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Site-Selective 1,1-Difunctionalization of Unactivated Alkenes Enabled by Cationic Palladium Catalysis Jinwon Jeon, Ho Ryu, Changseok Lee, Dasol Cho, Mu-Hyun Baik, and Sungwoo Hong J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b04142 • Publication Date (Web): 31 May 2019 Downloaded from http://pubs.acs.org on May 31, 2019
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Journal of the American Chemical Society
Site-Selective 1,1-Difunctionalization of Unactivated Alkenes Enabled by Cationic Palladium Catalysis Jinwon Jeon, Ho Ryu, Changseok Lee, Dasol Cho, Mu-Hyun Baik,* and Sungwoo Hong* Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Korea Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon, 34141, Korea Supporting Information Placeholder
ABSTRACT: A palladium(II)-catalyzed 1,1-difunctionalization of unactivated terminal and internal alkenes via addition of two nucleophiles was developed using a cationic palladium(II) complex. The palladacycle generated in situ as a result of a regioselective addition of a nucleophile to the alkene can readily undergo regioselective β-hydride elimination and migratory insertion with a cationic palladium catalyst. The resulting η3-π-allyl palladium(II) complex is the key intermediate that reacts with a second nucleophile to furnish the desired 1,1-difunctionalization of the alkene. Under the optimized reaction conditions, a wide range of indoles and anilines add to alkene units of 3-butenoic or 4-pentenoic acid derivatives to afford the synthetically useful γ,γ- or δ,δ-difunctionalized products with excellent regiocontrol. Furthermore, by employing internal hydroxyl or acid groups and external carbon nucleophiles, this transformation enables unsymmetric 1,1-difunctionalization to forge challenging and important oxo quaternary carbon centers. Combining experiments and DFT calculations on the mechanism of the reaction is investigated in detail.
INTRODUCTION Palladium-catalyzed difunctionalization1 of alkenes is a powerful synthetic tool for rapidly accessing structural motifs found in a variety of valuable building blocks of pharmaceuticals and natural products.2 Through alkene polarization by π-Lewis acid activation of a transition metal, two functional groups could be installed across a double bond in an atom-economical fashion.3 Difunctionalization of alkenes catalyzed by high-valent palladium4 species was extensively explored by Michael,5 Muñiz,6 Sanford,7 Liu8 and Stahl.9 A strategy that uses special tethering has been widely used for the regioselective functionalization of unactivated alkenes. In particular, preorganized directing groups often allow a favorable substrate binding to the catalyst, which enables intramolecular reactions with high reactivity and regioselectivity.10 Recently, a series of palladium(II)catalyzed β,γ-vicinal difunctionalizations of unactivated alkenes11 was described by the Engle12 utilizing an amide-linked aminoquinoline (AQ) directing group for the regioselective addition to a Pd(II)-bound alkene. The palladacycle generated in this process is thought to undergo either protodepalladation or oxidative addition with electrophiles. Bidentate directing groups13 used in this transformation guide the regioselective installation of nucleophiles, wherein the conformational rigidity of the directing group is believed to suppress competing β-hydride (β-H) elimination reaction, allowing the alkylpalladium species to be intercepted by a proton source to give a hydrofunctionalized product.14 In contrast to the remarkable advances in 1,2-vicinal difunctionalization, a similar strategy for 1,1-geminal difunctionalization of unactivated alkenes by two nucleophiles has remained elusive to date,15-19 despite being tremendously attractive from synthetic perspectives. Sanford reported the 1,1-aryl halogenation of alkenes using arylstannanes,15 and Sigman16 and Toste17 have described Pd-catalyzed 1,1-diarylation and 1,1arylborylation of alkenes. Recently, Brown also reported the 1,1-arylboration of α-methyl vinyl arenes.18 In these examples, prefunctionalization of the aryl source as boronic acids or aryldiazonium salts are required for successful arylation. Moreover, these reactions were applied only to terminal alkenes limiting the overall synthetic flexibility. Finally, the formation of quaternary carbon centers has thus far remained out of reach.
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Scheme 1. State-of-Art Strategies for Pd-Catalyzed Alkene Difunctionalization. a) 1,1-Arylchlorination of terminal alkene (Sanford) Ph
Pd(II)
CuCl2
Ph-SnBu3
R
R Cl
b) 1,1-Diarylation and arylborylation of terminal alkene (Sigman, Toste) O Ar-N2BF4
OR
E
Pd(0)
E-X
CAPT cat
O
Ar OR E = Ar' or Bpin
c) Site selective difunctionalization of unactivated alkene O DG
R
Nu
Nu-H
R H Pd
This work
[Pd]+
Nu Nu R
Nu
O H
DG
Nu
O
Pd(II)
1,2-
DG
O
DG X = H+ or E+
regioselective
-H-elimination Nu
O
1,1- R
Pd H
(Engle)
X
R
DG
O
Nu
1,1-
H
R = Nu
DG
Drawing inspiration from the aforementioned studies, we wondered if a synthetically useful regioselective 1,1difunctionalization of nonconjugated alkenes could be developed via addition of two nucleophiles. We envisioned a strategy that takes advantage of β-H elimination from the palladacycle complex to regenerate an olefin moiety, which sets the stage for a second nucleopalladation. Such an approach has not been successful to date, largely because of the conformational rigidity of the stable palladium-bound bidentate directing group, suggesting that the structural flexibility should be increased to enable β-H elimination.14a,14b,20 The Engle group observed the formation of a 1,1-difunctionalized product using a 4-pentenoic-acid-derived substrate probably generated from a less stable six-membered palladacycle, although a mixture of hydrofunctionalized and 1,1difunctionalized products was obtained in 45% and 30% yield respectively.14b As depicted in Figure 1, we imagined that a cationic Pd(II)-bound bidentate directing group21 might enable β-H elimination of the palladacycle complex and subsequent olefin insertion,16c,22 which would present a new opportunity for a second nucleophile to form the 1,1-difunctionalized product. Herein, we report the discovery of a new catalytic platform by strategic use of a cationic palladium species to enable the 1,1difunctionalization of unactivated alkenes at either the γ- or δ- position, which is suitable and applicable to both terminal and internal alkene substrates. Moreover, this new protocol is highly effective in unsymmetric 1,1-difunctionalization of alkenes bearing tethered hydroxyl or carboxylic acid groups, which promotes regioselective palladation for the rapid buildup of molecular complexity with oxo quaternary carbon centers under mild reaction conditions. cationic Pd
O PdII
N N
no -H elimination
O PdII
N
bidentate DG
H N
-H elimination high 1,1-regioselectivity & reactivity
O PdII
N
low regioselectivity & reactivity
Figure 1. Design plan for cationic Pd(II)-catalyzed 1,1-difunctionalization of alkenes via addition of two nucleophiles.
RESULTS AND DISCUSSION First, we set out to develop a general method that invokes β-H elimination of a palladacycle intermediate and successfully enables 1,1-difunctionalization of unactivated alkenes. The feasibility of the proposed process was investigated using the 3-butenoic acid derivative 1a bearing an 8-aminoquinoline (AQ) directing group as the model substrate and methylindole 2a as the coupling partner (Table 1). In the presence of 10 mol % Pd(OAc)2 as the catalyst, only mono-indolylated product 3a’ could
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Journal of the American Chemical Society
be observed in 18% yield (entry 1). The addition of AgOAc did not promote the desired reaction and resulted in minimal yield (entry 2). Switching AgOAc to AgOH produced a higher yield of 37% of the mono-indolylated product 3a’ but failed to give detectable quantities of the 1,1-difunctionalized product 3a (entry 3). Remarkably, the addition of AgBF4 was critical for the success of the 1,1-difunctionalization process to afford the corresponding product 3a in 70% yield, with minimal formation of 3a’ (3a/3a’ = 25:1) (entry 4). Various metal salt sources were screened, and copper salts were also reactive under these conditions, although they afforded a diminished product yield of 67% of 3a (see the Table S2 for details). We continued our optimization efforts by evaluating the effect of counteranions, and AgSbF6 displayed the best activity, yielding the desired product 3a in 82% yield (entry 6). Among the solvents screened, acetonitrile was most efficient for this reaction. Interestingly, further optimization revealed that the addition of benzoquinone (BQ) accelerated the overall reaction rate, and the reaction was completed within 7 hours (entry 9). Finally, we found that by reducing the AgSbF6 loading to 10 mol%, the reaction performs comparably well and that 3a was generated in 80% yield, albeit requiring a longer reaction time (entry 10). As expected, control experiments confirmed that the Pd-catalyst was required for this reaction (entry 11). Table1. Optimization of Reaction Conditions.a
O N
N H
N
O AQ
N
O
50 C, O2
N (AQ)
1a
Pd(OAc)2 additive
2a
AQ 3a'
N 3a
Entry
additive (mol %)
solvent
yield (3a/3a’, %)b
1
-
MeCN
0 / 18
2
AgOAc (50)
MeCN
0/3
3
AcOH (50)
MeCN
0 / 37
4
AgBF4 (50)
MeCN
70 /
