Synthesis of 2-Aminoimidazolones and Imidazolones by (3 + 2) Annulation of Azaoxyallyl Cations

Article abstract of DOI:10.1021/acs.orglett.7b03719

The first examples of (3 + 2) annulations between azaoxyallyl cations and cyanamides and nitriles to give the corresponding 2-aminoimidazolones and imidazolones are reported. On the basis of the isolation of unexpected imidate products with certain substr

Full text of DOI:10.1021/acs.orglett.7b03719

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Synthesis of 2‑Aminoimidazolones and Imidazolones by (3 + 2)
Annulation of Azaoxyallyl Cations
Maria C. DiPoto and Jimmy Wu*
Department of Chemistry, Dartmouth College, Hanover, New Hampshire 03755, United States
*
S Supporting Information
ABSTRACT: The first examples of (3 + 2) annulations
between azaoxyallyl cations and cyanamides and nitriles to give
the corresponding 2-aminoimidazolones and imidazolones are
reported. On the basis of the isolation of unexpected imidate
products with certain substrates, it is proposed that the
reaction proceeds via fast kinetic O-alkylation followed by rearrangement to the thermodynamically favored 2-aminoimidazolones
and imidazolones. The method was applied to the formal synthesis of the antihypertensive drug irbesartan.
oth 2-aminoimidazolones and imidazolones are featured in
Scheme 1. Synthesis of Imidazolones and 2-
Aminoimidazolones
B
important biologically active compounds, such as
1
irbesartan (antihypertensive drug), leucettamine B (DYRK
2
,3
and CLK kinase inhibitor), diphenylimidazolone 3 (human
4
neuropeptide Y5 receptor antagonist, NPY5), and 2-amino-
5
diphenylimidazolone 4 (β-secretase inhibitor) (Figure 1).
Some of these compounds are quite potent and are active at
nanomolar concentrations.
the dearomative (3 + 2) annulation reaction between 3-
substituted indoles and azaoxyallyl cations to give pyrroloindo-
lines. In the intervening time, others have expanded upon our
initial work, thus reporting the (3 + 3), (3 + 2), and (3 + 1)
Figure 1. Biologically active compounds that contain the imidazolone
and 2-aminoimidazolone core.
16−19
reactions of azaoxyallyl cations with nitrones,
carbon-
20−24
25,26
27
28
yls,
isothiocyanates,
alkynes, sulfur ylides, thio-
29
30
cyanates, and others. In this manuscript, we report for the
first time annulation reactions between azaoxyallyl cations and
nitriles and cyanamides to give imidazolones and 2-amino-
imidazolones (Scheme 1).
Many of the existing methods for preparing these types of
compounds rely on condensation reactions of α-amino amide
derivatives such as 5 to give bonds b and c depicted in Scheme
6
−9
10
We began our studies by examining the reaction between
dimethylcyanamide 7a and α-bromoamide 9a. We found that,
in the presence of carbonate and amine bases, several Lewis
acids promoted the transformation to give desired product 10a
with a range of yields (Table 1; entries 1−4). Control
experiments reveal that Lewis acids were not necessary and
that Na CO alone was able to induce formation of the
1.
Zhu reported a process for making bonds c and d.
Retrosynthetically, we envisioned a complementary method
that targets bonds a and c for preparing these important
heterocycles. Such a disconnection would require synthons
represented by dipole 6 whose electronic criteria are satisfied by
azaoxyallyl cations.
2
3
Azaoxyallyl cations are a unique class of reactive
intermediates that have been shown to engage in (4 + 3)
1
1,12
annulation reactions with furan.
Jeffrey’s,
Recently, our group and
followed by Liao’s, published a novel method for
Received: November 30, 2017
1
3,14
15
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03719
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Optimization Studies
next explored annulation reactions of nitriles 8, which we
expected would lead to the formation of the corresponding
imidazolone products. Indeed, this reaction worked well with a
wide range of substituent types on the nitrile, including methyl,
ethyl, iPr, halogen, alkenyl, heterocyclic, and aryl. Although
imidazolone 11a was produced using MeCN as the nitrile
component, a reaction carried out entirely in MeCN as solvent
mol
time
(h)
yield
(%)
16,26
entry
base
catalyst
ZnBr2
(%)
solvent
failed.
As a final note, it was necessary to vary the relative
1
2
3
4
5
6
7
Na CO3
2
10
10
10
5
HFIP
HFIP
HFIP
MeOH
HFIP
iPOH
MeOH
24
24
24
24
18
18
24
53
95
20
94
92
95
67
amounts of haloamide versus nitrile or cyanamide to further
optimize yields.
Na CO3
2
Cu(OAc)2
NiBr2
Na CO3
2
Curiously, in the reaction between nitrile 8a and α-haloamide
9a (eq 1), we isolated an unexpected product in which the
amide 13C resonance was shifted upfield by approximately 20
ppm. These data are consistent with the presence of an imidate,
leading to our structural assignment of 12 as shown below. This
result is likewise consistent with experimental and computa-
tional studies from our group of related oxyallyl cation
intermediates that implicate O-alkylation as the kinetically
DIPEA
LiClO4
Na CO3
2
Na CO3
2
Na CO3
2
product. A brief solvent survey demonstrated that the
annulation proceeds well in both iPrOH and 1,1,1,3,3,3-
hexaisopropanol (HFIP) (entries 5 and 6). We were
encouraged by the success of iPrOH as a suitable solvent
because it was believed that powerful hydrogen bond donor
solvents such as HFIP were required for the formation of the
azaoxyallyl cation intermediate. However, because subsequent
reactions proved to be less efficient in iPrOH, we adopted
HFIP as the solvent of choice (entry 5).
31
preferred product. Others have also observed similar
17,21,23,30
phenomena.
Subsequent rearrangement is postulated
to deliver the lower energy N-alkylated product; although in
this case, treatment of 12 with 2 equiv of TFA at room
temperature for 1 h did not result in any rearrangement. At the
moment, it is unclear why this is the only substrate that results
in O-alkylation.
With optimized conditions in hand, we proceeded to
examine the scope of the reaction (Scheme 2). The synthesis
of 2-aminoimidazolones was amenable to the use of a
monosubstituted α-haloamide to give 10b, whereas starting
with t-butyl cyanamide led to efficient formation of 10c. We
We then applied the methodology to the formal synthesis of
the antihypertensive drug irbesartan (2) (Scheme 3). The (3 +
Scheme 2. Reaction Scope
Scheme 3. Formal Synthesis of Irbesartan 2
2
) annulation reaction between α-bromoamide 9b and
valeronitrile 8b proceeded as expected to provide imidazolone
1o. This was followed by cleavage of the N−O bond with
SmI to give 13, an intermediate that was used by Bernhart en
1
2
32
route to the synthesis of irbesartan 2.
In conclusion, we have reported the first examples of (3 + 2)
annulation reactions between nitriles and cyanamides to give
imidazolones and 2-aminoimidazolone products. The isolation
of imidate products under certain conditions suggests that the
mechanism may proceed via fast O-alkylation followed by
subsequent rearrangement to the thermodynamically favored
N-alkylated product. This method was applied to the formal
synthesis of irbesartan 2.
a
Reaction conditions: Nitrile (1 equiv), haloamide (2 equiv), Na CO
(
2
3
b
4 equiv) in 0.5 M HFIP at 60 ºC or rt. Nitrile (2 equiv or 5 equiv),
haloamide (1 equiv), Na CO (4 equiv) in 0.5 M HFIP at 60 ºC or rt.
2
3
B
DOI: 10.1021/acs.orglett.7b03719
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(
19) Lin, W.; Zhan, G.; Shi, M.; Du, W.; Chen, Y. Chin. J. Chem.
ASSOCIATED CONTENT
Supporting Information
■
2
017, 35, 857.
20) Zhang, K.; Yang, C.; Yao, H.; Lin, A. Org. Lett. 2016, 18, 4618.
*
S
(
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03719.
(21) Acharya, A.; Montes, K.; Jeffrey, C. S. Org. Lett. 2016, 18, 6082.
(22) Jiang, S.; Li, K.; Yan, J.; Shi, K.; Zhao, C.; Yang, L.; Zhong, G. J.
Org. Chem. 2017, 82, 9779.
(
23) Shao, P.-L.; Li, Z.-R.; Wang, Z.-P.; Zhou, M.-H.; Wu, Q.; Hu, P.;
He, Y. J. Org. Chem. 2017, 82, 10680.
24) Jia, Q.; Du, Z.; Zhang, K.; Wang, J. Org. Chem. Front. 2017, 4,
Experimental details, full optimization table, and
1
characterization of all new compounds, including H,
(
1
3
C NMR spectra, IR, and high-resolution mass
9
1.
spectrometry (PDF)
(25) Zhao, H.-W.; Zhao, Y.-D.; Liu, Y.-Y.; Du, J.; Pang, H.-L.; Chen,
X.-Q.; Song, X.-Q.; Feng, N.-N. Eur. J. Org. Chem. 2017, 2017, 3466.
26) Wang, G.; Zhao, S.; Chen, R.; Yang, L.; Wang, J.; Guo, H.; Wu,
M.; Domena, J.; Xing, Y.; Sun, S. Tetrahedron Lett. 2017, 58, 4308.
27) Wang, G.; Chen, R.; Wu, M.; Sun, S.; Luo, X.; Chen, Z.; Guo,
H.; Chong, C.; Xing, Y. Tetrahedron Lett. 2017, 58, 847.
28) Li, C.; Jiang, K.; Ouyang, Q.; Liu, T.-Y.; Chen, Y.-C. Org. Lett.
016, 18, 2738.
(
AUTHOR INFORMATION
Corresponding Author
■
*
(
E-mail: jimmy.wu@dartmouth.edu.
ORCID
(
2
Jimmy Wu: 0000-0002-0938-8019
Notes
(29) Jaguelin, S.; Robert, A.; Genetet, N.; Gayral, P. Eur. J. Med.
Chem. 1991, 26, 313.
(
30) Zhang, K.; Xu, X.; Zheng, J.; Yao, H.; Huang, Y.; Lin, A. Org.
Lett. 2017, 19, 2596.
31) Li, H.; Hughes, R. P.; Wu, J. J. Am. Chem. Soc. 2014, 136, 6288.
The authors declare no competing financial interest.
(
ACKNOWLEDGMENTS
J.W. acknowledges the generous support of the NIH NIGMS
R01GM111638).
■
(
(32) 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. J. Med. Chem. 1993, 36, 3371.
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DOI: 10.1021/acs.orglett.7b03719
Org. Lett. XXXX, XXX, XXX−XXX