Anti-markovnikov hydroalkylation of allylic amine derivatives via a palladium-catalyzed reductive cross-coupling reaction

Article abstract of DOI:10.1021/ja204080s

Palladium-catalyzed hydroalkylation of allylic amine derivatives by alkylzinc reagents is reported. This reductive cross-coupling reaction yields anti-Markovnikov products using a variety of allylic amine protecting groups. Preliminary mechanistic studies suggest that a reversible β-hydride elimination/hydride insertion process furnishes the primary Pd-alkyl intermediate, which then undergoes transmetalation followed by reductive elimination to form a new sp³-sp³ carbon-carbon bond.

Full text of DOI:10.1021/ja204080s

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pubs.acs.org/JACS
Anti-Markovnikov Hydroalkylation of Allylic Amine Derivatives via a
Palladium-Catalyzed Reductive Cross-Coupling Reaction
Ryan J. DeLuca and Matthew S. Sigman*
Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, Utah 84112, United States
S Supporting Information
b
Scheme 1. Pd-Alkyl Stabilization Using Conjugated Alkenes
ABSTRACT: Palladium-catalyzed hydroalkylation of allylic
amine derivatives by alkylzinc reagents is reported. This
reductive cross-coupling reaction yields anti-Markovnikov
products using a variety of allylic amine protecting groups.
Preliminary mechanistic studies suggest that a reversible
β-hydride elimination/hydride insertion process furnishes
the primary Pd-alkyl intermediate, which then undergoes
transmetalation followed by reductive elimination to form a
new sp3ꢀsp3 carbonꢀcarbon bond.
he functionalization of Pd-alkyl intermediates has classically
been difficult due to their propensity to undergo β-hydride
T
elimination. Advances in this field have focused primarily on
three general approaches to functionalize the Pd-alkyl: (1) rapid
oxidation of the intermediate to allow for either substitution or
reductive elimination of the resultant high oxidation state Pd
complex,1 (2) ligand control to slow β-hydride elimination,2 and/or
(3) substrate control through the use of stabilizing interactions
such as the formation of π-allyl3 or π-benzyl intermediates.1c,4
Using the latter approach, our laboratory has reported a series of
cross-coupling reactions of π-allyl5 (A, Scheme 1) or π-benzyl
(B) intermediates6 that are formed by in situ generation of a Pd-
hydride (through either alcohol oxidation or decomposition of a
Pd-alkyl) and subsequent insertion into a conjugated alkene.
One advantage of such a tactic to prepare Pd-alkyl intermedi-
ates is the utilization of an alkene as a surrogate for an alkyl
electrophile.2a Also, by using a conjugated alkene, a stabilized Pd-
alkyl is ultimately formed as the thermodynamic product through
reversible β-hydride elimination/hydride insertion processes,6a
enabling cross-coupling as well as the formation of a single con-
stitutional isomer. Unfortunately, this approach is limited to
alkene coupling partners, which provide formal stabilization.
Specifically, without stabilization, reversible β-hydride elimina-
tion/hydride insertion processes lead to complex mixtures of
alkene isomers and coupled products.6 Therefore, to overcome
this limitation, we envisioned applying alternative stabilizing
motifs that could enable the selective reductive cross-coupling
of a nonconjugated alkene and an organometallic, thereby
significantly expanding the scope of alkene substrates.
Scheme 2. Feringa and Co-workers’ Wacker Oxidation and
Our Proposed Hydroalkylation Approach
phthalimide group is uniquely suited for directing the Wacker
oxidation to the anti-Markovnikov position, as other allylic amine
derivatives lead to mixtures of products.7 The authors suggest the
high selectivity may be attributed to chelation of the phthalimide
group to the Pd catalyst prior to oxypalladation. Encouraged by
Feringa’s results, we pursued the evaluation of allylic phthalimides
in order to hypothetically direct the formation of and stabilize the
resultant Pd-alkyl complex for subsequent cross-coupling. Herein,
we report the development and preliminary mechanistic investiga-
tion of a highly selective anti-Markovnikov hydroalkylation reac-
tion of allylic amine derivatives, wherein, a broad range of
functional groups at the allylic position are permitted.
To this effect, a functional group that can act as a versatile
synthetic handle and can be easily incorporated into the alkene
substrate would be most attractive. A recent report by Feringa
and co-workers7 demonstrated the use of phthalimide-protected
allylic amines to achieve aldehyde-selective anti-Markovnikov
Wacker oxidations (Scheme 2). It should be noted that the
Received: May 3, 2011
Published: July 05, 2011
r
2011 American Chemical Society
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|

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Table 1. Reaction Optimization
Table 2. Pd-Catalyzed Cross-Coupling of Phthalimide-Pro-
tected Allylic Amines with Alkylzinc Reagents
entry
1
2c Pd(IiPr)(OTs)2
catalyst
temp
additive
% conv.a % yielda lin:brb
no Pd
rt
rt
rt
ꢀ
<2
<2
85
86
88
95
99
ꢀ
ꢀ
80
81
80
86
91
ꢀ
Cu(OTf)2, O2
ꢀ
3
4
5
6
7
Pd(IiPr)(OTs)2
ꢀ
ꢀ
ꢀ
15:1
16:1
17:1
17:1
17:1
Pd(MeCN)2(OTs)2 rt
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
rt
0 °C ꢀ
0 °C 3 Å MS
a Measured by GC using an internal standard. b Ratio of linear:
branched product isomers determined by GC. Yields are a combina-
tion of both linear and branched products. c Zn(OTf)2 and BQ were
not added.
Preliminary investigations utilized the optimal conditions for
the previously reported Pd(IiPr)(OTs)2-catalyzed hydroalkyla-
tion of styrene derivatives6c with organozinc reagents. Using
allylic phthalimide 1a, an 80% GC yield of 2a was delivered in
high selectivity for the linear product (entry 3, Table 1). Control
studies of the reaction conditions involved the removal of the
NHC ligand (entry 4) and the use of Pd(MeCN)2Cl2 as the
catalyst (entry 5) resulted in similar yields and selectivity,
prompting the use of these simplified conditions in further
optimization. Lowering the temperature and utilizing molecular
sieves resulted in excellent yield and 17:1 selectivity favoring the
linear over the branched product (entry 7).
Evaluation of the scope initially focused on the use of various
organozinc reagents with 1a. Simple alkyl organozinc reagents
performed well, giving linear products 2a and 2b with high
selectivity. Functionalized organozinc reagents were then exam-
ined, which led to products containing a TBDPS-protected
alcohol (2c), an alkyl chloride (2d), and an ester (2e). Methyl-
cyclohexyl zinc bromide, which contains substitution at the β-
position, gave product 2f in 46% yield with excellent selectivity.
We next examined the effect of varying groups on the allylic
phthalimide substrate.
Lower selectivity for the linear product (2:1) was observed
when the substrate lacks additional substitution at the carbon
bearing the phthalimide group (2g, Table 2). Introduction of a
benzyl group (2h) resulted in a 91% yield with modestly
diminished selectivity for the linear product. Substrates contain-
ing a benzyl ether (2i) and a heteroaromatic (2j) both gave
moderate yields with >20:1 selectivity. Although these substrates
could potentially competitively coordinate to Pd, they produced
the anti-Markovnikov product selectively. Substrates containing
larger groups adjacent to the phthalimide (2k, 2l) also gave good
yields with high selectivity for the linear product.
Ratio of linear:branched product isomers determined by GC, 1H NMR
integration, and/or yields of isolated products. a 8 equiv of BrZn-R
was used. b The reaction was performed at room temperature. All yields
represent an average of two experiments on at least 0.5 mmol scale.
disparate amine protecting groups also gave the linear hydroalkyla-
tion product (Table 3). Several attractive and commonly em-
ployed amine protecting groups were evaluated, including dou-
bly protected N-Cbz-N-Boc allylic amines (3a, 3b), suggesting
that this strategy may be more general than anticipated. Addi-
tionally, a variety of singly protected amines were tolerated under
the reaction conditions, including a Cbz-protected amine, which
gave the coupled product in 82% yield with >20:1 selectivity for
the linear product (3c). Electron-poor protecting groups such as
trichloroacetamide (TAc, 3d), and sulfonamide-protected amines,
gave the cross-coupled products in excellent selectivity (3e, 3f).
These cases are especially interesting in that the Lewis basicity of
the carbonyl or sulfonyl groups should be significantly reduced,
raising questions about our previous hypothesis involving chela-
tion to the catalyst. Finally, the use of N-tosyl allyl amine, which
also lacks additional substitution at the amine-bearing carbon,
It was initially believed, based on Feringa’s report, that allylic
phthalimides were uniquely suited to stabilize the resultant Pd-
alkyl intermediates, potentially through chelation,7,8 and selec-
tively deliver the linear product. Therefore, it was surprising
that, under our optimized conditions, a variety of electronically
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Table 3. Scope of Protecting Groups
Scheme 3. Deuterium Labeling Study and Evaluation of
Retention of Enantiomeric Excess
Ratio of linear:branched product isomers determined by GC, 1H NMR
integration, and/or yields of isolated products. All yields represent an
average of two experiments on at least 0.5 mmol scale.
gave the anti-Markovnikov product in >20:1 selectivity (3f), in
contrast to the related phthalimide-protected product 2g.
Encouraged by the successful coupling of various protected
allylic amines, we subjected a protected allylic alcohol, a ubiqui-
tous intermediate in organic synthesis, to our reductive cross-
coupling reaction conditions. To our delight, a benzoyl-protected
allylic alcohol (4a) gave the corresponding product 5a in 65%
yield and >20:1 selectivity (eq 1). Submission of dodecene to the
reaction conditions resulted in alkene isomerization and trace
amounts of product isomers, suggesting that allylic substitution
is required to achieve selectivity for the anti-Markovnikov
product.9
and the ability to successfully use electron-poor allylic amine
derivatives suggest that the success of this reaction arises from
slowing β-hydride elimination at the allylic position in combina-
tion with a relatively fast cross-coupling of the primary Pd-alkyl
intermediate.
In summary, we have reported a Pd-catalyzed hydroalkylation
reaction of various protected allylic amines, which we have also
extended to an allylic alcohol derivative. This process features the
ability to incorporate a remote stereocenter in regions devoid of
other functionality. Initial mechanistic studies suggest a rever-
sible β-hydride elimination/hydride insertion process to arrive at
a primary Pd-alkyl intermediate, which predominantly undergoes
cross-coupling. While the precise role of the protecting group on
the amine remains unclear, it is required to achieve selective anti-
Markovnikov addition products. Future work will be focused on
exploring the synthetic utility of this method and elucidating the
features required to control β-hydride elimination in related
processes.
Considering the breadth of protecting groups allowed and the
generally high selectivity for the anti-Markovnikov product, an
important mechanistic consideration is whether insertion into
the Pd-hydride is selectively directed by the allylic amine. To
probe this, a perdeuterated alkylzinc reagent was prepared and
submitted to the hydroalkylation reaction conditions (Scheme 3).
Surprisingly, 91% deuterium incorporation results, with a similar
amount of deuterium incorporation observed at both alkene
carbons. This suggests that, after formation of a Pd-hydride
(deuteride, C) via transmetalation with the organozinc reagent
and β-hydride elimination,6c coordination and insertion of the
allylic amine (A) can result in either a 1,2-insertion (D0) or a 2,1-
insertion (D). In the case of a 2,1-insertion, intermediate D
rearranges to the primary Pd-alkyl complex (F) via a β-hydride
elimination (E) followed by a migratory insertion. Primary Pd-
alkyl intermediates F and D0 then undergo transmetalation
followed by reductive elimination. It should be noted that no
deuterium is incorporated into the allylic position, which is con-
sistent with the observed stereochemical retention when using
an enantioenriched substrate (Scheme 3). This information
’ ASSOCIATED CONTENT
S
Supporting Information. Optimization data, experimen-
b
tal procedures, and characterization data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
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’ AUTHOR INFORMATION
Corresponding Author
sigman@chem.utah.edu
’ ACKNOWLEDGMENT
This work was supported by the National Institutes of Health
(NIGMS RO1 GM3540). We are grateful to Johnson Matthey
for the gift of various Pd salts. We also thank Susanne Podhajsky
for performing key preliminary experiments.
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