Engaging Alkenes and Alkynes in Deaminative Alkyl-Alkyl and Alkyl-Vinyl Cross-Couplings of Alkylpyridinium Salts

Article abstract of DOI:10.1021/acs.orglett.9b03899

An alkyl-alkyl cross-coupling of Katritzky alkylpyridinium salts and organoboranes, formed in situ via hydroboration of alkenes, has been developed. This method utilizes the abundance of both alkyl amine precursors and alkenes to form C(sp³)-C(sp³) bonds. This strategy is also effective with alkynes, enabling a C(sp³)-C(sp²) cross-coupling. Under these mild conditions, a broad range of functional groups, including protic groups, is tolerated. As seen with previous alkylpyridinium cross-couplings, mechanistic studies support an alkyl radical intermediate.

Full text of DOI:10.1021/acs.orglett.9b03899

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Engaging Alkenes and Alkynes in Deaminative Alkyl−Alkyl and
Alkyl−Vinyl Cross-Couplings of Alkylpyridinium Salts
Kristen M. Baker, Diana Lucas Baca, Shane Plunkett, Mitchell E. Daneker, and Mary P. Watson*
Department of Chemistry & Biochemistry, University of Delaware, Newark, Delaware 19716, United States
S
* Supporting Information
ABSTRACT: An alkyl−alkyl cross-coupling of Katritzky
alkylpyridinium salts and organoboranes, formed in situ via
hydroboration of alkenes, has been developed. This method
utilizes the abundance of both alkyl amine precursors and
alkenes to form C(sp3)−C(sp3) bonds. This strategy is also
effective with alkynes, enabling a C(sp3)−C(sp2) cross-
coupling. Under these mild conditions, a broad range of
functional groups, including protic groups, is tolerated. As
seen with previous alkylpyridinium cross-couplings, mecha-
nistic studies support an alkyl radical intermediate.
Scheme 1. Deaminative Alkyl−Alkyl Couplings
lkyl amines are inexpensive and widely abundant
feedstock chemicals, making them ideal precursors for
A
further functionalization.1 The amino group is also present in
many advanced intermediates and products, enabling oppor-
tunities for late-stage derivatization.1,2 Although reactions of
both simple and complex alkyl amines have classically centered
on the preparation of nitrogen-containing products, deami-
native reactions via C−N bond activation of Katritzky
pyridinium salts 3 have emerged as useful transformations of
the highly versatile amino functional group.3 Specifically, we
and others have developed arylations,4 vinylations,5 alkynyla-
tions,6 allylations,7 and borylations8 of pyridinium salts.
However, deaminative alkylation of pyridinium salts to form
C(sp3)−C(sp3) bonds remains limited, despite the potential of
such reactions as a powerful, albeit noncanonical, disconnec-
tion in synthesis, particularly if both starting materials can arise
from ubiquitous substrate classes. Toward such a deaminative
alkylation, we reported a Negishi alkylation of alkylpyridinium
salts (Scheme 1A).9 Although this cross-coupling tolerated
primary and secondary alkylpyridinium salts and a range of
functional groups, the harsh conditions prevented the use of
benzylic pyridinium salts and base-sensitive functional groups.
Han, Wang, Yan, and co-workers recently reported several
examples of reductive alkylation, but these were limited to
forging C−C bonds between primary alkyl groups.4g We thus
pursued the use of an alternative, milder nucleophilic partner
to provide broad scope in both primary and secondary
alkylpyridiniums, as well as excellent functional group
tolerance. In particular, we envisioned that the use of
alkylboranes, generated in situ via hydroboration of simple
alkenes, would fulfill our requirement for mild, neutral
conditions and also enable the use of abundant alkenes as
starting materials.10
catalytic generation of alkyl radicals, which were subsequently
trapped with either styrenes or electron-poor alkenes (Scheme
1A).11,12 However, these reactions are limited to activated
alkenes as well as activated alkyl groups on the pyridinium salt
for Glorius’s three-component coupling. While this paper was
in preparation, Martin et al. published a cross-coupling of
alkylpyridinium salts with alkenes, reduced in situ with a
silane.13 Herein, we report our development of an alkyl−alkyl
cross-coupling of alkylpyridinium salts with alkenes, including
Other groups have also utilized alkenes in alkylations of
alkylpyridinium salts. Glorius and Aggarwal reported photo-
Received: October 31, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03899
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
unactivated examples, via in situ formation of organoboranes.
These conditions also enable vinylation when alkyne starting
materials are used.
could be decreased without lowering the yield (entry 6).
Considering the sensitivity of the yield to the fluoride activator,
we hypothesized that efficient formation of the boronate via
fluoride coordination to the organoborane was critical. To
promote formation of this intermediate, KF was added in the
hydroboration step; by combining (9-BBN)2, alkene, and KF
at 60 °C before the addition of the other reagents, we
increased the yield to 95% (entry 7). Control experiments
showed the importance of this preligation and the need for
both nickel and base in this reaction (entries 8−10).
We selected the reaction of pyridinium salt 3a and
commercially available acrolein acetal for our initial studies.
We used (9-BBN) as our hydroboration agent based on its
high hydroboration regioselectivities and precedent in the use
of this type of alkylborane in other cross-couplings.10,14 Our
initial studies focused on examining both ligand and base in the
cross-coupling of pyridinium 3a and preformed alkylborane
using high-throughput experimentation (HTE) techniques
(scale: 8.3 μmol pyridinium 3a). We used a combination of
Ni(acac)2 and Ni(cod)2 to ensure successful in situ formation
of Ni(I).15 Among the 36 ligands examined, 2,6-bis(pyrazol-1-
yl)pyridine (1-bpp) provided the best yield of desired product
6.16 In addition, we found that only KF provided product of
the eight activating agents tested. Using 1-bpp and KF,
quantitative yield of 6 was observed on the HTE scale. When
we applied these conditions to a 0.1 mmol scale experiment;
however, only 16% yield was observed (Table 1, entry 1).
Under these optimized conditions, a variety of both primary
and secondary alkylpyridinium salts were successfully alkylated
(Scheme 2). Notably, although benzylic pyridinium salts failed
a
Scheme 2. Scope of Alkyl−Alkyl Coupling
a
Table 1. Optimization
b
entry
1
[Ni]
base
yield (%)
Ni(cod)2/Ni(acac)2
NiCl2·DME
NiCl2·DME
Ni(acac)2
Ni(acac)2
Ni(acac)2
KF
KF
KF
KF
CsF
KF
KF
KF
KF
none
16
12
55
67
30
68
95
81
7
cd
2
3
4
5
6
7
8
9
de
de
d
def
defg
Ni(acac)2
Ni(acac)2
efg
, ,
efg
None
efg
h
10
Ni(acac)2
n.d.
a
Conditions: alkene (3.0 equiv) and 9-BBN (0.5 M in THF, 3.0
equiv), then pyridinium salt 3a (0.10 mmol, 1.0 equiv), [Ni] (10 mol
%), ligand (12 mol %), KF (3.3 equiv), 3:2 THF:MeCN (0.1 M), 60
b
1
°C, 24 h, unless noted otherwise. Determined by H NMR using
c
1,3,5-trimethoxybenzene as internal standard. KF oven-dried.
Nickel and 1-bpp stirred for 15 min in MeCN before addition to
other reagents. KF spray-dried, oven-dried, and sieved. 9-BBN (0.5
M in THF, 2.5 equiv), alkene (2.5 equiv), KF (2.5 equiv), 1:1
THF:MeCN (0.1 M). 9-BBN, KF, and alkene heated at 60 °C for 30
min before addition of other reagents. n.d. = not detected.
d
e
f
a
g
Conditions: alkene (2.5 equiv), 9-BBN (0.5 M in THF, 2.5 equiv),
h
KF (2.75 equiv), then pyridinium salt 3 (1.0 mmol, 1.0 equiv), [Ni]
(10 mol %), 1-bpp (12 mol %), MeCN (0.5 mL), 80 °C, 24 h.
Average isolated yield of duplicate experiments ( 4%).
Under these conditions, we found that the use of air-stable
NiCl2·DME provided a comparable, albeit low, yield (entry 2)
and thus switched to this simpler catalyst system to determine
why yields were inconsistent between the HTE and 0.1 mmol
scale reactions. In our HTE campaign, we used spray-dried and
carefully sieved KF but had used only oven-dried KF in the 0.1
mmol experiments. By switching to spray-dried and sieved KF
on the 0.1 mmol scale, yield increased substantially (entry 3).
With Ni(acac)2, an even higher yield of 67% was observed
(entry 4). Notably, other fluoride sources, such as CsF,
resulted in a significant drop in yield (entry 5). Under these
conditions, the equivalents of (9-BBN)2, alkene, and base
under our previous, more basic Negishi alkylation conditions,9
benzylic pyridinium salts (11−13), worked under these
conditions.17 This method also shows high tolerance for a
variety of functional groups on the pyridinium salt, including
acetals (7), protected amines (8), esters (10), ethers (6, 14−
19, 22, 24, 25), tertiary amines (25), and aryl fluorides (25).
These examples include base-sensitive substrates, such as the
pyridinium salt of a β-amino ester (10). Our previous Negishi
coupling failed for these types of substrates.9 Pyridinium salts
containing a range of heterocycles also underwent alkylation in
B
DOI: 10.1021/acs.orglett.9b03899
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
good yields: azetidines (8), pyridines (9), pyrimidines (12),
pyrroles (13), pyrans (6, 14−19), and morpholines (25). With
a diastereomerically pure pyridinium salt prepared from
cyclohexane amino ether (22), a 1:1 ratio of diastereomeric
products was isolated, consistent with a radical intermediate.
With a more constrained system (23), a single diastereomer of
product was isolated. To highlight the utility of this method for
late-stage functionalization of amines, pharmaceutical inter-
mediates and natural products were investigated. Both
pinanamine and mexilitine were successfully alkylated (23,
24).18 Alkylation of the pyridinium salt derived from an amine
intermediate in the Mosapride synthesis also worked well
(25).19
formation of an alkyl radical, TEMPO adduct 31 is observed
upon addition of TEMPO and cyclopropane 3q underwent
ring-opening (Scheme 4).
Scheme 4. Mechanistic Studies
On the alkene side, broad functional group tolerance was
also observed, including acetals (6−13, 20, 22−25), ethers
(18, 21), and aryl fluorides (17) (Scheme 2). Notably,
unprotected alcohols (19) are even tolerated, highlighting the
mild conditions and representing a significant advance over our
previous Negishi conditions.9 In addition to aliphatic alkenes,
styrenes can also be used in this chemistry (15, 21). We were
also pleased to find that allylic arenes can serve as the alkene
partner (17, 18); alkene isomerization did not pose a major
problem. Unfortunately, however, 1,1- and 1,2-disubstituted
alkenes were not effective in this reaction.
While investigating the scope of this alkylation method, we
were also intrigued by the possibility of starting with a simple
alkyne. We have previously reported the vinylation of benzylic
pyridinium salts with vinyl boronic acids,5a and installation of
styrenyl groups can also be accomplished with boronic acids or
via a Heck-type reaction.5b−d Excitingly, our hydroboration/
cross-coupling conditions can be applied to alkyne substrates,
providing a vinylated product. The functional group tolerance
includes ethers (26−29), aryl bromides (27), nitriles (28), and
phthalimides (29) (Scheme 3). Notably, this vinylation is
successful with nonbenzylic pyridinium salts and can install
nonstyrenyl vinyl groups (30), complementing the methods
previously developed.
In summary, we have developed a nickel-catalyzed alkyl−
alkyl cross-coupling of alkylpyridinium salts with alkenes, via
organoborane intermediates. This method harnesses ubiqui-
tous functional groups (amines and alkenes) in both partners,
and it is successful even with unactivated alkenes. In addition,
this method can also be applied to alkynes to effectively
provide the vinylation of unactivated pyridinium salts. Broad
functional group tolerance, including benzylic pyridinium salts
and protic functional groups, is seen with both of these
methods.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b03899.
Experimental details and NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mpwatson@udel.edu.
ORCID
a
Scheme 3. Vinylation Scope
Mary P. Watson: 0000-0002-1879-5257
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank NIH (R01 GM111820, R35 GM131816) and
University of Delaware for a Bigelow Summer Scholars
Fellowship (M.E.D.). We thank Olivia Bercher (UD) for
providing several pyridinium salts. 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).
a
Conditions: alkene (2.5 equiv), 9-BBN (0.5 M in THF, 2.5 equiv),
KF (2.75 equiv), then pyridinium salt 3 (1.0 mmol, 1.0 equiv), [Ni]
(10 mol %), 1-bpp (12 mol %), MeCN (0.5 mL), 80 °C, 24 h.
REFERENCES
■
(1) (a) Lawrence, S. A. Amines: Synthesis, Properties and Applications;
Cambridge University Press: New York, 2004. (b) Nugent, T. C.
Chiral Amine Synthesis; Wiley-VCH Verlag GmbH & Co. KGaA:
Weinheim, 2010.
(2) (a) Ruiz-Castillo, P.; Buchwald, S. L. Applications of Palladium-
Catalyzed C−N Cross-Coupling Reactions. Chem. Rev. 2016, 116
(19), 12564−12649. (b) McGrath, N. A.; Brichacek, M.; Njardarson,
J. T. A Graphical Journey of Innovative Organic Architectures That
Similar to previously developed pyridinium cross-cou-
plings,3d,4a we propose that this reaction proceeds through a
single-electron transfer (SET) from a Ni(0) or Ni(I)
intermediate to the alkylpyridinium salt. Fragmentation of
the neutral pyridyl radical gives an alkyl radical, which can
recombine with a Ni(I) or Ni(II) intermediate to provide the
product after reductive elimination. Consistent with the
C
DOI: 10.1021/acs.orglett.9b03899
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Have Improved Our Lives. J. Chem. Educ. 2010, 87 (12), 1348−1349.
(c) Liu, Y.; Ge, H. Site-selective C−H arylation of primary aliphatic
amines enabled by a catalytic transient directing group. Nat. Chem.
2017, 9 (1), 26−32.
Photoinduced Deaminative Borylation of Alkylamines. J. Am. Chem.
Soc. 2018, 140 (34), 10700−10704.
(9) Plunkett, S.; Basch, C. H.; Santana, S. O.; Watson, M. P.
Harnessing Alkyl Pyridinium Salts as Electrophiles in De-aminative
Alkyl-Alkyl Cross-Couplings. J. Am. Chem. Soc. 2019, 141 (6), 2257−
2262.
(10) Brown, H. C.; Chen, J. Hydroboration. 57. Hydroboration with
9-borabicyclo[3.3.1]nonane of alkenes containing representative
functional groups. J. Org. Chem. 1981, 46 (20), 3978−3988.
(11) Klauck, F. J. R.; Yoon, H.; James, M. J.; Lautens, M.; Glorius, F.
Visible-Light-Mediated Deaminative Three-Component Dicarbofunc-
tionalization of Styrenes with Benzylic Radicals. ACS Catal. 2019, 9
(1), 236−241.
(12) Wu, J.; Grant, P. S.; Li, X.; Noble, A.; Aggarwal, V. K. Catalyst-
Free Deaminative Functionalizations of Primary Amines by Photo-
induced Single-Electron Transfer. Angew. Chem., Int. Ed. 2019, 58
(17), 5697−5701.
(13) Sun, S. Z.; Romano, C.; Martin, R. Site-Selective Catalytic
Deaminative Alkylation of Unactivated Olefins. J. Am. Chem. Soc.
2019, 141 (41), 16197−16201.
(3) (a) Bapat, J.B.; Blade, R.J.; Boulton, A.J.; Epsztajn, J.; Katritzky,
A.R.; Lewis, J.; Molina-Buendia, P.; Nie, P.-L.; Ramsden, C.A.
Pyridines as Leaving Groups in Synthetic Transformations:
Nucleophilic Displacements of Amino Groups, and Novel Prepara-
tions of Nitriles and Isocyanates. Tetrahedron Lett. 1976, 17, 2691−
2694. (b) Katritzky, A. R.; Marson, C. M. Pyrylium Mediated
Transformations of Primary Amino Groups into Other Functional
Groups. Angew. Chem., Int. Ed. Engl. 1984, 23, 420−429. (c) Sowmiah,
S.; Esperanca̧ , J. M. S. S.; Rebelo, L. P. N.; Afonso, C. A. M.
Pyridinium salts: from synthesis to reactivity and applications. Org.
Chem. Front. 2018, 5, 453−493. (d) Kong, D.; Moon, P. J.; Lundgren,
R. J. Radical Coupling from Alkyl Amines. Nat. Catal. 2019, 2, 473−
476.
(4) (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
(15), 5313−5316. (b) Liao, J.; Guan, W.; Boscoe, B. P.; Tucker, J. W.;
Tomlin, J. W.; Garnsey, M. R.; Watson, M. P. Transforming Benzylic
Amines into Diarylmethanes: Cross-Couplings of Benzylic Pyridinium
Salts via C−N Bond Activation. Org. Lett. 2018, 20 (10), 3030−3033.
(c) Hoerrner, M. E.; Baker, K. M.; Basch, C. H.; Bampo, E. M.;
Watson, M. P. Deaminative Arylation of Amino Acid-derived
Pyridinium Salts. Org. Lett. 2019, 21 (18), 7356−7360. (d) Klauck,
F. J. R.; James, M. J.; Glorius, F. Deaminative Strategy for the Visible-
Light-Mediated Generation of Alkyl Radicals. Angew. Chem., Int. Ed.
2017, 56 (40), 12336−12339. (e) James, M. J.; Strieth-Kalthoff, F.;
Sandfort, F.; Klauck, F. J. R.; Wagener, F.; Glorius, F. Visible-Light-
Mediated Charge Transfer Enables C−C Bond Formation with
Traceless Acceptor Groups. Chem. - Eur. J. 2019, 25 (35), 8240−
8244. (f) See also: Martin-Montero, R.; Yatham, V. R.; Yin, H.;
Davies, J.; Martin, R. Ni-catalyzed Reductive Deaminative Arylation at
sp(3) Carbon Centers. Org. Lett. 2019, 21 (8), 2947−2951. (g) 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, eaaw9516.
(h) Yi, J.; Badir, S. O.; Kammer, L. M.; Ribagorda, M.; Molander, G.
A. Deaminative Reductive Arylation Enabled by Nickel/Photoredox
Dual Catalysis. Org. Lett. 2019, 21 (9), 3346−3351. (i) 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. (j) Zhu, Z.-F.; Zhang, M.-M.; Liu, F. Radical alkylation
of isocyanides with amino acid-/peptide-derived Katritzky salts via
photoredox catalysis. Org. Biomol. Chem. 2019, 17 (6), 1531−1534.
(5) (a) Guan, W.; Liao, J.; Watson, M. P. Vinylation of Benzylic
Amines via C−N Bond Functionalization of Benzylic Pyridinium
Salts. Synthesis 2018, 50 (16), 3231−3237. (b) Jiang, X.; Zhang, M.
M.; Xiong, W.; Lu, L. Q.; Xiao, W. J. Deaminative (Carbonylative)
Alkyl-Heck-type Reactions Enabled by Photocatalytic C-N Bond
Activation. Angew. Chem., Int. Ed. 2019, 58 (8), 2402−2406. (c) Yang,
Z.-K.; Xu, N.-X.; Wang, C.; Uchiyama, M. Photoinduced C(sp3)−N
Bond Cleavage Leading to the Stereoselective Syntheses of Alkenes.
Chem. - Eur. J. 2019, 25 (21), 5433−5439. (d) Hu, J.; Cheng, B.;
Yang, X.; Loh, T. P. Transition-Metal-Free Deaminative Vinylation of
Alkylamines. Adv. Synth. Catal. 2019, 361, 4902.
(14) (a) Ishiyama, T.; Abe, S.; Miyaura, N.; Suzuki, A. Palladium-
Catalyzed Alkyl-Alkyl Cross-Coupling Reaction of 9-Alkyl-9-BBN
Derivatives with Iodoalkanes Possessing β-Hydrogens. Chem. Lett.
1992, 21 (4), 691−694. (b) Choi, J.; Fu, G. C. Transition metal-
catalyzed alkyl-alkyl bond formation: Another dimension in cross-
coupling chemistry. Science 2017, 356 (6334), eaaf7230.
(15) Arendt, K. M.; Doyle, A. G. Dialkyl Ether Formation by Nickel-
Catalyzed Cross-Coupling of Acetals and Aryl Iodides. Angew. Chem.,
Int. Ed. 2015, 54 (34), 9876−9880.
(16) See the Supporting Information.
(17) Only primary benzylic pyridinium salts can be prepared
effectively; secondary benzylic pyridinium salts decompose upon
synthesis. See ref 4b.
(18) Koppe, H.; Zeile, K.; Kummer, W.; Stahle, H.; Danneberg, P. 1-
(2′,6′-Dimethyl-phenoxy)-2-amino-alkanes and salts thereof. U.S.
Patent US3954872A, 1976.
(19) Kato, S.; Morie, T.; Yoshida, N. Synthesis and Biological
Activities of Metabolites of Mosapride, a New Gastroprokinetic
Agent. Chem. Pharm. Bull. 1995, 43 (4), 699−702.
(6) Ociepa, M.; Turkowska, J.; Gryko, D. Redox-Activated Amines
in C(sp3)−C(sp) and C(sp3)−C(sp2) Bond Formation Enabled by
Metal-Free Photoredox Catalysis. ACS Catal. 2018, 8 (12), 11362−
11367.
(7) Zhang, M.-M.; Liu, F. Visible-light-mediated allylation of alkyl
radicals with allylic sulfones via a deaminative strategy. Org. Chem.
Front. 2018, 5 (23), 3443−3446.
(8) (a) Hu, J.; Wang, G.; Li, S.; Shi, Z. Selective C−N Borylation of
Alkyl Amines Promoted by Lewis Base. Angew. Chem., Int. Ed. 2018,
57 (46), 15227−15231. (b) Wu, J.; He, L.; Noble, A.; Aggarwal, V. K.
D
DOI: 10.1021/acs.orglett.9b03899
Org. Lett. XXXX, XXX, XXX−XXX