Selective intermolecular amination of C-H bonds at tertiary carbon centers

Article abstract of DOI:10.1002/anie.201304238

C-H insertion: A method for intermolecular amination of tertiary C-H bonds is described that uses limiting amounts of substrate and a convenient phenol-derived nitrogen source. Structure-selectivity and mechanistic studies suggest that steric interaction between the substrate and active oxidant is the principal determinant of product selectivity. Copyright

Full text of DOI:10.1002/anie.201304238

Angewandte
Chemie
DOI: 10.1002/anie.201304238
C–H Functionalization
À
Selective Intermolecular Amination of C H Bonds at Tertiary Carbon
Centers**
Jennifer L. Roizen, David N. Zalatan, and J. Du Bois*
The preparation of tetrasubstituted amine derivatives
We have recently provided evidence that the dirhodium
tetracarboxylate catalyst, [Rh2(esp)2],[5] when subjected to
C–H amination reaction conditions, undergoes competitive
one-electron oxidation to a red, mixed-valent Rh2+/Rh3+
dimer.[4,6] Fortuitously, this species is reduced under the
reaction conditions by tBuCO2H, a byproduct of the hyper-
valent iodine oxidant used to drive the amination event.[4a]
Our understanding of this process has resulted in a modifica-
tion of the reaction conditions to include PhMe2CCO2H,
a carboxylic acid additive that serves as an effective reducing
agent and offers improved catalyst turnover numbers in
intermolecular amination reactions of benzylic substrates.[4a,7]
Application of these conditions to the oxidation of isoamyl-
benzoate 1 (1.0 equiv), however, furnishes only a small
amount of the desired amine 2 (Figure 2).
À
through intermolecular amination of tertiary C H bonds
remains an outstanding challenge in methods development
given the allure of such a technology for streamlining
synthesis (Figure 1).[1,2] While there exist a small number of
reports in which this reaction has been demonstrated, almost
all examples require superstoichiometric amounts of sub-
strate.[3] Owing to recent insights gained through mechanistic
studies, we now report a general method for the selective
amination of tertiary C–H centers.[4] The reaction is opera-
tionally simple, tolerant of most common functional groups,
and delivers a protected amine that is easily liberated. The
influence of different nitrogen sources on product selectivity
is also highlighted along with mechanistic studies that
implicate steric effects as a principal determinant of site
selectivity.
Careful analysis of the oxidation of 1 has revealed that the
nitrogen
source,
2,2,2-trichloroethoxysulfonamide
(TcesNH2), is largely consumed in spite of the poor yield of
2.[8] The low mass recovery of TcesNH2 suggests that
oxidation of the methylene center of the alkoxysulfonamide
may be occurring. For this reason, we have examined
alternative sulfonamide derivatives, including aryl- and phe-
nolic-based reagents. Results from reactions performed
with [Rh2(esp)2] (1 mol%), PhI(OAc)2, and PhMe2CCO2H
(0.5 equiv) demonstrate enhanced catalyst turnover numbers
(TONs) when aryloxysulfonamide reagents are employed
(Figure 2).[9] Of these, the sulfamate prepared from 2,6-
difluorophenol, DfsNH2, has proven optimal. Empirical
studies reveal that the inclusion of both MgO and 5 ꢀ
molecular sieves further improves catalyst TONs, as does an
initial substrate concentration of 1.0m.[10–12] The reaction
Figure 1. Synthesis of tetrasubstituted amine derivatives through inter-
À
molecular, Rh-catalyzed tertiary C H bond amination. TcesNH2 =2,2,2-
trichloroethoxysulfonamide; esp=a,a,a’,a’-tetramethyl-1,3-benzenedi-
propionate.
[*] D. N. Zalatan, Prof. J. Du Bois
Department of Chemistry, Stanford University
Stanford, CA 94305-5080 (USA)
E-mail: jdubois@stanford.edu
Prof. J. L. Roizen
Department of Chemistry, Duke University
3236 French Science Center, 124 Science Drive
Durham, NC 27708-0346 (USA)
[**] We are grateful to Theresa McLaughlin (Stanford University Mass
Spectrometry) for help with mass spectrometry experiments and to
Prof. Barry Trost for allowing use of instrumentation. Funding for
this project was provided by the National Science Foundation
Center for Stereoselective C-H Functionalization (CCHF, CHE-
1205646). J.L.R. is a Ruth Kirschstein NIH postdoctoral fellow
(F32GM089033) and a fellow of the Center for Molecular Analysis
and Design (CMAD) at Stanford. D.N.Z. was supported by an
Achievement Rewards for College Scientists (ARCS) Foundation
Stanford Graduate Fellowship. Generous research support has also
been provided to our lab from Pfizer and Novartis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201304238.
Figure 2. Influence of sulfonamide on reaction efficiency.
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mixture appears as a green slurry from which product 2 can be
isolated in 57% yield (12 h).[13,14]
despite the presence of four tertiary C H bonds (Table 1,
entry 3). Other examples include the menthol derivative
shown in entry 4 for which reaction occurs exclusively at the
A collection of disparate substrates possessing tertiary
À
À
C H bonds and assorted functional groups can be oxidized
C H bond of the cyclohexyl tertiary carbon center. The direct
smoothly using DfsNH2 as the nitrogen source (Table 1). As
a general rule, the mass balance of this reaction is primarily
accounted for by unreacted starting material and the reported
product. The amination reaction is responsive to the prox-
imity of electron-withdrawing groups to the site of oxidation;
product yields generally improve as the distance between the
preparation of substituted diamino acids and 1,5-diamines in
a single step from common starting materials is also of
particular note (Table 1, entries 5,6).
Oxidation of a bridged bicyclic substrate (Table 1, entry 7)
furnishes the product of secondary methylene oxidation in
62% yield and as a single stereoisomer. Selectivity for
À
À
C H bond to be oxidized and polar substituents increases
amination of the exo-C H bond can be rationalized on the
basis of both steric and stereoelectronic effects. The inability
(Table 1, entries 1,2).[4b,15] Both electronic and steric elements
can be exploited to influence positional selectivity in mole-
cules containing multiple tertiary C–H centers. Oxidation of
the acylated natural product cycloheximide is exemplary in
this regard, as only a single product isomer is generated
À
to functionalize the bridgehead C H bond is unsurprising,
since Rh-catalyzed electrophilic amination processes gener-
À
ally disfavor reactions of C H bonds that are rich in s-orbital
character.[17] By contrast, bridgehead C H bonds in
À
unstrained bicyclic systems, such as those found in adaman-
tane, smoothly engage in this reaction. In the example shown
in entry 8, the product is a masked form of memantine, an N-
methyl-d-aspartate (NMDA) receptor antagonist that is used
clinically for the treatment of late-stage Alzheimerꢁs dis-
ease.[3d,18]
À
Table 1: A generalized procedure for tertiary C H bond amination with
a limiting amount of alkane substrate.[a]
C–H amination products derived from DfsNH2 may be
free based in refluxing aqueous CH3CN; no additional
additives are required to effect this transformation. Selective
cleavage of the aryloxysulfonamide occurs without incident to
benzoate, pivaloate, and arenesulfonyl functional groups
(Figure 3). The product amines are isolated as trifluoroace-
tate salts after purification by reverse-phase HPLC.
Figure 3. Hot aqueous CH3CN effects amine deprotection.
Comparative amination studies conducted with DfsNH2
and TcesNH2 indicate that the choice of the nitrogen source
can influence reaction selectivity. We have noted previously
that oxidation of isoamylbenzene 7 with TcesNH2 affords
a 1:8 product ratio favoring benzylic sulfonamide 8B (Table 2,
entry 1). Under the same reaction conditions, the sulfamate
ester derived from neopentyl alcohol generates a 1:4 product
ratio of 8T and 8B (Table 2, entry 2). Conversely, reaction of
7 and DfsNH2 furnishes a 1.5:1 mixture of 8Tand 8B, slightly
favoring the product of tertiary C–H amination (Table 2,
entry 3). Other sulfamate derivatives (Table 2, entries 4,5),
which are competent for intermolecular tertiary C–H oxida-
tion (see Figure 2), give results similar to DfsNH2 (i.e., ca. 1:1
8T/8B).
[a] Reactions performed in iPrOAc with 1.0 equiv of substrate, 1.2 equiv
of DfsNH2, 2.0 equiv of PhI(OAc)2 and MgO, 0.5 equiv of PhMe2CCO2H,
5 ꢀ MS, and 1 mol% of [Rh2(esp)2].[16] [b] Yields are based on isolated
material following chromatography on silica gel. Bbs=p-bromobenze-
nesulfonyl.
We wish to understand whether the observed, albeit small,
variations in product selectivity (i.e., 8T versus 8B) manifest
as a result of 1) steric interactions between the nitrogen
2
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Table 2: Influence of sulfamate ester on product selectivity.
Entry
ROSO2NH2
8T
8B
1
2
3
4
5
Cl3CCH2OSO2NH2
Me3CCH2OSO2NH2
2,6-F2C6H3OSO2NH2
(CF3)2CHOSO2NH2
p-tBuC6H4OSO2NH2
1
1
1.5
1
1
8
4
1
1
1
source, catalyst, and substrate, or 2) a change in mechanism
between stepwise or concerted asynchronous C–H oxidation.
When using either DfsNH2 or TcesNH2 as the nitrogen
source,[4b] stereospecific insertion into an optically active
tertiary substrate is noted (Figure 4). Such a finding is
Figure 5. Primary KIE values for intermolecular C–H amination, as
determined by 13C NMR integration. Values in parentheses are
obtained by HRMS; see the Supporting Information for details.
experimental and theoretical evidence supports a concerted
nitrenoid C–H insertion event.
Amination reactions using a cyclopropane clock, cis-11,
have been performed in an attempt to identify a short-lived
radical intermediate on the pathway to product (Figure 6).
À
Figure 4. Enantiospecific insertion into a C H bond at a tertiary
carbon center.
Figure 6. Cis-trans isomerization implicates transient cyclopropyl-car-
binyl radical formation.
consistent with C–H functionalization occurring through
a concerted asynchronous nitrenoid insertion event or a step-
wise C–H abstraction/radical rebound pathway involving
a short-lived radical pair. The plausibility of the latter
pathway for [Rh2(esp)2]-catalyzed intermolecular C–H ami-
nation with TcesNH2 is supported by recent density functional
theory calculations by Bach and co-workers,[19] and by
desorption electrospray ionization mass spectrometry
(DESI-MS) experiments from Perry et al.[20] DESI-MS stud-
ies have identified two dirhodium nitrene species that differ in
oxidation state (i.e., Rh2+/Rh2+ versus Rh2+/Rh3+), at least
The rate constant for ring opening of trans-11 has been
measured at 7 ꢂ 1010 sÀ1, which is appropriate for detection of
radicals having picosecond lifetimes.[26] In the amination
event with cis-11, generation of 1–4% of trans-cyclopropane
12 gives evidence for the intermediacy of a cyclopropylcar-
binyl radical, which undergoes subsequent reversible cyclo-
propane ring opening. The identical outcomes for TcesNH2
and DfsNH2 in this, the KIE, and stereospecificity experi-
ments lead us to conclude that steric effects between the
nitrenoid complex and substrate principally govern product
selectivity (see Table 2). While it appears that the cyclo-
propane clock results are consistent with a stepwise process
for intermolecular C–H amination,[19] DESI-MS[20] and UV/
Vis spectroscopic data[4a,6] are commensurate with the pres-
ence of more than one dirhodium complex following initia-
tion of the reaction. Thus, it is possible that different catalyst
species present in solution at disparate concentrations
promote C–H amination through mechanistically distinct
pathways.
À
one of which is capable of H-atom abstraction from C H
À
bonds (e.g., CH2Cl2, C H bond dissociation energy (BDE) =
97 kcalmolÀ1).[21]
To further query the properties of TcesNH2 and DfsNH2,
a comparative kinetic isotope measurement has been con-
ducted with monodeuterated ethyl benzene and dideutero-
adamantane (Figure 5). These data establish that KIEs for
both sulfamate agents are equivalent within error, irrespec-
À
tive of the nature of the C H bond undergoing oxidation (i.e.,
benzylic or tertiary). The magnitudes of the recorded KIEs
are surprisingly large (5.2–6.9, 13C NMR analysis) and are
suggestive of a transition structure for intermolecular C–H
We have developed an effective process for generating
tetrasubstituted amine derivatives through selective, inter-
À
À
amination in which extensive C H bond breaking has
molecular tertiary C H bond amination. The optimized
occurred.[22] Ruthenium- and copper-catalyzed nitrene-inser-
tion reactions displaying similar primary KIE values are
generally believed to follow a stepwise rather than concerted
asynchronous course.[3c,23,24] A measured KIE of 2.6 Æ 0.2 has
been determined for an analogous Rh2(OAc)4-catalyzed
intramolecular amination event,[25] for which a large body of
reaction is performed with limiting amounts of substrate,
1 mol% of commercially available [Rh2(esp)2], and inexpen-
sive PhI(OAc)2 as the terminal oxidant. The identification of
aryloxysulfonamides, in particular DfsNH2, as functional
nitrogen sources has been an instrumental find. Competition
À
studies with substrates possessing disparate C H bond types
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[11] Molecular sieves have previously been employed in C – H
amination reactions, see, for example: D. N. Zalatan, J.
Du Bois, J. Am. Chem. Soc. 2008, 130, 9220 – 9221.
[12] For nonpolar substrates that fail to dissolve completely in this
solvent, 1:1 mixtures of iPrOAc with benzene or trifluoro-
methyltoluene are also found to be acceptable. An initial report
of iPrOAc as a solvent for C – H amination: J. Chan, K. D.
Baucom, J. A. Murry, J. Am. Chem. Soc. 2007, 129, 14106 –
14107.
reveal variations in product selectivity, which derive solely
from the choice of sulfamate ester. Future studies are aimed
at providing a unified mechanistic model for Rh-catalyzed
C–H amination that explains these data and that guides our
efforts to further advance such technologies.
Received: May 17, 2013
Published online: && &&, &&&&
[13] Product conversions are not demonstrably improved at higher
catalyst loadings (e.g., 2 mol%) or through portionwise addition
of catalyst.
[14] Despite the persistent green color of the reaction mixture after
12 h of stirring, control experiments suggest that the rhodium
complex(es) is no longer catalytically active; however, some
fraction of unreacted iodine oxidant remains.
[15] Similar observations have been noted in carbenoid and oxenoid
C–H functionalization reactions. For leading references, see:
a) M. S. Chen, M. C. White, Science 2007, 318, 783 – 787;
b) H. M. L. Davies, T. Hansen, M. R. Churchill, J. Am. Chem.
Soc. 2000, 122, 3063 – 3070; For a discussion on the influence of
strain on site selectivity, see: c) K. Chen, A. Eschenmoser, P. S.
Baran, Angew. Chem. 2009, 121, 9885 – 9888; Angew. Chem. Int.
Ed. 2009, 48, 9705 – 9708.
[16] Product isolation by chromatography on silica gel can be
complicated by the presence of PhMe2CCO2H, see the Support-
ing Information for details.
[17] A similar observation has been noted in C – H hydroxylation
reactions with dioxiranes, see: R. Mello, M. Fiorentino, C. Fusco,
R. Curci, J. Am. Chem. Soc. 1989, 111, 6749 – 6757.
[18] a) M. K. Madhra, M. Sharma, C. H. Khanduri, Org. Process Res.
Dev. 2007, 11, 922 – 923; b) J. M. Reddy, G. Prasad, V. Raju, M.
Ravikumar, V. Himabindu, G. M. Reddy, Org. Process Res. Dev.
2007, 11, 268 – 269; c) J. G. Henkel, J. T. Hane, G. Gianutsos, J.
Med. Chem. 1982, 25, 51 – 56; d) T. Sasaki, S. Eguchi, T. Katada,
O. Hiroaki, J. Org. Chem. 1977, 42, 3741 – 3743.
[19] A. Nçrder, S. A. Warren, E. Herdtweck, S. M. Huber, T. Bach, J.
Am. Chem. Soc. 2012, 134, 13524 – 13531. Additionally, Bach and
co-workers report a primary KIE of 4.8 Æ 0.7 at a benzylic
methylene position for the [Rh2(esp)2]-catalyzed insertion
reaction involving TcesNH2.
Keywords: amination · amines · C–H insertion · isotope effect ·
rhodium
.
[1] a) Special issue: C-H Functionalization in Organic Synthesis,
Chem. Soc. Rev. 2011, 40, Issue 4; b) “C-H Activation”, Topics in
Current Chemistry, (Eds.: J.-Q. Yu, Z. Shi), Springer, Berlin,
2010, pp. 1 – 384.
[2] Recent reviews of carbenoid- and nitrenoid-mediated C–H
insertion: a) H. Lebel “Catalyzed Carbon-Heteroatom Bond
Formation”, (Ed.: A. Yudin), Wiley-VCH, Weinheim, 2011,
137 – 156; b) G. Dequirez, V. Pons, P. Dauban, Angew. Chem.
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J. Org. Chem. 2011, 4071 – 4088; f) M. P. Doyle, R. Duffy, M.
Ratnikov, L. Zhou, Chem. Rev. 2009, 109, 704 – 724; g) F. Collet,
R. H. Dodd, P. Dauban, Chem. Commun. 2009, 5061 – 5074;
h) M. M. Dꢃaz-Requejo, P. J. Pꢄrez, Chem. Rev. 2008, 108, 3379 –
3394. A recent example of intramolecular C – H functionaliza-
tion: E. T. Hennessy, T. A. Betley, Science 2013, 340, 591 – 595.
À
[3] Selected examples of aminations of C H bonds at tertiary
carbon centers: a) C. Lescot, B. Darses, F. Collet, P. Retailleau, P.
Dauban, J. Org. Chem. 2012, 77, 7232 – 7240; b) M. Ochiai, K.
Miyamoto, T. Kaneaki, S. Hayashi, W. Nakanishi, Science 2011,
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Dalton Trans. 2010, 39, 10401 – 10413; d) D. N. Barman, P. Liu,
K. N. Houk, K. M. Nicholas, Organometallics 2010, 29, 3404 –
3412; e) H. Baba, H. Togo, Tetrahedron Lett. 2010, 51, 2063 –
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[20] R. H. Perry, T. J. Cahill, J. L. Roizen, J. Du Bois, R. N. Zare,
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[21] Y.-R. Luo, Comprehensive Handbook of Chemical Bond Ener-
gies, Taylor & Francis, Boca Raton, pp. 19 – 145.
[22] A KIE of 3.5 has been measured for Rh2(OAc)4-catalyzed
amination of 10 with p-NO2C6H4SO2N = IPh, see: I. Nꢆgeli, C.
Baud, G. Bernardinelli, Y. Jacquier, M. Moran, P. Mꢅller, Helv.
Chim. Acta 1997, 80, 1087 – 1105. A KIE of 4.5 was recorded for
[Rh2{(S)-nta}4]-catalyzed insertion of 9 with N-(p-toluenesul-
fonyl)-p-toluenesulfonimidamide as the nitrogen source; see
reference [3b].
[4] a) D. N. Zalatan, J. Du Bois, J. Am. Chem. Soc. 2009, 131, 7558 –
7559; b) K. W. Fiori, J. Du Bois, J. Am. Chem. Soc. 2007, 129,
562 – 568.
[5] C. G. Espino, K. W. Fiori, M. Kim, J. Du Bois, J. Am. Chem. Soc.
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b) K. P. Kornecki, J. F. Berry, Eur. J. Inorg. Chem. 2012, 562 –
568.
[23] Primary KIE values ranging from 4.8 – 11 have been reported for
Ru-catalyzed, intermolecular C – H amination: S. K.-Y. Leung,
W.-M. Tsui, J.-S. Huang, C.-M. Che, J.-L. Liang, N. Zhu, J. Am.
Chem. Soc. 2005, 127, 16629 – 16640, and references therein.
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[7] A. Nçrder, P. Herrmann, E. Herdtweck, T. Bach, Org. Lett. 2010,
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[8] TcesNH2 was first employed as a nitrene precursor in alkene
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Chem. Soc. 2002, 124, 13672 – 13673.
[9] Under the same reaction conditions, para-substituted benzene
sulfonamides fail to give more than traces of product 2.
[10] MgO is frequently used as an additive in C – H amination
reactions. For an initial report, see: C. G. Espino, J. Du Bois,
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40, 598 – 600.
[26] S.-Y. Choi, P. H. Toy, M. Newcomb, J. Org. Chem. 1998, 63,
8609 – 8613.
4
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Angewandte
Chemie
Communications
C–H Functionalization
J. L. Roizen, D. N. Zalatan,
J. Du Bois*
&&&& — &&&&
À
Selective Intermolecular Amination of C
H Bonds at Tertiary Carbon Centers
C–H insertion: A method for intermolec-
tivity and mechanistic studies suggest
À
ular amination of tertiary C H bonds is
that steric interaction between the sub-
strate and active oxidant is the principal
determinant of product selectivity.
described that uses limiting amounts of
substrate and a convenient phenol-
derived nitrogen source. Structure-selec-
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
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