A cascade approach to 3D cyclic carbamates: Via an ionic decarboxylative functionalization of olefinic oxamic acids

Article abstract of DOI:10.1039/c9cc07709j

An m-CPBA-mediated intramolecular epoxidation-decarboxylative alkoxylation cascade reaction of olefinic oxamic acids has been developed. The distinct ionic decarboxylative mechanism was preliminarily revealed. The protocol features mild reaction conditions and operational simplicity, allowing the construction of diverse medicinally valuable 5-7 membered 3D cyclic carbamate architectures in moderate to high yields.

Full text of DOI:10.1039/c9cc07709j

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A cascade approach to 3D cyclic carbamates
via an ionic decarboxylative functionalization
of olefinic oxamic acids†
Cite this: Chem. Commun., 2020,
56, 86
Received 1st October 2019,
Accepted 22nd November 2019
Huaqiang Fan,‡a Yi Wan,‡a Peng Pan,a Wenbin Cai,a Shihui Liu,a Chuanxu Liu*b and
a
Yongqiang Zhang
*
DOI: 10.1039/c9cc07709j
rsc.li/chemcomm
An m-CPBA-mediated intramolecular epoxidation-decarboxylative radical-engaged decarboxylation of oxamic acids, an ionic
alkoxylation cascade reaction of olefinic oxamic acids has been decarboxylation approach enabled by imine epoxidation was
developed. The distinct ionic decarboxylative mechanism was preliminarily disclosed for C–O bond formation. This protocol
preliminarily revealed. The protocol features mild reaction condi- features mild and metal-free reaction conditions and opera-
tions and operational simplicity, allowing the construction of tional simplicity, serving as a powerful tool for the synthesis of
diverse medicinally valuable 5–7 membered 3D cyclic carbamate structurally diverse and medicinally valuable three-dimensional
architectures in moderate to high yields.
(3D) cyclic carbamates bearing a quaternary carbon centre ortho to
the oxygen atom (Fig. S1, ESI†).10–15 Interestingly, in addition
One of the central goals of organic synthesis is to develop new to the 5/6-membered 3D cyclic carbamates with better stability,
reactions for the synthesis of complex and biologically impor- the synthesis of challenging 7-membered structures is also
tant targets using readily accessible starting materials. Realiz- achieved.
ing this challenging goal relies on uncovering new reactivity,
which can transform into a powerful strategy for distinct bond 2-quinolinone 2a by using a hypervalent iodine(III)-mediated
connection and functionalization. intramolecular decarboxylative Heck-type reaction of 2-(prop-1-
In our exploration of a new method for the synthesis of
Oxamic acids are conveniently prepared with great structural en-2-yl) phenyloxamic acid 1a,8 unexpectedly, a six-membered
diversity by the direct coupling of various amines with the cyclic carbamate bearing a quaternary carbon center ortho to
feedstock oxalic acid or oxalyl chloride. Intensive research has the oxygen atom 3a (confirmed by single X-ray crystal structure
been focused on the utilization of carbamoyl radicals in situ analysis, see Scheme S1 in the ESI† for details) was produced in
generated via the oxidative decarboxylation of oxamic acids, a low yield (21%, entry 2, Table 1) when 4-FC6H4I was used as
which enables the construction of amide, carbamate and urea the catalyst and m-CPBA (85%) as the oxidant.
functionalities through C–C, C–O or C–N bond formation.1–7 In
our previous work, the hypervalent iodine(III)-mediated intra-
molecular decarboxylative Heck-type reaction of 2-vinyl-phenyl
oxamic acids was also realized by following a radical pathway,
enabling the synthesis of diverse 2-quinolinone structures
(Scheme 1a).8 Herein we wish to report an unprecedented
intramolecular epoxidation-decarboxylative alkoxylation cascade
reaction of olefinic oxamic acids using m-CPBA9 as the sole
promoter (Scheme 1b). Distinct from the well-documented
a State Key Laboratory of Bioengineering Reactor, Shanghai Key Laboratory of New
Drug Design and School of Pharmacy, East China University of Science and
Technology, Shanghai 200237, P. R. China. E-mail: yongqiangzhang@ecust.edu.cn
b Department of Hematology, Xinhua Hospital, Shanghai Jiao Tong University
School of Medicine, Shanghai, 200092, P. R. China. E-mail: lioucx@gmail.com
† Electronic supplementary information (ESI) available: Full experimental details
and NMR spectra. CCDC 1902836 and 1902837. For ESI and crystallographic data
Scheme 1 The intramolecular decarboxylative funtionalization of olefinic
in CIF or other electronic format see DOI: 10.1039/c9cc07709j
oxamic acids.
‡ These two authors contributed equally to this paper.
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Table 1 Investigation of the m-CPBA mediated intramolecular epoxidation-
decarboxylative alkoxylation cascade reactiona
Entry
Oxidant (equiv.)
Time (h)
2ab
3ab (%)
1
2
3
4
5
6
7
8
4-FPhI(OAc)2 (1.5)
m-CPBA (1.5)
m-CPBA (1.5)
m-CPBA (2.0)
m-CPBA (2.2)
m-CPBA (2.5)
m-CPBA (2.2)
m-CPBA (2.2)
m-CPBA (2.2)
m-CPBA (2.2)
m-CPBA (2.2)
m-CPBA (2.2)
24
24
24
24
24
24
24
24
24
36
24
24
80%
—
—
—
—
—
—
—
—
—
—
—
—
21c
39
74
88 (79)d
79
o10e
o10 f
42g
9
10
11
12
84
56h
69d,i
a
Reaction conditions: 1a (0.15 mmol, 1.0 equiv.), oxidant (1.5–2.5 equiv.),
CHCl3 (3.0 mL), rt, otherwise noted. b Yields were determined by 1H NMR
using CH2Br2 as an internal standard. c 0.2 equiv. of 4-FC6H4I was employed.
d
f
e
Isolated yields were reported. 2.2 equiv. of NaHCO3 was employed.
g
2.2 equiv. of KF was employed. 2.2 equiv. of TFA was employed.
Performed at 50 1C. Performed on 1.5 g scale.
h
i
This unexpected outcome inspired us to systematically
investigate the interesting process. The use of m-CPBA (85%)
as the sole promoter also led to the generation of 3a in a higher
yield (39% yield, entry 3) and 2.2 equivalents proved to be the
optimal (39–88% yields, entries 3–6). The other oxidants such as
hydrogen peroxide (30% H2O2) and oxone (2KHSO5ꢀKHSO4ꢀK2SO4)
were also able to promote the reaction albeit with inferior
reaction efficiency (Table S1, ESI†). These results, as well as
the control experimental studies (Table S1, ESI†), suggest that
Scheme 2 The substrates bearing different substituents on the aromatic
ring.a a Reaction conditions: see the general procedure B for experimental
details, and the isolated yields are reported, unless otherwise noted.
epoxidation plays a crucial role in this transformation. The these groups at the 5 position displayed slightly inferior reac-
addition of base such as NaHCO3 and KF, which were reported tion efficiency (3i–3o, 70–80% yields). Notably, the oxidation-
to facilitate m-CPBA-mediated epoxidation,17,18 was detrimental sensitive alkynyl group was well tolerated (3h, 68% yield).
to the process (entries 7 and 8). This result indicates that an Introducing strong electron-donating groups on the benzene
epoxide ring-opening reaction promoted by the in situ generated ring was more pronounced detrimental to the reaction (3p–3r,
3-chlorobenzoic acid might be involved in this process. However, 48–65% yields), which could be attributed to the undesired
the use of strong acid TFA as an additive led to a dramatic oxidative side reactions of these highly electron-rich methoxy-
decrease of the yield (entry 9, 42% yield). Screening of solvents aniline structures. Both the methyl group at the 3 position and
revealed that CHCl3 was optimal for this reaction (Table S2, the fused benzene ring at the 3 and 4 positions distinctly
ESI†). Furthermore, neither running the reaction at a higher reduced the reaction efficiency (3s–3t, 60–64% yields) perhaps
temperature (50 1C) nor extending the reaction time to 36 h owing to the steric hindrance. It should be noted that chloride
further improved the reaction efficiency (56–84% yields, entries and cyano groups were well tolerated, providing handles for
10 and 11). Accordingly, the optimal reaction conditions are further functionalization. The N-methylated substrate was also
established as shown in entry 5 (m-CPBA 2.2 equiv., CHCl3, rt, proved to be an effective reactant (3u, 82% yield). Furthermore,
24 h). Under the optimal reaction conditions, the reaction can this protocol was compatible with the tetrahydroquinoline and
be scaled up to 1.5 g and provide the product with 69% isolated indoline derived 2-vinyl phenyloxamic acids, enabling the synthesis
yield (entry 12).
Having established the optimal reaction conditions, we next synthetically useful yields (3v–3w, 56–61% yields).
sought to evaluate the substrate scope by varying the substitu- The cyclic carbamatation of the phenyloxamic acids with
of therapeutically valuable tricyclic carbamate structures19 in
ents on the aromatic ring of 2-(prop-1-en-2-yl)phenyloxamic different alkene moieties at the ortho position was then inves-
acid (Scheme 2). The reactions proceeded well for the sub- tigated (Scheme 3). The 2-vinyl phenyloxamic acids without any
strates bearing both electron-withdrawing and weak electron- substituents on the alkene group or with the phenyl group at
donating moieties at the 4 or 6 position, providing the products the 10 position (R3 = Ph, R4 = R5 = H) performed well under
in excellent yields (3b–3g, 80–91% yields). The substrates with the reaction conditions (5a–5h, 66–83% yields). However, strong
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Scheme 4 The synthesis of 7- and 5-membered 3D cyclic carbamates.
facilely accessed in a good yield with our method (5q, 62%
yield).
To further establish the general application of this transfor-
mation, we next sought to examine the feasibility of our method
in the synthesis of other ring sized cyclic carbamates (Scheme 4).
To our delight, this strategy was also proved to be effective
for constructing the 7-membered cyclic carbamate structure
(7a, 41% yield), which is difficult to synthesize via the existing
methods.20–26 Furthermore, 2-phenylprop-2-en-1-amine derived
oxamic acid 8a was also amendable to this protocol, providing
5-membered cyclic carbamate 9a in a synthetically useful yield
(32% yield).
We sought to elucidate the mechanistic aspects of this
interesting reaction. The addition of TEMPO in the reaction
has little effect on the outcome (Scheme S2B, ESI†), suggesting
that the reaction proceeds with a non-radical decarboxylation
mechanism. As far as we are aware, the decarboxylation process
with oxamic acids often proceeds via a radical pathway.1–7 The
treatment of the methyl esterified 2-vinyl phenyloxamic acid
11a with the reaction conditions provided an oxidative cleavage
product of terminal alkene 12a (Scheme S2C, ESI†), which
further concludes that epoxidation of the olefin is involved in
the process (Scheme S3, ESI†).27,28 Considering the fact that the
use of a methylene group in place of the amide carbonyl group
of oxamic acid failed to produce the cyclic carbamate structure
(Scheme S2D, ESI†); it is believed that the amide group might
participate in the intramolecular epoxide ring-opening reaction
as a nucleophile to form the benzoxazine intermediate III
(Scheme 5).
Scheme 3 The substrates with structural variation of alkenes.a a Reaction
conditions: see the general procedure B for experimental details, and the
isolated yields are reported, unless otherwise noted. b not detected.
c Diastereomeric ratio (d.r.) determined using 1H NMR spectroscopy: 5j,
dr = 3.7 : 1 (4j, E:Z = 3.2:1); 5l and 5m, dr 4 20 : 1 (4l and 4m, E:Z 4 20 : 1).
electron-withdrawing substituents such as the trifluoromethyl
group (R3 = CF3) completely shut down the reaction (5i). The
reactants with the methyl group at the terminal position of alkene
reacted smoothly, giving the products in excellent yields (5j–5k,
84–86% yields). In contrast, the use of phenyl and thienyl groups
at this position resulted in a dramatic decrease of the yields
(5l–5m, 47–48% yields). The stabilizing effect of aryl on the
carbocation might result in a decrease of the eletrophilicity of
the epoxide intermediate, which helps to explain this result.
However, the steric hindrance effect cannot be totally excluded.
It is to be noted that the configuration of alkene (Z or E) has little
effect on the reaction efficiency, thus stereoretentively producing
the products 5j, 5l and 5m.
Based on these studies,
a plausible mechanism was
proposed (Scheme 5). The reaction is initiated through the
epoxidation of alkene to produce the epoxide intermediate I. An
SN2 type intramolecular ring-opening reaction of protonated
epoxide II enables the generation of a benzoxazine carboxylic
In light of the high importance of sp3 and spiro-enriched
cyclic carbamates in drug discovery,10,16 we further tested the
reactivities of substrates with various cycloalkenyl groups. We
found that the reactions of this class of substrates proceeded
smoothly to deliver the corresponding sp3-enriched spirocyclic
carbamates in moderate to high yields with excellent trans-
stereoselectivity (5n–5s, 52–82% yields). This stereospecificity
suggests that an SN2 type ring-opening reaction of epoxide
might be involved in this process. Notably, the key intermediate
for the synthesis of an antihypotensive drug candidate12 can be
Scheme 5 Proposed mechanism.
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with inferior reaction efficiency and with a handle for further
synthetic elaboration (10a–10d, 38–57% yields, Scheme 6).
In conclusion, we describe here an unprecedented metal-
free intramolecular epoxidation-decarboxylative alkoxylation
cascade reaction of readily accessible and easily handled olefinic
oxamic acids using m-CPBA as the sole promoter. Distinct from
the well-established radical-engaged decarboxylation of oxamic acids,
the new process follows an ionic pathway in which imine epoxida-
tion enables the decarboxylative C–O bond formation. The new
reactivity transforms into an alternative approach for the synthesis
of structurally diverse and medicinally valuable 5–7 membered 3D
cyclic carbamate architectures. Furthermore, this protocol is mild
and operationally simple and displays excellent functional group
tolerance and broad substrate scope. Further exploration of the
asymmetric version of this transformation and validation of the
proposed mechanism are still ongoing in our laboratory.
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Financial support from the program of the National Natural
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Conflicts of interest
There are no conflicts to declare.
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