Arylation of aldehyde homoenolates with aryl bromides

Article abstract of DOI:10.1021/ol4008876

A mild palladium catalyzed coupling of reactive aldehyde homoenolates with aryl bromides is described. Aldehyde homoenolates are generated by ring opening of cyclopropanols via a C-C cleavage step. The coupling generates aldehyde products at room temperature in 59-93% yield.

Full text of DOI:10.1021/ol4008876

ORGANIC
LETTERS
2013
Vol. 15, No. 9
2298–2301
Arylation of Aldehyde Homoenolates
with Aryl Bromides
Kevin Cheng and Patrick J. Walsh*
Roy and Diana Vagelos Laboratories, Penn/Merck Laboratory for High-Throughput
Experimentation, Department of Chemistry, University of Pennsylvania,
231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States
pwalsh@sas.upenn.edu
Received April 1, 2013
ABSTRACT
A mild palladium catalyzed coupling of reactive aldehyde homoenolates with aryl bromides is described. Aldehyde homoenolates are generated
by ring opening of cyclopropanols via a CÀC cleavage step. The coupling generates aldehyde products at room temperature in 59À93% yield.
The R-arylationofcarbonylcompoundswitharyl halides
has become a powerful synthetic method since its intro-
duction by Buchwald,1À5 Hartwig,6À10 and Miura.11À13 An
analogous method for β-arylation would likewise be
useful but has lagged because it is more difficult to access
metalated homoenolate intermediates.14À21 Although homo-
enolates of ketones and esters22À28 have been arylated, only
one aldehyde homoenolate has succumbed to arylation
(Scheme 1). In pioneering work, Nakamura, Kuwajima,
and co-workers22 demonstrated that a silylated cyclopro-
panol generated an aldehyde homoenolate with catalytic
palladium and underwent coupling with two aryl triflates
(58À65% yield).
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Although the scope of this transformation has not been
expanded beyond Scheme 1, some limitations are evident.
The reaction was successful only with aryl triflates and
the polar solvent HMPA. The requirement of triflates
and polar solvent were rationalized to favor the formation
of a cationic palladium intermediate necessary to promote
siloxy cyclopropane ring opening. Given the well-known
utility of aldehydes in synthesis, we set out to develop a
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r
10.1021/ol4008876
Published on Web 04/24/2013
2013 American Chemical Society

practical method for the β-arylation of aldehyde homo-
enolates with aryl bromides.
Triphenylphosphine, which gave moderate yields with the
aryl triflates employed by Nakamura, Kuwajima, and
co-workers,22 resulted in a low yield (entry 1). Buchwald’s
monodentate phosphines JohnPhos, DavePhos, and
t-BuXPhos also gave very low yields under our conditions
(entries 2À4). In contrast, Hartwig’s QPhos resulted in
near-quantitative formation of the aldehyde homoenolate
coupling product (entry 5). The ferrocene-based bis-
(phosphine) ligands performedpoorlyunderthese reaction
conditions (entries 6À7). The reaction with QPhos and
Pd(OAc)2 led to an isolated yield of 86% on laboratory
scale.
Scheme 1. β-Arylation of Aldehyde Homoenolate Generated
from Silylated Cyclopropanol
We recently reported a straightforward synthesis of trans-
cyclopropanols from R-chloro aldehydes and CH2(ZnI)2
(Scheme 2).29,30 The high trans selectivity is the result of
equilibration of the diastereomeric cyclopropoxy intermedi-
ates. Inspired by observations by Cha and co-workers,31,32
who demonstrated that tertiary cyclopropanols underwent
palladium mediated ring opening to form R,β-unsaturated
ketones more rapidly than their silylated analogues, we
applied our cyclopropanols to the generation and arylation
of aldehyde homoenolates.
Table 1. Identification of Ligands for the AldehydeHomoenolate
Arylation with Bromobenzene
assay
entry
ligand =
PPh3
yield (%)a
1
2
3
4
5
6
7
14
<5
8
Scheme 2. Diastereoselective Synthesis of Cyclopropanols
JohnPhos
DavePhos
t-BuXPhos
QPhos
<5
98b
12
7
Dppf
Dtbpf
a Yields determined by integration of 1H NMR spectra of the crude
reaction mixtures against an internal standard. b 86% isolated yield.
We envisioned a key intermediate in the generation of
the palladium homoenolate would be the palladium cyclo-
propoxide. Although a variety of bases can be used to form
palladium alkoxides, we were attracted to the use of mild
amine bases, as demonstrated by the work of Stoltz,33
Uemura,34,35 and Sigman.36,37 Thus using triethylamine,
a handful of the most successful mono- and bidentate
ligands in cross-coupling chemistry were screened in the
presence of Pd(OAc)2 (5 mol %), bromobenzene (limiting
reagent), and 2 equiv of triethylamine at rt (Table 1).38
With suitable conditions in hand, we examined the scope
of racemic cyclopropanols (Table 2). In addition to the
n-hexyl (entry 1), n-butyl and cyclohexyl substituted cyclo-
propanols (entries 2À3) furnished aldehydes in 93% and
88% yield, respectively. Aldehyde homoenolates with silyl
or trityl protected β- or δ-hydroxy groups (entries 4À8)
were arylated in 59À83% yield. Substrates 1e and 1f,
however, required an increase in loading to 10 mol %
Pd(OAc)2. The indole substrate (entry 9) gave the desired
aldehyde in 61% yield at 50 °C.
We then examined the scope of aryl bromides in homoeno-
late cross-coupling with (()-trans-2-n-hexylcyclopropanol
(Table 3). Electron-rich aryl bromides are very good
substrates (73À81% yield, entries 1À4). 2-Bromotoluene
resulted in a diminished yield (59%, entry 5), most likely
due to the increased steric hindrance. The electron-poor
aryl bromides furnished products in 79À83% yields
(entries 6À8). Our coupling exhibited interesting chemos-
electivity: both unprotected 4-bromobenzyl alcohol and
4-bromophenol generated the corresponding β-arylated
aldehydes in 84% and 66% isolated yields, respectively
(entries 9 and 10). The result in entry 10 indicates that
phenol arylation is slower than homoenolate arylation.23
(29) Cheng, K.; Carroll, P. J.; Walsh, P. J. Org. Lett. 2011, 13, 2346.
(30) Kim, H. Y.; Walsh, P. J. Acc. Chem. Res. 2012, 45, 1553.
(31) Park, S.-B.; Cha, J. K. Org. Lett. 2000, 2, 147.
(32) Parida, B. B.; Das, P. P.; Niocel, M.; Cha, J. K. Org. Lett. 2013,
15, 1780.
(33) Ebner, D. C.; Bagdanoff, J. T.; Ferreira, E. M.; McFadden,
R. M.; Caspi, D. D.; Trend, R. M.; Stoltz, B. M. Chem.;Eur. J. 2009,
15, 12978.
(34) Nishimura, T.; Uemura, S. Synlett 2004, 201.
(35) Nishimura, T.; Onoue, T.; Ohe, K.; Uemura, S. Tetrahedron
Lett. 1998, 39, 6011.
(36) Schultz, M.; Park, C. C.; Sigman, M. S. Chem. Commun. 2002,
3034.
(37) Schultz, M.; Adler, R. S.; Zierkiewicz, W.; Privalov, T.; Sigman,
M. S. J. Am. Chem. Soc. 2005, 127, 8499.
(38) Using less than 2.0 equiv of cyclopropanol resulted in slightly
diminished yields; however, excess cyclopropanol can be recovered
quantitatively after column chromotography.
Org. Lett., Vol. 15, No. 9, 2013
2299

Table 2. Scope of Cyclopropanols
Table 3. Scope of Aryl Bromides
a Yield based on isolation of reduced aldehyde. b 2-trans-
Benzylcyclopropanol.
a 10 mol % Pd(OAc)2, 20 mol % QPhos. b Reaction run at 50 °C.
the desired arylated product was isolated in 98% yield
(1.34 g).
Finally, replacing trans-2-n-hexylcyclopropanol with trans-
2-benzylcyclopropanol (entries 11 and 12) and reaction
with 4-bromoanisole and 4-bromo-N,N-dimethylaniline
provided the desired aldehydes in 89% and 73% yield,
respectively. It is noteworthy that no R-arylation of the
aldehyde products was detected, presumably because the
mild conditions do not result in the generation of enolate
intermediates.39
Scheme 3. Scale-up Cross-Coupling between 1a and Bromo-
benzene
To determine the scalability of the reaction, we con-
ducted the arylation of trans-2-hexylcyclopropanol with
bromobenzene on 6.3 mmol scale. As shown in Scheme 3,
Given the observed regioselectivity of the cyclopropane
ring opening, we hypothesized that enantioenriched
(39) Vo, G. D.; Hartwig, J. F. Angew. Chem., Int. Ed. 2008, 47, 2127.
2300
Org. Lett., Vol. 15, No. 9, 2013

Scheme 4. Enantioselective Synthesis of β-Arylated Aldehyde
Scheme 5. Plausible Reaction Pathway
cyclopropanols should allow ring opening and cross-
coupling without loss of stereochemistry (Scheme 4).
Enantioenriched 2-trans-chlorooctanal was synthesized
according to MacMillan’s method (96% ee)40 and sub-
jected to our cyclopropanation reaction with CH2(ZnI)2
to yield the corresponding cyclopropanol (1a, 60% yield,
Scheme 2). Use of 1a in the homoenolate arylation
afforded the desiredβ-arylated aldehyde (2a) in 75% yield
with 95% ee. Thus, little or no erosion of ee occurs during
the cyclopropanation or the arylation steps.
A possible catalytic cycle is pictured in Scheme 5 based
on Uemura41À43 and Martın’s44,45 work on the ring open-
ing of cyclobutanols to provide γ-arylated ketones. After
oxidative addition of the aryl bromide to palladium(0),
the aryl palladium intermediate is proposed to bind
the alcohol. Deprotonation by triethylamine is expected
to generate the palladium alkoxide. β-Carbon elimina-
tion then gives the palladium homoenolate intermediate.
Because QPhos is a monodentate ligand, it is likely that
the aldehyde carbonyl binds to the palladium. Such an
interaction would stabilize the intermediate with respect
to β-hydride elimination, which we have not observed in
this system. Reductive elimination then occurs to give the
β-arylated aldehyde and regenerates Pd(0).
In conclusion, we have developed a mild method for the
CÀC bond cleavage of cyclopropanols to form intermedi-
ate aldehyde homoenolates that undergo arylations cata-
lyzed by a QPhos-based palladium catalyst. The reaction
was determined to be easily scalable. Unlike prior meth-
ods, which required more expensive aryl triflates and very
high boiling, polar, and toxic HMPA, our method gives
good results with more readily available aryl bromides
in THF. Additionally, we have demonstrated that the
arylation proceeds without loss of stereochemistry with
enantiomerically enriched cyclopropanols.
Acknowledgment. We thank the NSF [CHE-0848460
(GOALI) and 1152488] for financial support and Drs.
Simon Berritt and Ana Bellomo (Penn/Merck Laboratory,
University of Pennsylvania) for helpful discussions.
(40) Amatore, M.; Beeson, T. D.; Brown, S. P.; MacMillan, D. W. C.
Angew. Chem., Int. Ed. 2009, 48, 5121.
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(42) Matsumura, S.; Maeda, Y.; Nishimura, T.; Uemura, S. J. Am.
Chem. Soc. 2003, 125, 8862.
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1455.
Supporting Information Available. Procedures and full
characterization are available. This material is available
free of charge via the Internet at http://pubs.acs.org.
(44) Ziadi, A.; Martın, R. Org. Lett. 2012, 14, 1266.
(45) Flores-Gaspar, A.; Martın, R. Synthesis 2013, 45, 563.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 9, 2013
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