Catalytic hydroacylation as an approach to homoaldol products

Article abstract of DOI:10.1021/ol202663p

A method has been developed for the intermolecular hydroacylation of homoallyl alcohols with salicylaldehydes to furnish homoaldol products in 50-98% yields. The method also applies to the hydroacylation of 2-hydroxystyrenes. This work highlights the use of hydroacylation as a unified approach to both aldol and homoaldol products.

Full text of DOI:10.1021/ol202663p

ORGANIC
LETTERS
2011
Vol. 13, No. 23
6216–6219
Catalytic Hydroacylation as an Approach
to Homoaldol Products
Stephen K. Murphy, David A. Petrone, Matthew M. Coulter, and Vy M. Dong*
Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario
M5S 3H6, Canada
vdong@chem.utoronto.ca
Received October 3, 2011
ABSTRACT
A method has been developed for the intermolecular hydroacylation of homoallyl alcohols with salicylaldehydes to furnish homoaldol products in
50À98% yields. The method also applies to the hydroacylation of 2-hydroxystyrenes. This work highlights the use of hydroacylation as a unified
approach to both aldol and homoaldol products.
While significant progress has been made in aldol technol-
ogy, these advances do not generally apply to the related
homoaldol transformation. In contrast to enolates, homo-
enolates are difficult to prepare and readily undergo irrever-
sible cyclization to oxyanionic cyclopropanes rather than
desirable nucleophilic addition to electrophiles.1 Given the
importance of these “umpolung” or “reverse polarity” motifs
in CÀC bond construction,2 much work has been devoted to
generating homoenolate equivalents.1,3 Nonetheless, no gen-
eral catalytic strategy exists for targeting both the aldol
structure and its homologue. Our laboratory is interested in
studying hydroacylation as an atom economical and efficient
strategy for organic synthesis.4,5 In this context, we envi-
sioned that hydroxyl-directed hydroacylation could provide
a unified strategy for preparing both aldol and homoaldol
products as shown in Scheme 1.
By using cooperative catalysis, we recently achieved the
branched-selective hydroacylation6 of allyl alcohols to
form aldol products.7 This transformation is promoted
by a phosphinite catalyst that binds the alcohol and metal
catalyst simultaneously to promote the olefin functionali-
zation. With this strategy, Bedford developed a method for
ortho-arylation of phenols, and Breit and Tan more re-
cently achieved branched-selective hydroformylation of
(1) Kuwajima, I.; Nakamura, E. Top. Curr. Chem. 1990, 155, 1.
(2) Seebach, D. Angew. Chem., Int. Ed. 1979, 18, 239.
(6) For hydroacylation of simple olefins using a double chelation
approach, see: (a) Coulter, M. M.; Kou, K. G. M.; Galligan, B.; Dong,
V. M. J. Am. Chem. Soc. 2010, 132, 16330. (b) Imai, M.; Tanaka, M.;
Tanaka, K.; Yamamoto, Y.; Imai-Ogata, N.; Shimowatari, M.; Nagumo,
S.; Kawahara, N.; Suemune, H. J. Org. Chem. 2004, 69, 1144.
(7) Murphy, S. K.; Coulter, M. M.; Dong, V. M. Chem. Sci. (DOI:
10.1039/c1sc00634g).
(8) For ortho-arylation of phenols using phosphinites, see: (a) Bedford,
R. B.; Coles, S. J.; Hursthouse, M. B.; Limmert, M. E. Angew. Chem.,
Int. Ed. 2003, 42, 112. (b) Bedford, R. B.; Limmert, M. E. J. Org. Chem.
2003, 68, 8669. For branched-selective hydroformylation of alkenyl
alcohols using phosphorus-based ligands that reversibly bind the alco-
(3) For reviews on the homoaldol reaction, see: (a) Hoppe, D.
Synthesis 2009, 1, 43. (b) Crimmins, M. T.; Nantermet, P. G. Org. Prep.
Proc. 1993, 25, 43. (c) Kuwajima, I.; Nakamura, E. In Comprehensive
Organic Synthesis, Vol. 2; Trost, B. M., Fleming, I., Eds.; Pergammon:
Oxford, 1991; p 441. For a comprehensive full paper on the homoaldol
reaction, see: (d) Lettan, R. B., II; Galliford, C. V.; Woodward, C. C.;
Scheidt, K. A. J. Am. Chem. Soc. 2009, 131, 8805.
(4) Trost, B. M. Science 1991, 254, 1471.
(5) For reviews on hydroacylation, see: (a) Willis, M. C. Chem. Rev.
2010, 110, 725. (b) Fu, G. C. In Modern Rhodium-Catalyzed Reactions;
Evans, P. A., Ed.; Wiley-VCH: New York, 2005; p 79. For selected
examples of activated or strained olefins in Rh-catalyzed intermolecular
olefin hydroacylation, see: (c) Osborne, J. D.; Willis, M. C. Chem.
Commun. 2008, 5025. (d) Tanaka, K.; Shibata, Y.; Suda, T.; Hagiwara,
Y.; Hirano, M. Org. Lett. 2007, 9, 1215. (e) Osborne, J. D.; Randell-Sly,
H. E.; Currie, G. S.; Cowley, A. R.; Willis, M. C. J. Am. Chem. Soc. 2008,
130, 17232. (f) Kokubu, K.; Matsumasa, K.; Nishinaka, Y.; Miura, M.;
Nomura, M. Bull. Chem. Soc. Jpn. 1999, 72, 303. (g) Stemmler, R. T.;
Bolm, C. Adv. Synth. Catal. 2007, 349, 1185. (h) Phan, D. H. T.; Kou,
K. G. M.; Dong, V. M. J. Am. Chem. Soc. 2010, 132, 16354.
€
hol, see: (c) Grunanger, C. U.; Breit, B. Angew. Chem., Int. Ed. 2008, 120,
€
7456. (d) Grunanger, C. U.; Breit, B. Angew. Chem., Int. Ed. 2010, 49,
967. (e) Usui, I.; Nomura, K.; Breit, B. Org. Lett. 2011, 13, 612. (f) Ueki,
Y.; Ito, H.; Usui, I.; Breit, B. Chem.;Eur. J. 2011, 17, 8555. For a recent
review, see: (g) Rousseau, G.; Breit, B. Angew. Chem., Int. Ed. 2011, 50,
2450. (h) Lightburn, T. E.; Dombrowski, M. T.; Tan, K. L. J. Am. Chem.
Soc. 2008, 130, 9210. (i) Lightburn, T. E.; De Paolis, O. A.; Cheng, K. H.;
Tan, K. L. Org. Lett. 2011, 13, 2686. (j) Worthy, A. D.; Joe, C. L.;
Lightburn, T. E.; Tan, K. L. J. Am. Chem. Soc. 2010, 132, 14757. For a
recent review, see: (k) Tan, K. L. ACS Catal. 2011, 1, 877.
r
10.1021/ol202663p
Published on Web 11/07/2011
2011 American Chemical Society

alkenyl alcohols.8 Onthebasisoftheseresults, weimagined
that homoallyl alcohols could undergo hydroacylation by
hydroacylation over olefin migration. Indeed, changing
the solvent from (CH2Cl)2 to THF afforded the desired
homoaldol product 3a in 97% yield as a single regioisomer
after 2.5 h (Table 1, entry 2). Reducing the catalyst loading
further to 1 mol % [Rh(COD)Cl]2 afforded the product in
70% yield after 9 h (Table 1, entry 3). No catalytic activity
was observed when the phosphinite ligand was replaced
with triphenylphosphine (Table 1, entry 4), which supports
the role of Ph2POMe as an exchangeable directing group.
Scheme 1. Hydroacylation as a Unified Approach to both Aldol
and Homoaldol Products
Table 1. Optimization of Hydroacylation of Homoallyl Alcohol
with Salicylaldehydea,b
the analogous pathway shown in Scheme 2; however, two
key challenges must be overcome. First, the homoallyl
phosphinite intermediate, which is generated by the rever-
sible exchange of homoallyl alcohol with methyl diphenyl-
phosphinite (Ph2POMe), would have to undergo hydro-
acylation via a six-membered metallacycle which would be
the largest chelate size reported for intermolecular olefin
hydroacylation.9 Second, competitive decarbonylation and
olefin migration may be expected to cause substantial
catalyst deactivation and side product formation because
reactivity diminishes with the increased chelate size.10
To explore these challenges, we studied the reaction of
salicylaldehyde with homoallyl alcohol using [Rh(COD)Cl]2
as the precatalyst in the presence of Ph2POMe and catalytic
NaOAc (Table 1). We chose salicylaldehyde because its
phenolic group is known to coordinate to Rh and promote
hydroacylation.5f By applying conditions similar to those
yield
(%)c
time
(h)
entry
x
y
ligand
solvent
1
2
3
4
5
50
25
10
20
Ph2POMe
Ph2POMe
Ph2POMe
PPh3
(CH2Cl)2
THF
60
97
70d
0e
18
2.5
9
2.5
1
THF
5
THF
48
a Stoichiometry: salicylaldehyde (0.25 mmol, 1.0 equiv), olefin (1.5
equiv). b The branched-to-linear selectivity was >20:1 by 1H NMR analysis
of the crude reaction mixtures for entries 1À3. c Isolated yield. d Salicylal-
dehyde (1 mmol, 1 equiv). e No product could be detected by GC-MS.
Nine sterically and electronically diverse salicylaldehydes
were investigated as coupling partners for homoallyl alcohol
under our optimized conditions (Table 1, entry 2). The
corresponding R-branched ketones were obtained as single
regioisomers in 75À98% yields (Table 2). Both fluoro and
chloro substituents were well tolerated (Table 2, entries 2
and 3), and 5-iodosalicylaldehyde produced the desired
hydroacylation product in good yield without any obser-
vable MizorokiÀHeck coupling or proto-deiodination
(Table 2, entry 4).11 Electron-rich methoxysalicylaldehydes
(Table 2, entries 5À7) and substrates with increased steric
bulk at the 3- or 6-positions (Table 2, entries 7 and 8)
provided excellent reactivity. The Lewis basic pyridine ring
in 5-(4-pyridyl)salicylaldehyde did not inhibit catalysis de-
spite its potential to compete with the substrate for metal
coordination sites, and the desired R-branched ketone was
isolated in 75% yield (Table 2, entry 9).
A series of γ-hydroxyketones were prepared by coupling
salicylaldehyde with six homoallyl alcohols (Table 3).
Disubstituted olefins are difficult substrates for intermo-
lecular hydroacylation; however, cis-andtrans-3-hexen-1-ol
underwent coupling to the desired branched ketones in
moderate yields under our optimized conditions (Table 3,
entries 2 and 3). Substitution at the R and β positions of
Scheme 2. Branched-Selective Hydroacylation of Homoallyl
Alchols Promoted by Phosphinites (Ar = 2-hydroxyphenyl)
our group previously reported for hydroacylation of allyl
alcohols (Table 1, entry 1),7 the desiredhomoaldol product
3a was observed in only 60% yield along with products of
olefin migration. Because these two products diverge
from a common acyl-Rh-alkyl intermediate via competing
reductive elimination and β-hydride elimination, we
predicted that a coordinating solvent might promote
(9) Bishomoallylic alcohols have been reported to undergo phosphi-
nite-promoted hydroformylation via seven-membered metallacycles; see
ref 8d.
(10) (a) Khan, H. A.; Kou, K. G. M.; Dong, V. M. Chem. Sci. 2011, 2,
407. (b) See ref 6b.
(11) For examples of Rh-catalyzed Heck reactions, see: (a) Sugihara,
T.; Satoh, T.; Miura, M.; Nomura, M. Angew. Chem., Int. Ed. 2003, 42,
4672. (b) Martinez, R.; Voica, F.; Genet, J-P.; Darses, S. Org. Lett. 2007, 9,
3213.
Org. Lett., Vol. 13, No. 23, 2011
6217

Table 2. Regioselective Hydroacylation of Homoallyl Alcohol
with Salicylaldehydesa,b
Table 3. Regioselective Hydroacylation of Homoallyl Alcohols
with Salicylaldehydea,b
entry
1
R
yield (%)c
time (h)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
H
97
88
92
75
92
86
83
98
75
2.5
3.5
3.5
3.5
3
5-F
5-Cl
5-I
4-OMe
5-OMe
3-OMe
6-Me
5-(4-py)
2.5
4
1g
1h
1i
3
4
a Stoichiometry: salicylaldehyde (0.25 mmol, 1.0 equiv), olefin
(1.5 equiv). b The branched-to-linear selectivity was >20:1 by 1H
NMR analysis of the crude reaction mixtures in all cases. c Isolated yield.
homoallyl alcohol (Table 3, entries 4 and 5) was tolerated,
although the secondary alcohol 2e required a longer
reaction time. The diastereoselectivities were moderate
in both cases and were not improved when 2f was
employed as the coupling partner despite the increased
A(1,3) strain present in that molecule (Table 3, entry 6).
Homoallylbenzylether did not furnish any hydroacyla-
tion products, likely because this substrate cannot under-
go phosphinite exchange (Table 3, entry 7). Additionally,
the further homologated alcohol 2h provided only trace
amounts of the desired hydroacylation product along
a Stoichiometry: salicylaldehyde (0.25 mmol, 1.0 equiv), olefin
1
(1.5 equiv). b The branched-to-linear selectivity was >20:1 by H NMR
analysis of the crude reaction mixtures in all cases. c Isolated yield.
d [Rh(COD)Cl]2 (1 mol %), Ph2POMe (10 mol %), salicylaldehyde
(1 mmol), 9 h. e dr = 64:36. f dr = 71:29. g dr = 63:37. h No product could
be identified by GC-MS after 24 h.
1
with products of olefin isomerization as detected by H
NMR analysis of the crude reaction mixture. We attri-
bute the lower reactivity of this substrate to the larger
distance between the directing group and olefin compared
to the homoallyl alcohol.
was slightly less efficient. The challenging disubstituted
olefin 2-hydroxy-β-methylstyrene underwent efficient
hydroacylation to yield the R-aryl ketone in 86% yield
after 18 h (Table 4, entry 4).
We next explored 2-hydroxystyrene substrates, which
undergo hydroacylation via six-membered metallacylces
similar to homoallyl alcohols, and found that they were
highly reactive toward hydroacylation under our opti-
mized conditions (Table 4). 2-Hydroxystyrene under-
went coupling to yield the R-aryl ketone product as a
single regioisomer in 88% yield after 4 h (Table 4, entry 1).
We considered that the phenolic group of 2-hydroxys-
tyrene could coordinate to Rh under basic reaction
conditions and promote a background reaction. Because
no products were observed when Ph2POMe was replaced
with PPh3, the phosphinite likely undergoes exchange
with the phenolic group and promotes the reaction. The
effects of olefin electronics and substitution on reaction
efficiency were investigated next. The electron-deficient
olefin 5-fluoro-2-hydroxystyrene (Table 4, entry 2) un-
derwent rapid hydroacylation, whereas the electron-rich
olefin 4-methoxy-2-hydroxystyrene (Table 4, entry 3)
During our scope studies, we found that the products of
homoallyl alcohol hydroacylation equilibrate to hemike-
tals upon storage. This cyclization prompted us to search
for conditions to synthesize substituted heterocycles. We
found that reduction of 3a using sodium borohydride and
subsequent treatment with aqueous HCl afforded tetrahy-
drofuran 5in 78% yield with 33:1 diastereoselectivity in favor
of the trans stereoisomer (Scheme 3).12 Although the product
of 2-hydroxystyrene hydroacylation 6 did not undergo ap-
preciable equilibration to its hemiketal isomer compared to
3a, we found that treatment of 6 with trifluoroacetic acid in
dichloromethane resulted in near quantitative conversion to
the 1,2-disubstituted benzofuran 7 (Scheme 3).
To conclude, we have reported a highly branched-
selective method for hydroacylation of homoallyl alcohols
(12) The stereochemistry was assigned by comparison to trans-
2-phenyl-3-methyltetrahydrofuran, see: Schmitt, A.; Reiβig, H.-U.
Eur. J. Org. Chem. 2000, 3893.
6218
Org. Lett., Vol. 13, No. 23, 2011

Table 4. Regioselective Hydroacylation of 2-Hydroxystyrene
Derivatives with Salicylaldehydea,b
Scheme 3. Synthesis of Substituted Tetrahydrofuran and Benzo-
furan Derivatives (Ar = 2-hydroxyphenyl).
demonstrated the use of hydroacylation as an approach
to both aldol and homoaldol products. Future work will
focus on extending this strategy beyond salicylaldehyde
substrates, mechanistic studies, and the development of
enantioselective variants.
Acknowledgment. We thank the University of Toronto,
the Canada Foundation for Innovation, the Ontario
Research Fund, the National Science and Engineering
Council of Canada (NSERC), AstraZeneca (Canada), and
Boehringer Ingelheim (Canada) Ltd. for funding. V.M.D. is
grateful for an Alfred P. Sloan Fellowship, S.K.M. for a
Canada Graduate Scholarship (CGS), and M.M.C. for an
Ontario Graduate Scholarship (OGS).
a Stoichiometry: salicylaldehyde (0.25 mmol, 1.0 equiv), olefin
(1.5 equiv). b The branched-to-linear selectivity was >20:1 by 1H
NMR analysis of the crude reaction mixtures in all cases. c Isolated
yield. d No product was detected under the conditions in Table 1, entry 4.
Supporting Information Available. Experimental pro-
cedures, characterization data for new compounds. This
information is available free of charge via the Internet at
http://pubs.acs.org.
and 2-hydroxystyrenes. In conjunction with our pre-
vious work on allyl alcohol hydroacylation, we have
Org. Lett., Vol. 13, No. 23, 2011
6219