Catalytic intermolecular linear allylic C-H amination via heterobimetallic catalysis

Article abstract of DOI:10.1021/ja710206u

A novel heterobimetallic Pd(II)sulfoxide/(salen)Cr(III)Cl-catalyzed intermolecular linear allylic C-H amination (LAA) is reported. This reaction directly converts densely functionalized α-olefin substrates (1 equiv) to linear (E)-allylic carbamates with good yields and outstanding regio- and stereoselectivities (>20:1). Chiral bis-homoallylic and homoallylic oxygen, nitrogen, and carbon substituted α-olefins undergo allylic C-H amination with good yields, excellent selectivities, and no erosion in enantiomeric purity. Streamlined routes to (E)-allylic carbamates that can be further elaborated to medicinally and biologically relevant allylic amines are also demonstrated. Valuable ¹⁵N-labeled allylic amines may be generated directly from allyl moieties at late stages of synthetic routes by using the readily available ¹⁵N-(methoxycarbonyl)-p-toluenesulfonamide nucleophile. Evidence is provided that this reaction proceeds via a heterobimetallic mechanism where Pd/sulfoxide mediates allylic C-H cleavage to form a π-allylPd intermediate, and (salen)Cr(III)Cl/BQ work together to promote functionalization with the nitrogen nucleophile. Copyright

Full text of DOI:10.1021/ja710206u

Published on Web 02/27/2008
Catalytic Intermolecular Linear Allylic C-H Amination via Heterobimetallic
Catalysis
Sean A. Reed and M. Christina White*
Roger Adams Laboratory, Department of Chemistry, UniVersity of Illinois, Urbana, Illinois 61801
Received November 10, 2007; E-mail: white@scs.uiuc.edu
Table 1. Development of the Intermolecular LAA Reaction
Nitrogen functionality is prevalent in synthetic and natural small
molecules with significant biological activities.1 Current state-of-
the-art methods for installing nitrogen into complex organic
frameworks generally proceed through oxygen.2 While these
methods feature high selectivities and predictable reactivities, they
lengthen synthetic sequences by requiring unproductive chemical
manipulations to install and maintain oxygen functionality. Reac-
tions that selectively convert C-H directly to C-N stand to
significantly streamline synthetic sequences by providing obvious
disconnections that avoid handling oxidized materials.3 While
significant advances have been made in developing preparatively
useful intramolecular C-H aminations,4a,5 catalytic intermolecular
C-H aminations are scarce and often require excess substrate.6,7
We report herein the first general, catalytic, intermolecular allylic
C-H amination reaction. This reaction directly converts a wide
range of R-olefins to linear (E)-allylic amines with good yields and
outstanding regio- and stereoselectivities (>20:1) using limiting
amounts of the starting olefin. Critical for achieving this catalytic
reactivity is a heterobimetallic system composed of Pd/bis-sulfoxide
and Cr(salen) catalysts.
Our study began by examining the reaction of allyl cyclohexane
with N-(methoxycarbonyl)-p-toluenesulfonamide under our previ-
ously reported intramolecular amination conditions (Table 1, entry
1). Although we observed no reactivity, we were encouraged by
stoichiometric studies that showed 1 maintained its ability to
promote C-H cleavage to form a π-allylPd intermediate in the
presence of an excess (2 equiv) of free nitrogen nucleophile (Vide
infra). Independent studies performed in our labs indicated that Cr-
(III)(salen) complexes increase the rate of π-allylPd functionaliza-
tion with acetate, suggesting that this catalyst may promote π-allyl
functionalization.11 We found that the addition of 6 mol %
commercial (salen)Cr(III)Cl complex 212,13 with 10 mol % com-
In addition to reactivity and regioselectivity challenges, inter-
molecular allylic C-H aminations face an additional chemoselec-
tivity issue of competing reactivity with the olefin.6d In palladium-
mediated processes, addition of nitrogen nucleophiles to the olefin
(aminopalladation) is the dominant reaction pathway.8 We recently
reported that bis-sulfoxide/Pd(OAc)2 catalyst 1 promotes intramo-
lecular allylic C-H amination of R-olefins with a weak, tethered
N-tosyl carbamate nucleophile.4a We hypothesized that a catalytic,
intermolecular allylic C-H amination would be feasible if we could
identify conditions that promote functionalization without interfering
with the electrophilic C-H cleavage step. Known activation
approaches for Pd(0)-mediated allylic substitutions, such as adding
stoichiometric base to activate the nucleophile or strongly σ-donat-
ing ligands to activate the π-allylPd electrophile, may attenuate
the electrophilicity of the Pd(II) species required for C-H
cleavage.2b,9,4b Herein we disclose that a heterobimetallic Pd(II)-
Cr(III) catalytic system promotes intermolecular linear allylic C-H
amination (LAA). We provide evidence that the Pd(II)/bis-sulfoxide
catalyst promotes allylic C-H cleavage and that the Cr(III)(salen)
catalyst together with benzoquinone (BQ) promotes amination of
the π-allylPd intermediate. This represents a rare example of hetero-
bimetallic catalysis in which two different transition metals present
in catalytic amounts are required to effect product formation.10
mercial bis-sulfoxide/Pd(OAc)2
1 gave linear (E)-allylic amine 4
in encouraging yield (43% based on olefin 3) and with remarkable
regio- and stereoselectivities (>100:1 L/B, 65:1 E/Z, entry 3). It is
significant to note that this is the first time that linear regioselectivity
has been observed in an allylic C-H oxidation process with bis-
sulfoxide/Pd(OAc)2 catalyst 1.14 Chromium catalyst 2 gave no
reactivity in the absence of Pd catalyst 1, clearly showing that a
dual metal-catalyst system is required for reactivity (entry 2). We
next examined the role of ligands in this reaction. In the absence
of bis-sulfoxide ligand, Pd(OAc)2 furnished only 17% of the
aminated product (entry 4). Free chromium (III) salts shut down
reactivity (entry 5), whereas chromium (III) in a porphyrin
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C O M M U N I C A T I O N S
Table 2. Scope of the Intermolecular LAA Reaction
Scheme 1
known SSAO inhibitor, was generated in 72% yield as a single
isomer (Table 2, entry 2).15 Although unsubstituted hydrocarbon
substrates, such as 1-decene, show a decrease in regioselectivity
(L/B, 7:1; entry 3), incorporation of a branching carbon, oxygen,
or nitrogen moiety in the remote bis-homoallylic position restores
high levels of selectivity (L/B > 20:1, entries 4-6).
a Average of two runs at 0.3 mmol. Products were isolated as one regio-
Asymmetric allylations of aldehydes,16a,b imines,16c and enolates16d,e
provide rapid access to stereodefined homoallylic oxygen, nitrogen,
and carbon substituted R-olefins. These substrates undergo linear
allylic C-H amination in good yields, excellent selectivities, and
no erosion in enantiomeric purity (Figure 1). Thus, this reaction
provides a highly simplifying transform for chiral 1,4-difunction-
alized allylic amines that can be further elaborated to motifs
common in natural products and medicinally valuable compounds.
For example, tripeptide isostere (+)-15 was readily synthesized in
optically pure form via an asymmetric allylation/allylic C-H
amination sequence.17 Densely functionalized amino alcohol (+)-
12 is an intermediate toward glycamines.18
and olefin isomer (1H NMR). b Mixture of 7:1 L/B and 17:1 E/Z (1H NMR).
framework also gave allylic aminated product, albeit in diminished
yields (entry 6). Under optimized reaction parameters (TBME, entry
7), a variety of salen porphyrin, and phthalocyanine metal com-
plexes were evaluated (entries 7-10). Notably, (salen)Mn(III)Cl
was the only other complex found to catalyze the reaction with
significant product yields (entry 10). Examination of other O-
protected N-tosylcarbamate nucleophiles indicated that benzyl- was
comparable under these conditions (entry 11) whereas tert-butyl-
and 9-fluorenylmethyl-N-tosylcarbamates presently give diminished
yields (entries 12 and 13, respectively).
On the basis of our previous work,4 we anticipated incorporation
of nitrogen using selective C-H to C-N bond-forming reactions
would significantly streamline the synthesis of nitrogen-containing
compounds. In this vein, we compared the route to a rigidified
analogue of the antibiotic deoxynegamycin (+)-19 enabled by the
linear allylic C-H amination to a previous state-of-the-art route
based on allylic C-O substitution (Scheme 1).19 Starting with
commercial â-homoallylglycine (-)-16, nitrogen was incorporated
in only two steps at the correct oxidation state using the linear allylic
amination. In contrast, beginning with aspartic acid derivative 20,
incorporation of nitrogen via an allylic oxygenate intermediate
proceeded in seven steps and required further oxidation-state
manipulation of nitrogen. Overall, the C-H to C-N bond-forming
route to optically pure deoxynegamycin analogue (+)-19a pro-
ceeded with five fewer steps, five fewer functional group manipula-
tions (FGMs), and higher overall yield than the alternative C-O
to C-N bond-forming route.
The utility of the linear allylic C-H amination reaction as a
means of selectively incorporating nitrogen during complex mol-
ecule synthesis was probed by investigating its scope with respect
to the R-olefin substrate (Table 2 and Figure 1). A wide range of
polar groups that can serve as functional handles for further
elaboration (e.g., silyl and benzyl ethers, Weinreb amides, benzy-
loxycarbonyl (Cbz)- and phthalimide(Pht)-protected amines) may
be present on the substrate. Aromatic substrates undergo allylic
C-H amination with good yields and outstanding selectivities. For
example, safrole derived allylic amine 6, a direct precursor for a
Scheme 2
Linear allylic C-H amination also provides a direct route to
valuable 15N-labeled compounds by using 15N-(methoxycarbonyl)-
p-toluenesulfonamide (readily available in two steps from 15NH4-
Figure 1. Streamlined synthesis of chiral 1,4-difunctionalized allylic
amines.
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C O M M U N I C A T I O N S
Supporting Information Available: Detailed experimental pro-
Cl, 99.7% enriched). Installation of labeled nitrogen functionality
late in a route minimizes loss of this valuable material that would
otherwise be incurred by early-stage incorporation. As with all of
the tosyl-protected amine compounds, detosylation can be effected
under mild, reductive conditions without affecting the carbamate
moiety. Detosylation of 15N-labeled (+)-12 followed by cleavage
of the methoxy carbamate with NaOH afforded isotopically enriched
free amine product (+)-22 (99.7% enriched, Scheme 2).
1
cedures, full characterization, H and 13C NMR spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
References
(1) Kibayashi, C. Chem. Pharm. Bull. 2005, 53, 1375.
(2) (a) Mitsunobu, O. Synthesis 1981, 1. (b) Trost, B. M.; Van Vranken, D.
L. Chem. ReV. 1996, 96, 395. (c) Johannsen, M.; Jorgensen, K. A. Chem.
ReV. 1998, 98, 1689 and references therein. (d) Hayashi, T.; Kishi, K.;
Yamamoto, A.; Ito, Y. Tetrahedron Lett. 1990, 31, 1743. (e) Ohmura,
T.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 15164.
Scheme 3. Stoichiometric Studies To Evaluate the Role of
(salen)CrCl 2
(3) 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.
For examples of late stage C-H hydroxylation and amination, see: (d)
Chen, M. S.; White, M. C. Science 2007, 318, 783. (e) Wender, P. A.;
Hilinski, M. K.; Mayweg, A. V. W. Org. Lett. 2005, 7, 79. (f) Hinman,
A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510.
(4) (a) Fraunhoffer, K. J.; White, M. C. J. Am. Chem. Soc. 2007, 129, 7274.
(b) The addition of 1 equiv of Bu4NOAc to the intramolecular C-H
amination significantly reduced yields, see ref 4a.
(5) Intramolecular C-H amination via nitrenes: (a) Espino, C. G.; Fiori, K.
W.; Kim, M.; Du Bois, J. J. Am. Chem. Soc. 2004, 126, 15378 and
references therein. (b) Lebel, H.; Huard, K.; Lectard, S. J. Am. Chem.
Soc. 2005, 127, 14198.
(6) Intermolecular C-H aminations via nitrenes: (a) Fiori, K. W.; Du Bois,
J. J. Am. Chem. Soc. 2007, 129, 562. (b) Liang, C.; Robert-Peillard, F.;
Fruit, C.; Muller, P.; Dodd, R. H.; Daubin, P. Angew. Chem., Int. Ed.
2006, 45, 4641. (c) Yang, J.; Weinberg, R.; Breslow, R. Chem. Commun.
2000, 531. (d) Yu, X.-Q.; Huang, J.-S.; Zhou, X.-G.; Che, C.-M. Org.
Lett. 2000, 2, 2233. (e) Liang, C.; Collet, F.; Peillard, F. R.; Muller, P.;
Dodd, R. H.; Dauben, P. J. Am. Chem. Soc. 2007, 130, 343.
(7) Intermolecular allylic C-H aminations using excess olefin: (a) Kalita,
B.; Nicholas, K. M. Tetrahedron Lett. 2005, 46, 1451. (b) Aburel, P. S.;
Zhuang, W.; Hazell, R. G.; Jorgensen, K. A. Org. Biomol. Chem. 2005,
3, 2344.
(8) Rogers, M. M.; Kotov, V.; Chatwichien, J.; Stahl, S. S. Org. Lett. 2007,
9, 4331, and references therein.
(9) Trost, B. M.; Keinan, E. J. Org. Chem. 1979, 44, 3451.
(10) For examples of cooperative heterobimetallic catalysis see: (a) Kamijo,
S.; Yamamoto, Y. In Multimetallic Catalysts in Organic Synthesis;
Shibasaki, M., Yamamoto, Y., Eds.; Wiley-VCH: New York, 2004;
Chapter 1. For examples from asymmetric catalysis see: (b) Sawamura,
M.; Sudoh, M.; Ito, Y. J. Am. Chem. Soc. 1996, 118, 3309. (c) Sammis,
G. M.; Danjo, H.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 9928.
(11) Covell, D. J.; White, M. C. Manuscript in preparation.
Stoichiometric studies were performed to evaluate the roles of
Pd(II)/bis-sulfoxide catalyst 1 and Cr(III)(salen) catalyst 2 in the
intermolecular allylic C-H amination reaction. When a stoichio-
metric mixture of 1-decene, catalyst 1, and 2 equiv of N-
(methoxycarbonyl)-p-toluenesulfonamide nucleophile were heated
for 4 h, a π-allylPd complex was trapped as the corresponding
chloride dimer 23, which was isolated in 66% yield (Scheme 3).
We next evaluated the effect of chromium catalyst 2 on synthetic
π-allylPd complex 24 under mock catalytic conditions. We found
that the combination of Cr catalyst 2 with BQ was uniquely effective
at promoting formation of aminated product 7 in 25% yield with
regio- and stereoselectivities similar to those observed under
standard catalytic conditions (Scheme 3; Table 2, entry 3).20
Consistent with 2/BQ working together to promote functionaliza-
tion, sterically hindered quinones such as 2,6-dimethyl quinone
result in significantly diminished yields (10%, see Supporting
Information, [SI]) under otherwise standard catalytic conditions.
These results suggest that Pd catalyst 1 mediates allylic C-H
cleavage, while Cr catalyst 2 and BQ promote functionalization.
The exact mechanism by which 2/BQ promote functionalization is
currently under investigation.21
(12) Commercial (1S,2S)-(+)-[1,2-cyclohexanediamino-N,N′-bis(3,5-di-tert-
butylsalicylidene)]Cr(III)Cl was used.
(13) Increasing 2 loadings gave an increased rate of conversion but a decrease
in product yields (SI). Gas chromatograph (GC) peaks consistent with
olefin isomerization were observed with higher loadings of 2.
(14) Branched regioselectivity with 1: (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) Reference 4a.
In summary, we report the first general and highly selective,
catalytic intermolecular allylic C-H amination reaction. The
excellent levels of regio- and stereoselectivity as well as the
outstanding functional group compatibility make this reaction
immediately applicable to complex molecule synthesis. Mechanistic
studies support a heterobimetallic Pd(II)-Cr(III) catalytic system
in which each metal effects different product-forming steps in the
catalytic cycle. Given the excellent selectivities and broad scope
of the linear allylic C-H amination, we anticipate that it, and other
reactions like it, will significantly enable the streamlining of small
molecule synthesis.
(15) Conn, C.; Shimmon, R.; Cordaro, F.; Hargraves, T. L.; Ibrahim, P. Bioorg.
Med. Chem. Lett. 2001, 11, 2565.
(16) (a) Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, 56, 401. (b) Kubota,
K.; Leighton, J. L. Angew. Chem., Int. Ed. 2003, 42, 946. (c) Cogan, D.
A.; Liu, G.; Ellman, J. Tetrahedron 1999, 55, 8883. (d) Evans, D. A.;
Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982, 104, 1737. (e) Myers,
A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J.; Gleason,
J. L. J. Am. Chem. Soc. 1997, 119, 6496.
(17) Reginato, G.; Gaggini, F.; Mordini, A.; Valacchi, M. Tetrahedron 2005,
61, 6791.
(18) Norrild, J. C.; Pedersen, C.; Sotofte, I. Carbohydr. Res. 1997, 297, 261.
(19) Raju, B.; Anandan, S.; Gu, S.; Herradura, P.; O’Dowd, H.; Kim, B.;
Gomez, M.; Hackbarth, C.; Wu, C.; Wang, W.; Yuan, Z.; White, R.; Trias,
J.; Patel, D. V. Bioorg. Med. Chem. Lett. 2004, 14, 3103.
(20) Allylic acetates were the other major product observed (see SI). This is
consistent with the catalytic reaction where allylic acetates are the major
byproduct. When allylic acetates are exposed to the reaction conditions,
only trace (∼6%) allylic carbamate is formed with different regio- and
stereoselectivities than those observed under catalytic conditions (SI).
(21) Cr(salen) may bind to and enhance the π-acidity of the BQ, thereby
activating the π-allylPd species towards functionalization. Cr(salen) has
been demonstrated to activate BQ towards Diels-Alder reactions: Jarvo,
E. R.; Lawrence, B. M.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2005,
44, 6043. Cr(salen) may deliver the carbamate nucleophile while BQ
activates the π-allylPd towards functionalization. Cr(salen) has been shown
to activate azide nucleophiles: Hansen, K. B.; Leighton, J. L.; Jacobsen,
E. N. J. Am. Chem. Soc. 1996, 118, 10924. For BQ acting as a π-acidic
ligand to promote functionalization of π-allylPd with acetate in an allylic
C-H oxidation reaction, see ref 14a.
Acknowledgment. This paper is dedicated to Professor Peter
Beak for his mentorship and encouragement to “look at nitrogen”.
M.C.W. thanks the A.P. Sloan Foundation, Merck Research
Laboratories, and the NIH/NIGMS (GM076153) for financial
support. M.C.W. is the recipient of a Lilly Grantee Award, the
Bristol-Myers Squibb “Freedom to Discover” Grant, and the Pfizer
Award for Creativity in Organic Chemistry. S.A.R. is a recipient
of the R.C. Fuson graduate fellowship. We thank Aldrich Chemical
Co. for a generous gift of commercial bis-sulfoxide/Pd(OAc)2
catalyst 1. We thank Mr. Erik Stang for checking the experimental
procedure in Table 1, entry 7.
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