Nickel-catalyzed negishi alkylations of styrenyl aziridines

Article abstract of DOI:10.1021/ja3013825

A nickel-catalyzed cross-coupling reaction between N-sulfonyl aziridines and organozinc reagents is reported. The catalytic system comprises an inexpensive and air-stable Ni(II) source and dimethyl fumarate as ligand. Regioselective synthesis of β-substituted amines is possible under mild and functional-group-tolerant conditions. The stereoselectivity of the reaction is consistent with a stereoconvergent mechanism wherein the sulfonamide directs C-C bond formation.

Full text of DOI:10.1021/ja3013825

Communication
pubs.acs.org/JACS
Nickel-Catalyzed Negishi Alkylations of Styrenyl Aziridines
Chung-Yang (Dennis) Huang and Abigail G. Doyle*
Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States
S
* Supporting Information
temperature C−C bond formation between styrenyl aziridines
and a broad range of organozinc reagents (eq 2). This
operationally simple method affords β-substituted amines with
complete regioselectivity and unconventional diastereoselectiv-
ity.
ABSTRACT: A nickel-catalyzed cross-coupling reaction
between N-sulfonyl aziridines and organozinc reagents is
reported. The catalytic system comprises an inexpensive
and air-stable Ni(II) source and dimethyl fumarate as
ligand. Regioselective synthesis of β-substituted amines is
possible under mild and functional-group-tolerant con-
ditions. The stereoselectivity of the reaction is consistent
with a stereoconvergent mechanism wherein the sulfona-
mide directs C−C bond formation.
The chief barriers to progress in the development of cross-
coupling reactions with alkyl electrophiles have been associated
with oxidative addition and β-hydride elimination. In the case
of aziridines, Hillhouse7 and Wolfe8 have demonstrated that
oxidative addition with Ni and Pd is relatively facile, affording
isolable azametallacyclobutane intermediates from insertion
into the less hindered C−N bond of aliphatic N-sulfonyl
aziridines (eq 1). Nevertheless, coupling reactions that proceed
by metal insertion into the C−N bond of an aziridine are not
known. Instead, the reaction of Pd(0) with aziridines has been
shown to afford imines by a β-hydride-elimination-initiated
isomerization.9 Alternatively, since CO insertion can out-
compete β-hydride elimination, aziridines have been converted
to β-lactams by various transition-metal catalysts.10
ransition-metal-catalyzed cross-coupling reactions have
T
evolved to be one of the most powerful methods for
constructing carbon−carbon bonds. Whereas the field of alkyl
halide cross-coupling has undergone many significant advances
over the past 10 years,1 comparatively little progress has been
made toward the coupling of non-halogen-containing alkyl
electrophiles such as ethers and amines.2 Given that ethers and
amines are readily available and have orthogonal reactivity to
alkyl halides, practical methods that allow cross-coupling would
be extremely attractive for complex molecule synthesis. During
the past year, we have described the development of nickel-
To overcome this challenge, we chose a Negishi coupling as
our starting point. We hypothesized that organozinc reagents
might be effective organometallic partners for cross-coupling
with aziridines, as their azaphilicity would facilitate trans-
metalation. The numerous advantages pertaining to organozinc
reagents, including their high functional-group tolerance and
preparation under mild conditions, were also key factors in our
selection of this reaction manifold.11 Initial attempts to cross-
couple unactivated alkyl aziridines under a range of conditions
(Ni source, ligand, solvent) gave no desired product. Instead,
we identified a catalyst system that facilitated alkylation of
styrenyl aziridines (Table 1).12 Under the optimal conditions,
coupling of n-butylzinc bromide with 2-phenyl-N-tosylaziridine
2a in the presence of 5 mol% of a Ni catalyst afforded the cross-
coupled product 3 in 71% yield (entry 1).13 In the absence of a
metal catalyst, no product formation was observed (entry 2). In
the presence of Ni, C−C bond formation takes place with
complete regioselectivity for the internal position, presumably
3
catalyzed methods that effect Csp −C bond formation with
classic ether-containing electrophiles, including styrenyl epox-
ides3 and allylic N,O-acetals.4 As part of this program, we
became interested in developing cross-coupling reactions with
aziridines due to their significant value in the preparation of β-
substituted amines.5
3
due to the lability of the benzylic Csp −N bond and the stability
of the resulting complex. These standard conditions are
straightforward to execute:14 the relatively air-stable
NiCl2·glyme precatalyst provides an inexpensive and conven-
ient source of Ni, allowing the reaction to be set up on the
benchtop rather than in a glovebox.
A screen of privileged ligands, such as phosphines and
amines, revealed that none were effective (Table 1, entry 5).
Instead, the electron-deficient olefin, dimethyl fumarate 1, was
found to be optimal (compare entries 1 and 6−8).15 In its
Established methods for alkylation and arylation of aziridines
require the use of strong nucleophiles and often afford poor
regioselectivity.6 A transition-metal-catalyzed coupling reaction
offers a potentially mild, general, and regioselective solution to
these problems. Furthermore, such a process could deliver
complementary diastereoselectivity to aziridine ring-opening
reactions that classically proceed by inversion of configuration.
Here we describe a novel catalyst system that effects room-
Received: February 10, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja3013825 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Table 1. Evaluation of Reaction Conditions
a
ab
,
entry
conditions
yield (%)
conv (%)
1
2
3
4
5
6
7
8
9
standard conditions
71
<2
46
4
>99
7
no NiCl2·glyme
Ni(cod)2 instead of NiCl2·glyme
no dimethyl fumarate (1)
>99
26
10% PPh3, PCy3, BINAP, or bpy instead of 1
10% 4-fluorostyrene instead of 1
10% maleic anhydride instead of 1
10% dimethyl maleate instead of 1
<2
5
12−25
47
8
62
69
<2
>99
10
with 10% bipyridine and 10% 1
a
b
Determined by HPLC, 0.05 mmol scale. N-Tosyl-2-phenylethylamine (reduced product) was the major byproduct.
a
absence, only trace product was detected (entry 4). Electron-
deficient olefins have been shown to accelerate reductive
elimination by association to a metal center,16 and Knochel has
utilized electron-withdrawing styrenes as ligands in catalytic
cross-coupling reactions of alkyl electrophiles.17 We propose
that dimethyl fumarate plays a similar role, accelerating
reductive elimination from a dialkylorganonickel intermediate.
To evaluate this proposal, we performed a stoichiometric study
between azametallacyclobutane 4, prepared according to the
procedure of Hillhouse,7 and n-BuZnBr. Only in the presence
of 1 did C−C bond formation take place to afford 3 (eq 3).
The result provides preliminary support for the role of 1 in
facilitating C−C bond formation. Nevertheless, the reaction
efficiency of this stoichiometric process was quite low due to
the presence of bipyridine as a ligand, which was required for
isolation of 4 but is itself a poor ligand in the catalytic reaction
(Table 1, entries 5 and 9).
Table 2. Scope of Styrenyl Aziridines
a
b
Yields are the average of two runs, 0.50 mmol scale. One run, 0.15
c
mmol scale. 5.3:1 dr (unassigned), see SI for details.
The scope of this methodology was first examined by varying
the aziridine component. Electron-deficient and electron-rich
para- and meta-substituted styrenyl aziridines reacted with high
efficiency (Table 2, 3−10, 13, 14). As a probe for the relative
reactivity of the electrophile, a substrate bearing a p-chloro
substituent was subjected to the standard reaction conditions.
This substrate underwent coupling in 80% yield, with the aryl
chloride remaining intact (7).18 The orthogonal reactivity of
the aziridine and chloro groups provides a useful opportunity
for elaboration of the amine products by cross-coupling.
Various functional groups that are incompatible with the strong
nucleophiles required for traditional aziridine ring-opening
protocols were also tolerated, including a protic amine (10),
benzaldehyde (13), and ketone (16), as was ortho-substitution
(15). Finally, promising reactivity was observed with
heteroaryl-containing substrates (12) despite the presence of
a strongly Lewis basic site that could poison the catalyst system.
To demonstrate the practicality of the protocol, a gram-scale
reaction was performed with p-fluoroaziridine 2e to afford 8 in
77% yield.
The scope of the zinc reagents was explored next. We found
that a wide variety of functional groups were tolerated,
including alkyl chlorides (18), silyl ethers (19), acetals (20),
boronate esters (21), and nitriles (22) (Table 3). However,
unhindered Lewis basic functional groups in addition to
secondary alkyl groups proved problematic.19 Notably, the
use of an aryl nucleophile results in modest reactivity (24) and
provides an attractive complement to Friedel−Crafts arylations
of styrenyl aziridines with electron-rich arenes.20
The reaction is not limited to terminal aziridines. 1,2-
Disubstituted aziridines are also suitable substrates, although
higher catalyst loading is required. For instance, the indene-
derived aziridine 25 underwent coupling to afford 26 in 52%
yield (eq 4). Especially interesting is that the reaction delivered
26 exclusively as the cis diastereomer, a stereochemical outcome
inaccessible to conventional nucleophilic aziridine ring-opening
reactions.21 Since the enantiomeric excess of 25 was completely
conserved in the formation of product, it appears that C−C
bond formation outcompetes β-hydride elimination/hydride
B
dx.doi.org/10.1021/ja3013825 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
Table 3. Scope of Organozinc Reagents
Scheme 1. Proposed Catalytic Cycle
a
b
Yields are the average of two runs, 0.50 mmol scale. n-PentylZnI.
c
PhZnBr inTHF.
coupling reactions with alkyl halides.26 Nevertheless, it is less
clear how a SET mechanism would afford predominantly
inversion in the alkylation of (R)-2a.
insertion processes. Additionally, cross-coupling with the
aziridine derived from trans-methyl cinnamate 27 gave the α-
amino acid derivative 28 in 70% yield (eq 5). In line with the
results for indene-derived aziridine 25, C−C bond formation
with 27 proceeded primarily with retention of configuration,
delivering 28 in 7.5:1 dr.22
Both mechanisms are consistent with the results obtained
with aziridines 25 and 27. It is expected that sulfonamide
coordination to Ni directs radical recombination and
subsequent C−C bond formation.27 In the case of indene-
derived aziridine 25, the n-butyl group is delivered on the same
face of the indenyl ring as the sulfonamide via metallacycle 29.
In the case of the trans-methyl cinnamate-derived aziridine 27,
the major diastereomer is obtained from the more stable trans-
azametallacycle 30. Sulfonamide coordination may also be
important in preventing β-H elimination by limiting the
conformational flexibility of intermediate alkylnickel species.28
Although a Ni(I)/Ni(III) cycle cannot be precluded, a Ni(0)/
Ni(II) cycle is proposed since the Ni(II)-azametallacycle 4 was
a competent substrate for C−C bond formation. Finally,
dimethyl fumarate 1 is expected to accelerate reductive
elimination by association to the metal center.
In conclusion, we have developed a Ni-catalyzed ring-
opening reaction of styrenyl aziridines with organozinc
reagents. The alkyl cross-coupling reaction is accomplished by
a novel catalytic system consisting of a Ni(II) source and
dimethyl fumarate as ligand. In contrast to traditional
nucleophilic aziridine ring-opening chemistry, the mild
conditions of this protocol tolerate a wide variety of functional
groups. We propose that a sulfonamide-directed C−C bond-
forming mechanism is responsible for the high diastereose-
lectivity. Our future efforts will be directed at elucidating the
mechanism of this process and its synthetic scope.
To gain a better mechanistic understanding of the stereo-
chemical course of these reactions, we subjected enantiopure
styrenyl aziridine (R)-2a to the standard reaction conditions
(eq 6). The cross-coupled product 3 was generated in 11% ee,
with the major enantiomer corresponding to inversion of
configuration. In addition, the ee of recovered aziridine 2a
remained unchanged throughout the course of the reaction. An
SN2-type oxidative addition accompanied by reversible
homolysis of the benzylic Ni−C bond,23 or an irreversible
single-electron transfer (SET) oxidative addition, could account
for these data (Scheme 1, path a or b). Hillhouse7 and Wolfe8
have demonstrated that an SN2 mechanism is operative for
oxidative addition of Ni and Pd to aliphatic N-Ts aziridines. A
few features of our catalytic system, however, are not entirely
consistent with this mechanism and prior observations.
Namely, aliphatic aziridines are unreactive and styrenyl
aziridines undergo alkylation with regioselectivity opposite to
that expected in an SN2 process.24,25 This substrate dependence
and regioselectivity are more consistent with a SET oxidative
addition, which has been proposed for Ni-catalyzed cross-
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, details of optimization studies, and
spectroscopic data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
agdoyle@princeton.edu
Notes
The authors declare no competing financial interest.
C
dx.doi.org/10.1021/ja3013825 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
(18) When the corresponding p-bromo substrate was utilized, only
trace (<5%) desired product and debrominated aziridine were
detected. The mass balance was recovered starting material, which
suggests that Ni was trapped upon reaction with the C−Br bond.
(19) See SI for details.
(20) Representative examples: (a) Yadav, J. S.; Reddy, B. V. S.; Rao,
R. S.; Veerendhar, G.; Nagaiah, K. Tetrahedron Lett. 2001, 42, 8067.
(b) Bera, M.; Roy, S. Tetrahedron Lett. 2007, 48, 7144. (c) Bera, M.;
Roy, S. J. Org. Chem. 2010, 75, 4402 See also ref 6..
(21) A rare example of syn-selectivity: Bertolini, F.; Woodward, S.;
Crotti, S.; Pineschi, M. Tetrahedron Lett. 2009, 50, 4515.
(22) For reasons not yet clear to us, a trans-β-methylstyrene-derived
aziridine gave only 12% yield, and the aziridine derived from stilbene
as well as cis-27 were unreactive.
ACKNOWLEDGMENTS
■
We thank Scott Semproni for X-ray crystallographic structure
determination of 26 and (S)-3, and Lotus Separations for chiral
separations of 3 and 25. Financial support provided by
Princeton University is gratefully acknowledged.
REFERENCES
■
(1) Recent reviews: (a) Netherton, M. R.; Fu, G. C. Adv. Synth. Catal.
2004, 346, 1525. (b) Frisch, A. C.; Beller, M. Angew. Chem., Int. Ed.
2005, 44, 674.
(2) Allylic ethers: (a) Nomura, N.; Rajanbabu, T. V. Tetrahedron Lett.
1997, 38, 1713. (b) Moser, R.; Nishikata, T.; Lipshutz, B. H. Org. Lett.
2010, 12, 28 and references therein. Benzyl ethers: (c) Guan, B.-T.;
Xiang, S.-K.; Wang, B.-Q.; Sun, Z.-P.; Wang, Y.; Zhao, K.-Q.; Shi, Z.-J.
J. Am. Chem. Soc. 2008, 130, 3268. Allylic amines: (d) Trost, B. M.;
Spagnol, M. D. J. Chem. Soc., Perkin Trans. 1 1995, 2083.
(3) Nielsen, D. K.; Doyle, A. G. Angew. Chem., Int. Ed. 2011, 50,
6056.
(4) Graham, T. J. A.; Shields, J. D.; Doyle, A. G. Chem. Sci. 2011, 2,
980.
(5) Aziridines and Epoxides in Organic Synthesis; Yudin, A., Ed.; Wiley-
VCH: Weinheim, 2006.
(6) Reviews: (a) Hu, X. E. Tetrahedron 2004, 60, 2701. (b) Lu, P.
Tetrahedron 2010, 66, 2549.
(23) Study on Ni−benzyl bond energies: Schofield, M. H.; Halpern,
J. Inorg. Chim. Acta 2003, 345, 353.
(24) The aziridine derived from α-methylstyrene gave N-tosyl-2-
phenylpropylamine (reduced product) in 47% yield, presumably
because reductive elimination to generate a quaternary carbon is
unfavorable. An SN2 oxidative addition would be unlikely with this
substrate.
(25) A reaction that exhibits similar regioselectivity in ring opening of
epoxides with Grignard reagents: Taber, D. F.; He, Y. J. Org. Chem.
2005, 70, 7711.
(26) Selected examples: (a) Stille, J. K.; Cowell, A. B. J. Organomet.
Chem. 1977, 124, 253. (b) Arp, F. O.; Fu, G. C. J. Am. Chem. Soc.
(7) Lin, B. L.; Clough, C. R.; Hillhouse, G. L. J. Am. Chem. Soc. 2002,
124, 2890.
(8) Ney, J. E.; Wolfe, J. P. J. Am. Chem. Soc. 2006, 128, 15415.
(9) Wolfe, J. P.; Ney, J. E. Org. Lett. 2003, 5, 4607.
́
2005, 127, 10482. (c) Gonzalez-Bobes, F.; Fu, G. C. J. Am. Chem. Soc.
2006, 128, 5360. (d) Jones, G. D.; Martin, J. L.; McFarland, C.; Allen,
O. R.; Hall, R. E.; Haley, A. D.; Brandon, R. J.; Konovalova, T.;
Desrochers, P. J.; Pulay, P.; Vicic, D. A. J. Am. Chem. Soc. 2006, 128,
(10) (a) Khumtaveeporn, K.; Alper, H. Acc. Chem. Res. 1995, 28, 414
and references therein. (b) Piotti, M. E.; Alper, H. J. Am. Chem. Soc.
1996, 118, 111. (c) Davoli, P.; Moretti, I.; Prati, F.; Alper, H. J. Org.
Chem. 1999, 64, 518. (d) Mahadevan, V.; Getzler, Y. D. Y. L.; Coates,
G. W. Angew. Chem., Int. Ed. 2002, 41, 2781. (e) Lu, S.-M.; Alper, H. J.
Org. Chem. 2004, 69, 3558.
(11) (a) Organozinc Reagents, A Practical Approach; Knochel, P.,
Jones, P., Eds.; Oxford: New York, 1999. (b) Erdik, E. Organozinc
Reagents in Organic Synthesis; CRC Press: Boston, 1996. (c) Knochel,
P.; Singer, R. D. Chem. Rev. 1993, 93, 2117. (d) Knochel, P.; Almena
Perea, J. J.; Jones, P. Tetrahedron 1998, 54, 8275. (e) Boudier, A.;
Bromm, L. O.; Lotz, M.; Knochel, P. Angew. Chem., Int. Ed. 2000, 39,
4414.
́
13175. (e) Phapale, V. B.; Bunuel, E.; García-Iglesias, M.; Cardenas, D.
̃
J. Angew. Chem., Int. Ed. 2007, 46, 8790. Recent review on mechanistic
considerations of Ni-catalyzed cross-coupling reactions with alkyl
halides: (f) Hu, X. Chem. Sci. 2011, 2, 1867.
(27) Recent examples of transition metal-catalyzed amine-directed
C−C bond formation: (a) Worthy, A. D.; Joe, C. L.; Lightburn, T. E.;
Tan, K. L. J. Am. Chem. Soc. 2010, 132, 14757. (b) Zhang, X.; Cao, B.;
Yu, S.; Zhang, X. Angew. Chem., Int. Ed. 2010, 49, 4047. (c) Lu, Z.;
Wilsily, A.; Fu, G. C. J. Am. Chem. Soc. 2011, 133, 8154. (d) DeLuca,
R. J.; Sigman, M. S. J. Am. Chem. Soc. 2011, 133, 11454.
(28) Zhang, L.; Zetterberg, K. Organometallics 1991, 10, 3806.
(12) Review on alkyl nucleophiles in cross-coupling: Jana, R.; Pathak,
T. P.; Sigman, M. S. Chem. Rev. 2011, 111, 1417.
(13) Other N-protecting groups showed inferior reactivity: N-Boc,
25% yield; N-Ns, 10% yield.
(14) Experimental procedure: In the air, a threaded tube was charged
with NiCl2·glyme (0.05 equiv), dimethyl fumarate (0.10 equiv), and
aziridine (1.0 equiv), and the tube was sealed and evacuated/refilled
with argon three times. DMA, dioxane, and then the zinc reagent (3.0
equiv as a 1.6 M solution in DMA) were added. The mixture was
stirred at room temperature under argon. See SI for more details.
(15) Review of olefin additives in cross-coupling reactions: Johnson,
J. B.; Rovis, T. Angew. Chem., Int. Ed. 2008, 47, 840.
(16) (a) Yamamoto, T.; Yamamoto, A.; Ikeda, S. J. Am. Chem. Soc.
1971, 93, 3350. (b) Yamamoto, T.; Yamamoto, A.; Ikeda, S. J. Am.
Chem. Soc. 1971, 93, 3360. (c) Goliaszewski, A.; Schwartz, J. J. Am.
Chem. Soc. 1984, 106, 5028. (d) Kurosawa, H.; Emoto, M.; Urabe, A.;
Miki, K.; Kasai, N. J. Am. Chem. Soc. 1985, 107, 8253. (e) Kurosawa,
H.; Emoto, M.; Ohnishi, H.; Miki, K.; Kasai, N.; Tatsumi, K.;
Nakamura, A. J. Am. Chem. Soc. 1987, 109, 6333. (f) Per
́
ez-Rodríguez,
M.; Braga, A. A. C.; García-Melchor, M.; Perez-Temprano, M. H.;
́
́
Casares, J. A.; Ujaque, G.; de Lera, A. R.; Alvarez, R.; Maseras, F.;
Espinet, P. J. Am. Chem. Soc. 2009, 131, 3650.
(17) (a) Giovannini, R.; Studemann, T.; Gaelle, D.; Knochel, P.
̈
Angew. Chem., Int. Ed. 1998, 37, 2387. (b) Giovannini, R.; Knochel, P.
J. Am. Chem. Soc. 1998, 120, 11186. (c) Giovannini, R.; Studemann,
̈
T.; Devasagayaraj, A.; Dussin, G.; Knochel, P. J. Org. Chem. 1999, 64,
3544. (d) Jensen, A. E.; Knochel, P. J. Org. Chem. 2002, 67, 79.
D
dx.doi.org/10.1021/ja3013825 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX