Photocatalytic Three-Component Umpolung Synthesis of 1,3-Diamines

Article abstract of DOI:10.1021/acs.orglett.8b02923

A visible-light-mediated photocatalytic umpolung synthesis of 1,3-diamines from in situ-generated imines and dehydroalanine derivatives is described. Pivoting on a key nucleophilic addition of photocatalytically generated α-amino radicals to electron-deficient alkenes, this three-component coupling reaction affords 1,3-diamines efficiently and diastereoselectively. The mild protocol tolerates a wide variety of functionalities including heterocycles, pinacol boronates, and aliphatic chains. Application to biologically relevant α-amino-γ-lactam synthesis and extension to 1,3-aminoalcohols is also demonstrated.

Full text of DOI:10.1021/acs.orglett.8b02923

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Photocatalytic Three-Component Umpolung Synthesis of 1,3-
Diamines
Thomas Rossolini,† Jamie A. Leitch,† Rachel Grainger,‡ and Darren J. Dixon*,†
†Department of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford OX1 3TA, United
Kingdom
‡Astex Pharmaceuticals, Ltd., 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom
S
* Supporting Information
ABSTRACT: A visible-light-mediated photocatalytic umpo-
lung synthesis of 1,3-diamines from in situ-generated imines
and dehydroalanine derivatives is described. Pivoting on a key
nucleophilic addition of photocatalytically generated α-amino
radicals to electron-deficient alkenes, this three-component
coupling reaction affords 1,3-diamines efficiently and diaster-
eoselectively. The mild protocol tolerates a wide variety of
functionalities including heterocycles, pinacol boronates, and
aliphatic chains. Application to biologically relevant α-amino-γ-lactam synthesis and extension to 1,3-aminoalcohols is also
demonstrated.
ecent advances in visible-light photoredox catalysis have
otherwise be difficult to access. Structures possessing the 1,3-
Rfacilitated unique approaches to rapidly access complex diamine motif are ubiquitous in natural products, useful
organic molecules.1 The new reactivity enabled by in situ
synthetic molecules, and play key roles as ligands for catalysis
as well as in pharmaceutical research.8 Despite their widespread
generation of free-radical intermediates under mild reaction
application and relevance in bioactive compounds, limited
methods for the direct formation of 1,3-diamines have been
reported.8,9 Consequently, novel synthetic approaches to access
such 1,3-diamine constructs from abundant and commercially
available starting materials would be of general interest and high
synthetic value. Inspired by Jui’s elegant work on the generation
of heteroaryl amino acids,10 we sought to investigate the
reactivity of dehydroalanine (DHA) derivatives as electrophilic
species to engage in radical conjugate addition reactions with in-
situ-generated α-amino radicals. Encouraged by successful
studies on radical conjugate addition to alkenes,4b,11 we
considered the role of DHAs as Michael acceptors in a new
synthetic methodology for the formation of unsymmetric 1,3-
diamine constructs, and, herein, we wish to report our findings.
Preliminary investigations focused on the reaction between
fluorine-tagged imine 1 and bis-N-Boc DHA derivative 2 (1
equiv) under blue light-emitting diode (LED) light irradiation in
dimethyl sulfoxide (DMSO) using commercial Hantzsch ester
(HE1) as the stoichiometric reductant. Pleasingly, the desired
reactivity was achieved, and 1,3-diamine derivative 3 was formed
in 47% isolated yield employing 1 mol % [Ir(dF(CF3)-
ppy)2(dtbbpy)]PF6 as photoredox catalyst (see Table 1).
Importantly, the yield of this transformation was increased
when 2 equiv of DHA were employed (Table 1, entry 2) and
further improved with in situ imine formation, affording the
desired product in 93% yield (Table 1, entry 3). Additional
conditions has led to a variety of new and synthetically powerful
carbon−carbon and carbon−heteroatom bond-forming reac-
tions.2 Significant achievements include novel umpolung
transformations that have unleashed new reactivity between
nontraditional coupling partners. Notably, the reductive
coupling of imines and electrophilic species via a putative α-
amino radical has received great attention in recent years and
consists of imine allylation,3 alkylation including pinacol
coupling,4 and arylation (see Scheme 1).5,6
In a continuation of our research program on photocatalytic
amine synthesis,3b,7 we aimed to further explore imine
umpolung chemistry toward new electrophilic coupling partners
to generate valuable amine-containing products that would
Scheme 1. Photocatalytic Platform for Umpolung Chemistry
of Imines: Applications to 1,3-Diamine Synthesis
Received: September 12, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02923
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Organic Letters
Letter
Table 1. Optimization of Photocatalytic Umpolung Diamine Synthesis.12
a
b
entry
1
HE
solvent
3
(%)
diastereomeric ratio, dr
c
d
1
preformed
preformed
in situ
in situ
in situ
in situ
in situ
in situ
in situ
HE1
HE1
HE1
HE1
HE2
HE3
HE3
HE3
HE3
HE3
HE3
HE3
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
MeOH
EtOH
EtOH/DMSO (4:1)
EtOH/DMSO (3:2)
MeOH/DMSO (7:3)
MeOH/DMSO (3:2)
47
79
93
0
15
96
16
32
76
1.5:1
1.5:1
1.4:1
d
d
2
3
4
e
5
6
7
8
9
10
11
12
1.5:1
2:1
3:1
3.6:1
3.2:1
3.2:1
4.1:1
4:1
in situ
in situ
in situ
100
69
d
100 (99)
a
Reaction conditions: aldehyde (0.2 mmol), aniline (0.2 mmol), 2 (0.4 mmol, 2 equiv), [Ir(dF(CF3)ppy)2(dtbbpy)]PF6 (1 mol %), HE (0.3
b
c
d
e
mmol). 19F{1H} NMR yield. 1 equiv of 2. Isolated yield. No photocatalyst.
optimization experiments were then conducted in an attempt to
increase the diastereomeric ratio (dr). The use of a substituted
Hantzsch ester (HE3) was found to be beneficial by improving
the dr to 2:1 without affecting reaction yield (Table 1, entry 6).
Notably, switching to a binary MeOH/DMSO solvent system
allowed improvement of diastereoselectivity (Table 1, entries
9−12). Following further optimization, MeOH/DMSO (3:2)
led to full conversion while imparting good diastereoselectivity;
compound 3 was obtained in 99% isolated yield as a 4:1
(anti:syn) separable mixture of diastereoisomers (Entry 12).
The relative stereochemical configuration of the major
diastereoisomeric product of 3 was confirmed as anti by
single-crystal X-ray diffraction (Scheme 2B).
With the optimized conditions established, the scope of the
photocatalytic umpolung coupling, with respect to both the
aldehyde and amine components, was explored (Scheme 2).
Initially, the effect of electronic variation on the in situ-
generated α-amino radical was examined by changing the para
substituents of the arylaldehyde (3−10). Excellent reaction
outcomes were observed with both electron-withdrawing and
electron-releasing functional groups; although a small drop in
reactivity was observed with the strongly electron-withdrawing
CF3 substituent (10).13 These results tentatively support the
proposed intermediacy of a nucleophilic α-amino radical
species, a conclusion that was further supported by results
obtained with pyridyl aldehydes (11, 12), where the more
electron rich aromatic ring gave excellent yield and good
diastereoselectivity. The substrate scope of this transformation
was also successfully expanded to include further heterocyclic
rings such as furan, thiophene, pyrrole, and imidazole (13−16)
with moderate to good yields. Encouraged by these successful
results using substrates with challenging functionalities, we
looked to expand the scope of this reaction to include aliphatic
carboxaldehyde starting materials. Pleasingly, cyclic (17), α-
branched (18), and linear aliphatic chains (19) afforded the
desired products with good to excellent yields and good
diastereoselectivity. Good efficiency was achieved with boronic
acid pinacol ester (20), opening up the possibility of combining
this transformation to downstream transition metal cross-
coupling reactions. To demonstrate the potential application
of this methodology in medicinal chemistry, we sought to
expand the range of substrates to include more elaborate
examples of N-containing heterocycles. Pleasingly, pyrrolo[2,3-
b]pyridine derivative 21 and N-Boc-protected azetidine 22 were
synthesized from their respective carboxaldehydes in one step
with synthetically useful yields.
We next turned our attention to investigate the scope with
respect to the aniline moiety, using p-fluorobenzaldehyde as a
model substrate. Pleasingly, a broad range of aniline derivatives,
from electron-rich to electron-poor, were compatible with this
chemistry (23−31). Notably, no undesired downstream cascade
reaction was observed when alkyne 28 was formed, and the
expected product was obtained with excellent yield and good
diastereoselectivity. 3-Aminopyridine (32) and 4-aminophenol
(33) derivatives were synthesized with moderate reaction
efficiency but good diastereomeric ratio. Moreover, heterocyclic
rings such as unprotected benzotriazole, indazole, and
benzothiazole were found to be competent amine substrates
for in situ imine generation, followed by radical conjugate
addition with highly efficient product formation (34−36).
Following the broad range of functional groups tolerated in this
reaction, we sought to expand its versatility for the synthesis of
analogous 1,3-aminoalcohols via the reductive coupling of
carboxaldehydes with DHA derivative 2. β-Amino alcohols are
important target structures, because of their abundance in
bioactive natural products and broad therapeutic utility.14
B
DOI: 10.1021/acs.orglett.8b02923
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Scheme 2. (A) Scope of the Three-Component Direct Photocatalytic Umpolung Synthesis of Unsymmetrical 1,3-Diamines. (B)
Single-Crystal X-ray Structure of Major Diastereoisomer 3; Other Compounds Assigned by Analogy. (C) Extension to 1,3-
a
Aminoalcohols
a
PMP = p-methoxyphenyl; PFP = p-fluorophenyl; Pin = pinacol. Combined isolated yields given for minor and major diastereoisomers; see the
b
Supporting Information (SI) for experimental details. Reaction time = 48 h.
Moreover, great interest for this functionality has been
developed, because of its pivotal role as the source of chirality
in asymmetric synthesis.15 We envisaged that the omission of the
aniline moiety in our transformation would lead to the ketyl
radical, which could be intercepted by the dehydroalanine
electrophile to generate the desired 1,3-aminoalcohol relation-
ship. Accordingly, we subjected 4-fluorobenzaldehyde to blue
light irradiation with DHA derivative 2, in the presence of the
C
DOI: 10.1021/acs.orglett.8b02923
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Letter
optimal iridium photocatalyst and HE3 as the stoichiometric
reductant. We were delighted to observe the formation of β-
amino alcohol 37 in excellent yield and moderate diaster-
eoselectivity (see Scheme 2C).
To substantiate the synthetic utility of this methodology in
drug discovery applications, γ-lactam 39, which is a key
intermediate towards many CB-1 receptor inverse agonists,
was identified as a suitable test case.16 Photocatalytic
construction of desired 1,3-diamine product 38 was achieved
in 99% yield and good diastereomeric ratio from commercially
available benzaldehyde and 4-trifluoromethoxyaniline (see
Scheme 3A). Pleasingly, one-step cyclization/deprotection of
Subsequent single electron reduction and protonation of the
addition intermediate would afford the 1,3-diamine product 3.
In conclusion, the first efficient photocatalytic one-pot
umpolung coupling of imines and a DHA derivative 2 for the
diastereoselective construction of 1,3-diamine products has
been developed in high yield and moderate to good
diastereoselectivity. A broad functional group tolerance has
been demonstrated, with respect to both the aldehyde and the
amine moiety, showcasing its potential in medicinal chemistry
applications. Remarkable reaction efficiency was demonstrated
for heterocyclic compounds and imines derived from aliphatic
aldehydes. Further extension of the photocatalytic platform to β-
amino alcohol synthesis and derivatization to biologically
relevant γ-lactams illustrate the applicability of this new
umpolung coupling methodology. Efforts to develop this
concept further and establish enantioselective variants are
ongoing.
Scheme 3. (A) Derivatization and Application to Drug
Synthesis. (B) Plausible Mechanism
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b02923.
Synthetic procedures and full characterization data of
compounds (PDF)
Accession Codes
CCDC 1857913 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
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: darren.dixon@chem.ox.ac.uk.
ORCID
Jamie A. Leitch: 0000-0001-6997-184X
Darren J. Dixon: 0000-0003-2456-5236
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
major isomer 38 under acidic conditions afforded functionalized
γ-lactam 39 in good yield. Condensation of aminolactam 39
with a series of functionalized ketones, followed by the addition
of trimethylaluminum as previously reported,17 is known to give
access to a variety of drug candidates such as 40, which has been
shown to exhibit antagonistic activity in the low micromolar
range.18
D.J.D. and T.R. wish to thank Astex Pharmaceuticals, Ltd., for
generous financial support and Dr. Steven Howard (Astex
Pharmaceuticals, Ltd.) for fruitful discussion. J.A.L. would like to
thank the Leverhulme Trust (RPG-2017-069) for a research
fellowship. We also thank Heyao Shi (University of Oxford) for
X-ray structure determination and Dr. Amber L. Thompson and
Dr. Kirsten E. Christensen (Oxford Chemical Crystallography)
for X-ray mentoring and help.
From a mechanistic standpoint, aligned with previous
investigations,3 we suggest that initially the Hantzsch ester is
capable of reducing the photoexcited iridium catalyst, generating
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