Copper(II)-catalyzed enantioselective intramolecular cyclization of N-alkenylureas

Article abstract of DOI:10.1021/acs.orglett.5b00131

The first Cu(II)-catalyzed highly enantioselective intramolecular cyclization of N-alkenylureas was developed for the concise assembly of chiral vicinal diamino bicyclic heterocycles. Facile removal of carbonyl group of the carbamido moiety allowed for ready access to enantioenriched cyclic vicinal diamines.

Full text of DOI:10.1021/acs.orglett.5b00131

Letter
pubs.acs.org/OrgLett
Copper(II)-Catalyzed Enantioselective Intramolecular Cyclization of
N‑Alkenylureas
Shaomin Fu,† Honghao Yang,† Guoqiang Li,‡ Yuanfu Deng,† Huanfeng Jiang,† and Wei Zeng*,†
†School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510641, China
‡Analysis and Testing Center, Jinan University, Guangzhou 510632, China
S
* Supporting Information
ABSTRACT: The first Cu(II)-catalyzed highly enantioselec-
tive intramolecular cyclization of N-alkenylureas was devel-
oped for the concise assembly of chiral vicinal diamino bicyclic
heterocycles. Facile removal of carbonyl group of the
carbamido moiety allowed for ready access to enantioenriched
cyclic vicinal diamines.
Scheme 1. Metal-Catalyzed Diamination of Alkenes
icinal diamine-containing heterocycles are commonly
encountered in natural products and many biologically
V
active molecules.1 Direct diamination of alkenes presents a
powerful tool to construct such 1,2-diamine motifs.1a,c,d In
recent years, much significant progress toward developing
intermolecular diamination processes has been achieved.2
Notably, the Shi, Chemler, and Michael groups have
successively employed diaziridinones,2l sulfonylamides,2o and
N-fluorobenzenesulfonimides2n as nitrogen sources, in combi-
nation with Pd or a copper salt/chiral ligand catalytic system, to
realize the more challenging asymmetric intermolecular
diamination of olefins. Meanwhile, transition-metal-catalyzed
fully intramolecular diamination (FID) of alkenes has also
attracted great interest because this transformation provides an
atom- and step-economic strategy for rapidly assembling a
complex polycyclic nucleus. Compounds containing chiral
vicinal diamino polycyclic units have already demonstrated
distinctive bioactivity.3 In this context, transition-metal Pd(II),4
Ni(II),5 Au(I,)6 and Cu(I)7 catalysts have been employed to
enable the FID of various functionalized alkenes by Muniz and
̃
Chiba, respectively. Moreover, Chemler and co-workers found
that stoichiometric copper(II) acetate could also efficiently
promote the FID of alkenyl sulfamides.8 However, in
comparison with the Cu(II)-catalyzed asymmetric intra-
molecular carbonamination9 and Cu(II)-catalyzed asymmetric
intermolecular diamination (Scheme 1a)2o of monoamide-
containing alkenes, transition-metal-catalyzed intramolecular
asymmetric diamination of olefins has not achieved any
breakthrough up to now, possibly due to two inherent vicinal
amino anchors (−NHXNH−, X = CO or SO2) from alkene
molecules easily forming cyclometal complexes such as B
(Scheme 1b),10 thereby inhibiting the external chiral ligand-
induced enantioselectivity to some degree. Nevertheless,
considering that transition-metal-catalyzed FID of alkenes
involved a key syn-aminometalation process4b,6,8 in which the
stereochemistry-determining C−N bond-forming step oc-
curred,9,11 we believe that a proper chiral ligand on central
metal ions can play remarkably enantionselective induction by
microcontrolling electronic and steric environments around the
1,2-diamine-reactive centers. Herein we describe the first highly
enantioselective intramolecular diamination of alkenes using
cheap and readily available chiral bis(oxazoline) copper(II)
catalyst (Scheme 1c).
Considering the fact that chiral N-heterocyclic carbenes and
bidentate nitrogen ligands have already been successfully
applied to asymmetric intermolecular diamination2p and
intramolecular carboamination9,11,12 of alkenes, respectively,
we initially screened 2,2′-bipyridine (L1) and crowned
imidazole (L2) to trace the achiral ligand type which could
possibly realize Cu(OTf)2-catalyzed intramolecular diamination
of alkenes with various vicinal diamino groups under the MnO2
(3.0 equiv)/Li2CO3 (2.0 equiv) conditions at 115 °C for 24 h.
Received: January 14, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00131
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
To our delight, we quickly found bipyridine L1 (45 mol %)
could enhance the intramolecuar diamination of N-tosylcarba-
mido-substituted alkene (1d) in the presence of a catalytic
amount of Cu(OTf)2 (35 mol %) to afford 40% yield of the
desired 2d (Table 1, compare entries 1−3 with 4).
Disappointingly, no enhancement was achieved with regard
to the crowned imidazole L2, although its crown-ether ring
(N15C5) can complex with alkali metal cations and play a role
in phase-transfer catalyst.
Table 1. Optimization for Reaction Conditions
With a promising achiral ligand type in hand, we then
directly turned our attention to screening various chiral
nitrogen-containing ligands by employing alkene 1d as the
model substrate. At first, we evaluated chiral N,P-chelating
ligands (L3 and L4) and found (R,R)-L3 could afford 23% yield
of the diamination product 2d with an enantiomeric excess (ee)
of 8% (entry 6 vs 7). Although the enantioselectivity of 2d was
very poor, this positive result encouraged us to further
investigate the chiral induction of chiral N,N-chelating
bidentate oxazoline ligands with different backbones (entries
8−18). Gratifyingly, among the tested chiral ligands, (R,R)-L15
was the most effective ligand which furnished 2d in 73% yield
with an excellent ee value (90%) (entry 18); other substituted
alkenes were prepared in order to investigate the generality of
the reaction. As shown in Table 2, the reactivity of substrates 1
was partly dependent on the bisoxazoline ligands such as (R,R)-
L11 and (S,S)-L14 afforded 2d with moderate to good
enantioselectivity (61−79% ee) (entries 14 and 17). Of
particular note is that alkali metal lithium carbonates exerted
significantly enhanced enantioselective catalytic performance
compared with Na2CO3, and NaHCO3, etc. (compare entries
19−22 with 18).13 Especially for Cs2CO3, basically no desired
2d was observed (entry 22). Moreover, employing the AgSbF6
(70 mol %) could increase the yield of 2d to 95%, but with the
enantioselectivity of 2d dropping to 29% ee (entry 23). Finally,
reducing the amount of copper catalyst Cu(OTf)2 and chiral
ligand L15 led to poorer yield and ee value (entry 24) (see the
Supporting Information for the more details about screening of
reaction conditions).
With these optimized conditions in hand, a representative
selection of N-sulfonylcarbamido-substituted alkenes was
prepared in order to investigate the generality of the reaction.
The intramolecular diamination of N-arylsulfonyl-substituted
substrates 1d−n consistently produced the desired optically
active bicyclic compounds (2d−n) in moderate to good yields
with excellent enantioselectivity (entry 1, 61−79% yield, 89−
96% ee). Para- or meta-substitution of N-sulfonyl phenyl rings
with electron-donating (Me, MeO) or electron-withdrawing
(CF3, NO2, halogen, etc.) groups does not significantly affect
the yield and enantioselectivity. Moreover, N-methyl, N-(2-
thienyl), and N-(1-naphthyl) sulfonyl group substituted alkenes
(1o−q) could also exhibit good reactivity with excellent 90−
98% ee (2o−q), no matter whether the N-sulfonyl moiety
varies in size. Besides the δ,δ-diphenyl substituted alkenes, δ,δ-
dimethyl substituted olefin (1s) was also compatible for this
reaction and provided the diamination products 2s (71% yield)
with 86% ee (entry 3). However, N-(2-allylphenyl)urea
derivative 1r and 1-allyl-1-carbamidomethylcyclohexane 1t
afforded the corresponding cyclization products in 67% and
72% yield with a moderate enantioselectivity (49% ee for 2r
and 65% ee for 2t) probably owing to their conformation
rigidity and steric reasons (entries 2 and 4). Unfortunately, in
the absence of δ-substitution, alkene 1u could not furnish the
desired product 2u due to the lack of a Thorpe−Ingold effect,14
a
All the reactions were carried out using alkenes (1) (0.10 mmol) and
L15 (45 mol %) with Cu(OTf)2 (35 mol %) in the presence of MnO2
(3.0 equiv) and Li2CO3 (2.0 equiv) in PhCF3 (2.0 mL) at 115 °C for
24 h under Ar in a sealed reaction tube, followed by flash
b
c
chromatography on SiO2. Isolated yield. Determined by HPLC
d
using a Phenomenex Lux 15u cellulose-1 Chiralpak. nr = no reaction.
e
f
g
Decomposed. Not determined. CuBr2 (35 mol %)/AgSbF6 (70 mol
h
%) system was used. Cu(OTf)2 (20 mol %) and L15 (25 mol %) was
used.
and the starting material 1u was recovered completely (entry
5). Finally, we were gratified to find that this transformation is
not limited to δ,δ-geminal disubstituted alkenes; the racemic δ-
B
DOI: 10.1021/acs.orglett.5b00131
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 2. Substrate Scope
Table 2. continued
f
chiral product; Not determined. The enantiomers could not be
separated by HPLC on a chiral stationary phase.
monoalkyl- and δ-monoaryl-substituted alkenes (1v and 1w)
could also participate successfully in the enantioselective
intramolecular diamination and provided 2v (42% yield) and
2w (46% yield) with 53% ee and 90% ee (entry 6),
respectively.15 More importantly, the reaction system still
enabled β-methyl- or β-phenyl-substituted alkenes 1x and 1y to
furnish the chiral quaternary carbon-containing diamination
product 2x (69% yield with 93% ee) and 2y (49% yield),
respectively (see entry 7).
Finally, we determined the absolute configuration of these
optically active bicycles via X-ray analysis of 2l, which proved to
be the 2-(4-iodobenzenesulfonyl)-6,6-diphenylhexahydro-(S)-
pyrrolo[1, 2-c]imidazo-3-one.16 Hence, the other remaining
cyclization products in Table 2 were also assigned S
stereochemistry by assuming an analogous reaction pathway.
To demonstrate the utility of the optically active bicycles, we
were subsequently able to remove the carbonyl group of the
carbamido moiety of the product (S)-2e by treatment with
Ba(OH)2·8H2O/aq EtOH at 140 °C for 12 h to give 81% yield
of (S)-pyrrolidine 2e-1, which could be further condensed with
formaldehyde to furnish the (S)-hexahydropyrrolo[1,2-c]-
imidazole 2e-2 in 85% yield with 90% ee (Scheme 2).
Scheme 2. Synthetic Application for This Transformation
In summary, we have developed the first example of Cu(II)-
catalyzed asymmetric intramolecular cyclization of N-alkenylur-
eas, which provides a useful method for the rapid assembly of
chiral vicinal diamino bicyclic heterocycles in moderate to good
yields with high to excellent enantioselectivity (up to 98% ee).
The readily available N,N-chelating bidentate oxazoline ligand
in conjunction with alkali metal lithium carbonates plays a key
role for obtaining high enantioselectivity. Further applications
of this transformation toward the synthesis of bioactive chiral
vicinal diamines are underway.
ASSOCIATED CONTENT
* Supporting Information
■
S
Analytical data for all isolated compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: zengwei@scut.edu.cn.
Notes
The authors declare no competing financial interest.
a
All the reactions were carried out using alkenes (1) (0.10 mmol) and
L15 (45 mol %) with Cu(OTf)2 (35 mol %) in the presence of MnO2
(3.0 equiv) and Li2CO3 (2.0 equiv) in PhCF3 (2.0 mL) at 115 °C for
24 h under Ar in a sealed reaction tube, followed by flash
ACKNOWLEDGMENTS
■
We thank the NSFC (No. 21072063 and 21372085) and the
GNSF (No. 10351064101000000) for financial support. The
authors are grateful to Prof. S. R. Chemler (SUNY-Buffalo) for
her valuable suggestions.
b
c
chromatography on SiO2. Isolated yield. Determined by HPLC
d
using a Phenomenex Lux 15u cellulose-1 Chiralpak. nr = no reaction.
e
No diastereoisomer was observed from the1H NMR spectrum of the
C
DOI: 10.1021/acs.orglett.5b00131
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(14) (a) Ingold, C. K.; Sako, S.; Thorpe, J. F. J. Chem. Soc. 1922,
1117. (b) Smith, S. W.; Newmann, M. S. J. Am. Chem. Soc. 1968, 88,
1253.
(15) It is interesting that substrate 1w would lead to the formation of
racemic diasteroisomer 2w and 2w-1 (2w/2w-1 = 2.3:1) in 77%
REFERENCES
■
(1) For reviews on vicinal diamines: (a) Cardona, F.; Goti, A. Nat.
Chem. 2009, 1, 269. (b) Lucet, D.; Gall, T. L.; Mioskowski, C. Angew.
Chem., Int. Ed. 1998, 37, 2580. (c) de Figueiredo, R. M. Angew. Chem.,
Int. Ed. 2009, 48, 1190. (d) Muniz, K.; Martínz, C. J. Org. Chem. 2013,
̃
overall yield using Muniz’s Pd-catalytic conditions (see ref 6), and 2w-
̃
1 was already isolated and characterized by its corresponding 1H NMR
78, 2168. (e) Michalson, E. T.; Szmuszkovicz, J. Prog. Drug Res. 1989,
33, 135. (f) Kotti, S. R. S. S; Timmons, C.; Li, G. Chem. Biol. Drug Des.
2006, 250, 1530. (g) Kotti, S. R. S. S.; Timmons, C.; Li, G. Chem. Biol.
Drug Res. 2006, 67, 101. (h) Zhu, Y.; Cornwall, R. G.; Du, H.; Zhao,
B.; Shi, Y. Acc. Chem. Res. 2014, 47, 3665.
and 13C NMR spectrum (see the Supporting Information). On the
1
other hand, only chiral 2w was detected by using TLC and H NMR
methods under our Cu(II)/(R, R)-L15 conditions, and no diaster-
oisomer 2w-1 was observed.
(2) For the transition-metal-catalyzed intermolecular diamination of
alkenes, see: (a) Sibbald, P. A.; Rosewall, C. F.; Swartz, R. D.; Michael,
F. E. J. Am. Chem. Soc. 2009, 131, 15945. (b) Sibbald, P. A.; Michael, F.
E. Org. Lett. 2009, 11, 1147. (c) Bar, G. L. J.; Lloyd-Jones, G. C.;
Booker-Milburn, K. I. J. Am. Chem. Soc. 2005, 127, 7308. (d) Du, H.;
Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2007, 129, 762. (e) Zhao, B.; Du,
H.; Cui, S.; Shi, Y. J. Am. Chem. Soc. 2010, 132, 3523. (f) Du, H.; Yuan,
W.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2007, 129, 7496. (g) Wang, B.;
Du, H.; Shi, Y. Angew. Chem., Int. Ed. 2008, 47, 8224. (h) Yuan, W.;
Du, H.; Zhao, B.; Shi, Y. Org. Lett. 2007, 9, 2589. (i) Zhao, B.; Yuan,
W.; Du, H.; Shi, Y. Org. Lett. 2007, 9, 4943. (j) Du, H.; Zhao, B.; Shi,
Y. Org. Lett. 2008, 10, 1087. (k) Sequeira, F. C.; Turnpenny, B. W.;
Chemler, S. R. Angew. Chem., Int. Ed. 2010, 49, 6350. For the
transition-metal-catalyzed intermolecular asymmetric diamination of
alkenes, see: (l) Du, H.; Yuan, W.; Zhao, B.; Shi, Y. J. Am. Chem. Soc.
2007, 129, 11688. (m) Du, H.; Zhao, B.; Shi, Y. J. Am. Chem. Soc.
2008, 130, 8590. (n) Ingalls, E. L.; Sibbald, P. A.; Kaminsky, W.;
Michael, F. E. J. Am. Chem. Soc. 2013, 135, 8854. (o) Turnpenny, B.
W.; Chemler, S. R. Chem. Sci. 2014, 5, 1786. (p) Xu, L.; Shi, Y. J. Org.
Chem. 2008, 73, 749.
(16) For X-ray analysis details, see the Supporting Information.
(3) (a) Olliaro, P.; Delgado-Romero, P.; Keiser, J. J. Antimicrob.
Chemother. 2014, 49, 863. (b) Fenwick, A.; Keiser, J.; Utzinger, J.
Drugs Future 2006, 31, 413.
(4) For Pd(II)-catalyzed fully intramolecular diamination of alkenes,
see: (a) Streuff, J.; Hovelmann, C. H.; Nieger, M.; Muniz, K. J. Am.
̈
̃
Chem. Soc. 2005, 127, 14586. (b) Streuff, J.; Hovelmann, C. H.;
̈
Nieger, M.; Muniz, K. J. Am. Chem. Soc. 2008, 130, 763. (c) Muniz, K.;
Streff, J.; Hovelmann, C. H.; Nunez, A. Angew. Chem., Int. Ed. 2007,
46, 7125. (d) Muniz, K. J. Am. Chem. Soc. 2007, 129, 14542.
(5) For Ni(II)- catalyzed fully intramolecular diamination of alkenes:
̃
̃
̈
́
̃
̃
Muniz, K.; Streff, J.; Hovelmann, C. H.; Nunez, A. Angew. Chem., Int.
̃
̈
́
̃
Ed. 2007, 46, 7125.
(6) For Au(I)-catalyzed fully intramolecular diamination of alkenes,
see: Iglesias, A.; Muniz, K. Chem.Eur. J. 2009, 15, 10563.
̃
(7) For Cu(I)-catalyzed fully intramolecular diamination of alkenes,
see: Wang, Y.−F.; Zhu, X.; Chiba, S. J. Am. Chem. Soc. 2012, 134,
3679.
(8) For Cu(II)-catalyzed fully intramolecular diamination of alkenes,
see: (a) Zabawa, T. P.; Kasi, D.; Chemler, S. R. J. Am. Chem. Soc. 2005,
127, 11250. (b) Zabawa, T. P.; Chemler, S. R. Org. Lett. 2007, 9, 2035.
(9) Zeng, W.; Chemler, S. R. J. Am. Chem. Soc. 2007, 129, 12948.
(10) (a) Jilek, R. E.; Tomson, N. C.; Scott, B. L.; Boncella, J. M.
Inorg. Chim. Acta 2014, 422, 78. (b) Edwards, A.; Hogarth, G.;
Hollingsworth, N.; Oller, J. Inorg. Chem. Commun. 2011, 14, 1932.
(11) For Cu(II)-catalyzed asymmetric intramolecular cyclization of
alkenes via a syn-aminometalation process, see: (a) Fuller, P. H.; Kim,
J. W.; Chemler, S. R. J. Am. Chem. Soc. 2008, 130, 17638. (b) Liwosz,
T. W.; Chemler, S. R. J. Am. Chem. Soc. 2012, 134, 2020. (c) Bovino,
M. T.; Chemler, S. R. Angew. Chem., Int. Ed. 2012, 51, 3923.
(12) Yip, K. T.; Yang, M.; Law, K. L.; Zhu, N. Y.; Yang, D. J. Am.
Chem. Soc. 2006, 128, 3130.
(13) For selected examples about alkali metal bases significantly
affecting the enantioselectivity of asymmetric reactions, see: (a) Chu,
L.; Wang, X. C.; Moore, C. E.; Rheigold, A. L.; Yu, J. Q. J. Am. Chem.
Soc. 2013, 135, 16344. (b) Lykke, L.; Halskov, K. S.; Carlsen, B. D.;
Chen, V. X.; Jørgensen, K. A. J. Am. Chem. Soc. 2013, 135, 4692.
(c) Nagao, K.; Yokobori, U.; Makida, Y.; Ohmiya, H.; Sawamura, M. J.
Am. Chem. Soc. 2012, 134, 8982.
D
DOI: 10.1021/acs.orglett.5b00131
Org. Lett. XXXX, XXX, XXX−XXX