Construction of vicinal tertiary and all-carbon quaternary stereocenters via Ir-catalyzed regio-, diastereo-, and enantioselective allylic alkylation and applications in sequential Pd catalysis

Article abstract of DOI:10.1021/ja4052075

Highly congested vicinal stereocenters comprised of tertiary and all-carbon quaternary centers were generated via Ir-catalyzed asymmetric allylic alkylation of β-ketoesters. These catalytic reactions proceed in excellent yields with a broad scope on either reaction partner and with outstanding regio-, diastereo-, and enantiocontrol. Implementation of a subsequent Pd-catalyzed alkylation affords dialkylated products with pinpoint stereochemical control of both chiral centers.

Full text of DOI:10.1021/ja4052075

Communication
pubs.acs.org/JACS
Construction of Vicinal Tertiary and All-Carbon Quaternary
Stereocenters via Ir-Catalyzed Regio‑, Diastereo‑, and
Enantioselective Allylic Alkylation and Applications in Sequential Pd
Catalysis
Wen-Bo Liu, Corey M. Reeves, Scott C. Virgil, and Brian M. Stoltz*
Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical
Engineering, California Institute of Technology, Pasadena, California 91125, United States
S
* Supporting Information
ABSTRACT: Highly congested vicinal stereocenters
comprised of tertiary and all-carbon quaternary centers
were generated via Ir-catalyzed asymmetric allylic
alkylation of β-ketoesters. These catalytic reactions
proceed in excellent yields with a broad scope on either
reaction partner and with outstanding regio-, diastereo-,
Figure 1. Selected Phosphoramidite and PHOX Ligands.
and enantiocontrol. Implementation of a subsequent Pd-
catalyzed alkylation affords dialkylated products with
pinpoint stereochemical control of both chiral centers.
Scheme 1. Ir-Catalyzed Allylic Substitutions
he asymmetric construction of sterically encumbered
Tvicinal stereogenic centers is of great interest to synthetic
chemists due to the prevalence of such structural arrangements
in natural products and bioactive compounds.1 The limited
number of methods that provide selective access to vicinal
tertiary and all-carbon quaternary stereocenters highlights the
challenging nature of this task. Enantioselective approaches for
accessing this structural dyad have generally relied on
asymmetric Michael additions2 and Claisen rearrangements.3
Among the methods available for forging this motif, only a
relatively small number have been reported to do so by
employing transition metals in a catalytic, asymmetric
fashion.4,5 Thus, further investigations into the development
of metal-catalyzed methods to directly and selectively generate
such stereochemical arrays should prove valuable.
Allylic alkylation chemistry represents a successful strategy
for the assembly of highly congested chemical architectures,6
and within this domain, Ir-catalyzed processes are among the
most selective and highest yielding.7,8 Initial reports from the
Helmchen9 and Hartwig10 groups demonstrated the utility of
Ir-catalyzed allylic substitutions for the synthesis of enantioen-
riched 3,3-disubstituted (branched) allyl compounds.8 As this
research area has developed, Ir/phosphoramidite catalysts (i.e.,
[Ir(cod)Cl]2/L1, Figure 1)11 have emerged as privileged
scaffolds for the regio- and enantioselective allylic alkylation
of achiral nucleophiles, such as malonate derivatives and ketone
enolates.12 However, methods for Ir-catalyzed intermolecular
allylic alkylation that employ prochiral nucleophiles and display
high (1) regio-, (2) diastereo-, and (3) enantioselectively
remain elusive (Scheme 1).13 To date, only two reports,14 from
the laboratories of Takemoto and Hartwig, detail success in
attaining all three of these goals; however, in these accounts,
the nucleophiles investigated were limited to amino acid
derivatives and azlactones.15 Herein, we report the develop-
ment of a highly regio-, diastereo-, and enantioselective Ir-
catalyzed α-allylic alkylation of cyclic β-ketoesters that forges
vicinal tertiary and all-carbon quaternary centers in one step
and in excellent yields. Moreover, we describe the deployment
of a novel 2-(trimethylsilyl)-ethyl β-ketoester, which serves as
an oxycarbonyl-protected enolate, enabling sequential catalyst-
controlled α-allylic alkylations and, in turn, the ability to select
the diastereomer produced within the nascent stereochemical
dyad.
Our preliminary studies focused on probing the effects of
different ligands, bases, additives, and solvents on the efficiency
and selectivity of the reaction. Cyclic β-ketoester 1a, cinnamyl
carbonate 2a, and [Ir(cod)Cl]2/phosphoramidite complexes16
were chosen as standard reaction components at the outset of
our investigations.17 Selected results of these experiments are
summarized in Table 1. Our investigations commenced with
commonly used phosphoramidite ligand L1,18 and we were
pleased to find that the proposed reaction proceeded smoothly
under the conditions described (Table 1), delivering α-
quaternary β-ketoester 3aa in >95% conversion and in 96%
ee. Unfortunately, no diastereoselectivity was observed in this
Received: May 23, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja4052075 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
or electron-withdrawing (−Br, −CF3) groups on the aromatic
ring gave remarkably high dr, ee, and yields (99% ee and 20:1
dr, Table 2, entries 1−4). The branched to linear ratio (i.e.,
Table 1. Optimization of Reaction Parameters
Table 2. Substrate Scope of Ir-Catalyzed Allylic Alkylation of
a
β-Ketoesters
base or additive
(equiv)
dr of
b
ee of
3aa(%)
b
c
entry
L
3aa:4aa
3aa
d
1
2
L1
L2
L3
L3
L3
L3
L3
L3
L3
L3
L4
L5
L3
NaH (2)
NaH (2)
NaH (2)
−
Et3N (2)
Cs2CO3 (2)
K3PO4 (2)
LiOt-Bu (2)
LiCI (1)
LiBr (1)
LiBr (1)
LiBr (1)
LiBr (1)
>95:5
>95:5
95:5
1:1
1:2
96 (99)
e
32 (3)
98
3
>20:1
11:1
11:1
6:1
4
80:20
77:23
63:37
63:37
95:5
96
5
97
6
93
7
4:1
90
8
>20:1
14:1
>20:1
12:1
−
99
9
88:12
95:5
98
10
11
>99
96
80:20
12:88
95:5
f
12
−
99
g
13
>20:1
a
Reactions performed with 0.1 mmol of 2a, 0.2 mmol of 1a at 0.1 M in
THF at 20 °C and allowed to proceed to complete consumption of 2a.
b
Determined by 1H NMR and UHPLC-MS analysis of the crude
c
mixture. Determined by chiral HPLC analysis of the major
diastereomer. (ee) of the alternate diastereomer. (ee) of the major
diastereomer. Measured after 60 h at 60% conversion. 1 mol %
d
e
f
g
[Ir(cod)Cl]2 and 2 mol % L3 were used.
case (Table 1, entry 1). Use of ligand L2, a diastereoisomer of
L1, again produced a high yielding reaction but in significantly
diminished ee (32%) and modest 1:2 dr (entry 2). Inspired by
the You group’s use of Ir-N-arylphosphoramidite complexes
(derived from [Ir(cod)Cl]2 and L3)19 to effect the diastereo-
and enantioselective intramolecular allylation of indoles and
pyrroles,20 we envisioned that analogous Ir complexes may
prove valuable for the generation of all-carbon quaternary
stereocenters. We were delighted to discover that the use of N-
aryl-phosphoramidite ligand L3 furnished the desired product
in 98% ee, >20:1 dr, and 95:5 branched to linear ratio (entry 3).
Extensive exploration of various bases, including organic and
inorganic bases, revealed that the use of LiOt-Bu afforded the
desired product in comparable selectivities as NaH (entries 4−
8). Previous reports demonstrating the marked effect of LiCl
over the regioselectivity12b,j,13b in Ir-catalyzed allylic alkylations
prompted us to investigate this and related additives. As a result
of these efforts (entries 9−10), the combination of LiBr and
THF, at 25 °C, was found to provide 3aa in >20:1 dr, 95:5
branched:linear ratio, and with >99% ee (Table 1, entry 10).
Under these superior conditions, several more ligands were
examined. Use of ligand L419b afforded 3aa in 96% ee and 12:1
dr (entry 11). Employment of N-aryl-phosphoramidite scaffolds
proved critical to maintaining high diastereoselectivity in the
reaction. Phosphinooxazoline (PHOX) type ligands (e.g., L5),
first used in Ir-catalyzed allylation by Helmchen,9 were also
examined but were found to be poorly suited for our reaction
(entry 12). Finally, we found that the catalyst loading could be
reduced to 1 mol % (entry 13) without loss of selectivity.
With optimized conditions in hand, the scope of substrates
tolerated in the reaction was explored. We found that cinnamyl
derived carbonates bearing either electron-donating (−OMe)
a
Reactions performed under the conditions of Table 1, entry 10.
b
c
Determined by 1H NMR analysis of the crude mixture. Isolated yield
d
of 3 and 4. Determined by chiral HPLC or SFC analysis of the major
diastereomer.
3:4) tended to decrease as the electron deficiency of the aryl
substituents increased (from 95:5 to 71:29, with 4-OMe-C6H4
to 4-CF3-C6H4, respectively, entries 2−4). Heteroaryl sub-
stituents, such as 3-pyridyl, 2-thienyl and 2-furanyl, were also
installed with uniformly excellent enantioselectivities and high
diastereoselectivities (95−98% ee and 10:1−17:1 dr, entries 5−
7).
In addition to aromatic substituents, methyl sorbyl carbonate
was also well tolerated in the chemistry providing diene 3ah,
although with a slight decrease in dr and ee (8:1 dr and 90% ee,
entry 8).21 Moreover, the reaction proceeded smoothly with
ethyl β-ketoester 1b, providing the α-allyl β-ketoester 3ba with
excellent yield and selectivity (entry 9). Gratifyingly, aliphatic
cyclic ketones also proved to be viable participants in the
reaction. Cyclopentanone- and cyclohexanone-based substrates
delivered the products 3ca and 3da in 98−99% ee and 8:1−
20:1 dr, respectively (entries 10−11). Vinylogous ester,
tetrahydropyran-4-one, and 4-piperidinone derivatives fur-
nished the corresponding products (3fa−3ha) in high yields
(85−99%), good diastereoselectivites (13:1−20:1), and
enantioselectivities (97−99%, entries 13−15, Table 2). The
absolute stereochemistry of the product 3af (>99% ee) was
determined as (R,R) by single-crystal X-ray analysis.
During the course of our investigations we became intrigued
by the possibility of developing a sequential allylic alkylation
reaction, in which allylation of a dicarbonyl-stabilized enolate
B
dx.doi.org/10.1021/ja4052075 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
would be followed by decarboxylative allylic alkylation and,
thus, engender the ability to select among all four possible
stereochemical outcomes.22,23 In order to realize such a
consecutive allylic alkylation, we devised a novel oxycarbonyl-
protected enolate, which we hypothesized would successfully
undergo Ir-catalyzed allylic alkylation and be poised to
subsequently participate in Pd catalysis. Specifically, we
envisioned that treatment of 2-(trimethylsilyl)ethyl β-ketoester
5 with fluoride would trigger the release of fluorotrimethylsi-
lane, ethylene, and CO2 to reveal prochiral enolate 6 (Scheme
2). Enolate 6 could then be intercepted and engage in Pd-
entry 1). Use of (S)-t-BuPHOX ligand (S)-L5 resulted in
modest reversal of the inherent diastereoselectivity to generate
9a predominantly (entry 2). Furthermore, we were interested
to find that use of ligand (S)-L7, possessing both an
electronically modified phosphine and a smaller i-Pr substituent
on the oxazoline ring, in contrast to the more standard t-Bu,
produced 9a with improved diastereoselectivity (8a:9a, 1:8 dr)
and 91% yield (entry 3). Alternatively, through judicious choice
of ligand (e.g., (R)-L8), the inherent selectivity of the system
could be enhanced to afford 8a with up to 18:1 dr (entries 4−
5). Cursory investigation revealed that 2-aryl and 2-alkyl
substitutions at the allyl-carbonate are well tolerated: allylic
alkylation products 8b and 8c were obtained in good yields and
with excellent diastereoselectivities.
Scheme 2. Strategic Enolate Protection
In summary, a highly regio-, diastereo-, and enantioselective
method for the synthesis of vicinal tertiary and all-carbon
quaternary centers was realized through the use of an
[Ir(cod)Cl]2/N-aryl-phosphoramidite (L3) catalyst system.
Varied substitutions were well tolerated on both the β-ketoester
and allyl carbonate fragments. A sequential Ir/Pd-catalyzed
dialkylation protocol was also established to deliver bis-allylated
α-quaternary ketones with excellent stereoselectivity, while
affording access to either product diastereomer with catalyst
control. Further studies exploring the mechanisms of these
reactions and exploiting their applications in the total synthesis
of complex natural products are underway in our laboratory.
catalyzed allylic alkylation to deliver α-quaternary ketone 7. In
the case at hand, where β-ketoester 5 contains a chiral branched
R group at the α position we anticipated that with careful
choice of catalyst, we could control the newly generated
stereocenter independent of the absolute stereochemistry of the
side chain.
We were pleased to find that 2-(trimethylsilyl)ethyl β-
ketoester 1e is a highly competent substrate for Ir-catalyzed
allylic alkylation and, under standard conditions, gave the
desired product (3ea) with excellent yield and selectivity
(Table 2, entry 12). Moreover, exposure of 3ea to catalytic
Pd2(dba)3/L6 (Table 3) in the presence of allyl methylcar-
bonate and tetrabutylammonium difluorotriphenylsilicate
(TBAT) generated the desired diallylated α-quaternary ketone
8a in good yield. The use of achiral PHOX ligand L6 revealed
that substrate 3ea displays inherent selectivity under Pd
catalysis, furnishing 8a24 as the major diastereomer (Table 3,
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, characterization data, single crystal X-
ray analysis. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
stoltz@caltech.edu
■
Notes
Table 3. Development of Pd-Catalyzed Diastereoselective
Decarboxylative Allylic Alkylation of TMSE-β-Ketoesters
The authors declare no competing financial interest.
a
ACKNOWLEDGMENTS
■
The authors wish to thank NIH-NIGMS (R01GM080269),
Amgen, the Gordon and Betty Moore Foundation, and Caltech
for financial support. Shanghai Institute of Organic Chemistry
(SIOC) is thanked for a postdoctoral fellowship to W.-B.L. Dr.
Mona Shahgholi and Naseem Torian are acknowledged for
mass spectrometry assistance. Lawrence Henling is acknowl-
edged for X-ray crystallographic structural determination. The
authors thank Mr. Jeff Holder for the preparation of [Ir(cod)
Cl]2. The authors are thankful to Professor Shu-Li You and Mr.
Robert Craig for L3 and (R)-L8, respectively, and for helpful
discussions.
b
c
entry
product (8/9)
ligand
% yield
dr (8:9)
1
2
3
4
5
6
7
8a/9a: R = H
8a/9a: R = H
8a/9a: R = H
8a/9a: R = H
8a/9a: R = H
8b/9b: R = Ph
8c/9c: R = Me
L6
91
79
91
73
85
87
70
2:1
1:2
(S)-L5
d
(S)-L7
(R)-L5
(R)-L8
(R)-L8
(R)-L8
1:8
12:1
18:1
12:1
13:1
REFERENCES
■
(1) Selected reviews: (a) Douglas, C. J.; Overman, L. E. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 5363. (b) Christoffers, J.; Baro, A.
Quaternary Stereocenters: Challenges and Solutions for Organic Synthesis;
Wiley-VCH: Weinheim, 2005. (c) Trost, B. M.; Jiang, C. Synthesis
2006, 369.
(2) Reviews: (a) Krause, N.; Hoffmann-Roder, A. Synthesis 2001,
̈
a
Reactions performed with 1.2 equiv of TBAT and 1.2 equiv of allyl
171. (b) Christoffers, J.; Koripelly, G.; Rosiak, A.; Rossle, M. Synthesis
̈
b
c
methylcarbonate at 0.03 M. Isolated yield of 8 and 9. Determined by
1H NMR analysis of the crude mixture and confirmed by GC analysis.
2007, 1279. Examples: (c) Barnes, D. M.; Ji, J.; Fickes, M. G.;
Fitzgerald, M. A.; King, S. A.; Morton, H. E.; Plagge, F. A.; Preskill, M.;
Wagaw, S. H.; Wittenberger, S. J.; Zhang, J. J. Am. Chem. Soc. 2002,
d
10 mol % ligand was used.
C
dx.doi.org/10.1021/ja4052075 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
124, 13097. (d) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2003,
125, 11204. (e) Mase, N.; Thayumanavan, R.; Tanaka, F.; Barbas, C.
F., III Org. Lett. 2004, 6, 2527. (f) Li, H.; Wang, Y.; Tang, L.; Wu, F.;
Liu, X.; Guo, C.; Foxman, B. M.; Deng, L. Angew. Chem., Int. Ed. 2005,
44, 105. (g) Bencivenni, G.; Wu, L.-Y.; Mazzanti, A.; Giannichi, B.;
Pesciaioli, F.; Song, M.-P.; Bartoli, G.; Melchiorre, P. Angew. Chem.,
Int. Ed. 2009, 48, 7200. (h) Ding, M.; Zhou, F.; Liu, Y.-L.; Wang, C.-
H.; Zhao, X.-L.; Zhou, J. Chem. Sci. 2011, 2, 2035. (i) Chauhan, P.;
Chimni, S. S. Adv. Synth. Catal. 2011, 353, 3203. (j) Mailhol, D.;
Duque, M. d. M. S.; Raimondi, W.; Bonne, D.; Constantieux, T.;
Coquerel, Y.; Rodriguez, J. Adv. Synth. Catal. 2012, 354, 3523.
(3) Reviews: (a) Ito, H.; Taguchi, T. Chem. Soc. Rev. 1999, 28, 43.
(b) Martín Castro, A. M. Chem. Rev. 2004, 104, 2939. (c) Ilardi, E. A.;
Stivala, C. E.; Zakarian, A. Chem. Soc. Rev. 2009, 38, 3133. Selected
communication: (d) Yoon, T. P.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2001, 123, 2911. (e) Helmboldt, H.; Hiersemann, M. Tetrahedron
(14) (a) Kanayama, T.; Yoshida, K.; Miyabe, H.; Takemoto, Y.
Angew. Chem., Int. Ed. 2003, 42, 2054. (b) (a) Chen, W.; Hartwig, J. F.
J. Am. Chem. Soc. 2013, 135, 2068.
(15) Following submission of this manuscript, a diastereoselective
allylic alkylation of aldehydes was reported: Krautwald, S.; Sarlah, D.;
Schafroth, M. A.; Carreira, E. M. Science 2013, 340, 1065.
(16) Ir-phosphoramidite complex was generated in situ by treatment
of [Ir(cod)Cl]2 and ligand with TBD: (a) Welter, C.; Koch, O.;
Lipowsky, G.; Helmchen, G. Chem. Commun. 2004, 896. (b) Shu, C.;
Leitner, A.; Hartwig, J. F. Angew. Chem., Int. Ed. 2004, 43, 4797 and
reference 19b below.
(17) Methyl 2-oxocyclohexanecarboxylate was previously employed
in Ir-catalyzed allylation with 95% ee and 1:1 dr, see ref 13b for detail.
(18) Use of phosphoramidite ligands in asymmetric catalysis:
Teichert, J. F.; Feringa, B. L. Angew. Chem., Int. Ed. 2010, 49, 2486.
(19) (a) Liu, W.-B.; He, H.; Dai, L.-X.; You, S.-L. Synthesis 2009,
2076. (b) Liu, W.-B.; Zheng, C.; Zhuo, C.-X.; Dai, L.-X.; You, S.-L. J.
Am. Chem. Soc. 2012, 134, 4812.
2003, 59, 4031. (f) Abraham, L.; Korner, M.; Schwab, P.; Hiersemann,
̈
M. Adv. Synth. Catal. 2004, 346, 1281. (g) Linton, E. C.; Kozlowski,
M. C. J. Am. Chem. Soc. 2008, 130, 16162. (h) Uyeda, C.; Jacobsen, E.
(20) (a) Wu, Q.-F.; He, H.; Liu, W.-B.; You, S.-L. J. Am. Chem. Soc.
2010, 132, 11418. (b) Zhuo, C.-X.; Liu, W.-B.; Wu, Q.-F.; You, S.-L.
Chem. Sci. 2012, 3, 205. (c) Wu, Q.-F.; Zheng, C.; You, S.-L. Angew.
N. J. Am. Chem. Soc. 2008, 130, 9228. (i) Uyeda, C.; Rotheli, A. R.;
̈
Jacobsen, E. N. Angew. Chem., Int. Ed. 2010, 49, 9753.
Chem., Int. Ed. 2012, 51, 1680.
Using Ir-complex/Lewis acid:
(4) Streuff, J.; White, D. E.; Virgil, S. C.; Stoltz, B. M. Nat. Chem.
2010, 2, 192.
(d) Schafroth, M. A.; Sarlah, D.; Krautwald, S.; Carreira, E. M. J. Am.
Chem. Soc. 2012, 134, 20276.
(21) Poor regioselectivity was observed when aliphatic allyl
carbonates, such as crotyl carbonate, were employed.
(22) We and others have extensively investigated the enantioselective
decarboxylative allylic alkylation of cyclic systems: (a) Mohr, J. T.;
Stoltz, B. M. Chem. Asian J. 2007, 2, 1476. (b) Behenna, D. C.; Stoltz,
B. M. J. Am. Chem. Soc. 2004, 126, 15044. (c) Mohr, J. T.; Behenna, D.
C.; Harned, A. M.; Stoltz, B. M. Angew. Chem., Int. Ed. 2005, 44, 6924.
(d) Behenna, D. C.; Mohr, J. T.; Sherden, N. H.; Marinescu, S. C.;
(5) (a) Doyle, A. G.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2007, 46,
3701. (b) Trost, B. M.; Cramer, N.; Silverman, S. M. J. Am. Chem. Soc.
2007, 129, 12396. (c) Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2007,
129, 14548. (d) Trost, B. M.; Miller, J. R.; Hoffman, C. M., Jr. J. Am.
Chem. Soc. 2011, 133, 8165. (e) Trost, B. M.; Silverman, S. M.;
Stambuli, J. P. J. Am. Chem. Soc. 2011, 133, 19483. (f) Tan, J.; Cheon,
C.-H.; Yamamoto, H. Angew. Chem., Int. Ed. 2012, 51, 8264.
(6) (a) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921.
(b) Helmchen, G.; Kazmaier, U.; Forster, S. In Catalytic Asymmetric
̈
́
Harned, A. M.; Tani, K.; Seto, M.; Ma, S.; Novak, Z.; Krout, M. R.;
Synthesis, 3rd ed.; Ojima, I., Ed; Wiley: Hoboken, NJ, 2010, p 497.
(7) First example: Takeuchi, R.; Kashio, M. Angew. Chem., Int. Ed.
Engl. 1997, 36, 263.
McFadden, R. M.; Roizen, J. L.; Enquist, J. A., Jr.; White, D. E.; Levine,
S. R.; Petrova, K. V.; Iwashita, A.; Virgil, S. C.; Stoltz, B. M. Chem.
Eur. J. 2011, 17, 14199. (e) Trost, B. M.; Xu, J. J. Am. Chem. Soc. 2005,
127, 2846. (f) Nakamura, M.; Hajra, A.; Endo, K.; Nakamura, E.
Angew. Chem., Int. Ed. 2005, 44, 7248. (g) Burger, E. C.; Barron, B. R.;
Tunge, J. A. Synlett 2006, 2824. (h) Trost, B. M.; Bream, R. N.; Xu, J.
Angew. Chem., Int. Ed. 2006, 45, 3109.
(8) Recent reviews: (a) Helmchen, G.; Dahnz, A.; Dubon, P.;
̈
Schelwies, M.; Weihofen, R. Chem. Commun. 2007, 675. (b) Helm-
chen, G. In Iridium Complexes in Organic Synthesis; Oro, L. A.; Claver,
C., Eds.; Wiley-VCH: Weinheim, 2009; p 211. (c) Hartwig, J. F.; Pouy,
M. J. Top. Organomet. Chem. 2011, 34, 169. (d) Tosatti, P.; Nelson, A.;
Marsden, S. P. Org. Biomol. Chem. 2012, 10, 3147. (e) Liu, W.-B.; Xia,
J.-B.; You, S.-L. Top. Organomet. Chem. 2012, 38, 155.
(23) Attempts to establish a single-vessel diallylation protocol have,
thus far, proved unsuccessful. Subjecting allyl 2-oxocyclohexanecarbox-
ylate to the optimized reaction conditions resulted in nonstereose-
lective decarboxylative allylic alkylation. Sequential addition of all
reaction components to substrate 3ea also failed.
(9) Janssen, J. P.; Helmchen, G. Tetrahedron Lett. 1997, 38, 8025.
(10) Ohmura, T.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 15164.
(11) Mechanistic studies: (a) Kiener, C. A.; Shu, C.; Incarvito, C.;
Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 14272. (b) Madrahimov, S.
T.; Markovic, D.; Hartwig, J. F. J. Am. Chem. Soc. 2009, 131, 7228.
(24) See SI for the determination of the relative configuration.
(c) Spiess, S.; Raskatov, J. A.; Gnamm, C.; Brodner, K.; Helmchen, G.
̈
Chem.Eur. J. 2009, 15, 11087. (d) Raskatov, J. A.; Spiess, S.;
Gnamm, C.; Brodner, K.; Rominger, F.; Helmchen, G. Chem.Eur. J.
̈
2010, 16, 6601. (e) Madrahimov, S. T.; Hartwig, J. F. J. Am. Chem. Soc.
2012, 134, 8136. (f) Raskatov, J. A.; Jakel, M.; Straub, B. F.; Rominger,
̈
F.; Helmchen, G. Chem.Eur. J. 2012, 18, 14314.
Review:
(g) Hartwig, J. F.; Stanley, L. M. Acc. Chem. Res. 2010, 43, 1461.
(12) Examples: (a) Lipowsky, G.; Miller, N.; Helmchen, G. Angew.
Chem., Int. Ed. 2004, 43, 4595. (b) Alexakis, A.; Polet, D. Org. Lett.
2004, 6, 3529. (c) Graening, T.; Hartwig, J. F. J. Am. Chem. Soc. 2005,
127, 17192. (d) Weix, D. J.; Hartwig, J. F. J. Am. Chem. Soc. 2007, 129,
7720. (e) He, H.; Zheng, X.-J.; Li, Y.; Dai, L.-X.; You, S.-L. Org. Lett.
2007, 9, 4339. (f) Spiess, S.; Welter, C.; Franck, G.; Taquet, J.-P.;
Helmchen, G. Angew. Chem., Int. Ed. 2008, 47, 7652. (g) Liu, W.-B.;
He, H.; Dai, L.-X.; You, S.-L. Org. Lett. 2008, 10, 1815. (h) Chen, W.;
Hartwig, J. F. J. Am. Chem. Soc. 2012, 134, 15249. (i) Hamilton, J. Y.;
Sarlah, D.; Carreira, E. M. J. Am. Chem. Soc. 2013, 135, 994. (j) Bartels,
B.; Helmchen, G. Chem. Commun. 1999, 741 and references therein.
(13) (a) Dahnz, A.; Helmchen, G. Synlett 2006, 697. (b) Polet, D.;
Alexakis, A.; Tissot-Croset, K.; Corminboeuf, C.; Ditrich, K. Chem.
Eur. J. 2006, 12, 3596. (c) Xu, Q.-L.; Dai, L.-X.; You, S.-L. Adv. Synth.
Catal. 2012, 354, 2275.
D
dx.doi.org/10.1021/ja4052075 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX