Enabling Catalytic Arene C-H Amidomethylation via Bis(tosylamido)methane as a Sustainable Formaldimine Releaser

Article abstract of DOI:10.1021/acs.orglett.9b01183

Addition of catalytic arene C-H to formaldimines has been enabled by Ru(II)-catalyzed amidomethylation with bis(tosylamido)methane as a catalytic formaldimine releaser. The new process provides an atom-efficient and sustainable solution to address the challenges of formaldimines in this type of transformation. Furthermore, new synthetic routes based on this catalytic system have been developed for step-efficient access to N-heterotricyclic core structures that are pharmaceutically relevant.

Full text of DOI:10.1021/acs.orglett.9b01183

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Enabling Catalytic Arene C−H Amidomethylation via
Bis(tosylamido)methane as a Sustainable Formaldimine Releaser
Zhong-Yuan Li, Hetti Handi Chaminda Lakmal, and Xin Cui*
Department of Chemistry, Mississippi State University, Mississippi State, Mississippi 39762, United States
*
S Supporting Information
ABSTRACT: Addition of catalytic arene C−H to formaldimines has been enabled by Ru(II)-catalyzed amidomethylation with
bis(tosylamido)methane as a catalytic formaldimine releaser. The new process provides an atom-efficient and sustainable
solution to address the challenges of formaldimines in this type of transformation. Furthermore, new synthetic routes based on
this catalytic system have been developed for step-efficient access to N-heterotricyclic core structures that are pharmaceutically
relevant.
ransition metal-catalyzed additions of unactivated C−H
bonds to polarized π bonds represent an efficient and
strong electrophilicity and minimum steric hindrance (Scheme
1B). These potential aminomethylation processes are highly
desirable as they would enable access to various α-substituted
methylamines, including benzylamine derivatives, directly from
hydrocarbons.
T
powerful approach for constructing molecules bearing
1
heteroatom-based functionality. Among different systems,
the catalytic addition of C−H to CN bonds is particularly
applicable for making various amine products, which are
closely related to biologically active molecules and pharma-
2
Metal-catalyzed sp C−H activation assisted by directing
groups provides a general way to access metal aryl species,
which would be aminomethylated by formaldimines. Among
different directing groups, 2-pyridyl is particularly attractive as
the resulting 2-(2-pyridyl)benzenemethanamine units are
prevalent in biologically and pharmaceutically important
2
ceuticals. In recent years, a wide spectrum of aldimines with
various C substituents, including alkyl, aryl, and electron-
withdrawing groups, has been developed for the synthesis of α-
3
branched amine derivatives (Scheme 1A). However, direct
4
molecules, such as potassium channel blockers and
addition of C−H to the C-unsubstituted imines, namely
formaldimines, has not been developed, although this unique
type of imine would feature even higher reactivity due to its
5
6
MAPKAPK2 inhibitors, as well as fluorescent chemosensors
Scheme 1C). Moreover, N-heterotricyclic skeletons that have
recently been revealed as key backbones in HIV replication
(
7
8
inhibitors and HMG-CoA reductase inhibitors can also be
readily accessed from the products of C−H amidomethylation.
Therefore, development of an effective catalytic system for the
C−H addition of arenes, especially 2-arylpyridines, to
formaldimines is highly desirable.
Scheme 1. Catalytic Addition of C−H to C-Substituted
Imines and Formaldimines
During the past decade, several transition metal catalysts
have been developed for the addition of C−H to various C-
substituted imines (Scheme 2A). Pioneered by the groups of
Ellman, Bergman, and Shi, Rh(III) catalysts have been shown
3b,d−g,j−m,o,p
to be highly effective and general.
The method of
using Co(III) species as capable catalysts has been developed
3h,i,n
by the group of Kanai and Matsunaga.
Remarkably, the
Received: April 4, 2019
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01183
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
1
0
Scheme 2. Catalytic C−H Amidomethylation for the
Synthesis of Benzylamine Derivatives
selective addition reactions. The Lewis acidic and protic
environment associated with the catalytic C−H activation
process would cause quick decomposition and various
homoadditions of formaldimines as side reactions (Scheme
10a,11
2
B).
The fast consumption of formaldimine will disable
the formation of the key intermediate I. Even when
intermediate I is formed, its Lewis acid-activated formaldimine
moiety would undergo faster side reactions with surrounding
free imines than the desired insertion. To address these
selectivity issues, identifying suitable precursors that could
catalytically release the formaldimines at a proper rate appears
to be crucial. We envision that a robust precursor that
undergoes slower decomposition to formaldimines than the
C−H activation step would promote the selective formation of
intermediate III. The subsequently formed metal formaldimine
complex IV would prefer the insertion reactions due to the
suppressed concentration of free formaldimines in the system.
Once the selectivity issues are addressed, the intrinsically
reactive formaldimines would conduct productive C−H
addition processes.
As a result, herein we wish to report the development of
bis(tosylamido)methane (BTM) as a highly selective and
sustainable formaldimine releaser for the catalytic arene C−H
addition reactions (Scheme 2C). While Ru(II) species
3
Huang group first demonstrated a palladium-catalyzed sp
3q
addition of C−H to aldimines. Very recently, the group of
Li and Zeng has developed an intramolecular addition of C−H
12
3a
commonly tolerate imines as directing groups and have
to the trisubstituted imine moiety by palladium catalysts.
1
3
barely been shown to catalyze addition of C−H to imines,
Furthermore, early transition metals, ytterbium and lutetium,
[
Ru(p-cymene)Cl ] has been proven to be highly effective for
have just been disclosed as effective and stereoselective
2 2
3c
catalysts for the addition of pyridyl C−H to aldimines.
this amidomethylation system. Reagent BTM is synthesized in
11
Despite the rich development with C-substituted imines,
formaldimines remain as a challenging class of π bond systems
water with formaldehyde and tosylamide, which is the only
byproduct from the catalytic process. Considering the
recyclable tosylamide, the overall production generates water
as the sole stoichiometric byproduct. Moreover, the catalytic
system employs only a catalytic amount of sodium salts, with
9
for catalytic C−H addition.
Known for their challenging instability and excessive
reactivity, formaldimines often require specific strategies for
a
Table 1. Catalytic C−H Amidomethylation with Different Formaldimine Sources under Varied Conditions
b
entry
imine source
base
additive
solvent
yield (%)
1
2
3
4
5
6
7
8
9
TsNCH (sol) (2a)
−
−
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
KOAc
ClCH CH Cl
<5
40
<5
81
57
92 (86)
nr
68
trace
87
64
86
70
2
2
2
TsNHCH NHTs (2b)
ClCH CH Cl
2 2
2
2a
2b
2b
2b
Na CO3
Na CO3
Na CO3
Na CO3
Na CO3
Na CO3
Li CO3
ClCH CH Cl
2 2
2
ClCH CH Cl
2
2
2
toluene
2
c
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
2
d
2b
2
(TsNCH ) (2c)
2
3
2
2b
2b
2b
2b
2b
2b
2b
2b
2
10
11
12
13
14
15
16
K CO3
2
Cs CO3
Na CO3
Na CO3
Na CO3
Na CO3
Na CO3
2
2
−
2
MesCO H
47
62
49
2
2
Ph POH
2
2
PPh3
2
a
Reaction conditions: 1a (0.1 mmol), 2 (0.2 mmol), [Ru(p-cymene)Cl ] (2.5 mol %), base (20 mol %), additive (10 mol %), solvent (0.5 mL),
2
2
b
1
c
d
1
00 °C, 10 h, under N . The yield was determined by crude H NMR with PhNO as the internal standard. Isolated yield in parentheses. In the
2
2
absence of the Ru catalyst.
B
DOI: 10.1021/acs.orglett.9b01183
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
no need for silver salts that are commonly required in other
systems, or other stoichiometric additives. As applications, new
synthetic routes based on this catalytic system have been
demonstrated for more atom-economic and step-efficient
syntheses of two drug-related tricyclic skeletons.
Table 2. Bis(tosylamido)methane as an Effective
Formaldimine Source for Ru(II)-Catalyzed Arene C−H
a
Amidomethylation
Initial experiments were performed seeking an effective
amidomethylative reagent for the proposed C−H addition
(
Table 1). Using 2-phenylpyridine (1a) as the model substrate
and [Ru(p-cymene)Cl ] as the catalyst, formaldimine sources
2
2
are investigated in the presence of 10 mol % NaOAc, which is
commonly used to facilitate the metalation−deprotonation
1
4
step. Attempts started with a freshly prepared N-tosyl
formaldimine (2a) solution, which was used successfully in
15
our amidomethylative [2+2+2] reactions. However, it was
shown to be an ineffective reagent in this C−H addition
system (Table 1, entry 1). Bis(tosylamido)methane (2b,
13
BTM), which is readily synthesized under basic conditions,
would be a promising reagent as it could be activated by Lewis
acids to form formaldimine 2a. If the metal species can
decompose it into 2a at a matching rate, a productive reaction
would be observed. As expected, the same conditions with
BTM resulted in the desired N-[2-(pyridin-2-yl)benzyl]-
sulfonamide 3a in 40% yield (Table 1, entry 2). A slightly
more basic condition with a catalytic amount of Na CO led to
2
3
a significantly increased yield of 81% with BTM, while hardly
any reaction was observed again with a fresh 2a solution
(
Table 1, entries 3 and 4, respectively). Solvent screening
revealed better performance in dioxane, giving the product in
2% NMR yield (Table 1, entries 5 and 6). After confirming
9
the necessity of the Ru(II) catalyst (Table 1, entry 7), we
introduced 1,3,5-tritosyl-1,3,5-triazinane (2c) as another imine
source, which ended up with a yield significantly lower than
that under the optimal conditions (Table 1, entry 8). A
possible reason may be that disassembly of this trimer was not
able to cleanly generate the imine monomer. Subsequent
experiments examined the cationic effects of the system with
BTM (Table 1, entries 9−12). These indicated that Na and K
salts are generally effective while Li CO has slowed the
2
3
a
+
Reaction conditions: 1 (0.1 mmol), 2b (0.2 mmol), [Ru(p-
reaction, presumably due to a stronger complexation of Li
cymene)Cl ] (2.5 mol %), Na CO (20 mol %), NaOAc (10 mol
2
2
2
3
with acetate anions. It is interesting to note that the reaction
proceeded even without acetate as the additive, albeit with a
lower yield (Table 1, entry 13). To improve our understanding
of the additive effects, sterically hindered acid, secondary
phosphine oxide, and triphenylphosphine were tested instead
of the acetate (Table 1, entries 14−16, respectively). While
they did not stifle the reactions, only moderate yields were
observed. Notably, no silver salts are needed in these catalytic
reactions.
After BTM has been identified as a highly effective reagent
that enables the C−H amidomethylation reaction with 2-
phenylpyridine, continued efforts were focused on the
substrate scope (Table 2). As expected, the amidomethylation
exhibits high reactivity and tolerance to functional groups with
different electronic properties, as exemplified by substrates
%
), 1,4-dioxane (0.5 mL), 100 °C, 10 h, under N . Isolated yields
2
were recorded.
yields, respectively (3p and 3q, respectively). Finally, electroni-
cally diverse directing groups, such as the 4-formyl pyridyl,
pyrimidinyl, and pyrazolyl groups, have all been shown to
smoothly afford the corresponding products (3r−3t, respec-
tively).
3
b−3i with varied electron-donating and -withdrawing para
substituents. Generally good yields were also observed with
substrates with methyl, ester, ketone, and nitro groups as meta
substituents of the 2-phenylpyridines (3j−3m, respectively).
Furthermore, ortho substituents on the phenyl and pyridyl
rings have been shown to be effective, as demonstrated by
products 3n and 3o. Moreover, sterically encumbered 1-
phenylisoquinoline with a fused ring on the directing group
side and 2-(naphthalen-2-yl)pyridine afforded 76% and 91%
To further test the practicality of the catalytic system, a half-
gram-scale reaction was carried out under the standard
conditions and afforded product 3a in 85% isolated yield,
indicating a good scalability of the process (eq 1). Notably,
even in this larger-scale reaction, no bis-amidomethylated
product 4a was detected. The complete selectivity of
monoamidomethylation was further confirmed by the negative
C
DOI: 10.1021/acs.orglett.9b01183
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
result from a reaction with 3a as the reactant under the
standard conditions (eq 2).
Scheme 4. Synthetic Applications for Heterotricyclic
Backbones
Previous mechanistic studies of the addition of C−H to C-
substituted imines set a foundation for a plausible mechanism
1a−d,16
for this Ru(II)-catalyzed amidomethylation (Scheme 3).
Scheme 3. A Plausible Mechanism for Ru(II)-Catalyzed C−
H Amidomethylation with Bis(tosylamido)methane
both core structures would provide general access, with
increased step economy, to various functionalized targets.
In summary, catalytic addition of C−H to formaldimines has
been developed as an effective and practical tool for the
amidomethylation of arenes. Bis(tosylamido)methane has been
revealed as a sustainable and readily available reagent that
enabled the amidomethylation of 2-phenylpyridine derivatives.
The hypothesized dual roles of the Ru(II) catalyst, including
the catalytically controlled release of the formaldimine species,
has led to the development of the working system.
Furthermore, new synthetic routes based on this catalytic
system have been developed for atom-economic and step-
efficient syntheses of pharmaceutically relevant N-heterotricy-
clic structures.
Upon activation of the precatalyst [Ru(p-cymene)Cl ] , it is
2
2
hypothesized that intermediate I would undergo a faster C−H
activation to form a five-membered ruthenacycle II rather than
to decompose BTM (for the H/D exchange reaction, see the
Supporting Information). HRMS study of the reaction system
indicated a major species matching cationic intermediate II
without the acetate anion (see the Supporting Information for
details). As a weak ligand, BTM would substitute the acetate in
intermediate II to afford III, which might undergo a Lewis
acid-facilitated decomposition to form Ru-imine intermediate
IV. To our delight, cationic intermediate IV is also supported
by the HRMS experiment. The catalytic formation of the imine
units would largely suppress the concentration of the free
formaldimine and thus promote the desired insertion reaction
toward intermediate V. The major HRMS peak for Ru-
formaldimine intermediate IV is consistent with the hypothesis
that C−H activation is likely to have a rate faster than that of
the decomposition of BTM. Finally, protonolysis of
intermediate V occurred to produce 3a and regenerate the
catalyst.
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01183.
Experimental details and analytical data for all new
compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
The BTM-enabled catalytic system provides atom- and step-
economic access to drug-relevant tricyclic structures, including
*
E-mail: xcui@chemistry.msstate.edu.
ORCID
5
-sulfonyl-5,6-dihydrobenzo[c][1,5]naphthyridine that is the
7
Xin Cui: 0000-0001-8689-7100
Notes
backbone of a class of HIV replication inhibitors and 6-
sulfonyl-6,7-dihydro-5H-benzo[c]pyrido[2,3-e]azepine that is
the core of a class of HMG-CoA reductase inhibitors (Schemes
The authors declare no competing financial interest.
8
1
and 4). While the existing syntheses generally relied on the
preinstallation of functional groups on both aryl and pyridyl
ACKNOWLEDGMENTS
7
,8
■
sides for the closure of the central N-heterocycle, we have
designed new synthetic routes for both types of tricyclic
backbones based on C−H amidomethylation. The access to 5
became promising when the catalytic process was proven to be
successful with 2-phenylpyridine 1u bearing a sterically
hindered o-bromo atom. The resulting 3u was smoothly
transformed to tricyclic model compound 5 via Pd-catalyzed
C−N coupling in satisfying yield. A new route to 6 was realized
upon the successful tolerance of an o-hydroxymethyl group in
the catalytic formation of 3v, which was then readily cyclized
to afford 6 via a Mitsunobu reaction. The new pathways to
The authors are grateful for financial support from the
Mississippi State University Office of Research and Economic
Development and Department of Chemistry.
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