An Ugi Reaction Incorporating a Redox-Neutral Amine C-H Functionalization Step

Article abstract of DOI:10.1021/acs.orglett.5b03529

Pyrrolidine and 1,2,3,4-tetrahydroisoquinoline (THIQ) undergo redox-neutral α-amidation with concurrent N-alkylation upon reaction with aromatic aldehydes and isocyanides. Reactions are promoted by acetic acid and represent a new variant of the Ugi reacti

Full text of DOI:10.1021/acs.orglett.5b03529

Letter
pubs.acs.org/OrgLett
An Ugi Reaction Incorporating a Redox-Neutral Amine C−H
Functionalization Step
Zhengbo Zhu and Daniel Seidel*
Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, United
States
S
* Supporting Information
ABSTRACT: Pyrrolidine and 1,2,3,4-tetrahydroisoquinoline (THIQ)
undergo redox-neutral α-amidation with concurrent N-alkylation upon
reaction with aromatic aldehydes and isocyanides. Reactions are
promoted by acetic acid and represent a new variant of the Ugi
reaction.
gi reactions are among the most powerful multicomponent
transformations; their many variants provide rapid access
from the reactions outlined in eqs 1−3, a decarboxylative version
of the Ugi reaction was recently reported that employs proline as
the starting material (eq 4).4,5 Here, we report a new type of Ugi
variant that enables the α-amidation of cyclic amines via redox-
neutral α-C−H bond functionalization (eq 5).6,7
U
to a remarkable wealth of structures.1 Reactions of isocyanides
with secondary amines and aldehydes/ketones represent a
special case, as the prototypical Mumm rearrangement cannot
take place.2
As part of a continuing program, our group developed a range
of transformations that enable the redox-neutral α-C−H bond
functionalization of amines.8−10 As is commonly the case in a
number of classic name reactions such as the Strecker, Mannich,
and Friedel−Crafts reactions, these redox reactions involve the
condensation of a secondary amine with an aldehyde/ketone in
the presence of a (pro)nucleophile. C−H functionalization is
achieved via an isomerization step in which azomethine ylides
feature as reactive intermediates.8a Carboxylic acids play
important roles as catalysts or promotors in most of these
transformations. The scope of this chemistry was shown to be
remarkably broad and includes intra- and intermolecular variants.
In order to determine whether our general concept is
applicable to Ugi-type reactions with isocyanides as the
nucleophiles, we selected pyrrolidine, fluorenone, and cyclohexyl
isocyanide as test substrates. While we have recently identified
2,6-dichlorobenzaldehyde as an efficient carbonyl reaction
partner for pyrrolidine in these types of transformations, it was
subsequently shown by Jana et al. that fluorenone is particularly
suitable to bring about redox-isomerization,9c a prerequisite for
C−H functionalization. Key results of our initial survey are
summarized in Table 1. Heating a 5:2:1 mixture of pyrrolidine,
fluorenone, and cyclohexyl isocyanide under reflux in toluene
resulted in the formation of desired product 1a in trace amounts
only (entry 1). Addition of acetic acid (20 mol %) allowed for the
isolation of 1a in 6% yield (entry 2). A gradual increase in the
amount of acetic acid led to dramatically improved results, with 5
equiv proving optimal (entry 4). Xylenes, n-butanol, and DMF
were inferior to toluene as the solvent (entries 6−8). 2-
Ethylhexanoic acid and benzoic acid were also capable of
promoting the title transformation but did so less effectively than
In recent years, a number of oxidative Ugi variants have been
reported.3 Secondary amines can be oxidized in situ to the
corresponding imines, which subsequently participate in typical
Ugi reactions that provide diamide products (eq 1). When
tertiary amines are used as starting materials, oxidation leads to
iminium ions that are subsequently trapped by an isocyanide. In
the presence of a carboxylic acid reaction partner, imides are
obtained as the final products (eq 2). Alternatively, the
intermediate nitrilium ion can be trapped by water, leading to
the formation of aminoamides (eq 3). Mechanistically distinct
Received: December 12, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03529
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Evaluation of Reaction Conditions
Scheme 1. Substrate Scope
entry solvent (molarity) additive (equiv) time (h) yield of 1a (%)
1
2
3
4
5
6
7
8
9
PhMe (0.1)
PhMe (0.1)
PhMe (0.1)
PhMe (0.1)
PhMe (0.1)
xylenes (0.1)
n-BuOH (0.1)
DMF (0.1)
PhMe (0.1)
PhMe (0.1)
PhMe (0.25)
PhMe (0.5)
PhMe (0.25)
PhMe (0.25)
36
48
48
20
20
20
20
18
20
20
18
15
20
20
trace
6
AcOH (0.2)
AcOH (1)
AcOH (5)
AcOH (10)
AcOH (5)
AcOH (5)
AcOH (5)
2-EHA (5)
BzOH (5)
AcOH (5)
AcOH (5)
AcOH (5)
AcOH (5)
28
73
52
53
55
52
32
63
89
75
53
85
b
10
11
12
13
14
c
d
a
Reactions were performed with 0.5 mmol of cyclohexylisocyanide.
Yields are isolated yields of chromatographically purified compounds.
b
c
Reaction was performed at 135 °C. With 3 equiv of pyrrolidine.
d
With 10 equiv of H2O.
acetic acid (entries 9 and 10).11 A significant improvement in
efficiency was observed upon increasing the concentration from
0.1 to 0.25 M. In this instance, product 1a was isolated in 89%
yield (entry 11). A further increase in molarity to 0.5 led to a
reduction in yield (entry 12). Lowering the amount of
pyrrolidine from 5 to 3 equiv also led to a drop in yield (entry
13). Interestingly, addition of 10 equiv of water (later shown to
be beneficial for most substrate combinations, vide infra) had
little effect on the overall transformation (entry 14).12
The scope of the new transformation was evaluated under the
optimized conditions (Scheme 1). Isocyanides other than
cyclohexyl isocyanide engaged in redox−Ugi reactions with
pyrrolidine and THIQ. In addition to fluorenone, mesitaldehyde
and 2,6-dichlorobenzaldehyde were viable substrates in reactions
with pyrrolidine. The scope of the aldehyde in reactions with
THIQ was found to be broad. Aromatic aldehydes with various
substitution patterns provided moderate to good yields of amide
products. Electron-donating and electron-withdrawing substitu-
ents in any ring position were well tolerated. In addition,
heterocyclic aldehydes also participated in redox−Ugi reactions.
Selected redox−Ugi products were subjected to a number of
subsequent transformations. Cleavage of the N-benzyl group in
1h was achieved via hydrogenolysis to provide tetrahydroiso-
quinoline 2 in 65% yield. Interestingly, under the reaction
conditions, N-ethyl product 3 was obtained as a byproduct in
20% yield (eq 6). Exposure of 1k to Pd/C in the absence of
hydrogen gas under reflux in mesitylene led to cleavage of the
PMB group and aromatization of the ring system to provide
isoquinoline 4 in 71% yield (eq 7).
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b03529.
In conclusion, we have demonstrated the ability of isocyanides
to act as nucleophiles in Ugi-type reactions that incorporate an
amine α-C−H bond functionalization step. This process is
facilitated by simple acetic acid.
■
S
B
DOI: 10.1021/acs.orglett.5b03529
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Experimental procedures and characterization data (PDF)
Letter
2011, 111, 1215. (h) Pan, S. C. Beilstein J. Org. Chem. 2012, 8, 1374.
(i) Mitchell, E. A.; Peschiulli, A.; Lefevre, N.; Meerpoel, L.; Maes, B. U.
W. Chem. - Eur. J. 2012, 18, 10092. (j) Zhang, C.; Tang, C.; Jiao, N.
Chem. Soc. Rev. 2012, 41, 3464. (k) Jones, K. M.; Klussmann, M. Synlett
2012, 159. (l) Peng, B.; Maulide, N. Chem. - Eur. J. 2013, 19, 13274.
(m) Platonova, A. Y.; Glukhareva, T. V.; Zimovets, O. A.; Morzherin, Y.
Y. Chem. Heterocycl. Compd. 2013, 49, 357. (n) Prier, C. K.; Rankic, D.
A.; MacMillan, D. W. C. Chem. Rev. 2013, 113, 5322. (o) Girard, S. A.;
Knauber, T.; Li, C.-J. Angew. Chem., Int. Ed. 2014, 53, 74. (p) Haibach,
M. C.; Seidel, D. Angew. Chem., Int. Ed. 2014, 53, 5010. (q) Wang, L.;
Xiao, J. Adv. Synth. Catal. 2014, 356, 1137. (r) Vo, C.-V. T.; Bode, J. W. J.
Org. Chem. 2014, 79, 2809. (s) Seidel, D. Org. Chem. Front. 2014, 1, 426.
(t) Qin, Y.; Lv, J.; Luo, S. Tetrahedron Lett. 2014, 55, 551. (u) Beatty, J.
W.; Stephenson, C. R. J. Acc. Chem. Res. 2015, 48, 1474.
(7) Selected reviews on other types of redox-neutral transformations:
(a) Burns, N. Z.; Baran, P. S.; Hoffmann, R. W. Angew. Chem., Int. Ed.
2009, 48, 2854. (b) Mahatthananchai, J.; Bode, J. W. Acc. Chem. Res.
2014, 47, 696. (c) Ketcham, J. M.; Shin, I.; Montgomery, T. P.; Krische,
M. J. Angew. Chem., Int. Ed. 2014, 53, 9142. (d) Huang, H.; Ji, X.; Wu,
W.; Jiang, H. Chem. Soc. Rev. 2015, 44, 1155.
X-ray crystal structure of product 1k (CIF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: seidel@rutchem.rutgers.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the NIH-NIGMS (R01GM101389) is
gratefully acknowledged. We thank Dr. Tom Emge (Rutgers
University) for crystallographic analysis.
REFERENCES
■
(1) Selected reviews on the Ugi reaction: (a) Domling, A.; Ugi, I.
Angew. Chem., Int. Ed. 2000, 39, 3168. (b) Zhu, J. Eur. J. Org. Chem. 2003,
̈
(8) (a) Seidel, D. Acc. Chem. Res. 2015, 48, 317. Selected examples
from our laboratory: (b) Zhang, C.; De, C. K.; Mal, R.; Seidel, D. J. Am.
Chem. Soc. 2008, 130, 416. (c) Ma, L.; Chen, W.; Seidel, D. J. Am. Chem.
Soc. 2012, 134, 15305. (d) Das, D.; Sun, A. X.; Seidel, D. Angew. Chem.,
Int. Ed. 2013, 52, 3765. (e) Dieckmann, A.; Richers, M. T.; Platonova, A.
Y.; Zhang, C.; Seidel, D.; Houk, K. N. J. Org. Chem. 2013, 78, 4132.
(f) Chen, W.; Seidel, D. Org. Lett. 2014, 16, 3158. (g) Richers, M. T.;
Breugst, M.; Platonova, A. Y.; Ullrich, A.; Dieckmann, A.; Houk, K. N.;
Seidel, D. J. Am. Chem. Soc. 2014, 136, 6123. (h) Kang, Y.; Richers, M.
T.; Sawicki, C. H.; Seidel, D. Chem. Commun. 2015, 51, 10648. (i) Ma,
L.; Seidel, D. Chem. - Eur. J. 2015, 21, 12908. (j) Kang, Y.; Chen, W.;
Breugst, M.; Seidel, D. J. Org. Chem. 2015, 80, 9628.
2003, 1133. (c) Domling, A. Chem. Rev. 2006, 106, 17. (d) Akritopou-
lou-Zanze, I. Curr. Opin. Chem. Biol. 2008, 12, 324. (e) El Kaim, L.;
̈
Grimaud, L. Tetrahedron 2009, 65, 2153. (f) Domling, A.; Wang, W.;
̈
Wang, K. Chem. Rev. 2012, 112, 3083. (g) Isocyanide Chemistry:
Applications in Synthesis and Material Science; Nenajdenko, V. G., Ed.;
Wiley-VCH: Weinheim, 2012. (h) Van Berkel, S. S.; Bogels, B. G. M.;
̈
Wijdeven, M. A.; Westermann, B.; Rutjes, F. P. J. T. Eur. J. Org. Chem.
2012, 2012, 3543. (i) Rotstein, B. H.; Zaretsky, S.; Rai, V.; Yudin, A. K.
Chem. Rev. 2014, 114, 8323. (j) El Kaïm, L.; Grimaud, L. Eur. J. Org.
Chem. 2014, 2014, 7749. (k) Sharma, U. K.; Sharma, N.; Vachhani, D.
D.; Van Der Eycken, E. V. Chem. Soc. Rev. 2015, 44, 1836.
(2) Tron, G. C. Eur. J. Org. Chem. 2013, 2013, 1849.
(9) Related studies by others: (a) Zheng, Q.-H.; Meng, W.; Jiang, G.-J.;
Yu, Z.-X. Org. Lett. 2013, 15, 5928. (b) Lin, W.; Cao, T.; Fan, W.; Han,
Y.; Kuang, J.; Luo, H.; Miao, B.; Tang, X.; Yu, Q.; Yuan, W.; Zhang, J.;
Zhu, C.; Ma, S. Angew. Chem., Int. Ed. 2014, 53, 277. (c) Haldar, S.;
Mahato, S.; Jana, C. K. Asian J. Org. Chem. 2014, 3, 44. (d) Rahman, M.;
Bagdi, A. K.; Mishra, S.; Hajra, A. Chem. Commun. 2014, 50, 2951. (e) Li,
J.; Wang, H.; Sun, J.; Yang, Y.; Liu, L. Org. Biomol. Chem. 2014, 12, 2523.
(f) Lin, W.; Ma, S. Org. Chem. Front. 2014, 1, 338. (g) Mahato, S.;
Haque, M. A.; Dwari, S.; Jana, C. K. RSC Adv. 2014, 4, 46214.
(h) Mandal, S.; Mahato, S.; Jana, C. K. Org. Lett. 2015, 17, 3762.
(i) Haldar, S.; Roy, S. K.; Maity, B.; Koley, D.; Jana, C. K. Chem. - Eur. J.
2015, 21, 15290. (j) Shao, G.; He, Y.; Xu, Y.; Chen, J.; Yu, H.; Cao, R.
Eur. J. Org. Chem. 2015, 2015, 4615. (k) Cheng, Y.-F.; Rong, H.-J.; Yi, C.-
B.; Yao, J.-J.; Qu, J. Org. Lett. 2015, 17, 4758.
(10) Other recent examples of mechanistically distinct, redox-neutral
amine C−H functionalizations: (a) He, Y.-P.; Wu, H.; Chen, D.-F.; Yu,
J.; Gong, L.-Z. Chem. - Eur. J. 2013, 19, 5232. (b) Kang, Y. K.; Kim, D. Y.
Chem. Commun. 2014, 50, 222. (c) Mori, K.; Kurihara, K.; Akiyama, T.
Chem. Commun. 2014, 50, 3729. (d) Mori, K.; Kurihara, K.; Yabe, S.;
Yamanaka, M.; Akiyama, T. J. Am. Chem. Soc. 2014, 136, 3744. (e) Cao,
W.; Liu, X.; Guo, J.; Lin, L.; Feng, X. Chem. - Eur. J. 2015, 21, 1632.
(f) Wang, P.-F.; Jiang, C.-H.; Wen, X.; Xu, Q.-L.; Sun, H. J. Org. Chem.
2015, 80, 1155.
(3) Examples of Ugi reactions that involve oxidative amine C−H
functionalization: (a) Ngouansavanh, T.; Zhu, J. Angew. Chem., Int. Ed.
2007, 46, 5775. (b) Jiang, G.; Chen, J.; Huang, J.-S.; Che, C.-M. Org.
Lett. 2009, 11, 4568. (c) Ye, X.; Xie, C.; Pan, Y.; Han, L.; Xie, T. Org. Lett.
2010, 12, 4240. (d) Ye, X.; Xie, C.; Huang, R.; Liu, J. Synlett 2012, 23,
409. (e) Rueping, M.; Vila, C. Org. Lett. 2013, 15, 2092. (f) Chen, Y.;
Feng, G. Org. Biomol. Chem. 2015, 13, 4260. (g) de Graaff, C.; Bensch,
L.; van Lint, M. J.; Ruijter, E.; Orru, R. V. A. Org. Biomol. Chem. 2015, 13,
10108.
(4) Dighe, S. U.; K. S., A. K.; Srivastava, S.; Shukla, P.; Singh, S.;
Dikshit, M.; Batra, S. J. Org. Chem. 2015, 80, 99.
(5) Examples of related decarboxylative coupling reactions: (a) Cohen,
N.; Blount, J. F.; Lopresti, R. J.; Trullinger, D. P. J. Org. Chem. 1979, 44,
4005. (b) Zheng, L.; Yang, F.; Dang, Q.; Bai, X. Org. Lett. 2008, 10, 889.
(c) Zhang, C.; Seidel, D. J. Am. Chem. Soc. 2010, 132, 1798. (d) Bi, H.-P.;
Teng, Q.; Guan, M.; Chen, W.-W.; Liang, Y.-M.; Yao, X.; Li, C.-J. J. Org.
Chem. 2010, 75, 783. (e) Zhang, C.; Das, D.; Seidel, D. Chem. Sci. 2011,
2, 233. (f) Yang, D.; Zhao, D.; Mao, L.; Wang, L.; Wang, R. J. Org. Chem.
2011, 76, 6426. (g) Das, D.; Richers, M. T.; Ma, L.; Seidel, D. Org. Lett.
2011, 13, 6584. (h) Firouzabadi, H.; Iranpoor, N.; Ghaderi, A.;
Ghavami, M. Tetrahedron Lett. 2012, 53, 5515. (i) Richers, M. T.; Deb,
I.; Platonova, A. Y.; Zhang, C.; Seidel, D. Synthesis 2013, 45, 1730.
(j) Kaboudin, B.; Karami, L.; Kato, J. Y.; Aoyama, H.; Yokomatsu, T.
Tetrahedron Lett. 2013, 54, 4872. (k) Manjappa, K. B.; Jhang, W.-F.;
Huang, S.-Y.; Yang, D.-Y. Org. Lett. 2014, 16, 5690. (l) Samala, S.; Singh,
G.; Kumar, R.; Ampapathi, R. S.; Kundu, B. Angew. Chem., Int. Ed. 2015,
54, 9564. (m) Jin, Z. N.; Jiang, H. J.; Wu, J. S.; Gong, W. Z.; Cheng, Y.;
Xiang, J.; Zhou, Q. Z. Tetrahedron Lett. 2015, 56, 2720. (n) Tang, M.;
Tong, L.; Ju, L.; Zhai, W.; Hu, Y.; Yu, X. Org. Lett. 2015, 17, 5180.
(6) Selected reviews on amine C−H functionalization, including
redox-neutral approaches: (a) Murahashi, S.-I. Angew. Chem., Int. Ed.
Engl. 1995, 34, 2443. (b) Matyus, P.; Elias, O.; Tapolcsanyi, P.; Polonka-
Balint, A.; Halasz-Dajka, B. Synthesis 2006, 2006, 2625. (c) Campos, K.
R. Chem. Soc. Rev. 2007, 36, 1069. (d) Murahashi, S.-I.; Zhang, D. Chem.
Soc. Rev. 2008, 37, 1490. (e) Li, C.-J. Acc. Chem. Res. 2009, 42, 335.
(f) Jazzar, R.; Hitce, J.; Renaudat, A.; Sofack-Kreutzer, J.; Baudoin, O.
Chem. - Eur. J. 2010, 16, 2654. (g) Yeung, C. S.; Dong, V. M. Chem. Rev.
(11) No appreciable amount of product formation was observed with a
range of other promoters, including Lewis acids such as LiCl and Cu(2-
EH)2.
(12) Please see the Supporting Information for additional optimization
studies.
C
DOI: 10.1021/acs.orglett.5b03529
Org. Lett. XXXX, XXX, XXX−XXX