Ni-Catalyzed Iterative Alkyl Transfer from Nitrogen Enabled by the in Situ Methylation of Tertiary Amines

Article abstract of DOI:10.1021/acs.joc.0c01274

Current methods to achieve transition-metal-catalyzed alkyl carbon-nitrogen (C-N) bond cleavage require the preformation of ammonium, pyridinium, or sulfonamide derivatives from the corresponding alkyl amines. These activated substrates permit C-N bond cleavage, and their resultant intermediates can be intercepted to affect carbon-carbon bond-forming transforms. Here, we report the combination of in situ amine methylation and Ni-catalyzed benzalkyl C-N bond cleavage under reductive conditions. This method permits iterative alkyl group transfer from tertiary amines and demonstrates a deaminative strategy for the construction of Csp3-Csp3 bonds. We demonstrate PO(OMe)3 (trimethylphosphate) to be a Ni-compatible methylation reagent for the in situ conversion of trialkyl amines into tetraalkylammonium salts. Single, double, and triple benzalkyl group transfers can all be achieved from the appropriately substituted tertiary amines. Transformations developed herein proceed via recurring events: The in situ methylation of tertiary amines by PO(OMe)3, Ni-catalyzed C-N bond cleavage, and concurrent Csp3-Csp3 bond formation.

Full text of DOI:10.1021/acs.joc.0c01274

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Article
Ni-catalyzed Iterative Alkyl Transfer from Nitrogen
Enabled by the In Situ Methylation of Tertiary Amines
Chideraa Iheanyi Nwachukwu, Timothy McFadden, and Andrew George Roberts
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01274 • Publication Date (Web): 16 Jul 2020
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The Journal of Organic Chemistry
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Ni-catalyzed Iterative Alkyl Transfer from Nitrogen
Enabled by the In Situ Methylation of Tertiary Amines
Chideraa Iheanyi Nwachukwu,† Timothy Patrick McFadden† and Andrew George Roberts*,†
†Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, Utah 84112, United States
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Ni-catalyzed deaminative transforms; iterative alkyl transfer from nitrogen
O
P
MeO
OMe
OMe
Ni catalyst
N
Ph
N
Ph
+
1
Me
1
1
Me
Me
Ph
Me
Mn (reductant)
Ph
C−C bond formation
2 × C−N cleavage
excised
nitrogen atom
PO(OMe)3
Ni catalyst
R1 R1
R2 R2
N
R1 R2
R2
+
Me
R1
tertiary amines
Mn (reductant)
cross
dimeric
intermolecular, radical mechanism
ABSTRACT: Current methods to achieve transition-metal-catalyzed alkyl C–N bond cleavage require the preformation of
ammonium, pyridinium or sulfonamide derivatives from the corresponding alkyl amines. These activated substrates permit
C–N bond cleavage and their resultant intermediates can be intercepted to affect C–C bond forming transforms. Here we
report the combination of in situ amine methylation and Ni-catalyzed benzalkyl C–N bond cleavage under reductive
conditions. This method permits iterative alkyl group transfer from tertiary amines and demonstrates a deaminative strategy
for the construction of Csp3–Csp3 bonds. We demonstrate PO(OMe)3 (trimethylphosphate) to be a Ni-compatible
methylation reagent for the in situ conversion of trialkyl amines into tetraalkylammonium salts. Single, double, and triple
benzalkyl group transfers can all be achieved from the appropriately substituted tertiary amines. Transformations developed
herein proceed via recurring events: the in situ methylation of tertiary amines by PO(OMe)3, Ni-catalyzed C–N bond
cleavage and concurrent Csp3–Csp3 bond formation.
e,11,12
1. INTRODUCTION
N-benzalkyl trimethylammonium (R1 = benzalkyl)9e,13,14
and N-alkyl pyridinium (R1 = alkyl) salts15 have been employed
for the selective metal-catalyzed transfer of aryl, benzyl and
alkyl groups from nitrogen, respectively. Additionally, visible
light mediated methods for alkyl C–N bond cleavage from N-
benzalkyl trimethylammonium16 and N-alkyl pyridinium salts
(R1 = alkyl) have also been reported.17
1.1. Background. Given the abundance of nitrogen present
within chemical feedstocks,1 pharmaceuticals,2 and natural
products,3 methods to construct carbon–carbon (C–C) bonds
from amines via selective carbon–nitrogen (C–N) bond
cleavage processes—where the nitrogen atom is retained
(rearranged)4 or excised5—would be of high value for complex
molecule synthesis and chemical diversification strategies.
Indeed, multistep syntheses that incorporate a Stevens
rearrangement, a strategic and predictable C–N bond cleavage
method, exemplify the power of nitrogen atom rearrangement
chemistry for Csp3–Csp3 bond formation.6 Despite the
considerable understanding of C–N bond cleavage reactions,7
nitrogen atom excision processes that occur with transition
metal mediated functionalization of the cleaved C–N bond are
The practical advantages of ammonium and pyridinium
substrates as stable carbon transfer reagents (R1), include their
ready availability from amine precursors,15a and if necessary,
their facile enantioenrichment by recrystallization.9e Moreover,
recent strategies have highlighted the latent advantage of
tertiary amines employed through multistep sequences to direct
electrophilic
aromatic
substitution9c,12b
or
C–H
functionalization chemistries13e,18 prior to their stepwise
removal by quaternization (e.g., permethylation) and
chemoselective C–N bond cleavage.
known to
a
lesser extent.8,9 Certainly, metal-catalyzed
hydrodenitrogenation (HDN) processes serve to remove
nitrogen atoms from petroleum feedstocks; however, the high
temperatures and pressures are generally viewed as non-
translatable for precise transformations in a more complex
setting.10 Recent studies using transition-metal catalysis have
described the reactivity of amine derivatives as the electrophilic
carbon-based partners (R1) in cross-coupling reactions (Figure
1a).8,9 In particular, N-aryl trimethylammonium (R1 = aryl),9b-
Despite these advances, and the varied mechanisms
proposed for C–N bond cleavage, known carbon group transfer
reactions (e.g., R1) from a nitrogen atom occur as singular
events (Figure 1a). In such reactions, only one group is cleaved
(e.g., R1) and reacted with a nucleophilic partner (R2). These
steps can be mediated by a transition metal to facilitate
subsequent cross-coupling to yield products of type R1–R2.
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substituted variants D’ (LnNiR1R1X or LnNiR2R2X, not
a) known: transition metal-catalyzed cross-coupling of amine derivatives
amine derivatives
cross-products
1
2
3
4
5
6
7
8
depicted) would provide cross- and dimeric products
respectively—with unknown selectivity.20,21 The impact of
generated radical intermediates and liberated tertiary amines on
Ni-catalyzed steps, as well as the potential disruption of
beneficial Ni–ligand interactions, were also unknown. The
discovery of a Ni-compatible methylation reagent (MeX), with
chemoselectivity for tertiary amine intermediates, would render
this multi-step proposal achievable in a one-pot fashion.
Overall, the transformation could be described as a reductive
deamination wherein two C–N bonds are cleaved and one C–C
bond formed.
+
R1
!
-
R2
!
R1
R1 R2
Me3N
X
M
Ni or Pd
catalyst
NiII
or
Ln
X
Ph
Ph
Ph
Me3N or
Ph
N
X
N
R1
1 × C−N cleavage
Ph
Ph
discarded byproducts
b) proposed: Ni-catalyzed iterative alkyl group transfer from amines;
in situ alkylation and reductive deamination to form Csp3−Csp3 bonds
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step i
R1
MeX
MeX
N
R1
Ni0
NiII
X
Ln
Ln
The advent of cross-electrophile coupling chemistry has
indeed inspired the development of related Ni-catalyzed
transformations that involve concurrent C–O/C–X bond
cleavages (Figure 2a).20,21,22 Cao and Shi report a dual C–O
cleavage transform using a Ni-catalyst in combination with a
stoichiometric reductant (e.g., Zn) and bis(pinacolato)diboron
(B2pin2) to affect iterative benzalkyl C–O bond cleavages.22b
The reaction converts dibenzalkylethers into cross- and
dimeric- 1,2-diarylethane products with net excision of oxygen
atom. To the best of our knowledge, the analogous deaminative
transform of a dibenzalkyl tertiary amine is unknown.5,23
R2
step ii
step iii
Ni catalyst
Y
Me
N
R1
X
Mn
tertiary
amine
‘template’
N
R2
R2
(reductant)
Y
Y
Me
A
D
B
R1
R1
R1 R2
cross-
NiI
NiIII R2
X
NiI
Ln
Ln
Ln
X
step iv
step v
R1 R1
R2 R2
Me
N
+
X
N
N
R2
Y
Y
Me
Me
Y
Me
dimeric-
Me
Me
C
E
2 × C−N cleavage
R2 R1
radical species
For our study of iterative benzalkyl group transfers from
nitrogen, we were encouraged by a report from the Martin
group.13c They concluded that the reductive carboxylation of
benzalkyl trimethylammonium salts proceeded via a Ni-
catalyzed benzylic C–N bond cleavage event (Figure 2b). By
using an atmosphere of CO2, and Mn as a stoichiometric
reductant, only benzalkyl carboxylic acids were obtained.
Homodimeric products (e.g., 1,2-diarylethanes) were not
observed. We reasoned that similar conditions, performed
under an inert atmosphere, would permit C–C coupling events
(homodimerization). In addition, the electrochemical
homodimerization of benzalkyl trimethylammonium salts
provides fundamental reactivity precedent for C–N cleavage
and C–C bond forming events that are proposed to occur via
radical homocoupling.24,25
Figure 1. Transition metal-catalyzed cleavage and
functionalization of carbon–nitrogen (C–N) bonds.
Similar visible light mediated processes that are proposed to
generate and intercept alkyl radical intermediates have also
been studied.16,17 In most cases, the trimethylamine or 2,4,6-
triphenylpyridine byproduct is discarded.16 Thus, the utility of
tertiary amines and their corresponding ammonium derivatives
in multi-step transforms is underexplored.
1.2. Proposed strategy for iterative alkyl transfer from
nitrogen. A fundamental understanding of iterative alkyl
group transfer from nitrogen would significantly distinguish
alkylammonium substrates from their alkyl halide and alkyl
pyridinium counterparts. Theoretically, alkyl amines could
permit iterative group transfers via alkyl ammonium
intermediates, enabling up to three C–N bond cleavages from a
tertiary amine, whereas alkyl halides or alkyl pyridiniums can
only affect single group transfer, one C–X or C–N bond
cleavage, respectively (Figure 1a).
We hypothesized that benzalkyl trimethylammonium salts
could be efficiently dimerized under reductive Ni-catalysis
conditions. Until recently,13f Ni-catalyzed reductive coupling
reactions of benzalkyl trimethylammonium salts with
electrophiles other than CO2 were unknown.13c During the
course of our investigation, Shu and coworkers demonstrated
the use of benzalkyl trimethylammonium salts as effective
electrophilic partners for C–N/C–O cross-electrophile coupling
with alkenyl and aryl acetates.13f Notably, dimeric products that
a) Ni-catalyzed deoxgenation of ethers, benzylic C−O bond cleavage
Accordingly, we proposed that tertiary amines could serve
to template the programmed construction of Csp3–Csp3 bonds
with the net excision of a nitrogen atom (Figure 1b). Our
objective of study was to understand the operative
mechanism(s) and conditional requirements for iterative
deamination chemistry. We envisioned a reductive Ni-
catalyzed process could permit the in situ methylation of
tertiary amine intermediates.13c In this instance, R1 and R2 are
viewed as transferable carbon-based electrophiles and Y is
representative of a non-transferrable substituent. We posited
that iterative steps, including amine methylation by a
hypothetical reagent, MeX (steps i and iii), and Ni-catalyzed C–
N cleavage of the resultant ammonium salt intermediates A and
C (steps ii and iv), could produce a Ni-III intermediate D,
bearing a combination of the transferrable groups, R1 and R2. A
stoichiometric reductant, such as Mn, would regulate the
oxidation state of key Ni-intermediates.19 Reductive
elimination (step iv) from D (LnNiR1R2X) or the symmetrically
Ar1
B2pin2
Ni catalyst
Ar1
Ar2
Ar2
Ar1
Ar2
Ar1
[O]
+
+
O
Ar2
Zn, THF/PhMe
cross-
2 × C−O cleavage
ethers
dimeric-
b) Ni-catalyzed carboxylation of benzylic C−N bonds with CO2
1 atm CO2
Ni catalyst
R
R
R
Ar1
X
NMe3
+
+
Me3N
Ar1
Ar1
Ar1
CO2H
Mn, DMF
R
ammoniums
carboxylic acids
dimeric-
1 × C−N cleavage
not observed
Figure 2. Ni-catalyzed cleavage of benzylic C–O and C–N
bonds.
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The Journal of Organic Chemistry
of benzalkyl deleterious effect on the yield. A representative ligand screen
result
from
the
homocoupling
1
trimethylammonium salts are reported. An improved
understanding of such homodimerization events could be
applied for the discovery of a method wherein a tertiary amine
could serve to template the construction of Csp3–Csp3 bonds
(Scheme 1b). Herein, we disclose results that detail the
discovery of a method for iterative benzalkyl group transfer
from a nitrogen atom center, enabling the formation of cross-
and dimeric- 1,2-diarylethane products.
L2–L4 (entries 7-9) highlights a preference for bidentate
ligands and demonstrates the efficiency of Xantphos (L1, entry
1) for this transformation.26 We found the use of 1,10-
phenanthroline-based ligands to be less effective13c (for a
complete ligand screen, see Table S1). Consistent with related
benzalkyl C–N bond cleavage methods, this reaction proceeds
without ligand (entry 10), albeit with diminished efficiency.9e
Control experiments demonstrate the crucial role of Ni (entry
11 and 12) and Mn (entry 13). Intriguingly, the addition of
(2,2,6,6-Tetramethylpiperidin-1-yl)oxyl (TEMPO, entry 14)
resulted in a slight decrease in yield albeit with no detectable
TEMPO adducts (Table 1).13c,27 Next, we examined the impact
of tertiary amine additives on catalysis efficiency. Although the
presumed reaction byproduct, trimethylamine (b.p. 2.9 °C), can
be tentatively identified by its characteristic fishy odor during
reaction workup, its low boiling point precludes facile
quantitative analysis. Control studies found that stoichiometric
addition of triethylamine (1 equiv, b.p. 89 °C, entry 15) or
dimethylbenzylamine (1 equiv, b.p. 180 °C, entry 16) resulted
in slightly diminished yields. This suggests that liberated
tertiary amines would be tolerated in reactions that require
iterative methylation and C–N bond cleavage processes. During
efforts to address the mechanistic inquiry of benzyl iodide
intermediates that may be formed in situ, we identified an
alternatively effective, iodide-free process. Here, we define
2
3
4
5
6
7
8
9
2. RESULTS AND DISCUSSION
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2.1. Development of conditions for the reductive
dimerization of benzalkylammonium salts. We began our
studies with the systematic examination of conditions for the
reductive dimerization of benzalkyl ammonium salts (Table 1).
Optimization
efforts
found
the
reaction
of
benzyltrimethylammonium iodide (1a) with NiI2 (10 mol%),
Xantphos (L1, 15 mol%),26 and Mn (3.0 equiv) in N,N-
dimethylacetamide (DMA, 0.4 M) at 120 °C for 24 h to provide
1,2-diphenylethane (2a) in 65% isolated yield (entry 1, ‘System
I’). The use of Zn as an alternative co-reductant (entry 2), other
NiII sources (entries 3 and 4), or dimethylformamide (DMF) in
place of DMA (entry 5) were all found to result in a lower yield
of 2a. Furthermore, the use of excess ligand (L1, entry 6) had a
Table 1. Optimization of reaction conditions for the Ni-
catalyzed reductive cleavage of benzylic C–N bonds and
control experiments.
‘System
II’
(entry
17),
as
the
reaction
of
benzyltrimethylammonium triflate (3a) with Ni(OTf)2 (10
mol%), Xantphos (L1, 15 mol%), and Mn (3.0 equiv) in DMA
(0.4 M) at 120 °C for 24 h to provide homodimer 2a in 69%
yield. System II-type conditions might find application in
settings wherein benzylic halide intermediates are detrimental
to product outcome and selectivity. Indeed, iodide introduced
with the Ni-source, 3a with NiI2 (10 mol%, entry 18), or, with
the substrate, 1a with Ni(OTf)2 (10 mol%, entry 19) proceeds
with slightly diminished yields.
System I
10 mol% NiI2
15 mol% L1
Me
Me
Ph
Me
Me
Ph
N
N
+
Me
3.0 equiv Mn
0.4 M DMA
120 ºC, 24 h
Me
Ph
R
X
1a X = I
3a X = OTf
2a
Me Me
R
N
N
2.2. Reductive deaminative dimerization scope and
limitations. With optimized conditions (System I), we
evaluated the scope of the Ni-catalyzed reductive dimerization
of benzalkyl trimethylammonium iodides (Table 2). A
representative examination of benzalkyl ammonium iodides
(1a–1l) found dimeric products (2a–2l) as the sole observable
reaction products, isolable in 58% average yield (12 examples,
Table 2)). Interestingly, ortho-substitution is tolerated, with the
ortho-methoxy variant (1i) providing dimer (2i) with improved
isolated yield relative to substrates bearing and ortho-methyl
and ortho-fluoro substituent (1h, 1j). This is suggestive of a
beneficial substrate (1i) Ni-chelation in C–N bond cleavage
and/or C–C bond forming events.13c
O
Me
Me
N
N
PPh2
PPh2
Xantphos (L1)
4,4’-dmbpy, R = Me (L2)
4,4’-dtbbpy, R = t-Bu (L3)
6,6’-dmbpy (L4)
entry
1
deviation from standard conditions
none
2a (%)[a]
65
2
Zn instead of Mn
NiBr2 (10 mol%)
NiBr2ꢀglyme) (10 mol%)
DMF as solvent
L1 (30 mol%)
47
3
33
4
50
5
40
6
40
7
L2 as ligand
42
8
L3 as ligand
57
9
L4 as ligand
46
10
11
12
13
14
15
16
17
18
19
ꢆ
no ligand
19
Certain substrates (1m–1r) undergo efficient Ni-catalyzed
benzylic C–N bond cleavage, yet dimerization events to access
products 2m–2r appear to compete with a reduction pathway
(4m–4r). Extended π systems (1n, 1o) permit access to dimers
(2n, 2o) as major products alongside reduced derivatives (4n,
4o) as minor products. Electron-deficient substrates (1p, 1q)
favor reduction products almost exclusively (4p, 4q), a result
that may be reflective of the difficulty to affect their
dimerization by reductive elimination. An overtly electron-rich
substrate (1r) provided access to brittonin a (2r) alongside
reduction product 4r. Overall, these results (17 examples, 54%
average yield) suggest that the developed procedure is a general
method for benzylic C–N bond cleavage with successive C–C
bond formation.
no NiI2
trace
trace
trace
ꢁꢂ
ꢂꢃ
ꢄꢅ
69[b]
55
no NiI2, no ligand
no Mn
TEMPO (1 equiv)
triethylamine (1 equiv)
dimethylbenzylamine (1 equiv)
3a (X = OTf), Ni(OTf)2 (10 mol%) (System II)
3a (X = OTf)
Ni(OTf)2 (10 mol%)
60ꢆ
aReaction conditions: 1a or 3a (1.34 mmol), NiI2 (10 mol%),
Xantphos (L1) (15 mol%), Mn (3 equiv, 4.02 mmol), DMA (0.4
M) at 120 °C for 24 h; yields of isolated 2a are provided as an
average of two independent runs. bYield of isolated 2a provided as
an average of four independent runs.
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Table 2. An examination of Ni-catalyzed benzylic C–N bond Scheme 1. Discovery of reaction conditions for the in situ
1
2
cleavage and the homodimerization reactivity of
ammonium substrates.
methylation and Ni-catalyzed cleavage of benzylic C–N
bonds from tertiary amines.
3
4
5
6
7
8
9
System I
10 mol% NiI2
15 mol% Xantphos
a) System I
4 equiv MeX
10 mol% NiI2
Ar1
Me
Me
Ph
Ar1
Me
15 mol% Xantphos
N
Me
Ph
Ph
N
+
Ar1
+ Me2NMe2X
Me
3.0 equiv Mn
0.4 M DMA
120 ºC, 24 h
Ar1
2a−2r
3.0 equiv Mn
0.4 M DMA
120 ºC, 24 h
Me
I
Ph
5
2a
1a−1r
4m−4r
Me
Me
System I
N
Me
X
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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26
27
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30
31
32
33
34
35
36
37
38
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60
MeI
MeOTf
PO(OMe)3
4 equiv MeX =
2
2
2
2
2
2
2
6
isolated yield (2a)
(18%)
(35%)
(70%)
H
Me
MeO
MeO
F
F
b) System II
2a (65%)
2b (67%)
Me
2c (58%)
2f (70%)
2d (65%)
2g (44%)
4 equiv PO(OMe)3
10 mol% Ni(OTf)2
15 mol% Xantphos
Ph
Me
Ph
N
+ Me2NMe2X
3.0 equiv Mn
0.4 M DMA
120 ºC, 24 h
Me
Ph
2a (70%)
2e (68%)
5
c) in situ methylation; C−N cleavage and carboxylation
2
2
2
Me
Me
Me
OMe
2i (80%)
F
2h (52%)
2j (54%)
N
N
1 atm CO2
n equiv MeX
10 mol% NiBr2•diglyme
O
n-Bu
n-Bu
(L5)
2
2
O
Me
26 mol% L5
F3C
Ph
N
+ Me2NMe2X
Ph
CO2H
2k (61%)
2l (15%)
2.0 equiv Mn
0.4 M DMF
100 ºC, 24 h
Me
5
7
Me
Me
1 equiv
4 equiv
2 equiv
2
2
2
MeI
MeI
PO(OMe)3
(35%)
MeX =
t-Bu
t-Bu
+ 4m (5%)
EtO2C
EtO2C
+ 4p (40%)
Me
isolated yield (7)
(7%)
(0%)
2m (67%)
2n (70%)
2p (4%)
unoptimized
Me
2
aYields of isolated products (2a) and (7) are provided as an average
of two independent runs.
NC
2q (not detected)
NC
+ 4n (15%)
Me
+ 4q (83%)
Me
MeO
MeO
We hypothesized two possible productive scenarios that
could be operative: (1) the combination of iodide, from NiI2,
and PO(OMe)3 in DMA would produce low concentrations of
MeI, and, MeI would react preferentially with 5 to form a Ni-
reactive ammonium salt intermediate (6), or, (2) PO(OMe)3
reacts directly with 5 to form a Ni-reactive ammonium salt
intermediate (6). We tested these hypotheses by the comparison
of ‘System I’ and ‘System II’ type conditions. Interestingly,
System I conditions provide homodimer 2a in 70% yield when
4 equiv of PO(OMe)3 is employed, whereas the respective
reactions with 4 equiv of MeI (18%) or 4 equiv of MeOTf
(35%) are less effective (Scheme 1a). The control reaction of 5
with PO(OMe)3 in DMA at 120 °C for 24 h afforded
benzyltrimethylammonium dimethylphosphate salt 6 (X =
OPO(OMe)2) in 35% isolated yield. Only a single methyl group
is transferred to the amine.28 System II also affords homodimer
2a in 70% yield (Scheme 1b). Additionally, using known
catalysis conditions and PO(OMe)3 as an additive (2 equiv),
N,N-dimethylbenzylamine 5 can be converted to phenylacetic
acid 7 (35%) (Scheme 1c). This unoptimized yield is
significantly improved relative to the previously reported use of
MeI (1 equiv, 7% and 4 equiv, 0%) as an in situ methylation
reagent.13c Collectively, these studies suggest that 5 is
methylated in situ by PO(OMe)3 and the in situ formation of
MeI is neither required nor beneficial for these transforms.
Overall, this understanding of the reactivity of PO(OMe)3 for
the in situ methylation of tertiary amines is significant and
supportive of the development of one-pot methods for Ni-
2
2
MeO
MeO
OMe
OMe
+ 4r (36%)
2o (56%)
+ 4o (17%)
2r (15%)
brittonin a
aReaction conditions: 1a–1r (1.34 mmol), NiI2 (10 mol%),
Xantphos (15 mol%), Mn (3 equiv, 4.02 mmol), DMA (0.4 M) at
120 °C for 24 h; yields of isolated products (2a–2r) and (4m –4r)
are provided as an average of two independent runs.
2.3. Discovery of a Ni-compatible reagent for the in situ
methylation of amines. Due to our familiarity with the
reactivity of benzalkyl trimethylammonium salts (1a, 3a), we
studied the one-pot conversion of N,N-dimethylbenzylamine
(5) into 1,2-diphenylethane (2a) (Scheme 1). For this, we
examined a series of methylation reagents (MeI, MeOTf,
PO(OMe)3) in their ability to serve as Ni-compatible in situ
methylators for the conversion of 5 into ammonium salts
(confer 6, Scheme 1).13c,28 The choice of trimethylphosphate
(PO(OMe)3) was inspired by a report from Hartwig and co-
workers that described the slow generation of MeI from the in
situ reaction of LiI with PO(OMe)3.29 Accordingly, we
wondered if PO(OMe)3 could be used as an electrophile for in
situ amine alkylation. Although PO(OMe)3 is known to affect
the controlled alkylation of anilines,28 it was unclear if this
electrophile would undergo deleterious reactions (e.g.,
oxidative addition) at Ni, thereby precluding its desired utility.
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catalyzed cleavage and functionalization of benzylic C–N reaction mixture and support the claim of singular benzyl
1
2
3
4
5
6
7
8
transfer (see the Supporting Information). Attempts to prepare
tetrabenzylammonium iodide were unsuccessful. We attribute
this to a presumed facile nucleophilic dealkylation by the iodide
counterion, as tribenzylamine is recovered from attempted
alkylations with benzyl iodide. Instead, tetrabenzylammonium
tosylate 10 could be prepared, however, this substrate was not
productive under catalytic conditions (see the Supporting
Information).
bonds.
2.4. Trimethylphosphate for iterative benzalkyl transfer
from ammoniums and amines. The abovementioned results
support the chemoselectivity of PO(OMe)3 for tertiary amine
methylation in the presence of low-valent Ni-intermediates.
Conversion for one benzalkyl transfer event, defined herein as
1 × methylation and 1 × C–N cleavage, occurs with 70% overall
yield using either System I, or System II conditions. This
efficiency suggested that iterative benzalkyl transfer chemistry
could be possible. We first examined the reactivity of mono-
(1a), di- (8), tri- (9) and tetra- (10) benzylammonium salts
(Table 3). Based on our nascent understanding, we expect
benzyl trialkylammonium salts (1a, 8–10: (PhCH2)mNMenI,
where m + n = 4), reacted under control conditions without
PO(OMe)3 (System I), to only transfer a single benzyl group.
This benzyl group transfer event would generate the respective
tertiary amine represented by the formula: (PhCH2)m-1NMen.
Interestingly, singular benzyl group transfer proceeds with
increasing efficiency for the series (1a, 8–9). Substrates 1a, 8,
and 9, provide homodimer (2a) in 65%, 70% and 76% yield,
respectively. The tertiary amines liberated from experiments
with 8 and 9, benzyl dimethylamine and dibenzyl methylamine,
respectively, can be observed by 1H NMR analysis of the crude
We next examined C–N cleavage efficiency for the series of
benzyl trialkylammonium salts (1a, 8–9) in the presence of 4
equiv of PO(OMe)3 (Table 3). We observe a diminished yield
for the conversion of 1a into 2a (42%). For a transformation
that does not require methylation, this result suggests that
excessive PO(OMe)3 may exhibit a deleterious effect on
catalysis. Conversely, when PO(OMe)3 can be utilized,
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
dibenzyl
dimethylammonium
(8)
and
tribenzyl
methylammonium (9) salts permit double and triple benzyl
transfers, to form 2a with 46% and 47% overall efficiency,
respectively. To better understand reactivity trends of benzyl
group transfer across varied substrates, we define the efficiency
of a single transfer event as the overall yield of three combined
events [1 × methylation, 1 × C–N bond cleavage, 1 × C–C bond
formation]# of iterations. From this definition, iterative yields can be
calculated for double, [68%]2 = 46%, and triple, [78%]3 = 47%,
benzyl transfer reactions. Again, the trend of increasing group
transfer efficiency appears to track with the increasing electron
density for the initial ammonium substrate (Table 3: double
from 8, [68%]; triple from 9, [78%]). These results are
significant and demonstrate the efficiency of optimized
conditions for iterative benzyl group transfers. For example, no
fewer than six discrete events must take place during the
conversion of tribenzyl methylammonium 9 into homodimer
2a: 2 × methylations, 3 × C–N bond cleavages, and concomitant
C–C bond formation. No benzyl tertiary amine byproducts are
observable in all reactions conducted with 4 equiv PO(OMe)3.
It is also noteworthy that these iterative transfers are achievable
without an increase in catalyst, ligand or reductant loading.
Table 3. An examination of iterative alkyl transfer
efficiency from benzyl ammonium substrates. Support for
single, double and triple benzylic C–N bond cleavage events.
a) iterative benzyl transfer from tetraalkyl ammoniums
4 equiv PO(OMe)3
10 mol% NiI2
15 mol% Xantphos
Ph
+ Me3N
+ Me4NX
(PhCH2)mNMen
3.0 equiv Mn
0.4 M DMA
120 ºC, 24 h
Ph
I
1a, 8
(m + n = 4)
−
10
2a
(PhCH2)m-1NMen
ammonium
substrate
observable by 1H NMR for
control reactions 0 equiv PO(OMe)3
The efficiency of the abovementioned results suggested that
intermediary tertiary amines (5, 11, 12) methylated in situ by
PO(OMe)3 under catalysis conditions would also exhibit
benzalkyl group transfer chemistry (Table 4). Control
experiments demonstrate that benzyl transfer will not occur
without methylation (i.e., benzyl transfer is not possible using
System I conditions). In situ methylation with PO(OMe)3 would
eliminate the need for the preparation and isolation of
intermediary ammonium salts. As anticipated from experiments
with 5 (Scheme 1, 70% of 2a), tertiary amines 11 and 12 also
reacted under the same catalytic conditions with 4 equiv of
PO(OMe)3 to permit two and three benzyl transfers, calculated
as [60%]2 = 36% and [69%]3 = 33% of homodimer 2a,
respectively. Here the trend of increasing efficiency for the
series (11, 12) is also observed by comparison of iterative
yields, double, [60%] and triple, [69%], respectively. The
decreasing overall yields for the series (5, 11, 12) are attributed
to the difficulty of the initial methylation event (see the
Supporting Information). Notwithstanding the inefficiency of
the first methylation, the one-pot conversion of tribenzylamine
12 with PO(OMe)3 into homodimer 2a must involve no fewer
than seven discrete events, including, 3 × methylations, 3 × C–
N cleavages, as well as concomitant C–C bond formation. A
stepwise breakdown indicates that at least seven events must
proceed with an overall efficiency per event of [85%]7 = 33%.
b) theoretical and observed benzyl group transfers:[a]
control:
0 equiv
4 equiv
PO(OMe)3
(theoretical isolated (theoretical
PO(OMe)3
isolated
2a (%)
transfers) 2a (%)
transfers)
Me
N
Me
Me
1a
8
1 benzyl
1 benzyl
65
70
1 benzyl
42
Ph
I
I
Me Me
N
2 benzyls
46
Ph
Ph
Ph
Ph
calc. [68%]2
Me
N
9
1 benzyl
1 benzyl
76
3 benzyls
4 benzyls
47
I
calc. [78%]3
Ph
Ph
ND[b]
- -
10
Ph
N
Ph
TsO
Ph
aYields of isolated products (2a) are provided as an average of two
independent runs. Yields are calculated on the basis of available
benzyl groups for each substrate. For example, 1 mol of compound
8, bearing two benzyl groups, can theoretically provide 1 mol of
1,2-diphenylethane (2a). For reactions run in the absence of
trimethylphosphate, the generated tertiary amines can be observed
quantitatively by 1H NMR analysis of the crude reaction mixture.
bHomodimer 2a is not detected [ND] upon 1H NMR analysis of the
crude reaction mixture.
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Table 4. An examination of iterative alkyl transfer tertiary amine 13, followed by indiscriminate C–N bond
cleavage (R1 or R2, R1 depicted as first cleavage) from
ammonium 14 would generate a benzalkylated Ni-intermediate
(B). Intermediate B could proceed along two pathways
proposed as follows: (1) the disproportionation of Ni-
intermediate B would generate a low-valent Ni intermediate, a
dissociated tertiary amine (15 or 5) and a mixture of benzylic
radical species; with benzylic radical intermediates ultimately
leading to a mixture of cross, 16, and dimeric products, 2a and
2b (pathway I), or alternatively; (2) significant tertiary amine
coordination during reduction and methylation events could
provide proposed intermediate C along an amine-coordinated
path (pathway II). The generation of an ammonium in
proximity to a low-valent Ni-intermediate (C) could enable
cross-selective oxidative addition to access intermediate D. The
overall conversion of B to D with selectivity for cross-product
1
2
3
4
5
6
7
8
efficiency from benzyl amine substrates. Support for single,
double and triple benzylic C–N bond cleavage events.
a) iterative benzyl transfer from tertiary amines
4 equiv PO(OMe)3
10 mol% NiI2
15 mol% Xantphos
Ph
+ Me3N
+ Me4NX
(PhCH2)mNMen
3.0 equiv Mn
0.4 M DMA
120 ºC, 24 h
Ph
5, 11, 12
(m + n = 3)
2a
9
tertiary amine
substrate
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
b) theoretical and observed benzyl group transfers:[a]
control:
0 equiv
PO(OMe)3
(theoretical
transfers)
4 equiv
PO(OMe)3
(theoretical
transfers)
isolated
2a (%)
(16) formation would support
a molecule-to-molecule
transformation consistent with pathway II.
Me
N
5
0 benzyls
1 benzyl
70
Ph
An examination of reaction mechanism by evaluation of a
non-symmetric amine (13, entry A) and relevant crossover
experiments (entries B–F) is presented in Table 5. As a
hypothetical reference point, a statistical distribution of
16:2a:2b, 0.5:0.25:0.25, is provided as part of Table 5 (entry
F). All product distributions (16:2a:2b) for these experiments
are normalized ratios (see the Supporting Information).
Me
Me
11
0 benzyls
2 benzyls
36
Ph
N
N
Ph
calc. [60%]2
12
0 benzyls
3 benzyls
33[b]
calc. [69%]3
Ph
Ph
Ph
Table 5. An examination of reaction mechanism by
evaluation of an unsymmetrical tertiary amine substrate
aYields of isolated products (2a) are provided as an average of two
independent runs. bReaction performed with excess PO(OMe)3 (8
equiv, 120 °C, 5 d.
a) mechanistic probe
cross-
homo-
2a
4 equiv PO(OMe)3
10 mol% NiI2
15 mol% Xantphos
Ar2
Ar1
Ar2
2.5. Proposed reaction pathways and a mechanistic study:
reductive deamination of an unsymmetrical tertiary amine.
Next we studied this reductive deamination process in the
context of an unsymmetrical tertiary amine substrate (13),
bearing R1 = benzyl and R2 = para-methylbenzyl substituents
(Scheme 2). We reasoned that the reactivity of this substrate, as
measured by product ratios, compared to a series of related
crossover experiments would provide mechanistic insight. As
proposed, we anticipated the in situ methylation of a benzalkyl
Ar1
Ar2
N
Ar1
Ar1
Ar2
Me
16
+
+
3.0 equiv Mn
0.4 M DMA
120 ºC, 24 h
13
Ar1 = C6H5
Ar2 = C6H4(p-CH3)
2b
b) evaluated substrates:
I
Ar1
Ar2
I
Ar1
Ar1
Ar2
N
NMe3
Ar2
N
Me Me
I
Me
NMe3
Scheme 2. Proposed pathways for the in situ methylation of
tertiary amines; Ni-catalyzed C–N bond cleavage and Csp3–
Csp3 bond formation.
entry A — 13
entry B — 14
entry C — 1a + 1b
Ar1
Ar2
Ar1
Ar2
Br
Br
Br
Br
at
120 ºC
at
23 ºC
+ R1
R2
R1
R2
!
PO(OMe)3
entry D — 17a + 17b
entry E — 17a + 17b
N
N
Me Me
14
Me
13
LnNiIIX2
LnNi0
X
c) normalized product distributions:
½ MnIIX2
Ar2
Ar1
Ar2
R2
R1
or
Ar1
Ar1
Ar2
½ Mn0
entry
radical species
16
+
2a
+
2b
R1
oxidative
addition
+
NiI
0.45
0.10
0.45
A
B
C
D
NiI
NiII
Ln
Ln
Ln
X
X
X
R2
R2
16 R1 R2
N
N
pathway I
B
0.43
0.46
0.41
0.41
0.18
0.39
+
2a R1 R1
+
Me Me
Me Me
15 or (5)
reductive
elimination
radical
½ Mn0
0.15
0.23
0.39
2b R2 R2
R1
R1
½ MnIIX2
NiIII R2
X
NiI
Ln
Ln
0.36
R1
NiI
R2
N
D
pathway II
coordinated
Ln
Me Me
0.34
0.26
E
F
R2
N
oxidative
addition
Me
PO(OMe)3
Me Me
C
O
P
0.50
0.25
0.25
O
OMe
statistical product distribution for any cross-electrophile coupling
OMe
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Using optimal conditions, tertiary amine 13 with 4 equiv
(Scheme 2, reduction; in situ tertiary amine methylation), we
do not observe product distributions consistent with a molecule-
to-molecule transformation (i.e. the direct conversion of 13 à
16 at a single Ni-center).
1
2
3
4
5
6
7
8
PO(OMe)3 afforded cross-product and dimeric products
(16:2a:2b) with a 0.45:0.10:0.45 ratio (Table 5, entry A). The
pre-methylated variant, ammonium iodide (14), afforded a
similar product distribution 0.45:0.18:0.39 (entry B), albeit with
improved overall conversion. The comparison of these product
distributions (entry A and entry B) suggests the tertiary amine
(13) and the ammonium substrate (14) operate along a similar
mechanistic pathway. This is consistent with our understanding
of in situ methylation and the compatibility of this step with
concurrent C–N bond cleavage events. Furthermore, the
crossover experiment of two different ammonium iodide salts
(0.5 equiv 1a, 0.5 equiv 1b) produced nearly the same ratio of
products, 0.46:0.15:0.39 (entry C). This result suggests that
amine coordination events (Scheme 2, confer B à C, pathway
II) do not augment cross-product (16) formation selectivity.
However, there is a marked selectivity observed for the
homodimeric products (2a:2b, ~1:3). We attribute this outcome
to the relative stability of the para-methyl benzyl radical
leading to the favorable formation of homodimer 2b.30
Additional control crossover experiments with comparable
organohalide substrates, benzyl bromide (17a) and para-methyl
benzyl bromide (17b) were also informative. Using the
conditions optimized for ammonium substrates (120 °C,
PO(OMe)3 excluded), 0.5 equiv 17a with 0.5 equiv 17b
provided products in a 0.41:0.23:0.36 ratio (entry D). The same
reaction run at room temperature afforded a largely statistical
product distribution consistent with benzalkyl radical coupling
(0.41:0.34:0.26, entry E).31 Again, the higher temperature
experiment supports the dependence of product outcome on the
stability of benzylic radical intermediates.32 Overall, these
deaminative coupling (entries A–C) and benzalkyl bromide
crossover experiments (entries D–E) support the Ni-catalyzed
coupling of benzylic radical intermediates (Scheme 2).20,26c,33
3. CONCLUSION
In summary, we have demonstrated a method for Ni-
catalyzed iterative alkyl transfer from tertiary amines and
ammoniums. We reveal the utility of trimethylphosphate,
PO(OMe)3, as a Ni-compatible reagent for achieving in situ
methylation of tertiary amines. In combination with Ni-
catalysis, this inexpensive reagent permits iterative
methylation, Csp3–N bond cleavage and Csp3–Csp3 bond
forming events. We show the use of this method for the
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
homodimerization
or
carboxylation
of
benzalkyl
dimethylamines and benzalkyl trimethylammonium salts. We
anticipate the adoption of PO(OMe)3 as a Ni-compatible
methylation reagent to streamline related reactions that involve
benzalkyl C–N bond cleavage of ammonium salt
intermediates.9 An understanding of dual C–N bond cleavage
permits the deamination of dibenzalkyl methylamines to access
1,2-diarylethane scaffolds. Up to three benzyl group transfers
are possible from a single tertiary amine substrate. A
preliminary survey of deaminative, as well as related crossover
experiments, support the involvement of benzylic radical
intermediates consistent with proposed pathway I. Future
studies will evaluate conditions to favor tertiary amine
coordination events and/or ammonium ion pairing18 with the
Ni-catalyst in an effort to promote cross-selectivity in these
deaminative transforms.
4. EXPERIMENTAL SECTION
General information. Solvents and reagents were purchased from
commercial distributors and used as received. It is worthy to note that
N,N-dimethylacetamide (DMA) purchased from Merck Millipore was
superior. Manganese powder -325 mesh was purchased from Sigma
Aldrich. All Ni-catalyzed reactions were performed under a positive
pressure of N2 in a round bottom flask equipped with a reflux
condenser. 1H and 13C NMR spectra were obtained either on a Varian
400 or 500 MHz Unity INOVA spectrometer. All 1H NMR spectra are
reported in parts per million (ppm) relative to residual CHCl3 (7.26
ppm) or H2O (4.79 ppm). Coupling constants, J, are reported in Hertz
(Hz). All 13C NMR spectra are reported in ppm relative to residual
CHCl3 (77.2 ppm). High resolution mass spectra were recorded at the
Mass Spectrometry Facility in the Department of Chemistry at the
University of Utah on a Finnigan MAT® 95 double focusing high
resolution mass spectrometer. Low resolution mass spectra were
recorded on Advion expression compact mass spectrometer (CMS).
Column chromatography was carried out using 230-400 mesh silica gel
purchased from Silicycle and used as received. Melting points are
reported in degrees Celsius (°C) with a Mel-Temp II melting point
apparatus. N,N-dimethylbenzylamines were prepared either from the
corresponding benzyl amines using Eschweiler–Clarke conditions34 or
via alkylation of dimethylamine with the corresponding benzyl
halides.35,36 The amines were used without purification.
Our product distributions are also in agreement with the
related deoxygenative transforms reported by the Shi group.22b
In this related transform, dual C–O bond cleavage events must
proceed in a stepwise fashion. The dual C–N bond cleavage
results presented here are consistent in this aspect. Likewise,
the key reagents, B2pin2 for C–O bond activation, and
PO(OMe)3 for C–N bond activation, are compatible with
reductive Ni-catalysis. The statistical distribution of cross- and
dimeric products in both transforms support a mechanism
involving Ni-benzalkyl intermediates.22b,24,26c,27 Recent studies
from the Shu laboratory support a similar convergence of
benzylic radical intermediates for the Ni-catalyzed cleavage of
ammonium salts (C–N bond) coupled with aryl tosylates (C–O
bond) under reductive conditions.13f
2.6. Proposed mechanism. Based upon our findings and
related transforms,13c,13f,20a,26c we propose a mechanism for the
deamination of tertiary amines consistent with pathway I
(Scheme 2). First, the in situ methylation of a tertiary amine
(13) forms an activated ammonium intermediate (14).
Oxidative addition affords benzalkylated Ni-intermediate B.
The generation and interception of benzylic radical species by
this intermediate (B) leads to dibenzalkylated intermediates, D
(LnNiR1R2X) and D’ (LnNiR1R1X or LnNiR2R2X, not shown).
Reductive elimination affords both cross, 16, and dimeric
products, 2a and 2b, in largely statistical distributions.22b,26c
Finally, reduction of the resultant Ni(I) intermediate by Mn
serves to regenerate Ni(0). Intermediary tertiary amines (e.g., 5,
15) are methylated by PO(OMe)3 and processed by Ni-
catalyzed C–N bond cleavage events. Although we cannot
exclude events proposed along coordinated pathway II
General procedure for the preparation of mono-benzyl ammonium
iodides. Synthesis of 1a-1r. Dimethylbenzylamine (1 equiv.) was
dissolved in ethyl acetate (1.0 M). Methyl iodide (3 equiv.) was added
dropwise at room temperature, and the entire mixture stirred at room
temperature for 1 h. The resultant precipitate was filtered, and the
filtrate washed with ethyl acetate (10 mL ´ 4) to afford the
corresponding salt. If necessary, the benzyl trimethylammonium iodide
salt was recrystallized from a 4:1 mixture of 2-propanol:toluene.
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N,N,N-trimethyl-1-phenylmethanaminium iodide (1a).37 Reaction
performed with 16 mmol of amine in 16 mL ethyl acetate. 1a was
recrystallized to afford white needle-like crystals (4.2 g, 96%); mp:
176–177 °C; 1H NMR (400 MHz, CDCl3): δ 7.66 (d, J = 7.9 Hz, 2H),
7.49 – 7.40 (m, 3H), 5.05 (s, 2H), 3.40 (s, 9H); 13C{1H} NMR (125
MHz, D2O): δ 132.9, 130.9, 129.3, 127.4, 69.6, 52.6; LRMS (ESI+):
Calcd. for C10H16N [M-I]: 150.13, found 150.23.
N,N,N-trimethyl-1-(p-tolyl)methanaminium iodide (1b).37 Reaction
performed with 7.1 mmol of amine in 7 mL ethyl acetate. 1b was
isolated as a white solid (1.7 g, 80%) and recrystallized; mp: 208–210
°C; 1H NMR (400 MHz, CDCl3): δ 7.51 (d, J = 7.7 Hz, 2H), 7.18 (d, J
= 7.5 Hz, 2H), 4.95 (s, 2H), 3.37 (s, 9H), 2.36 (s, 3H); 13C{1H} NMR
(125 MHz, CDCl3): δ 141.1, 133.0, 129.9, 124.2, 68.6, 52.7, 21.3;
LRMS (ESI+): Calcd. for C11H18N [M-I]: 164.14, found 164.23.
175 °C; 1H NMR (500 MHz, CDCl3): δ 7.92 (td, J = 7.4, 1.8 Hz, 1H),
7.52 (d, J = 7.3 Hz, 1H), 7.34 – 7.27 (m, 1H), 7.19 (t, J = 9.1 Hz, 1H),
5.01 (s, 2H), 3.47 (s, 9H); 13C{1H} NMR (125 MHz, D2O): δ 162.4 (d,
JCF = 244.5 Hz), 131.0 (d, JCF = 8.4 Hz), 128.82, 119.5 (d, JCF = 22.2
Hz), 117.8 (d, JCF = 20.9 Hz), 68.7, 52.6; HRMS (ESI+): Calcd. for
C10H15FN [M-I]: 168.1189, found 168.1188.
1-(benzo[d][1,3]dioxol-5-yl)-N,N,N-trimethylmethanaminium
iodide (1k).13c Reaction performed with 9.5 mmol of amine in 10 mL
ethyl acetate. 1k was isolated as a white solid (1.5 g, 50%); mp: 221–
222 °C; 1H NMR (400 MHz, D2O): δ 6.92 – 6.85 (m, 2H), 5.91 (s, 2H),
4.26 (s, 2H), 2.93 (s, 9H); 13C{1H} NMR (125 MHz, D2O): δ 149.2,
147.7, 127.5, 120.7, 112.4, 108.8, 101.8, 69.4, 52.2; LRMS (ESI+):
Calcd. for C11H16NO2 [M-I]: 194.12, found 194.21.
N,N,N-trimethyl-1-(4-(trifluoromethyl)phenyl)methanaminium
iodide (1l). Reaction performed with 20 mmol of amine in 20 mL ethyl
acetate. 1l was isolated as a white solid (6.5 g, 96%); mp: 175–176 °C;
1H NMR (500 MHz, CDCl3): δ 7.93 (d, J = 7.9 Hz, 2H), 7.71 (d, J =
7.9 Hz, 2H), 5.30 (s, 2H), 3.46 (s, 9H); 13C{1H} NMR (125 MHz,
CDCl3): δ 133.8, 133.2, 131.1, 126.2, 124.5, 67.2, 53.1; HRMS (ESI+):
Calcd. for C11H15F3N [M-I]: 218.1157, found 218.1161.
1-(4-(tert-butyl)phenyl)-N,N,N-trimethylmethanaminium iodide
(1m).37 Reaction performed with 7.0 mmol of amine in 7 mL ethyl
acetate. 1m was isolated as a white solid (1.7 g, 73%); mp: 211–212
°C. 1H NMR (400 MHz, CDCl3): δ 7.56 (d, J = 8.0 Hz, 2H), 7.45 (d, J
= 8.0 Hz, 2H), 4.95 (s, 2H), 3.40 (s, 9H), 1.29 (s, 9H); 13C{1H} NMR
(125 MHz, CDCl3): δ 154.3, 132.9, 126.2, 124.2, 68.6, 52.8, 34.9, 31.2;
LRMS (ESI+): Calcd. for C14H24N [M-I]: 206.19, found 206.25.
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1-(4-methoxyphenyl)-N,N,N-trimethylmethanaminium
iodide
(1c).37 Reaction performed with 16 mmol of amine in 16 mL ethyl
acetate. 1c was isolated as a white solid (3.7 g, 77%); mp: 157–158 °C;
1H NMR (400 MHz, CDCl3): δ 7.57 (d, J = 8.5 Hz, 2H), 6.93 (d, J =
8.5, 2H), 4.96 (s, 2H), 3.81 (s, 3H), 3.35 (s, 9H); 13C{1H} NMR (125
MHz, CDCl3): δ 161.4, 134.5, 119.1, 114.6, 68.3, 55.5, 52.5; LRMS
(ESI+): Calcd. for C11H18NO [M-I]: 180.14, found 180.25.
1-(4-fluorophenyl)-N,N,N-trimethylmethanaminium iodide (1d).13c
Reaction performed with 16 mmol of amine in 16 mL ethyl acetate. 1d
was isolated as a white solid (4.6 g, 95%); mp: 238–239 °C; 1H NMR
(500 MHz, D2O): δ 7.46 (dd, J = 8.7, 5.6 Hz, 1H), 7.16 (t, J = 8.7 Hz,
2H), 4.37 (s, 2H), 2.98 (s, 9H); 13C{1H} NMR (125 MHz, D2O) 163.9
(d, JCF = 248.3 Hz), 134.9 (d, JCF = 9.1 Hz), 123.4, 116.1 (d, JCF = 22.0
Hz), 68.7, 52.2; LRMS (ESI+): Calcd. for C10H15FN [M-I]: 168.12,
found 168.08.
N,N,N-trimethyl-1-(naphthalene-2-yl)methanaminium
iodide
(1n).13c Reaction performed with 17 mmol of amine in 17 mL ethyl
acetate. 1n was isolated as a pale orange solid (3.7 g, 65%); mp: 179–
N,N,N-trimethyl-1-(m-tolyl)methanaminium
iodide
(1e).13c
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180 °C; H NMR (500 MHz, CDCl3): δ 8.18 (s, 1H), 7.98 – 7.78 (m,
Reaction performed with 5.3 mmol of amine in 6 mL ethyl acetate. 1e
was isolated as a white solid (1.1 g, 71%); mp: 200–201 °C; 1H NMR
(500 MHz, CDCl3): δ 7.51 – 7.40 (m, 2H), 7.33 – 7.26 (m, 2H), 4.98
(s, 2H), 3.42 (s, 9H), 2.36 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3):
δ 139.2, 133.5, 131.7, 130.2, 129.2, 127.1, 70.0, 52.9, 21.4; LRMS
(ESI+): Calcd. for C11H18N [M-I]: 164.14, found: 164.07.
3H), 7.71 (dd, J = 8.4, 1.7 Hz, 1H), 7.63 – 7.43 (m, 2H), 5.26 (s, 2H),
3.46 (s, 9H); 13C{1H} NMR (125 MHz, CDCl3): δ 133.9, 133.7, 132.8,
129.2, 129.0, 128.5, 127.9, 127.8, 127.1, 124.5, 68.8, 53.0; LRMS
(ESI+): Calcd. for C14H18N [M-I]: 200.14, found 200.28.
N,N,N-trimethyl-1-(naphthalene-1-yl)methanaminium iodide (1o).
Reaction performed with 17 mmol of amine in 17 mL ethyl acetate. 1o
was isolated as a white solid (2.9 g, 52%) and recrystallized; mp: 213–
1-(3-methoxyphenyl)-N,N,N-trimethylmethanaminium
iodide
(1f).13c Reaction performed with 16 mmol of amine in 16 mL ethyl
acetate. 1f was obtained as a white solid (3.4 g, 70%); mp: 140–141
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215 °C; H NMR (500 MHz, DMSO-d6): δ 8.54 (d, J = 8.6 Hz, 1H),
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8.14 (d, J = 8.3 Hz, 1H), 8.06 (d, J = 8.1 Hz, 1H), 7.82 (d, J = 7.1 Hz,
1H), 7.76 – 7.50 (m, 3H), 5.11 (s, 2H), 3.13 (s, 9H); 13C{1H} NMR
(125 MHz, DMSO-d6): δ 134.11,134.08, 133.3, 131.8, 129.5, 127.8,
126.8, 125.8, 125.0, 124.6, 64.2, 52.7; HRMS (ESI+): Calcd. for
C14H18N [M-I]: 200.1434, found 200.1438.
1-(4-(methoxycarbonyl)phenyl)-N,N,N-trimethylmethammonium
iodide (1p). Reaction performed with 8.6 mmol of amine in 9 mL ethyl
acetate. 1p was isolated as a white solid (2.6 g, 92%); mp: 196–197 °C;
1H NMR (500 MHz, CDCl3): δ 8.09 (d, J = 7.9 Hz, 2H), 7.82 (d, J =
8.1 Hz, 2H), 5.25 (s, 2H), 3.95 (s, 3H), 3.46 (s, 4H); 13C{1H} NMR
(125 MHz, CDCl3): δ 166.0, 133.3, 132.6, 131.7, 130.3, 67.7, 53.1,
52.6; HRMS (ESI+): Calcd. for C12H18NO2 [M-I]: 208.1338, found
208.1339.
1-(4-cyanophenyl)-N,N,N-trimethylmethanaminium iodide (1q).
Reaction performed with 13 mmol of amine in 13 mL ethyl acetate. 1q
was isolated as a white solid (2.86 g, 71%); mp: 232–233 °C; 1H NMR
(500 MHz, D2O): δ 7.80 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.3 Hz, 2H),
4.48 (s, 2H), 3.02 (s, 2H); 13C{1H} NMR (125 MHz, D2O): δ 133.5,
133.1, 132.4, 118.7, 113.5, 68.5, 52.6; HRMS (ESI+): Calcd. for
C11H15N2 [M-I]: 175.1230, found 175.1237.
°C; H NMR (500 MHz, CDCl3): δ 7.37 – 7.32 (m, 1H), 7.30 – 7.29
(m, 1H), 7.20 (dt, J = 7.6, 1.3 Hz, 1H), 7.01 (dt, J = 8.4, 1.4 Hz, 1H),
5.01 (s, 2H), 3.83 (s, 3H), 3.42 (s, 9H); 13C{1H} NMR (125 MHz,
CDCl3): δ 160.0, 130.3, 128.4, 125.1, 118.5, 116.7, 68.8, 55.9, 53.1;
LRMS (ESI+): Calcd. for C11H18NO [M-I]: 180.14, found 180.12.
1-(3-fluorophenyl)-N,N,N-trimethylmethanaminium iodide (1g).
Reaction performed with 9.3 mmol of amine in 10 mL ethyl acetate. 1g
was isolated as a white solid (1.7 g, 62%) and recrystallized; mp: 184–
185 °C; 1H NMR (400 MHz, CDCl3): δ 7.53 (d, J = 7.8 Hz, 1H), 7.49
– 7.38 (m, 2H), 7.21 – 7.17 (m, 1H), 5.14 (s, 2H), 3.42 (s, 9H); 13C{1H}
NMR (125 MHz, CDCl3): δ 161.9 (d, JCF = 250.7 Hz), 135.4 (d, JCF
=
2.1 Hz), 133.7 (d, JCF = 8.6 Hz), 125.5 (d, JCF = 3.8 Hz), 116.4 (d, JCF
= 21.9 Hz), 114.8 (d, JCF = 13.8 Hz), 62.7, 53.3; HRMS (ESI+): Calcd.
for C10H15FN [M-I]: 168.1189, found 168.1189.
N,N,N-trimethyl-1-(m-tolyl)methanaminium
iodide
(1h).37
Reaction performed with 16 mmol of amine in 16 mL ethyl acetate. 1h
was isolated as a white solid (2.7 g, 89%); mp: 210–212 °C; 1H NMR
(500 MHz, CDCl3): δ 7.64 (d, J = 7.6 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H),
7.29 – 7.21 (m, 2H), 4.98 (s, 2H), 3.44 (s, 9H), 2.53 (s, 3H); 13C{1H}
NMR (125 MHz, CDCl3): δ 139.9, 134.6, 132.0, 131.0, 126.6, 125.76,
66.5, 53.1, 21.2; LRMS (ESI+): Calcd. for C11H18N [M-I]: 164.14,
found 164.09.
(3,4,5-trimethoxyphenyl)-1-N,N,N-trimethylammoniun
iodide
(1r). Reaction performed with 3.1 mmol of amine in 3 mL ethyl acetate.
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1r was isolated as a white solid (879 mg, 77%); mp: 207–209 °C; H
1-(3-methoxyphenyl)-N,N,N-trimethylmethanaminium
iodide
(1i).13c Reaction performed with 6.0 mmol of amine in 6 mL ethyl
acetate. 1i was isolated as a white solid (1.5 g, 81%); mp: 151–152 °C;
1H NMR (500 MHz, D2O): δ 7.43 (t, J = 8.3 Hz, 1H), 7.32 (d, J = 7.6
Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H), 6.97 (t, J = 7.5 Hz, 1H), 4.34 (s, 2H),
3.75 (s, 3H), 2.95 (s, 9H); 13C{1H} NMR (125 MHz, D2O): δ 158.8,
134.8, 132.9, 120.8, 115.6, 112.1, 63.8, 55.5, 52.6; LRMS (ESI+):
Calcd. for C11H18NO [M-I]: 180.14, found 180.13.
1-(2-fluorophenyl)-N,N,N-trimethylmethanaminium iodide (1j).
Reaction performed with 6.5 mmol of amine in 7 mL ethyl acetate. 1j
was isolated as a white solid (1.8 g, 94%) and recrystallized; mp: 174–
NMR (500 MHz, CDCl3): δ 7.00 (s, 1H), 4.97 (s, 2H), 3.86 (s, 6H),
3.81 (s, 3H), 3.38 (s, 9H); 13C{1H} NMR (125 MHz, CDCl3): δ 153.5,
139.8, 122.6, 110.6, 68.7, 60.9, 57.0, 53.0; HRMS (ESI+): Calcd. for
C13H22NO3 [M-I]: 240.1600, found 240.1604.
General procedure for reductive homodimerization.
Synthesis of 2a-2r: A 25 mL oven dried round bottom flask equipped
with a magnetic stir bar was evacuated and charged with catalyst NiI2
(42 mg, 0.134 mmol) and Xantphos (115 mg, 0.2 mmol) under positive
pressure of nitrogen. Degassed DMA (3.4 mL, 0.4 M) was added via a
syringe and the entire mixture stirred for 5 mins at 120 °C (oil bath)
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Page 9 of 13
The Journal of Organic Chemistry
after which the solution became homogeneous and the color changed
127.90, 120.2, 110.2, 55.3 30.5. LRMS (EI+): Calcd. for C16H18O2
[M+]: 242.13, found 242.20.
from grey to red. Manganese (219 mg, 4 mmol) and benzyl
trimethylammonium salt (1.34 mmol) were then added to the mixture.
The flask was then equipped with a condenser and the entire mixture
stirred under nitrogen at 120 °C (oil bath) for 24 h. The mixture was
cooled to room temperature and subsequently extracted with ether (20
mL ´ 3). The combined organic extract was washed with water (20
mL´ 2), followed by brine (10 mL). The organic layer was then dried
over Na2SO4, filtered and solvent removed under reduced pressure. The
crude mixture was purified by flash column chromatography on silica
gel.
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1,2-bis(2-fluorophenyl)ethane (2j).39 Isolated as a white solid (79 mg,
0.36 mmol, 54%) via flash column chromatography with hexanes as
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the eluent; Rf = 0.40 (hexanes). H NMR (400 MHz, CDCl3) δ 7.20 –
7.13 (m, 4H), 7.06 – 7.02 (m, 4H), 2.97 (s, 4H). 13C{1H} NMR (125
MHz, CDCl3): δ 161.2 (d, JCF = 245.0 Hz), 130.7 (d, JCF = 5.1 Hz),
127.8 (d, JCF = 8.1 Hz), 123.9 (d, JCF = 3.7 Hz), 115.2 (d, JCF = 22.0
Hz), 112.9 (d, JCF = 21.1 Hz), 29.7; LRMS (EI+): Calcd. for C14H12F2
[M+]: 218.09, found 218.20.
1,2-bis(benzo[d][1,3]dioxo-5-yl)ethane (2k).41 Isolated as a white
solid (110 mg, 0.4 mmol, 61%) via flash column chromatography with
a 12:1 mixture of hexanes/ethyl acetate as the eluent. Rf = 0.40 (10:1
Hex/EtOAc). 1H NMR (400 MHz, CDCl3) δ 6.70 (d, J = 7.8, 2H), 6.64
(d, J = 1.7, 2H), 6.58 (dd, J = 7.9, 1.8, 2H), 5.90 (s, 4H), 2.77 (s, 4H);
13C{1H} NMR (125 MHz, CDCl3): δ 147.5, 145.7, 135.5, 121.2, 108.9,
108.1, 100.8, 37.9; LRMS (EI+): Calcd. for C16H14O4 [M+]: 270.09,
found 270.20.
1,2-bis(4-(trifluoromethyl)phenyl)ethane (2l).41 Isolated as a white
solid (32 mg, 0.1 mmol, 15%) via flash column chromatography with
hexanes as the eluent; Rf = 0.47 (hexanes); 1H NMR (400 MHz,
CDCl3): δ 7.52 (d, J = 8.0 Hz, 4H), 7.24 (d, J = 7.8 Hz, 4H), 2.98 (s,
4H); 13C{1H} NMR (101 MHz, CDCl3): δ 145.0, 128.7, 128.5, 125.3,
37.2; LRMS (EI+): Calcd. for C16H12F6 [M+]: 318.08, found 318.20.
1,2-bis(4-(tert-butyl)phenyl) ethane (2m).39 Isolated as a white solid
(131 mg, 0.45 mmol, 67%) via flash column chromatography with
hexanes as the eluent; Rf = 0.40 (hexanes); 1H NMR (400 MHz,
CDCl3): δ 7.33 (d, J = 8.3 Hz, 4H), 7.18 (d, J = 8.2 Hz, 4H), 2.89 (s,
4H), 1.32 (s, 18H); 13C{1H} NMR (101 MHz, CDCl3): δ 148.7, 139.0,
128.0, 125.2, 37.4, 34.4, 31.4; LRMS (EI+): Calcd. for C22H30 [M+]:
294.23, found 294.30.
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1,2-Diphenylethane (2a).38 Isolated as an off-white solid (79 mg, 0.43
mmol, 65%) via flash column chromatography with hexanes as the
eluent; Rf = 0.56 (hexanes); 1H NMR (400 MHz, CDCl3): δ 7.31 – 7.29
(m, 4H), 7.22 – 7.20 (m, 6H), 2.91 (s, 4H); 13C{1H} NMR (101 MHz,
CDCl3): δ 141.8, 128.5, 128.4, 126.0, 38.0; LRMS (EI+): Calcd. for
C14H14 [M+]: 182.11, found 182.20.
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1,2-di-p-tolylethane (2b).39 Isolated as a white solid (94 mg, 0.45
mmol, 67%) via flash column chromatography with hexanes as the
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eluent; Rf = 0.40 (hexanes); H NMR (400 MHz, CDCl3): δ 7.09 (s,
5H), 2.86 (s, 4H), 2.32 (s, 6H); 13C{1H} NMR (101 MHz, CDCl3): δ
138.9, 135.0, 129.0, 128.3, 37.6, 21.0; LRMS (EI+): Calcd. for C16H18
[M+]: 210.14; found 210.20.
1,2-bis(4-methoxyphenyl)ethane (2c).40 Isolated as a white solid (94
mg, 0.38 mmol, 58%) via flash column chromatography with a 20:1
mixture of hexanes/ethyl acetate as the eluent; Rf = 0.40 (20:1
Hex/EtOAc); 1H NMR (400 MHz, CDCl3): δ 7.09 (d, J = 8.6 Hz, 4H),
6.83 (d, J = 8.6 Hz, 4H), 3.79 (s, 6H), 2.84 (s, 4H); 13C{1H} NMR (101
MHz, CDCl3): δ 157.8, 134.0, 129.4, 113.7 55.2, 37.3; LRMS (EI+):
Calcd. for C16H18O2 [M+]: 242.13, found 242.20.
1,2-bis(4-fluorophenyl)ethane (2d).39 Isolated as a white solid (92 mg,
0.42 mmol, 63%) via flash column chromatography with hexanes as
the eluent; Rf = 0.37 (hexanes); 1H NMR (400 MHz, CDCl3)δ 7.11 (dd,
J = 8.6, 5.6 Hz, 4H), 6.98 (t, J = 8.7 Hz, 4H), 2.90 (s, 4H); 13C{1H}
1-(tert-butyl)-4-methylbenzene (4m).42 The reduced product (4m)
was also isolated a white solid (9.5 mg, 0.048 mmol, 5%); Rf = 0.50
(hexanes); 1H NMR (400 MHz, CDCl3):δ 7.28 (d, J = 8.3 Hz, 2H), 7.11
(d, J = 8.1 Hz, 2H), 2.31 (s, 3H), 1.30 (s, 9H).
NMR (125 MHz, CDCl3): δ 161.4 (d, JCF = 243.6 Hz), 137.0 (d, JCF
=
1,2-di(naphthalen-2-yl)ethane (2n).41 Isolated as a white solid (0.47,
132 mg, 70%) via flash column chromatography with a 20:1 mixture
of hexanes/ethyl acetate as the eluent.; Rf = 0.34 (20:1 hexanes/EtOAc);
1H NMR (400 MHz, CDCl3): δ 7.89 – 7.73 (m, 6H), 7.66 (s, 2H), 7.47
– 7.40 (m, 4H), 7.36 (d, J = 8.4 Hz, 2H), 3.18 (s, 4H); 13C{1H} NMR
(125 MHz, CDCl3): δ 139.2, 133.6, 132.1, 127.9, 127.6, 127.5, 127.4,
126.5, 126.0, 125.2, 38.0. LRMS (EI+): Calcd. for C22H18 [M+]: 282.14,
found 282.20.
3.1 Hz), 129.9 (d, JCF = 7.7 Hz), 115.1 (d, JCF = 21.0 Hz), 37.2; 19F
NMR (282 MHz, CDCl3): δ -117.8; LRMS (EI+): Calcd. for C14H12F2
[M+]: 218.09, found 218.20.
1,2-di-m-tolylethane (2e).39 Isolated as a colorless oil (95.4 mg, 0.45
mmol, 68%) via flash column chromatography with hexanes as the
eluent; Rf = 0.40 (hexanes); 1H NMR (400 MHz, CDCl3): δ 7.21 (t, J =
7.4 Hz, 2H), 7.16 – 6.92 (m, 6H), 2.89 (s, 4H), 2.36 (s, 6H); 13C{1H}
NMR (101 MHz, CDCl3): δ 141.9, 137.9, 129.3, 128.3, 126.7, 125.4,
38.0, 21.4; LRMS (EI+): Calcd. for C16H18 [M+]: 210.14, found 210.20.
1,2-bis(3-methoxyphenyl)ethane (2f).38 Isolated as a white solid
(113.2 mg, 0.47 mmol, 70%) via flash column chromatography with a
20:1 mixture of hexanes/ethyl acetate as the eluent; Rf = 0.48 (20:1
Hex/EtOAc); 1H NMR (400 MHz, CDCl3): δ 7.34 – 7.16 (m, 1H), 6.88
– 6.72 (m, 2H), 3.80 (s, 2H), 2.93 (s, 1H); 13C{1H} NMR (101 MHz,
CDCl3): δ 159.7, 143.4, 129.3, 120.9, 114.2, 111.3, 55.1, 37.9; LRMS
(EI+): Calcd. for C16H18O2 [M+]: 242.13, found 242.20.
2-methylnaphthalene (4n).43 The reduced product (4n) was also
isolated as a colorless oil (25 mg, 0.17 mmol, 15%) with hexanes; Rf =
1
0.4 (hexanes/EtOAc); H NMR (400 MHz, CDCl3): δ 7.79 – 7.72 (m,
3H), 7.60 (s, 1H), 7.41(d, J = 6.9 Hz, 2H), 7.31 (d, J = 8.4 Hz, 1H),
2.51 (s, 3H).
1,2-di(naphthalen-1-yl)ethane (2o).40 Isolated as a white solid (105
mg, 0.37 mmol, 56%) via flash column chromatography with a 20:1
mixture of hexanes/ethyl acetate as the eluent; Rf = 0.34 (20:1
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1,2-bis(3-fluorophenyl)ethane (2g).39 Isolated as a white solid (64 mg,
0.29 mmol, 44%) via flash column chromatography with hexanes as
the eluent; Rf = 0.40 (hexanes); 1H NMR (400 MHz, CDCl3) δ 7.18 (td,
J = 7.7, 1.6 Hz, 2H), 7.25 – 7.20 (m, 2H), 6.93 – 6.85 (m, 6H), 2.91 (s,
4H); 13C{1H} NMR (125 MHz, CDCl3): δ 162.9 (d, JCF = 245.3 Hz),
143.8 (d, JCF = 7.1 Hz), 129.8 (d, JCF = 8.5 Hz), 124.1 (d, JCF = 2.8 Hz),
115.3 (d, JCF = 20.9 Hz), 113.0 (d, JCF = 21.3 Hz), 37.2 (d, JCF = 1.8
Hz); LRMS (EI+): Calcd. for C14H12F2 [M+]: 218.09, found 218.20.
1,2-di-o-tolylethane (2h).39 Isolated as a white solid (73 mg, 0.35
mmol, 52% yield via flash column chromatography with hexanes as the
eluent; Rf = 0.40 (hexanes); 1H NMR (400 MHz, CDCl3): δ 7.19 – 7.17
(m, 8H), 2.89 (s, 4H), 2.35 (s, 6H); 13C{1H} NMR (101 MHz, CDCl3):
δ 140.2, 135.9, 130.2, 128.9, 126.13, 126.0, 34.2, 19.3; LRMS (EI+):
Calcd. for C16H18 [M+]: 210.14, found 210.20.
1,2-bis(2-methoxyphenyl)ethane (2i).38 Isolated as a white solid (129
mg, 0.53 mmol, 80%) via flash column chromatography with a 20:1
mixture of hexanes/ethyl acetate as the eluent; Rf = 0.40 (20:1
Hex/EtOAc); 1H NMR (400 MHz, CDCl3) δ 7.18 (td, J = 7.7, 1.6 Hz,
2H), 7.12 (dd, J = 7.2, 1.8 Hz, 2H), 6.89-6.72 (m, 4H), 3.82 (s, 6H),
2.90 (s, 1H); 13C{1H} NMR (101 MHz, CDCl3): δ 157.6, 130.9, 129.9,
hexanes/EtOAc); H NMR (400 MHz, CDCl3): δ 8.12 (d, J = 8.0 Hz,
2H), 7.89 (dd, J = 8.0, 1.6 Hz, 2H), 7.75 (dd, J = 8.1, 1.3 Hz, 2H), 7.58
– 7.46 (qd, J = 7.0, 1.6 Hz, 4H), 7.41 (t, J = 7.5 Hz, 2H), 7.35 (dd, J =
7.0, 1.4 Hz, 2H), 3.52 (s, 4H); 13C{1H} NMR (125 MHz, CDCl3): δ
138.1, 134.0, 131.9, 128.9, 126.9, 126.0, 125.7, 125.6, 123.7, 34.1;
LRMS (EI+): Calcd. for C22H18 [M+]: 282.14, found 282.20.
1-methylnaphthalene (4o).43 The reduced product (4o) was also
isolated as a colorless oil (43 mg, 0.3 mmol, 23% yield) with hexanes;
Rf = 0.4 (hexanes/EtOAc); 1H NMR (400 MHz, CDCl3): δ 8.01 (d, J =
8.0 Hz, 1H), 7.86 (dd, J = 8.0, 1.6 Hz, 1H), 7.72 (dd, J = 8.1, 1.3 Hz,
2H), 7.55 – 7.47 (qd, J = 7.0, 1.6 Hz, 2H), 7.39 (t, J = 7.5 Hz, 1H), 7.33
(dd, J = 7.0, 1.4 Hz, 1H), 2.71 (s, 3H).
Dimethyl 4,4’-(ethane-1,2-diyl)dibenzoate (2p).44 Isolated as a white
solid (7 mg, 0.035 mmol, 4%) via flash column chromatography with
a 4:1 mixture of hexanes/ethyl acetate as the eluent; Rf = 0.35 (5:1
1
hexanes/EtOAc), H NMR (400 MHz, CDCl3): δ 7.92 (d, J = 8.3 Hz,
4H), 7.18 (d, J = 8.3 Hz, 4H) 3.89 (s, 6H), 2.97 (s, 4H).
Methyl-4-methylbenzoate (4p).45 The reduced product (4p) was also
isolated as colorless oil (79 mg, 0.53 mmol, 40%) with a 10:1 mixture
of hexanes/ethyl acetate as the eluent; Rf = 0.34 (10:1 hexanes/EtOAc);
1H NMR (400 MHz, CDCl3): δ 7.91 (d, J = 7.9 Hz, 2H), 7.22 (d, J =
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7.9 Hz, 2H), 3.88 (s, 3H), 2.39 (s, 3H); 13C{1H} NMR (125 MHz,
N-benzyl-N,N-dimethyl-1-(p-tolyl)methaneammonium iodide (14).
CDCl3): δ 167.2, 143.5, 129.6, 129.1, 129.0, 127.5, 51.9, 21.6.
4-methylbenzonitrile (4q).46 The reduced product (4q) was isolated as
a colorless oil (61 mg, 0.52 mmol, 83%) with a 20:1 mixture of
hexanes/ethyl acetate as the eluent; Rf = 0.6 (15:1 hexanes/EtOAc); 1H
NMR (400 MHz, CDCl3): δ 7.49 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 8.5
Hz, 2H), 2.38 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ 143.7,
132.0, 129.8, 119.1, 109.3, 21.8.
1,2-bis(3,5,6-trimethoxyphenyl)ethane (2r).38 Isolated as an off-
white solid (36 mg, 0.1 mmol, 15%) via flash column chromatography
with a 1:1 mixture of hexanes/ethyl acetate as the eluent; Rf = 0.40 (1:1
hexanes/EtOAc); 1H NMR (400 MHz, CDCl3): δ 6.37 (s, 4H), 3.83 (s,
18H), 2.86 (s, 4H), 13C{1H} NMR (125 MHz, CDCl3): δ 153.1, 137.4,
136.2, 105.5, 60.9, 56.1, 38.5; HRMS (ESI+): Calcd. for C20H26O6
[M+Na]+: 385.1627, found 385.1630.
1,2,3-trimethoxy-5-methylbenzene (4r).47 The reduction product (4r)
was also isolated as a white solid (88 mg, 0.48 mmol, 36%) via flash
column chromatography with a 10:1 mixture of hexanes/ethyl acetate
as the eluent; Rf = 0.48 (10:1 Hex/EtOAc); 1H NMR (400 MHz,
CDCl3): δ 6.38 (s, 2H), 3.83 (s, 6H), 3.81 (s, 3H), 2.30 (s, 3H), 2.34 (s,
3H).
Reaction was performed with 6.7 mmol of amine in 7 mL acetonitrile
to afford a white solid filtration (1.4 g, 57%). mp: 189–190 °C; 1H
NMR (500 MHz, CDCl3): δ 7.65 (d, J = 7.2 Hz, 2H), 7.51 (d, J = 7.7
Hz, 2H), 7.45 – 7.38 (m, 3H), 7.19 (d, J = 7.7 Hz, 2H), 5.12 (s, 2H),
5.14 (s, 2H), 5.10 (s, 2H), 3.10 (s, 6H), 2.34 (s, 3H); 13C{1H} NMR
(125 MHz, CDCl3): δ 141.1, 133.4,133.3, 130.7, 129.8, 129.2, 127.1,
124.0, 67.1, 67.0, 48.2, 21.4; HRMS (ESI+): Calcd. for C17H22N [M-I]:
240.1747, found 240.1749.
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5
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7
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General procedure for preparation of dibenzyl amines.
Synthesis of 11, 13: Amine (23 mmol), alkyl iodide (26 mmol) were
9
dissolved in acetonitrile (230 mL, 0.1 M) in a round bottom flask. N,N-
diisopropylethylamine (1.5 equiv.) was then added. The entire mixture
was stirred at rt for 2 h. Solvent was then removed in vacuo and the
resultant residue dissolved in dichloromethane (20 mL). The organic
layer was subsequently washed once with water (5 mL) and the
aqueous layer washed with dichloromethane (10 mL ´ 3). The
combined organic layer was dried over anhydrous Na2SO4, filtered and
the solvent removed again in vacuo. The crude mixture was purified by
flash column chromatography to afford pure amine compound.
N,N-dibenzyl-methylamine (11). Isolated as a light-yellow oil (4.36
g, 90%) with a mixture of 20:1 hexanes/ethyl acetate. 1H NMR (500
MHz, CDCl3): δ 7.48 – 7.34 (m, 10H), 3.62 (s, 4H), 2.29 (s, 3H);
13C{1H} NMR (125 MHz, CDCl3): δ 139.6, 129.1, 128.4, 127.2, 62.1,
42.5; HRMS (ESI+): Calcd. for C15H17N [M+H]+: 212.1439, found
212.1439.
N,N-benzyl-N-methyl-1-(p-tolyl)methaneamine (13). Isolated as a
colorless oil (4.2 g, 81%) with a mixture of 20:1 hexanes/ethyl acetate;
1H NMR (500 MHz, CDCl3): δ 7.49 (d, J = 8.5 Hz, 2H), 7.44 (t, J = 8.4
Hz, 2H), 7.39 – 7.34 (m, 3H), 7.26 (d, J = 7.8 Hz, 2H), 3.63 (s, 2H),
3.62 (s, 2H), 2.46 (s, 3H), 2.30 (s, 3H); 13C{1H} NMR (125 MHz,
CDCl3): δ 139.6, 136.5, 136.4, 129.1, 129.0, 128.3, 61.9, 61.8, 42.3,
21.3; HRMS (ESI+): Calcd. for C16H20N [M+H]+: 226.1596, found
226.1599.
Synthesis of 2,9-dibutyl-4,7-dimethyl-1,10-phenanthroline, L5
To a solution of 4,7-dimethyl-1,10-phenanthroline (480 mg, 2.3 mmol)
in anhydrous toluene (11.5 mL) at 0 °C was added slowly n-BuLi (6
mL, 1.6 M, 9.6 mmol) over 5 mins. The entire mixture was allowed to
slowly warm up to room temperature and further stirred for 12 h at this
temperature. The reaction was then quenched by addition of water (30
mL) and the organic layer extracted twice with dichloromethane (30
mL ´ 2). The combined organic extract was stirred with activated
MnO2 (1.24 g, 14.24 mmol) for 4 h. The slurry was then filtered
through a pad of Celite and solvent removed under reduced pressure.
The crude extract was purified by flash column chromatography with
a mixture of 10:1 hexane/ethyl acetate as the eluent. L5 was obtained
as a pale-yellow solid (530 mg, 69%).
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Procedure for Ni-catalyzed carboxylation of N,N-dimethylbenzyl
amine.
A 10 mL oven dried round bottom flask equipped with a magnetic stir
bar was evacuated and charged with catalyst NiBr2·glyme (22 mg,
0.067 mmol) and 2,9-dibutyl-4,7-dimethyl-1,10-phenanthroline (32
mg, 0.15 mmol) under positive pressure of nitrogen. Degassed DMF
(3.4 mL, 0.4 M) was added via a syringe. Manganese (74 mg, 1.32
mmol), benzyl amine (1.34 mmol) and trimethylphosphate were added
to the mixture, and the entire mixture evacuated and refilled three times
under carbon-dioxide atmosphere. The flask was equipped with a
condenser and the entire mixture stirred under an atmosphere of CO2 at
100 °C (oil bath) for 24 h. The mixture was then cooled to room
temperature, and carefully diluted with 2M HCl. The organic layer was
extracted with ethyl acetate (20 mL ´ 3) and the combined extract
washed with brine (10 mL) and then dried over Na2SO4. The crude
product was purified by flash column chromatography with a 4:1
mixture of hexanes/ethyl acetate. 7 was isolated as an off-white solid
(32 mg, 0.26 mmol, 35%). Phenylacetic acid (7).13c 1H NMR (500
MHz, CDCl3): δ 11.29 (b, 1H), 7.49 – 7.14 (m, 5H), 3.68 (s, 2H);
13C{1H} NMR (125 MHz, CDCl3): δ 178.2, 134.0, 133.4, 130.3, 129.5,
128.8, 127.5.1, 41.3.
General procedure for preparation of di, tri and tetra- benzyl
ammonium iodides.
Synthesis of 8, 9, 10, 14: Amine (1 equiv.) and alkyl iodide (1.5 equiv.)
or alkytosylate were dissolved in acetonitrile (1 M) in a round bottom
flask. The entire mixture was refluxed (90°C in an oil bath) for 12 h.
The resultant precipitate was filtered and the filtrate washed with ether
(10 mL ´ 4) to afford the corresponding iodide salt (see Table S2 in the
SI).
2,9-dibutyl-4,7-dimethyl-1,10-benzyl-phenanthroline (L5).13c 1H NMR
(500 MHz, CDCl3): δ 7.93 (s, 2H), 7.34 (s, 2H), 3.16 (t, J = 7.9 Hz,
4H), 2.75 (s, 6H), 1.93 – 1.51 (m, 4H), 1.52 (h, J = 7.4 Hz, 4H), 1.00
(t, J = 7.4 Hz, 6H).
General procedure for Ni-catalyzed iterative alkyl group transfer
from amines and ammonium salts with and without
trimethylphosphate
A 25 mL oven dried round bottom flask equipped with a magnetic stir
bar was evacuated and charged with catalyst NiI2 (42 mg, 0.134 mmol)
and Xantphos (115 mg, 0.2 mmol) under positive pressure of nitrogen.
Degassed DMA (3.4 mL, 0.4 M) was added via a syringe and the entire
mixture stirred for 5 min at 120 °C (oil bath), after which the solution
became homogeneous and the color changed from grey to red. Mn (219
mg, 4 mmol), either the benzyl amine or the corresponding ammonium
salt (1.34 mmol), or with or without trimethyl phosphate (5.36 mmol)
were added to the mixture. The flask was equipped with a condenser
and the entire mixture stirred under nitrogen at 120 °C (oil bath) for 24
h. The mixture was the cooled to room temperature and subsequently
extracted with diethyl ether (20 mL ´ 3). The combined organic extract
was washed with water (20 mL ´ 2), followed by brine (10 mL). The
organic layer was then dried over Na2SO4, filtered and solvent removed
under reduced pressure. The crude mixture was purified by flash
column chromatography on silica gel with hexanes as the eluent. Yield
N-benzyl-N,N-dimethyl-phenylmethanaminium
iodide
(8).
Reaction performed with 22 mmol of amine in 22 mL acetonitrile. 8
1
was isolated as an off white solid (1.8 g, 35%); mp: 189–190 °C; H
NMR (500 MHz, CDCl3): δ 7.69 (d, J = 7.3 Hz, 4H), 7.45 – 7.39 (m,
6H), 5.18 (s, 4H), 3.14 (s, 6H). 13C{1H} NMR (125 MHz, CDCl3): δ
133.4, 130.8, 129.2, 127.1, 67.2, 48.2; HRMS (ESI+): Calcd. for
C16H20N [M-I]: 226.1596, found 226.1599.
N,N,N-tribenzyl-methyl ammonium iodide (9). Reaction was
performed with 7.0 mmol of amine in 7 mL acetonitrile to afford a
white solid (1.3 g, 42%); mp: 180–181 °C; 1H NMR (500 MHz,
CDCl3): δ 7.66 (d, J = 6.9 Hz, 6H), 7.56 – 7.43 (m, 9H), 5.08 (s, 6H),
2.80 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 133.5, 130.9, 129.4,
126.4, 64.6, 45.2; HRMS (ESI+): Calcd. for C22H24N [M-I]: 302.1903,
found 302.1914.
N,N,N,N-tetrabenzyl-methyl ammonium tosylate (10). Reaction
performed with 3.5 mmol of amine in 4 ml acetonitrile, and 10 was
isolated as a white solid (0.7 g, 37%). 1H NMR (500 MHz, CDCl3): δ
7.66 (d, J = 6.9 Hz, 6H), 7.56 – 7.43 (m, 9H), 4.25 (s, 4H), 4.24 (s, 4H),
2.80 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 139.9, 131.2, 129.9,
129.4, 128.8,126,2, 66.0, 21.4; HRMS (ESI+): Calcd. for C21H22N [M-
PhCH2OTs+H]+: 288.1752, found 288.1755.
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reported as an average of at least two independent runs. Yield of
isolated diphenyl ethane (2a) was calculated based on total possible
benzyl transfers with or without trimethyl phosphate additive.
1793. (b) Han, D.; He, Q.; Fan, R., Formal group insertion into aryl C–
N bonds through an aromaticity destruction-reconstruction process.
Nat. Commun. 2018, 9, 3423. (c) Woods, B. P.; Orlandi, M.; Huang,
C.-Y.; Sigman, M. S.; Doyle, A. G. Nickel-Catalyzed Enantioselective
Reductive Cross-Coupling of Styrenyl Aziridnes J. Am. Chem. Soc.
2017, 139, 5688–5691.
(5) A reductive, one-pot excision of a nitrogen atom: Joshua, H.; Gans,
R.; Mislow, K., Stereochemistry of 9-Dimethylamino-9,10-dihydro-
4,5-dimethylphenanthrene J. Am. Chem. Soc. 1968, 90, 4884–4892.
(6) The Stevens rearrangement: (a) Stevens, Thomas S.; Creighton, E.
M.; Gordon, A. B.; Macnicol, M. CCCCXXI 11. Degradation of
Quaternary Ammonium Salts. Part I; 1928; pp 3193. (b) Doyle, M. P.
Stevens Rearrangement - an overview ScienceDirect Topics. 1995. (c)
Pine, S. H. The Base-Promoted Rearrangements of Quaternary
Ammonium Salts. John Wiley & Sons, Inc.: Hoboken, NJ, USA, 2011;
pp 403-464. (d) Li, J. J., Stevens rearrangement. Springer International
Publishing: Cham, 2014; pp 580-581.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website at DOI:
Materials and methods, general experimental procedures,
characterization data and spectra for the synthesis of substrates
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and ligands, and reaction analysis by H NMR and GC-MS
(PDF)
(7) Selected reviews on C–N cleavage: (a) White, E. H.; Woodcock, D.
J. Cleavage of the carbon-nitrogen bond. In the chemistry of Amino
groups, Patai, S., Ed. John Wiley & Sons, Ltd.: New York, 1968; pp
407-497. (b) Baumgarten, R. J.; Curtis, V. A., Deaminations (carbon–
nitrogen bond cleavages). Wiley Blackwell: 2010; Vol. 2, pp 929-997.
(8) Selected reviews: (a) Ouyang, K.; Hao, W.; Zhang, W. X.; Xi, Z.,
Transition-Metal-Catalyzed Cleavage of C-N Single Bonds. Chem.
Rev. 2015, 115, 12045–12090. (b) Wang, Q.; Su, Y.; Li, L.; Huang, H.
Transition-metal catalysed C–N bond activation. Chem. Soc. Rev.
2016, 45, 1257–1272.
(9) For selected methods: (a) Akiyama, F.; Miyazaki, H.; Kaneda, K.;
Teranishi, S.; Fujiwara, Y.; Abe, M.; Taniguchi, H. Arylation and
Alkylation of Olefins by Arylamines or Hydrazines Via the Carbon-
Nitrogen Bond Cleavage in the Presence of Palladium(II) Salts. J. Org.
Chem. 1980, 45, 2359–2361. (b) Wenkert, E.; Han, A.-L.; Jenny, C.-J.
Nickel-induced conversion of carbon–nitrogen into carbon–carbon
bonds. One-step transformations of aryl, quaternary ammonium salts
into alkylarenes and biaryls. J. Chem. Soc., Chem. Commun. 1988,
975–976. (c) Simon, B. B.; MacMillan, D. W. C, The First Suzuki
Cross-Couplings of Aryltrimethylammonium Salts. J. Am. Chem. Soc.
2003, 125, 6046–6047. (d) Li, M. B.; Tang, X. L.; Tian, S. K. Cross-
coupling of grignard reagents with sulfonyl-activated sp3 carbon-
nitrogen bonds. Adv. Synth. Catal. 2011, 353, 1980–1984. (e) Maity,
P.; Shacklady-Mcatee, D. M.; Yap, G. P. A.; Sirianni, E. R.; Watson,
M. P. Nickel-catalyzed cross couplings of benzylic ammonium salts
and boronic acids: Stereospecific formation of diarylethanes via C-N
bond activation. J. Am. Chem. Soc. 2013, 135, 280–285.
AUTHOR INFORMATION
Corresponding Author
*E-mail: roberts@chem.utah.edu
Author Contributions
The manuscript was written through contributions of all authors.
All authors have given approval to the final version of the
manuscript.
ORCID
Chideraa I. Nwachukwu: 0000-0002-9143-3228
Timothy P. McFadden: 0000-0003-0336-5446
Andrew G. Roberts: 0000-0002-2221-534X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful for financial support from the University of
Utah. We thank Prof. Matthew S. Sigman and Prof. Ryan E.
Looper for thoughtful discussions. We also thank Emily K.
Kirkeby (University of Utah) and Professor Oscar Verho
(Uppsala University) for helpful discussions and proofreading
of the manuscript. NMR results included in this report were
recorded at the David M. Grant NMR Center, a University of
Utah Core Facility. Funds for construction of the Center and the
helium recovery system were obtained from the University of
Utah and the National Institutes of Health awards
(10) Furimsky, E.; Massoth, F. E., Hydrodenitrogenation of
Petroleum. Catalysis Reviews 2005, 47 , 297–489.
(11) Selected references on transition metal catalyzed C–N cleavage
in aryl ammonium substrates: (a) Xie, L.-G.; Wang, Z.-X. Nickel-
Catalyzed Cross-Coupling of Aryltrimethylammonium Iodides with
Organozinc Reagents. Angew. Chem. Int. Ed. 2011, 123 , 5003–5006.
(b) Yang, X.; Wang, Z. X. Mono- and dinuclear pincer nickel catalyzed
activation and transformation of C–Cl, C–N, and C–O bonds.
Organometallics 2014, 33, 5863–5873. (c) Wang, D. Y.; Kawahata,
M.; Yang, Z. K.; Miyamoto, K.; Komagawa, S.; Yamaguchi, K.; Wang,
C.; Uchiyama, M. Stille coupling via C-N bond cleavage. Nat.
Commun. 2016, 7, 12937.
(12) For selected references on transition metal catalyzed C–N
cleavage in aryl amine derivatives: (a) Ueno, S.; Chatani, N.; Kakiuchi,
F. Ruthenium-catalyzed carbon-carbon bond formation via the
cleavage of an unreactive aryl carbon–nitrogen bond in aniline
derivatives with organoboronates. J. Am. Chem. Soc. 2007, 129, 6098–
6099. (b) Tobisu, M.; Nakamura, K.; Chatani, N. Nickel-catalyzed
reductive and borylative cleavage of aromatic carbon-nitrogen bonds
in N-aryl amides and carbamates. J. Am. Chem. Soc. 2014, 136, 5587–
5590. (c) Cong, X.; Fan, F.; Ma, P.; Luo, M.; Chen, H.; Zeng, X. Low-
Valent, High-Spin Chromium-Catalyzed Cleavage of Aromatic
1C06RR017539-01A1
and
3R01GM063540-17W1,
respectively. NMR instruments were purchased with support of
the University of Utah and the National Institutes of Health
award 1S10OD25241-01.
REFERENCES
1) Froidevaux, V.; Negrell, C.; Caillol, S.; Pascault, J.-P.; Boutevin, B.
Biobased Amines: From Synthesis to Polymers; Present and Future.
Chem. Rev. 2016, 116, 14181–14224.
(2) Hartwig, J. F.; Shekhar, S.; Shen, Q.; Barrios-Landeros, F.,
Synthesis of Anilines. John Wiley & Sons, Ltd: Chichester, UK, 2009.
(3) Thomson, J. S.; Green, J. B.; McWilliams, T. B.; Yu, S. K. T.,
Analysis of amines in petroleum. J. High. Resolut. Chromatogr. 1994,
17, 415–426.
(4) For selected recent examples, see: (a) Lucas, E. L.; Hewitt, K. A.;
Chen, P.-P.; Castro, A. J.; Hong, X.; Jarvo, E. R. Engaging
Sulfonamides: Intramolecular Cross-Electrophile Coupling Reaction
of Sulfonamides with Alkyl Chlorides. J. Org. Chem. 2020, 85, 1775–
Carbon-Nitrogen Bonds at Room Temperature:
A Combined
Experimental and Theoretical Study. J. Am. Chem. Soc. 2017, 139,
15182–15190. (d) Zhang, Z.; Zheng, D.; Wan, Y.; Zhang, G.; Bi, J.;
Liu, Q.; Liu, T.; Shi, L., Selective Cleavage of Inert Aryl C-N Bonds
in N-Aryl Amides. J. Org. Chem. 2018, 83, 1369–1376. (e) Zhang, Z.
B.; Ji, C. L.; Yang, C.; Chen, J.; Hong, X.; Xia, J. B. Nickel-Catalyzed
11
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The Journal of Organic Chemistry
Page 12 of 13
Kumada Coupling of Boc-Activated Aromatic Amines via Nondirected
Deaminative Strategy for the Visible-Light-Mediated Generation of
Selective Aryl C-N Bond Cleavage. Org. Lett. 2019, 21, 1226–1231.
(13) Selected references on transition metal catalyzed C–N cleavage
in benzyl ammonium substrates: (a) Thompson, S. J.; Dong, G.,
Alkylation of rhodium porphyrins using ammonium and quinolinium
salts. Organometallics 2014, 33, 3757–3767. (b) Zhang, H.; Hagihara,
S.; Itami, K., Making Dimethylamino a Transformable Directing
Group by Nickel-Catalyzed C-N Borylation. Chem. Eur. J. 2015, 21,
16796–16800. (c) Moragas, T.; Gaydou, M.; Martin, R. Nickel-
Catalyzed Carboxylation of Benzylic C−N Bonds with CO2. Angew.
Chem. Int. Ed. 2016, 55, 5053–5057. (d) Sasagawa, A.; Yamaguchi,
M.; Ano, Y.; Chatani, N., Nickel-Catalyzed Benzylation of C−H Bonds
in Aromatic Amides with Benzyltrimethylammonium Halides. Isr. J.
Chem. 2017, 57, 964–967. (e) Türtscher, P. L.; Davis, H. J.; Phipps, R.
J. Palladium-Catalysed Cross-Coupling of Benzylammonium Salts
with Boronic Acids under Mild Conditions. Synthesis 2018, 50, 793–
802. (f) He, R. D.; Li, C. L.; Pan, Q. Q.; Guo, P.; Liu, X. Y.; Shu, X.
Z. Reductive Coupling between C-N and C-O Electrophiles. J. Am.
Chem. Soc. 2019, 141, 12481–12486.
(14) Selected alternative methods for selective cleavage of benzalkyl
C–N bonds in benzalkyl amine derivatives: (a) Movassaghi, M.;
Ahmad, O. K.; Lathrop, S. P., Directed heterodimerization:
Stereocontrolled assembly via solvent-caged unsymmetrical diazene
fragmentation. J. Am. Chem. Soc. 2011, 133, 13002–13005. (b) Weng,
Z. T.; Li, Y.; Tian, S. K., Catalytic asymmetric α-alkylation of ketones
and aldehydes with N-benzylic sulfonamides through carbon-nitrogen
bond cleavage. J. Org. Chem. 2011, 76, 8095–.8099 (c) Lathrop, S. P.;
Movassaghi, M. Application of diazene-directed fragment assembly to
the total synthesis and stereochemical assignment of (+)-desmethyl-
meso-chimonanthine and related heterodimeric alkaloids. Chem. Sci.
2014, 5, 333–340. (d) Carlson, E.; Tam, W. Type 1 Ring-Opening
Reactions of Cyclopropanated 7-Azabenzonorbornadienes with
Organocuprates. Org. Lett. 2016, 18, 2134–2137. (e) Yang, F.; Chen,
J.; Xu, J.; Ma, F.; Zhou, Y.; Shinde, M. V.; Fan, B. Palladium/Lewis
Acid Co-catalyzed Divergent Asymmetric Ring-Opening Reactions of
Azabenzonorbornadienes with Alcohols. Org. Lett. 2016, 18, 4832–
4835. (f) Gui, Y.; Tian, S. K., Stereospecific Nucleophilic Substitution
of Enantioenriched Tertiary Benzylic Amines via in Situ Activation
with Benzyne. Org. Lett. 2017, 19, 1554–1557. (g) Zhang, W.; Chen,
J.; Zeng, G.; Yang, F.; Xu, J.; Sun, W.; Shinde, M. V.; Fan, B.
Asymmetric Ring-Opening Reactions of Aza- and Oxa-bicyclic
Alkenes with Boronic Acids Using a Palladium/Zinc Co-catalytic
System. J. Org. Chem. 2017, 82, 2641–2647. (h) Chen, Z.; Han, L.;
Tian, S. K., Activation and Substitution of 1-Ferrocenylalkylamines
with Allenones: Application to Three-Component Synthesis of 4-(1-
Ferrocenylalkyl)pyrazoles. Org. Lett. 2017, 19, 5852–5855.
Alkyl Radicals. Angew. Chem. Int. Ed. 2017, 56, 12336–12339. (b)
Wu, J.; He, L.; Noble, A.; Aggarwal, V. K. Photoinduced Deaminative
Borylation of Alkylamines. J. Am. Chem. Soc. 2018, 140, 10700–
10704.
(18) An orthogonal utility of benzalkylammonium salts is their ability
to direct C–H functionalization chemistries through ion-pairing: (a)
Davis, H. J.; Mihai, M. T.; Phipps, R. J. Ion Pair-Directed Regiocontrol
in Transition-Metal Catalysis: A Meta-Selective C–H Borylation of
Aromatic Quaternary Ammonium Salts. J. Am. Chem. Soc. 2016, 138,
12759–12762. (b) Mihai, M.; Phipps, R., Ion-Pair-Directed meta-
Selective C–H Borylation of Aromatic Quaternary Ammonium Salts.
Synlett 2017, 28, 1011–1017.
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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) Richmond, E.; Moran, J. Recent Advances in Nickel Catalysis
Enabled by Stoichiometric Metallic Reducing Agents. Synthesis 2018,
50, 499–513.
(20) (a) Biswas, S.; Weix, D. J. Mechanism and selectivity in nickel-
catalyzed cross-electrophile coupling of aryl halides with alkyl halides.
J. Am. Chem. Soc. 2013, 135, 16192–16197. (b) Weix, D. J., Methods
and Mechanisms for Cross-Electrophile Coupling of Csp3 Halides with
Alkyl Electrophiles. Acc. Chem. Res. 2015, 48, 1767–1775.
(21) Lucas, E. L.; Jarvo, E. R. Stereospecific and stereoconvergent
cross-couplings between alkyl electrophiles. Nat. Rev. Chem. 2017, 1,
0065.
(22) Ni-catalyzed C–O/C–X cleavage for oxygen atom rearrangement:
(a) Tollefson, E. J.; Erickson, L. W.; Jarvo, E. R., Stereospecific
Intramolecular Reductive Cross-Electrophile Coupling Reactions for
Cyclopropane Synthesis. J. Am. Chem. Soc. 2015, 137, 9760–9763. Ni-
catalyzed dual C–O cleavage for oxygen atom excision: (b) Cao, Z.-C.;
Shi, Z.-J. Deoxygenation of Ethers To Form Carbon–Carbon Bonds via
Nickel Catalysis. J. Am. Chem. Soc. 2017, 139, 6546–6549.
(23) For a method that involves the reductive homodimerization of
pyridinium and ammonium salts see: (a) Buszek, K. R.; Brown, N. N-
vinylpyridinium and -ammonium tetrafluoroborate salts: new
electrophilic coupling partners for Pd(0)-catalyzed Suzuki cross-
coupling reactions. Org. Lett. 2007, 9, 707–710. (b) Gao, G.; Brown,
N.; Minatoya, M.; Buszek, K. R. N-Vinylpyridinium tetrafluoroborate
salts as reagents for the stereoselective and regioselective synthesis of
symmetrical (2E,4E)-1,6-dioxo-2,4-dienes. Tetrahedron Lett. 2008,
49, 6491–6494.
(24) An example and discussion of Ni(0) oxidative addition of a benzyl
trimethylammmonium salt: Tsou, T. T.; Kochi, J.; K. Mechanism of
Oxidative Addition. Reaction of Nickel(0) Complexes with Aromatic
Halides. J. Am. Chem. Soc. 1979, 101, 6319–6332.
(25) Selected references on the electrochemical generation of
benzalkyl radicals and their reactivity: (a) Finkelstein, M.; Petersen, R.
C.; Ross, S. D. The Electrochemical Degradation of Quaternary
Ammonium Salts. J. Am. Chem. Soc. 1959, 81, 2361–2364. (b) Ross,
S. D.; Finkelstein, M.; Petersen, R. C. The Electrochemical
Degradation of Quaternary Ammonium Salts. II. The Mechanism of
the Coupling Reaction. J. Am. Chem. Soc. 1960, 82, 1582–1585. (c)
Mayell, J. S.; Bard, A. J. The Electroreduction of Quaternary
Ammonium Compounds. J. Am. Chem. Soc. 1963, 85, 421–425. (d)
Finkelstein, M.; Petersen, R. C.; Ross, S. D. Electrolysis of phenyl and
benzyl quaternary ammonium salts. Electrochim. Acta. 1965, 10, 465–
469.
(26) The development of Xantphos: (a) Hillebrand, S.; Bruckmann, J.;
Krüger, C.; Haenel, M. W. Bidentate phosphines of heteroarenes: 9,9-
dimethyl-4,5-bis(diphenylphosphino)xanthene. Tetrahedron Lett.
1995, 36, 75–78. (b) Kranenburg, A. M.; Van Der Burgt, Y. E. M.;
Kamer, P. C. J.; Van Leeuwen, P. W. N. M.; Van't Hoff, J. H.; Goubitz,
K.; Fraanje, J. New Diphosphine Ligands Based on Heterocyclic
Aromatics Inducing Very High Regioselectivity in Rhodium-
Catalyzed Hydroformylation: Effect of the Bite. Organometallics
1995, 14, 3081–3089. Recent studies on (Xantphos)Ni(I)-mediated
processes: (c) Diccianni, J. B.; Katigbak, J.; Hu, C.; Diao, T.
Mechanistic Characterization of (Xantphos)Ni(I)-Mediated Alkyl
Bromide Activation: Oxidative Addition, Electron Transfer, or
Halogen-Atom Abstraction J. Am. Chem. Soc. 2019, 141, 1788–1796.
(27) Poremba, K. E.; Kadunce, N. T.; Suzuki, N.; Cherney, A. H.;
Reisman, S. E., Nickel-Catalyzed Asymmetric Reductive Cross-
(15) Alkyl pyridinium salts as substrates for transition metal promoted
alkyl C–N cleavage: (a) Basch, C. H.; Liao, J.; Xu, J.; Piane, J. J.;
Watson, M. P. Harnessing Alkyl Amines as Electrophiles for Nickel-
Catalyzed Cross Couplings via C-N Bond Activation. J. Am. Chem.
Soc. 2017, 139, 5313–5316. (b) Liao, J.; Basch, C. H.; Hoerrner, M. E.;
Talley, M. R.; Boscoe, B. P.; Tucker, J. W.; Garnsey, M. R.; Watson,
M. P. Deaminative Reductive Cross-Electrophile Couplings of
Alkylpyridinium Salts and Aryl Bromides. Org. Lett. 2019, 21, 2941–
2946. (c) Plunkett, S.; Basch, C. H.; Santana, S. O.; Watson, M. P.,
Harnessing Alkylpyridinium Salts as Electrophiles in Deaminative
Alkyl-Alkyl Cross-Couplings. J. Am. Chem. Soc. 2019, 141, 2257–
2262. (d) Yue, H.; Zhu, C.; Shen, L.; Geng, Q.; Hock, K. J.; Yuan, T.;
Cavallo, L.; Rueping, M. Nickel-catalyzed C-N bond activation:
Activated primary amines as alkylating reagents in reductive cross-
coupling. Chem. Sci. 2019, 10, 4430–4435. (e) Ni, S.; Li, C.-X.; Mao,
Y.; Han, J.; Wang, Y.; Yan, H.; Pan, Y. Ni-catalyzed deaminative
cross-electrophile coupling of Katritzky salts with halides via C─N
bond activation. Sci. Adv. 2019, 5, 9516.
(16) In this visible light promoted benzalkyl C–N cleavage the
liberated trimethylamine is further utilized as a reductant: Liao, L.-L.;
Cao, G.-M.; Ye, J.-H.; Sun, G.-Q.; Zhou, W.-J.; Gui, Y.-Y.; Yan, S.-
S.; Shen, G.; Yu, D.-G., Visible-Light-Driven External-Reductant-Free
Cross-Electrophile Couplings of Tetraalkyl Ammonium Salts. J. Am.
Chem. Soc. 2018, 140, 17338-17342.
(17) Alkyl pyridinium salts as substrates for visible light promoted
alkyl C–N cleavage: (a) Klauck, F. J. R.; James, M. J.; Glorius, F.
12
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The Journal of Organic Chemistry
Coupling To Access 1,1-Diarylalkanes. J. Am. Chem. Soc. 2017, 139,
5684–5687.
2877.
(39) Sahoo, S. K. An Unprecedented Oxidative Intermolecular Homo
Coupling Reaction between Two Csp3–Csp3 Centers under Metal-Free
Condition. Tetrahedron Lett. 2016, 57, 3476–3480.
(40) Zou, X.; Zou, J.; Yang, L.; Li, G.; Lu, H. Thermal Rearrangement
of Sulfamoyl Azides: Reactivity and Mechanistic Study. J. Org. Chem.
2017, 82, 4677–4688.
(41) Fallon, B. J.; Corcé, V.; Amatore, M.; Aubert, C.; Chemla, F.;
Ferreira, F.; Perez-Luna, A.; Petit, M. A Well-Defined Low-Valent
Cobalt Catalyst Co(PMe3)4 with Dimethylzinc: A Simple Catalytic
Approach for the Reductive Dimerization of Benzyl Halides. New J.
Chem. 2016, 40, 9912–9916.
1
2
3
4
5
6
7
8
(28) Trimethylphosphate for the controlled methylation of anilines: (a)
Billman, J. H.; Radike, A.; Mundy, B. W. Alkylation of Amines. I. J.
Am. Chem. Soc. 1942, 64, 2977–2978. (b) Thomas, D. G.; Billman, J.
H.; Davis, C. E. Alkylation of Amines. II. N,N-Dialkylation of Nuclear
Substituted Anilines. J. Am. Chem. Soc. 1946, 68, 895–896.
(29) He, Z. T.; Li, H.; Haydl, A. M.; Whiteker, G. T.; Hartwig, J. F.,
Trimethylphosphate as a Methylating Agent for Cross Coupling: A
Slow-Release Mechanism for the Methylation of Arylboronic Esters.
J. Am. Chem. Soc. 2018, 140, 17197–17202.
9
(30) Selectivity in benzalkyl transfer from
a
dibenzalkyl
dimethylammonium salt: Hilhorst, E.; Iskander, A. S.; Chen, T. B. R.
A.; Pandit, U. K. Alkyl transfer from quaternary ammonium salts to
cobalt (I): Model for the cobalamin-dependent methionine synthase
reaction. Tetrahedron 1994, 50, 8863–8870.
(31) Park, G.; Yi, S. Y.; Jung, J.; Cho, E. J.; You, Y., Mechanism and
Applications of the Photoredox Catalytic Coupling of Benzyl
Bromides. Chem. Eur. J. 2016, 22, 17790–17799.
(32) Dust, J. M.; Arnold, D. R. Substituent Effects on Benzyl Radical
ESR Hyperfine Coupling Constants. The sa·Scale Based upon Spin
Delocalization. J. Am. Chem. Soc. 1983, 105, 1221–1227.
(33) Benzalkyl mesylates are employed to control cross-electrophile
coupling selectivity. Homodimerization events are favored for the
corresponding benzalkyl halides. For further discussion, see: L. K. G.;
Anka-Lufford, L. L.; Naodovic, M.; Weix, D. J. Cobalt co-catalysis for
cross-electrophile coupling: Diarylmethanes from benzyl mesylates
and aryl halides. Chem. Sci. 2015, 6, 1115–1119.
(42) Cooper T.; Novak, A.; Humphreys, L. D.; Walker, M. D.;
Woodward, S. User-Friendly Methylation of Aryl and Vinyl Halides
and Pseudo halides with DABAL-Me3. Adv. Synth. Catal. 2006, 348,
686–690.
(43) Guan, B.-T.; Xiang, S.-K.; Wu, T.; Sun, Z.-P.; Wang, B.-Q.;
Zhao, K.-Q.; Shi, Z.-J. Methylation of arenes via Ni-catalyzed aryl C–
O/F activation. Chem. Commun. 2008, 1437–1439.
(44) Sato, K.; Inoue, Y.; Mori, T.; Sakaue, A.; Tarui, A.; Omote, M.
Kamadaki, I.; Ando, A. Csp3–Csp3 Homocoupling Reaction of Benzyl
Halides Catalyzed by Rhodium. Org. Lett. 2014, 16, 3756–3759.
(45) Rhee, H.; Kim, J. Y. A simple one-pot procedure for the
Conversion of Aldehydes to Methyl Esters. Tetrahedron Lett. 1998, 39,
1365-1386.
(46). Cristau, H.-J.; Ouali, A.; Spindler, J.-F.; Taillefer, M. Mild and
Efficient Copper-Catalyzed Cyanation of Aryl Iodides and Bromides.
Chem. Eur. J. 2005, 11, 2483–2492.
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
(47). Wang, J.; Zhao, J.; Gong, H. Nickel-catalyzed methylation of aryl
halides/tosylates with methyl tosylate Chem. Commun. 2017, 53,
10180– 10183.
(34) Alles, R. N. Icke, B. B; Wisegnarver, G. A.
β-
phenylethyldimethylamine. Org. Synth. 1945, 25, 89.
(35) Murugesan, D.; Mital, A.; Kaiser, M.; Shackleford, D. M.;
Morizzi, J.; Katneni, K.; Campbell, M.; Hudson, A.; Charman, S. A.;
Yeates, C.; Gilbert, I. H. Discovery and Structure−Activity
Relationships of Pyrrolone Antimalarials. J. Med. Chem. 2013, 56,
2975–2990.
(36) Tayama, E.; Kimura, H. Asymmetric Sommelet–Hauser
Rearrangement Of N-Benzylic Ammonium Salts. Angew. Chemie Int.
Ed. 2007, 46, 8869–8871.
(37) Guijarro, D.; Martínez, P. J.; Nájera, C.; Yus, M. Benzyllithium
from Methylated Benzylamine and Its Ammonium Salt via
Naphthalene-Catalyzed Carbon-Nitrogen Bond Reductive Cleavage.
Arkivoc 2004, 4, 5–13.
(38) Blangetti, M.; Fleming, P.; O’Shea, D. F. Homo- and Hetero-
Oxidative Coupling of Benzyl Anions. J. Org. Chem. 2012, 77, 2870–
13
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