Direct stereospecific synthesis of unprotected N-H and N-Me aziridines from olefins

Article abstract of DOI:10.1126/science.1245727

Despite the prevalence of the N-H aziridine motif in bioactive natural products and the clear advantages of this unprotected parent structure over N-protected derivatives as a synthetic building block, no practical methods have emerged for direct synthesis of this compound class from unfunctionalized olefins. Here, we present a mild, versatile method for the direct stereospecific conversion of structurally diverse mono-, di-, tri-, and tetrasubstituted olefins to N-H aziridines using O-(2,4-dinitrophenyl)hydroxylamine (DPH) via homogeneous rhodium catalysis with no external oxidants. This method is operationally simple (i.e., one-pot), scalable, and fast at ambient temperature, furnishing N-H aziridines in good-to-excellent yields. Likewise, N-alkyl aziridines are prepared from N-alkylated DPH derivatives. Quantum-mechanical calculations suggest a plausible Rh-nitrene pathway.

Full text of DOI:10.1126/science.1245727

Direct Stereospecific Synthesis of Unprotected N-H and N-Me
Aziridines from Olefins
Jawahar L. Jat et al.
Science 343, 61 (2014);
DOI: 10.1126/science.1245727
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REPORTS
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could be distinguished (figs. S6 to S9). We also could be combined with techniques for detecting
tested the repeatability of our method by collect- multiple depths per pixel (24). The system we
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the mannequin. We found our first-photon im- background-light suppression (25), range gating
ager to consistently demonstrate qualitative and (26), and advances in single-photon detector tech-
quantitative improvement over pointwise process- nology (27, 28).
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Acknowledgments: This work was supported by the Defense
Advanced Research Projects Agency InPho program through
U.S. Army Research Office award W911NF-10-1-0404, the
U.S. NSF under grant number 1161413, a Qualcomm
Innovation Fellowship, a Samsung Scholarship, and a Microsoft
Ph.D. Fellowship. The authors thank H. S. Yang for assistance
with figure preparation and the Research Laboratory of
Electronics for hosting external database S1 (www.rle.mit.edu/
first-photon-imaging), which contains the experiment’s data
and computer codes for Figs. 2 to 4, movie S2, and the parts of
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3 October 2013; accepted 20 November 2013
Published online 28 November 2013;
10.1126/science.1246775
predominantly N-H and to a lesser extent N-alkyl,
also appears in biologically active natural products
(e.g., azinomycins and mitomycins) (7–9). As a
result, the synthesis and chemistry of aziridines
have been the subject of intense research during
the past 25 years, resulting in multiple aziridina-
tion methods (10–23). Most of these methods rely
either on the transfer of substituted nitrenes, which
are generated by using strong external oxidants, to
the C=C bond of olefins or the transfer of sub-
stituted carbenes to the C=N bond of imines. Nor-
mally, the result is an aziridine bearing a strongly
electron-withdrawing N-protecting group (e.g., Ts:
para-toluenesulfonyl; Ns: para-nitrophenylsulfonyl);
removal of these N-sulfonyl protecting groups is
problematic as it often results in the undesired
Direct Stereospecific Synthesis of
Unprotected N-H and N-Me Aziridines
from Olefins
Jawahar L. Jat,1 Mahesh P. Paudyal,1 Hongyin Gao,1 Qing-Long Xu,1 Muhammed Yousufuddin,2
Deepa Devarajan,3 Daniel H. Ess,3*† László Kürti,1*† John R. Falck1*†
Despite the prevalence of the N-H aziridine motif in bioactive natural products and the clear
advantages of this unprotected parent structure over N-protected derivatives as a synthetic building
block, no practical methods have emerged for direct synthesis of this compound class from
unfunctionalized olefins. Here, we present a mild, versatile method for the direct stereospecific
conversion of structurally diverse mono-, di-, tri-, and tetrasubstituted olefins to N-H aziridines
using O-(2,4-dinitrophenyl)hydroxylamine (DPH) via homogeneous rhodium catalysis with no
external oxidants. This method is operationally simple (i.e., one-pot), scalable, and fast at
ambient temperature, furnishing N-H aziridines in good-to-excellent yields. Likewise, N-alkyl
aziridines are prepared from N-alkylated DPH derivatives. Quantum-mechanical calculations
suggest a plausible Rh-nitrene pathway.
1Division of Chemistry, Department of Biochemistry, University
of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
2Center for Nanostructured Materials, University of Texas at
Arlington, Arlington, TX 76019, USA. 3Department of Chem-
istry and Biochemistry, Brigham Young University, Provo, UT
84602, USA.
ziridines, the triangular, comparably high- molecules because of their versatility in myriad
ly strained nitrogen analogs of epoxides, regio- and stereoselective transformations (ring
*These authors contributed equally to this work.
†Corresponding author. E-mail: laszlo.kurti@utsouthwestern.
edu (L.K.); j.falck@utsouthwestern.edu (J.R.F.); dhe@chem.
A
are important synthetic intermediates (i.e., openings and expansions, as well as rearrange-
building blocks) en route to structurally complex ments) (1–6). The aziridine structural motif, byu.edu (D.H.E.)
www.sciencemag.org SCIENCE VOL 343 3 JANUARY 2014
61

REPORTS
opening of the aziridine ring. In addition, the high phatic olefin substrates (entries 1 to 3, Fig. 2) 2,3- disubstituted furans 10kk and 10mm in 84%
reactivity of N-protected nitrenes might give rise either did not react or reacted sluggishly (i.e., days) and 61% yields, respectively. By contrast, when
to nonproductive allylic C-H amination products, when 1 mol % of catalyst 2 was used; however, olefin 9k was exposed to 5 mol % loading of
as well as the loss of stereospecificity. Clearly, the increasing the catalyst loading to 5 mol % led to catalyst 2 and 1.2 equivalents of 1a at 25°C, the
direct synthesis of N-H (i.e., N-unprotected) and rapid conversion at room temperature to the cor- expected N-H aziridine 10k (entry 12) was formed
N-alkyl aziridines would alleviate the above prob- responding N-H aziridines (10a to 10c). We em- in just 2 hours and isolated in 69% yield. As
lems. However, a practical, functional group-tolerant pirically found that in some of the reactions (i.e., anticipated, when the rate of N-H aziridination is
and environmentally benign direct preparation of entries 4, 5, 7, 9, 11, 14, and 20), addition of the slow and elevated temperatures are used, sec-
N-H aziridines from structurally diverse olefins has catalyst in several 1 mol % portions minimized ondary processes (i.e., intramolecular annulation)
so far eluded synthetic chemists (24–31). Here, decomposition of both the catalyst and aminating that consume the initially formed N-H aziridines
we report an operationally simple, inherently safe, agent and invariably led to higher isolated yield can dominate. Apparently, a fivefold increase
chemoselective and stereospecific conversion of a of product. Notably, the N-H aziridination took in catalyst loading increased the rate of N-H
wide range of olefins to the corresponding N-H or place efficiently in the presence of a labile termi- aziridination sufficiently that it could take place
N-Me aziridines via a rhodium-catalyzed pathway nal epoxide (10c), as well as an unprotected primary rapidly at ambient temperature.
free of external oxidants.
alcohol (10a); these functionalities typically inter-
Cyclohexene 9n (entry 15) was aziridinated
Recently, we developed a metal-free protocol fere with currently used aziridination protocols. In at room temperature to afford cyclic N-H aziridine
for primary amination of arylboronic acids using case of the transformation 9c→10c, only the pro- 10n; no traces of allylic C-H amination (i.e.,
only O-(2,4-dinitrophenyl)hydroxylamine (DPH, duct was detected in the crude reaction mixture by 1-amino-2-cyclohexene) could be detected by
1a, Fig. 1) as the stoichiometric aminating agent NMR analysis. In the presence of 1 mol % of cat- 1H-NMR analysis (≤2% sensitivity), in sharp con-
(32). The transformation proceeds under neutral alyst 2, both cis- and trans-1,2-disubstituted ali- trast with other metal nitrene-based aziridination
or basic conditions and can be conducted on a phatic olefins (entries 4 to 10, Fig. 2) underwent methods (37). Geraniol (9o, entry 16) and geranyl
multigram scale to provide structurally diverse smooth and stereospecific N-H aziridination at acetate (9q, entry 18), which incorporate two
primary arylamines. The versatility and robust- room temperature as established by 13C-NMR trisubstituted C=C double bonds, were N-H
ness of 1a prompted us to explore other uses of analysis (≤2% sensitivity). The presence of an aziridinated regioselectively, favoring the double
this aminating agent, specifically for the direct unprotected secondary alcohol in substrate 9i bond at the D6,7-position over the D2,3-position
functionalization of readily available and in- (entry 9) did not influence the stereochemical in both cases.
expensive olefins. Our investigations began by outcome of the N-H aziridination and 10i was
subjecting 1:1.5 mixtures of cis-methyl oleate isolated as a 1:1 mixture of diastereomers.
The shift of the regioisomeric ratio from 1:5
in 10o to 1:14 in 10q suggests a subtle directing
(7)/1a, as well as styrenes (3a and 3b)/1a, to a
Benzoyloxy and acetyloxy cis-olefins 9k and effect of the free allylic alcohol and/or an induc-
vigorous screening with various transition metal 9m (entries 11 and 14), when exposed to 1 mol % tive deactivation by the acetate; perhaps the ex-
complexes (tables S1 and S2). This initial screen of catalyst 2 and 1.2 equivalents of aminating tent of H-bonding in the solvent also plays a role.
identified Rh2(OAc)4 as a promising catalyst for agent 1a at 50°C, were smoothly aziridinated Entry 17 stands as a testament to the extraordi-
vic-amino-oxyarylation of olefins. Further evalu- followed by an in situ aziridine ring-opening (via narily mild reaction conditions as trisubstituted
ation of dimeric rhodium dicarboxylate complexes transacylation) to yield the corresponding trans- olefin 9p, which possesses a highly sensitive epoxy
(table S3) revealed that just 1 mol % loading of Du
Bois’ catalyst (33–36) (2, Fig. 1) in acetonitrile
(MeCN) leads to amino-oxyarylated styrenes 4a
A
Initial screening of catalytic systems:
and 4b at room temperature in 56% and 75% iso-
lated yields, respectively. These promising results
prompted us to conduct a thorough solvent screen.
In methanol, we observed the incorporation
of the MeO group at the benzylic position (5) in
addition to the amino-oxyarylated product 4b; these
compounds were isolated in a combined yield of
78%. At this juncture, we reasoned that a highly
polar, hydroxylic, and nonnucleophilic solvent such
as 2,2,2-trifluoroethanol (CF3CH2OH, TFE) would
completely avoid the incorporation of solvent
into the products. Indeed, 3b was cleanly amino-
oxyarylated in TFE, and 4b was isolated in 66%
yield. It was unclear whether the transformation
3b→4b involved the opening of a highly reactive
aziridine (6) or an alternative process. Surpris-
ingly, when 7 was reacted in trifluoroethanol as
solvent, cis-N-H aziridine 8 was isolated in excel-
lent yield (83%) instead of the expected amino-
oxyarylated product. The transformation proceeded
with complete stereospecificity as no traces of
the trans-N-H aziridine were detected by 1H- and
13C–nuclear magnetic resonance (13C-NMR) anal-
ysis (≤2% sensitivity).
DPH (1a) (1.5 equiv)
OAr
NH2
Rh2(esp)2 (1 mol%), Me CN, rt
R
R
3a (R = H); 3b (R = OMe)
DP H 1a
4a (56%); 4b (7 5%)
OAr = 2,4-dinitrophenoxy
(
) (1.5 equiv)
Rh2(esp)2 (1 mo l% )
CF3CH2OH, rt, 2 h
NO2
DPH 1a
(
)
(1 .5 equ iv)
Rh2(esp)2
(5 mol%)
MeOH
O2N
O
HN
1a, (R = H; DP H)
1b, (R = Me; N-Me-DPH)
R
MeO
NH
rt, 6 h
6
Me
Me
Me
Me
O
O
Rh
OMe
O
O
OAr
NH2
O
O
O
MeO
Me
Me
MeO
NH2
Rh
O
Me
Me
5 (56%)
+4b (22%)
4b (6 6%)
single product
DuBois' catalyst 2, Rh2(esp)2
B Formation of an N-H aziridine:
H
O
DP H (1a) (1.2 equiv)
Rh2(esp)2 (1 mo l% )
O
N
Me
Me
OMe
( )7
( )7
( )7 OMe
( )7
CF3CH2OH [0.1 M], rt, 3 h
7, cis-methyl oleate
8 (83%), cis-N-H Aziridine
Encouraged by this unexpected result, we
initiated a systematic study using representative
aliphatic olefins with a wide range of substitution
Fig. 1. Exploration of DPH (1a) as a versatile aminating agent. (A) Rh2(esp)2 is an effective catalyst
for olefin difunctionalization. (B) In 2,2,2-trifluoroethanol (TFE or CF3CH2OH), 7 undergoes direct
patterns and functionalities (Fig. 2). Terminal ali- aziridination to N-H aziridine 8 in excellent isolated yield.
62
3 JANUARY 2014 VOL 343 SCIENCE www.sciencemag.org

REPORTS
alcohol, was aziridinated rapidly and efficiently to come, confirmed by single-crystal x-ray analysis In general, styrenes were more reactive than ali-
epoxy N-H aziridine 10p in excellent yield. The of 10ss (a crystalline derivative of 10s), suggests a phatic olefins, and often lower temperatures (–10° to
transformation 9q→10q (entry 18) could be readily directing effect by the adjacent C(3)-b-alcohol 25°C) were adequate. Conspicuously, cis-b-methyl
scaled up (6 mmol) with minimal erosion of the not observed in conformationally more mobile styrene 11d furnished the corresponding cis-2-Ph-
isolated yield to provide gram quantities of 10q. acyclic molecules such as 9i. The success with 3-Me N-H aziridine (12d, entry 24) without isom-
N-H aziridination of limonene 9r (entry 19) fa- cholesterol and other natural products (7, 9h, 9i, 9o erization. Similarly, trans-b-methyl styrene 11c
vored the trisubstituted ring double bond with and 9r; Figs. 1 and 2) highlights the prospective readily furnished trans-2-Ph-3-Me N-H aziridine
9:1 regioselectivity; however, the chiral center had utility of this method in the straightforward (12c, entry 23) even on a 1- to 8-mmol scale. The
no evident influence on the diastereoselectivity elaboration of molecules of biomedical interest N-H aziridine derived from 2-Me indene (12h,
(1:1 drdr, diastereomeric ratio). In contrast with the (e.g., for 15N-labeling studies).
lack of stereoselectivity in 9i, cholesterol 9s (entry Next, we turned our attention to the direct activity, but instead reduced in situ to amine 12hh.
entry 28) was not isolated owing to its high re-
20) exclusively yielded the b-N-H aziridine 10s in N-H aziridination of di-, tri- and tetrasubstituted Evaluation of the effect of catalyst loading on the
71% yield; this unexpected stereochemical out- styrenes and stilbene (entries 21 to 28, Fig. 3A). reaction 11f→12f (entry 26) revealed that the
H
N
NO2
R4
R3
R2
R1
R2
R1
R4
R3
2, Rh2(esp)2
O2N
O
+
CF3CH2OH [0.1 M]
0.5 mmol scale
NH2
(1.0 equiv)
9a-s
1a
10a-s
Structure of N-H Aziridines
(Entry): Compound #; T (oC), t (h), Isolated Yield (%), Regio - and diastereoselectivity [ratios]
N-H Aziridination of aliphatic mono-, di-, and tri-substituted olefins:
H
N
H
HN
HN
N
HN
Ph
O
OH
OTBS
Me
OH
( )3
(3): 10c
( )2
TBDPSO
( )7
( ): 10d
O
(1): 10a
(2): 10b
(5): 10e
4
1a (1.2 equiv), 2 (5 mol%) 1a (1.2 equiv), 2 ( mol%)
1a (2 equiv), 2 (5 mol%)
1a (1.2 equiv), 2 (2x1 mol%)
1a (1.2 equiv), 2 (3x1 mol%)
5
25 oC, 2 h; 59%
25 oC, 2 h; 72%
25 oC, 5 h; 77%
25 oC, 3 h; 64%
25 oC, 36 h; 78%
H
N
H
O
OH
O
O
N
HN
O
HN
Me
HN
TBS
Me
Me
TBS
Me
( )2
( )6
OMe
( )7
O
( )5
( )7 OMe
Me
O
Ph
(6): 10f
(7): 10g
(8): 10h
(9): 10i
(10): 10j
1a (1.2 equiv), 2 (1 mol%) 1a (1.2 equiv), 2 (2 x 1 mol%) 1a (1.2 equiv), 2 (1 mol%)
1a (1.2 equiv), 2 (3x1 mol%)
25 oC, 6 h; 82% [1:1 dr]
1a (1.2 equiv), 2 (1 mol%)
25 oC, 1 h; 86% + 4% of 10jj
25 oC, 4 h; 72%
25 oC, 29 h; 55%
25 oC, 2 h; 91%
Ph
H
N
H
N
O
O
O
1a (1.2 equiv), 2 (5 mol%)
Me
Me
Me
O
Me
25 oC, 2 h; 69%
O
Ph
O
Ph
O
Me
9m
9k
O
(12): 10k
10jj
O
Ph
H
HN
Me
Me
H
N
N
1a (1.2 e uiv)
q
1a (1.2 equiv)
O
Me
O
2 (4 x 1 mol%)
2
(4 x 1 mol%)
50 oC, 51 h
61%
O
Me
(13): 10l
Me
50 oC, 96 h
84%
O
1a (1.2 equiv), 2 (1 mol%)
O
25 oC, 1.5 h; 83%
(11): 10kk
(14): 10mm
Me
Me
Me
Me
Me
Me
O
7
Me
7
Me
NH
7
Me
Me
NH
OH
3
OAc
OH
3
3
Me
6
HN
2
6
6
HN
2
HN
2
(15): 10n
(16): 10o
(17): 10p
(18): 10q
(19): 10r
1a (1.2 equiv), 2 (1 mol%) 1a (1.2 eq.), 2 (1 mol%)
1a (1.2 eq.), 2 (1 mol%)
0-5 oC, 4 h; 84%
[1:1 dr]
1a (1.2 eq. ), 2 (1 mol%), 25 oC, 3 h
81% [1:14 regiosel. favoring 6,7]
72% of 10p on 6 mmol scale
1a (1.2 eq.), 2 (1 mol%)
0 to 25 oC, 12 h; 72%
[1:1 dr]; 9:1 regiosel.
25 oC, 3 h; 71%
25 oC, 5 h; 71%
[1:5 regiosel. favoring 6,7]
CHMe
2
CHMe2
(20): 10s
Me
Me
1a
(2.2 equiv)
Me
Me
2 (2x1 mol%)
THF:TFE (1:1)
25 oC, 48 h; 71%
Converted to
H
Me
H
Me
O
H
H
10ss m. p. =
157-158 oC
Me
O
H
H
N
HO
10ss for x-ray
10ss
HN
Ts
Fig. 2. Direct and stereospecific N-H aziridination of olefins. Reactions were conducted at 0.1 M using 2,2,2-trifluoroethanol as solvent and at 0.5-mmol
scale unless otherwise indicated. To obtain crystalline material, 10s was O-acetylated and N-tosylated (Ts, para-toluenesulfonyl) to afford derivative 10ss.
(TBS, tert-butyl-dimethylsilyl; TBDPS, tert-butyl-diphenylsilyl)
www.sciencemag.org SCIENCE VOL 343 3 JANUARY 2014
63

REPORTS
R
N
NO2
R4
R3
R2
R1
R2
R1
2,
R4
R3
Rh2(esp)2
O2N
O
+
CF3CH2OH [0.1 M]
0.5 mmol scale
HN
R
(1.0 equiv)
11a-h
12a-h (R = H);
13a-f (R = Me)
1a (R = H); 1b (R = Me)
Structure of N-H and N-Me Aziridines
(Entry): Compound #; T (oC), t (h), Isolated Yield (%),
Regio - and diastereoselectivity [ratios]
N-H Aziridination of di-, tri-, and tetra-substituted styrenes:
A
NH
O2N
O
NO2 (22): 12b
1a (1.2 equiv)
Me
(23): 12c
1a (1.2 equiv)
2 (1 mol%)
-10 oC, 14 h; 53%
52% of 12c
on 8 mmol scale
HN
NH
HN
Me
(24): 12 d
1a (1.2 equiv)
2 (3x1 mol%)
-10 oC, 68 h; 76%
Me
(21): 12a
2 (1 mol%)
0 to 4 oC, 2 h; 73%
The aziridine is
observed but
(25): 12e
1a (1.3 equiv), 2 (2x1 mol%)
THF:TFE (2:3)
NH2
1a (1.2 equiv), 2 (1 mol%)
0 oC, 2 h; 64%
25 oC, 23 h; 51%
can not be isolated!
NH
Me
NH
NH
Me
Me
Pd/C/H2
Me
Me
Me
(26): 12f
Me
12g
25 oC, 15 h
60% (2 steps)
NH2
12h (not isolated)
12hh
(27):
1a
2
(1.1 equiv), (1 mol%)
25 oC, 3 h; 92%
(28): 12h
1a (1.2 equiv)
2 (1 mol%)
25 oC, 1.5 h; 70 %
1a (1.2 equiv), 2 (2x1 mol%)
0-5 oC, 5 h
81% of 12f on 8 mmol scale
N-Me Aziridination of di- and tri-substituted aliphatic olefins and styrenes:
B
NMe
Me
Me
N
Me
Me
O2N
NO2
O
O
MeN
( )6
7
Me
N
Me
Me
( )7
Me
MeN
OAc
OMe
3
( )7
( )7
Me
OMe
6
2
O
(29): 13a
1b (1.4 equiv)
13 c
NHMe
(30): 13b
1b (1.6 equiv)
(31):
(32): 13d
1b (1.4 equiv)
2
(1.25 mol%)
25 oC, 4 h; 81%
13f
1b (1.4 equiv), 2 (1.25 mol%)
(33): 13e
13e
25 oC, 4 h; 83%
1b (1.2 equiv), 2 (1 mol%)
0
oC, 2 h; 24% + 13f (15%)
2
(1.5 mol%)
25 oC, 4 h; 78%
2
(2 mol%)
25 oC, 6 h; 80%
[>1:30 regioisomers favoring 6,7]
Ring opening transformations of N-H aziridines:
C
N3
OMe
CS A (1. 1 equiv)
Na N3 (3 equiv)
MeCN, 50 oC
NH
Me
NH
Me
Pd/C/H2
Me
CSA (1 equiv)
Me
Me
Me
Me
Ph
Ph
12f
Ph
Ph
Ph
MeOH, 0-40 oC
rt, 16 h; 99%
MeOH, rt, 16 h
94%
12c
NH2
16
15
14
NH2
NH2
46 h; 79%
Fig. 3. Direct and stereospecific N-H and N-Me aziridination of olefins. Reactions were conducted at 0.1 M using 2,2,2-trifluoroethanol as solvent and
at 0.5-mmol scale unless otherwise indicated. CSA, camphorsulfonic acid.
lowest practical loading of catalyst 2, without de- this end, several di- and trisubstituted aliphatic the ring-opening of trisubstituted N-H aziridine 12f
creasing the isolated yield or drastically increasing olefin and styrene substrates (entries 29 to 33, with sodium azide furnished azidoamine 16 in 79%
the reaction time, was 0.5 mol %. This low cat- Fig. 3B) were examined in the presence of 1b as yield. These transformations by example illustrate
alyst loading renders the process economical and the stoichiometric aminating agent and 1 to 2 mol how readily a nitrogen atom can be introduced into
environmentally friendly. A further fivefold reduc- % of catalyst 2. The N-Me aziridination of olefins molecules.
tion in catalyst loading (from 0.5 to 0.1 mol %) also proceeded stereospecifically (entries 29 and
We also examined prospective reaction mech-
resulted in a 25-fold increase in reaction time and 30) and, in the case of geraniol acetate 9q, the anisms using quantum mechanical density-functional
a 30% drop in the isolated yield of 12f. Tetra- regioselectivity increased from 1:14 (in 10q) to theory calculations (Fig. 4). Our (U)M06 calcu-
substituted olefin 11g (entry 27) was easily N-H >1:30 (in 13c), favoring the D6,7-olefin in both lations were carried out in Gaussian 09 (38) using
aziridinated at room temperature; 12g was iso- cases.
a polarizable conductor continuum solvent model
lated in 70% yield. The attempted direct N-H
Two of the N-H aziridine products (12c and for trifluoroethanol. Details of calculated transi-
aziridination of 1-Ph-1-cyclopropylethene (11b) 12f) were subjected to ring-opening transforma- tion states and intermediates are given in the sup-
yielded only amino-oxyarylated product 12b; the tions (Fig. 3C). Upon catalytic hydrogenation, plementary materials.
complete lack of cyclopropane ring-opening pro- aziridine 12c afforded a 94% yield of ampheta-
We first examined plausible rhodium nitrene
ducts corroborate an aziridination pathway that mine 15, the active pharmaceutical ingredient in pathways. Generation of a rhodium nitrene in-
does not involve long-lived radical or carbocation Adderall, an approved medication for attention termediate is possible if the amino group of 1a
intermediates (see more detailed discussion of the deficit hyperactivity disorder, as well as narco- coordinates to Rh2(esp)2 followed by loss of
mechanism in the computation section and in Fig. 4). lepsy, that is marketed as a mixture of enantio- dinitrophenol (pathway A, Fig. 4). Calculations
The practicality and broad scope of the pre- mers. Under acidic conditions, at slightly elevated suggest that the triplet-spin state of the nitrene
ceding direct and stereospecific N-H aziridination temperature (40°C) in MeOH, 12c was converted (317) is more than 8 kcal/mol lower in energy
of olefins (Fig. 2 and Fig. 3A) prompted an in- to O-Me-norephedrine 14 with complete regiose- than the open-shell singlet, and reaction pathways
vestigation of direct N-Me aziridination. Toward lectivity and in nearly quantitative yield. Likewise, identified on the triplet-spin energy surface were
64
3 JANUARY 2014 VOL 343 SCIENCE www.sciencemag.org

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R
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=
O
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19
∆G/∆H =
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∆
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20
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Acknowledgments: J.R.F. thanks NIH (GM31278, DK38226)
and the Robert A. Welch Foundation (grant GL625910) for
funding. L.K. gratefully acknowledges the generous financial
support of the UT Southwestern Endowed Scholars in
Biomedical Research Program (W.W. Caruth Jr. Endowed
Scholarship in Biomedical Research), the Robert A. Welch
Foundation (grant I-1764), the American Chemical
3
route for stereospecific aziridination if 17 re-
acts with alkenes by forming the first C–N bond
via triplet transition state TS1 followed by spin
interconversion along the pathway to diradical
intermediate 19 or fast spin interconversion at
the diradical intermediate (41). After spin inter-
conversion, the second C–N bond is formed by
the coupling of singlet-paired electrons without
a barrier and leads directly to aziridine 20.
As alternatives to nitrene pathways, we also
explored polar mechanisms involving Rh-amine
and Rh-alkene coordination modes (see supple-
mentary materials). One of several possible polar
mechanisms is outlined as pathway B in Fig. 4.
This pathway is akin to the mechanism proposed
for amination of aryl boronic acids with 1a (32).
Although this mechanism may account for amino-
oxyarylated products (e.g., 4a and 4b) observed
under some experimental conditions, the calculated
barrier for this mechanism, as well as alternative
polar mechanisms, is higher in energy than the nitrene
mechanism presented in pathway A.
Society–Petroleum Research Fund (grant 51707-DNI1), and
the American Cancer Society and Simmons Cancer Center
Institutional Research Grant (New Investigator Award in
Cancer Research, ACS-IRG 02-196). D.H.E. thanks Brigham
Young University and the Fulton Supercomputing Lab. M.Y.
acknowledges a grant from UT Arlington to support the
upgrade of the x-ray facility. We also thank K. Schug,
M. Kukula, and the Shimadzu Center for Advanced Analytical
Chemistry (SCAAC, UT Arlington) for assistance in the full
characterization of new compounds. The generous donation
of 100 g of aminating agent 1a and 5 g of aminating agent
1b by Corvinus Chemicals, LLC (Dallas, TX), as well as 20 kg
of 2,2,2-trifluoroethanol (TFE) by Joyant Pharmaceuticals,
Inc. (Dallas, TX), is also gratefully acknowledged. We thank
P. S. Baran, J. Du Bois, E. M. Carreira, A. J. Catino, M. P. Doyle,
M. Krische, and R. Sarpong for helpful commentary. Metrical
parameters for the structure of compound 10ss are available
free of charge from the Cambridge Crystallographic Data
Centre under reference no. CCDC-959664.
Supplementary Materials
www.sciencemag.org/content/343/6166/61/suppl/DC1
Materials and Methods
Figs. S1 to S5
Tables S1 to S8
References (42–69)
References and Notes
1. W. McCoull, F. A. Davis, Synthesis 2000, 1347–1365 (2000).
2. J. B. Sweeney, Chem. Soc. Rev. 31, 247–258 (2002).
9 September 2013; accepted 19 November 2013
10.1126/science.1245727
19. D. Karila, R. H. Dodd, Curr. Org. Chem. 15, 1507 (2011).
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