Ni-Catalyzed Regioselective β,δ-Diarylation of Unactivated Olefins in Ketimines via Ligand-Enabled Contraction of Transient Nickellacycles: Rapid Access to Remotely Diarylated Ketones

Article abstract of DOI:10.1021/jacs.8b03163

We disclose a [(PhO)₃P]/NiBr₂-catalyzed regioselective β, δ-diarylation of unactivated olefins in ketimines with aryl halides and arylzinc reagents. This diarylation proceeds at remote locations to the carbonyl group to afford, after simple H⁺ workup, diversely substituted β, δ-diarylketones that are otherwise difficult to access readily with existing methods. Deuterium-labeling and crossover experiments indicate that diarylation proceeds by ligand-enabled contraction of transient nickellacycles.

Full text of DOI:10.1021/jacs.8b03163

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Communication
Ni-Catalyzed Regioselective #,#-Diarylation of Unactivated
Olefins in Ketimines via Ligand-Enabled Contraction of Transient
Nickellacycles: Rapid Access to Remotely Diarylated Ketones
Prakash Basnet, Roshan K Dhungana, Surendra Thapa, Bijay
Shrestha, Shekhar KC, Jeremiah M. Sears, and Ramesh Giri
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b03163 • Publication Date (Web): 12 Jun 2018
Downloaded from http://pubs.acs.org on June 12, 2018
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Ni-Catalyzed Regioselective β,δ-Diarylation of Unactivated Olefins
in Ketimines via Ligand-Enabled Contraction of Transient Nickel-
lacycles: Rapid Access to Remotely Diarylated Ketones
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Prakash Basnet,† Roshan K. Dhungana,† Surendra Thapa,† Bijay Shrestha,† Shekhar KC,† Jeremiah M.
Sears,§ and Ramesh Giri†*
†Department of Chemistry & Chemical Biology, The University of New Mexico, Albuquerque, NM 87131, USA.
§Sandia National Laboratories, Advanced Materials Laboratory, 1001 University Blvd. SE, Albuquerque, NM 87106, USA.
Supporting Information Placeholder
ABSTRACT: We disclose a [(PhO)3P]/NiBr2-catalyzed regiose-
lective β,δ-diarylation of unactivated olefins in ketimines with
aryl halides and arylzinc reagents. This diarylation proceeds at
remote locations to the carbonyl group to afford, after simple H+
workup, diversely substituted β,δ-diarylketones that are otherwise
difficult to access readily with existing methods. Deuterium-
labelling and crossover experiments indicate that diarylation pro-
ceeds by ligand-enabled contraction of transient nickellacycles.
Scheme 2. Pd Redox relay and interception of C(sp3)-NiX
species during 1,3-diarylation of unactivated olefins
Interception of in situ-generated Heck C(sp3)-MX intermediates
by organometallic reagents is a powerful method to difunctional-
ize unactivated olefins (Scheme 1).1 This process creates two new
Unactivated olefins on aliphatic backbones also readily undergo
isomerization7 by redox relay that involves a series of C(sp3)-MX
carbon-carbon (C-C) bonds across an olefin with new stereocen-
ters2 and enables to build complex molecules rapidly,3 the access
species generated through sequential β-H elimination/M-H migra-
tory insertion steps.8 In some cases, such isomerization can be
for which would otherwise require multiple steps from readily
harnessed for remote functionalization.9 In a recent report, Sig-
available chemicals with the known methods. However, develop-
ment of such a method for acyclic alkenes remains incredibly
man and coworkers demonstrated that unactivated olefins tethered
challenging primarily due to the flexible alkyl chain and the high
to carbonyl compounds would undergo such a process involving a
propensity of the Heck C(sp3)-MX species to undergo β-hydride
(β-H) elimination that leads to the formation of Heck products
(Scheme 1, A). Due to these complications, regioselective olefin
dicarbofunctionalization has generally remained successful with
dienes and styrenes,4 a class of substrates that tender internal sta-
bilization of Heck C(sp3)-MX species by generating π-allyl/π-
benzyl complexation and furnish 1,2- or 1,4-difunctionalized
products (Scheme 1, B).5 In some cases, olefins that lack intrinsic
stabilizing factors follow a Heck carbometallation, β-H elimina-
tion and [M]-H reinsertion steps prior to transmetalation to give
1,1-difunctionalized products (Scheme 1, C).6
Pd-catalyzed Heck reaction10 until the C(sp3)-PdX species result
in β-H elimination from α-position to furnish terminally arylated
α,β-unsaturated carbonyl compounds (Scheme 2).11 Herein, we
demonstrate that one of such redox-relay Heck C(sp3)-MX species
generated at the β-position of carbonyl derivatives can be inter-
cepted with arylzinc reagents to furnish β,δ-diarylketones
(Scheme 2). This process was rendered successful by utilizing
(PhO)3P/NiBr2 as a new catalyst and modifying the carbonyl
group to an imine for intercepting the redox-relay Heck C(sp3)-
NiX species by coordination-assisted formation of transient nick-
ellacycles.12 Preliminary studies by deuterium-labelling and
crossover experiments indicate that the reaction proceeds by a
(PhO)3P-promoted contraction of six-membered transient nickel-
lacycles to five-membered nickellacycles.
In our continued efforts to expand the scope of coordination-
assisted olefin difunctionalization to synthetically important car-
bonyl compounds,13 we examined olefins in simple aliphatic ke-
tone-derived imines.14 Unfortunately, our preliminary examina-
tion of diarylation of imine 1 derived from 5-hexenone and aniline
under our previously reported conditions13 either did not form any
product or only produced the Heck product 2 in 74% yield
(Scheme 3).15 We reasoned that the fluxional characteristics of the
Scheme 1. Strategies for olefins dicarbofunctionalization
and the complication by β-H elimination
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six-membered transient nickellacycle 3 could be responsible for
and generates only Heck product 2 in 18% yield in the absence of
(PhO)3P (entries 11-12). Altering the phenyl group in imine elec-
tronically with p-F and p-Me substituents or replacing it with nBu
group also formed the diarylated product 5 in lower yields (entries
13-15). Shorter reaction time decreased the yield of the product 5
(entry 16). Other catalysts based on Pd, Fe, Co and Cu did not
catalyze the diarylation reaction (entry 17). Control experiments
with the parent ketone as a substrate both with and without
(PhO)3P formed neither the diarylated nor the Heck product (en-
tries 18-19). These experiments highlight the critical roles played
by (PhO)3P and the imine group in promoting Heck carbometalla-
tion and nickellacycle contraction, and stabilizing the resultant
transient nickellacycles.
the Heck reaction by making it harder to stabilize the C(sp3)-NiX
species and prompting them to undergo rapid β-H elimination.
We then hypothesized that such transient nickellacycles could be
stabilized in situ by intercepting them with exogenous ligands that
could create a comparatively rigid, higher coordinate organonick-
el species. Examination of a variety of ligands with NiBr2 indeed
revealed that (PhO)3P was an excellent ligand to promote diaryla-
tion of unactivated olefins in ketimines with aryl iodides and aryl-
zinc reagents (Table 1, entry 1). Surprisingly, the unactivated
olefin underwent 1,3-diarylation, rather than 1,2-diarylation, fur-
nishing β,δ-diarylketone 5 along with the Heck product 2 in 54%
and 12% yields, respectively. No product arising from β-H elimi-
nation from α-position of the carbonyl group was observed. Fur-
ther examination of other solvents (entries 2-5) showed that the
diarylated product 5 was formed in best yield in MeCN (entry 2).
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After optimizing the reaction conditions, we examined the scope
of the current reaction for β,δ-diarylation of imine 1 with 4-
(trifluoromethyl)phenylzinc iodide and different aryl iodides (Ta-
ble 2). The reaction proceeds with both electron-rich and electron-
poor aryl iodides16 and tolerates substituents such as alkyl, OMe,
Cl, F, CO2Me and CF3 on aryl iodides. In addition, the reaction
also tolerates ortho-substitution on aryl iodides as demonstrated
by ortho-Me and 1-naphthyl (31 and 37).
We further examined the scope of the current β,δ-diarylation reac-
tion with respect to different ketimines, aryl iodides and arylzinc
reagents (Table 3).17 The reaction typically works well with elec-
tron-deficient arylzinc reagents.16 The reaction tolerates functional
groups such as Me, F, Cl and CF3 on arylzinc reagents and alkyl,
OMe, F, Cl, CN and CF3 on aryl iodides. The aryl iodides and
arylzinc reagents can be used in different combinations with sev-
eral ketimines to furnish variously substituted β,δ-diarylketones.
The reaction also proceeds well with ketimines derived from ke-
tones with substitutions at α-carbons both at distal (51-53) and
proximal (54-64) locations to the unactivated olefins. The diaryla-
tion reactions with these substituted ketones gave products in
nearly 1:1 diastereomeric ratios (54-64).
Scheme 3. Formation of Heck product via a fluxional six-
membered transient metallacycle
Table 1. Optimization of reaction conditionsa
We further conducted deuterium-labelling and crossover experi-
ments in order to understand the process of metallacycle contrac-
tion, and propose a catalytic cycle (Scheme 6). We subjected the
imine 1-d2 labelled with deuterium (86% D) at the allylic position
(β-d2) to our standard reaction condition for diarylation (Scheme
4). Analysis of the diarylated product 5-d2 revealed that one of
two allylic deuteriums migrated quantitatively (85% D) to γ-
position of the carbonyl group. We then conducted a crossover
experiment between the imine 1 and the styryl imine 65 (Scheme
5), a Heck product that serves as an intermediate during redox
relay. Analysis of the products showed that the product 35 arising
Table 2. Scope with aryl iodidesa
a0.1 mmol scale reactions in 0.5 mL solvent. b1H NMR yields
using pyrene as an internal standard. Value in parenthesis is the
c
isolated yield from 0.5 mmol. 80% remaining starting material.
dPd(OAc)2, CoCl2, FeCl2 or CuI.
The results with triarylphosphines, trialkylphosphines, tri-
arylphosphites and trialkylphosphites (entries 6-10) indicate that
the 1,3-diarylation reaction requires an electron-deficient ligand.
The reaction does not form the diarylated product 5 without NiBr2
aIsolated from 0.5 mmol. 5-10% Heck products observed.
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Table 3. Scope with ketone derivatives, aryl iodides and arylzinc reagentsa
1
2
3
4
5
6
7
8
R1
5 mol % NiBr2
5 mol % (PhO)3P
PhN
R2
O
MeCN, 60 °C, 2-14 h
then H+ workup
+
ZnI
+
I
R2
R1
R
1.5 equiv
R
R3
R3
1.2 equiv
Me
38-64
Cl
Cl
Cl
F
F
F
Cl
Cl
O
O
O
O
O
O
O
Me
Me
Ph
Me
Me
Me
Me
tBu
( )2
Me
Me
CF3
CN
44
, 65%
43, 48%b
9
iPr
38, 52%
39, 51%
40, 42%
41, 61%
42, 51%
Cl
10
11
12
13
14
15
16
17
18
19
20
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23
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25
26
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29
30
31
32
33
34
35
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60
Cl
F
F
F
F
CF3
O
O
O
O
O
O
Ph
Ph
Me
Me
Me
OMe
( )2
( )2
Ph
( )2
( )2
( )2
( )2
Me
F
Me
F
49, 74%
50, 52%
45, 81%
46, 61%
CF3
47, 62%
48, 76%
OMe
R
CF3
F
F3C
CF3
CF3
O
Me
O
O
OMe
R'
OMe
Me
Me
Me
O
iPr
O
OMe
Me
55, 51% (dr, 1:1.2)
O
56, 63% (dr, 1:1.2)
51, R = CF3; R' = p-OMe, 62%
52, R = Cl; R' = m-OMe, 63%
53, R = CF3; R' = p-Me, 55%
Me
Me
61
, 62% (dr, 1:1)
54
60
, 45% (dr, 1:1)
, 43%, (dr, 1:1.4)
61
)
X-ray (
Cl
CF3
F
F
CF3
F
F
Cl
Cl
O
Me
O
CF3
O
iPr
O
O
O
57, 56% (dr, 1:1.2)
58, 62% (dr, 1:1)
59, 58%, (dr, 1:1.5)
62, 41% (dr, 1:1.3)
63, 61% (dr, 1:1.3)
64, 44% (dr, 1:1.3)
aIsolated from 0.5 mmol. 5-10% Heck products observed. b50 °C.
from the imine 1 was generated predominantly along with traces
of the product 32. These results, along with the observation of 5-
10% Heck products in all reactions, indicate that the contraction
of the six-membered transient nickellacycle 68 proceeds while Ni
remains mostly bound to the substrate (Scheme 6).11e Such ring
contraction to the five-membered nickellacycle 71 proceeds by β-
H elimination from a β-carbon followed by H-NiX reinsertion to
olefin prior to transmetalation/reductive elimination to furnish
β,δ-diarylketones.18 Since no product is observed without
(PhO)3P, we believe that the ligand facilitates ring contraction. In
addition, (PhO)3P, an electron-deficient ligand, could also facili-
tate reductive elimination.19
1
+
P(OPh)
3
NiBr2
+
O
Ar'
Ar'ZnX
(−Ar'Ar')
Ar
Me
(H+ workup)
Me
PhN
Me
Ar
X
PhN
(PhO)3P
Ni
1
Me
RE
P(OPh)3
Me
66
Ar
PhN
PhN
NiII
II
Ni
(PhO)3
P
Me
67
X
Ar'
Ar
72
ZnX2
Ar'ZnX
(PhO)3P
PhN
X
II
Ni
Ar
Me
PhN
Me
H
69
Ar
PhN
Ar
NiII
NiII
86% D
5 mol % NiBr2
5 mol % (PhO)3P
O
Ar'
Me
(PhO)3P
71
(rigid, stable)
68
X
PhN
Me
P(OPh)3
X
D
D
ArI
+
Ar'
+
ZnI
Ar
(fluxional
unstable)
Me
Ar
70
PhN
X
MeCN, 60 °C, 2 h
(H+ workup)
68%
D
NiII
D
1-d2
(PhO)3
P
(PhO)3
P
86% D
Ar = 4-MeC6H4; Ar' = 4-CF3C6H4
H
5-d2
85% D
Transient Metallacycle Contraction Steps
Scheme 4: Deuterium-labelling experiment
Scheme 6: Proposed catalytic cycle
O
Ar'
PhN
MeO2C
I
Ph
Ar
Ph
Me
Me
65
5 mol % NiBr2
5 mol % (PhO)3
ASSOCIATED CONTENT
Supporting Information
Ar
(
I)
P
32
, 2%
(0.20 mmol)
+
+
+
+
Ar'
MeCN, 60 °C, 2 h
(H+ workup)
PhN
O
F3C
ZnI
Me
Me
Experimental procedures, characterization data for all com-
pounds, and crystallographic data (CIF). This material is
available free of charge via the Internet at
http://pubs.acs.org.
Ar
(
'ZnI)
1
35
, 30%
(0.10 mmol)
Scheme 5: Crossover experiment
In summary, we have developed a new (PhO)3P/NiBr2 catalyst for
regioselective 1,3-diarylation of unactivated olefins in ketimines
with aryl iodides and arylzinc reagents to furnish variously substi-
tuted β,δ-diarylketones. This remote diarylation was made feasi-
ble by the combination of (PhO)3P as a ligand and imine as a co-
ordinating group that enabled to intercept transient Heck C(sp3)-
NiX intermediates. Deuterium-labelling and crossover experi-
ments indicate that the reaction proceeds by the contraction of six-
membered nickellacycles to five-membered nickellacycles ena-
bled by the presence of (PhO)3P.
AUTHOR INFORMATION
Corresponding Author
rgiri@unm.edu
Notes
The authors declare no competing financial interests.
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Brennessel, W. W.; Weix, D. J.; Holland, P. L. J. Am. Chem. Soc. 2014,
ACKNOWLEDGMENT
136, 945; (f) Gauthier, D.; Lindhardt, A. T.; Olsen, E. P. K.; Overgaard, J.;
Skrydstrup, T. J. Am. Chem. Soc. 2010, 132, 7998; (g) Larionov, E.; Li,
H.; Mazet, C. Chem. Commun. 2014, 50, 9816.
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Weinstein, A. B.; Stahl, S. S. Angew. Chem. Int. Ed. 2012, 51, 11505; (c)
Aspin, S.; Goutierre, A.-S.; Larini, P.; Jazzar, R.; Baudoin, O. Angew.
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1
2
3
4
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We thank the University of New Mexico (UNM) and the
National Science Foundation (NSF CHE-1554299) for fi-
nancial support, and upgrades to the NMR (NSF grants
CHE08-40523 and CHE09-46690) and MS Facilities. The
Bruker X-ray diffractometer was purchased via an NSF
CRIF:MU award to UNM (CHE04-43580). Sandia Nation-
al Laboratories (See the SI).
8
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(6) (a) Saini, V.; Sigman, M. S. J. Am. Chem. Soc. 2012, 134, 11372;
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(10) Zhang, C.; Santiago, C. B.; Kou, L.; Sigman, M. S. J. Am. Chem.
Soc. 2015, 137, 7290.
(11) For redox relay Heck arylation of olefin-tethered alcohols, see: (a)
Werner, E. W.; Mei, T.-S.; Burckle, A. J.; Sigman, M. S. Science 2012,
338, 1455; (b) Xu, L.; Hilton, M. J.; Zhang, X.; Norrby, P.-O.; Wu, Y.-D.;
Sigman, M. S.; Wiest, O. J. Am. Chem. Soc. 2014, 136, 1960; (c) Patel, H.
H.; Sigman, M. S. J. Am. Chem. Soc. 2016, 138, 14226; (d) Chen, Z.-M.;
Hilton, M. J.; Sigman, M. S. J. Am. Chem. Soc. 2016, 138, 11461; (e)
Hilton, M. J.; Xu, L.-P.; Norrby, P.-O.; Wu, Y.-D.; Wiest, O.; Sigman, M.
S. J. Org. Chem. 2014, 79, 11841; (f) Dang, Y.; Qu, S.; Wang, Z.-X.;
Wang, X. J. Am. Chem. Soc. 2014, 136, 986.
(12) For selected examples of coordination-assisted Ni-catalyzed
Negishi coupling, see: (a) Owston, N. A.; Fu, G. C. J. Am. Chem. Soc.
2010, 132, 11908; (b) Lu, Z.; Wilsily, A.; Fu, G. C. J. Am. Chem. Soc.
2011, 133, 8154; (c) Wilsily, A.; Tramutola, F.; Owston, N. A.; Fu, G. C.
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Biscoe, M. R. Org. Lett. 2011, 13, 1218.
(13) (a) Shrestha, B.; Basnet, P.; Dhungana, R. K.; Kc, S.; Thapa, S.;
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Dhungana, R. K.; Magar, R. T.; Shrestha, B.; Kc, S.; Giri, R. Chem. Sci.
2018, 9, 904.
(14) For other examples of olefin dicarbofunctionalization using a
coordinating group, see: (a) Gu, J.-W.; Min, Q.-Q.; Yu, L.-C.; Zhang, X.
Angew. Chem. Int. Ed. 2016, 55, 12270; (b) Li, W.; Boon, J. K.; Zhao, Y.
Chem. Sci. 2018, 9, 600; (c) Yahiaoui, S.; Fardost, A.; Trejos, A.; Larhed,
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N.; Chen, J. S.; Engle, K. M. J. Am. Chem. Soc. 2017, 139, 10657; (e) Liu,
Z.; Zeng, T.; Yang, K. S.; Engle, K. M. J. Am. Chem. Soc. 2016, 138,
15122. For fluorarylation and dioxygenation of olefins using a coordinat-
ing group, see: (f) Talbot, E. P. A.; Fernandes, T. d. A.; McKenna, J. M.;
Toste, F. D. J. Am. Chem. Soc. 2014, 136, 4101; (g) Neufeldt, S. R.;
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(15) For directed Heck reaction, see: (a) Oestreich, M. In Directed
Metallation; Chatani, N., Ed.; Springer Berlin Heidelberg: Berlin,
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2011, 133, 19020; (d) Tasker, S. Z.; Gutierrez, A. C.; Jamison, T. F.
Angew. Chem. Int. Ed. 2014, 53, 1858; (e) Harris, M. R.; Konev, M. O.;
Jarvo, E. R. J. Am. Chem. Soc. 2014, 136, 7825; (f) Liu, C.; Tang, S.; Liu,
D.; Yuan, J.; Zheng, L.; Meng, L.; Lei, A. Angew. Chem. Int. Ed. 2012,
51, 3638; (g) Gøgsig, T. M.; Kleimark, J.; Nilsson Lill, S. O.; Korsager,
S.; Lindhardt, A. T.; Norrby, P.-O.; Skrydstrup, T. J. Am. Chem. Soc.
2012, 134, 443; (h) Desrosiers, J.-N.; Hie, L.; Biswas, S.; Zatolochnaya,
O. V.; Rodriguez, S.; Lee, H.; Grinberg, N.; Haddad, N.; Yee, N. K.;
Garg, N. K.; Senanayake, C. H. Angew. Chem. Int. Ed. 2016, 55, 11921;
(i) Huihui, K. M. M.; Shrestha, R.; Weix, D. J. Org. Lett. 2017, 19, 340.
(16) Since the reaction is strongly influenced by electronic changes on
ArZnI but not on ArI and only 1,3-diarylated products are formed without
1,2-diarylation, we believe that either the transmetalation or the reductive
elimination could be rate-limiting.
(17) Heteroaryl iodides formed products in <10% yields. We also
examined N,6-diphenylhex-5-en-2-imine and N-phenylhept-6-en-2-imine
containing internal and longer chain olefins, which did not form any
product.
(7) (a) Kocen, A. L.; Klimovica, K.; Brookhart, M.; Daugulis, O.
Organometallics 2017, 36, 787; (b) Kita, M. R.; Miller, A. J. M. Angew.
Chem. Int. Ed. 2017, 56, 5498; (c) Crossley, S. W. M.; Barabé, F.; Shenvi,
R. A. J. Am. Chem. Soc. 2014, 136, 16788; (d) Larsen, C. R.; Grotjahn, D.
B. J. Am. Chem. Soc. 2012, 134, 10357; (e) Chen, C.; Dugan, T. R.;
(18) 1,2-Diarylation is not observed due to the faster rate of β-H elimi-
nation from 68 than its transmetalation with ArZnI. The Heck product is
not formed as a major product due to the (PhO)3P-promoted [Ni]-H rein-
sertion into the olefin.
(19) Binger, P.; Doyle, M. J. J. Organomet. Chem. 1978, 162, 195.
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