Acyclic stereocontrol in the catalytic C-H amination of benzylic methylene groups

Article abstract of DOI:10.1021/ol101517v

Diastereotopos-differentiation is the key feature of the catalytic C-H amination at the benzylic position of substrate 1. Essentially independent of the functional group X (X = COOMe, PO(OEt)₂, SO₂Ph, NO₂, CN, OAc), the de

Full text of DOI:10.1021/ol101517v

ORGANIC
LETTERS
2010
Vol. 12, No. 16
3690-3692
Acyclic Stereocontrol in the Catalytic
C-H Amination of Benzylic Methylene
Groups
Anike No¨rder,† Pavel Herrmann,† Eberhard Herdtweck,‡ and Thorsten Bach*,†
Lehrstuhl fu¨r Organische Chemie I and Catalysis Research Center, and Lehrstuhl fu¨r
Anorganische Chemie and Catalysis Research Center, Technische UniVersita¨t
Mu¨nchen, Lichtenbergstr. 4, 85747 Garching, Germany
thorsten.bach@ch.tum.de
Received July 2, 2010
ABSTRACT
Diastereotopos-differentiation is the key feature of the catalytic C-H amination at the benzylic position of substrate 1. Essentially independent
of the functional group X (X ) COOMe, PO(OEt)2, SO2Ph, NO2, CN, OAc), the depicted products 2 are formed with good (dr ) 80/20) to
excellent (dr > 95/5) diastereoselectivity. The reaction proceeds without racemization and possesses potential for the C-H amination of
open-chain substrates.
The direct catalytic amination of alkanes is one of the most
important methods for aliphatic C-H bond functionaliza-
tion.1 In this process, an appropriate nitrene precursor is often
employed in the presence of a suitable metal catalyst to
generate a reactive metal nitrene complex, which then
undergoes C-H insertion according to an “outer sphere”
mechanism.2 Rhodium is the most important metal for the
amination, and a wide range of rhodium catalysts can be
applied to this transformation.3 To the best of our knowledge,
there have yet been no studies regarding the stereochemical
outcome of this reaction in the case that a methylene group
of an acyclic substrate is attacked intermolecularly4 under
C-H amination conditions.
Our interest in this transformation stems from the fact that
we have recently observed a significant differentiation of the
two diastereotopic faces in the reactions of chiral cations of
type 1 (Figure 1).5 Hence, we wondered whether a dif-
ferentiation6 of the diastereotopic hydrogen atoms in sub-
strates of type 2 could also be possible and what preference
(3) (a) Espino, C. G.; Du Bois, J. Angew. Chem., Int. Ed. 2001, 40,
598–600. (b) Espino, C. G.; Wehn, P. M.; Chow, J.; Du Bois, J. J. Am.
Chem. Soc. 2001, 123, 6935–6936. (c) Fiori, K. W.; Fleming, J. J.; Du
Bois, J. Angew. Chem., Int. Ed. 2004, 43, 4349–4352. (d) Espino, C. G.;
Fiori, K. W.; Kim, M.; Du Bois, J. J. Am. Chem. Soc. 2004, 126, 15378–
15379. (e) Kim, M.; Mulcahy, J. V.; Espino, C. G.; Du Bois, J. Org. Lett.
2006, 8, 1073–1076. (f) Liu, Y.; Xiao, W.; Wong, M.-K.; Che, C.-M. Org.
Lett. 2007, 9, 4107–4110. (g) Fiori, K. W.; Du Bois, J. J. Am. Chem. Soc.
2007, 129, 562–568. (h) Liang, C.; Collet, F.; Robert-Peillard, F.; Mu¨ller,
P.; Dodd, R. H.; Dauban, P. J. Am. Chem. Soc. 2008, 130, 343–350. (i)
Olson, D. E.; Du Bois, J. J. Am. Chem. Soc. 2008, 130, 11248–11249. (j)
Huard, K.; Lebel, H. Chem.sEur. J. 2008, 14, 6222–6230. (k) Zalatan,
D. N.; Du Bois, J. J. Am. Chem. Soc. 2008, 130, 9220–9221.
† Lehrstuhl fu¨r Organische Chemie I.
‡ Lehrstuhl fu¨r Anorganische Chemie.
(1) Reviews: (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) Mu¨ller, P.; Fruit, C. Chem. ReV. 2003, 103, 2905–
2920. (c) Dauban, P.; Dodd, R. H. Synlett 2003, 1571–1586. (d) Davies,
H. M. L.; Long, M. S. Angew. Chem., Int. Ed. 2005, 44, 3518–3520. (e)
Davies, H. M. L. Angew. Chem., Int. Ed. 2006, 45, 6422–6425. (f) Davies,
H. M. L.; Manning, J. R. Nature 2008, 451, 417–424. (g) D´ıaz-Requejo,
M. M.; Pe´rez, P. J. Chem. ReV. 2008, 108, 3379–3394. (h) Collet, F.; Dodd,
R. H.; Dauban, P. Chem. Commun. 2009, 5061–5074.
(4) Intermolecular catalytic C-H aminations: (a) Na¨geli, I.; Baud, C.;
Bernardinelli, G.; Jacquier, Y.; Moraon, M.; Mu¨ller, P. HelV. Chim. Acta
1997, 80, 1087–1105. (b) Yamawaki, M.; Tsutsui, H.; Kitagaki, S.; Anada,
M.; Hashimoto, S. Tetrahedron Lett. 2002, 43, 9561–9564. (c) Liang, J.-
L.; Yuan, S.-X.; Chan, P. W. H.; Che, C.-M. Org. Lett. 2002, 4, 4507–
4510. (d) Reddy, R. P.; Davies, H. M. L. Org. Lett. 2006, 8, 5013–5016.
(e) Liang, C.; Robert-Peillard, F.; Fruit, C.; Dodd, R. H.; Dauban, P. Angew.
Chem., Int. Ed. 2006, 45, 4641–4644. (f) Lebel, H.; Huard, K. Org. Lett.
2007, 9, 639–642. (g) References 3d, g, h, j.
(2) (a) Dick, A. R.; Sanford, M. S. Tetrahedron 2006, 62, 2439–2463.
(b) Crabtree, R. H. J. Chem. Soc., Dalton Trans. 2001, 2437–2450.
10.1021/ol101517v  2010 American Chemical Society
Published on Web 07/22/2010

Table 1. Diastereotopos-Differentiation in C-H Amination
Reactions at the Benzylic Position of Chiral Substrates 2
entrya
substrate
X
yield [%]b
drc
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
COOMe
PO(OEt)2
SO2Ph
NO2
CN
OAc
81
65
56
63
86
40d
82/18
>95/5
>95/5
91/9
80/20
86/14
Figure 1. Diastereoselective reactions at the prostereogenic carbon
atom in cations of type 1 and in hydrocarbons of type 2.
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 after
16 h. b Yields of the diastereomeric mixture based on nitrene source
H2NTces. c The diastereomeric ratio (dr ) 3/4) was determined by 1H NMR.
d Incomplete conversion; impure H2NTces was reisolated.
would be observed. Herein, we report on our preliminary
results in this area.
Our first experiments were aimed at identifying an
appropriate nitrene precursor and a sufficiently active catalyst.
It was found for our test substrates that the combination of
a trichloroethoxysulfonyl-substituted amine (H2NTces) with
bis[rhodium(R,R,R′,R′-tetramethyl-1,3-benzenedipropi-
onate)] [Rh2(esp)2] as the catalyst and diacetoxyiodobenzene
as the oxidant, as previously described by Du Bois,3d,g was
superior to other published reagent combinations. Various
chiral substrates of type 2 reacted under the conditions that
are outlined in Scheme 1 and described in detail in the
Supporting Information.
(entry 6), also afforded the major diastereomer 3 with good
selectivity. A reversal of the selectivity in favor of diaste-
reomer 4 was not observed in any case. To secure high
conversion of the reactive nitrene precusor, H2NTces was
used as the limiting reagent. In most cases (entries 1-5) it
was not reisolated. If a 1:1 ratio of H2NTces and substrate
2 was used, the yields were lower. For example substrate
2b gave a 45% yield for a ratio H2NTces:2b ) 1:1 and a
60% yield if the ratio was 1:1.5.
The relative configuration of the major diastereomers 3a, 3b,
3c, 3d, and 3f was determined by X-ray crystal structure
analysis. As an example, the relative configuration of product
3a is depicted in Figure 2. In this case, the structure could be
Scheme 1
.
C-H Amination of Substrate 2 to the Diastereomeric
Products 3 and 4
Remarkably, the reactions proceeded with good to excel-
lent diastereoselectivity with a range of substituents (X) on
the stereogenic center adjacent to the benzylic methylene
group (Table 1). Most noteworthy is the fact that, in contrast
to the reactions of cations of type 1, the size of the substituent
(X) has a negligible effect on the direction of the selectivity.
Although, the best selectivities were obtained with the
formally biggest groups PO(OEt)2 (entry 2) and SO2Ph (entry
3), other groups that are according to their A-value7
significantly smaller than the methyl substituent, for example,
COOMe (entry 1), NO2 (entry 4), CN (entry 5), or OAc
Figure 2. Proof of relative configuration of the product 3a by crystal
structure analysis.
confirmed following cleavage of the protecting group (Zn/Cu
1
in MeOH/HOAc, then AcCl in MeOH) by comparing the H
NMR spectra of the deprotected amine with the literature data.8
The relative configuration of the acetate 3f was confirmed in
the same manner.9 Using the Pinner reaction,10 nitrile 3e was
transformed into methyl ester 3a, the configuration of which
was known from its crystal structure.
(5) (a) Mu¨hlthau, F.; Schuster, O.; Bach, T. J. Am. Chem. Soc. 2005,
127, 9348–9349. (b) Mu¨hlthau, F.; Stadler, D.; Goeppert, A.; Olah, G. A.;
Prakash, G. K. S.; Bach, T. J. Am. Chem. Soc. 2006, 128, 9668–9675. (c)
Stadler, D.; Mu¨hlthau, F.; Rubenbauer, P.; Herdtweck, E.; Bach, T. Synlett
2006, 2573–2576. (d) Stadler, D.; Bach, T. Chem. Asian J. 2008, 3, 272–
284. (e) Stadler, D.; Goeppert, A.; Rasul, G.; Olah, G. A.; Prakash, G. K. S.;
Bach, T. J. Org. Chem. 2009, 74, 312–318.
(8) (a) Seerden, J.-P. G.; Kuypers, M. M. M.; Scheeren, H. W.
Tetrahedron: Asymmetry 1995, 6, 1441–1450. (b) Kobayashi, S.; Kobayashi,
J.; Ishiani, H.; Ueno, M. Chem.sEur. J. 2002, 8, 4185–4190.
(6) Review: Hoffmann, R. W. Synthesis 2004, 2075–2090.
(7) Eliel, E. L.; Wilen, S. H.; Mander, L. N. In Stereochemistry of
Organic Compounds; John Wiley & Sons: New York, 1994; p 696.
(9) Evans, J. W.; Ellman, J. A. J. Org. Chem. 2003, 68, 9948–9957.
Org. Lett., Vol. 12, No. 16, 2010
3691

In the case of substrate 2f, we attempted to improve the
yield by substituting the acetyl group with different oxygen
protecting groups. Although the selectivities increased, the
yields were lower. As an example, the corresponding
benzoate was obtained with a selectivity of dr ) 95/5, but
in only 24% yield. Interestingly, the compound, which is
homologous to 2f, bearing a CH2OAc group (X ) CH2OAc)
on the stereogenic center exhibited significantly lower
selectivity (dr ) 60/40) but a higher yield (70%).
Enantiomerically pure substrate (-)-2a, which was ob-
tained by an auxiliary-controlled alkylation,11 was employed
to prove that the C-H amination did not lead to racemization
(Scheme 2). The reaction proceeded in complete analogy to
responsible for the formation of the corresponding byproduct
4. A preference for rotamer 2′ over rotamer 2′′ may be the
result of dipole minimization with the substituents X and
p-methoxyphenyl being oriented in an antiperiplanar fashion.
Although preliminary DFT calculations support this hypoth-
esis, additional work is required to further elucidate the
selecitivity parameters.
In a final set of experiments, which have yet to be
optimized, we tested whether the scope of the substrates
could be increased by variation of the oxidant. In a recent
report it was indicated that the use of PhI(OOCCMe2Ph)2
could significantly improve the catalytic performance of
Rh2(esp)2 in intermolecular C-H amination reactions, be-
cause the respective carboxylic acid is more effective than
HOAc or HOPiv in reducing [Rh2(esp)2]+.14
Indeed, the less reactive substrates 5a and 5b, which gave
very low yields with PhI(OAc)2 or PhI(OPiv)2 as the oxidant,
could be converted into the respective products in 43% and
50% yield when PhI(OOCCMe2Ph)2 was used as the oxidant.
As in the previous example (Table 1, entry 6), in which a
moderate yield was recorded, the substrates 5a and 5b as
well as the nitrene precursor H2NTces were reisolated. It
appears as if the less than perfect yields stem from unwanted
oxidant decomposition rather than from any unselective
reactions of the substrates 2f and 5.
Scheme 2
.
Proof of Configurational Stability in the C-H
Amination of Ester (-)-2a
the reaction of racemate 2a. Both diastereomeric products
3a and 4a possessed, according to HPLC analysis, the same
enantiomeric excess (>99% ee) as the starting material.
On the basis of the mechanistic experiments of Du Bois
et al. with H2NTces, PhI(OPiv)2 and Rh2(esp)23g,12 it can be
assumed that the reaction is concerted and proceeds via a
singlet nitrene complex. The reaction takes place at the most
nucleophilic C-H bond because the intermediate nitrene
complex is electrophilic.4a,13 Assuming a staggered confor-
mation to be preferred for compounds 2, the two conforma-
tions 2′ and 2′′ should be predominantly responsible for the
reaction outcome (Figure 3). The marked C-H bond, which
Figure 4. Structure of less reactive substrates 5a and 5b.
In summary, the C-H amination of arylalkanes possessing
a stereogenic center at the ꢀ-position occurs at the R-position
with amazingly high diastereoselectivity. The reaction pro-
ceeds without racemization of a stereogenic center in the
ꢀ-position and is therefore suitable for the preparation of
functionalized amines in the context of acyclic stereocontrol.
The elucidation of the exact course of the reaction and the
substantiation of the diastereotopos-differentiation require
further investigations, which are currently in progress.
Acknowledgment. This project was supported by an
Alexander von Humboldt postdoctoral research fellowship to P.H.
and by the Deutsche Forschungsgemeinschaft (Ba 1372-12).
Figure 3. Conformations 2′ and 2′′ of the substrate 2 in the studied
diastereoselective C-H amination.
Supporting Information Available: Representative ex-
perimental procedures and spectral data for all new com-
pounds; crystallographic data (CIF format) for compounds
3a, 3b, 3c, 3d, and 3f. This material is available free of
charge via the Internet at http://pubs.acs.org.
is positioned antiperiplanar to the C-H bond at the stereo-
genic center, should exhibit electron density higher than that
of the synclinal C-H bond and should be more reactive.
The C-H amination of the starting material in conformation
2′ gives the major product 3, and the rotamer 2′′ is
OL101517V
(12) Fiori, K. W.; Espino, C. G.; Brodsky, B. H.; Du Bois, J. Tetrahedron
2009, 65, 3042–3051.
(10) Mandal, A. N.; Raychaudhun, S. R.; Chaterjee, A. Synthesis 1983,
727–729.
(13) Lin, X.; Zhao, C.; Che, C.-M.; Ke, Z.; Phillips, D. L. Chem. Asian
J. 2007, 2, 1101–1108.
(11) Gage, J. R.; Evans, D. A. Organic Synthesis; Wiley: New York,
1993; Collect. Vol. VIII, pp 339-343; Org. Synth. 1993, 68, 83-87.
(14) Zalatan, D. N.; Du Bois, J. J. Am. Chem. Soc. 2009, 131, 7558–
7559.
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