Activation of alcohols with carbon dioxide: Intermolecular allylation of weakly acidic pronucleophiles

Article abstract of DOI:10.1021/ol502023d

The direct coupling of allyl alcohols with nitroalkanes, nitriles, and aldehydes using catalytic Pd(PPh₃)₄ has been accomplished via activation of C-OH bonds with CO₂. The in situ formation of carbonates from alcohols and CO₂ facilitates oxidative addition to Pd to form reactive π-allylpalladium intermediates. In addition, the formation of a strong base activates nucleophiles toward the reaction with the π-allylpalladium electrophile. Overall, this atom economical reaction provides a new C-C bond without the use of an external base and generates water as the only byproduct.

Full text of DOI:10.1021/ol502023d

Letter
pubs.acs.org/OrgLett
Open Access on 08/04/2015
Activation of Alcohols with Carbon Dioxide: Intermolecular Allylation
of Weakly Acidic Pronucleophiles
Simon B. Lang, Theresa M. Locascio, and Jon A. Tunge*
Department of Chemistry, The University of Kansas, 2010 Malott Hall, 1251 Wescoe Hall Drive, Lawrence, Kansas 66045, United
States
The KU Center For Environmentally Beneficial Catalysis, The University of Kansas, 1501 Wakarusa Drive, LSRL Building A, Suite
110, Lawrence, Kansas 66047, United States
S
* Supporting Information
ABSTRACT: The direct coupling of allyl alcohols with nitro-
alkanes, nitriles, and aldehydes using catalytic Pd(PPh3)4 has
been accomplished via activation of C−OH bonds with CO2. The
in situ formation of carbonates from alcohols and CO2 facilitates
oxidative addition to Pd to form reactive π-allylpalladium intermediates. In addition, the formation of a strong base activates
nucleophiles toward the reaction with the π-allylpalladium electrophile. Overall, this atom economical reaction provides a new
C−C bond without the use of an external base and generates water as the only byproduct.
llylic alcohols are intriguing surrogates to traditional
activated electrophiles used in transition-metal-catalyzed
allylation of weakly acidic nucleophiles such as nitroalkanes,
nitriles, and aldehydes.
Based on Yamamoto’s findings we imagined that nucleophilic
attack of the allyl alcohol on CO2 would form an allyl carbonate
that is activated toward oxidative addition (Scheme 2).
A
allylation reactions due to their wide availability, facile
synthesis, and low toxicity. The condensation of an alcohol
with a C−H bond to eliminate water and form a new C−C
bond is topologically obvious in addition to being step and
atom economical.1 However, alcohols often possess low
reactivity because the C−O bond is strong and hydroxide is a
poor leaving group.2 This challenge has resulted in the
development of methods utilizing Lewis3,4 or Brønsted acids5
to activate allylic alcohols toward coupling with a variety of
substrates. We sought to find a straightforward method using
relatively benign reagents to activate allyl alcohols directly
toward the allylation of weakly acidic pronucleophiles.6 Herein
we report an in situ activation of allylic alcohols with CO2 that
simultaneously generates active electrophiles and a requisite
base to activate pronucleophiles (Scheme 1).
Scheme 2. Proposed CO2-Catalyzed C−O Bond Activation
Scheme 1. CO2-Catalyzed Allylation
Decarboxylation of the resulting bicarbonate to generate CO2
and hydroxide might allow deprotonation of even weakly acidic
C−H bonds to activate pronucleophiles.10 Subsequent
nucleophilic attack on the palladium π-allyl complex is expected
to form a new C−C bond and regenerate the active catalyst
while producing water as the only byproduct.
An initial screen of reaction conditions revealed that the use
of a polar aprotic solvent, Pd(PPh3)4, and 1 atm of CO2 heated
in a sealed vial overnight afforded 1a in good yield (eq 1).
Since it is known that alcohols react reversibly with carbon
dioxide to form carbonic acids and carbonates in situ,7 CO2
should activate alcohols toward transition-metal-catalyzed
allylic alkylation reactions. Importantly, Yamamoto has
demonstrated that CO2 can activate allyl alcohols toward
substitution; however, the C−C bond formation was limited to
highly stabilized malonate-like enolates (pKa ∼11−14 in
DMSO).8,9 Using these initial results as inspiration, we sought
to develop a synthetically useful method for the intermolecular
Received: July 10, 2014
© XXXX American Chemical Society
A
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Organic Letters
Letter
When the CO2 was replaced with argon no appreciable amount
of 1a was detected by H NMR spectroscopy of the crude
β-ethers (1e,f). Allylation also occurred in high yield directly
from β-methallyl alcohol (1j).
1
Unfortunately, allyl alcohols such as prenyl and crotyl alcohol
which bear alkyl substituents were not compatible with the
standard reaction conditions.
reaction mixture.
Lastly, the allylation could be performed in just 20 min under
microwave irradiation, although additional equivalents of
alcohol were required (1k). Again, replacing CO2 with Ar
under microwave conditions did not produce significant
quantities of the desired product.
While it was exciting that nitroalkanes could be allylated in
high yield under conditions of CO2 activation, nitroalkanes are
relatively acidic (pKa ∼17 in DMSO).14 To probe the strength
of the base generated in situ under our reaction conditions, we
turned our attention toward the allylation of tertiary nitriles
(pKa ∼23−25 in DMSO).15
To begin, the reaction scope was explored utilizing
commercially available nitriles as well as those synthesized via
methylation, benzylation, or Knoevenagel condensation
(Scheme 4). As with the nitroalkanes, CO2 activation allowed
To investigate the substrate scope, the aforementioned
reaction conditions were applied to the reactions of other
nitroalkanes (Scheme 3). Under these conditions, a variety of
substrates that were readily derived from Diels−Alder,11
Baylis−Hillman,12 and Henry13 reactions were allylated in
good to excellent yields.
a
,b
Scheme 3. Allylation of Nitroalkanes via CO2 Activation
Scheme 4. Allylation of Nitriles with Allyl Alcohol Activated
a
,b
by CO2
a
Nitrile (0.3 mmol) and allyl alcohol (0.6 mmol) in 0.5 mL of DMSO
b
c
d
under 1 atm of CO2. Isolated yields. 2 mL of DMSO used. Ar
replaced CO2 (% conversion via GC/MS). Reaction at 80 °C.
e
the allylation of a variety of nitriles in high yield. The method
was found to tolerate halogens (2b,c), aryl ether (2d), ketone
(2f), and indole substituents (2h). However, allylation of a
sterically congested ortho-disubstitued nitrile was unsuccessful
under the given reaction conditions (2g). Further, a more
acidic diarylalkyl nitrile substrate was successfully allylated at a
lower reaction temperature (80 °C) and resulted in a higher
isolated yield (2i). Lastly, when argon replaced the CO2
atmosphere, a significant decrease in yield was observed
(0%−28%, entries 2b−2f and 2i) thus supporting the
requirement of CO2 as an in situ activator of allyl alcohol for
nucleophilic allylation.
a
Nitroalkane (0.3 mmol) and allyl alcohol (0.45 mmol) in 1.75 mL of
b
c
DMSO under 1 atm of CO2. Isolated yields. Ar replaced CO2 (%
conversion via crude 1H NMR). d Allyl alcohol (0.9 mmol), 160 °C, 20
min in a microwave reactor.
Both cyclic and acyclic nitroalkanes were activated by the
standard reaction conditions. A variety of functional groups
including olefins (1a,c,h), an α,β-unsaturated ester (1l), ethers
(1e,f), and indole (1d) were compatible with the reaction
conditions. Good to excellent diastereoselectivities were
observed with cyclic nitroalkanes (1a,c,h,j). In addition, 1,2-
stereocontrol was good even with acyclic nitroalkanes bearing
Aldehydes, which are prone to aldol dimerization, were also
allylated in high yield utilizing similar conditions (Scheme 5).16
B
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Letter
a
a b
,
,b
Scheme 5. Allylation of Aldehydes
Table 1. Scope of Allyl Alcohols
a
Aldehyde (0.30 mmol) and alcohol (0.45 mmol) in 2.0 mL of DMSO
b
c
under 1 atm of CO2. Isolated yields. Ar replaced CO2 (%
conversion via GC/MS).
Acyclic (3a−3g) and cyclic (3h, 3i) α-aryl aldehydes bearing
various electron-donating (p-Me, p-OMe) and -withdrawing (o-
F, p-OCHF3) groups reacted quickly (1−2 h) and gave high
yields of allylated products. Substrates with α-benzyl sub-
stituents (3k, 3l), including a protected amino aldehyde (3j),
required longer reaction times but still provided good yields of
product. Control reactions again revealed that a CO2
atmosphere was required for good reactivity.
Next, the scope of the reaction of nitriles and aldehydes with
substituted allylic alcohols was examined. Gratifyingly, except
for the prenyl alcohol (4i), isolated reaction yields with
substituted allylic alcohols were found to be comparable to
those utilizing the unsubstituted allyl alcohol (Table 1). Both
alkyl and aryl substituted allylic alcohols provided the allylated
products in good to excellent yields with generally good
selectivity for formation of the linear allyl regioisomer.17 One
exception is crotyl alcohol, which showed only slight selectivity
for the linear trans product (4c);18 this selectivity was
significantly enhanced upon increasing the substituent size to
ethyl or propyl (4d, 4e). The linear selectivity of the CO2-
activated intermolecular variant is thought to arise from an
outer-sphere C-allylation mechanism, and the observed increase
in trans selectivity with substituent size may be attributed to a
higher bias for the syn-palladium π-allyl intermediate.19
a
Nitrile (0.3 mmol) and allylic alcohol (0.6 mmol) in 2 mL of DMSO
b
c
under 1 atm of CO2. Reaction at 90 °C in 0.5 mL of DMSO. 1:2.5
d
e
f
(cis/trans). 1:14.3 (cis/trans). 1:4.6 (cis/trans). Reaction time 4 h.
g
h
Reaction time 19 h. 1:5.3 (cis/trans). Reaction time 8 h; a 23%
i
conversion in the control reaction was observed. Reaction time 7 h.
In conclusion, we have shown that CO2 can activate allyl
alcohols toward oxidative addition of palladium. In addition to
activating the alcohol, the conditions provide a base strong
enough to activate weakly acidic pronucleophiles with a pKa up
to ∼25. Thus, CO2 participates in both the activation of the
electrophile and the nucleophile toward C−C bond formation.
C
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Letter
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, 1H, 13C, 19F NMR spectra, and
characterization data of all novel products. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: tunge@ku.edu.
(14) Matthews, W. S.; Bares, J. E.; Bartmess, J. E.; Bordwell, F. G.;
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PhCH(Me)CN (23.0), and p-MeOC6H4CH2CN (23.8). (a) Bordwell,
F. G.; Cheng, J. P.; Bausch, M. J.; Bares, J. E. J. Phys. Org. Chem. 1988,
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Science Foundation (CHE-1058855),
the KU Center for Environmentally Beneficial Catalysis, and
the Kansas Bioscience Authority Rising star program for
financial support. We thank Dr. Victor Day molecular
structures group, University of Kansas for X-ray crystallographic
analysis using a diffractometer purchased with NSF-MRI Grant
CHE-0923449. Support for the NMR instrumentation was
provided by NSF Academic Research Infrastructure Grant No.
9512331, NIH Shared Instrumentation Grant No.
S10RR024664, and NSF Major Research Instrumentation
Grant No. 0320648.
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