Trapping of N-Acyliminium Ions with Enamides: An Approach to Medium-Sized Diaza-Heterocycles

Article abstract of DOI:10.1021/acs.orglett.8b01407

Enamides equipped with N-acyliminium ion precursors were obtained through reduction of ynamides tethered to N-imides. Intramolecular TMSOTf-mediated trapping of N-acyliminium ions provided a variety of polyfunctionalized medium-sized diaza-heterocycles of putative pharmacological interest.

Full text of DOI:10.1021/acs.orglett.8b01407

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Trapping of N‑Acyliminium Ions with Enamides: An Approach to
Medium-Sized Diaza-Heterocycles
Lucile Andna and Laurence Miesch*
Laboratoire de Chimie Organique Synthet
Strasbourg, France
́
ique, Institut de Chimie, CNRS-UdS, UMR 7177, 4, rue Blaise Pascal, CS 90032, 67081
*
S Supporting Information
ABSTRACT: Enamides equipped with N-acyliminium ion
precursors were obtained through reduction of ynamides
tethered to N-imides. Intramolecular TMSOTf-mediated
trapping of N-acyliminium ions provided a variety of
polyfunctionalized medium-sized diaza-heterocycles of putative
pharmacological interest.
namines as their parent silicon enolates have been
prepared from anhydrides 1a−j and monoprotected diamines
2a−c in refluxing AcOH, followed by the application of
E
extensively used as nucleophiles in aldol-type reactions
1
14
via aza-ene-type mechanism to form C−C bonds. Later, the
Hsung’s copper-catalyzed N-alkynylation reaction, affording
more stable secondary enamides bearing an electron-with-
the corresponding ynesulfonamides 4a−n (Scheme 1).
2
15
drawing group on the nitrogen emerged as powerful
Among other methods, tertiary enamides can be obtained
16
nucleophiles in a large variety of Lewis acid catalyzed reactions,
whereas tertiary enamides were initially claimed to be
via reduction of ynamides. When nonsymmetrical N-imides
were used, the reduction step led to mixtures of regioisomers.
Whereas ynamides 4a−l bearing an ester group could be
reduced in the desired enamides tethered to a NAI precursor
3
unreactive toward electrophiles. However, recent work on
tertiary enamides has proven that those substrates display4
enaminic reactivity toward several classes of electrophiles,
through a one-pot procedure, the enamides bearing an aryl
5
6
7
8
17
including epoxides, carbonyls, imines, nitriliums, and
activated alkynes.
group 4m−n were reduced with NiP2, followed by NaBH
4
9
reduction. It is worth noting that NiP2 reduction of ynamides
N-Acyliminium ions (NAIs) are highly reactive electrophiles
that have been widely used in intramolecular cyclizations and
intermolecular additions for accessing structurally diverse
provides a new way to provide exclusive access to Z-enamides
5m−n, wherein Lindlar reduction fails, and the starting
material was fully recovered (Scheme 2).
With the enamides 6a−n equipped with an N-acyliminium
ion precursor in hand, we began our investigations by
18
10
scaffolds of broad biological interest. Protonation of the
hydroxyl group at the α-position of the N-acyl group is the
most common means of producing a leaving group to generate
examining the treatment of those compounds with BF ·OEt .
3 2
1
1
NAIs.
Bicyclic diazepine 7a was obtained with good yield through
intramolecular trapping of the N-acyliminium ion with tertiary
enamide 6a (Scheme 3).
Tertiary enamides equipped with N-acyliminium ion
precursors, e.g., hydroxylated pyrrolidone derivatives, have not
been exploited, although they are attractive substrates for the
synthesis of heterocycles of putative pharmacological interest
Screening of Lewis and Brønsted acids revealed that different
acids were able to accomplish this cyclization, although with
great yield variations (Table 1). Brønsted acids (Table 1,
1
2
(Figure 1).
13
19
Our recent interest in ynamide chemistry prompted us to
entries 2 and 3) were not as effective in promoting this
20
3
investigate this attractive field. To this end, the required N-
imides tethered to ynesulfonamides 4a−n were readily
cyclization reaction. Y(OTf)
led to the desired diazepine 7a
with acceptable yield (Table 1, entry 6), although heating is
essential (Table 1, entry 5), and stoichiometric amounts of the
Lewis acid led to better yields (Table 1, entry 7).
Moderate yields of diazepine 7a were obtained using FeCl ,
3
21
TiCl , and InCl (Table 1, entries 4, 8, and 9). TMSOTf
4
3
proved to be the most efficient Lewis acid in this cyclization
reaction (Table 1, entry 11), although a lower loading of
TMSOTf was not beneficial for the cyclization reaction even by
increasing the reaction time (Table 1, entry 10). A more
Received: May 3, 2018
Figure 1. Biologically active benzodiazepines.
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01407
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Synthesis of N-Imide Tethered to
Ynesulfonamide
Scheme 2. Synthesis of Enamides Tethered to NAI
Precursors
a
c
Yield for isolated compounds.
Scheme 3. Intramolecular Trapping of NAI with Tertiary
Enamide
a
Yield for isolated compound.
Table 1. Screening of Brønsted and Lewis Acids
a
entry
acid (equiv)
reaction conditions
CH Cl , rt, 0.5 h
yield (%)
1
2
3
4
5
6
7
8
9
BF ·OEt (1.2)
78
24
18
42
0
3
2
2
2
p-TsOH (1.2)
CH Cl , rt, 3 h
2 2
CSA (1.2)
CH Cl , rt, 3.5 h
2 2
FeCl (1.0)
DCE, rt, 1 h, MS
3
Y(OTf) (0.9)
PhCl, rt, 21 h, MS
3
Y(OTf) (0.1)
PhCl, 80 °C, 2.5 h, MS
PhCl, 80 °C, 1 h, MS
DCE, rt, 5 h, reflux, 30 min, MS
CH Cl , rt, 4.5 h
42
64
38
38
traces
83
76
3
Y(OTf) (1.2)
3
TiCl (1.2)
4
InCl (1.2)
3
2
2
1
1
1
0
1
2
TMSOTf (0.1)
TMSOTf (1.2)
TBSOTf (1.2)
CH Cl , rt, 20 h
2 2
CH Cl , rt, 0.75 h
2
2
CH Cl , rt, 0.5 h
2
2
a
Yield of isolated compounds.
The solvent effect was then examined (Figure 2). Whereas
CH Cl proved to be the best solvent for this reaction, MeCN,
2
2
toluene, DCE, and MeNO led to diazepine 7a in acceptable
2
a
yields. A significant drop in yield was observed with Et O, THF,
Reaction conditions: Unless otherwise specified, the first reaction was
2
and acetone. CHCl led to total degradation of the starting
carried out with 1a−j (1 equiv), NaOAc (3 equiv), 2a−c (1 equiv),
3
II
acetic acid, reflux, 24 h. Cu reaction with 3a−l (1 equiv), CuSO ·
material, whereas in DMF starting material 6a was fully
recovered.
4
5
H O (15 mol %), 1,10-phenanthroline (30 mol %), K CO (2.5
2 2 3
equiv), 1-bromo-1-alkyne (1.15 equiv), toluene, 85 °C, 4 to 24 h.
Having found that TMSOTf in CH Cl favors best trapping
2
2
b
Yield for isolated compounds.
of NAI by tertiary enamides, we evaluated the scope of the
reaction by using various NAI precursors, different spacer
lengths, as well as different substituents on the enamide moiety
(Scheme 4). β-Substituted enamides with aryl or phenyl groups
hindered silyl trifluoromethanesulfonate TBSOTf (Table 1,
entry 12) was as efficient as BF ·OEt (Table 1, entry 1).
3
2
B
DOI: 10.1021/acs.orglett.8b01407
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 5. Plausible Mechanism
Figure 2. Solvent screening (isolated yields).
6
m−n were tolerated, providing diazepines with good yields
Scheme 4. Substrate Scope
(7m, 7n).
With bicyclic NAI precursors, the cyclization went smoothly
to afford the corresponding diazepines (7c, 7d, 7g). The
chemical structure of compound 7d was confirmed by X-ray
crystallography (Scheme 4). Unsaturated and spiro NAI
precursors were both effective in this cyclization reaction,
providing diazepines 7f and 7j in 59 and 63% yields,
respectively. Unsymmetrical gem-dimethyl and fluorinated
phthalimide NAI precursors 6e and 6h led to mixtures of
diazepines 7e (ratio 1:6) and 7h (ratio 1:3).
Three methylene units for the spacer length were also
allowed (6k, 6n), providing diazocanes (7k, 7n) with tertiary
enamides substituted with either an electron-withdrawing
group or a phenyl group. Even homologue 6l with four
methylene units could undergo this cyclization reaction,
providing diazonane 7l, although in a rather moderate yield.
The 1,3-diazepine 8 was also observed in this case, obtained by
direct trapping of NAI by a nitrogen atom.
To explain the formation of diaza-heterocycles 7a−n, we
propose the following mechanism. After formation of the N-
acyliminium ion B in the presence of Brønsted or Lewis acids,
enamidic attack of B to the acyliminium ion provides
intermediate C. The bicyclic diazepine evolves upon deproto-
nation of the β-disubstituted enamide C (Scheme 5).
In conclusion, we have shown that enamides equipped with
N-acyliminium precursors are accessible through reduction of
the corresponding ynamides. These versatile tools lead to
functionalized medium-sized diaza-heterocycles prevalent in
biologically active molecules. Monocyclic, bicyclic, as well as
enamides substituted with ester and aryl groups were tolerated.
1
,5-Diazocanes and -diazonanes are accessible through this
process, allowing the expansion of synthesis of various diaza-
heterocycles attractive in the field of drug design.
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01407.
Experimental procedures, synthesis of starting materials,
1
13
and compound characterization data; H and C NMR
spectra (PDF)
Accession Codes
a
b
CCDC 1831780 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 Cambridge
Yield for isolated compound. Crystallographic data has been
deposited with the CCDC.
C
DOI: 10.1021/acs.orglett.8b01407
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
(14) Zhang, Y.; Hsung, R. P.; Tracey, M. R.; Kurtz, K. C. M.; Vera, E.
L. Org. Lett. 2004, 6, 1151.
1
EZ, UK; fax: +44 1223 336033.
(
15) Selected references for the preparation of enamides from
ynamides: (a) Evano, G.; Michelet, B.; Zhang, C. C. R. Chim. 2017, 20,
48 and references cited therein. Selected references for preparation
AUTHOR INFORMATION
■
*
6
Corresponding Author
E-mail: lmiesch@unistra.fr.
of enamides: (b) Jiang, L.; Job, G. E.; Klapars, A.; Buchwald, S. L. Org.
Lett. 2003, 5, 3667. (c) Gooßen, L. J.; Rauhaus, J. E.; Deng, G. Angew.
Chem., Int. Ed. 2005, 44, 4042. (d) Bolshan, Y.; Batey, R. A. Angew.
Chem., Int. Ed. 2008, 47, 2109. (e) Yamagishi, M.; Nishigai, K.; Hata,
T.; Urabe, H. Org. Lett. 2011, 13, 4873. (f) Panda, N.; Mothkuri, R. J.
Org. Chem. 2012, 77, 9407. (g) Kim, S. M.; Lee, D.; Hong, S. H. Org.
Lett. 2014, 16, 6168. (h) Li, H.; Ma, T.; Li, X.; Zhao, Z. RSC Adv.
ORCID
Laurence Miesch: 0000-0002-0369-9908
Notes
2
2
015, 5, 84044. (i) Panda, N.; Yadav, S. A.; Giri, S. Adv. Synth. Catal.
017, 359, 654.
The authors declare no competing financial interest.
(
16) (a) Zhang, X.; Zhang, Y.; Huang, J.; Hsung, R. P.; Kurtz, K. C.
ACKNOWLEDGMENTS
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Support for this work was provided by CNRS and Universite
Strasbourg. L.A. thanks M.R.T. for a research fellowship.
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DOI: 10.1021/acs.orglett.8b01407
Org. Lett. XXXX, XXX, XXX−XXX