Photoredox Approach to N-Acyl-N′-aryl-N,N′-aminals Using Enamides and Their Conversion to γ-Lactams

Article abstract of DOI:10.1021/acs.orglett.7b03946

A photoredox catalytic approach to synthetically valuable N-acyl-N′-aryl-N,N′-aminals is described. This method uses the addition of a radical precursor to enamides, with subsequent interception of the cationic iminium intermediate with an arylamine. The reaction has been shown to be compatible with electron-rich and electron-deficient arylamines, and moderate to good levels of diastereoselectivity can be attained using a chiral enamide. Furthermore, the N-acyl-N′-aryl-N,N′-aminal reaction products can be readily cyclized, providing a novel synthetic route to valuable γ-lactams.

Full text of DOI:10.1021/acs.orglett.7b03946

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Photoredox Approach to N‑Acyl-N′-aryl‑N,N′-aminals Using
Enamides and Their Conversion to γ‑Lactams
†
†
‡
,†
Olusesan K. Koleoso, Mark R. J. Elsegood, Simon J. Teat, and Marc C. Kimber*
†Department of Chemistry, Loughborough University, Loughborough, Leicestershire LE11 3TU, U.K.
‡ALS, Berkeley Laboratory, 1 Cyclotron Road, MS2-400, Berkeley, California 94720, United States
*
S Supporting Information
ABSTRACT: A photoredox catalytic approach to synthetically valuable N-acyl-N′-aryl-N,N′-aminals is described. This method
uses the addition of a radical precursor to enamides, with subsequent interception of the cationic iminium intermediate with an
arylamine. The reaction has been shown to be compatible with electron-rich and electron-deficient arylamines, and moderate to
good levels of diastereoselectivity can be attained using a chiral enamide. Furthermore, the N-acyl-N′-aryl-N,N′-aminal reaction
products can be readily cyclized, providing a novel synthetic route to valuable γ-lactams.
he N-acyl-N′-aryl-N,N′-aminal structural motif (Figure 1,
1) is prevalent within a wide range of biologically important
Scheme 1. Synthetic Approaches to N-Acyl-N′-aryl-N,N′-
T
aminals 1
7a
Previous work by Masson and co-workers has established
that radical photoredox mediated addition of a CF equivalent to
3
electron-rich styrene (11) derivatives followed by trapping of the
intermediate carbocation by an electron-poor arylamine can lead
to modest to good yields of the addition product 13 (Scheme 2).
In that report, the authors explored the use of easily oxidizable
anilines such as p-anisidine where poor or little conversion to the
desired products was observed. However, the authors could get
Figure 1. Biologically relevant N-acyl-N′-aryl-N,N′-aminal.
compounds. It is an essential motif within γ-lactams such as 2, an
Scheme 2. Radical/Cationic Approach to N-Acyl-N′-aryl-
N,N′-aminals 17
important heterocycle within many biologically relevant drug
1
candidates; 1 is a core of the dihydroquinazolones (3), a
2
privileged heterocyclic structure in medicinal chemistry; 1 is
central to gem-diamino acids (4), a significant class of amino acid
3
isosters; and finally, 1 is key to many natural product classes,
4
,5
such as the pyrroloindolines.
Typical approaches to the N-acyl-N′-aryl-N, N′-aminal motifs
(
1), whether cyclic or acyclic, have relied on the addition of an
arylamine 7 to an N-acyliminium species 8, or conversely, for
example in the construction of pyrroloindolines, the addition of
an amide or an equivalent (9) to an N-aryliminium such as 10
(Scheme 1). These approaches can be perceived as comple-
mentary, but their scope and functional group variability are
ultimately predicated on the successful formation of an N-acyl
6
and N-aryliminium species (8 and 10, respectively). Addition-
ally, the stability of 1 is predicated on the electron-withdrawing
Received: December 19, 2017
group as well as the electron density of the arylamine.
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03946
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
the reaction to take place, without oxidation, by the judicious
choice of an electron-deficient aniline, e.g., p-bromoaniline and p-
had a detrimental effect in yield (entry 6), and no conversion to
the product 21 was observed in the absence of light (entry 7).
With conditions identified for the synthesis of 21a, a range of
electron-rich and electron-deficient anilines were examined to
ascertain substrate scope (Scheme 4).
p-Toluidine delivered N,N′-aminal 21b in a significantly
higher yield (84%) than 21a, presumably due to its increased
nucleophilicity; additionally, we were able to obtain suitable
crystals for single-crystal X-ray analysis. m-Toluidine also reacted,
(
ethoxycarbonyl)aniline.
Therefore, with this report in mind, we sought to employ this
7
b−d
8
radical/cationic pathway
on enamides in the presence of electron-poor and, importantly,
via the use of photoredox catalysis
9
electron-rich arylamines (16) to access these N,N′-aminals (17)
(
Scheme 2). The success of this approach would be predicated
10
on ensuring the integrity and compatibility of electron-rich and
electron-poor arylamines, and while Masson and co-workers had
previously shown the compatibility of enamides within this
7c
radical/cationic pathway, they have not, as yet, demonstrated
this approach with arylamines and enamides to deliver N,N′-
aminals. As a consequence, we now report our work on the
synthesis of N-acyl-N′-aryl-N,N′-aminals such as 17 using this
method as well as the successful utilization of both electron-rich
and electron-poor arylamines in the reaction pathway. Addition-
ally, the synthetic utility of these product aminals will be
highlighted by their successful cyclization, yielding valuable γ-
lactams.
Scheme 4. Arylamine Substrate Scope
We began our study by examining the use of arylamines in the
photoredox addition of bromide 20 to enamides (Scheme 3).
Scheme 3. Optimization of the Synthesis of N,N’-Aminal 21a
7c
Using adapted conditions of Masson, we explored the Ir-
catalyzed (complex 22) reaction of enamide 18 and bromide 20
with a large excess of the arylamine, aniline 19 (Table 1).
Pleasingly, these conditions with 10 equiv of 19 and after 18 h
reaction time gave the desired product 21a in a promising 56%
isolated yield (entry 1).
a
Table 1. Optimization of the Synthesis of N,N’-Aminal 21a
a
b
entry
22 (mol %)
time (h)
19 (equiv)
yield (%)
1
2
3
4
5
6
2.5
2.5
1.5
1.5
1.5
1.5
1.5
18
18
18
6
10
5
56
62
60
61
72
38
0
5
5
3
5
3
2
c
7
3
5
a
Reactions were performed under an Ar atmosphere in MeCN (10
mL) with 22 (amount shown in table body), light (465 nm), 18 (1.00
mmol), 20 (2.00 mmol), Et N (2.00 mol), and the arylamine unless
3
b
c
otherwise stated. Isolated chemical yields. In the absence of light
(
465 nm).
Isolation of the N,N′-aminal product 21 was nontrivial and was
further complicated by the reversibility of the nucleophile
addition highlighted in Scheme 1. The identification of 21 was
1
13
determined using a mixture of H NMR and C NMR with a key
signal for the CH aminal being seen at δ 5.37 (t, J = 7.2 Hz, 1H).
We were able to reduce the amount of 19 within the reaction
mixture to 5 equiv (entry 2) as well as the amount of 22 (entry 3)
and the reaction time to 3 h (entries 4 and 5), ultimately giving
2
1 in a higher isolated yield of 72%. A reduction to 2 equiv of 19
B
DOI: 10.1021/acs.orglett.7b03946
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
giving N,N′-aminal 21c in 88% isolated yield. The 2,3- and 2,6-
dimethylaniline gave the N,N′-aminals 21d and 21e in 71% and
via acid-catalyzed cyclization with N,N′-aminals 21a−c, 21i, 21l,
and 21n (Scheme 6). In each case, the cyclization proved
6
2
0% yields, respectively; furthermore, sterically encumbered
,4,6-trimethylaniline gave N,N′-aminal 21f in 64% yield. o-
Scheme 6. Synthesis of N-Aryl γ-Lactams
Anisidine furnished N,N′-aminal 21g in 76% yield, although, it
was found that this product slowly degraded upon standing to
give the imine, possibly due to the electron-rich nature of the
aniline. However, we were able to obtain crystals of 21g, suitable
for single-crystal X-ray analysis, which definitely assigned the
structure as shown. The 2-OCF analogue 21h could also be
3
obtained in 77% isolated yield, and this product 21h also
demonstrated increased stability compared to 21g. The reaction
could accommodate electron-withdrawing groups, highlighted
by 3-(trifluoromethyl)aniline and 3,5-bis(trifluoromethyl)-
aniline, giving derivatives 21i and 21j, respectively. Anilines
with halogen substitutions such as 3,4-dichloro, 4-bromo, and 2-
fluoro all performed well in this reaction, with the latter two
generating products with suitable crystals for single-crystal X-ray
analysis. 3-(Ethoxycarbonyl)aniline also gave the desired N,N′-
aminal 21m in 70% isolated yield. N-Methylaniline was
acceptable within these reaction conditions, with no observed
effective, but regrettably, modest diastereoselectivity was
11b
13
oxidation of the N-methyl group, delivering N,N′-aminal 21o
in 61% yield; and diphenylamine gave N,N′-aminal 21p in 56%
isolated yield, illustrating that sterically encumbered anilines are
also tolerated. Finally, disubstituted E-enamide 23 was exposed
to our conditions with p-toluidine. Pleasingly, this gave the N,N′-
aminal 21q in 53% isolated yield and essentially as a single
diastereoisomer, in line with the results previously reported by
observed for all. The major and minor diastereoisomers were
identified using a combination of NOE experiments, and the
major diastereoisomer in each is shown in Scheme 6;
furthermore, the diastereomeric ratio for each could be
14
determined using diagnostic signals around the γ-lactam ring.
Essentially, all cyclized products exhibited a slight preference for
the anti product, with the one exception being the p-tolyl γ-
lactam 26b. The diastereoselectivity ratio could also be partially
influenced by the inclusion of an ortho substituent on the aryl
ring, as exemplified by the 2-fluoroaryl γ-lactam 26f.
With this cyclization strategy in mind, we then applied it to the
synthesis of γ-lactam 28, as this would resemble the core
structure of the Gram-positive antibiotic Linezolid and could
plausibly function as new building block platform through
palladium-catalyzed coupling of the bromide (Scheme 7).
7
c
Masson.
To the best of our knowledge, there have been limited
7
c,d
investigations
on the diastereoselectivity or the enantiose-
lectivity of radical/cationic reactions with enamides, and none
11
that involve the formation of N,N′-aminals. As a consequence,
1
we exposed chiral enamide 24 (Scheme 5; R = Bn) to our
conditions with three anilines.
Scheme 5. Enamide (S)-24 and Its Influence on
Diastereoselectivity
Scheme 7. Formation of γ-Lactam 28
Treatment of enamide 18 with 2-fluoro-4-bromoaniline
furnished the addition product 27 in good isolated yield, which
upon treatment with acetic acid gave the aryl γ-lactam 21.
Pleasingly, this γ-lactam gave crystals upon standing that were
identified as the major diastereoisomer 28a after performing
single crystal X-ray analysis. Interestingly, upon dissolving the
crystals in chloroform-d, this single diastereoisomer reverted
back to the mixture indicated in Scheme 7. This evidence
plausibly suggests that the diastereomeric ratio observed for the
γ-lactam 28 (and 26a−f) is an equilibrium mixture.
p-Toluidine and m-toluidine both gave their N,N′-aminal
products 25a and 25b, respectively, in good isolated yields (58%
and 61%, respectively) and appreciable levels of diastereose-
lectivity. This diastereoselectivity could be improved by the use
of a more electron-withdrawing arylamine such as 3,5-
bis(trifluoromethyl)aniline, which gave the N,N′-aminal 25c in
6
0% yield and essentially as one single enantiomer. Note that in
all of the additions described the separation of the two
diastereomers could not be undertaken, and the diastereomeric
ratio most likely represents an equilibrium (see Scheme 1).
To highlight the synthetic utility of these products, they were
In summary, we have used a photoredox method for the
synthesis of medicinally valuable N-acyl-N′-aryl-N,N′-aminals
from readily available enamides. The process demonstrates that
1
,12
cyclized to their corresponding γ-lactams. This was achieved
C
DOI: 10.1021/acs.orglett.7b03946
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
electron-rich and poor arylamines are tolerant of the photoredox
reaction conditions and that moderate to good levels of
diastereoselectivity can be achieved when a chiral enamide is
used. Additionally, we have demonstrated that these reaction
products can be conveniently cyclized to give valuable γ-lactams.
Our efforts in expanding this protocol using allenyl substrates are
in progress and will be reported in due course.
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ASSOCIATED CONTENT
■
́
(
*
S
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03946.
Experimental procedures, characterization tables, NMR
data, and X-ray table data for 21b, 21lg, 21l, 21n, 21p, and
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CCDC 1539632−1539636 and 1587445 contain the supple-
mentary 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 Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
(
2
(
(c) Courant, T.; Masson, G. Chem. - Eur. J. 2012, 18, 423. (d) Carboni,
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AUTHOR INFORMATION
Corresponding Author
■
*
Res. 2015, 48, 1474. (b) Angnes, R. A.; Li, Z.; Correia, C. R. D.;
Hammond, G. B. Org. Biomol. Chem. 2015, 13, 9152. (c) Prier, C. K.;
Rankic, D. A.; MacMillan, D. W. C. Chem. Rev. 2013, 113, 5322.
E-mail: m.c.kimber@lboro.ac.uk. Tel. +44 (0) 1509 22 2570.
(
d) Wallentin, C. J.; Nguyen, J. D.; Stephenson, C. R. J. Chimia 2012, 66,
ORCID
3
94. (e) Xuan, J.; Xiao, W. J. Angew. Chem., Int. Ed. 2012, 51, 6828.
Marc C. Kimber: 0000-0003-2943-1974
Notes
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R.; Stephenson, C. R. J. Chem. Soc. Rev. 2011, 40, 102.
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10) For a review on the fate of amine radicals in photoredox, see:
(a) Hu, J.; Wang, J.; Nguyen, T. H.; Zheng, N. Beilstein J. Org. Chem.
013, 9, 1977. For recent examples of arylamine functionalization under
The authors declare no competing financial interest.
1
(
ACKNOWLEDGMENTS
We gratefully acknowledge financial support from Lough-
borough University and the Tertiary Education Trust Fund
■
2
photoredox conditions, see: (b) Yu, L. − C.; Gu, J. − W.; Zhang, S.;
Zhang, X. J. Org. Chem. 2017, 82, 3943. (c) Fava, E.; Millet, A.;
Nakajima, M.; Loescher, S.; Rueping, M. Angew. Chem., Int. Ed. 2016, 55,
(
(
TETFund) Abuja, Nigeria (O.K.K.). We thank Dr. Mark Edgar
Loughborough) for NMR structure determination. The
6
776. (d) Cheng, J.; Deng, X.; Wang, G.; Li, Y.; Cheng, X.; Li, G. Org.
Advanced Light Source is supported by the Director, Office of
Science, Office of Basic Energy Sciences, of the U.S. Department
of Energy under Contract No. DE-AC02-05CH11231. We
acknowledge support of the EPSRC via grant EP/M027341/1.
Lett. 2016, 18, 4538.
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