Application of Diazaphospholidine/Diazaphospholene-Based Bisphosphines in Room-Temperature Nickel-Catalyzed C(sp2)-N Cross-Couplings of Primary Alkylamines with (Hetero)aryl Chlorides and Bromides

Article abstract of DOI:10.1021/acscatal.8b01005

We report herein on the synthesis and catalytic application of a family of o-phenylene-bridged bisphosphine ancillary ligands featuring a bulky N-heterocyclic phosphine (NHP) donor fragment paired with an adjacent PR₂ donor group (R = alkyl, aryl), whereby the incorporation of phosphorus into either a saturated or unsaturated heterocyclic ring serves as a means of modulating the donicity of the NHP fragment. Screening of these ancillary ligands in representative nickel-catalyzed C(sp²)-N cross-coupling test reactions allowed for the identification of one variant, featuring a saturated NHP structure and an adjacent diphenylphosphino donor group (i.e., NHP-DalPhos), as being particularly effective in reactions involving primary alkylamines. Notably, application of the derived precatalyst (NHP-DalPhos)NiCl(o-tolyl) (C1) enabled the typically challenging monoarylation of structurally diverse primary alkylamines with (hetero)aryl chlorides or bromides at room temperature. Also described are the results of our comparative density functional theory computational analysis of nickel-catalyzed primary alkylamine C(sp²)-N cross-couplings employing PAd-DalPhos or NHP-DalPhos.

Full text of DOI:10.1021/acscatal.8b01005

Subscriber access provided by Kaohsiung Medical University
Article
Application of Diazaphospholidine/Diazaphospholene-Based Bisphosphines
in Room Temperature Nickel-Catalyzed C(sp2)-N Cross-Couplings
of Primary Alkylamines with (Hetero)aryl Chlorides and Bromides
Alexandre Gatien, Christopher M. Lavoie, Raymond N. Bennett, Michael J Ferguson,
Robert McDonald, Erin R Johnson, Alexander W. H. Speed, and Mark Stradiotto
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b01005 • Publication Date (Web): 01 May 2018
Downloaded from http://pubs.acs.org on May 1, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 41
ACS Catalysis
1
2
3
4
5
6
7
8
9
Application of Diazaphospholidine/DiazaphospholeneꢀBased
Bisphosphines in Room Temperature NickelꢀCatalyzed
C(sp2)ꢀN CrossꢀCouplings of Primary Alkylamines with
(Hetero)aryl Chlorides and Bromides
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Alexandre V. Gatien,1 Christopher M. Lavoie,1 Raymond N. Bennett,1 Michael J. Ferguson,2
Robert McDonald,2 Erin R. Johnson,1 Alexander W. H. Speed,1,* and Mark Stradiotto1,*
1Department of Chemistry, Dalhousie University, 6274 Coburg Road, PO Box 15000, Halifax,
Nova Scotia, Canada, B3H 4R2
2XꢀRay Crystallography Laboratory, Department of Chemistry, University of Alberta,
Edmonton, Alberta, Canada, T6G 2G2
1
ACS Paragon Plus Environment

ACS Catalysis
Page 2 of 41
1
2
3
4
5
6
7
8
9
ABSTRACT. We report herein on the synthesis and catalytic application of a family of orthoꢀ
phenylene bridged bisphosphine ancillary ligands featuring a bulky Nꢀheterocyclic phosphine
(NHP) donor fragment paired with an adjacent PR2 donor group (R = alkyl or aryl), whereby the
incorporation of phosphorus into either a saturated or unsaturated heterocyclic ring serves as a
means of modulating the donicity of the NHP fragment. Screening of these ancillary ligands in
representative nickelꢀcatalyzed C(sp2)ꢀN crossꢀcoupling test reactions allowed for the
identification of one variant, featuring a saturated NHP structure and an adjacent
diphenylphosphino donor group (i.e., NHPꢀDalPhos), as being particularly effective in reactions
involving primary alkylamines. Notably, application of the derived preꢀcatalyst (NHPꢀ
DalPhos)NiCl(oꢀtolyl) (C1) enabled the typically challenging monoarylation of structurally
diverse primary alkylamines with (hetero)aryl chlorides or bromides at room temperature. Also
described are the results of our comparative density functional theory computational analysis of
nickelꢀcatalyzed primary alkylamine C(sp2)ꢀN crossꢀcouplings employing PAdꢀDalPhos or NHPꢀ
DalPhos.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
KEYWORDS: nickel, CꢀN crossꢀcoupling, amination, ligand design, density functional theory
2
ACS Paragon Plus Environment

Page 3 of 41
ACS Catalysis
1
2
3
4
1. Introduction
5
6
7
8
Transition metalꢀcatalyzed crossꢀcoupling reactions are ubiquitous in modern synthetic
chemistry, enabling the assembly of complex molecular structures from easily procured starting
materials.1 The success of such methods often hinges on the application of an appropriate metalꢀ
coordinated ancillary ligand as a means of achieving desired catalytic properties (e.g., activity,
selectivity, etc).2 The palladiumꢀcatalyzed C(sp2)ꢀN crossꢀcoupling of NH substrates and aryl
electrophiles (i.e., BuchwaldꢀHartwig Amination,3 BHA) in particular has experienced
tremendous advances in the last twenty years arising from developments in ancillary ligand
design. These advances have led to the emergence of broadly useful BHA protocols, which are
employed in the synthesis of pharmaceuticals, agrochemicals, fine chemicals, and beyond.4 The
use of sterically hindered and strongly electronꢀreleasing ligands, typically monophosphines
(including Buchwald’s biarylmonophosphines5) or Nꢀheterocyclic carbenes,6 has proven crucial
in enabling the generation of lowꢀcoordinate, electronꢀrich LnPd0 species7 that are capable of
promoting otherwise challenging C(sp2)ꢀX bond oxidative additions, including those in cheap
and abundant (hetero)aryl chlorides.8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Notwithstanding the efficacy of BHA protocols, the relative scarcity and high cost of
palladium creates a scenario in which the development of alternative base metal catalysis is
appealing.9 The use of copper in C(sp2)ꢀN crossꢀcouplings is wellꢀestablished;10 however, the
requirement of elevated reaction temperatures, in combination with relatively activated
(hetero)aryl electrophiles (commonly bromides and iodides), can render such protocols less
desirable relative to BHA. Conversely, nickel catalysis has emerged as a competitive alternative
to palladiumꢀbased methods,11 including in amine arylation crossꢀcoupling chemistry.12 In
addition to being more abundant and less expensive than palladium, the enhanced propensity of
3
ACS Paragon Plus Environment

ACS Catalysis
Page 4 of 41
1
2
3
4
5
6
7
8
9
nickel to engage in C(sp2)ꢀX bond oxidative additions in typically less reactive (hetero)aryl
chlorides8 or alternative electrophiles derived from phenols makes nickel particularly wellꢀsuited
to supplant palladium in C(sp2)ꢀN crossꢀcoupling applications.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Whereas sterically demanding and electronꢀrich monophosphines or Nꢀheterocyclic
carbenes have proven optimal in palladiumꢀcatalyzed C(sp2)ꢀN crossꢀcoupling chemistry (vide
14
15
supra), bisphosphines including DPPF,13 JosiPhos CyPFꢀCy,13c,
and PAdꢀDalPhos13c,
currently represent a topꢀtier ligand class in analogous nickelꢀcatalyzed transformations (Scheme
1). This observation highlights the inconsistent nature of ‘repurposing’ ligands developed for use
with palladium in nickel chemistry – a trend that arises in part due to the differing size and
electronic properties of nickel versus palladium.11a Following an initial report from our group
establishing nickelꢀcatalyzed ammonia monoarylation by use of CyPFꢀCy,14a, 16 we turned our
attention to rationally developing, for the first time, an ancillary ligand (i.e., PAdꢀDalPhos15a) for
use more broadly in nickelꢀcatalyzed C(sp2)ꢀN crossꢀcouplings.17 Unlike the electronꢀrich and
sterically demanding ancillary ligands that are particularly effective in palladiumꢀcatalyzed
C(sp2)ꢀN crossꢀcouplings, the bulky but more modestly electronꢀdonating phosphaadamantane18
fragment in PAdꢀDalPhos15a and variants15d was utilized so as to facilitate presumptive turnoverꢀ
limiting C(sp2)ꢀN bond reductive elimination within a Ni0/NiII catalytic cycle – an assertion for
which we have recently gained computational support.15c, 19 The application of PAdꢀDalPhos as
well as CyPAdꢀDalPhos has enabled a number of reactivity breakthroughs, including the first
nickelꢀcatalyzed roomꢀtemperature C(sp2)ꢀN crossꢀcouplings involving ammonia or primary
alkylamines,15a, 15d as well as the first nickelꢀcatalyzed C(sp2)ꢀN crossꢀcouplings of primary
amides and lactams.15b
4
ACS Paragon Plus Environment

Page 5 of 41
ACS Catalysis
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1. A selection of useful ancillary ligands for nickelꢀcatalyzed C(sp2)ꢀN crossꢀcouplings.
Encouraged by the success of PAdꢀDalPhos, we turned our attention toward developing
complementary and modular new classes of bisphosphines, so as to diversify the ancillary ligand
‘toolkit’ and to address substrate scope challenges in nickelꢀcatalyzed C(sp2)ꢀN crossꢀcouplings.
Building on the successful use of diaminophosphine oxideꢀderived, saturated Nꢀheterocyclic
phosphine (NHP) ancillary ligands in nickelꢀcatalyzed C(sp2)ꢀC(sp2) crossꢀcouplings by
Ackermann and coꢀworkers (A, Chart 1),20 we became interested in developing orthoꢀphenylene
bridged bisphosphine ancillary ligands in which a sterically demanding neutral NHP donor
fragment21,22 is paired with an easily varied PR2 donor group (R = alkyl or aryl), whereby the
incorporation of phosphorus into either a saturated or unsaturated heterocyclic ring may serve as
an additional means of modulating the donicity of the NHP fragment, in keeping with Nꢀ
heterocyclic carbene23 ancillary ligands.24 Although no ancillary ligands of the type reported
herein had been disclosed previously in the literature, our targeted saturated and unsaturated
NHPꢀbisphosphine ligand class represents a hybrid of the bidentate Nꢀheterocyclic phosphenium
ligand (B) developed by Thomas and coꢀworkers,25 and the NHPꢀbenzenesulfonato ancillary
ligand (C) that was employed by Caporaso, Mecking, GöttkerꢀSchnetmann, and coꢀworkers26 as
a means of controlling regioselectivity in palladiumꢀcatalyzed MizorokiꢀHeck reactions.
5
ACS Paragon Plus Environment

ACS Catalysis
Page 6 of 41
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Chart 1. Some previously reported bidentate NHPꢀtype ancillary ligands, and the new NHPꢀ
DalPhos ancillary ligand developed herein.
In this contribution we describe our synthetic and catalytic investigations of new orthoꢀ
phenylene bridged NHPꢀbisphosphine ancillary ligands in the context of nickelꢀcatalyzed C(sp2)ꢀ
N crossꢀcoupling chemistry. This work establishes that the use of (NHPꢀDalPhos)NiCl(oꢀtolyl)
(C1), featuring the new NHPꢀDalPhos ancillary ligand (Chart 1), enables the monoarylation of
primary alkylamines with (hetero)aryl chlorides or bromides at room temperature – a reaction for
which few effective nickel catalyst systems are known.13c, 15a, 15d, 27 To complement this
experimental work, the results of our comparative DFT analysis of nickelꢀcatalyzed primary
alkylamine C(sp2)ꢀN crossꢀcoupling employing PAdꢀDalPhos or NHPꢀDalPhos are also
presented.
2. Results and Discussion
2.1. Synthesis of Ligands L1–L6
The targeted series of new saturated and unsaturated orthoꢀphenylene bridged NHPꢀ
bisphosphines (L1ꢀL6) was prepared as outlined in Scheme 2. In all cases ligands featuring
sterically demanding Nꢀmesityl groups on the NHP fragment were pursued in an effort to
promote C(sp2)ꢀN bond reductive elimination at nickel in crossꢀcoupling applications.
6
ACS Paragon Plus Environment

Page 7 of 41
ACS Catalysis
1
2
3
4
5
6
7
8
9
Cyclohexyl, phenyl, and orthoꢀtolyl substituents were incorporated as substituents on the
adjacent phosphine donor fragment, to allow for the structural features of the NHPꢀbisphosphine
structure to be varied further (Scheme 2). The new ligands L1ꢀL6 were fully characterized on the
basis of NMR spectroscopic and mass spectrometric data; restricted rotation of the bulky NꢀMes
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
groups is evident to various extents in the H and C{1H} spectra of L1ꢀL6 at 300 K. For each
of L1, L2, and L4, the solid state structure was established on the basis of singleꢀcrystal Xꢀray
data (Figure 1). Comparison of the geometrical parameters in these three structures revealed no
systematic variation of either the PꢀN or PꢀC distances, or the angles at phosphorus, within the
NHP fragment. While the heterocyclic CꢀN distances in L1 and L2 (~1.47 Å) are only modestly
longer than those in L4 (~1.42 Å), as expected a much longer heterocyclic C7ꢀC8 linkage is
found in the saturated diazaphospholidine ligands (L1: 1.505(3) Å; L2: 1.517(3) Å) versus the
unsaturated diazaphospholene (L4: 1.3307(18) Å).
1
13
Scheme 2. Synthesis of the NHPꢀbisphosphines L1-L6.
7
ACS Paragon Plus Environment

ACS Catalysis
Page 8 of 41
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 1. Crystallographically determined structures of L1 (left), L2 (middle), and L4 (right),
represented with thermal ellipsoids at the 30% probability level. Selected hydrogen atoms are
omitted for clarity.
2.2. Screening of Ligands L1-L6 in Nickel-Catalyzed C(sp2)-N Cross-Couplings
With the NHPꢀbisphosphines L1ꢀL6 in hand, their utility in promoting the nickelꢀ
catalyzed C(sp2)ꢀN crossꢀcoupling of (hetero)aryl chlorides was evaluated in a preliminary
screen employing Ni(COD)2/L precatalyst mixtures. In this regard, 1ꢀchloronaphthalene (E1), 4ꢀ
chlorobenzonitrile (E2), 3ꢀchloroanisole (E3), and 5ꢀchlorobenzo[b]thiophene (E4) were
employed as representative orthoꢀsubstituted, paraꢀsubstituted electronꢀpoor, metaꢀsubstituted
electronꢀpoor, and heterocyclic test electrophiles, respectively, while furfurylamine (N1),
morpholine (N2), and indole (N3) were employed as representative primary alkylamine,
secondary cyclic dialkylamine, and heterocyclic NH reaction partners, respectively. Both PAdꢀ
DalPhos (L7)15a and DPPF (L8)13a, b were screened alongside L1ꢀL6, so as to provide a direct
comparison to stateꢀofꢀtheꢀart ligands in nickelꢀcatalyzed C(sp2)ꢀN crossꢀcoupling. The reaction
preferences exhibited by L1ꢀL6 are presented in Scheme 3; for full tabulated catalytic results,
see the Supporting Information, Figures S1ꢀS4.
8
ACS Paragon Plus Environment

Page 9 of 41
ACS Catalysis
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 3. Screening of NHPꢀbisphosphine ligands in nickelꢀcatalyzed C(sp2)ꢀN crossꢀ
couplings. Results are estimated on the basis of calibrated GC data using dodecane as an internal
standard.
The results of our screen employing our new NHPꢀbisphosphines L1ꢀL6, as well as L7
and L8, in the nickelꢀcatalyzed C(sp2)ꢀN crossꢀcoupling of (hetero)aryl chlorides with
furfurylamine (N1) suggest that these new NHPꢀbisphosphine ligands hold promise in such
crossꢀcouplings of primary alkylamines. Under the conditions employed, the performance of L2
(NHPꢀDalPhos) in particular was consistently competitive with, or superior to, both the other
NHPꢀbisphosphines surveyed, as well as the highly effective PAdꢀDalPhos (L7).15a In many but
not all cases, structurally analogous ancillary ligands featuring a saturated NHP moiety (L1-L3)
outꢀperformed analogous unsaturated variants (L4-L6) in the crossꢀcoupling of E1ꢀE4 with N1.28
Unlike L7, NHPꢀbisphosphines bearing a P(oꢀtolyl)2 donor fragment (i.e., L3 and L6) performed
consistently worse than the other NHPꢀbisphosphine ligands examined herein as well as L7 in
the monoarylation of N1, including generating the highest percentage of byꢀproducts resulting
from hydrodehalogenation and other undesired offꢀcycle events. Such reactivity differences are
likely the result of steric rather than electronic factors, given the similar σꢀdonor properties of
PPh3 and P(oꢀtolyl)3.29 In turning our attention to crossꢀcouplings involving morpholine or
indole, the performance of DPPF (L8) was found to be superior to that of L1ꢀL6 in all of the
9
ACS Paragon Plus Environment

ACS Catalysis
Page 10 of 41
1
2
3
4
5
6
7
8
9
transformations examined; only in the particular pairing of 4ꢀchlorobenzonitrile (E2) and indole
(N3) did L2 and L6 offer competitive performance relative to L8. Collectively, the reactivity
profile displayed by the NHPꢀbisphosphines reported herein, and L2 (NHPꢀDalPhos) in
particular, in the nickelꢀcatalyzed C(sp2)ꢀN crossꢀcoupling of amines is analogous to that of L7
(PAdꢀDalPhos).13c
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2.3. Nickel Coordination Chemistry Employing L2
Having identified L2 as being a suitably effective ancillary ligand for use in the nickelꢀ
catalyzed C(sp2)ꢀN crossꢀcoupling of primary alkylamines, we turned our attention to preparing
derived nickel precatalysts of the type (L2)NiX(aryl). Such precatalysts are attractive in that they
can provide direct access to (L2)Ni0 species under standard amination conditions in the absence
of potential inhibition by COD,30 thereby enabling more mild reaction conditions (e.g. low
loadings, room temperature, etc) to be employed.31 Given that the choice of X and aryl within
LnNiX(aryl) structures can impact the stability and reactivity of such precatalysts,32 we elected to
synthesize two variants: (L2)NiCl(oꢀtolyl) (C1) and (L2)NiBr(Mes) (C2). Our initial synthetic
efforts were directed toward the preparation of (L2)NiCl2 as a precursor to C1. Treatment of
NiCl2(DME) with L2 afforded (L2)NiCl2 as an analytically pure orange solid in 85% isolated
yield (Scheme 4). The crystallographically determined structure of (L2)NiCl2 (Figure 2) features
a distorted square planar geometry at nickel, whereby the observed NiꢀCl distances of 2.2487(10)
Å (trans to NHP) and 2.2073(10) Å (trans to the PPh2) suggest that the NHP is a stronger transꢀ
directing group relative to the triarylphosphine moiety. Both of the NiꢀP distances in (L2)NiCl2
(NiꢀNHP 2.1373(11) Å, NiꢀPPh2 2.1263(10) Å) are shorter than those in (L7)NiCl2 (NiꢀCgP
2.1766(8) Å, NiꢀP(oꢀtolyl)2 2.2263(8) Å), whereas the corresponding NiꢀCl distances in
(L2)NiCl2 (vide supra) are modestly longer than those in (L7)NiCl2;15a this observation would
10
ACS Paragon Plus Environment

Page 11 of 41
ACS Catalysis
1
2
3
4
5
6
7
8
9
appear to suggest that L2 binds nickel more tightly than does L7, despite the considerable steric
demands of the NHP group in the former. With this in mind, and given the negligible difference
in the NiꢀNHP and NiꢀPPh2 distances within (L2)NiCl2, it is plausible that a shorter than
expected NiꢀNHP interaction in (L2)NiCl2 arises in part due to πꢀbackbonding phenomena.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
While the crystal structure of a conceptually related (κ2ꢀP,P)NiCl2 complex comprising a
chelated neutral variant of B (Chart 1) featuring a PꢀCl linkage has been reported by Thomas and
coꢀworkers,25 the bonding in this complex varies significantly from that observed in (L2)NiCl2.
NiCl2(DME)
THF, 25 oC, 3 h
NiBr2
Mes N
N Mes
(L2)NiCl2
(L2)NiBr2
P
85%
90%
PPh2
(NHP-DalPhos)
THF, 65 oC, 2 h
L2
MesMgBr
THF, 0-25 oC
18 h
(TMEDA)NiCl(o-tolyl)
THF, 65 oC, 3 h
(L2)NiBr(Mes), C2
(L2)NiCl(o-tolyl), C1
+
98%
N
N
P
Ni
Br
P
Ph2
C3
Scheme 4. Nickel coordination complexes derived from L2.
11
ACS Paragon Plus Environment

ACS Catalysis
Page 12 of 41
1
2
3
4
5
6
7
8
9
Figure 2. Singleꢀcrystal Xꢀray structures of (L2)NiCl2 (left) and C1 (right), represented with
thermal ellipsoids at the 30% probability level. Selected hydrogen atoms are omitted for clarity.
Selected interatomic distances (Å) for (L2)NiCl2: NiꢀP1 2.1373(11); NiꢀP2 2.1263(10); NiꢀCl1
2.2487(10); NiꢀCl2 2.2073(10). Selected interatomic distances (Å) for C1: NiꢀP1 2.2010(7); Niꢀ
P2 2.1217(7); NiꢀCl 2.1886(7); NiꢀC51 1.949(3).
While treatment of (L2)NiCl2 with (oꢀtolyl)MgCl under various conditions afforded the
target complex C1 as the major product on the basis of 31P NMR data, the quantitative formation
of C1 was achieved upon combination of L2 with (TMEDA)NiCl(oꢀtolyl),33 as outlined in
Scheme 4. Precatalyst C1 was thus obtained as an analytically pure yellow solid (98% yield),
and was characterized by use of spectroscopic and Xꢀray crystallographic techniques (Figure 2).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
31
The solution P{1H} NMR spectrum of C1 (THFꢀd8, 300 K) features only two doublets (120.3
1
and 57.0 ppm) in keeping with the existence of a single diastereomer in solution, while the H
NMR spectrum of this complex features signals consistent with a C1ꢀsymmetric structure
whereby NiꢀC(oꢀtolyl) bond rotation is apparently slow on the NMR timescale. A distorted
square planar geometry is observed about nickel in the crystal structure of C1, with chloride
positioned trans to the triarylphosphine moiety. While it is likely that a combination of steric and
electronic factors contribute the observed cisꢀdisposed NHP and chloride donors in C1, it is
worth noting that in the corresponding PAdꢀDalPhos complex (L7)NiCl(oꢀtolyl), chloride is
preferentially positioned trans to the phosphaadamantane group. In keeping with the stronger
transꢀdirecting character of an aryl group relative to chloride, the NiꢀNHP distance in C1
(2.2010(7) Å) is significantly longer than the related distance in (L2)NiCl2 (vide supra), whereas
the NiꢀPPh2 contact in C1 (2.1217(7) Å) is indistinguishable from that found in (L2)NiCl2.
In the pursuit of C2, L2 was treated with NiBr2 as outlined in Scheme 4, thereby
affording (L2)NiBr2 as an analytically pure red solid in 90% isolated yield. Subsequent exposure
of (L2)NiBr2 to MesMgBr employing literature methods32a afforded what we tentatively assign
as a mixture (~10:1) of diastereomers of the target complex C2, along with approximately 10%
12
ACS Paragon Plus Environment

Page 13 of 41
ACS Catalysis
1
2
3
4
31
of an additional byꢀproduct (C3), on the basis of P NMR data obtained from a sample of the
5
6
7
8
crude reaction mixture. Although we have thus far been unable to obtain useful quantities of
analytically pure C2 free of contamination by C3, Xꢀray crystallographic analysis (Figure 3) of a
minute quantity of crystalline C2 confirmed the identity of this species as the distorted square
planar complex (L2)NiBr(Mes), whereby the mesityl group is trans to the NHP fragment, and
the NiꢀP and NiꢀC(aryl) distances are comparable to those found in C1. In one instance we were
also fortuitously able to isolate a small quantity of crystalline C3, which we were able to
characterize on the basis of data obtained from 31P NMR, elemental analysis, and Xꢀray
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
31
crystallographic experiments. Whereas the P NMR data allowed us to confirm the identity of
this material as being the same as that formed as a byꢀproduct in the synthesis of C2 (i.e., C3,
vide supra), the Xꢀray data obtained for C3 (corroborated by elemental analysis data) allowed for
the identification of this species as a distorted square planar complex as arising from
cyclometallation of an orthoꢀmethyl of an NHPꢀmesityl group, with net loss of mesitylene
(Figure 3). The tridentate nature of the cyclometallated ancillary ligand in C3, along with the
presence of a weakly transꢀdirecting bromide ligand, results in C3 having the shortest NiꢀNHP
distance (2.0929(5) Å) amongst the complexes reported herein. Given the apparent complexities
associated with the synthesis of C2, in moving forward we opted to employ C1 exclusively as a
preꢀcatalyst.
Figure 3. Singleꢀcrystal Xꢀray structures of C2 (left) and C3 (right), represented with thermal
ellipsoids at the 30% probability level. Selected hydrogen atoms are omitted for clarity. Selected
13
ACS Paragon Plus Environment

ACS Catalysis
Page 14 of 41
1
2
3
4
5
6
interatomic distances (Å) for C2: NiꢀP1 2.2220(7); NiꢀP2 2.1305(7); NiꢀBr 2.3091(4); NiꢀC51
1.950(3). Selected interatomic distances (Å) for C3: NiꢀP1 2.0929(5); NiꢀP2 2.1907(5); NiꢀBr
2.3668(3); NiꢀC17 1.9921(17).
7
8
9
2.4. Scope of Reactivity Employing Precatalyst C1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Having prepared an appropriate precatalyst, the substrate scope enabled by use of C1 in
the nickelꢀcatalyzed Nꢀarylation of primary alkylamines at room temperature was surveyed
(Scheme 5). In keeping with our preliminary catalytic testing (Scheme 3), the crossꢀcoupling of
furfurylamine (N1) with electrophiles E1ꢀE4 afforded the targeted monoarylation products 1aꢀ1d
in high isolated yield; 1ꢀbromonapthalene also proved compatible in this chemistry. In
conducting the largerꢀscale crossꢀcoupling of E1 and N1 using C1 (5.37 mmol E1), the desired
product 1a was obtained in excellent yield (1.13 g, 94%).
Scheme 5. Substrate scope for the crossꢀcoupling of primary alkylamines and (hetero)aryl
halides employing C1 as a preꢀcatalyst. Conditions: NaO(tꢀBu) (1.5ꢀ2 equiv), (hetero)aryl halide
a
(1.0 equiv), and amine (1.1 equiv), with isolated yields shown. Estimated yield on the basis of
b
calibrated GC data using dodecane as an internal standard. Conditions: NaO(tꢀBu) (2.5 equiv),
(hetero)aryl halide (1.0 equiv), and ethylammonium chloride (1.2 equiv) at 80 ○C.
14
ACS Paragon Plus Environment

Page 15 of 41
ACS Catalysis
1
2
3
4
5
6
7
8
9
A range of other (hetero)aryl halides were employed successfully, including those
featuring orthoꢀsubstitution (1e, 1i), trifluoromethyl (1f), ether (1k), nitrile (1l), or ketone (1m)
functionalities. Heterocyclic electrophiles also proved to be useful coupling partners, including
those featuring benzothiophene (1d), pyridine (1e), quinoxaline (1g, 1h) and quinoline (1j) core
structures. A diverse array of primary alkylamines were successfully coupled in the course of
this reactivity survey, featuring benzylic (1j, 1k), allylic (1l), aliphatic (1m), and heteroaryl
functionalities (1a-d, 1i). In the case of 1l, no rearrangement of the allylic fragment was seen.
Small nucleophilic reagents were also transformed efficiently, using commercially available
stock solutions of methylamine and ethylamine to afford the monoarylated product exclusively
(1e-g). In the case of 1e and 1f, the volatile nature of the crossꢀcoupled product led to material
loss while drying in vacuo; however, the high conversion achieved in these reactions was
confirmed on the basis of GC analysis. The viability of using commercially available ammonium
salts, which are more easily handled than their volatile liquid analogues, was also explored
briefly. In this vein, the crossꢀcoupling of ethylammonium chloride and 6ꢀchloroquinoxaline
leading to 1h was readily achieved, adding to the few known examples of nickelꢀcatalyzed crossꢀ
coupling of alkylammonium salts.15a, 15d, 16 Throughout the course of these crossꢀcouplings
employing C1 as a preꢀcatalyst, no undesired polyarylated species were detected as byꢀproducts.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Although for convenience we opted to employ 5 mol% C1 in the substrate scope
exploration presented in Scheme 5, we became interested in examining if lower loadings, and/or
alternative nickel precatalysts featuring L2, might be effective in such transformations.
Moreover, we sought to learn more about the relative reactivity behavior of (L)NiCl(oꢀtolyl)
precatalysts (L = L2, NHPꢀDalPhos; L = L7, PAdꢀDalPhos). In studying the crossꢀcoupling of 5ꢀ
15
ACS Paragon Plus Environment

ACS Catalysis
Page 16 of 41
1
2
3
4
5
6
7
8
9
chlorobenzo[b]thiophene (E4, 1 equiv) and furfurylamine (N1, 1.1 equiv) to give 1d as a test
reaction (2 equiv NaO(tꢀBu), toluene, 16 h, 25 ˚C), quantitative conversion to 1d was achieved
by use of 2 mol% C1. In using (TMEDA)NiCl(oꢀtolyl)/L2 mixtures under analogous room
temperature conditions, high (~85%) but incomplete conversion to 1d was detected, and no
conversion to product was achieved by use of (TMEDA)NiCl(oꢀtolyl) alone. Our finding that the
addition of TMEDA (1 equiv) to C1 did not inhibit room temperature catalysis suggests that the
inferior performance of (TMEDA)NiCl(oꢀtolyl)/L2 mixtures under these conditions is likely
attributable to incomplete formation of C1 in situ. While clean conversion to 1d was also
achieved with (L7)NiCl(oꢀtolyl) under the test conditions, the use of either (L2)NiCl2 or
Ni(COD)2/L2 mixtures (2 mol% Ni) in the presence or absence of PhBPin as an activator15c
afforded ≤10 % conversion to 1d, thereby establishing the inferiority of such catalyst systems.
Upon lowering the loading of C1 to the 1 mol% level, only 40% conversion to 1d (50% in the
presence of 1 equiv PhBPin) was achieved; conversely, >90% conversion to 1d was achieved by
use of (L7)NiCl(oꢀtolyl) (1 mol%), in keeping with our previous reports.15a, 15c In an effort to
learn more about the relative activity of catalysts generated from (L)NiCl(oꢀtolyl) (L = L2 or
L7), we elected to monitor the room temperature crossꢀcoupling of 3ꢀchloroanisole (E3, 1 equiv)
and furfurylamine (N1, 1.1 equiv) to give 1c. Under the test conditions employed (2 mol% Ni, 2
equiv NaO(tꢀBu), toluene, 25 ˚C), quantitative conversion to 1c was achieved after 0.25 h with
(L7)NiCl(oꢀtolyl), at which timeꢀpoint <20% conversion to 1c was observed when using
(L2)NiCl(oꢀtolyl) (C1); 1.5 h was required in order to achieve full conversion to 1c when using
C1 under these conditions, in the absence of an observable induction period. Collectively, these
experiments reaffirm the particular utility of employing (L)NiCl(oꢀtolyl) precatalysts31 in C(sp2)ꢀ
N crossꢀcoupling applications. While in headꢀtoꢀhead reactivity comparisons PAdꢀDalPhos (L7)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
16
ACS Paragon Plus Environment

Page 17 of 41
ACS Catalysis
1
2
3
4
5
6
7
8
9
was found to outꢀperform NHPꢀDalPhos (L2) to a modest extent, the catalytic performance of
C1 establishes L2 as being a member of a small subset of ligands (along with PAdꢀDalPhos15a
and CyPAdꢀDalPhos15d) that have proven capable of enabling the nickelꢀcatalyzed
monoarylation of primary alkylamines with (hetero)aryl chlorides at room temperature with
broadly useful scope.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
To gain some preliminary insights into the electrophile reactivity preferences of C1, we
conducted a (pseudo)halide competition study using limiting furfurylamine (N1). An aryl
chloride, bromide, and tosylate were compared under standard reaction conditions, with
substituents on the aryl moiety bearing similar steric and electronic characteristics so as to focus
solely on the inherent reactivity behavior of the (pseudo)halide electrophile (Scheme 6). In
competitions involving an aryl chloride and an aryl bromide, a 2:1 preference for the bromide
electrophile was observed, with full conversion of furfurylamine. When an aryl chloride and an
aryl tosylate were compared, a 3:1 preference for the chloride was noted, although a significant
decrease in overall product formation was found. The same trend was seen in the competition of
an aryl bromide and an aryl tosylate, with a 20:1 preference for the bromide. Collectively, these
results highlight the potential inhibitory effect of aryl tosylates (and possibly sulfonates more
generally) on C1, a phenomenon that has been observed in our previous studies involving
CyPAdꢀDalPhos in nickelꢀcatalyzed C(sp2)ꢀN crossꢀcouplings.15d
17
ACS Paragon Plus Environment

ACS Catalysis
Page 18 of 41
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 6. (Pseudo)halide competition study employing C1. Reported product distributions and
total conversions to 1n and 1o estimated on the basis of calibrated GC data.
2.5. Computational Comparison of NHP-DalPhos (L2) and PAd-DalPhos (L7)
To understand more fully the behavior of L2 versus L7 in nickelꢀcatalyzed C(sp2)ꢀN
crossꢀcoupling chemistry, we chose to model one potential reaction pathway within a
presumptive Ni0/NiII cycle15c for the crossꢀcoupling of chlorobenzene and furfurylamine (N1) to
yield Nꢀphenylꢀfuranmethanamine (1p) via density functional theory (DFT) calculations
(Scheme 7). The B3LYPꢀXDM34 method and the 6ꢀ311+G(2d,2p) basis set were used, which are
wellꢀsuited for calculating 3d transition metalꢀligand binding energies.34d The geometry
optimizations and frequency calculations were performed with a smaller, mixed basis set, and
frequencies were used to assign stationary points as either minima (no imaginary frequencies) or
transition states (one imaginary frequency). The following steps were modeled: (i) arene
exchange between (L)Ni(η2ꢀtoluene) (IN-1) and chlorobenzene to afford (L)Ni(η2ꢀPhCl) (IN-2);
(ii) CꢀCl oxidative addition to give (L)Ni(Ph)Cl (IN-3) via TS-1; (iii) reaction with
furfurylamine and tertꢀbutoxide to give (L)Ni(Ph)(NH(CH2ꢀfuryl)) (IN-4); (iv) CꢀN reductive
elimination to afford (L)Ni(η2ꢀNꢀphenylꢀfuranmethanamine) (IN-5) via TS-2; and (v) arene
exchange from IN-5 to regenerate IN-1 and liberate Nꢀphenylꢀfuranmethanamine product (1p).
18
ACS Paragon Plus Environment

Page 19 of 41
ACS Catalysis
1
2
3
4
5
6
7
8
9
Exchange of toluene for chlorobenzene in the conversion of IN-1 to IN-2 is modestly
exergonic for both L2 (ꢀ1.5 kcal molꢀ1) and L7 (ꢀ3.5 kcal molꢀ1). Consistent with the view that Cꢀ
Cl bond oxidative addition of chloroarenes to phosphine supported P2Ni0 complexes is relatively
facile,11a, 15c, 35 the freeꢀenergy activation barriers for chlorobenzene oxidative addition (via TS-1)
were found to be small (L2: 7.7 kcal molꢀ1, L7: 7.2 kcal molꢀ1), and the formation of IN-3 from
IN-2 is highly exergonic (L2: ꢀ24.0 kcal molꢀ1, L7: ꢀ26.1 kcal molꢀ1). Owing to the lack of clarity
involving the role of the base, we did not attempt to locate a transition state leading to the
formation of IN-4. Nonetheless, the reaction was found to be exergonic for both ligands (L2: ꢀ
11.7 kcal molꢀ1, L7: ꢀ11.4 kcal molꢀ1). The CꢀN reductive elimination to afford IN-5 is exergonic
for both L2 (ꢀ8.8 kcal molꢀ1) and L7 (ꢀ6.1 kcal molꢀ1) pathways. However, it is notable that the
L2 derived pathway (19.2 kcal molꢀ1) suffers from a comparatively higher barrier to CꢀN
reductive elimination (via TS-2) versus the L7 based pathway (16.0 kcal molꢀ1), which may in
part form the basis of the superior reactivity of L7 versus L2 in room temperature Nꢀarylations of
furfurylamine (vide supra) within a putative Ni0/NiII cycle.15c Indeed, when conducting the crossꢀ
coupling of chlorobenzene and furfurylamine (N1) using 1 mol% of C1 or (L7)NiCl(oꢀtolyl) at
room temperature under experimental conditions outlined in Scheme 5, 70% conversion to Nꢀ
phenylꢀfuranmethanamine 1p was observed after only 1 h with (L7)NiCl(oꢀtolyl); conversely, in
using L2ꢀcontaining C1 only 30% of the desired product 1p was obtained under such conditions
(with the remainder being unreacted starting materials). To complete the cycle, IN-1 is
regenerated via arene exchange of bound 1p by toluene, the overall reaction of which is
approximately thermoneutral (L1: ꢀ0.6 kcal molꢀ1, L2: 0.6 kcal molꢀ1). Decomposition of the
computed barriers into dispersion and base DFT contributions (see the Supporting Information,
Table S1) reveals that dispersion stabilization in TS-2 involving L2 or L7 is not significant. The
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
19
ACS Paragon Plus Environment

ACS Catalysis
Page 20 of 41
1
2
3
4
5
6
7
8
9
difference in barriers primarily arises from the base density functional, indicating that electronic
effects are the dominant contributors to the difference in the TS-2 barrier. It is expected that the
less electronꢀrich ligand, L7, should lower the elimination barrier, in agreement with the relative
baseꢀfunctional energies.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 7. Comparative reaction profile (relative freeꢀenergies, kcal molꢀ1) calculated by use of
DFT methods for the nickelꢀcatalyzed C(sp2)ꢀN crossꢀcoupling of chlorobenzene and
furfurylamine (N1) involving (L2/L7)Ni species (R = CH2ꢀfuryl).
20
ACS Paragon Plus Environment

Page 21 of 41
ACS Catalysis
1
2
3
4
5
6
3. Conclusion
7
8
9
A series of new orthoꢀphenylene bridged bisphosphine ancillary ligands based on the Nꢀ
heterocyclic phosphine (NHP) structural motif has been prepared and tested in nickelꢀcatalyzed
C(sp2)ꢀN crossꢀcoupling reactions. In the course of such studies, an ancillary ligand variant
featuring a saturated NHP group paired with an adjacent diphenylphosphino donor group (i.e.,
NHPꢀDalPhos, L2) emerged as being particularly effective in transformations of primary
alkylamines. Subsequent application of the derived preꢀcatalyst (NHPꢀDalPhos)NiCl(oꢀtolyl)
(C1) allowed for roomꢀtemperature crossꢀcouplings of primary alkylamines with (hetero)aryl
chlorides or bromides to be achieved – a typically challenging class of reactions for which only
PAdꢀDalPhos, L715a and CyPAdꢀDalPhos15d have proven capable with broadly useful scope. In
comparing the catalytic behavior of L2 and L7 in such transformations, nickel catalysts derived
from the latter were found to outꢀperform the former to a modest extent on the basis of the
catalyst turnover number and frequency; this trend that can be attributed in part to a larger barrier
to C(sp2)ꢀN bond reductive elimination in the case of L2, as evidenced by the results of our DFT
computational studies reported herein. This work establishes for the first time the utility of NHPꢀ
derived bisphosphines in challenging nickelꢀcatalyzed C(sp2)ꢀN crossꢀcouplings, and contributes
toward expanding the ancillary ligand ‘toolkit’ for such synthetically useful transformations.
4. Experimental Section
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General Considerations. Unless otherwise indicated, all experimental procedures were
conducted in a nitrogenꢀfilled, inertꢀatmosphere glovebox using ovenꢀdried glassware and
purified solvents, with the exception of the workup of catalytic reaction mixtures which was
conducted on the benchꢀtop in air using unpurified solvents. Toluene and pentane were sparged
21
ACS Paragon Plus Environment

ACS Catalysis
Page 22 of 41
1
2
3
4
5
6
7
8
9
with nitrogen and passed through a doubleꢀcolumn purification system containing alumina and
copperꢀQ5 reactant. Diethyl ether and tetrahydrofuran (THF) were dried over Na/benzophenone
and distilled under a nitrogen atmosphere. Dichloromethane (DCM) and acetonitrile were purged
with nitrogen, while deuterated NMR solvents were freezeꢀpumpꢀthaw degassed three times. In
all cases, solvents purified as outlined above for use within the glovebox were stored over
activated 4 Å molecular sieves in bulbs fitted with Teflon taps for a minimum of 24 h prior to
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
use.
2ꢀChloroꢀ1,3ꢀdimesitylꢀ1,3,2ꢀdiazaphospholidine,36
2ꢀbromoꢀ1,3ꢀdimesitylꢀ1,3,2ꢀ
diazaphospholene,37 and 4ꢀbutylphenyl tosylate15d were prepared according to established
literature procedures. Otherwise, all other solvents, reagents, and materials were used as received
from commercial sources. Flash chromatography was carried out on silica gel using Silicycle
SiliaFlash 60 silica (particle size 40−63 ꢁm; 230−400 mesh), with the exception of the largeꢀ
scale synthesis of 1a, where automated flash chromatography was carried out on a Biotage
Isolera One automated flash purification system using 100 g Biotage SNAP KPꢀSIL (particle
size 30−90 ꢁm) with a gradient of 2−8−2 column volumes and a flow rate of 40 mL/min. Unless
otherwise indicated, NMR spectra were recorded on a Bruker AV 300 MHz or Bruker AV 500
MHz spectrometer at 300 K, with chemical shifts (in ppm) referenced to residual protio solvent
peaks (1H), deuterated solvent peaks (13C{1H}), or external 85% H3PO4 (31P{1H}). Splitting
patterns are indicated as follows: br, broad; s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet. All coupling constants (J) are reported in hertz (Hz). In some cases, fewer than
expected carbon resonances were observed despite prolonged acquisition times. Elemental
analyses were performed by Galbraith Laboratories, Inc., Knoxville, TN. Mass spectra were
obtained using ion trap electrospray ionization (ESI) instruments operating in positive mode. Gas
22
ACS Paragon Plus Environment

Page 23 of 41
ACS Catalysis
1
2
3
4
5
6
chromatography (GC) data were obtained on an instrument equipped with a SGE BPꢀ5 column
(30 m, 0.25 mm i.d.).
7
8
9
Synthesis of L1. A glass vial was charged with (2ꢀbromophenyl)dicyclohexylphosphine (0.253
g, 0.716 mmol), diethyl ether (4 mL), a magnetic stir bar and was cooled to ꢀ30 °C. Magnetic
stirring of the solution was initiated, resulting in a clear and colorless solution. To this mixture
was added 2.5 M nBuLi in hexanes (0.300 mL, 0.752 mmol) leading to the immediate formation
of a white opaque solution. The resulting mixture was warmed to room temperature and stirred
for 1 h, forming a pale yellow and opaque solution. 2ꢀChloroꢀ1,3ꢀdimesitylꢀ1,3,2ꢀ
diazaphospholidine (0.272 g, 0.752 mmol) was added and the resulting solution was stirred for
48 h at room temperature. An opaque orange solution resulted. The solvent was removed in
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
vacuo, yielding a pale yellow solid, which was washed with cold (~0 C) pentane (3 x 1 mL).
The offꢀwhite solid was recrystallized via slow evaporation of a hexanes solution (initially 5 mL)
1
to afford the title compound as a white solid (0.184 g, 0.308 mmol, 43%). H NMR (500 MHz;
C6D6): δ 8.27 – 8.19 (m, 1H), 7.34 – 7.24 (m, 2H), 7.14 – 7.10 (m, 1H), 6.76 (br. s, 4H), 3.93 –
3.84 (m, 2H), 3.16 – 3.07 (m, 2H), 2.35 (very br., 12H), 2.15 (s, 6H), 1.84 (br. s, 3H), 1.72 (br. s,
3H), 1.54 (br. s, 2H), 1.45 (br. s, 4H), 1.34 – 1.30 (br. m, 2H), 1.09 (m, 4H), 0.99 – 0.91 (m, 2H),
13
0.57 (m, 2H). C{1H} NMR (125.8 MHz, C6D6): δ 155.7 (d, J = 23.4 Hz), 155.3 (d, J = 23.5
Hz), 140.8 – 140.4 (overlapping signals), 137.5, 134.4, 132.4, 131.2 (d, J = 7.5 Hz), 130.0 (d, J =
4.0 Hz), 129.5, 127.9, 127.1, 52.2 (d, J = 6.0 Hz), 34.2 – 34.0 (overlapping signals), 30.2 (d, J =
16.6 Hz), 28.8 (d, J = 10.2 Hz), 27.1 (d, J = 11.5 Hz), 27.0 (d, J = 8.3 Hz), 26.3, 20.6 – 20.2
31
(overlapping signals). P{1H} (202.4 MHz, CDCl3): δ 86.1 (d, J = 185.7 Hz, 1P), ꢀ13.5 (br. m,
1P). HRMSꢀESI (m/z): Calc’d for C38H53N2P2 [M+H]+ : 599.3678. Found: 599.3522.
23
ACS Paragon Plus Environment

ACS Catalysis
Page 24 of 41
1
2
3
4
Synthesis of L2 (NHP-DalPhos).
A
glass vial was charged with (2ꢀ
5
6
7
8
bromophenyl)diphenylphosphine (1.00 g, 2.93 mmol), diethyl ether (10 mL), a magnetic stirbar,
and was cooled to ꢀ30 °C. Magnetic stirring of the solution was initiated, resulting in a clear and
colorless solution. To this solution was added 2.5 M nBuLi in hexanes (1.23 mL, 3.08 mmol)
leading to the immediate formation of a dark red solution. The resulting mixture was warmed to
room temperature and stirred for 1 h, forming a dark red and opaque solution. The solvent was
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
then removed in vacuo and the residue was washed with cold (~0 C) pentane (3 x 8 mL) and
subsequently dried in vacuo, affording a red residue. 2ꢀChloroꢀ1,3ꢀdimesitylꢀ1,3,2ꢀ
diazaphospholidine (1.11 g, 3.08 mmol) and toluene (10 mL) were consecutively added and the
resulting solution was stirred for 48 h at room temperature. An opaque brown solution resulted.
The mixture was filtered through a Celite/silica plug. The eluent was collected, from which the
solvent was removed in vacuo to afford an offꢀwhite solid. This crude solid was triturated with
o
cold (~0 C) pentane (4 mL) and dried in vacuo, affording the title compound as a white solid
(0.687 g, 1.17 mmol, 40%). 1H NMR (500 MHz; C6D6): δ 8.20 (br. s, 1H), 7.24 (br. s, 1H), 7.02
(br. s, 6H), 6.88 (br. s, 6H), 6.71 (br. s, 4H), 3.85 (br. s, 2H), 3.10 (br. s, 2H), 2.29 (br. s, 12H),
2.13 (br. s, 6H).13C{1H} NMR (125.7 MHz, C6D6): δ 153.2 (d, J = 25.1 Hz), 152.8 (d, J = 25.1
Hz), 143.3 – 143.0 (overlapping signals), 141.1 (d, J = 14.9 Hz), 139.0 (d, J = 8.6 Hz), 138.9 (d,
J = 8.6 Hz), 137.7, 135.0, 134.4 – 134.3 (overlapping signals), 131.0 (d, J = 7.3 Hz), 130.6,
130.0, 128.7, 128.5, 52.8 (d, J = 5.9 Hz), 21.2 – 20.8 (overlapping signals). 31P{1H} (121.4 MHz,
CDCl3): δ 86.8 (d, J = 199.0 Hz, 1P), ꢀ15.5 (d, J = 199.0 Hz, 1P). HRMSꢀESI (m/z): Calc’d for
C38H41N2P2 [M+H]+ : 587.2739. Found: 587.2739.
Synthesis of L3. A glass vial was charged with (2ꢀbromophenyl)di(orthoꢀtolyl)phosphine (0.400
g, 1.08 mmol), diethyl ether (4 mL), a magnetic stir bar and was cooled to ꢀ30 °C. Magnetic
24
ACS Paragon Plus Environment

Page 25 of 41
ACS Catalysis
1
2
3
4
5
6
7
8
9
stirring of the solution was initiated, resulting in a clear and colorless solution. To this solution
was added 2.5 M nBuLi in hexanes (0.455 mL, 1.14 mmol) leading to the immediate formation
of an offꢀwhite and milky solution. The resulting mixture was warmed to room temperature and
stirred for 1 h, forming a pale yellow and opaque solution. The solvent was removed in vacuo
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
following stirring and the residue was washed with cold (~0 C) pentane (3 x 3 mL) and
subsequently dried in vacuo, affording a pale yellow residue. 2ꢀChloroꢀ1,3ꢀdimesitylꢀ1,3,2ꢀ
diazaphospholidine (0.410 g, 1.14 mmol) and toluene (4 mL) were added consecutively and the
resulting solution was stirred for 48 h at room temperature. An opaque yellow solution resulted.
o
The mixture was cooled to ꢀ30 C and then filtered through a Celite/silica plug. The eluent was
collected and the solvent was removed in vacuo to afford an offꢀwhite solid. The crude material
was dissolved in DCM, cooled to ꢀ30 oC and filtered through a Celite/silica plug. The eluent was
collected and the solvent was removed in vacuo to yield a white solid (0.194g, 0.316 mmol,
1
29%). H NMR (500 MHz; C6D6): δ 8.18 – 8.10 (m, 1H), 7.41 – 7.36 (m, 1H), 7.15 (t, J = 7.4
Hz, 1H), 7.09 – 7.04 (m, 2H), 7.04 – 6.99 (m, 2H), 6.80 (t, J = 7.3 Hz, 2H), 6.69 (br. s, 5H), 6.52
(dd, J = 3.7, 7.4 Hz, 2H), 4.18 – 4.10 (m, 2H), 3.44 – 3.37 (m, 2H), 2.20 (s, 6H), 2.15 (br. s,
12H), 2.03 (s, 6H). C{1H} NMR (125.7 MHz, C6D6): δ 152.4 (d, J = 24.5 Hz), 152.0 (d, J =
13
24.5 Hz), 142.1 (d, J = 26.8 Hz), 141.2 (d, J = 14.2 Hz), 140.9 (d, J = 14.1 Hz), 137.0, 136.2 (d,
J = 8.9 Hz), 136.1 (d, J = 9.0 Hz), 134.2, 133.3, 133.2 (d, J = 4.8 Hz), 130.9 (d, J = 7.4 Hz),
129.5, 129.4 (d, J = 4.9 Hz), 129.2, 128.3, 127.8, 127.7, 125.5, 52.2 (d, J = 5.8 Hz), 21.0 – 20.1
(overlapping signals). P{1H} (121.4 MHz, CDCl3): δ 87.6 (d, J = 199.6 Hz, 1P), ꢀ28.1 (d, J =
31
199.6 Hz, 1P). HRMSꢀESI (m/z): Calc’d for C40H45N2P2 [M+H]+ : 615.3052. Found: 615.3052.
Synthesis of L4. A glass vial was charged with (2ꢀbromophenyl)dicyclohexylphosphine (0.288
g, 0.815 mmol), diethyl ether (4 mL), a magnetic stir bar and was cooled to ꢀ30 °C. Magnetic
25
ACS Paragon Plus Environment

ACS Catalysis
Page 26 of 41
1
2
3
4
5
6
7
8
9
stirring of the solution was initiated, resulting in a clear and colorless solution. To this solution
was added 2.5 M nBuLi in hexanes (0.342 mL, 0.857 mmol) leading to the immediate formation
of an opaque and white solution. The resulting mixture was warmed to room temperature and
stirred for 1 h, forming a pale yellow and opaque solution. The solvent was then removed in
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
vacuo and the residue was washed with cold (~0 C) pentane (3 x 2 mL) and subsequently dried
in vacuo, affording a pale yellow residue. 2ꢀBromoꢀ1,3ꢀdimesitylꢀ1,3,2ꢀdiazaphospholene (0.345
g, 0.857 mmol) and toluene (4 mL) were added consecutively and the resulting solution was
stirred for 48 h at room temperature. An opaque orange solution resulted. The mixture was
filtered through a Celite/silica plug. The eluent was collected and the solvent was removed in
vacuo to afford an orange solid. The crude solid was recrystallized from acetonitrile (7 mL) to
1
afford the title product as an orange powder (0.185 g, 0.310 mmol, 38%). H NMR (500 MHz;
C6D6): δ 8.61 – 8.59 (m, 1H), 7.27 – 7.24 (m, 2H), 7.13 – 7.12 (m, 1H), 6.82 (br. s, 2H), 6.66 (br.
s, 2H), 5.68 (s, 2H), 2.66 (br. s, 6H), 2.14 (s, 6H), 1.96 (br. s, 6H), 1.86 (br. s, 2H), 1.69 (br. s,
2H), 1.57 (br. s, 2H), 1.51 – 1.47 (m, 4H), 1.28 – 1.25 (m, 2H), 1.10 – 0.95 (m, 8H), 0.47 – 0.46
(m, 2H). C{1H} NMR (125.7 MHz, C6D6): δ 152.2 (d, J = 27.1 Hz), 151.7 (d, J = 26.9 Hz),
13
140.9 (d, J = 14.5 Hz), 138.7 (d, J = 20.9 Hz), 138.5 (d, J = 20.8 Hz), 137.6, 136.8, 135.1, 133.0,
132.4 (d, J = 8.8 Hz), 130.4 (d, J = 27.1 Hz), 129.8, 120.3 (d, J = 5.4 Hz), 35.2 (d, J = 5.9 Hz),
35.1 (d, J = 5.9 Hz), 31.5 (d, J = 17.6 Hz), 29.4 (d, J = 8.7 Hz), 28.1, 27.9, 21.3, 20.8, 20.3.
31P{1H} (202.4 MHz, CDCl3): δ 81.4 (d, J = 192.1 Hz, 1P), ꢀ13.9 (br. d, J = 188.9 Hz, 1P).
HRMSꢀESI (m/z): Calc’d for C38H51N2P2 [M+H]+ : 597.3522. Found: 597.3522.
Synthesis of L5. A glass vial was charged with (2ꢀbromophenyl)diphenylphosphine (0.200 g,
0.587 mmol eq), diethyl ether (2 mL), a magnetic stir bar and was cooled to ꢀ30 °C. Magnetic
stirring of the solution was initiated, resulting in a clear and colorless solution. To this solution
26
ACS Paragon Plus Environment

Page 27 of 41
ACS Catalysis
1
2
3
4
5
6
7
8
was added 2.5 M nBuLi in hexanes (0.246 mL, 0.615 mmol) leading to the immediate formation
of an opaque and white solution. The resulting mixture was warmed to room temperature and
stirred for 1 h, forming a pale yellow and opaque solution. The solvent was then removed in
9
o
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
vacuo and the residue was washed with cold (~0 C) pentane (3 x 2 mL) and subsequently dried
in vacuo, affording a pale yellow residue. 2ꢀBromoꢀ1,3ꢀdimesitylꢀ1,3,2ꢀdiazaphospholene (0.248
g, 0.615 mmol) and toluene (2 mL) were consecutively added and the resulting solution was
stirred for 48 h at room temperature. An opaque dark orange solution resulted. The mixture was
filtered through a Celite/silica plug. The eluent was collected and the solvent was removed in
vacuo to afford a dark orange residue. The crude material was washed with pentane (3 x 3 mL)
and dried in vacuo to afford the title compound as an orange solid (0.130 g, 0.222 mmol, 38%).
1H NMR (500 MHz; C6D6): δ 8.51 – 8.47 (m, 1H), 7.21 (doublet of triplets, J = 7.3, 0.8 Hz, 1H),
7.05 – 6.93 (overlapping multiplets, 12H), 6.84 – 6.61 (br. m, 4H), 5.70 – 5.68 (m, 2H), 2.58 (br.
13
s, 6H), 2.14 (s, 6H), 1.92 (br. s, 6H). C{1H} NMR (125.7 MHz, C6D6): δ 148.4 (d, J = 27.9
Hz), 148.0 (d, J = 28.1 Hz), 140.4 (d, J = 14.0 Hz), 139.8 (d, J = 14.4 Hz), 139.6 (d, J = 14.3
Hz), 138.5 (d, J = 7.2 Hz), 138.4 (d, J 7.1 Hz), 137.2 (d, J = 12.4 Hz), 135.3, 134.7, 134.6,
134.4, 131.6 (d, J = 8.8 Hz), 130.9, 130.5, 129.4, 128.9 (d, J = 6.4 Hz), 120.2 (d, J = 5.4 Hz),
31
21.4, 20.5. P{1H} (202.4 MHz, CDCl3): δ 82.8 (d, J = 195.4 Hz, 1P), ꢀ15.4 (d, J = 195.3 Hz).
HRMSꢀESI (m/z): Calc’d for C38H39N2P2 [M+H]+ : 585.2583. Found: 585.2583.
Synthesis of L6. A glass vial was charged with (2ꢀbromophenyl)di(orthoꢀtolyl)phosphine (0.400
g, 1.08 mmol), diethyl ether (4 mL), a magnetic stir bar and was cooled to ꢀ30 °C. Magnetic
stirring of the solution was initiated, resulting in a clear and colorless solution. To this mixture
was added 2.5 M nBuLi in hexanes (0.455 mL, 1.14 mmol) leading to the immediate formation
of an opaque and white solution. The resulting mixture was warmed to room temperature and
27
ACS Paragon Plus Environment

ACS Catalysis
Page 28 of 41
1
2
3
4
stirred for 1 h, forming a pale yellow and opaque solution. The solvent was removed in vacuo
5
6
o
and the residue was washed with cold (~0 C) pentane (3 x 2 mL) and subsequently dried in
7
8
9
vacuo, affording a pale yellow residue. 2ꢀBromoꢀ1,3ꢀdimesitylꢀ1,3,2ꢀdiazaphospholene (0.459 g,
1.14 mmol) and toluene (4 mL) were consecutively added and the resulting solution was stirred
for 48 h at room temperature. An opaque orange solution resulted. The mixture was filtered
through a Celite/silica plug. The eluent was collected and the solvent was removed in vacuo to
afford an orange residue. The crude material was washed with pentane (3 x 3 mL) and dried in
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
vacuo to afford the title compound as an orange solid (0.094 g, 0.153 mmol, 14%). H NMR
(500 MHz; C6D6): δ 8.61 – 8.57 (m, 1H), 7.23 – 7.18 (m, 1H), 6.97 – 6.92 (overlapping
multiplets, 4H), 6.90 – 6.86 (m, 2H), 6.85 – 6.79 (overlapping multiplets, 4H), 6.76 – 6.53 (br.
overlapping multiplets, 4H), 5.69 – 5.68 (m, 2H), 2.54 (br. s, 6H), 2.09 (s, 6H), 2.07 (s, 6H), 1.94
(br. s, 6H). 13C{1H} NMR (125.7 MHz, C6D6): δ 149.1 (d, J = 26.3 Hz), 148.7 (d, J = 26.2 Hz),
143.2 (d, J = 26.3 Hz), 140.2 (d, J = 14.5 Hz), 138.9 (d, J = 13.2 Hz), 138.6 (d, J = 13.1 Hz),
136.7 (d, J = 7.3 Hz), 136.6 (d, J = 7.4 Hz), 135.1, 134.3, 134.1 (d, J = 3.6 Hz), 132.4 (d, J = 8.1
Hz), 131.1, 130.8 (d, J = 4.5 Hz), 130.5, 129.3, 129.2, 128.9, 126.7, 120.5 (d, J = 4.2 Hz), 21.7,
31
21.6, 21.3, 20.8, 20.4 (br. m). P{1H} (202.4 MHz, CDCl3): δ 81.9 (d, J = 193.4 Hz, 1P), ꢀ28.7
(d, J = 193.4 Hz, 1P). HRMSꢀESI (m/z): Calc’d for C40H43N2P2 [M+H]+ : 613.2896. Found:
613.2896.
Synthesis of (L2)NiCl2. A glass vial was charged with NiCl2(DME) (0.017 g, 0.078 mmol), L2
(0.048 g, 0.082 mmol), THF (0.782 mL) and a magnetic stir bar before being sealed with a cap
o
containing a PTFE septum. The reaction mixture was magnetically stirred at 25 C for 3 h ,
affording an opaque orange solution. The solvent was removed in vacuo, affording a reddish
o
orange solid which was washed with cold (~0 C) pentane (3 x 1 mL). The crude residue was
28
ACS Paragon Plus Environment

Page 29 of 41
ACS Catalysis
1
2
3
4
5
6
7
8
9
dissolved in DCM (1 mL) and quickly filtered through a Celite plug. The solvent was removed in
vacuo and the dark orange residue washed with pentane (3 x 1 mL) and dried in vacuo to afford
the title compound as an orange powder (0.047 g, 0.066 mmol, 85%). 31P{1H} (202.4 MHz,
1,1,2,2ꢀTetrachloroethaneꢀd2): δ 111.6 (d, J = 75.5 Hz), 58.0 (d, J = 75.2 Hz). Anal. Calcd for
C38H40Br2N2NiP2 : C, 63.72; H, 5.63; N, 3.91. Found : C, 63.54; H, 5.71; N, 3.88.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Synthesis of C1. A glass vial was charged with (TMEDA)NiCl(oꢀtolyl) (0.049 g, 0.162 mmol),
L2 (0.100 g, 0.170 mmol), THF (3.2 mL), and a magnetic stir bar, forming a clear orange
solution upon initiation of stirring. The vial was sealed with a cap containing a PTFE septum,
o
magnetic stirring was initiated, and the mixture was heated to 65 C for 3 h. A clear amber
solution resulted. The reaction mixture was allowed to cool to room temperature and pentane (13
mL) was added, resulting in the immediate formation of an opaque orange solution. The solution
was stirred at room temperature for 3 h. An opaque yellow suspension formed while stirring. The
solvent was removed in vacuo yielding a bright yellow residue, which was washed with cold (~0
oC) pentane (3 x 3 mL) and dried in vacuo affording the title compound as a yellow solid (0.123
1
g, 0.159 mmol, 98%). H NMR (500 MHz; THFꢀd8): δ 8.27 – 8.21 (m, 1H), 7.61 – 7.52
(overlapping multiplets, 3H), 7.43 – 7.35 (m, 2H), 7.34 – 7.28 (m, 1H), 7.26 – 7.20 (m, 1H), 7.16
– 7.09 (m, 2H), 7.06 (s, 1H), 6.98 – 6.92 (m, 2H), 6.82 (s, 1H), 6.69 (s, 1H), 6.55 (m, 1H), 6.50
(s, 1H), 6.39 (m, 2H), 6.32 (m, 1H), 6.19 (m, 1H), 6.07 (m, 1H), 4.39 – 4.32 (m, 1H), 4.18 – 4.09
(m, 1H), 3.98 – 3.91 (m, 2H), 2.96 (s, 3H), 2.75 (s, 3H), 2.33 (s, 3H), 2.16 (s, 3H), 1.97 (s, 3H),
13
1.38 (s, 3H), 1.09 (s, 3H). C{1H} NMR (125.7 MHz, THFꢀd8): δ 158.8 (d, J = 39.3 Hz), 158.0
(d, J = 39.5 Hz), 155.6 (d, J = 19.5 Hz), 155.3 (d, J = 19.8 Hz), 144.3, 140.3, 139.0 (d, J = 10.7
Hz), 138.7 (d, J = 38.6 Hz), 138.5, 138.3 (d, J = 38.3 Hz), 138.2, 137.3 (d, J = 11.6 Hz), 136.0,
135.9, 134.8, 133.6 (d, J = 12.0 Hz), 133.2 (d, J = 9.1 Hz), 132.0, 131.8 (d, J = 14.8 Hz), 131.5,
29
ACS Paragon Plus Environment