Palladium-catalyzed cross-coupling of n -sulfonylaziridines with boronic acids

Article abstract of DOI:10.1021/ja410686v

A mild palladium-catalyzed cross-coupling of unsubstituted and 2-alkyl-substituted aziridines with arylboronic acid nucleophiles is presented. The reaction is highly regioselective and compatible with diverse functionality. A catalytic amount of base, a sterically demanding triarylphosphine ligand, and a phenol additive are critical to the success of the reaction. Coupling of a deuterium-labeled substrate established that ring opening of the aziridine occurs with inversion of stereochemistry.

Full text of DOI:10.1021/ja410686v

Communication
pubs.acs.org/JACS
Palladium-Catalyzed Cross-Coupling of N‑Sulfonylaziridines with
Boronic Acids
Megan L. Duda and Forrest E. Michael*
Department of Chemistry, University of Washington, Box 351700, Seattle, Washington 98195-1700, United States
S
* Supporting Information
Scheme 1. Previously Reported Aziridine Couplings
ABSTRACT: A mild palladium-catalyzed cross-coupling
of unsubstituted and 2-alkyl-substituted aziridines with
arylboronic acid nucleophiles is presented. The reaction is
highly regioselective and compatible with diverse function-
ality. A catalytic amount of base, a sterically demanding
triarylphosphine ligand, and a phenol additive are critical
to the success of the reaction. Coupling of a deuterium-
labeled substrate established that ring opening of the
aziridine occurs with inversion of stereochemistry.
he β-phenethylamine motif is the structural basis for a
Tlarge number of small molecules with distinctive and often
desirable biological properties. This privileged structure is
present in many important neurotransmitters and is used
extensively in syntheses of drug targets for the treatment of
depression and anxiety disorders, as well as Parkinson’s and
Alzheimer’s diseases.1 A high value is therefore placed on the
development of efficient methods for the synthesis of
substituted phenethylamine analogues.
One method for the synthesis of such compounds is the ring
opening of aziridines with organometallic nucleophiles.2
Generally, this requires the use of lithium diorganocuprates,
often in the presence of a strong Lewis acid. This reaction,
however, is inherently limited by the functional group
compatibility of the cuprates and Lewis acids. As has been
demonstrated amply with other reactions,3 by using an
appropriate catalyst it should be possible to replace the reactive
organocuprates with boronic acid nucleophiles, which are much
milder and generally more functional-group-compatible re-
agents.
report the first cross-coupling of unsubstituted and 2-alkyl-
substituted aziridines in which the nucleophilic components are
boronic acids.7
We began our investigation using N-tosylaziridine and
phenylboronic acid as model coupling partners and conditions
broadly resembling those in ref 5a, but found none of the
desired product. Addition of water to the reaction mixture,
however, gave a 25% yield of phenethylamine product 3aa
(Scheme 2). Notably, the remainder of the starting material had
Scheme 2. Initial Conditions
Hillhouse4 and Wolfe5 have previously demonstrated that
Ni(0) and Pd(0) complexes readily oxidatively add the C−N
bond of aziridines. The resulting azametallacycles are isolable,
and Wolfe was able to develop this finding into a catalytic
isomerization of N-tosylaziridines to N-tosylimines, presumably
via β-hydride elimination of the key metallacycle intermediate.5a
Until recently, the potential cross-coupling ability of these
alkylmetal complexes had not been exploited.
Within the last year, Doyle has reported a key advance in this
field in the form of two sets of conditions for Ni-catalyzed
coupling of aziridines with a variety of organozinc nucleophiles
(Scheme 1). The first conditions work well for 2-arylaziridines
but not for 2-alkylaziridines,6a while the second are successful
for 2-alkylaziridines but require a custom sulfonamide
protecting group. This second procedure also suffers from
moderate regioselectivity (∼4:1 linear:branched).6b Herein, we
been converted to p-toluenesulfonamide. We suspected this
byproduct was the result of β-hydride elimination and
hydrolysis of the consequent imine.
After switching to the more reactive N-nosylaziridine 1c, we
conducted an extensive optimization of ligand, solvent, base,
and ROH additive and found that the conditions in Table 1
gave the highest yield of the desired product (entry 1). The
lower reactivity of the tosylaziridine is evident from the low
yield in entry 2. In contrast to the nickel-catalyzed reaction,6b
only the regioisomer derived from opening at the unsubstituted
carbon atom was observed (>20:1 linear:branched). The effects
Received: October 22, 2013
Published: November 25, 2013
© 2013 American Chemical Society
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Journal of the American Chemical Society
Communication
a
Table 1. Effects of Variation from Optimal Conditions
Table 2. Boronic Acid Scope
a
entry
variation from the above conditions
yield, %
1
none
82
32
0
2
Ts protecting group on aziridine
PCy3 instead of PNp3
P(t-Bu)3 instead of PNp3
P(o-tol)3 instead of PNp3
P(2,4-Me2C6H3)3 instead of PNp3
1 equiv of Cs2CO3
3
4
0
5
44
63
0
6
7
8
no Cs2CO3
75
24
19
53
61
9
K2CO3 instead of Cs2CO3
no m-ClC6H4OH
10
11
12
H2O instead of m-ClC6H4OH
phenol instead of m-ClC6H4OH
a
NMR yields using 1,3-dinitrobenzene as internal standard.
of variation of key reaction components are illustrated in Table
1.
Tri-1-naphthylphosphine was determined to be the optimal
ligand. The steric demand of this ligand likely plays an
important role in inhibiting β-hydride elimination.8 Other
sterically hindered triarylphosphines also afforded the desired
product, but in reduced yield (Table 1, entries 5 and 6).
Surprisingly, only unreacted aziridine was observed when
sterically bulky trialkylphosphine ligands were used with the
new optimized conditions (entries 3 and 4).
a
b
Isolated yields. 2 mmol scale.
a
Table 3. Aziridine Scope
Catalytic amounts of cesium carbonate were necessary for
the highest yield. Replacing Cs2CO3 with K2CO3 resulted in a
large drop in yield (entry 9), as did increasing the amount of
base to 1 equiv (entry 7). Omission of the base gave a minor
reduction in yield (entry 8). Unlike most traditional cross-
couplings, the present reaction does not necessarily require
stoichiometric base, due to the basicity of the sulfonamide
leaving group, but it appears that catalytic quantities do
improve the yield, possibly by assisting transmetalation.
We found m-chlorophenol to be a crucial additive in this
reaction. In its absence, little desired product is formed (entry
10). Using other acidic proton donors such as water and phenol
gave somewhat lower yields (entries 11 and 12).
The optimized conditions were applied to the coupling of
aziridine 1c with an array of substituted arylboronic acids
(Table 2). Though the differences were minor, electron-rich
arylboronic acids gave generally higher yields of product, while
electron-poor arylboronic acids were sometimes accompanied
by slightly lower yields (3cl,cg,cf). The reaction is highly
tolerant of diverse functional groups such as ketone, amide,
aldehyde, acetal, ether, thioether, and nitro functionalities. It is
also tolerant of boronic acids with functional groups bearing
acidic hydrogens, such as phenol (3cj) and amide (3ck). The
reaction of 1c and 2a was performed on a 2 mmol scale and
gave 3ca in nearly identical yield (75% vs 77%). The attempted
coupling of alkylboronic acids under these conditions did not
give the desired product.
a
b
Isolated yields. Conditions: 5 mol % of Pd(dba)2, 12 mol % of
PNp3, 10 mol % of Cs2CO3, 4 equiv of m-ClC6H4OH, THF, 35 °C.
The scope of the reaction with regard to the aziridine
component was also investigated (Table 3). The reaction can
be applied to the unsubstituted aziridine 1d and several 2-alkyl-
substituted aziridines (1e−g). Good to excellent yields are
obtained with arylboronic acids possessing both electron-
donating and electron-withdrawing functionalities. In all cases
excellent regioselectivity (>20:1) was observed. Unfortunately,
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Journal of the American Chemical Society
Communication
the present conditions do not appear to be applicable to 2,2-
disubstituted and 2,3-disubstituted aziridines.
To probe the mechanism of this reaction, deuterium-labeled
aziridine 1h-d was prepared and subjected to the standard
reaction conditions (Scheme 3). The coupled product, 3ha-d,
with arylboronic acid nucleophiles. The reaction is promoted
by the use of sterically demanding triarylphosphine ligands, the
presence of catalytic base, and addition of a suitable protic
additive which presumably plays a role in transmetalation.
Furthermore, the reaction is highly regioselective and tolerant
of a wide range of functionalities, allowing for quick and
efficient synthesis of highly desirable substituted β-phenethyl-
amine products.
Scheme 3. Deuterium-Labeled Substrate Coupling
ASSOCIATED CONTENT
* Supporting Information
Text and figures giving experimental procedures, spectral
characterizations, and additional data. This material is available
free of charge via the Internet at http://pubs.acs.org.
■
S
was formed as a single diastereomer in 89% yield. Pictet−
Spengler cyclization established that ring opening had occurred
with 100% inversion of stereochemistry. This is consistent with
the stoichiometric studies of Hillhouse and Wolfe establishing
that oxidative addition occurs by an SN2 mechanism and is in
contrast to the stereochemical scrambling observed by Doyle.
A plausible catalytic cycle for this coupling reaction is
depicted in Scheme 4. Oxidative addition of the aziridine to
AUTHOR INFORMATION
Corresponding Author
michael@chem.washington.edu
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the University of Washington and the National
Science Foundation for financial support of this project.
■
Scheme 4. Proposed Catalytic Cycle
REFERENCES
■
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addition of the unsubstituted C−N bond and clean inversion of
stereochemistry are consistent with previous stoichiometric
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take place. However, since the coupling largely fails in the
absence of ROH additive, direct transmetalation of the boronic
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procedure for coupling 2-alkyl-substituted N-nosylaziridines
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dx.doi.org/10.1021/ja410686v | J. Am. Chem. Soc. 2013, 135, 18347−18349