Directed nickel-catalyzed negishi cross coupling of alkyl aziridines

Article abstract of DOI:10.1021/ja4076716

Herein we report a nickel-catalyzed C-C bond-forming reaction between simple alkyl aziridines and organozinc reagents. This method represents the first catalytic cross-coupling reaction employing a nonallylic and nonbenzylic Csp³-N bond as an electrophile. Key to its success is the use of a new N-protecting group (cinsyl or Cn) bearing an electron-deficient olefin that directs oxidative addition and facilitates reductive elimination. Studies pertinent to elucidation of the mechanism of cross coupling are also presented.

Full text of DOI:10.1021/ja4076716

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Article
Directed Nickel-Catalyzed Negishi Cross Coupling of Alkyl Aziridines
Daniel K Nielsen, Chung-Yang (Dennis) Huang, and Abigail G. Doyle
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja4076716 • Publication Date (Web): 20 Aug 2013
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Directed Nickel-Catalyzed Negishi Cross Coupling of Alkyl
Aziridines
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Daniel K. Nielsen, Chung-Yang (Dennis) Huang, and Abigail G. Doyle*
Department of Chemistry, Princeton University, Princeton, New Jersey 08544
Supporting Information Placeholder
tion-initiated isomerization.9
ABSTRACT: Herein we report a nickel-catalyzed C–C bond-
forming reaction between simple alkyl aziridines and or-
ganozinc reagents. This method represents the first catalytic
Previous work:
cross-coupling reaction employing a non-allylic and non-
NiII, RZnBr, 1
MeOOC
R
NTs
(1)
(2)
COOMe
benzylic Csp3−N bond as an electrophile. Key to its success is
the use of a new N-protecting group (cinsyl or Cn) bearing an
electron-deficient olefin that directs oxidative addition and
facilitates reductive elimination. Studies pertinent to elucida-
tion of the mechanism of cross coupling are also presented.
NHTs
Ar
Ar
1
rt
This work:
NiII, RZnBr
rt
NHCn
R
NCn
R
NHCn
alkyl
alkyl
alkyl
O
O
easily synthesized on 100 g scale
S
INTRODUCTION
Cn =
enables coupling with unactivated Csp
removable directing group
3–N bonds
The past five years have witnessed the rapid development of
innovative cross-coupling methods that enable functionaliza-
tion of the C–O and C–N bonds of organic substrates. These
reactions benefit from the wide availability, low toxicity, and
orthogonal reactivity of ethers and amines compared with tra-
ditional organic halide electrophiles. Whereas significant pro-
gress has been made toward the coupling of aryl, alkenyl,1 and
activated allylic2 and benzylic3 C–O/N bond-containing elec-
trophiles, the coupling of substrates bearing unactivated Csp3–
O/N bonds remains essentially unknown.4 To exploit the full
potential of C–O/N activation in cross coupling, it is critical
that catalysts and strategies be developed that engage the
broad range of less activated amine and ether substrates.
We recently disclosed the first example of catalytic cross
coupling of N-sulfonyl aziridines with organozinc reagents (eq
1).5 Good yields and high regio- and diastereoselectivities
were obtained in the synthesis of a variety of β-substituted
amines. Unfortunately, however, this reaction was limited to
styrenyl aziridine substrates, which undergo relatively facile
oxidative addition due to: (i) attenuation of the C–N bond
strength at the benzylic site and/or (ii) pre-coordination of the
nickel catalyst with the arene.6 Also, the organometallic inter-
mediates resulting from oxidative addition to a styrenyl aziri-
dine likely benefit from greater stability to β-hydride elimina-
tion based on π-benzyl stabilization. Indeed, although Hill-
house7 and Wolfe8 have shown that transition metals can un-
dergo stoichiometric oxidative addition to aliphatic N-tosyl
aziridines, no catalytic coupling reactions exploiting this reac-
tivity have been reported. Instead, the reaction of Pd(0) with
this class of aziridines affords imines by a β-hydride elimina-
MeOOC
Herein we report our efforts to expand the substrate scope of
our previously reported method to include simple alkyl aziri-
dines. To do so, we considered whether it would be possible to
use the protecting group on the nitrogen to coordinate a transi-
tion-metal catalyst and accelerate the rate of a desired cross-
coupling event. In this article, we present the successful design
of such a protecting group and its application to cross-
coupling reactions of unactivated aziridines (eq 2). To the best
of our knowledge, this method represents the first catalytic
cross coupling using an electrophile bearing a non-benzylic or
allylic Csp3–N bond.
The design of the new aziridine protecting group was influ-
enced by two observations made during our work with
styrenyl aziridines.5a First, and consistent with stoichiometric
studies using nickel7 and palladium,8 we noted that styrenyl
aziridines bearing electron-withdrawing protecting groups
were uniquely capable of undergoing productive oxidative
addition with a nickel catalyst. Furthermore, we observed that
electron-deficient olefin ligands, such as dimethyl fumarate 1,
promoted efficient cross coupling by accelerating reductive
elimination, whereas more traditional phosphine or amine-
based ligands were unreactive (or led to exclusive β-hydride
elimination).10 Thus, we predicted that a protecting group that
combined both of these features would be highly effective: it
would activate the alkyl C–N bond toward oxidative addition,
stabilize intermediates prone to β-hydride elimination by co-
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ordination, and assist in C–C bond-forming reductive elimina-
tributed to the reaction of LiCl with aziridine 2, generating a
tion. An additional attractive feature of this strategy, which
distinguishes it from other examples of olefin-directed transi-
tion metal-catalyzed reactions,8,11 would be that the protecting
group could be cleaved post cross coupling, thus serving as a
removable directing group.12
β-chloroamine intermediate that serves as the active electro-
phile in the Negishi arylation.16 However, control experiments
suggest that this intermediate is not responsible for the ob-
served increase in product formation (see SI for details). Other
possibilities include that the lithium salt serves to break up
polymeric zinc aggregates,17 assists in oxidative addition,18 or
promotes transmetalation via the generation of higher order
zincates.19 All of these effects have been previously invoked in
the context of lithium halide-promoted Negishi coupling reac-
tions and may be responsible for the observed increase in reac-
tivity.
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RESULTS & DISCUSSION
Optimization studies. Our studies commenced with an ex-
amination of a variety of alkene-bearing amide, carbamate,
phosphoramide, and sulfonamide-protected aziridines (Table
1).13 Among these, aziridines bearing aryl sulfonyl groups
proved uniquely effective (2 and 3), with 2 undergoing cross
coupling under the influence of 7.5 mol% NiBr2ŸDME, 2
equivalents p-TolZnBr and 5 equivalents LiCl, to afford a
mixture of two regioisomeric products in 69% yield.14 All
other classes of aziridine protecting group provided recovered
starting material or starting material decomposition by β-
hydride elimination (5–7). In accord with our previous obser-
vations and our hypothesis that an alkene is required to direct
C–C bond formation, an aziridine protected with a simple to-
syl group was also unreactive. Further studies indicated that
modulation of the electronic properties of the alkene moder-
ately influences yield (2 vs. 3), whereas the spatial arrange-
ment of alkene is critical for reactivity (2 vs. 4). Based on the-
se studies, the aryl sulfonyl protecting group bearing a cin-
namate backbone (2) was selected for further studies. This
protecting group, which we have abbreviated as cinsyl (Cn),
can be easily synthesized on 100 gram scale in two steps from
inexpensive sodium 2-formylbenzenesulfonate.15
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Table 2. Evaluation of reaction conditions.
NiBr2·DME (7.5 mol%)
p-TolZnBr (2 equiv)
NHCn
p-Tol
p-Tol
NCn
NHCn
n-Bu
n-Bu
n-Bu
LiCl (5 equiv)
THF, 23 °C, 12 h
2
L
B
entry
conditions
standard conditions
no LiCl
conv (%)
100
yield (%)a
L:B
3.8:1
1.9:1
1
2
3
4
69
44
100
3.0 equiv LiCl
85
99
54
42
3.5:1
5.0:1
MgCl2 instead of LiCl
5
6
7
8
no NiBr2•DME
7
<2
56
<2
30
N/A
3.8:1
N/A
100
100
100
Ni(cod)2 instead of NiBr2•DME
DMA instead of THF
Table 1. Evaluation of alkene-containing protecting
groups.a
15% dimethyl fumarate 1
3.0:1
PG
NiBr2·DME (7.5 mol%)
p-TolZnBr (2 equiv)
NHCn
p-Tol
p-Tol
N
NHCn
n-Bu
1
aYields and regioselectivity determined by H NMR using tri-
n-Bu
n-Bu
LiCl (5 equiv)
THF, 23 °C, 12 h
2–7
linear (L)
branched (B)
phenylene as a quantitative internal standard.
CO2Me
Evaluation of other reaction parameters revealed a Ni cata-
lyst is necessary for productive C–C bond formation (entries 5
and 6). Use of DMA as solvent, which was found to be im-
portant for the cross coupling of styrenyl aziridines, was in
fact detrimental in this protocol (entry 7). Furthermore, inclu-
sion of dimethyl fumarate 1, a necessary ligand additive for
styrenyl aziridine cross coupling, resulted in depressed reac-
tion efficiency, presumably by outcompeting the cinsyl pro-
tecting group for Ni coordination (entry 8).
It is worth noting that under the standard reaction conditions,
cross coupling with 2 delivers a mixture of two regioisomers
in 3.8:1 linear:branched ratio. Formation of the linear isomer
as the major product is likely due to more facile oxidative
addition of Ni to the less hindered C–N bond of the substrate.
Notably, the regioselectivity is higher with the inclusion of
halide additives (entries 2–4). This improvement would be
expected if one of the roles of the halide additive, as discussed
above, is to facilitate oxidative addition by the generation of
an anionic and bulkier Ni catalyst. Additionally, it appears that
the identity of the protecting group has a small but significant
influence on the product ratio (Table 1). This influence on
regioselectivity may arise from initial association of the Ni
catalyst to the protecting group prior to oxidative addition. The
SO2
SO2
SO2
N
N
N
n-Bu
n-Bu
n-Bu
2
3
4
<5% yield
69% yield
3.8:1 L:B
44% yield
5.8:1 L:B
O
N
O
O
O
O
P
N
2
N
n-Bu
n-Bu
n-Bu
5
<5% yield
6
<5% yield
7
<5% yield
1
aYields and regioselectivity determined by H NMR using tri-
phenylene as a quantitative internal standard.
During our optimization studies with 2 we observed that in-
clusion of a superstoichiometric amount of LiCl afforded a
substantial increase in the yield of cross-coupled product (en-
tries 2 and 3, Table 2). By contrast, other metal halide addi-
tives showed a marginal or negative influence on reactivity
(entry 4 and SI). We considered that this effect could be at-
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data suggest the potential for future optimization by modula-
tion of the protecting group.
Silyl ethers (25), alkyl chlorides (26), and furanyl esters (27)
were well tolerated. Notably, the regioselectivity for the cou-
pling reactions remained relatively invariant for these distinct
terminal aziridines (and the range of nucleophiles examined in
Table 3), in line with our proposal that the regioselectivity
arises from a steric influence on oxidative addition. However,
a similar regioisomeric ratio was obtained in the arylation of
an aziridine bearing α-branching (29). This outcome is not
entirely consistent with a steric argument and requires further
study. Given this result, we were interested in how a 1,2-
disubstituted aziridine and a styrenyl aziridine would perform
under the coupling conditions. Exposure of 1,2-disubstituted
30 to the Ni-catalyzed conditions furnished the desired ary-
lated product in a 1.5:1 L:B ratio favoring C–C bond for-
mation at the expected less-hindered C2-position. For cinsyl
protected styrenyl aziridine 31, comparable yield to that ob-
tained via our earlier work with the N-Ts analogue of 31 was
observed. This reaction is selective for the branched product,
suggesting that weakening of the benzylic C−N bond overrides
steric control. Finally, our investigation has identified certain
limitations in the electrophile scope. A 1,1-disubstituted (32)
and an acrylate-derived (33) aziridine did not undergo produc-
tive coupling due to the formation of stable β-hydride elimina-
tion byproducts. In addition, although trans-30 was reactive, a
cis-substituted, cyclohexene-derived aziridine (34) underwent
decomposition by conjugate addition, which can be rational-
ized based on the known difference in ring-opening reactivity
between cis- and trans-aziridines.20
Scope elucidation. The scope of the reaction was first ex-
plored by varying the identity of the nucleophile partner. As
shown in Table 3, aziridine 2 was found to couple with an
array of arylzinc reagents, including ortho-, meta-, and para-
substituted nucleophiles (9–11). Sterically-hindered nucleo-
philes are also viable in this new reaction, including 2,6-
dimethylphenyl zinc bromide (12). The method is compatible
with both electron-rich (13) and electron-poor (14–16) cou-
pling partners, as well as arylzinc reagents bearing a variety of
synthetically-valuable functional groups (17–19). Notably, the
use of a heteroaromatic nucleophile also led to cross coupling,
albeit in moderate yield (20). Attempts to further expand the
scope of the nucleophiles to aryl nitrile and ester-substituted
zinc reagents were unfruitful, which may result from competi-
tive binding of the unhindered Lewis basic groups to Ni. On
the other hand, we were pleased to find that alkyl zinc reagents
are suitable nucleophiles (22), even though the method was
optimized for couplings with arylzinc reagents. For example,
alkyl zinc reagents with a tertiary nitrile (23) and acetal (24)
substitution underwent coupling in 74 and 53% yield under
otherwise identical reaction conditions.
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Table 3. Evaluation of nucleophile scope.
NiBr2·DME (7.5 mol%)
NHCn
R
NCn
(2 equiv)
R
ZnBr
R
NHCn
n-Bu
n-Bu
8–24-L
n-Bu
LiCl (5 equiv)
THF, 23 °C, 12 h
2
8–24-B
Table 4. Evaluation of electrophile scope.a
NiBr2•DME (7.5 mol%)
p-TolZnBr (2 equiv)
NHCn
p-Tol
p-Tol
Me
NCn
NHCn
NCn
R
R
R
LiCl (5 equiv)
Me
THF, 23 °C, 12 h
25–34
L
B
Me
Me
11
77% yield
4.2:1 L:B
Me
8
9
75% yield
4.2:1 L:B
10
80% yield
3.8:1 L:B
12
67% yieldb
4.4:1 L:B
77% yield
3.9:1 L:B
NCn
NCn
O
O
TBSO
Cl
3
2
4
O
25
26
27
F
F
66% yield
2.6:1 L:B
56% yield
3.3:1 L:B
58% yield
3.2:1 L:B
OMe
CF3
F
NCn
NCn
NCn
3
NCn
15c
16
77% yield
4.0:1 L:B
Ph
13
61% yield
3.8:1 L:B
14
71% yield
4.3:1 L:B
Me
2
64% yield
3.9:1 L:B
2
Me
28
29
(±)-30
31
69% yield
3.6:1 L:B
39% yield
3.6:1 L:B
53% yield
43% yield
1:>20 L:B
1.5:1 major:minorb
Cl
N
Me
Unsuccesful electrophiles:
OMe
NCn
17
68% yield
3.8:1 L:B
18
50% yield
4.7:1 L:B
19
59% yield
3.8:1 L:B
20
26% yield
3.2:1 L:B
Me
NCn
NCn
Me
MeO2C
3
32
33
34
<5% yield
<5% yield
<5% yield
CN
O
O
n-Bu
aIsolated yields are the average of two runs, 0.08 mmol scale.
bAddition at the C2-position of the aziridine afforded the major
product.
Me Me
21
66% yield
4.1:1 L:B
22
68% yield
4.9:1 L:B
23
74% yield
2.5:1 L:B
24
53% yield
3.6:1 L:B
aIsolated yields are the average of two runs, 0.08 mmol scale.
bReaction was run at 50 °C. cReaction was run at 60 °C.
To further demonstrate the practicality of this protocol, a
gram-scale reaction set up on the benchtop using aziridine 2
afforded β-substituted amine 9 in 68% yield. Additionally, a
The scope of the electrophile was examined next (Table 4).
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NiBr2•DME (7.5 mol%)
p-TolZnBr (2 equiv)
preliminary study indicated that the cinsyl group can be re-
moved under standard conditions for Ts deprotection; subse-
quent protection with an Fmoc-group provided an unoptimized
46% yield for the two-step sequence (see SI for details).
NHCn
p-Tol
p-Tol
NCn
NHCn
n-Bu
LiCl (5 equiv)
THF, 23 °C, 12 h
(3)
n-Bu
n-Bu
2
9-L
9-B
5
99% ee
99% ee
24% ee
6
7
8
9
Mechanistic studies. Our proposed catalytic cycle is shown
in Figure 1. Initial reduction of NiII to Ni0 in the presence of
LiCl may generate an anionic Ni0–Cl complex primed for oxi-
dative addition. Transient association of this metal complex
with the cinsyl group likely occurs next (A), approximating
the metal center to the aziridine, which would facilitate oxida-
tive addition into the C–N bond (B).21 Subsequent transmeta-
lation with the organozinc reagent cleaves the metallacyclic
Ni–N bond (C), thereby allowing effective coordination of the
Ni to the electron-deficient π-system (D). Assisted by this
olefin ligand, reductive elimination furnishes the cross-
coupled product.
The outcome of cross coupling with aziridine 35 containing
an adjacent cyclopropyl group was also in line with an
SN2/homolysis mechanism. Specifically, two ring-opened
products, 36 and 37, were isolated in a 2.5:1 ratio when 35
was subjected to the standard reaction conditions (eq 4). Both
of these products arise from oxidative addition at the more
substituted carbon of the aziridine, presumably due to the fact
that a cyclopropyl group, like the aromatic ring in substrate 31,
facilitates oxidative addition at the adjacent electrophilic site
by π-donation. Subsequent cyclopropane ring opening, fol-
lowed by C–C bond formation would deliver 36 and 37. This
outcome implies the intermediacy of a radical intermediate:25
the major product (36) would derive from a secondary radical
at C3 whereas the minor product (37) would originate from a
less-stable primary radical at C2.
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BrZn NSO2Ar
R
alkyl
NSO2Ar
Cl
Li
alkyl
[Ni0]
Cn
NiBr2•DME (7.5 mol%)
p-TolZnBr (2 equiv)
N
36 + 37
(4)
Ph
Ph
O
3
1
Li
LiCl (5 equiv)
THF, 23 °C, 12 h
O2S
N
SO2
Li
BrZn
alkyl
2
47% yield
2.5:1 rr
COOMe
N
±35
[NiII]
R
alkyl
[Ni0]
Cl
H
N
2
COOMe
Cl
3
Me
O
Cn
1
D
A
2
H
N
ArSO2N [NiII] Cl
Ph
O
Li
Cn
3
1
ZnBr
Li
Me
36 (major)
ArSO2N
R
alkyl
37 (minor)
B
[NiII]
Cl
alkyl
RZnBr
C
We also prepared deuterium-labeled cis- and trans-38 to de-
termine whether oxidative addition of Ni to the terminal posi-
tion occurs by a mechanism similar to that for internal cou-
pling. Performing a cross-coupling reaction with trans-38 (uti-
lizing alkyl zinc reagent 39 as nucleophile) gave 40 in 57%
yield and 2.8:1 L:B ratio. In order to determine the stereo-
chemical composition of 40, both isomers of 40 were convert-
ed into piperidine 41 and its regioisomer (not shown) by a
Figure 1. Proposed catalytic cycle.
To better understand the mechanism of oxidative addition,
we evaluated two other substrates, one an enantiopure aziri-
dine (2) and the other a cyclopropyl-substituted aziridine (35).
Starting from 2, we observed the generation of linear and
branched β-substituted amines 9-L and 9-B in a 3.8:1 ratio.
Branched product 9-B showed substantially eroded ee (24%),
whereas the linear product 9-L was obtained in 99% ee (eq 3).
One explanation for this result is that oxidative addition occurs
by a single-electron transfer (SET) pathway. Alternatively,
oxidative addition could proceed by SN2 addition of Ni to 2
followed by racemization of an ensuing reaction intermediate
due to the configurational instability of the Ni–C bond.22 The
latter mechanism is most consistent with observation of pre-
dominantly linear product since a SET pathway would be ex-
pected to favor formation of the more substituted organic radi-
cal. Mechanistic studies of stoichiometric reactions with Ni
and Pd by Hillhouse7 and Wolfe8 also support an SN2 oxida-
tive addition over a SET pathway.23,24 Additionally, the fact
that we observe no erosion in ee in the linear product 9-L im-
plies that racemization must occur during or after an irreversi-
ble step in the catalytic cycle.
2
three-step procedure. H-NMR analysis of 41 and comparison
with authentic material prepared by an alternative synthetic
protocol (see SI for details) revealed that 40L was formed as a
mixture of diastereoisomers and suggests that oxidative addi-
tion to the terminal position proceeds by the same
SN2/homolysis mechanism as that for internal addition. As
further confirmation, we found that the same diastereomeric
mixture of products (41) was obtained when the reaction was
initiated with cis-38.
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Cn
see: (b) Yatsumonji, Y.; Ishida, Y.; Tsubouchi, A.; Takeda, T. Org.
Lett. 2007, 9, 4603–4606.
N
n-Hex
NiBr2•DME
(7.5 mol%)
NHCn
D
(3) For leading references on the use of benzylic C–O/N bond-
containing substrates as electrophiles, see: (a) Yu, D.-G.; Wang, X.;
Zhu, R.-Y.; Luo, S.; Zhang, X.-B.; Wang, B.-Q.; Wang, L.; Shi, Z.-
J. J. Am. Chem. Soc. 2012, 134, 14638–14641. (b) Zhou, Q.; Srinivas,
H. D.; Dasgupta, S.; Watson, M. P. J. Am. Chem. Soc. 2013, 135,
3307–3310. (c) Li, M.-B.; Tang, X.-L.; Tian, S.-K. Adv. Synth.
Catal. 2011, 353, 1980–1984. (d) Maity, P.; Shacklady-McAtee, D.
M.; Yap, G. P. A.; Sirianni, E. R.; Watson, M. P. J. Am. Chem. Soc.
2013, 135, 280–285.
(4) For examples of reductive coupling of non-activated epoxides
with aldehydes and alkynes, see: (a) Molinaro, C.; Jamison, T. F. J.
Am. Chem. Soc. 2003, 125, 8076–8077. (b) Molinaro, C.; Jamison, T.
Angew. Chem., Int. Ed. 2005, 44, 129–132. (c) Beaver, M. G.;
Jamison, T. F. Org. Lett. 2011, 13, 4140–4143.
(5) (a) Huang, C.-Y. D.; Doyle, A. G. J. Am. Chem. Soc. 2012, 134,
9541–9544. For Suzuki couplings of epoxides, see: (b) Nielsen, D. K.;
Doyle, A. G. Angew. Chem., Int., Ed. 2011, 50, 6056–6059.
(6) (a) Tsou, T. T.; Kochi, J. K. J. Am. Chem. Soc. 1979, 101, 6319–
6332. (b) Giovannini, R.; Stüdemann, T.; Devasagayaraj, A.; Dussin,
G.; Knochel, P. J. Org. Chem. 1999, 64, 3544–3553. (c) Ariafard, A.;
Lin, Z. Organometallics 2006, 25, 4030–4033. (d) Li, Z.; Zhang, S.-
L.; Fu, Y.; Guo, Q.-X.; Liu, L. J. Am. Chem. Soc. 2009, 131, 8815–
8823.
(7) Lin, B. L.; Clough, C. R.; Hillhouse, G. L. J. Am. Chem. Soc.
2002, 124, 2890–2891.
(8) Ney, J. E.; Wolfe, J. P. J. Am. Chem. Soc. 2006, 128, 15415–
15422.
(9) Wolfe, J. P.; Ney, J. E. Org. Lett. 2003, 5, 4607–4610.
(10) Johnson, J. B.; Rovis, T. Angew. Chem., Int. Ed. 2008, 47, 840–
871.
(11) For the use of electron-withdrawing styrenes as ligands in cata-
lytic cross coupling of alkyl electrophiles, see: (a) Giovannini, R.;
Stüdemann, T.; Gaelle, D.; Knochel, P. Angew. Chem., Int. Ed. 1998,
37, 2387–2390. (b) Giovannini, R.; Knochel, P. J. Am. Chem. Soc.
1998, 120, 11186–11187. (c) Giovannini, R.; Stüdemann, T.; Devasa-
gayaraj, A.; Dussin, G.; Knochel, P. J. Org. Chem. 1999, 64, 3544–
3553. (d) Jensen, A. E.; Knochel, P. J. Org. Chem. 2002, 67, 79–85.
(12) Rousseau, G.; Breit, B. Angew. Chem., Int. Ed. 2011, 50, 2450–
2494.
± trans-38
n-Hex
(5)
OTBS
LiCl (5 equiv)
THF, 23 °C, 12 h
D
TBSO
ZnBr
±40
39
57% yield
2.8:1 L:B
Cn
N
3 steps
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23
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60
mixture of diastereoisomers
as determined by 2H-NMR
(also from cis-38)
±40-L
n-Hex
D
±41
CONCLUSIONS
In conclusion, we have developed a novel aziridine protect-
ing group, which is able to sequentially activate an aziridine
toward oxidative addition, direct the nickel catalyst to the C–N
bond, and promote reductive elimination. This system repre-
sents the first use of a non-benzylic or allylic Csp3–N bond as
an electrophile in metal-catalyzed cross coupling and affords
phenylethylamine derivatives.26 We have shown that C–C
bond formation occurs in a stereoconvergent manner most
consistent with an SN2/homolysis mechanism for oxidative
addition. Efforts to utilize alkene-containing directing groups
to enable cross coupling with other traditionally unreactive
electrophiles, as well as further mechanistic studies, are cur-
rently underway.
ASSOCIATED CONTENT
Supporting Information.
Experimental details, characterization data, optimization ta-
bles, mechanism studies. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
(13) See the SI for the evaluation of other alkene-containing protect-
ing groups.
Corresponding Author
agdoyle@princeton.edu
(14) Side products arising from conjugate addition of the aryl zinc
reagent to the starting material/product, as well as uncharacterized
polymeric material, account for the mass balance of most reactions.
(15) Ahn, K. H.; Baek, H.-H.; Lee, S. J.; Cho, C.-W. J. Org. Chem.
2000, 65, 7690–7696.
(16) For Negishi couplings of alkyl chlorides, see: (a) Zhou, J.; Fu,
G. C. J. Am. Chem. Soc. 2003, 125, 12527–12530. (b) Hadei, N.;
Achonduh, G. T.; Valente, C.; O’Brien, C. J.; Organ, M. G. Angew.
Chem., Int. Ed. 2011, 50, 3896–3899. For a Suzuki coupling of β-
chloroamines, see: (c) Lu, Z.; Wilsily, A.; Fu, G. C. J. Am. Chem.
Soc. 2011, 133, 8154–8157.
(17) (a) Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2004,
43, 3333–3336. (b) Ochiai, H.; Jang, M.; Hirano, K.; Yorimitsu, H.;
Oshima, K. Org. Lett. 2008, 10, 2681–2683.
(18) Fagnou, K.; Lautens, M. Angew. Chem., Int. Ed. 2002, 41, 26–
47.
(19) (a) Achonduh, G. T.; Hadei, N.; Valente, C.; Avola, S.; O'Brien,
C. J.; Organ, M. G. Chem. Commun. 2010, 46, 4109–4111. (b)
Hunter, H. N.; Hadei, N.; Blagojevic, V.; Patschinski, P.; Achonduh,
G. T.; Avola, S.; Bohme, D. K.; Organ, M. G. Chem. Eur. J. 2011, 17,
7845–7851. (c) Fleckenstein, J. E.; Koszinowski, K. Organometallics
2011, 30, 5018–5026. (d) McCann, L. C.; Hunter, H. N.; Clyburne, J.
A. C.; Organ, M. G. Angew. Chem., Int. Ed. 2012, 51, 7024–7027.
(20) For examples, see compound 27 in ref. 5a and: (a) Stamm, H.;
Sommer, A.; Woderer, A.; Wiesert, W.; Mall, T.; Assithianakis, P. J.
Org. Chem. 1985, 50, 4946–4955. (b) Mall, T.; Stamm, H. J. Org.
Funding Sources
No competing financial interests have been declared.
ACKNOWLEDGMENT
Financial support was provided by Princeton University, Bris-
tol-Myers Squibb, and Eli Lilly. A.G.D. is an Alfred P. Sloan
Foundation Fellow, Eli Lilly Grantee, Amgen Young Investi-
gator, and Roche Early Excellence in Chemistry Awardee. The
authors also thank Lotus Separations for chiral separation of 2
and Istvan Pelczer for the help of NMR experiments.
REFERENCES
(1) For a review on the functionalization of Csp2–O bonds, see: (a)
Rosen, B. M.; Quasdorf, K. W.; Wilson, D. A.; Zhang, N.; Resmerita,
A.-M.; Garg, N. K.; Percec, V. Chem. Rev. 2010, 111, 1346–1416.
For a recent example of the functionalization of Csp2–N bonds, see:
(b) Koreeda, T.; Kochi, T.; Kakiuchi, F. J. Am. Chem. Soc. 2009, 131,
7238–7239.
(2) For a leading reference on allylic C–N bond activation, see: (a)
Li, M.-B.; Wang, Y.; Tian, S.-K. Angew. Chem., Int. Ed. 2012, 51,
2968–2971. For a leading reference on allylic C–O bond activation,
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Chem. 1987, 52, 4812–4814. (c) Park, G.; Kim, S.-C.; Kang, H.-Y.
Bull. Korean Chem. Soc. 2005, 26, 1339–1343.
(21) For a review on 2-azametallacyclobutanes, see: Dauth, A.; Love,
J. A. Dalton Trans. 2012, 41, 7782–7791.
(22) Bellos, K.; Stamm, H.; Speth, D. J. Org. Chem. 1991, 56, 6846–
6849.
2
3
4
5
6
(23) Alkyne-directed oxidative addition to the terminal position of
epoxides also goes through an SN2 pathway. See: Beaver, M. G.;
Jamison, T. F. Org. Lett. 2011, 13, 4140–4143.
7
8
9
(24) It is noteworthy that the authors of refs 7, 8 and 23 do not ob-
serve racemization using a similar class of substrates to the ones re-
ported in this manuscript. One explanation to address this discrepancy
is that the distinct ligands (bipyridines and phosphines) and reaction
conditions used in their studies impart greater configurational stability
to the resulting azametallacyclic intermediates. Alternatively, in our
system, racemization by reversible Ni–C bond homolysis may occur
at an intermediate other than B in Figure 1.
(25) A non-radical mechanism analogous to the elementary step in
intramolecular [5+2] cycloaddition of vinylcyclopropanes could also
provide the ring-opening products but a 36:37 ratio favoring 37 would
be expected: Rubin, M.; Rubina, M.; Gevorgyan, V. Chem. Rev. 2007,
107, 3117–3179.
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(26) Medicinally relevant phenylethylamine derivatives: Berry, M. D.
J. Neurochem. 2004, 90, 257–271.
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O
O
S
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NiII
NHCn
R
NCn
Cn =
R
NHCn
alkyl
alkyl
major
alkyl
RZnBr
minor
MeOOC
24 examples, 26–80% yield
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