Synthesis of N?H Bearing Imidazolidinones and Dihydroimidazolones Using Aza-Heck Cyclizations

Article abstract of DOI:10.1002/anie.201806295

The synthesis of unsaturated, unprotected imidazolidinones via an aza-Heck reaction is described. This palladium-catalyzed process allows for the cyclization of N-phenoxy ureas onto pendant alkenes. The reaction has broad functional group tolerance, can b

Full text of DOI:10.1002/anie.201806295

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International Edition: DOI: 10.1002/anie.201806295
German Edition: DOI: 10.1002/ange.201806295
Aza-Heck Reaction
À
Synthesis of N H Bearing Imidazolidinones and Dihydroimidazolones
Using Aza-Heck Cyclizations
Feiyang Xu+, Scott A. Shuler+, and Donald A. Watson*
[9]
À
Abstract: The synthesis of unsaturated, unprotected imidazo-
lidinones via an aza-Heck reaction is described. This palla-
dium-catalyzed process allows for the cyclization of N-
phenoxy ureas onto pendant alkenes. The reaction has broad
functional group tolerance, can be applied to complex ring
topologies, and can be used to directly prepare mono- and bis-
unprotected imidazolidinones. By addition of Bu4NI, di-
hydroimidazolones can be accessed from the same starting
materials. Improved conditions for preparing unsaturated,
unprotected lactams are also reported.
imidazolidinones with a free N H. Furthermore, none
À
(including C H functionalization) can prepare bis-unpro-
tected imidazolidinones (Figure 2).
I
midazolidinones are common motifs in both synthetic and
natural bioactive compounds of medicinal relevance.[1] Such
compounds have shown activity against a range of conditions,
including leukemia, lung cancer, metabolic disorders, and
HIV. Particularly common amongst these bioactive com-
pounds are imidazolidinones bearing unsaturation or other
Figure 2. State-of-the-Art in Imidazolidinone Synthesis.
functionality vicinal to one of the nitrogen centers, or those
[2]
À
bearing free N H groups (Figure 1). Imidazolidinones can
also serve as versatile synthetic intermediates as they can be
converted into other functional groups such as diamines and
guanidines.[1o,3]
Recently, Heck-type cyclizations of nitrogen electrophiles
have emerged as a powerful and flexible strategy for
preparing nitrogen-containing heterocycles,[10,11] and we
À
have shown that unsaturated lactams bearing free N H
groups can be prepared via the palladium-catalyzed cycliza-
tion of O-phenyl hydroxamates onto pendant alkenes.[12] We
À
hypothesized that the synthesis of N H bearing imidazolidi-
nones from N-phenoxy ureas might also be possible, which
would allow for the direct synthesis of unprotected imidazo-
lidinone scaffolds bearing unsaturation vicinal to one of the
nitrogen centers. Herein, we describe the successful realiza-
tion of that goal, and report conditions for the preparation of
unsaturated, unprotected imidazolidinones using an aza-Heck
strategy. Using easily accessed starting materials, and com-
mercially available catalytic components, we show that the
reaction enjoys broad functional group tolerance and is highly
flexible with respect to accessible ring topologies. Further, by
the addition of iodide additives, isomeric dihydroimidazo-
lones can also be prepared from the same starting materials.
These studies have also revealed catalytic conditions that are
easier to implement than our earlier aza-Heck cyclizations,
and we have demonstrated that these new conditions can also
be used in unsaturated lactam preparation.
Figure 1. Representative Bioactive Imidazolidinones.
Because of their considerable value, various transition
metal-catalyzed approaches to imidazolidinones have been
described. These include Wacker-type cyclizations,[4] carboa-
minations,[5] alkene diamination,[6] C H functionalization,
[7]
À
and other methods.[8] However, with the exception of C H
À
functionalization, all require protection or acidification of the
nitrogen centers, and result in N-protected or N-functional-
ized imidazolidinones; none of these methods can deliver
To start our investigation, we required easy access to N-
phenoxy ureas. Inspired by the work of Beauchemin,[13] we
designed a convenient two-pot, three component sequence
that allows the assembly of the substrates from unsaturated
carbonyls, amines, and 4-nitrophenyl 1-phenoxycarbamate in
up to 85% yield over two steps (1, Scheme 1).[14]
[*] F. Xu,[+] Dr. S. A. Shuler,[+] Prof. Dr. D. A. Watson
Department of Chemistry and Biochemistry, University of Delaware
Newark, DE 19716 (USA)
E-mail: dawatson@udel.edu
[+] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201806295.
Our study began by utilizing our previously optimal
catalytic system of (COD)Pd(CH2SiMe3)2 (2) and tris(2,2,2-
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Table 1: Reaction Optimization.
Scheme 1. Access to N-Phenoxy Ureas.
Entry Pd Catalyst [mol%]
Additive [mol%] Yield [%, 4/5][a]
1
2
3
4
5
6
(COD)Pd(CH2SiMe3)2 [10] none
79/4
0/6
9/18
29/31
62/24
86/6
(MeCN)2PdCl2 [10]
(MeCN)2PdCl2 [10]
(MeCN)2PdCl2 [5]
none
Mg0 [300]
PhMgBr [10]
PhMgBr [5]
PhMgBr [5]
AgOTs [10]
trifluoroethyl)phosphite, and we were delighted to observe
the desired cyclization of 3 in reasonable yield (Table 1,
entry 1). We recognized, however, that 2 has limited com-
mercial availability and is somewhat thermally sensitive.[15] As
such, we investigated the use of more accessible palladium
precatalysts. Consistent with a Pd0/PdII catalytic cycle, the use
of (MeCN)2PdCl2 without an external reductant gave no
desired product (entry 2). With the addition of metallic
reducing agents, such as magnesium, small amounts of
product were observed (entry 3). The use of soluble
PhMgBr as the reducing agent proved more effective, even
at half the catalyst loading (entry 4), and [(cinnamyl)PdCl]2
proved to be superior as precatalyst (entry 5). At this point,
the major byproducts in the reaction were due to alkene
isomerization of both the product (to form dihydroimidazo-
lone 5) and the starting material. Previous reports have shown
that silver additives can suppress alkene isomerization in
traditional Heck-cyclizations.[16] Thus, we investigated the use
of silver salts and found that the addition of substoichiometric
AgOTs dramatically reduced alkene isomerization, allowing
the desired product 4 to be formed in 86% yield with only
minimal formation of byproduct 5 (entry 6). Subsequent
studies, however, showed silver is not required in all reactions
to prevent alkene isomerization (see below).
[(cinnamyl)PdCl]2 [2.5]
[(cinnamyl)PdCl]2 [2.5]
[a] Yield calculated by 1H NMR with 1,3,5-trimethoxybenzene as internal
standard.
The scope of reaction was next investigated (Scheme 2).
The model substrate 4 was isolated in 84% yield, and closely
related derivatives were prepared with similar efficiency (6–
11). More substituted alkenes, including tetrasubstituted
alkene, also participate well in the reaction (12–14). Notably,
the latter two cases result in imidazolidinones bearing fully
substituted carbon centers. In addition, in these cases (as well
as others noted in the table) alkene isomerization was not an
issue and silver additives were not required. Longer alkenyl
derivatives were also tolerated (15–16). Excitingly, these
transformations also demonstrate that bis-unprotected imi-
dazolidinones can be prepared in good yield, allowing access
to this motif for the first time via a metal-catalyzed strategy.
A variety of ring topologies could also be prepared using
this method. Examination of [6,5]-fused bicycle (17) gave
Scheme 2. Substrate Scope.
2
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a near quantitative yield, albeit in a 60:40 isomeric ratio of
By adding iodide, in the form of Bu4NI, selective formation of
allylic-to- homoallylic urea. The closely related compound 18
was produced without alkene isomerization, suggesting
a potential role of the Lewis basic pyridine in the isomer-
ization of 17. [6,5]-spirocyclic ureas can also be prepared in
good yield (19–21). Interestingly, both 19 and 20 were also
obtained as alkene mixtures under the standard conditions. In
contrast, with the use of 2 as precatalyst, this isomerization of
the benzyl- (19) or para-methoxyphenyl-protected (PMP, 21)
products could be avoided. Although these latter conditions
do not allow access to the unprotected urea 20, the tolerance
of the PMP-group provides a protecting group whose removal
is compatible with alkenes, enabling efficient access to these
unprotected ureas.
dihydroimidazolone is possible (Scheme 4). With the model
substrate 3, 80% isolated yield of dihydroimidazolone 5 was
obtained. A number of related examples are shown in
Scheme 4, which demonstrates that highly substituted, and
functionalized dihydroimidazolones can be obtained in good
yields. Thus, simply by appropriate selection of additives,
either imidazolidinones or dihydroimidazolones can be
accessed from the same starting materials.
One limitation that we have found is that tertiary
substituents on the non-reacting nitrogen are not tolerated
(22), presumably due to adverse steric interactions.
As with other aza-Heck cyclizations, 5-membered ring
formation is considerably more efficient than for larger rings
(23). Increased substitution on the 5-membered ring, how-
ever, is well tolerated (24), as is substitution on the alkyl
group (25). A broad range of functional groups are also
compatible with the cyclization, including ethers (6, 9, 21, 23,
29), esters (8, 33), isolated alkenes (35), aromatic halogens
(10–11, 28), trifluoromethyl groups (7), protic functionalities
(15–16, 20, 24, 26, 33), and a range of heterocycles (17–18, 26–
27).
Although stereocenters exo to the forming rings do not
provide stereocontrol (29), endocyclic stereocenters provide
good to excellent levels of stereocontrol in ring formation
(17–18, 30–33).[17]
Urea-forming aza-Heck reactions can also be sequenced
with our earlier aza-Heck protocol to rapidly build up
complex nitrogen-containing polycycles. For example, aza-
Heck cyclization of O-phenyl hydroxamate 36 using the
previously reported aza-Heck strategy results in spirocyclic
lactam 37 in good yield.[12] Two steps covert 37 to N-phenoxy
urea 38, which can then be converted to fused tricyclic
product 39 in 93% isolated yield as single diastereomer using
the urea-forming protocol (Scheme 3).
Scheme 4. Preparation of Dihydroimidazolones.
To further demonstrate the utility of this transformation,
we investigated the synthesis of factor Xa inhibitor 49, which
has potential use as an anti-coagulant (Scheme 5).[19] The aza-
Heck cyclization of N-phenoxy urea 45 worked efficiently on
gram scale to produce imidazolidinone 46. Alkylation with
mesylate 47 yielded the cyanourea 48 in 72% yield, which can
be converted into 49 using a known procedure.[19]
As mentioned before, isomeric dihydroimidazolones were
identified as the major byproduct in early optimization
studies. Although we were able to avoid this byproduct
under the conditions described above, we recognized that
deliberate formation of the dihydroimidazolones would also
be useful due to their prevalence in bioactive compounds.[18]
Scheme 5. Preparation of Factor Xa Inhibitor 49.
Finally, we have found that the catalytic conditions
developed for this aza-Heck cyclization also work with
cyclizations of O-phenyl hydroxamates. Compared to our
previously published reaction conditions, which required the
use of thermally sensitive 2,[12,15] the yields using these new
conditions are either comparable or higher with much lower
catalyst loading (Scheme 6). More importantly, these new
conditions only require widely available precatalyst compo-
nents, which considerably lowers the barrier for application of
this method.
In summary, we have developed a mild, catalytic method
for the synthesis of unprotected, unsaturated imidazolidi-
Scheme 3. Access to Tricyclic Imidazolidinone Using Aza-Heck Strat-
egies.
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E. Furfine, Y. Gray-Nunez, A. Spaltenstein, L. Wright, Bioorg.
Med. Chem. Lett. 2004, 14, 5685 – 5687; h) H.-J. Shue, X. Chen,
N.-Y. Shih, D. J. Blythin, S. Paliwal, L. Lin, D. Gu, J. H. Schwerdt,
S. Shah, G. A. Reichard, J. J. Piwinski, R. A. Duffy, J. E.
Lachowicz, V. L. Coffin, F. Liu, A. A. Nomeir, C. A. Morgan,
G. B. Varty, Bioorg. Med. Chem. Lett. 2005, 15, 3896 – 3899; i) S.-
H. Kwak, S.-C. Bang, H.-H. Seo, H.-R. Shin, K.-C. Lee, L. T. A.
Hoang, S.-H. Jung, Arch. Pharmacal Res. 2006, 29, 721 – 727; j) B.
Pirard, H. Matter, J. Med. Chem. 2006, 49, 51 – 69; k) H.-J. Shue,
X. Chen, J. H. Schwerdt, S. Paliwal, D. J. Blythin, L. Lin, D. Gu,
C. Wang, G. A. Reichard, H. Wang, J. J. Piwinski, R. A. Duffy,
J. E. Lachowicz, V. L. Coffin, A. A. Nomeir, C. A. Morgan, G. B.
Varty, N.-Y. Shih, Bioorg. Med. Chem. Lett. 2006, 16, 1065 – 1069;
l) J. J. Li, J. C. Sutton, A. Nirschl, Y. Zou, H. Wang, C. Sun, Z. Pi,
R. Johnson, S. R. Krystek, R. Seethala, R. Golla, P. G. Sleph,
B. C. Beehler, G. J. Grover, A. Fura, V. P. Vyas, C. Y. Li, J. Z.
Gougoutas, M. A. Galella, R. Zahler, J. Ostrowski, L. G.
Hamann, J. Med. Chem. 2007, 50, 3015 – 3025; m) S. Sun, Z.
Zhang, V. Kodumuru, N. Pokrovskaia, J. Fonarev, Q. Jia, P.-Y.
Leung, J. Tran, L. G. Ratkay, D. G. McLaren, C. Radomski, S.
Chowdhury, J. Fu, B. Hubbard, M. D. Winther, N. A. Dales,
Bioorg. Med. Chem. Lett. 2014, 24, 520 – 525; n) B. Forte, B.
Malgesini, C. Piutti, F. Quartieri, A. Scolaro, G. Papeo, Mar.
Drugs 2009, 7, 705 – 753; o) Y. Ma, S. De, C. Chen, Tetrahedron
2015, 71, 1145 – 1173.
Scheme 6. Examples of Lactam Substrates.
nones and dihydroimidazolones. Identification of PhMgBr as
an external reductant allowed for the use of a cheaper, more
accessible palladium(II) precatalyst in lower catalyst loadings
compared to our earlier aza-Heck protocols. This method
tolerates a wide array of functional groups, ring topologies,
and functionalized alkenes, and can also be directly applied to
the synthesis of bioactive molecules.
[2] a) R. P. Robinson, E. R. Laird, K. M. Donahue, L. L. Lopresti-
Morrow, P. G. Mitchell, M. R. Reese, L. M. Reeves, A. I. Rouch,
E. J. Stam, S. A. Yocum, Bioorg. Med. Chem. Lett. 2001, 11,
1211 – 1213; b) G. A. Reichard, C. Stengone, S. Paliwal, I.
Mergelsberg, S. Majmundar, C. Wang, R. Tiberi, A. T. McPhail,
J. J. Piwinski, N.-Y. Shih, Org. Lett. 2003, 5, 4249 – 4251; c) D. M.
Robinson, M. P. Curran, K. A. Lyseng-Williamson, Drugs 2007,
67, 1359 – 1378.
Acknowledgements
The University of Delaware, the Research Corp. Cottrell
Scholars Program, and the NIH NIGMS (P20 GM104316) are
gratefully acknowledged for support. Dr. Glenn P. A. Yap,
Lotus Separations, LLC, and Dr. Kirk W. Shimkin are
thanked for X-ray crystallography, help with chromato-
graphic separations, and useful suggestions, respectively.
Data was acquired at UD on instruments obtained with the
assistance of NSF and NIH funding (NSF CHE-0421224,
CHE-1229234, CHE-1048367, and CHE-0840401; P30
GM110758, S10 RR026962, and S10 OD016267).
[3] A. Viso, R. Fernꢀndez de laPradilla, A. Garcꢁa, A. Flores, Chem.
Rev. 2005, 105, 3167 – 3196.
[4] a) Y. Tamaru, M. Hojo, H. Higashimura, Z. Yoshida, J. Am.
Chem. Soc. 1988, 110, 3994 – 4002; b) H. Harayama, H. Okuno,
Y. Takahashi, M. Kimura, K. Fugami, S. Tanaka, Y. Tamaru,
Tetrahedron Lett. 1996, 37, 7287 – 7290; c) W.-H. Rao, X.-S. Yin,
B.-F. Shi, Org. Lett. 2015, 17, 3758 – 3761; d) K. Shen, Q. Wang,
Chem. Sci. 2015, 6, 4279 – 4283; e) P. Xiong, F. Xu, X.-Y. Qian, Y.
Yohannes, J. Song, X. Lu, H.-C. Xu, Chem. Eur. J. 2016, 22,
4379 – 4383; f) K. Shen, Q. Wang, J. Am. Chem. Soc. 2017, 139,
13110 – 13116.
Conflict of interest
[5] a) J. A. Fritz, J. S. Nakhla, J. P. Wolfe, Org. Lett. 2006, 8, 2531 –
2534; b) J. P. Wolfe, Eur. J. Org. Chem. 2007, 571 – 582; c) J. A.
Fritz, J. P. Wolfe, Tetrahedron 2008, 64, 6838 – 6852; d) B. A.
Hopkins, J. P. Wolfe, Angew. Chem. Int. Ed. 2012, 51, 9886 –
9890; Angew. Chem. 2012, 124, 10024 – 10028; e) N. R. Babij,
J. P. Wolfe, Angew. Chem. Int. Ed. 2013, 52, 9247 – 9250; Angew.
Chem. 2013, 125, 9417 – 9420; f) K. Shen, Q. Wang, Chem. Sci.
2017, 8, 8265 – 8270; g) J. Jia, Y. A. Ho, R. F. Bꢂlow, M. Rueping,
Chem. Eur. J. 2018, https://doi.org/10.1002/chem.201802907.
[6] a) G. L. J. Bar, G. C. Lloyd-Jones, K. I. Booker-Milburn, J. Am.
Chem. Soc. 2005, 127, 7308 – 7309; b) F. C. Sequeira, B. W.
Turnpenny, S. R. Chemler, Angew. Chem. Int. Ed. 2010, 49,
6365 – 6368; Angew. Chem. 2010, 122, 6509 – 6512; c) K. MuÇiz,
C. Martꢁnez, J. Org. Chem. 2013, 78, 2168 – 2174; d) Y. Zhu,
R. G. Cornwall, H. Du, B. Zhao, Y. Shi, Acc. Chem. Res. 2014, 47,
3665 – 3678; e) S. Fu, H. Yang, G. Li, Y. Deng, H. Jiang, W. Zeng,
Org. Lett. 2015, 17, 1018 – 1021; f) M.-S. Wu, T. Fan, S.-S. Chen,
Z.-Y. Han, L.-Z. Gong, Org. Lett. 2018, 20, 2485 – 2489.
[7] a) M. Kim, J. V. Mulcahy, C. G. Espino, J. Du Bois, Org. Lett.
2006, 8, 1073 – 1076; b) S. Nicolai, C. Piemontesi, J. Waser,
Angew. Chem. Int. Ed. 2011, 50, 4680 – 4683; Angew. Chem.
2011, 123, 4776 – 4779; c) I. I. Strambeanu, M. C. White, J. Am.
Chem. Soc. 2013, 135, 12032 – 12037.
The authors declare no conflict of interest.
Keywords: aza-Heck reaction · catalysis · dihydroimidazolones ·
imidazolidinones · palladium
[1] a) W. B. Wright, H. J. Brabander, R. A. Hardy, A. C. Osterberg,
J. Med. Chem. 1966, 9, 852 – 857; b) E. J. Lien, M. Hussain, M. P.
Golden, J. Med. Chem. 1970, 13, 623 – 626; c) C.-D. Li, S. L.
Mella, A. C. Sartorelli, J. Med. Chem. 1981, 24, 1089 – 1092;
d) F. G. Salituro, C. T. Baker, J. J. Court, D. D. Deininger, E. E.
Kim, B. Li, P. M. Novak, B. G. Rao, S. Pazhanisamy, M. D.
Porter, W. C. Schairer, R. D. Tung, Bioorg. Med. Chem. Lett.
1998, 8, 3637 – 3642; e) F. Moreau, D. Florentin, A. Marquet,
Tetrahedron 2000, 56, 285 – 293; f) R. S. Meissner, J. J. Perkins,
L. T. Duong, G. D. Hartman, W. F. Hoffman, J. R. Huff, N. C.
Ihle, C.-T. Leu, R. M. Nagy, A. Naylor-Olsen, G. A. Rodan, S. B.
Rodan, D. B. Whitman, G. A. Wesolowski, M. E. Duggan,
Bioorg. Med. Chem. Lett. 2002, 12, 25 – 29; g) W. M. Kazmierski,
4
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These are not the final page numbers!

Angewandte
Communications
Chemie
[8] a) J.-O. Baeg, C. Bensimon, H. Alper, J. Am. Chem. Soc. 1995,
[11] a) N. J. Race, I. R. Hazelden, A. Faulkner, J. F. Bower, Chem.
117, 4700 – 4701; b) B. M. Trost, D. R. Fandrick, J. Am. Chem.
Soc. 2003, 125, 11836 – 11837; c) T. Munegumi, I. Azumaya, T.
Kato, H. Masu, S. Saito, Org. Lett. 2006, 8, 379 – 382; d) H. Li,
R. A. Widenhoefer, Org. Lett. 2009, 11, 2671 – 2674; e) B. D. W.
Allen, C. P. Lakeland, J. P. A. Harrity, Chem. Eur. J. 2017, 23,
13830 – 13857.
Sci. 2017, 8, 5248 – 5260; b) B. Vulovic, D. A. Watson, Eur. J. Org.
Chem. 2017, 4996 – 5009.
[12] S. A. Shuler, G. Yin, S. B. Krause, C. M. Vesper, D. A. Watson, J.
Am. Chem. Soc. 2016, 138, 13830 – 13833.
[13] M. A. Allen, R. A. Ivanovich, D. E. Polat, A. M. Beauchemin,
Org. Lett. 2017, 19, 6574 – 6577.
[9] While this manuscipt was under review, an additional method for
[14] See Supporting Information.
À
accessing mono N H bearing imidazolidinones appeared. See:
A.-D. Manick, S. Aubert, B. Yalcouye, T. Prangꢃ, F. Berhal, G.
Prestat, Chem. Eur. J. 2018, 24, 11485 – 11492.
[15] Y. Pan, G. B. Young, J. Organomet. Chem. 1999, 577, 257 – 264.
[16] a) M. M. Abelman, T. Oh, L. E. Overman, J. Org. Chem. 1987,
52, 4130 – 4133; b) K. Karabelas, C. Westerlund, A. Hallberg, J.
Org. Chem. 1985, 50, 3896 – 3900; c) M. Oestreich, The Mizor-
oki-Heck Reaction, Wiley, Chichester, 2009.
[17] Note: The structure and stereochemistry of product 33 com-
pared to that of the starting material are consistant with anti-b-
hydride elimination. Such events are rare, but have been
observed in other Heck-type reactions. Additional details are
provided in the Supporting Information. Also see: a) M. Beller,
T. H. Riermeier, Eur. J. Inorg. Chem. 1998, 29 – 35; b) R. J.
Deeth, A. Smith, K. K. Hii, J. M. Brown, Tetrahedron Lett. 1998,
39, 3229 – 3232.
[18] a) D. B. Reitz, D. J. Garland, G. M. Olins, C. S. Markos, C. J.
Gresk, J. W. Litschgi, B. R. McKinnis, Bioorg. Med. Chem. Lett.
1994, 4, 111 – 114; b) D. B. Reitz, D. J. Garland, M. B. Norton,
J. T. Collins, E. J. Reinhard, R. E. Manning, G. M. Olins, S. T.
Chen, M. A. Palomo, E. G. McMahon, K. F. Koehler, Bioorg.
Med. Chem. Lett. 1993, 3, 1055 – 1060; c) J. J. Bronson, K. L.
DenBleyker, P. J. Falk, R. A. Mate, H.-T. Ho, M. J. Pucci, L. B.
Snyder, Bioorg. Med. Chem. Lett. 2003, 13, 873 – 875.
[19] T. P. Maduskuie, R. A. Galemmo, C. Dominguez, M. L. Quan,
K. A. Rossi, P. F. W. Stouten, J.-H. Sun, B. L. Wells (DuPont
Pharmaceuticals Company), U.S. Patent, US5925635A, 1999.
[10] a) H. Tsutsui, K. Narasaka, Chem. Lett. 1999, 28, 45 – 46; b) H.
Tsutsui, K. Narasaka, Chem. Lett. 2001, 30, 526 – 527; c) J.
Helaja, R. Gottlich, Chem. Commun. 2002, 720 – 721; d) M.
Kitamura, K. Narasaka, Chem. Rec. 2002, 2, 268 – 277; e) S.
Zaman, M. Kitamura, K. Narasaka, Bull. Chem. Soc. Jpn. 2003,
76, 1055 – 1062; f) S. Chiba, M. Kitamura, O. Saku, K. Narasaka,
Bull. Chem. Soc. Jpn. 2004, 77, 785 – 796; g) S. Zaman, K.
Mitsuru, A. D. Abell, Org. Lett. 2005, 7, 609 – 611; h) J. Ichikawa,
R. Nadano, N. Ito, Chem. Commun. 2006, 4425 – 4427; i) J.-L.
Zhu, Y.-H. Chan, Synlett 2008, 1250 – 1254; j) J.-L. Zhu, Y.-L. Su,
Y.-H. Chang, I. C. Chen, C.-C. Liao, Heterocycles 2009, 78, 369;
k) A. Faulkner, J. F. Bower, Angew. Chem. Int. Ed. 2012, 51,
1675 – 1679; Angew. Chem. 2012, 124, 1707 – 1711; l) A. Faulk-
ner, J. S. Scott, J. F. Bower, Chem. Commun. 2013, 49, 1521 –
1523; m) N. J. Race, J. F. Bower, Org. Lett. 2013, 15, 4616 – 4619;
n) A. Faulkner, N. J. Race, J. S. Scott, J. F. Bower, Chem. Sci.
2014, 5, 2416 – 2421; o) A. Faulkner, J. S. Scott, J. F. Bower, J.
Am. Chem. Soc. 2015, 137, 7224 – 7230; p) I. R. Hazelden, X. Ma,
T. Langer, J. F. Bower, Angew. Chem. Int. Ed. 2016, 55, 11198 –
11202; Angew. Chem. 2016, 128, 11364 – 11368; q) N. J. Race, A.
Faulkner, M. H. Shaw, J. F. Bower, Chem. Sci. 2016, 7, 1508 –
1513; r) N. J. Race, A. Faulkner, G. Fumagalli, T. Yamauchi, J. S.
Scott, M. Ryden-Landergren, H. A. Sparkes, J. F. Bower, Chem.
Sci. 2017, 8, 1981 – 1985; s) I. R. Hazelden, R. C. Carmona, T.
Langer, P. G. Pringle, J. F. Bower, Angew. Chem. Int. Ed. 2018,
57, 5124 – 5128; Angew. Chem. 2018, 130, 5218 – 5222.
Manuscript received: May 31, 2018
Version of record online: && &&, &&&&
Angew. Chem. Int. Ed. 2018, 57, 1 – 6
ꢀ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Aza-Heck Reaction
F. Xu, S. A. Shuler,
D. A. Watson*
&&&& — &&&&
À
Synthesis of N H Bearing
Imidazolidinones and
Dihydroimidazolones Using Aza-Heck
Cyclizations
A palladium-catalyzed process gives
access to unsaturated, unprotected imi-
dazolidinones through the cyclization of
N-phenoxy ureas onto pendant alkenes.
The reaction has broad functional group
and substrate tolerance and allows
access to doubly unprotected imidazoli-
dinones. By addition of Bu4NI, dihydro-
imidazolones can be accessed from the
same starting materials.
6
www.angewandte.org
ꢀ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2018, 57, 1 – 6
These are not the final page numbers!