Cobalt-Catalyzed Intermolecular Markovnikov Hydroamination of Nonactivated Olefins: N2-Selective Alkylation of Benzotriazole

Article abstract of DOI:10.1021/acs.orglett.9b04375

Cobalt-catalyzed Markovnikov-selective hydroamination of nonactivated olefins was developed. Hydrogen atom transfer from a catalytically generated cobalt(III)-hydride complex to the olefins proceeded regioselectively, and the nucleophilic addition of benzotriazoles occurred selectively at their N²-positions. The synthetic utility of the obtained N²-alkylated benzotriazoles as stable amine protecting groups under various reaction conditions was demonstrated, and the products were also transformed into primary amines by zinc-mediated reduction.

Full text of DOI:10.1021/acs.orglett.9b04375

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Cobalt-Catalyzed Intermolecular Markovnikov Hydroamination of
Nonactivated Olefins: N2‑Selective Alkylation of Benzotriazole
Kenzo Yahata,* Yuki Kaneko, and Shuji Akai*
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan
S
* Supporting Information
ABSTRACT: Cobalt-catalyzed Markovnikov-selective hydroamination of non-
activated olefins was developed. Hydrogen atom transfer from a catalytically
generated cobalt(III)−hydride complex to the olefins proceeded regioselec-
tively, and the nucleophilic addition of benzotriazoles occurred selectively at
their N2-positions. The synthetic utility of the obtained N2-alkylated
benzotriazoles as stable amine protecting groups under various reaction
conditions was demonstrated, and the products were also transformed into
primary amines by zinc-mediated reduction.
mines are one of the most important and ubiquitous
suffer from several problems, such as side reactions via olefin
Afunctional groups found in a wide range of molecules, isomerization7b,d and/or scope limitations to sulfonamide and
imidazolidinone nucleophiles, which frequently engender
difficulties during deprotection of the HA products.8
such as natural products, medicines, and materials. The
intermolecular hydroamination (HA) reaction of olefins is a
challenging but attractive method for the regioselective
introduction of amines because of its high atom economy
and the high abundance of olefins. Although various HA
reactions have been developed to date, most reports are limited
to the use of allylamines, styrenes, dienes, acrylic acid
derivatives, or strained olefins,1 and the HA of simple
nonactivated olefins remains underdeveloped. Miura and
Buchwald independently reported copper-catalyzed HA
reactions, and their asymmetric versions were also developed
with excellent enantioselectivity.2 While these copper-mediated
reactions give anti-Markovnikov adducts for nonactivated
olefins, the Markovnikov adduct is the major product for
activated olefin substrates, such as styrenes. Nicewicz has
reported an organophotoredox-catalysis-mediated anti-Mar-
kovnikov HA reaction.3 The anti-Markovnikov HA has also
been accomplished by the addition of N-centered radicals to
alkenes by Knowles, Schmidt, and Xu.4 Compared with the
anti-Markovnikov HA reaction, Markovnikov HA is less
developed, and the available amination reagents for this
purpose are still limited. Carreira developed a cobalt-catalyzed
Markovnikov HA reaction of nonactivated olefins.5 In these
reactions, alkyl radical intermediates, which are generated
regioselectively with hydrogen atom transfer (HAT) from the
cobalt hydride complex to the olefins, react with radicalophilic
amination reagents, azodicarboxylate esters or tosyl azide, to
form the Markovnikov HA products. Recently, Zhu reported a
cobalt-catalyzed Markovnikov HA reaction of nonactivated
olefins with tosylimide wherein a bimetallic coupling
mechanism between the alkylcobalt and cobalt-nucleophile
complex was proposed. However, only two examples were
demonstrated in that study.6 Markovnikov HA reactions
involving nucleophilic amination have also been developed
by using Brønsted acids or π acids.7 However, these reactions
We speculated that a nucleophilic amination with benzo-
triazole (BT) from its N2-position would widen the utility of
the Markovnikov HA reaction because of the facile cleavage of
the relatively weak N−N single bonds in the formed iso-BT
products to deliver the free primary amines.9 Furthermore, N-
alkylated BTs are widely found in synthetic chemistry,
coordination chemistry, and pharmaceutical and materials
science (Figure 1).10,11 Alkylation of BTs is one of the most
straightforward routes to access N2-substituted BTs. However,
N2-selective alkylation is challenging because of the decreased
aromaticity in the formed products.12 In addition, most trials
of BT alkylation typically result in nonselective or N1-selective
alkylation,13,14 and few solutions for this problem have been
reported to date.15 In 2011, Kitamura reported an N2-selective
Figure 1. Selected applications of N2-alkylated benzotriazoles.
Received: December 6, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b04375
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
alkynylation using alkynyl hypervalent iodine reagents,
although the N1/N2 selectivity was moderate.15a Breit reported
rhodium-catalyzed N2-selective alkylation of BTs with allenes
in 2014,15b and in 2018 Zhang and Sun reported a rhodium
mediated N2-selective alkylation of BTs with diazo compounds
and enynones.15c Recently, Zhu and Wang revealed that the
NIS-mediated β-iodoalkylation of olefins with BTs proceeds
selectively at the N2-position. However, the regioselectivity at
the olefinic carbons and at N1/N2 was lower for nonactivated
olefin substrates.15d Despite these advances in N2 selectivity,
the alkylation of BTs still requires further improvements. The
developed methodologies described above require activated
coupling partners, such as iodonium salts, allenes, diazo
compounds, enynones, and styrenes, to ensure reactivity and
regioselectivity at the desired nitrogen position on the BTs and
the required carbon position on the alkylating groups (e.g.,
allenes and styrenes).
We report herein a Markovnikov-selective HA reaction of
nonactivated olefins with BTs that aims to expand the reaction
to include simple unactivated olefins. This reaction provides
excellent chemo- and N2 selectivity on a variety of BTs. The
key advantage of this method lies in the use of the BT moiety
in the product as an amine protecting group, which can be
easily transformed into the free amino group via zinc-mediated
reduction.
We began the study with the HA reaction between 4-
phenylbutene (1a) and benzotriazole (2a). After screening
several combinations of reagents, we found that the
appropriate choice of solvent, silane, oxidant, and cobalt
complex is crucial to obtain optimal results (Table 1).16,17
Among the solvents tested, only toluene and CPME gave
satisfactory yields of 57% and 51%, respectively (entries 4 and
5). The use of hydrosilane reagents other than PhSiH3
decreased both the yield and the selectivity (entries 6 and
7). Also, changing 1-fluoro-2,4,6-trimethylpyridinium tetra-
fluoroborate (TMFP-BF4) to TMFP-OTf or FP-BF4 dramat-
ically decreased the yield (entries 8 and 9). Although a
reduction in the amount of TMFP-BF4 did not affect the result,
dilution improved the yield slightly (entry 10). Aiming for
further improvement of the yield, we screened several cobalt
complexes (entries 11−15) and found that Co6, which has the
( )-1,2-diphenylethylenediamine backbone, is the best catalyst
for this reaction (entry 15). Finally, lowering the reaction
temperature to 0 °C improved the yield (entry 16).
With the optimized conditions in hand, we explored the
substrate scope of this HA reaction (Scheme 1). The
developed reaction displayed high chemoselectivity. The
presence of bromo and ester groups did not affect the yield
(3b and 3c). Furthermore, a wide range of hydroxyl protecting
groups, such as Bn, MOM, Ac, TBS, and TBDPS groups, were
tolerated under the reaction conditions (3d−h). Allyltrime-
thylsilane was also suitable for the developed reaction
conditions (3j). Importantly, the HA reaction proceeded
with remarkable Markovnikov selectivity and excellent N2
selectivity. Internal olefins were also applicable to the method,
although the yields were moderate (3k−n). BTs bearing
functional groups such as methyl, chloro, and ester were also
alkylated at the N2-position selectively to furnish the HA
products in high yields (3o−q). Interestingly, when
triazolopyridine was used instead of a BT, the N2-alkylated
product 3r was isolated in 42% yield along with a significant
amount of the N3-alkylated product 3r′. However, the N1-
alkylated product was not observed.
Table 1. Optimization of Intermolecular Hydroamination
yield
c
b
entry
solvent
Co
silane
oxidant
N1:N2
(%)
1
2
3
4
5
6
7
8
9
MeCN
CH2Cl2
THF
Co1
Co1
Co1
Co1
Co1
Co1
Co1
Co1
Co1
Co1
Co2
Co3
Co4
Co5
Co6
Co6
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
Ph2SiH2
TMDS
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
TMFP-BF4
TMFP-BF4
TMFP-BF4
TMPF-BF4
TMFP-BF4
TMFP-BF4
TMFP-BF4
TMFP-OTf
FP-BF4
TMFP-BF4
TMFP-BF4
TMFP-BF4
TMFP-BF4
TMFP-BF4
TMFP-BF4
TMFP-BF4
65:35
35:65
1
5
8:92 12
4:96 51
11:89 57
49:51 22
62:38 37
14:86
<1:99
5:95 65
20:80 37
7:93 38
CPME
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
7
1
d
10
11
12
13
14
15
16
d
d
d
24:76
−
2:98 84
9
0
d
d
de
,
2:98 98 (76)
a
Reaction conditions: 2a (1 equiv), 1a (2 equiv), Co cat. (20 mol %),
silane (4 equiv), oxidant (4 equiv), solvent (0.04 M), rt, 24 h.
Determined by GC. GC yields. Isolated yield in parentheses.
b
c
d
e
Oxidant (2 equiv) with toluene (0.01 M) was used. At 0 °C.
To demonstrate the synthetic utility of the N2-alkylated HA
products, we examined further transformations of the obtained
iso-BTs. First, we investigated the reduction of the N−N single
bonds to produce primary amines. Although palladium-
catalyzed hydrogenation of an iso-BT has been reported, this
approach did not furnish any desired product, and hydro-
genation proceeded exclusively on the cyclohexadiene moiety.
To our delight, the desired primary amine was obtained by
zinc-mediated reduction in acidic media (Table 2). The
reduction proceeded smoothly in high yields on various iso-
BTs, including substrates carrying Bn or TBDPS ethers
(entries 2 and 3). Iso-BT 3n derived from indene was also
reduced to benzylic amine 4e (entry 5). Furthermore, iso-BTs
bearing chloride and ester groups on the BT skeleton were also
reduced to amine 4a (entries 6 and 7).
We also subjected the iso-BT products to other reaction
conditions to gain insight into their chemical behavior
(Scheme 2). The product 3a was almost quantitatively
recovered after treatment with acidic or basic conditions
over 3 days (Scheme 2a,b). The iso-BT structure was also
found to be stable toward LiBH4 reduction and Grignard
alkylation conditions (Scheme 2c,d). Selective deprotection of
the TBDPS group with TBAF was also possible (Scheme 2e).
On the basis of the above experiments, the N2-alkylated BT
moiety can be regarded as a protected primary amine, which
B
DOI: 10.1021/acs.orglett.9b04375
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Substrate Scope
Table 2. Transformation of Isobenzotriazoles into Primary
Amines
a
Method A: Zn (10 w/w), conc. HCl(aq)/EtOH (1:2, 0.02 M),
reflux, overnight. Method B: Zn (10 w/w), AcOH (0.02 M), reflux,
overnight. The generated amines were isolated after Boc protection
with Boc2O (4 equiv) and Et3N (5 equiv) in CH2Cl2 (0.08 M) at rt.
b
Yields are of isolated N-Boc products.
Scheme 2. Chemical Properties of the Isobenzotriazoles
a
All yields are of isolated N2-alkylated products. N1/N2 ratios were
determined with GC. Unless otherwise noted, all reactions were
carried out with 2 (0.15 mmol, 1 equiv), 1 (2 equiv), Co6 (20 mol
%), PhSiH3 (4 equiv), and TMFP-BF4 (2 equiv) in toluene (0.01 M)
b
c
at 0 °C for 24 h. 2a (1.0 mmol) was used. 2a (2.0 mmol) with
toluene (0.04 M) was used. 2a (0.068 mmol) was used. 1 (4 equiv)
and PhSiH3 (8 equiv) were used. 5,6-Dimethylbenzotriazole
d
e
f
monohydrate was used at rt.
can tolerate a broad range of pH and nucleophiles and can be
deprotected under mild conditions.
During the optimization, we observed that changing the
silane reagent resulted in a different N1/N2 ratio (Table 1,
entries 5−7). We conducted control experiments to under-
stand the role of the silane in this reaction (Scheme 3a) by
using 1-(trimethylsilyl)-1H-benzotriazole (2b) with two differ-
ent silanes, PhSiH3 and Ph2SiH2. In the case of PhSiH3, the
yield and the ratio were similar to those of entry 5 in Table 1,
while the use of Ph2SiH2 dramatically changed the ratio from
49:51 to 6:94 (Table 1, entry 6). These results suggest the
intermediacy of a silylated BT in the reaction pathway,
although the reason for the differences in the ratios with
different silyl groups is not clear. We also tested the
nonracemic cobalt complexes (R,R)-Co1 and (R,R)-Co6
(Scheme 3b) to explore asymmetric induction. Although the
enantioselectivities with both catalysts were poor, slight
asymmetric inductions were observed. These results suggest
that the cobalt catalyst interacts with the substrate during the
C−N bond formation and that the reaction does not proceed
via free radical or achiral cation intermediates. We next tried
alkylation of benzotriazoles 2a and 2b using Carreira’s cobalt-
catalyzed hydroamination conditions5e and observed no
alkylated benzotriazole product (Scheme 3c). Furthermore,
C
DOI: 10.1021/acs.orglett.9b04375
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Control Experiments Using (a) 1-
(Trimethylsilyl)benzotriazole, (b) Nonracemic Cobalt
Complexes, (c) Carreira’s Conditions, and (d) Radical
Conditions
Scheme 4. Proposed Reaction Mechanism
nucleophiles and can be deprotected under mild zinc-mediated
reduction conditions. The development of the asymmetric
version of this reaction is currently underway in our research
group.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04375.
AIBN-assisted radical reaction between benzotriazoles and
alkyl bromide 6 also did not afford any coupling product
(Scheme 3d). These results eliminate the possibility of the
reaction between benzotriazoles and alkyl radicals or
alkylcobalt(III) intermediates.
All experimental procedures, analytical data, and copies
1
of H and 13C NMR spectra of all newly synthesized
products (PDF)
On the basis of the experiments shown in Scheme 3, we
propose the reaction mechanism depicted in Scheme 4. First,
cobalt(III)−fluoride intermediate B is produced by oxidation
of Co(II) species A with TMFP-BF4. This intermediate
undergoes transmetalation with PhSiH3 to generate cobalt-
(III)−hydride complex D. During these steps, cationic
cobalt(III) complex C and the silyl fluoride are also produced.
The silyl fluoride reacts with BT to generate silylated-BT G.
Co−H complex D reacts with the olefin substrates 1 through
the HAT mechanism to afford branched alkylcobalt(III)
intermediate E regioselectively. The cationic cobalt(III)
complex C generated earlier goes back to the cobalt(II)
catalytic cycle via oxidation of alkylcobalt(III) E to cationic
alkylcobalt(IV) complex F.18,19 Finally, an SN2-like displace-
ment of F with silylated-BT G takes place to give the
hydroamination product 3 and regenerate cobalt(II) catalyst A.
In conclusion, we have developed a Markovnikov-selective
intermolecular hydroamination reaction of nonactivated
olefins. The reaction proceeds with excellent regioselectivity
at the carbon position of the olefin and remarkable N2
selectivity on the benzotriazole. The mild conditions are
applicable to a wide range of substrates bearing various
functional groups, including TBS, Bn, Ac, bromo, ester, and so
on. We also demonstrated the synthetic utility of the N2-
alkylated benzotriazoles as protected amines. The isobenzo-
triazole moiety can tolerate a wide range of pH values and
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: yahata-k@phs.osaka-u.ac.jp.
*E-mail: akai@phs.osaka-u.ac.jp.
ORCID
Kenzo Yahata: 0000-0002-6991-9221
Shuji Akai: 0000-0001-9149-8745
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported in part by a JSPS Grant-in-Aid for
Young Scientists (Grant JP18K14868), the Teijin Pharma
Award in Synthetic Organic Chemistry Japan, a Grant-in-Aid
from the Tokyo Biochemical Research Foundation, the
Keihanshin Consortium for Fostering the Next Generation of
Global Leaders in Research (K-CONNEX), established by
Building of Consortia for the Development of Human
Resources in Science and Technology, MEXT, and the
Platform Project for Supporting Drug Discovery and Life
Science Research (Basis for Supporting Innovative Drug
Discovery and Life Science Research (BINDS)) from AMED
(Grant JP19am0101084).
D
DOI: 10.1021/acs.orglett.9b04375
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
1641. (g) Bandar, J. S.; Pirnot, M. T.; Buchwald, S. L. J. Am. Chem.
Soc. 2015, 137, 14812−14818. (h) Niu, D.; Buchwald, S. L. J. Am.
Chem. Soc. 2015, 137, 9716−9721. (i) Nishikawa, D.; Hirano, K.;
Miura, M. J. Am. Chem. Soc. 2015, 137, 15620−15623. (j) Yang, Y.;
Shi, S.-L.; Niu, D.; Liu, P.; Buchwald, S. L. Science 2015, 349, 62−66.
(k) Zhu, S.; Niljianskul, N.; Buchwald, S. L. Nat. Chem. 2016, 8, 144−
150. (l) Shi, S.-L.; Wong, Z. L.; Buchwald, S. L. Nature 2016, 532,
353−356. (m) Lu, G.; Liu, R. Y.; Yang, Y.; Fang, C.; Lambrecht, D.
S.; Buchwald, S. L.; Liu, P. J. Am. Chem. Soc. 2017, 139, 16548−
16555. (n) Ichikawa, S.; Zhu, S.; Buchwald, S. L. Angew. Chem., Int.
Ed. 2018, 57, 8714−8718. (o) Zhou, Y.; Engl, O. D.; Bandar, J. S.;
Chant, E. D.; Buchwald, S. L. Angew. Chem., Int. Ed. 2018, 57, 6672−
6675. (p) Takata, T.; Nishikawa, D.; Hirano, K.; Miura, M. Chem. -
Eur. J. 2018, 24, 10975−10978. (q) Takata, T.; Hirano, K.; Miura, M.
Org. Lett. 2019, 21, 4284−4288.
REFERENCES
■
(1) For selected reviews, see: (a) Mu
1998, 98, 675−703. (b) Mu
̈
ller, T. E.; Beller, M. Chem. Rev.
ller, T. E.; Hultzsch, K. C.; Yus, M.;
̈
Foubelo, F.; Tada, M. Chem. Rev. 2008, 108, 3795−3892. (c) Coman,
S. M.; Parvulescu, V. I. Org. Process Res. Dev. 2015, 19, 1327−1355.
(d) Huang, L.; Arndt, M.; Gooßen, K.; Heydt, H.; Gooßen, L. J.
Chem. Rev. 2015, 115, 2596−2697. For selected examples, see:
(e) Coulson, D. R. Tetrahedron Lett. 1971, 12, 429−430. (f) Parker,
K. A.; O’Fee, R. P. J. Org. Chem. 1983, 48, 1547−1550.
(g) Casalnuovo, A. L.; Calabrese, J. C.; Milstein, D. J. Am. Chem.
Soc. 1988, 110, 6738−6744. (h) Dorta, R.; Egli, P.; Zurcher, F.;
̈
Togni, A. J. Am. Chem. Soc. 1997, 119, 10857−10858. (i) Bell, K. E.;
Coogan, M. P.; Gravestock, M. B.; Knight, D. W.; Thornton, S. R.
Tetrahedron Lett. 1997, 38, 8545−8548. (j) Kawatsura, M.; Hartwig, J.
F. J. Am. Chem. Soc. 2000, 122, 9546−9547. (k) Gravestock, M. B.;
Knight, D. W.; Malik, K. M. A.; Thornton, S. R. J. Chem. Soc., Perkin
Trans. 2000, 1, 3292−3305. (l) Hartung, C. G.; Breindl, C.; Tillack,
(3) (a) Nguyen, T. M.; Nicewicz, D. A. J. Am. Chem. Soc. 2013, 135,
9588−9591. (b) Nguyen, T. M.; Manohar, N.; Nicewicz, D. A. Angew.
Chem., Int. Ed. 2014, 53, 6198−6201.
̈
A.; Beller, M. Tetrahedron 2000, 56, 5157−5162. (m) Lober, O.;
(4) (a) Musacchio, A. J.; Lainhart, B. C.; Zhang, X.; Naguib, S. G.;
Sherwood, T. C.; Knowles, R. R. Science 2017, 355, 727−730.
(b) Zhu, Q.; Graff, D. E.; Knowles, R. R. J. Am. Chem. Soc. 2018, 140,
741−747. (c) Lardy, S. W.; Schmidt, V. A. J. Am. Chem. Soc. 2018,
140, 12318−12322. (d) Miller, D. C.; Ganley, J. M.; Musacchio, A. J.;
Sherwood, T. C.; Ewing, W. R.; Knowles, R. R. J. Am. Chem. Soc.
2019, 141, 16590−16594. (e) Li, H.; Shen, S.-J.; Zhu, C.-L.; Xu, H. J.
Am. Chem. Soc. 2019, 141, 9415−9421.
Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 4366−
4367. (n) Kawatsura, M.; Hartwig, J. F. Organometallics 2001, 20,
1960−1964. (o) Pawlas, J.; Nakao, Y.; Kawatsura, M.; Hartwig, J. F. J.
Am. Chem. Soc. 2002, 124, 3669−3679. (p) Li, K.; Horton, P. N.;
Hursthouse, M. B.; Hii, K. K. J. Organomet. Chem. 2003, 665, 250−
257. (q) Utsunomiya, M.; Kuwano, R.; Kawatsura, M.; Hartwig, J. F. J.
Am. Chem. Soc. 2003, 125, 5608−5609. (r) Kemper, J.; Studer, A.
Angew. Chem., Int. Ed. 2005, 44, 4914−4917. (s) Anderson, L. L.;
Arnold, J.; Bergman, R. G. J. Am. Chem. Soc. 2005, 127, 14542−
14543. (t) Munro-Leighton, C.; Blue, E. D.; Gunnoe, T. B. J. Am.
Chem. Soc. 2006, 128, 1446−1447. (u) Hu, A.; Ogasawara, M.;
Sakamoto, T.; Okada, A.; Nakajima, K.; Takahashi, T.; Lin, W. Adv.
(5) (a) Waser, J.; Carreira, E. M. Angew. Chem., Int. Ed. 2004, 43,
4099−4102. (b) Waser, J.; Carreira, E. M. J. Am. Chem. Soc. 2004,
126, 5676−5677. (c) Waser, J.; Nambu, H.; Carreira, E. M. J. Am.
́
́
Chem. Soc. 2005, 127, 8294−8295. (d) Waser, J.; Gonzalez-Gomez, J.
C.; Nambu, H.; Huber, P.; Carreira, E. M. Org. Lett. 2005, 7, 4249−
4252. (e) Waser, J.; Gaspar, B.; Nambu, H.; Carreira, E. M. J. Am.
Chem. Soc. 2006, 128, 11693−11712.
́
Synth. Catal. 2006, 348, 2051−2056. (v) Marcsekova, K.; Doye, S.
Synthesis 2007, 2007, 145−154. (w) Beauchemin, A. M.; Moran, J.;
́
Lebrun, M.-E.; Seguin, C.; Dimitrijevic, E.; Zhang, L.; Gorelsky, S. I.
(6) Zhou, X.-L.; Yang, F.; Sun, H.-L.; Yin, Y.-N.; Ye, W.-T.; Zhu, R.
J. Am. Chem. Soc. 2019, 141, 7250−7255.
Angew. Chem., Int. Ed. 2008, 47, 1410−1413. (x) Zhou, J.; Hartwig, J.
F. J. Am. Chem. Soc. 2008, 130, 12220−12221. (y) MacDonald, M. J.;
Schipper, D. J.; Ng, P. J.; Moran, J.; Beauchemin, A. M. J. Am. Chem.
Soc. 2011, 133, 20100−20103. (z) Guimond, N.; MacDonald, M. J.;
Lemieux, V.; Beauchemin, A. M. J. Am. Chem. Soc. 2012, 134, 16571−
16577. (aa) Zhao, S.-B.; Bilodeau, E.; Lemieux, V.; Beauchemin, A.
M. Org. Lett. 2012, 14, 5082−5085. (ab) MacDonald, M. J.; Hesp, C.
R.; Schipper, D. J.; Pesant, M.; Beauchemin, A. M. Chem. - Eur. J.
2013, 19, 2597−2601. (ac) Germain, S.; Schulz, E.; Hannedouche, J.
ChemCatChem 2014, 6, 2065−2073. (ad) Ickes, A. R.; Ensign, S. C.;
Gupta, A. K.; Hull, K. L. J. Am. Chem. Soc. 2014, 136, 11256−11259.
(ae) Huehls, C. B.; Lin, A.; Yang, J. Org. Lett. 2014, 16, 3620−3623.
(af) Ensign, S. C.; Vanable, E. P.; Kortman, G. D.; Weir, L. J.; Hull, K.
L. J. Am. Chem. Soc. 2015, 137, 13748−13751. (ag) Hesp, C. R.;
MacDonald, M. J.; Zahedi, M. M.; Bilodeau, D. A.; Zhao, S.-B.;
Pesant, M.; Beauchemin, A. M. Org. Lett. 2015, 17, 5136−5139.
(ah) Yu, F.; Chen, P.; Liu, G. Org. Chem. Front. 2015, 2, 819−822.
(ai) Xi, Y.; Butcher, T. W.; Zhang, J.; Hartwig, J. F. Angew. Chem., Int.
Ed. 2016, 55, 776−780. (aj) Gurak, J. A., Jr.; Yang, K. S.; Liu, Z.;
Engle, K. M. J. Am. Chem. Soc. 2016, 138, 5805−5808. (ak) Blieck, R.;
Bahri, J.; Taillefer, M.; Monnier, F. Org. Lett. 2016, 18, 1482−1485.
(al) Park, S.; Malcolmson, S. J. ACS Catal. 2018, 8, 8468−8476.
(am) Luo, X.; Wang, S.; Xi, C. Org. Chem. Front. 2018, 5, 1184−1187.
(an) Park, S.; Kang, S.; Lee, Y. Adv. Synth. Catal. 2019, 361, 1071−
(7) (a) Karshtedt, D.; Bell, A. T.; Tilley, T. D. J. Am. Chem. Soc.
2005, 127, 12640−12646. (b) Zhang, J.; Yang, C.-G.; He, C. J. Am.
Chem. Soc. 2006, 128, 1798−1799. (c) Liu, X.-Y.; Li, C.-H.; Che, C.-
M. Org. Lett. 2006, 8, 2707−2710. (d) Rosenfeld, D. C.; Shekhar, S.;
Takemiya, A.; Utsunomiya, M.; Hartwig, J. F. Org. Lett. 2006, 8,
4179−4182. (e) Li, Z.; Zhang, J.; Brouwer, C.; Yang, C.-G.; Reich, N.
W.; He, C. Org. Lett. 2006, 8, 4175−7178. (f) McBee, J. L.; Bell, A.
T.; Tilley, T. D. J. Am. Chem. Soc. 2008, 130, 16562−16571.
́
(g) Giner, X.; Najera, C. Org. Lett. 2008, 10, 2919−2922. (h) Zhang,
Z.; Lee, S. D.; Widenhoefer, R. A. J. Am. Chem. Soc. 2009, 131, 5372−
5373.
(8) Wuts, P. G. M. Greene’s Protective Groups in Organic Synthesis,
5th ed.; Wiley, 2014; pp 1091−1115.
(9) Robiette, R.; Tran, T.-V.; Cordi, A.; Tinant, B.; Marchand-
Brynaert, J. Synthesis 2010, 2010, 3138−3142.
(10) For selected books and reviews, see: (a) Joule, J. A.; Mills, K.
Heterocyclic Chemistry; Wiley: Chichester, U.K., 2010; Chapters 32
and 33. (b) Rachwal, S. In Comprehensive Heterocyclic Chemistry III;
Katritzky, A. R., Ramsden, C. A., Scriven, E. F. V., Taylor, R. J. K.,
Eds.; Elsevier Science & Technology: Oxford, U.K., 2008; Vol. 5, pp
1−209. (c) Katritzky, A. R.; Rachwal, S. Chem. Rev. 2010, 110, 1564−
1610. (d) Kale, R. R.; Prasad, V.; Mohapatra, P. P.; Tiwari, V. K.
Monatsh. Chem. 2010, 141, 1159−1182. (e) Katritzky, A. R.; Rachwal,
S. Chem. Rev. 2011, 111, 7063−7120. (f) Balan, A.; Baran, D.;
Toppare, L. Polym. Chem. 2011, 2, 1029−1043. (g) Ren, Y.; Zhang,
L.; Zhou, C.-H.; Geng, R.-X. Med. Chem. 2014, 4, 640−662.
(h) Briguglio, I.; Piras, S.; Corona, P.; Gavini, E.; Nieddu, M.;
Boatto, G.; Carta, A. Eur. J. Med. Chem. 2015, 97, 612−648.
(i) Loukopoulos, E.; Kostakis, G. E. Coord. Chem. Rev. 2019, 395,
193−229.
́
1083. (ao) Zelenay, B.; Munton, P.; Tian, X.; Díez-Gonzalez, S. Eur. J.
Org. Chem. 2019, 2019, 4725−4730. (ap) Vanable, E. P.; Kennemur,
J. L.; Joyce, L. A.; Ruck, R. T.; Schultz, D. M.; Hull, K. L. J. Am. Chem.
Soc. 2019, 141, 739−742.
(2) For a review, see: (a) Pirnot, M. T.; Wang, Y.-M.; Buchwald, S.
L. Angew. Chem., Int. Ed. 2016, 55, 48−57. For articles, see: (b) Miki,
Y.; Hirano, K.; Satoh, T.; Miura, M. Angew. Chem., Int. Ed. 2013, 52,
10830−10834. (c) Zhu, S.; Niljianskul, N.; Buchwald, S. L. J. Am.
Chem. Soc. 2013, 135, 15746−15749. (d) Zhu, S.; Buchwald, S. L. J.
Am. Chem. Soc. 2014, 136, 15913−15916. (e) Miki, Y.; Hirano, K.;
Satoh, T.; Miura, M. Org. Lett. 2014, 16, 1498−1501. (f) Niljianskul,
N.; Zhu, S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2015, 54, 1638−
(11) For selected examples of N2-alkylated benzotriazoles having
́
functions, see: (a) Bretner, M.; Baier, A.; Kopanska, K.; Najda, A.;
Schoof, A.; Reinholz, M.; Lipniacki, A.; Piasek, A.; Kulikowski, T.;
Borowski, P. Antivir. Chem. Chemother. 2005, 16, 315−326. (b) Das,
E
DOI: 10.1021/acs.orglett.9b04375
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
J.; Rao, C. V. L.; Sastry, T. V. R. S.; Roshaiah, M.; Sankar, P. G.;
Khadeer, A.; Kumar, M. S.; Mallik, A.; Selvakumar, N.; Iqbal, J.;
Trehan, S. Bioorg. Med. Chem. Lett. 2005, 15, 337−343.
(c) Paluchowska, M. H.; Bugno, R.; Charakchieva-Minol, S.;
(14) We prepared authentic samples of N1-alkylated benzotriazole
via SN2 alkylation, which gave a nonselective product mixture (see the
Supporting Information for details).
(15) (a) Kitamura, T.; Morshed, M. H.; Tsukada, S.; Miyazaki, Y.;
Iguchi, N.; Inoue, D. J. Org. Chem. 2011, 76, 8117−8120. (b) Xu, K.;
Thieme, N.; Breit, B. Angew. Chem., Int. Ed. 2014, 53, 7268−7271.
(c) Wang, K.; Chen, P.; Ji, D.; Zhang, X.; Xu, G.; Sun, J. Angew.
Chem., Int. Ed. 2018, 57, 12489−12493. (d) Zhu, L.-L.; Tian, L.;
Zhang, H.; Xiao, L.; Luo, W.; Cai, B.; Wang, H.; Wang, C.; Liu, G.;
Pei, C.; Wang, Y. Adv. Synth. Catal. 2018, 361, 1117−1123.
(16) See the Supporting Information for optimization details.
(17) Although intramolecular hydroamination using similar
conditions was pioneered by Shigehisa previously, the intermolecular
hydroamination reaction between 1a and 2a under the reported
conditions resulted in low yield (21% GC yield) and no selectivity
(N1/N2 = 1:1). See: (a) Shigehisa, H.; Koseki, N.; Shimizu, N;
Fujisawa, M.; Niitsu, M.; Hiroya, K. J. Am. Chem. Soc. 2014, 136,
13534−13537. (b) Shigehisa, H. Synlett 2015, 26, 2479−2484.
(c) Shigehisa, H.; Hiroya, K. Yuki Gosei Kagaku Kyokaishi 2015, 73,
788−797.
(18) Discolo, C. A.; Touney, E. E.; Pronin, S. V. J. Am. Chem. Soc.
2019, 141, 17527−17532.
(19) The generation of the cationic alkyl cobalt(IV) complex by the
reaction of the alkylcobalt(III) complex and Co(III)BF4 was
supported by DFT calculations. See: Ebisawa, K.; Izumi, K.; Ooka,
Y.; Kato, H.; Kanazawa, S.; Komatsu, S.; Nishi, E.; Hiroya, K.;
Shigehisa, H. ChemRxiv 2019, DOI: 10.26434/chemrxiv.9981395.v1.
́
́
Bojarski, A. J.; Tatarczynska, E.; Chojnacka-Wojcik, E. Arch. Pharm.
2006, 339, 498−506. (d) Dixit, P. P.; Patil, V. J.; Nair, P. S.; Jain, S.;
Sinha, N.; Arora, S. K. Eur. J. Med. Chem. 2006, 41, 423−428.
(e) Carta, A.; Loriga, M.; Piras, S.; Paglietti, G.; Ferrone, M.;
Fermeglia, M.; Pricl, S.; Colla, P. L.; Collu, G.; Sanna, T.; Loddo, R.
Med. Chem. 2007, 3, 520−532. (f) Balan, A.; Gunbas, G.; Durmus, A.;
Toppare, L. Chem. Mater. 2008, 20, 7510−7513. (g) Balan, A.; Baran,
D.; Gunbas, G.; Durmus, A.; Ozyurt, F.; Toppare, L. Chem. Commun.
2009, 6768−6770. (h) Price, S. C.; Stuart, A. C.; Yang, L.; Zhou, H.;
You, W. J. Am. Chem. Soc. 2011, 133, 4625−4631. (i) Tam, T. L. D.;
Ye, W.; Tan, H. H. R.; Zhou, F.; Su, H.; Mhaisalkar, S. G.; Grimsdale,
A. C. J. Org. Chem. 2012, 77, 10035−10041. (j) Vankadari, S. R.;
Mandala, D.; Pochampalli, J.; Tigulla, P.; Valeru, A.; Thampu, R. Med.
Chem. Res. 2013, 22, 5912−5919. (k) Liu, X.; Cai, P.; Chen, Z.;
Zhang, L.; Zhang, X.; Sun, J.; Wang, H.; Chen, J.; Peng, J.; Chen, H.;
Cao, Y. Polymer 2014, 55, 1707−1715. (l) Venkatesan, N.; Singh, V.;
Rajakumar, P.; Mishra, A. K. RSC Adv. 2014, 4, 53484−53489.
(m) Lee, M.-H.; Kim, J.; Kang, M.; Kim, J.; Kang, B.; Hwang, H.;
Cho, K.; Kim, D.-Y. ACS Appl. Mater. Interfaces 2017, 9, 2758−2766.
(n) Tang, A.; Song, W.; Xiao, B.; Guo, J.; Min, J.; Ge, Z.; Zhang, J.;
Wei, Z.; Zhou, E. Chem. Mater. 2019, 31, 3941−3947.
́
(12) (a) Tomas, F.; Abboud, J.-L. M.; Laynez, J.; Notario, R.;
́
Santos, L.; Nilsson, S. O.; Catalan, J.; Claramunt, R. M.; Elguero, J. J.
Am. Chem. Soc. 1989, 111, 7348−7353. (b) Katritzky, A. R.;
Yannakopoulou, K.; Anders, E.; Stevens, J.; Szafran, M. J. Org.
Chem. 1990, 55, 5683−5687. (c) Ueno, L. T.; Ribeiro, R. O.; Rocha,
́
M. S.; Suarez-Iha, M. E. V.; Iha, K.; Machado, F. B. C. J. Mol. Struct.:
́
́
THEOCHEM 2003, 664−665, 207−215. (d) Catalan, J.; Perez, P.
́
Chem. Phys. Lett. 2005, 404, 304−308. (e) Poznanski, J.; Najda, A.;
Bretner, M.; Shugar, D. J. Phys. Chem. A 2007, 111, 6501−6509.
(13) For a review, see: (a) Katritzky, A. R.; Lan, X.; Yang, J. Z.;
Denisko, O. V. Chem. Rev. 1998, 98, 409−548. For selected
examples, see: (b) Katritzky, A. R.; Wu, J. Synthesis 1994, 1994, 597−
600. (c) Gandelman, M.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2005,
44, 2393−2397. (d) Duan, H.; Yan, W.; Sengupta, S.; Shi, X. Bioorg.
Med. Chem. Lett. 2009, 19, 3899−3902. (e) Lee, H.-G.; Won, J.-E.;
Kim, M.-J.; Park, S.-E.; Jung, K.-J.; Kim, B. R.; Lee, S.-G.; Yoon, Y.-J. J.
Org. Chem. 2009, 74, 5675−5678. (f) Yan, W.; Wang, Q.; Chen, Y.;
Petersen, J. L.; Shi, X. Org. Lett. 2010, 12, 3308−3311. (g) Lv, J.; Wu,
H.; Wang, Y. Eur. J. Org. Chem. 2010, 2010, 2073−2083. (h) Le, Z.-
G.; Zhong, T.; Xie, Z.-B.; Lu, X.-X.; Cao, X. Synth. Commun. 2010, 40,
̈
2525−2530. (i) Liu, W.; Zhang, D.; Zheng, S.; Yue, Y.; Liu, D.; Zhao,
X. Eur. J. Org. Chem. 2011, 2011, 6288−6293. (j) Yan, W.; Ye, X.;
Weise, K.; Petersen, J. L.; Shi, X. Chem. Commun. 2012, 48, 3521−
3523. (k) Niedermann, K.; Fruh, N.; Senn, R.; Czarniecki, B.; Verel,
̈
R.; Togni, A. Angew. Chem., Int. Ed. 2012, 51, 6511−6515. (l) Zhang,
M.; Guo, X.-W.; Zheng, S.-C.; Zhao, X.-M. Tetrahedron Lett. 2012, 53,
6995−6998. (m) Yuan, Y.; Hou, W.; Zhang-Negrerie, D.; Zhao, K.;
Du, Y. Org. Lett. 2014, 16, 5410−5413. (n) Aruri, H.; Singh, U.;
Sharma, S.; Gudup, S.; Bhogal, M.; Kumar, S.; Singh, D.; Gupta, V. K.;
Kant, R.; Vishwakarma, R. A.; Singh, P. P. J. Org. Chem. 2015, 80,
1929−1936. (o) Singh, M. K.; Akula, H. K.; Satishkumar, S.; Stahl, L.;
Lakshman, M. K. ACS Catal. 2016, 6, 1921−1928. (p) Aruri, H.;
Singh, U.; Kumar, M.; Sharma, S.; Aithagani, S. K.; Gupta, V. K.;
Mignani, S.; Vishwakarma, R. A.; Singh, P. P. J. Org. Chem. 2017, 82,
1000−1012. (q) Siva Reddy, A.; Leela Siva Kumari, A.; Swamy, K. C.
K. Tetrahedron 2017, 73, 2766−2773. (r) Davydov, D. V.;
Oprunenko, Y. F.; Beletskaya, I. P. Tetrahedron Lett. 2017, 58,
́
4465−4467. (s) Bernar, I.; Fiser, B.; Blanco-Ania, D.; Gomez-Bengoa,
E.; Rutjes, F. P. J. T. Org. Lett. 2017, 19, 4211−4214. (t) Wu, J.;
Zhou, Y.; Zhou, Y.; Chiang, C.-W.; Lei, A. ACS Catal. 2017, 7, 8320−
8323. (u) Berthold, D.; Breit, B. Org. Lett. 2018, 20, 598−601.
(v) Song, C.; Dong, X.; Yi, H.; Chiang, C.-W.; Lei, A. ACS Catal.
2018, 8, 2195−2199.
F
DOI: 10.1021/acs.orglett.9b04375
Org. Lett. XXXX, XXX, XXX−XXX