Alkenyl Carbonyl Derivatives in Enantioselective Redox Relay Heck Reactions: Accessing α,β-Unsaturated Systems

Article abstract of DOI:10.1021/jacs.5b04289

A highly enantioselective and site-selective Pd-catalyzed arylation of alkenes linked to carbonyl derivatives to yield α,β-unsaturated systems is reported. The high site selectivity is attributed to both a solvent effect and the polarized nature of the carbonyl group, both of which have been analyzed through multidimensional analysis tools. The reaction can be performed in an iterative fashion allowing for a diastereoselective installation of two aryl groups along an alkyl chain.

Full text of DOI:10.1021/jacs.5b04289

Communication
pubs.acs.org/JACS
Alkenyl Carbonyl Derivatives in Enantioselective Redox Relay Heck
Reactions: Accessing α,β-Unsaturated Systems
Chun Zhang, Celine B. Santiago, Lei Kou, and Matthew S. Sigman*
Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, Utah 84112, United States
*
S Supporting Information
metallic at the carbon distal to the alcohol is still under
investigation, the vast majority of the studies point to a remote
electronic effect that is modestly influenced by alkene
substituent size. The electronic effect is thought to arise from
reducing the dipole during the formation of the C−C bond
through the orientation of the alcohol and the arene (compare
TS A and B). Therefore, changing the substituent on the arene
and the distance between the alcohol and alkene influences site
selectivity.
ABSTRACT: A highly enantioselective and site-selective
Pd-catalyzed arylation of alkenes linked to carbonyl
derivatives to yield α,β-unsaturated systems is reported.
The high site selectivity is attributed to both a solvent
effect and the polarized nature of the carbonyl group, both
of which have been analyzed through multidimensional
analysis tools. The reaction can be performed in an
iterative fashion allowing for a diastereoselective installa-
tion of two aryl groups along an alkyl chain.
This hypothesis provides the impetus for further exploration
of the substrate scope in terms of replacing the alcohol with an
alternative functional group. We were attracted to carbonyls
due to three factors. First, the products of the enantioselective
relay Heck reaction are remotely functionalized α,β-unsaturated
carbonyls, which are envisioned to be useful for further
elaboration and would be difficult to access using conventional
strategies (Figure 1b). Second, the diversity of carbonyls would
presumably allow for a wider range of observed site selectivity
as a function of such groups, providing the basis for additional
eveloping methods for site selective migratory insertion
D
into relatively unbiased multisubstituted alkenes would be
1
an enabling approach to synthesis. Of specific interest is
precisely functionalizing internal alkenes with enantiocontrol
2
−6
and site control for remotely installing groups in molecules.
However, this prospect is difficult to achieve, as alkenes of this
sort are distantly located from a discriminating functional
group, which removes obvious innate factors for governing site
8
mechanistic understanding and enhancing selectivity. Finally,
1
selectivity. In this regard, our discovery that alkenes positioned
reduction of the resultant α,β-unsaturated carbonyl provides an
at various distances from an alcohol undergo site selective
allylic alcohol, which would be suitable for an iterative relay
7
7a
addition of an aryl-Pd intermediate is unique (Figure 1a). The
Heck reaction (Figure 1b). However, we also envisioned
origin of this site selectivity has been investigated through
empirical exploration of the scope in combination with
many potential issues including further reaction of the α,β-
unsaturated carbonyl products under the reaction conditions,
isomerization of the alkenes into conjugation since Pd-hydrides
are formed in these reactions, and the potential deleterious
effect of these new functional groups on enantioselectivity and
yield. Herein, we present the successful development of an
enantioselective relay Heck reaction of alkenes linked to
carbonyl derivatives, which allows access to an array of α,β-
unsaturated carbonyl products with remotely installed aryl
groups. Of particular interest, these arylations have enhanced
site selectivity compared to the previous variants using alkenols
and provide an opportunity for further interrogation of site
selective migratory insertion of unbiased alkenes.
8
8c
8d
computational, labeling, and correlative studies. While the
detailed origin of selectivity for the addition of the organo-
7
Based on our previous reports, our study commenced with
the reaction of phenylboronic acid (1a) and (Z)-dec-4-enal
(
2a) catalyzed by Pd ligated with PyrOx under oxidative Heck-
type conditions (Table 1, entry 1). To our delight, the reaction
performed well yielding the product in 73% and a 98:2 er
without the need for a copper cocatalyst, thus allowing a
reduction in the overall ligand loading. Under these conditions,
the site selectivity was modest favoring the δ product in a 5.8:1
ratio. No reaction of the α,β-unsaturated aldehyde product is
Figure 1. (a) Previously reported enantioselective relay Heck reactions
of alkenols including mechanistic analysis. (b) Proposed new
enantioselective relay Heck reaction of alkenes linked to carbonyl
derivatives and resultant iterative Heck reaction.
Received: April 24, 2015
©
XXXX American Chemical Society
A
DOI: 10.1021/jacs.5b04289
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Table 1. Optimization of the Enantioselective Relay Heck
Reaction of 2a
Sterimol B value of the substituent R to the measured site
1
a
11
selectivity. This relationship was validated using Leave-One-
2
Out analysis with a Q = 0.96. As illustrated by the coefficients
in the regression model, decreasing the I
and increasing the
CO
Sterimol B of the R group of the solvent result in higher site
1
selectivity. This suggests that the polarization model for site
selectivity described in the introduction is impacted by both the
dipole and orientation of the solvent. It should be noted that
improved site selectivity does not necessary lead to higher
yields and DMA was found to balance both of these
requirements.
Using DMA as solvent under the optimal conditions, the
scope of aryl substituted boronic acid (1) was probed in the
formation of various δ-aryl substituted α,β-unsaturated
aldehydes (Table 2). In general, modest to good yields using
either electron-rich or -deficient aryl substituted boronic acids is
observed as a single geometrical alkene isomer. In all cases, the
enantiomeric ratios are excellent. Previously, we found a
significant reduction in site selectivity when electron-rich aryl
boronic acids were employed. In fact, the best site selectivity
previously observed for the formation of a δ-aryl product was
yield of 3a
er
b
c
d
entry
Pd source
solvent
DMF
(%)
(3a)
δ:γ
1
2
3
4
5
6
7
8
Pd(MeCN) (OTs)
73
98:2
−
−
5.8
−
2
2
none
DMF
−
e
f
Pd(MeCN) (OTs)
DMF
trace
trace
65
−
−
2
2
2
2
2
2
2
Pd(MeCN) (OTs)
DMF
−
2
g
Pd(MeCN) (OTs)
DMF
98:2
99:1
98:2
98:2
5.2
15
7.8
9.3
2
Pd(MeCN) (OTs)
DMA
78
2
Pd(MeCN) (OTs)
1,4-dioxane
THF
73
2
Pd(MeCN) (OTs)
38
2
a
Conditions: 1a (0.75 mmol, 3.0 equiv), 2a (0.25 mmol, 1.0 equiv),
Pd] (0.01875 mmol, 7.5 mol %), ligand (0.0225 mmol, 9 mol %),
[
b
solvent (3 mL), O (1 atm), rt, 24 h. Reported yields are of isolated
2
c
3
a as a >20:1 ratio of the E-alkene isomer. Determined by SFC
d e
equipped with a chiral stationary phase. Determined by NMR. ln the
f
g
absence of 3 Å MS. ln the absence of ligand. Using air (1 atm). DMF
a
Table 2. Aryl Boronic Acid Scope
=
N,N-dimethylformamide; DMA = N,N-dimethylacetamide; THF =
tetrahydrofuran.
observed suggesting that the catalyst prefers reaction with
9
electron-rich alkenes. Control experiments confirmed the
requirement of Pd (Table 1, entry 2), molecular sieves (entry
3
), and PyrOx (entry 4). Slightly reduced yields are observed
using air instead of pure O as the terminal oxidant albeit in
2
excellent enantioselectivity (entry 5). As a significant goal of
this project was to increase site selectivity, we further explored
the choice of solvent. Interestingly, when DMA was used as
solvent, the site selectivity significantly increased favoring the δ
product in a 15:1 ratio with modestly enhanced yield and er
(
entry 6). Other solvents were also competent but did not
improve the results further (entries 7−8).
This observed improvement in site selectivity is notable and
inspired us to investigate the potential origin of the solvent
effect. Therefore, an array of various substituted amide
solvents were evaluated in the reaction (Figure 2). To correlate
these results, we performed multidimensional analysis relating
1
0
‡
the measured ΔΔG for site selectivity to various parameters
describing the different amide solvents (see Supporting
Information for details). An excellent correlation was achieved
relating the IR intensity of the carbonyl stretch (I
) and
CO
a
Standard reaction conditions: 1 (0.75 mmol, 3.0 equiv), 2a (0.25
mmol, 1.0 equiv), Pd(MeCN) (OTs)2 (0.019 mmol, 7.5 mol%),
2
ligand (0.023 mmol, 9 mol %), DMA (3 mL), 3 Å Ms (50 mg), O (1
2
atm), rt, 24 h. Yields are of isolated 3, >20:1 E-alkene product.
Enantioselectivity determined by SFC equipped with a chiral
b
Figure 2. Multidimensional correlation of solvent parameters with site
stationary phase. Cu(OTf) (0.013 mmol, 5 mol %), ligand (0.035
2
selectivity.
mmol, 14 mol%) were used.
B
DOI: 10.1021/jacs.5b04289
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
:1 with an electron-poor boronic acid. In this system, the site
selectivity is >9:1 favoring the δ-product for both electron-rich
and -poor partners with electron-poor coupling partners
providing even higher levels of control (often >30:1). Of
Communication
7
point charges on a number of atoms and IR frequencies and
intensities of the functional groups. A good correlation was
found between the NBO charge of the carbonyl oxygen (Figure
14
3) and the measured site selectivity. The aldehyde substrate
note, some yields were improved by the addition of Cu(OTf)
2
1
2,13
(see Table 2).
The second stage of scope evaluation was focused on the
nature of the carbonyl linked to the alkene (Table 3). As
Table 3. Evaluation of Functional Group Tolerance of the
a
Alkene Substituent
Figure 3. Correlation of observed site selectivity to the NBO charge of
the carbonyl oxygen.
corresponding to product 3a with the least negative NBO
charge on the carbonyl oxygen resulted in the highest site
selectivity, while the ester substrate corresponding to product
3
t, which has the greatest negative NBO charge on the carbonyl
oxygen, resulted in the lowest site selectivity. Despite the
distance of the functional group from the alkene, the optimized
geometries of the substrates illustrate bending of the substrate
to allow alignment of the carbonyl with the alkene (see
Supporting Information). Additionally, the greatest NBO
charge difference between the alkene carbons (C =C ) was
δ
γ
observed for the substrate that provided the highest site
selectivity (2a), illustrating the remote effect of alkene
polarization on the migratory insertion step.
As this method provides direct access to highly enantiomeri-
cally enriched α,β-unsaturated aldehydes, we envisioned
exploiting these products in iterative relay Heck reactions.
This three-step approach would facilitate the 1,3 difunctional-
ization of a simple alkyl chain in a modular fashion. To test this
possibility, the carbonyl of product 3a was reduced to yield an
allylic alcohol (5), which upon treatment with an aryl
diazonium salt under conditions from our previously reported
a
Standard reaction conditions: 1a (0.75 mmol, 3.0 equiv), 2 (0.25
mmol, 1.0 equiv), Pd(MeCN) (OTs)2 (0.019 mmol, 7.5 mol%),
ligand (0.023 mmol, 9 mol%), DMA (3 mL), 3 Å Ms (50 mg), O (1
atm), rt, 24 h. Yields of isolated 3, >20:1 E-alkene product
Enantioselectivty determined by SFC equipped with a chiral stationary
2
2
b
phase. Yields are a combination of 3 and 4, >20:1 E-alkene product.
7a
relay Heck reaction forms product 6 in high diastereose-
discussed above, we believed that this would be an opportunity
to further probe the origin of site selectivity. In general, a wide
range of functional groups are compatible with the reaction
including a ketone (3p) and a carboxylic acid (3q). Various
esters are excellent substrates for the reaction (3r−t) including
the highly versatile and sensitive p-nitrophenol derived
substrate (3u). Both a nitrile (3v) and amide (3w) perform
well in the reaction although a 5:1 mixture of alkene
geometrical isomers is observed using the smaller nitrile.
Finally, a substrate containing an α,β-unsaturated aldehyde
yields the conjugated product 3x with a ζ-aryl substitution in
excellent enantioselectivity and site selectivity. Unfortunately,
site selectivity and yield diminish significantly as the chain
length is extended between the alkene and the aldehyde (3y−z)
lectivity (eq 1). Using the enantiomer of the ligand provides
7b
similar to our previous report.
access to the other diastereomer in good albeit modestly
reduced diastereoselectivity (eq 2), suggesting mainly catalyst
controlled addition.
In conclusion, we have reported a unique method to produce
α,β-unsaturated carbonyls containing an aryl group δ to the
carbonyl in high enantioselectivity. The scope of the reaction is
broad in both the aryl coupling partners and the carbonyl
On the basis of the range of selectivity observed as a function
of the substrate carbonyl, we explored how the carbonyl may be
impacting site selectivity. To accomplish this, the substrates
containing only the C H11 group with different carbonyls were
5
submitted for geometry minimizations and IR frequency
8
d
calculations. Various parameters were compiled including
C
DOI: 10.1021/jacs.5b04289
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
derivatives. Of particular interest is the evolving understanding
of substrate substituent effects on site selective migratory
insertion. The subtle influence of the remote carbonyl has been
studied through correlative tools providing further evidence
that polarization of the substrate during migratory insertion is
essential for effective site control. This important finding
should allow us to design more versatile catalysts and systems
to achieve greater site selection at even more remote sites.
Exploring this goal in the context of further expansion of the
enantioselective relay Heck reaction is underway.
(7) (a) Werner, E. W.; Mei, T.-S.; Burckle, A. J.; Sigman, M. S. Science
2
012, 338, 1455. (b) Mei, T.-S.; Werner, E. W.; Burckle, A. J.; Sigman,
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(
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ASSOCIATED CONTENT
Supporting Information
Experimental procedures, analytical data for products, NMR
spectra of products. The Supporting Information is available
free of charge on the ACS Publications website at DOI:
and solvent, see: (a) Reichardt, C. Angew. Chem., Int. Ed. Engl. 1979,
■
1
1
8, 98. (b) MacManus, D. A.; Vulfson, E. N. Enzyme Microb. Technol.
997, 20, 225.
*
S
(11) Verloop, A. In Drug Design; Academic Press: New York, 1976.
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(a) Campbell, A. N.; Stahl, S. S. Acc. Chem. Res. 2012, 45, 851. (b) Wu,
1
0.1021/jacs.5b04289.
W.; Jiang, H. Acc. Chem. Res. 2012, 45, 1736. (c) Shi, Z.; Zhang, C.;
Tang, C.; Jiao, N. Chem. Soc. Rev. 2012, 41, 3381. (d) Sigman, M. S.;
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AUTHOR INFORMATION
Corresponding Author
sigman@chem.utah.edu
■
*
Notes
(
13) For selected reviews on Cu-catalyzed aerobic oxidative
reactions, see: (a) Zhang, C.; Tang, C.; Jiao, N. Chem. Soc. Rev.
012, 41, 3464. (b) Wendlandt, A. E.; Suess, A. M.; Stahl, S. S. Angew.
The authors declare no competing financial interest.
2
ACKNOWLEDGMENTS
This research was supported by the National Institutes of
Health under Award Number RO1GM063540.
■
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DOI: 10.1021/jacs.5b04289
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX