Gold-Catalyzed Intermolecular Ynamide Amination-Initiated Aza-Nazarov Cyclization: Access to Functionalized 2-Aminopyrroles

Article abstract of DOI:10.1021/acs.orglett.6b01503

A novel gold-catalyzed intermolecular ynamide amination-initiated aza-Nazarov cyclization has been developed, allowing the facile and efficient synthesis of various 2-aminopyrroles in moderate to good yields. Furthermore, a mechanistic rationale for this

Full text of DOI:10.1021/acs.orglett.6b01503

Letter
pubs.acs.org/OrgLett
Gold-Catalyzed Intermolecular Ynamide Amination-Initiated Aza-
Nazarov Cyclization: Access to Functionalized 2‑Aminopyrroles
Chao Shu,† Yong-Heng Wang,† Cang-Hai Shen,† Peng-Peng Ruan,† Xin Lu,*,† and Long-Wu Ye*,†,‡
†State Key Laboratory of Physical Chemistry of Solid Surfaces & The Key Laboratory for Chemical Biology of Fujian Province,
College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, China
S
* Supporting Information
ABSTRACT: A novel gold-catalyzed intermolecular ynamide amination-initiated aza-Nazarov cyclization has been developed,
allowing the facile and efficient synthesis of various 2-aminopyrroles in moderate to good yields. Furthermore, a mechanistic
rationale for this tandem sequence, especially for the observed high regioselectivity, is also well supported by DFT (density
functional theory) computations. The high flexibility, broad substrate scope, and mild nature of this reaction render it a viable
alternative for the construction of 2-aminopyrroles.
Scheme 1. Gold-Catalyzed Nazarov-Type Cyclization
he Nazarov cyclization is a stereospecific 4π-electro-
Tcyclization that, in its typical manifestation, converts
divinyl ketones into cyclopentenones via a conrotatory
cyclization. In the past decades, this cyclization has been
proven to be a powerful method for the synthesis of five-
membered carbo- or heterocycles;1 however, metal carbene
involved Nazarov-type cyclization is less explored.2 Recent
rapid development in homogeneous gold catalysis offers a
highly attractive approach for accessing this cyclization. For
example, Liu et al. reported a gold-catalyzed formal [4 + 1]
cycloaddition between 3-en-1-ynamides and quinoline oxide via
oxa-Nazarov cyclization to afford various 2-aminofurans in 2012
(Scheme 1a).3 Simultaneously, Zhang et al. also demonstrated
an elegant protocol for the efficient synthesis of substituted 2,3-
dihydro-1H-pyrrolizines through gold-catalyzed aza-Nazarov
cyclization of linear azidoenynes, but requiring electron-
withdrawing groups in the 5-position (Scheme 1b).4 Despite
these significant achievements, it is still highly desirable to
explore new reactions based on such a gold carbene5 involved
Nazarov cyclization, especially in an intermolecular and atom-
economic way. In our recent study on the ynamide
chemistry,6−8 we first disclosed that benzyl azides could serve
as efficient nitrene transfer reagents to react with ynamides to
intermolecularly generate the α-imino gold carbenes,9,10
allowing the site-selective synthesis of versatile 2-aminoindoles
and 3-amino-β-carbolines.8b Inspired by these results, we
envisioned that the gold-catalyzed intermolecular ynamide
amination-initiated formal aza-Nazarov cyclization might be
achieved by reaction of benzyl azides with 3-en-1-ynamides
(Scheme 1c). Herein, we describe the realization of such a
formal aza-Nazarov cyclization, thus leading to the highly
regioselective synthesis of various 2-aminopyrroles, which are
common structural motifs found in a variety of bioactive
molecules (Figure 1).11 Moreover, a mechanistic rationale for
this tandem reaction, especially for the observed high
regioselectivity, is also supported by DFT (density functional
theory) calculations.
At the outset, 3-en-1-ynamide 1a was chosen as a model
substrate for our initial study, and some of the results are
outlined in Table 1. To our delight, the expected 2-
Received: May 24, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01503
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 2. Reaction Scope Study
Figure 1. Selected examples of bioactive 2-aminopyrroles.
a
Table 1. Optimization of Reaction Conditions
b
entry
gold catalyst
IPrAuNTf2
conditions
yield (%)
1
2
3
4
5
6
7
8
9
4 Å MS, DCE, 80 °C, 30 h
4 Å MS, DCE, 80 °C, 30 h
4 Å MS, DCE, 80 °C, 30 h
4 Å MS, DCE, 80 °C, 30 h
4 Å MS, DCE, 80 °C, 30 h
4 Å MS, DCE, 80 °C, 30 h
4 Å MS, DCE, 80 °C, 30 h
4 Å MS, DCE, 60 °C, 48 h
3 Å MS, DCE, 60 °C, 48 h
3 Å MS, DCE, 60 °C, 48 h
65
60
<5
<5
<5
<5
6
SIPrAuNTf2
Me3PAuNTf2
Ph3PAuNTf2
XPhosAuNTf2
BrettPhosAuNTf2
(4-CF3C6H4)3PAuNTf2
IPrAuNTf2
69
74
80
IPrAuNTf2
c
10
IPrAuNTf2
a
b
c
Reaction conditions: [1a] = 0.1 M; DCE: 1,2-dichloroethane.
Estimated by H NMR using diethyl phthalate as internal reference.
3 equiv of 2a were used.
1
1
aminopyrrole 3a was indeed formed in 65% H NMR yield
under our previously developed conditions (IPrANTf2, 4 Å MS,
DCE)8b by using 3-bromobenzyl azide 2a as a nitrene transfer
reagent (Table 1, entry 1). Importantly, this tandem reaction is
highly regioselective and no 2-aminoindole formation was
observed.8b Then, various typical gold catalysts with a range of
electronic and steric characteristics were screened, and it was
found that they failed to give an improved yield (Table 1,
entries 2−7). The reaction yield could be slightly improved at
60 °C albeit with a long reaction time (Table 1, entry 8).
Gratifyingly, a 74% yield was obtained by replacing 4 Å MS
with 3 Å MS (Table 1, entry 9). In addition, it was found that
the yield could be further improved to 80% by employing 3
equiv of 2a (Table 1, entry 10). Finally, it should be mentioned
that other typical transition metals such as PtCl2, AgNTf2, and
Zn(OTf)2 were not effective in promoting this reaction
(<5%).12
Under the optimal reaction conditions, the generality of this
novel formal [4 + 1] cycloaddition was then evaluated with a
variety of 3-en-1-ynamide derivatives 1. As shown in Table 2,
various ynamides with aromatic or aliphatic substituents at the
α or β position were first investigated, and it was found that the
reaction could work smoothly to produce the expected 2-
aminopyrroles 3b−3g in 60−72% yields (Table 2, entries 2−7).
In addition, the reaction was also compatible with ynamides
bearing substituents at both the α and β positions, affording the
corresponding pyrroles 3h−3i in good yields (Table 2, entries
a
Reactions run in vials; [1] = 0.1 M; isolated yields are reported.
Reaction time: 72 h.
b
8−9). To our satisfaction, cyclopentenyl and cycloheptenyl
substituted ynamides 1j and 1k were also suitable substrates for
this reaction, thus delivering the desired fused 2-aminopyrroles
B
DOI: 10.1021/acs.orglett.6b01503
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
3j and 3k in 74% and 50% yield, respectively (Table 2, entries
10−11). Notably, this tandem reaction is highly regioselective
and no 2-aminoindole formation was observed in all these
cases. Ynamides with different R3 were also effective substrates
and provided the desired products 3l−3n in 65−72% yields
(Table 2, entries 12−14). Finally, it should be mentioned that a
longer reaction time was needed in some cases (Table 2, entries
11−13). The molecular structure of 3d was further confirmed
by X-ray crystallography (Figure 2). Thus, this protocol
computations.12 The benzyl azide 2a first attacked Au-activated
alkyne A, leading to the generation of Au-substituted alkene B
by overcoming a moderate free-energy barrier of 19.0 kcal/mol.
Departure of N2 readily gave the imine-containing gold−
carbene intermediate C. Intramolecular cyclization occurred
preferentially between the imine and terminal alkene, rather
than between the gold−carbene and N-phenyl group. Finally,
the as-formed intermediate D underwent proton transfer8b and
ligand exchange to furnish product 3b. The whole process was
highly exothermic with free-energy release of 104.9 kcal/mol.
In summary, we have developed a convenient and viable
alternative for the synthesis of structurally diverse 2-amino-
pyrroles through gold-catalyzed intermolecular formal [4 + 1]
cycloaddition of 3-en-1-ynamides with azides. Compared with
the relevant intramolecular alkyne amination,4 where an
electron-deficient alkene is required to be conjugated with
the alkyne, this intermolecular protocol demonstrates more
flexibility and a wider substrate scope. Moreover, the
mechanistic rationale for this novel intermolecular amination
reaction, especially for the observed unique regioselectivity, is
also strongly supported by DFT calculations. Further
investigations into the synthetic applications of the current
reaction are underway.
Figure 2. X-ray structure of 3d.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01503.
■
provides a highly convenient and efficient route for the
preparation of synthetically useful 2-aminopyrroles. To our
disappointment, attempts to expand this chemistry to tosyl-
protected ynamide were not successful.12
Besides 3-bromobenzyl azide 2a, it was found that other
bromo-substituted benzyl azides 2b−2c also worked well to
afford the desired 2-aminopyrroles 3o−3p in good yields (eq
1). Similar to our previous protocol,8b benzyl azide 2d gave a
S
Experimental procedures and spectral data for all new
compounds (PDF)
X-ray crystallographic data for 3d (CIF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: longwuye@xmu.edu.cn.
*E-mail: xinlu@xmu.edu.cn.
Notes
decreased yield (eq 1) and the reaction proceeded with low
efficiency (<30%) when the benzyl azides were substituted with
electron-donating groups such as methyl and methoxyl.
A possible mechanism to rationalize the formation of 3b was
presented in Scheme 2 along with the relative free energies of
key intermediates and transition states predicted by DFT
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of China (Nos. 21272191, 21273177, and
21572186), the Natural Science Foundation of Fujian Province
for Distinguished Young Scholars (No. 2015J06003), the
President Research Funds from Xiamen University (No.
20720150045), NFFTBS (No. J1310024), and XMU Under-
graduate Innovation and Entrepreneurship Training Programs
(201510384008).
Scheme 2. M06(SMD, DCE)/6-31G(d,p)/SDD-Computed
Relative Free Energies for the Reaction of 1b with 2a
REFERENCES
■
(1) For recent reviews on the Nazarov reaction, see: (a) Di Grandi,
M. J. Org. Biomol. Chem. 2014, 12, 5331. (b) Spencer, W. T., III;
Vaidya, T.; Frontier, A. J. Eur. J. Org. Chem. 2013, 2013, 3621.
́
(c) Audran, G.; Bremond, P.; Feuerstein, M.; Marque, S. R. A.;
Santelli, M. Tetrahedron 2013, 69, 8325. (d) Vaidya, T.; Eisenberg, R.;
Frontier, A. J. ChemCatChem 2011, 3, 1531. (e) Shimada, N.; Stewart,
C.; Tius, M. A. Tetrahedron 2011, 67, 5851. (f) Grant, T. N.; Rieder,
C. J.; West, F. G. Chem. Commun. 2009, 45, 5676. (g) Nakanishi, W.;
West, F. G. Curr. Opin. Drug Discovery Dev. 2009, 12, 732.
(2) For recent selected examples, see: (a) Chen, M.; Sun, N.; Xu, W.;
Zhao, J.; Wang, G.; Liu, Y. Chem. - Eur. J. 2015, 21, 18571. (b) Alford,
C
DOI: 10.1021/acs.orglett.6b01503
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
J. S.; Spangler, J. E.; Davies, H. M. L. J. Am. Chem. Soc. 2013, 135,
11712. (c) Sanz, R.; Miguel, D.; Rodríguez, F. Angew. Chem., Int. Ed.
2008, 47, 7354. (d) Sohel, S. M. A.; Lin, S.-H.; Liu, R.-S. Synlett 2008,
2008, 745. (e) Zhang, L.; Wang, S. J. Am. Chem. Soc. 2006, 128, 1442.
(3) Dateer, R. B.; Pati, K.; Liu, R.-S. Chem. Commun. 2012, 48, 7200.
(4) Yan, Z.-Y.; Xiao, Y.; Zhang, L. Angew. Chem., Int. Ed. 2012, 51,
8624.
(5) For recent selected reviews on the generation of gold carbenes,
see: (a) Zheng, Z.; Wang, Z.; Wang, Y.; Zhang, L. Chem. Soc. Rev.
2016, DOI: 10.1039/C5CS00887E. (b) Liu, L.; Zhang, J. Chem. Soc.
Rev. 2016, 45, 506. (c) Huple, D. B.; Ghorpade, S.; Liu, R.-S. Adv.
Synth. Catal. 2016, 358, 1348. (d) Dorel, R.; Echavarren, A. M. Chem.
Rev. 2015, 115, 9028. (e) Qian, D.; Zhang, J. Chem. Soc. Rev. 2015, 44,
677. (f) Wang, Y.; Muratore, M. E.; Echavarren, A. M. Chem. - Eur. J.
2015, 21, 7332. (g) Wei, F.; Song, C.; Ma, Y.; Zhou, L.; Tung, C.-H.;
Xu, Z. Sci. Bull. 2015, 60, 1479. (h) Yeom, H.-S.; Shin, S. Acc. Chem.
Res. 2014, 47, 966. (i) Fensterbank, L.; Malacria, M. Acc. Chem. Res.
2014, 47, 953. (j) Obradors, C.; Echavarren, A. M. Acc. Chem. Res.
2014, 47, 902. (k) Zhang, L. Acc. Chem. Res. 2014, 47, 877.
(l) Hashmi, A. S. K. Acc. Chem. Res. 2014, 47, 864. (m) Obradors, C.;
Echavarren, A. M. Chem. Commun. 2014, 50, 16.
(11) For recent selected examples, see: (a) Kumar, T. B.; Sumanth,
C.; Vaishaly, S.; Rao, M. S.; Sekhar, K. B. C.; Meda, C. L. T.; Kandale,
A.; Rambabu, D.; Krishna, G. R.; Reddy, C. M.; Kumar, K. S.; Parsa, K.
V. L; Pal, M. Bioorg. Med. Chem. Lett. 2012, 22, 5639. (b) Frolova, L.
V.; Evdokimov, N. M.; Hayden, K.; Malik, I.; Rogelj, S.; Kornienko, A.;
Magedov, I. V. Org. Lett. 2011, 13, 1118. (c) Jalani, H. B.; Pandya, A.
N.; Baraiya, A. B.; Kaila, J. C.; Pandya, D. H.; Sharma, J. A.;
Sudarsanam, V.; Vasu, K. K. Tetrahedron Lett. 2011, 52, 6331.
(d) Wallace, M. B.; Adams, M. E.; Kanouni, T.; Mol, C. D.; Dougan,
D. R.; Feher, V. A.; O’Connell, S. M.; Shi, L.; Halkowycz, P.; Dong, Q.
Bioorg. Med. Chem. Lett. 2010, 20, 4156. (e) Onnis, V.; De Log, A.;
Cocco, M. T.; Fadda, R.; Meleddu, R.; Congiu, C. Eur. J. Med. Chem.
2009, 44, 1288. (f) Katritzky, A. R. Comprehensive Heterocyclic
Chemistry III, 1st ed.; Elsevier: Amsterdam, 2008. (g) Fan, H.; Peng,
J.; Hamann, M. T.; Hu, J.-F. Chem. Rev. 2008, 108, 264. (h) Biava, M.;
Porretta, G. C.; Manetti, F. Mini-Rev. Med. Chem. 2007, 7, 65. (i) Oda,
H.; Hanami, T.; Iwashita, T.; Kojima, M.; Itoh, M.; Hayashizaki, Y.
Tetrahedron 2007, 63, 12747. (j) Sessler, J. L.; Pantos, G. D.; Gale, P.
A.; Light, M. E. Org. Lett. 2006, 8, 1593. (k) Walsh, C. T.; Garneau-
Tsodikova, S.; Howard-Jones, A. R. Nat. Prod. Rep. 2006, 23, 517.
(l) Bellina, F.; Rossi, R. Tetrahedron 2006, 62, 7213. (m) Bullington, J.
L.; Fan, X.; Jackson, P. F.; Zhang, Y.-M. PTC Int. Appl. 2004, WO
2004029040 A1 20040408.
(6) For recent reviews on ynamide reactivity, see: (a) Evano, G.;
Theunissen, C.; Lecomte, M. Aldrichimica Acta 2015, 48, 59.
(b) Wang, X.-N.; Yeom, H.-S.; Fang, L.-C.; He, S.; Ma, Z.-X.;
Kedrowski, B. L.; Hsung, R. P. Acc. Chem. Res. 2014, 47, 560.
(c) DeKorver, K. A.; Li, H.; Lohse, A. G.; Hayashi, R.; Lu, Z.; Zhang,
Y.; Hsung, R. P. Chem. Rev. 2010, 110, 5064. (d) Evano, G.; Coste, A.;
Jouvin, K. Angew. Chem., Int. Ed. 2010, 49, 2840.
(12) For details, please see the Supporting Information (SI).
(7) For our recent study on the transition-metal-catalyzed oxidation-
initiated tandem reactions based on ynamides, see: (a) Li, L.; Zhou, B.;
Wang, Y.-H.; Shu, C.; Pan, Y.-F.; Lu, X.; Ye, L.-W. Angew. Chem., Int.
Ed. 2015, 54, 8245. (b) Pan, F.; Shu, C.; Ping, Y.-F.; Pan, Y.-F.; Ruan,
P.-P.; Fei, Q.-R.; Ye, L.-W. J. Org. Chem. 2015, 80, 10009. (c) Li, L.;
Zhou, B.; Ye, L.-W. Youji Huaxue 2015, 35, 655. (d) Li, L.; Shu, C.;
Zhou, B.; Yu, Y.-F.; Xiao, X.-Y.; Ye, L.-W. Chem. Sci. 2014, 5, 4057.
(e) Pan, F.; Liu, S.; Shu, C.; Lin, R.-K.; Yu, Y.-F.; Zhou, J.-M.; Ye, L.-
W. Chem. Commun. 2014, 50, 10726. (f) Shen, C.-H.; Li, L.; Zhang,
W.; Liu, S.; Shu, C.; Xie, Y.-E.; Yu, Y.-F.; Ye, L.-W. J. Org. Chem. 2014,
79, 9313.
(8) For our recent study on the gold-catalyzed amination-initiated
tandem reactions based on ynamides, see: (a) Pan, Y.; Chen, G.-W.;
Shen, C.-H.; He, W.; Ye, L.-W. Org. Chem. Front. 2016, 3, 491.
(b) Shu, C.; Wang, Y.-H.; Zhou, B.; Li, X.-L.; Ping, Y.-F.; Lu, X.; Ye,
L.-W. J. Am. Chem. Soc. 2015, 137, 9567. (c) Zhou, A.-H.; He, Q.; Shu,
C.; Yu, Y.-F.; Liu, S.; Zhao, T.; Zhang, W.; Lu, X.; Ye, L.-W. Chem. Sci.
2015, 6, 1265. (d) Xiao, X.-Y.; Zhou, A.-H.; Shu, C.; Pan, F.; Li, T.; Ye,
L.-W. Chem. - Asian J. 2015, 10, 1854. (e) Shen, C.-H.; Pan, Y.; Yu, Y.-
F.; Wang, Z.-S.; He, W.; Li, T.; Ye, L.-W. J. Organomet. Chem. 2015,
795, 63.
(9) For a recent review on the generation of α-imino gold carbenes,
see: Davies, P. W.; Garzon, M. Asian J. Org. Chem. 2015, 4, 694.
́
(10) For recent selected examples on the generation of α-imino gold
carbenes, see: (a) Jin, H.; Huang, L.; Xie, J.; Rudolph, M.; Rominger,
F.; Hashmi, A. S. K. Angew. Chem., Int. Ed. 2016, 55, 794. (b) Gillie, A.
D.; Reddy, R. J.; Davies, P. W. Adv. Synth. Catal. 2016, 358, 226.
(c) Zhu, L.; Yu, Y.; Mao, Z.; Huang, X. Org. Lett. 2015, 17, 30.
(d) Pawar, S. K.; Sahani, R. L.; Liu, R.-S. Chem. - Eur. J. 2015, 21,
10843. (e) Prechter, A.; Henrion, G.; dit Bel, P. F.; Gagosz, F. Angew.
́
Chem., Int. Ed. 2014, 53, 4959. (f) Garzon, M.; Davies, P. W. Org. Lett.
2014, 16, 4850. (g) Tokimizu, Y.; Oishi, S.; Fujii, N.; Ohno, H. Org.
Lett. 2014, 16, 3138. (h) Chatzopoulou, E.; Davies, P. W. Chem.
Commun. 2013, 49, 8617. (i) Xiao, Y.; Zhang, L. Org. Lett. 2012, 14,
4662. (j) Davies, P. W.; Cremonesi, A.; Dumitrescu, L. Angew. Chem.,
Int. Ed. 2011, 50, 8931. (k) Lu, B.; Luo, Y.; Liu, L.; Ye, L.; Wang, Y.;
Zhang, L. Angew. Chem., Int. Ed. 2011, 50, 8358. (l) Wetzel, A.;
Gagosz, F. Angew. Chem., Int. Ed. 2011, 50, 7354. (m) Li, C.; Zhang, L.
Org. Lett. 2011, 13, 1738. (n) Gorin, D. J.; Davis, N. R.; Toste, F. D. J.
Am. Chem. Soc. 2005, 127, 11260.
D
DOI: 10.1021/acs.orglett.6b01503
Org. Lett. XXXX, XXX, XXX−XXX