syn-1,2-amino alcohols via diastereoselective allylic C-H amination

Article abstract of DOI:10.1021/ja071905g

A novel Pd/sulfoxide catalyzed diastereoselective allylic C-H amination reaction of chiral homoallylic N-tosyl carbamates is reported. Densely oxygenated ∞-olefin substrates with multiple stereogenic centers undergo allylic C-H amination in excellent yiel

Full text of DOI:10.1021/ja071905g

Published on Web 05/22/2007
syn-1,2-Amino Alcohols via Diastereoselective Allylic C-H Amination
Kenneth J. Fraunhoffer and M. Christina White*
Roger Adams Laboratory, Department of Chemistry, UniVersity of Illinois, Urbana, Illinois 61801
Received March 22, 2007; E-mail: white@scs.uiuc.edu
Table 1. Allylic C-H Amination Reaction Optimization and Scope
syn-1,2-Amino alcohols are prevalent motifs in a diverse range
of important small molecules such as natural products, pharma-
ceuticals, and asymmetric catalysts. The majority of methods for
selectively constructing 1,2-amino alcohols rely on functional group
interconversions or C-C bond-forming reactions using preoxidized
materials.1 Selective methods for directly installing nitrogen
functionality into inert C-H bonds have the potential to streamline
the synthesis of these important compounds by avoiding the
functional group manipulations (FGMs) required for working with
oxidized materials.2,3 Herein we present a novel route for accessing
chiral syn-1,2-amino alcohols enabled by the discovery of a Pd-
(II)/sulfoxide-catalyzed, diastereoselective allylic C-H amination
reaction of chiral homoallylic N-tosyl carbamates (eq 1). To the
best of our knowledge, this represents the first example of a general
and stereoselective, catalytic allylic C-H amination reaction.4 We
demonstrate that this reaction enables the streamlined synthesis of
a diverse collection of syn-1,2-amino alcohols because of its broad
scope and the versatility of its vinyl anti-oxazolidinone products.
a Average of two runs at 0.3 mmol. b Determined by GC analysis of the
crude reaction mixture. c Reaction run at 0.33 M. d Reaction run using 10
mol % Pd(OAc)2 (no sulfoxide ligand). e Determined by NMR analysis of
the crude reaction mixture. f Reaction run using 5 mol % additional bis-
sulfoxide ligand.
Palladium(II)-promoted addition of nitrogen nucleophiles to
olefins (aminopalladation) is a well-established process that has
led to many interesting catalytic reactions such as oxidative
amination,5 aminoacetoxylation,6 aminohalogenation,7 and diami-
nation.8 Alternatively, Pd(II)-promoted allylic C-H amination
processes are rare.4b To avoid aminopalladation, the C-H cleavage
step is generally done in the absence of a nitrogen nucleophile
resulting in a two-step sequence that is stoichiometric in palladium.9
We previously discovered that the addition of bis-sulfoxide
ligands to Pd(OAc)2 promotes allylic C-H cleavage of R-olefins
versus oxypalladation in the presence of weak oxygen nucleophiles
(i.e., carboxylic acids). This finding has resulted in several general
allylic C-H esterification reactions of this important olefin class.10
We hypothesized that eq 1 could effect a similar catalytic allylic
C-H amination reaction of R-olefins using weak nitrogen nucleo-
philes such as N-tosyl carbamates. We reasoned that the weak Lewis
basicity of this nucleophile would prevent it from interfering with
the electrophilic C-H cleavage step. Moreover, because the N-H
proton of N-tosyl carbamate is relatively acidic,11 we anticipated
that it may become activated toward functionalization by depro-
tonation with the acetate counterion of the Pd(II) catalyst. Impor-
tantly, acetate may be regenerated throughout the catalytic cycle
during benzoquinone (BQ) mediated reoxidation of palladium.12
Herein we report the successful development of this allylic C-H
amination reaction and the exploration of its scope and synthetic
utility. Furthermore, we provide evidence in support of a mechanism
that proceeds via a Pd(II)/sulfoxide-promoted allylic C-H cleavage
to furnish a π-allylPd intermediate followed by acetate counterion-
promoted functionalization with the tethered N-tosyl carbamate
nucleophile.
Our study began by examining the allylic C-H amination of
2-methylhex-5-en-3-yl N-tosylcarbamate 2a under standard allylic
C-H oxidation conditions (Table 1).13 We found that 10 mol %
phenyl bis-sulfoxide/Pd(OAc)2 1/BQ (2 equiv) formed the desired
oxazolidinone product 3a in a modest overall yield (37%) with a
good level of diastereoselectivity (7:1 anti/syn) (Table 1, entry 1).
Significantly, in the absence of bis-sulfoxide ligand, only 3% of
the allylic amination product was formed (entry 2). Increasing the
substrate concentration (0.33 M f 0.66 M) improved the yield to
50% (entry 3). A screen of commercially available quinones
revealed phenyl-benzoquinone (PhBQ) was superior to BQ (entry
4), and when added in slight excess (1.05 equiv) provides a 72%
overall yield with only a modest decrease in diastereoselectivity
(6:1 diastereomeric ratio (dr), entry 5). The addition of 5 mol %
extra ligand provided a slightly higher yield (entry 6).
A variety of homoallylic N-tosyl carbamate substrates containing
one stereogenic center were cyclized to test the generality of this
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C O M M U N I C A T I O N S
method (Table 1, entries 6-10).14 One branching element adjacent
to the N-tosyl carbamate provides the best balance of reactivity
and diastereoselectivity (entries 6 and 9). Unbranched substrates
provided good yields but poor levels of diastereoselectivity (R )
n-Pr and TBDPSOCH2, entries 8 and 10), while a bulky quaternary
alkyl substituent provided a poor yield but excellent diastereose-
lectivity (R ) t-Bu, entry 7). The mildness of this method and its
potential utility for generating densely functionalized compounds
is illustrated by the allylic C-H amination of a substrate containing
a proximal diethyl acetal moiety (entry 9). Significantly, diaste-
reomerically pure oxazolidinone products can be obtained using
standard column chromatography.
Scheme 3
Scheme 1 a
We hypothesized that routes based on selective C-H to C-N
bond-forming reactions would streamline the syntheses of nitrogen
containing compounds. To evaluate this, we compared the route
enabled by allylic C-H amination relative to a previous state-of-
the-art route based on allylic C-O substitution for the synthesis of
oxazolidinone (-)-15 (Scheme 3). This heterocycle is a known
intermediate toward L-acosamine derivative (-)-16, an aminosugar
that is key to the medicinal properties of clinically used chemo-
therapeutic agent epirubicin.19 Starting from aldehyde (-)-11,
enantiopure allylic C-H amination substrate (+)-12 was synthe-
sized in only two steps with no FGMs. By way of contrast,
beginning from the same starting material enantiopure allylic C-O
substitution substrate 14 had required five steps with two FGMs.1a
Hydrocarbon (+)-12 readily cyclized via allylic C-H amination
with very good diastereoselectivity (9:1 dr) to give a 70% isolated
yield of desired anti-(-)-15. Significantly, the C-H to C-N route
to enantio- and diastereomerically pure (-)-15 proceeded in half
the total number of steps, no FGMs, and comparable overall yield
to the alternative C-O to C-N bond-forming route.1a
a Conditions: (a) RuCl3 (5 mol %), NaIO4 (5 equiv), CH3CN/CCl4/H2O
(2:2:3), room temp (82%); (b) sodium naphthalene (8 equiv), DME, -78
°C; (c) 6 M HCl, 100 °C (63%, two steps).
An important feature of this chemistry is that it enables the rapid
synthesis of stereochemically defined oxazolidinones. Not only does
this product comprise the skeleton of a very important class of
antibiotics,15 but oxazolidinones can be further elaborated to a wide
range of medicinally and biologically relevant 1,2-amino alcohols.
For example, (+)-(2R,3S)-3-hydroxyleucine, an unnatural â-hy-
droxy-R-amino acid present in the antitumor agent lactacystin,16 is
readily obtained from anti-oxazolidinone (-)-3a. Enantioenriched
homoallylic N-tosyl carbamate (-)-2a, easily accessed via asym-
metric allylboration, undergoes allylic C-H amination with good
diastereoselectivity (6:1) to give a 61% isolated yield of the
diastereomerically pure anti-(-)-3a with no erosion in enantiomeric
purity (Scheme 1). The vinyl moiety of (-)-3a was further
elaborated to carboxylic acid (+)-4 via ruthenium tetraoxide-
catalyzed oxidative cleavage. Mild, reductive detosylation and
oxazolidinone hydrolysis under acidic conditions afforded hydroxy-
leucine (+)-5 (Scheme 1).17
Scheme 4
Scheme 2 a
Stoichiometric studies were performed to test the hypothesis that
allylic C-H amination proceeds via a C-H cleavage mechanism
involving a π-allylPd intermediate. When a stoichiometric mixture
of N-tosyl carbamate 2a and Pd(OAc)2/bis-sulfoxide 1 were heated
for 2 h, 1H NMR analysis indicated approximately 24% conversion
of starting material 2a to oxazolidinone product 3a.20 Significantly,
a π-allylPd species was not observed. We next evaluated Pd(TFA)2/
bis-sulfoxide in an analogous experiment (Scheme 4). Using this
alternative palladium(II) source having a counterion that is a much
weaker base, 1H NMR analysis at the same 2 h time point revealed
predominant formation of a π-allylPd complex (ca. 61%) and no
significant formation of product 3a (<5%).21 Importantly, the
addition of an external acetate source to this π-allylPd intermediate
led to the formation of 3a with a similar yield and identical
diastereoselectivity to that observed under standard catalytic condi-
tions (Scheme 4 and Table 1, entry 5).
a Conditions: (a) 1 (10 mol %), 5 mol % additional bis-sulfoxide, PhBQ
(1.05 equiv), THF (0.66 M), 45 °C, 72 h; (b) BCl3 (5 equiv), CH2Cl2, room
temp, 72%.
In substrates containing multiple stereogenic centers, the dia-
stereomeric outcome is controlled by the stereocenter that bears
the N-tosyl carbamate. Both syn- and anti-diols (-)-6 and (+)-7
gave anti-oxazolidinone products [(-)-8 and (-)-9, respectively]
with good to modest diastereoselectivities and in excellent yields
(Scheme 2). Debenzylation of stereochemically and functionally
dense oxazolidinone (-)-8 with BCl3 afforded a known diol
intermediate (-)-10 used in the synthesis of 1,4-dideoxy-1,4-imino-
L-xylitol, a pyrrolidine with promising activity as a glycosidase
inhibitor (see Supporting Information).18
An alternative mechanism involving olefin isomerization fol-
lowed by aminopalladation and â-hydride elimination was also
considered. In that vein, internal (E)- and (Z)- olefins 17 and 18
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C O M M U N I C A T I O N S
Org. Chem. 1998, 63, 1339. (c) Hayashi, T.; Yamamoto, A.; Ito, Y.
Tetrahedron Lett. 1988, 29, 99. (d) Bystrom, S. E.; Aslanian, R.; Backvall,
J.-E. Tetrahedron Lett. 1985, 26, 1749. (e) Hayashi, T.; Kishi, K.;
Yamamoto, A.; Ito, Y. Tetrahedron Lett. 1990, 31, 1743. (f) Evans, P.
A.; Robinson, J. E.; Nelson, J. D. J. Am. Chem. Soc. 1999, 121, 6761. (g)
Ohmura, T.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 15164. Olefin
aminohydroxylation: (h) Kolb, H. C.; Sharpless, K. B. In Transition
Metals for Organic Synthesis, 2nd ed.; Beller, M., Bolm, C., Eds.; Wiley-
VCH Verlag: Weinheim, Germany, 2004; p 309. Mannich: (i) Trost, B.
M.; Terrell, L. R. J. Am. Chem. Soc. 2003, 125, 338. (j) Matsunaga, S.;
Yoshida, T.; Morimoto, H.; Kumagai, N.; Shibasaki, M. J. Am. Chem.
Soc. 2004, 126, 8777. (k) Ramasastry, S. S. V.; Zhang, H.; Tanaka, F.;
Barbas, C. F. J. Am. Chem. Soc. 2007, 129, 288.
were independently synthesized and subjected to the reaction
conditions (Table 2). In contrast to R-olefin substrate 2a, both
internal olefins afford oxazolidinone product 3a with poorer yields
and higher diastereoselectivities that decrease over time (Table 2,
entry 3 vs entries 1 and 2). The latter is most likely due to formation
of Pd-H in the oxidative aminopalladation pathway that mediates
olefin isomerization to 2a. Significantly, with R-olefin substrate
2a, olefin isomers 17 or 18 were not detected under standard
reaction conditions,22 and no change in the diastereoselectivity of
oxazolidone product 3a is observed during the course of the reaction
(Table 2, entry 3).
(2) Streamlining syntheses via late stage C-H oxidation see: (a) Fraunhoffer,
K. J.; Bachovchin, D. A.; White, M. C. Org. Lett. 2005, 7, 223. (b) Covell,
D. J.; Vermeulen, N. A.; Labenz, N. A.; White, M. C. Angew. Chem.,
Int. Ed. 2006, 45, 8217. (c) Hoffman, R. W. Synthesis 2006, 21, 3531.
Elegant examples of late stage C-H hydroxylation and amination see:
(d) Wender, P. A.; Hilinski, M. K.; Mayweg, A. V. W. Org. Lett. 2005,
7, 79. (e) Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510.
(3) C-H amination via metal nitrenes: (a) Espino, C. G.; Du Bois, J. Angew.
Chem., Int. Ed. 2001, 40, 598. (b) Kim, M.; Mulcahy, J. V.; Espino, C.
G.; Du Bois, J. Org. Lett. 2006, 8, 1073. (c) Lebel, H.; Huard, K.; Lectard,
S. J. Am. Chem. Soc. 2005, 127, 14198.
Table 2. Testing for a Possible Aminopalladation Mechanism
(4) For single examples of catalytic allylic C-H amination: (a) ref 3b. (b)
Larock, R. C.; Hightower, T. R.; Hasvold, L. A.; Peterson, K. P. J. Org.
Chem. 1996, 61, 3584.
(5) (a) Hegedus, L. S.; Allen, G. F.; Waterman, E. L. J. Am. Chem. Soc.
1976, 98, 2674. (b) Ronn, M.; Backvall, J. E.; Andersson, P. G.
Tetrahedron Lett. 1995, 36, 7749. (c) ref. 4b. (d) Overman, L. E.;
Remarchuk, T. P. J. Am. Chem. Soc. 2002, 124, 12. (e) Brice, J. L.; Harang,
J. E.; Timokhin, V. I.; Anastasi, N. R.; Stahl, S. S. J. Am. Chem. Soc.
2005, 127, 2868.
(6) (a) Alexanian, E. J.; Lee, C.; Sorensen, E. J. J. Am. Chem. Soc. 2005,
127, 7690. (b) Lui, G.; Stahl, S. S. J. Am. Chem. Soc. 2006, 128, 7179.
(7) Manzoni, M. R.; Zabawa, T. P.; Kasi, D.; Chemler, S. R. Organometallics
2004, 23, 5618.
olefin
isolated
5 h drb
72 h drb
entry
isomer
yield 3a
(anti/syn)
(anti/syn)
1
2
3
E isomer (17)
Z isomer (18)
R-olefin (2a)
20%
9%
72%
9:1
13:1
6:1
8:1
11:1
6:1
a Reaction run using 1 (10 mol %), PhBQ (1.05 equiv), THF (0.66 M),
45 °C, 72 h. b GC.
(8) (a) Backvall, J.-E. Tetrahedron Lett. 1978, 19, 163. (b) Streuff, J.;
Hovelmann, C. H.; Nieger, M.; Muniz, K. J. Am. Chem. Soc. 2005, 127,
14586. (c) Zabawa, T. P.; Kasi, D.; Chemler, S. R. J. Am. Chem. Soc.
2005, 127, 11250.
(9) (a) Akermark, B.; Akermark, G.; Hegedus, L. S.; Zetterberg, K. J. Am.
Chem. Soc. 1981, 103, 3037. (b) Trost, B. M. Tetrahedron 1977, 33, 2615
and references therein.
(10) (a) Chen, M. S.; Prabagaran, N.; Labenz, N. A.; White, M. C. J. Am.
Chem. Soc. 2005, 127, 6970. (b) Fraunhoffer, K. J.; Prabagaran, N.; Sirois,
L. E.; White, M. C. J. Am. Chem. Soc. 2006, 128, 9032. (c) Delcamp, J.
H.; White, M. C. J. Am. Chem. Soc. 2006, 128, 15076. (d) Chen, M. S.;
White, M. C. J. Am. Chem. Soc. 2004, 126, 1346.
Collectively, this data strongly supports a mechanism for allylic
C-H amination involving Pd(II)/bis-sulfoxide promoted allylic
C-H cleavage to form a π-allylPd intermediate followed by acetate-
mediated functionalization. The acetate most likely acts as a base
to deprotonate the N-tosyl carbamate nucleophile.23 A key to this
catalytic amination reactivity is the ability to use catalytic quantities
of acetate base that can be regenerated via quinone-mediated Pd-
(0) oxidation. The use of stoichiometric base significantly attenuates
this reactivity, most likely by interfering with the electrophilic C-H
cleavage step of the catalytic cycle.24
(11) pKa (H2O) of EtOC(O)NHTs ) 3.7. Taylor, L. D.; Pluhar, M.; Rubin, L.
E. J. Polym. Sci., Part B: Polym. Phys. 1967, 5, 77.
(12) 2 equiv AcOH + BQ + Pd(0) f DHQ + Pd(OAc)2. Only ca. 1% of the
allylic acetate product observed (Supporting Information, SI-23).
(13) Other homoallylic carbamates -OC(O)NH2, OC(O)NHC(O)CCl3, and
-OC(O)NH(p-OMe)Ph with less acidic N-H bonds showed poor
reactivities. Addition of 10 mol% Hunig’s base to p-anisyl carbamate
substrate gave no significant improvement (SI-9 and ref 24).
(14) (a) 1,1-disubstituted and 1,2-disubstituted olefin substrates proceeded with
poor conversions (30%) and yields (ca. 8-12% as mixtures of oxidative
amination products). (b) Methyl 2-(tosylcarbamoyloxy)pent-4-enoate gave
a complex mixture of products (ca. 30% anti-oxazolidinone identified)
(SI-8,9).
In summary, this method represents the first general and
stereoselective Pd(II)-catalyzed allylic C-H amination reaction. The
good levels of diastereoselectivity and functional group tolerance
demonstrated for this method enable the synthesis of densely
functionalized anti-oxazolidinone products that can be rapidly
transformed into useful syn-1,2-amino alcohols. Mechanistic studies
support a Pd(II)/bis-sulfoxide mediated C-H cleavage to form a
π-allylPd intermediate followed by a Pd(II) counterion-mediated
deprotonation of the nitrogen nucleophile to achieve functional-
ization. The latter aspect of this mechanism may provide a general
approach for achieving activation of weak nucleophiles without
attenuating the reactivity of an electrophilic metal catalyst.25 Current
studies are focused on further exploration of the scope and
mechanism of this reaction.
(15) Ross, J. E.; Fritsche, T. R.; Sader, H. S.; Jones, R. N. Int. J. Antimicrob.
Agents 2007, 29, 295.
(16) Nagamitsu, T.; Sunazuka, T.; Tanaka, H.; Omura, S.; Sprengeler, P. A.;
Smith, A. B. J. Am. Chem. Soc. 1996, 118, 3584.
(17) For alternative syntheses see: Bonini, C.; Righi, G. Tetrahedron 2002,
58, 4981.
(18) Lei, A.; Liu, G.; Lu, X. J. Org. Chem. 2002, 67, 974.
(19) Weymouth-Wilson, A. C. Nat. Prod. Rep. 1997, 14, 99.
(20) Unlike allylic C-H oxidation, Pd/sulfoxide-catalyzed allylic C-H ami-
nation does not require quinone for functionalization and therefore does
not proceed via a serial ligand catalysis mechanism. See ref 10a.
(21) 1-Phenyl-3-buten-1-N-tosyl carbamate substrate gives 4-phenyl-1,3-buta-
diene. This result is consistent with â-N-tosyl carbamate elimination from
a π-allylPd intermediate (SI-22).
(22) 1H NMR monitoring at 5, 24, 48, and 72 h (signal/noise > 500:1) (SI-
24). The possibility that trace levels of 17 and/or 18 form under standard
reaction conditions and contribute to formation of 3a cannot be rigorously
excluded.
Acknowledgment. M.C.W. thanks the Henry Dreyfus Founda-
tion, the A.P. Sloan Foundation, the University of Illinois (UIUC),
Merck Research Laboratories, and the NIH/NIGMS (Grant
GM076153) for financial support. We thank Johnson Matthey for
a generous gift of Pd(OAc)2. We thank Mr. G. Rice for checking
the experimental procedure in Table 1, entry 6.
(23) Previous work (ref 1a and ref 1b) in Pd(0)-mediated allylic substitution
reactions has shown that the poor nucleophilic properties of carbamates
require the use of their respective anions to achieve reactivity with
π-allylpalladium intermediates.
Supporting Information Available: Detailed experimental pro-
cedures and full characterization. This material is available free of
charge via the Internet at http://pubs.acs.org.
(24) Addition of 1 equiv of Bu4NOAc to the catalytic reaction conditions gave
3a in 20% yield.
(25) For an alternative approach to this see: Lafrance, M.; Fagnou, K. J. Am.
Chem. Soc. 2006, 128, 16496.
References
(1) C-O to C-N catalyzed by Pd(0): (a) Trost, B. M.; Sudhakar, A. R. J.
Am. Chem. Soc. 1987, 109, 3792. (b) Trost, B. M.; Patterson, D. E. J.
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