Palladium-catalyzed intermolecular aminoacetoxylation of alkenes and the influence of PhI(OAc)2 on aminopalladation stereoselectivity

Article abstract of DOI:10.1021/jo400671q

A modified protocol has been identified for Pd-catalyzed intermolecular aminoacetoxylation of terminal and internal alkenes that enables the alkene to be used as the limiting reagent. The results prompt a reassessment of the stereochemical course of these reactions. X-ray crystallographic characterization of two of the products, together with isotopic labeling studies, show that the amidopalladation step switches from a cis-selective process under aerobic conditions to a trans-selective process in the presence of diacetoxyiodobenzene.

Full text of DOI:10.1021/jo400671q

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Note
Palladium Catalyzed Intermolecular Aminoacetoxylation of Alkenes
and the Influence of PhI(OAc)2 on Aminopalladation Stereoselectivity
Claudio Martinez, Yichen Wu, Adam B Weinstein, Shannon S. Stahl, Guosheng Liu, and Kilian Muniz
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo400671q • Publication Date (Web): 15 May 2013
Downloaded from http://pubs.acs.org on May 16, 2013
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Palladium Catalyzed Intermolecular
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Aminoacetoxylation of Alkenes and the Influence of
PhI(OAc)2 on Aminopalladation Stereoselectivity
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Claudio Martínez,† Yichen Wu,‡ Adam B. Weinstein,§ Shannon S. Stahl,*,§ Guosheng Liu,*,‡
and Kilian Muñiz*,†,¶
†Institute of Chemical Research of Catalonia (ICIQ), 43007 Tarragona, Spain
kmuniz@iciq.es
‡Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 200032, P.R.
China
gliu@mail.sioc.ac.cn
§Department of Chemistry, University of Wisconsin–Madison, Madison, Wisconsin 53706,
United States
stahl@chem.wisc.edu
¶Catalan Institution for Research and Advanced Studies (ICREA), Pg. Lluís Companys 23,
08010 Barcelona, Spain
Abstract
A modified protocol has been identified for Pd-catalyzed intermolecular aminoacetoxylation of terminal
and internal alkenes that enables the alkene to be used as the limiting reagent. The results prompt a
reassessment of the stereochemical course of these reactions. X-ray crystallographic characterization of
two of the products, together with isotopic labeling studies, show that the amidopalladation step switches
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from a cis-selective process under aerobic conditions to a trans-selective process in the presence of
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diacetoxyiodobenzene.
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In recent years, a number of palladium-catalyzed methods have been reported for aminoacetoxylation1
and diamination2 of alkenes with diacetoxyiodobenzene [PhI(OAc)2] as the stoichiometric oxidant. These
difunctionalization reactions are initiated by nucleopalladation of the alkene,3 followed by PhI(OAc)2-
induced oxidative cleavage of the Pd–C bond, presumably via PdIII or PdIV intermediates.4 In 2006, Liu
and Stahl reported a method for intermolecular aminoacetoxylation of terminal alkenes that employs two
equivalents of alkene with respect to the nitrogen nucleophile (Scheme 1a).1b Recently, Martínez and
Muñiz identified modified conditions that enabled regio- and diastereoselective intermolecular
diamination of internal alkenes with the alkene as the limiting reagent (Scheme 1b).2c Here, we show that
similar modified conditions are effective in intermolecular aminoacetoxylation reactions (Scheme 1c). In
the course of this work, we obtained new mechanistic insights into the stereochemical course of these
reactions, which prompted a reassessment of the originally proposed mechanistic pathway. The data show
that PhI(OAc)2 can alter the stereochemical course of the aminopalladation pathway relative to aerobic
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oxidative amination reactions.
Scheme 1. 1,2-Difunctionalization of Alkenes
The catalyst conditions recently reported for diamination of alkenes (Scheme 1b2c) were used as a
starting point to explore improved aminoacetoxylation conditions. Switching from PhI(OPiv)2 to
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PhI(OAc)2 as the oxidant enabled selectivity for aminoacetoxylation products (Scheme 1c). The scope of
this reaction is similar to that observed for the diamination chemistry (Table 1). Representative terminal
allyl ethers undergo the aminoacetoxylation in good yields (entries 1-4), as expected based on the earlier
precedents. In addition, three allyl benzenes are successful (entries 5-7). These compounds are commonly
difficult substrates in palladium catalysis, as they can undergo isomerization to the internal alkene in the
presence of the palladium catalyst. Nevertheless, moderate yields could be obtained in the
aminoacetoxylation reaction. Internal alkenes, such as (Z)-β-methylstyrene and (Z)-cinnamyl methyl ether,
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also undergo aminoacetoxylation without the formation of side products (entries 8-9). Only one
diastereomer of the product is obtained.
Table 1. Aminoacetoxylation of Alkenes
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The relative stereochemistry of compound 2i was established by single-crystal X-ray diffraction
analysis to be the threo isomer, and this product is formed exclusively under the optimized reaction
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conditions (Figure 1). This stereochemical assignment is opposite to that proposed in the
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aminoacetoxylation reactions reported previously.1b The latter study proposed formation of erythro-2i on
the basis of previously reported NMR characterization data for this compound.6 The single-crystal X-ray
diffraction data reported here reveal that the NMR characterization data were inaccurate. Control
experiments, summarized in Scheme 2, show that threo-2i is the sole aminoacetoxylation product
obtained under several different catalytic conditions, including those from the original report by Liu and
Stahl.1b The stereochemical course of these aminoacetoxylation reactions match that of the diamination
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reaction in Scheme 1b, which was similarly supported by X-ray crystallography.2c
Figure 1. X-Ray Crystal Structure of threo-2i.
Scheme 2. Exclusive formation threo-2i across related catalyst
systems.
The relative stereochemistry of product 2i is controlled by the stereochemical course of the individual
steps in the mechanism (Scheme 3). Following cis- or trans-aminopalladation of the alkene, oxidation of
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the Pd–alkyl species in the presence of PhI(OAc)2 is expected to generate a high-valent Pd–alkyl species
that undergoes facile reductive elimination (for simplicity, the high-valent intermediate is illustrated as a
PdIV species). This intermediate could undergo reductive elimination of the aminoacetoxylated product
either by an SN2-type transition state with inversion of stereochemistry,7 or by a concerted three-centered
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transition state with retention of stereochemistry. 8 , 9 Thus, threo-2i could be generated via cis-
aminopalladation of the alkene and acetoxylation with retention of stereochemistry or trans-
aminopalladation of the alkene and acetoxylation with inversion of stereochemistry.
Scheme 3. Stereochemical Pathways for the Aminoacetoxylation of Substrate 1i.
Liu and Stahl previously tested the reactivity of substrate 1i under aerobic oxidation conditions [i.e., in
the absence of PhI(OAc)2], and found that a Pd(OAc)2/O2 catalyst system converts 1i into Wacker-type
amination product (Z)-3 in 20% yield (Scheme 4).1b The conversion of 1i to (Z)-3 rather than (E)-3 is
indicative of a cis-aminopalladation pathway. No Wacker-type amination products are observed with 1i
under the aminoacetoxylation conditions. Formation of product threo-2i via cis-aminopalladation implies
that C–O reductive elimination proceeds with retention of stereochemistry, which has limited precedent.10
Scheme 4. Oxidative Amination of Substrate 1i Under Aerobic Conditions (ref. 1b).
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The identity of the oxidant [O2 vs. PhI(OAc)2] could influence the stereochemistry of the reactions,
and we sought a substrate probe that could be used to assess the aminopalladation stereochemistry under
aerobic vs. aminoacetoxylation reactions conditions. Fortuitously, substrate 1b yields a small amount of
the Wacker-type amination product 4 under aminoacetoxylation conditions (Scheme 5). This result
enables the use of deuterated substrate (E)-1b-d1 as a probe for the stereoselectivity of the
aminopalladation step. Wacker-type oxidative amination could afford products (E)-4-d1 or (Z)-4-d1, and
aminoacetoxylation could afford threo-2b-d1 or erythro-2b-d1,11 and the product identity can be used to
gain insight into the stereochemical course of the reactions (Scheme 6).
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Scheme 5. Aminoacetoxylation of 1b Yields Wacker-Type
Amination Byproduct 4.
Scheme 6. Stereochemical Pathways for the Reaction of Deuterated Substrate (E)-1b-d1.
Use of substrate (E)-1b-d1 under aminoacetoxylation conditions yielded Wacker-type oxidative
amination product (Z)-4-d1 and a diastereomeric mixture of aminoacetoxylation products threo-2b-d1 and
erythro-2b-d1 (Scheme 7a-b). Formation of enimide (Z)-4-d1 is the product expected from trans-
aminopalladation of the alkene. Since none of the cis-aminopalladation product (E)-4-d1 is detected, the
mixture of aminoacetoxylation products is believed to arise from poor stereoselectivity in the reductive
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elimination of the primary alkyl–PdIV intermediate. The origin of this poor selectivity is not presently
understood. 12 When substrate (E)-1b-d1 was subjected to aerobic conditions analogous to the
aminoacetoxylation conditions (Scheme 7b vs. 7c), the oxidative amination product (E)-4-d1 was
observed as the sole product [5% yield; 70% recovered (E)-1b-d1]. In spite of the poor yield, this product
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arises from a cis-aminopalladation pathway (cf. Scheme 6), consistent with the conclusion reached from
the reaction of substrate 1i under aerobic conditions in the previous study (cf. Scheme 4).1b,13
Scheme 7. Reaction of Deuterated Substrate 4-d1 Under Aminoacetoxylation and Aerobic Amidation Conditions.
Collectively, these results indicate that PhI(OAc)2 alters the stereochemical course of the
aminopalladation step. Prior studies have shown that ligands play a critical role in modulating of
nucleopalladation stereoselectivity.14 Most germane to the reactivity described here, Weinstein and Stahl
recently demonstrated that Pd(TFA)2 exhibits greater proclivity for trans-aminopalladation relative to
Pd(OAc)2 in Wacker-type oxidative amidation reactions.14d This trend can be rationalized by recognizing
that substitution of an anionic ligand by an alkene in the trans-aminopalladation pathway will be more
facile with less basic (i.e., less strongly coordinating) anionic ligands. Basic anionic ligands facilitate
deprotonation of the amide nucleophile to afford a Pd–amidate intermediate that undergoes cis-
aminopalladation of the alkene.15 In light of these considerations, we speculate that the Lewis acidic
character of PhI(OAc)2 facilitates displacement of acetate from Pd(OAc)2 by the alkene and favors a
trans-aminopalladation pathway.16,17
Conclusions
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We have identified reaction conditions that enable the alkene substrate to be used as the limiting
reagent in the aminoacetoxylation of terminal and internal alkenes. Furthermore, we have obtained
evidence that PhI(OAc)2 influences the stereochemical course of Pd(OAc)2-mediated aminopalladation of
alkenes, shifting the reaction from a cis- to a trans-selective process.
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Experimental Section
General considerations: MS (ESI-LCMS) experiments were performed using a C8 (5 cm x 4.6 mm, 5
µm particles) column with a linear elution gradient from 100% H2O (0.5% HCO2H) to 100% MeCN in 13
min at a flow rate of 0.5 mL/min.
General procedure for the aminoacetoxylation reaction (Table 1): A Pyrex tube equipped with a
stirrer bar is charged with 59 mg phthalimide (0.4 mmol, 1.0 eq) and 15 mg
bis(benzonitrile)palladiumdichloride (0.04 mmol, 0.1 eq). Then, 0.6 mL of absolute dichloroethane are
added via syringe and the solution is stirred at 70 ºC for 1h. At this point, 260 mg iodosobenzene
diacetate (0.80 mmol, 2.0 eq) and a previously prepared solution of 0.40 mmol of alkene with 14 mg of 4-
tert-butylcatechol (0.08 mmol, 20%) are added. The resulting solution is sealed and stirred at 70 ºC for
12h. After cooling to room temperature, the solution is washed with a 2%-solution of KOH (5 mL) and
extracted with CH2Cl2 (4 x 10 mL). The organic phases were combined, dried over Na2SO4 and
evaporated under reduced pressure. The crude product was purified by chromatography (silica gel,
neutralized with n-hexane/Et3N (3%) and then n-hexane/ethyl acetate, 3/1, v/v) to give the pure product.
3-Butoxy-2-(1,3-dioxoisoindolin-2-yl)propyl acetate (2a). Obtained as colorless oil; 92 mg, 72% of
yield. 1H NMR (400 MHz, CDCl3): δ = 0.84 (t, J = 7.4 Hz, 3H), 1.36–1.16 (m, 2H), 1.54–1.42 (m, 2H),
2.00 (s, 3H), 3.41 (dt, J = 9.3, 6.5 Hz, 1H), 3.48 (dt, J = 9.3, 6.5 Hz, 1H), 3.83 (dd, J = 10.0, 6.7 Hz, 1H),
3.91 (dd, J = 10.0, 8.1 Hz, 1H), 4.62–4.44 (m, 2H), 4.73 (tdd, J = 8.2, 6.6, 5.1 Hz, 1H), 7.74 (dd, J = 5.5,
3.1 Hz, 2H), 7.86 (dd, J = 5.4, 3.1 Hz, 2H). 13C NMR (126 MHz, CDCl3): δ = 13.8, 19.1, 20.7, 31.6, 50.2,
61.7, 67.3, 70.9, 123.3, 131.8, 134.0, 168.3, 170.6. IR ν(cm-1): 2958, 2932, 2871, 1743, 1709. HRMS:
calcd for C17H21NO5Na: 342.1317, found: 342.1304.
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3-(Benzyloxy)-2-(1,3-dioxoisoindolin-2-yl)propyl acetate (2b). Obtained as colorless oil; 93 mg, 66%
of yield. 1H NMR (400 MHz, CDCl3): δ = 2.00 (s, 3H), 3.89 (dd, J = 9.9, 6.4 Hz, 1H), 3.98 (dd, J = 9.9,
8.1 Hz, 1H), 4.64–4.44 (m, 4H), 4.86–4.73 (m, 1H), 7.42–7.13 (m, 5H), 7.74 (dd, J = 5.5, 3.0 Hz, 2H),
7.86 (dd, J = 5.4, 3.1 Hz, 2H). 13C NMR (126 MHz, CDCl3): δ = 20.7, 50.2, 61.6, 66.7, 73.0, 123.4,
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127.6, 127.7, 128.4, 131.8, 134.1, 137.6, 168.2, 170.6. IR ν(cm-1): 3063, 3031, 2950, 2871, 1741, 1707.
HRMS: calcd for C20H19NNaO5: 376.1161, found: 376.1150.
3-Acetoxy-2-(1,3-dioxoisoindolin-2-yl)propyl benzoate (2c). Obtained as yellow oil; 104 mg, 71% of
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yield. H NMR (400 MHz, CDCl3): δ = 2.05 (s, 3H), 4.66 (dd, J = 6.9, 4.5 Hz, 2H), 4.75 (dd, J = 11.4,
5.7 Hz, 1H), 4.81 (dd, J = 11.4, 7.7 Hz, 1H), 4.90-4.96 (m, 1H), 7.41 (t, J = 7.8 Hz, 2H), 7.55 (t, J = 7.5
Hz, 1H), 7.76 (dd, J = 5.4, 3.0 Hz, 2H), 7.88 (dd, J = 5.5, 3.0 Hz, 2H), 7.97 (d, J = 7.1 Hz, 2H). 13C NMR
(126 MHz, CDCl3): δ = 20.8, 49.7, 61.3, 61.9, 123.6, 128.5, 129.9, 131.7, 133.3, 134.4, 166.1, 168.1,
170.6. IR ν(cm-1): 3023, 2961, 2929, 1175, 1711, 1601. HRMS: calcd for C20H17NNaO6: 390.0954,
found: 390.0936.
2-(1,3-Dioxoisoindolin-2-yl)-3-(octyloxy)propyl acetate (2d). Obtained as yellow oil; 60 mg, 40% of
yield. 1H NMR (400 MHz, CDCl3): δ = 0.87 (t, J = 7.1 Hz, 3H), 1.18-1.28 (m, 10H), 1.48-1.51 (m, 2H),
2.01 (s, 3H), 3.40 (dt, J = 9.3, 6.6 Hz, 1H), 3.49 (dt, J = 9.1, 6.4 Hz, 1H), 3.83 (dd, J = 10.0, 6.0 Hz, 1H),
3.93 (dd, J = 10.0, 8.3 Hz, 1H), 4.47-4.57 (m, 2H), 4.71-4.77 (m, 1H), 7.75 (dd, J = 5.5, 3.1 Hz, 2H), 7.87
(dd, J = 5.4, 3.0 Hz, 2H). 13C NMR (126 MHz, CDCl3): δ = 14.2, 20.9, 22.8, 26.2, 29.3, 29.5, 29.6, 31.9,
50.3, 61.8, 67.4, 71.4, 123.5, 131.9, 134.2, 168.4, 170.8. IR ν(cm-1): 2926, 2855, 1776, 1710. HRMS:
calcd for C21H29NNaO5: 398.1943, found: 398.1940.
2-(1,3-Dioxoisoindolin-2-yl)-3-phenylpropyl acetate (2e). Obtained as colorless oil; 73 mg, 56% of
yield. 1H NMR (400 MHz, CDCl3): δ = 1.99 (s, 3H), 3.20 (dd, J = 13.9, 6.4 Hz, 1H), 3.36 (dd, J = 14.0,
10.0 Hz, 1H), 4.50 (dd, J = 11.3, 4.7 Hz, 1H), 4.62 (dd, J = 11.3, 9.3 Hz, 1H), 4.88–4.75 (m, 1H), 7.37–
7.08 (m, 5H), 7.70 (dd, J = 5.5, 3.0 Hz, 2H), 7.79 (dd, J = 5.4, 3.1 Hz, 2H). 13C NMR (126 MHz,
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CDCl3): δ = 20.7, 34.9, 51.8, 63.4, 123.2, 126.8, 128.6, 128.9, 131.6, 133.9, 136.8, 168.2, 170.6. IR
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ν(cm-1): 3062, 3028, 2927, 1771, 1707. HRMS: calcd for C19H17NNaO4: 346.1055, found: 346.1067.
3-(2-(Benzyloxy)phenyl)-2-(1,3-dioxoisoindolin-2-yl)propyl acetate (2f). Obtained as yellow oil; 90
mg, 50% of yield. 1H NMR (400 MHz, CDCl3): δ = 1.93 (s, 3H), 3.30 (dd, J = 7.8, 5.1 Hz, 2H), 4.47 (dd,
J = 11.2, 4.9 Hz, 1H), 4.63 (dd, J = 11.3, 9.1 Hz, 1H), 4.93-4.99 (m, 1H), 5.06-5.12 (m, 2H), 6.75 (t, J =
7.2 Hz, 1H), 6.86 (d, J = 8.1 Hz, 1H), 7.06 (dd, J = 7.4, 1.7 Hz, 1H), 7.12 (td, J = 7.9, 1.7 Hz, 1H), 7.33 (d,
J = 7.3 Hz, 1H), 7.40 (t, J = 7.6 Hz, 2H), 7.49 (d, J = 7.3 Hz, 2H), 7.66 (dd, J = 5.5, 3.0 Hz, 2H), 7.74 (dd,
J = 5.4, 3.0 Hz, 2H). 13C NMR (126 MHz, CDCl3): δ = 20.8, 30.6, 50.5, 63.9, 70.2, 111.8, 120.8, 123.2,
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125.8, 127.4, 127.9, 128.4, 128.6, 130.9, 131.8, 133.9, 137.2, 156.9, 168.3, 170.6. IR ν(cm-1): 3064, 3030,
2929, 2871, 1738, 1708. HRMS: calcd for C26H23NNaO5: 452.1474, found: 452.1474.
2-(1,3-Dioxoisoindolin-2-yl)-3-(2-methoxyphenyl)propyl acetate (2g). Obtained as yellow oil; 76 mg,
51% of yield. 1H NMR (400 MHz, CDCl3): δ = 1.98 (s, 3H), 3.19-3.28 (m, 2H), 3.79 (s, 3H), 4.48 (dd, J
= 11.4, 4.7 Hz, 1H), 4.68 (dd, J = 11.4, 9.6 Hz, 1H), 4.90 (tdd, J = 9.3, 6.3, 4.7 Hz, 1H), 6.76 (td, J = 7.4,
1.1 Hz, 1H), 6.80 (dd, J = 8.3, 1.0 Hz, 1H), 7.06 (dd, J = 7.5, 1.8 Hz, 1H), 7.15 (td, J = 7.9, 1.8 Hz, 1H),
13
7.69 (dd, J = 5.5, 3.0 Hz, 2H), 7.79 (dd, J = 5.4, 3.1 Hz, 2H). C NMR (126 MHz, CDCl3): δ = 20.9,
30.5, 50.6, 55.3, 63.7, 110.4, 120.5, 123.2, 125.4 128.4, 130.9, 131.9, 133.9, 157.8, 168.4, 170.7. IR
ν(cm-1): 3020, 2959, 2937, 1774, 1709. HRMS: calcd for C20H19NNaO5: 376.1161, found: 376.1168.
2-(1,3-Dioxoisoindolin-2-yl)-1-phenylpropylacetate (2h). Obtained as a white solid; 105 mg, 81% of
1
yield. m.p: 112-113 ºC (CH2Cl2/hexane). H NMR (400 MHz, CDCl3): δ = 1.60 (d, J = 6.9 Hz, 3H),
2.10 (s, 3H), 4.75 (dq, J = 9.1, 6.9 Hz, 1H), 6.30 (d, J = 9.2 Hz, 1H), 7.14-7.21 (m, 3H), 7.33 (dd, J = 8.1,
1.6 Hz, 2H), 7.62 (dd, J = 5.4 and 3.0 Hz, 2H), 7.69 (dd, J = 5.4, 3.0 Hz, 2H). 13C NMR (126 MHz,
CDCl3): δ = 15.3, 21.3, 50.4, 76.2, 123.2, 127.8, 128.4, 128.6, 131.6, 134.0, 137.5, 167.8, 169.9. IR
ν(cm-1): 3035, 2984, 2927, 2854, 1770, 1704. HRMS: calcd for C19H17NO4Na: 346.1055, found:
346.1072.
Synthesis of deuterated substrate probe (E)-1b-d1:
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1. (C5H5)2ZrHCl, THF, r.t.
KOH
Br
+
OBn
D
OBn
(E)-1b-d1
BnOH
2. D2O
DMSO
0 °C -> r.t.
6
7
8
9
A solution of KOH (2.69 g, 48 mmol) in DMSO (25 mL) was cooled in an ice bath and treated
sequentially with benzyl alcohol (6.48 g, 60 mmol) and propargyl bromide (4.76 g, 40 mmol). The
reaction mixture was stirred for 1 h at r.t. before being diluted with Et2O and H2O. The organic layer was
separated, washed with H2O, dried (Na2SO4), filtered, and concentrated in vacuo. Flash chromatography
afforded benzyl propargyl ether (5.07 g, 87 %).
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The benzyl propargyl ether (1.46 g, 10 mmol) was treated with (C5H5)2ZrHCl (Schwartz reagent, 3.23
g, 12.5 mmol) in anhydrous THF (45 mL). After 10 min, the solution turned black, and the reaction was
then quenched with D2O (7.4 mL), and stirring was continued overnight. The mixture was then diluted
with Et2O, dried over MgSO4, filtered and concentrated. The mixture was then purified by
chromatography giving 1.26 g (86 %) of the product.
D
OBn
(E)-1b-d1
Compound (E)-1b-d1 is a known compound.18 1H NMR (400 MHz, CDCl3): δ 7.30 (m, 5H), 5.96 (dtt, J
13
= 17.2, 6, 1.6 Hz), 5.30 (dt, J = 17.2, 1.6 Hz, 1H), 4.53 (s, 2H), 4.03 (dd, J = 6, 4.4 Hz, 2H). C NMR
(100 MHz, CDCl3): δ 138.3, 134.6, 128.4, 127.7, 127.6, 72.1, 71.1 (t, J = 1.9 Hz).
Procedures for the reaction of deuterated substrate (E)-1b-d1 (Scheme 7):
Stereochemical assignments of products (Z)-4-d1 and (E)-4-d1 were achieved from NOESY-1D analysis of
419 (see the supporting information). The stereochemical assignments of products erythro-2b-d1 and
1
threo-2b-d1 were achieved after derivatization and H NMR spectroscopic analysis (see below and the
supporting information).
(a) With PhI(OAc)2 as oxidant
In a dried glass tube, Pd(CH3CN)2Cl2 (5.2 mg, 0.02 mmol, 10 mol %), PhI(OAc)2 (128.8 mg, 0.04
mmol, 2 equiv.), phthalimide (29.4 mg, 0.2 mmol, 1.0 equiv.) were dissolved in DCE (0.25 mL), and then
(E)-1b-d1 (59.6 mg, 0.4 mmol, 2.0 equiv.) was added. After the reaction mixture was stirred at 70 °C for
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24 h, the residue was purified by column chromatography on silica gel with a gradient eluant of petroleum
ether and ethyl acetate to afford (Z)-4-d1, erythro-2b-d1 and threo-2b-d1.
7
8
(b) With O2 as the oxidant
9
In a dried glass tube, Pd(OAc)2 (4.5 mg, 0.02 mmol, 10 mol %), phthalimide (29.4 mg, 0.2 mmol, 1.0
equiv.) were dissolved in DCE (0.4 mL), charged with oxygen and then (E)-1b-d1 (59.6 mg, 0.4 mmol, 2
equiv.) was added. After the reaction mixture was stirred at 70 °C for 18 h, the residue was purified by
column chromatography on silica gel with a gradient eluant of petroleum ether and ethyl acetate to afford
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(E)-4-d1.
NPhth
D
OBn
(Z)-4-d1
1H NMR (400 MHz, CDCl3): δ 7.88 (m, 2H), 7.75 (m, 2H), 7.27 (m, 5H), 5.65 (s, 1H), 4.53 (s, 2H), 4.36
(s, 2H).
NPhth
OBn
D
(E)-4-d1
1H NMR (400 MHz, CDCl3): δ 7.88 (m, 2H), 7.75 (m, 2H), 7.27 (m, 5H), 5.43 (s, 1H), 4.54 (s, 2H), 4.35
(s, 2H).
AcO
H
NPhth
H
CH2OBn
AcO
D
H
NPhth
H
CH2OBn
+
D
erythro-2b-d1
threo-2b-d1
1H NMR (400 MHz, CDCl3) δ 1.98 (s, 3H), 3.87 (dd,J = 6.4, 3.6 Hz, 1H), 3.96 (dd, J = 80, 1.6 Hz, 1H),
4.48-4.57 (m, 3H), 4.74-4.81 (m, 1H), 7.24-7.28 (m, 5H), 7.71-7.74 (m, 2H), 7.83-7.85 (m, 2H). 13C
NMR (100 MHz, CDCl3) δ 20.7, 50.0, 61.2 (t, J = 22.4 Hz), 66.6, 72.9, 123.3, 127.6, 127.7, 128.3, 131.7,
134.0, 137.5, 168.2, 170.6. HRMS: calcd for C20H22DN2O5: 372.1664, found: 372.1668. IR ν(cm-1): 3088,
3063, 3031, 2868, 1740, 1708.
The structure of isomers erythro-2b-d1 and threo-2b-d1 were characterized by conversion to a
heterocyclic product with diagnostic J-coupling and chemical shift differences. Protio-derivative 2b was
converted to 5b20 to identify the chemical shifts of the two protons H1a and H2a. The chemical shifts of H1a
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and H2a were assigned based on the J-values in the 1H NMR spectrum of 5b in benzene-d6 (see figure S3
in the supporting information). 2b-d1 was similarly converted to 5b-d1, and the ratio of H1b : H2b
corresponded to the ratio of isomers erythro-2b-d1 : threo-2b-d1 (see figure S4 in the supporting
9
information).
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1.
O
H2N
NH2
triphosgene
NaHCO3
NPhth
OBn
NH2
NH
EtOH, reflux
O
AcO
H1a H2a
2b
HO
OBn
OBn
toluene/H2O
2. KOH
H1b
H2b
5b
O
O
O
NPhth
OBn
NPhth
OBn
as above
NH
NH
+
AcO
AcO
+
O
OBn
OBn
D
D
D
D
threo-2b-d1
erythro-2b-d1
threo-5b-d1
erythro-5b-d1
1H NMR (400 MHz, C6D6) δ 7.15 (m, 5H), 6.19 (br, s, 1H), 4.07 (s, 2H), 3.58 (dd, J = 8.7, 8.7 Hz, 1H),
3.46 (dd, J = 8.7, 5.3 Hz, 1H), 3.13 (m, 1H), 2.70 (m, 2H).
1H NMR (400 MHz, C6D6) δ 7.15 (m, 5H), 6.26 (br, s, 1H), 4.07 (s, 2H), 3.56 (d, J = 8 Hz, 0.42H), 3.45
(d, J = 5.2 Hz, 0.57H), 3.13 (dt, J = 6, 6 Hz, 1H), 2.75-2.67 (m, 2H).
Associated Content
Supporting Information: 1H NMR spectra for stereochemical analyses; 1H and 13C NMR spectra of new
compounds; X-ray crystallographic data. This material is available free of charge via the Internet at
http://pubs.acs.org/.
Author Information
Corresponding Authors
* E-mail: kmuniz@iciq.es; gliu@mail.sioc.ac.cn; stahl@chem.wisc.edu
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Notes
5
6
The authors declare no competing financial interest.
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8
Acknowledgements
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KM and CM thank the Spanish Ministerio de Economía y Competitividad (CTQ2011-25027) for financial
support. The authors thank Dr. J. Benet-Buchholz, Dr. E. C. Escudero-Adán, Dr. M. Martínez-Belmonte
and Dr. E. Martin for the crystal structure analyses. YW and GL thank National Natural Science
Foundation of China (No. 21202185) for financial support. ABW and SSS thank the NIH (R01
GM067173) for financial support.
References
(1) (a) Alexanian, E. J.; Lee, C.; Sorensen, E. J. J. Am. Chem. Soc. 2005, 127, 7690–7691. (b)
Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2006, 128, 7179–7181. (c) For a related
aminoetherification reaction, see: Desai, L. V.; Sanford, M. S. Angew. Chem. Int. Ed. 2007, 46,
5737–5740.
(2) (a) Iglesias, A.; Pérez, E. G.; Muñiz, K. Angew. Chem. Int. Ed. 2010, 49, 8109–8111. (b)
Muñiz, K.; Kirsch, J.; Chávez, P. Adv. Synth. Catal. 2011, 353, 689–694. (c) Martínez, C.;
Muñiz, K. Angew. Chem. Int. Ed. 2012, 51, 7031–7034.
(3) (a) Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104, 2285–2309. (b) Beccali, E. M.; Broggini,
G.; Martinelli, M.; Sottocornola, S. Chem. Rev. 2007, 107, 5318–5365. (c) Minatti, A.; Muñiz K.
Chem. Soc. Rev. 2007, 36, 1142–1152. (d) Kotov, V.; Scarborough, C. C.; Stahl, S. S. Inorg.
Chem. 2007, 46, 1910–1923. (e) Jensen, K. H.; Sigman, M. S. Org. Biomol. Chem. 2008, 6,
4083–4088. (f) McDonald, R. I.; Liu, G. S.; Stahl, S. S. Chem. Rev. 2011, 111, 2981–3019.
(4) For leading references, see: (a) Canty, A. J.; Denney, M. C.; Skelton, B. W.; White, A. H.
Organometallics 2004, 23, 1122–1131. (b) Dick, A. R.; Kampf, J. W.; Sanford, M. S. J. Am.
Chem. Soc. 2005, 127, 12790–12791. (c) Powers, D. C.; Ritter, T. Nat. Chem. 2009, 1, 302–209.
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(d) Deprez, N. R.; Sanford, M. S. J. Am. Chem. Soc. 2009, 131, 11234–11241. (e) Powers, D. C.;
Lee, E.; Ariafard, A.; Sanford, M. S.; Yates, B. F.; Canty, A. J.; Ritter, T. J. Am. Chem. Soc.
2012, 134, 12002–12009. (f) Powers, D. C.; Ritter, T. Acc. Chem. Res. 2012, 45, 840–850. (g)
Muñiz, K. Angew. Chem. Int. Ed. 2009, 48, 9412–9423. (h) Hickman, A. J.; Sanford, M. S.
Nature 2012, 484, 177–185.
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( 5 ) Additionally, single crystal X-ray analysis of 2h also established the relative
stereochemistry to be threo, which suggests a unified pathway for internal alkenes (see the
supporting information for details).
(6) Fles, D.; Majhofer, B.; Kovac, M. Tetrahedron 1968, 24, 3053–3057.
(7) (a) Sibbald, P. A.; Rosewall, C. F.; Swartz, R. D.; Michael, F. E. J. Am. Chem. Soc. 2009,
131, 15945–15951. (b) Iglesias, Á.; Álvarez, R.; de Lera, A. R.; Muñiz, K. Angew. Chem. Int.
Ed. 2012 51, 2225–2228. Reductive elimination from PdIV–alkyl complexes with inversion of
stereochemistry is also supported by analogy to fundamental studies of PtIV–alkyl complexes: (c)
Williams, B. S.; Goldberg, K. I. J. Am. Chem. Soc. 2001, 123, 2576–2587. (d) Stahl, S. S.;
Labinger, J. A.; Bercaw, J. E. Angew. Chem. Int. Ed. 1998, 37, 2182–2192 and references therein.
(8) Byers, P. K.; Canty, A. J.; Crespo, M.; Puddephatt, R. J.; Scott, J. D. Organometallics 1988,
7, 1363–1367.
(9) For examples of discrete PdII complexes in which oxidative cleavage of a PdII–C bond may
proceed with either inversion or retention of stereochemistry, see: (a) Coulson, D. R. J. Am.
Chem. Soc. 1969, 91, 200–202. (b) Wong, P. K.; Stille, J. K. J. Organomet. Chem. 1974, 70,
121–132. (c) Bäckvall, J.-E. Tetrahedron Lett. 1977, 18, 467–468. (d) Bäckvall, J.-E.
Tetrahedron Lett. 1978, 19, 163–166. (e) Zhu, G.; Ma, S.; Lu, X.; Huang, Q. J. Chem. Soc.,
Chem. Commun. 1995, 271–273.
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(10) (a) Desai, L. V.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 9542–9543. (b)
For a relevant precedent involving Csp3–O reductive elimination from PtIV, see: Khusnutdinova, J.
R.; Newman, L. L.; Zavalij, P. Y.; Lam, Y. F.; Vedernikov, A. N. J. Am. Chem. Soc. 2008, 130,
2174–2175.
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(11) Substrate (E)-1b-d1 also avoids the complication associated with potential reversible β-
hydride elimination leading to a more thermodynamically favored product rather than the
diagnostic alkene isomer. For example, substrate 1i could exhibit this complication, as depicted
below (we thank Prof. Datong Song, University of Toronto, for drawing our attention to this
potential complexity):
trans-amino-
palladation
PdII
Ph
NPhth
OMe
+
HNPhth
OMe
Ph
1i
!-hydride
elimination
NPhth
OMe
H
Pd
NPhth
OMe
-PdH
Ph
Ph
(E)-3
olefin
reinsertion
!-hydride
elimination
PdII
"-bond
rotation
OMe
OMe
NPhth
NPhth
-PdH
PdII
Ph
OMe
Ph
NPhth
(Z)-3
Ph
(12) The poor diastereoselectivity observed for reductive elimination of aminoacetoxylation
product erythro- vs. threo-2b contrasts the excellent stereoselectivity observed for reductive
elimination of aminoacetoxylation product threo-2i (cf. Scheme 3) and products derived from
other internal alkene substrates. Presumably, the different selectivity is associated with the
different reactivity of secondary benzylic vs. primary aliphatic alkyl–Pd intermediates.
(13) A similar analysis of cis- vs. trans-aminopallation has been employed in the
aminoetherification reaction in ref. 1c.
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(14) For discussion of the factors that contribute to nucleopalladation stereoselectivity, see
reference 3f and (a) Nakhla, J. S.; Kampf, J. W.; Wolfe, J. P. J. Am. Chem. Soc. 2006, 128, 2893–
2901. (b) Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2007, 129, 6328–6335. (c) Keith, J. A.; Henry,
P. M. Angew. Chem. Int. Ed. 2009, 48, 9038–9049. (d) Weinstein, A. B.; Stahl, S. S. Angew.
Chem. Int. Ed. 2012, 51, 11505–11509.
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(15) For further analysis of anionic ligand effects in amidopalladation reactions, see: (a) Ye,
X.; Liu, G.; Popp, B. V.; Stahl, S. S. J. Org. Chem. 2011, 76, 1031-1044. (b) Ye, X.; White, P.
B.; Stahl, S. S. J. Org. Chem. 2013, 78, 2083-2090.
(16) NMR spectroscopic analysis of solutions of Pd(OAc)2 and PhI(OAc)2 did not provide
evidence for a ground-state interaction between these species, but this result cannot exclude a
kinetic effect in which iodine(III) facilitates displacement of acetate by an alkene.
( 17 ) Reactions between phthalimide and PhI(OAc)2 could afford hypervalent iodine–
phthalimide adducts, such as PhI(OAc)(NPhth) and PhI(NPhth)2; however, it is not clear how the
formation of such species would alter the stereochemical course of amidopalladation of the
alkene. For references describing species such as PhI(OAc)(NPhth) and PhI(NPhth)2, see the
following: (a) Hadjiarapoglou, L.; Spyroudis, S.; Varvoglis, A. Synthesis 1983, 207–208. (b)
Kim, H. J.; Kim, J.; Cho, S. H.; Chang, S. J. Am. Chem. Soc. 2011, 133, 16382–16385. (c)
Moriyama, K.; Ishida, K.; Togo, H. Org. Lett. 2012, 14, 946–949.
(18) Yagi, K.; Oikawa, H.; Ichihara, A. Biosci. Biotech. Bioch. 1997, 61, 1038–1040.
(19) 4 is a known compound: Rogers, M. M.; Kotov, V.; Chatwichien, J.; Stahl, S. S. Org. Lett.
2007, 9, 4331–4334.
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(20) Product 5b is a known compound. The 1H NMR was consistent with the data in the
literature: Bégis, G.; Cladingboel, D. E.; Jerome, L.; Motherwell, W. B.; Sheppard, T. D. Eur. J.
Org. Chem. 2009, 1532–1548.
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TOC Graphic:
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10 % PdCl2(NCPh)2
1 equiv phthalimide
Nphth
OAc
R
R'
or
R
R
PhI(OAc)2 or O2
R'
1 equiv
R'
NPhth
9
Aminopalladation
Stereochemistry
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Oxidant
O2
Major Product
Enamine derivative
cis
PhI(OAc)2 Aminoalcohol derivative
trans
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