-fluoro-3-(4-fluorophenyl)-1-methylisoquinoline (2e): Isolated as gray amorphous solid (28 mg, 0.11
mmol, 88% yield); Rf = 0.4 (petroleum ether : EtOAc = 8 : 1); 1H NMR (300 MHz, CDCl3): δ 8.16–8.08
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(3H, m), 7.80 (1H, s), 7.45–7.41 (1H, m), 7.34–7.29 (1H, m), 7.20–7.14 (2H, m), 3.01 (3H, s) ppm; C
NMR (75 MHz, CDCl3): δ 164.9 (d, J = 9.5 Hz), 161.6 (d, J = 13.3 Hz), 158.5, 150.0, 138.5 (d, J = 10.3
Hz), 135.5, 128.8 (d, J = 8.3 Hz), 128.7 (d, J = 9.6 Hz), 123.7, 117.0 (d, J = 25.0 Hz), 115.6 (d, J = 21.5
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Hz), 114.4 (d, J = 5.0 Hz), 110.7 (d, J = 20.5 Hz), 22.7 ppm; F NMR (282 MHz, CDCl3): δ –108.5, –
113.7 ppm; HRMS (ESI) m/z calculated for C16H12NF2 [M+H]+ 256.0938, found 256.0933.
6-bromo-3-(4-bromophenyl)-1-methylisoquinoline (2f): Isolated as gray amorphous solid (33 mg, 0.09
mmol, 70% yield); Rf = 0.5 (petroleum ether : EtOAc = 8 : 1); 1H NMR (300 MHz, CDCl3): δ 8.01–7.95
(4H, m), 7.77 (1H, s), 7.65–7.59 (3H, m), 2.99 (3H, s) ppm; 13C NMR (75 MHz, CDCl3): δ 158.9, 149.8,
138.2, 137.9, 131.9, 130.4, 129.6, 128.5, 127.4, 125.1, 124.9, 123.1, 113.9, 22.6 ppm; HRMS (ESI) m/z
calculated for C16H12NBr2 [M+H]+ 375.9336, found 375.9304.
6-chloro-3-(4-chlorophenyl)-1-methylisoquinoline (2g): Isolated as gray amorphous solid (27 mg, 0.10
mmol, 76% yield); Rf = 0.6 (petroleum ether : EtOAc = 8 : 1); 1H NMR (300 MHz, CDCl3): δ 8.09–8.03
(3H, m), 7.82–7.78 (2H, m), 7.52–7.44 (3H, m), 3.00 (3H, s) ppm; 13C NMR (75 MHz, CDCl3): δ 158.7,
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(ESI) m/z calculated for C16H12NCl2 [M+H]+ 288.0347, found 288.0358.
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8-chloro-3-(2-chlorophenyl)-1-methylisoquinoline (2h): Isolated as white amorphous solid (18 mg, 0.06
mmol, 51% yield); Rf = 0.5 (petroleum ether : EtOAc = 8 : 1); 1H NMR (300 MHz, CDCl3): δ 7.86 (1H,
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s), 7.77–7.65 (3H, m), 7.55–7.48 (2H, m), 7.40–7.30 (2H, m), 3.36 (3H, s) ppm; C NMR (75 MHz,
CDCl3): δ 158.1, 148.9, 139.1, 138.6, 132.5, 132.4, 131.9, 130.24, 130.2, 129.6, 129.4, 127.4, 127.0,
124.8, 120.4, 29.4 ppm; HRMS (ESI) m/z calculated for C16H12NCl2 [M+H]+ 288.0347, found 288.0364.
7-chloro-3-(3-chlorophenyl)-1-methylisoquinoline (2i): Isolated as white amorphous solid (29 mg, 0.10
mmol, 81% yield); Rf = 0.7 (petroleum ether : EtOAc = 8 : 1); 1H NMR (300 MHz, CDCl3): δ 8.15–8.09
(2H, m), 8.01–7.97 (1H, m), 7.87 (1H, s), 7.80 (1H, d, J = 8.7 Hz), 7.64–7.60 (1H, m), 7.45–7.35 (2H,
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m), 3.00 (3H, s) ppm; C NMR (75 MHz, CDCl3): δ 157.9, 148.8, 141.2, 134.9, 134.8, 132.6, 131.1,
129.9, 129.3, 128.5, 127.3, 127.1, 124.9, 124.8, 115.0, 22.6 ppm; HRMS (ESI) m/z calculated for
C16H12NCl2 [M+H]+ 288.0347, found 288.0342.
6-methoxy-3-(4-methoxyphenyl)-1-methylisoquinoline (2j): Isolated as yellow oil (19 mg, 0.07 mmol, 55%
1
yield); Rf = 0.2 (petroleum ether : EtOAc = 8 : 1); H NMR (300 MHz, CDCl3): δ 8.08–7.98 (3H, m),
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7.75 (1H, s), 7.17–7.13 (1H, m), 7.08–7.00 (3H, m), 3.95 (3H, s), 3.87 (3H, s), 2.96 (3H, s) ppm; C
NMR (75 MHz, CDCl3): δ 160.6, 160.0, 157.7, 150.4, 138.9, 132.7, 128.2, 127.4, 121.9, 119.0, 114.1,
113.7, 105.0, 55.4, 55.3, 22.5 ppm; HRMS (ESI) m/z calculated for C18H18NO2 [M+H]+ 280.1338, found
280.1354.
8-methoxy-3-(2-methoxyphenyl)-1-methylisoquinoline (2k): Isolated as yellow oil (22 mg, 0.08 mmol,
1
63% yield); Rf = 0.2 (petroleum ether : EtOAc = 8 : 1); H NMR (300 MHz, CDCl3): δ 7.98–7.95 (2H,
m), 7.54–7.49 (1H, m), 7.38–7.32 (2H, m), 7.13–7.08 (1H, m), 7.01 (1H, d, J = 8.4 Hz), 6.86 (1H, d, J =
7.8 Hz), 3.99 (3H, s), 3.88 (3H, s), 3.16 (3H, s) ppm; 13C NMR (75 MHz, CDCl3): δ 158.1, 157.8, 157.3,
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147.8, 139.2, 131.4, 129.9, 129.2, 121.1, 120.1, 119.5, 119.1, 111.6, 106.0, 55.7, 55.4, 28.9 ppm; HRMS
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(ESI) m/z calculated for C18H18NO2 [M+H]+ 280.1338, found 280.1322.
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7-methoxy-3-(3-methoxyphenyl)-1-methylisoquinoline (2i): Isolated as yellow oil (21 mg, 0.07 mmol, 59%
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yield); Rf = 0.2 (petroleum ether : EtOAc = 8 : 1); H NMR (300 MHz, CDCl3): δ 7.89 (1H, s), 7.82–
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7.69 (3H, m), 7.45–7.30 (3H, m), 6.98–6.95 (1H, m), 4.01 (3H, s), 3.95 (3H, s), 3.03 (3H, s) ppm; C
NMR (75 MHz, CDCl3): δ 160.1, 158.2, 156.8, 148.1, 141.5, 132.2, 129.7, 129.2, 127.7, 122.7, 119.2,
115.2, 113.9, 112.1, 103.6, 55.5, 55.4, 22.8 ppm; HRMS (ESI) m/z calculated for C18H18NO2 [M+H]+
280.1338, found 280.1328.
General Procedure for Cross-Coupling of the Oxime Esters: Ethyl or phenyl aryl oxime ester (0.125
mmol), acetophenone oxime ester (0.375 mmol), Pd(OAc)2 (11.4 mg, 0.05 mmol) and 6 mL of
anhydrous toluene were added to a sealed tube under N2. The reaction mixture was heated to 150 oC (oil
bath) for 24 h. Following cooling to rt, the solvent was evaporated to give a residue, which was purified
by flash column chromatography to afford the isoquinoline product.
1,3-diphenylisoquinoline (4a): Isolated as yellow oil (21 mg, 0.08 mmol, 60% yield); Rf = 0.6 (petroleum
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ether : EtOAc = 20 : 1); H NMR (300 MHz, CDCl3): δ 8.24–8.20 (2H, m), 8.15–8.12 (1H, m), 8.08
(1H, s), 7.95–7.92 (1H, m), 7.84–7.80 (2H, m), 7.71–7.66 (1H, m), 7.57–7.45 (6H, m), 7.44–7.38 (1H,
13
m) ppm; C NMR (75 MHz, CDCl3): δ 160.4, 150.2, 139.9, 139.6, 137.8, 130.2, 130.0, 128.7, 128.6,
128.4, 128.3, 127.5, 127.4, 127.1, 126.9, 125.8, 115.7 ppm; HRMS (ESI) m/z calculated for C21H16N
[M+H]+ 282.1283, found 282.1282.
3-(4-chlorophenyl)-1-phenylisoquinoline (4b): Isolated as yellow oil (29 mg, 0.09 mmol, 74% yield); Rf =
0.5 (petroleum ether : EtOAc = 20 : 1); 1H NMR (300 MHz, CDCl3): δ 8.19–8.11 (3H, m), 8.04 (1H, s),
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7.92 (1H, d, J = 6 Hz), 7.81–7.78 (2H, m), 7.71–7.66 (1H, m), 7.59–7.44 (6H, m), ppm; C NMR (75
MHz, CDCl3): δ 160.5, 148.9, 139.7, 138.0, 137.7, 134.5, 130.2, 130.1, 128.8, 128.7, 128.29, 128.28,
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127.6, 127.4, 127.1, 125.9, 115.6 ppm; HRMS (ESI) m/z calculated for C21H15NCl [M+H]+ 316.0893,
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found 316.0908.
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3-(4-fluorophenyl)-1-phenylisoquinoline (4c): Isolated as yellow oil (26 mg, 0.09 mmol, 70% yield); Rf =
0.3 (petroleum ether : EtOAc = 20 : 1); 1H NMR (300 MHz, CDCl3): δ 8.22–8.11 (3H, m), 8.02 (1H, s),
7.92 (1H, d, J = 8.4 Hz), 7.82–7.78 (2H, m), 7.71–7.66 (1H, m), 7.59–7.48 (4H, m), 7.20–7.15 (2H, m)
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ppm; C NMR (75 MHz, CDCl3): δ 164.9, 161.6, 160.4, 149.2, 139.7, 137.8, 135.7 (d, J = 3.2 Hz),
130.14, 130.13, 128.8, 128.7 (d, J = 6.8 Hz), 128.3, 127.5 (d, J = 15.4 Hz), 126.9, 125.7, 115.5 (d, J =
21.5 Hz) 115.3 (d, J = 0.8 Hz) ppm; 19F NMR (282 MHz, CDCl3): δ –114.0 ppm; HRMS (ESI) m/z
calculated for C21H15NF [M+H]+ 300.1189, found 300.1179.
1-ethyl-3-phenylisoquinoline (4d): Isolated as yellow oil (19 mg, 0.08 mmol, 65% yield); Rf = 0.7
(petroleum ether : EtOAc = 8 : 1); 1H NMR (300 MHz, CDCl3): δ 8.20–8.16 (3H, m), 7.92 (1H, s), 7.86
(1H, d, J = 8.1 Hz), 7.68–7.63 (1H, m), 7.59–7.47 (3H, m), 7.42–7.37 (1H, m), 3.41 (2H, q, J = 7.5 Hz),
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1.53 (3H, t, J = 7.5 Hz) ppm; C NMR (75 MHz, CDCl3): δ 162.7, 149.8, 140.0, 137.1, 129.7, 128.7,
128.2, 127.8, 126.9, 126.6, 125.9, 125.2, 114.9, 28.5, 13.3 ppm; HRMS (ESI) m/z calculated for
C17H16N [M+H]+ 234.1283, found 234.1282.
1-ethyl-3-(p-tolyl)isoquinoline (4e): Isolated as white amorphous solid (16 mg, 0.06 mmol, 51% yield); Rf
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= 0.8 (petroleum ether : EtOAc = 8 : 1); H NMR (300 MHz, CDCl3): δ 8.19 (1H, d, J = 8.4 Hz), 8.11
(2H, d, J = 8.1 Hz), 7.92 (1H, s), 7.88 (1H, d, J = 8.1 Hz), 7.70–7.55 (2H, m), 7.33 (2H, d, J = 8.4 Hz),
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3.43 (2H, q, J = 7.5 Hz), 2.46 (3H, s), 1.55 (3H, t, J = 7.5 Hz) ppm; C NMR (75 MHz, CDCl3): δ
165.0, 162.7, 149.9, 138.2, 137.1, 129.7, 129.4, 127.8, 126.8, 126.5, 125.7, 125.2, 114.5, 28.5, 21.3, 13.4
ppm; HRMS (ESI) m/z calculated for C18H18N [M+H]+ 248.1439, found 248.1423.
methyl 4-(1-ethylisoquinolin-3-yl)benzoate (4f): Isolated as colorless oil (26 mg, 0.09 mmol, 71% yield);
Rf = 0.5 (petroleum ether : EtOAc = 8 : 1); 1H NMR (300 MHz, CDCl3): δ 8.29–8.14 (5H, m), 7.99 (1H,
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s), 7.88 (1H, d, J = 7.8 Hz), 7.70–7.56 (2H, m), 3.95 (3H, s), 3.41 (2H, q, J = 7.5 Hz), 1.53 (3H, t, J =
7.5 Hz) ppm; 13C NMR (75 MHz, CDCl3): δ 167.1, 163.0, 148.4, 144.2, 136.8, 130.0, 129.6, 128.0,
127.2, 126.7, 126.2, 125.2, 115.8, 52.1, 28.4, 13.2 ppm; HRMS (ESI) m/z calculated for C19H18NO2
[M+H]+ 292.1338, found 292.1331.
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1-ethyl-3-(4-(trifluoromethyl)phenyl)isoquinoline (4g): Isolated as yellow oil (25 mg, 0.08 mmol, 66%
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yield); Rf = 0.6 (petroleum ether : EtOAc = 8 : 1); H NMR (300 MHz, CDCl3): δ 8.35–8.26 (2H, m),
8.25–8.15 (1H, m), 7.97–7.85 (2H, m), 7.76–7.55 4H, m), 3.41 (2H, q, J = 7.5 Hz), 1.53 (3H, t, J = 7.5
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Hz) ppm; C NMR (75 MHz, CDCl3): δ 163.1, 148.1, 143.3, 136.8, 130.0, 128.0 (q, J = 275.7 Hz),
127.9, 127.3, 127.1 (2C), 126.3, 125.6 (q, J = 3.8 Hz), 125.2, 115.7, 28.4, 13.2 ppm; 19F NMR (282
MHz, CDCl3): δ –62.5 ppm; HRMS (ESI) m/z calculated for C18H15NF3 [M+H]+ 302.1157, found
302.1148.
1-ethyl-3-(4-fluorophenyl)isoquinoline (4h): Isolated as yellow oil (19 mg, 0.08 mmol, 61% yield); Rf =
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0.6 (petroleum ether : EtOAc = 8 : 1); H NMR (300 MHz, CDCl3): δ 8.25–8.10 (3H, m), 7.95–7.80
(2H, m), 7.74–7.58 (2H, m), 7.25–7.15 (2H, m), 3.51 (2H, q, J = 7.2 Hz, 6.9 Hz), 1.54 (3H, t, J = 7.5
Hz) ppm; 13C NMR (75 MHz, CDCl3): δ 165.0, 163.2, 161.7, 148.0, 137.3, 130.8, 129.1 (d, J = 8.4 Hz),
128.5 (d, J = 9.1 Hz), 127.9, 127.3, 126.7, 125.7, 125.5, 115.7 (d, J = 21.5 Hz) 27.8, 13.7 ppm; 19F NMR
(282 MHz, CDCl3): δ –113.6 ppm; HRMS (ESI) m/z calculated for C17H15NF [M+H]+ 252.1189, found
252.1186.
3-(4-bromophenyl)-1-ethylisoquinoline (4i): Isolated as yellow oil (20 mg, 0.06 mmol, 51% yield); Rf =
1
0.6 (petroleum ether : EtOAc = 8 : 1); H NMR (300 MHz, CDCl3): δ 8.18–8.15 (1H, m), 8.09–8.04
(2H, m), 7.89 (1H, s), 7.84 (1H, d, J = 8.1 Hz), 7.68–7.54 (4H, m), 3.39 (2H, q, J = 7.5 Hz), 1.52 (3H, t,
J = 7.5 Hz) ppm; 13C NMR (75 MHz, CDCl3): δ 162.9, 148.5, 138.8, 136.9, 131.7, 129.9, 128.5, 127.8,
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126.9, 126.0, 125.2, 122.6, 114.8, 28.4, 13.2 ppm; HRMS (ESI) m/z calculated for C17H15NBr [M+H]+
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312.0386, found 312.0388.
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3-(4-chlorophenyl)-1-ethylisoquinoline (4j): Isolated as slightly yellow oil (21 mg, 0.08 mmol, 63% yield);
Rf = 0.7 (petroleum ether : EtOAc = 8 : 1); 1H NMR (300 MHz, CDCl3): δ 8.18ꢀ8.11 (3H, m), 7.89 (1H,
s), 7.87ꢀ7.84 (1H, m), 7.69–7.55 (2H, m), 7.48–7.44 (2H, m), 3.39 (2H, q, J = 7.5 Hz), 1.52 (3H, t, J =
7.5 Hz) ppm; 13C NMR (75 MHz, CDCl3): δ 162.9, 148.5, 138.4, 136.9, 134.3, 129.9, 128.8, 128.1,
127.8, 126.9, 126.0, 126.2, 114.8, 28.4, 13.2 ppm; HRMS (ESI) m/z calculated for C17H15NCl [M+H]+
268.0893, found 268.0884.
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3-(2-chlorophenyl)-1-ethylisoquinoline (4k): Isolated as yellow oil (13 mg, 0.05 mmol, 39% yield); Rf =
0.3 (petroleum ether : EtOAc = 8 : 1); 1H NMR (300 MHz, CDCl3): δ 8.20 (1H, d, J = 8.4 Hz), 7.88 (1H,
s), 7.85 (1H, s), 7.74–7.59 (3H, m), 7.52–7.49 (1H, m), 7.41–7.29 (2H, m), 3.40 (2H, q, J = 7.5 Hz, 7.8
13
Hz), 1.49 (3H, t, J = 7.5 Hz) ppm; C NMR (75 MHz, CDCl3): δ 163.0, 149.1, 139.6, 136.3, 132.6,
132.0, 130.2, 129.9, 129.0, 127.8, 127.2, 126.9, 125.6, 125.2, 119.8, 28.6, 14.0 ppm; HRMS (ESI) m/z
calculated for C17H15NCl [M+H]+ 268.0893, found 268.0866.
3-(3-chlorophenyl)-1-ethylisoquinoline (4l): Isolated as slightly yellow oil (24 mg, 0.09 mmol, 71% yield);
Rf = 0.6 (petroleum ether : EtOAc = 8 : 1); 1H NMR (300 MHz, CDCl3): δ 8.21–8.19 (1H, m), 8.16 (1H,
s), 8.07ꢀ8.03 (1H, m), 7.91 (1H, s), 7.86 (1H, d, J = 7.8 Hz), 7.69–7.55 (2H, m), 7.44–7.35 (2H, m), 3.39
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(2H, q, J = 7.5 Hz), 1.52 (3H, t, J = 7.8 Hz) ppm; C NMR (75 MHz, CDCl3): δ 163.0, 148.2, 141.8,
136.9, 134.7, 129.94, 129.85, 128.2, 127.9, 127.1, 127.0, 126.1, 125.2, 124.9, 115.2, 28.4, 13.3 ppm;
HRMS (ESI) m/z calculated for C17H15NCl [M+H]+ 268.0893, found 268.0888.
1-ethyl-3-(4-methoxyphenyl)isoquinoline (4m): Isolated as slightly yellow oil (11 mg, 0.04 mmol, 34%
1
yield); Rf = 0.4 (petroleum ether : EtOAc = 8 : 1); H NMR (300 MHz, CDCl3): δ 8.15–8.11 (3H, m),
7.83 (1H, s), 7.81 (1H, s), 7.65–7.49 (2H, m), 7.04–7.01 (2H, m), 3.87 (3H, s), 3.38 (2H, q, J = 7.5 Hz),
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1.51 (3H, t, J = 7.5 Hz) ppm; C NMR (75 MHz, CDCl3): δ 162.2, 160.0, 149.5, 137.2, 132.0, 129.7,
128.1, 127.6, 126.3, 125.5, 125.1, 114.1, 113.8, 55.4, 28.4, 13.3 ppm; HRMS (ESI) m/z calculated for
C18H18NO [M+H]+ 264.1383, found 264.1398.
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1-ethyl-3-(2-methoxyphenyl)isoquinoline (4n): Isolated as yellow oil (9 mg, 0.03 mmol, 27% yield); Rf =
0.4 (petroleum ether : EtOAc = 8 : 1); 1H NMR (300 MHz, CDCl3): δ 8.16 (1H, d, J = 8.4 Hz), 8.09 (1H,
s), 8.02–7.99 (1H, m), 7.84 (1H, d, J = 8.1 Hz), 7.67–7.53 (2H, m), 7.39–7.33 (1H, m), 7.14–7.02 (2H,
m), 3.90 (3H, s), 3.39 (2H, q, J = 7.5 Hz), 1.49 (3H, t, J = 7.5 Hz) ppm; 13C NMR (75 MHz, CDCl3): δ
162.4, 157.2, 136.7, 131.5, 129.51, 129.49, 129.47, 129.2, 128.0, 126.6, 125.4, 125.1, 121.1, 119.8,
111.6, 55.7, 28.5, 13.8 ppm; HRMS (ESI) m/z calculated for C18H18NO [M+H]+ 264.1383, found
264.1379.
1-ethyl-3-(3-methoxyphenyl)isoquinoline (4o): Isolated as slightly yellow oil (15 mg, 0.06 mmol, 46%
1
yield); Rf = 0.4 (petroleum ether : EtOAc = 8 : 1); H NMR (300 MHz, CDCl3): δ 8.16 (1H, d, J = 8.4
Hz), 7.91 (1H, s), 7.86 (1H, d, J = 8.1 Hz), 7.80–7.72 (2H, m), 7.68–7.53 (2H, m), 7.43–7.38 (1H, m),
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6.97–6.93 (1H, m), 3.92 (3H, s), 3.40 (2H, q, J = 7.5 Hz), 1.52 (3H, t, J = 7.5 Hz) ppm; C NMR (75
MHz, CDCl3): δ 162.7, 160.1, 149.5, 137.0, 129.82, 129.78, 129.6, 127.8, 126.7, 126.0, 125.2, 119.3,
115.1, 114.0, 112.5, 55.3, 28.4, 13.3 ppm; HRMS (ESI) m/z calculated for C18H18NO [M+H]+ 264.1383,
found 264.1408.
1-isopropyl-3-phenylisoquinoline (4p): Isolated as yellow oil (12 mg, 0.05 mmol, 39% yield); Rf = 0.5
(petroleum ether : EtOAc = 8 : 1); 1H NMR (300 MHz, CDCl3): δ 8.32–8.22 (3H, m), 7.97 (1H, s), 7.90
(1H, d, J = 8.1 Hz), 7.70–7.65 (1H, m), 7.61–7.50 (3H, m), 7.48–7.38 (1H, m), 4.06–3.97 (1H, m), 1.55
(6H, d, J = 6.9 Hz) ppm; 13C NMR (75 MHz, CDCl3): δ 165.8, 165.0, 149.3, 137.3, 129.5, 128.7, 128.3,
128.0, 126.8, 126.6, 125.4, 124.8, 114.4, 31.4, 22.3 ppm; HRMS (ESI) m/z calculated for C18H18N
[M+H]+ 248.1439, found 248.1449.
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1-isopropyl-3-(p-tolyl)isoquinoline (4q): Isolated as yellow oil (10 mg, 0.04 mmol, 31% yield); Rf = 0.8
(petroleum ether : EtOAc = 8 : 1); 1H NMR (300 MHz, CDCl3): δ 8.22–8.12 (3H, m), 7.89 (1H, s), 7.84
(1H, d, J = 8.1 Hz), 7.65–7.50 (2H, m), 7.32–7.29 (2H, m), 4.01–3.92 (1H, m), 2.42 (3H, s), 1.50 (6H, d,
J = 6.6 Hz) ppm; 13C NMR (75 MHz, CDCl3): δ 165.6, 149.3, 138.1, 137.3, 129.4, 129.3, 127.9, 126.7,
126.3, 125.2, 124.7, 113.9, 105.0, 31.4, 22.3, 21.3 ppm; HRMS (ESI) m/z calculated for C19H20N
[M+H]+ 262.1596, found 262.1585.
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1-isopropyl-3-(3-methoxyphenyl)isoquinoline (4r): Isolated as yellow oil (8 mg, 0.03 mmol, 23% yield);
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Rf = 0.4 (petroleum ether : EtOAc = 20 : 1); H NMR (300 MHz, CDCl3): δ 8.21 (1H, d, J = 8.4 Hz),
7.92 (1H, s), 7.89–7.78 (3H, m), 7.66–7.53 (2H, s), 7.43–7.38 (1H, m), 6.97–6.93 (1H, m), 4.02–3.93
(1H, m), 3.93 (3H, s), 1.51 (6H, d, J = 6.9 Hz) ppm; 13C NMR (75 MHz, CDCl3): δ 165.7, 160.0, 148.9,
141.5, 137.2, 129.6, 129.5, 128.0, 126.6, 125.4, 124.7, 119.2, 114.5, 113.9, 112.5, 55.3, 31.4, 22.3 ppm;
HRMS (ESI) m/z calculated for C19H20NO [M+H]+ 278.1545, found 278.1536.
General Procedure for Synthesis of 6a and 6b: Ethyl or phenyl aryl oxime ester (0.125 mmol), methyl
pyruvate oxime ester (25 mg, 0.125 mmol), Pd(OAc)2 (5.7 mg, 0.025 mmol) and 3 mL of anhydrous
o
toluene were added to a sealed tube under N2. The reaction mixture was heated to 150 C (oil bath) for
12 h. Following cooling to rt, the solvent was evaporated to give a residue, which was purified by flash
column chromatography to afford the isoquinoline product.
methyl 1-ethylisoquinoline-3-carboxylate (6a): Isolated as yellow oil (11 mg, 0.05 mmol, 41% yield);
Rf = 0.4 (petroleum ether : EtOAc = 2 : 1); 1H NMR (300 MHz, CDCl3): δ 8.44 (1H, s), 8.24–8.21 (1H,
m), 7.97–7.94 (1H, m), 7.77–7.69 (2H, m), 4.04 (3H, s), 3.41 (2H, q, J = 7.5 Hz), 1.45 (3H, t, J = 7.5
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Hz) ppm; C NMR (75 MHz, CDCl3): δ 166.6, 164.1, 140.6, 135.9, 130.4, 129.3, 128.9, 128.1, 125.5,
122.9, 52.8, 29.0, 14.1 ppm; HRMS (ESI) m/z calculated for C13H14NO2 [M+H]+ 216.1025, found
216.1020.
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methyl 1-phenylisoquinoline-3-carboxylate (6b): Isolated as gray amorphous solid (15 mg, 0.06 mmol,
59% yield); Rf = 0.4 (petroleum ether : EtOAc = 8 : 1); 1H NMR (300 MHz, CDCl3): δ 8.59 (1H, s), 8.13
(1H, d, J = 8.4 Hz), 8.02 (1H, d, J = 8.1 Hz), 7.80–7.63 (4H, m), 7.56–7.49 (3H, m), 4.04 (3H, s) ppm;
13C NMR (75 MHz, CDCl3): δ 166.6, 161.2, 140.9, 138.9, 136.6, 130.7, 130.1, 129.4, 128.9, 128.43,
128.38, 128.2, 127.8, 123.3, 52.8 ppm; HRMS (ESI) m/z calculated for C17H14NO2 [M+H]+ 264.1025,
found 264.1024.
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methyl 1-methylisoquinoline-3-carboxylate (6c): Acetophenone oxime ester (82 mg, 0.375 mmol),
methyl pyruvate oxime ester (25 mg, 0.125 mmol), Pd(OAc)2 (11.4 mg, 0.05 mmol) and 6 mL of
anhydrous toluene were added to a sealed tube under N2. The reaction mixture was heated to 150 oC (oil
bath) for 12 h. Following cooling to rt, the solvent was evaporated to give a residue, which was purified
by flash column chromatography to afford 6c as gray amorphous solid (16 mg, 0.08 mmol, 64% yield);
Rf = 0.2 (petroleum ether : EtOAc = 2 : 1); 1H NMR (300 MHz, CDCl3): δ 8.46 (1H, s), 8.20–8.16 (1H,
m), 7.96–7.93 (1H, m), 7.79–7.70 (2H, m), 4.04 (3H, s), 3.04 (3H, s) ppm; 13C NMR (75 MHz, CDCl3):
δ 166.5, 159.4, 140.4, 135.5, 130.7, 129.4, 129.0, 128.7, 125.8, 123.0, 52.8, 22.7 ppm; HRMS (ESI) m/z
calculated for C12H12NO2 [M+H]+ 202.1079, found 202.1074.
1-phenyl-3-(prop-1-en-2-yl)isoquinoline (6d): Benzophenone oxime ester (35 mg, 0.125 mmol),
compound 5d (25 mg, 0.125 mmol), Pd(OAc)2 (5.7 mg, 0.025 mmol) and 3 mL of anhydrous toluene
o
were added to a sealed tube under N2. The reaction mixture was heated to 150 C (oil bath) for 12 h.
Following cooling to rt, the solvent was evaporated to give a residue, which was purified by flash
column chromatography to afford 6d as yellow oil (6 mg, 0.03 mmol, 20% yield); Rf = 0.6 (petroleum
ether : EtOAc = 8 : 1); 1H NMR (300 MHz, CDCl3): δ 8.15–8.07 (1H, m), 7.95–7.82 (1H, m), 7.80–7.60
(4H, m), 7.56–7.45 (4H, m), 6.27 (1H, s), 5.34 (1H, s), 2.33 (3H, s) ppm; 13C NMR (75 MHz, CDCl3): δ
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20.5 ppm; HRMS (ESI) m/z calculated for C18H16N [M+H]+ 246.1283, found 246.1280.
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2-(2-acetylphenyl)-1-phenylethan-1-one (7): Compound 7b was prepared according to Ogoshi’s
procedure.23 Compound 7c was prepared according to Lee’s procedure.24 To a solution of 7c (206 mg, 1
mmol) in 5 mL of dichloromethane was bubbled with O3 at –78 oC. After the color of the solution turned
to blue (about 5 min), turned off O3. To the solution was added a solution of PPh3 (786 mg, 3 mmol) in
10 mL of dichloromethane at –78 oC under N2 atmosphere. After 30 min at that temperature, the solvent
was evaporated to give a residue, which was purified by flash column chromatography to afford 7 (198
1
mg, 0.83 mmol, 83% yield) as white amorphous solid; Rf = 0.2 (petroleum ether : EtOAc = 8 : 1); H
NMR (300 MHz, CDCl3): δ 8.07–8.03 (2H, m), 7.88–7.85 (1H, m), 7.60–7.39 (5H, m), 7.27–7.24 (1H,
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m), 4.66 (2H, s), 2.58 (3H, s) ppm; C NMR (75 MHz, CDCl3): δ 201.2, 197.3, 137.3, 137.1, 135.2,
133.0, 132.9, 132.0, 130.1, 128.6, 128.1, 127.2, 44.6, 28.7 ppm.
2,2-dimethyl-1-(((1-(2-(2-oxo-2-phenylethyl)phenyl)ethylidene)amino)oxy)propan-1-one O-pivaloyl oxime
(8): Prepared using the general procedures as described above. Isolated as colorless gum; Mixture of
(E,Z)ꢀisomers (66 mg, 0.15 mmol, 75% yield); Rf = 0.4 (petroleum ether : EtOAc = 2 : 1); 1H NMR (300
MHz, CDCl3): δ 7.70–7.58 (3.1H, m), 7.37–7.15 (12.5H, m), 7.05–7.02 (0.6H, m), 4.47 (1.9H, s), 4.41
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(0.6H, s), 2.30 (1.4H, s), 2.28 (0.9H, s), 2.23 (2.8H, s), 2.21 (1H, s), 2.16 (2.8H, s), 1.33 (9H, s), 1.22
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(4.3H, s), 1.16 (2.6H, s), 0.98 (4.1H, s) ppm; C NMR (75 MHz, CDCl3): δ 174.9, 174.7, 168.6, 166.5,
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164.7, 164.3, 164.0, 163.6, 135.3, 135.1, 134.9, 134.1, 133.9, 133.7, 133.5, 130.7, 130.6, 130.5, 129.9,
129.8, 129.4, 129.2, 128.8, 128.61, 128.58, 128.53, 127.9, 127.7, 127.6, 127.4, 127.04, 126.95, 126.89,
125.6, 38.8, 38.6, 38.3, 32.6, 32.3, 32.2, 27.3, 27.13, 27.06, 26.9, 22.1, 19.7, 17.6 ppm; HRMS (ESI) m/z
calculated for C26H32KN2O4 [M+K]+ 475.1999, found 475.1967.
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Synthesis of 2a from 8: Bisꢀoxime ester 8 (66 mg, 0.15 mmol), Pd(PPh3)4 (175 mg, 0.15 mmol) and 3
mL of anhydrous toluene was added to a sealed tube under N2. The reaction mixture was heated to 140
oC (oil bath) for 1.5 h. Following cooling to rt, the solvent was evaporated to give a residue, which was
purified by flash column chromatography to afford 2a (18 mg, 0.08 mmol, 55% yield).
Single time point kinetic experiments using 1a, 1a-d3, and 1a-d5: The Pd(OAc)2ꢀcatalyzed selfꢀ
coupling of 1a, 1a-d3, and 1a-d5 in toluene was carried out under the optimized reaction conditions
except for the reaction was cooled to rt after 2.5 h. The reaction mixture was spotted on a TLC plate and
developed using a solvent of hexanes:ethyl acetate (4:1). The TLC plate was airꢀdried and imaged using
the ChemiDoc XRS+ system (BioꢀRad, Hercules, CA, USA) equipped with transꢀUV light source (302
nm) and a supercooled highꢀresolution CCD camera with 1.44 megapixel resolution. Both 1a’s and 2a’s
are UV active. Their UV images were acquired and analyzed by Image Lab software version 3.0 (Bioꢀ
Rad, Hercules, CA, USA) using manufacturerꢀprogramed imaging quantification function. The UV
adsorption of 2a’s was quantified and normalized against that of 1a’s before the relative quantities of
2a’s being compared. The following ratio was observed: 2a:2a-d5 = 1:1.03, 2a:2a-d3 = 2.03:1.
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Supporting Information. Experimental procedures and spectra data for all new compounds. This
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material is available free of charge via the Internet at http://pubs.acs.org
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AUTHOR INFORMATION
Corresponding Author
* yang@mail.chem.tamu.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank Mr. YanꢀJiun Lee of Department of Chemistry, Texas A&M University for assistance in
analyzing the deuteriumꢀlabeling experiments. We thank Prof. Guangbin Dong of University of Texas
Austin for helpful discussions. The financial support by the National Science Foundation (CHEꢀ
1150606) and the Robert A. Welch Foundation (Aꢀ1700) is acknowledged.
REFERENCES
1
(a) Carey, F. A.; Sundberg, R. J. in Advanced Organic Chemistry. Part B. Reactions and
Synthesis, 5th Ed. Springer, 2008. (b) Carreira E. M; Kvaerno, L. in Classics in Stereoselective
Synthesis. WileyꢀVCH Verlag GmbH & C0. KGaA, Weiheim, 2009.
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