Catalytic intermolecular amination of C-H bonds: Method development and mechanistic insights

Article abstract of DOI:10.1021/ja0650450

Reaction methodology for intermolecular C-H amination of benzylic and 3° C-H bonds is described. This process uses the starting alkane as the limiting reagent, gives optically pure tetrasubstituted amines through stereospecific insertion into enantiomeric 3° centers, displays high chemoselectivity for benzylic oxidation, and enables the facile preparation of isotopically enriched ¹⁵N-labeled compounds. Access to substituted amines, amino alcohols, and diamines is thereby made possible in a single transformation. Important information relevant to understanding the initial steps in the catalytic cycle, reaction chemoselectivity, the nature of the active oxidant, and pathways for catalyst inactivation has been gained through mechanistic analysis; these studies are also presented.

Full text of DOI:10.1021/ja0650450

Published on Web 01/03/2007
Catalytic Intermolecular Amination of C-H Bonds:
Method Development and Mechanistic Insights
Kristin Williams Fiori and J. Du Bois*
Contribution from the Department of Chemistry, Stanford UniVersity,
Stanford, California 94305-5080
Received July 15, 2006; E-mail: jdubois@stanford.edu
Abstract: Reaction methodology for intermolecular C-H amination of benzylic and 3° C-H bonds is
described. This process uses the starting alkane as the limiting reagent, gives optically pure tetrasubstituted
amines through stereospecific insertion into enantiomeric 3° centers, displays high chemoselectivity for
benzylic oxidation, and enables the facile preparation of isotopically enriched 15N-labeled compounds. Access
to substituted amines, amino alcohols, and diamines is thereby made possible in a single transformation.
Important information relevant to understanding the initial steps in the catalytic cycle, reaction chemose-
lectivity, the nature of the active oxidant, and pathways for catalyst inactivation has been gained through
mechanistic analysis; these studies are also presented.
Introduction
The invention of efficient and selective chemical methods
for C-H bond oxidation poses a formidable challenge in
reaction design. While versatile protocols for both C-H
amination and hydroxylation have become available in recent
years, the vast majority of such processes are directed by
attendant functional groups through covalent or noncovalent
attachments.1,2 The power of these methods notwithstanding,
high yielding, chemoselective intermolecular oxidation of C-H
centers remains a most alluring problem of great potential
reward.3 This report documents a catalytic intermolecular
oxidation method made possible through the advent of Rh2-
(esp)2 (Figure 1).4-6 Combining this unique dimeric Rh tetra-
Figure 1. Amine synthesis through intermolecular C-H amination.
carboxylate with an appropriate nitrogen source and an inex-
pensive terminal oxidant provides ready access to value-added
amine derivatives. Importantly, the intermediate Rh-nitrene
shows discriminate reactivity, oxidizing preferentially benzylic
C-H groups over all others. Reactions are typically conducted
using limiting amounts of the starting alkane, a second
distinguishing feature of this process. Consequently, select
mono- and diamines, amino alcohols, and amino esters are
afforded in a single step.
(1) (a) Espino, C. G.; Du Bois, J. In Modern Rhodium-Catalyzed Organic
Reactions; Evans, P. A., Ed.; Wiley-VCH: Weinheim, 2005; pp 379-
416. (b) Davies, H. M. L. Angew. Chem., Int. Ed. 2006, 45, 6422-6425.
(c) Lebel, H.; Leogane, O.; Huard, K.; Lectard, S. Pure Appl. Chem. 2006,
78, 363-375. (d) Halfen, J. A. Curr. Org. Chem. 2005, 9, 657-669. (e)
Mu¨ller, P.; Fruit, C. Chem. ReV. 2003, 103, 2905-2919. (f) Dauban, P.;
Dodd, R. H. Synlett 2003, 1571-1586.
(2) For some recent examples, see: (a) Fraunhoffer, K. J.; Prabagaran, N.;
Sirois, L. E.; White, M. C. J. Am Chem. Soc. 2006, 128, 9032-9033. (b)
Giri, R.; Liang, J.; Lei, J.-G.; Li, J.-J.; Wang, D.-H.; Chen, X.; Naggar,
I. C.; Guo, C.; Foxman, B. M.; Yu, J.-Q. Angew. Chem., Int. Ed. 2005, 44,
7420-7424. (c) Desai, L. V.; Hull, K. L.; Sanford, M. S. J. Am. Chem.
Soc. 2004, 126, 9542-9543. (d) Wong, M.-K.; Chung, N.-W.; He, L.; Yang,
D. J. Am. Chem. Soc. 2003, 125, 158-162. (e) Dangel, B. D.; Johnson,
J. A.; Sames, D. J. Am. Chem. Soc. 2001, 123, 8149-8150.
(3) For representative examples of intermolecular C-H amination, see: (a)
Fruit, C.; Mu¨ller, P. Tetrahedron: Asymmetry 2004, 15, 1019-1026. (b)
D´ıaz-Requejo, M. M.; Belderra´ın, T. R.; Nicasio, M. C.; Trofimenko, S.;
Pe´rez, P. J. J. Am. Chem. Soc. 2003, 125, 12078-12079. (c) Yamawaki,
M.; Tsutsui, H.; Kitagaki, S.; Anada, M.; Hashimoto, S. Tetrahedron Lett.
2002, 43, 9561-9564. (d) Liang, J.-L.; Yuan, S.-X.; Chan, P. W. H.; Che,
C.-M. Org. Lett. 2002, 4, 4507-4510. (e) Yu, X.-Q.; Huang, J.-S.; Zhou,
X.-G.; Che, C.-M. Org. Lett. 2000, 2, 2233-2236. (f) Yang, J.; Weinberg,
R.; Breslow, R. Chem. Commun. 2000, 531-532.
Results and Discussion
Reaction Optimization. Early studies to define favorable
reaction conditions for promoting effective intermolecular
amination of C-H bonds focused on the choice of amide
nitrogen source. The availability and stability of sulfamate esters
make them particularly attractive reagents for such a process.7
In model reactions performed with 2 mol % Rh2(esp)2, 1 equiv
of ethylbenzene as substrate, and an iodine(III) oxidant, sulfa-
mate esters derived from aliphatic alcohols (Table 1, entries 1,
2) proved superior to all other sulfonamides and amides tested.
In addition, we determined soon after initiating these studies
that slow addition of oxidant (∼3 h) was beneficial for effecting
high product yield.8 To perform the reaction in this manner,
(4) Espino, C. G.; Fiori, K. W.; Kim, M.; Du Bois, J. J. Am. Chem. Soc. 2004,
126, 15378-15379.
(5) A recent report by Mu¨ller, Dauban, and Dodd demonstrates highly efficient
and diastereoselective, intermolecular C-H amination reactions under Rh2-
((S)-nttl)2 catalysis using limiting amounts of the starting hydrocarbon,
see: Liang, C.; Robert-Peillard, F.; Fruit, C.; Mu¨ller, P.; Dodd, R. H.;
Dauban, P. Angew. Chem., Int. Ed. 2006, 45, 4641-4644.
(6) While this manuscript was in submission, Reddy and Davies reported
enantioselective intermolecular C-H insertion reactions using a dirhodium
catalyst derived from adamantyl S-glycine, see: Reddy, R. P.; Davies,
H. M. L. Org. Lett. 2006, 8, 5013-5016.
(7) Du Bois, J. Chemtracts: Org. Chem. 2005, 18, 1-13.
(8) A 1-hour dropwise addition reduced product yields by ∼15%.
9
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Catalytic Intermolecular Amination of C
−
H Bonds
A R T I C L E S
Table 2. Comparison of Rh2(esp)2 to Other Rodium Catalysts
Table 1. Varying the Influence of the Nitrene Precursor on C-H
Insertion
a Product conversion estimated by integration of the 1H NMR spectrum
of the unpurified reaction mixture. b Isolated yield in parentheses.
ineffective at promoting C-H amination in this model reac-
tion.14,15 This complex is assembled from two benzene-linked
diproline units and is extraordinarily effective at catalyzing
carbene C-H insertion and alkene cyclopropanation. The
reasons for the inability of Rh2(S-biTIPS)2 to effect C-H
amination, particularly in view of the results with Rh2(esp)2,
are unclear at this time.
a Rh2(esp)2 ) Rh2(R,R,R′,R′-tetramethyl-1,3-benzenedipropionate)2. b Reac-
tions performed with 1 equiv of ethylbenzene and H2NR, 2 equiv of
PhI(O2CtBu)2, and 2 mol % catalyst in C6H6 at 23 °C. Oxidant was added
dropwise as a C6H6 solution over 3 h.
Delineating the Substrate Scope. Conditions formulated for
the reaction of ethylbenzene with TcesNH2 enable oxidation of
a number of functionalized starting materials (Table 3). Sub-
strates possessing benzylic C-H bonds are especially effective,
giving disparate amine, diamine, amino alcohol, and amino ester
products in yields ranging from 50% to 74% (entries 1-8).
Importantly, these yields are cited for reactions performed with
limiting amounts of the alkane. The efficiency of this method
using a single equivalent of starting material is noteworthy, as
most other reported C-H oxidation reactions of this type rely
on excess (5 or more equiv) substrate to effect high product
conversion.16
Oxidation reactions conducted with starting hydrocarbons
having two inequivalent benzylic sites (entries 5-8) show
preferential reactivity at the more sterically accessible and/or
more electron-rich carbon center. An example with 6-methox-
ytetralin (entry 5), for which steric effects do not serve as a
controlling element, gives a 7:1 mixture of C1/C4 amide
products.17 The electronic bias observed in this reaction is
consistent with the reactivity of an electrophilic oxidant.7
Substrates possessing 3° C-H centers can be functionalized
to generate tetrasubstituted carbamine derivatives. Despite the
higher intrinsic reactivity of 3° C-H bonds vis-a`-vis benzylic
centers (vide infra), product yields with 3°-derived starting
materials are surprisingly reduced. Steric effects between the
substrate and dirhodium catalyst likely influence the rate at
which the reactive oxidant is trapped. Presumably, if the putative
nitrenoid is not intercepted quickly, deleterious side reactions
ensue, which result in catalyst decomposition. This rationale
forms the basis for our current mechanistic model and explains
why intermolecular insertion is most effective for substrates
having a number of sterically accessible reactive sites. Other
data bolster this conclusion, including the reaction of cis-1,4-
PhI(O2CtBu)2 was prepared as a surrogate to PhI(OAc)2.9 The
former is now commercially available, stable to prolonged
storage, and, unlike PhI(OAc)2, dissolves easily in nonpolar
solvents such as C6H6, thus enabling a timed delivery of the
oxidant solution. Following this protocol, we were surprised to
discover that the electron-deficient trichloroethylsulfamate
(TcesNH2, entry 1) afforded a significantly higher product yield
than the neopentyl analogue (entry 2).10 Although we do not,
at this time, have a definitive explanation for this difference,
subsequent competition studies have revealed a 5-fold enhanced
rate for the insertion reaction with TcesNH2 in comparison to
its isosteric counterpart.
Intermolecular C-H insertion may be accelerated further by
employing C6H6 as solvent. In comparison to CH2Cl2, C-H
amination in C6H6 is markedly faster (∼2.5 times).11 Although
individual rate analyses were not performed for other solvents,
those tested, which include EtOAc, toluene, C6H5Cl, and C6H5-
CF3, gave suboptimal results with respect to product yield.12
While TcesNH2, dropwise addition of PhI(O2CtBu)2, and
C6H6 as solvent are all essential components of the optimized
process, the choice of catalyst is of foremost consequence.
Reactions executed with other tetracarboxylate Rh dimers fail
to match the performance demonstrated by Rh2(esp)2 (Table 2).13
The robustness of this complex under the reaction conditions
has been ascribed to the strapped dicarboxylate design, which
seemingly disfavors ligand dissociation from the dirhodium
core.4. It is interesting to note, however, that Rh2(S-biTISP)2 is
(9) Prepared from PhI(OAc)2 in a single step; see Supporting Information for
details. Stang, P. J.; Boehshar, M.; Wingert, H.; Kitamura, T. J. Am. Chem.
Soc. 1988, 110, 3272-3278.
(10) TcesNH2 was first employed for alkene aziridination reactions, see:
Guthikonda, K.; Du Bois, J. J. Am. Chem. Soc. 2002, 124, 13672-13673.
(11) Reaction rates in C6H6 and CH2Cl2 were measured in intramolecular C-H
amination experiments, the details of which will appear in a forthcoming
article: Fiori, K. W.; Espino, C. G.; Brodsky, B. H.; Du Bois, J., manuscript
in preparation.
(12) Following a recent publication by Mu¨ller, Dauban, and Dodd (see ref 5),
we have conducted reactions in 3:1 CH2Cl2/MeOH at 23 °C and at reduced
temperatures (-40 f 20 °C). Under these conditions with Rh2(esp)2 as
the catalyst and TcesNH2 as the nitrogen source, reaction yields are greatly
diminished (<10%) from those reported in Tables 1-3.
(13) Rh2(S-TCPTAD)4 is the dirhodium tetracarboxylate complex derived from
N-tetrachlorophthalimidoyl-protected S-adamantylglycine. This catalyst has
been recently reported to promote efficient asymmetric intermolecular C-H
amination of benzylic substrates (5 equiv) using NsNH2 and PhI(OAc)2,
see ref 6.
(14) Rh2(S-biTISP)2
) bis-{1,3-[N,N′-di(2,4,6-triisopropylbenzenesulfonyl)-
(2S,2′S),(5R,5′R)-prolinate]benzene} dirhodium. Davies has reported the
design and reactivity of this bridging prolinate complex. For leading
references, see: (a) Davies, H. M. L.; Lee, G. H. Org. Lett. 2004, 6, 2117-
2120. (b) Davies, H. M. L.; Venkataramani, C. Org. Lett. 2003, 5, 1403-
1406.
(15) Rather surprisingly, the efficiency of this catalyst for promoting intramo-
lecular C-H amination is also greatly reduced from that of Rh2(esp)2.
(16) Reports by Che and Mu¨ller, Dauban, and Dodd also describe amination
reactions using limiting amounts of substrate, see refs 3e and 5, respectively.
(17) Isolable amounts (15-20%) of the C1/C4-diaminated products are also
generated.
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A R T I C L E S
Fiori and Du Bois
Table 3. Intermolecular C-H Amination Catalyzed by Rh2(esp)2
Figure 2. Direct method for preparing 15N-labeled amines.
sulfonyl group is possible to give the free base after workup
(Figure 2).18
Exploring the Reaction Mechanism: The Initial Steps.
Efforts to develop improved catalysts and protocols for C-H
amination are tied intimately to a deeper understanding of the
mechanistic details of the oxidation reaction. The intriguing
reactivity differences between TcesNH2 and tBuCH2OSO2NH2
have given clues relevant for deducing the first steps in the
reaction cycle. Our original hypothesis posited that Rh-nitrene
formation would occur through the intermediacy of an iminoio-
dinane species (i.e., ROSO2NdIPh).19 Control experiments have
demonstrated that TcesNdIPh 1 does indeed react with 2 mol
% Rh2(esp)2 and ethylbenzene to give 33% of the amine product
(eq 1).20 Although the yield for this reaction is substantially
lower than that recorded in entry 1 of Table 1, this finding
establishes iminoiodinane 1 as a chemically competent inter-
mediate on the reaction cycle. Moreover, when TcesNH2 and
PhI(O2CtBu)2 are combined in C6D6 in the absence of catalyst,
a small amount (e10%) of a new product, assigned as TcesNd
IPh 1, is generated.21
a Tces ) SO3CH2CCl3. b All reactions were performed at 23 °C in C6H6
with 2 mol % Rh2(esp)2, 1 equiv of substrate and H2NSO3CH2CCl3, and 2
equiv of PhI(O2CtBu)2. c 7:1 mixture of C1/C4 isomers in addition to ∼15%
of C1,C4-diaminated product. d Cis/trans ) 1:1. e Cis/trans ) 7:1. f 8:1
mixture of C4/C1 isomers in addition to ∼20% of C1,C4-diaminated
products. g Obtained as a single diastereomer. h Yield in parentheses is based
on 5 equiv of substrate. i Optical purity was determined by HPLC.
By contrast, no sign of iminoiodinane formation is observed
(within the limits of 1H NMR detection) when the same
experiment is conducted with BuCH2OSO2NH2 and oxidant.
Collectively, these data suggested to us that the condensation
reaction between sulfamate and oxidant is an equilibrium process
that largely favors the starting materials.
t
dimethylcyclohexane, which gives a 46% yield of oxidized
product (entry 9) due to the availability of two 3° C-H bonds.
In addition, improved reaction performance is always noted
when more than 1 equiv of substrate is used (entries 10-12).
Although efficient intermolecular amination of stoichiometric
quantities of 3° C-H substrates remains a primary challenge,
reactions with meso or chiral agents (entries 9 and 11,
respectively) demonstrate unequivocally that oxidation is ste-
reospecific. This property is a hallmark of Rh-mediated nitrene
insertion and makes optically pure tetrasubstituted amines
directly available from enantiomeric starting materials.7
To validate the reversible nature of the reaction between
sulfamate and PhI(O2CtBu)2, we sought a reagent that would
react exclusively with ROSO2NdIPh. Thioanisole, PhSMe, was
identified in this context and is oxidized solely to the sulfilimine
in the absence of any added catalyst. Accordingly, treatment of
either TcesNH2 or tBuCH2OSO2NH2 with oxidant and PhSMe
in C6D6 for >100 h produced sulfilimines 3 and 4 in 85% and
65%, respectively (Figure 3). Although both reactions are slow,
competition experiments and initial rate data establish that
sulfilimine 3 is generated 5 times faster than 4, thus mirroring
the differences in C-H insertion reactivity for the two sulfamate
As a final note, intermolecular C-H amination presents a
convenient and direct method for the preparation of 15N-labeled
materials. We have developed a protocol, easily conducted on
a multigram scale, for the synthesis of Cl3CCH2OSO215NH2.
Oxidation reactions performed with this 15N source furnish
isotopically enriched amine-derivatives. As with all of the Tces-
amine protected compounds, cleavage of the trichloroethoxy-
(18) See Supporting Information for details.
(19) Iminoiodinanes of the general form RSO2NdIPh have found extensive use
as nitrene equivalents, particularly for metal-catalyzed alkene aziridination
reactions, see ref 1.
(20) TcesNdIPh was prepared from TcesNH2 and PhI(OAc)2 using KOH, see:
Liang, J.-L.; Yuan, S.-X.; Huang, J.-S.; Che, C.-M. J. Org. Chem. 2004,
69, 3610-3619.
(21) Assignment is based on comparison of the NMR spectrum to that of
authentic TcesNdIPh.
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A R T I C L E S
Figure 3. Sulfilimine formation gives evidence for equilibrium reaction
between sulfamate and oxidant.
Figure 5. Cyclopropyl clock substrate shows no ring-opening.
Figure 4. Disparate chemoselectivity in intra- and intermolecular reactions.
esters. While these data corroborate the proposed equilibrium
reaction for ROSO2NdIPh formation, the stepwise details for
this condensation process are still open to debate and remain
subject to investigation in our lab.22
Exploring the Reaction Mechanism: A Rh-Nitrene Oxi-
dant. Studies to assess the differential reactivities of disparate
C-H bonds have been conducted through a series of intramo-
lecular competition experiments.7,11 Substrates such as 5, when
treated with PhI(OAc)2 and 2 mol % Rh2(esp)2, cyclize to give
a mixture of two possible products (Figure 4). The ratio of these
compounds (not corrected for statistical factors) provides a
relative assessment of the influence of substituents on C-H
bond activity. As seen with sulfamate 5 and Rh2(esp)2, 3° C-H
bond insertion is favored over benzylic oxidation.23 Rather
surprisingly, however, when an analogous, intermolecular
experiment was performed, the ratio of benzylic to 3° C-H
amination was reversed. One inference that is drawn from such
opposing results posits that the nature of the oxidizing species
is different for the two types of reaction processes. For
intramolecular C-H oxidation, data from our lab strongly
implicate a Rh-bound nitrene as the active oxidant, which inserts
into a C-H bond through a concerted asynchronous transition
state.7 Given the striking divergence in the aforementioned
results, we were compelled to conduct related mechanistic
studies in the intermolecular manifold.
Figure 6. Hammett analysis through competition experiments with
p-substituted ethylbenzene substrates.
a radical clock substrate 7 (Figure 5).25 This same cyclopropane
derivative has been employed to establish the concerted nature
of the dioxirane-mediated C-H hydroxylation reaction.26 In our
hands, high yields (78%) of insertion product were obtained
using 5 equiv of 7 with no indication of cyclopropane
fragmentation having occurred. A related phenyl-substituted
cyclopropane substrate was tested in the intramolecular reaction
and also affords none of the ring cleavage products.7,11 If a C-H
abstraction/radical rebound mechanism was operative, the
lifetime of the putative radical would have to be exceedingly
short (ca. 200 fs).26
The electronic nature of the transition state for intermolecular
C-H amination was further assessed by way of Hammett
analysis. Competition experiments performed using a series of
4-substituted ethylbenzene derivatives confirmed a small, but
discernible preference for oxidation of electron-rich arene
substrates (Figure 6). Plotting these data as log(kAr/kPh) versus
Although stereospecific C-H insertion on optically active
3° substrates (entries 9 and 11, Table 3) is consistent with a
singlet nitrene or nitrenoid reacting through a concerted oxida-
tion event, this result alone does not discount a C-H abstraction/
fast radical rebound pathway.24 To differentiate between these
two mechanistic scenarios, C-H amination was performed with
σ
+ yielded a F-value of -0.73 (R2 ) 0.98).27 Correlation with
σ+ and the small, negative F-value indicate that cationic charge
stabilization (δ+) in the transition state at the oxidizing carbon
center is due in part to resonance contribution. The Hammett
results, in combination with the outcome of the cyclopropane
clock experiment, give compelling evidence for a concerted
asynchronous transition state model for the Rh-mediated nitrene
(22) Currently, we speculate that ROSO2NdIPh formation proceeds through a
dissociative (SN1-like) mechanism involving [PhI(O2CtBu)]+ generation.
Exchange reactions conducted in C6D6 using equimolar amounts of PhI-
(OAc)2 and PhI(O2CtBu)2 give rise within minutes to PhI(OAc)(O2CtBu).
Such data are consistent with carboxylate dissociation and iodonium ion
formation. Details of these experiments will be reported shortly.
(24) For general discussions on mechanisms of C-H hydroxylation, see: (a)
Groves, J. T. J. Inorg. Biochem. 2006, 100, 434-447. (b) Newcomb, M.;
Toy, P. H. Acc. Chem. Res. 2000, 33, 449-455.
(23) Our observed trends in C-H bond reactivity parallel those observed for
Rh-catalyzed diazoalkane insertion reactions. For leading references, see:
(a) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for
Organic Synthesis with Diazo Compounds: From Cyclopropanes to Ylides;
Wiley and Sons, Ltd.: New York, 1998. (b) Davies, H. M. L.; Beckwith,
R. E. J. Chem. ReV. 2003, 103, 2861-2903. Also see: Davies, H. M. L.;
Hansen, T.; Churchill, M. R. J. Am. Chem. Soc. 2000, 122, 3063-3070.
(25) The rate constant for fragmentation of the cyclopropylcarbinyl radical
formed from 7 has been measured at k ) 7 × 1010 s-1, see: Choi, S.-Y.;
Toy, P. H.; Newcomb, M. J. Org. Chem. 1998, 63, 8609-8613.
(26) Simakov, P. A.; Choi, S.-Y.; Newcomb, M. Tetrahedron Lett. 1998, 39,
8187-8190.
(27) Plotting these data versus σP gives an R2 of 0.87. See Supporting Information
for additional details.
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Figure 8. Side products isolated from intermolecular C-H amination.
Figure 7. Chiral catalyst leads to modest enantioselectivity.
intra- and intermolecular experiments. At this time, we have
little appreciation for the manner in which a substrate must orient
to undergo productive reaction with the Rh-nitrene. The
approach of the substrate is influenced by the ligand architecture
on the catalyst, and perhaps such steric effects, which would
necessarily slow the rate of the insertion event, are exacerbated
for 3° C-H centers. Clearly, more studies are needed to achieve
a greater understanding of the mechanistic subtleties that control
efficiency and selectivity in the intermolecular C-H amination
reaction. These issues aside, it is of note that intermolecular
C-H insertion with diazoalkanes and Rh catalysts is highly
successful on benzylic substrates, but generally fails for 3° C-H
derivatives.23
insertion reaction.28 Such a mechanism is in keeping with the
trends in C-H bond reactivity noted for intramolecular oxida-
tion, which follow a qualitative rate scale of 3° > R-ethereal g
benzylic > 2° . 1°.7 In addition, the -0.73 F-value is similar
to the value measured in our labs for intramolecular C-H
amination (F ) -0.55),11,29 and for both intra- and intermo-
lecular Rh-catalyzed carbene insertion (F ) -0.78 and -1.27,
respectively).30,31 Taken together, these data argue strongly in
favor of a common nitrene-like oxidant for both intra- and
intermolecular amination reactions. In addition, they intimate
certain parallels between Rh-catalyzed nitrene and carbene C-H
functionalization.
Side Reactions and Catalyst Arrest. The asymmetric
induction observed with Rh2(S-bls)2 together with the stereospe-
cific nature of the amination event, cyclopropyl clock experi-
ments, and Hammett studies implicate a Rh-nitrene as the active
oxidant in both intra- and intermolecular insertion reactions.7
Rapid trapping of this reactive intermediate is thought to be
essential for high catalyst turnover and efficient product
formation. Thus, we wish to understand in detail alternative
pathways by which the nitrenoid species reacts and through
which catalyst decomposition occurs. Analytical studies on the
intermolecular insertion reaction have identified a small number
of byproducts whose formation suggests a secondary, radical-
based pathway may initiate when C-H insertion is slow.
Specifically, the production of dimethylaziridine (Figure 8),
generated in modest yields in most of our intermolecular
amination reactions, is explained through radical decarboxylation
of tBuCO2H to afford isobutylene, which itself is then oxidized.
In addition to the Tces-aziridine, acetophenone has also been
isolated. Formation of the ketone is not the result of overoxi-
dation of the benzylic Tces-amine, as control experiments have
shown. Importantly, these types of side products have never
been characterized in Rh-catalyzed intramolecular insertion
reactions, nor are they observed to form when excess substrate
is employed for intermolecular oxidation. Products from C-H
abstraction, thus, seem to appear only when the intermediate
metallo-nitrene is not intercepted rapidly by the substrate.
Additional efforts to identity and quantify all products from
amination reactions with moderately effective substrates have
given us cause to examine the fate of the sulfamate ester. In
such cases, mass balance of TcesNH2 from spent reaction
mixtures does not account for all of the material employed.
Speculating that an N-centered radical might be, in part,
responsible for triggering pathways that lead to the formation
of products such as dimethylaziridine and acetophenone, we
assumed that fragmentation of such a species would also occur
to liberate trichloroethoxy radical. To test this hypothesis, the
cyclopropyl-derived sulfamate ester 9 was prepared and sub-
jected to the intermolecular amination conditions (Figure 9).
Alkoxyl radicals such as 13 are known to ring-open to give
unsaturated carbonyl products (e.g., cinnamaldehyde 11). Reac-
tion of 9 in the presence of ethylbenzene, while affording 20%
Reactions with optically active dinuclear catalysts offer a most
convenient method for determining if the metal and nitrene
oxidant are associated in the C-N bond-forming event. Fol-
lowing our work to develop strapped dicarboxylate complexes
such as Rh2(esp)2, we have engineered and tested chiral variants
of similar design.32 Although product enantiomeric ratios have
been modest to date, the observation that asymmetric Rh dimers
such as Rh2(S-bls)2 can afford some degree of stereoinduction
gives strong circumstantial support for a metal-bound nitrene
(i.e., nitrenoid) as the active oxidant in our reaction (Figure 7).33
Future efforts are aimed at developing new chiral complexes
that lead to improved levels of product enantio-control. The
modularity of the bis-sulfonamide ligand is well suited for this
purpose.
The collective body of experimental data has led us to
conclude that intra- and intermolecular C-H amination reactions
are mechanistically analogous, both processes following through
a Rh-nitrene intermediate that inserts directly into the C-H
bond. How then does one explain the disparate trends in
chemoselectivity between these two reaction manifolds (see
Figure 4)? For intermolecular C-H amination, we conclude that
selectivity manifests as a function of the rate in which the active
oxidant is trapped by the substrate versus the rate at which said
oxidant decomposes through nonproductive pathways (vide
infra). Benzylic starting materials containing two equally
reactive C-H bonds can intercept the nitrene faster than a
substrate bearing only a single 3° site. This explanation alone,
however, is incomplete, and other factors must be at play to
account for the magnitude of the selectivity differences between
(28) Our findings are in accord with prior work by Mu¨ller’s lab, for which a
F-value of -0.90 (vs σ+) was recorded in experiments with PhIdNNs as
oxidant, see: (a) Mu¨ller, P.; Baud, C.; Na¨geli, I. J. Phys. Org. Chem. 1998,
11, 597-601. (b) Na¨geli, I.; Baud, C.; Bernardinelli, G.; Jacquier, Y.;
Moran, M.; Mu¨ller, P. HelV. Chim. Acta 1997, 80, 1087-1105.
(29) For consistency, all F-values have been calculated against σ+-constants.
(30) Wang, J.; Chen, B.; Bao, J. J. Org. Chem. 1998, 63, 1853-1862.
(31) Davies, H. M. L.; Jin, Q.; Ren, P.; Kovalevsky, A. Y. J. Org. Chem. 2002,
67, 4165-4169.
(32) Preparation of and reactions with this catalyst will be described in a future
manuscript, see: Kim, M.; Du Bois, J., manuscript in preparation.
(33) For other examples of asymmetric C-H amination under Rh-catalysis,
see: (a) Fruit, C.; Mu¨ller, P. HelV. Chim. Acta 2004, 87, 1607-1615. (b)
Liang, J.-L.; Yuan, S.-X.; Chan, P. W. H.; Che, C.-M. Tetrahedron Lett.
2003, 44, 5917-5920. Also, see ref 3c.
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Catalytic Intermolecular Amination of C−H Bonds
A R T I C L E S
evidence that CH2Cl2 oxidation occurs (likely through C-H
abstraction) as a side reaction and explain why C6H6 is the
preferred solvent for the intermolecular process. In C6H6, no
solvent oxidation takes place;38 without a strong axial ligand to
stabilize the higher Rh2+/Rh3+ state, it appears that an oxidized
Rh species is either catalytically active for C-H amination or
the red complex is somehow reduced back to Rh2(esp)2. The
latter scenario possibly occurs through a disproportionation
reaction between two mixed-valent dimers, thereby reducing
the total concentration of active catalyst over time.39
To summarize, our data indicate that C-H amination follows
through a concerted asynchronous two-electron oxidation
pathway. The inability to intercept rapidly the Rh-nitrene oxidant
leads to deleterious side reactions involving the production of
free radical species and a mixed-valent form of the Rh2(esp)2
catalyst. The activity and/or fate of the red [Rh2(esp)2]+ adduct
in C6H6 remains unknown at this time. Knowledge of how it is
formed, its stability in C6H6, and its pathway(s) for decomposi-
tion is essential for improving the performance of our intermo-
lecular amination method. Studies to gain such information are
in progress.
Figure 9. Cyclopropanol-derived sulfamate gives mechanistic clues.
Conclusions
Rh2(esp)2-catalyzed intermolecular C-H amination serves as
a uniquely effective method for amine synthesis from benzylic
and 3° substrates. Distinctive elements of this process include
the use of limiting amounts of starting material, stereospecific
modification of 3° sites, chemoselectivity toward benzylic C-H
centers, the ready availability of both TcesNH2 and Tces15NH2,
and the facility of removing the Tces group to afford the
corresponding amine. Continued efforts to explore the mecha-
nistic underpinnings of this novel transformation should give
way to additional methodological advances.
Figure 10. (-) UV/vis spectrum for Rh2(esp)2; (-) mixed-valent [Rh2-
(esp)2]Cl formed via one-electron oxidation with TcesNH2 and oxidant;
(-) reaction of oxidized species with Zn returns Rh2(esp)2.
of the benzylic amine 10, also gave equivalent amounts of
aldehyde 11.34,35 Presently, we do not appreciate the steps that
would lead to formation of an N-sulfamoyl radical such as 12.
At a minimum, however, this finding offers some explanation
for the incomplete recovery of sulfamate in reactions that do
not proceed well.
As a final point in this discussion, it is interesting to consider
the consequence to the rhodium catalyst in the event that an
N-sulfamoyl radical is produced. One indication that the catalyst
is changing form is suggested by the color of the reaction
solution. In either C6H6 or CH2Cl2, an immediate change from
the deep green of the Rh2+/Rh2+ dimer to a bright red is noted
upon addition of PhI(O2CtBu)2 to a solution of Rh2(esp)2 and
TcesNH2.36 The UV/vis spectrum for this red species is quite
Experimental Procedures
General Experimental Procedures. All reagents were obtained
commercially unless otherwise noted. Reactions were performed using
oven-dried glassware under an atmosphere of nitrogen. Organic
solutions were concentrated under reduced pressure (∼15 Torr) by
rotary evaporation. Freshly purified solvents were employed unless
otherwise noted. Dichloromethane, benzene, and toluene were dried
by passage through activated alumina columns under 12 psi of N2.
Preparation of Rh2(esp)2 followed a modified version of a previously
published protocol.4,40
General Procedure for Intermolecular C-H Amination. A flask
containing TcesNH2 (137 mg, 0.60 mmol) in 0.6 mL of C6H6 was
charged with Rh2(esp)2 (9 mg, 12 µmol, 0.02 equiv) and substrate (0.60
mmol). To this bright green mixture was added 1.4 mL of a 0.83 M
C6H6 solution of PhI(O2CtBu)2 (1.2 mmol, 2.0 equiv) via syringe pump
over 3 h. During the addition of PhI(O2CtBu)2, a change in the reaction
color to brown or red was generally observed. Following the transfer
of oxidant, the solution was stirred at 23 °C for 1-2 h. Dichloromethane
(5 mL) and 2 mL of a saturated aqueous solution of thiourea were
then added, and the orange biphasic mixture was stirred vigorously
for 30 min.41 The contents were transferred to a separatory funnel, and
similar to that previously recorded for the mixed-valent Rh2+
/
Rh3+ tetraacetate (λmax ) 850 nm (ꢀ ) 406 M-1 cm-1), 489
nm (ꢀ ) 1012 M-1 cm-1)) (Figure 10).37 In addition, we have
demonstrated that the green Rh2+/Rh2+ complex is restored upon
addition of 1 equiv of a one-electron reducing agent such as
Cp2Fe or 0.5 equiv of powdered Zn. When these experiments
are conducted in CH2Cl2, spectral shifts from the UV/vis data,
in addition to HRMS analysis of the red product, indicate that
Cl- is coordinated axially to the Rh2+/Rh3+ complex. This
adduct, Rh2(esp)2Cl, is stable for prolonged periods even at
ambient temperature, but is completely inactive as a catalyst
for C-H amination. Such findings offer incontrovertible
(34) The reaction of 9 with 5 equiv of PhCH2CH3 yields 55% of the benzylic
amine 10 and <10% of 11.
(38) Gas chromatography and HPLC analysis of spent reaction mixtures have
never revealed products of benzene amination/aziridination.
(39) Disporportion of tetracarboxylate Rh2+/Rh3+ complexes has been described,
see ref 37 and: Kadish, K. M.; Das, K.; Howard, R.; Dennis, A.; Bear,
J. L. Bioelectrochem. Bioenerg. 1978, 5, 741-753.
(35) For ring-opening of a cyclopropylalkoxy radical, see: DePuy, C. H.;
Dappen, G. M.; Hausser, J. W. J. Am. Chem. Soc. 1961, 83, 3156-3157.
(36) In general, the solution color changes from green to red for all reactions as
the dropwise addition of oxidant nears completion. When an excess of
substrate is employed, the green color persists throughout the reaction
course.
(40) Rh2(esp)2 is readily prepared on scale (40 g) and is available from Aldrich
Chemical Co.
(41) Thiourea is used to decomplex any remaining Rh2(esp)2 catalyst, thereby
facilitating product purification.
(37) Wilson, C. R.; Taube, H. Inorg. Chem. 1975, 14, 2276-2279.
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J. AM. CHEM. SOC. VOL. 129, NO. 3, 2007 567

A R T I C L E S
Fiori and Du Bois
the organic phase was collected. The aqueous layer was extracted with
2 × 10 mL of CH2Cl2. The combined organic extracts were washed
with 2 × 10 mL of a 0.1 M pH 7 Na2HPO4/NaH2PO4 buffer, dried
over MgSO4, and concentrated under reduced pressure. Purification of
the isolated material by chromatography on silica gel (conditions given
in the Supporting Information) afforded the desired product.
recipient of both National Science Foundation and Amgen
fellowships. The National Science Foundation, Amgen, Boehr-
inger-Ingelheim, Bristol-Myers Squibb, Merck, and Pfizer are
acknowledged for their generous support of this work.
Supporting Information Available: Analytical data for all
new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
Acknowledgment. We are grateful to Professors John Brau-
man and Dan Stack for their valuable insights, and we thank
Professor Huw Davies for graciously providing samples of both
Rh2(S-biTIPS)2 and Rh2(S-TCPTAD)4 catalysts. K.W.F. is the
JA0650450
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