A newly designed heterodiene and its application to construct six-membered heterocycles containing an N-O bond

Article abstract of DOI:10.1039/c9cc05694g

A new type of zwitterionic nitrosoalkene generated in situ from dehydrohalogenation of α-halo-N-alkylhydroxamic acids was designed. [4+2] cycloadditions of this heterodiene to olefins provide a facile route to construct six-membered heterocycles containing an N-O bond and a new protocol for 1,2-syn carbohydroxylate alkenes with a hydroxyl and acetamide group. DFT calculations support a concerted cycloaddition pathway and the solvent HFIP can stabilize the transition state through H-bonding interaction.

Full text of DOI:10.1039/c9cc05694g

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DOI: 10.1039/C9CC05694G
Journal Name
ARTICLE
A Newly Designed Heterodiene and Its Application to Construct
Six-Membered Heterocycles Containing an N-O Bond
Wenzhi Ji,a† Chen-Long Li,b† Hui Chen,a Zhi-Xiang Yu*b and Xuebin Liao*a
Received 00th January 20xx,
Accepted 00th January 20xx
A new type of zwitterionic nitrosoalkenes generated in situ from dehydrohalogenation of α-halo-N-
alkylhydroxamic acids was designed. [4+2] cycloadditions of this heterodiene to olefines provide a facile route
to construct six-membered heterocycles containing an N-O bond and a new protocol to 1,2-syn
carbohydroxylate alkenes with a hydroxyl and acetamide group. DFT Calculations support a concerted
cycloaddition pathway and the solvent HFIP can stabilize the transition state through H-bonding interaction.
DOI: 10.1039/x0xx00000x
www.rsc.org/
dehydrohalogenation of the corresponding α-haloxoimes or Ag+
induced dehalogenation of α-halonitrones.6,7 Due to the lability of
Introduction
OH
The hetero-Diels-Alder (HAD) reaction is among the most powerful
transformations for the synthesis of functionalized heterocyclic rings
with high regio-, diastereoselectivity and bond-forming economy.1
This efficient method has found tremendous applications in the
synthesis of natural products and biologically relevant compounds.2
During the past decades, numerous heterodienes have been
discovered and significantly expanded the utility of this
transformation.1 However, HDA cycloadditions are often slow and
require either thermal activation or the use of chemical promoters
(such as Lewis acids) for the in situ generation of reactive
heterodiene.1 Thus, it remains challenging to design novel versatile
heterdienes and develop robust HAD reactions which can be
conducted under mild and environment-friendly conditions.
H
O
O
O
HN
O
O
N
H
N
OH
H
H
N
N
O
HOOC
S
O
O
MeO
O
O
OMe
O
trichodermamide A
() homolactivicin
(+) Phyllantidine
F
O
O
N
NH2
I
F
N
OH
O
O
OH
O
HO
H
N
H
OH
H
F
O
O
O
NH
O
H
O
NH
OHC
N
OH
H
asiaticumine B
CH4987655 (MEK inhibitor)
FR900482 (anticancer activity)
Fig. 1 Examples of natural products and pharmacologically active
compounds featuring heterocycles containing an N-O bond.
Heterocycles such as the derivatives of tetrahydro-1,2-oxazines
and 1,2-oxazinane-3-ones, are present in many natural products and
pharmacologically active compounds (Fig. 1).3 To date, common
strategies for the construction of six-membered heterocycles
containing N-O bonds include: [4+2] cycloadditions of dienes to
nitroso compounds;4 Lewis acid catalyzed [3+3] cycloaddition of
nitrones to donor-acceptor(DA) cyclopropanes or allenes;5 hetero
Diels-Alder (HDA) cycloadditions of olefins to conjugated
nitrosoalkenes or nitroalkenes (Fig 2 a).6 Nitrosoalkenes 1 are useful
heterodienes which are usually generated in situ from
a) previous work
R2
R2
R2
R1
R1
base
R1
X
N
(1)
N
O
N
HO
O
1
b) this work
O
R1 R2
O
aCollaborative Innovation Center for Diagnosis and Treatment of Infectious
Diseases, School of Pharmaceutical Sciences,
Tsinghua University, Beijing, 100084 (China)
O
R2
R1
R3
R2
R3
Et3N
(2)
N
N
O
N
O
R1
R3
X
OH
HFIP, rt
E-mail: liaoxuebin@mail.tsinghua.edu.cn
2
bBeijing National Laboratory for Molecular Science(BNLMS)
Key Laboratory of Bioorganic Chemistry and Molecular Engineering of
Ministry Of Education, College of Chemistry
Fig. 2 (a) Hetero Diels-Alder reaction of olefins to nitrosoalkenes . (b)
This work: newly designed heterodiene 2 and its applications.
Peking University, Beijing, 100871 (China)
E-mail: yuzx@pku.edu.cn.
† These authors contributes equally to this work.
nitrosoalkenes 1 and their tendency toward polymerization, the
cycloadditions of nitrosoalkenes to olefins often require great excess
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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of olefins, long reaction times, high dilution and afford Cyclic Oxime collected data are shown in Scheme 1. Functional gVroieuwpAsrticsluecOhnlianes
Ethers in moderate yield.8 In addition, the specific structures further methoxyl, halogens, and esters were aDllOIw: 1e0ll.1-t0o3l9e/rCa9teCdC05u6n9d4eGr
limit the scope and applications of these reactions.9 Recently, standard conditions. The reactions with styrenes bearing electron-
azaxoyallyl cations have emerged as a versatile intermediates in donating groups resulted in the desired products in excellent yields
cycloaddition reactions.10 Our group has also explored the (5b-d). The reactions with styrenes substituted by electron-
azaoxyallyl cations as synthons towards the total synthesis of (±)- withdrawing groups provided the desired product in moderate yields
minfiensine and developed a transition-metal-free synthesis of N- (5f-h). Reactions with 1,2-disubstituted or 1,1-disubstituted styrenes
hydroxy oxindoles based on azaoxyally cations.11 Inspired by these were conducted under the optimized conditions and generated the
works, we postulated that disconnection of alkoyl group in cycloadduct 5i or 5j in 81% or 86% yield, respectively. Furthermore,
azaoxyally cations into a hydroxyl group and alkyl group will make reactions with other aromatic olefins, such as 2-vinylnaphthalene
the oxygen a new nucleophilic site, and generate a novel zwitterionic and 5-vinylindole, proceeded smoothly to give 5k and 5l in good
intermediate 2 with the retention of the fascinating characteristics yields. Notably, cycloaddition occurred with the C-C
of azaoxyally cations. Herein, we describe our newly designed
heterodiene 2 generated in situ from α-halo-N-alkylhydroxamic
acids and its applications to construct six-membered heterocycles
containing an N-O bond and other related scaffolds.
Cl Cl
O
Et3N
Cl
Cl
O
Cl
Me
N
+
HFIP, rt
N
OH
O
Me
3
4a
5
Results and discussion
5b
5c
5d
5e
5f
R= p-Me 90%
Cl Cl
Cl Cl
R= p-OMe 87%
R= o-Me 81%
R= p-Br 74%
R= m-Cl 70%
R= p-F 61%
O
O
N
N
To initiate our investigation, we chose styrene 3a and 2,2,2-trichloro-
N-hydroxy-N-methylacetamide 4a as model substrates (Table 1). The
desired product was obtained in 51% yield under our previous
reaction conditions.11c Further screenings of bases showed that Et3N
is an optimal base for the reaction, generating the annulation
product 5a in 85% yield (entry 5). The solvent was crucial to the
reaction, and conducting the reaction in non-fluorinated solvents led
to trace (< 5%, LC-MS) or no desired product detected (entries 7-11).
Interestingly, performing the reaction under the classical HDA
cycloaddition of nitrosoalkenes conditions only rendered trace
desired product (entries 12, 13).8
O
Me
O
Me
R
5g
5h
R= p-CO2Me 65%
5i
81%
Cl Cl
Cl Cl
Cl Cl
O
O
O
N
N
N
O
Me
O
Me
O
Me
Me
N
Ac
5j
5k
5l
75%
86%
Cl Cl
77%
Cl Cl
Cl Cl
O
O
O
O
N
N
O
Me
N
O
Me
O
Me
65%
Cl Cl
Table 1. Optimization of the reaction conditions.
5m
5n
5o
77%
85%
Cl Cl
Cl Cl
O
H
O
O
Cl Cl
N
O
O
O
Me
N
N
Cl
Cl
base
O
Me
O
O
Me
Cl
Me
H
Ph
N
N
+
5p
5q
5r
92%
dr > 20:1
85%
82%
O
Me
solvent, rt
OH
Cl Cl
Cl Cl
3a
4a
5a
Cl Cl
O
O
O
Entry
1
Base
Yield(%)
51
Solvent
HFIP
N
N
KHCO3
K2CO3
DMAP
DBU
N
O
Me
O
Me
O
Me
Me
5u
2
63
HFIP
Cl Cl
3
5s
5v
5t
51%
84%
Cl Cl
79%
Cl Cl
77
HFIP
O
4
83
HFIP
5
Et3N
O
85
HFIP
O
N
O
O
Me
6
Et3N
24
CF3CH2OH
MeOH
CH2Cl2
THF
Me
N
TMS
N
O
Me
7
Et3N
trace
trace
n.d.
n.d.
n.d.
trace
trace
O
Me
8
Et3N
5w
5x
82%
39%
21%
9
Et3N
10
11
12
13
Et3N
MeCN
toluene
DCM
Et3N
Na2CO3
Na2CO3
Scheme 1. Scope of the alkenes. Yield was that of the isolated
product. Reaction conditions: 3 (0.30 mmol, 1.0 equiv) 4a (0.60 mmol,
2.0 equiv) and Et3N (2.0 equiv) in HFIP (1.5 mL) at room temperature.
Et2O
3a
4a
(2.0 equiv), base (2.0
Reaction conditions:
equiv ) in solvent (1.5 mL) at rt. aYields was that of isolated product. n.d.
(0.30 mmol, 1.0 equiv),
= not detected
double bond in indene (5m) or furan (5n). Conjugated alkenes
preferred to react in good yields. 1,3-cyclohexadiene gave 5o in 77%
yield, while previous nitrosoalkenes tends to serve as 2π-
component.12 Note that if the molecule contained both a C-C triple
Using the optimized reaction conditions, we explored the scope of
alkenes. A variety of alkenes were subjected to the reaction and the
2 | J. Name., 2012, 00, 1-3
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bond and a C-C double bond, cycloaddition took place with the deprotonation by the amine with an estimated activationenergy of
View Article Online
DOI: 10.1039/C9CC05694G
double bond exclusively (5p). The reaction also worked very well with about 23 kcal/mol (see the Supporting Information). The followed
phenyl vinyl ether (5q) or strained olefins such as norbornene (5r), [4+2] cycloaddition is a concerted process with a computed
generating the desired product in 82% and 92% yield, respectively. activation free energy of 13.7 kcal/mol. From Fig. 3a, we can find that
Aliphatic olefins such as cyclohexene or tetramethylethylene the product 5a formation via TS1 is the favorable pathway, while the
performed well under the optimized conditions. When trisubstituted product regio-5a formation pathway via TS1-regio is disfavored by
olefin (1-methylcyclopentene) was subjected to the reaction, 5u was 1.5 kcal/mol comparing to TS1. The rate-determining step is the
obtained as the sole product in 79% yield. The reactivities of other generation of zwitterionic heterodiene if considering that [4+2]
noncyclic simple aliphatic olefins (5v, 5w) decreased dramatically, process is easy. The [4+2] process is an inverse electron demanded
and the cyclized products were obtained in low yields. However, process,15 where alkene provides its HOMO to interact with the
cycloaddition with allyltrimethylsilane resulted in a higher yield of 5x LUMO of the heterodiene. The HFLP molecules could lower the
at 82% yield. The enhanced reactivity was probably ascribed to the LUMO of enophile and facilitate the cycloaddition (see this discussion
silicon effect.13
in the Supporting Information). We can also understand the
regiochemistry from frontier molecular orbitals(FMOs).16,17 The
dichlorine attached carbon atom of the heterodiene (Int1), which has
a larger orbital coefficient in its LUMO than the terminal oxygen atom,
prefers to react with the terminal vinyl carbon of styrene, which has
a bigger orbital coefficient than that of the internal vinyl carbon in
the HOMO of styrene (see Fig. 3b)
Next, the scope of α-halo-N-alkylhydroxamic acids was explored,
results are shown in Scheme 2. Cycloaddition of norbornene 3r with
N-benzyl-2,2,2-trichloro-acetohydroxamic acid under standard
conditions resulted in the cycloadduct 6a in 86% yield. 2,2,2-
Tribromo-N-methylacetohydroxamic acid is another alternative
reagent for 1,4-dipolar cycloaddition (6b). Slightly diminished
reactivity
was
obtained
when
α-phenyl-α-halo-N-
B3LYP/6-311+G(d,p)//B3LYP/6-31+G(d)
solvent = 2,2,2-trifluoroethanol
kcal/mol
Gsol
(a)
HFIP
Me
methylacetohydroxamic acids were subjected to the reaction,
generating the corresponding products 6c and 6d in 47% and 54%
yield, respectively. The reaction was attempted with simple α-alkyl
substituted substrates such as 2-bromo-2-dimethylacetohydroxamic
acid 6e, failed to provide any desired product. To demonstrate the
versatility of the cycloaddition products, the compound 5a was
rapidly converted into different products (see supporting
information Scheme-S1, S-pg10).
O
Cl
Cl
16.0
N
TS1-regio
HFIP
O
14.5
Ph
Ph
TS1
HFIP
Me
NEt3?HCl
O
Cl Cl
0.8
Cl
Cl
HFIP
Ph
-36.3
O
N
Int1
HFIP
0
O
N
HFIP
O
Me
4a
O
regio-5a
Ph
HFIP
Cl
Me
HFIP
N
O
Cl Cl
-41.3
O
Cl
Cl
Cl
HFIP
O
Cl
Me
H
5a
N
O
HFIP
N
R1 R2
O
Ph
O
Me
R2
R1
R3
O
Et3N
+ NEt3
OCH(CF3)2
N
+
HFIP
H
N
X
OH
O
R3
HFIP, rt
3r
4
6
Int1
Br Br
Cl Cl
H
H
H
O
O
H
O
N
N
O
O
H
N
O
Me
H
6a
6b
X = Br
dr > 20:1
86%
X = Cl
dr > 20:1
78%
6c
47%
Cl
O
X= Cl
dr > 20:1
Me Me
O
H
H
TS1
O
TS1-
regio
N
O
N
Me
Me
(b)
larger orbital coefficient
6d
X = Br
dr >20:1
6e
54%
0%
X = Br
larger orbital coefficient
HFIP
2pz: -0.02
3pz: -0.01
Cl
O
2pz: -0.36
3pz: -0.31
C
C
2pz: 0.21
C
3pz: 0.13
C
Cl
Me
N
2pz: 0.37
2pz: 0.31
3pz: 0.22
O
Ph
3pz: 0.31
Scheme 2. Scope of the α-halo-N-alkylhydroxamic acids. Yield was
that of the isolated product. Reaction conditions: 3r (0.30 mmol, 1.0
equiv) 4 (0.60 mmol, 2.0 equiv) and Et3N (2.0 equiv) in HFIP (1.5 mL)
at room temperature.
2pz: -0.34
3pz: -0.26
HFIP
Int1
styrene
LUMO of
HOMO of
Fig. 3 (a) DFT calculations on the reaction of 4a and styrene. (b)
LUMO of Int1, HOMO of styrene and their orbital coefficients.
Then, DFT calculations at the B3LYP/6-311+G(d,p)//B3LYP/6-
31+G(d)14 level were carried out (see the Supporting Information for
details) to understand the reaction mechanism and regiochemistry
(Fig. 3a). Calculations indicate that the reactant binding with two
HFIP molecules can generate the heterodiene through the
Conclusions
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In conclsion, a novel type of zwitterionic nitrosoalkenes
generated in situ from dehydrohalogenation of α-halo-N-
alkylhydroxamic acids was designed. The [4+2] cycloadditions of
this heterodiene to alkenes offer a facile route construct 1,2-
oxazinane-3-ones and
a
new protocol to 1,2-syn
carbohydroxylate alkenes with a hydroxyl and acetamide group.
Computational studies support a concerted pathway and the
solvent HFIP plays a crucial role in the stabilization of
intermediates. We anticipate that this new heterodiene
synthon could be widely applied in other related reactions.
Further studies on the application of this new intermediate are
underway in our laboratory.
6
7
8
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Conflicts of interest
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Perkin. Trans. 1. 1983,6, 1275; (b)T. L. Gilchrist, T. G. Roberts,
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There are no conflicts to declare.
Acknowledgements
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This work was supported by the Collaborative Innovation Center for
Diagnosis and Treatment of Infectious Diseases, Tsinghua-Peking
Centre for Life Sciences and “1000 Talents Recruitment Program”
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