Metal-free, regio- and stereoselective synthesis of linear (E)-allylic compounds using C, N, O, and S nucleophiles

Article abstract of DOI:10.1021/acs.orglett.5b00862

A variety of allylic acetates and derivatives were synthesized by an efficient two-step protocol that employs readily available terminal alkenes as starting materials. This method is highly regio- and stereoselective, affording the linear (E)- isomer as the sole adduct. This process tolerates several functional groups including halogen-containing molecules, and it is general for weak oxygen, carbon, nitrogen, and sulfur nucleophiles. Furthermore, adducts were obtained in good to excellent yields.

Full text of DOI:10.1021/acs.orglett.5b00862

Letter
pubs.acs.org/OrgLett
Metal-Free, Regio- and Stereoselective Synthesis of Linear (E)‑Allylic
Compounds Using C, N, O, and S Nucleophiles
Xiaojun Huang, Brandon Fulton, Kana White, and Alejandro Bugarin*
Department of Chemistry and Biochemistry, University of Texas at Arlington, Arlington, Texas 76019, United States
S
* Supporting Information
ABSTRACT: A variety of allylic acetates and derivatives were
synthesized by an efficient two-step protocol that employs readily
available terminal alkenes as starting materials. This method is highly
regio- and stereoselective, affording the linear (E)- isomer as the sole
adduct. This process tolerates several functional groups including
halogen-containing molecules, and it is general for weak oxygen,
carbon, nitrogen, and sulfur nucleophiles. Furthermore, adducts were
obtained in good to excellent yields.
a
Table 1. Optimization of Reaction Conditions
llylic acetates and related functional groups are abundant
Ain natural products as well as organic materials. Moreover,
b
entry
AcOR (mol %)
base (2 equiv)
solvent
yield (%)
c
1
Pd(OAc)2 (50)
Pd(OAc)2 (50)
AcOH (110)
AcOH (110)
AcOH (110)
AcOH (110)
AcOH (110)
AcOH (110)
AcOH (110)
AcOH (110)
AcOH (110)
AcOH (110)
AcOH (110)
AcOH (110)
AcOH (110)
AcOH (110)
AcOH (0)
none
DMSO
DMSO
DMSO
DMSO
DMA
24
83
0
c
Figure 1. General approach toward linear (E) allylic compounds.
2
K2CO3
none
3
4
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
DBU
84
60
50
<5
<5
85
85
71
<5
46
53
32
57
they represent versatile building blocks that are used in diverse
carbon−carbon and carbon−heteroatom bond-forming reac-
tions.1 As such, the development of methods for rapid and
efficient synthesis of allylic compounds remains an active area
of research.2 For example, advances in the synthesis of allylic
acetates from monosubstituted olefins has been achieved via
C−H oxidation.3 These methods rely on palladium catalysts in
combination with a stoichiometric oxidant or molecular oxygen
under high pressure. Nevertheless, these processes afford highly
regio- and stereoselective allylic acetates directly from terminal
alkenes. In 2004, White and co-workers documented that the
combination of Pd(OAc)2, benzoquinone (BQ), and DMSO or
a bis(sulfoxide) ligand promoted the regio- and stereoselective
allylic acetoxylation of terminal alkenes.3b Kaneda et al.
reported a regioselective method for the synthesis of linear
allylic acetates using PdCl2 and molecular oxygen as the sole
oxidant; in this case, high pressures of O2 (6 atm) were
required.3e,4 Incorporation of bipyrimidines as ligands were also
found to improve the allylic acetoxylation of olefins,5 as well as
the employment of additives such as bases for the Pd-catalyzed
oxidation of terminal alkenes.3a More recently, Stahl and co-
workers have developed an elegant method that enables the use
of O2 (1 atm) as the terminal oxidant.3d Although these
methods present advantages such as broad substrate scope and
readily available starting materials, they often generate mixtures
of (E/Z) and linear/branched allylic acetates. Correspondingly,
White and co-workers recently reported the extension of their
allylic acetoxylation protocol (oxygen nucleophiles),6 using
d
5
d
6
DMF
d
7
toluene
THF
d
8
9
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
10
11
12
13
14
15
16
17
Na2CO3
DMAP
Et3N
i-Pr2EtN
KOtBu
KOH
e
DBU
0
a
Reactions were carried out with 2a (0.2 mmol, 55.6 mg, 1 equiv),
base (2 equiv), and AcOH (110 mol %) at 22 °C in 1.0 mL of solvent
for 4 h. Isolated yields (average of 2−3 runs) by silica gel flash
chromatography. 50 mol % of Pd(OAc)2 was employed. The starting
b
c
d
e
material was recovered. For details, see the Supporting Information.
similar reaction conditions, to carbon nucleophile (alkylation)7
and nitrogen nucleophile (amination)8 reactions. In these
studies, highly stereo- and regioselective syntheses were
observed, albeit in moderate yields. Despite progress, all of
these methods rely on palladium, an expensive and precious
Received: March 23, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00862
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Organic Letters
Letter
Table 2. Substrate Scope of the Two-Step Protocol
a
b
Reactions were carried out with alkene 1 (4 mmol, 530 mg, 1 equiv) and bromine (1.05 equiv) at 0 °C in 15.0 mL of CHCl3 for 10 min. Isolated
c
yields (average of 2−3 runs) by silica gel flash chromatography. Reactions were carried out with dibromide 2 (0.2 mmol, 1 equiv) and AcOH (1.1
equiv) at rt in 1.0 mL of DMSO for 4 h. 2 equiv of bromine was used. One-pot procedure; 2m not isolated.
d
e
metal. As such, we sought to develop a complementary mild,
metal-free approach toward allylic compounds. Herein, we
report an efficient, two-step protocol that commences from
readily available terminal olefins and is highly regio- and
stereoselective. Moreover, the method is compatible with a
wide-range of nucleophiles, including carbon, nitrogen, oxygen,
and sulfur nucleophiles (Figure 1).
stereoselectivity compared to DMA, DMF, toluene, and THF
(entries 4−8); other nonpolar or protic solvents were not
effective. The bases KOH, KO-t-Bu, Et3N, i-Pr2EtN, and
DMAP promoted the reaction, but the yields were low
compared to K2CO3. High yields were observed when
Na2CO3, K2CO3, and Cs2CO3 were employed, with Cs2CO3
affording the highest yield (85%, entry 9). DBU also proved to
be highly effective and was comparable to the use of Cs2CO3
(85%, entry 10). We decided to employ DBU11 for further
investigations.
Having optimized conditions for the conversion of
dibromide 2a to allylic acetate 3a, we next investigated the
scope of the two-step protocol. A variety of terminal olefins
(1a−m) were initially treated with bromine at 0 °C to room
temperature in chloroform.10,12 As expected, the dibromide
adducts 2a−m were obtained in good to excellent yields (Table
2, left). Importantly, the dibromination process was general and
tolerated electron-rich, electron-poor, sterically hindered, and
heteroaryl substrates. However, it is important to note that
upon addition of 2.0 equiv of bromine, 4-allyl-1,2-dimethox-
ybenzene (1i) and 2-allylthiophene (1k) also underwent a
selective aromatic bromination reaction to afford the
tribrominated adducts 2i and 2k in 90% and 88% yield,
respectively (Table 2, entries 9 and 11). In addition to
monosubstituted olefins, we prepared the disubstituted
dibromide 2m from α-methylstyrene (1m) (Table 2, entry
13). However, this adduct was used in the subsequent step
without purification.
Our optimization of reaction conditions commenced from an
observation made while investigating the Pd(OAc)2-mediated
aerobic oxidation9 of (2,3-dibromopropyl)benzene (2a) to (Z)-
2-bromo-3-phenylacrylaldehyde. We observed that in the
presence of 50 mol % of Pd(OAc)2 the formation of the linear
(E)-allylic acetate (3a) resulted, albeit in a modest 24% yield
(Table 1, entry 1). Of note, the addition of K2CO3 significantly
increased the yield of 3a to 83% (entry 2). We speculated that
palladium was unnecessary and that acetic acid could serve as
the nucleophilic source. To explore the potential of acetic acid
as nucleophile in promoting the substitution reaction, we
examined different reaction conditions in the presence of 2.0
equiv of a base and focused on the conversion of 2a to 3a. The
essential bromination of terminal olefins10 proceeded in
straightforward manner, and dibromide 2a was obtained in
high yield. In DMSO, no reaction was observed in the absence
of K2CO3 (Table 1, entry 3). However, addition of K2CO3 (2
equiv) afforded the allylic acetate in 84% yield (entry 4). Other
quantities of K2CO3 provided no improvement (not shown).
DMSO proved to be the best solvent, delivering the product in
excellent yield while maintaining a high level of regio- and
B
DOI: 10.1021/acs.orglett.5b00862
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Organic Letters
Letter
a
Table 3. Scope of Nucleophiles
Scheme 1. Synthetic Utility of Allylic Adducts
derivative afforded a lower yield (58%), likely due to steric
effects and deacetylation of phenol (entry 8). Additionally, this
AcOH/DBU mixture afforded excellent yields for aromatic and
heteroaromatic halogenated molecules (entries 9−12). Of note,
functional groups such as bromobenzene derivatives, which
could prove problematic with palladium-catalyzed processes,13
are well tolerated. A notable example from Table 2 includes the
reaction of (1,2-dibromopropan-2-yl)benzene (2m), which
gave 43% yield. The lower yield obtained in this case is the
result of incomplete reaction due to the nature of the starting
material (lack of benzylic protons); extended reaction times will
likely provide increased yields. Overall, we believe that the data
in Table 2 provide strong certification for the general scope
inherent in our approach.
Encouraged by these results and because (E)-allylic acetates
and their corresponding derivatives are valuable synthetic
intermediates, we next explored the generality and synthetic
utility of the DBU-mediated regio- and stereoselective trans-
formation toward different nucleophiles (Table 3). We were
pleased to discover that our approach is viable for use with
nucleophiles other than AcOH. For example, good results were
obtained with a variety of other oxygen-containing nucleo-
philes, such as aliphatic- and aromatic-derived acids. Tetrade-
canoic acid gave the adduct 4a in 76% yield (entry 2). Electron-
rich and electron-poor benzoic acids were also good substrates
for this transformation with yields up to 79% (Table 3, entries
3−5). In addition, trans-cinnamic acid afforded the allylic ester
in 55% yield after 4 h. Carbon-based nucleophiles such as
dimethyl malonate and diethyl malonate were also tolerated
and afforded the desired products in 93% and 82% yield,
respectively (entries 7 and 8). However, other carbon
nucleophiles exhibited diminished reactivity, presumably due
to their pKa, and were less efficient (entries 9 and 10). To our
gratification, nitrogen nucleophiles such as phthalamide and 3-
acetylindole afforded the allylic amination adduct in 48% yield
and 51% yield, respectively (entries 11 and 12) and 3-
acetylindole in 36% yield (entry 13). Likewise, sulfur-based
nucleophiles such as thiobenzoic acid with 71% yield and
thioacetic acid with 62% yield were also compatible (entries 14
and 15).
a
Reactions were carried out with 2a (0.2 mmol, 55.6 mg, 1 equiv),
DBU (2 equiv), and NuH (1.1 equiv) at 22 °C in 1.0 mL of DMSO
b
for 4 h. Isolated yields (average of 2−3 runs) by silica gel flash
chromatography. Excess of 2a did not increase the yield.
c
With the dibrominated adducts in hand, we investigated the
scope of this two-step protocol by examining the reactivity of
the previous freshly prepared dibromides 2a−m in the presence
of AcOH and DBU at room temperature (Table 2, right). Most
reactions were quenched after 4 h for comparison purposes,
although starting material still remained. In all cases, the
reaction proceeded smoothly in the presence of DBU and the
weak nucleophile (AcOH) to afford the corresponding allyl
acetates adducts, in good to high yields, at room temperature.
For para-substituted benzene dibromides, the system is very
efficient (entry 1). The reaction of para-halogenated benzene
dibromides delivered the products in 72% yield (Br), 75% yield
(Cl), and 76% yield (F) (entries 2−4). The adduct of electron-
poor p-(trifluoromethyl)benzene dibromide is obtained in 94%
yield and p-Ph in 96% (entries 5 and 6). The naphthalene
derivative afforded an 88% yield. The ortho-substituted
C
DOI: 10.1021/acs.orglett.5b00862
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Organic Letters
Letter
In order to elucidate the mechanistic details of this system, a
comprehensive set of experiments was performed.14 Based on
the data acquired, we propose that an E2 elimination, facilitated
by DBU, followed by nucleophilic displacement in an SN2
fashion is occurring. Also, it is likely that the E2 elimination is
the rate-determining step. In this regard, we prepared and
treated (E)-(3-bromoprop-1-en-1-yl)benzene under the stand-
ard reaction conditions, which afforded allylic acetate (3a) in
quantitative yield after 15 min, supporting the high reaction
rate for SN2 reaction. Additional details for the high regio- and
stereoselectivity observed are described in the Supporting
Information.14
To demonstrate the synthetic utility and practicality of this
method, the reaction was performed on gram scale using a one-
pot procedure. Importantly, this streamlined procedure does
not compromise the efficiency of the transformation, as the
product was isolated in 81% yield (Scheme 1, eq 1) Although a
number of synthetic transformations could be envisioned for
the allylic adducts, we focused on a couple of functional group
manipulation that highlight the utility of using DBU mediated
allylation reactions. The allylic adducts derived from carbon
nucleophiles are useful for elaboration of new molecular
entities. To highlight this, we prepared the unnatural α-amino
acid precursor 5 from allylbenzene (1) in three simple steps (eq
2). Likewise, we prepared the core of wutaienin15 by reduction
of 4i, which could be prepared in two steps, in 91% yield with
3:2 dr (Scheme 1, eq 3).
In conclusion, we have documented a new entry to linear (E)
allylic compounds obtained directly from terminal alkenes. The
method complements existing approaches based on palladium
allylic C−H activation. Furthermore, evaluation of the reaction
considerations indicates that the reaction conditions using DBU
and NuH in DMSO are optimal for carbon, oxygen, nitrogen,
and sulfur nucleophiles. Across the board, this reaction protocol
results in linear (E) allylic products. Thus, this methodology
not only broadens the application of traditional Tsuji−Trost
adducts, but also provides direct disconnections for rapidly
building organic frameworks, an important consideration in
many synthetic studies.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, full characterization data, and NMR
spectra. The Supporting Information is available free of charge
on the ACS Publications website at DOI: 10.1021/
acs.orglett.5b00862.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: bugarin@uta.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the University of Texas at Arlington for
financial support of this work. We also acknowledge Profs.
Javier Read de Alaniz (UCSB) and Richard B. Timmons
(UTA) for helpful discussions, the Shimadzu Center for MS
data collection, and the NSF (Grant Nos. CHE-0234811 and
CHE-0840509) for additional instrumentation.
D
DOI: 10.1021/acs.orglett.5b00862
Org. Lett. XXXX, XXX, XXX−XXX