Synthesis of 2-Aza-1,3-butadienes through Gold-Catalyzed Intermolecular Ynamide Amination/C-H Functionalization

Article abstract of DOI:10.1021/acs.orglett.6b02267

A novel gold-catalyzed tandem intermolecular ynamide amination/C-H functionalization has been developed. A variety of highly functionalized 2-aza-1,3-butadienes can be obtained readily by utilizing this strategy. In addition, α-imino gold carbene intermediates are proposed in this amination reaction and with support by DFT (density functional theory) calculations.

Full text of DOI:10.1021/acs.orglett.6b02267

Letter
pubs.acs.org/OrgLett
Synthesis of 2‑Aza-1,3-butadienes through Gold-Catalyzed
Intermolecular Ynamide Amination/C−H Functionalization
Chao Shu,† Cang-Hai Shen,† Yong-Heng Wang,† Long Li,† Tao Li,† 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 tandem intermolecular
ynamide amination/C−H functionalization has been devel-
oped. A variety of highly functionalized 2-aza-1,3-butadienes
can be obtained readily by utilizing this strategy. In addition, α-
imino gold carbene intermediates are proposed in this
amination reaction and with support by DFT (density
functional theory) calculations.
Scheme 1. Gold-Catalyzed Intermolecular Reaction of
Ynamides with Azides
unctionalized 2-aza-1,3-butadienes have proved to be a
1,2
Fvery fundamental class of compounds.
For example,
they have been widely used as key building blocks in the
synthesis of nitrogen heterocycles,1,2 which are common
structural motifs found in a very large number of bioactive
natural and non-natural molecules. It is surprising, however,
that only a few preparative methods have been reported.3
Therefore, novel approaches, especially those with high
flexibility, efficiency, and good modularity, are in high demand
to access this important structural motif.
Recently, the generation of α-imino gold carbenes4 through
gold-catalyzed alkyne amination has received considerable
attention, as this chemistry would offer great potential to
build structurally complex nitrogen-containing molecules,
especially the nitrogen heterocycles.5,6 In 2015, our group
demonstrated for the first time that benzyl or indolyl azides
could serve as efficient nitrene-transfer reagents to react with
ynamides7,8 for the intermolecular generation of α-imino gold
carbenes, thus leading to the efficient synthesis of versatile 2-
aminoindoles and 3-amino-β-carbolines skeletons (Scheme
1).9a On the basis of this work, we very recently developed
the gold-catalyzed intermolecular ynamide amination initiated
aza-Nazarov cyclization reaction, which afforded highly
functionalized 2-aminopyrroles (Scheme 1).9b In this paper,
we describe herein the realization of such an Au-catalyzed
amination-initiated C−H functionalization, allowing the facile
and efficient synthesis of various 2-aza-1,3-butadienes in
generally moderate to good yields. In addition, relevant
DFT (density functional theory) computations were also
carried out to elucidate the reaction mechanism, especially for
the observed high regioselectivity.
study by using ynamide 1a bearing electron-deficient aryl
group and p-methylbenzyl azide 2a as the model substrates so
as to inhibit the background 2-aminoindole formation. To our
delight, the desired tandem ynamide amination/C−H
functionalization proceeded well, affording the corresponding
2-aza-1,3-butadiene 3a in 90% yield albeit with poor Z/E
selectivity under the previously optimized reaction conditions
(Table 1, entry 1).9a Importantly, neither triazole nor 2-
aminoindole formation was detected in this case.10 Then,
various typical gold catalysts with different electronic and
steric characteristics were investigated but failed to improve
the reaction (entries 2−5). In addition, the yield was slightly
improved by replacing 4 Å MS with 3 Å MS (entry 6).
Gratifyingly, excellent Z/E selectivity was achieved when the
reaction was performed at a reduced temperature (entry 7).
Further screening of other solvents such as toluene and PhCl
led to a significantly decreased yield (entries 8 and 9). Finally,
In our previous work, the formation of 2-aza-1,3-butadiene
could be observed when the benzyl azides were substituted
with electron-donating groups as nitrene-transfer reagents to
react with ynamides.9a Inspired by this result, we began our
Received: July 31, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02267
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Organic Letters
Letter
a
extend the reaction to alkyl-substituted and terminal ynamides
only gave a complicated mixture of products, and no desired
2-azabutadienes were detected.11 Besides 4-methylbenzyl azide
2a, it was found that other arylmethyl azides 2b−d also
worked well to produce the desired 2-azabutadienes 3n−q in
good yields (entries 14−17). Of note, higher temperature and
longer reaction time were needed in some cases (entries 8−13
and 15−17). The molecular structure of 3n was further
confirmed by X-ray crystallography (Figure 1). Finally, it
Table 1. Optimization of Reaction Conditions
yield
b
c
entry
1
catalyst
conditions
(%)
Z/E
IPrAuNTf2
4 Å MS, DCE, 80 °C,
90
88
11
80
14
94
95
60
<1
<1
<1
<1
<1
2.2:1
2.0:1
>20:1
1.2:1
1.5:1
2.3:1
>20:1
1.3:1
15 h
2
SIPrAuNTf2
Ph3PAuNTf2
4 Å MS, DCE, 80 °C,
15 h
d
3
4 Å MS, DCE, 80 °C,
15 h
4
Cy-JohnPhosNTf2 4 Å MS, DCE, 80 °C,
15 h
e
5
BrettPhosAuNTf2 4 Å MS, DCE, 80 °C,
15 h
6
7
8
IPrAuNTf2
IPrAuNTf2
IPrAuNTf2
IPrAuNTf2
AgNTf2
3 Å MS, DCE, 80 °C,
15 h
3 Å MS, DCE, 60 °C,
24 h
3 Å MS, toluene, 80 °C,
15 h
f
9
3 Å MS, PhCl, 80 °C,
15 h
Figure 1. X-ray structure of 3n.
f
10
3 Å MS, DCE, 80 °C,
15 h
should be mentioned that no triazole formation was observed
in any case. Thus, this protocol provides a facile, efficient, and
viable alternative for the synthesis of valuable 2-azabutadienes.
In addition, we also tested whether sterically hindered (1-
azidoethyl)benzene 2e could serve as the nitrene-transfer
reagent. As shown in eq 1, the reaction of ynamides 1a and
g
11
PtCl2
3 Å MS, DCE, 80 °C,
30 h
h
12
Zn(OTf)2
3 Å MS, DCE, 80 °C,
15 h
f
13
3 Å MS, DCE, 80 °C,
15 h
a
b
c
Reaction conditions: [1a] = 0.05 M. DCE: 1,2-dichloroethane.
1
Estimated by H NMR using diethyl phthalate as internal reference.
Determined by 1H NMR spectroscopy of the crude reaction mixtures.
d
e
71% of 1a remained unreacted. 84% of 1a remained unreacted.
>95% of 1a remained unreacted. 65% of 1a remained unreacted, and
3aa was obtained in 30% yield. 3ab was obtained in 75% yield.
f
g
h
1h with azide 2e proceeded smoothly under the optimal
reaction conditions, affording the corresponding 2-azabuta-
dienes 3r and 3s in 74% and 60% yield, respectively.
Further chemical transformation of the as-synthesized 2-aza-
1,3-butadienes was also explored, as depicted in eq 2. For
it was found that other typical transition metals such as
AgNTf2, PtCl2, and Zn(OTf)2 were not effective in promoting
this reaction (entries 10−12), and no 2-azabutadiene was
formed in the absence of gold catalyst (entry 13). Of note,
triazole 3aa was obtained as the main product by employing
PtCl2 as catalyst (entry 11).10
With the optimized reaction conditions in hand, we then
explored the substrate scope with various ynamides (1a−m)
and azides (2a−d). The reaction was found to be quite
general as illustrated in Table 2. Besides ynamide 1a, the
reaction also worked for ynamides with other phenyl
substituents such as fluoro and chloro, affording the desired
products 3b,c in excellent yields with excellent Z/E selectivity
(entries 2 and 3). Notably, when ynamide 1d was employed,
2-aminoindole 3da could be formed in 21% yield (entry 4).
Then, various alkyl-substituted ynamides were investigated,
and the reaction furnished the corresponding 2-azabutadienes
3e−h in 60−85% yields with good to excellent Z/E selectivity
(entries 5−8). In addition, ynamides bearing different Ar1
groups were also suitable substrates for this reaction to deliver
the desired products 3i−m in moderate to good yields with
good to excellent Z/E selectivity (entries 9−13). Attempts to
example, aza-Diels−Alder reaction of 2-azabutadienes 3 with
tetracyanoethylene in toluene could furnish the corresponding
adducts 4 in good yields with good diastereoselectivity.12
A plausible mechanism to rationalize the formation of 3a is
presented in Scheme 2 along with the relative free energies of
key intermediates and transition states on the basis of DFT
calculations.11 First, azide 2a attacked the Au-activated alkyne
A, forming the Au-substituted alkene B by overcoming a free
energy barrier of 17.5 kcal/mol. Subsequent departure of N2
from B with a small barrier of 4.1 kcal/mol gave the gold
carbene intermediate C. Intermediate C underwent preferen-
tially a concerted deprotonation/protodeauration process to
B
DOI: 10.1021/acs.orglett.6b02267
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Letter
a
Table 2. Reaction Scope Study
a
Reactions run in vials; [1] = 0.05 M; isolated yields (combined yields of Z and E) are reported; Z/E was determined by 1H NMR spectroscopy of
b
c
d
e
f
the crude reaction mixtures. 21% of 2-aminoindole 3da was isolated. Reaction time: 72 h. Reaction run at 80 °C, 72 h. 2b was used. 2c was used.
g
2d was used.
Scheme 2. M06(SMD,DCE)/6-31G(d,p)/SDD-Computed
Relative Free Energies for the Reaction of 1a with 2a
regeneration of intermediate A. The whole process was highly
exothermic with free energy release up to 79.1 kcal/mol.
In summary, we have developed an efficient, flexible, and
viable alternative strategy for the preparation of synthetically
useful 2-aza-1,3-butadienes through gold-catalyzed intermo-
lecular ynamide amination/C−H functionalization reaction of
ynamides with azides. Other notable features of this method
include widespread availability of the substrates, compatibility
with broad functional groups, simple procedure, mild reaction
conditions, and in particular, no need to exclude moisture or
air (“open flask”). Moreover, the mechanistic rationale for this
novel intermolecular amination reaction, especially for the
observed high regioselectivity, is also well supported by
theoretical calculations. Further investigations into the
synthetic applications of the current reaction are ongoing in
our group.
ASSOCIATED CONTENT
■
form intermediate D with a barrier of 10.5 kcal/mol, rather
than the previously observed9a intramolecular cycloaddition of
the gold carbene moiety to either 4-Br-phenyl or 4-Me-phenyl
to form, respectively, intermediate E or F. Finally, ligand
exchange with ynamide 1a delivered product 3a along with
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02267.
C
DOI: 10.1021/acs.orglett.6b02267
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Experimental procedures and spectral data for all new
Letter
(6) 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.; Jannapu Reddy, R.; 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) Xiao, X.-Y.; Zhou, A.-H.; Shu, C.; Pan, F.; Li, T.; Ye, L.-
W. Chem. - Asian J. 2015, 10, 1854. (f) Shen, C.-H.; Pan, Y.; Yu, Y.-
F.; Wang, Z.-S.; He, W.; Li, T.; Ye, L.-W. J. Organomet. Chem. 2015,
795, 63. (g) Prechter, A.; Henrion, G.; Faudot dit Bel, P.; Gagosz, F.
compounds (PDF)
X-ray crystallographic data for 3n (CIF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: longwuye@xmu.edu.cn.
*E-mail: xinlu@xmu.edu.cn.
Notes
́
Angew. Chem., Int. Ed. 2014, 53, 4959. (h) Garzon, M.; Davies, P. W.
Org. Lett. 2014, 16, 4850. (i) Tokimizu, Y.; Oishi, S.; Fujii, N.;
Ohno, H. Org. Lett. 2014, 16, 3138. (j) Chatzopoulou, E.; Davies, P.
W. Chem. Commun. 2013, 49, 8617. (k) Xiao, Y.; Zhang, L. Org. Lett.
2012, 14, 4662. (l) Davies, P. W.; Cremonesi, A.; Dumitrescu, L.
Angew. Chem., Int. Ed. 2011, 50, 8931. (m) Lu, B.; Luo, Y.; Liu, L.;
Ye, L.; Wang, Y.; Zhang, L. Angew. Chem., Int. Ed. 2011, 50, 8358.
(n) Wetzel, A.; Gagosz, F. Angew. Chem., Int. Ed. 2011, 50, 7354.
(o) Li, C.; Zhang, L. Org. Lett. 2011, 13, 1738. (p) Gorin, D. J.;
Davis, N. R.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 11260.
(7) 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.
(8) For our recent study on the transition-metal-catalyzed 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) Li, L.;
Zhou, B.; Wang, Y.-H.; Shu, C.; Pan, Y.-F.; Lu, X.; Ye, L.-W. Angew.
Chem., Int. Ed. 2015, 54, 8245. (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) 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. (e) Li, L.;
Shu, C.; Zhou, B.; Yu, Y.-F.; Xiao, X.-Y.; Ye, L.-W. Chem. Sci. 2014,
5, 4057. (f) Pan, F.; Liu, S.; Shu, C.; Lin, R.-K.; Yu, Y.-F.; Zhou, J.-
M.; Ye, L.-W. Chem. Commun. 2014, 50, 10726. (g) 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.
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), and NFFTBS (No.
J1310024).
REFERENCES
■
(1) For recent reviews, see: (a) Masson, G.; Lalli, C.; Benohoud,
M.; Dagousset, G. Chem. Soc. Rev. 2013, 42, 902. (b) Monbaliu, J.-C.
M.; Masschelein, K. G. R.; Stevens, C. V. Chem. Soc. Rev. 2011, 40,
4708.
(2) For recent selected examples, see: (a) Novikov, M. S.;
Khlebnikov, A. F.; Rostovskii, N. V.; Tcyrulnikov, S.; Suhanova, A.
A.; Zavyalov, K. V.; Yufit, D. S. J. Org. Chem. 2015, 80, 18.
(b) Watanabe, Y.; Washio, T.; Krishnamurthi, J.; Anada, M.;
Hashimoto, S. Chem. Commun. 2012, 48, 6969. (c) Sasada, T.;
Sawada, T.; Ikeda, R.; Sakai, N.; Konakahara, T. Eur. J. Org. Chem.
2010, 2010, 4237. (d) Sarkar, N.; Banerjee, A.; Nelson, S. G. J. Am.
Chem. Soc. 2008, 130, 9222. (e) Palacios, F.; Vicario, J.; Maliszewska,
A.; Aparicio, D. J. Org. Chem. 2007, 72, 2682. (f) Movassaghi, M.;
Hill, M. D. J. Am. Chem. Soc. 2006, 128, 4592. (g) Nicolaou, K. C.;
Nevalainen, M.; Safina, B. S.; Zak, M.; Bulat, S. Angew. Chem., Int.
Ed. 2002, 41, 1941. (h) Jnoff, E.; Ghosez, L. J. Am. Chem. Soc. 1999,
121, 2617.
(3) For representative examples, see: (a) Manan, R. S.; Kilaru, P.;
Zhao, P. J. Am. Chem. Soc. 2015, 137, 6136. (b) Smetanin, I. A.;
Novikov, M. S.; Rostovskii, N. V.; Khlebnikov, A. F.; Starova, G. L.;
Yufit, D. S. Tetrahedron 2015, 71, 4616. (c) Okamoto, K.;
Shimbayashi, T.; Tamura, E.; Ohe, K. Chem. - Eur. J. 2014, 20,
1490. (d) Okamoto, K.; Watanabe, M.; Mashida, A.; Miki, K.; Ohe,
K. Synlett 2013, 24, 1541. (e) Okamoto, K.; Mashida, A.; Watanabe,
M.; Ohe, K. Chem. Commun. 2012, 48, 3554. (f) Ghosez, L.; Bayard,
P.; Nshimyumukiza, P.; Gouverneur, V.; Sainte, F.; Beaudegnies, R.;
Rivera, M.; Frisque-Hesbain, A.-M.; Wynants, C. Tetrahedron 1995,
51, 11021.
(4) For recent selected reviews on the generation of gold carbenes,
see: (a) Zheng, Z.; Wang, Z.; Wang, Y.; Zhang, L. Chem. Soc. Rev.
2016, 45, 4448. (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.
(5) For a recent review on the generation of α-imino gold carbenes,
(9) (a) 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. (b) Shu, C.; Wang,
Y.-H.; Shen, C.-H.; Ruan, P.-P.; Lu, X.; Ye, L.-W. Org. Lett. 2016, 18,
3254.
(10) For selected examples on the transition metal-catalyzed [3 +
2] cycloadditions of ynamides and azides, see: (a) Oppilliart, S.;
́
Mousseau, G.; Zhang, L.; Jia, G.; Thuery, P.; Rousseau, B.; Cintrat, J.
C. Tetrahedron 2007, 63, 8094. (b) Zhang, X.; Li, H.; You, L.; Tang,
Y.; Hsung, R. P. Adv. Synth. Catal. 2006, 348, 2437. (c) IJsselstijn,
M.; Cintrat, J.-C. Tetrahedron 2006, 62, 3837. (d) Zhang, X.; Hsung,
R. P.; You, L. Org. Biomol. Chem. 2006, 4, 2679.
(11) For details, see the Supporting Information.
(12) The relative stereochemistry of compounds 4 was determined
by comparison with literature data based on both the chemical shift
and coupling constant; see: Palacios, F.; Alonso, C.; Rubiales, G.;
Tobillas, C.; Ezpeleta, J. M. Heterocycles 2003, 61, 493.
́
see: Davies, P. W.; Garzon, M. Asian J. Org. Chem. 2015, 4, 694.
D
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