Remote Directed Isocyanation of Unactivated C(sp3)-H Bonds: Forging Seven-Membered Cyclic Ureas Enabled by Copper Catalysis

Article abstract of DOI:10.1021/acs.orglett.9b04542

Reported herein is an unprecedented copper-catalyzed site-selective ?-C(sp³)-H bonds activation of aliphatic sulfonamides for constructing the synthetically useful seven-membered N-heterocycles. A key to success is the use of in-situ-formed amide radicals, to activate the inert C(sp³)-H bond, and inexpensive TMSNCO, as a coupling reagent under mild conditions. To the best of our knowledge, this represents the first use of alkylamine derivatives as a five-membered synthon to prepare a seven-membered N-heterocycles.

Full text of DOI:10.1021/acs.orglett.9b04542

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Letter
Remote Directed Isocyanation of Unactivated C(sp3)−H Bonds:
Forging Seven-Membered Cyclic Ureas Enabled by Copper Catalysis
Hongwei Zhang,* Peiyuan Tian, Lishuang Ma, Yulu Zhou, Cuiyu Jiang, Xufeng Lin, and Xiao Xiao
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ABSTRACT: Reported herein is an unprecedented copper-
catalyzed site-selective δ-C(sp3)−H bonds activation of aliphatic
sulfonamides for constructing the synthetically useful seven-
membered N-heterocycles. A key to success is the use of in-situ-
formed amide radicals, to activate the inert C(sp3)−H bond, and
inexpensive TMSNCO, as a coupling reagent under mild
conditions. To the best of our knowledge, this represents the
first use of alkylamine derivatives as a five-membered synthon to
prepare a seven-membered N-heterocycles.
edium-ring nitrogen heterocycles exhibit a wide range
M
of pharmaceutical activities, and they have found a
myriad of applications.1 Among them, the seven-membered
cyclic urea scaffold is the core motif in a family of bioactive
agents, such as highly potent HIV protease inhibitors,
including structurally symmetrical DMP 323 and DMP 450,
and the unsymmetrical yet intriguing β-lactamase inhibitor
NXL-104 (see Figure 1).2 Besides, it also appears in natural
Figure 1. Selected bioactive and natural compounds containing seven-
membered cyclic urea.
products, such as aquiledine.3 As a consequence, developing
efficient and selective process for the assembly of such skeleton
has been a long-standing pursuit for synthetic chemists.
However, probably due to the unfavorable entropic and/or
enthalpic factors associated with medium-ring synthesis,4
methods to construct such seven-membered cyclic urea
compounds are sparsely disclosed with limited catalytic
versions.5 By manipulating highly functionalized substrates,
several Pd-catalyzed5a and Ru-catalyzed5b intramolecular
strategies were disclosed. In sharp contrast, transition-metal-
catalyzed intermolecular strategies are rather limited (Figure
2). For instance, McElwee-White and co-workers5c developed
W-catalyzed carbonylation of symmetric diamine under 80 atm
of toxic CO atmosphere (see Figure 2a, left). The Bower
Figure 2. Catalytic intermolecular strategies for preparing seven-
membered cyclic urea.
group5d reported one elegant example via Rh-catalyzed
carbonylative heterocyclization of cyclopropyl urea (Figure
2a, right). Alper5e reported the Pd-catalyzed [5 + 2]
cycloaddition between 2-vinylpyrrolidines and aryl isocyanates
Received: December 18, 2019
https://dx.doi.org/10.1021/acs.orglett.9b04542
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
Table 1. Optimization of the C(sp3)−H Activation for
to get the seven-membered urea (Figure 2b). However, these
catalytic methods often suffer from the need of cumbersome
steps to prepare the highly functionalized materials, the use of
expensive metal catalysts to cleave the polarized C−C or C−N
bond, toxic reagents, or harsh conditions with low efficiency.
Consequently, it is still highly desirable to develop novel
practical methods for the facile synthesis of seven-membered
a
Preparing Seven-Membered Cyclic Urea
b
entry
ligand
base
solvent
MeCN
yield (%)
urea.
6
c
1
−
−
−
0
20
58
53
61
22
42
60
57
48
67
57
61
56
69
74
63
0
̈
On the other hand, the Hofmann−Loffler−Freytag (HLF)
2
3
4
5
6
7
8
9
BC
BC
BC
NC
Phen
L1
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DCM
reaction constitutes a key breakthrough via nitrogen-centered
radicals triggered a 1,n-hydrogen atom transfer (HAT) process
during the activation of inert C(sp3)−H bonds for versatile
transformations, including the formation of nitrogen hetero-
cycles. Over a century, some elegant examples for preparing
five-7 and six-membered8 nitrogen heterocycles have been
disclosed. However, since the 1,5-HAT is kinetically more
favored,9 the construction of seven-membered ones is still
challenging and remains largely unexplored. In view of this,
coupled with recent discovery from several groups10 and us11
that Cu(I) could easily reduce N-fluoro-tosylamide, to form
the key amidyl radical, we envisioned that this strategy can
make the N-fluoro-tosylamide as a five-membered synthon,
since the selective 1,5-HAT process will generate the carbon
radicals that is located in the δ-position relative to the amide
group. Furthermore, by trapping the radical with a suitable
two-membered synthon such as an isocyanate group, selective
isocyanation might occur, and subsequent intramolecular
nucleophilic addition will provide a new alternative for getting
the seven-membered nitrogen heterocycles. While conceptually
feasible, to get such site-selective isocyanation of inert C(sp3)−
H bond is nontrivial, and it faces several difficulties. First, the
super reactivity of the isocyanate group might make it difficult
to be compatible with the reaction conditions.12 Second,
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
HCOONa
EtONa
tBuONa
K2CO3
LiOAc
DCE
10
11
12
13
14
15
16
1,4-dioxane
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
d
17
18
NaOAc
NaOAc
e
a
Reactions were performed with 1a (0.2 mmol), in 2 mL of solvent
b
c
under a N2 atmosphere, unless noted otherwise. Isolated yield. The
reaction was performed for 24 h. Under 80 °C. Under 25 °C.
d
e
Muniz and co-workers have reported that such substrates may
̃
a ligand could deliver 2a with 61% yield (Table 1, entries 5−
7). Further optimization of reaction solvents indicated that
EtOAc is best for this transformation and the yield can reach
67% (Table 1, entries 8−11). In order to further increase the
efficiency, other bases, such as LiOAc, K2CO3, HCOONa,
EtONa, and tBuONa, were also checked, with LiOAc
exhibiting the best yield (74%) (see Table 1, entries 13−16).
Inferior yield was observed by either elevating or decreasing
the reaction temperature (see Table 1, entries 17 and 18).
The scope of the sulfonamide protecting groups was
examined first, and these results are summarized in Scheme
1. Arylsulfonamides bearing both electron-donating and
electron-withdrawing electronic properties provided moderate
to good yields of corresponding seven-membered cyclic urea
2a−2f (58%−74%), and the efficiency of these with electron-
donating groups is better than that of electron-withdrawing
ones. The configuration of compound 2a was unambiguously
established by single-crystal X-ray analyses.
easily undergo intramolecular cyclization to form five- or six-
membered N-cycles under Cu(I) catalysis.8d Third, the
plausible fluorination via trapping the carbon radical with
another N−F substrate also should be avoided.13 Herein, we
wish to report an unprecedented protocol for the facile
preparation of seven-membered cyclic urea by coupling the
readily available N−F sulfonamide with inexpensive
TMSNCO, using Cu catalysis (Figure 2c). By successfully
overcoming these aforementioned competitive side reactions,
our method allows one to synthesize seven-membered cyclic
urea under mild conditions with good functional group
tolerance and high regioselectivity.
We commenced the optimal condition screen by using 5
mol % CuOAc, N-fluoro-tosylamide (1a, 0.20 mmol) and
inexpensive TMSCNO (1.5 equiv) as the isocyanation source,
with absolute MeCN as the solvent and the reaction was
operating at 60 °C for 12 h under a N2 atmosphere (for full
details, please see the Supporting Information, as well as Table
1). While no desired product was observed without ligand,
adding 5 mol % of 2,9-dimethyl-4,7-diphenyl-1,10-phenanthro-
line (BC), to our delight, enabled the isolation of anticipated
2a with 20% yield (Table 1, entries 1 and 2). Considering that
the base might be helpful to enhance the nucleophilicity of
sulfonamide, NaOAc was tested and it turns out that adding
0.3 equiv could improve the yield to 53% (Table 1, entry 3).
Encouraged by this, a systematic screening of copper salts
bearing different anions showed that CuOAc was the best
choice (not shown in Table 1). Screening other commercially
available ligands indicated that the use of neocuproine (NC) as
Scheme 1. Scope of Sulfonamide
B
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Next, under the optimal conditions, the alkyl substituent
scope of the reaction was examined; these results are
summarized in Scheme 2. The reaction of TMSNCO with
urea products (2r, 2s, 2t, 2u, and 2v) could be obtained in
yields of 49%−75%, albeit with low stereoselectivity.
As expected, remote C(sp3)−H isocyanation and tandem
cyclization beside an O atom was also achieved, to provide the
oxa-seven-membered cyclic urea product 2w (69%). Moreover,
the structure of 2w was unambiguously established by single
crystal X-ray analyses. Besides, substrates bearing benzylic C−
H bonds could also deliver the products 2x−2ad smoothly in
moderate to good yield (30%−87%). Notably, these cyclic
ureas are very similar to some diazepanone derivatives or
analogues, which were used as 11β-hydroxysteroid dehydro-
genase 1 (11β-HSD1) inhibitors.14 Furthermore, we could use
a convenient approach to remove the Ts group of the cyclic
urea product 2y to obtain the corresponding free urea. (For
details, please see the Supporting Information.) In a ternary
competition between δ/ε secondary C−H bonds and a ζ
benzylic C−H bond, only the product of 1,5-HAT was
observed 2af (65%). For a congener substrate in which the ζ-
position had a methoxy substituent, only the 1,5-HAT product
2ag (72%) was obtained. The reaction also worked with
tertiary inert C−H bonds, such that 1ah could give the
corresponding product 2ah in medium yield (51%). The
tertiary benzylic position C−H bonds also provide the
corresponding cyclic urea product 2ai in 52% yield. For the
five- and six-membered cyclic systems such 1aj and 1ak, the
corresponding cyclic urea products 2aj and 2ak were isolated
with low yields of 41% and 30%, respectively. To our delight,
the unactivated primary C−H bonds also participated well in
the reaction, affording the cyclic urea product 2al (36%).
To further demonstrate the functional-group compatibility
and the potential application of this methodology, late-stage
functionalization of both medicinal and natural product
derivatives was examined under standard reaction conditions,
and these results are summarized in Scheme 3. The reaction of
celecoxib- and pregabalin-derived substrates 1am and 1an
worked well under the standard conditions, delivering the
corresponding cyclic urea products 2am and 2an in moderate
yields. In addition, natural product derivatives 1ao (from
Scheme 2. Scope of the C(sp3)−H Activation for Preparing
a
Seven-Membered Cyclic Urea
a
Reactions were performed using 1 (0.2 mmol), TMSNCO (1.5
equiv), CuOAc (0.05 equiv), NC (0.05 equiv), LiOAc (0.3 equiv),
and 2 Ml absolute ethyl acetate at 60 °C under a N2 atmosphere for
12 h (TLC analysis indicated the full conversion of 1), unless
otherwise stated. Values shown beside compound identifications
represent the yield of the isolated product.
Scheme 3. Late-Stage Functionalization of Medicine
Derivatives and Natural Product Derivatives
various N-fluoro-tosylamide derivatives afforded the desired
seven-membered cyclic ureas 2 in 30%−87% yields. For
secondary alkyl-substituted inert C−H bonds, amination
occurred with complete regioselectivity and could be
converted to the desired seven-membered cyclic urea (2g,
2h) in 62% and 86%, respectively.
The reaction has very good functional group compatibility.
For example, substrates 1i−1o, which contain ester, alkenyl,
alkynyl, bromo, amide, and azido groups, also worked well in
the reaction, affording the desired cyclic urea (2i−2o) in good
yields (42%−82%). These functional groups provide the
opportunity for further modification. In order to examine the
stereoselectivity of this method, some nonactivated, simple
cyclohexyl and cyclopentyl groups were first tested; we could
get paracyclic products 2p (53%, diastereomeric ratio (dr) =
4:1), and 2q (63%, dr = 1.5:1) in good yields, albeit with
moderate diastereoselectivity. Next, open-chain substrates
having 1,4-, 1,3-, and 1,2-stereoinductive effects, such as 1r,
1s, 1t, 1u, and 1v, were tested, and the corresponding cyclic
C
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Letter
estrone) and 1ap (from dehydrocholic acid), can also give the
desired cyclic urea products 2ao and 2ap in 50% and 46%
yields, respectively.
In order to shed light on the mechanism, a series of control
experiments was conducted (Scheme 4). First, the reaction of
undergo C(sp3)−H isocyanation to generate alkyl isocyanate 3
at first; subsequently, intramolecular nucleophilic cyclization to
form cyclic urea will happen smoothly, with the assistance of a
base.
Based on these preliminary studies, a plausible mechanism
was proposed (Figure 3). Initially, reduction of N-fluoro-
Scheme 4. Mechanistic Investigation
Figure 3. Proposed mechanism.
tosylamide 1 by a ligand coordinated [Cu(I)] via a single-
electron-transfer mechanism produced F[Cu(II)] F and
amidyl radical E. Subsequently, amidyl radical E underwent
intramolecular 1,5-HAT to afford the carbon-centered radical
G. The strong affinity16 of F and Si would promote ligand
transfer of F[Cu(II)] with TMSNCO, delivering intermediate
H. Upon radical rebound with G, OCN-[Cu(III)]R species I
could be formed,17 and the following reductive elimination
would produce the remote C(sp3)−H isocyanation product 3
with concurrent regeneration of the catalytic Cu(I) species
(“path a” in Figure 3). Noteworthy, the isocyanate group
transfer step was confirmed by density functional theory
(DFT) calculation, indicating that a lower energy was needed
for the process involving Cu(III) intermediate I than that
needed for direct radical substitution to the isocyanate in H.18
(For details, please see Figure S1 in the Supporting
Information.) Finally, 3 underwent cyclization to form cyclic
urea 2 with the assistance of LiOAc.19 Alternatively, G might
also be trapped by F, forming intermediate J at first.
Subsequent trapping of TMSNCO with the amide group of
G enables the generation of K, and the final reductive
elimination will give rise to 2 and Cu(I) (“path b” in Figure 3).
In summary, we report an unprecedented copper-catalyzed
site-selective δ-C(sp3)−H bonds activation of aliphatic
sulfonamides for constructing the synthetically innate, and
difficult yet very useful seven-membered N-heterocycles for the
first time, enabling the preparation of versatile seven-
membered urea under mild reaction conditions. This also
represents the first construction of seven-membered N-
heterocycles using the 1,5-HAT process of the Hofmann−
[D1]-1x with TMSCNO under standard reaction conditions
afforded [D1]-2x/2x in a ratio of 4:1, indicating an intra-
molecular KIE value of 4:1 (Scheme 4a). A side-by-side kinetic
experiment using 1x and [D2]-1x provided an intermolecular
KIE value of 1:1 (Scheme 4b). These data indicated that the
1,5-HAT, which represents an off-catalytic cycle process,
contributed only minimally to the overall reaction rate.15
Second, δ-C(sp3)−H activation was completely inhibited in
the presence of 1.5 equiv of 2,2,6,6-tetramethyl-1-piperidiny-
loxy (TEMPO) (Scheme 4c), indicating that the reaction
might work through a radical mechanism. Furthermore,
“radical clock” experiment with cyclopropane 4 delivered the
ring-opened product 5 (Scheme 4d), indicating that an
intramolecular 1,5-HAT process might be involved.
Moreover, while performing the reaction of 1ak with
TMSNCO under standard conditions, we could isolate the
key proposed alkyl isocyanate 3a with 35% yield (see eq 1 in
Scheme 5). Furthermore, it is identified that this alkyl
isocyanate 3a could be transformed to the desired 2ak with
25% yield, under base condition cyclization (see eq 2 in
Scheme 5). This result indicated that the reaction might
Scheme 5. Characterization of Key Isocyanate Intermediates
̈
Loffler−Freytag reaction, and this can be used for the late-
stage functionalization of pharmaceutical and natural product
derivatives. Applying the current strategy to asymmetric
versions is ongoing in our laboratory.
D
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Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04542.
■
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Details of experimental procedures; H and 13C NMR
spectra (PDF)
1
Accession Codes
CCDC 1958759 and 1958760 contain the supplementary
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Cambridge Crystallographic Data Centre, 12 Union Road,
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AUTHOR INFORMATION
Corresponding Author
■
Hongwei Zhang − Department of Chemistry, College of Science,
China University of Petroleum (East China), Qingdao 266580,
People’s Republic of China; orcid.org/0000-0002-1480-
6326; Email: zhanghw919@upc.edu.cn
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Authors
Peiyuan Tian − Department of Chemistry, College of Science,
China University of Petroleum (East China), Qingdao 266580,
People’s Republic of China
Lishuang Ma − Department of Chemistry, College of Science,
China University of Petroleum (East China), Qingdao 266580,
People’s Republic of China
Yulu Zhou − Department of Chemistry, College of Science, China
University of Petroleum (East China), Qingdao 266580,
People’s Republic of China; orcid.org/0000-0002-2859-
0626
Cuiyu Jiang − Department of Chemistry, College of Science,
China University of Petroleum (East China), Qingdao 266580,
People’s Republic of China
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Xufeng Lin − Department of Chemistry, College of Science,
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Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This project was supported by the National Natural Science
Foundation of China (No. 21801250), the Fundamental
Research Funds for the Central Universities (No.
18CX02141A), and the Shandong Provincial Natural Science
Foundation (No. ZR2019QB002). We thank the reviewers for
their constructive suggestions.
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F
https://dx.doi.org/10.1021/acs.orglett.9b04542
Org. Lett. XXXX, XXX, XXX−XXX