A catalytic, Bronsted base strategy for intermolecular allylic C-H amination

Article abstract of DOI:10.1021/ja903939k

A Bronsted base activation mode for oxidative, Pd(II)/sulfoxide- catalyzed, intermolecular C-H allylic amination is reported. N,N-diisopropylethylamine was found to promote amination of unactivated terminal olefins, forming the corresponding linear allylic amine products with high levels of stereo-, regio-, and chemoselectivity. The predictable and high selectivity of this C-H oxidation method enables latestage incorporation of nitrogen into advanced synthetic intermediates and natural products.

Full text of DOI:10.1021/ja903939k

Published on Web 07/31/2009
A Catalytic, Brønsted Base Strategy for Intermolecular Allylic
C-H Amination
Sean A. Reed, Anthony R. Mazzotti, and M. Christina White*
Department of Chemistry, Roger Adams Laboratory, UniVersity of Illinois,
Urbana, Illinois 61801
Received May 14, 2009; E-mail: white@scs.uiuc.edu
Abstract: A Brønsted base activation mode for oxidative, Pd(II)/sulfoxide-catalyzed, intermolecular C-H
allylic amination is reported. N,N-diisopropylethylamine was found to promote amination of unactivated
terminal olefins, forming the corresponding linear allylic amine products with high levels of stereo-, regio-,
and chemoselectivity. The predictable and high selectivity of this C-H oxidation method enables late-
stage incorporation of nitrogen into advanced synthetic intermediates and natural products.
branched6 or linear7 allylic amines directly from terminal olefins
with predictable and high regioselectivities.8 Moreover, we have
Introduction
The ubiquitous C-H bond has emerged as a viable precursor
to many functional groups through several transition metal-
catalyzed reactions.1 The practical utility of such reactions for
complex molecule synthesis is governed by their ability to
operate with predictable and high levels of chemo-, stereo-,
regio- and site selectivity. The strategic application of selective
C-H oxidation reactions at late stages of syntheses has been
demonstrated to increase product diversity1d as well as eliminate
functional group interconversions and/or oxidation state changes,
which are often required when working with oxidized interme-
diates.2
demonstrated that direct installation of nitrogen functionality
from C-H bonds can have a powerful streamlining effect on
synthetic routes. For example, the intermolecular C-H to C-N
bond-forming route to a rigidified (+)-deoxynegamycin ana-
logue proceeded with five fewer steps, five fewer FGM, and a
higher overall yield than the alternative C-O to C-N bond-
forming route.7 Despite this, the intermolecular allylic C-H
amination reaction suffered from several limitations associated
with the requirement for a Lewis acid activator [Cr(salen)Cl 2]
to effect functionalization. Incompatibilities with Lewis basic
functionality, and isomerization of terminal olefins on electron-
deficient substrates could limit the applicability of this otherwise
useful and general method. With the goal of further developing
this significant transformation, herein we report a novel nu-
cleophile activation strategy for promoting intermolecular allylic
C-H amination that operates Via electrophilic Pd(II) catalysis
The prevalence of nitrogen functionality in biologically
important small molecules, accompanied by the extensive
functional group manipulations (FGM) commonly employed to
install nitrogen, underscores the utility of direct C-H to C-N
bond transformations.3 For example, routine synthesis of linear
allylic amines involves oxidative, nucleophilic, and often
reductive conditions to access the requisite allylic alcohol, which
is generally converted into a leaving group before displacement
with nitrogen.4,5 We recently reported Pd(II)/bis-sulfoxide-
catalyzed allylic C-H amination reactions that furnish either
(3) Aliphatic/benzylic: (a) Liang, C.; Collet, F.; Peillard, F. R.; Mu¨ller,
P.; Dodd, R. H.; Dauban, P. J. Am. Chem. Soc. 2007, 130, 343. (b)
Lebel, H.; Huard, K.; Lectard, S. J. Am. Chem. Soc. 2005, 127, 14198.
(c) Olson, D. E.; Du Bois, J. J. Am. Chem. Soc. 2008, 130, 11248. (d)
Milczek, E.; Boudet, N.; Blakey, S. Angew. Chem., Int. Ed. 2008, 47,
6825. Aryl: (e) Li, J. J.; Mei, T. S.; Yu, J.-Q. Angew. Chem., Int. Ed.
2008, 47, 6452. (f) Jordan-Hore, J. A.; Johansson, C. C. C.; Gulias,
M.; Beck, E. M.; Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 16184.
(g) Thu, H.-Y.; Yu, W.-Y.; Che, C.-M. J. Am. Chem. Soc. 2006, 128,
9048. (h) Tsang, W. C.; Zheng, N.; Buchwald, S. L. J. Am. Chem.
Soc. 2005, 127, 14560. (i) Brasche, G.; Buchwald, S. L. Angew. Chem.,
Int. Ed. 2008, 47, 1932.
(4) Linear allylic amination Via oxygenated intermediates: Pd(0) catalysis.
(a) Trost, B. M.; Keinan, E. J. Org. Chem. 1979, 44, 3451. Overman
rearrangement. (b) Overman, L. E. Acc. Chem. Res. 1980, 13, 218.
Mitsunobu amination. (c) Mulzer, J.; Funk, G. Synthesis 1995, 1, 101.
(5) Amination reviews: (a) Cheikh, R. B.; Chaabouni, R, Synthesis 1983,
9, 685. (b) Johannsen, M.; Jørgensen, K. A. Chem. ReV. 1998, 98,
1689.
(1) (a) Muller, P.; Fruit, C. Chem. ReV. 2003, 103, 2905. (b) Dick, A. R.;
Sanford, M. S. Tetrahedron 2006, 62, 2439, and references therein.
(c) Alberico, D.; Scott, M. E.; Lautens, M. Chem. ReV. 2007, 107,
174. (d) Chen, M. S.; White, M. C. Science 2007, 318, 783. (e) Davies,
H. M. L.; Manning, J. R. Nature 2008, 451, 417. (f) Lewis, J. C.;
Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2008, 41, 1013. (g)
Labinger, J. A.; Bercaw, J. E. Nature 2002, 417, 507. (h) Crabtree,
R. H. J. Organomet. Chem. 2004, 689, 4083.
(6) Fraunhoffer, K. J.; White, M. C. J. Am. Chem. Soc. 2007, 129, 7274.
(7) Reed, S. A.; White, M. C. J. Am. Chem. Soc. 2008, 130, 3316.
(8) For seminal work on allylic CsH amination see: Pd(II). (a) Larock,
R. C.; Hightower, T. R.; Hasvold, L. A.; Peterson, K. P. J. Org. Chem.
1996, 61, 3584. Nitrenes. (b) References 3a-d. Ene reactions. (c)
Kalita, B.; Nicholas, K. M. Tetrahedron Lett. 2005, 46, 1451.
(2) (a) Fraunhoffer, K. J.; Bachovchin, D. A.; White, M. C. Org. Lett.
2005, 7, 223. (b) Hoffmann, R. W. Synthesis 2006, 21, 3531. (c)
Covell, D. J.; Vermeulen, N. A.; Labenz, N. A.; White, M. C. Angew.
Chem., Int. Ed. 2006, 45, 8217.
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A R T I C L E S
Reed et al.
with acidic N-tosylcarbamate nucleophiles (pKa ≈ 3.5).9 This
strategy employs exogenous catalytic amine base to elevate the
concentration of anionic carbamate nucleophile that is not
associated with the Pd counterion, resulting in one of the most
mild and selective C-H oxidation reactions reported to date
(eq 1).
alization without requiring a tether.12 In addition to providing
a novel Brønsted base activation mode for intermolecular
oxidative Pd(II) systems, this strategy has the potential to
overcome several challenges faced by the Lewis acid/BQ
system, such as incompatibilities with Lewis basic functionality
and isomerization of terminal olefins on electron-deficient
substrates.
Reaction Optimization. Two features of the catalytic base
additive were predicted to be critical to the success of this
activation mode: (1) sufficiently high basicity to generate an
elevated concentration of deprotonated nucleophile in solution,
(2) a weak binding affinity for the highly electrophilic Pd(II)
catalyst.
Results and Discussion
Design Principles. We previously introduced Pd(II)/sulfoxide
catalysts (e.g., 1) as electrophilic promoters of a heterolytic,
allylic C-H cleavage event to generate π-allylPd intermediates;
this eliminates the need for preoxidized allylic precursors, as
required in Pd(0) substitution reactions (Figure 1, A).
Table 1. Exogenous, Catalytic Brønsted Base Additives for Direct
Allylic C-H Amination
entry
additive
yield(%)a
L:Bb
E:Zc
1
2
3
4
5
6
7
8
9
none
(S,S)-Cr(salen)Cl 2
pyridine
2,6-di-tert-butylpyridine
N-isopropylamine
N,N-diisopropylamine
triethylamine
1d
50
9
-
-
66
60
66
9
-
-
11:1
12:1
-
19:1
14:1
-
Figure 1. Activation strategies for catalytic, allylic C-H oxidation
reactions.
-
-
12:1
14:1
11:1
6:1
15:1
15:1
17:1
10:1
Although both Pd(0) and Pd(II) manifolds proceed through
a common π-allylPd intermediate, they require very different
strategies for promoting functionalization (Figure 1, B). The
basic, reducing conditions of Pd(0)-mediated allylic substitution
reactions are compatible with strong nucleophiles (i.e., stoichio-
metric anionic nucleophiles) and σ-donating ligands.10 However,
both of these strategies for promoting functionalization are
incompatible with electrophilic Pd(II)-mediated allylic C-H
oxidation reactions that proceed under acidic conditions. We
have alternatively delineated two general activation strategies
for functionalization with acidic N-tosylcarbamate pro-nucleo-
philes. The first involves the use of π-acidic ligands [benzo-
quinone (BQ)11] acting with a Lewis acid cocatalyst [Cr(III)(s-
alen)Cl, 2] to promote intermolecular functionalization, possibly
by activating electrophilic π-allylPd intermediates toward nu-
cleophilic attack.7 The second strategy harnesses palladium
carboxylate counterions as a source of endogenous base to
deprotonate and thereby activate tethered pro-nucleophiles
(Figure 1, B).6 Unfortunately, this mild strategy proved inef-
fective for promoting intermolecular functionalization. We
hypothesized that the addition of an exogenous base in catalytic
amounts would increase the concentration of deprotonated
nitrogen nucleophile in solution, thereby promoting function-
N,N-diisopropylethylamine
MeOC(O)NTs-DIPEAHe
a Isolated yield of linear product. b Linear/branched ratio determined
by HPLC of crude reaction mixture. c Determined by 1H NMR after
d
chromatography. 1H NMR yield by comparison with internal standard.
e 2.0 equiv of the preformed salt was used instead of MeOC(O)NHTs.
Table 1 provides a summary of the experiments exploring
these criteria. As previously demonstrated, only a trace amount
(∼1%) of intermolecular allylic C-H amination product was
detected under the endogenous catalytic base conditions that
promote intramolecular C-H amination with this type of
nucleophile (Table 1, entry 1). In the presence of Lewis acid
activator and quinone [i.e., Cr(salen)Cl 2 (6 mol %) and 1,4-
benzoquinone (BQ, 2 equiv)], Pd/sulfoxide catalyst 1 (10 mol
%) furnished intermolecular allylic C-H amination product 4
with good yields and selectivities (Table 1, entry 2). To test
the hypothesis that an external base could replace Lewis acid
activation and alternatively promote functionalization by direct
deprotonation of the nitrogen pro-nucleophile, we surveyed a
series of common organic Brønsted bases as catalytic additives.
Pyridine (6 mol %) exhibited low reactivity, potentially due to
its ability to serve as a ligand for Pd (Table 1, entry 3). In an
effort to prevent a possible binding event, sterically congested
2,6-di-tert-butylpyridine was screened; even this additive failed
to promote the reaction (Table 1, entry 4), supporting the
hypothesis that a minimum level of basicity may also be needed
for this activation strategy. Coordinating, primary amines with
an increased level of basicity such as N-isopropylamine gave
similarly poor results (Table 1, entry 5). Significantly, however,
strongly basic yet sterically encumbered amines such as N,N-
diisopropylamine, triethylamine, and N,N-diisopropylethylamine
(DIPEA) generated 4 in good yields (Table 1, entries 6-8) and
selectivities for the linear (E)-amine product. Although a certain
(9) Taylor, L. D.; Pluhar, M.; Rubin, L. E. J. Polym. Sci., Part B: Polym.
Phys. 1967, 5, 77.
(10) Pd(0)-catalyzed allylic alkylations with neutral enamines have also
been reported: (a) Ibrahem, I.; Co´rdova, A. Angew. Chem., Int. Ed.
2006, 45, 1952. (b) Bihelovic, F.; Matovic, R.; Vulovic, B.; Saicic,
R. N. Org. Lett. 2007, 9, 5063.
(11) (a) Chen, M. S.; White, M. C. J. Am. Chem. Soc. 2004, 126, 1346.
(b) Chen, M. S.; Prabagaran, N.; Labenz, N. A.; White, M. C. J. Am.
Chem. Soc. 2005, 127, 6970. For a single report of BQ/Pd(II)
binding: (c) Albe´niz, A. C.; Espinet, P.; Mart´ın-Ruiz, B. Chem.sEur.
J. 2001, 7, 2481.
(12) For catalytic base strategies for direct arylation reactions see: Lafrance,
M.; Lapointe, D.; Fagnou, K. Tetrahedron 2008, 64, 6015 and refer-
ences therein.
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Base Strategy for Intermolecular C-H Amination
A R T I C L E S
Table 2. Scope and Comparison of the Brønsted Base vs Lewis
Acid-Promoted Allylic C-H Amination
Figure 2. Effect of DIPEA concentration on reactivity for linear allylic
C-H amination.
concentration of deprotonated nucleophile is clearly needed for
reactivity, addition of stoichiometric amounts of preformed
anionic nucleophile, MeOC(O)NTs-DIPEAH, generated only
small amounts of product (Table 1, entry 9). This suggests that
one or more steps in the catalytic cycle are incompatible with
high concentrations of even a weakly coordinating anionic
nucleophile. Accordingly, the concentration of Brønsted base
additive was found to have a dramatic effect on reaction yields
(Figure 2). Adding between 3 and 10 mol % DIPEA dramati-
cally increased the yield of 4, whereas increasing the amount
of DIPEA to 25 mol % or higher was deleterious to product
formation. The observed trend is most likely due to attenuation
of the electrophilicity of the Pd/bis-sulfoxide catalyst 1 at high
concentrations of base, although inhibition of acid-mediated
catalyst reoxidation cannot be ruled out.13
Reaction Scope. These newly discovered DIPEA-base amination
conditions provide an improvement in product yield and chemose-
lectivity with N-tosylcarbamate nucleophiles, which enabled a
substantial broadening in substrate scope (Table 2). Generally, we
found that the Cr conditions led to low yields of product for
substrates possessing isomerization-prone olefins. In contrast,
aliphatic and aromatic substrates containing these types of olefins
worked well under the DIPEA conditions (Table 2, entries 1 and
5). Gratifyingly, aromatic substrates containing widely used
synthetic handles such as esters, aldehydes, nitriles, and phenols
all underwent efficient reaction to their corresponding allylic amine
products under the DIPEA conditions (Table 2, entries 2-6).
Products 6-10 represent powerful bifunctional aryl building blocks,
a Average of at least two runs at 0.3 mmol. Products were isolated as
one regio- and olefin isomer (1H NMR). b 18:1 E/Z. c 13:1 E/Z.
d Reported in ref 7. e 48 h reaction time. f 10 mol % DIPEA, CCl4
solvent, 24 h reaction time; Fm ) 9-fluorenylmethyl.
with the potential for subsequent manipulation. Aryl triflates are
also well tolerated, displaying the orthogonality of this Pd(II)
reaction to traditional Pd(0) methodologies (Table 2, entry 5).
Epoxides are valuable intermediates in complex molecule
synthesis, because they can be readily elaborated. For example,
chiral (S,S)-Cr(salen) complex 2 is known to catalyze asymmetric
epoxide ring-opening reactions.14 Expectedly, terminal epoxide
substrates exposed to 2 led to complex mixtures, providing none
of the desired products (Table 2, entries 6-8). In contrast, DIPEA
conditions yielded allylic amination products with high selectivities
and good yields (Table 2, entries 6-9). Even highly reactive
glycidol moieties are preserved under these reaction conditions
(Table 2, entry 6). Products such as (-)-10 can be ring-opened to
generate several important structural motifs, such as those found
in beta-blocker15 and cystic fibrosis drugs.16 Di- and trisubstituted
epoxides have the advantage of being capable of regioselective
ring-opening as a means of generating structural diversity (Table
(13) A similar parabolic behavior between nitrogen base concentration and
reactivity has been observed for several Pd(II)/Pd(0) alcohol oxidation
systems, although these reactivity trends were largely attributed to
ligand effects. See: (a) Steinhoff, B. A.; Guzei, I.; Stahl, S. S. J. Am.
Chem. Soc. 2004, 126, 11268. (b) Schultz, M. J.; Adler, R. S.;
Zierkiewicz, W.; Privalov, T.; Sigman, M. S. J. Am. Chem. Soc. 2005,
127, 8499.
(14) Chiral (S,S)-Cr(salen) complex 2 is known to catalyze asymmetric
epoxide ring-opening reactions, see: (a) Hansen, K. B.; Leighton, J. L.;
Jacobsen, E. N. J. Am. Chem. Soc. 1996, 118, 10924. (b) Jacobsen,
E. N.; Kakiuchi, F.; Konsler, R. G.; Larrow, J. F.; Tokunaga, M.
Tetrahedron Lett. 1997, 38, 773.
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A R T I C L E S
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Figure 4. Late-stage oxidation of natural product derivatives Via di-
rect allylic C-H amination; (a) 1 (10 mol %), DIPEA (6 mol %),
MeOC(O)NHTs (2.0 equiv), BQ (2.0 equiv), 0.66 M TBME, 45 °C,
72 h.
Figure 3. Versatility of the N-tosyl carbamate functional group, (a) K2CO3,
MeOH, 25 °C, 3.5 h; (b) Na-C10H8, -78 °C, DME, 10 min; (c) NaOH,
H2O/EtOH, 110 °C, 4 h; (d) LiAlH4, THF, reflux, 5 h.
mild base or a one-electron reductant, respectively. Upon
removal of the tosyl moiety, the carbamate can either be
hydrolyzed to yield the free allylic amine or reduced to the
corresponding methylamine. It is significant to note that all of
these transformations can be performed on densely functional-
ized molecules while preserving the valuable internal olefin.
Late-stage C-H Amination of Natural Product Derivatives.
Late stage C-H activation approaches can be particularly
powerful when applied to the diversification of complex
natural products or the functionalization of late-stage inter-
mediates in a total synthesis. We targeted estrone deriva-
tives19 (+)-24/(+)-26 for the amination reaction, as linear
amines have been used to generate steroid-antibiotic hybrid
compounds capable of selectively destroying estrogen recep-
tor-rich cancer cells (Figure 4, A).20
Protected (+)-23 underwent smooth conversion to the cor-
responding linear allylic amine product with outstanding
selectivity (Figure 4, A, >20:1 E/Z, L/B). Remarkably, the
unprotected diol (+)-25 was also an excellent substrate for the
Brønsted base-promoted amination reaction.21 R-Cedrene de-
rived (-)-27, also containing an unprotected secondary alcohol
moiety as well as a sterically hindered all-carbon quaternary
center in the homoallylic position, underwent efficient amination
to give product (-)-28 in high yield with exceptional selectivity
(Figure 4, B). Tolerance of unprotected alcohol moieties on
substrates (+)-25 and (-)-27 further distinguishes this versatile
amination method, since most C-H amination systems face
chemoselectivity issues with free alcohols.8b These examples
highlight the potential of highly chemoselective C-H oxidation
reactions to directly diversify natural products, without the need
for functional group manipulations characteristic of traditional
carbon-heteroatom bond-forming processes.
2, entries 8 and 9).17 Site-selective olefin epoxidations of di- and
trisubstituted olefins followed by allylic C-H amination of terminal
olefins enables the streamlined construction of bifunctional building
blocks as exemplified by (-)-12 and (+)-13. As previously shown
with the Cr/BQ system, amino sugar precursor (+)-14 under the
DIPEA conditions was isolated as a single diastereomer, indicating
no change in configuration at the adjacent stereocenter (Table 2,
entry 10).7
Additionally, a variety of different N-tosylcarbamate esters
were examined to evaluate nucleophile scope. Using allyl
cyclohexane as a substrate, substantial increases in yield were
found for both the methyl- and benzyl N-tosylcarbamate under
the DIPEA conditions relative to the Cr/BQ system (Table 2,
entries 11 and 12). Yields with tert-butyl- and 9-fluorenylmethyl
N-tosylcarbamates could also be increased to above 50%;
however, at this time optimal conditions utilize 10 mol %
DIPEA and carbon tetrachloride solvent to achieve good yields
with these nucleophiles (Table 2, entries 13 and 14).18 Overall,
product yields under the DIPEA conditions were consistently
higher than those under conditions employing Cr/BQ.
As a final point, the intermolecular linear allylic amination
presents a convenient method for rapidly accessing a variety of
valuable, nitrogen-containing compounds. N-Tosylcarbamate
nucleophiles can be easily synthesized on a multigram scale by
reacting commercially available N-tosylisocyanate with the
desired alcohol to afford crystalline, bench-stable reagents
(Figure 3, A). Moreover, the allylic N-tosyl carbamate moiety
can be transformed into a variety of diverse compounds in high
yields (Figure 3, B). For example, both the carbamate and the
tosyl groups can be selectively removed by employing either
Mechanistic Considerations. On the basis of the data de-
scribed above and our previous work, we favor a catalytic cycle
for Brønsted base-promoted intermolecular allylic C-H ami-
nation as illustrated in Figure 5, A.
The DIPEA base initially deprotonates the N-tosylcarbamate
to generate nucleophilic species A that participates in π-allylPd
(15) Kitaori, K.; Furukawa, Y.; Yoshimoto, H.; Otera, J. Tetrahedron 1999,
55, 14381.
(16) Hirsh, A. J.; Molino, B. F.; Zhang, J.; Astakhova, N.; Geiss, W. B.;
Sargent, B. J.; Swenson, B. D.; Usyatinsky, A.; Wyle, M. J.; Boucher,
R. C.; Smith, R. T.; Zamurs, A.; Johnson, M. R. J. Med. Chem. 2006,
49, 4098.
(17) Davis, C. E.; Bailey, J. L.; Lockner, J. W.; Coates, R. M. J. Org.
Chem. 2003, 68, 75.
(19) Fevig, T. L.; Katzenellenbogen, J. A. J. Org. Chem. 1987, 52, 247.
(20) Kuduk, S. D.; Zheng, F. F.; Sepp-Lorenzino, L.; Rosen, N.; Dan-
ishefsky, S. J. Bio. Med. Chem. Lett. 1999, 9, 1233.
(18) The NsNHCO2Me nucleophile was also tested under the following
sets of conditions: Cr(salen)Cl: 38% yield; DIPEA (6 mol %)/TBME:
16% yield; DIPEA (10 mol %)/CCl4: 24% yield (average of 2 runs).
(21) The reaction using our previous Cr(salen)Cl conditions gave product
(+)-26 in 34% yield.
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Base Strategy for Intermolecular C-H Amination
A R T I C L E S
Table 3. Effect of Quinone Sterics on Lewis Acid vs Brønsted
Base C-H Amination Systems
Figure 5. Proposed catalytic cycle for Brønsted base-catalyzed, linear allylic
C-H amination.
functionalization to afford product and trialkylammonium acetate
species B (Figure 5, A). Under these acidic conditions, it is
unlikely that DIPEA base is regenerated during the course of
the catalytic cycle. Accordingly, we suggest that, after the first
turnover, species B serves as the base for subsequent deproto-
nations.22 Consistent with this proposal, increasing the concen-
tration of acetate anion in solution by addition of (n-Bu)4NOAc
or [(i-Pr)2EtH]NOAc afforded the product in comparable yield
to that obtained with addition of DIPEA (Figure 5, B).23
These results clearly establish that intermolecular allylic C-H
amination can be promoted Via nucleophile activation. Regard-
ing the Cr system, however, two modes of Lewis acid-promoted
functionalization could still be operating: activation of the
electrophilic π-allyl intermediate toward nucleophilic attack, or
activation of the N-tosylcarbamate nucleophile toward depro-
tonation. Seminal studies performed in our laboratories on an
asymmetric allylic oxidation reaction indicated that Cr(III)(salen)
complexes increase the rate of BQ-mediated π-allylPd func-
tionalization by binding to a proposed π-allylPd(BQ) complex
and increasing its electrophilicity (eq 2).24
a Average isolated yield of linear product after at least two runs at
0.3 mmol. b BQ (1.0 equiv) was used.
trends in reactivity. As expected, the Brønsted base-promoted
system shows no dependence on the nature of the quinone for
reactivity; even when methyl groups shield both olefins of the
quinone, high yields for the linear allylic amine product are
observed (Table 3, entries 1-6). These data are consistent with
our proposed mechanism in which Brønsted base-promoted
intermolecular allylic C-H amination proceeds by nucleophile
activation. In stark contrast, the Lewis acid system [Cr(salen)Cl
2] requires unhindered quinones for promoting product formation
(Table 3, entries 1-4). Even quinones with only a single olefin
blocked (such as 2-methylbenzoquinone and 2,3-dimethylbenzo-
quinone) lead to diminished product yields under Lewis acid
conditions. When both olefins of the quinone are sterically blocked
from binding to the π-allylPd complex, very low reactivity
corresponding to low conversion is observed (Table 3, entries 5
and 6). Additionally, while both systems use quinone as a terminal
oxidant, suprastoichiometric loadings of BQ (2 equiv) are needed
for optimal reactivity with the Cr system, whereas the DIPEA
system operates equally well with no excess quinone (Table 3, entry
2). All of these data are consistent with the Lewis acid working
with a π-allylPd(BQ) complex to promote functionalization and
suggest that Lewis acid/BQ and Brønsted base activation proceed
Via distinct pathways for promoting allylic amination.24 Mechanistic
On the basis of this model, we hypothesized that if a promoter
is acting Via an electrophile activation mode that is mediated by
BQ, the use of more sterically encumbered quinones (which do
not bind well to the π-allylPd intermediate) should impede product
formation.24-26 Alternatively, a promoter that proceeds by activat-
ing the nucleophile through deprotonation should show little or
no dependence on the quinone’s steric environment. To investigate
the role of a Pd-quinone interaction for promoting amination, we
subjected both sets of reaction conditions (Cr and DIPEA) to a
variety of methyl-substituted benzoquinones and evaluated the
(22) In contrast to the Cr(salen)Cl conditions, no acetate (or any other)
1
byproducts were observed under the DIPEA conditions by crude H
NMR. Given this and the high conversion of the starting material, the
remainder of the mass balance may be polymeric material.
(23) The hygroscopic nature of (n-Bu)4NOAc led to variability under our
air atmosphere/wet solvent conditions, leading us to pursue DIPEA
for its operational simplicity.
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General Procedure for the Allylic C-H Amination. A 1 dram,
screw-top vial under air atmosphere was charged with terminal
olefin (0.3 mmol, 1.0 equiv), followed by tert-butylmethyl ether
(0.450 mL). Catalyst 1 (15.1 mg, 0.03 mmol, 0.10 equiv), 1,4-
benzoquinone (64.9 mg, 0.6 mmol, 2.0 equiv), N-methyl tosylcar-
bamate (137.6 mg, 0.6 mmol, 2.0 equiv), and a magnetic stir bar
were then sequentially added. N,N-Diisopropylethylamine (3.14 µL,
0.018 mmol, 0.06 equiv) was added last Via syringe. The vial was
fitted with a Teflon cap, magnetically stirred, and placed in a 45
°C oil bath. After 72 h, the vial was removed, allowed to cool to
room temperature, and thoroughly rinsed into a 125 mL separatory
funnel with ether (∼30 mL). The organic phase was washed with
5% aq K2CO3 (6 × 10 mL), and the combined aqueous rinses were
back-extracted with ether (2 × 30 mL). The combined organic
extracts were dried over MgSO4 or Na2SO4 (epoxides and alde-
hydes), filtered through a 1:1 mixture of Celite/silica gel, and
evaporated to dryness (30-40 °C, 30 Torr). The crude mixture was
purified by flash chromatography on silica gel (ethyl acetate/
hexanes), and evaporated to dryness to afford the aminated product.
studies are ongoing to elucidate the details of the Lewis acid/BQ
activation mode.
Conclusion
In summary, we report the first catalytic Brønsted base
strategy for nucleophile activation under the acidic, electrophilic
conditions of oxidative Pd(II) catalysis. This discovery provides
a novel way to activate acidic pro-nucleophiles for intermo-
lecular π-allylPd functionalization without attenuating the
electrophilicity of the catalyst (1) required for C-H cleavage.
Significantly, this mild activation mode affords one of the most
chemoselective C-H oxidations reported to date, enabling
sensitive moieties such as terminal epoxides and unprotected
alcohols to be present in the allylated starting materials. This
advance should further the use of the direct C-H allylic
amination reaction toward the streamlined synthesis and diver-
sification of complex molecules. Moreover, we anticipate that
this novel catalytic base strategy will find general use for
promoting functionalization Via pro-nucleophile activation in
electrophilic transition metal-catalyzed processes that are not
tolerant of strongly basic conditions.
Acknowledgment. Financial support was provided by NIH/
NIGMS (Grant no. GM076153), and kind gifts were received from
Eli Lilly, Bristol-Myers Squibb, Pfizer, Amgen, a R.C. Fuson
graduate fellowship, and a James R. Beck graduate fellowship (to
S.A.R.). We thank the Aldrich Chemical Co. and Strem Chemicals,
Inc. for generous gifts of commercial bis(sulfoxide)/Pd(OAc)2
catalyst 1. We thank Mr. N. Vermeulen for checking the experi-
mental procedure outlined in Table 2, entry 2.
Experimental Procedures
Synthesis of Methyl N-Tosylcarbamate. To a 1 L flame-dried
round-bottom flask (under nitrogen) was added dry methanol (500
mL) and a stir bar. The flask was cooled in an ice bath cooled at
0 °C, and p-toluenesulfonylisocyanate (100 mL, 0.657 mol, 1.0
equiv) was added dropwise Via syringe. The reaction was then
allowed to warm to room temperature. After stirring 2 h, removal
of the solvent in Vacuo produced a colorless syrup that crystallized
spontaneously. The solids were then triturated with pentane (2 ×
50 mL) and ether (1 × 50 mL), followed by drying under high
vacuum (0.5 Torr) to yield white plates (141 g, 615 mmol, 94%
yield).
Supporting Information Available: Detailed experimental
1
procedures, full compound characterization, and H NMR and
13C NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
JA903939K
(24) Covell, D. J.; White, M. C. Angew. Chem., Int. Ed. 2008, 47, 6448.
(25) Previous mechanistic studies indicated that BQ acts as a π-acidic ligand
to promote carboxylate functionalization of π-allyl intermediates; 2,6-
DMBQ does not promote carboxylate functionalization of π-allyl-
PdOAc dimer to branched allylic acetate, presumably due to an
inability to bind as a π-acidic ligand, see ref 11b.
(26) At this time, we cannot rule out the possibility that BQ acts to promote
formation of the active Cr species that subsequently activates the
N-tosylcarbamate nucleophile.
9
11706 J. AM. CHEM. SOC. VOL. 131, NO. 33, 2009