A general strategy for the synthesis of enantiomerically pure azetidines and aziridines through nickel-catalyzed cross-coupling

Article abstract of DOI:10.1002/chem.201500886

Abstract In this communication, we report a straightforward synthesis of enantiomerically pure 2-alkyl azetidines. The protocol is based on a highly regioselective nickel-catalyzed cross-coupling of aliphatic organozinc reagents with an aziridine that fea

Full text of DOI:10.1002/chem.201500886

DOI: 10.1002/chem.201500886
Communication
&
Asymmetric Synthesis
A General Strategy for the Synthesis of Enantiomerically Pure
Azetidines and Aziridines through Nickel-Catalyzed Cross-
Coupling
Kim L. Jensen, Dennis U. Nielsen, and Timothy F. Jamison*[a]
Abstract: In this communication, we report a straightfor-
ward synthesis of enantiomerically pure 2-alkyl azetidines.
The protocol is based on a highly regioselective nickel-cat-
alyzed cross-coupling of aliphatic organozinc reagents
with an aziridine that features a tethered thiophenyl
group. Activation by methylation transforms the sulfide
into an excellent leaving group and triggers the formation
of the 2-substituted azetidine core structure by cyclization.
In addition, we have expanded this concept to the synthe-
sis of enantiomerically pure, terminal alkyl aziridines. Cou-
pling of a TMS-protected aziridine alcohol, followed by
acidic work-up to remove the silyl group, provides 1,2-
amino alcohol products that are readily cyclized to aziri-
dines. Both of these sequences display excellent functional
group tolerance and deliver the desired azetidine and azir-
idine products in good to excellent yields.
Scheme 1. Synthetic strategies for 2- and 3-substituted azetidines. API=Ac-
tive pharmaceutical ingredient.
Azetidines constitute an interesting class of molecules among
the family of saturated nitrogen heterocycles. Besides being
found in a number of naturally occurring molecules, the azeti-
dine core has become an important target structure in the me-
functionalize azetidines at the 2-position.[5] Enantioselectivity of
dicinal and agrochemical industries due to the remarkable bio-
logical and pharmacological properties displayed by molecules
possessing this moiety.[1] Historically, azetidines have received
considerably less attention than their five- and six-membered
nitrogen heterocycle counterparts, largely because of profound
challenges associated with their synthesis.[2] Nevertheless, a va-
riety of strategies for the formation of azetidines have been
evaluated in recent decades (Scheme 1).
up to 84% ee was documented when a super-stoichiometric
amount of a chiral ligand was employed.[5a] Examples of ring
expansion of aziridines with dimethylsulfoxonium methylide
have also been demonstrated.[1] Recently, a three-step protocol
based on ring contraction of a-bromo pyrrolidinones to give
racemic a-carbonylated azetidines was reported.[6] More
common synthetic strategies rely on 4-exo cyclizations of
open-chain structures.[1d] Although a number of successful
asymmetric approaches have been reported,[7] many are of
somewhat limited generality and result in moderate yields due
to the kinetically unfavorable cyclization. In addition, many of
these syntheses are greater than seven steps in length and re-
quire several functional group manipulations.[8] Finally, the 2-
substituent is often introduced early in the synthetic sequence,
thus making structure-activity relationship (SAR) studies trou-
blesome. Consequently, we envisioned that a protocol for the
synthesis of 2-substituted azetidines that allows for the incor-
poration of the substituent at a late stage in the synthesis
would be of high value. Since stereochemistry plays such
a vital role in medicinal chemistry, we undertook the develop-
ment of an asymmetric synthesis.
Over the past few years, a number of protocols have been
reported to synthesize 3-substituted azetidines through cross-
coupling reactions from the corresponding 3-halo-azetidines.[3]
However, this strategy is not applicable for the preparation of
2-substituted azetidines and, consequently, this isomer is syn-
thesized using different methods.[4] Hodgson, for example, has
developed a lithiation-electrophilic substitution sequence to
[a] Dr. K. L. Jensen, D. U. Nielsen, Prof. Dr. T. F. Jamison
Department of Chemistry
Massachusetts Institute of Technology
Cambridge, MA 02139 (USA)
E-mail: tfj@mit.edu
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201500886.
Chem. Eur. J. 2015, 21, 1 – 6
1
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
We recently developed a highly regioselective nickel-cata-
lyzed cross-coupling of aliphatic aziridines and aliphatic orga-
nozinc reagents to form sulfonamides in high yields.[9] The pro-
tocol uses an air- and moisture stable nickel(II)-phenanthroline
precatalyst[10] and works well for both commercially available
and in situ prepared organozinc reagents.[11] We hypothesized
that an aziridine encompassing a tethered leaving group could
easily be transformed into 2-substituted azetidines through
a straightforward two-step protocol (Scheme 1). Furthermore,
we knew from our previous study that the absolute stereo-
chemistry of the aziridines is retained in the coupling reaction,
thus making it possible to access the azetidines in enantiomer-
ically pure form. At the outset of our studies, we targeted
a substructure that could function as an excellent leaving
group for the cyclization and at the same time display excel-
lent stability during the coupling reaction. To this end, we se-
lected sulfides for the following reasons: 1) Sulfides are stable
under a variety of reaction conditions, 2) they function as ex-
cellent leaving groups upon activation with electrophiles, and
3) the corresponding aziridine starting material could be ac-
cessed readily from the a-amino acid methionine. Unfortunate-
ly, we found that the aziridine derived from methionine was
unstable, undergoing rapid polymerization upon standing at
ambient temperature. At this stage, we reasoned that a less
nucleophilic sulfide in the form of an aryl sulfide would be
more stable. Indeed, aziridine 1, obtained in five steps from
commercially available homoserine lactone, was stable. More-
over, despite the potential of catalyst inhibition by coordina-
tion of sulfur, the thiophenyl group was well-tolerated in the
nickel-catalyzed cross-coupling. Accordingly, when 1 was treat-
ed with pentylzinc bromide using 1,10-phenanthroline/NiCl2
(10 mol%, 1.25:1 ratio) precatalyst in 1,2-dimethoxyethane
(DME) at 358C, full conversion was observed. Desired sulfona-
mide 2 was obtained in 78% isolated yield and with complete
enantiomeric integrity (99% ee) [Eq. (1)].[12] Reduction of the
catalyst loading to 5 mol% resulted in prolonged reaction
times (>36 h), and thus for practical reasons 10 mol% of the
Ni precatalyst was employed. As shown in our previous study,
addition of LiCl is critical for reactivity, probably to accelerate
transmetalation, as lithium chloride and organozinc reagents
are known to form lithium organozincates, RZnX2Li, which gen-
erally display improved nucleophilicity.[13]
Scheme 2. Potential challenges associated with the methylation/cyclization
sequence.
ble transposition of the methyl group from the sulfur atom to
the sulfonamide nitrogen atom.[16]
Consequently, in order for this strategy to be successful, we
required conditions that allowed for selective methylation of
the sulfide over the sulfonamide nitrogen atom. Gratifyingly,
when coupling product 2a was treated with 1.2 equivalents of
Meerwein’s salt (Me3OBF4) in CH2Cl2 at ambient temperature,
the sulfide was selectively methylated to form 3a (R=pentyl
and X=BF4) [Eq. (2)].
In order to prevent undesired methylation of the nitrogen
atom by the remaining trimethyloxonium species during the
cyclization step, we decided to use a protic solvent to quench
any remaining Meerwein’s salt. Accordingly, dilution of the re-
action mixture with ethanol followed by addition of K2CO3
(5.0 equiv) and heating to 458C induced cyclization to form
the desired azetidine product 4a (<90 min), with PhSMe as
the only observed byproduct.[17] Analysis by NMR spectroscopy
indicated that the sulfonium salt had formed as a 1:1 mixture
of diastereoisomers in the methylation step; nevertheless, both
diastereoisomers were smoothly converted to enantiomerically
pure (99% ee) azetidine 4a in nearly quantitative yield.
After having identified optimal conditions for both the cou-
pling reaction [Eq. (1)] and the subsequent one-pot methyla-
tion/cyclization sequence [Eq. (2)], we evaluated this two-step
synthesis of azetidines over a range of organozinc reagents
(Scheme 3).
Performing the reaction with pentylzinc bromide provided
the azetidine product 4a in 82% isolated yield. The yield of
this telescoped sequence is slightly better than the stepwise
approach, which afforded 4a in approximately 78% yield. The
reaction also worked well for a branched and a fluoride con-
taining organozinc reagent as demonstrated by the formation
of product 4b and 4c. Application of homobenzyl nucleo-
philes furnished 4d–f in similar high yields (72–78%). In order
to expand the utility of this method we examined nucleophiles
containing useful functional groups for subsequent structural
diversification. Gratifyingly, the reaction worked well in the
presence of an alkene and ester, providing products 4g and
Next, we evaluated the azetidine formation by electrophilic
activation of the sulfide. Sulfonium salts are known to induce
kinetically unfavorable cyclization reactions, and thus we con-
structed 3 by methylation (Scheme 2).[14] It should be noted
that, although 4-exo-tet cyclizations are kinetically challeng-
ing,[15] this mode of cyclization should still be favored over the
alternative 6-endo-tet pathway that would lead to an irreversi-
&
&
Chem. Eur. J. 2015, 21, 1 – 6
www.chemeurj.org
2
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Communication
rely on routes from readily accessible 1,2-amino alcohols.[23] Ja-
cobsen and co-workers reported a synthesis of enantioen-
riched terminal aziridines from the corresponding epoxides
using a hydrolytic kinetic resolution (HKR),[24] followed by nu-
cleophilic opening of the remaining enantioenriched epoxide
with a sulfonyl-protected amine nucleophile.[25] As an alterna-
tive that would complement these protocols and with the
above azetidine method in hand, we designed a general aziri-
dine precursor that would serve as an entry to a wide range of
enantiomerically pure aliphatic aziridines. At the outset we in-
vestigated a number of activated aziridine alcohols derived
from the a-amino acid serine (Scheme 4). Interestingly and
Scheme 3. Evaluation of organozinc reagents for the synthesis of 2-substitut-
ed azetidines. Yields shown are for entire sequence (overall isolated yield
from 1). DMA=N,N-dimethylacetamide.
4h in 63% and 69% yield, respectively. In addition, a cyano
group was tolerated in the sequence furnishing 4i in a similar
yield (67%) and, notably, providing an entry to both ketones
through organometallic additions and amines through reduc-
tion. Though a TBS-protected alcohol was tolerated in the cou-
pling, unfortunately the following azetidine formation proved
problematic, resulting in a low yield (not shown). We were
able to circumvent this limitation by employing a masked alco-
hol in the form of a pinacol boronate (B(pin)) via a binucleophil-
ic coupling reagent that afforded product 4j in 68% yield.[18]
Importantly, no products corresponding to transmetalation of
the boronate were observed. It should be noted that in order
to obtain reactivity similar to the other reagents, it was neces-
sary to employ 1.5 equivalents of LiCl to the organozinc re-
agent. This requirement is presumably due to a reversible in-
teraction of the boronate with the chloride ion that is required
to enhance the nucleophilicity of the organozinc reagent, as
noted above.[13]
Scheme 4. Evaluation of precursors for aziridine synthesis. Ms=mesyl sulfo-
nyl, Ts=tosyl, phen=1,10-phenanthroline.
somewhat surprisingly, we found that the tosylated and mesy-
lated alcohols did not provide the desired cross-coupling prod-
ucts, instead affording N-allyl-tosylamide as the major product
(Scheme 4a), possibly by way of oxidative insertion of Ni into
the CÀO bond, followed by ring-opening of the aziridine and
concurrent formation of the olefin. Consequently, in order to
temper the reactivity of the CÀO bond and favor CÀN bond in-
sertion, we protected the alcohol as a TMS silyl ether (5)
(Scheme 4b). This modification turned out to be successful, de-
livering the coupling product 6a in 68% yield, even at 5 mol%
catalyst loading. The TMS protecting group displayed excellent
stability to chromatography on silica gel. However, when sub-
jected to aqueous hydrochloric acid conditions during work-
up, the silyl group was efficiently removed to yield the corre-
sponding unprotected 1,2-amino alcohol. Subjecting this inter-
mediate to cyclization conditions using TsCl and KOH in THF
furnished the desired aliphatic terminal aziridine product 7a.
When performing the two-step protocol without purification
of the amino alcohol intermediate, the aziridine 7a was isolat-
ed in 57% overall yield from 5. Furthermore, as anticipated,
the reaction sequence proceeded with complete chirality trans-
fer, giving the aziridines in high enantiomeric purity.
After having successfully developed the synthesis of enantio-
merically pure 2-substituted azetidines, we decided to expand
the reaction concept to the synthesis of terminal mono-substi-
tuted aziridines, which are of great importance in modern
chemical synthesis.[19] Although numerous syntheses of aziri-
dines have been reported,[20] only a few of the protocols have
proven amenable to the synthesis of enantiomerically en-
riched, terminal aliphatic aziridines.[21] The majority are based
on transition-metal-catalyzed aziridination of alkenes through
nitrene insertion reactions. Moderate to good enantioselectivi-
ties have been achieved, but the reactions generally proceed
in low to moderate yields.[22] Notably, Katsuki and co-workers
used a Ru(CO)(salen) complex to furnish the aziridine products
in good yields and enantioselectivities.[22c] Many approaches
To demonstrate the utility of this sequence, a number of or-
ganozinc reagents were evaluated (Scheme 5). In general, the
reaction furnished the desired products in moderate to good
Chem. Eur. J. 2015, 21, 1 – 6
www.chemeurj.org
3
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
wards, M. Wan, J. Kincaid, M. G. Kelly, Org. Lett. 2008, 10, 3259; b) G. A.
Molander, K. M. Traister, B. T. O’Neill, J. Org. Chem. 2014, 79, 5771. For
examples using iron and cobolt catalysis, see: c) B. Barrꢁ, L. Gonnard, R.
Campagne, S. Reymond, J. Marin, P. Ciapetti, M. Brellier, A. Guꢁrinot, J.
Cossy, Org. Lett. 2014, 16, 6160; d) D. Parmar, L. Henkel, J. Dib, M. Ruep-
ing, Chem. Commun. 2015, 51, 2111. For a palladium-catalyzed example
using a 3-organozinc-azetidine, see: e) S. Billotte, Synlett 1998, 379.
[4] For an example of anodic acetoxylation of N-tosylazetidine, see: T.
Shono, Y. Matsumura, K. Uchida, F. Nakatani, Bull. Chem. Soc. Jpn. 1988,
61, 3029.
[5] a) D. M. Hodgson, J. Kloesges, Angew. Chem. Int. Ed. 2010, 49, 2900;
Angew. Chem. 2010, 122, 2962; b) D. M. Hodgson, C. I. Pearson, A. L.
Thompson, J. Org. Chem. 2013, 78, 1098; c) D. M. Hodgson, C. L. Mor-
timer, J. M. McKenna, Org. Lett. 2015, 17, 330.
[6] N. Kern, A.-S. Felten, J.-M. Weibel, P. Pale, A. Blanc, Org. Lett. 2014, 16,
6104.
Scheme 5. Representative examples of synthesized aliphatic aziridines. Yields
shown are for entire sequence (overall isolated yield from 5).
[7] For decarboxylative cyclization of 1,3-amino alcohols using 1,1’-carbon-
yldiimidazole under heating and vacuum to form 2,3-disubstituted aze-
tidines, see: a) A. Mꢂnch, B. Wendt, M. Christmann, Synlett 2004, 2004,
2751; b) R. M. de Figueiredo, R. Frçhlich, M. Christmann, J. Org. Chem.
2006, 71, 4147.
[8] For representative examples, see: a) D. Enders, J. Gries, Z.-S. Kim, Eur. J.
Org. Chem. 2004, 4471; b) M. Tiecco, L. Testaferri, A. Temperini, R. Terliz-
zi, L. Bagnoli, F. Marini, C. Santi, Org. Biomol. Chem. 2007, 5, 3510; c) M.
Medjahdi, J. C. Gonzꢃlez-Gꢄmez, F. Foubelo, M. Yus, J. Org. Chem. 2009,
74, 7859.
[9] a) K. L. Jensen, E. A. Standley, T. F. Jamison, J. Am. Chem. Soc. 2014, 136,
11145; For related studies, see: b) D. K. Nielsen, C.-Y. Huang, A. G. Doyle,
J. Am. Chem. Soc. 2013, 135, 13605; c) C.-Y. Huang, A. G. Doyle, J. Am.
Chem. Soc. 2012, 134, 9541; For an excellent review on transition-metal-
catalyzed reactions with three-membered ring heterocycles, see: d) C. Y.
Huang, A. G. Doyle, Chem. Rev. 2014, 114, 8153.
[10] For a review on the development of nickel(II) precatalysts, see: B. M.
Rosen, K. W. Quasdorf, D. A. Wilson, N. Zhang, A.-M. Resmerita, N. K.
Garg, V. Percec, Chem. Rev. 2011, 111, 1346.
yields (44–58%). Both linear and branched aliphatic reagents
worked smoothly (7a,b). More importantly, organozinc re-
agents containing functional groups such as a fluorine atom
(7c), an alkene (7d), an aryl group (7e), and an ester (7 f) were
also tolerated. The alkene containing product 7d complements
nitrene-based aziridination approaches, as selective mono-aziri-
dination is generally challenging.
In summary, we have developed general and straightforward
approaches towards the syntheses of enantiomerically pure ali-
phatic 2-substituted azetidines and terminal aliphatic aziri-
dines. Both strategies employ a highly regioselective nickel-cat-
alyzed ring-opening reaction of enantiomerically pure terminal
aziridines with aliphatic organozinc reagents. For the azetidines
a methylation/cyclization sequence of a tethered thiophenyl
group was used and, in the case of aziridines, a tosylation/cyc-
lization sequence of the 1,2-amino alcohol intermediate was
applied. Both sequences tolerate a broad range of organozinc
reagents, giving the products in good overall yield and in
enantiomerically pure form. These methods provide direct
access to a wide variety of enantiomerically pure azetidines
and aziridines, thus enabling further investigations of these im-
portant nitrogen heterocycles.
[11] For a procedure for the preparation of aliphatic organozinc reagents,
see: a) S. Huo, Org. Lett. 2003, 5, 423; For a review on alkyl-organome-
tallic reagents in cross-coupling reactions, see: b) R. Jana, T. P. Pathak,
M. S. Sigman, Chem. Rev. 2011, 111, 1417.
[12] In our previous study (Ref. [9a]) 1,2-dichloroethane (DCE) was applied
as solvent. However, it should be noted that the DCE is able to act as
an oxidant by reaction with the nickel(0) catalyst when full conversion
of the aziridine was obtained. This oxidation resulted in homo-coupling
of the remaining organozinc reagent. The formation of this byproduct
could potentially complicate the purification of the product. For reac-
tions with the aziridines applied in this study we found that 1,2-dime-
thoxyethane (DME) could be used in place of DCE, thus lowering the
formation of the homo-coupled byproduct to 10 mol% (from precata-
lyst activation). For a reference on this type of this type of oxidative re-
action, see: S. Takahashi, Y. Suzuki, N. Hagihara, Chem. Lett. 1974, 3,
1363.
Acknowledgements
[13] For a representative example, see: J. E. Fleckenstein, K. Koszinowski, Or-
ganometallics 2011, 30, 5018.
[14] a) O. Miyata, Y. Fujiwara, I. Ninomiya, T. Naito, J. Chem. Soc. Perkin Trans.
1 1993, 2861; b) S. P. Fritz, J. F. Moya, M. G. Unthank, E. M. McGarrigle,
V. K. Aggarwal, Synthesis 2012, 44, 1584.
K.L.J. and D.U.N. would like to thank the Lundbeck Foundation
for a postdoctoral fellowship and the Villum Foundation, re-
spectively.
[15] J. E. Baldwin, J. Chem. Soc., Chem. Commun. 1976, 734.
[16] Although intermolecular, irreversible rearrangement of the methyl
group from the sulfhur atom to the sulfonamide nitrogen atom could
not be ignored, studies have shown that this transformation is disfa-
vored in polar protic solvents, see: H. Castejon, K. B. Wiberg, S. Sklenak,
W. Hinz, J. Am. Chem. Soc. 2001, 123, 6092.
[17] It should be noted that the cyclization did not proceed in anhydrous
ethanol, suggesting that water plays a critical role in this step.
[18] In order to prevent transesterification and decomposition of the boro-
nate during the cyclization step the reaction was performed using ace-
tone in place of ethanol.
Keywords: asymmetric synthesis · azetidines · aziridines ·
nickel-catalysis · organozinc reagents
[1] a) N. H. Cromwell, B. Phillips, Chem. Rev. 1979, 79, 331; b) Y. Dejaegher,
N. M. Kuz’menok, A. M. Zvonok, N. De Kimpe, Chem. Rev. 2002, 102, 29;
c) B. Alcaide, P. Almendros, C. Aragoncillo, Chem. Rev. 2007, 107, 4437;
d) A. Brandi, S. Cicchi, F. M. Cordero, Chem. Rev. 2008, 108, 3988.
[2] a) J. Royer Asymmetric Synthesis of Nitrogen Heterocycles, Wiley-VCH,
Weinheim, 2009; b) G. W. Bemis, M. A. Murcko, J. Med. Chem. 1996, 39,
2887; c) A. H. Lipkus, Q. Yuan, K. A. Lucas, S. A. Funk, W. F. Bartelt, R. J.
Schenck, A. J. Trippe, J. Org. Chem. 2008, 73, 4443.
[19] a) A. K. Yudin, Aziridines and Epoxides in Organic Synthesis, Wiley-VCH,
Weinheim, 2006; b) D. Tanner, Angew. Chem. Int. Ed. Engl. 1994, 33, 599;
Angew. Chem. 1994, 106, 625; c) X. E. Hu, Tetrahedron 2004, 60, 2701;
[3] For examples using nickel catalysis, see: a) M. A. J. Duncton, M. A. Es-
tiarte, D. Tan, C. Kaub, D. J. R. O’Mahony, R. J. Johnson, M. Cox, W. T. Ed-
&
&
Chem. Eur. J. 2015, 21, 1 – 6
www.chemeurj.org
4
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Communication
d) P. Lu, Tetrahedron 2010, 66, 2549; e) J. B. Sweeney, Chem. Soc. Rev.
2002, 31, 247.
[20] a) E. N. Jacobsen in Comprehensive Asymmetric Catalysis II (Eds.: E. N. Ja-
cobsen, A. Pfaltz, H. Yamamoto), Springer, Berlin, 1999; b) L. Degennaro,
P. Trinchera, R. Luisi, Chem. Rev. 2014, 114, 7881; c) H. Pellissier, Adv.
Synth. Catal. 2014, 356, 1899.
[21] For a copper-catalyzed, stereospecific synthesis of enantioenriched azir-
idines by a substitution reaction of an N-Trityl aziridinylmethyl tosylate,
see: C. E. Jamookeeah, C. D. Beadle, R. F. W. Jackson, J. P. A. Harrity, J.
Org. Chem. 2008, 73, 1128.
Uchida, T. Katsuki, Chem. Commun. 2012, 48, 7188. For a general
method towards racemic terminal aziridines, see: d) Q. Xu, D. H. Appel-
la, Org. Lett. 2008, 10, 1497.
[23] For a review on the synthesis of 1,2-amino alcohols, see: S. C. Bergmei-
er, Tetrahedron 2000, 56, 2561.
[24] M. Tokunaga, J. F. Larrow, F. Kakiuchi, E. N. Jacobsen, Science 1997, 277,
936.
[25] S. K. Kim, E. N. Jacobsen, Angew. Chem. Int. Ed. 2004, 43, 3952; Angew.
Chem. 2004, 116, 4042.
[22] For reports that include examples of enantioselective aziridinations of
terminal olefins, see: a) H. Kawabata, K. Omura, T. Uchida, T. Katsuki,
Chem. Asian J. 2007, 2, 248; b) V. Subbarayan, J. V. Ruppel, S. Zhu, J. A.
Perman, X. P. Zhang, Chem. Commun. 2009, 4266–4268; c) C. Kim, T.
Received: March 5, 2015
Published online on && &&, 0000
Chem. Eur. J. 2015, 21, 1 – 6
www.chemeurj.org
5
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
COMMUNICATION
&
Asymmetric Synthesis
K. L. Jensen, D. U. Nielsen, T. F. Jamison*
&& – &&
A General Strategy for the Synthesis
of Enantiomerically Pure Azetidines
and Aziridines through Nickel-
Catalyzed Cross-Coupling
One ring to rule them both! General
and straightforward procedures for the
efficient synthesis of enantiomerically
pure aliphatic 2-substituted azetidines
and terminal aziridines were developed.
The protocols are based on a highly re-
gioselective nickel-catalyzed cross-cou-
pling reaction followed by cyclization.
The products are obtained in good
yields for a broad selection of organo-
zinc reagents.
&
&
Chem. Eur. J. 2015, 21, 1 – 6
www.chemeurj.org
6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!