Harnessing Alkylpyridinium Salts as Electrophiles in Deaminative Alkyl-Alkyl Cross-Couplings

Article abstract of DOI:10.1021/jacs.9b00111

A Negishi cross-coupling of alkylpyridinium salts and alkylzinc halides has been developed. This is the first example of alkyl-alkyl bond formation via cross-coupling of an alkyl amine derivative with an unactivated alkyl group, and allows both primary and secondary alkylpyridinium salts to react with primary alkylzinc halides with high functional group tolerance. When combined with formation of the pyridinium salts from primary amines, this method enables the noncanonical transformation of NH₂ groups into a wide range of alkyl substituents with broad functional group tolerance.

Full text of DOI:10.1021/jacs.9b00111

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Communication
Harnessing Alkyl Pyridinium Salts as Electrophiles
in Deaminative Alkyl-Alkyl Cross-Couplings
Shane Plunkett, Corey H. Basch, Samantha O. Santana, and Mary P. Watson
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b00111 • Publication Date (Web): 25 Jan 2019
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Harnessing Alkyl Pyridinium Salts as Electrophiles in
Deaminative Alkyl-Alkyl Cross-Couplings
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Shane Plunkett, Corey H. Basch, Samantha O. Santana, Mary P. Watson*
Department of Chemistry & Biochemistry, University of Delaware, Newark, Delaware 19716, United States
Supporting Information Placeholder
veloped Minisci arylation, alkynylation, and boryla-
ABSTRACT: A Negishi cross-coupling of alkyl pyridinium
salts and alkylzinc halides has been developed. This is
the first example of alkyl–alkyl bond formation via
cross-coupling of an alkyl amine derivative with an un-
activated alkyl group, and allows both primary and sec-
ondary alkyl pyridinium salts to react with primary al-
kylzinc halides with high functional group tolerance.
When combined with formation of the pyridinium salts
from primary amines, this method enables the non-
canonical transformation of NH2 groups into a wide
range of alkyl substituents with broad functional group
tolerance.
tions.9 These exciting reports demonstrate the potential
of alkyl pyridinium salts in synthesis, and offer avenues
to convert ubiquitous NH2 groups into C(sp2) and C(sp)
substituents. However, no current methods enable
C(sp3)–C(sp3) formation via cleavage of these unactivat-
ed alkyl pyridinium salts.10
Scheme 1. Alkyl amine derivatives in cross-coupling
reactions.
A. Alkyl amine derivatives used in cross-couplings
O
[N]
R
R
[N]
Ar
[N]
OR
Ar
Doyle
Jamison
[N]
Wang
Tian
Watson
Tian
electronically activated
strain-activated
B. Alkyl pyridinium salts with unactivated alkyl groups
Alkyl amines are abundant molecules ranging from
simple starting materials to complex natural products
and drug candidates.1 As an example of their preva-
lence, a search of Pfizer’s internal chemical store re-
vealed over 47,000 alkyl primary amines vs. about
28,000 primary and secondary alkyl halides.2 In addi-
tion, the use of alkyl amines as intermediates is advan-
tageous, because they can be prepared directly and
convergently with simultaneous formation of the amine
and C–C bonds via classic reactions, such as Mannich,
Petasis, Strecker, and others.3 Due to their ubiquity,
methods that allow alkyl amines to be converted into
electrophiles for cross-coupling reactions present an
exciting opportunity for development. However, the
utilization of amine-derived alkyl electrophiles remains
limited with cross-couplings largely restricted to alkyl
amine derivatives with electronic or strain activation of
the C(sp3)–N bond (Scheme 1A).4,5,6 We recently over-
came this limitation by developing a Suzuki–Miyaura
arylation of Katritzky pyridinium salts, which are easily
and selectively prepared from primary alkyl amines
(Scheme 1B).7,6m, 6n,5b, 8 This reaction was the first cross-
coupling of an alkyl amine derivative with an unactivat-
ed alkyl group. Recognizing that our proposed alkyl radi-
cal intermediate could also be formed via photoredox
catalysis, Glorius, Gryko, Aggarwal, Li and Shi then de-
R2
R1
Ph
Alkyl Radical
Intermediate
Ar–B(OH)2
cat. Ni(OAc)2·4H2O/BPhen
Ph
BF4
Ph
BF4
Ph
R1 NH2
R1 Ar
R2
Ph
O
Ph
N
KOtBu
Watson
R2
R1 R2
1, Katritzky
pyridinium salts
C(sp3)–C(sp2)
C: This work: Alkyl–alkyl cross-couplings
Ph
BF4
Ph
Ph
Alkyl–ZnX
cat. [Ni]
BF4
Ph
R1 NH2
R1 Alkyl
R2
Ph
O
R2
Ph
N
C(sp3)–C(sp3)
1° or 2° alkyl
R1 R2
1
The prevalence of C(sp3)–C(sp3) bonds in bioactive
molecules has led to intense efforts to develop methods
to incorporate fully saturated C–C bonds in complex
products.11 In particular, Negishi cross-couplings have
emerged as a reliable and functional group tolerant
method.6a, 6d, 12 Motivated by the myriad advantages of
alkyl amine derivatives as alkyl electrophiles, we envi-
sioned a Negishi cross-coupling for the generation of
C(sp3)–C(sp3) bonds from alkyl pyridinium salts (Scheme
1C). However, despite the precedent with other alkyl
electrophiles, we were concerned that competitive nu-
cleophilic addition of the organozinc to the pyridinium
ring and/or deprotonation of the acidic a-proton of the
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alkyl pyridinium salts would prevent the desired cross-
8
Ni(acac)2·xH2O
Ni(acac)2·xH2O
none
ttbtpy
ttbtpy
ttbtpy
none
81
80
3
1
2
3
4
5
6
7
8
coupling. Overcoming these challenges, we have devel-
oped the first example of alkyl–alkyl bond formation via
cross-coupling of an alkyl amine derivative with an un-
activated alkyl group. This method allows both primary
and secondary alkyl pyridinium salts to react with pri-
mary alkylzinc halides with high functional group toler-
ance. In combination with efficient pyridinium for-
mation, this reaction enables the non-canonical trans-
formation of amino groups into alkyl substituents,
providing unprecedented entry to complex, saturated
organic frameworks via versatile and attractive amine
intermediates.
9d
10
11
Ni(acac)2·xH2O
9
O
O
BrZn
(1.6 equiv)
10 mol % NiCl2·DME
12 mol % ligand
Ph
Ph
O
N
O
THF/DMA (2:1)
60 °C, 17 h
BF4
9
Ph
1b
3
10
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12
13
14
NiCl2·DME
NiCl2·DME
NiCl2·DME
ttbtpy
tpy
18
68
83
1-bpp
We selected the cross-coupling of phenethyl pyridini-
um salt 1a and commercially available (2-(1,3-dioxolan-
2-yl)ethyl)zinc bromide for our initial studies. We priori-
tized the use of alkyl zinc halides, as opposed to dialkyl
zinc reagents, due to their greater commercial availabil-
ity, higher functional group tolerance, and ease of han-
dling.13 Using bathophenanthroline (BPhen), the opti-
mal ligand for our Suzuki–Miyaura arylation, resulted in
<20% yield. However, with NiCl2·DME/4,4’,4’’-tri-tert-
butyl terpyridine (ttbtpy) as catalyst and DMA as a polar
co-solvent, 68% yield was observed (Table 1, entry 1).14
Increasing the amount of organozinc halide further im-
proved the yield (entry 2); however, more than 1.6
equivalents led to decreased product formation (see
Supporting Information). The use of other redox non-
innocent ligands also resulted in lower yields (entries 3–
6). To maximize the practicality, less expensive NiII
sources and lower catalyst loadings were examined.
Although NiCl2·6H2O was ineffective (entry 7),
Ni(acac)2·xH2O gave slightly higher yields than
NiCl2·DME (entry 8). Lowering the Ni(acac)2·xH2O and
ttbtpy loading to 5 and 6 mol %, furnished a similar
yield (entry 9). Control experiments confirmed that
both nickel and ligand are required (entries 10 and 11).
a
Conditions: Pyridinium salt 1a (0.1 mmol), [Ni] (10 mol
%), ligand (12 mol %), AlkZnBr (1.6 equiv), THF/DMA (2:1,
0.2 M), 60 °C, 16–22 h, unless noted otherwise. Deter-
mined by H NMR spectroscopic analysis using 1,3,5-
b
1
c
trimethoxybenzene as internal standard. AlkZnBr (1.4
equiv). d 5 mol % [Ni], 6 mol % ligand.
Although ttbtpy proved effective for primary alkyl pyr-
idinium salts, only 18% yield was observed with sec-
ondary alkyl pyridinium salt 1b (Table 1, entry 12).
However, 2,6-bis(N-pyrazolyl)pyridine (1-bpp) promoted
the cross-coupling with high efficiency (entry 14). This
ligand has been used previously in Negishi cross-
couplings, including those of bulky alkylzinc iodides.12f,
12g
Notably, tpy also bested the more hindered ttbtpy
(entries 12 vs. 13), suggesting that steric hindrance of
the ligand may be primarily responsible for the success
of 1-bpp.12g
Wide scope of primary and secondary alkyl pyridini-
um salts was observed (Scheme 2). Aryl and heteroaryl
groups were tolerated, including thiophene (4), benzo-
dioxole (6), pyridine (7), and pyrimidine (15). Products
with saturated heterocycles, such as piperazine 5, mor-
pholine 16, pyrans 9 and 13, piperidines 11 and 15, pyr-
rolidine 12, and strained azetidine 8, also formed in
good yields. Highlighting the potential for late-stage
functionalization, pyridinium salts of several drugs,
pharmaceutical intermediates, and natural products
underwent alkylation. Alkylations of the pyridinium
salts of amine intermediates in the synthesis of the gas-
trointestinal drug Mosapride (16) and Lipitor (18–20)
were effective.15 A single diastereomer of 19 was ob-
served, indicating that stereocenters bearing acidic pro-
tons are not epimerized. The unprotected carboxylic
acid of 20 is tolerated in both the pyridinium formation
and cross-coupling, demonstrating orthogonality of the
Table 1. Reaction Optimizationa
O
O
BrZn
(1.6 equiv)
10 mol % [Ni]
Ph
Ph
O
12 mol % ligand
N
O
THF/DMA (2:1)
60 °C, 16–22 h
BF4
Ph
1a
2
entry
[Ni]
ligand
ttbtpy
ttbtpy
tpy
yield (%)b
1c
2
3
4
5
6
7
NiCl2·DME
NiCl2·DME
NiCl2·DME
NiCl2·DME
NiCl2·DME
NiCl2·DME
68
75
47
14
15
49
20
amine and carboxylate groups, either of which can be
phen
used to generate alkyl radicals.12h,
The pyridinium
16
dtbbpy
1-bpp
ttbtpy
salts of natural cis-myrtanylamine (17), pinanamine
(21), the anti-arrhythmic drug Mexiletine (22) and anti-
viral Tamiflu (23) also coupled well.17 The cross-coupling
NiCl2·6H2O
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of the Tamiflu pyridinium salt demonstrates that a high
because we cannot yet form them from unconstrained
tertiary alkyl amines.9e To simplify set-up, a single-
component catalyst, Ni(1-bpp)Cl2, can be used (see 11,
15).
1
2
3
4
degree of steric hindrance and chemical complexity is
tolerated. However, this method is limited to primary
and secondary alkyl 2,4,6-triphenyl pyridinium salts,
Scheme 2. Reaction Scopea
5
6
7
8
9
tBu
Alk–ZnX (1.6 equiv)
5 mol % Ni(acac)2·xH2O
6 mol % ttbtpy or 1-bpp
Ph
R1
Ph
BF4
R1 Alk
R2
N
N
N
N
N
N
THF/DMA (2:1)
60 °C, 18 h
N
R2 Ph
N
N
tBu
ttbtpy
tBu
1-bpp
1
10
11
12
13
14
15
16
17
18
19
20
21
22
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60
for primary alkyl pyridinium salts
for secondary alkyl pyridinium salts
A. Primary alkyl pyridinium salts (ttbtpy)
C. From natural products, pharmaceuticals, and pharmaceutical intermediates
O
O
N
CO2Et
O
N
Me
BocN
OEt
S
O
F
5, 57%b
Me
2, 68%
4, 67%
Boc
16, 66%
17, 54%b
Me
Me
O
O
N
N
from Mosapride intermediate
from cis-Myrtanylamine
Me
N
O
8, 57%b
6, 59%
7, 59%
Me
Me
Me
Me
O
Me
C10H21
O
CO Me
Me
2
O
O
B. Secondary alkyl pyridinium salts (1-bpp)
O
O
Me
O
BPin
O
O
tBuO2C
tBuO2C
HO2C
N
O
O
19, 56%
20, 38%e
Me
N
18, 54%b
Boc
O
single diastereomer
from Lipitor® intermediate
10, 69%b
11, 88%c
3, 75%
9, 73%
with Ni(1-bpp)Cl2: 85%c,d
O
CO2Et
BPin
Me
Me
CF3
Me
N
Me
O
C5H11
Me
F3C
Me HN
Me
N
N
BPin
Cl
Me
O
Me
Me
N
O
Me Me
21, 67%b
N
O
Boc
22, 80%
23, 58%b,f
2.2:1 dr
14, 57%
15, 80%c
5-mmol scale, Ni(1-bpp)Cl2: 83%b,c,d
12, 78%b
13, 63%b
single diastereomer
from Pinanamine
from Mexilitene
from Tamiflu®
a Conditions: Pyridinium salt 1 (1 mmol), Ni(acac)2·xH2O (5 mol %), ttbtpy or 1-bpp (6 mol %), Alk–ZnX (X = Br or I, 1.6 equiv),
b
THF/DMA (2:1, 0.2 M), 60 °C, 18 h. Average isolated yield (±4%) from duplicate experiments. Alk–ZnX generated in DMA
(no THF). NBu4I (3.2 equiv) added. c Single experiment. d Ni(1-bpp)Cl2 (5 mol %) as catalyst. e Alk–ZnX (3.0 equiv). 0.5 mmol
f
scale.
Both commercial and prepared primary alkyl zinc hal-
ides proved effective (Scheme 2). We used Hou’s meth-
od to generate organozinc reagents due to its high func-
tional group tolerance.18 In line with findings by
Organ,19 a salt additive was crucial for maintaining high
reactivity of non-commercial organozinc reagents, with
NBu4I as the optimal additive.20 Homemade organozinc
halides were generated in DMA (no THF present). In
terms of steric hindrance, b-branching is tolerated (6,
19), including quaternary carbons (13). However, sec-
ondary and tertiary alkylzinc halides do not undergo the
desired cross-coupling. Instead, a non-nickel-catalyzed
addition to the 4-position of the pyridinium ring oc-
curs.21 Regarding functional group tolerance, various
groups can be incorporated in the alkylzinc halide, in-
cluding acetal (2, 3, 9, 20), ester (4, 16, 19), alkene (5,
17), nitrile (7, 11, 22), trifluoromethyl (12), and oxetane
(13). Notably, the pyridinium group couples preferen-
tially in the presence of an alkyl chloride (14). Methyl-
zinc iodide is also effective (8, 23). When coupled with
formation of the pyridinium salt, this strategy allows
NH2 to be replaced with a steric isostere CH3, offering
opportunities for efficient structure-activity relationship
studies.22
Finally, synthetically versatile a-
methylpinacolboronate (CH2Bpin) can also be installed
(10, 15, 21). To our knowledge, this is the first example
utilizing a-methylpinacolboronate zinc bromide in a
Negishi cross-coupling.23 Product 15 is formed in 83%
yield on a 5-mmol scale with the single-component cat-
alyst. Further, we demonstrated the versatility of the
newly installed Bpin by converting it to an alcohol
(22),6g bromide (23),24 and thiophene (24, Scheme 3).25
Scheme 3. Elaboration of Boronic Ester
NH2
BPin
OH
2 steps
61%
N
N
H2O2, KOH
N
N
N
N
N
N
N
CF3
15
CF3
25, 97%
CF3
24
S
Br
Li
S
N
N
3,5-(CF3)2C6H3Li
then NBS
then NBS
N
N
N
N
CF3
26, 77%
CF3
27, 74%
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To facilitate use of this chemistry in parallel medicinal
scope of alkyl groups and pursue detailed mechanistic
understanding.
1
2
3
4
5
6
7
8
chemistry and other synthesis efforts, we developed
conditions for the one-pot transformation of amines
directly to the alkylated products. By increasing the
equivalents of alkylzinc halide, similar yields were ob-
tained in this one-pot procedure as the two-step meth-
od (Scheme 4). Notably, these conditions are not se-
quential addition; primary amine and pyrylium tetra-
fluoroborate are simply added in place of the pyridini-
um salt under the previous conditions.
ASSOCIATED CONTENT
Supporting Information.
The Supporting Information is available free of charge on
the ACS Publications website.
Experimental details and data (PDF)
9
AUTHOR INFORMATION
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11
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Corresponding Author
Scheme 4. One-pot activation and cross-coupling
*mpwatson@udel.edu
[Ph3C5H2O][BF4] (1 equiv), Alk–ZnX (3 equiv)
O
5 mol % Ni(acac)2·xH2O, 6 mol % ttbtpy
ORCID
NH2
NH2
Ph
Bu4NI (3.2 equiv)
THF/DMA (2:1), 60 °C, 18 h
O
Ph
28
29
2, 45%
2-step yield: 60%
Mary P. Watson: 000-0002-1879-5257
[Ph3C5H2O][BF4] (1 equiv), Alk–ZnX (3 equiv)
5 mol % Ni(acac)2·xH2O, 6 mol % 1-bpp
O
Notes
O
Bu4NI (3.2 equiv)
THF/DMA (2:1), 60 °C, 18 h
The authors declare no competing financial interest.
3, 57%
2-step yield: 56%
ACKNOWLEDGMENT
In analogy to Negishi cross-couplings of other alkyl
electrophiles, our arylation of alkyl pyridinium salts,7, 12f,
We thank NIH (R01 GM111820) and University of Dela-
ware (UD) for a University Graduate Fellowship (C.H.B.).
We thank Drs. Michelle Garnsey, Joe Tucker, and Brian
Boscoe for helpful discussions. Data were acquired at UD
on instruments obtained with assistance of NSF and NIH
funding (NSF CHE0421224, CHE1229234, CHE0840401,
and CHE1048367; NIH P20 GM104316, P20 GM103541,
and S10 OD016267).
and other reactions of alkyl pyridinium salts,9a, 9b, 26
12g
we hypothesize that this reaction proceeds through
single-electron transfer (SET) to the alkyl pyridinium salt
from a Ni(I) intermediate or a Ni(II) cation with a re-
duced ligand.12g Fragmentation of the resulting neutral
pyridyl radical then gives an alkyl radical, which recom-
bines with a Ni(II) intermediate to then deliver the
product. Consistent with an alkyl radical intermediate,
we observe ring-opened 30 in the reaction of cyclo-
propylmethyl pyridinium salt and TEMPO-adduct 31
when TEMPO is added (Scheme 5). No cross-coupled
product 2 is observed upon addition of TEMPO.
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Scheme 5. Support for Alkyl Radical Intermediate
Alk–ZnBr (1.6 equiv)
Ph
5 mol % Ni(acac)2·xH2O
6 mol % ttbtpy
O
BF4
Ph
Alk
+
N
THF/DMA (2:1)
60 °C, 18 h
O
Ph
30, 69% (1H NMR)
1u
0%
Alk–ZnBr (1.6 equiv)
5 mol % Ni(acac)2·xH2O
6 mol % ttbtpy
Me
Me
Ph
Ph
BF4
Ph
+
2, 0%
N
Ph
N
THF/DMA (2:1)
60 °C, 18 h
TEMPO (2.0 equiv)
O
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Me
Ph
Me
31, 20% (1H NMR)
1a
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In summary, we have developed the first example of
an alkyl–alkyl cross-coupling of alkyl amine derivatives
with unactivated alkyl groups, specifically alkyl pyridini-
um salts. When combined with chemoselective pyri-
dinium formation from primary amines, this Negishi
reaction provides the ability to convert NH2 into a range
of alkyl groups with broad functional group tolerance.
The reaction appears to proceed via an alkyl radical in-
termediate, likely generated after SET from a Ni species
to the pyridinium cation. Future efforts will expand the
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2008, 130, 1566-1567; (f) Shi, S.; Meng, G.; Szostak, M. Synthesis of
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Alk–ZnX (1.6 equiv)
5 mol % Ni(acac)2·xH2O
6 mol % ttbtpy or 1-bpp
1
2
3
4
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8
Ph
R1
Ph
BF4
R1 NH2
R1 Alk
R2
N
THF/DMA (2:1)
60 °C, 18 h
C(sp3)–C(sp3)
R2
R2 Ph
1° or 2° alkyl
Me
O
Me
CO2Me
O
CO2Et
N
Me
O
Me
BPin
N
N
F3C
Me AcN
H
Me
59% (2.2:1 dr)
tBuO2C
(from Lipitor® intermediate)
83%, 5-mmol scale
with Ni(1-bpp)Cl2
56%
(from Tamiflu®
)
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7
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