Stereoselective Synthesis of Methylene Oxindoles via Palladium(II)-Catalyzed Intramolecular Cross-Coupling of Carbamoyl Chlorides

Article abstract of DOI:10.1021/jacs.6b08925

We report a highly robust, general and stereoselective method for the synthesis of 3-(chloromethylene)oxindoles from alkyne-tethered carbamoyl chlorides using PdCl₂(PhCN)₂ as the catalyst. The transformation involves a stereo- and regioselective chloropalladation of an internal alkyne to generate a nucleophilic vinyl Pd^II species, which then undergoes an intramolecular cross-coupling with a carbamoyl chloride. The reaction proceeds under mild conditions, is insensitive to the presence of moisture and air, and is readily scalable. The products obtained from this reaction are formed with >95:5 Z:E selectivity in nearly all cases and can be used to access biologically relevant oxindole cores. Through combined experimental and computational studies, we provide insight into stereo- and regioselectivity of the chloropalladation step, as well as the mechanism for the C-C bond forming process. Calculations provide support for a mechanism involving oxidative addition into the carbamoyl chloride bond to generate a high valent Pd^IV species, which then undergoes facile C-C reductive elimination to form the final product. Overall, the transformation constitutes a formal Pd^II-catalyzed intramolecular alkyne chlorocarbamoylation reaction.

Full text of DOI:10.1021/jacs.6b08925

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Article
Stereoselective Synthesis of Methylene Oxindoles via Palladium(II)-
Catalyzed Intramolecular Cross-Coupling of Carbamoyl Chlorides
Christine M. Le, Theresa Sperger, Rui Fu, Xiao Hou, Yong
Hwan Lim, Franziska Schoenebeck, and Mark Lautens
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b08925 • Publication Date (Web): 04 Oct 2016
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Stereoselective Synthesis of Methylene Oxindoles via Palladium(II)-
Catalyzed Intramolecular Cross-Coupling of Carbamoyl Chlorides
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Christine M. Le,† Theresa Sperger,‡ Rui Fu,† Xiao Hou,† Yong Hwan Lim,† Franziska Schoenebeck*,‡
and Mark Lautens*,†
†Davenport Research Laboratories, Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario,
Canada, M5S 3H6
†Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
ABSTRACT: We report a highly robust, general and stereoselective method for the synthesis of 3ꢀ(chloromethylene)oxindoles
from alkyneꢀtethered carbamoyl chlorides using PdCl2(PhCN)2 as the catalyst. The transformation involves a stereoꢀ and regioselecꢀ
tive chloropalladation of an internal alkyne to generate a nucleophilic vinyl PdII species, which then undergoes an intramolecular
crossꢀcoupling with a carbamoyl chloride. The reaction proceeds under mild conditions, is insensitive to the presence of moisture
and air, and is readily scalable. The products obtained from this reaction are formed with >95:5 Z:E selectivity in nearly all cases
and can be used to access biologicallyꢀrelevant oxindole cores. Through combined experimental and computational studies, we
provide insight into stereoꢀ and regioselectivity of the chloropalladation step, as well as the mechanism for the C−C bond forming
process. Calculations provide support for a mechanism involving oxidative addition into the carbamoyl chloride bond to generate a
high valent PdIV species, which then undergoes facile C−C reductive elimination to form the final product. Overall, the transforꢀ
mation constitutes a formal PdIIꢀcatalyzed intramolecular alkyne chlorocarbamoylation reaction.
importance of having steric bulk at the terminal alkynyl
position is exemplified by substrate 1b’ (R = Ph), which
INTRODUCTION
failed to undergo the desired chlorocarbamoylation reac-
tion with a range of Pdo catalysts commonly employed for
carbon−halogen reductive eliminations.5
Methylene oxindoles represent a privileged scaffold in
medicinal chemistry, as they are prevalent in a range of
pharmaceutical agents and biologically-active molecules
(Figure 1).1 In addition to their therapeutic value, they are
also useful intermediates in total synthesis, frequently
exploited in cycloaddition reactions to gain access to
spirocyclic oxindole natural products.2 Despite numerous
reports outlining the synthesis of methylene oxindoles,3
there are a limited number of highly stereoselective
methods to access 3-(halomethylene)oxindoles 1—an
attractive entry point to libraries of medicinally-relevant
molecules.4
In 2007, Li and co-workers disclosed a PdII-catalyzed
carbonylative annulation reaction with 2-alkynylanilines
using CuCl2 as a stoichiometric oxidant (Scheme 1a).4a
Depending on the substrate employed, the E:Z-
selectivities varied between 2.7:1 to >99:1. Complementary
to the work of Li and others,4b-f our group recently
demonstrated that alkyne-tethered carbamoyl chlorides
are also suitable precursors for the synthesis of 3-
(chloromethylene)oxindoles via a Pd0-catalyzed intramo-
lecular chlorocarbamoylation reaction (Scheme 1b).4g The
use of hindered alkynes, in combination with a bulky
phosphine ligand (PA-Ph = 1,3,5,7-Tetramethyl-6-phenyl-
2,4,8-trioxa-6-phosphaadamantane), was crucial for pro-
moting the final Csp2−Cl reductive elimination step and
enabling exclusive trans-selectivity in the cyclization. The
Figure 1. Potential entry to biologicallyꢀactive oxindoles via
functionalization of 3ꢀ(halomethylene)oxindoles 1
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effective for this transformation, giving full conversion of
Scheme 1. Methods for the synthesis of 3-
(halomethylene)oxindoles
1
2
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7
the starting material and providing Z-1b as the major
product (entries 1-2). The use of either PdCl2 or
PdBr2(PhCN)2 led to inferior results, which can be at-
tributed to their low solubility in toluene (entries 3-4).
Upon switching the solvent to THF, PdBr2(PhCN)2 could
promote the desired transformation, albeit with lower
1
yields and Z:E-selectivities (entry 5). By H NMR analysis,
8
9
we did not observe significant quantities of the brominat-
ed oxindole or quinolinone products for entry 5. Our
calculations reveal that the PdBr2(PhCN)2 catalyst can
undergo halide exchange with carbamoyl chloride 1b’ to
form a mixed PdClBr(PhCN) species, which slightly favors
chloropalladation over bromopalladation in the alkyne
insertion step (∆∆G‡ = 0.3 kcal/mol).16 As the reaction
progresses, an increasing amount of PdCl2(PhCN) is
formed, leading to mainly chloride incorporation in the
products.17 Although Pd(OAc)2 was a competent catalyst
for this reaction, lower yields, regio- and stereoselectivi-
ties were also observed in this case (entry 6). The use of
Na2PdCl4 led to poor results, demonstrating the benefit of
using neutral over anionic Pd catalysts (entry 7). Upon
further reaction optimization, we found that
PdCl2(PhCN)2 slightly outperformed PdCl2(MeCN)2 at
lower catalyst loadings and ambient reaction tempera-
tures, furnishing 1b in 82% yield (>95:5 Z:E) and quino-
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In an effort to increase the diversity of products ob-
tained—particularly scaffolds of high pharmaceutical
value—we were prompted to investigate alternative reac-
tion pathways, wherein the difficult Csp2−Cl reductive
elimination could be avoided. Cognizant of the well-
established reactivity of PdII alkyne complexes,6 we envis-
aged generating a nucleophilic vinyl PdII species in situ via
alkyne chloropalladation,7 which could subsequently
activate the carbamoyl chloride through a C−C bond
forming process (Scheme 1c). The proposed method offers
several advantages, as it would avoid the use of air-
sensitive Pd0 catalysts, toxic CO gas and/or oxidative
conditions. At the outset of this project we were con-
cerned about the ability to achieve high regio- and stere-
oselectivities for the chloropalladation step, which has
proven to be very challenging with unactivated, unsym-
metrical internal alkynes.8 Although the trapping of vinyl
or aryl PdII species with various unsaturated polar func-
tional groups (e.g. aldehydes, ketones, esters and nitriles)
has been previously reported,9-13 the analogous reaction
with carbamoyl chlorides remains a challenge.14-15 Despite
these aforementioned issues, we herein present our de-
velopment of an intramolecular PdII-catalyzed alkyne
chlorocarbamoylation reaction, for which the key step
proceeds through the intramolecular coupling of a car-
bamoyl chloride with an in situ-generated vinyl Pd spe-
cies.
1
linone 2b in 16% yield by H NMR (entry 8). It should be
highlighted that the reaction is complete within 8 h and is
unaffected by the presence of air and moisture, thus
greatly simplifying the experimental set-up.
Table 1. Reaction Optimizationa
RT = room temperature; N.Y. = NMR yield; 12ꢀCꢀ4 = 12ꢀ
RESULTS AND DISCUSSION
a
crownꢀ4. Conversions, NMR yields and isomeric ratios
determined by 1H NMR analysis of the crude reaction mixꢀ
ture using 1,3,5ꢀtrimethoxybenzene as internal standard.
To establish a protocol for the cyclization of 1b’, a
number of Pd catalysts, commonly employed in the chlo-
ropalladation of alkynes, were screened (Table 1). We
found that both PdCl2(MeCN)2 and PdCl2(PhCN)2 were
c
bWith THF as solvent. Reaction concentration = 0.2 M;
reaction conducted under air. dReaction conducted at 50 °C.
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In stark contrast to previous reports on the chloropal-
stereochemical assignments, X-ray crystal structures of
methylene oxindole Z-1v and quinolinone 2z were ob-
tained, while the isomeric ratios for all other examples
were determined by comparing analogous chemical shifts
in the 1H NMR spectra.16
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2
3
4
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7
8
ladation of alkynes, increasing the free chloride concen-
tration with various additives did not influence the Z:E-
selectivities (entries 9-11). In fact, attempts to increase the
chloride solubility in toluene by employing a combination
of LiCl/12-crown-4 or nBu4NCl led to a further decrease or
complete shut down in reactivity (entries 12-13). This
observation suggests that internal chloride delivery via
cis-chloropalladation predominates over external chloride
delivery via trans-chloropalladation under these reaction
conditions.18 As expected, in the absence of the Pd cata-
lyst no reaction occurs (entry 10). In general, the use of
highly coordinating solvents, phosphine or amine ligands
proved to be detrimental to the reaction, thus emphasiz-
ing the importance of having a coordinatively unsaturated
Pd catalyst.16 The stereoselectivity of the reaction is par-
ticularly noteworthy, as it is complementary to all other
Table 2. Substrate Scope
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previous
reports
on
the
synthesis
of
3-
(halomethylene)oxindoles.4 Additionally, the regioselec-
tivity of the chloropalladation step, represented by the
ratio of 1b:2b, is higher than one would expect for a rela-
tively unbiased diarylacetylene substrate.4a,19 Though it is
possible that the carbamoyl group can direct the chloro-
palladation step by coordinating to the Pd catalyst,20 ste-
ric effects likely have a greater influence on this addition
process (see Mechanistic and Computational Studies
section).
With the optimized conditions in hand, we evaluated
the substrate scope (Table 2). Overall, the reaction toler-
ates a diverse range of substituents at the distal alkynyl
position R1, including a biologically-relevant scaffold in 1j
and a 2-thienyl group in 1y. With the exception of 1i,
which possesses a sterically-hindered aryl ring, >95:5 Z:E
selectivity was observed in all cases. It should be men-
tioned that literature examples featuring highly selective
cis-chloropalladation pathways remain rare, thus illustrat-
ing the potential utility of this method.21 Substrates bear-
ing alkyl chains at the R1 position also demonstrated ex-
cellent reactivity and stereoselectivity in the cyclization;
however, full separation of the regioisomers by silica gel
chromatography could not be achieved in these cases.16
Polyhalogenated oxindoles 1m, 1p and 1w can be readily
accessed using this method owing to the stability of
Csp2−X bonds under PdII catalysis, thereby providing the
potential for further derivatization via cross-coupling. In
addition, different N-protecting groups and substitution
patterns on the aromatic backbone were accommodated
without any adverse effects on yield and selectivity. How-
ever, diminished reactivity was observed with 1s’, likely
due to competitive binding of the nitrile group with the
Pd catalyst. Notably, we were able to gain access to the
core scaffold of anticancer drug nintedanib using this
protocol (1q). Although not shown in Table 2, substrates
possessing heteroatoms in close proximity to the reacting
alkyne showed poor reactivity, possibly due to unproduc-
tive chelation with the catalyst. Furthermore, the reaction
can be conducted on gram-scale with carbamoyl chloride
1b’ using only 2 mol% [Pd]. To confirm our structural and
Unless otherwise stated, reactions were conducted on a
0.25 mmol scale under air with 5 mol% [Pd]. Combined
isolated yields for 1 are reported in the Table. Values in
brackets represent ratios of 1:2, which were determined by
a
1H NMR analysis of the crude reaction mixture. Reaction
conducted on gramꢀscale (2.90 mmol) with 2 mol% [Pd].
c
d
bReaction conducted at 50 °C. 72:28 Z:E ratio. 85% yield
brsm.
To demonstrate the synthetic utility of the products ob-
tained from this protocol, various transformations of 3-
(chloromethylene)oxindole Z-1b were conducted (Scheme
2a). Nucleophilic substitution reactions using p-anisidine
(1ba), morpholine (1bb) and benzyl mercaptan (1bc)
proceeded in high yields with excellent Z-selectivity in all
cases. The stereochemical assignments were confirmed by
selective 1D or 2D NOESY experiments and by X-ray crys-
tallographic analysis in the case of Z-1bc.16 The vinyl chlo-
ride moiety can also be fully reduced using Pd/C and H2
to give 3-substituted oxindole 1bd. Interestingly, subject-
ing Z-1b to standard Suzuki cross-coupling conditions22
using p-tolylboronic acid resulted in the formation of E-
1be with >95:5 selectivity, which is the opposite isomer we
expected (Scheme 2b). We reasoned that this may be due
to an in situ olefin isomerization to the more stable iso-
mer in either the starting material or product. However,
when we tested Z-1f under identical conditions using
phenylboronic acid instead, Z-1be was formed with >95:5
selectivity. This stereoinversion could be a result of a
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cis→trans vinyl PdII isomerization after oxidative addition
the regiomeric outcome, a nucleophilic vinyl Pd species is
into the C−Cl bond of Z-1,23 or a mechanism involving
carbopalladation of the olefin in Z-1 by an ArPdIIX species,
followed by stereospecific syn-β-Cl elimination (See Sec-
tion 5.2 in Supporting Information). At this stage, further
studies on the mechanism of this cross-coupling process
are warranted. Nevertheless, we have shown that both 3-
(diarylmethyelene)oxindole isomers can be readily ac-
cessed by using the appropriate coupling partners.
produced (IA or IB), which can subsequently react with
the carbamoyl chloride in an intramolecular fashion to
give methylene oxindole 1b or quinolinone 2b.
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Two possible mechanisms (paths A or B) can be envis-
aged for this C−C bond forming step. Analogous to the
reactivity of aldehydes and ketones with nucleophilic PdII
species, carbopalladation of the carbonyl functionality
(path A) leads to Pd alkoxide species IIA,9-10 which can
then undergo β-Cl elimination to form the final prod-
uct.7,24 An alternative pathway involves oxidative addition
into the carbamoyl chloride bond (path B) to form a high
valent PdIV species (IIB), which upon C−C reductive elim-
ination furnishes the product and regenerates the diva-
lent Pd catalyst.25 To gain deeper insight into the mecha-
nism of this transformation, as well as the regio- and
stereoselectivities observed, we describe combined exper-
imental and computational studies in the following sec-
tions.
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Scheme
2.
Synthetic
transformations
of
3-
(chloromethylene)oxindoles
Scheme 3. Proposed mechanism
MECHANISTIC AND COMPUTATIONAL STUDIES
Proposed Mechanism: A general catalytic cycle for this
transformation begins with complexation of 1b’ with the
electrophilic PdII catalyst, followed by chloropalladation
of the coordinated alkyne (Scheme 3). Ultimately, the
regioselectivity (α vs. β) and stereoselectivity (cis vs.
trans) of this insertion process is what determines the
final product distribution. In the α-addition pathway, Pd
ends up in the α position of the alkyne, proximal to the
carbamoyl chloride. Under all circumstances, α-cis-
addition is the predominant pathway, leading to high
selectivities for Z-1b. In the β-addition pathway, chloro-
palladation occurs with the opposite regioselectivity, in
which Pd ends up distal to the carbamoyl chloride. While
this step can also occur with either cis- or trans-
selectivity, only one intermediate (IB) is able to cyclize,
while the other species (IC) leads to a potentially unpro-
ductive pathway. We cannot rule out the possibility of
vinyl PdII species IC undergoing a cis→trans isomeriza-
tion to form IB, which can then cyclize to furnish product
2b. The stereoisomerization of similar vinyl PdII complex-
es is well-documented in the literature.23b-j Regardless of
Stereoselectivity of Chloropalladation Step: It is cer-
tainly possible that the formation of E-1b could arise from
an in situ Z→E isomerization of Z-1b. To assess the feasi-
bility of this process, the reaction was first conducted at
80 °C instead of RT, which led to significant amounts of
E-1b being formed after 18 h (76:24 Z:E) (Scheme 4a).
When an isolated sample of 1b (96:4 Z:E) was subjected to
the same reaction conditions, a similar isomeric ratio was
obtained (78:22 Z:E) (Scheme 4b). However, in the ab-
sence of the electrophilic PdII catalyst, the extent of this
isomerization was minimal (93:7 Z:E) (Scheme 4c). Over-
all, these studies suggest that while α-trans-
chloropalladation pathways may be occurring in concert
with α-cis-chloropalladation, E-1b can also be formed
through a PdII-mediated isomerization of Z-1b, which
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Journal of the American Chemical Society
with the carbamoyl group, as well as the sole coordination
occurs more readily at elevated temperatures.26,27 Regard-
of PdII to carbamoyl group, were found to be energetically
unfavorable, i.e. led to energetically less stable species.
For the catalyst PdCl2(PhCN)2 to be able to coordinate to
the alkyne, one of the benzonitrile ligands needs to disso-
ciate to render mono-acetonitrile PdCl2(PhCN) as the
catalytically active species. After coordination of the cata-
lyst to the alkyne, chloropalladation (i.e. alkyne insertion)
can occur with α- or β-selectivity via an internal, concert-
ed transition state. Calculations suggest that while α-
addition is kinetically favored by ∆∆G‡ = 1.6 kcal/mol,
both α- and β-chloropalladation are fully reversible and α-
addition is favored due to a slight thermodynamic prefer-
ence of ∆G = 0.5 kcal/mol. Since β-addition results in the
formation IC, which cannot undergo direct intramolecu-
lar cross-coupling, the reaction can reverse and undergo
the favorable α-addition.
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less of the exact mechanism for the formation of the E-
isomer, it should be reiterated that only very small
amounts of this product (<5%) are observed under the
standard conditions.
Scheme 4. Isomerization studies
Ph
Ph
Cl
PdCl2(PhCN)2
(10 mol%)
Cl
9
Ph
O
O
+
a)
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O
PhMe (0.1 M)
80 °C, 18 h
N
Cl
N
N
Bn
Bn
Bn
1b'
1b
2b
74% N.Y.
11% N.Y.
76:24 Z:E
Ph
Cl
Ph
PdCl2(PhCN)2
(10 mol%)
Cl
O
Ph
O
Cl
+
b)
O
PhMe (0.1 M)
80 °C, 18 h
N
N
N
Bn
Bn
Bn
1b
1b
E-
1b
Zꢀ
Mechanism for Intramolecular Activation of Car-
bamoyl Chloride: Two mechanistic scenarios could be
envisioned for the C−C bond forming event (Scheme 3).
Carbopalladation (i.e. 1,2-addition) of the carbamoyl
group would result in the formation of a PdII alkoxide that
could then undergo β-Cl elimination to form 1b (path A).
Alternatively, oxidative addition of PdII to the C−Cl bond
of the carbamoyl chloride would form a PdIV intermediate
and subsequent C−C bond formation could take place via
reductive elimination (path B). Both mechanistic path-
ways were studied by means of computations, which indi-
cate that the formation of PdIV via oxidative addition
(path B) is favored over 1,2-addition by ∆∆G‡ = 11.0
kcal/mol.
96:4
78:22
Z:E
Z:E
Ph
Cl
Ph
Cl
Ph
O
Cl
no Pd
+
c)
O
O
PhMe (0.1 M)
80 °C, 18 h
N
N
N
Bn
Bn
1b
Bn
1b
1b
E-
Z-
96:4
93:7
Z:E
Z:E
Regioselectivity of Chloropalladation Step: While we
anticipated that the carbamoyl moiety may act as a direct-
ing group in steering regioselectivity (α- vs. β-addition),
calculations at the CPCM (toluene) M06L/def2-
TZVP//B3LYP/6-31G(d) level of theory28,29 indicate that
the most favorable interaction of the PdII catalyst is its
coordination to the alkyne. All additional interactions
Scheme 5. Calculated selectivities of cis-chloropalladation: α- (right) versus β-cis-addition (left).a
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aGibbs free energies (in kcal/mol, relative to isolated reactants, PdCl2(PhCN)2 and substrate) at the CPCM (toluene) M06L/def2ꢀ
1
TZVP//B3LYP/6ꢀ31G(d)(LANL2DZ)
level
of
theory.
2
3
4
5
6
7
8
9
Both oxidative addition and reductive elimination display
facile activation barriers of ∆G‡ = 13.5 and 14.7 kcal/mol,
respectively. Due to the necessity of an empty coordina-
tion site at the PdII center, both oxidative addition and 1,2-
addition occur via a mono-acetonitrile coordinated transi-
tion state. In contrast, mono- and bis-acetonitrile transi-
tion states were considered for reductive elimination,
which demonstrated the monoligated transition state to
be favored by ∆∆G‡ = 15.3 kcal/mol.
Side product 2b could arise from initial β-trans-
chloropalladation (red) to form intermediate IB.30 Analo-
gous to the formation of the five-membered ring in 1b,
two mechanistic pathways for the formation of the six-
membered ring in 2b are plausible. C−C bond formation
can occur via either PdII or PdII/PdIV pathways. Similar to
1b, an oxidative addition/reductive elimination sequence
involving the formation of a PdIV intermediate was shown
to be favored over the alternative 1,2-addition/β-Cl elimi-
nation by ∆∆G‡ = 9.2 kcal/mol. While oxidative addition
to form the 7-membered PdIV intermediate (leading to 2b)
displays a larger activation barrier compared to the analo-
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Full Energetic Pathway: Full energetic pathways were
calculated
at
CPCM
(toluene)
M06L/def2-
TZVP//B3LYP/6-31G(d) level of theory using Gaussian 09,
revision D.01 (Scheme 6).28,29 Both Z-1b and E-1b form via
analogous routes from initial cis (blue) or trans (green) α-
chloropalladation, respectively. Subsequent C−C bond
formation is predicted to occur via an oxidative addi-
tion/reductive elimination sequence involving the for-
mation of PdIV intermediate IIB. Alternative pathways
involving 1,2-addition/β-Cl elimination were found ener-
getically disfavored by ∆∆G‡ = 11.0 and 12.1 kcal/mol, for Z-
and E-1b respectively.
gous formation of six-membered IIB (leading to 1b; ∆G‡
OA
= 18.2 and 13.5 kcal/mol, respectively), the subsequent
reductive elimination to form the 6-membered ring in 2b
is much more facile (∆G‡ = 3.0 kcal/mol) than for the
RE
corresponding formation of the 5-membered ring in 1b
(∆G‡ = 14.7 kcal/mol). Overall, calculations indicate
RE
oxidative addition (TSOA) to be the reactivity limiting step
and C−C bond formation to occur via a PdII/PdIV pathway
rather than a redox-neutral PdII-catalyzed cycle.
Scheme 6. Full energetic pathways for the formation of Z- and E-1b as well as side product 2b.a
aGibbs free energies (in kcal/mol, relative to the isolated reactants, PdCl2(PhCN)2 and substrate) calculated at the CPCM (toluene)
M06L/def2ꢀTZVP//B3LYP/6ꢀ31G(d) level of theory.
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September 22, 2005. (d) Grandinetti, C. A.; Goldspiel, B. R. Pharmaꢀ
CONCLUSION
cotherapy 2007, 27, 1125. (e) Hilberg, F.; Roth, G. J.; Krssak, M.;
Kautschitsch, S.; Sommergruber, W.; TontschꢀGrunt, U.; GarinꢀChesa, P.;
Bader, G.; Zoephel, A.; Quant, J.; Heckel, A.; Rettig, W. J. Cancer Res.
2008, 68, 4774.
(2) (a) Trost, B. M.; Cramer, N.; Bernsmann, H. J. Am. Chem. Soc. 2007,
129, 3086. (b) Trost, B. M.; Cramer, N.; Silverman, S. M. J. Am. Chem.
Soc. 2007, 129, 12396. (c) Lin, S.; Danishefsky, S. J. Angew. Chem. Int.
Ed. 2011, 40, 1967.
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In conclusion, we have developed a highly stereoselec-
tive method for the synthesis of 3-(chloromethylene)
oxindoles that takes advantage of an in situ-generated
vinyl PdII species. Excellent regio- and stereoselectivities
are observed for the alkyne chloropalladation step, which
is particularly rare for relatively unbiased, internal al-
kynes. High regioselectivities are achieved by virtue of the
reversibility of the cis-chloropalladation step. We demon-
strate that the vinyl chloride functionality in the products
can be functionalized through a variety of transfor-
mations, thus providing a divergent route to access a
library of medicinally-relevant scaffolds. Our calculations
support a mechanism involving a PdII/IV cycle, wherein
C−C bond reductive elimination is the driving force for
the reaction. Overall, carbamoyl chlorides are extremely
versatile intermediates in organic synthesis and their
application in Pd-catalyzed cross-couplings can provide
efficient entry to a range of nitrogen-containing heterocy-
cles.
(3) Selected examples: (a) Fielding, M. R.; Grigg, R.; Urch, C. J. Chem.
Commun. 2000, 2239. (b) Gabriele, B.; Salerno, G.; Veltri, L.; Costa, M.;
Massera, C. Eur. J. Org. Chem. 2001, 4607. (c) Teichert, A.; Jantos, K.;
Harms, K.; Studer, A. Org. Lett. 2004, 6, 3477. (d) Cheung, W. S.; Patch,
R. J.; Player, M. R. J. Org. Chem. 2005, 70, 3741. (e) Kamijo, S.; Sasaki,
Y.; Kanazawa, C.; Schüßeler, T.; Yamamoto, Y. Angew. Chem. Int. Ed.
2005, 44, 7718. (f) Shintani, R..; Yamagami, T.; Hayashi, T. Org. Lett.
2006, 8, 4799. (g) Miura, T.; Takahashi, Y.; Murakami, M. Org. Lett.
2007, 9, 5075. (h) Yang, T.ꢀM. Liu, G. J. Comb. Chem. 2007, 9, 86. (i)
Pinto, A.; Neuville, L.; Zhu, J. Angew. Chem. Int. Ed. 2007, 46, 3291. (j)
Park, J. H.; Kim, E.; Chung, Y. K. Org. Lett. 2008, 10, 4719. (k) Miura,
T.; Toyoshima, T.; Takahashi, Y.; Murakami, M. Org. Lett. 2009, 11,
2141.
(4) (a) Tang, S.; Yu, Q.ꢀF.; Peng, P.; Li, J.ꢀH.; Zhong, P.; Tang, R.ꢀY.
Org. Lett. 2007, 9, 3413. (b) Pedras, M. S. C.; Soresen, J. L.; Okanga, F.
I.; Zaharia, I. L. Bioorg. Med. Chem. 1999, 9, 3015. (c) Cantagrel, G.; de
CarnéꢀCarnavalet, B.; Meyer, C.; Cossy, J. Org. Lett. 2009, 11, 4262. (d)
Beccalli, E. M.; Marchesini, A. Tetrahedron 1994, 50, 12697. (e) Beccalli,
E. M.; Marchesini, A. Tetrahedron 1995, 51, 2353. (f) Sassatelli, M.;
Debiton, E.; Aboab, B.; Prudhomme, M.; Moreau, P. Eur. J. Med. Chem.
2006, 41, 709. (g) Le, C. M.; Hou, X.; Sperger, T.; Schoenebeck, F.;
Lautens, M. Angew. Chem. Int. Ed. 2015, 54, 15897.
(5) For reviews on C−X reductive elimination, see: (a) Petrone, D. A.; Le,
C. M.; Newman, S. G.; Lautens, M. Pd0ꢀCatalyzed Carboiodination: Early
Developments and Recent Advances. In New Trends in CrossꢀCoupling:
Theory and Application; Colacot, T. J., Ed.; RSC: Cambridge, 2015; pp
276. (b) Jiang, X.; Liu, H.; Gu, Z. Asian J. Org. Chem. 2012, 1, 16. (c)
Chen, C.; Tong, X. Org. Chem. Front. 2014, 1, 439. (d) Hartwig, J. F.
Inorg. Chem. 2007, 46, 1936. (e) Petrone, D. A.; Ye, J.; Lautens, M.
Chem. Rev. 2016, 116, 8003. For selected examples of Csp2−X reductive
elimination from PdII, see: (f) Newman, S. G.; Lautens, M. J. Am. Chem.
Soc. 2010, 132, 11416–11417. (g) Quesnel, J. S.; Arndtsen, B. A. J. Am.
Chem. Soc. 2013, 135, 16841. (h) Shen, X.; Hyde, A. M.; Buchwald, S. L.
J. Am. Chem. Soc. 2010, 132, 14076. (i) Roy, A. H.; Hartwig, J. F. J. Am.
Chem. Soc. 2001, 123, 1232. (j) Le, C. M.; Menzies, P. J. C.; Petrone, D.
A.; Lautens, M. Angew. Chem. Int. Ed. 2015, 54, 254. Also see ref 4g.
(6) (a) Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104, 2285. (b) Tsuji, J.
Pd(0)ꢀ and Pd(II)ꢀCatalyzed Reactions of Alkynes and Benzynes. In
Palladium Reagents and Catalysts: New Perspectives for the 21st Century;
Tsuji, J., Ed.; John Wiley & Sons: West Sussex, 2005; pp 565ꢀ599.
(7) (a) Lu, X. PalladiumꢀCatalyzed Reaction via Halopalladation of πꢀ
Compounds. In Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E.ꢀI, Ed.; John Wiley & Sons: New York, 2002; pp
2267ꢀ2287 and references therein. (b) Ogawa, A. PalladiumꢀCatalyzed
SynꢀAddition Reactions of X−Pd Bonds (X=Group 15, 16, and 17 Eleꢀ
ments). In Handbook of Organopalladium Chemistry for Organic Syntheꢀ
sis; Negishi, E.ꢀI., Ed.; John Wiley & Sons: New York, 2002; pp 2841ꢀ
2849 and references therein. (c) Lu, X.; Zhu, G.; Wang, Z. Synlett 1998,
115 and references therein.
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ASSOCIATED CONTENT
Supporting Information. Experimental procedures, spectral data
for all new compounds and crystallographic data (CIF). This
material is available free of charge via the Internet at
http://pubs.acs.org.”
AUTHOR INFORMATION
Corresponding Authors
*franziska.schoenebeck@rwthꢀaachen.de
*mlautens@chem.utoronto.ca
Present Addresses
†Department of Chemistry, University of Toronto, Davenport
Laboratories, 80 St. George St., Toronto M5S 3H6, Canada
‡Institute of Organic Chemistry, RWTH Aachen University,
Landoltweg 1, 52074 Aachen, Germany
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank Alphora Inc., the Natural Sciences and Engineering
Research Council of Canada (NSERC) and the University of
Toronto (U of T) for financial support. M. L. (O.C.) thanks Canaꢀ
da Council for the Arts for a Killam Fellowship. C.M.L. thanks
NSERC for a postgraduate scholarship. We thank Renhe (Tony)
Li for the synthesis of starting materials, Dr. Alan J. Lough (U of
T) for obtaining the crystal structures of Zꢀ1v, 2z, and Z-1bc, and
Dr. Ivan Franzoni for helpful discussions. T.S. and F.S. thank the
RWTH Aachen, MIWF NRW and the Evonik Foundation (docꢀ
toral scholarship to T.S.) for funding.
(8) Selected examples with electronically or sterically biased alkynes: (a)
Ma, S.; Lu, X. J. Chem. Soc., Chem. Comun. 1990, 733. (b) Ma, S.; Lu, X.
J. Org. Chem. 1993, 58, 1245. (c) Huang, X.; Sun, A. J. Org. Chem. 2000,
65, 6561. (d) Huang, J.ꢀM.; Dong, Y.; Wang, X.ꢀX.; Luo, H.ꢀC. Chem.
Commun. 2010, 46, 1035. (e) Chen, X.; Kong, W.; Cai, H.; Kong, L.; Zhu,
G. Chem. Commun. 2011, 47, 2164. (f) Chen, D.; Cao, Y.; Yuan, Z.; Cai,
H.; Zheng, R.; Kong, L.; Zhu, G. J. Org. Chem. 2011, 76, 4071. (g) Cai,
H.; Yuan, Z.; Zhub, W.; Zhu, G. Chem. Commun. 2011, 47, 8682. (h) Lu,
Z.; Kong, W.; Yuan, Z.; Zhao, X.; Zhu, G. J. Org. Chem. 2011, 76, 8524.
(i) Peng, H.; Liu, G. Org. Lett. 2011, 13, 772.
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(10) Select examples with ketones: (a) Quan, L. G.; Gevorgyan, V.;
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(12) Seminal report with nitriles: Larock, R. C.; Tian, Q.; Pletnev, A. A.
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(24) Zhu, G.; Lu, X. Organometallics 1995, 14, 4899.
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oxidative addition into a carbamoyl chloride, see: (a) Li, X.; Pan, J.; Song,
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(16) See Supporting Information for more details.
(17) Subjecting 1b’ to 0.5 equiv of PdBr2(PhCN)2 in THF (0.1 M) at 50 °C
for 18 h provided 1b (X=Cl) in 68% yield by NMR. Although clean
formation of brominated oxindole or quinolinone byproducts were not
observed by crude 1H NMR analysis, brominated species corresponding to
a direct halogen exchange product were detected by HRMS (DART)
(Calc’d for [C22H17BrNO]+ [M+H]+ 390.04935 found 390.04845).
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(27) We cannot rule out the possibility of isomerization occurring after the
αꢀcisꢀchloropalladation step via a zwitterionic vinyl PdII species. See refs
23bꢀj for examples.
(28) Calculations at the CPCM (toluene) M06L/def2ꢀTZVP//B3LYP/6ꢀ
31G(d) level of theory were conducted using Gaussian 09, revision D.01:
M. J. Frisch, et al., (see Supporting Information for full reference).
(29) For appropriateness of method, see: (a) Sperger, T.; Sanhueza, I. A.;
Kalvet, I.; Schoenebeck, F. Chem. Rev. 2015, 115, 9532. Also see ref 4g.
(30) transꢀChloropalladation was excluded from the computational invesꢀ
tigation, since it occurs via an external attack of chloride and as such
involves an anionic transition state. Due to the challenging nature of
describing charged species via DFT, a direct comparison of anionic (transꢀ
chloropalladation) and neutral (cisꢀchloropalladation) pathways is probꢀ
lematic and was thus not attempted. For a discussion of this challenge,
see: (a) Sperger, T.; Fisher, H. C.; Schoenebeck, F. WIREs Comput. Mol.
Sci. 2016, 6, 226. (b) Tsang, A. S. K.; Sanhueza, I. A.; Schoenebeck, F.
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tallics 2007, 26, 550.
(22) Conditions for Suzuki crossꢀcoupling adapted from: Li, P.; Lü, B.;
Fu, C.; Ma, S. Org. Biomol. Chem. 2013, 11, 98.
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