Rhodium-Catalyzed Alkene Difunctionalization with Nitrenes

Article abstract of DOI:10.1002/chem.201600393

The Rh^II-catalyzed oxyamination and diamination of alkenes generate 1,2-amino alcohols and 1,2-diamines, respectively, in good to excellent yields and with complete regiocontrol. In the case of diamination, the intramolecular reaction provides

Full text of DOI:10.1002/chem.201600393

DOI: 10.1002/chem.201600393
Full Paper
&
Amination
Rhodium-Catalyzed Alkene Difunctionalization with Nitrenes
Jennifer Ciesielski,[a] Geoffroy Dequirez,[a] Pascal Retailleau,[a] Vincent Gandon,*[a, b] and
Philippe Dauban*[a]
Abstract: The RhII-catalyzed oxyamination and diamination
of alkenes generate 1,2-amino alcohols and 1,2-diamines, re-
spectively, in good to excellent yields and with complete re-
giocontrol. In the case of diamination, the intramolecular re-
action provides an efficient method for the preparation of
pyrrolidines, and the intermolecular reaction produces vici-
nal amines with orthogonal protecting groups. These alkene
difunctionalizations proceed by aziridination followed by nu-
cleophilic ring opening induced by an Rh-bound nitrene
generated in situ, details of which were uncovered by both
experimental and theoretical studies. In particular, DFT calcu-
lations show that the nitrogen atom of the putative [Rh]2=
NR metallanitrene intermediate is electrophilic and support
an aziridine activation pathway by N···N=[Rh]2 bond forma-
tion, in addition to the N···[Rh]2=NR coordination mode.
Introduction
mination reactions involve the addition of the same amino
groups. Accordingly, the search for conditions allowing the re-
gioselective intermolecular difunctionalization of alkenes re-
mains a challenge that has been successfully addressed in only
a limited number of studies.[10,11]
1,2-Amino alcohols[1] and vicinal diamines[2] are two important
classes of functional groups that are readily found in natural
products and pharmaceuticals, and can act as ligands in asym-
metric catalysis. Given their abundance and significance in or-
ganic synthesis, chemists have sought efficient methods for
their preparation. Alkenes are ideal prochiral platforms for the
design of one-step 1,2-oxyamination and 1,2-diamination reac-
tions.[3] However, the development of these processes is
fraught with numerous barriers, such as issues of regioselectivi-
ty, functional-group compatibility, and toxicity of the reagents.
Additionally, 1,2-diamination would ideally generate a 1,2-dia-
mine in which the two amino groups could be easily differenti-
ated.
Catalytic nitrene-transfer reactions[12] have recently emerged
as an efficient method for 1,2-difunctionalization of alkenes.
The intramolecular additions of nitrenes generated from carba-
mates or sulfamates in the presence of an iodine(III) oxidant
and a dirhodium(II) complex allow for regioselective transfor-
mation of various alkenes, indolic substrates, and glycals into
oxyamidated products in very good yields.[13] This strategy has
also been extended to the diamination of alkenes and trypta-
mines.[14] We aimed to tackle the problem of intermolecular
oxyamination and diamination by developing conditions that
would regioselectively install the two functional groups in
a single step and, in the case of diamination, with orthogonal
protecting groups (Scheme 1). Our recently published oxyami-
nation of indoles, enamides, and simple alkenes underscored
the unprecedented capacity of the Rh nitrene species generat-
ed in situ to act as a Lewis acid.[15] Herein, we give a full ac-
count of our investigations, the development of this reaction
with alkenes, its extension to diamination, and our theoretical
studies to elucidate its mechanism and uncover the role of the
Rh-bound nitrene Lewis acid that is generated during the pro-
cess.
Recently, a number of significant advances in the area of
oxyamination[4] and diamination[5] have addressed the afore-
mentioned issues. In general, these processes can occur under
both metal-mediated[6,7] and metal-free conditions.[8,9] Howev-
er, the regioselectivity in all these catalytic alkene oxyamina-
tion reactions relies on the intramolecular addition of one of
the functional groups. Similarly, most of the intermolecular dia-
[a] Dr. J. Ciesielski, Dr. G. Dequirez, Dr. P. Retailleau, Prof. V. Gandon,
Dr. P. Dauban
Institut de Chimie des Substances Naturelles, CNRS UPR 2301
UniversitØ Paris-Sud, UniversitØ Paris-Saclay, 1
av. de la Terrasse, 91198 Gif-sur-Yvette (France)
Fax: (+33)1-6907-7247
E-mail: philippe.dauban@cnrs.fr
[b] Prof. V. Gandon
Institut de Chimie MolØculaire et des MatØriaux d’Orsay, CNRS UMR 8182
UniversitØ Paris-Sud, UniversitØ Paris-Saclay
bâtiment 420, 91405 Orsay CEDEX (France)
E-mail: vincent.gandon@u-psud.fr
Supporting information and ORCID from two of the authors for this article
can be found under http://dx.doi.org/10.1002/chem.201600393.
Scheme 1. Rh-catalyzed alkene oxyamination and diamination.
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Table 1. Optimization studies for intermolecular oxyamination.[a]
Entry
RNH2
Catalyst
Solvent
Yield[b] [%]
1
2
3
4
5
6
7
8
TcesNH2
TsNH2
[Rh2(esp)2]
[Rh2(esp)2]
[Rh2(esp)2]
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
CH2Cl2
70[c]
40
90
mixture
51
no reaction
degradation
degradation
82
54
66
mixture[e]
mixture[e]
TcesNH2
TcesNH2
TcesNH2
TcesNH2
TcesNH2
TcesNH2
TcesNH2
TcesNH2
TcesNH2
TcesNH2
TcesNH2
[Rh2(CF3CONH)4]
[Rh2(OAc)4]
[Rh2(CF3CO2)4]
CuOTf[d]
[d]
Cu(OTf)2
9
[Rh2(esp)2]
[Rh2(esp)2]
[Rh2(esp)2]
[Rh2(esp)2]
[Rh2(esp)2]
10
11
12
13
toluene
trifluorotoluene
AcOiPr
CH3CN
[a] Reaction conditions: styrene (0.6 mmol), TcesNH2 (1.5 equiv), PhI(OAc)2
(2 equiv), catalyst (2 mol%), acetic acid (12 equiv) in solvent (1.7 mL) at
room temperature. [b] Yields of isolated products. [c] After 3 h.
[d] 5 mol%. [e] A mixture of 2a and the aziridine was obtained after 60 h
at room temperature or at 408C.
Results and Discussion
We began by screening conditions for the oxyamination of sty-
rene (Table 1). Thus, when styrene was treated with trichlor-
oethyl sulfamate (TcesNH2) and [Rh2(esp)2] (H2esp=a,a,a’,a’-
tetramethyl-1,3-benzenedipropionic acid)[16] as catalyst in the
presence of PhI(OAc)2 and acetic acid, the desired product was
obtained in 70% yield after 3 h (Table 1, entry 1). The yield of
the oxyaminated product increased to 90% with a longer reac-
tion time of 16 h (Table 1, entry 3). Additionally, compound 2a
was produced as a single regioisomer in which the acetate
group was introduced solely at the benzylic position. We
screened various rhodium and copper complexes, but to no
avail (Table 1, entries 4–8). In all cases, low yields or complex
mixtures were obtained. Several solvents were also tested, in-
cluding toluene, acetonitrile, trifluorotoluene, and isopropyl
acetate, but again only low yields or complex mixtures were
observed (Table 1, entries 10–13). Dichloromethane also
proved to be an efficient solvent for the reaction (82% yield of
the oxyaminated product) and thus could be an alternative to
benzene (Table 1, entry 9). We also examined other nitrogen
sources, such as TsNH2; however, the yield dropped significant-
ly from 70 to 40% (Table 1, entry 2). The optimal conditions for
the oxyamination were then used to examine the scope of the
reaction. We began by exploring the reactivity of aromatic al-
kenes.
Scheme 2. Oxyamination with aromatic alkenes. [a] After 48 h. [b] 2:1 mix-
ture of isomers. [c] 2:1 mixture of cis:trans isomers. [d] 1.4:1 mixture of
trans:cis isomers.
aziridine 2g after 48 h. We hypothesized that the enhanced
electron-withdrawing capabilities of the NO2 group prevented
formation of the proposed carbocation intermediate and thus
subsequent nucleophilic attack of the acetate.
Next, we examined the effect of substituents on the alkene.
a-Substituted styrenes, such as a-methylstyrene, 2-isopropyle-
nenaphthalene, and (1-bromomethylvinyl)benzene, furnished
the desired oxyaminated products 2i, 2j, and 2k in high yields
(84, 70, and 78%, respectively). trans-b-Methylstyrene gave 1,2-
amino alcohol 2l in 82% yield as a mixture of diastereomers.
Difunctionalization was also successful with cyclic alkenes such
as indene and 1,2-dihydronapththalene, which provided com-
pounds 2m and 2n in good yields as mixtures of diastereo-
mers. A diene, namely, 1-phenylbutadiene (1o), reacted in ac-
cordance with the results of Yoon et al.[10e] to produce the oxy-
aminated product at the terminal olefin in 65% yield with
complete chemoselectivity.
We also explored the reactivity of aliphatic alkenes. The cor-
responding 1,2-amino alcohols were generated in moderate
yields (up to 58%) as single regioisomers (Scheme 3). The only
exception was 2,5-dimethylhexa-2,4-diene (1u), for which the
1,4-addition product was generated besides oxyaminated
product 2u. In general, the yields that were obtained for the
oxyamination of the aliphatic alkenes were slightly lower than
those observed for the aromatic alkenes. We postulated that
Various substituted styrenes were converted to the corre-
sponding 1,2-oxyaminated products in good to excellent yields
(Scheme 2). Both electron-donating (p-OMe: 2c) and electron-
withdrawing (p-Br: 2d, o-Cl: 2e, p-OAc: 2 f) groups were toler-
ated. p-Bromostyrene and o-chlorostyrene required longer re-
action times, and p-nitrostyrene gave only the corresponding
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benzoic acid (2w), phenylacetic acid (2x), and cyclohexanecar-
boxylic acid (2y), generated the expected amino alcohols in
good yields.
We found that preparation of the corresponding hypervalent
iodine reagents was necessary to ensure the presence of
a single acid during the reaction. Intramolecular cyclization
was also successful. trans-Styrylacetic acid, 5-norbornene-2-car-
boxylic acid, and 2-vinylbenzoic acid generated the desired lac-
tones 2z, 2aa, and 2bb in 89, 62, and 61% yield, respectively.
In the case of trans-styrylacetic acid, lactone 2z was produced
as a single diastereomer, and the relative stereochemistry was
confirmed by X-ray crystallography.[15c] This selectivity is de-
rived from the stereochemistry of the alkene, that is, stereospe-
cific aziridination followed by intramolecular ring-opening dia-
stereoselectively furnishes the oxyaminated product. Alcohols
also proved to be efficient nucleophiles in both inter- and in-
tramolecular reactions. Addition of methanol gave the corre-
sponding methoxy derivative 2cc in 74% yield, and propargyl
alcohol provided compound 2dd in 74% yield. The intramolec-
ular reaction with trans-styrylethanol furnished trans-tetrahy-
drofuran 2ee in 55% yield as a single diastereomer. Amino
acids were also screened. Glycine and l-proline gave 2 ff and
2gg in 83 and 80% yield, respectively, and thus this method
can be used to generate highly functionalized products from
simple starting materials.
Scheme 3. Oxyamination with aliphatic alkenes. [a] After 48 h. [b] The 1,2-
amino alcohol was also isolated in 48% yield.
the proposed carbocation formed during the reaction is less
stable for aliphatic alkenes compared to aromatic alkenes, and
thus nucleophilic attack is hampered.[17]
Finally, we extended the reaction to other nucleophiles
(Scheme 4). Various carboxylic acids, such as pivalic acid (2v),
Given the success of the oxyamination, we then turned our
attention to diamination, which has been recently investigated
along with the chemistry of nitrenes.[14,15a] We initially focused
on intramolecular diamination, which could provide an effi-
cient method to generate functionalized pyrrolidine-type prod-
ucts in a single step. As shown in Table 2, we first applied the
optimal conditions used for oxyamination, but with PhI(OPiv)2
(OPiv=pivaloyl) instead of PhI(OAc)2. We hypothesized that in
this case intramolecular cyclization would occur faster than in-
termolecular addition of the pivalate. The desired pyrrolidine
4a was thus produced in 45% yield (Table 2, entry 2). However,
after screening a variety of reaction conditions (Table 2, en-
tries 2–10), we found that higher yields were obtained in the
presence of PhI(OAc)2, and the optimal conditions (2 mol%
[Rh2(esp)2], PhI(OAc)2 in chlorobenzene/benzene (3/1) at
08C[18]) enabled the formation of pyrrolidine 4a in 74% yield
as a single diastereomer within 2 h (Table 2, entry 9).[19] The rel-
ative stereochemistry was confirmed by X-ray crystallography
(see Supporting Information). Thus, the intramolecular diami-
nation is completely diastereoselective, like the intramolecular
oxyamination.
With the optimal conditions in hand, we explored the scope
of the cyclization (Scheme 5). With a variety of substituents, in-
cluding p-OMeC6H4 (4b), p-ClC6H4 (4c), 2-naphthyl (4e), and 2-
thienyl (4 f), the desired cyclized product was produced in
good yields as a single diastereomer. However, when a substitu-
ent was placed at the ortho position, a complex mixture of
products was obtained. We, then, sought to use this reaction
to build quaternary centers. Diphenyl-substituted substrate 3g
generated the desired product in 77% yield, but the reaction
was not successful when one of the phenyl groups was re-
placed with a methyl group (3h). Terminal alkenes 3i and 3j
Scheme 4. Oxyamination with various nucleophiles. [a] Reaction with
8 equiv of PhCO2H. [b] Reaction with PhI(OCOtBu)2. [c] 1:1 d.r.
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with different nitrogen nucleophiles such as phthali-
mide, saccharin, sodium azide, and trimethylsilyl
azide. However, they all afforded exclusively the oxy-
aminated product 2a, which was isolated in 50–60%
yield. This, clearly, highlights the need to avoid the
use of iodine(III) oxidants with O ligands to suppress
the competitive oxyamination reaction arising from
nucleophilic attack of the carboxylic acid released
after formation of the iminoiodinane.
Table 2. Optimization studies for intramolecular diamination.[a]
Entry
Solvent
c
PhI(X)2
Rh
Yield
[%][b]
[m]
1
2
3
4
5
6
7
8
9
10
C6H6
C6H6
C6H6
C6H6
C6H5Cl
C6H5Cl
C6H5Cl
C6H5Cl
C6H5Cl/C6H6 (3/1)
C6H5Cl/C6H6 (1/1)
0.10
0.10
0.10
0.20
0.20
0.20
0.20
0.10
0.10
0.10
PhI(OPiv)2
PhI(OPiv)2
PhI(OPiv)2
PhI(OPiv)2
PhI(OPiv)2
PhI(OPiv)2
PhI(OPiv)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
[Rh2(esp)2]
[Rh2(esp)2]
[Rh2(esp)2]
[Rh2(esp)2]
[Rh2(esp)2]
[Rh2(tfacam)2]
[Rh2(OAc)4]
[Rh2(esp)2]
[Rh2(esp)2]
[Rh2(esp)2]
45
57
45
41
65
59
[c]
This hypothesis led us to take inspiration from
recent studies of MuÇiz et al., who reported the
preparation of the bis-imido iodine(III) oxidant
PhI(NTs2)2 and its use for the diamination of alke-
nes,[11c] by generating the nitrene species in the pres-
ence of a nitrogen nucleophile. Indeed, application of
our reaction conditions in the presence of PhI(NTs2)2
provided the desired diaminated product 5a, but its
formation was accompanied by that of compound 6
resulting from the noncatalytic diamination described
by MuÇiz et al. (Table 3, entry 1). We, thus, hypothe-
sized that increasing the amount of the catalyst
should suppress this side reaction, and by using
[d]
complex mixture
72
74
65
[a] Reaction conditions: substrate (0.2 mmol), TcesNH2 (1.5 equiv), PhI(X)2 (2.0 equiv),
catalyst (2 mol%) in solvent (0.6 mL) at 08C. [b] Yields of isolated products. [c] Slow
addition of PhI(OPiv)2. [d] 2.3 equiv MgO.
5 mol% of catalyst we obtained 5a and 6 as a 16:1 mixture
(Table 3, entry 2). We then decreased the number of equiva-
lents of PhI(NTs2)2 to 1.5, and thus obtained 5a as the sole
product in 57% yield (Table 3, entry 3). Using benzene as sol-
vent decreased the ratio of the desired to the undesired prod-
uct, even when different concentrations were used (Table 3,
entries 4 and 6). Interestingly, the substituents of the imide in-
fluence the course of the reaction, since using PhI[N(SO2Ph)2]2
gave larger amounts of the undesired diamino compound 6
(Table 3, entry 5). When the reaction was carried out in the ab-
sence of [Rh2(esp)2], 6 was obtained as the sole product
(Table 3, entry 7), which indicates that a nitrene formed in situ
is responsible for the formation of diamine 5a.
Several orthogonally protected vicinal diamines were gener-
ated from p-chlorostyrene, p-acetoxystyrene, 2-vinylnapththa-
lene, and o-chlorostyrene (Table 4, entries 3–6). We attributed
the lower yields obtained in diamination, relative to oxyamina-
tion, to the lower nucleophilicity of the ditosylamine compared
to a carboxylic acid or an alcohol. However, with p-methoxys-
tyrene and a-methylstyrene (Table 4, entries 2 and 7), complex
mixtures were obtained. We postulated that these substrates
were too reactive, and the aziridine intermediates formed in
situ were decomposing before addition of the nitrogen nucleo-
phile.
We then investigated the mechanism of this reaction. First,
we sought to confirm the presence of an aziridine intermedi-
Scheme 5. Intramolecular diamination of alkenes. [a] Reaction mixture was
warmed to room temperature for 2 h.
1
ate by monitoring the reaction with styrene by H NMR spec-
troscopy. This revealed that the reaction does indeed proceed
via an aziridine, which is gradually transformed into the oxya-
minated product 2a.[15c] Next, we sought to clarify the mecha-
nism of the aziridine ring opening and, to our surprise, the
oxyaminated product could only be generated from the aziri-
dine under the reaction conditions for oxyamination.[15c,20] This
suggests that the metallanitrene may act as a Lewis acid that
can activate the aziridine towards ring opening. In a test ex-
both generated the expected cyclized product, in 34 and 53%
yield, respectively.
We, then, turned our attention to the more challenging in-
termolecular alkene diamination with the aim of finding reac-
tion conditions that allow the introduction of two differently
substituted nitrogen centers. The conditions developed for the
oxyamination reaction were applied to reactions of styrene
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suggest the involvement of intermediates with signif-
icant cationic character. Test experiments with nor-
bornene and a-cyclopropylstyrene were performed
to trigger a possible rearrangement that would give
support to the hypothetical formation of a carbocat-
ion. However, the reaction with norbornene only
gave the aziridine 8 [Scheme 6, Eq. (2)], whereas the
cyclopropyl derivative led to the oxyaminated prod-
uct 2hh in 60% yield [Scheme 6, Eq. (3)]. In the latter
case, any products arising from ring opening of the
cyclopropane could be observed. Accordingly, should
a positive charge be generated at the position that
undergoes nucleophilic addition, its amount will not
be sufficient to induce a rearrangement, a hypothesis
in line with the DFT calculations, which suggest
lengthening of the C(Ph)ÀN bond, but not its cleav-
age (see below).
Table 3. Optimization studies for intermolecular diamination.[a]
Entry
Catalyst PhI(X)2
loading
Solvent
Ratio
5a:6
Yield
of 5a [%][b]
1
2
3[c]
4
2 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
–
PhI(NTs2)2
C6H5Cl/benzene (3/1)
C6H5Cl/benzene (3/1)
C6H5Cl/benzene (3/1)
benzene
6.5:1
—
—
57
–
–
–
PhI(NTs2)2
PhI(NTs2)2
PhI(NTs2)2
PhI(N(SO2Ph)2)2 benzene
PhI(NTs2)2
PhI(NTs2)2
16:1
>20:1
14:1
4:1
8:1
0:100 65
5
6[d]
7[d]
benzene
benzene
[a] Reaction conditions: styrene (0.2 mmol), TcesNH2 (1.5 equiv), PhI(X)2 (2.0 equiv),
[Rh2(esp)2] (mol%) in solvent (2 mL, c=0.1m) at room temperature. [b] Yields of isolat-
ed products. [c] 1.5 equiv of PhI(NTs2)2. [d] 0.3m
Hence, we proposed the mechanism depicted in
Scheme 7. Formation of the metallanitrene I, which
Table 4. Intermolecular diamination of alkenes.[a]
occurs by the reaction between TcesNH2, PhI(OAc)2, and
[Rh2(esp)2], followed by alkene aziridination furnishes II
(cycle A). Opening of the aziridine would be facilitated by the
rhodium-bound nitrene I, which gives cationic species III. The
latter is then rapidly trapped by the nucleophile to yield the
oxyaminated product IV and regenerate I (cycle B).[21]
Entry
R1
R2
Ratio 5:6
Yield [%]
To clarify the role of the Rh-bound nitrene, we performed
DFT calculations. All structures were optimized with Gaussi-
an 09[22] at the BPW91/6-31G*[Rh-RSC+4f] level of theory, as
described previously.[23,24] Single-point energies were calculated
at the M06/def2-TZVPP level of theory. The M06/6-
311G(2d,2p)[Rh-RSC+4f] level of theory was also used, but the
results were similar, so they are not presented. Zero-point cor-
rection and thermal correction to the enthalpy were obtained
at the optimization level of theory. Solvation correction (ben-
zene) was obtained by the CPCM method. We used
[Rh2(O2CH)4] (A or [Rh]2) and Rh2(O2CH)4(NTces) (C or [Rh]2=
1
2
3
4
5
6
7
Ph
H
H
H
H
H
H
Me
>20:1
–
57 (5a)
complex mixture (5b)
58 (5c)
60 (5d)
47 (5e)
4-MeOPh
4-ClPh
4-AcOPh
2-naphthyl
2-ClPh
Ph
>20:1
14.4:1
9.5:1
>20:1
–
47 (5 f)
complex mixture (5g)
[a] Reaction conditions: substrate (0.2 mmol), TcesNH2 (1.5 equiv),
PhI(NTs2)2 (2.0 equiv), [Rh2(esp)2] (5 mol%) in C6H5Cl/benzene (2.0 mL, 3/1)
at 08C. [b] The reaction mixture was heated at 658C for 24 h.
periment involving a “catalytic” quantity of the metallanitrene NTces) as model organometallic frameworks.[25] Although the
generated in situ, the expected product was obtained from Lewis acid A and its Lewis base adducts are obviously closed-
styrene in 79% yield [Scheme 6, Eq. (1)].
shell species, the spin multiplicity of rhodium nitrenes can be
The nature of the aziridine ring opening was also investigat- singlet or triplet. According to calculations, C has a triplet
ed. The mixtures of cis/trans products isolated from trans-b- ground state (Est =EsingletÀEtriplet =1.5 kcalmolÀ1
; DGst(solv)=
methylstyrene (1k), indene (1l), and dihydronaphthalene (1m) 0.9 kcalmolÀ1), yet as previously noted for related systems,[23]
the singlet–triplet gap is rather small, so the two spin states
could coexist in solution. While the LUMO of A is, as expected,
concentrated on the rhodium atoms, two large lobes are
found on both the terminal rhodium atom and the nitrene ni-
trogen atom in triplet C (Figure 1), which suggests that this
complex is also electrophilic at the nitrogen center.
Coordination of A to aziridine 7 was then been studied com-
putationally (Scheme 8). Two adducts were modeled: complex
B1, which has an NÀRh bond, and complex B2, in which the
dirhodium species is bound to one oxygen atom of the Tces
group. Both are formed exergonically. The former is more
stable than the latter by 3.5 kcalmolÀ1. The coordination of 7
through the aziridine nitrogen or one Tces oxygen atom to the
3
triplet [Rh2]=NTces rhodium nitrene (C) leading to D1 and D2
Scheme 6. Experimental studies on the mechanism.
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was then considered. Encouraged by the MO analysis men-
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Scheme 7. Proposed mechanism.
3
Figure 1. LUMO of A (left) and beta LUMO of (C) (right) with distances in
angstrom.
3
Figure 2. Geometries of B1 (top), (D1) (middle), and 1(D3) (bottom) with dis-
tances in angstrom.
in 1(D3) the aziridine core is activated towards nucleophilic
attack at C(Ph). Addition of AcOH to B1 to give F was found to
be endergonic by 5.2 kcalmolÀ1 (Scheme 9). Formation of the
experimentally observed product 2a and concomitant regener-
ation of A by proton transfer is then strongly exergonic by
3
Scheme 8. Coordination of [Rh2]=NTces A and (C) to aziridine 7 and the cor-
responding DG298(solv) [kcalmolÀ1] values.
3
tioned above, we also investigated NÀN bonding, which even-
tually led to D3. While the triplet state is preferred for D1 (Est =
5.1 kcalmolÀ1; DGst(solv)=4.5 kcalmolÀ1) and D2 (Est =2.4 kcal
molÀ1; DGst(solv)=2.0 kcalmolÀ1), complex D3 is much more
stable as a singlet species (Est =12.0 kcalmolÀ1; DGst(solv)=
13.9 kcalmolÀ1), which means that the nitrene character is lost.
28.5 kcalmolÀ1. Addition of AcOH to (D1) is slightly exergonic
by 0.4 kcalmolÀ1, and the proton transfer is again largely exer-
1
gonic by 29.6 kcalmolÀ1. As for (D3), the reaction with AcOH
is this time markedly exergonic by 25.5 kcalmolÀ1. The proton
3
transfer to give the separated fragments 2a and (C) is moder-
ately endergonic by 6.7 kcalmolÀ1 [26]
Thus, after the first cycle
.
1
Each coordination mode is exergonic, yet (D3) is significantly
more stable than the other complexes.
(cycle A in Scheme 7) has produced the aziridine, 2a could be
formed by the following sequences: 3(C)+7! 3(D1)//3(D1)+
3
3
1
The O coordination of [Rh]2 or [Rh]2=NTces in B2 or (D2)
AcOH! (G)!2a+3(C) or 3(C)+7! (D3)//1(D3)+AcOH!
leaves the three-membered ring of the aziridine virtually un-
perturbed, and the three bond lengths of the aziridine core lie
in the range 1.48–1.50 Š, as in the free molecule. On the other
1(H)!2a+3(C).
Unfortunately, all attempts to model a transition state corre-
sponding to the addition of acetic acid failed. Indeed, it is
often difficult to obtain such transition states in the bimolecu-
lar series. Thus, an intramolecular addition was modeled, and
3
1
hand, the N coordination in B1, (D1), or (D3) causes elonga-
tion of the C(Ph)ÀN bond to 1.54–1.55 Š (Figure 2). Thus, even
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Scheme 9. Overview of the calculated species on a DG298(solv) [kcalmolÀ1] scale.
NTces, respectively). On the other hand, the cyclization of the
NÀN bonded species 1(K) requires only 1.8 kcalmolÀ1 of free
energy of activation. Moreover, it is also the only exergonic re-
action of the three (À5.3 kcalmolÀ1).
Intramolecular addition of an amino group was also exam-
ined (Scheme 11). Although all reactions in this case are exer-
gonic, the same conclusions can be reached. Again the activa-
tion of the aziridine by [Rh]2=NTces through NÀRh or NÀN co-
ordination leads to more accessible transition states than with
[Rh]2. Formation of an NÀN bond prior to CÀN bond formation
Scheme 10. Calculated intramolecular nucleophilic additions of a carboxylic
acid and their DG2°98(solv) and DG298(solv [kcalmolÀ1] values.
the intramolecular addition transition states could be located
on the potential-energy surface (Scheme 10).
3
1
Figure 3 shows the LUMOs of I, (J), and (K) at the same
contour value. Notably, the lobe at C(Ph), which is the attacked
3
1
carbon atom, is rather small in I and (J), but very large in (K).
This coincides, for the first two reactions, with Gibbs free ener-
gies of activation of similar magnitude, yet with a preference
for [Rh]2=NTces, when the RhÀN coordination mode is adopt-
ed (DG°298(solv)=15.2 and 12.2 kcalmolÀ1 for [Rh]2 and [Rh]2=
Scheme 11. Calculated intramolecular nucleophilic additions of an amine
and their DG°298(solv) and DG298(solv) [kcalmolÀ1] values.
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portantly, with complete regioselectivity. Intramolecular diami-
nation leads to pyrrolidines. Therefore, these reactions, provide
useful building blocks that could find potential application in
natural products synthesis and medicinal chemistry. They also
enhance the scope of synthetic nitrene chemistry, which is
mostly devoted to alkene aziridination and C(sp3)ÀH amina-
tion.[12]
The course of these alkene 1,2-difunctionalizations funda-
mentally relies on the careful choice of the iodine oxidant. It
also involves the rhodium-bound nitrene, which plays a dual
role in the reaction. It first allows the expected alkene aziridi-
nation. Then, as confirmed by DFT calculations, it behaves as
a Lewis acid that activates the aziridine towards the nucleo-
philic attack of carboxylic acids, alcohols, or bis(sulfonyl)i-
mides.[27] Work is in progress to develop the catalytic asymmet-
ric version of the alkene difunctionalization.
Experimental Section
General procedure for oxyamination
[Rh2(esp)2] (9 mg, 12 mmol, 0.02 equiv), the substrate (0.60 mmol,
1.0 equiv), and the nucleophile (7.20 mmol, 12.0 equiv) were added
to a solution of TcesNH2 (206 mg, 0.90 mmol, 1.5 equiv) in benzene
(1.7 mL). To this mixture was added PhI(OR)2 (1.20 mmol, 2.0 equiv).
During the addition of PhI(OR)2 a color change from green to
brown was generally observed. The reaction mixture was stirred at
room temperature (258C) for 16 h. A saturated aqueous solution of
NaHCO3 (3 mL) was then added. The aqueous layer was extracted
with CH2Cl2 (2”10 mL) and the combined organic extracts were
stirred for 30 min with a saturated aqueous solution of thiourea
(5 mL). After separation, the organic phase was washed with brine
(10 mL), dried over MgSO4, filtered, and concentrated under re-
duced pressure. The isolated material was purified by flash chro-
matography on silica gel with varying gradients of petroleum
ether and ethyl acetate to afford the pure oxyamination product.
1
Figure 3. LUMOs of I and (K) and beta LUMO of 3(K) at a contour value of
0.012057 and geometries of the cyclization transition states with distances
in angstrom.
yields a more modest cyclization barrier (1.8 kcalmolÀ1, identi-
cal to that calculated with the alcohol) and the highest exergo-
nicity.
General procedure for intramolecular diamination
Thus, by combining the results exposed above, it transpires
that [Rh2]=NTces is a relevant Lewis acid for the activation of
aziridines. However, and against all odds, the activation (which
takes place in the singlet spin state) may proceed by NÀN
rather than NÀRh coordination, and follows the mechanism
shown in Scheme 12.
[Rh2(esp)2] (2.2 mg, 2.9 mmol, 0.02 equiv) and the substrate
(0.15 mmol, 1.0 equiv) were added to a solution of TcesNH2 (51 mg,
0.22 mmol, 1.5 equiv) in chlorobenzene/benzene (3/1, 1.5 mL). To
this mixture was added PhI(OAc)2 (96 mg, 0.30 mmol, 2.0 equiv).
During the addition of PhI(OAc)2 a color change from green to red-
brown was generally observed. The reaction mixture was stirred at
08C for 2 h. A saturated aqueous solution of NaHCO3 (1 mL) was
then added. The aqueous layer was extracted with CH2Cl2 (2”
5 mL) and the combined organic extracts were stirred for 30 min
with a saturated aqueous solution of thiourea (1 mL). After separa-
tion, the organic phase was washed with brine (5 mL), dried over
MgSO4, filtered, and concentrated under reduced pressure. The iso-
lated material was purified by flash chromatography on silica gel
with varying gradients of petroleum ether and ethyl acetate to
afford the pure pyrrolidine product.
Scheme 12. Proposed mechanism for the activation of aziridines by [Rh]2=
NTces.
General procedure for intermolecular deamination
[Rh2(esp)2] (7.6 mg, 2.9 mmol, 0.02 equiv) and the substrate
(0.20 mmol, 1.0 equiv) were added to a solution of TcesNH2 (50 mg,
0.22 mmol, 1.5 equiv) in chlorobenzene/benzene (3/1, 2.0 mL). To
this mixture was added PhI(NTs2)2 (256 mg, 0.30 mmol, 1.5 equiv).
During the addition of PhI(NTs2)2 a color change from green to red-
Conclusion
We have demonstrated that the rhodium-catalyzed intermolec-
ular addition of nitrenes to alkenes affords direct access to 1,2-
amino alcohols or 1,2-diamines in good yields and, most im-
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brown was generally observed. The reaction mixture was stirred at
room temperature (258C) for 24 h. A saturated aqueous solution of
NaHCO3 (1 mL) was then added. The aqueous layer was extracted
with CH2Cl2 (2”5 mL) and the combined organic extracts were
stirred for 30 min with a saturated aqueous solution of thiourea
(1 mL). After separation, the organic phase was washed with brine
(5 mL), dried over MgSO4, filtered, and concentrated under reduced
pressure. The isolated material was purified by flash chromatogra-
phy on silica gel with varying gradients of petroleum ether and
ethyl acetate to afford the pure pyrrolidine product.
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Acknowledgements
Support and sponsorship from the EC (IEF to J.C.; PIEF-GA-
2013-623255) are kindly acknowledged. We wish to thank the
Institut de Chimie des Substances Naturelles for financial sup-
port and fellowships (G.D.). This work is supported by a public
grant overseen by the French National Research Agency (ANR)
(program n8 ANR-11-IDEX-0003-02 and CHARMMMAT ANR-11-
LABX-0039). V.G. thanks UPS and IUF for financial support. V.G.
also thanks Pr. T. Mallah for useful discussion. We used the
computing facility of the CRIHAN (project 2006–2013).
Keywords: amination · oxyamination · reaction mechanisms ·
rhodium · synthetic methods
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[17] Examples of alkenes that do not react or give a complex mixture of
products: a-pinene, nerol, cyclohexadiene, ethyl (2E,4E)-5-phenylpent-
2,4-dienoate, and ethyl acrylate.
[18] The reaction also proceeds in other solvents, such as trifluorotoluene,
CH2Cl2, and acetonitrile, but the yields are significantly lower or the re-
action results in complex mixtures.
[19] Different protecting groups, such as 4-nitrobenzenesulfonyl (Ns) and
tert-butoxycarbonyl (Boc), were also screened for this cyclization. The
corresponding Ns-protected analogue of 3a generated the desired cy-
clized product in 68% yield (see Supporting Information). However,
when Boc was used as a protecting group, only a complex mixture was
obtained.
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[26] The DFT calculations suggest that protolysis of the NÀRh bond of 1(H)
would lead to the formation of the corresponding hydrazine and A.
The process is exergonic by À19.0 kcalmolÀ1. Test reactions with aziri-
dine 7 in the presence of 0.5 equiv of [Rh2(esp)2], the iodine oxidant,
and TcesNH2 were carried out to isolate the putative hydrazine, albeit
with no success.
[27] The Lewis acidic character of rhodium-bound nitrenes is reminiscent of
that reported for dirhodium carboxamidates: a) X. Wang, C. Weigl, M. P.
Doyle, J. Am. Chem. Soc. 2011, 133, 9572–9579; b) X. Xu, X. Wang, Y.
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Received: January 27, 2016
[20] For examples of aziridine ring opening with O nucleophiles, see: a) X. E.
Hu, Tetrahedron 2004, 60, 2701–2743; b) B. M. Trost, T. Zhang, Angew.
Published online on June 3, 2016
Chem. Eur. J. 2016, 22, 9338 – 9347
www.chemeurj.org
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