XuPhos-Catalyzed Enantioselective Carboiodination of

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Palladium/XuPhos-Catalyzed Enantioselective Carboiodination of Olefin-tethered Aryl Iodides Zhan-Ming Zhang, Bing Xu, Lizuo Wu, Lujia Zhou, Danting Ji, Yu Liu, Zhiming Li, and Junliang Zhang J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b04332 • Publication Date (Web): 09 May 2019 Downloaded from http://pubs.acs.org on May 9, 2019

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Journal of the American Chemical Society

Palladium/XuPhos-Catalyzed Enantioselective Carboiodination of Olefin-tethered Aryl Iodides Zhan-Ming Zhang,†,§,‡ Bing Xu,§,‡ Lizuo Wu,# Lujia Zhou,§ Danting Ji,§ Yu Liu,# Zhiming Li*,† and Junliang Zhang*,†,§ † Department

of Chemistry, Fudan University, 2005 Songhu Road, Shanghai, 200438, P.R.China Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China # College of Chemistry and Life Science, Advanced Institute of Materials Science, Changchun University of Technology, Changchun 130012, China Supporting Information Placeholder § Shanghai

ABSTRACT: A highly enantioselective palladium-catalyzed iodine atom transfer cycloisomerization of unactivated alkenes has been developed. This represents the first example of highly enantioselective carboiodination of olefin-tethered aryl iodides, which provides a perfect atom economy method to construct a series of optically active 2,3-dihydrobenzofuran, indolines and chromane bearing an alkyl iodide group in moderate to good yields. Moreover, the use of readily available starting materials, a broad substrate scope, high selectivity, mild reaction conditions, as well as versatile transformation of the product make this approach pretty attractive. The mechanism of this Pd(0)-catalyzed asymmetric carboiodination of alkenes has been investigated with density functional theory.

From various natural product and bioactive molecules to materials, and clean energy, organic halides undoubtedly represent versatile synthetic precursors even directly as target molecules.1 Over past decades, transition-metal catalyzed synthesis of racemic organic halides have attracted tremendous attention.2 Notably, Lautens3 disclosed a perfect atom economical strategy (Pd-catalyzed carboiodination reaction) to construct 2,3-dihydrobenzofuran bearing an alkyl iodide group by a domino sequence involving the oxidative addition of aryl iodide, alkene insertion and C(sp3)-I reductive elimination from a Pd(II) intermediate (Scheme 1a). A particular focus was on the rate-determing reductive elimination step, which need an exceptionally bulky and electron rich phosphine ligand such as QPhos or P(tBu)3 facilitated the C(sp3)-I reductive elimination by limiting the formation of tetracoordinated intermediates.4 By the employment of excess electron-rich bisphosphine ligand DPPF, Tong5 realized an elegant example of Pd(0)-catalyzed carboiodination reaction of (Z)-1-iodo-1,6-diene. The Ni-catalyzed intramolecular carboiodination reaction was also realized to generate valuable halogenated 3,3-disubstituted heterocycles and a moderately enantioselective process has also been reported.6 Despite much elegant progress in the racemic7 or diastereoselective synthesis8 has been made, the development of transition-metal especially palladium-catalyzed asymmetric carboiodination reaction in high effciency remains extremely challenging, besides the enantioselectivity,5,6,7a “there are few ligands known to promote the key reductive elimination" mentioned by Lautens8a (Scheme 1b). Thus, the development of the highly

efficient and enantioselective transition-metal catalyzed carboiodination is in highly desired. Scheme 1. Transition-metal catalyzed carboiodination reaction a) Pd-catalyzed Racemic Carboiodination (Lautens, Tong) R1

I R Y

n

R1

[Pd]/L R

Y = N, O

n

L [Pd] I

Bulky Electron-rich ligand

Challenge

Y tricoordinate intermediates

R1 R

I n

Y

reductive elimination

Bulky electron-rich phosphine ligand is crucial to this type of reaction b) Transition-metal catalyzed Asymmetric Carboiodination I Tong (2011, Ref. 5) Lautens (2018, Ref. 6) Lautens (2011, Ref. 7a) I Me R2 Me Me Ph  I I    N O R NTs N O Ph O Me 1 example 1 example 1 example 4 examples Pd2(dba)3 Pd(OAc)2 Pd2(dba)3 NiI2/L4 & L5 Walphos (L2) Josiphos (L1) (S)-BINAP (L3) 14%, 94% ee 65%, 2:1 dr, 40% ee 10%, 56% ee 50-84%, 30-78% ees c) This work: Pd-catalyzed Asymmetric Carboiodination R

I R

X Oxidative addition

R

Pd(0)/L*

HCO2Na

[Pd] X

R R1

L*

H

R1

L*

I

Alkene insertion

[Pd] X

R1

Previous work

[Pd] X

X= O, N

L*

I

R

Pd(0)/L*

1

R

R

R1

H

X Reductive Heck product L* I [Pd] 1 R This work R X

R1

I

X

Challenges:  How to facilitate the reductive elimination of C(sp3)-I  How to achieve high enantioselectivity and efficiency  How to inhibit reductive Heck and direct reduction reaction

Very recently, we reported a palladium-catalyzed asymmetric intramolecular reductive Heck reaction9 for the synthesis of 3,3disubstituted 2,3-dihydrobenzofurans using sodium formate as a hydride donor.9b During this study, we envisaged that the catalytic asymmetric carboiodination reaction might be realized by the simple removal of the hydride donor (Scheme 1c). To examine this hypothesis, substrate 1a was selected as the model substrate and was subjected to the previously developed conditions9b only leading to the reductive Heck product 2a’ in 70% yield. Removing the sodium formate failed to give any product and most of 1a was recovered (eq. 1). The use of Cs2CO3 instead of the hydride donor

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sodium formate still deliver the reductive Heck product 2a’ in 56% yield. These results indicated that the catalytic asymmetric carboiodination reaction is indeed very challenging at least not as we thought at the beginning, due to the following reasons: (1) the reductive elimination step of tricoordinated palladium intermediate is the rate-determining step for the halogen-transfer process,4 but the enantioselective carbopalladation will generate a tetracoordinated intermediate, thus, the dissociation one bindingsite of bidentate ligand from palladium complex is necessary; (2) the competitive direct reduction reaction and reductive Heck reaction; (3) how to achieve both high efficiency and enantioselectivity. I Me

O 1a

7.5 mol% N-Me-Xu3 2.5 mol% Pd2(dba)3•CHCl3

Me

(1)

+

x equiv HCO2Na MeOH/PhMe, 90 °C

O

2.0 equivs HCO2Na:9b

O

2a

2a'

0%

70%

no HCO2Na:

0%

0%

Cs2CO3 instead of HCO2Na:

0%

56%

PPh2 Ph2P

PtBu2 Ar2P Fe

Me

O PPh2 PPh2

PAr2 PAr2

Fe

Ar = 3,5-(CF3)2-C6H3 Josiphos (L1)

Walphos (L2)

(S)-BINAP (L3): Ar = Ph L4: Ar = 4-Me-C6H4

NMe2 Fe

PPh2

(R)-(S)-PPFA (L6)

O MeO MeO

PAr2 PAr2

Ar

t Bu S N R'

PR2 Ar = 3,5-(tBu)2-4-MeOC6H2

(S)-DTBM-BIPHEP (L7)

PPh3, Qphos, P(tBu)3 (more details in SI). Thus, we made the entN-Me-Xu3 with the opposite configuration to Table 1. Effect of Reaction Parametersa

L5

R = Cy, Ar = Ph N-Me-Xu1: R' = Me Ar = 3,5-(tBu)2-4-MeOC6H2 Xu3: R = Cy, R' = H N-Me-Xu3: R = Cy, R' = Me M1: R = Ph, R' = H

Figure 1. Chiral ligands used in literatures and this work Cutting the long-story in short, we finally find that 80% yield of 2a with 95.5:4.5 er could be obtained under the optimal conditions with Pd2(dab)3•CHCl3 as the precatalyst, N-Me-Xu3 as the chiral ligand and K2CO3 as the additive in iPr2O at 100 oC after many attempts (Table 1, entry 1). Any variation from the optimal conditions would lead to lower yield and er. No desired product was obtained with the use of same class of chiral ligands N-Me-Xu1 with a small Ar group (Ar = Ph), Xu3 without methyl protecting group (R’ = H), and M1 with an aryl phosphine group (R = Ph), which further confirms that this reaction is very sensitive to the structure of the ligand and bulky ligand benefits the reductive elimination step (Table 1, entries 2−4). Nevertheless, changing to Josiphos (L1)7a as the chiral ligand, no desired product could be obtained (Table 1, entry 5). Other comercially available chiral ligands were also examined, showing almost no catalytic activity (entries 6−8). Of note, the reaction can not give a complete conversion in the absence of the K2CO3, indicating that the base may accelerate the reductive elimination (entry 9).8a However, only 14% yield of the product was obtained with the employment of Cs2CO3 as the base additive (entry 10). The use of amine base instead of K2CO3 led to slightly lower yield and er (Table 1, entries 11−13). Other palladium salts delivered lower er values and yields (entries 14−15). The toluene is the second best choice to give 94.5:5.5 er (entry 16). Changing iPr2O to DCM led to no reaction (entry 17). Either addition of water or lowering the temperature decreased the yield (entries 18−19). With optimal conditions in hand, we next examined the reaction scope by variation of o-iodophenol-derived allyl ether (Scheme 2). It is not surprising to obseve that the synthesis of the recamic product is often quite difficult with the use of achiral ligand. For example, changing the methyl to ethyl group of alkene, the chiral product 2b was obtained in 61% yield, but the racemic reaction failed with the test of a series of known phosphine ligands such as

5 mol% Pd2(dba)3•CHCl3 20 mol% N-Me-Xu3

I O

Me

2.0 equivs K2CO3 i

1a

entry 1 2

Me Me

I

Page 2 of 6

3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

Me

I

O

Pr2O, 100 °C

2a

variation from the “standard” conditions

conv. (%)b

yield (%)b,

er (%)c

None N-Me-Xu1 instead of N-MeXu3 Xu3 instead of N-Me-Xu3 M1 instead of N-Me-Xu3 L1 instead of N-Me-Xu3 L3 instead of N-Me-Xu3 L6 instead of N-Me-Xu3 L7 instead of N-Me-Xu3 No K2CO3 Cs2CO3 instead of K2CO3 Et3N instead of K2CO3 PMP instead of K2CO3 iPr NEt instead of K CO 2 2 3 Pd(OAc)2 instead of Pd2(dab)3•CHCl3 Pd(TFA)2 instead of Pd2(dab)3•CHCl3 PhMe instead of iPr2O DCM instead of iPr2O Added H2O (1.0 equiv) At 90 oC

100

80d

95.5:4.5

20:1 dr

20 mol% ent-N-Me-Xu3 was used.

Ar

R1

5 mol% Pd2(dba)3•CHCl3 20 mol% N-Me-Xu3

6 I

N Boc

MeO

I

O 2v: 76%, 95:5 er ent-2v: 78%, 5:95 er

N

MeO2C

N

O

Ph Ts

I

4g: 84%, 96.5:3.5 er ent-4g: 82%, 3.5:96.5 er

Toluene, 100 °C

i-Pr

2u: 83%, 95:5 er ent-2u: 80%, 5:95 er

Me

Scheme 4 Effect of o-iodoaniline-derived allyl amine

I

I

O

Me

4d: 87%, 96.5:3.5 er

6 O

O 4f: 66%, 95:5 er ent-4fa: 68%, 5:95 er

5 I

I

Me

In order to gain deep insight into the reaction mechanism, density functional theory (DFT) calculations were carried out using the Gaussian 09 software package.12,13 In view of the complicated structure of the ligand N-Me-Xu3, the corresponding structures were optimized using B3LYP method and combined basis set. That is, 6-31G(d) for the reactant 1a fragment (except the three hydrogen atoms on the phenyl ring far from the reaction site), the heteroatoms P, N, S, O on the ligand N-Me-Xu3 and the carbon atoms linked with the above mentioned heteroatoms, Lanl2DZ for Pd and I atoms, and 3-21G basis set for all the other atoms. Truhlar and coworkers’ SMD solvation model was employed to consider the solvent effect (iPr2O).14 The other calculation details were provided in the Supporting Information.

R

N

N

O

Me

I

20 mol% ent-N-Me-Xu3 was used.

X

O

N

I

4e: 72%, 95.5:4.5 er a

Me

4c: 80%, 95.5:4.5 er n-C5H11 I MeO

N

O

O

2k: 75%, 95:5 er ent-2k: 73%, 5:95 er

t-Bu

O

Me

O

I

O

Me

O

4b: 87%, 95.5:4.5 er

Ph

I

n

O

O

O

I

I

Ph Me

I

t-Bu

4a: 83%, 96.5:3.5 er

2f: 74%, 96.5:3.5 er 2g: 69%, 95.5:4.5 er 2h: 90%, 96.5:3.5 er 2i: 80%, 95:5 er ent-2f: 79%, 3.5:96.5 er ent-2g: 67%, 4.5:95.5 er ent-2h: 94%, 4:96 er ent-2i: 78%, 5:95 er F Cl Ph CO2Me

2j: 82%, 95.5:4.5 er ent-2j: 80%, 4.5:95.5 er

Me

I

2e: 75%, 96:4 er ent-2e: 75%, 4.5:95.5 er

O

R

2.0 equivs K2CO3 i Pr2O, 100 °C

O S t N Bu Me PCy2 Ar = 3,5-tBu2-4-MeOPh N-Me-Xu3

I

4a-4g

Me

O

O

R1

n

3a-3g

I

O

2d: 72%, 95:5 er ent-2d: 75%, 5:95 er

O

Me

n-C5H11

I O

R

O S t N Bu Me PCy2 Ar = 3,5-tBu2-4-MeOPh N-Me-Xu3

I

O 2b-2y

O O QPhos: NR 2c: 75%, 95:5 er 2b: 61%, 95.5:4.5 er ent-2c: 76%, 5:95 er ent-2ba: 63%, 4.5:95.5 er i-Pr

R1

R1

5 mol% Pd2(dba)3 20 mol% N-Me-Xu3

I

O 1a-Br

Me

2.0 equivs K2CO3 i

Pr2O, 100 °C 50%, 95:5 er

Me

I (2)

O 2a

The free energy profiles of the preferred reaction pathways from 1a to the two enantiomers 2a catalyzed by palladium/XuPhos



are shown in Figure 2. The black line refers to the general oxidative addition process of aryl iodide, while the blue and red lines corresponds to the following alkene insertion (B to D) and C-I reductive elimination (D to E) for R- and S-2a, respectively.4c In the case of R-2a, the activation free energies for the latter two processes are 30.9 and 26.2 kcal/mol, respectively. Thus the rate-determining step for the whole catalytic cycle is the alkene insertion process, not the reductive elimination. The similar situation can be found in S2a as well. The difference between the two activation barrier of the alkene insertion step for the two enantiomers is even up to 4.8 kcal/mol, which guarantees the generation of the highly enantioselectivity of this reaction, for the chiral center is generated in this step. The result is also in good agreement with the high er value in the experiment (the theorectical value 99.9:0.1, experimental 95.5:4.5). At the same time, this conclusion is different from that in Lautens and Houk’s work, where the reductive elimination is rate-determining step with the use of (tBu)3P as the ligand.4c Compared to (tBu)3P, N-Me-Xu3 has more than one coordination sites such as S, O, P, N atoms. According to t Bu Me N S Ar O I Cy2 P Pd

I t Bu Me N S Ar O Cy2 P Pd

O Me Me t Bu N S O Cy2P Pd Ar

Me t Bu N S O Cy2P Pd I O Ar

1a + PdXu3 0.0

TSCD 11.8

Me O

t Bu Me N S Ar O Cy2 P Pd

Me

A -10.0

Me

B -19.1

Ar Ar

Me t Bu N S O

Cy2P Pd I O

t

Me Me I

TSDE 2.0

(R)

Bu

N

Ar

S

O I Cy2 Pd P

Me (R)

O

O

I

E -9.1

O t

Me

t

Ar

(S)

I

TSDE-en 7.0

Me N S

O Cy2 Pd P

Me

O

Me O t Bu

Ar

TSAB -5.9

t Bu Me N S Ar O Cy2 Pd P

t Bu Me N S Ar O I Cy2 P Pd

C-en 4.4

Me O

Me

Me t Bu N S O I Cy2P Pd O

our calculation, the structure is more stable when Pd is coordinated with P and O atoms. Our computation results also shows that, during the reaction process, nearly all the intermediates remain tetracoordinated, as shown in Figure 2, although the O atom connected with the S atom almost always characters weakly coordination, such as in TSAB, TSCD and TSDE structures. For example, the Wiberg bond index of Pd-O in TSCD is only 0.08 (Figure S1), while this consistent coordination states may facilitate the reductive elimination process and thus stabilize the transition state structure compared to the case of ligand (tBu)3P. An incomplete pathway was also located for S-2a (Figure S2, the green line). During the alkene insertion and reductive elimination, Pd and 1a fragments are removed from the ligand. This makes the reductive elimination hard to proceed and reveals the importance of the ligand N-Me-Xu3 to favor the reductive elimination as well. In addition, the total barrier of the reaction path for the two enantiomers is 11.3 and 16.6 kcal/mol, respectively. Both are lower than that of the reaction where (tBu)3P as ligand (17.6 kcal/mol). This may account for the high yield obtained in our reaction.

TSCD-en 16.6

C 8.6

I

Page 4 of 6

Bu Me N S O Cy2 Pd P I

Me

Bu

N

Ar

D-en -19.1 D -24.2

Me

O I Cy2 Pd P O

(S)

O

S

t Bu Me N S Ar O Cy2 Pd P I

Me

E-en -9.2 Me (S)

I

(R)

O

2a + PdXu3 -18.1 2a-en + PdXu3 -18.1 Me

Me (R)

I

(S)

O

O

Figure 2. Free-energy reaction proﬁles (kcal mol−1) calculated at the SMD (iPr2O) B3LYP/combined basis set level at 373 K. In summary, we have developed the first highly AUTHOR INFORMATION enantioselective palladium-catalyzed carboiodination of Corresponding Author unactivated alkenes with the use of N-Me-Xu3 as the chiral ligand and K2CO3 as the additive, which provides an efficient synthesis of [email protected], [email protected] chiral 3,3-disubstituted 2,3-dihydrobenzofuran, indolines and chromane bearing an alkyl iodide and one all-carbon quaternary Author Contributions stereocenter. The mechanism of this Pd(0)-catalyzed asymmetric carboiodination of alkenes has been investigated with density ‡These authors contributed equally to this work. functional theory. The DFT calculations indicated that the alkene insertion rather than the reductive elimination is the rateNotes determining step and accounts for the enantioselectivity and high The authors declare no competing financial interests. reactivity. Moreover, further direction will focus on the development of asymmetric domino carbopalladation-initiated ACKNOWLEDGMENT reactions and will be reported in the due course. We gratefully acknowledge the funding support of NSFC (21425205, 21672067, 21801078), 973 Program (2015CB856600), ASSOCIATED CONTENT and the Program of Eastern Scholar at Shanghai Institutions of Supporting Information Higher Learning. Experimental procedure, optimization tables, characterization data for all the products (PDF).

REFERENCES


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Q.; Cao, J.; Xu, Z.; Xu, L.-W. Enantioselective Cross-Exchange between C−I and C−C σ-Bonds. Angew. Chem. Int. Ed. 10.1002/anie.201902029. (8) (a)Petrone, D. A.; Yoon, H.; Weinstabl, H.; Lautens, M. Additive Effects in the Palladium-Catalyzed Carboiodination of Chiral N-Allyl Carboxamides. Angew. Chem., Int. Ed. 2014, 53, 7908−7912. (b) Petrone, D. A.; Malik, H. A.; Clemenceau, A.; Lautens, M. Functionalized Chromans and Isochromans via a Diastereoselective Pd(0)-Catalyzed Carboiodination. Org. Lett. 2012, 14, 4806−4809. (9) For selected review, see: (a) Ping, Y.; Li, Y.; Zhu, J.; Kong, W. Construction of Quaternary Stereocenters by PalladiumCatalyzed Carbopalladation-Initiated Cascade Reactions. Angew. Chem. Int. Ed. 2018, 58, 1562–1573. For selected examples, see: (b) Zhang, Z.-M.; Xu, B.; Qian, Y.; Wu, L.; Wu, Y.; Zhou, L.; Liu, Y.; Zhang, J. Palladium-Catalyzed Enantioselective Reductive Heck Reactions: Convenient Access to 3,3Disubstituted 2,3-Dihydrobenzofuran. Angew. Chem. Int. 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A New Type of Chiral Sulfinamide Monophosphine Ligands: Stereodivergent Synthesis and Application in Enantioselective Gold(I)-Catalyzed Cycloaddition Reactions. Angew. Chem., Int. Ed. 2014, 53, 4350–4354. (b) Zhang, Z.-M.; Xu, B.; Xu, S.; Wu, H.-H.; Zhang, J. Diastereo- and Enantioselective Copper(I)-Catalyzed Intermolecular [3+2] Cycloaddition of Azomethine Ylides with β-Trifluoromethyl β,βDisubstituted Enones. Angew. Chem., Int. Ed. 2016, 55, 6324–6328. For PC-Phos ligands, see: (f) Wang, Y.; Zhang, P.; Di, X.; Dai, Q.; Zhang, Z.M.; Zhang, J. Gold-Catalyzed Asymmetric Intramolecular Cyclization of NAllenamides for the Synthesis of Chiral Tetrahydrocarbolines. Angew. Chem., Int. Ed. 2017, 56, 15905–15909. (g) Wang, L.; Chen, M.; Zhang, P.; Li, W.; Zhang, J. Palladium/PC-Phos-Catalyzed Enantioselective Arylation of General Sulfenate Anions: Scope and Synthetic Applications. J. Am. Chem. Soc. 2018, 140, 3467–3473. (11) (a) Zhou, J. (Steve); Fu, G. C. Suzuki Cross-Couplings of Unactivated Secondary Alkyl Bromides and Iodides. J. Am. Chem. Soc. 2004, 126, 1340–1341. (b) González-Bobes, F.; Fu, G. C. Amino Alcohols as Ligands for Nickel-Catalyzed Suzuki Reactions of Unactivated Alkyl Halides, Including Secondary Alkyl Chlorides, with Arylboronic Acids. J. Am. Chem. Soc. 2006, 128, 5360–5361. (12) (a) Becke, A. D. Density‐functional thermochemistry. III. The role of exact exchange. J. Chem. Phys. 1993, 98, 5648-5652. (b) Stephens, P. J.; Devlin, F. J.; Chabalowski, C. F.; Frisch, M. J. Ab Initio Calculation of Vibrational Absorption and Circular Dichroism Spectra Using Density Functional Force Fields. J. Phys. Chem. 1994, 98, 11623-11627. (c) Lee, C.; Yang, W.; Parr, R. G. Development of the Colle-Salvetti correlationenergy formula into a functional of the electron density. Phys. Rev. B 1988, 37, 785-789. (13) Gaussian 09, Revision D.01, Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, N. J.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, Ö.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian, Inc., Wallingford CT, 2009. (14) Marenich, A. V.; Cramer,C. J.; Truhlar, D. G. Universal Solvation Model Based on Solute Electron Density and on a Continuum Model of the Solvent Defined by the Bulk Dielectric Constant and Atomic Surface Tensions. J. Phys. Chem. B 2009, 113, 6378-6396.



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Insert Table of Contents artwork here I R1 X

R2

Chiral Pd-catalyst 1-2 R2

53-96% yield up to 96.5.5:3.5 er

R1

X

I 1-2

All-carbon quarternary stereocenter Perfect atom economy Broad substrate scope Good yield and high stereoselectivity


6

XuPhos-Catalyzed Enantioselective Carboiodination of

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