Deconstructive Oxygenation of Unstrained Cycloalkanamines

Article abstract of DOI:10.1002/anie.201914623

A deconstructive oxygenation of unstrained primary cycloalkanamines has been developed for the first time using an auto-oxidative aromatization promoted C(sp³)?C(sp³) bond cleavage strategy. This metal-free method involves the substitution reaction of cycloalkanamines with hydrazonyl chlorides and subsequent auto-oxidative annulation to in situ generate pre-aromatics, followed by N-radical-promoted ring-opening and further oxygenation by 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) and m-cholorperoxybenzoic acid (mCPBA). Consequently, a series of 1,2,4-triazole-containing acyclic carbonyl compounds were efficiently produced. This protocol features a one-pot operation, mild reaction conditions, high regioselectivity and ring-opening efficiency, broad substrate scope, and is compatible with alkaloids, osamines, and peptides, as well as steroids.

Full text of DOI:10.1002/anie.201914623

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Accepted Article
Title: Deconstructive Oxygenation of Unstrained Cycloalkanamines
Authors: Jian-Wu Zhang, Yuan-Rui Wang, Jia-Hao Pan, Yi-Heng He,
Wei Yu, and Bing Han
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10.1002/anie.201914623
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Deconstructive Oxygenation of Unstrained Cycloalkanamines
Jian-Wu Zhang, Yuan-Rui Wang, Jia-Hao Pan, Yi-Heng He, Wei Yu, and Bing Han*
Abstract: A deconstructive oxygenation of unstrained primary cyclo-
alkanamines has been developed for the first time via an auto-
oxidative aromatization promoted C(sp3)-C(sp3) bond cleavage
strategy. This metal-free method involves the substitution reaction of
cycloalkanamines with hydrazonyl chlorides and subsequent auto-
oxidative annulation to in-situ generate pre-aromatics, followed by N-
radical-promoted ring-opening and further oxygenation by 2,2,6,6-
tetramethylpiperidin-1-yl)oxy (TEMPO) and m-cholorperoxybenzoic
acid (mCPBA). Consequently, a series of 1,2,4-triazole-containing
acyclic carbonyl compounds were efficiently produced. This protocol
features one-pot operation, mild conditions, high regioselectivity and
ring-opening efficiency, broad substrates scope, and is compatible
with alkaloids, osamines, peptides as well as steroids.
Aliphatic rings are a vital structural element in various kinds of
organic compounds including drugs, natural products, and func-
tional materials.[1] The deconstruction of such cycloalkane deriv-
atives via ring-opening constitutes a highly attractive scaffold
hopping strategy in organic synthesis.[2] However, the C-C bond
cracking of unstrained aliphatic rings has long been viewed as
an extremely challenging problem owing to the high C-C bond
dissociation energy.[3,4] One promising strategy to solve this
problem is to take advantage of the high reactivity of oxygen
radicals to facilitate the ring-opening via C-C bond cleavage. In
this context, elegant methods have been developed based on
the cycloalkoxy radical-promoted ring opening.[5] The ring-
opening rates of alkoxy radicals are several orders of magnitude
Scheme 1. Heteroatom radical-mediated ring-opening of naphthenes and rate
constants.
higher than those of the reverse cyclization (Scheme 1a, kopen
≈
≈
products.[11] However, to the best of our knowledge, the ring-
opening of unstrained cycloalkanamines has not been reported.
We report herein for the first time an aminyl radical-mediated
ring-opening of unstrained primary cycloalkanamines by intro-
ducing aromatization as both dynamic and thermodynamic driv-
ing forces (Scheme 1c). Aromatization has been applied in C-C
bond cleavage as a momentous thermodynamic driving force,[12]
but this strategy is still unappreciated because of the difficulty in
generating pre-aromatics in situ.[4f] In this context, the present
one-pot protocol employs a convenient mean for the in-situ
formation of heterocyclic pre-aromatics 3,4-dihydro-1,2,4-trizoles
by the substitution reaction of cycloalkanamines with hydrazonyl
chloride followed by subsequent auto-oxidative annulation using
air as the terminal oxidant. The further auto-oxidation of such
pre-aromatics by air realizes the aminyl radical-promoted C-C
bond cleavage ring-opening. Thus, a series of 1,2,4-triazole-
featured acyclic carboxylic acids/carbonyls are efficiently pro-
duced by the oxygenation of the C-centered radical by TEMPO
and mCPBA (Scheme 1c).
The study commenced by stirring the mixture of cyclohexyl-
amine a1 (0.3 mmol), N-phenylbenzohydrazonoyl chloride b1
(0.39 mmol), and Et3N (0.45 mmol) in dimethylacetamide (DMA)
(2 mL) under Ar at RT for 1 h, and then the mixture was stirred
for additional 72 h under air. Indeed, the desired auto-oxidative
ring-opening took place and gave the self-coupling product c1 in
20% yield as the only separable product (Figure 1a). Apparently,
c1 was produced through trapping the ring-opened C-radical by
unopened aminyl radical RN (Figure 1a). This result was
attributed to the high stability of the formed aminyl radical RN,
108 s-1 >> k-1cyclization ≈ 104 s-1 and kopen ≈ 107 s-1 >> k-1
cyclization
105 s-1 for 5- and 6-membered ring, respectively),[6] and thus
their ring-opening process is thermodynamically favorable as
well as kinetically favorable. Besides cycloalkoxy radicals, it is
also possible other types of radicals can also be exploited to
cleavage the unstrained aliphatic rings, but so far, few effective
methods have been reported in this line.
Cycloalkyliminyl and cycloalkylaminyl radicals-involved ring-
opening reactions have attracted much attention in recent
years.[7-9] For example, the groups of Zard,[7a,7c] Leonori,[7f]
Xiao,[7e] and Guo[7g] have developed iminyl radical-mediated ring-
opening of strained rings by using oxime esters or ethers as the
substrates (Scheme 1b). Meanwhile, Zheng[8a-c] and Waser[8e]
have independently reported ring-opening reconstruction and
functionalization of strained cyclopropylamines and cyclobutyla-
mines. However, different from alkoxyl radicals, those reactions
are limited to strained rings, while the ring-opening of unstrained
ring still remains a big challenge. This situation can be attributed
to their high reverse 5-exo cyclization rate constant onto nitrile
and imine (k-1cyclization ≈ 107 s-1), [10] respectively.
Cyclic amines are widely found in drugs and natural
[*]
J.W. Zhang, Y.R. Wang, J.H. Pan, Y.H. He, Prof. Dr. W. Yu, Prof. Dr.
B. Han
State Key Laboratory of Applied Organic Chemistry, College of
Chemistry and Chemical Engineering, Lanzhou University, Lanzhou,
730000, P. R. China
E-mail: hanb@lzu.edu.cn
Supporting information for this article is given via a link at the end of the
document.
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10.1002/anie.201914623
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COMMUNICATION
which could be directly detected by using the reaction mixture in
(1a) via electron paramagnetic resonance (EPR) (Figure 1b).[13]
Data analysis verifed that N-centered radical was generated (g =
oxygenated product 1,2,4-triazole-featured acyclic carboxylic
acid e1 in 67% yield after the treatment with mCPBA in a
sequential one-pot process (Table 1, Entry 1). Increasing the
2.0037; hpfc: 0.65 G (2H); 1.95 G (1H); 3.23 G (1N); 6.45 G (1N); reaction temperature of auto-oxidative stage would reduce the
7.74 G (1N)). In addition, the formation of stable radical RN was
also confirmed by HRMS measurement (see Supporting
Information (SI)). This high stability was due to the delocalization
of single-electron spin density over three N-atoms, which was
also validated by DFT calculation (Figure 1c).
reaction time and improve the product yields (Table 1, Entries 2
and 3). The usage amount of TEMPO was essential for an
efficient reaction (Table 1, Entries 4-6). When the reaction was
conducted under Ar, the product e1 was remarkably reduced to
16% yield (Table 1, Entry 7). Solvent screening results showed
that DMA was a better choice than CH3CN, dichloroethane
(DCE), toluene, and methanol (Table 1, Entries 8-11).
With the optimal conditions established, we proceeded to
evaluate the scope of the protocol with respect to primary
cycloalkanamines. As shown in Scheme 2, a large variety of
cycloalkanamines including monocyclic, bicyclic, bridged, and
complex natural product derivatives were efficiently ring-opened
and oxygenized. First, the regioselectivity of C-C bond cleavage
as well as the substituent tolerance were investigated by
introducing various functional groups at different sites on
cyclohexylamine. 4-Substituted symmetric cyclohexylamines a2-
4 bearing Me, COOEt, and CF3 groups were well compatible in
the transformation, affording acyclic acids e2-4 in good yields.
Incorporation of substituents such as Me, OH, OBn (Bn =
Benzyl), and NHBoc (Boc = tButyloxycarbonyl) at the 2-position
of cyclohexanamine significantly increased the diversity of
deconstructive products, as demonstrated in the cases of a5-8,
the corresponding linear ketone e5, carboxylic acid e1, ester e7,
and amide e8 were produced in good yields. 3-Substituted
cyclohexanamine was also suitable for this conversion and the
C–C bond was selectively cut at the less steric hindrance side
(e9). Notably, six-membered heterocyclic amines embedding
heteroatoms such as N- and O-atoms were also good
candidates, providing the desired ring-opening products e10 and
e10’ in a combined yield of 81% and e11 and e11' in a
combined yield of 85%, respectively. When cyclopentanamine
a12 participated in the procedure, e12 was produced in 95%
yield. Similarly, heteroatoms O- and N-substituents could also
be incorporated into the 5-membered heterocyclic alkanamines,
delivering formiate e13 and formamide e14 in excellent yields
and high regioselectivity. Cycloalkanamines of the varying of ring
sizes could also be transformed to the corresponding chain
carboxylic acids e15-19. Except e15 was easy to decarboxylate
to e15’ during column chromatograph, e16-19 were formed in
excellent yields. Next, aryl-fused bicyclic alkanamines were
explored for this protocol. 1-Indanamines a20-27 bearing
substituents with a variety of electronic properties at 4-, 5-, and
6- position on the phenyl ring were all compatible in this tactic,
producing biaryl carboxylic acids e20-27 in 70-98% yields. The
reaction of 2-indanamine was also performed well, giving rise to
e28 in 77% yield. This process also made promise for benzo-,
furo- and thieno-cyclohexylamines and gave the acyclic
carboxylic acids bearing biaryl and biheteroaryl in decent yields
over one-pot (e29-31). In addition, a variety of bridged cyclic
amines, such as 2-amantadine, tropine amine, 3-pinanamine,
and 3-amino-quinuclidine, were all smoothly converted to the
desired products with good regioselectivity and yields (e32-36).
After successfully converting simple unstrained cycloamines, we
turned our attention to drugs and natural product derivatives
Figure 1. (a) a1 (0.3 mmol), b1 (0.39 mmol), and Et3N (0.45 mmol) in DMA (2
mL) was stirred under Ar at RT for 1 h, and then stirred for additional 72 h
under air. (b) EPR spectrum (X band, 9.4 GHz, RT): the reaction mixture in (a)
was derectly used for EPR measurement. (c) The caculated spin density of RN.
To prevent the formation of c1, a well-known C-centered
radical scavenger TEMPO[14] was employed in the reaction. To
our delight, when TEMPO (3.5 equiv.) was charged in the auto-
oxidative stage, the self-coupling was totally inhibited and the
TEMPO-trapped ring-opening product d1 was afforded in 74%
yield. Significantly, d1 could be easily converted to the desired
Table 1. Optimization of the Reaction Conditions.[a]
Entry
Variation of
conditions of Step 2
RT, 72 h
Yield
(d1, %)[b,c]
Yield
(e1, %)[b]
67
1
2
74
83
92
68
76
86
16
40 oC, 64 h
75
3
none
80
4
TEMPO (1.5 equiv.)
TEMPO (2.5 equiv.)
TEMPO (5 equiv.)
under Ar
60
5
70
6
72
7
-
8
CH3CN instead of DMA
DCE instead of DMA
toluene instead of DMA
CH3OH instead of DMA
53
9
36
10
11
trace
39
[a] A mixture of a1 (0.3 mmol), b1 (0.39 mmol), and Et3N (0.45 mmol) in DMA
(2 mL) was stirred under Ar at RT for 1 h, and then TEMPO (3.5 equiv.) was
added in the reaction mixture and stirred at 50 oC under air for additional 20 h.
After remove DMA, the miture was treated with mCPBA (3 equiv.) in DCM (10
mL) at 0 oC for 10 min. [b] Isolated yield. [c] Without step 3. TEMPO = 2,2,6,6-
tetramethyl-1-piperidinyloxy, mCPBA = m-Cl-peroxybenzoic acid, DMA = N,N-
dimethylacetamide, DCE = 1,2-dichloroethane, DCM = dichloromethane.
containing
cycloamine
moiety.
D-glucosamine
was
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10.1002/anie.201914623
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Scheme 2. Scope of cycloalkanamines. [a] Isolated yields. [b] Reaction conditions, see note [a] in Table 1. [c] Bn = Benzyl. [d] Boc = tButyloxycarbonyl. [e]
The reaction was conducted on 3 mmol scale.
regioselectively deconstructed to the corresponding acid e37,
despite the latter is easy to decarboxylate to e37’.
Indomethacin derivative a38 can also be readily transformed
the corresponding product e38 in 72% yield. Bi- and tri-
peptides containing aminoproline were deconstructed very
well in this tactic (e39 and e40). The reaction enables the
efficient and regioselective cleavage of A ring of steroids in
diosgenin and cholesterol derivatives (e41 and e42). This C-C
bond dissociation can also be used on acyclic substrates
containing ethylamine moiety, as demonstrated in the case of
pregnenolone derivative a43, providing e43 and methyl-1,2,4-
trizole e15’ in good yields. Notably, this protocol can be
conducted on
a gram-scale without any difficulty, as
demonstrated in the case of e20 in 84% yield (0.893 g). By
utilizing decarboxylative functionalization, e20 can be easily
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transformed to diversified molecules (see SI).
In summary, we have developed
a
deconstructive
Considering that 1,2,4-triazole scaffold possesses good
biocompatibility and tissue bioactivity,[15] which are found in
antimicrobial agents such as terconazole, fluconazole, and
itraconazole as well as in aromatase inhibitors anastrozole
and letrozole, we also explored the scope of hydrazonyl
chlorides for the tactics. Gratifyingly, as depicted in Scheme 3,
a series of aryl and alkyl substituted hydrazonyl chlorides are
all suitable for this conversion, affording 1,3,5-trisubstituted-
1,2,4-triazoles in moderate to excellent yields.
oxygenation of unstrained primary cycloalkanamines through
an aromatization driven C(sp3)-C(sp3) single-bond cleavage
ring opening for the first time. The present tactic not only
exploits in-situ forming pre-aromatics as the source of the
aromatization driving force but also realizes auto-oxidative
ring-opening of unstrained aliphatic rings under mild conditions.
The synthetic practicability of this strategy has been
demonstrated by regioselective deconstructive oxygenation of
a great variety of substrates including mono-, fused, and
bridged cyclic alkanamines as well as alkaloids, osamines,
peptides, and steroids. Consequently, a series of 1,2,4-
triazole-featured acyclic carbonyl compounds have been
efficiently produced. Further research about deconstructive
functionalization of unstrained aliphatic rings is ongoing in our
laboratory.
Acknowledgments
We thank the National Natural Science Foundation of China
(Nos. 21873041, 21632001, and 21422205) and the “111”
project for financial support.
Scheme 3. Scope of hydrazonyl chlorides. [a] Isolated yield. [b] Reaction
conditions, see note [a] in Table 1.
Keywords: aminyl radical • auto-oxidation • cycloalkanamines
• C-C bond cleavage • oxygenation
Based on literatures and our observations, a plausible
mechanism for the protocol was postulated as shown in
Scheme 4. Cycloalkanamine first reacts with hydrazonyl
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I
via nucleophilic
substitution. I is subsequently auto-oxidized by air to generate
the hydrazonyl radical II [16] which then experiences a cascade
1,5-H-atom transfer and further oxidation/ annulation process
to form the pre-aromatics III (see SI for the isolation and
identification of intermediates I-1 and III-1). The succeeding
auto-oxidation of III by air yields the aminyl radical IV. The
latter undergoes radical C-C bond cleavage enabled by the
aromatization driving force to afford the distal alkyl radical V
which is immediately intercepted by TEMPO to give ring-
opening product VI. The treatment of VI with mCPBA to
produce the intermediate N-oxide VII which immediately
experiences Cope-elimination to give 1,2,4-triazole-containing
acyclic carbonyl compound e.[17] Under the present conditions,
acyclic aldehyde can be further transformed to acyclic
carboxylic acid through Baeyer-Villiger oxidation.[18,19]
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104, 4105; (b) A. Horn, U. Kazmaier, Eur. J. Org. Chem. 2018, 2531.
[19] For the final step Baeyer-Villiger oxidation of aldehydes, the acyclic
acids e1-4, e9, e12, and e15-31 were formed because the migration
tendency of the H group is higher than the alkyl group. Formamide e10’
and formate e11’ were produced along with the formation of acyclic ac-
ids e10 and e11 due to the similar migration ability of the groups H- and
R-N-CH2- and R-O-CH2-. In the cases of e13, e14, e35, and e38-42,
the reaction stopped at aldehydes because themselves were already
formates/formamides/allylaldehydes which cannot be further trans-
formed under the standard conditions.
This article is protected by copyright. All rights reserved.

10.1002/anie.201914623
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Jian-Wu Zhang, Yuan-Rui Wang, Jia-
Hao Pan, Yi-Heng He, Wei Yu, and Bing
Han*
Page No. – Page No.
Deconstructive Oxygenation of Un-
strained Cycloalkanamines
A regioselective deconstructive oxygenation of unstrained cycloalkanamines has
been developed for the first time. This metal-free method involves the substitution
reaction of cycloalkanamines with hydrazonyl chlorides and subsequent auto-
oxidative annulation to in-situ generate pre-aromatics, followed by N-radical-
promoted aromatizative ring-opening and further oxygenation by TEMPO and
mCPBA.
This article is protected by copyright. All rights reserved.