De novo synthesis of troc-protected amines: Intermolecular rhodium-catalyzed C-H amination with N-tosyloxycarbamates

Article abstract of DOI:10.1021/ol062953t

The rhodium-catalyzed intermolecular C-H insertion of the nitrene derived from 2,2,2-trichloroethyl-N-tosyloxycarbamate proceeded in good to excellent yields to produce a variety of Troc-protected amines. With cyclic aliphatic alkanes, it is possible to use only 2 equiv of substrate, whereas the reaction with aromatic alkanes is run neat. Not only does the nitrene insertion proceed in benzylic, secondary, and tertiary C-H bonds but also primary C-H insertion products were obtained in good yields. Finally, the use of chiral rhodium catalysts to provide an enantioselective version of this process is discussed.

Full text of DOI:10.1021/ol062953t

ORGANIC
LETTERS
2007
Vol. 9, No. 4
639-642
De Novo Synthesis of Troc-Protected
Amines: Intermolecular
Rhodium-Catalyzed C−H Amination with
N-Tosyloxycarbamates
He´le`ne Lebel* and Kim Huard
De´partement de chimie, UniVersite´ de Montre´al, P.O. Box 6128, Station Downtown,
Montre´al, Que´bec, Canada, H3C 3J7
helene.lebel@umontreal.ca
Received December 6, 2006
ABSTRACT
The rhodium-catalyzed intermolecular C
to excellent yields to produce a variety of Troc-protected amines. With cyclic aliphatic alkanes, it is possible to use only 2 equiv of substrate,
whereas the reaction with aromatic alkanes is run neat. Not only does the nitrene insertion proceed in benzylic, secondary, and tertiary C
bonds but also primary C H insertion products were obtained in good yields. Finally, the use of chiral rhodium catalysts to provide an
−H insertion of the nitrene derived from 2,2,2-trichloroethyl-N-tosyloxycarbamate proceeded in good
−H
−
enantioselective version of this process is discussed.
Synthetic methods to access amines are of primary impor-
tance due to the major role of nitrogen-containing molecules
in the pharmaceutical industries. Recent advances have led
to the development of various processes to produce amines,1
including the hydrogenation of enamides,2 the reductive
amination of carbonyl compounds,3 and the addition of
organometallic reagents to imines.4 Among them, very
efficient catalytic enantioselective versions have been re-
ported leading to R-chiral amines.2-4 In contrast to the
previous processes based on functional group transforma-
tions, the C-H amination reactions5 allow the direct
transformation of a C-H bond into a C-N bond. Hyper-
valent oxidative iodine reagents6 are typically used in
transition-metal-catalyzed C-H insertion reactions of nitrene
species. Whereas a number of intramolecular C-H amina-
tions have been reported,7 only a few intermolecular pro-
cesses have been developed8 and examples of highly
enantioselective reactions are even more limited.9 We have
(1) Review: Salvatore, R. N.; Yoon, C. H.; Jung, K. W. Tetrahedron
2001, 57, 7785-7811.
(2) (a) Hsiao, Y.; Rivera, N. R.; Rosner, T.; Krska, S. W.; Njolito, E.;
Wang, F.; Sun, Y. K.; Armstrong, J. D.; Grabowski, E. J. J.; Tillyer, R. D.;
Spindler, F.; Malan, C. J. Am. Chem. Soc. 2004, 126, 9918-9919. (b)
Bunlaksananusorn, T.; Rampf, F. Synlett 2005, 2682-2684. (c) Dai, Q.;
Yang, W. R.; Zhang, X. M. Org. Lett. 2005, 7, 5343-5345. (d) Clausen,
A. M.; Dziadul, B.; Cappuccio, K. L.; Kaba, M.; Starbuck, C.; Hsiao, Y.;
Dowling, T. M. Org. Process Res. DeV. 2006, 10, 723-726. (e) Kubryk,
M.; Hansen, K. B. Tetrahedron: Asymmetry 2006, 17, 205-209.
(3) Nugent, T. C.; Ghosh, A. K.; Wakchaure, V. N.; Mohanty, R. R.
AdV. Synth. Catal. 2006, 348, 1289-1299 and references therein.
(4) Reviews: (a) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem.
Res. 2002, 35, 984-995. (b) Groger, H. Chem. ReV. 2003, 103, 2795-
2827. (c) Cordova, A. Acc. Chem. Res. 2004, 37, 102-112. (d) Ding, H.;
Friestad, G. K. Synthesis 2005, 2815-2829. (e) Vilaivan, T.; Bhanthum-
navin, W.; Sritana-Anant, Y. Curr. Org. Chem. 2005, 9, 1315-1392.
(5) Reviews: (a) Muller, P.; Fruit, C. Chem. ReV. 2003, 103, 2905-
2919. (b) Dauban, P.; Dodd, R. H. Synlett 2003, 1571-1586. (c) Halfen, J.
A. Curr. Org. Chem. 2005, 9, 657-669. (d) Davies, H. M. L.; Long, M. S.
Angew. Chem., Int. Ed. 2005, 44, 3518-3520. (e) Du Bois, J. Chemtracts
2005, 18, 1-13.
(6) Wirth, T. Angew. Chem., Int. Ed. 2005, 44, 3656-3665.
(7) Recent examples: (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) Espino, C. G.; Fiori,
K. W.; Kim, M.; Du Bois, J. J. Am. Chem. Soc. 2004, 126, 15378-15379.
(d) Cui, Y.; He, C. Angew. Chem., Int. Ed. 2004, 43, 4210-4212. (e) Fiori,
K. W.; Fleming, J. J.; Du Bois, J. Angew. Chem., Int. Ed. 2004, 43, 4349-
4352. (f) Kim, M.; Mulcahy, J. V.; Espino, C. G.; Du Bois, J. Org. Lett.
2006, 8, 1073-1076.
10.1021/ol062953t CCC: $37.00
© 2007 American Chemical Society
Published on Web 01/23/2007

recently reported a rhodium-catalyzed intramolecular C-H
insertion using N-tosyloxycarbamates, the first alternative
method that does not require the use of hypervalent oxidative
iodine reagents.10 In this communication, we now present
the first intermolecular rhodium-catalyzed C-H amination
of 2,2,2-trichloroethyl-N-tosyloxycarbamate to produce amines
in high yields. Furthermore, chiral rhodium catalysts were
evaluated for the preparation of R-chiral amines.
Table 1. Intermolecular Rhodium-Catalyzed C-H Amination
using Various N-Tosyloxycarbamates (Equation 2)
Our recent publication showed that a variety of oxazoli-
dinones could be synthesized from N-tosyloxycarbamates in
the presence of potassium carbonate and a rhodium(II)
triphenylacetate dimer as the catalyst, via an intramolecular
C-H insertion reaction (eq 1).10
Intermolecular nitrene insertion processes are more chal-
lenging due to the propensity of the metal nitrene species to
readily decompose.11 Furthermore, competition between
intermolecular and intramolecular reactions must be avoided,
and thus an intermolecular reaction also requires a N-
tosyloxycarbamate reagent with no (or less) reactive C-H
bonds that could compete via an intramolecular pathway.
We prepared a number of N-tosyloxycarbamate derivatives12
to be tested as reagents in the intermolecular C-H insertion
of cyclohexane (Table 1). Initially, we used 10 equiv of
cyclohexane and the same reaction conditions developed for
the intramolecular process. Both methyl- and ethyl-N-
tosyloxycarbamates were found to be quite unstable under
the reaction conditions and readily decomposed (entries 1
and 2). Primary C-H bonds of the tert-butyl-N-tosyloxy-
carbamate were reactive enough to lead to the formation of
the corresponding oxazolidinone in 41% yield (entry 3).
Allyl- and benzyl-N-tosyloxycarbamates, in which the reac-
tive C-H bond is replaced by an alkene or a phenyl group,
led to a mixture of products (entries 4-6). Conversely,
a Isolated yields. bIntramolecular insertion product isolated in 41% yield.
replacing the reactive C-H bond by a carbon-halogen bond,
such as in 2,2,2-trifluoroethyl- or 2,2,2-trichloroethyl-N-
tosyloxycarbamate, proved to be successful (entries 7 and
8). The 2,2,2-trifluoroethyl-N-tosyloxycarbamate is prone to
readily decompose and led mostly to the corresponding
carbamate (CF3CH2OC(O)NH2). This is probably due to the
strong electronegativity of the fluorine atom. Using the 2,2,2-
trichloroethyl-N-tosyloxycarbamate, which contained less
electronegative chlorine atoms, led to higher yields, and the
desired Troc-carbamate product was obtained in 71% yield
(entry 8). Generating amines containing a Troc protecting
group is very convenient, as it can be readily and selectively
removed using mild reaction conditions.13
We have optimized the reaction conditions for the
intermolecular C-H insertion of 2,2,2-trichloroethyl-N-
tosyloxycarbamate with cyclohexane and Indane using vari-
ous catalysts and solvents (see Supporting Information for
details). We found that a higher concentration helps the
desired intermolecular reaction. Furthermore, for aliphatic
alkanes, a more polar and aprotic solvent such as tetrachlo-
roethane led to a better yield for the C-H insertion product.
Indeed, when using 10 equiv of cyclohexane, 92% yield of
the desired amine was obtained (Table 2, entry 1). Decreasing
the number of equivalents of cyclohexane to 5 and 2 provided
the protected cyclohexylamine in 85% and 73% yield,
respectively. Similar yields were obtained with cyclooctane
(entry 2). For substrates containing different C-H bonds,
moderate yields were obtained, due to a lack of selectivity
(entries 3-5). For instance, adamantane furnished a 3:1 ratio
of tertiary C-H vs secondary C-H insertion products using
the standard reaction conditions with Rh2(TPA)4. Other
achiral catalysts such as Rh2(OAc)4 or Rh2(oct)4 led to a
better selectivity but with low reactivity.14 Conversely, chiral
(8) Recent example: (a) Albone, D. P.; Challenger, S.; Derrick, A. M.;
Fillery, S. M.; Irwin, J. L.; Parsons, C. M.; Takada, H.; Taylor, P. C.; Wilson,
D. J. Org. Biomol. Chem. 2005, 3, 107-111. (b) Fructos, M. R.; Trofimenko,
S.; Diaz-Requejo, M. M.; Perez, P. J. J. Am. Chem. Soc. 2006, 128, 11784-
11791. (c) Fiori, K. W.; DuBois, J. J. J. Am. Chem. Soc. 2007, 129, 562-
568.
(9) (a) Kohmura, Y.; Katsuki, T. Tetrahedron Lett. 2001, 42, 3339-
3342. (b) Yamawaki, M.; Tsutsui, H.; Kitagaki, S.; Anada, M.; Hashimoto,
S. Tetrahedron Lett. 2002, 43, 9561-9564. (c) Liang, J. L.; Yuan, S. X.;
Huang, J. S.; Yu, W. Y.; Che, C. M. Angew. Chem., Int. Ed. 2002, 41,
3465-3468. (d) Liang, J. L.; Huang, J. S.; Yu, X. Q.; Zhu, N. Y.; Che, C.
M. Chem.-Eur. J. 2002, 8, 1563-1572. (e) Liang, C. G.; Robert-Pedlard,
F.; Fruit, C.; Muller, P.; Dodd, R. H.; Dauban, P. Angew. Chem., Int. Ed.
2006, 45, 4641-4644. (f) Reddy, P. R.; Davies, H. M. L. Org. Lett. 2006,
8, 5013-5016.
(10) (a) Lebel, H.; Huard, K.; Lectard, S. J. Am. Chem. Soc. 2005, 127,
14198-14199. (b) Lebel, H.; Leogane, O.; Huard, K.; Lectard, S. Pure
Appl. Chem. 2006, 78, 363-375.
(11) In spite of that, others have established the feasibility of performing
such a reaction even with a single equivalent of starting material: see ref
8 and 9 for details.
(12) These N-tosyloxycarbamate reagents have been chosen, as neither
contained reactive C-H bonds (entries 1 and 5-8) that could compete via
an intramolecular pathway. Furthermore, substrates containing primary C-H
bonds or terminal alkenes (which are typically less reactive) were also tested
(entries 2-4).
9e
catalyst Rh2[(S)-NTTL]4 showed good selectivity and
(13) Mineno, T.; Choi, S. R.; Avery, M. A. Synlett 2002, 883-886.
Org. Lett., Vol. 9, No. 4, 2007
640

bamate and the rhodium catalyst were soluble enough to
perform the reaction (Table 3). Using 5 equiv of substrate,
Table 2. Rhodium-Catalyzed Intermolecular C-H Insertion
with Aliphatic Alkanes (Equation 3)
Table 3. Rhodium-Catalyzed Intermolecular C-H Insertion
with Aromatic Alkanes (Equation 4)
a Isolated yield. b6 mol % of TCE (0.5 M). c5 mol % of DCM (0.5 M).
d10 equiv of substrate. e2 equiv of substrate. f10 equiv of substrate in DCM
g
(0.1 M). Ratio of tertiary C-H insertion vs secondary C-H insertion.
reactivity, thus the desired tertiary and secondary amines
were obtained in good yields (58-84%) using 5 equiv of
starting material (Figure 1).
a Isolated yield. bRh2[(S)-NTTL]4 (5 mol %) as catalyst in DCM (0.5
M).
61-78% yields were obtained for benzylic secondary C-H
insertion products (entries 1-3). Primary C-H insertion was
also possible using toluene or mesitylene as substrate. Better
yields could be obtained by using 15 equiv of substrate or
Rh2[(S)-NTTL]4 as catalysts (entries 4 and 5).
We have also examined the enantioselectivity of the
reaction using various chiral dirhodium tetracarboxylate
catalysts, particularly, the one derived from tert-leucine.12
The best results were achieved using Rh2[(S)-NTTL]4,9e and
product 6 was isolated in 56% and 2.57:1 er (eq 4, Table
4).15 In contrast to previous results reported with preformed
or in situ generated sulfonyliminophenyliodinane,9b,f catalysts
derived from tetrachlorophtaloyl led to lower enantioselec-
tivity. This clearly illustrates that the decomposition of
tosyloxycarbamates to a nitrene metal species may involve
a different pathway, and further experiments will have to be
performed to explain these intriguing results. Furthermore,
these results also suggest that a new catalyst design will be
necessary to achieve high enantioselectivities.16
In conclusion, we have devised the first tosyloxycarbamate
reagent to perform intermolecular C-H insertion reactions.
(14) For instance, C-H insertion into adamantane with 5 mol % of Rh2-
(OAc)4 led to 27% of the desired amine 4 with a ratio of tertiary C-H
insertion vs secondary C-H insertion, of 21:1, whereas 5 mol % of Rh2-
(Oct)4 gave 42% yield of amine 4 with a 15:1 ratio.
Figure 1. Chiral rhodium complexes.
(15) The enantiomeric ratio was measured on the crude material. A
purification procedure cannot be used as an argument to explain the
enantiomeric enrichment, thus the chiral catalyst must be involved to account
for the observed enantioselectivity.
With aromatic alkanes, it was possible to run the reaction
without solvent, as both 2,2,2-trichloroethyl-N-tosyloxycar-
Org. Lett., Vol. 9, No. 4, 2007
641

desired amine products with good yields. With cyclic
aliphatic alkanes, it is possible to use only 2 equiv of
substrate. Furthermore, this process is one of the rare
examples which provides primary C-H insertion products
in decent yields. Studies are currently underway to develop
novel reagents and chiral catalysts to reach high enantio-
selectivities.
Table 4. Rhodium-Catalyzed Intermolecular Enantioselective
C-H Insertion with Indane (Equation 5)
entry
Rh2(O2CR)4
temp
era
Acknowledgment. This research was supported by
NSERC (Canada), the CFI (Canada), AstraZeneca Canada
Inc., Boehringer Ingelheim (Canada) Ltd., Merck Frosst
Canada Ltd., and the Universite´ de Montre´al. K.H. thanks
NSERC (Canada) for a graduate scholarship. We thank the
Charette group (Universite´ de Montre´al) and the Davies
group (University of New York at Buffalo) for generous gifts
of chiral rhodium catalysts.
1
2
3
4
5
6
Rh2[(S)-PPTL]4
Rh2[(S)-TCPTTL]4
Rh2[(S)-NTTL]4
Rh2[(S)-NTTL]4
Rh2[(S)-Br-NTTL]4
Rh2[(S)-TCPTAD]4
25 °C
25 °C
25 °C
-20 °C
25 °C
25 °C
1.83:1
1.78:1
2.08:1
2.57:1 (56% yield)
1.95:1
1.67:1
a Determined by HPLC using a Chiralcel OD column.
This very practical rhodium-catalyzed process does not
require the use of hypervalent iodine reagents and led to the
Supporting Information Available: Experimental pro-
cedures, compound characterization data, and 1H spectra of
all the products. This material is available free of charge
via the Internet at http://pubs.acs.org.
(16) We do not think that the low er’s are due to a background reaction,
as under our reaction conditions in the absence of the rhodium catalyst
N-tosyloxycarbamates only decomposed to lead to the corresponding
carbamate ROC(O)NH2.
OL062953T
642
Org. Lett., Vol. 9, No. 4, 2007