Selective Cleavage and Tunable Functionalization of the C-C/C-N Bonds of N-Arylpiperidines Promoted by tBuONO

Article abstract of DOI:10.1021/acs.orglett.9b00226

In this paper, selective cleavage and tunable functionalization of the inert C-C/C-N bonds in N-arylpiperidines promoted by ^tBuONO under metal-free conditions is presented. To be specific, when the reaction was run in acetonitrile in the presence of molecular sieves, the synthetically useful acyclic N-formyl nitriles are formed. On the other hand, when alcohol was used as the reaction medium, the corresponding reactions afforded N-nitroso chain esters as dominating products via a mechanistically different pathway.

Full text of DOI:10.1021/acs.orglett.9b00226

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Selective Cleavage and Tunable Functionalization of the C−C/C−N
t
Bonds of N‑Arylpiperidines Promoted by BuONO
Yan He,* Zhi Zheng, Yajie Liu, Jiajie Qiao, Xinying Zhang, and Xuesen Fan*
Henan Key Laboratory of Organic Functional Molecules and Drug Innovation, Key Laboratory for Yellow River and Huai River
Water Environmental Pollution Control, Ministry of Education, Collaborative Innovation Center of Henan Province for Green
Manufacturing of Fine Chemicals, School of Environment, School of Chemistry and Chemical Engineering, Henan Normal
University, Xinxiang, Henan 453007, China
S
* Supporting Information
ABSTRACT: In this paper, selective cleavage and tunable functionalization of
the inert C−C/C−N bonds in N-arylpiperidines promoted by tBuONO under
metal-free conditions is presented. To be specific, when the reaction was run
in acetonitrile in the presence of molecular sieves, the synthetically useful
acyclic N-formyl nitriles are formed. On the other hand, when alcohol was
used as the reaction medium, the corresponding reactions afforded N-nitroso
chain esters as dominating products via a mechanistically different pathway.
ecause of its wide applications in rebuilding complex
molecules that would be unapproachable from other
4l). Meanwhile, it was also noted that most of the
transformations reported therein were related to C−N bond
cleavage, and selective cleavage of the C−C bond in unstrained
cyclic amines is very limited. Very recently, Sarpong et al.
disclosed the transformation of N-benzoyl cyclic amines into
fluorine-containing acyclic amine derivatives via AgBF4
promoted fluorination and cleavage of the C−C bond (Scheme
1, ref 5a).
B
methods, cleavage and functionalization of the inert C−C/C−
N bonds represents a powerful class of chemical trans-
formation.1−3 Among them, the deconstructive functionaliza-
tion of cyclic amines is particularly important given their
ubiquity and ready availability. However, efficient accomplish-
ment of this kind of transformation is still challenging due to
the high bond dissociation energy of the inert C−C/C−N
bonds.4,5 Recent studies found that transition-metal-catalyzed
C−N bond cleavage via iminium, ammonium, and/or enamine
species are efficient and reliable for activateing the saturated N-
containing compounds.4a,b,f−j However, some of these
protocols suffer from high reaction temperature, use of
expensive metal catalyst, or formation of side products due
to unselective oxidation. Lately, Jia et al. disclosed some
interesting multifunctionalization of the inert C−H and C−N
Inspired by the above-mentioned elegant pioneering studies,
we report here a 2,2,6,6-tetramethyl-1-oxopiperidin-1-ium
−
tetrafluoroborate (T+BF4 ) and TBN-promoted cleavage and
functionalization of the inert C−C bond in saturated cyclic
amines to produce N-(3-cyanopropyl)-N-formamides with the
simultaneous construction of both cyano and formamide units
(Scheme 1, a). In addition, when alcohol was used as the
reaction medium instead of acetonitrile, selective cleavage and
functionalization of the C−N bond occurred to generate the
interesting N-nitroso chain ester products (Scheme 1, b).
Compared with literature reports, notable features of these
novel protocols include (1) selective cleavage and tunable
functionalization of inert C−C bond and C−N bond without
using any metal catalyst and (2) multiple synthetically useful
building blocks constructed in a one-pot manner.6
t
bonds in N-arylazacycles via a BuONO (TBN)-initiated
radical process under metal-free conditions (Scheme 1, ref
Scheme 1. Previous Work and This Work
As a continuation of our interest in cyclic amine
functionalization,4i,j,7 we have initially envisioned a direct
synthesis of nitroso-substituted heterocycles (I) through the
oxidative C(sp3)−H bond nitrosation of saturated cyclic
amines by using T+BF4 as a generally stable oxidant8 and
−
TBN as an easily obtainable and convenient to handle
nitrosation reagent.4k,l,9,10 Thus, 1-phenylpiperidine (1a) was
treated with T+BF4− and TBN in acetone at room temperature
Received: January 18, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00226
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
under air for 1 h. To our surprise, an unexpected product, N-
(3-cyanopropyl)-N-phenylformamide (2a), was isolated in a
yield of 10% (Table 1, entry 1). Considering the merits of this
After establishing an efficient synthesis of 2a, we continued
to search for reaction conditions favoring the formation of 3a
(Table 1, entry 6). For this purpose, the loading of T+BF4− was
increased to 1.5 equiv. As a result, the yield of 3a was improved
to 35% (entry 18). In another aspect, elevating the reaction
temperature from rt to 50 °C resulted in a slight reduction of
efficiency (entry 19). Finally, we were delighted to find that
prolonging the reaction time from 1 to 6 h improved the
efficiency of this transformation considerably, and 3a could be
formed in a yield of 64% (entry 20).
Table 1. Optimization Studies for the Formation of 2a and
a
3a
With the establishment of the optimum reaction conditions,
the substrate scope for the synthesis of 2 was explored. First, a
number of 1-arylpiperidines 1 with different substituents
attached on the phenyl ring were tested. It turned out that
the corresponding reactions proceeded efficiently to afford
2a−k in 34−74% yields (Scheme 2). Remarkably, functional
b
yield (%)
entry oxidant (equiv) additive (equiv)
solvent
2a
10
3a
1
2
3
4
5
6
7
T+BF4 (1)
acetone
CH3CN
DCE
DMSO
dioxane
EtOH
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
EtOH
−
T+BF4 (1)
20
−
T+BF4 (1)
trace
trace
trace
−
T+BF4 (1)
−
a,b
T+BF4 (1)
−
Scheme 2. Substrate Scope for the Synthesis of 2
T+BF4 (1)
25
−
T+ClO4 (1)
11
−
8
9
T+OTf− (1)
DDQ (1)
trace
trace
trace
31
28
30
28
26
24
61
10
11
12
13
14
15
16
K2S2O8 (1)
T+BF4 (1.5)
−
c
T+BF4 (1.5)
−
d
T+BF4 (1.5)
−
T+BF4 (1.5)
BF3·Et2O (1)
CaO (1)
NaHCO3 (1)
−
T+BF4 (1.5)
−
T+BF4 (1.5)
−
e
−
17
T+BF4 (1.5)
−
18
19
T+BF4 (1.5)
35
33
64
f
T+BF4 (1.5)
EtOH
EtOH
−
g
−
20
T+BF4 (1.5)
a
Reaction conditions: 0.2 mmol of 1a, 0.6 mmol of TBN, 1 mL of
b
c
solvent, room temperature, air, 1 h. Isolated yields. 0.4 mmol of
TBN. 0.8 mmol of TBN. In the presence of 4 Å MS (100 mg). 50
°C. 6 h.
d
e
f
g
reaction as mentioned above, we decided to screen the reaction
conditions to improve the efficiency of this transformation.
First, various solvents such as CH3CN, DCE, DMSO, and
dioxane were attempted (entries 2−5). Among them, CH3CN
was found to be more favorable than other solvents (entry 2 vs
1 and 3−5). Subsequently, the reaction was carried out in
ethanol, and we were surprised to find that another product,
ethyl 4-(nitroso(phenyl)amino)butanoate (3a), bearing useful
nitroso and ester groups, was selectively formed in a yield of
25% (entry 6). Then different TEMPO salts as well as other
kinds of oxidant were screened (entries 7−10). It turned out
a
−
Reaction conditions: 0.2 mmol of 1, 0.3 mmol of T+BF4 , 0.6 mmol
of TBN, 4 Å molecule sieves (100 mg), CH3CN (1 mL), rt, air, 1 h.
b
Isolated yields.
groups such as fluoro, chloro, bromo, cyano, methyl, and
methoxy were well tolerated. In addition, 1-biphenyl and 1-
naphthylpiperidine underwent this cascade transformation
smoothly to give 2l and 2m in 53% and 50% yields,
respectively. Second, when substrates bearing a methyl or
phenyl unit on the piperidine ring were used, corresponding
products 2n−q could also be obtained in 34−51% yields.
Third, this transformation was equally amenable to 1-
arylpyrrolidine, delivering the target product 2r in 20% yield.
Next, the substrate scope for the synthesis of 3 was studied.
The results listed in Scheme 3 showed that 1 bearing different
substituents on the 1-aryl unit underwent this transformation
smoothly to afford 3a−j in moderate to good yields. Various
functional groups, from electron-withdrawing fluoro, chloro,
bromo, trifluoromethyl, and cyano to electron-donating
methyl, were well tolerated. Notably, 3e and 3f were obtained
in lower yields, probably owing to electronic effect. Besides,
when a chloro unit was attained at the ortho-position of the
that T+BF4 is the most efficient oxidant for the formation of
−
2a (entry 2). Increasing the loading of T+BF4 to 1.5 equiv
−
improved the yield of 2a to 31% (entry 11). Further studies in
varying the loading of TBN did not give more positive results
(entries 12 and 13). To see whether the presence of an acidic
or basic additive could improve the reaction, BF3·Et2O, CaO,
and NaHCO3 were used.11 However, a slight decrease in the
yield of 2a was observed (entries 14−16). To our delight,
using 4 Å molecular sieves to remove water possibly existing in
the reaction system could substantially improve the yield of 2a
to 61% (entry 17), most likely due to the postulation that
water is beneficial to C−N bond cleavage4l other than the C−
C bond cleavage needed for the formation of 2a.
B
DOI: 10.1021/acs.orglett.9b00226
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Letter
a,b
Scheme 3. Substrate Scope for the Synthesis of 3
Scheme 4. Control Experiments
a
−
Reaction conditions: 0.2 mmol of 1, 0.3 mmol of T+BF4 , 0.6 mmol
b
of TBN, alcohol (1 mL), rt, air, 6 h. Isolated yields.
benzene ring, the corresponding product was formed only in
trace amounts, probably due to steric hindrance (3k).
Moreover, N-biphenyl-substituted piperidine could be
smoothly transformed into the desired product 3l in 58%
yield. In addition, substrates bearing a methyl or phenyl group
on the para-position of the piperidine ring could also take part
in this reaction to give 3m−p in yields ranging from 51 to 70%.
In another respect, other primary alcohols such as methanol, n-
butanol, and 2-methylpropanol and secondary alcohols such as
2-propanol were found to be suitable substrates for this
reaction, furnishing the corresponding products 3q−t in
moderate yields.
is crucial for the formation of 3a. Afterward, an 18O-labeling
experiment with H218O for the preparation of 3a was carried
out (Scheme 4, (8)), from which [16O]-3a, [18O1]-3a, and
[18O2]-3a were formed in a ratio of 1.1:1:0.2 as determined by
HRMS analysis (see the SI). It indicates that H2O might not
be the sole source of the oxygen atoms of nitroso and ester
moieties embedded in 3a. In trying to locate the position of the
18O atom on [18O1]-3a, the 261 ion was selected and subjected
to MSMS fragmentation, and the results showed the 18O atom
is located either on the ester or on the nitroso functional group
(see the SI). Then, in order to further determine the ratio of
[C18OOEt]-3a and [N18O]-3a, the nitroso groups in the
mixture of [16O]-3a, [18O1]-3a, and [18O2]-3a (1.1:1:0.2) were
reduced to the amine unit to give [16O]-4 and [18O1]-4 in a
ratio of 1.6:1 as determined by HRMS analysis (Scheme 4,
(9)). Thus, the ratio of [C18OOEt]-3a and [N18O]-3a was
calculated as 2.4:1. Finally, 16O-3a was treated with H218O
under the standard reaction conditions (Scheme 4, (10)). The
following HRMS study of the product thus obtained excludes
the possibility of O atom exchange between water and
functional groups (nitoso and ester) existing in 3a as only
16O-3a (95%) was obtained (see the SI).
To gain some insight into the reaction mechanism, some
control experiments were conducted. First, 2,2,6,6-tetrame-
thylpiperidinooxy (TEMPO) as a radical scavenger was added
to the standard reaction systems for the synthesis of 2a and 3a.
As a result, the formation of 2a and 3a was not detected
(Scheme 4, (1) and (2)), indicating that these reactions should
follow a radical pathway. Second, HRMS studies on the
reaction mixture for the formation of 2a and 3a were
conducted. A zwitterion species trifluoro(((1-phenyl-5,6-
dihydropyridin-1-ium-3(4H)-ylidene)amino)oxy)borate
(calcd, 279.0887; found, 279.0891) consisting of iminium and
−
borate was detected, which hits the promoting effect of T+BF4
On the basis of the above results and previous reports,7a,8,12
a plausible mechanism accounting for the formation of 2a is
for the construction of 2a (Scheme 4, (3)). On the other hand,
N-(4-ethoxy-5-oxopentyl)-N-phenylnitrous amide (calcd,
273.1210; found, 273.1219) was detected in the reaction
mixture leading to 3a. This result suggests that a decarbon-
ylation process might be involved in the formation of 3a
(Scheme 4, (4)). Third, the reactions for the formation of 2a
and 3a were carried out under argon instead of air (Scheme 4,
(5) and (6)). From these reactions, 2a and 3a were formed in
slightly decreased yields of 56% and 49% compared with those
obtained under air, indicating that the presence of molecular
oxygen in air should have some effect on the formation of 2a
and 3a. Fourth, the reaction for the formation of 3a was
implemented in the presence of 4 Å molecule sieves (Scheme
4, (7)). Under this circumstance, 3a was obtained only in a
trace amount. This result indicated that the presence of water
−
proposed in Scheme 5. Initially, 1a is oxidized by T+BF4 to
give an iminium intermediate A.8 Subsequent β-hydrogen
Scheme 5. Proposed Mechanism Accounting for the
Formation of 2a
C
DOI: 10.1021/acs.orglett.9b00226
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Letter
elimination occurs with A to produce an enamine intermediate
B.7a Next, nitrosation of B by TBN affords intermediate C.12a
In the presence of BF3, the isomerization of C occurs to deliver
charge-separated intermediate D,12b which then undergoes an
intramolecular nucleophilic attack to form E. Then N−O and
C−C bond cleavage of E occur to furnish product 2a.12
As for the formation of 3a, it should also involve an initial in
situ formation of enamine B. Then EtO• generated from the
reaction medium undergoes a radical addition on B to provide
intermediate F.4l,13 The following oxidation of F produces an
iminium intermediate G. Then hydrolysis and C−N bond
cleavage of G take place to afford acyclic intermediate H,4l
which subsequently captures an NO or NO radical to form
intermediate I.14a Next, with the aid of tBuO•, decarbonylation
of I occurs to give radical intermediate J,14b which is
hydrolyzed and/or oxidized into product 3a (Scheme 6).9c
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00226.
■
S
Experimental procedure, characterization data, and
NMR spectra of all products (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: heyan@htu.cn.
*E-mail: xuesen.fan@htu.cn.
ORCID
Yan He: 0000-0003-2679-2547
Xinying Zhang: 0000-0002-3416-4623
Xuesen Fan: 0000-0002-2040-6919
Notes
Scheme 6. Proposed Mechanism Accounting for the
Formation of 3a
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (21702050, 21572047), Plan for Scientific Innovation
Talents of Henan Province (184200510012), and 111 Project
(D17007) for financial support.
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