Catalyst-controlled Wacker-type oxidation of protected allylic amines

Article abstract of DOI:10.1002/anie.201004156

On the contrary: Utilizing the [Pd-(quinox)]-TBHP catalyst system, protected allylic amines were oxidized with high selectivity for the methyl ketone product. This is contrary to the results obtained by the substrate-controlled Tsuji-Wacker oxidation, which highlights the catalyst-controlled system presented here (see scheme). A variety of N-pro-tecting groups undergo selective oxidation with high ketone selectivity. TBHP = tert-butylhydroperoxide.

Full text of DOI:10.1002/anie.201004156

Communications
DOI: 10.1002/anie.201004156
Synthetic Methods
Catalyst-Controlled Wacker-Type Oxidation of Protected Allylic
Amines**
Brian W. Michel, Jessica R. McCombs, Andrea Winkler, and Matthew S. Sigman*
The Tsuji–Wacker oxidation provides access to methyl
ketones from terminal olefins and is commonly utilized in
complex molecule synthesis.[1] However, this reaction is under
substrate control, which can lead to a mixture of aldehyde and
ketone products, especially when the alkene bears a proximal
heteroatom.[2,3] An excellent example of exploiting this was
recently reported by Feringa and co-workers wherein allylic
phthalimides provided high selectivity (> 95:5) for anti-
Markovnikov oxidation of olefins to b-amino aldehydes
(Scheme 1a).[4] In contrast, an example of an o-nosyl-pro-
variants of the Tsuji–Wacker oxidation will lead to the
desired product for a given substrate.
A goal of our research program is to use ligands on PdII to
control oxidative processes.[5] In this regard, we recently
reported
a
tert-butylhydroperoxide (TBHP) mediated
Wacker-type oxidation, which was shown to be highly
selective for the methyl ketone product in the oxidation of
terminal olefins, including protected allylic alcohols.[6] The
system was designed to overcome substrate control by using a
bidentate ligand (Quinox) along with TBHP (Scheme 1b). It
is believed that TBHP undergoes a syn-oxypalladation
mechanism, which would preclude the interaction of the
group adjacent to the olefin with the Pd center (Scheme 1c).[7]
Therefore, using the Pd(Quinox)–TBHP catalyst system
under modestly modified reaction conditions, the phthalimide
substrate used by Feringa and co-workers (1) gives high
ketone selectivity in excellent yield, overcoming the inherent
substrate control (Table 1, entry 1). The crude reaction
mixture was analyzed by 1H NMR spectroscopy and gas
chromatography (GC), which revealed the ketone was
favored in a 96:4 ratio. This highlights our TBHP-mediated
oxidation as a complimentary method to access a-amino
ketones, which are highly versatile building blocks for
targeted synthesis.
Scheme 1. a) Allylic phthalimides give high aldehyde selectivity under
Tsuji–Wacker conditions, as reported by Feringa and co-workers.[4]
b) Proposed intermediate in [Pd(Quinox)]–TBHP catalyst system.
c) [Pd(Quinox)]–TBHP represents a catalyst-controlled oxidation
system for protected allylic amines. PG=protecting group.
Table 1: Oxidation of allylic phthalimides and comparison to results
under Tsuji–Wacker conditions.
tected allylic amine yields mainly methyl ketone product.[4]
The proposed difference in selectivity between these two
protecting groups is that the Lewis basic phthalimide can
chelate with Pd-directing anti-Markovnikov oxidation, while
the o-nosyl group is a relatively poor directing group. An
underlying problem is the difficulty in predicting which
protecting groups and which of the numerous possible
Entry
Substrate
Yield [%][a]
t
Ketone/
Aldehyde[b]
1
91
(Tsuji) 91
19 h
3 d
96:4
<1:99
2[c]
3
79
(Tsuji) 84
18 h
3 d
>95:5
40:60
4[d]
[*] B. W. Michel, J. R. McCombs, A. Winkler, Prof. Dr. M. S. Sigman
Department of Chemistry, University of Utah
315 South 1400 East, Salt Lake City, UT 84112 (USA)
Fax: (+1)801-581-8433
5[e]
6[f]
82
(Tsuji) 73
20 min
3 d
>95:5
85:15
E-mail: sigman@chem.utah.edu
[**] This work was supported by the National Institutes of Health
(NIGMS RO1 GM63540). We are grateful to Johnson Matthey for
the gift of various Pd salts. We thank Dr. Ryan Looper and Diachi Ito
for providing synthetic intermediates.
[a] All yields represent an average of two experiments on at least 1 mmol
scale. [b] Ratios determined by GC, 1H NMR integrations, and/or yields
of isolated products. [c] As reported by Feringa and co-workers; see
Ref. [4]. [d] Single experiment: 40 mol% PdCl2, 1 equiv CuCl, DMF/H2O
(7:1), O2, RT. [e] Reaction started at 08C. [f] Single experiment: 30 mol%
PdCl2, 1 equiv CuCl, DMF/H2O (7:1), O2, RT.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201004156.
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Using our conditions, we initially evaluated some addi-
tional allylic and homoallylic phthalimide substrates and
compared the results to the Tsuji–Wacker oxidation (Table 1).
In all cases, the TBHP-mediated system provided the methyl
ketone product with high selectivity (Table 1, entry 3).
Interestingly, under Tsuji–Wacker conditions using
40 mol% PdCl2, allyl phthalimide (Table 1, entry 4) gave a
mixture of ketone and aldehyde in a 40:60 ratio. This is
further support for substrate control under Tsuji–Wacker
conditions, as the selectivity is diminished in a substrate which
does not have assistance from a Thorpe–Ingold effect. The
homoallylic phthalimide is oxidized rapidly to the methyl
ketone using 5 mol% [Pd(Quinox)] in high yield (Table 1,
entry 5). The Tsuji–Wacker conditions also provide the
ketone, albeit in an 85:15 ratio, where a substantially higher
loading of Pd (30 mol%) and extended reaction times are
required (Table 1, entry 6).
As a result of the successful oxidation of phthalimide
substrates, the scope of the protecting group on the allylic
amine was evaluated. Due to ease of synthesis, a number of
protected allyl amine substrates were subjected to oxidation.
Substrates singly protected with either benzyl carbamate
(Cbz) or tert-butyl carbamate (Boc) were oxidized to the
methyl ketone products in good yields (Table 2, entries 1 and
2), and substrates with two protecting groups on the nitrogen
provided the ketone products in excellent yields (Table 2,
entries 3 and 5). To emphasize the selectivity of the [Pd-
(Quinox)]–TBHP system, the N-Cbz-N-Boc allyl amine was
evaluated under Tsuji–Wacker conditions. Using 20 mol% of
PdCl2 and extended reaction times, nearly full conversion
(6% recovered starting material) was observed to provide a
57:43 mixture of ketone to aldehyde products.
Allylic carbamates with additional substitution at the
allylic position were prepared to investigate whether this
would affect ketone selectivity. While a degradation in
selectivity is observed with the Cbz-protected substrate
(Table 2, entry 6), the ketone is still favored in a synthetically
useful ratio. High ketone selectivity is regained with the
doubly and orthogonally protected substrate (Table 2,
entry 7). Somewhat surprisingly, the labile trichloracetamide
(TAc) protecting group remained intact and provided only
the ketone product; however, some starting material was
recovered from the reaction mixture (Table 2, entry 8).
Allylic sulfonamides were oxidized cleanly and with short
reaction times in high yields (Table 2, entries 9 and 10).
Highlighting the utility to prepare optically active a-
amino ketones, an enantiomerically enriched substrate 4
(>99% ee) derived from l-serine[8] was oxidized to give the
methyl ketone product 5 in high selectivity and good yield,
and with no erosion of enantiomeric excess (Scheme 2). The
Table 2: Scope of protecting groups.
Entry
Substrate
Yield [%][a]
t
Ketone/
Aldehyde[b]
1[c]
2[c]
81
74
50 min
2.5 h
>95:5
>95:5
3
95
(Tsuji) 85
2.5 h
3 d
>95:5
57:43
4[d]
5
6
93
2.5 h
12 h
>95:5
Scheme 2. a) Examination of the retention of enantiomeric excess and
b) comparison to the Tsuji–Wacker oxidation.
74[e]
90:10
7
76
14 h
>95:5
same substrate was evaluated under Tsuji–Wacker conditions.
Again, high loadings of PdCl2 and extended reaction times
were required to achieve 56% yield (32% recovered starting
material) of an inseparable mixture of 5 and 6 in a 60:40
ratio.[9]
When N-methyl-N-benzoyl allyl amine 7a was subjected
to the reaction conditions an inseparable mixture of the
formal deallylation product 10a, in addition to ketone 8a, and
aldehyde 9a was observed (Scheme 3). It is not evident
whether the deallylation is a result of Pd–allyl chemistry or an
E1CB elimination from the aldehyde. An electrophilic palla-
dium species has been reported to catalytically deallylate the
same substrate;[10] however, the aldehyde 9a was observed to
decompose to 10a on silica and during gas chromatography.
Regardless of the mechanism, it is likely that the poor
8[f]
9
67[g]
90
23 h
2 h
>95:5
>95:5
>95:5
10[f]
88
4 h
[a] All yields represent an average of two experiments on at least 1 mmol
scale. [b] Ratios determined by GC, 1H NMR integrations, and/or yields
of isolated products. [c] Reactions started at 08C. [d] 20 mol% PdCl2,
1 equiv CuCl, DMF/H2O (7:1), O2, RT. [e] Yield represents both ketone
and aldehyde. [f] Reaction performed on 0.5 mmol scale. [g] An average
of 12% starting material was recovered.
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Communications
Scheme 5. Improved one-pot synthesis of the Quinox ligand.
Scheme 3. N-Methyl benzoyl protected allylic amines proved to be a
limitation and a mechanistic tool.
which either provide substrate-controlled anti-Markovnikov
oxidation or incomplete oxidation under Tsuji–Wacker con-
ditions. This is further support for the mechanistic hypothesis
that coordination sites on PdII are blocked with a bidentate
ligand and an oxidant, which promotes syn-oxypalladation of
the substrate. Enantiomerically pure substrates do not
undergo racemization under the reaction conditions. This
provides facile access to the a-amino ketone synthon, which
can be diastereoselectively reduced to give a syn or anti b-
amino alcohol by proper selection of reducing conditions and
protecting groups. Finally, a one-pot synthesis of the Quinox
ligand was reported, which makes this chemistry more
accessible for use in targeted synthesis. Future work is
ongoing to further extend the applications of this catalyst
system and to gain a more precise understanding of the
factors resulting in catalyst control.
outcome of this reaction is due to coordination of the
electron-rich benzoyl group to the palladium center. Qual-
itative examination of electronically disparate benzoyl groups
supports this hypothesis as 4-Cl benzoyl 7b provided a greater
ratio of ketone 8b to a mixture of 9b and 10b. Conversely, a
more electron-rich substrate, 4-OMe benzoyl 7c, led to less 8c
than 9c and 10c.[11]
To further emphasize the utility of the a-amino ketones
produced using this method, the corresponding b-amino
alcohols with either a 1,2-syn or 1,2-anti relationship were
accessed. By using LiAl(tBuO)3H to reduce the Cbz-pro-
tected a-amino ketone 11, the chelation-controlled reduction
product 12 (anti) was obtained with excellent diastereoselec-
tivity (Scheme 4a).[12] With the addition of a Boc group and
Experimental Section
General procedure for [Pd(Quinox)]–TBHP oxidation: In the dark,
AgSbF6 (43 mg, 0.125 mmol, 0.125 equiv) and [Pd(Quinox)Cl2]
(19 mg, 0.05 mmol, 0.05 equiv) were added to a 25 mL round-
bottomed flask equipped with a magnetic stir bar. The flask was
charged with CH2Cl2 (3.3 mL) and the mixture was stirred for 10 min,
after which aqueous 70% wt/wt TBHP (1.7 mL, 12 mmol, 12 equiv)
and remaining CH2Cl2 (5.0 mL) were added. The mixture, which
turned a deep orange, was stirred for 10 min before the substrate
(1.0 mmol, 1 equiv) was added. Once thin-layer chromatography
(TLC) indicated complete consumption of starting material, the
reaction was cooled to 08C and quenched with saturated aqueous
Na2SO3 (15 mL) to consume excess TBHP. The mixture was
transferred to
a separatory funnel and diluted with hexanes
Scheme 4. Diastereoselective reductions to provide both a) anti and
b) syn b-amino alcohols.
(25 mL). The aqueous layer was extracted with hexanes (25 mL).
Note: For polar substrates (Rf = 0.25, ꢀ 40% EtOAc in hexanes
needed) the aqueous portion was extracted with EtOAc (25 mL). The
combined organics were washed with H2O (4 ꢀ 10 mL) and brine
(25 mL), dried over MgSO4, filtered, and concentrated under reduced
pressure. The crude material was purified by silica gel flash
chromatography and the product containing fractions were combined
and concentrated under reduced pressure.
use of NaBH4, 13 was reduced predominately to the Felkin–
Anh product, which undergoes a concomitant cyclization on
the benzyl carbamate to give 14 (syn) (Scheme 4b).
Finally, we would like to report an improved one-pot
synthesis of the Quinox ligand, which utilizes the commer-
cially available HCl salt of 2-chloroethylamine (Scheme 5).
Following the standard amide coupling procedure, the solvent
is switched to methanol and addition of KOH promotes the
cyclization to the oxazoline ring. The [Pd(Quinox)Cl2] com-
plex can then be prepared quantitatively by stirring Quinox
with [Pd(CH3CN)2Cl2].[13]
In conclusion, we have reported the [Pd(Quinox)]–TBHP
catalyst system as providing a catalyst-controlled oxidation of
protected allylic amines. The methyl ketone is provided with
high selectivity and good to excellent yields for substrates,
Received: July 7, 2010
Published online: August 26, 2010
Keywords: catalyst control · homogeneous catalysis · oxidation ·
.
palladium complexes · Wacker-type reaction
[1] For relevant reviews see: a) J. Tsuji, Synthesis 1984, 369 – 384;
b) J. M. Takacs, X.-t. Jiang, Curr. Org. Chem. 2003, 7, 369 – 396;
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c) C. N. Cornell, M. S. Sigman, Inorg. Chem. 2007, 46, 1903 –
1909.
18043; g) E. W. Werner, K. B. Urkalan, M. S. Sigman, Org. Lett.
2010, 12, 2848 – 2851.
[2] For a review on aldehyde formation through Wacker oxidation
see: J. Muzart, Tetrahedron 2007, 63, 7505 – 7521.
[6] B. W. Michel, A. M. Camelio, C. N. Cornell, M. S. Sigman, J. Am.
Chem. Soc. 2009, 131, 6076 – 6077.
[3] For N-based directed Wacker oxidations: a) M. Mori, Y.
Watanabe, K. Kagechika, M. Shibasaki, Heterocycles 1989, 29,
2089 – 2092; b) T. Hosokawa, S. Aoki, M. Takano, T. Nakahira,
Y. Yoshida, S. Murahashi, J. Chem. Soc. Chem. Commun. 1991,
1559 – 1560; c) R. A. Alonso, C. S. Burgey, B. V. Rao, G. D. Vite,
R. Vollerthun, M. A. Zottola, B. Fraser-Reid, J. Am. Chem. Soc.
1993, 115, 6666 – 6672; d) R. Stragies, S. Blechert, J. Am. Chem.
Soc. 2000, 122, 9584 – 9591; e) G. K. Friestad, T. Jiang, A. K.
Mathies, Org. Lett. 2007, 9, 777 – 780.
[7] H. Mimoun, R. Charpentier, A. Mitschler, J. Fischer, R. Weiss, J.
Am. Chem. Soc. 1980, 102, 1047 – 1054.
[8] P. N. Collier, A. D. Campbell, I. Patel, T. M. Raynham, R. J. K.
Taylor, J. Org. Chem. 2002, 67, 1802 – 1815.
[9] Due to the poor reactivity and selectivity the retention of
enantiomeric excess was not evaluated under Tsuji–Wacker
conditions.
[10] N. Ohmura, A. Nakamura, A. Hamasaki, M. Tokunaga, Eur. J.
Org. Chem. 2008, 5042 – 5045.
[4] B. Weiner, A. Baeza, T. Jerphagnon, B. L. Feringa, J. Am. Chem.
Soc. 2009, 131, 9473 – 9474.
[11] Analysis based on crude 1H NMR integrations. Quantitative
1
analysis proved difficult due to rotomers convoluting H NMR
[5] a) M. S. Sigman, D. R. Jensen, Acc. Chem. Res. 2006, 39, 221 –
229; b) C. N. Cornell, M. S. Sigman, J. Am. Chem. Soc. 2005, 127,
2796 – 2797; c) C. N. Cornell, M. S. Sigman, Org. Lett. 2006, 8,
4117 – 4120; d) Y. Zhang, M. S. Sigman, J. Am. Chem. Soc. 2007,
129, 3076 – 3077; e) K. H. Jensen, T. P. Pathak, Y. Zhang, M. S.
Sigman, J. Am. Chem. Soc. 2009, 131, 17074 – 17075; f) K. B.
Urkalan, M. S. Sigman, J. Am. Chem. Soc. 2009, 131, 18042 –
spectra and decomposition of the analyte.
[12] R. V. Hoffman, N. Maslouh, F. Cervantes-Lee, J. Org. Chem.
2002, 67, 1045 – 1056.
[13] For preparation of the [Pd(Quinox)Cl2] complex and full
analytical data see Ref. [6]. See the Supporting Information
for the one-pot synthesis procedure.
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