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Nickel-Catalyzed 1,2-Diarylation of Simple Alkenyl Amides Joseph Derosa, Roman Kleinmans, Van T. Tran, Malkanthi K. Karunananda, Steven R. Wisniewski, Martin D. Eastgate, and Keary M. Engle J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b11942 • Publication Date (Web): 07 Dec 2018 Downloaded from http://pubs.acs.org on December 7, 2018
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Journal of the American Chemical Society
Nickel-Catalyzed 1,2-Diarylation of Simple Alkenyl Amides Joseph Derosa‡, Roman Kleinmans†‡, Van T. Tran†‡, Malkanthi K. Karunananda‡, Steven R. Wisniewski§, Martin D. Eastgate§, and Keary M. Engle‡* ‡
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States Chemical & Synthetic Development, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, New Jersey 08903, United States Supporting Information Placeholder
§
ABSTRACT: A nickel-catalyzed conjunctive cross-coupling
of simple alkenyl amides with aryl iodides and aryl boronic esters is reported. The reaction is enabled by an electrondeficient olefin (EDO) ligand, dimethyl fumarate, and delivers the desired 1,2-diarylated products with excellent regiocontrol. Under optimized conditions, a wide range of amides derived from 3-butenoic acid, 4-pentenoic acid, and allyl amine are compatible substrates. This method represents the first example of regiocontrolled 1,2-diarylation directed by a native amide functional group. Computational analysis sheds light on potential substrate binding mode and the role of EDO ligand in the reductive elimination step.
Alkene starting materials serve as diversifiable chemical feedstocks for rapid build-up of molecular complexity.1 From the perspective of synthetic chemists, the ability to regioselectively install two unique components across an alkene of interest is attractive. One approach toward alkene difunctionalization that has rapidly garnered interest in recent years is conjunctive cross-coupling, a strategy in which alkene starting materials can be used as ambiphilic reagents to unite various electrophiles and organometallic nucleophiles under transition metal catalysis.2 In the context of regioselective 1,2-diarylation specifically, this potentially powerful synthetic strategy can be difficult to implement on electronically unactivated, non-conjugated alkenes. Recent advances in transition-metal-catalyzed 1,2-diarylation of alkenes have generally relied on the formation of a stabilized alkylmetal intermediate after an initial migratory insertion event (Scheme 1). Due to the inherent reactivity of alkylmetal species, the alkene substrates are often limited to 1,3-dienes3 or styrenes4 that react to form electronically stabilized π-allyl or π-benzyl intermediates, respectively. In these cases, electronic stabilization allows for regiocontrolled addition of an aryl organometallic reagent to afford the desired 1,2-diarylated product. Several groups have made major contributions to styrene 1,2-diarylation under palladium and
nickel catalysis, showcasing the ability of this method to lead to complex polyarylated alkanes (Scheme 1A).4 With non-conjugated alkenes it is more difficult to overcome undesired β-hydride elimination from the alkylmetal intermediates. As a consequence, the scope of nonconjugated alkenes via this mode of reactivity has been classically limited to special cases, such as norbornene-type substrates.5 In an effort to employ more synthetically useful substrates, several research groups, including our own, have employed strongly coordinating directing groups tethered to the alkene to stabilize the putative alkylmetal species and facilitate selective 1,2-diarylation under nickel catalysis (Scheme 1B).6 Though this approach has enabled robust 1,2difunctionalization, the need to install and then remove the directing auxiliary detracts from the practicality of these methods. With more weakly coordinating directing groups, Scheme 1. Background and Synopsis of Current Work A. Transition-metal-catalyzed 1,2-diarylation of styrenes R1
[M] R1
cat. [M]
R2
Ar–X
Ar R1
Ar–[M]
R2
Ar
[M] = Pd, Ni
R2
Ar
[electronically stabilized]
B. Nickel-catalyzed 1,2-diarylation of alkenes using a directing group strategy
N
R2 Si
NPh
O R
N H
NPh R1
N cat. Ni Ar–ZnX Ar–X
cat. Ni Alkyl–ZnX or Ar–ZnX [C(sp 2)]–X
[Giri, 2017]
[Engle, 2017]
R2 cat. Ni + cat. Ag/Cu Ar–ZnX Ar–X
cat. Ni Ar–ZnX Ar–X [Giri, 2018]
[Giri, 2018]
[requires installation of strongly coordinating auxiliaries]
C. Nickel-catalyzed 1,3-diarylation of non-conjugated alkenes H N
N
cat. Ni(cod) 2 cat. dppm Ar–X Ar–B(OH)2
N
NPh
H N
N N
R1 Ar
Ar
R2
[Zhao, 2018]
cat. NiBr 2 cat. P(OPh) 3 Ar–X Ar–ZnX [Giri, 2018]
O
Ar
Ar
R1 R2 [after H + workup]
D. Nickel-catalyzed 1,2-diarylation of simple alkenyl amides (this work) O
X NiII Ar
MeO 2C O
CO 2Me
[Ar–B(OR) 2] O Ar Ar Ar carbonickelation R 2N R 2N transmetalation / n n n reductive elimination n = 1, 2 • innate directivity • broad aryl scope • diverse amide compatibility • mild conditions • ligand-enabled NiII
R 2N
alkylnickelacycles are prone to rapid β-hydride elimination/reinsertion, which the Zhao and Giri groups have cleverly exploited in 1,3-diarylation processes (Scheme 1C).6c,7,8 Giri recently reported that 1,2-diarylation can be promoted
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in such systems through addition of copper or silver additives.6e It is important to note that alkyl radical addition to alkenes and interception with metalloradical species has also been shown to be a viable strategy toward 1,2difunctionalization of non-conjugated alkenes,14 but this strategy has not been demonstrated in the context of 1,2diarylation. The goal of the present study was to develop an efficient alkene 1,2-diarylation directed by simple monodentate functional groups. Our inspiration for this approach originated from a series of seminal publications by Fu and coworkers, in which simple amides and other carbonyl-containing compounds were used to effectively direct C–X oxidative addition and stabilize the resulting intermediate for a variety of enantioselective crosscoupling reactions under nickel catalysis.9 Given our group’s interest in nickel-catalyzed alkene difunctionalization,10 we wondered if previously employed, strongly coordinating directing groups such as 8-aminoquinoline (AQ) could be replaced with simple amides. Practically speaking, this advance would be advantageous in that it would allow use of diverse amide directing groups, including those that are readily cleavable as well as those that are native to the target compound of interest. Conceptually, it would present the opportunity to engage weakly coordinating carbonyl directing groups, rather than more commonly used N(sp2)-based directing groups, and to identify ancillary ligands that can bind to the open coordination site around nickel to facilitate key steps in catalysis. Table 1. Variations from Standard Reaction Conditionsa 15 mol% Ni(cod) 2 15 mol% L 2 equiv NaOH
O R
+ Ph
N H
I
+
(1.5 equiv)
1a
Ph
B
R= OMe
i-BuOH, RT, 12 h
(1.5 equiv) O
MeO
O R
B(nep)
O
Me
Ph
2aa
Me
[B(nep)]
Ph
N H
MeO 2C
CO 2Me
L = dimethyl fumarate
variation from standard conditions
% Yieldb 2aa
1
none
92 (88)c
2
no ligand
Entry
n.d.
3
PPh 3 or PCy 3 instead of dimethyl fumarate
n.d.
4
bipyridine or phenathroline instead of dimethyl fumarate
n.d.
5
bromobenzene instead of iodobenzene
45
6
PhB(OH) 2 instead of PhB(nep)
78
7
PhBpin instead of PhB(nep)
65
8
dioxane instead of i-BuOH
40
9
1.0 equiv of both iodobenzene and PhB(nep) instead of 1.5 equiv
59
10
KOAc instead of NaOH
n.d.
11 12
10 mol% Ni(cod) 2 NiCl 2, NiBr 2, Ni(acac) 2, or NiI 2 instead of Ni(cod) 2
75 n.d.
13
NiCl 2, NiBr 2, Ni(acac) 2, or NiI 2
with Mn 0
instead of Ni(cod) 2
n.d.
a
Reaction conditions: 1a (0.1 mmol), 0.2 M i-BuOH. bPercentages represent 1H NMR yields using CH2Br2 as internal standard unless noted otherwise; n.d. = not detected. cParentheses represent isolated yield.
To initiate our investigation, we surveyed a range of monodentate amides and found that among many that were effective, electron-rich N-benzyl amides consistently gave high yields. For this reason, we elected to use 2,4-dimethoxy benzyl amide 1a as the pilot alkene substrate, along with iodo-
benzene and phenylboronic acid neopentyl glycol ester (PhB(nep)) as coupling partners, and Ni(cod)2 as precatalyst (Table 1). Considering the difficulty in promoting productive 1,2-diarylation with a weakly coordinating amide, we reasoned that an electron-withdrawing L-type ligand could potentially (1) prevent β-hydride elimination, (2) facilitate C–C reductive elimination, and (3) encourage substrate binding to the nickel catalyst. Electron-deficient olefins (EDOs) represent a unique class of ligands that have been demonstrated to enable various cross-coupling reactions by promoting the reductive elimination step and preventing βhydride elimination.11,12 To our delight, the use of dimethyl fumarate as ligand under optimized reaction conditions delivered the desired product in 88% isolated yield (Entry 1).13 Interestingly, removal of the ligand or substitution for more commonly employed phosphine and bipyridyl-based ligands did not lead to the formation of the desired product, but instead gave ~25% of the biphenyl Suzuki–Miyaura product (Entries 2 and 3). Both free boronic acid and pinacol boronic esters also gave the corresponding product in 78% and 65% yield, respectively (Entries 5 and 6). Despite numerous attempts to use Ni(II) precatalysts, Ni(cod)2 was ultimately the most competent nickel source for this reaction (Entries 11 and 12). Having identified optimal conditions, we next sought to test the electrophile and nucleophile scope of this nickelcatalyzed 1,2-diarylation reaction (Table 2). First, we elected to evaluate the nucleophile scope using iodobenzene as the electrophile (2a–2m). With respect to the B(nep) component, both electron-donating and electron-withdrawing groups in the para-position gave the desired products in good to excellent yields (2a–2f). Tethered alcohol- (2e) and chloride-containing (2f) aryl fragments were also tolerated, allowing for further downstream diversification. Aryl nucleophiles with substituents at the meta-position (2g–2l) were also competent, including ketones (2i) and sulfones (2k). Given the potential sensitivity of the steric environment around the putative metalacycle, we were encouraged by the compatibility of ortho-Me substituted B(nep), which gave the desired product in 60% yield (2m). Next, we explored the electrophile scope using PhB(nep) as the nucleophile (2n-2z). In general, alkylated aryl iodides performed well under the optimized conditions (2n–2q). Electron-rich aryl iodides also gave the desired products in moderate yields, tolerating O-, S-, and N-heteroatoms (2r– 2t). Interestingly, the presence of a second amide on the electrophilic component could also be accommodated (2y). In addition, 1,1-disubstituted vinyl iodides were reactive under optimized conditions (2z). Electron-poor aryl iodides were substantially less reactive, and heterocyclic aryl iodides and boronic esters were not suitable coupling partners in this reaction (see Supporting Information). After the evaluation of our coupling partner scope, we turned our attention to other alkene substrates. Gratifyingly, 1,1-disubstituted alkenes could serve as competent sub-
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strates to set all-carbon quaternary centers, albeit in modest yield (3a). Upon treating γ,δ-unsaturated alkene substrate 3b to the standard reaction conditions with iodobenzene and phenyl B(nep), we were pleased to observe the exclusive formation of 1,2-diarylation product 4ba in 67% yield. Furthermore, hetero-diarylation could also be achieved (4bb and 4bc). This method is not without its limitations. In particular, δ,ε-unsaturated alkenes, α-substituted alkenes, and
internal alkenes were found to be unreactive at this stage of development (3c–3f). In comparison, our previously reported AQ-directed dicarbofunctionalization is compatible with the last three of those four alkenyl amide subtypes (3d–3f).6a Gratifyingly, a wide range of N-substituted amides were suitable substrates under the reaction conditions previously optimized for amide 1a (Table 3).
Table 2. Electrophile, Nucleophile, and Alkene Scopea O R
N H
+
+
R1
B R2
1a
15 mol% Ni(cod) 2 15 mol% L 2 equiv NaOH
Me Me
O
I
O
R2 O R
i-BuOH, RT, 12 h
[B(nep)]
R1
MeO
OMe
R
Ph
OMe
Me
N H
O R
O Ph
N H
R
2a, 88% (0.2 mmol) 85% (2.0 mmol) [X-ray] Me
F 3C
O
OH
CF3
R
2g, 93%
N H
O Ph
N H
R
N H
2b, 92%
Cl
O Ph
2h, 77%
O
O Ph
R
N H
2d, 89%
F
O R
N H
2c, 82%
Me
Ph
R
R
Ph
Ph
N H
2e, 63%
2f, 79%
O
CF3
O Ph
N H
t-Bu
Ph
2aa, 88% homo-diarylation
R
L = dimethyl fumarate
2a–2z
nucleophile scope O
CO 2Me
MeO 2C
R=
N H
O Ph
N H
SO2Me
R
2i, 73%
O Ph
N H
R
2j, 90%
O Ph
N H
R
2k, [ArB(OH) 2] 39%
N H
O Ph
R
2l, 80%
Me Ph
N H
2m, 60%
electrophile scope O R
N H
R
Ph
O R
2n, (R 2o, (R 2p, (R 2q, (R
= Me) 83% = Et) 80% = i-Pr) 79% = Ph) 75%
OMe
Ph
O R
N H
2r, 67%
O
SMe
Ph
O R
N H
2s, 50%
N H
N
Ph
O R
N H
2t, 59%
Ph iPr
2u, 81%
Me O R
N H
Ph
O Me
2v, 87%
R
N H
Ph
O R
2w, 34%
Me
N H
Ph
O R
2x, 92%
NHAc
Ph
O R
N H
2y, 55%
N H
Ph Me Me
2z, 63%
alkene scope
O
Me
O Me
N H MeO
OMe
Ph
unreactive alkenes
Me
MeO
[1,1-disubstituted alkene]
OMe
MeO
4a, 30%
N H MeO
N H MeO
OMe
3b
[γ,δ-unsaturated alkene]
a
OMe
MeO
OMe
3c
O R2
OMe
4ba, (R1 = H, R 2 = H) 67% R1 [X-ray] 4bb, (R1 = H, R 2 = Me) 44% 4bc, (R1 = Me , R 2 = H) 54%
MeO
OMe
O Me
N H
3e
[E-internal alkene]
Me
3d
[α-substituted alkene]
[δ,ε-unsaturated alkene]
O O
N H
N H
N H
3a
O
O
N H MeO
OMe
Et
3f
[Z-internal alkene]
Reactions performed on 0.2 mmol scale unless stated otherwise. Percentages represent isolated yields.
Removal of one methoxy group from the standard amide substrate had only a minor impact on reactivity, as 81% yield of the desired product 6a was still obtained. Unfortunately, no stereoinduction was observed when using chiral benzylamine substrates (6b). Cyclopropyl, cyclobutyl-, cyclohexyl-, and adamantyl-derived amides reacted to give desired products in good yields (6c–6f). Alkenyl amides with tethered heteroatoms and heterocycles also per-
formed well (6g–6i). The reaction was found to be chemoselective in that in exclusively functionalized the terminal alkene over the distal trisubstituted alkene (6i). Table 3. β,γ-unsaturated Amide Scopea
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O
I
+
[N]
15 mol% Ni(cod) 2 15 mol% L 2 equiv NaOH
B(nep)
+
[N]
Me
5a–5l
Me
O
i-BuOH, RT, 12 h
6a–6l
amide scope [N] =
Me N H
N H
MeO
6b, 73% (1.1:1
6a, 81%
N H
d.r.)b
N H
6c, 68%
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similar results to the earlier system (8ea–8ed). Noncarbonyl-containing Bn-protected allyl amine did not react (8f). Based on these findings, we concluded that a carbonyl-directed model was consistent with the observed reactivity trends.
N H
6d, 80%
Scheme 2. Initial Rate Trends
6e, 74%
O
(standard conditions) PhO
N H
6f, 75%
H 2N
O
N H
N H
6g, 93%
6h, 42%c
Bn
Bn
N
N H
Bn
Me
6l, 74%c
1a + Ar1 –I + Ar2–Bnep N H
Bn
N Ph
6m, 84%c
minimal electronic influence
a
Somewhat surprisingly, N,N-dibenzyl amide still delivered the 1,2-diarylated product in good yield (6l). With other tertiary amides, we observed that sterically bulky groups attenuated reactivity (6m–6o). This observation, viewed in conjunction with the result with the chiral benzyl amine (i.e., negligible chirality transfer) led us to speculate that the reaction may be proceed via carbonyl coordination rather than nitrogen atom coordination. Table 4. Protected Allylic Amine Scopea PG
I
+
N H
7a–7f
15 mol% Ni(cod) 2 15 mol% L 2 equiv NaOH
B(nep)
+
Me
i-BuOH, RT, 12 h
PG
N H Me
8a–8f
protected allylic amines PG = O
O
Me
O
t-Bu
8a, 20%b
O
t-BuO
8c, 29%c [X-ray]
8b, 70%
O
Ad
Ph
8d, 70%
8ea, 81%
Ph
8f, n.d.
O O Ph
I
+ R1
N H
B(nep)
(as above)
Ph
N H
+ R2
8ea–8ed
7e
R1 R2
representative coupling partner scope O Ph
O N H
8eb, 34%
Ph OMe
O N H
Ph
8ec, 69%
N H
8ed, 75% F OMe
a Reactions performed on 0.2 mmol scale unless stated otherwise. Percentages represent isolated yield. b NaOt-Bu (1 equiv) used in place of NaOH. c NaOH (1 equiv).
In order to gain further insight into the coordination mode of the amide directing group and expand the substrate scope, we next examined substrates in which the nitrogen atom would be incorporated within the putative nickelacycle intermediate, namely protected allyl amines. Excitingly, this class of substrates also reacted under standard nickelcatalyzed 1,2-diarylation conditions in a regiocontrolled fashion (Table 4). Ac-, Piv-, and Boc-protecting groups served as competent directing groups in this reaction (8a– 8c). With benzoyl-protected allyl amine, we tested representative coupling partner combinations and obtained
Ar1
X = OMe ~ Me ~ H ~ Cl ~ CF3
X
Reactions performed on 0.2 mmol scale unless stated otherwise. Percentages represent isolated yields. bThe d.r. by crude 1H NMR wass 1.0:1; d.r. of isolated compound was 1.1:1. c NaOH (1 equiv)
Ar2
initial rates
+
6o, 43%c
N H
I
Bnep
N t-Bu
6n, 65%c
R
coupling partners
6j, 84%
6i, 86%
N
Bn
6k, 19%
S
I
Bnep
Y = OMe ~ H ~ Me >> Cl > CF3
+ Y
substantial electronic influence
The dramatic reactivity enhancement enabled by the EDO ligand and the broad amide directing group scope prompted us to examine the reaction mechanism through kinetics and computation. First, we evaluated reaction rates with a series of electronically diverse aryl iodides and boronates (see Scheme 2 and SI). We found that the electronic properties of the aryl Bnep component had a negligible influence on rate, while electron-neutral and -rich aryl iodides reacted faster than electron-poor electrophiles. The former trend is inconsistent with a scenario in which transmetalation is rate-limiting, while the latter is inconsistent with a scenario where oxidative addition is rate limiting. One plausible explanation is that migratory insertion of the arylnickel intermediate into the alkene is the slow step in the catalytic cycle. To shed more light on the preferred coordination mode of the substrate with nickel and the impact of the EDO ligand on the reductive elimination step (where it was expected to play a beneficial role), we performed computational analysis using density functional theory (DFT). Notably, despite a plethora of elegant experimental evidence regarding the beneficial effects of EDO ligands in promoting reductive elimination in nickel-catalyzed cross-coupling, a head-tohead comparison of the effect of these ligands on reductive elimination has not been quantified from a computational perspective.12c,15 Our calculations indicate that for each of the proposed intermediates, the corresponding carbonylbound nickel species are 3–8 kcal/mol lower in energy compared to their nitrogen-bound counterparts, supporting the hypothesis that the carbonyl group directs catalysis (see Supporting Information). The computed transition state for reductive elimination with dimethyl fumarate (TS1) has an activation energy of ΔG‡ = 2.6 kcal/mol, significantly lower than the corresponding transition states for ethylene-bound nickel (ΔG‡ = 14.6 kcal/mol, TS2)16 and solvent-bound nickel (ΔG‡ = 37.4 kcal/mol, TS3). Figure 1. Computed Transition States for Reductive Elimination
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Journal of the American Chemical Society R E
R
NH
R
NH
O
O
NiII
NiII
X-ray data for compound 2a (CIF)
NH
O
X-ray data for compound 4ba (CIF)
NiII
L
E
X-ray data for compound 8c (CIF) TS1 E =CO 2Me
TS2
TS3 L= i-BuOH
NMR Data (ZIP)
AUTHOR INFORMATION Corresponding Author
*
[email protected] Author Contributions TS2 ΔG = 14.6 kcal/mol
TS1 ΔG = 2.6 kcal/mol
TS3 ΔG = 37.4 kcal/mol
A mechanism consistent with the observations made thus far is proposed in Scheme 3. First, the nickel catalyst oxidatively adds into the aryl iodide and coordinates with the amide and alkene moieties of the substrate. Next, the arylnickel(II) species undergoes rate-limiting 1,2-migratory insertion to yield the corresponding 5- or 6-membered nickelacycle. Transmetalation with ArB(nep) and subsequent reductive elimination, promoted by the EDO ligand, yields the desired 1,2-diarylation product and regenerates the catalyst. Scheme 3. Proposed Catalytic Cycle O R
N R
O
Ar2 Ar1
Ar1 I + R N R
LnNi 0
n
reductive elimination
NR 2
NR 2 E
n
oxidative addition/ substrate coordination
O NiII E Ar2
O I NiII Ar1
n Ar1
transmetalation Ar2 Bnep
NaOH
NR 2
RO Bnep E
O NiII
n
n
E OH E = CO 2Me
Ar1
NaI
migratory insertion/ ligand exchange
In conclusion, we have developed a regioselective, nickelcatalyzed 1,2-diarylation of simple, non-conjugated alkenyl amides using aryl iodides and aryl boronates by employing dimethyl fumarate as ligand. The reaction was found to proceed with a broad range of aryl electrophiles and aryl nucleophiles, and allows for both β,γ- and γ,δ-diarylation of carbonyl compounds. Computational analysis determined that an oxygen-bound nickelacycle is energetically preferred and that the EDO ligand dramatically lowers the activation energy of the reductive elimination step. ASSOCIAT ED CONT ENT Supporting Information The Supporting Information is available free of charge via the Internet at http://pubs.acs.org. Experimental details, analytical data, and 1H, 13C and 19F NMR spectra (PDF)
†
R. K. and V. T. T. contributed equally.
Notes The authors declare no competing financial interest.
A CKNOWLEDGMENT This work was financially supported by The Scripps Research Institute (TSRI), Pfizer, Inc., Bristol-Myers Squibb (Unrestricted Grant), and the National Science Foundation (CHE1800280). We further acknowledge the NSF for a Graduate Research Fellowship (NSF/DGE-1346837, J.D.). We thank Dr. Jacob T. Edwards (Celgene), Tyler G. Saint-Denis (Yu lab, TSRI), and Vincent A. van der Puyl (Shenvi lab, TSRI) for helpful discussion. We further thank Prof. Arnold L. Rheingold, Dr. Milan Gembicky and Dr. Curtis E. Moore for X-ray crystallographic analysis (UCSD).
REFERENCES (1) For representative reviews on alkene functionalization, see: (a) Saini, V.; Stokes, B. J.; Sigman, M. S. Transition-Metal-Catalyzed LaboratoryScale Carbon-Carbon Bond-Forming Reactions of Etyhlene. Angew. Chem., Int. Ed. 2013, 52, 11206–11220. (b) Coombs, J. R.; Morken, J. P. Catalytic Enantioselective Functionalization of Unactivated Terminal Alkenes. Angew. Chem., Int. Ed. 2016, 55, 2636–2649. (2) For representative reviews on conjunctive cross-coupling, see: (a) Derosa, J.; Tran, V. T.; van der Puyl, V. A.; Engle, K. M. Carbon–Carbon π-Bonds as Conjunctive Reagents in Cross-Coupling. Aldrichimica Acta 2018, 51, 21–32. (b) Giri, R.; KC, S. Strategies toward Dicarbofunctionalization of Unactivated Olefins by Combined Heck Carbometalation and Cross-Coupling. J. Org. Chem. 2018, 83, 3013–3022. (3) For palladium-catalyzed 1,2-diarylation of 1,3-dienes, see: Stokes, B. J.; Liao, L.; de Andrade, A. M.; Wang, Q.; Sigman, M. S. A PalladiumCatalyzed Three-Component-Coupling Strategy for the Differential Vicinal Diarylation of Terminal 1,3-Dienes. Org. Lett. 2014, 16, 4666– 4669. (4) For transition-metal-catalyzed 1,2-diarylation of styrenes, see: (a) Urkalan, K. B.; Sigman, M. S. Palladium-Catalyzed Oxidative Intermolecular Difunctionalization of Terminal Alkenes with Organostannanes and Molecular Oxygen. Angew. Chem., Int. Ed. 2009, 48, 3146–3149. (b) Kuang, Z.; Yang, K.; Song, Q. Pd-Catalyzed 1,2-Diarylation of Vinylarenes at Ambient Temperature. Org. Chem. Front. 2017, 4, 1224– 1228. (c) KC, S.; Dhungana, R. K.; Shrestha, B.; Thapa, S.; Khanal, N.; Basnet, P.; Lebrun, R. W.; Giri, R. Ni-Catalyzed Regioselective Alkylarylation of Vinylarenes via C(sp3)–C(sp3)/C(sp3)–C(sp2) Bond Formation and Mechanistic Studies. J. Am. Chem. Soc. 2018, 140, 9801– 9805. (d) Gao, P.; Chen, L.-A.; Brown, M. K. Nickel-Catalyzed Stereoselective Diarylation of Alkenylarenes. J. Am. Chem. Soc. 2018, 140, 10653– 10657. (5) (a) Catellani, M.; Chiusoli, G. P.; Concari, S. A New PalladiumCatalyzed Synthesis of cis,exo-2,3-diarylsubstituted bicycle[2.2.1]heptanes or bicycle[2.2.1]hept-2-enes. Tetrahedron 1989, 45,
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5263–5268. (b) Shaulis, K. M.; Hoskin, B. L.; Townsend, J. R.; Goodson, F. E.; Incarvito, C. D.; Rheingold, A. L. Tandem Suzuki Coupling– Norbornadiene Insertion Reactions. A Convenient Route to 5,6Diarylnorbornene Compounds. J. Org. Chem. 2002, 67, 5860–5863. (6) (a) Derosa, J.; Tran, V. T.; Boulous, M. N.; Chen, J. S.; Engle, K. M. Nickel-Catalyzed β,γ-Dicarbofunctionalization of Alkenyl Carbonyl Compounds via Conjunctive Cross-Copupling. J. Am. Chem. Soc. 2017, 139, 10657–10660. (b) Shrestha, B.; Basnet, P.; Dhungana, R. K.; KC, S.; Thapa, S.; Sears, J. M.; Giri, R. Ni-Catalyzed Regioselective 1,2Dicarbofunctionalization of Olefins by Intercepting Heck Intermediates as Imine-Stabilized Transient Metallacycles. J. Am. Chem. Soc. 2017, 139, 10653–10656. (c) Li, W.; Boon, J. K.; Zhao, Y. Nickel-Catalyzed Difunctionalization of Allyl Moieties using Organoboronic Acids and Halides with Divergent Regioselectivities. Chem. Sci. 2018, 9, 600–607. (d) Thapa, S.; Dhungana, R. K.; Magar, R. T.; Shrestha, B.; KC, S.; Giri, R. Ni-Catalysed Regioselective 1,2-Diarylation of Unactivated Olefins by Stabilized Heck Intermediates as Pyridylsilyl-coordinated Transient Metallacycles. Chem. Sci. 2018, 9, 904–909. While this manuscript was in preparation, Giri reported that copper or silver additives promote 1,2diarylation, presumably by generating cationic organonickel intermediates via halide abstraction: (e) Basnet, P.; KC, S., Dhungana, R. K.; Shrestha, B.; Boyle, T. J.; Giri, R. Synergistic Bimetallic Ni/Ag and Ni/Cu Catalysis for Regioselective γ,δ-Diarylation of Alkenyl Ketimines: Addressing β-H Elimination by in situ Generation of Cationic Ni(II) Catalysts. J. Am. Chem. Soc. 2018, 140, 15586–15590. (7) In Ref. 6c, 1,2-dicarbofunctionalization is observed when an alkenyl bromide electrophile is used, but aryl iodides lead preferentially to 1,3diarylated products. (8) KC, S.; Dhungana, R. K.; Shrestha, B.; Thapa, S.; Khanal, N.; Basnet, P.; Lebrun, R. W.; Giri, R. Ni-Catalyzed Regioselective β,δ-Diarylation of Unactivated Olefins in Ketimines via Ligand-Enabled Contraction of Transient Nickellacycles: Rapid Access to Remotely Diarylated Ketones. J. Am. Chem. Soc. 2018, 140, 7782–7786. (9) For examples of chelating electrophiles in C(sp3)–C(sp3) crosscoupling, see: (a) Owston, N. A.; Fu, G. C. Asymmetric Alkyl–Alkyl Cross-Couplings of Unactivated Secondary Alkyl Electrophiles: Stereoconvergent Suzuki Reactions of Racemic Acylated Halohydrins. J. Am. Chem. Soc. 2010, 132, 11908–11909. (b) Lu, Z.; Wilsily, A.; Fu, G. C. Stereoconvergent Amine-Directed Alkyl–Alkyl Suzuki Reactions of Unactivated Secondary Alkyl Chlorides. J. Am. Chem. Soc. 2011, 133, 8154– 8157. (c) Zultanski, S. L.; Fu, G. C. Catalytic Asymmetric γ-Alkylation of Carbonyl Compounds via Stereoconvergent Suzuki Cross-Couplings. J. Am. Chem. Soc. 2011, 133, 15362–15364. (d) Wilsily, A.; Tramutola, F.; Owston, N. A.; Fu, G. C. New Directing Groups for Metal-Catalyzed Asymmetric Carbon–Carbon Bond-Forming Processes: Stereoconvergent Alkyl–Alkyl Suzuki Cross-Couplings of Unactivated Electrophiles. J. Am. Chem. Soc. 2012, 134, 5794–5797. (10) (a) Derosa, J.; van der Puyl, V. A.; Tran, V. T.; Liu, M.; Engle, K. M. Directed Nickel-Catalyzed 1,2-Dialkylation of Alkenyl Carbonyl Com-
pounds. Chem. Sci. 2018, 9, 5278–5283. (b) van der Puyl, V. A.; Derosa, J.; Engle, K. M. Directed, Nickel-Catalyzed Umpolung 1,2Carboamination of Alkenyl Carbonyl Compounds. ACS Catal. 2018, DOI: 10.1021/acscatal.8b04516. (11) For a review on olefin ligands in catalysis, see: Johnson, J. B.; Rovis, T. More than Bystanders: The Effect of Olefins on Transition-MetalCatalyzed Cross-Coupling Reactions. Angew. Chem., Int. Ed. 2008, 47, 840–871. (12) For representative reports on applications of electron-deficient olefin ligands in nickel-catalyzed cross-coupling, see: (a) Giovannini, R.; Stüdemann, T.; Dussin, G.; Knochel, P. An Efficient Nickel-Catalyzed CrossCoupling between sp3 Carbon Centers. Angew. Chem., Int. Ed. 1998, 37, 2387–2390. (b) Giovannini, R.; Knochel, P. Ni(II)-Catalyzed CrossCoupling between Polyfunctional Arylzinc Derivatives and Primary Alkyl Iodides. J. Am. Chem. Soc. 1998, 120, 11186–11187. (c) Giovannini, R.; Stüdemann, T.; Devasagayaraj, A.; Dussin, G.; Knochel, P. New Efficient Nickel-Catalyzed Cross-Coupling Reaction between Two Csp3 Centers. J. Org. Chem. 1999, 64, 3544–3553. (d) Jensen, A. E.; Knochel, P. NickelCatalyzed Cross-Coupling between Functionalzied Primary or Secondary Alkylzinc Halides and Primary Alkyl Halides. J. Org. Chem. 2002, 67, 79–85. (e) Huang, C.-Y.; Doyle, A. G. J. Am. Chem. Soc. 2012, 134, 9541–9544. (f) Nielsen, D. K.; Huang, C.-Y.; Doyle, A. G. Directed Nickel-Catalyzed Negishi Cross Coupling of Alkyl Aziridines. J. Am. Chem. Soc. 2013, 135, 13605– 13609. (g) Huang, C.-Y.; Doyle, A. G. Electron-Deficient Olefin Ligands Enable Generation of Quaternary Carbons by Ni-Catalyzed Cross-Coupling. J. Am. Chem. Soc. 2015, 137, 5638–5641.
(13) Dimethyl fumarate performed the best compared to other electrondeficient olefin ligands. See Supporting Information for optimization data. (14) (a) García-Dominguez, A.; Li, Z.; Nevado, C. Nickel-Catalyzed Reductive Dicarbofunctionalization of Alkenes. J. Am. Chem. Soc. 2017, 139, 6835–6838. (b) Zhao, X.; Tu, H.-Y.; Guo, L.; Zhu, S.; Qing, F.-L.; Chu, L. Intermolecular Selective Carboacylation of Alkenes via Nickel-Catalyzed Reductive Radical Relay. Nat. Commun. 2018, 9, 3488. For related examples involving conjugated alkenes, namely enamides and acrylates, respectively, see: (c) Qin, T.; Cornella, J.; Li, C.; Malins, L. R.; Edwards, J. T.; Kawamura, S.; Maxwell, B. D.; Eastgate, M. D.; Baran, P. S. A General Alkyl-Alkyl CrossCoupling Enabled by Redox-Active Esters and Alkylzinc Reagents. Science 2016, 352, 801−805. (d) Gu, J.-W.; Min, Q.-Q.; Yu, L.-C.; Zhang, X. Tandem Difluoroalkylation-Arylation of Enamides Catalyzed by Nickel. Angew. Chem., Int. Ed. 2016, 55, 12270–12274.
(15) Skold, C.; Kleimark, J.; Trejos, A.; Odell, L. R.; Nilsson Lill, S. O.; Norrby, P.-O.; Larhed, M. Transmetallation Versus β-Hydride Elimination: the Role of 1,4-Benzoquinone in Chelation-Controlled Arylation Reactions with Arylboronic Acids. Chem. Eur. J. 2012, 18, 4714–4722. (16) Ethylene-bound nickel was used as a model for alkene-bound nickel species that may be formed under the reaction conditions (e.g., from COD or substrate coordination)
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Insert Table of Contents artwork here O
O [N]
n n = 1, 2
or PG
N H
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Ar1 Ar2
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