Diastereotopos-differentiation in the Rh-catalyzed amination of benzylic methylene groups in the α-position to a stereogenic center

Article abstract of DOI:10.1021/ja3066682

The diastereoselectivity of the Rh-catalyzed C-H amination was examined with 18 chiral open-chain substrates, which bear a benzylic methylene group in the α-position to a stereogenic center (-CHMeX), and with four chiral cyclic tetralins, in which the stereogenic center was positioned at carbon atom C2. The C-H amination was performed using trichloroethoxysulfonyl-substituted amine (H₂NTces) as the nitrogen source, a diacyloxyiodobenzene as the oxidant, and bis[rhodium(α,α,α',α'-tetramethyl-1,3- benzenedipropionate)] [Rh₂(esp)₂] as the catalyst. For acyclic substrates a high syn diastereoselectivity (dr > 95/5) was found if the substituent X was Br, PO(OEt)₂, SO₂Ph, or OOCCF ₃ (eight examples). Moderate to good syn selectivities (dr = 80/20 to 91/9) were found for X = NO₂, OAc, COOMe, and CN (eight examples). Only two substrates gave a low diastereoselectivity. Kinetic isotope effect (KIE) experiments revealed that there is no secondary KIE when replacing -CHMeCOOMe by -CDMeCOOMe, but there is a significant primary KIE at the benzylic methylene position (4.8 ± 0.7). Deuteration experiments provided evidence that the reaction proceeds stereospecifically with retention of configuration. A preferred conformation is proposed, which explains the outcome of the reaction. In this conformation the X substituent is antiperiplanar to the C-H bond, which is diastereoselectively attacked, and steric strain between the remaining substituents at the stereogenic and the prostereogenic center is minimized. DFT calculations support this model. They suggest, however, that the reaction is not concerted but occurs via hydrogen atom abstraction and subsequent radical rebound. Further support for an antiperiplanar attack relative to a given substituent X = Br, COOMe, or CN was obtained with the respective 2-substituted tetralins. Attack at C1 provides almost exclusively the trans-amination product. If the size of the X substituent increases [Br < CN < COOMe < PO(OEt)₂], attack at the carbon atom C4 prevails, delivering the respective trans-amination products at this position.

Full text of DOI:10.1021/ja3066682

Article
pubs.acs.org/JACS
Diastereotopos-Differentiation in the Rh-Catalyzed Amination of
Benzylic Methylene Groups in the α‑Position to a Stereogenic Center
Anike Norder, Sarah A. Warren, Eberhardt Herdtweck, Stefan M. Huber, and Thorsten Bach*
̈
Department Chemie and Catalysis Research Center (CRC) Technische Universitat Munchen, D-85747 Garching, Germany
̈
̈
S
* Supporting Information
ABSTRACT: The diastereoselectivity of the Rh-catalyzed C−
H amination was examined with 18 chiral open-chain
substrates, which bear a benzylic methylene group in the α-
position to a stereogenic center (−CHMeX), and with four
chiral cyclic tetralins, in which the stereogenic center was
positioned at carbon atom C2. The C−H amination was
performed using trichloroethoxysulfonyl-substituted amine
(H2NTces) as the nitrogen source, a diacyloxyiodobenzene
as the oxidant, and bis[rhodium(α,α,α′,α′-tetramethyl-1,3-benzenedipropionate)] [Rh2(esp)2] as the catalyst. For acyclic
substrates a high syn diastereoselectivity (dr > 95/5) was found if the substituent X was Br, PO(OEt)2, SO2Ph, or OOCCF3
(eight examples). Moderate to good syn selectivities (dr = 80/20 to 91/9) were found for X = NO2, OAc, COOMe, and CN
(eight examples). Only two substrates gave a low diastereoselectivity. Kinetic isotope effect (KIE) experiments revealed that there
is no secondary KIE when replacing −CHMeCOOMe by −CDMeCOOMe, but there is a significant primary KIE at the benzylic
methylene position (4.8 0.7). Deuteration experiments provided evidence that the reaction proceeds stereospecifically with
retention of configuration. A preferred conformation is proposed, which explains the outcome of the reaction. In this
conformation the X substituent is antiperiplanar to the C−H bond, which is diastereoselectively attacked, and steric strain
between the remaining substituents at the stereogenic and the prostereogenic center is minimized. DFT calculations support this
model. They suggest, however, that the reaction is not concerted but occurs via hydrogen atom abstraction and subsequent
radical rebound. Further support for an antiperiplanar attack relative to a given substituent X = Br, COOMe, or CN was obtained
with the respective 2-substituted tetralins. Attack at C1 provides almost exclusively the trans-amination product. If the size of the
X substituent increases [Br < CN < COOMe < PO(OEt)2], attack at the carbon atom C4 prevails, delivering the respective trans-
amination products at this position.
INTRODUCTION
■
Acyclic stereocontrol1 has revolutionized the way organic
chemists conceive and solve synthetic challenges in the total
synthesis of complex natural products. For example, the
prototypical question of facial diastereoselectivity in carbonyl
addition reactions to α-chiral ketones or aldehydes2 has been
the source of literally hundreds of imaginative studies, which in
turn have accumulated a wealth of information on the subject.
There is a legion of diastereoselective substrate-induced
reactions,3 and the number continues to grow to this date.
Studies in this area have most commonly been concerned with
the differentiation of diastereotopic faces at prostereogenic
carbon atoms in double bonds. Less attention has been devoted
to the differentiation of diastereotopic atoms or diastereotopic
groups. Reactions, which occur with significant selectivity
toward diastereotopic atoms or groups, are called
diastereotopos-differentiating reactions.4,5 In connection with
our interest in the facial diastereoselectivity of reactions at
benzylic cation centers,6 we have some time ago performed
some preliminary studies in the field of diastereotopos-
differentiating C−H activation reactions.7 The key question
was whether the two diastereotopic C−H bonds in benzylic
substrates of type A (Figure 1) can be differentiated as a
Figure 1. General structure of amination substrates A with the
diastereotopic hydrogen atoms marked in α-position and more specific
structures 1 and 2 of compounds used in the present study.
consequence of the steric and electronic properties of the
substituents X, R, and H at the adjacent stereogenic center. As a
test reaction the nitrene insertion (amination)8,9 of trichlor-
oethoxysulfonyl-substituted amine (H2NTces) with bis-
[rhodium(α,α,α′,α′-tetramethyl-1,3-benzenedipropionate)]
[Rh2(esp)2] as the catalyst and diacetoxyiodobenzene as the
oxidant was chosen. This protocol has been successfully
elaborated by Du Bois et al. and has shown its value for
catalytic intermolecular amination reactions.10 No attempt was
made on our part to improve the Du Bois protocol; rather, it
served as a well-established test reaction to investigate the
question of acyclic diastereotopos-differentiation.
Received: July 9, 2012
Published: August 6, 2012
© 2012 American Chemical Society
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It was found in preliminary work11 that substrates 1 [X =
PO(OEt)2, SO2Ph, NO2, OAc, COOMe, CN] deliver an
unexpectedly high diastereoselectivity in amination reactions
and produce major diastereoisomers, in which the Tces-
protected amino group resides syn to the methyl group in the
representation chosen in Figure 1. The reaction was shown to
proceed racemization-free if compounds of type 1 were used in
enantiomerically pure form and therefore does hold some
promise for diastereoselective C−H insertion reactions under
acyclic stereocontrol. In order to collect further data about the
effects, which are responsible for the diastereotopos-differ-
entiation, additional studies have now been conducted with
different precursors of general type A. In addition, DFT
calculations have been performed, which support mechanistic
conclusions drawn from the reaction of acyclic substrates 1 and
of cyclic amination precursors 2. Details of this work are
reported in the present account.
Table 1. Diastereotopos-Differentiation in C−H Amination
Reactions at the Benzylic Position of Chiral Substrates 1
a
b
c
entry
substrate
X
yield [%]
dr
1
1a
1b
1c
1d
1e
1f
Br
89
65
56
>95/5
>95/5
>95/5
>95/5
91/9
2
PO(OEt)2
SO2Ph
3
d
4
OOCCF3
NO2
28
5
63
d
6
OAc
40
86/14
82/18
80/20
62/38
60/40
7
1g
1h
1i
COOMe
CN
81
86
44
70
8
9
CH2OTBS
CH2OAc
10
1j
a
H2NTces (0.5 mmol) and Rh2(esp)2 (0.01 mmol) were dissolved in
benzene (1.5 mL). Substrate 1 (1.0 mmol) was added to the stirred
solution at 25 °C, and the oxidant (0.75 mmol) was added in portions
over 2 h. The reaction was quenched with a saturated aqueous solution
b
of thiourea (5 mL) after 16 h. Yields of the diastereomeric mixture
RESULTS AND DISCUSSION
c
■
based on nitrene source H2NTces. The diastereomeric ratio (dr =
d
syn/anti) was determined by 1H NMR. Incomplete conversion;
Acyclic Diastereotopos-Differentiation. Reactions with
substrates 1 were performed in benzene solution using
H2NTces as the nitrogen source, PhI(OAc)2 as the
stoichiometric oxidant, and Rh2(esp)2 as the catalyst (Scheme
1). The diastereomeric products syn-3 and anti-3 were isolated
impure H2NTces was reisolated.
uous evidence, the major product syn-3d was converted into
acetate syn-3f by reduction (NaBH4 in MeOH)13 to the free
alcohol and subsequent acetylation (Ac2O, DMAP, NEt3).14
Acetate 1f belongs together with nitro compound 1e (entry 5),
ester 1g (entry 7), and nitrile 1h (entry 8) to the substrates,
which gave moderate to good selectivities (dr = 80/20 to 91/
9). While the relative configuration of products syn-3e and syn-
3g were also proven by X-ray analysis,11 the configuration of
nitrile syn-3h was elucidated by its conversion into methyl ester
syn-3g employing the Pinner reaction15 (HCl in MeOH). The
protected primary alcohol derivatives 1i (entry 9) and 1j (entry
10) exhibited only low diastereoselectivity, and no effort was
made to determine the relative configuration of the major
diastereoisomer. However, on the bases of analogy and
mechanistic considerations (vide infra) it appears likely that
the major diastereoisomer was the syn product. In general, no
H2NTces was recovered in the amination reaction, and the
reaction was complete regarding its conversion. Only in two
cases (entries 4 and 6) was it apparent that the reaction had not
gone to completion. Since the separation of H2NTces from the
products was difficult, the amount of recovered H2NTces could
not be quantified, and the relative low yields in these cases were
due to incomplete conversion and separation problems. The
yields provided in Table 1 refer to pure products 3 and are not
based on recovered starting material.
Electronic and steric factors regarding the substituent X
limited the scope of the study in a few directions. For large
groups X (X = t-Bu, CMe2OAc) there were only traces of
product detectable, and the nitrogen source was largely
reisolated. If the substituent X was an oxygen substituent,
which was not acceptor substituted, e.g. X = OH, OMe, OTMS,
there was no conversion at all. From a synthetic point of view
the results, in which a single diastereoisomer was the exclusive
product, are certainly most useful. A few substrates related to
phosphonate 1b and sulfone 1c were synthesized and
submitted to the amination conditions (Scheme 2). It turned
out that the reactions proceeded equally selective for precursors
4 and 6, giving stereoselective access to β-amino substituted
phosphonates and sulfones 5 and 7. Diastereomerically pure
(dr > 95/5) products were isolated, to which the syn
configuration was assigned on the basis of analogy. The
Scheme 1
as a mixture of diastereoisomers. Their relative ratio (dr) was
1
determined by integration of appropriate signals in the H
NMR spectrum. It was shown that the diastereomeric ratio
remained within an error limit of 5%, unchanged upon
purification. However, a precise determination of the dr in
the crude product mixture was difficult because unreacted
substrate and reagents were still present. For better accuracy in
the determination of the dr it was favorable to employ the
purified mixture of diastereomers rather than the crude product
mixture. It was ensured that the complete product was collected
and that no change of the dr could occur. Indeed, most
diastereoisomeric products showed identical Rf values. If this
was not the case, the sample collection was followed by careful
TLC analysis. When in doubt, the dr of the pure product
mixtures was checked against the crude product.
The results of this comprehensive study are summarized in
Table 1, in which the substrates are listed according to
decreasing diastereoselectivity. The most selective reactions (dr
> 95/5) were observed for heteroatomic substituents X = Br
(entry 1), X = PO(OEt)2 (entry 2), X = SO2Ph (entry 3), and
X = OOCCF3 (entry 4). The relative configuration of products
syn-3a,12 syn-3b, and syn-3c was determined by single crystal X-
ray crystallography. The relative configuration of product syn-
3d was assigned on the basis of analogy to the relative
configuration determined by X-ray analysis for the major
acetate diastereoisomer syn-3f (entry 6). To obtain unambig-
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gave the respective C−H amination product in 59% yield and
with a dr > 95/5 (see SI for further details).
Scheme 2
Reaction of Deuterated Substrates. Two deuterated
substrates 1g-d1 (Scheme 4) and 1g-d2 (Scheme 5) were
Scheme 4
Scheme 5
functional group tolerance of the amination conditions toward
the indole core and the tert-butoxycarbonyl (Boc) group is
notable. Despite the fact that synthetic optimization of the
amination reaction was not the focus of this work, the finding
by Du Bois et al.,16 that PhI(OOCCMe2Ph)2 is in many cases
an oxidant superior to diacetoxyiodobenzene, could be
corroborated. Yields in the reaction of indole derivatives 5
were significantly higher with the former oxidation reagent than
with the latter.
By choosing substrates 8 with a moderately strong directing
group X (X = COOMe) at the stereogenic center, it was
explored whether the para substituent R in the benzylic
substrate exerts a significant influence on the diastereoselectiv-
ity (Scheme 3). For this study, PhI(OOCCMe2Ph)2 turned out
prepared in order to obtain possible information about the
reaction course via kinetic isotope effects (KIEs). In the first
experiment, ester 1g-d1, which was readily available by
quantitative deprotonation of ester 1g and subsequent quench
with D2O, was subjected to the amination reaction conditions
in an intermolecular competition experiment with the
undeuterated substrate 1g. No secondary KIE was observed
(Scheme 4). The products 3g and 3g-d1 were obtained in a 50/
1
50 ratio at the detection level of H NMR spectroscopy. The
Scheme 3
predominant product was the syn product, syn-3g-d1, and there
were no differences in the diastereomeric ratio compared to
that of the undeuterated product syn-3g.
A second experiment was performed with a doubly
deuterated substrate 1g-d2, which carried both deuterium
atoms in the benzylic position. The substrate was readily
available by alkylation of methyl propionate with
p-methoxybenzyl bromide-d2 (see Supporting Information).
In the amination experiments a significant primary KIE was
detected. The deuterated substrate, 1g-d2, reacted significantly
more slowly than the undeuterated substrate, 1g (Scheme 5).
The diastereomeric ratio remained unchanged, and the α-
monodeuterated product 3g-d1α was formed also predom-
inantly as the syn-diastereoisomer.
Deuterated substrates were also employed to address the
question of stereospecifity in the amination reaction. The
monodeuterated compounds syn-1g-d1 and anti-1g-d1 were
obtained by reduction of the respective alcohols with Et3SiH or
Et3SiD (see Supporting Information), which occurs with high
diastereoselectivity (dr = 94/6) via chiral benzylic carboca-
tions.6 If the amination proceeds with retention of config-
uration, it is expected that the amination provides a maximum
of two products. Given the preference for hydrogen abstraction
over deuterium abstraction (KIE = 4.8) and given the observed
diastereoselectivity in the amination of substrate 1g (dr = 82/
18), it was anticipated that substrate anti-1g-d1 would provide
essentially a single product, in what could be considered a
matched situation. Indeed, product syn-3g-d1α was observed as
to be the superior oxidant. In the case of N-acetylaniline 8d the
oxidant was added by syringe pump. In all other cases it was
added over 2 h in portions. The diastereoselectivity of the
reactions varied little as compared to those of the reaction of
the p-methoxy-substituted substrate 1g (Table 1, entry 7, dr =
82/18), and a significant influence of R was not detected. The
reactivity of the substrates was sufficient, and products 9 were
obtained in good to moderate yields (40−65%). If the
substituent R was strongly electron withdrawing (R = NO2),
no amination reaction was observed. The latter observation is
in accord with the electrophilic nature of the putative rhodium
nitrenoid intermediate (vide infra).
The stereochemical outcome was not dependent on the
choice of the amine protecting group. Reactions performed
with p-nitrobenzenesulfonyl-protected amine (NsNH2)17 under
otherwise identical conditions resulted in the same
diastereoselectivity. As an example, conversion of bromide 1a
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the predominant product together with minor amounts (4%) of
anti-3g (Scheme 6).
Scheme 6
Figure 2. Conformations I−III responsible for the formation of either
anti or syn diastereomeric products in the reaction of substrates 1
(PMP = p-methoxyphenyl).
substituent is eventually attached, has positive partial charge in
the transition state of the amination reactions, we had earlier
considered11 conformation II to be responsible for the
diastereoselection, because we speculated that the incipient
positive charge would be best stabilized by an antiperiplanar
C−H bond. As a result, the favored transition state should be
transition state TSsyn‑II (Figure 3), which emanates from
In the mismatched situation expected for substrate syn-1g-d1
and under the provision that the reaction proceeds stereo-
specifically, two products should be formed in almost equal
amounts. Indeed, when submitting substrate syn-1g-d1 to the
typical reaction conditions of the amination reaction (Table 1)
we observed a relatively slow reaction, which led to two
products, i.e. the nondeuterated product syn-3g (dr > 95/5)
and the deuterated product anti-3g-d1α (dr = 95/5). The
product ratio was 58/42 (Scheme 7).
Scheme 7
Figure 3. Transition states TSsyn‑II and TSsyn‑I of a diastereoselective
amination reaction evolving from two of the conformations depicted in
Figure 2.
conformation II and in which the syn hydrogen atom is
abstracted. In this graphic, [Rh] symbolizes a ligated rhodium
metal center. The question whether the reaction proceeds
stepwise or concerted is not relevant to this discussion but will
be addressed further below. A normal (positive) secondary KIE
was expected if such a hyperconjugative stabilization was
significant. In the reaction of 1g-d1 (Scheme 4) no KIE was
detectable (kH/kD = 1.0), however, and there was no change in
diastereoselectivity when comparing the respective products, 3g
and 3g-d1. Although it is well established that secondary kinetic
deuterium isotope effects are not high,21 the results raised
doubts about the initial hypothesis. This was more true as it was
not clear why conformation syn-II would be different from
conformation anti-I (Figure 2) with an antiperiplanar C−H
bond to the “wrong” hydrogen atom (anti-H). In addition, the
repulsion of the substituent X with the partially negative charge
at the reactive nitrogen atom was not taken into account. This
interaction would be minimized in conformations I (for syn-H)
via TSsyn‑I (Figure 3) and III (for anti-H).
In order to obtain a more detailed picture about the C−H
insertion reaction, DFT calculations were performed. A related
theoretical study on the intramolecular amidation of carbamates
by Che et al.22 came to the conclusion that Rh2II,II−nitrene
complexes are the actual NR-delivering intermediates, with the
respective triplet species being slightly more favorable than the
singlet species. Two feasible reaction pathways were inves-
tigated: namely, a concerted insertion mechanism by a singlet
nitrenoid and a radical abstraction/recombination pathway by a
triplet nitrenoid. Che et al. found the singlet reaction pathway
to be more favorable overall for the intramolecular trans-
formation they studied. Since the findings of Che et al.22 were
in accord with experimental results by Espino and Du Bois,23
we chose to employ the same computational method for our
investigations, i.e. the Becke BPW91 functional24 with a 6-31G*
basis set for all atoms except Rh, for which the LANL2DZ25
The latter study provides unambiguous evidence that the
amination at the benzylic methylene group of substrates 1
proceeds stereospecifically with retention of configuration. This
result is in line with previously reported experiments performed
at tertiary benzylic C−H bonds, which was also shown to occur
stereospecifically.10b
Mechanistic Considerations and DFT Calculations. It is
generally accepted that Rh-catalyzed nitrene insertion reactions
proceed via an intermediate Rh nitrene complex, in which the
nitrene is bound to the free coordination site of the binuclear
Rh complex. In analogy to the Rh-catalyzed carbene insertion
reaction the insertion of a rhodium nitrenoid into a C−H bond
has been described to occur in a “concerted but highly
asynchronous manner” (concerted mechanism).18,19 Alterna-
tively, the reaction pathway can be envisaged to include a
complete hydrogen abstraction by the nitrenoid complex and a
subsequent rapid C−N bond formation (rebound mecha-
nism).20 In either case, the electrophilic nitrogen atom pulls off
the hydrogen atom from the carbon atom, to which the latter is
bound. An incipient positive charge develops at the carbon
atom, and the nitrogen atom becomes negatively charged.
When considering possible staggered conformations I−III of
substrates 1 (Figure 2), it is obvious that C−H insertion into
the carbon−hydrogen bond marked by a red box provides the
anti products anti-3, whereas C−H insertion into the carbon−
hydrogen bond marked in blue gives the syn products syn-3.
Upon its way to the transition state the hydrogen atom
becomes detached from the prostereogenic carbon center. On
the basis of the fact that the carbon atom, to which the nitrogen
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basis set with the corresponding pseudopotential was used (for
more details see the Supporting Information). For computa-
tional efficiency, the p-methoxyphenyl substituent and the
acetate ligands were replaced by a phenyl substituent and
formate ligands, respectively. The nitro group was chosen as a
prototypical X substituent, and for all possible conformations of
the substrate (denoted I to III in analogy to Figure 2), the
corresponding transition states for the reaction with the
Rh2II,II−nitrene complex were determined.
Despite various attempts to find concerted transition states
on the singlet energy surface, no such species could be
obtained. Instead, singlet transition states corresponding to a
hydride transfer from the substrate to the nitrogen atom of the
nitrene species were found. Thus, in stark contrast to the
findings by Che et al. for an intramolecular transformation (see
above), the intermolecular reaction considered here seems to
proceed on the singlet surface via a hydrogen atom transfer/
recombination pathway. The most favorable of the singlet
transition states, however, corresponding to the reaction of syn-
I with the nitrenoid, was less favorable by about 9.5 kJ/mol in
free energy than the most favorable triplet transition state
(TSsyn‑I, see below).
The two alternative transition states for the abstraction of the
syn hydrogen of the substrate (Figure 2) are 47 kJ/mol
(TSsyn‑II) and 16 kJ/mol (TSsyn‑III) higher in free energy and
feature activation barriers of at least 69 kJ/mol (TSsyn‑III). The
most favorable transition state TSsyn‑I, shown in Figure 4,
explains the experimental findings presented above (Table 1,
substrate 1e), assuming that the two radicals formed in the
hydrogen abstraction step quickly recombine in a subsequent
step. In TSsyn‑I, the hydrogen abstraction proceeds via a quasi-
linear arrangement of C−H−N (173°), with a C−H distance of
1.30 Å (vs 1.10 Å in the isolated substrate) and a H−N distance
of 1.40 Å. Other notable differences in geometrical features of
the transition state compared to those of the starting materials
include a somewhat narrower Rh−N−S angle within the
nitrenoid part (128° vs 133° in the isolated nitrenoid) and a
C−C bond of the carbon at the hydrogen abstraction site that is
shortened with respect to that in the phenyl moiety (1.47 Å vs
1.52 Å in the isolated substrate). In addition, the sum of angles
of the three unreactive bonds around the carbon atom of the
hydrogen abstraction site indicate that the substrate is already
markedly planarized (345° vs 333° in the isolated substrate and
360° in the radical). Mulliken atomic spin densities show that
the spin is mainly located at the nitrogen of the nitrenoid
(0.70) and the carbon of the hydrogen abstraction site (0.30),
whereas the hydrogen atom itself carries only negligible spin
density (−0.02).
Further insight into the nature of the transition state was
sought by an analysis of the charge densities, obtained by a
natural bond order (NBO)28 analysis. Analogous to the
situation discussed above for the concerted singlet mechanism,
the nitrogen atom of the nitrenoid is markedly more negatively
charged (−0.73 vs −0.52 in the isolated nitrenoid), while the
carbon atom of the abstraction site and the hydrogen atom
itself are somewhat more positively charged (−0.42 vs −0.51
and +0.34 vs +0.26 in the transition state vs the pure substrate,
respectively). Overall, the substrate fragment without the
leaving hydrogen atom is almost neutral in the transition
state (overall charge +0.01), while the nitrenoid part features a
negative charge that is essentially equivalent (in absolute terms)
to the positive charge of the hydrogen atom (−0.35 vs +0.34).
The energetic preference of TSsyn‑I over the five alternative
transition states is likely based on steric and electronic reasons.
For instance, in the transition states TSanti‑I and TSsyn‑II, both
the X (nitro) and the methyl substituent of the saturated
carbon atom next to the hydrogen abstraction site point toward
the nitrenoid, likely causing increased steric hindrance in
comparison with the four remaining alternative transition states,
which feature at least one hydrogen atom pointing toward the
nitrenoid instead. In the fragment −CHMeNO2 the nitro group
bears a significant negative charge (−0.20). It is therefore likely
that the electrostatic repulsion between the nitro group and the
nitrogen atom of the nitrenoid force the nitro group to adopt a
conformation that is antiperiplanar to the abstracted hydrogen
atom (Scheme 8).
On the triplet energy surface, transition states for the
hydrogen atom abstraction by the nitrenoid were determined
for all six reactive orientations of the substrate (compare Figure
2).26 As already indicated, the most favorable transition state
was the one referring to syn-I, analogous to the singlet case.
This transition state, TSsyn‑I (Figure 4) features the lowest
Figure 4. Most favorable (triplet) transition state TSsyn‑I. Purple = Rh,
yellow = S, green = Cl, blue = N, red = O, gray = C, white = H. The
figure was prepared with CYLview.27
The same argument holds for all other substituents X, which
should encounter a similar repulsion. In order to get an idea
whether additional electronic effects might stabilize TSsyn‑I, we
took the geometries of the substrate part of the transition states
(without the leaving hydrogen atom) and determined the
relative stabilities of the respective radical species (i.e., without
reoptimizing the geometry). Indeed, the radical corresponding
to TSsyn‑I was significantly more stable than the ones referring
to the other transition states (with the next most stable ones,
relative free energy with respect to the other alternatives, as well
as the lowest activation barrier of all six hydrogen abstraction
processes (58 kJ/mol). More precisely, the transition states
corresponding to the abstraction of the anti hydrogen atom of
the substrate (as denoted in Figure 2) are approximately 39 kJ/
mol (TSanti‑I), 9 kJ/mol (TSanti‑II), and 14 kJ/mol (TSanti‑III
)
higher in energy and feature activation barriers of at least 67 kJ/
mol (TSanti‑III).
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range of 60−70% for all four cases studied. However, it was
found that the regioselectivity of the attack varied, depending
on the substituent X. For X = Br (entry 1) the expected C1-
amination product 10a was exclusively formed, whereas all
other substrates (entries 2−4) gave product mixtures, in which
both C1- and C4-amination products could be detected.
Although the purpose of these experiments was to study the
diastereoselectivity of the amination reaction at C1 (products
10), the observation of C4-amination products 11 is interesting
and will be discussed further below. Regarding the diaster-
eoselectivity at C1, it is notable that in all four cases a high
selectivity was observed for the formation of one diaster-
eoisomer (dr = 90/10 to >95/5).
Scheme 8
corresponding to TSanti‑II and TSanti‑I, being respectively 4 and 9
kJ/mol less stable).
The structure elucidation of products 10 (Figure 6) could
only be performed for products 10a, 10c, and 10d. The
reaction of phosphonate 2b resulted in insufficient quantities of
product 10b, which in addition was difficult to separate from
other diastereo- and regioisomers. The relative configuration of
product 10d was unequivocally established by single-crystal X-
ray analysis as trans (trans-10d).30 A remarkable feature of the
product conformation, which was further corroborated by
NMR data, is the perfectly antiperiplanar position of the cyano
group at C2 and the NHTces group at C1. The coupling
constant for the protons at C1 and C2 is low (3J = 3.3 Hz)
indicating that this conformation is also prevalent in solution.
The relative configuration of bromide 10a was elucidated by
comparison with compound trans-10a, which was independ-
ently prepared by the stereospecific anti-aminobromination31 of
the respective 3,4-dihydronaphthalene (see SI for further
details). The major diastereomeric C−H amination product
obtained from substrate 2a was in all respects identical to this
compound. As observed for trans-10d, the low coupling
constant for the protons at C1 and C2 (3J = 2.7 Hz) indicates
a preferred antiperiplanar orientation of the two substituents at
C1 and C2. The trans-configuration was also assigned to the
major diastereoisomer obtained by C−H amination of ester 2c.
In this case the compound was independently synthesized from
diastereomerically pure nitrile trans-10d by a Pinner reaction.
Despite the fact that the Pinner reaction did not proceed in
high yields (see SI), the identity of the compounds could be
The primary KIE for a reaction via transition state TSsyn‑I was
estimated computationally by replacing the abstracted hydro-
gen atom by a deuterium atom. The obtained value was
approximately 5.7 (see Supporting Information), which is
slightly higher than the experimental value (Scheme 5).
However, it should be noted that primary KIEs between 3.5
and 5.029 have been reported9c,g,20b for related Rh-catalyzed
amination reactions, for which the authors postulated a
concerted mechanism.
Cyclic Diastereotopos-Differentiation. Previous results
and the DFT calculations indicated that the diastereotopos-
differentiation might be due to a preferred C−H amination anti
to a given substituent X. In a cyclic array, a distinction between
an anti or syn approach relative to a given substituent is easily
possible. In substrates 2 for example the α-hydrogen atom at
position C1 of the tetralin is anti to the substituent X, whereas
the β-hydrogen atom is in a syn relationship (Figure 5). It
Figure 5. Chiral tetralin substrates 2 with two diastereotopic hydrogen
atoms Hα and Hβ and possible conformations IV and V.
should be possible for the substrates to adopt conformation IV
and V, in which either the substitutent X or the hydrogen atom
at C2 is antiperiplanar to the adjacent hydrogen atom at C1. If
the above-mentioned hypothesis was correct, a significant
preference for amination at the α-hydrogen atom was to be
observed leading to a trans-1,2-disubstituted tetralin.
Reactions with substrates 2 were performed under the
conditions previously employed for the reaction of acyclic
substrates 1. The chemoselectivity of the amination was
satisfactory (Scheme 9, Table 2), and yields were in the
1
clearly established by H NMR spectroscopy. The coupling
3
constant for the protons at C1 and C2 is J = 4.9 Hz.
From the results with substrates 2a, 2c, and 2d it is clear that
C−H insertion occurs at C1 selectively at the α-hydrogen atom
leading to the respective trans products. It is very likely that the
reaction proceeds via conformation IV (Figure 5), in which the
X substituent adopts an axial position and in which the axial
hydrogen atom is attacked. This conformation gets more
disfavored the larger the X substituent becomes. There is
apparently no reaction at C1 via conformation V with an
equatorial X substituent and an axial hydrogen atom at C2.
Instead of a reaction at C1 the respective amination takes place
at the C4−H bond. In line with a previous result10b the
respective attack leads to trans-configured products. For methyl
ester 11c and cyanide 11d, the configuration of the major
diastereoisomers was elucidated by single-crystal X-ray analysis
and the relative configuration confirmed to be trans-11c32 and
trans-11d.33 In the products, the substituents X are located
equatorially, and the NHTces is in an axial position. Like the
trans products, trans-10, the trans products at C4 are likely to
result also from an amination at the axial C−H bond.
Scheme 9
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Journal of the American Chemical Society
Article
Table 2. Regio- and Diastereoselectivity in C−H Amination Reactions at the Benzylic Position of Chiral Tetralin Substrates 2
a
b
c
d
e
entry
substrate
X
yield [%]
rr
dr (10)
dr (11)
1
2
3
4
2a
2b
2c
2d
Br
80
58
68
66
>95/5
20/80
57/43
83/17
>95/5
90/10
95/5
―
PO(OEt)2
COOMe
CN
>95/5
88/12
80/20
95/5
a
H2NTces (0.5 mmol) and Rh2(esp)2 (0.01 mmol) were dissolved in benzene (1.5 mL). Substrate 2 (1.0 mmol) was added to the stirred solution at
25 °C, and the oxidant (0.75 mmol) was added in portions over 2 h. The reaction was quenched with a saturated aqueous solution of thiourea (5
b
c
1
mL) after 16 h. Yields of the product mixture based on nitrene source H2NTces. The regioisomeric ratio (rr = 10/11) was determined by H
NMR. The diastereomeric ratio (dr = trans/cis) of compounds 10 was determined by H NMR. The diastereomeric ratio (dr = trans/cis) of
compounds 11 was determined by H NMR.
d
e
1
1
ACKNOWLEDGMENTS
■
This project was supported by the Deutsche Forschungsgemein-
schaft (Ba 1372-12) and by the TUM Graduate School. S.M.H.
acknowledges the Fonds der Chemischen Industrie for a Liebig
fellowship. We thank Dr. Markus Drees (TU Munchen) for
̈
helpful discussions regarding the computation of KIEs.
Figure 6. Products trans-10a, trans-10c, and trans-10d obtained by
diastereoselective C−H amination ot tetralins.
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■
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ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed experimental procedures, characterization data for new
compounds, X-ray crystallographic data, and details of the DFT
calculations. This material is available free of charge via the
Internet at http://pubs.acs.org.
Peillard, F.; Muller, P.; Dodd, R. H.; Dauban, P. J. Am. Chem. Soc.
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Int. Ed. 2008, 47, 9961−9964. (g) Huard, K.; Lebel, H. Chem.Eur. J.
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AUTHOR INFORMATION
Corresponding Author
thorsten.bach@ch.tum.de
■
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Notes
The authors declare no competing financial interest.
13530
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Journal of the American Chemical Society
Article
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̈
(12) syn-3a: colorless column, C12H15BrCl3NO4S, Mr = 455.57;
monoclinic, space group P21/n (No. 14), a = 11.1241(4) Å, b =
9.1560(3) Å, c = 17.8862(6) Å, β = 103.4214(15)°, V = 1772.00(11)
Å3, Z = 4, λ(Mo Kα) = 0.71073 Å, μ = 2.904 mm−1, ρcalcd = 1.708 g
cm−3, T = 123(1) K, F(000) = 912, θmax: 25.38°, R1 = 0.0252 (3126
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monoclinic, space group P21/c (No. 14), a = 10.2165(3) Å, b =
18.2740(6) Å, c = 10.1200(3) Å, β = 111.3324(12)°, V = 1759.92(9)
Å3, Z = 4, λ(Mo Kα) = 0.71073 Å, μ = 0.660 mm−1, ρcalcd = 1.561 g
cm−3, T = 123(1) K, F(000) = 848, θmax: 25.40°, R1 = 0.0254 (3078
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orthorhombic, space group Pca21 (No. 29), a = 18.4231(5) Å, b =
9.1321(3) Å, c = 10.0716(3) Å, V = 1694.46(9) Å3, Z = 4, λ(Mo Kα) =
0.71073 Å, μ = 0.686 mm−1, ρcalcd = 1.622 g cm−3, T = 123(1) K,
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̅
= 14.5195(4) Å, α = 88.5906(14)°, β = 78.7501(11)°, γ =
80.8585(12)°, V = 915.32(5) Å3, Z = 2, λ(Mo Kα) = 0.71073 Å, μ
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13531
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