Synthesis of β-Phenethylamines via Ni/Photoredox Cross-Electrophile Coupling of Aliphatic Aziridines and Aryl Iodides

Article abstract of DOI:10.1021/jacs.0c01724

A photoassisted Ni-catalyzed reductive cross-coupling between tosyl-protected alkyl aziridines and commercially available (hetero)aryl iodides is reported. This mild and modular method proceeds in the absence of stoichiometric heterogeneous reductants and uses an inexpensive organic photocatalyst to access medicinally valuable β-phenethylamine derivatives. Unprecedented reactivity was achieved with the activation of cyclic aziridines. Mechanistic studies suggest that the regioselectivity and reactivity observed under these conditions are a result of nucleophilic iodide ring opening of the aziridine to generate an iodoamine as the active electrophile. This strategy also enables cross-coupling with Boc-protected aziridines.

Full text of DOI:10.1021/jacs.0c01724

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Synthesis of β‑Phenethylamines via Ni/Photoredox Cross-
Electrophile Coupling of Aliphatic Aziridines and Aryl Iodides
Talia J. Steiman, Junyi Liu,† Amanuella Mengiste,† and Abigail G. Doyle*
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ABSTRACT: A photoassisted Ni-catalyzed reductive cross-coupling
between tosyl-protected alkyl aziridines and commercially available
(hetero)aryl iodides is reported. This mild and modular method
proceeds in the absence of stoichiometric heterogeneous reductants
and uses an inexpensive organic photocatalyst to access medicinally
valuable β-phenethylamine derivatives. Unprecedented reactivity was
achieved with the activation of cyclic aziridines. Mechanistic studies
suggest that the regioselectivity and reactivity observed under these
conditions are a result of nucleophilic iodide ring opening of the
aziridine to generate an iodoamine as the active electrophile. This
strategy also enables cross-coupling with Boc-protected aziridines.
the development of complementary catalytic methods is
necessary to expand the generality and practicality of this
approach for the synthesis of β-phenethylamines.
INTRODUCTION
■
The β-phenethylamine scaffold is an important nitrogen-
containing motif in medicinal chemistry, with thousands of
reported derivatives possessing varied pharmacological activity
(Figure 1A).1 Phenethylamine itself is a monoaminergic
neuromodulator. Numerous phenethylamine derivatives are
naturally occurring and bioactive, such as dopamine,
norepinephrine, and adrenaline.2 Synthetic derivatives belong
to a range of different drug classes, such as antidepressants,
anti-Parkinson agents, appetite suppressants, and decongest-
ants. For example, amphetamine and its derivatives are
important for central nervous system treatments. As a result
of the strong interest in accessing the β-phenethylamine
substructure, a variety of synthetic approaches have been
devised.3
Over the past decade, our lab and the Jamison lab have
reported Ni-catalyzed Negishi cross-coupling reactions of
aziridines (Figure 1B).7 Moreover, Zhou and co-workers
have reported a Ni/photoredox cross-coupling of styrenyl
aziridines and potassium benzyltrifluoroborates.8 However,
identification of a general and selective protocol to access β-
phenethylamine products, particularly α-substituted phenethyl-
amines, has been challenging.9,10 Recently, we reported a
reductive cross-electrophile coupling of tosyl-protected (N-Ts)
styrenyl aziridines with aryl iodides that selectively yielded the
branched isomeric product (Figure 1C).11,12 The use of widely
available and bench stable aryl iodide electrophiles, without the
need to pregenerate organometallic reagents, provided a
practical advantage over conventional Ni-catalyzed cross-
coupling procedures with aziridines. Albeit, this strategy was
still not applicable to the preparation of α-substituted β-
phenethylamine products, as aliphatic aziridines were un-
reactive.
The arylation of aliphatic aziridines represents a particularly
attractive retrosynthetic disconnection due to its modularity,
enabling the installation of diverse (hetero)aryl groups and
ethyl backbone substitutions in a single C−C bond-forming
step. Most examples in this context rely on the use of
organocuprates, generated from aryl lithium or Grignard
reagents, in combination with a strong Lewis acid, which can
lead to limited functional group compatibility and poor
regioselectivity (Figure 1B).4 In 2013, Michael and co-workers
reported a Pd-catalyzed Suzuki coupling of aliphatic aziridines
with aryl boronic acids that affords β-phenethylamines in high
regioselectivity.5a Recently, Zhao and co-workers reported a
Pd-catalyzed C−H coupling of benzoic acids and aliphatic
aziridines (Figure 1B).6 Although these reports significantly
advanced the state of the art, both methods relied on the use of
a precious metal catalyst and were only applicable to terminal
aliphatic aziridines.5b Additionally, the latter methodology
relied on a carboxylic acid to direct C−H activation. Therefore,
We report here the development of a photocatalytic Ni-
catalyzed cross-electrophile coupling strategy with aliphatic
aziridines and (hetero)aryl iodides that delivers a broad range
of β-phenethylamine scaffolds (Figure 1D). Recent studies
Received: February 12, 2020
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A

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Table 1. Optimization Table
deviation from standard
conversion of 1a
a
entry
yield [%]
conditions
[%]
1
2
3
4
none
100
82
100
30
59
0
57
0
4′-bromoacetophenone
Ir(dF-CF3-ppy)2(dtbbpy)PF6
no Et3N
5
no dtbbpy
61
0
6
7
no Ni
no 4CzIPN
100
11
0
0
b
8
no light
0
0
9
10
11
0.5 mmol scale
0.5 mmol scale for 48 h
photoreactor on 0.5 mmol scale
70
>95
100
46
76
82 (72)
c
a
Reaction run on 0.1 mmol scale. Yields are the average of two runs
and were determined using 1,3,5-trimethoxybenzene (1.0 equiv) as an
b
c
external standard. Reaction run at 40 °C. Isolated yield.
equiv of aryl iodide.15 Aryl bromides proved to be ineffective
for the transformation (Table 1, entry 2). The use of an Ir-
photocatalyst that has similar redox potentials to 4CzIPN was
also successful, delivering 2a in 57% yield (Table 1, entry 3).
However, 4CzIPN was elected for further study since it is
easily synthesized from inexpensive materials and avoids the
use of a precious metal. Control studies showed that Ni, ligand,
photocatalyst, light, and Et3N were all required in the reaction
(Table 1, entry 4−8). Lastly, for larger scale reactions (0.5
mmol), 82% yield was obtained by switching from the use of
34 W blue LEDs to a 450 nm photoreactor (Table 1, entry 9−
11).16
Substrate Scope. The generality of the transformation was
evaluated under the optimized conditions (Figure 2). In all
cases examined, terminal aliphatic aziridines yielded the linear
coupled product in high selectively. A wide range of para-
substituted aryl iodides containing either electron-withdrawing
or electron-donating functionality were tolerated, delivering
products with nitrile (2b), methoxy (2c), and silyl ether (2d)
groups in good yield. The reaction proceeded well with aryl
iodides containing functionality that would be challenging to
access with methods that use organozinc, organolithium, or
Grignard reagents, including chloride (2e), boronate ester
(2f), acetanilide (2g), protic (2h), and carbonyl (2i) groups.
Meta- and ortho-substituted aryl iodides were also tolerated
(2j−m). In contrast to previously reported aziridine cross-
coupling methodologies, heteroaryl iodides, a substrate class of
high value in medicinal chemistry and library drug design, were
competent coupling partners, providing the desired β-
heteroarylethylamine products 2n and 2o.17a
Figure 1. Bioactive and pharmaceutically relevant β-phenethylamines
and aziridine cross-coupling methodologies. bpp = 2,6-bis(N-
pyrazolyl)-pyridine.
have demonstrated that it is possible to use a visible-light
photoredox catalyst in conjunction with an amine as the
reductant in Ni-catalyzed cross-electrophile coupling reac-
tions.13 An advantage of this approach is that it addresses
challenges inherent to the use of heterogeneous reductants in
traditional protocols. The methodology reported here high-
lights that a photocatalytic cross-electrophile coupling can also
impart distinct and previously inaccessible reactivity compared
to cross-electrophile couplings with Mn as a reductant.
Mechanistic studies were performed to probe this variation
in reactivity.
RESULTS AND DISCUSSION
■
Optimization. Our initial investigations focused on the
coupling of aliphatic aziridine 1a with 4′-iodoacetophenone
jointly catalyzed by a nickel catalyst and a visible-light
photoredox catalyst (Table 1). Different amine-based reduc-
tants, solvents, catalyst loadings and reaction concentrations
were investigated (see SI Optimization Studies). We found
that linear isomer 2a could be obtained in 59% yield (l:b >
10:1) using NiBr2·DME/4,4′-di-tert-butylbipyridine (dtbbpy)
as the cross-coupling catalyst, 1,2,3,5-tetrakis(carbazol-9-yl)-
4,6-dicyanobenzene (4CzIPN) as the photocatalyst, and Et3N
as the reductant (Table 1, entry 1).14 While homocoupling is
often an issue in cross-electrophile coupling reactions,
therefore requiring a large excess of aryl halide, only 15% of
biaryl product was observed under these conditions using 1.5
We also investigated the scope of 2-alkyl-substituted tosyl-
protected aziridines. Amphetamine derivatives, which are
pharmaceutically valuable motifs, were obtained in moderate
to high yields (2p−t) from methyl-substituted aziridine with
variation in aryl functionality such as trifluoromethoxy or 4-
cyano-3-fluoro-phenyl groups. The unsubstituted ethylene-
derived aziridine provided the corresponding phenethylamine
2u in 67% yield. The reaction of an enantiopure aziridine
afforded product 2v with minimal erosion of enantioselectivity,
B
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Figure 2. Reaction substrate scope. Reactions were run on 0.5 mmol scale and yields are the average of two runs. a10 mol % Ni, 20 mol % dtbbpy,
and 1.25 equiv Ar−I. bReaction run for 48 h. cProduct contains 10% of branched isomer, reported yield is corrected to account for this. dAziridine
e
f
1
g
1
95% ee. Determined by HPLC. Reaction run for 72 h. Selectivity determined by H NMR. b:l ratio determined by H NMR.
suggestive of exclusive activation at the less-substituted C−N
bond. Photocatalytic cross-electrophile coupling proceeded
smoothly with aziridines containing synthetically versatile
functional groups such as benzylic 2w, aliphatic chloride 2x,
ester 2y, and phthalimide 2z. Introduction of β- and even α-
branching to the aziridine substrate showed no deterioration in
yield, with 2aa and 2ab generated in 64% and 53% yield,
respectively. However, aliphatic 2,2-disubstituted aziridines
showed limited reactivity.17b
aromatic and aliphatic aziridines, this photocatalytic strategy is:
cross-coupling with styrenyl aziridine afforded 2ae in 53% yield
as a mixture of branched and linear isomers in a 1.2:1 (b:l)
ratio. The generation of the linear product under the
photocatalytic coupling conditions was unexpected based on
prior work. For example, under our previously reported cross-
electrophile conditions with Mn, styrenyl aziridines delivered
exclusively the branched isomer with bpp or dtbbpy as the
ligand (Figure 1C).18
Notably, cyclic 2,3-disubstituted aziridines were competent
coupling partners. For instance, cross-coupling with cyclohexyl
aziridine furnished product 2ac in 14% yield and cyclopentyl
aziridine afforded product 2ad in 55% yield. Both products
were formed exclusively as trans diastereomers. It is likely that
the enhancement in yield of 2ad in comparison to 2ac arises
from an increase in ring strain leading to more effective
aziridine activation. To the best of our knowledge, no prior
catalytic aziridine cross-coupling methods have been successful
with this substrate class. Furthermore, whereas previous Ni-
catalyzed methodologies have not been general for both
Mechanistic Investigations. The b:l mixture observed for
styrenyl aziridine and the reactivity with cyclic aziridines are
unprecedented in Ni-catalyzed cross-coupling reactions. This
prompted us to examine the mechanism of the photoassisted
cross-coupling.
Previous Ni-catalyzed aziridine cross-coupling method-
ologies were proposed to proceed via aziridine oxidative
addition to Ni, an elementary step that has been studied across
various ligand and aziridine classes (Figure 3A). For example,
Hillhouse and Jamison have shown that oxidative addition of
bpy- or phen-ligated Ni0 to a N-Ts aliphatic aziridine occurs at
C
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Figure 3. Possible pathways for aziridine activation. SET = single
electron transfer.
the terminal C−N bond to yield 3-Me.19 In contrast, our
group has shown that for N-Ts styrenyl aziridines, oxidative
addition occurs through cleavage of the internal C−N bond
with [bpy]Ni(COD) to form 3-Ph.20 The nearly equal b:l
product regioselectivity for N-Ts styrenyl aziridine observed
under the photoassisted reaction conditions is inconsistent
with this regiochemical outcome of aziridine oxidative
addition. To provide additional evidence against this aziridine
activation mechanism, we conducted a competition experiment
between Ar−I (5.0 equiv) and aziridine 1a (5.0 equiv) with
[dtbbpy]Ni0(COD)(4) (1.0 equiv) (Figure 4A). Exclusive
reactivity of the Ar−I was observed in less than 10 min,
suggesting that aziridine activation by Ni0 is unlikely under
these reaction conditions.
For these reasons, we considered several alternative aziridine
activation mechanisms. First, direct single-electron reduction
of the aziridine by the photocatalyst could afford a radical
intermediate that is intercepted by Ni in cross-coupling (Figure
3B).8b Alternatively, the aziridine could undergo in situ ring
opening by iodide to generate a β-iodoamine, followed by
photocatalytic Ni-catalyzed cross-electrophile coupling to
render the product (Figure 3C).
As a mechanistic probe for direct reduction of the aziridine
by the photocatalyst, the reaction of aziridine 1a, Et3N, and
4CzIPN was evaluated in the presence of light. However, no
consumption of aziridine was observed. Furthermore, single-
electron reduction of 1a by either the photocatalyst or Ni
would favor the generation of a 2° versus 1° radical, ultimately
affording the branched cross-coupled product or racemization
of enantioenriched 2v if ring opening was reversible. Since
neither of these are observed, this suggests that single-electron
reduction of the aziridine is not taking place. Nevertheless, use
of aziridine 6 under the reaction conditions afforded cyclized
product 7 in 43% yield as a 54:46 mixture of cis:trans
diastereoisomers (Figure 4B). This provides support for the
involvement of a carbon-centered radical in cross-coupling.
In evaluating iodide ring opening as a mechanism for
aziridine activation (Figure 3C), we noted that the b:l
selectivity observed for the photocatalytic styrenyl and
aliphatic aziridine coupling reactions is similar to that reported
Figure 4. Mechanistic experiments. Standard conditions are the same
a
1
as in Figure 1, entry 1. Yields were determined by H NMR using
1,3,5-trimethoxybenzene (1.0 equiv) as an external standard. bIsolated
yield.
for halide ring opening of aziridines.21 The expansion in scope
to include cyclic aliphatic aziridines is also consistent with this
proposal since these aziridines have not been observed to
undergo oxidative addition with Ni or Pd, but secondary alkyl
iodides are competent in cross-electrophile coupling reac-
tions.22 Additionally, Weix and co-workers have reported Ni-
catalyzed epoxide cross-electrophile coupling reactions that are
proposed to proceed through in situ formation of an
iodohydrin using Et3N·HCl and NaI as exogenous additives
alongside Zn as a reductant.23
To further evaluate the iodide ring-opening proposal, we
sought evidence for the generation of β-iodoamine under the
1
reaction conditions. Monitoring the reaction of 1a by H
NMR, we observed formation of β-iodoamine 8 within the first
2 h (Figure 4C). As the reaction proceeded, 8 was present in
approximately 15% yield, while a decrease of aziridine 1a and
an increase in cross-coupled product 2a occurred. Detection of
8 in this reaction cannot be taken as direct evidence for its
involvement in cross-coupling since the mass balance is such
that it could be involved in unproductive chemistry. Evidence
in favor of the direct involvement of the iodoamine in cross-
coupling was obtained by subjecting a catalytic amount of 8
(0.1 equiv) in combination with aziridine 1b (0.9 equiv) to the
D
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reaction conditions (Figure 4D).24 In this case, product 2a was
observed in 10% yield (quantitative yield relative to β-
iodoamine 8) as well as product 2p in 71% yield.
To understand whether iodoamine formation is reliant on
Ni, aziridine 1a and 4′-iodoacetophone were subjected to the
photocatalytic conditions without Ni.25 Complete consump-
tion of the aziridine was observed, but the iodide-opened
intermediate 8 was not detected (Figure 5). Instead, sultam 9
Figure 6. Proposed catalytic cycle. HAA = halogen atom abstraction.
involves selective addition of NiI−I E to the aryl iodide,
followed by single-electron reduction and reaction of the
resulting NiI−aryl intermediate with iodoamine 8, is also
consistent with the data presented and a recent mechanistic
study by Diao and co-workers (see SI page S38).31,32
Figure 5. Photocatalytic reactions in the absence of Ni. aYields are the
average of two runs and were determined by H NMR using 1,3,5-
1
As previously noted, aliphatic aziridines were not effective
substrates in the Mn-mediated Ni-catalyzed reductive coupling.
In light of the above mechanistic studies, we hypothesized that
the difference in scope between the Mn and photocatalytic
protocol was due to the generation of HI under the
photocatalytic conditions, which facilitates aziridine ring
opening and subsequent cross-coupling. While iodide is also
a byproduct of the Mn-mediated coupling, it is likely more
strongly sequestered as the MnI2 salt, preventing the formation
of 8. Indeed, addition of MnI2 under our previously reported
Ni/Mn conditions (1.0 equiv) with aziridine 1a did not result
in any detectable cross-coupled product nor iodoamine 8.
However, the use of 8 (1.0 equiv) instead of aziridine 1a
generated 2a in 27% yield with bpp as ligand and 60% yield
using dtbbpy (see SI S35−S36).
trimethoxybenzene (1.0 equiv) as an external standard. ET/PT =
electron transfer/proton transfer.
was obtained in 45% yield. While unexpected, the generation
of sultam 9 provides indirect support for the intermediacy of
iodoamine 8 and suggests that iodide ring opening can occur
independent of Ni. While sultam is present in highest yields in
the absence of Ni, it was also detected in trace amounts under
the standard catalytic conditions (for example, see SI page
S12). Sultam 9 likely arises from aziridine 1a by iodide ring
opening to form 8, followed by photocatalytic alkyl iodide
reduction and intramolecular radical cyclization.26,27 Consis-
tent with this proposal, addition of a catalytic amount of
tetrabutylammonium iodide (TBAI) to the Ni-free reaction
resulted in an increase in yield of 9 (Figure 5, entry 2).
Moreover, subjecting iodoamine 8 directly to the photo-
catalytic conditions in the absence of Ni afforded 9 in 18%
yield (see SI page S34). In addition to providing support for
the mechanistic proposal, the photocatalytic isomerization of
N-Ts aziridines to sultams represents an attractive synthetic
approach to these medicinally valuable heterocycles.28
Prior mechanistic studies on C(sp3)−C(sp2) cross-electro-
phile coupling reactions have implicated the importance of NiI
intermediates for selective activation of the C(sp3) electro-
phile. Whereas our competition experiments between aziridine
and aryl iodide indicate that oxidative addition of Ni0 is
selective for iodoarene over aziridine, NiI−I E or NiI−Ar (as in
Figure S13) is likely selective for aziridine activation.15b,29,31
Under the Mn-reductive coupling conditions, NiI or Mn could
activate the aziridine via SET. Due to the stability of benzylic
radicals, styrenyl aziridines are expected to be more effective
reaction partners than aliphatic aziridines, thereby explaining
why only styrenyl aziridines are reactive under the Mn
conditions. Under the photocatalytic conditions, in situ
formation of iodoamine from the aliphatic aziridine restores
the ability of this substrate class to participate in cross-
electrophile coupling through SET or HAA with NiI or
photocatalyst.
Discussion. These data suggest that iodide ring opening is
a likely mechanism for aziridine activation in the photocatalytic
cross-electrophile coupling. A catalytic cycle that incorporates
an iodoamine and radical intermediate is proposed (Figure 6).
First, facile oxidative addition of the aryl iodide with Ni0
generates B. Concomitantly, nucleophilic iodide ring opening
of 1a is mediated by the in situ generation of HI (see SI page
S37) to form 8. SET of 8 (with either [dtbbpy]NiI−I E or
4CzIPN−•) or halogen atom abstraction (HAA) from E
generates C.29 This radical intermediate can be trapped with B
to generate D. The formation of D allows for reductive
elimination to yield the cross-coupled product and inter-
Expansion of the Methodology Based on Mechanistic
Findings. The new mechanistic inference led us to
hypothesize that the scope could be expanded to previously
unsuccessful substrates. For example, aryl bromides did not
provide the cross-coupled product presumably because
mediate E, which can be reduced by 4CzIPN−• (PC/PC−•
=
−1.21 vs SCE in MeCN, NiI/ Ni0 = −1.17 vs SCE in THF).30
While a Ni0/NiII/NiIII/NiI cycle is proposed, a mechanism that
E
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bromoamine is an ineffective electrophile under these
conditions. Consistent with this hypothesis, addition of TBAI
(10 mol %) to the aziridine coupling reaction with 4′-
bromoacetophenone restored reactivity to give 2a in 45% yield
(Figure 7A).
Experimental details, optimization studies, and charac-
terization data (PDF)
Crystallographic data (CIF)
AUTHOR INFORMATION
Corresponding Author
■
Abigail G. Doyle − Department of Chemistry, Princeton
University, Princeton, New Jersey 08544, United States;
orcid.org/0000-0002-6641-0833; Email: agdoyle@
princeton.edu
Authors
Talia J. Steiman − Department of Chemistry, Princeton
University, Princeton, New Jersey 08544, United States
Junyi Liu − Department of Chemistry, Princeton University,
Princeton, New Jersey 08544, United States
Amanuella Mengiste − Department of Chemistry, Princeton
University, Princeton, New Jersey 08544, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c01724
Figure 7. Expansion in scope based on mechanistic findings. Standard
conditions are the same as in Figure 1, entry 1. aYields are the average
of two runs and were determined by 1H NMR using 1,3,5-
trimethoxybenzene (1.0 equiv) as an external standard. bl:b ratio
determined by 1H NMR. cYields are the average of two isolated runs.
Author Contributions
†J.L. and A.M. contributed equally.
Notes
The authors declare no competing financial interest.
For previous Ni-catalyzed aziridine cross-coupling reactions,
the use of N-Ts protected aziridines was necessary to facilitate
oxidative addition of Ni to the aziridine.9,19,20 Since cross-
coupling is not mediated by Ni-aziridine oxidative addition
under the photocatalytic conditions, we wondered whether
alternative protecting groups that are easier to deprotect but
were previously unsuccessful in Ni-catalyzed aziridine cross-
coupling reactions could be used.33 Gratifyingly, employment
of N-Boc aziridine 10a yielded product 10b in 28% yield as a
3.4:1 l:b mixture (Figure 7B). These results further highlight
the opportunities available with this new strategy, which were
previously not possible with Ni-catalyzed aziridine cross-
coupling reactions.
ACKNOWLEDGMENTS
■
Financial support was provided by NIGMS R35 GM126986
and an F32 Ruth L. Kirschstein NRSA Fellowship under
Award No. F32 EB027587-01 (T.J.S). The authors gratefully
acknowledge Dr. Brian P. Woods for preliminary investigations
and Dr. Christoph Heinz for initial substrate scope isolations.
We thank Jesus I. Martinez Alvarado for help with emission
quenching studies. Dr. Phillip D. Jeffrey is acknowledged for X-
ray crystallography. Lotus Separations is thanked for assistance
with the purification of 7.
REFERENCES
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CONCLUSIONS
■
In summary, we have described a Ni-photoredox protocol that
enables the modular assembly of a large scope of β-
phenethylamine derivatives, allowing access to high value
substrate classes for medicinal chemists. Many of the substrates
have previously proven to be challenging for conventional
aziridine cross-coupling methodologies. More generally, the
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photocatalytic protocol can enable distinct scope compared
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aziridine activation mode differs in comparison to those in
previous TM-catalyzed methods that are reliant on oxidative
C−N bond activation. On the basis of the described
mechanistic details, ongoing studies are focused on utilizing
this activation strategy for other strained ring systems with
photocatalytic Ni cross-electrophile coupling catalysis.
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