Domino carbopalladation-cross-coupling for the synthesis of 3,3-disubstituted oxindoles

Article abstract of DOI:10.1021/ol301539p

This study examines a domino carbopalladation-cross-coupling reaction for the formation of valuable oxindole scaffolds. Furthermore, the reaction sequence forges vicinal stereocenters in a stereospecific manner through the formation of two carbon-carbon bonds and, thereby, rapidly generates complexity. The reaction gives high yields for a variety of acrylamide substrates, and various organoboranes have also been evaluated for the cross-coupling. This work offers insight into the relative rates determining a successful carbopalladation-cross- coupling reaction and how to favor the desired reaction pathway.

Full text of DOI:10.1021/ol301539p

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Domino CarbopalladationÀCross-Coupling
for the Synthesis of 3,3-Disubstituted
Oxindoles
Brinton Seashore-Ludlow† and Peter Somfai*,†,‡
Chemical Science and Engineering, Organic Chemistry, KTH Royal Institute of Technology,
100 44 Stockholm, Sweden, and Institute of Technology, University of Tartu, Nooruse 1,
50411 Tartu, Estonia
somfai@kth.se
Received June 4, 2012
ABSTRACT
This study examines a domino carbopalladationÀcross-coupling reaction for the formation of valuable oxindole scaffolds. Furthermore, the
reaction sequence forges vicinal stereocenters in a stereospecific manner through the formation of two carbonÀcarbon bonds and, thereby,
rapidly generates complexity. The reaction gives high yields for a variety of acrylamide substrates, and various organoboranes have also been
evaluated for the cross-coupling. This work offers insight into the relative rates determining a successful carbopalladationÀcross-coupling
reaction and how to favor the desired reaction pathway.
An important aspect of organic synthesis is the devel-
opment of efficient and practical reaction sequences.1 The
overall efficiency of a particular method or synthesis can
be evaluated based on a variety of criteria. These include
the yields and selectivities of individual reactions, as well as
the total atom, step, and protecting group efficiencies of
the entire route. One strategy to address efficiency in organic
synthesis is the use of domino processes to forge multiple
bonds in a single synthetic operation, since this leads to a net
reduction of the total number of manipulations necessary to
access a desired skeleton. Consequently, domino reactions
have received much attention in recent years.2
Transition-metal-mediated domino processes constitute
an important class of domino sequences.3 Expansions of
traditional cross-coupling methods, these reactions form
multiple bonds in a single step and allow for the synthesis
of complex scaffolds from relatively simple starting materials.
We have recently developed a domino carbopalladationÀ
carbonylation reaction for substrates possessing pendant
β-hydrogens.4 In this sequence the typical termination
event of the Heck reaction, β-hydride elimination, is
circumvented and, instead, a carbonylation event ensues.
One notable advantage of this sequence is that syn carbo-
palladation of the alkene moiety enforces the diastereo-
specific synthesis of vicinal stereocenters. We became
interested in capitalizing on this diastereocontrol for
domino carbopalladation sequences with other types of
termination events, such as cross-coupling (Scheme 1).
In such a sequence syn carbopalladation dictates the relative
† KTH Royal Institute of Technology.
‡ University of Tartu.
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T.; Baran, P. S.; Hoffmann, R. W. Chem. Soc. Rev. 2009, 38, 3010–3021.
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2173. (d) Pellissier, H. Tetrahedron 2006, 62, 1619–1665.
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r
10.1021/ol301539p
XXXX American Chemical Society

stereochemistry of the newly formed stereocenters and the
σ-alkylpalladium intermediate is captured in a cross-coupling
event instead of undergoing β-hydride elimination.
contains the molecular architecture we would like to
access, a quaternary stereocenter with an adjacent tertiary
stereocenter (Scheme 2).9 Similar synthetic scaffolds have
also been found to suppress the p53-MDM2 proteinÀ
protein interaction, which is important for tumor sup-
pression.10 Moreover, the natural products such as
perophoramidine11 (2) and the communesins12 (e.g., com-
munesin A (3)) with vicinally disposed quaternary centers
in their core structures have also inspired our synthetic
efforts.13 We envisioned that the proposed reaction
sequence, namely domino carbopalladationÀcross-coupling,
could provide a valuable synthetic tool for the stereo-
specific construction of the crowded scaffolds found in
these three natural products.
Scheme 1. Proposed Domino CarbopalladationÀCross-
Coupling Sequence
Domino reactions where carbopalladation is followed
by coupling with an organoborane have been explored
with considerable success in the literature and have often
been referred to as domino HeckÀSuzuki reactions.5
However, there are few examples of this type of domino
process in which the inherent diastereospecificity of syn
carbopalladation is exploited for the construction of
two vicinally disposed stereocenters.6 Therefore, we opted
to explore a domino carbopalladationÀcross-coupling
sequence aimed at accessing 3,3-disubsituted oxindoles
bearing a vicinal tertiary center. Oxindoles bearing a
quaternary center at C3 are found in a variety of naturally
occurring alkaloids and potential pharmaceutical lead
compounds and, furthermore, have been found to possess
significant biological activity.7,8 For example, spirotry-
prostatin B (1) has pronounced biological activity and
Scheme 2. Some Natural Products Containing the 3,3-Disub-
stituted Oxindole Scaffold
Initially, we began our investigation with amide 4a, in
which β-hydride elimination of alkylpalladium intermedi-
ate 6 is precluded. The desired reaction sequence would
yield product 7a, which is equipped with a vinyl moiety for
further functionalization and elaboration. First, we exam-
ined vinyl trifluoroborate 5a, since this has been shown to
be an air-stable organoborane that is competent in a
variety of Suzuki cross-couplings.14 Subjecting amide 4a
to conditions at 70 °C yielded none of the desired oxindole
7a (Table 1, entry 1).15 By simply warming the reaction to
90 °C, the desired domino product could be isolated in
79% yield (entry 2). Switching to Pd(PPh3)4 gave a slightly
higher yield in both toluene and dioxane (entries 3 and 4).
By decreasing the catalyst loading the desired product
could be obtained in 90% yield when using Pd(PPh3)4
(entry 6).16
(5) (a) Yanada, R.; Obika, S.; Inokuma, T.; Yanada, K.; Yamashita,
M.; Ohta, S.; Takemoto, Y. J. Org. Chem. 2005, 70, 6972–6975. (b) Oh,
C. H.; Lim, Y. M. Tetrahedron Lett. 2003, 44, 267–270. (c) Cheung,
W. S.; Patch, R. J.; Player, M. R. J. Org. Chem. 2005, 70, 3741–3744.
(d) Yu, H.; Richey, R. N.; Carson, M. W.; Coghlan, M. J. Org. Lett.
2006, 8, 1685–1688. (e) Guo, L.-N.; Duan, X.-H.; Hu, J.; Bi, H.-P.; Liu,
X.-Y.; Liang, Y.-M. Eur. J. Org. Chem. 2008, 1418–1425. (f) Couty, S.;
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Liegault, B.; Meyer, C.; Cossy, J. Org. Lett. 2004, 6, 2511–2514.
(g) Arthuis, M.; Pontikis, R.; Florent, J.-C. Tetrahedron Lett. 2007,
48, 6397–6400. (h) Marchal, E.; Cupif, J.-F.; Uriac, P.; van de Weghe, P.
Tetrahedron Lett. 2008, 49, 3713–3715. (i) Grigg, R.; Sansano, J. M.;
Santhakumar, V.; Sridharan, V.; Thangavelanthum, R.; Thornton-Pett,
M.; Wilson, D. Tetrahedron 1997, 53, 11803–11826.
(6) Grigg, R.; Sansano, J. M.; Santhakumar, V.; Sridharan, V.;
Thangavelanthum, R.; Thornton-Pett, M.; Wilson, D. Tetrahedron
1997, 53, 11803–11826.
(7) (a) Trost, B. M.; Brennan, M. K. Synthesis 2009, 3003–3025.
(b) Klein, J. E. M. N.; Taylor, R. J. K. Eur. J. Org. Chem. 2011, 6821–
6841. (c) Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46,
8748–8758. (d) Marti, M.; Carreira, E. M. Eur. J. Org. Chem. 2003,
2209–2219. (e) Zhou, F.; Liu, Y.-L.; Zhou, J. Adv. Synth. Catal. 2010,
352, 1381–1407.
With optimized conditions in hand we then explored the
influenceof theorganoborane on the domino reaction, and
(11) For a recent synthesis, see: Wu, H.; Xue, F.; Xiao, X.; Qin, Y.
J. Am. Chem. Soc. 2010, 132, 14052–14054.
(12) For a recent synthesis, see: Zuo, Z.; Ma, D. Angew. Chem., Int.
(8) Peddibhotla, S. Curr. Bioact. Compd. 2009, 5, 20–38.
(9) Cui, C.-B.; Kakeya, H.; Osada, H. Tetrahedron 1996, 52, 12651–
12666.
Ed. 2011, 50, 12008–12011.
(13) For a related domino approach to these compounds, see: Evans,
M. A.; Sacher, J. R.; Weinreb, S. M. Tetrahedron 2009, 65, 6712–6719.
(14) For example, see: Molander, G. A.; Rivero, M. R. Org. Lett.
2002, 4, 107–109.
(15) The relative stereochemistry is assigned in analogy to our
previous work, as the reactions are expected to proceed through similar
σ-alkylpalladium intermediates. In that case, syn carbopalladation of
the double bond was confirmed. For further detail, see ref 4.
(16) In entries 3 and 4 in Table 1 there was complete consumption of
the starting material, but the corresponding yields could not be isolated.
We reasoned that there could be an association of the product with the
catalyst and thus tried decreasing the catalyst loading to increase the
yield.
(10) (a) Shangary, S.; Qin, D.; McEachern, D.; Liu, M.; Miller, R. S.;
Qiu, S.; Nikolovska-Coleska, Z.; Ding, K.; Wang, G.; Chen, J.; Bernard,
D.; Zhang, J.; Lu, Y.; Gu, Q.; Shah, R. B.; Pienta, K. J.; Ling, X.; Kang,
S.; Guo, M.; Sun, Y.; Yang, D.; Wang, S. Proc. Natl. Acad. Sci. U.S.A.
2008, 105, 3933–3938. (b) Antonchick, A. P.; Gerding-Reimers, C.;
Catarinella, M.; Schurmann, M.; Preut, H.; Ziegler, S.; Rauh, D.;
Waldmann, H. Nat. Chem. 2010, 2, 735–740. (c) Ding, K.; Lu, Y.;
Nikolovska-Coleska, Z.; Qiu, S.; Ding, Y.; Gao, W.; Stuckey, J.;
Krajewski, K.; Roller, P. P.; Tomita, Y.; Parrish, D. A.; Deschamps,
J. R.; Wang, S. J. Am. Chem. Soc. 2005, 127, 10130–10131. (d) Ding, K.;
Lu, Y.; Nikolovska-Coleska, Z.; Wang, G.; Qiu, S.; Shangary, S.; Gao, W.;
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2006, 49, 3432–3435.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Optimization of Domino CarbopalladationÀ
Cross-Coupling Reaction of Amide 4a with Trifluoroborate
Salt 5aa
Table 3. Domino CarbopalladationÀCross-Coupling of Acryl-
amides 4aÀha
Pd
yield
(%)b
entry
Pd source
(mol %)
1c
2
PdCl2dppf
PdCl2dppf
Pd(PPh3)4
Pd(PPh3)4
PdCl2dppf
Pd(PPh3)4
10
10
10
10
2
0
79
84
83
70
90
3
4d
5
6
2
a Reactions run on a 0.08 mmol scale of 4a (1equiv),withPd(2À10 mol %
as in the Table), BF3K salt 5a (2 equiv), Cs2CO3 (3 equiv), dioxane/H2O
(10:1, 0.07 M) at 90 °C. b Isolated yield. c Reaction run at 70 °C. d Toluene was
used instead of dioxane.
Table 2. CarbopalladationÀCross-Coupling of Substrate 4a
with Various Organoboranesa
a Reactions were run on a 0.08 mmol scale of amide 4a (1 equiv) with
organoborane 5aÀe (2 equiv), Pd(PPh3)4 (2 mol %), Cs2CO3 (3 equiv),
in dioxane/water (10:1, 0.07 M). b Isolated yield.
a Reactions were run on a 0.13 mmol scale of amide 4 (1 equiv) with
organoborane 5 (2 equiv), Pd(PPh3)4 (2 mol %), Cs2CO3 (3 equiv), in
dioxane/water (10:1, 0.07 M). b Isolated yield. c 1.1 equiv of organoborane 5a
was used. d 5 mol % Pd(PPh3)4 e 50 μL of H2O, 5 mol % Pd(PPh3)4
f 3.0 equiv of organoborane 5e, 5 mol % Pd(PPh3)4, 50 μL of H2O, and
3.5 equiv of Cs2CO3 were used. g 3.5 equiv of organoborane 5b used. h NMR
yield based on the addition of 1-methoxynaphthalene as an internal standard.
several other organoboranes 5bÀe were evaluated in the
reaction sequence. The vinyl boronic ester 5b gave similar
results to the vinyl trifluoroborate salt5a(Table 2, entries 1
and 2). For phenyl organoboranes the boronic ester 5e
gave the highest yield and the boronic acid 5d gave the
lowest yield, with trifluoroborate salt5cin between (entries
3À5). This is a somewhat surprising trend, as the trifluo-
roborate salts are generally perceived as more reactive, and
trifluoroborate5c and boronic acid 5d are both expected to
transmetalate via the boronic acid.17 However, the three
organoboranes 5cÀe have different rates of hydrolysis and
protodeboronation under the reaction conditions, which
likely explains the observed results.18
(17) (a) Carrow, B. P.; Hartwig, J. F. J. Am. Chem. Soc. 2011, 133, 2116–
2119. (b) Butters, M.; Harvey, J. N.; Jover, J.; Lennox, A. J. J.; Lloyd-Jones,
G. C.; Murray, P. M. Angew. Chem., Int. Ed. 2010, 49, 5156–5160.
Org. Lett., Vol. XX, No. XX, XXXX
C

Next a variety of acrylamides 4bÀh were examined to
determine the scope of the domino reaction. Substituting
the aryl ring with electron-donating or -withdrawing
groups was well tolerated, giving good yields for both
products 7c and 7d (Table 3, entries 3,4). For para-bromo
substrate 4d a mixture of products was observed when
using 2 equiv of organoborane 5a. However, by decreasing
the amount of organoborane to 1.1 equiv, the desired
product 7e could be obtained in 75% yield as a single
product (entry 5). The lower yield can be attributed to
protodeboronation of organoborane 5a during the course
of the reaction, resulting in incomplete consumption of the
starting material. Changing to para-methoxy benzyl pro-
tected amide 4e gave the product 7f in good yield (entry 6).
However, when using the unprotected amide 4f, desired
domino product 7g was isolated in a poor yield (entry 7).
The major product of the reaction was noncyclized, cross-
coupled product 8, which was isolated in 62% yield (Figure 1).
Thisindicates thatthe tertiaryamide isessential fortherate
of carbopalladation to compete successfully with the rate
of early cross-coupling. Similar results were found in our
previous study, and in the case of carbonylation none of
the desired product was observed, indicating that the
carbonylation sequence is faster than the transmetalation
sequence.4b Initially, heteroaryl substrate 4g gave a low
yield of desired domino product 7h and the mass balance
was unconsumed amide 4g (entry 8). We reasoned that this
was due to a relatively slow cross-coupling step of the
intermediate Pd species corresponding to 6, which would
allow more time for protodeboronation of 5e to occur.
Thus, it was reasoned that decreasing the amount of water
would slow the rate of protodeboronation and thereby
increase the amount of the desired product. Indeed,
decreasing the amount of water did lead to an increase
in yield (entry 9). Furthermore, increasing the amount of
organoborane 5e, while using a decreased amount of
water, furnished product 7h in good yield (entry 10). The
Z-isomer of the double bond was also examined, providing
the diastereomeric product 7i (entry 11). In this case, the
cross-coupling of the intermediate corresponding to 6 was
also slow, as only 45% of the product was isolated using
the standard conditions with the mass balance being
starting material. Again, by increasing the amount of the
organoborane 5b, product 7i could be obtained in a higher
yield (entry 12).19
Figure 1. Product 8.
In conclusion we have developed a domino
carbopalladationÀcross-coupling reaction for the diastereo-
specific construction of 3,3-disubstituted oxindoles posses-
sing vicinal stereocenters. To our knowledge this is one of
the few examples of a domino reaction that exploits the
diastereocontrol that can be imparted by syn palladation.
This method furnishes the desired oxindole products in
good yields for a variety of acrylamides and organoborane
species. Key insights into the competing reaction mani-
folds were drawn, and comparisons of organoborane
species were made. Furthermore, how to improve the yield
with more recalcitrant substrates was discussed.
Acknowledgment. The authors would like to thank
the Knut and Alice Wallenberg Foundation, the Swedish
Research Council, and the Estonian Research Council
(Grant No. 7808) for funding.
Supporting Information Available. Preparation and
characterization of compounds 4aÀh, 7aÀi, and 8 are
included. This material is available free of charge via the
Internet at http://pubs.acs.org. The authors declare no
competing financial interest.
(18) Lennox, A. J. J.; Lloyd-Jones, G. C. J. Am. Chem. Soc. 2012,
134, 7431–7441.
(19) The5a and 5b perfomed similarly, see Table 2 entries 1 and 2. Also 5a
gave similar yields when increasing the amount of organoborane.
The authors declare no competing financial interest.
D
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