10.1002/anie.202005652
Angewandte Chemie International Edition
RESEARCH ARTICLE
Scheme 4C, we identified an optimum protocol starting with the
initial aminochlorination step (see Scheme 3, entry 3), followed by
basification with (i-Pr)2NEt (10 equiv.) and final in situ aziridinium
formation–ring opening reaction by addition of NaI (5.0 equiv.)
and Et2NH (5.0 equiv.) as a solution in CH3CN. This procedure
provided 60 in excellent yield, and importantly, streamlined its
preparation from a current 5 step synthesis to a single chemical
operation that took overall 19 h.[27]
yield. More advanced amine building blocks were easily
introduced and the chemistry was also expanded to both electron
rich (84 and 85) and electron poor (86 and 89) styrenes and
tolerated ortho (87) as well as meta (88) substituents.
When primary amines were used, the aminochlorination occurred
smoothly and upon basification a cyclization occurred leading to
the corresponding and stable aziridine, that could not be ring-
opened in situ (Scheme 6C). This procedure allowed the
introduction of amines of increasing steric hindrance (90–92) and
also worked well on disubstituted olefins (93). Overall, this
reactivity enabled a one-step access to all-alkyl substituted
aziridines, which are an underrepresented class of building blocks
currently elusive by nitrene-based approaches requiring multi-
step sequences.[29]
With this optimized procedure in hand, we focused our efforts on
establishing the scope for the olefin diamination reaction (Scheme
4D). Using piperidine as the aminium radical precursor and 4-
phenyl-butene 10 as the olefin, we then evaluated several other
N-nucleophiles. Pleasingly, we were able to use secondary cyclic
(61) as well as primary amines of both high steric hindrance (62)
and decreased nucleophilicity (63 and 64). In just these two cases
over the entire scope, the products were respectively obtained as
a 3:1 and 1.7:1 mixtures of isomers resulting from an unselective
aziridinium ring-opening, while benzothiazole-2-amine gave
selectively 65. Pleasingly, we could also introduce aromatic N-
heterocycles like pyrazole and 4-Ph-pyridine that gave the
desired product 66 and 67 in good yield. In the case of 65 and 67,
a basic work-up at the end of the aminochlorination step before
aziridinium formation was crucial in obtaining high reaction yield.
Other unsymmetrical 1,2-diamines were assembled by
generating the aminium radical from various N-heterocycles like
azepane and syn-2,6-dimethylmorpholine, that, following
aziridinium ring–opening with nortropinone and t-BuNH2, gave 68
and 69 in excellent yields. Acyclic amines were also amenable to
this reactivity as demonstrated by the sequential introduction of
Et2NH and t-BuNH2 on 4-pentenenitrile (70), whilst Me2NH and
thiomorpholine gave 71 also in high yields. Ester containing
olefins were compatible with the reactivity (72) and by using N-
Ts-allylamine as the alkene we prepared 73 in high yield that
represents a completely differentiated 1,2,3-triamine.
More complex building blocks were accessed by using a
protected glucosamine and L-proline methyl ester in the ring-
opening event that gave 74 and 75 respectively (1:1 mixture of
epimers). Implementation of 3-methylene-N-Boc-azetidine as the
olefin, piperidine as the aminium radical precursor, and 2-oxa-5-
azobicyclo[2.2.1]heptane as the final nucleophile gave 76 in good
yield, demonstrating that aziridinium formation at tertiary centres
is possible. A theophylline-containing olefin was reacted with
piperidine and the MAO inhibitor tranylcypromine to give 77 in
good yield (1:1 mixture of epimers). Finally, by sequentially using
N-Cbz-piperazine (aminium radical) and the biologically active
alkaloid cytisine (nucleophilic amine) we prepared 78 in high yield
(1:1 mixture of epimers).
The initial aminochlorination process represents an interesting
gateway to expand the number of potential products of amino-
functionalization. As aziridinium ions support a rich array of
chemistry, we have been able to engage 11 in several other
processes (Scheme 5B). Oxygen nucleophiles were competent
partners as demonstrated by the use of NaOMe and NaOH that
led to aminohydroxylated products 94 and 95 with opposite
selectivity in the ring-opening step. NaN3 could be used to access
the vicinal amino-azide 96 albeit as a mixture of isomers
(unselective aziridinium ion ring-opening). NaCN enabled
selective ring-opening resulting in the formation of a C–C bond
which delivered 97 with potential application to the synthesis of b-
aminoacids. Vicinal fluoro-amines are important and highly
sought-after building blocks in medicinal chemistry[19b, 30] but we
did not succeed in identifying reaction conditions for aziridinium
ring-opening with fluoride sources. Nevertheless, we found out
that direct addition of Et3N•3HF to 11 provided 98 in moderate
yield and as a single isomer. Finally, addition of LiAlH4 at 0 ºC
enabled efficient reduction (99), which gives direct access to
challenging products of Markovnikov hydroamination currently
prepared by reductive amination on ketones.[31] We have
showcased the potential utilization of this reactivity in the
preparation of the cough suppressant benproperine (103). In this
case, the commercial phenol 100 was allylated to give 101, which
underwent efficient aminochlorination with piperidine (102,
quant.). Aziridinium ion formation and selective LiAlH4 reduction
gave benproperine in just 3 steps.
Conclusions
Direct synthesis of vicinal alkyl diamines from olefins has been a
long-standing challenge and still requires multi-step synthesis. In
this article we have reported the development of a photoinduced
protocol for their efficient and selective assembly. This strategy
exploits the generation of aminium radicals from in situ generated
N-chloroamines and their ability to react with a broad range of
olefins with anti-Markovnikov selectivity. The resulting b-
chloroamines are powerful ambiphilic building blocks for further
elaboration as demonstrated by their direct conversion into the
corresponding aziridinium ions. The following in situ ring-opening
reaction with primary, secondary and aromatic amine
nucleophiles allowed regioselective diamination.
We also found that the diamination could be applied to a broad
range of styrene building blocks (Scheme 5A). In this case
however, addition of NaI to aid aziridinium ion formation was not
required due to the more activated nature of the analogous
benzylic b-chloroamine.[28] In line with the observed
aminohydroxylation reactivity, we found out that the addition of
the second amine nucleophile in the presence of Na2CO3 at the
end of the aminochlorination step immediately provided the
corresponding 1,2-diamines. Importantly, in this case the
substitution occurred at the more activated benzylic position,
which is in line with the known reactivity of aryl-substituted
aziridiniums. This process was compatible with the use of
secondary (79–81) and primary amines (82) as well as pyridine
that led to the isolation of the corresponding salt 83 in moderate
Overall, this reactivity enables, for the first time, the direct and
selective introduction of advanced amine building blocks across
olefins in a single chemical operation. The process tolerated a
broad range of functionalities, does not require the presence of
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