Silver Nitrate-Catalyzed Isocyanide Insertion/Lactamization Sequence to Imidazolones and Quinazolin-4-ones: Development and Application in Natural Product Synthesis

Article abstract of DOI:10.1021/acs.orglett.7b02334

Silver nitrate-catalyzed reaction of methyl α,α-disubstituted α-isocyanoacetates with primary amines afforded 3,5,5-trisubstituted imidazolones in good to excellent yields. A silver salt-catalyzed insertion of the isocyano group into the N-H bond of the amine followed by in situ lactamization accounted for the reaction outcome. The same transformation between methyl 2-isocyanobenzoate and amines afforded quinazolin-4-ones in excellent yields. The utility of this chemistry was illustrated by the development of concise syntheses of (±)-evodiamine and rutaecarpine.

Full text of DOI:10.1021/acs.orglett.7b02334

Letter
pubs.acs.org/OrgLett
Silver Nitrate-Catalyzed Isocyanide Insertion/Lactamization
Sequence to Imidazolones and Quinazolin-4-ones: Development and
Application in Natural Product Synthesis
Antonin Clemenceau, Qian Wang, and Jieping Zhu*
́ ́
Laboratory of Synthesis and Natural Products, Institute of Chemical Sciences and Engineering, Ecole Polytechnique Federale de
Lausanne, EPFL-SB-ISIC-LSPN, BCH 5304, 1015 Lausanne, Switzerland
S
* Supporting Information
ABSTRACT: Silver nitrate-catalyzed reaction of methyl α,α-
disubstituted α-isocyanoacetates with primary amines afforded
3,5,5-trisubstituted imidazolones in good to excellent yields. A silver
salt-catalyzed insertion of the isocyano group into the N−H bond of
the amine followed by in situ lactamization accounted for the
reaction outcome. The same transformation between methyl 2-
isocyanobenzoate and amines afforded quinazolin-4-ones in excellent
yields. The utility of this chemistry was illustrated by the
development of concise syntheses of ( )-evodiamine and
rutaecarpine.
structure.11−14 As part of our research program aimed at
exploiting the diverse reactivities of the isocyano group,15 we
recently reported metal triflate-catalyzed domino processes
initiated by the insertion of isocyanide into the N−H bond of
amines.16 We document herein the synthesis of 3,5,5-
trisubstituted imidazolones 1 and quinazolin-4-ones 2 by silver
nitrate-catalyzed reactions of primary amines with methyl α-
isocyanoacetates and 2-isocyanobenzoates, respectively (eq 2,
Scheme 1). The development of concise syntheses of
( )-evodiamine (5) and rutaecarpine (6) featuring this latter
reaction as a key step will also be presented.
We began our research using methyl α,α-dibenzyl-α-
isocyanoacetate (3a) and benzylamine (4a) as test substrates.
Key observations are summarized in Table 1. Cupric salts were
less efficient than cuprous salts in catalyzing this reaction
(entries 1−5),11a whereas ytterbium triflate was completely
ineffective (entry 6). Silver salts gave much better results, with
AgNO3 being superior to AgOTf (entries 7−9). In the presence
of 10 mol % AgNO3, the reaction of 3a and 4a in toluene (c 0.1
M) at 60 °C afforded 1a in 90% isolated yield (entry 9).
Reactions run at lower temperature (entry 10) and at lower
catalyst loading (entry 11) afforded 1a in diminished yields.
While a similar yield of 1a was obtained in ethyl acetate (entry
16), the reaction performed in other solvents afforded 1a in
reduced yields (entries 12−15).
midazolones 1 are structural motifs found in bioactive
1
Inatural products and are key elements responsible for the
luminescent properties of green fluorescent protein (GFP).2
Compounds containing this nonaromatic heterocycle display
potent inhibitory activities against fatty acid synthases3 and are
angiotensin II receptor antagonists.4 Indeed, it is the key motif
found in the marketed drug irbesartan for the treatment of
hypertension.5 Different synthetic routes have been developed,
focusing mainly on the functionalization of simple imidazo-
lones,6 the cyclization of α-amidoamides,7 of amino acid-
derived formamidines,8 transformation of azlactones,9 and base-
promoted cyclization of α-isocyanoacetamides (eq 1, Scheme
1)10
Metal-catalyzed isocyanide insertion reactions have attracted
much recent attention, and a variety of heterocycles are now
readily accessible by careful engineering of the substrate
Scheme 1. Synthesis of 3,5,5-Trisubstituted Imidazolones
With the optimum conditions in hand (toluene, 10 mol %
AgNO3, 60 °C), the scope of the reaction was next examined
(Scheme 2). Various alkylamines, both linear and branched,
including sterically demanding tert-butylamine, reacted with α-
isocyanoacetate 3a to afford the corresponding imidazolones in
Received: July 28, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02334
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Synthesis of 3,5,5-Trisubstituted Imidazolone 1a:
Survey of Reaction Conditions
Scheme 2. Silver-Catalyzed Synthesis of Imidazolones 1
a
b
entry
Lewis acid
solvent
t (°C)
yield (%)
1
2
CuO
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
dioxane
80
80
80
60
60
80
80
60
60
40
60
60
60
60
60
60
no reaction
Cu(OTf)2
CuCl2
10
3
30
4
Cu2O
48
5
CuCl
47
6
Yb(OTf)3
AgOTf
AgOTf
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
no reaction
7
75
76
8
c
9
quant (90 )
10
slow reaction
d
11
80
88
69
84
75
12
13
14
15
16
e
DCM
THF
DMF
AcOEt
c
quant (90 )
a
Standard conditions: 3a (0.1 mmol), 4a (0.12 mmol), solvent (1.0
b
mL), metal salt (10 mol %). Calculated on the basis of the 1H NMR
spectra using CH2Br2 as an internal standard. Yield of isolated
product in parentheses. AgNO3 (5 mol %). The reaction was
c
d
e
performed in a sealed tube.
excellent yields (1a−f, 1h). Functionalized amines such as
allylamine (1g), tryptamine (1i), enantioenriched α-amino
esters (1k−m), a chiral amine (1n), and unprotected amino
alcohols (1o, 1p) participated well in this reaction. It is
noteworthy that even thioether, known to have high affinity
with silver, was compatible with our reaction conditions (1m).
Different functional groups (COOMe, CN, N3, olefin) on the
α-isocyanoacetate were well-tolerated (1r−v). Spiroimidazo-
lones (1o, 1q) can also be prepared without event. Reaction of
diamines with 2 equiv of 3a afforded bisimidazolones (1w, 1x)
in good yields. On the other hand, the reaction of 4-
aminobenzylamine with 3a was highly chemoselective, affording
1y (94% yield) in which the aniline nitrogen was untouched.
However, when the reaction was performed at higher
temperature (120 °C), anilines regardless their electronic
nature participated in the reaction to afford the corresponding
N-arylimidazolones, albeit in moderate yields (1z−ac). 5-
Diphenylmethylene imidazolone (1ad), an analogue of the
GFP chromophore, could also be prepared from methyl 2-
isocyano-3,3-diphenylacrylate. Finally, the protocol could also
be applied to complex natural products. Thus, 3α-amino-5-
cholestene17 and 9-aminoquinidine were converted to their
imidazolone derivatives (1ae, 1af) in yields of 73% and 70%,
respectively. Derivatives of 3-amino-5-cholestene are important
cellular probes with potential medical applications.18 We
believe that such a late-stage functionalization protocol could
be a useful synthetic tool in medicinal chemistry. As expected,
α-nonsubstituted and α-monosubstituted α-isocyanoacetates
failed to participate in this reaction because of the competitive
formation of oxazoles.19
a
20 mol % AgNO3, toluene, 120 °C.
erosion of enantiopurity (Scheme 3a). Notably, the reaction
was also applicable to the synthesis of quinazolin-4(3H)-one, a
Scheme 3. Synthesis of C-5 Chiral Imidazolone (R)-1u and
Quinazolin-4-one 2
privileged scaffold in medicinal chemistry (Scheme 3b).21 Thus,
reaction of methyl 2-isocyanobenzoate (7) with 4a under the
standard conditions afforded quinazolin-4-one 2 in 86%
isolated yield.
A possible reaction pathway is shown in Scheme 4.
Coordination of the isocyanide and amine to silver would
afford complex B. Migratory insertion from B would afford C
and HX, which would undergo salt metathesis to produce
An enantioenriched methyl α,α-disubstituted α-isocyanoace-
tate (R)-3b, prepared according to a literature procedure,20
participated in the reaction to afford product (R)-1u without
B
DOI: 10.1021/acs.orglett.7b02334
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
In summary, we have developed a new protocol for the
synthesis of imidazolones and quinazolin-4-ones by silver
nitrate-catalyzed reactions of primary amines with methyl α,α-
disubstituted-α-isocyanoacetates and 2-isocyanobenzoates, re-
spectively. The utility of this method was illustrated by the
development of concise syntheses of ( )-evodiamine (5) and
rutaecarpine (6).
Scheme 4. Possible Reaction Pathway
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02334.
Experimental procedures, product characterization data,
and 1H and 13C NMR spectra for new compounds
(PDF)
amidine D with concurrent regeneration of the silver salt.
Lactamization of D would then furnish the observed product.
We note that no reaction took place in the absence of silver
nitrate and that the formation of amidine E was clearly
observed when the reaction was performed at 40 °C under
otherwise standard conditions.
Evodiamine (5) and rutaecarpine (6) are quinazolinecarbo-
line alkaloids isolated from the dried fruit of Evodia rutaecarpa,
a plant used in traditional Chinese medicine against headache,
dysentery, cholera, etc. Because of the medicinal importance of
these alkaloids, various synthetic routes have been developed.22
As an illustration of our methodology, the syntheses of
evodiamine and rutaecarpine were undertaken (Scheme 5).
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jieping.zhu@epfl.ch.
ORCID
Jieping Zhu: 0000-0002-8390-6689
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank EPFL (Switzerland) and the Swiss National Science
Foundation (SNSF) for financial support.
■
Scheme 5. Total Syntheses of ( )-Evodiamine and
Rutaecarpine
REFERENCES
■
(1) (a) Appleton, D. R.; Page, M. J.; Lambert, G.; Berridge, M. V.;
Copp, B. R. J. Org. Chem. 2002, 67, 5402. (b) Edrada, R. A.; Stessman,
C. C.; Crews, P. J. Nat. Prod. 2003, 66, 939.
(2) Day, R. N.; Davidson, M. W. Chem. Soc. Rev. 2009, 38, 2887.
(3) Bignan, G. C.; Connolly, P. J.; Lu, T. L.; Parker, M. H.; Ludovici,
D.; Meyer, C.; Meerpoel, L.; Smans, K.; Rocaboy, C. WO2014039769,
2014.
(4) Bernhart, C. A.; Perreaut, P. M.; Ferrari, B. P.; Muneaux, Y. A.;
Assens, J.-L. A.; Clement, J.; Haudricourt, F.; Muneaux, C. F.;
Taillades, J. E.; Vignal, M.-A.; Gougat, J.; Guiraudou, P. R.; Lacour, C.
A.; Roccon, A.; Cazaubon, C. F.; Brelier
J. Med. Chem. 1993, 36, 3371.
̀
e, J.-C.; Le Fur, G.; Nisato, D.
(5) https://www.drugbank.ca/drugs/DB01029.
(6) For examples of C-5 functionalization, see: (a) Gosling, S.; Rollin,
P.; Tatibouet, A. Synthesis 2011, 2011, 3649. (b) Wu, L.; Burgess, K. J.
̈
Am. Chem. Soc. 2008, 130, 4089. For examples of 2-substituted
imidazolones, see: (c) Muselli, M.; Baudequin, C.; Hoarau, C.;
Bischoff, L. Chem. Commun. 2015, 51, 745. (d) Muselli, M.;
Baudequin, C.; Perrio, C.; Hoarau, C.; Bischoff, L. Chem. - Eur. J.
2016, 22, 5520. (e) Gesu, A.; Pozzoli, C.; Torre, E.; Aprile, S.; Pirali,
̀
T. Org. Lett. 2016, 18, 1992.
(7) (a) Ye, P.; Sargent, K.; Stewart, E.; Liu, J.-F.; Yohannes, D.; Yu, L.
J. Org. Chem. 2006, 71, 3137. (b) He, X.; Bell, A. F.; Tonge, P. J. Org.
Lett. 2002, 4, 1523.
(8) (a) Ito, Y.; Inubushi, Y.; Saegusa, T. Synth. Commun. 1974, 4,
289. (b) Ito, Y.; Inubushi, Y.; Saegusa, T. Tetrahedron Lett. 1974, 15,
1283.
Silver nitrate-catalyzed condensation of tryptamine (4b) with 7
afforded quinazolinone 8, which without purification was
methylated with methyl triflate to afford N-methylated
intermediate 9. Adding HMPA to the reaction mixture and
heating the solution to 120 °C furnished ( )-evodiamine (5) in
48% overall yield. On the other hand, treatment of 8 with
TFAA afforded 10, which upon treatment with hydrogen
peroxide under basic conditions provided rutaecarpine (6) in
53% overall yield.
(9) (a) Kojima, S.; Ohkawa, H.; Hirano, T.; Maki, S.; Niwa, H.;
Ohashi, M.; Inouye, S.; Tsuji, F. I. Tetrahedron Lett. 1998, 39, 5239.
(b) Muselli, M.; Colombeau, L.; Hed
Synlett 2016, 27, 2819.
(10) (a) Matsumoto, K.; Suzuki, M.; Yoneda, N.; Miyoshi, M.
́
ouin, J.; Hoarau, C.; Bischoff, L.
Synthesis 1977, 1977, 249. (b) Schollkopf, U.; Hausberg, H.-H.; Segal,
̈
C
DOI: 10.1021/acs.orglett.7b02334
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
M.; Reiter, U.; Hoppe, I.; Saenger, W.; Lindner, K. Liebigs Ann. Chem.
1981, 1981, 439. (c) Bossio, R.; Marcaccini, S.; Paoli, P.; Papaleo, S.;
Pepino, R.; Polo, C. Liebigs Ann. Chem. 1991, 1991, 843.
(20) Buyck, T.; Wang, Q.; Zhu, J. Angew. Chem., Int. Ed. 2013, 52,
12714.
(21) Jafari, E.; Khajouei, M. R.; Hassanzadeh, F.; Hakimelani, G. H.;
Khodarahmi, G. A. Res. Pharm. Sci. 2016, 11, 1.
(22) Lee, S. H.; Son, J.-K.; Jeong, B. S.; Jeong, T.-C.; Chang, H. W.;
Lee, E.-S.; Jahng, Y. Molecules 2008, 13, 272.
(11) For earlier examples of insertion reactions of isocyanides, see:
(a) Saegusa, T.; Ito, Y.; Kobayashi, S.; Hirota, K.; Yoshioka, H.
Tetrahedron Lett. 1966, 7, 6121. (b) Saegusa, T.; Ito, Y.; Kobayashi, S.;
Hirota, K. J. Am. Chem. Soc. 1967, 89, 2240. (c) Saegusa, T.; Ito, Y.;
Kobayashi, S.; Hirota, K. Tetrahedron Lett. 1967, 8, 521. (d) Saegusa,
T.; Kobayashi, S.; Hirota, K.; Okumura, Y.; Ito, Y. Bull. Chem. Soc. Jpn.
1968, 41, 1638. (e) Saegusa, T.; Ito, Y.; Kobayashi, S. Tetrahedron Lett.
1968, 9, 935.
(12) Saluste, C. G.; Whitby, R. J.; Furber, M. Angew. Chem., Int. Ed.
2000, 39, 4156.
(13) For recent examples, see: (a) Senadi, G. C.; Hu, W.-P.;
Boominathan, S. S. K.; Wang, J.-J. Chem. - Eur. J. 2015, 21, 998.
(b) Liu, Y.-J.; Xu, H.; Kong, W.-J.; Shang, M.; Dai, H.-X.; Yu, J.-Q.
Nature 2014, 515, 389. (c) Mampuys, P.; Zhu, Y.; Vlaar, T.; Ruijter, E.;
Orru, R. V. A.; Maes, B. U. W. Angew. Chem., Int. Ed. 2014, 53, 12849.
(d) Thirupathi, N.; Babu, M. H.; Dwivedi, V.; Kant, R.; Reddy, M. S.
Org. Lett. 2014, 16, 2908. (e) Tang, T.; Fei, X.-D.; Ge, Z.-Y.; Chen, Z.;
Zhu, Y.-M.; Ji, S.-J. J. Org. Chem. 2013, 78, 3170. (f) Liu, J.; Liu, Z.;
Wu, N.; Liao, P.; Bi, X. Chem. - Eur. J. 2014, 20, 2154. (g) Bochatay, V.
N.; Boissarie, P. J.; Murphy, J. A.; Suckling, C. J.; Lang, S. J. Org. Chem.
2013, 78, 1471. (h) Ji, F.; Lv, M.-f.; Yi, W.-b.; Cai, C. Adv. Synth. Catal.
2013, 355, 3401. (i) Nanjo, T.; Yamamoto, S.; Tsukano, C.;
Takemoto, Y. Org. Lett. 2013, 15, 3754. (j) Lei, C.-H.; Wang, D.-X.;
Zhao, L.; Zhu, J.; Wang, M.-X. J. Am. Chem. Soc. 2013, 135, 4708.
(k) Qiu, G.; Chen, C.; Yao, L.; Wu, J. Adv. Synth. Catal. 2013, 355,
1579. (l) Geden, J. V.; Pancholi, A. K.; Shipman, M. J. Org. Chem.
2013, 78, 4158. (m) Vlaar, T.; Cioc, R. C.; Mampuys, P.; Maes, B. U.
W.; Orru, R. V. A.; Ruijter, E. Angew. Chem., Int. Ed. 2012, 51, 13058.
(n) Nanjo, T.; Tsukano, C.; Takemoto, Y. Org. Lett. 2012, 14, 4270.
(o) Wang, Y.; Wang, H.; Peng, J.; Zhu, Q. Org. Lett. 2011, 13, 4604.
(p) Jiang, H.; Liu, B.; Li, Y.; Wang, A.; Huang, H. Org. Lett. 2011, 13,
1028. (q) Miura, T.; Nishida, Y.; Morimoto, M.; Yamauchi, M.;
Murakami, M. Org. Lett. 2011, 13, 1429. (r) Tobisu, M.; Imoto, S.; Ito,
S.; Chatani, N. J. Org. Chem. 2010, 75, 4835. For a mechanistic study,
see: (s) Perego, L. A.; Fleurat-Lessard, P.; El Kaim, L.; Ciofini, I.;
Grimaud, L. Chem. - Eur. J. 2016, 22, 15491.
(14) For recent reviews, see: (a) Lygin, A. V.; de Meijere, A. Angew.
Chem., Int. Ed. 2010, 49, 9094. (b) Tobisu, M.; Chatani, N. Chem. Lett.
2011, 40, 330. (c) Qiu, G.; Ding, Q.; Wu, J. Chem. Soc. Rev. 2013, 42,
5257. (d) Lang, S. Chem. Soc. Rev. 2013, 42, 4867. (e) Vlaar, T.;
Ruijter, E.; Maes, B. U. W.; Orru, R. V. A. Angew. Chem., Int. Ed. 2013,
52, 7084. (f) Chakrabarty, S.; Choudhary, S.; Doshi, A.; Liu, F.-Q.;
Mohan, R.; Ravindra, M. P.; Shah, D.; Yang, X.; Fleming, F. F. Adv.
Synth. Catal. 2014, 356, 2135. (g) Song, B.; Xu, B. Chem. Soc. Rev.
2017, 46, 1103. (h) Giustiniano, M.; Basso, A.; Mercalli, V.;
Massarotti, A.; Novellino, E.; Tron, G. C.; Zhu, J. Chem. Soc. Rev.
2017, 46, 1295.
(15) (a) Odabachian, Y.; Tong, S.; Wang, Q.; Wang, M.-X.; Zhu, J.
Angew. Chem., Int. Ed. 2013, 52, 10878. (b) Buyck, T.; Wang, Q.; Zhu,
J. J. Am. Chem. Soc. 2014, 136, 11524. (c) Buyck, T.; Pasche, D.; Wang,
Q.; Zhu, J. Chem. - Eur. J. 2016, 22, 2278. (d) Qiu, G.; Mamboury, M.;
Wang, Q.; Zhu, J. Angew. Chem., Int. Ed. 2016, 55, 15377. (e) Kong,
W.; Wang, Q.; Zhu, J. Angew. Chem., Int. Ed. 2016, 55, 9714. (f) Qiu,
G.; Wang, Q.; Zhu, J. Org. Lett. 2017, 19, 270. (g) Tong, S.; Zhao, S.;
He, Q.; Wang, Q.; Wang, M.-X.; Zhu, J. Angew. Chem., Int. Ed. 2017,
56, 6599. (h) Tong, S.; Piemontesi, C.; Wang, Q.; Wang, M.-X.; Zhu,
J. Angew. Chem., Int. Ed. 2017, 56, 7958.
(16) (a) Tong, S.; Wang, Q.; Wang, M.-X.; Zhu, J. Angew. Chem., Int.
Ed. 2015, 54, 1293. (b) Tong, S.; Wang, Q.; Wang, M.-X.; Zhu, J.
Chem. - Eur. J. 2016, 22, 8332.
(17) Sun, Q.; Cai, S.; Peterson, B. R. Org. Lett. 2009, 11, 567.
(18) Boonyarattanakalin, S.; Hu, J.; Dykstra-Rummel, S. A.; August,
A.; Peterson, B. R. J. Am. Chem. Soc. 2007, 129, 268.
(19) (a) Zhu, J. Eur. J. Org. Chem. 2003, 2003, 1133. (b) Gulevich, A.
V.; Zhdanko, A. G.; Orru, R. V. A.; Nenajdenko, V. G. Chem. Rev.
2010, 110, 5235.
D
DOI: 10.1021/acs.orglett.7b02334
Org. Lett. XXXX, XXX, XXX−XXX