Development and Mechanistic Study of Quinoline-Directed Acyl C-O Bond Activation and Alkene Oxyacylation Reactions

Article abstract of DOI:10.1021/acs.joc.6b03011

The intramolecular addition of both an alkoxy and acyl substituent across an alkene, oxyacylation of alkenes, using rhodium catalyzed C-O bond activation of an 8-quinolinyl ester is described. Our unsuccessful attempts at intramolecular carboacylation of ketones via C-C bond activation ultimately informed our choice to pursue and develop the intramolecular oxyacylation of alkenes via quinoline-directed C-O bond activation. We provide a full account of our catalyst discovery, substrate scope, and mechanistic experiments for quinoline-directed alkene oxyacylation.

Full text of DOI:10.1021/acs.joc.6b03011

Article
pubs.acs.org/joc
Development and Mechanistic Study of Quinoline-Directed Acyl C−O
Bond Activation and Alkene Oxyacylation Reactions
Giang T. Hoang,†,⊥ Dylan J. Walsh,‡,⊥ Kathryn A. McGarry,§ Constance B. Anderson,
and Christopher J. Douglas*
Department of Chemistry, University of Minnesota−Twin Cities, 207 Pleasant St. SE, Minneapolis, Minnesota 55455, United States
S
* Supporting Information
ABSTRACT: The intramolecular addition of both an alkoxy and acyl substituent across an alkene, oxyacylation of alkenes, using
rhodium catalyzed C−O bond activation of an 8-quinolinyl ester is described. Our unsuccessful attempts at intramolecular
carboacylation of ketones via C−C bond activation ultimately informed our choice to pursue and develop the intramolecular
oxyacylation of alkenes via quinoline-directed C−O bond activation. We provide a full account of our catalyst discovery, substrate
scope, and mechanistic experiments for quinoline-directed alkene oxyacylation.
Scheme 1. Discovery and Development of C−C and C−O
Bond Activation with 8-Acyl Quinolines
INTRODUCTION
■
The activation and functionalization of C−C and C−O bonds
adjacent to carbonyl groups is a powerful new strategy for
catalysis in organic synthesis. The field of catalytic C−C bond
activation is rapidly growing and has been the subject of several
recent reviews and books.1 With the notable exception of
nitriles,2 much of the recent work in this area has focused on
strained ring systems.3 Our early efforts focused on metal
catalyzed activation of unstrained C−C bonds to trigger the
carboacylation of alkenes.4 Alkene carboacylation is an atom-
economical and complexity-building reaction when it is
initiated by C−C bond activation of a ketone. We employed
covalently attached directing groups to facilitate bond activation
of unstrained ketones for alkene carboacylation. Our initial
work used the quinoline ring system as the directing group. Our
work with quinoline ketones indirectly led us to the analogous
chemistry of esters that involves C−O bond activation.
In this article, we describe how byproduct analysis from failed
experiments aimed at ketone carboacylation via C−C bond
activation inspired our work in acyl C−O bond activation with
esters (Scheme 1). Acyl C−O bond activation of esters enables
the addition of the acyl group and the alkoxy group of an ester
across an alkene, a process we name alkene oxyacylation. We
present our mechanistic study and further optimization of the
alkene oxyacylation reaction. Our results show that the
mechanism of intramolecular alkene oxyacylation is similar,
but distinct, from alkene carboacylation.
The 8-subsituted-quinoline ring system has a long history in
the activation of carbon sigma bonds. Suggs pioneered the use
of quinoline directing groups in the C−H activation of 8-
Received: December 16, 2016
© XXXX American Chemical Society
A
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quinolinecarboxyaldehyde. The quinoline group forms a stable,
5-membered ring through cyclometalation, which prevents
decarbonylation and provides a chelate effect to promote
oxidative addition.5 Although C−C bond activation is more
challenging than C−H activation, Suggs and Jun were able to
use the quinoline directing group to activate α-ketone C−C
bonds. They selectively activated this C−C bond since the
ketone functionality weakens the adjacent bond and cyclo-
metalation preferentially forms 5 membered rings.6 We have
previously shown that quinoline-based directing groups can
facilitate intramolecular carboacylation of alkenes.4 Coordina-
tion of the quinoline directing group brings the catalyst close to
the desired C−C bond and stabilizes reactive intermediates in
the catalytic cycle, promoting alkene carboacylation. The
stability of the resulting metallacycle also slows decarbon-
ylation, which may occur after bond activation adjacent to a
carbonyl.7
Utilizing the 8-acyl quinoline directing group, we obtained
carboacylation products in up to 96% yield. Recognizing the
challenge of removing the quinoline directing group,8 we
proposed intramolecular carboacylation of a ketone using the
same directing group (Scheme 1, middle); successful C−C
bond activation and ketone carboacylation would generate an
ester, allowing for directing group cleavage.
Johnson has studied the mechanism of alkene carboacyla-
tion.9,10 He found that resting state resulted from coordination
of the rhodium metal to the nitrogen of the quinoline directing
group. We propose a similar step for ketone carboacylation to
generate intermediate A (Scheme 2). Next, we proposed that
rhodium(I) would undergo oxidative addition into the C−C
bond adjacent to the quinolinyl ketone to form metallacycle B.
In alkene carboacylation, Johnson showed that the C−C
activation step was rate-limiting. For our proposed ketone
carboacylation, intramolecular migratory insertion across the
ketone would generate intermediate C. Late-metal alkyl or aryl
groups rarely react with aldehydes or ketones via migratory
insertion;11 therefore, our proposed transformation hinges
upon this challenging migratory insertion event. Reductive
elimination of intermediate C would form the C−O bond in
ester D. Dissociation of the metal would then yield the product
and regenerate the active catalyst.
RESULTS AND DISCUSSION
■
Substrate Synthesis for Ketone Carboacylation. For
the initial investigation of intramolecular ketone carboacylation,
compounds 1a and 1b were synthesized (Scheme 3).12 8-
Bromoquinoline underwent lithium halogen exchange and the
resulting organolithium was added to PMB protected
salicylaldehyde. Oxidation of the resulting secondary alcohol
by IBX was followed by PMB deprotection using TFA to give
phenol 3 (64% yield over 3 steps).4 Initial attempts to convert
phenol 3 to ketone 1a via SN2 displacement indicated that once
ketone 1a formed, it underwent an intramolecular aldol
reaction to form product 2a. We obtained a 50% yield of 1a
along with a 31% yield of 2a by using a substoichiometric
amount of base (NaH 0.95 equiv) and carefully monitoring the
reaction by TLC. We could avoid the aldol reaction for methyl
ketone product 1b at low conversion of phenol 3. We obtained
a 35% yield of 1b and recovered 63% of 3, while only detecting
trace amounts of the aldol product 2b.
Attempted Ketone Carboacylation and Byproduct
Analysis. We began our attempts at ketone carboacylation
with Wilkinson’s catalyst based on its success in the alkene
carboacylation transformation.4 We heated ketone 1b with
1
Wilkinson’s catalyst. The H NMR spectrum of the crude
reaction mixture showed the formation of a new product
displaying geminal diastereotopic protons (Scheme 4a). We
expected these diastereotopic signals for the carboacylation
product; however, we also observed many unexpected aromatic
signals. Seeking to identify this new product, ketone 1b and
Wilkinson’s catalyst (1 equiv) were allowed to react for 4 h in
CH2Cl2 under ambient conditions. The same new compound
formed and we isolated it in 93% yield after column
chromatography.
Scheme 2. Proposed Catalytic Cycle for Ketone
Carboacylation
The 1H NMR spectrum of this new product showed
diastereotopic hydrogen signals at 4.4 and 4.0 ppm that were
consistent with the proposed 2,3-dihydrobenzofuran ring
structure (Scheme 4a). Additional aromatic signals remained
in the purified product. We turned to 31P NMR to determine if
these signals corresponded to triphenylphosphine. 31P NMR
showed two inequivalent phosphorus signals, 13.34 (dd, J =
128.1, J = 32.1 Hz), 10.94 (dd, J = 114.8, J = 32.1 Hz).13 We
assigned the smaller coupling constant to geminal 31P coupling
and the larger coupling to a rhodium center. The small
coupling constant suggested that two triphenylphosphine
ligands were cis to one another on a rhodium center.14 We
also observed only one carbonyl signal by IR. Characterization
of quinoline containing rhodium(III) complexes by Suggs and
Jun led us to tentatively assign the complex as 4 (Scheme 4c).15
Structure 4 was appealing since it could result from C−C bond
activation and migratory insertion. To test our hypothesis, we
scaled up the synthesis of this complex to obtain 13C NMR
data. We confirmed that only one carbonyl carbon was present,
however, the anticipated Rh splitting of the carbonyl carbon
was not observed. Instead, we observed a peak at 106.2 ppm, a
doublet with a coupling constant of 3.8 Hz (Scheme 4b).
B
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Scheme 3. Ketone Carboacylation Substrate Synthesis
Analysis of an HMBC spectrum revealed that the methyl
hydrogens were adjacent to the carbonyl carbon, a result not
consistent with structure 4. Additionally, we observed the
carbon at 106.2 ppm display long-range coupling to an aromatic
hydrogen on the quinoline group and additional aromatic
group (Scheme 4c and d). While these data forced us to rule
out structure 4, the diastereotopic signals require chirality in the
structure. Flummoxed, we sought to solve the structure by
single crystal X-ray diffraction.
After screening a variety of solvent systems, we obtained
single crystals from a dichloromethane:pentane mixture that
allowed us to assign the structure of the rhodium complex. The
crystal structure revealed that complex 5 incorporated O2
(Scheme 4e and f). Incorporation of O2 is known with
rhodium species, specifically with Wilkinson’s catalyst.16,17 We
know of only one other example in which molecular oxygen has
bonded to both a rhodium and a carbon atom.17 Heating the
complex resulted in the release of 1b, as determined by in situ
NMR spectroscopy. Prolonged heating led to slow formation of
triphenylphosphine oxide.
Concurrent with our investigation with Wilkinson’s catalyst,
we examined [Rh(C2H4)2Cl]2 for reactivity toward ketone
carboacylation. Upon treatment of 1a or 1b with [Rh-
(C2H4)2Cl]2 (5−20 mol%), we observed new compounds by
1H NMR in the crude reaction mixtures. The yields of these
compounds were dependent on the rhodium loading. When
rhodium loading was increased to 1 equiv (50 mol% of
[Rh(C2H4)2Cl]2), two compounds were isolated from the
reaction with 1a, and three compounds were isolated from the
reaction with 1b. To our surprise, none of these compounds
contained the quinoline directing group. We identified the new
compounds as alkene 6, trans-alkene 7, and alcohol 8 (Scheme
5). Treatment of 1a or 1b under the reaction conditions
without [Rh(C2H4)2Cl]2 indicated that 1a and 1b undergo
intramolecular aldol cyclizations to a small extent (<10%) at
high temperature; aldol byproducts 2a or 2b were observed in
most reactions.
We rationalized the formation of 6, 7, and 8 through the
mechanistic pathways outlined in Scheme 5. Upon heating,
[Rh(C2H4)2Cl]2 undergoes oxidative addition with 1a or 1b to
form an alkyl rhodium complex B with the loss of 1 equiv of
ethylene. The Rh(III)−C bond in B can then undergo
migratory insertion across the tethered ketone CO π or
the CC π bond of an ethylene ligand, forming complex C or
compound 6, respectively. In the reaction with 1b, intermediate
B also undergoes two ethylene insertion reactions, followed by
alkene isomerization, to form 7b. Rhodium complex C could
decompose to form alcohol 8. An alternative explanation for
the formation of alcohol 8 is the hydrolysis of ester D (our
desired product); however, we found no evidence for this ester.
On the contrary, others have reported the formation of alcohols
from rhodium(III) alkoxides analogous to C.11 Although Suggs
and Jun reported chemistry similar to the styrene formation, we
observed,18 we are unaware of reports on forming an alcohol
similar to 8 via C−C σ bond activation and migratory insertion
across CO π bond.
Since we were able to isolate alcohols 8a and 8b, but not the
desired ester product, we questioned if our proposed reductive
elimination was unfavorable. The formation of 8a and 8b
indicated intermediate C had formed. We then speculated that
oxidative addition of Rh(I) to an 8-carboxy quinoline ester
would be favorable, since the resulting complex would be
similar to intermediate C.19 To test this hypothesis, we
designed substrate 16 (Scheme 6) to attempt oxidative addition
into an ester followed by migratory insertion across a tethered
alkene. Reductive elimination would yield a ketone in a catalytic
manner.
Substrate Synthesis for Acyl C−O Bond Activation.
Scheme 6 shows the routes for synthesizing alkene oxyacylation
substrates. We synthesized phenols 10a−j and 15 by
C
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a
The Skraup reaction could be used to prepare 8-bromoquino-
line 11a or 8-bromo-6-methylquinoline 11b. These 8-
bromoquinolines were converted to the 8-quinolinecarboxylic
acids 12a−b via quenching the corresponding organolithium
reagents with CO2.21 A DCC esterification of the ortho allyl
phenols with the 8-quinolinecarboxylic acids yielded the target
substrates for alkene oxyacylation.
Scheme 4. Structural Determination of Rhodium Complex
Discovery of Intramolecular Alkene Oxyacylation
Reaction. We initially attempted alkene oxyacylation of 16a
with a variety of rhodium alkene complexes in toluene at 130
°C with no added ligands (Table 1, Entries 1−3). In the
reaction with Rh(cod)2OTf, we observed oxyacylation product
17a and phenol 10a, a byproduct resulting from formal
hydrolysis of ester 16a (Entry 3). Molecular sieves did not
improve the 17a:10a ratio (not shown). The rhodium
complex’s poor solubility in toluene led us to examine
alternative solvents. 1,2-Dichloroethane (DCE) gave homoge-
neous reaction mixtures and product 17a was obtained in 40%
yield with Rh(cod)2BF4 (Entry 4). The reaction with
Rh(cod)2OTf in DCE led to a complex mixture (Entry 5).
We selected Rh(cod)2BF4 in DCE for further optimization
with added phosphine ligands. During the initial attempts, we
noted a concentration effect; higher concentrations of 16a or
catalyst led to more byproduct 10a (not shown in Table 1).
Thus, in subsequent reactions, we used more dilute substrate
concentrations (0.05 M) and lower catalyst loadings (10 mol
%). We tested three bidentate phosphine ligands (Entries 6−8).
The ligand with the lowest bite angle (dppe, 82.55°) resulted in
no reaction. The intermediate bite angle ligand (dppp, 91.56°)
was more effective than the ligand with the largest bite angle
(dppb, 97.07°).22 The reaction using Rh(cod)2BF4 and dppp in
DCE at 130 °C gave the oxyacylation product in 82% yield
(isolated) with less than 10% yield of byproduct 10a (Table 1,
Entry 8).
a
1
Both the yield of 17a and ratio of 17a:10a were dependent
on reaction temperature. Treating 16a with the Rh(cod)2BF4/
dppp catalyst at 90 °C, we observed the oxyacylation product
17a, but the reaction did not reach completion in 24 h and the
ratio 17a:10a was 1:1 (Entry 9). Temperatures below 90 °C
only gave the byproduct 10a. Increasing the temperature
provided better conversion and lower amounts of byproduct
(Entries 10 and 11). Reaction at 150 °C in toluene:DCE (8:2)
proved optimal, providing the product in 85% isolated yield
with trace amount of 10a (Entry 11). A solvent mixture of
(a) H NMR of nonequivalent alkane hydrogens. (b) 13C NMR of
quaternary carbon. (c) Initially proposed reaction of 1b with
Wilkinson’s catalyst. (d) Diagnostic HMBC correlations. (e)
ORTEP drawing of complex 5. (f) Reaction of 1b with Wilkinson’s
catalyst.
Williamson ether synthesis to yield aryl ethers 9a−j and 15.
Subsequent Claisen rearrangements of 9a−j yielded ortho allyl
phenols 10a−j. Phenol 14 was synthesized in 2 steps from 2-
methoxybenzyl chloride according to a known procedure.20
Scheme 5. Proposed Mechanistic Pathway to Observed Products
D
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Scheme 6. Substrate Synthesis For Alkene Oxyacylation
Table 1. Initial Optimization for Alkene Oxyacylation
substituents on the aromatic linker gave oxyacylation products
in good yields (Entries 1−6), although substrates bearing
electron donating groups para to the phenolic oxygen required
longer reaction times (Entries 1 and 2). In the presence of
another ester group, acyl C−O bond activation occurred
exclusively at the 8-quinoline carboxylate ester, leaving the
other ester untouched (Entry 4). Substitution at the 6-position
of the aromatic linker improved the product to byproduct ratio.
We reasoned that the restricted rotation of the acyl group
forced the reacting ester group closer to the alkene, facilitating
the oxyacylation reaction (Entries 5 and 6). A brief screen of
the alkene moiety indicated a substituent is required for
oxyacylation to occur. We did not observe any oxyacylation
product 17h when R = H (16h), possibly due to facile β-
hydride elimination or alkene isomerization to the styrenyl
position (Entry 7). Substituting with ethyl and methyl benzyl
ether groups provided products in good yield (Entries 8 and 9).
Extending the alkene tether produced chroman 17k from 16k
(Entry 10). For allylic ether 16l, we observed oxyacylation at
130 °C (Entry 11), but at higher temperatures (150 °C) the
substrate predominantly underwent a Claisen rearrangement.
Substitution on the 6-position of the quinoline directing group
in 16m and 16n enabled the synthesis of 17m and 17n in
slightly diminished yields relative to congeners 17a and 17f
(Entries 12 and 13). We accomplished the oxyacylation
reaction of 16n on larger scale (0.75 mmol of 16n), providing
a better yield of 17n (88%) than a smaller scale reaction
(Entry13). Substrates without an aryl linkage between the ester
and alkene did not produce detectable quantities of oxy-
acylation products under the standard oxyacylation conditions.
Our attempt at an oxyacylation reaction of a substrate without a
directing group was unsuccessful.23
temp
yield of 17a
entry
catalyst
L
sol.
PhMe
(°C)
(10a)
1
2
3
4
5
Rh(PPh3)3Cl
[Rh(C2H4)2Cl]2
Rh(cod)2OTf
Rh(cod)2BF4
Rh(cod)2OTf
130
130
130
110
110
PhMe
PhMe
DCE
DCE
b
b
20% (37%)
40% (40%)
complex
mixture
6
Rh(cod)2BF4
Rh(cod)2BF4
Rh(cod)2BF4
Rh(cod)2BF4
Rh(cod)2BF4
Rh(cod)2BF4
dppe DCE
dppb DCE
dppp DCE
dppp DCE
dppp DCE
dppp DCE/
130
130
130
90
b
7
40%
c
8
82%
b
b
9
25% (25%)
65% (32%)
10
110
150
d
c
11
85%
PhMe
a
Entries 1−5: Rh catalyst 20 mol%, 0.1 M 16a, 24 h, entries 6−11:
Rh(cod)2BF4 (10 mol%), ligand (12 mol %), 0.05 M 16a, 24 h.
b
c
Determined by 1H NMR spectroscopy. Yield after chromatography.
d
Conditions used for further substrate evaluation. Legend: dppe = 1,2-
bis(diphenylphosphino)ethane, dppp = 1,3-bis(diphenylphosphino)-
propane, dppb = 1,4-bis(diphenylphosphino)butane, DCE = 1,2-
dichloroethane.
toluene and DCE (8:2) was chosen since it provided
homogeneous reactions with a wider variety of substrates
than DCE alone.
Mechanistic Studies of Alkene Oxyacylation. Reaction
optimization and mechanistic studies focused on substrate 16f
due to its clean conversion to product and incorporation of a
Substrate Scope Studies. Using the optimized conditions,
we examined the scope of the oxyacylation reaction of alkenes
(Table 2). Both electron-donating and electron-withdrawing
E
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Table 2. Reaction Scope for Alkene Oxyacylation
a
b
c
Conditions: substrate (0.1 mmol), Rh(cod)2BF4 (10 mol%), dppp (12 mol%), PhMe/DCE = 8:2, 150 °C, 24 h. Yield after chromatography 36 h.
d
e
f
70% brsm. 130 °C, 50% brsm. Conditions: substrate (0.3 mmol), Rh(cod)2BF4 (10 mol%), dppp (12 mol%), PhMe/DCE = 8:2, 150 °C, 24 h.
g
Substrate (0.238 g, 0.75 mmol), Rh(cod)2BF4 (10 mol%), dppp (12 mol%), PhMe/DCE = 8:2, 150 °C, 24 h.
methyl group that we use as a diagnostic NMR reporting signal
(see below, Table 3). Reactions were heated for 60 min over a
range of temperatures from 90 to 150 °C (Entries 1−4); no
product formation was observed at 90 °C while the reaction at
150 °C gave optimal conversion. Also, the short reaction time
under the optimized conditions made obtaining quantitative
initial rate kinetics challenging. Catalyst loadings were
examined from 1 to 10 mol% (Entries 1, 5−8); however,
conversion diminished below 5 mol% (Entries 6 and 8). A
longer reaction time (48 h) with 2 mol% catalyst loading led to
increased formation of the byproduct 10f without significantly
improving the yield of 17f (Entry 7). Variation in the ligand
loading with respect to rhodium revealed that a slight excess of
ligand was necessary for success (Entries 5, 9, and 10). A 2:1
dppp:Rh ratio gave only a trace amount (<1%) of product and
the NMR showed >95% of starting material 16f remaining
(Entry 10). Optimal conversion occurred in 5 min at 150 °C
with 10 mol% catalyst and 12 mol% ligand, providing 17f in
95% isolated yield with minimal formation of 10f (Entries 11
and 12).
equivalent of [Rh(cod)2]BF4 with 1.2 equiv of dppp resulted in
two product signals by 31P NMR. The major product signal at
10.55 ppm (doublet, JRh−P = 140 Hz) we assign to
[Rh(cod)dppp]+, while the minor product signal observed at
8.29 ppm (doublet, JRh−P = 130 Hz) we assign to
[Rh(dppp)2]+. The assignment of these NMR signals is in
good agreement with literature data for similar com-
pounds.24−27 When we allowed 2 equiv of dppp to react with
[Rh(cod)2]BF4, we observed only [Rh(dppp)2]+ and free dppp
by 31P NMR. Re-examining the results from experiments with
varied ligand loading, we obtained less than optimal results
when 0.5 equiv or 2 equiv of dppp were used (Table 3, Entries
5, 9, and 10). A slight excess of dppp gave the best results.
These results, along with the 31P NMR data suggest that the
active catalyst has one dppp ligand coordinated.
We performed crossover experiments to determine whether
the mechanism involved inter- or intramolecular steps. We
subjected substrates 16f and 16m to standard reaction
conditions in a single pot. After 24 h, we observed all four
possible products (Table 4, Entry 1), confirming that
intermolecular steps occur in alkene oxyacylation. Moreover,
complete crossover occurs in 5 min, which is approximately the
time the reaction takes to reach completion (Entry 2). This
To begin our examination of the oxyacylation mechanism, we
investigated the structure of the catalyst formed by mixing
stoichiometric Rh(cod)2BF4 and dppp. The reaction of one
F
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Table 3. Temperature, Catalyst, and Ligand Loading Optimization for Alkene Oxyacylation
NMR ratios
17f (10f)
entry
catalyst loading (mol%)
ligand loading (mol%)
temp (°C)
time (min)
16f
1
10
10
10
10
5
12
12
12
12
6
150
130
110
90
60
60
60
60
60
60
48 h
60
60
60
5
>95% (2%)
>95% (1%)
87% (2%)
0% (5%)
0%
2
2%
3
11%
95%
2%
4
5
150
150
150
150
130
130
150
150
91% (7%)
52% (2%)
31%(15%)
1% (0%)
6
3
3.6
2.4
1.2
2.5
10
12
12
46%
54%
>95%
85%
>95%
2%
7
2
8
1
9
5
15%(0%)
<1%(0%)
>95% (0%)
10
11
12
5
10
10
a
5
95% (0%)
2%
a
Isolated yield after chromatography.
Table 4. Crossover Reactions
NMR product ratios
entry
description
starting materials
time
17a
17f
17m
17n
a
1
2
3
4
5
6
7
starting material crossover
starting material crossover
product crossover
16f, 16m
16f, 16m
17f, 17m
17f, 17m
16f, 16m
16f, 16m
17f, 17m
24 h
23%
24%
11%
17%
16%
28%
24%
40%
33%
14%
26%
30%
35%
29%
48%
23%
22%
14%
21%
22%
a
5 min
5 min
24 h
product crossover
b
starting material crossover
starting material; no cat.
1 h
24 h
24 h
no reaction, no crossover
no reaction, no crossover
product; no cat.
a
b
Full conversion of starting materials. Reaction heated to 130 °C, yield of all products was 74% with 23% of unchanged 16f recovered.
indicates that most of the crossover in alkene oxyacylation
occurs during the initial formation of products, not through
reactivation and crossover after oxyacylation. Independently
subjecting purified products 17f and 17m to the reaction
conditions also provided a mixture of 17a, 17f, 17m, and 17n
(Entries 3 and 4), although not in the same ratio as obtained
when we performed crossover starting with esters 16f and 16m
in entries 1 and 2. After we allowed equimolar amounts of 17f
and 17m to react for 5 min (Entry 3), the ratio of ketones was
11:40:35:14 (17a:17f:17m:17n), which is skewed toward the
starting ketone pair. After we allowed 17f and 17m to react for
24 h (Entry 4), the ratio of ketones was 17:33:29:21
(17a:17f:17m:17n), which is closer to the ratio obtained in
the crossover experiments initiated with esters 16f and 16m.
These results suggest that the qualitative rate at which
crossover occurs in the products was slower than rate of
crossover when beginning with esters. Re-isolation of starting
materials after 1 h of heating to 130 °C confirmed that
crossover of the starting esters does not occur (Entry 5).
Control reactions confirmed the need for rhodium in the
G
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Table 5. Partial Crossover Reaction
NMR product ratios
NMR phenol ratios
entry
description
starting materials
time
17a
17f
10a
10f
1
2
3
4
5
6
starting material crossover
product crossover
16f, 10a
17f, 10a
16f, 12b
17m, 12b
16f, 10a
17f, 10a
1 h
53%
47%
72%
60%
64%
40%
36%
1 h
28%
starting material crossover
product crossover
12 h
12 h
12 h
12 h
no reaction
no reaction
no reaction
no reaction
starting material; no cat.
product; no cat.
Scheme 7. Alkene Oxyacylation Mechanism
crossover reaction as well as the alkene oxyacylation reaction
(Entries 6 and 7). Notably, we did not observe esters 16a or
16n in the reaction mixture from entry 6, indicating
transesterification of the starting materials is not the cause of
crossover. The results in Table 4 indicate that the crossover
event is catalyst mediated and that activation of the products by
the catalyst is also possible. This suggests that the reaction
mechanism contains reversible steps, and the product, through
interaction with the catalyst, can proceed back to an
intermediate capable of crossover.
After observing complete crossover above, as well as noting
the formation of phenol 10a and 10f (Table 1), we sought to
determine if independent fragments were able to intercept
crossover events by examining partial crossover reactions
H
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Article
(Table 5). After subjection of starting material 16f and phenol
10a to oxyacylation reaction conditions, we observed products
17a and 17f along with phenols 10a and 10f (Table 5, Entry 1).
This indicates that an exogenous phenol can intercept the
catalytic intermediates capable of crossover. Furthermore, when
purified 17f was resubjected to the reaction conditions with
phenol 10a, we observed crossover product 17a (Entry 2). We
attempted partial crossover reactions with carboxylic acid 12b
but did not observe 17a or 17f (Entries 3 and 4). This result
indicates that 12b is not a viable reactive intermediate, nor is
12b capable of intercepting reactive intermediates by crossover.
Control reactions for the partial crossover experiments further
confirmed the need for rhodium in the crossover reaction and
that background transesterification does not occur in the
presence of 10a (Entries 5 and 6).
These results are in contrast to Johnson’s findings on the
related intramolecular carboacylation reaction of 8-acyl quino-
line ketones. When studying the mechanism of alkene
carboacylation, Johnson and co-workers did not observe any
crossover products, indicating that the intermediates were
short-lived and could not undergo intermolecular exchange
during catalysis. We observed crossover from alkene oxy-
acylation reactions, indicating that the intermediates survive
long enough to undergo intermolecular exchange.
Based on these findings, we postulate that the alkene
oxyacylation mechanism begins with [Rh(cod)2]BF4 perform-
ing a ligand exchange with dppp (Scheme 7). The [Rh(cod)-
dppp]+ complex then enters the catalytic cycle through
dissociation of COD and coordination with substrate 16a
(intermediate E). Carbon−oxygen bond activation occurs next;
this step is believed to be irreversible due to the lack of
observed crossover between starting materials. We suggest that
the crossover event occurs at intermediate F. Substitution, of
phenoxide ligands at intermediate F is consistent with our
crossover and partial crossover experiments. (Table 5, Entry 1).
We propose two possible mechanisms for this crossover event.
Intermediate F could exchange an alkoxide ligand by associative
or dissociative substitution with phenol 10f. Alternatively,
intermediate F may associate with analogous intermediate F−
Me1, Me2 to form a bimetallic intermediate with bridging
alkoxide ligands. Dissociation of the bridging alkoxides to form
intermediates F−Me1 and F−Me2 would then explain cross-
over. We cannot distinguish between these cross over
mechanisms at this time. Intermediate F then undergoes
migratory insertion across the alkene tether followed by
reductive elimination to afford intermediate H. The catalyst
dissociates from the directing group to produce product 17a.
Reverse arrows are drawn from intermediate F to product 17a
to rationalize the crossover observed when the products 17
were re-subjected to the catalyst.
complete within 5 min, providing isolated yields as high as 95%.
Mechanistic studies provided insight into the intermolecular
nature of the reaction, which allowed us to map the reversible
steps in the catalytic cycle through crossover studies.
EXPERIMENTAL DETAILS
■
All reactions were carried out using flame-dried glassware under a
nitrogen or argon atmosphere unless aqueous solutions were
employed as reagents. Tetrahydrofuran (THF) was dried by
distillation from benzophenone/sodium. Dichloromethane (CH2Cl2)
and isopropanol were degassed by bubbling a stream of argon through
the liquid in a Schlenk flask then stored and used in a N2-filled
glovebox. All other chemicals were used as received. Analytical thin
layer chromatography (TLC) was carried out using 0.25 mm silica
plates. Eluted plates were visualized with UV light. Flash
chromatography was performed using 230−400 mesh (particle size
0.04−0.063 mm) silica gel.
1H NMR (300 and 500 MHz) and 13C NMR (75 and 125 MHz)
spectra were obtained on FT NMR instruments. NMR spectra were
reported as δ values in ppm relative to chloroform or TMS for H
1
(7.26 and 0.00 ppm respectively), chloroform for 13C (77.16 ppm). 1H
and 13C NMR coupling constants are reported in Hz; multiplicity was
indicated as follows; s (singlet); d (doublet); t (triplet); q (quartet);
quint (quintet); m (multiplet); dd (doublet of doublets); ddd (doublet
of doublet of doublets); dddd (doublet of doublet of doublet of
doublets); dt (doublet of triplets); td (triplet of doublets); ddt
(doublet of doublet of triplets); app (apparent); br (broad). Infrared
(IR) spectra were obtained as films from CH2Cl2. High-resolution
mass spectra (HRMS) in EI experiments were performed on a GC-MS
system and ESI experiments were performed on a TOF instrument.
Phenol 3 was synthesized according to a published procedure.4
(2-Hydroxyphenyl)(quinolin-8-yl)methanone (3). White solid;
1H NMR(500 MHz, CDCl3) δ 12.30 (s, 1H, D2O exchange), 8.90 (dd,
J = 4.2, 1.8 Hz, 1H), 8.24 (dd, J = 8.4, 1.7 Hz, 1H), 7.99 (dd, J = 8.2,
1.4 Hz, 1H), 7.72 (dd, J = 7.0, 1.5 Hz, 1H), 7.65 (t, J = 8.1 Hz, 1H),
7.49−7.44 (m, 2H), 7.15 (dd, J = 8.0, 1.7 Hz, 1H), 7.07 (d, J = 8.5 Hz,
1H), 6.70 (ddd, 8.3, 7.2, 1.2 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ
203.7, 163.1, 151.3, 145.9, 137.9, 136.8, 136.2, 134.1, 130.1, 128.4,
128.3, 125.9, 122.0, 120.9, 118.9, 118.4; HRMS (ESI) calcd for
C16H11NO2 [M+Na]+ m/z 272.0682, found 272.0688.
1-Phenyl-2-(2-(quinoline-8-carbonyl)phenoxy)ethan-1-one
(1a) and (3-Hydroxy-3-(quinolin-8-yl)-2,3-dihydrobenzofuran-
2-yl)(phenyl)methanone (2a). NaH (23 mg, 0.095 mmol) was
added to a solution of 2-hydroxyphenyl 8-quinolinyl ketone 3 (0.249 g,
1 mmol) in DMF (4 mL) at 0 °C, the mixture was stirred for 10 min.
Potassium iodide (0.166 g, 1 mmol) and 2-bromoacetophenone (0.4 g,
2 mmol) were added. The formation of products was monitored by
TLC. After 2 h, NH4Cl (sat.) was added and the mixture was extracted
with EtOAc (3 × 15 mL). The combined organic layers were washed
with 2 M LiCl (2 × 20 mL), brine, dried over Na2SO4, and
concentrated. The crude mixture was purified by flash column
chromatography to provide 1a (185 mg, 0.5 mmol, 50%) and the aldol
product 2a (113 mg, 0.31 mmol, 31%). 10% of the starting material
1
remained as determined by H NMR of the crude mixture.
1-Phenyl-2-(2-(quinoline-8-carbonyl)phenoxy)ethanone
(1a). Yellow solid (185 mg, 0.5 mmol, 50%); Rf = 0.21 (40% EtOAc/
CONCLUSION
1
■
Hex); H NMR (500 MHz, CDCl3) δ 8.72 (dd, J = 4.2, 1.8 Hz, 1H),
While our efforts toward ketone carboacylation have yet to
come to fruition, this research paved the way to our discovery
of alkene oxyacylation. Isolation of alcohol 8 suggested to us
that carbon−carbon bond activation and migratory insertion
across a ketone occurred readily, but reductive elimination may
not be favorable. We hypothesized that if reductive elimination
to form the ester functional group is unfavorable, then the
reverse, oxidative addition into an ester, could be utilized in
alkene addition reactions. The alkene oxyacylation using esters
proved to be effective and efficient, validating this hypothesis.
Moreover, we have found the reaction is rapid and can be
8.06 (dd, J = 8.3, 1.7 Hz, 1H), 7.86 (dd, J = 7.7, 1.3 Hz, 1H), 7.77 (dd,
J = 8.2, 1.3 Hz, 1H), 7.75 (dd, J = 7.1, 1.4 Hz, 1H), 7.61 (dd, J = 8.3,
1.2 Hz, 2H), 7.53−7.47 (m, 1H), 7.47−7.40 (m, 2H), 7.35−7.28 (m,
3H), 7.08 (app td, J = 7.5, 0.9 Hz, 1H) 6.81 (d, J = 8.4 Hz, 1H), 4.71
(s, 2H); 13C NMR (125 MHz, CDCl3) δ 196.6, 193.7, 157.6, 150.4,
145.8, 141.1, 135.9, 134.0, 133.8, 133.7, 131.4, 130.2, 130.0, 128.63,
128.59, 128.2, 127.8, 125.9, 121.9, 121.3, 114.1 72.1; IR (film) 3064,
2922, 1701, 1646, 1595, 1451, 1291, 1215 cm−1; HRMS (ESI) calcd
for C24H17NO3 [M+Na]+ m/z 390.1101, found 390.1118.
(3-Hydroxy-3-(quinolin-8-yl)-2,3-dihydrobenzofuran-2-yl)-
(phenyl)methanone (2a). White solid (113 mg, 0.31 mmol, 31%);
Rf = 0.38 (40% EtOAc/Hex); 1H NMR (500 MHz, CDCl3) δ 9.87 (s,
I
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1H, D2O exchange), 8.48 (dd, J = 4.3, 1.8 Hz, 1H), 8.24 (dd, J = 8.4,
1.8 Hz, 1H), 7.81 (dd, J = 8.2, 1.3 Hz, 1H), 7.75 (dd, J = 8.4, 1.9 Hz,
2H), 7.50 (app t, J = 7.4 Hz, 1H), 7.46−7.34 (m, 4H), 7.29−7.22 (m,
3H), 7.11 (d, J = 8.1 Hz, 1H), 7.03 (app td, J = 7.5, 0.9 Hz, 1H) 5.94
(s, 1H); 13C NMR (125 MHz, CDCl3) δ 196.2, 159.9, 147.5, 146.4,
139.4, 137.6, 137.2, 132.9, 131.8, 130.7, 129.6, 129.1,28 129.0, 128.4,
128.1, 126.8, 125.7, 122.2, 121.1, 110.8, 94.9, 88.6; IR (film) 3414,
3057, 1695, 1598, 1476, 1226 cm−1; HRMS (ESI) calcd for
C24H17NO3 [M+Na]+ m/z 390.1101, found 390.1099.
1-(2-(Quinoline-8-carbonyl)phenoxy)propan-2-one (1b) and
1-(3-Hydroxy-3-(quinolin-8-yl)-2,3-dihydrobenzofuran-2-yl)-
ethanone (2b). NaH (23 mg, 0.95 mmol) was added to a solution of
2-hydroxyphenyl 8-quinolinyl ketone 3 (0.249 g, 1 mmol) in DMF (4
mL) at 0 °C, the mixture was stirred for 10 min. Potassium iodide
(0.166 g, 1 mmol) and chloroacetone (0.32 mL, 4 mmol) were added.
The formation of products was monitored by TLC. After 4 h, NH4Cl
(sat.) was added and the mixture was extracted with EtOAc (3 × 15
mL). The combined organic layers were washed with 2 M LiCl (2 ×
20 mL), brine, dried over Na2SO4 and concentrated. The crude
mixture was purified by flash column chromatography to give 1b (87
mg, 0.28 mmol, 28%), starting material 3 (158 mg, 0.63 mmol, 63%),
and trace amounts of aldol 2b.
1-(2-(Quinoline-8-carbonyl)phenoxy)propan-2-one (1b). Yel-
low solid (87 mg, 0.28 mmol, 28%); Rf = 0.16 (40% EtOAc/Hex); 1H
NMR (500 MHz, CDCl3) δ 8.76 (dd, J = 4.1, 1.5 Hz, 1H), 8.15 (dd, J
= 8.3, 1.4 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.85 (d, J = 7.1 Hz, 1H),
7.79 (dd, J = 7.7, 1.4 Hz, 1H), 7.57 (t, J = 7.6 Hz, 1H), 7.43 (t, J = 8.4
Hz, 1H), 7.36 (dd, J = 8.3, 4.2 Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H), 6.74
(d, J = 8.4 Hz, 1H), 4.11 (s, 2H), 1.61 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 205.4, 196.3, 156.7, 150.6, 145.8, 140.6, 135.9, 133.6, 131.6,
130.4, 130.0, 128.9, 128.0, 125.9, 121.6, 121.4, 112.8, 73.5, 26.0; IR
(film) 3068, 2922, 1721, 1661, 1595, 1451, 1294, 1266 cm−1; HRMS
(ESI) calcd for C19H15NO3 [M+Na]+ m/z 328.0944, found 328.0955.
1-(3-Hydroxy-3-(quinolin-8-yl)-2,3-dihydrobenzofuran-2-yl)-
ethanone (2b). White solid; Rf = 0.42 (40% EtOAc/Hex); 1H NMR
(500 MHz, CDCl3) δ 9.98 (s, 1H, D2O exchange), 8.88 (dd, J = 4.3,
1.8 Hz, 1H), 8.27 (dd, J = 8.4, 1.7 Hz, 1H), 7.78 (dd, J = 8.2, 1.1 Hz,
1H), 7.51 (dd, J = 8.4, 4.3 Hz, 1H), 7.44 (app t, J = 7.5 Hz, 1H), 7.39
(app td, J = 7.0, 1.4 Hz, 1H), 7.30 (dd, J = 7.5, 0.8 Hz, 1H), 7.14 (dd, J
= 7.4, 1.3 Hz, 1H), 7.08−7.04 (m, 2H), 4.95 (s, 1H), 2.34 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 206.6, 159.8, 148.0, 146.2, 139.6, 137.8,
131.4, 130.8, 129.3, 129.1, 128.3, 126.6, 125.9, 122.3, 121.4, 110.7,
97.2, 88.0, 27.9; IR (film) 3420, 3048, 2963, 2922, 2849, 1716, 1599,
1475 cm−1; HRMS (ESI) calcd for C19H15NO3 [M+Na]+ m/z
328.0944, found 328.0944.
Attempted carboacylation reaction of 1a with [Rh(C2H4)2Cl]2. In a
nitrogen filled glovebox, a 1-dram reaction vial (polytetrafluoro-
ethylene cap) was charged with [Rh(C2H4)2Cl]2 (0.0518 g, 0.133
mmol, 0.5 equiv), phenyl ketone 1a (0.0980 g, 0.267 mmol), and
toluene (2.67 mL). The reaction mixture was maintained at 90 °C for
24 h. The mixture was then removed from the glovebox, filtered
through Celite , and concentrated to give a crude brown residue
(0.0983 g). The crude product was purified by flash column
chromatography (20% EtOAc in hexanes). Two products were
isolated: alkene 6a (0.0225 g, 0.0944 mmol, 35%) and alcohol 8a
(0.0042 g, 0.020 mmol, 7%).
1-Phenyl-2-(2-vinylphenoxy)ethanone (6a). Colorless solid
1
(22.5 mg, 0.0944 mmol, 37%); Rf = 0.47 (20% EtOAc in Hex); H
NMR (500 MHz, CDCl3) δ 8.02−8.00 (m, 2H), 7.62 (dddd, J = 6.9,
6.9, 1.3, 1.3 Hz, 1H), 7.52−7.49 (m, 3H), 7.22−7.18 (m, 1H), 7.14
(dd, J = 17.8, 11.2 Hz, 1H), 6.98 (app t, J = 7.3 Hz, 1H), 6.81 (dd, J =
8.3, 0.8 Hz, 1H), 5.80 (dd, J = 17.8, 1.5 Hz, 1H), 5.31−5.28 (m, 3H);
13C NMR (125 MHz, CDCl3) δ 194.6, 155.3, 134.7, 134.0, 131.5,
129.0, 128.9, 128.3, 127.5, 127.0, 121.8, 115.2, 112.5, 71.5; IR (thin
film, CH2Cl2) 3064, 3032, 2916, 1703, 1625, 1598 cm−1; HRMS (ESI)
calcd for C16H14O2 [M+Na]+ m/z 261.0886, found 261.0891.
3-Phenyl-2,3-dihydrobenzofuran-3-ol (8a). Colorless oil (4.2
mg, 0.020 mmol, 8%); Rf = 0.41 (20% EtOAc in Hex); 1H NMR (500
MHz, CDCl3) δ 7.52−7.49 (m, 2H), 7.39−7.36 (m, 2H), 7.33−7.29
(m, 2H), 7.11 (app d, J = 7.5 Hz, 1H), 6.98−6.94 (m, 2H), 4.71 (d, J =
10.3 Hz, 1H), 4.51 (d, J = 10.3 Hz, 1H), 2.29 (s, 1H); 13C NMR (125
MHz, CDCl3) δ 160.8, 142.7, 132.3, 130.8, 128.4, 127.7, 126.2, 124.5,
121.6, 110.9, 86.3, 82.7; IR (thin film, CH2Cl2) 3440, 3058, 3030,
2946, 1599 cm−1; HRMS (ESI) calcd for C14H12O2 [M+Na]+ m/z
235.0730, found 235.0731.
Following the general procedure above using methyl ketone 1b
(0.1000 g. 0.328 mmol, 1 equiv), three products were isolated: alkene
6b (0.0202 g, 0.115 mmol, 35%), trans-alkene 7b (0.0013 g, 0.0086
mmol, 3%), and alcohol 8b (0.0010 g, 0.0048 mmol, 2%)
1-(2-Vinylphenoxy)propan-2-one (6b). Colorless oil (20.2 mg,
1
0.1146 mmol, 35%); Rf = 0.35 (20% EtOAc in Hex); H NMR (500
MHz, CDCl3) δ 7.53 (dd, J = 7.6, 1.5 Hz, 1H), 7.22 (dt, J = 7.8, 1.6
Hz, 1H), 7.13 (dd, J = 17.8, 11.2 Hz, 1H), 6.99 (t, J = 7.5 Hz, 1H),
6.72 (d, J = 8.2 Hz, 1H), 5.79 (dd, J = 17.8, 1.2 Hz, 1H), 5.32 (dd, J =
11.2, 1.2 Hz, 1H), 4.54 (s, 2H), 2.31 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 206.1, 154.9, 131.2, 129.1, 127.2, 126.9, 121.9, 115.2, 111.9,
73.5, 27.0; IR (thin film, CH2Cl2) 3061, 3036, 3021, 2981, 2958, 2916,
2848, 1737, 1720, 1626, 1599, 1577 cm−1; HRMS (ESI) calcd for
C11H12O2 [M+Na]+ m/z 199.0730, found 199.0760.
(E)-1-(2-(But-1-en-1-yl)phenoxy)propan-2-one (7b). Colorless
1
oil (1.0 mg, 0.0049 mmol, 2%); Rf = 0.58 (20% EtOAc in Hex); H
Synthesis of Complex 5. Wilkinson catalyst (0.409 g, 0.442
mmol) was added to a solution of 1-(2-(quinoline-8-carbonyl)-
phenoxy)propan-2-one 1b (0.135 g, 0.442 mmol) in dichloromethane
(4 mL), The mixture was stirred at room temperature for 4 h and
product formation was monitored by TLC. The mixture was
concentrated and purified by gradient flash chromatography (20%
EtOAc:Hex to 100% EtOAc). Recrystallization in EtOAc and pentane
gave 5 as a brown solid (0.396 g, 0.409 mmol, 93% yield) which was
stored at −20 °C. Attempts to remove small amounts of residual
solvent led to decomposition.
NMR (500 MHz, CDCl3) δ 7.47 (dd, J = 7.7, 1.5 Hz, 1H), 7.15 (dt, J
= 9.0, 1.6 Hz, 1H), 6.96 (t, J = 7.6 Hz, 1H), 6.76 (d, J = 16.0 Hz, 1H),
6.69 (d, J = 8.2 Hz, 1H), 6.30 (ddd, J = 16.0, 6.5, 6.5 Hz, 1H), 4.54 (s,
2H), 2.32 (s, 2H), 2.30−2.27 (m, 2H), 1.14 (t, J = 7.5 Hz, 3H);); 13C
NMR (125 MHz, CDCl3) δ 206.5, 154.5, 134.1, 128.0, 127.6, 126.8,
123.0, 121.9, 111.9, 73.6, 27.0, 26.6, 13.8; COSY; IR (thin film,
CH2Cl2) 2963, 2919, 2873, 2849, 1723, 1598, 1579 cm−1; HRMS
(ESI) calcd for C13H16O2 [M+Na]+ m/z 227.1043, found 227.1065.
3-Methyl-2,3-dihydrobenzofuran-3-ol (8b).31 Colorless oil
1
(1.3 mg, 0.0087 mmol, 3%); Rf = 0.28 (20% EtOAc in Hex); H
Rhodium(III) Complex (5). Brown solid (0.396 g, 0.409 mmol,
93%); Rf = 0.35 (20% EtOAc in Hex); 1H NMR (500 MHz, CDCl3) δ
9.00−8.98 (m, 1H), 7.86 (d, J = 7.3 Hz, 1H), 7.69−6.77 (m, 37H),
6.51−6.48 (m, 1H), 4.32 (d, J = 15.7 Hz, 1H), 3.96 (d, J = 15.7 Hz,
1H), 1.24 (s, 3H); 13C NMR29 (125 MHz, CDCl3) δ 207.6, 157.6,
156.0, 142.7, 142.5, 138.6, 136.7, 136.7, 136.1, 136.0, 135.6, 135.6,
134.8 (br), 133.6, 130.7, 129.8, 129.2, 129.1, 129.1, 128.6, 128.0, 128.0,
127.7, 127.6, 127.4, 127.2, 127.1, 127.0, 126.9, 126.0, 125.9, 121.7,
119.5, 117.9, 106.3 (d, JRh−C = 3.9), 77.0, 26.5; 31P NMR (202 MHz,
NMR (500 MHz, CDCl3) δ 7.34 (d, J = 7.4 Hz, 1H), 7.27−7.24 (m,
1H), 6.96 (t, J = 7.4 Hz, 1H), 6.88 (d, J = 8.2 Hz, 1H), 4.50 (d, J =
10.1 Hz, 1H), 4.31 (d, J = 10.0 Hz, 1H), 1.96 (s, 1H), 1.69 (s, 3H); IR
(thin film, CH2Cl2) 3385 (br), 2969, 2917, 1610, 1600, 1479, 1465
cm−1; HRMS (EI) calcd for C9H10O2 [M]+ m/z 150.0675, found
150.0676.
Overall Scheme for the Synthesis of Ester Substrates. The
substrates 16a through 16l for the oxyacylation reaction were
synthesized according to literature procedure.12,32 Oxyacylation
reactions to form products 17a to 17l are also reported previously
reported in literature.12,32
CDCl3) δ 13.34 (dd, JRh−P = 128.1, JP−P = 32.1 Hz), 10.94 (dd, JRh−P
=
114.8, JP−P = 32.1 Hz); IR (film) 3055, 1714, 1483, 1435, 1191, 1118
cm−1; HRMS30 (ESI) calcd for C55H45ClNO5P2Rh [M+Na]+ m/z
1022.1409, found 1022.1408; DEPT; COSY; HMBC; HMQC; The
structure was confirmed by single crystal X-ray crystallography.
Synthesis of 6-Methylquinoline-8-carboxylic Acid. 8-Bromo-
6-methylquinoline (1.63 g, 7.3 mmol) and dry ether (30 mL) were
added to a flame-dried 3-necked 50 mL round-bottom flask under N2.
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The mixture was cooled to −78 °C then t-Bu Li (1.7 M) in pentane
(8.6 mL, 14.6 mmol) was added over 20 min. The mixture was
maintained at −78 °C for 10 min and then poured into a 1 L beaker
containing dry ice. After all remaining dry ice had sublimed, aqueous
HCl (1 M) was added until the reaction mixture became acidic (pH =
3). The mixture was extracted with chloroform (10 × 100 mL). The
combined organic layers were washed with brine, dried over anhydrous
Na2SO4, and concentrated under vacuum. The crude product was
further purified by high vacuum (>0.1 mmHg) at a temperature of 100
°C to yield 6-methylquinoline-8-carboxylic acid 12b (1.082 g, 5.79
mmol, 79%).
1H), 6.56 (d, J = 8.0 Hz, 1H), 3.98 (d, J = 16.4 Hz, 1H), 3.94 (d, J =
15.9 Hz, 1H), 3.44 (d, J = 15.9 Hz, 1H), 3.16 (d, J = 15.9 Hz, 1H),
2.50 (s, 3H), 1.66 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 204.2,
158.5, 149.7, 144.3, 139.8, 136.1, 135.7, 131.5, 130.1, 128.5, 127.9,
127.4, 125.3, 121.5, 120.2, 109.4, 87.6, 54.8, 41.6, 27.1, 21.5; IR (thin
film, CH2Cl2) 3048, 2970, 2929, 1682, 1596,1480, 1240 cm−1; HRMS
(ESI) calcd for C21H19NO2 [M+Na]+ m/z 340.1308, found 340.1309.
2-(2,7-Dimethyl-2,3-dihydrobenzofuran-2-yl)-1-(6-methyl-
quinolin-8-yl)ethanone (17n). Colorless oil (26 mg, 0.078 mmol,
78%); Rf = 0.47 (20% EtOAc in Hex); 1H NMR (500 MHz, CDCl3) δ
8.84 (dd, J = 4.1, 1.6 Hz, 1H), 8.07 (dd, J = 8.3, 1.6 Hz, 1H), 7.64 (s,
1H), 7.56 (d, J = 2.0 Hz, 1H), 7.38 (m, 2H), 6.96 (d, J = 7.3 Hz, 1H),
6.84 (t, J = 7.5 Hz, 1H), 6.72 (t, J = 7.4 Hz, 1H), 4.01 (d, J = 15.3 Hz,
1H), 3.82 (d, J = 15.3 Hz, 1H), 3.44 (d, J = 15.9 Hz, 1H), 3.13 (d, J =
15.9 Hz, 1H), 2.46 (s, 3H), 1.86 (s, 3H), 1.64 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 205.0, 157.1, 149.7, 144.3, 140.1, 136.1, 135.6, 131.2,
129.8, 129.1, 128.4, 126.4, 122.6, 121.5, 120.0, 119.6, 87.1, 55.1, 41.7,
27.6, 21.5, 15.1; IR (thin film, CH2Cl2) 3050, 2970, 2920, 1682,
1597,1466, 1237 cm−1; HRMS (ESI) calcd for C22H21NO2 [M+H]+
m/z 332.1645, found 332.1644. We obtained 17n as a colorless oil
(209.4 mg, 0.660 mmol, 88% yield) on larger scale reaction after
purification by column chromatography (isocratic 15% EtOAc in
6-Methylquinoline-8-carboxylic Acid (12b). Tan solid (1.082 g,
1
5.79 mmol, 79%); H NMR (500 MHz, CDCl3) δ 16.63 (br s, 1H)
8.83 (dd, J = 4.5, 1.7 Hz, 1H), 8.61 (d, J = 2.0 Hz, 1H), 8.32 (dd, J =
8.4, 1.7 Hz, 1H), 7.85 (d, J = 0.9 Hz, 1H), 7.57 (dd, J = 8.4, 4.4 Hz,
1H), 2.59 (s, 3H); 13C NMR (125 MHz, CDCl3) δ167.6, 147.6, 144.0,
138.1, 137.8, 137.5, 131.9, 128.5, 124.2, 121.8, 21.6; IR (film) 3426,
1640 cm−1; HRMS (ESI) calcd for C11H9NO2 [M+Na]+ m/z
210.0525, found 210.0524.
General Synthesis of Esters. In a flame-dried round-bottom flask,
8-quinolinecarboxylic acid 12 (1 equiv), N,N′-dicyclohexylcarbodii-
mine (1.5 equiv), 4-(dimethylamino)pyridine (1equiv), and phenol 10
(1−2 equiv) were dissolved in dichloromethane to generate a 0.1 M
solution with respect to 8-quinolinecarboxylic acid 12. The mixture
was refluxed for 24 h. Insoluble byproducts were removed by vacuum
filtration using fritted glass funnel. The filtrate was washed with
saturated aqueous NH4Cl twice, followed by a saturated NaHCO3
wash. The organic layer was dried over anhydrous Na2SO4 and
concentrated. The resulting crude product was purified by flash
chromatography (gradient, EtOAc:Hex) to provide the product ester
16.
2-(2-Methylallyl)phenyl 6-Methylquinoline-8-carboxylate
(16m). yellow oil (388 mg, 1.223 mmol, 64%); Rf = 0.35 (20%
EtOAc in Hex); 1H NMR (500 MHz, CDCl3) δ 9.01 (dd, J = 4.1, 1.6
Hz, 1H), 8.13 (dd, J = 8.2, 1.6 Hz, 1H), 8.08 (d, J = 1.8 Hz, 1H), 7.77
(s, 1H), 7.44 (dd, J = 8.2, 4.1 Hz, 1H), 7.38 (m, 1H), 7.33 (m, 2H),
7.24 (m, 1H), 4.82 (s, 1H), 4.70 (s, 1H), 3.53 (s, 2H), 2.61 (s, 3H),
1.74 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 166.2, 150.7, 149.7,
144.5, 144.2, 135.6, 135.5, 133.0, 132.0, 130.8, 130.7, 130.6, 128.6,
127.4, 126.1, 122.8, 121.8, 112.3, 38.6, 22.5, 21.5; IR (thin film,
CH2Cl2) 3085, 2972, 2925, 1750, 1650 cm−1; HRMS (ESI) calcd for
C21H19NO2 [M+H]+ m/z 318.1489, found 318.1489.
1
Hex); the H NMR matched that obtained from the smaller scale
experiment.
Crossover Reactions. In a nitrogen filled glovebox, Rh(cod)2BF4
(0.02 mmol, 0.1 equiv), 1,3-bis(diphenylphosphoino)propane (0.024
mmol, 0.12 equiv), and DCE (0.4 mL) were added to a 1 dram
reaction vial (polytetrafluoroethylene cap). The mixture was stirred at
room temp for 1 h and then transferred to a 20 mL scintillation vial
containing the mixture of starting material esters 16f and 16m or
products 17f and 17m (0.1 mmol each, 0.2 mmol total, 1 equiv total)
and toluene (1.6 mL). The reaction mixture was maintained at 150 °C
for a specified time. The mixture was then removed from the glovebox
and concentrated. The crude product was purified by flash column
chromatography (gradient, EtOAc:Hex) to afford the oxyacylation
product(s).
Partial Crossover Oxyacylation Reactions. In a nitrogen filled
glovebox, Rh(cod)2BF4 (0.01 mmol, 0.1 equiv), 1,3-bis-
(diphenylphosphoino)propane (0.012 mmol, 0.12 equiv), and DCE
(0.4 mL) were added to a 1 dram reaction vial (polytetrafluoro-
ethylene cap). The mixture was stirred at room temp for 1 h and then
transferred to a 1 dram vial containing starting material ester 16f or
product 17f (0.1 mmol, 1 equiv) and phenol 10a (0.1 mmol, 1 equiv)
in toluene (1.6 mL). The reaction mixture was maintained at 150 °C
for a specified amount of time. The mixture was then removed from
the glovebox and concentrated. The crude product was purified by
flash column chromatography (gradient, EtOAc:Hex) to afford the
oxyacylation product(s).
2-Methyl-6-(2-methylallyl)phenyl 6-Methylquinoline-8-car-
boxylate (16n). Yellow oil (354 mg, 1.068 mmol, 62%); Rf = 0.38
1
(20% EtOAc in Hex); H NMR (500 MHz, CDCl3) δ 8.97 (dd, J =
4.1, 1.5 Hz, 1H), 8.13−8.05 (m, 2H), 7.72 (s, 1H), 7.40 (dd, J = 8.2,
4.1 Hz, 1H), 7.24−7.15 (m, 3H), 4.87 (s, 1H), 4.76 (s, 1H), 3.60 (s,
2H), 2.58 (s, 3H), 2.46 (s, 3H), 1.78 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 165.9, 150.5, 148.5, 144.3, 144.2, 135.5, 135.5, 132.7, 132.2,
131.0, 130.9, 130.6, 129.1, 128.5, 128.2, 125.9, 121.7, 112.2, 38.7, 22.4,
21.4, 17.0; IR (thin film, CH2Cl2) 3072, 3022, 2968, 2921, 2854, 1749,
1651, 1597 cm−1; HRMS (ESI) calcd for C22H21NO2 [M+H]+ m/z
332.1645, found 332.1636.
General Alkene Oxyacylation Reaction. In a nitrogen filled
glovebox, Rh(cod)2BF4 (0.01 mmol, 0.1 equiv), 1,3-bis-
(diphenylphosphoino)propane (0.012 mmol, 0.12 equiv), and DCE
(0.4 mL) were added to a 1 dram reaction vial (polytetrafluoro-
ethylene cap). The mixture was stirred at room temp for 1 h and then
transferred to a 1 dram vial containing ester (0.1 mmol, 1 equiv) and
toluene (1.6 mL). The reaction mixture was maintained at 150 °C for
a specified amount of time. The mixture was then removed from the
glovebox and concentrated. The crude product was purified by flash
column chromatography (gradient, EtOAc:Hex) to afford the
oxyacylation product.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b03011.
NMR spectra for new compounds, tabulated X-ray
diffraction data, and NMR spectra for crossover experi-
ments (PDF)
X-ray crystallographic data for 5 (CIF)
AUTHOR INFORMATION
Corresponding Author
*cdouglas@umn.edu
■
2-(2-Methyl-2,3-dihydrobenzofuran-2-yl)-1-(6-methylquino-
ORCID
lin-8-yl)ethanone (17m). Colorless oil (22 mg, 0.069 mmol, 69%);
Christopher J. Douglas: 0000-0002-1904-6135
1
Rf = 0.49 (20% EtOAc in Hex); H NMR (500 MHz, CDCl3) δ 8.83
Present Addresses
(dd, J = 4.2, 1.8 Hz, 1H), 8.07 (dd, J = 8.3, 1.8 Hz, 1H), 7.66 (s, 1H),
7.56 (d, J = 2.0 Hz, 1H), 7.37 (dd, J = 8.3, 4.2 Hz, 1H), 7.13 (dd, J =
7.3, 0.9 Hz, 1H), 7.05 (t, J = 2.3 Hz, 1H), 6.81 (td, J = 7.4, 0.9 Hz,
†Department of Chemistry, National University of Singapore, 3
Science Drive 3, Singapore 117543
K
DOI: 10.1021/acs.joc.6b03011
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
‡Department of Chemical and Biomolecular Engineering,
University of Illinois at Urbana−Champaign, Urbana, Illinois,
61801, United States
(17) Dutta, S.; Peng, S.-M.; Bhattacharya, S. Inorg. Chem. 2000, 39,
2231−2234.
(18) Suggs, J. W.; Jun, C.-H. J. J. Chem. Soc., Chem. Commun. 1985,
92−93.
§Department of Chemistry, University of Wisconsin−Stevens
Point, D129 SCI, 2001 Fourth Avenue, Stevens Point, WI,
54481−3897, United States
(19) (a) Grotjahn, D. B.; Joubran, C.; Combs, D. J. J. Organomet.
Chem. 1999, 589, 115−121. (b) Grotjahn, D. B.; Joubran, C. Inorg.
Chim. Acta 2004, 357, 3047−3056.
(20) Yates, P.; Macas, T. Can. J. Chem. 1988, 66, 1−10.
(21) 8-Quinolinecarboxylic acid can also be obtained from
commercial sources.
Author Contributions
⊥G.T.H. and D.J.W. contributed equally to this work.
Notes
(22) Dierkes, P.; van Leeuwen, P. W. N. M. J. Chem. Soc., Dalton
This material is based upon work supported in part by the
National Science Foundation Graduate Research Fellowship
Program under Grant No. 00039202. Any opinions, findings,
and conclusions or recommendations expressed in this material
are those of the authors and do not necessarily reflect the views
of the National Science Foundation.
Trans. 1999, 1519−1530.
(23) Hoang, G. T.; Pan, Z.; Brethorst, J. T.; Douglas, C. J. J. Org.
Chem. 2014, 79, 11383−11394.
(24) James, B. R.; Mahajan, D. Can. J. Chem. 1979, 57, 180−187.
(25) Slack, D. A.; Baird, M. C. J. Organomet. Chem. 1977, 142, C69−
C72.
(26) Barbaro, P.; Bianchini, C.; Dal Santo, V.; Meli, A.; Moneti, S.;
Pirovano, C.; Psaro, R.; Sordelli, L.; Vizza, F. Organometallics 2008, 27,
2809−2824.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(27) Jacobi, A.; Huttner, G.; Winterhalter, U. J. Organomet. Chem.
1998, 571, 231−241.
■
The National Science Foundation (CAREER Award to C.J.D.,
CHE-1151547) and Research Corporation for Science
Advancement (Cottrell Scholar Award to C.J.D., Award No.
19985) funded this work. D.J.W. thanks the Heisig/Gleysteen
Chemistry Summer Research Program (UMN) for an under-
graduate research fellowship. C.B.A. thanks the National
Science Foundation for a Graduate Research Fellowship
(Grant No 00039202).
(28) Overlapping of two carbons signals.
(29) No attempt was made to assign 31P−13C coupling constants in
the aromatic region due to overlapped signals, peaks in this region are
listed as observed.
(30) The sample was dissolved in CH2Cl2 (∼2.5 mL) and 4−5 drops
of MeOH were added to the solution prior to injection into the ESI.
Attempts to record an MS after dissolving 5 in MeOH did not lead to
observation of a molecular ion.
(31) This compound was previously synthesized and our data is in
good agreement with the literature data: Liu, G.; Lu, X. Tetrahedron
2008, 64, 7324−7330.
(32) Hoang, G. T.; Reddy, V. J.; Nguyen, H. H. K.; Douglas, C. J.
Angew. Chem., Int. Ed. 2011, 50, 1882−1884.
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DOI: 10.1021/acs.joc.6b03011
J. Org. Chem. XXXX, XXX, XXX−XXX