Synthesis of 1-Amino-2 H-quinolizin-2-one Scaffolds by Tandem Silver Catalysis

Article abstract of DOI:10.1021/acs.orglett.8b03935

An efficient tandem cycloisomerization-amination reaction catalyzed by silver is described. This rapid and atom-economic reaction delivered 1-amino-2H-quinolizin-2-one scaffolds in high yields under mild conditions. The reaction could be extended to an asymmetric version albeit with moderate enantioselective excess of the products. In addition, the products can be easily reduced into various azabicycles containing 4-pyridones, which are important building blocks in organic synthesis.

Full text of DOI:10.1021/acs.orglett.8b03935

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of 1‑Amino‑2H‑quinolizin-2-one Scaffolds by Tandem
Silver Catalysis
Xiao-Long Min, Chao Sun, and Ying He*
School of Chemical Engineering, Nanjing University of Science & Technology, Nanjing, 210094, China
S
* Supporting Information
ABSTRACT: An efficient tandem cycloisomerization−amination reaction catalyzed by silver is described. This rapid and atom-
economic reaction delivered 1-amino-2H-quinolizin-2-one scaffolds in high yields under mild conditions. The reaction could be
extended to an asymmetric version albeit with moderate enantioselective excess of the products. In addition, the products can
be easily reduced into various azabicycles containing 4-pyridones, which are important building blocks in organic synthesis.
N-Heterocycles are among the most significant structural
components of pharmaceuticals, and more than half of the
FDA approved small-molecule drugs contain at least one N-
heterocyclic ring.1 Quinolizidines, as one family of N-
heterocycles, are extremely important components of modern
pharmaceuticals and serve as versatile building blocks in
organic synthesis.2 Meanwhile, quinolizidine derivatives are
also the indispensable frameworks of numerous natural
products, as shown in Figure 1.3 Inspired by their intriguing
Scheme 1. Transition Metal Catalyzed π-Activation of
Multiple Bonds
Figure 1. Natural products containing quinolizidine amine/amide
frameworks.
structures and biological significance, the construction of
quinolizidine frameworks has propagated much research effort
to develop novel and efficient methodologies.4
Consequently, a few examples of diamination of alkynes as a
new strategy for the construction of N-heterocycle skeletons
have been reported.7 However, they are generally prepared via
the double nucleophilic addition with assistance of a
stoichiometric oxidant (Scheme 1b). As an alternative
methodology, we sought to explore this regime through the
use of an electrophile to trap the vinyl-metal intermediates
instead of the protonation step during the catalytic cycle. In
Alkynes are very reactive compounds, and the triple bond
participates in a number of organic reactions. Along this line,
Lewis acids promoted cyclizations of alkyne to generate
heterocycle have emerged as an area of great interest.5 Early
work in this area revealed that the potent soft Lewis acidities of
transition metals, such as gold, silver, and copper, play a role in
activating alkenes, allenes, and alkynes (Scheme 1a).6 As such,
they could activate the multiple bonds, followed by the attack
of various nucleophiles affording the alkenyl-metal intermedi-
ates, which undergo protonation to obtain the desired product.
Received: December 10, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03935
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
this case, the diamination of an alkyne would be achieved
which provides the ability to synthesize N-heterocycles.
We started our proposal by using 4-phenyl-1-(pyridin-2-
yl)but-3-yn-2-one (1a) as the model substrate. Ideally, the
reaction would proceed via silver-catalyzed cyclization using a
pyridine moiety as a nucleophile, and then intermediate A
would prefer to transfer to the nucleophilic intermediate B. At
last, the intermediate B would be trapped by an electrophile di-
tert-butyl azodicarboxylate (DBAD) which afforded the desired
product C (Scheme 1c). However, to our surprise, product D
was obtained exclusively, and the product derived from the
vicinal diamination of alkynes was not observed. Encouraged
by this discovery, we set out to further optimize the reaction
conditions.
Scheme 2. Substrate Scope of the R Group
We initiated our optimization by examining the reaction
condition paramters such as solvent, catalyst, and reaction
time, using 1a and DBAD as the model reaction (Table 1). As
a
Table 1. Optimized Conditions for the Reaction
b
entry
cat.
time (h)
solvent
yield (%)
1
2
3
4
5
6
7
8
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgOAc
AgBF4
AgOTf
Ag2CO3
AgSbf6
AgNTf2
1.5
1.0
12
DCM
80
85
36
76
trace
76
38
58
85
72
41
75
74
1,2-DCE
Toluene
MeCN
DMF
MeOH
THF
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
0.5
0.5
1.5
1.2
4.0
1.0
1.5
6.0
2.0
1.0
a
Reaction conditions: 1 (0.1 mmol), DBAD (0.2 mmol), AgNO3 (10
mol %), 1,2-DCE (1.0 mL), rt. Yield of isolated product.
9
10
11
12
13
−MeO, and −Ph group reacted smoothly (Scheme 2,
compounds 3b−3d). However, the yield of the desired
product was decreased when para-substitution included an
electron-withdrawing group such as a halogen (Scheme 2,
compound 3e).8 The meta- and ortho-substituents on the
phenyl ring were also tested which provided the desired
products in good to excellent yields (Scheme 2, compounds
3f−3h). In addition, the phenyl group was amenable to bulky
and heterocycle groups, affording the products in 91% and
71% yield, respectively (Scheme 2, compounds 3i and 3j). The
alkyl groups were also tolerated in the reaction, albeit with a
23% yield of 3l (Scheme 2, compounds 3k and 3l). Finally, we
noticed that the reaction was compatible with an alkene,
leaving the double bond intact for further transformations
(Scheme 2, compound 3m).
With respect to the pyridine analogues, substituted groups
on pyridine ring were then tested (Scheme 3). A variety of
functional groups at the C3 position such as −Me, −OMe,
−Ph, and −CCPh were tolerated, affording the desired
products in moderate to excellent yields (Scheme 3,
compounds 3n−3q). However, the group at the C6 position
affected the reaction significantly, and no desired product was
obtained (Scheme 3, compound 3t).9 The substitutions at the
C4 and C5 positions were tolerated, forming the desired
products in 53% and 87% yields, respectively (Scheme 3,
compounds 3r and 3s). Notably, the pyridine ring in the
substrate 1 could be changed to other heterocycles such as
a
Reaction conditions: 1a (0.1 mmol), DBAD (0.2 mmol), cat. (10
b
mol %), solvent (1.0 mL), rt. Yield of isolated product.
could be seen in Scheme 2, 1,2-DCE was found to be effective
in the presence of AgNO3, and an 85% yield of product was
obtained (Table 1, entry 2). Toluene and THF were not
compatible for the reaction owing to the low solubility of
substrate 1a (Table 1, entries 3 and 7). A trace amount of
product was obtained when the reaction was performed in
DMF (Table 1, entry 5). Other solvents such as DCM, MeCN,
and MeOH gave us slightly lower yields of 76%−80% (Table
1, entries 1, 4, and 6). Most silver catalysts shown in Table 1
led to the desired products in good yields except for Ag2CO3
and AgOAc (Table 1, entries 8−13). While AgBF4 was found
to be comparable in efficiency (Table 1, entry 9), AgNO3 was
more economical and stable in air which was used as the best
catalyst.
With the optimized conditions in hand, we then explored
the scope and limitations of the reaction. The results were
summarized in Schemes 2 and 3. To our delight, a wide range
of alkynes were tolerated and all the reactions delivered the
desired products in good to excellent yields. Arylacetylene
bearing a series of para-substituents including the −Me,
B
DOI: 10.1021/acs.orglett.8b03935
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
In light of the axial chirality properties of the products 3, we
investigated the enantioselective version of the reaction. To
simplify the studies of the enantioselectivities, compound 4b
was used as the substrate for the reaction. A series of silver salts
and chiral ligands were surveyed (see Supporting Information
(SI) for the details). Finally, 3n could be obtained in 59% ee
with 46% yield in the presence of AgOTf (Scheme 5, eq 3).11
Scheme 3. Substrate Scope of Pyridine Ring and Diazenes
Scheme 5. Enantioselective Silver-Catalyzed C−H
Amination, Cycloisomerization−Amination, and
Cycloaddition Reaction
a
Reaction conditions: 1 (0.1 mmol), diazene (0.2 mmol), AgNO3 (10
mol %), 1,2-DCE (1.0 mL), rt. Yield of isolated product.
isoquinoline, pyrroline, and pyrazine which gave us the
products in good to high yields (Scheme 3, compounds 3u−
3w). This result extended our methodology to potential useful
building blocks in the synthesis of other nitrogen containing
pharmaceuticals. Last, different protecting groups of diazenes
were also tested which furnished the desired products in
excellent yields (Scheme 3, compounds 3x and 3y).10
In an effort to gain more insight into the cascade reaction,
the mechanism studies and control experiments were carried
out. First, the compound 4a was synthesized and subjected
into our reaction system. To our delight, the reaction
proceeded smoothly, affording 3a in 87% yield (Scheme 4,
eq 1), and no desired product was obtained in the absence of
the silver catalyst. This result suggests the rare direct C−N
bond formation of 4a by a silver catalyst. Second, the reaction
could also occur by stepwise operation which further indicated
the tandem cycloisomerization−amination process (Scheme 4,
eq 2).
Interestingly, a different configuration of the product was
obtained when the reaction was conducted at different
temperatures using 1n as the substrate (Scheme 5, eq 4).
This outcome convinced us that the reaction proceeded by
multiple pathways. In order to test our hypothesis, the
compound 5 was synthesized and its homocoupling reaction
was carried out. As a result, the reaction proceeded smoothly
and a 91% yield of 3a was obtained (Scheme 5, eq 5).12
Presumably, two competitive reactions may occur during the
catalytic process. For the first pathway, the Ag(I) complex first
activated the carbon−carbon triple bonds, followed by the
attack of pyridine to form 4a. The reason why no product
resulting from the vicinal diamination of 1a is obtained is
believed to the result of the fast protonation of intermediate B
(Scheme 1c). The silver-catalyzed C−H amination then
occurred to afford the desired product (Scheme 6, path 1).
Scheme 6. Proposed Mechanism of the Reaction
Scheme 4. Silver Catalyzed Direct C−H Amination and
Stepwise Cycloisomerization−Amination
C
DOI: 10.1021/acs.orglett.8b03935
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Alternatively, 1a was first activated by a silver catalyst to react
with DBAD, yielding the intermediate 5. Afterward, the
cycloisomerization proceeded to generate the desired product
(Scheme 6, path 2). Although we could not clearly distinguish
the two pathways, we surmised path 1 might be slightly more
competitive than path 2 based on the asymmetric induction of
3n in eqs 3 and 4.
To test the practicality of the synthesis of 1-amino-2H-
quinolizin-2-one derivatives, a gram-scale reaction of 1a with
DBAD was carried out. As expected, 3a was isolated in 82%
yield under the optimized conditions (Scheme 7, eq 6).
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03935.
■
S
Experimental procedures, detail reaction optimizations,
HPLC traces, and characterization details (PDF)
Accession Codes
CCDC 1875492 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Scheme 7. Gram-Scale Reaction
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yhe@njust.edu.cn.
ORCID
Finally, the selective reductions were carried out to obtain
versatile heterocyclic rings. The removal of Boc groups with
TFA and DCM, followed by treatment with the Zn/AcOH
system, afforded the amino derivative 7 (CCDC 1875492) in
65% isolated yield. A Pd/C-catalyzed hydrogenation that also
promoted the deprotection of the Boc groups converted 3a to
8 in 62% yield (Scheme 8).
Ying He: 0000-0001-9159-4606
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
a
We gratefully acknowledge the Natural Science Foundation of
Jiangsu Province (BK20180447) and the Fundamental
Research Funds for the Central Universities (30918011313)
for financial support. We thank M.-F.Lv. for assistance with the
X-ray crystallographic collection and analysis. We thank Prof.
H.-M. Wu from Nanjing Technology University for helpful
discussions.
Scheme 8. Selective Reductions of 3a
REFERENCES
■
(1) (a) Taylor, R. D.; MacCoss, M.; Lawson, A. D. G. J. Med. Chem.
2014, 57, 5845. (b) Zhang, T. Y. Adv. Heterocycl. Chem. 2017, 121, 1.
(2) (a) Vitaku, E.; Smith, D. T.; Njardarson, J. T. J. Med. Chem.
2014, 57, 10257. (b) Michael, J. P. Nat. Prod. Rep. 2008, 25, 139.
́
́
́
(c) Lu, Y.; Alujas-Burgos, S.; Oliveras-Gonzalez, C.; Vazquez-Jimenez,
́
́
́
L.; Rojo, P.; Alvarez-Larena, A.; Bayon, P.; Figueredo, M. Tetrahedron
a
TFA/DCM, 50 °C overnight; then Zn, AcOH, 10 h. (b) TFA/
2018, 74, 104.
DCM, 50 °C overnight; then Pd/C, H2 (1 atm), MeOH, rt for 3 h.
(3) For reviews, see: (a) Weinreb, S. M. Chem. Rev. 2006, 106, 2531.
́
(b) Konrath, E. L.; dos, S.; Passos, C.; Klein-Junior, L. C.; Henriques,
A. T. J. Pharm. Pharmacol. 2013, 65, 1701. (c) Jasiewicz, B.;
Pospieszny, T. Mini-Rev. Org. Chem. 2013, 10, 217. (d) Veerasamy,
N.; Carter, R. G. Tetrahedron 2016, 72, 4989.
In conclusion, we have developed a novel strategy to 1-
amino-2H-quinolizin-2-one scaffolds by silver catalysis. The
tandem cycloisomerization/amination process is attractive due
to a wide substrate scope. The preliminary mechanistic studies
indicated two possible pathways of the reaction. Moreover, the
rare direct site-selective C−H amination of the 2H-quinolizin-
2-one core was developed and extended to be an asymmetric
transformation. Large-scale reaction and selective reductions
were achieved, demonstrating the usefulness of the method-
ology to access a diversity of N-heterocyclic molecules.
Detailed mechanistic studies including the DFT calculations
and efforts to achieve high enantioselectivities of the C−H
amination are currently in progress in our laboratory.
(4) (a) Boekelheide, V.; Lodge, J. P. J. Am. Chem. Soc. 1951, 73,
3681. (b) Tehrani, K. A.; D’hooghe, M.; De Kimpe, N. Tetrahedron
2003, 59, 3099. (c) Natarajan, S. R.; Chen, M.-H.; Heller, S. T.;
Tynebor, R. M.; Crawford, E. M.; Minxiang, C.; Kaizheng, H.; Dong,
J.; Hu, B.; Hao, W.; Chen, S.-H. Tetrahedron Lett. 2006, 47, 5063.
(d) Fan, X.; He, Y.; Zhang, X.; Wang, J. Green Chem. 2014, 16, 1393.
(e) Shinde, P. S.; Shaikh, A. C.; Patil, N. T. Chem. Commun. 2016, 52,
8152. (f) James, M. J.; Grant, N. D.; O’Brien, P.; Taylor, R. J. K.;
Unsworth, W. P. Org. Lett. 2016, 18, 6256. (g) Enamorado, M. F.;
Connelly, C. M.; Deiters, A.; Comins, D. L. Tetrahedron Lett. 2015,
56, 3683.
(5) For selected recent papers on Lewis promoting cyclization of
alkyne, see: (a) Melen, R. L.; Wilkins, L. C.; Kariuki, B. M.;
Wadepohl, H.; Gade, L. H.; Hashmi, A. S. K.; Stephan, D. W.;
Hansmann, M. M. Organometallics 2015, 34, 4127. (b) Liu, L.; Zhang,
J. Angew. Chem., Int. Ed. 2009, 48, 6093. (c) Hansmann, M. M.;
Melen, R. L.; Rudolph, M.; Rominger, F.; Wadepohl, H.; Stephan, D.
D
DOI: 10.1021/acs.orglett.8b03935
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
W.; Hashmi, A. S. K. J. Am. Chem. Soc. 2015, 137, 15469. (d) Tamke,
̈
S.; Qu, Z.-W.; Sitte, N. A.; Florke, U.; Grimme, S.; Paradies, J. Angew.
Chem., Int. Ed. 2016, 55, 4336. (e) Yuan, K.; Wang, S. Org. Lett. 2017,
19, 1462.
(6) For selected recent reviews on soft Lewis acid activate multiple
bonds, see: (a) Dorel, R.; Echavarren, A. M. Chem. Rev. 2015, 115,
9028. (b) Chen, L.; Chen, K.; Zhu, S. Chem. 2018, 4, 1208. (c) Zi,
W.; Toste, F. D. Chem. Soc. Rev. 2016, 45, 4567. (d) Shu, X.-Z.; Shu,
D.; Schienebeck, C. M.; Tang, W. Chem. Soc. Rev. 2012, 41, 7698.
́
(e) Soriano, E.; Fernandez, I. Chem. Soc. Rev. 2014, 43, 3041.
(f) Shiroodi, R. K.; Gevorgyan, V. Chem. Soc. Rev. 2013, 42, 4991.
(g) Pellissier, H. Chem. Rev. 2016, 116, 14868. (h) Abbiati, G.; Rossi,
E. Beilstein J. Org. Chem. 2014, 10, 481.
(7) For selected papers on diamination of alkynes, see: (a) Rajesh,
M.; Puri, S.; Kant, R.; Reddy, M. S. J. Org. Chem. 2017, 82, 5169.
(b) Yao, B.; Wang, Q.; Zhu, J. Angew. Chem., Int. Ed. 2012, 51, 5170.
(c) Li, J.; Neuville, L. Org. Lett. 2013, 15, 1752. (d) Talbot, E. P. A.;
Richardson, M.; McKenna, J. M.; Toste, F. D. Adv. Synth. Catal. 2014,
356, 687.
(8) No desired product was obtained when R was H or a strong
electron-withdrawing group.
(9) The reason for no desired product may be attributed to the
methyl group at the C6 position which prohibits the cyclo-
isomerization.
(10) No desired products were obtained using (E)-1,2-diphenyldia-
zene and methyl (E)-2-(naphthalen-2-yl)diazene-1-carboxylate as the
electrophiles for the reaction. A trace amount of product was obtained
when using a strong electron-withdrawing group in a pyridine ring
such as −CN in the C3 position.
(11) Syntheses of products such as 3n−3p and 3t were also
attempted by asymmetric transformation. However, all of them were
obtained with low enantioselectivities.
(12) The homocoupling for the synthesis of 3m was also carried out,
and −4% ee of product was obtained. The consistency with the
reaction from 1m to 3m further indicated the existence of the path 2
of the reaction. See SI for the details.
E
DOI: 10.1021/acs.orglett.8b03935
Org. Lett. XXXX, XXX, XXX−XXX