Rhodium-Catalyzed, Enantioselective Hydroacylation of ortho-Allylbenzaldehydes

Article abstract of DOI:10.1021/acs.orglett.5b02559

The development of a rhodium catalyst for endo- and enantioselective hydroacylation of ortho-allylbenzaldehydes is reported. A catalyst generated in situ from [Rh(COD)Cl]₂, (R)-DTBM-SEGPHOS, and NaBARF promotes the desired hydroacylation reactions and minimizes the formation of byproducts from competitive alkene isomerization and ene/dehydration pathways. These rhodium-catalyzed processes generate the 3,4-dihydronaphthalen-1(2H)-one products in moderate-to-high yields (49-91%) with excellent enantioselectivities (96-99% ee).

Full text of DOI:10.1021/acs.orglett.5b02559

Letter
pubs.acs.org/OrgLett
Rhodium-Catalyzed, Enantioselective Hydroacylation of ortho-
Allylbenzaldehydes
Kirsten F. Johnson, Adam C. Schmidt, and Levi M. Stanley*
Department of Chemistry, Iowa State University, Ames, Iowa 50011, United States
S
* Supporting Information
ABSTRACT: The development of a rhodium catalyst for
endo- and enantioselective hydroacylation of ortho-allylbenz-
aldehydes is reported. A catalyst generated in situ from
[Rh(COD)Cl]2, (R)-DTBM-SEGPHOS, and NaBARF pro-
motes the desired hydroacylation reactions and minimizes the
formation of byproducts from competitive alkene isomer-
ization and ene/dehydration pathways. These rhodium-
catalyzed processes generate the 3,4-dihydronaphthalen-1(2H)-one products in moderate-to-high yields (49−91%) with
excellent enantioselectivities (96−99% ee).
he development of new catalysts has rendered intra-
molecular alkene hydroacylation a valuable strategy to
Scheme 1. Intramolecular Hydroacylation of ortho-
Allylbenzaldehydes
T
generate a wide variety of carbocyclic and heterocyclic
ketones.1−4 These transformations, which involve the formal
insertion of an aldehyde C−H bond into an alkene, can be
promoted by transition metal or N-heterocyclic carbene
(NHC) catalysts. The selection of transition metal or NHC
catalysts for enantioselective intramolecular hydroacylations is
often dictated by the desired regiochemical outcome of the
reaction. NHC-catalyzed intramolecular hydroacylations occur
with exo selectivity (formal Markovnikov selectivity),2 while
transition-metal-catalyzed hydroacylations can occur with either
endo selectivity (formal anti-Markovnikov selectivity)3 or exo
selectivity.4 The potential for complementary regioselectivity
makes the synthesis of two distinct ketone products from the
same substrate possible.
ortho-Allylbenzaldehydes are a class of substrates that
highlights the two potential regiochemical outcomes of alkene
hydroacylation. Endo-selective hydroacylations of ortho-
allylbenzaldehydes occur in the presence of an achiral rhodium
catalyst to form racemic 3,4-dihydronaphthalene-1(2H)-ones,5
while the complementary exo-selective processes occur in the
presence of an achiral nickel catalyst to form racemic 2,3-
dihydro-1H-inden-1-ones (Scheme 1a).6 During our studies,
Glorius et al. reported the first catalytic, exo- and
enantioselective hydroacylations of ortho-allylbenzaldehydes to
form 2,3-dihydro-1H-inden-1-ones containing an all-carbon
quaternary stereogenic center (Scheme 1b).7 However, an
endo- and enantioselective variant of the hydroacylation of
ortho-allylbenzaldehydes has not been reported.
In 2014, we reported enantioselective hydroacylation of N-
allylindole-2-carboxaldehydes and N-allylpyrrole-2-carbox-
aldehydes to generate six-membered ketone products with
exclusive endo selectivity.8 These reactions occur in the
presence of rhodium complexes containing a chiral bi-
sphosphine ligand and a weakly coordinating counteranion.
We envisioned that a related rhodium catalyst would promote
the endo-selective hydroacylation of ortho-allylbenzaldehydes to
form 3,4-dihydronaphthalen-1(2H)-ones with high enantiose-
lectivities (Scheme 1c).
To assess the feasibility of endo- and enantioselective
hydroacylation of ortho-allylbenzaldehydes, we evaluated the
reaction of 2-(2-methylallyl)benzaldehyde 1a in the presence of
a catalyst generated from [Rh(COD)Cl]2, (R)-BINAP, and
AgBF4 (eq 1). This reaction formed the desired hydroacylation
product 2a in 41% yield with 91% ee, the alkene isomerization
product 3 in 8% yield, and 2-methylnaphthalene 4 in 47% yield.
Although transition-metal-catalyzed hydroacylation reactions
often require high catalyst loadings to overcome competitive
decarbonylation,3c−g,9 decarbonylation of 1a was not observed
under these conditions.
Received: May 29, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02559
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Table 1. Identification of Catalysts for Hydroacylation of 2-
(2-Methylallyl)benzaldehyde 1a
The formation of 2-methylnaphthalene 4 from the reaction
of 1a was unexpected and has not been described in the context
of alkene hydroacylation. However, the formation of sub-
stituted naphthalene derivatives from ortho-allylbenzaldehydes
is known to occur by a sequence of Lewis acid catalyzed
intramolecular ene reaction and dehydration.10 To evaluate
whether the silver salt used to generate the active catalyst
promotes the formation of 4, 1a was exposed to 5 mol % AgBF4
in the absence of [Rh(COD)Cl]2 and the bisphosphine ligand
(eq 2). This reaction generated 4 in 91% yield and
demonstrates that AgBF4 is a noninnocent additive under our
catalytic reaction conditions.
ab
,
c
a
d
entry ligand yield 2a (%)
ee 2a (%) yield 3 (%)
ratio 2a:3a
1
2
3
4
5
6
7
L1
L2
L3
L4
L5
L5
L5
77 (56)
75 (75)
80 (72)
80 (80)
85 (81)
65 (63)
50 (52)
87
90
88
99
98
99
99
23
16
16
9
3.3:1
4.7:1
5.0:1
8.9:1
10.7:1
6.5:1
10:1
8
e
f
10
5
a
Yield determined by 1H NMR spectroscopy with dibromomethane as
b
the internal standard. Isolated yield of 2a is shown in parentheses.
To effect counteranion exchange and enable the in situ
generation of the active, cationic rhodium complex while
mitigating the silver-catalyzed ene/dehydration pathway, we
employed sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]-
borate (NaBARF) in place of AgBF4.11 We hypothesized the
absence of Ag(I) would eliminate the formation of 4. To test
this hypothesis, we evaluated the hydroacylation of 1a in the
presence of a catalyst generated from [Rh(COD)Cl]2, (R)-
BINAP, and NaBARF (Table 1, entry 1). The reaction
occurred to form the ketone product 2a in 77% yield and the
alkene isomerization product 3a in 23% yield. The formation of
2-methylnaphthalene 4 was not observed.
Although the in situ generated catalyst eliminates the ene
reaction/dehydration pathway to 4, the enhanced cationic
character of this rhodium complex increases the rate of alkene
isomerization relative to the rate of alkene hydroacylation.12,13
The ratio of hydroacylation to isomerization is 5.1:1 when the
catalyst contains the tetrafluoroborate counteranion; the ratio
decreases to 3.3:1 when the catalyst contains the tetraarylborate
counteranion.
We hypothesized that the steric and electronic properties of
the chiral bisphosphine ligand could be leveraged to improve
the rate of alkene hydroacylation relative to the rate of alkene
isomerization. Rhodium catalysts with less cationic character
should attenuate the rates of both alkene isomerization and
alkene hydroacylation.3c,d,12 However, bisphosphine ligands
with bulky aryl substituents on phosphorus should significantly
increase the overall rate of alkene hydroacylation relative to the
rate of alkene isomerization by increasing the rate of the
turnover-limiting reductive elimination to form the ketone
product.14,15
c
d
Determined by chiral HPLC analysis. Determined by 1H NMR
e
spectroscopy of the crude reaction mixture. [Rh(COD)2]BF4 (5 mol
%) used in place of [Rh(COD)Cl]2 and NaBARF. [Rh(COD)2]-
f
BARF (5 mol %) used in place of [Rh(COD)Cl]2 and NaBARF.
derived from a series of bisphosphine ligands with axially chiral
backbones (Table 1). The rhodium(I) complexes of (R)-MeO-
BIPHEP L2 and (R)-SEGPHOS L3, which are more electron-
rich than the complex derived from (R)-BINAP L1, catalyze the
reaction of 1a with improved ratios of hydroacylation to
isomerization (4.7:1 and 5.0:1) relative to the rhodium(I)
complex of L1 (compare entries 2 and 3 with entry 1). We then
conducted hydroacylations of 1a in the presence of rhodium
catalysts prepared from ligands containing bulky, electron-rich
3,5-di-tert-butyl-4-methoxyphenyl substituents on phosphorus.
The hydroacylation of 1a occurs with an 8.9:1 ratio of
hydroacylation to isomerization when the reaction is run in the
presence of the rhodium(I) complex of (R)-DTBM-MeO-
BIPHEP L4, and ketone product 2a is isolated in 80% yield
(entry 4). The ratio of hydroacylation to isomerization
products can be further improved by conducting the reaction
of 1a with a rhodium(I) complex of the more electron-rich (R)-
DTBM-SEGPHOS L5 (entry 5).16 In the presence of this
rhodium(I) catalyst, the hydroacylation of 1a occurs with a
10.7:1 ratio of hydroacylation to isomerization, and ketone 2a is
isolated in 85% yield. The absolute configuration of 2a was
determined to be (R) by comparison of optical rotation data
with literature values.17
Additional rhodium(I) precursors were evaluated for the
hydroacylation of 1a using the electron-rich (R)-DTBM-
SEGPHOS ligand L5. A significant decrease in the yield of
2a and the ratio of hydroacylation to isomerization products is
To evaluate the impact of steric and electronic properties of
the ligand, we conducted hydroacylations of 1a with catalysts
B
DOI: 10.1021/acs.orglett.5b02559
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Letter
observed when [Rh(COD)2]BF4 is employed as the catalyst
precursor for the hydroacylation of 1a (63% yield, 6.5:1)
(compare entries 5 and 6). Conducting the reaction of 1a in the
presence of a catalyst generated from [Rh(COD)2]BARF
results in a 10:1 ratio of hydroacylation to isomerization
products. However, the yield of 2a was comparatively low
(compare entries 5 and 7). Thus, we chose to evaluate the
scope of hydroacylations of additional ortho-allylbenzaldehydes
using the reaction conditions from entry 5.
With a practical catalyst system identified, we evaluated the
hydroacylations of a variety of ortho-allylbenzaldehydes
containing substitution around the aryl core and on the central
carbon of the allyl moiety (Scheme 2). Hydroacylations of 5-
fluoro-2-(2-methylallyl)benzaldehyde 1b and 4-fluoro-2-(2-
methylallyl)benzaldehyde 1c form the corresponding 3,4-
dihydronaphthalen-1(2H)-ones 2b and 2c in 88% and 60%
yield with 98% ee. The hydroacylation of 4-chloro-2-(2-
methylallyl)benzaldehyde 1d generated 2d in modest yield in
the presence of 5 mol % rhodium catalyst. However, the
reaction of 1d in the presence of 10 mol % catalyst formed 2d
in 91% yield with 96% ee.
The hydroacylations of electron-rich ortho-allylbenzaldehydes
also occur to form 3,4-dihydronaphthalen-1(2H)-ones in high
yields with excellent enantioselectivities. The hydroacylations of
4-methoxy-2-(2-methylallyl)benzaldehyde 1e and the pipero-
nal-derived 2-(2-methylallyl)benzaldehyde) 1f provide 3,4-
dihydronaphthalen-1(2H)-ones 2e and 2f in 84% and 85%
yields with 99% and 98% ee.
Alkyl and aryl substituents on the internal carbon of the allyl
moiety are also well tolerated. The hydroacylations of ortho-
allylbenzaldehydes 1g and 1h (R2 = n-Pr and Ph) generate 2g
and 2h in 89% and 87% yield with 96% and 97% ee.
Hydroacylations of ortho-allylbenzaldehydes 1j−1m containing
substituted aryl groups at the central carbon of the allyl moiety
generate the 3-aryl-3,4-dihydronaphthalen-1(2H)-one products
2j−2m in good yields (70−80%) with excellent enantiose-
lectivities (96−98% ee). In addition, the hydroacylation of 2-(2-
(thiophen-3-yl)allyl)benzaldehyde 1n forms 3,4-dihydro-
naphthalen-1(2H)-one 2n in 49% yield with 98% ee. The
hydroacylation of 2-allylbenzaldehyde 1o, which lacks sub-
stitution at the central carbon of the allyl moiety, exclusively
forms the 3,4-dihydronaphthalen-1(2H)-one 2o; the formation
of the five-membered ketone (2-methyl-2,3-dihydro-1H-inden-
1-one) is not observed with the current catalyst system.
Although we have developed a practical catalyst for
enantioselective hydroacylation of ortho-allylbenzaldehydes,
the catalyst performs poorly for substrates in which the alkene
and aldehyde units are not conformationally constrained. For
example, the reaction of 5-phenylhex-5-enal 5 forms alkene
isomerization product 6 in 78% yield, and the alkene
Scheme 2. Rh-Catalyzed Hydroacylation of ortho-
a
Allylbenzaldehydes 1a−i
1
hydroacylation product is not detected by H NMR spectros-
copy (eq 3). In addition, the hydroacylation of an ortho-
allylbenzaldehyde with substitution at the terminal position of
the allyl unit does not occur to form the expected 3,4-
dihydronaphthalen-1(2H)-one product. The reaction of a 1.3:1
E/Z mixture of 2-(but-2-en-1-yl)benzaldehyde 7 forms 2-ethyl-
2,3-dihydro-1H-inden-1-one 8 in 38% yield as a racemic
mixture (eq 4). We hypothesize the formation of 7 results from
endo-selective hydroacylation of alkene isomerization product 9,
but we cannot rule out exo-selective hydroacylation of 7 to form
8 at this time.
a
Yields of 2 are isolated yields after column chromatography.
Enantiomeric excesses were determined by chiral HPLC analysis.
Ratios of hydroacylation to alkene isomerization products (2b−o:3b−
o) were determined by 1H NMR analysis of the crude reaction
mixture. Values in parentheses are for the reaction of 1d in the
presence of 10 mol % rhodium catalyst. Isolated as 96:4 mixture of
b
c
In summary, we have developed a rhodium catalyst that
promotes the hydroacylation of ortho-allylbenzaldehydes to
2h:3h.
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Letter
J. B.; Duffin, T. O.; LaBarte, T. L.; Maddock, M. L.; Wheeler, O. W.
Tetrahedron Lett. 2012, 53, 1275. (c) Coulter, M. M.; Dornan, P. K.;
Dong, V. M. J. Am. Chem. Soc. 2009, 131, 6932. (d) Yang, F.; Jin, T.;
Yamamoto, Y. Tetrahedron 2012, 68, 5223.
(5) Beletskiy, E. V.; Sudheer, C.; Douglas, C. J. J. Org. Chem. 2012,
77, 5884.
generate 3,4-dihydronaphthalene-1(2H)-ones with excellent
enantioselectivities. These endo-selective processes are comple-
mentary to the recently reported exo- and enantioselective
NHC-catalyzed hydroacylations of the same substrates.7
Competitive alkene isomerization and ene/dehydration pro-
cesses are mitigated by a rhodium catalyst containing a bulky,
electron-rich bisphosphine ligand and a weakly coordinating
counteranion. This catalyst is prepared from readily available
precursors and promotes the desired hydroacylation reactions
to form products in high yields. Studies to exploit the features
of this catalyst system in additional classes of hydroacylation
reactions are ongoing in our laboratory.
(6) Hoshimoto, Y.; Hayashi, Y.; Suzuki, H.; Ohashi, M.; Ogoshi, S.
Angew. Chem., Int. Ed. 2012, 51, 10812.
(7) Janssen-Muller, D.; Schedler, M.; Fleige, M.; Daniliuc, C. G.;
̈
Glorius, F. Angew. Chem., Int. Ed. 2015, Ahead of Print (doi: 10.1002/
anie.201412302).
(8) Du, X.-W.; Ghosh, A.; Stanley, L. M. Org. Lett. 2014, 16, 4036.
(9) (a) Hyatt, I. F. D.; Anderson, H. K.; Morehead, A. T., Jr.; Sargent,
A. L. Organometallics 2008, 27, 135. (b) Roy, A. H.; Lenges, C. P.;
Brookhart, M. J. Am. Chem. Soc. 2007, 129, 2082.
(10) Jagdale, A. R.; Park, J. H.; Youn, S. W. J. Org. Chem. 2011, 76,
7204.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02559.
(11) (a) Nishida, H.; Takada, N.; Yoshimura, M.; Sonoda, T.;
Kobayashi, H. Bull. Chem. Soc. Jpn. 1984, 57, 2600. (b) Brookhart, M.;
Grant, B.; Volpe, A. F., Jr. Organometallics 1992, 11, 3920. (c) Yakelis,
N. A.; Bergman, R. G. Organometallics 2005, 24, 3579.
Experimental procedures and characterization data for all
new compound (PDF)
(12) For examples of olefin isomerization in intramolecular
hydroacylation and additional Rh-catalyzed processes, see: (a) Hassam,
M.; Taher, A.; Arnott, G. E.; Green, I. R.; van Otterlo, W. A. L. Chem.
Rev. 2015, 115, 5462. (b) Marder, T. B.; Roe, D. C.; Milstein, D.
Organometallics 1988, 7, 1451. (c) Campbell, R. E., Jr.; Lochow, C. F.;
Vora, K. P.; Miller, R. G. J. Am. Chem. Soc. 1980, 102, 5824.
(d) Okamoto, R.; Tanaka, K. Org. Lett. 2013, 15, 2112. (e) Tanaka, K.;
Fu, G. C. J. Am. Chem. Soc. 2001, 123, 11492. (f) Takeishi, K.;
Sugishima, K.; Sasaki, K.; Tanaka, K. Chem. - Eur. J. 2004, 10, 5681.
(g) Okamoto, R.; Okazaki, E.; Noguchi, K.; Tanaka, K. Org. Lett. 2011,
13, 4894. (h) Zhuo, L. G.; Yao, Z.-K.; Yu, Z.-X. Org. Lett. 2013, 15,
4634. (i) Vora, K. P.; Lochow, C. F.; Miller, R. G. J. Organomet. Chem.
1980, 192, 257.
(13) The isomerization of 1a does not occur via endocyclic β-hydride
elimination as recently reported for the rhodium-catalyzed isomer-
ization of 4-pentenals to 3-pentenals (Yip, S. Y. Y.; Aissa, C. Angew.
Chem., Int. Ed., 2015, 54, 6870). See the Supporting Information for
details on hydroacylation and isomerization of deuterated 1a.
(14) For the influence of ligand sterics and electronics on reductive
elimination, see: (a) Hartwig, J. F. Organotransition Metal Chemistry:
From Bonding to Catalysis; University Science Books: Sausalito, CA,
2010. (b) Brown, J. M.; Cooley, N. A. Chem. Rev. 1988, 88, 1031.
(c) Jones, W. D.; Kuykendall, V. L. Inorg. Chem. 1991, 30, 2615.
(d) Brown, J. M.; Guiry, P. J. Inorg. Chim. Acta 1994, 220, 249.
(e) Freixa, Z.; van Leeuwen, P. W. N. M. Dalton Trans. 2003, 1890.
(15) The kinetic isotope effect for the hydroacylation of 1a and d-1a
was determined to be 1.19. This value is consistent with reductive
elimination as the turnover-limiting step of the reaction mechanism.
See Supporting Information for experimental details.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: lstanley@iastate.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Iowa State University and the National Science
Foundation (CHE-CAREER 1353819) for financial support of
this work. We thank Professor Emeritus Richard Larock (Iowa
State University) for instrumentation and chemicals.
REFERENCES
■
(1) For selected reviews, see: (a) Willis, M. C. Chem. Rev. 2010, 110,
725. (b) Murphy, S. K.; Dong, V. M. Chem. Commun. 2014, 50, 13645.
(2) For selected examples, see: (a) Hirano, K.; Biju, A. T.; Piel, I.;
Glorius, F. J. Am. Chem. Soc. 2009, 131, 14190. (b) Biju, A. T.; Wurz,
N. E.; Glorius, F. J. Am. Chem. Soc. 2010, 132, 5970. (c) Padmanaban,
M.; Biju, A. T.; Glorius, F. Org. Lett. 2011, 13, 5624. (d) Piel, I.;
Steinmetz, M.; Hirano, K.; Frohlich, R.; Grimme, S.; Glorius, F. Angew.
̈
Chem., Int. Ed. 2011, 50, 4983. (e) Franz, J. F.; Fuchs, P. J. W.; Zeitler,
K. Tetrahedron Lett. 2011, 52, 6952. (f) Wang, Z.; Yu, Z.; Wang, Y.;
Shi, D. Synthesis 2012, 44, 1559. (g) Lu, H.; Lin, J.-B.; Liu, J.-Y.; Xu, P.-
F. Chem. - Eur. J. 2014, 20, 11659. (h) Alcaide, B.; Almendros, P.;
(16) (a) Shimizu, H.; Nagasaki, I.; Saito, T. Tetrahedron 2005, 61,
5405. (b) Shen, Z.; Dornan, P. K.; Khan, H. A.; Woo, T. K.; Dong, V.
M. J. Am. Chem. Soc. 2009, 131, 1077.
̀
Fernandez, I.; Martínez del Campo, T.; Naranjo, T. Chem. - Eur. J.
2015, 21, 1533.
(3) For selected examples, see: (a) Gulbis, J.; Everett, G. W., Jr.;
Frank, C. W. J. Am. Chem. Soc. 1976, 98, 1280. (b) Larock, R. C.;
Oertle, K.; Potter, G. F. J. Am. Chem. Soc. 1980, 102, 190. (c) Fairlie,
D. P.; Bosnich, B. Organometallics 1988, 7, 936. (d) Fairlie, D. P.;
Bosnich, B. Organometallics 1988, 7, 946. (e) Barnhart, R. W.; Wang,
X. Q.; Noheda, P.; Bergens, S. H.; Whelan, J.; Bosnich, B. J. Am. Chem.
Soc. 1994, 116, 1821. (f) Barnhart, R. W.; Bosnich, B. Organometallics
1995, 14, 4343. (g) Barnhart, R. W.; McMorran, D. A.; Bosnich, B.
Chem. Commun. 1997, 589. (h) Kundu, K.; McCullagh, J. V.;
Morehead, A. T., Jr. J. Am. Chem. Soc. 2005, 127, 16042. (i) Arnold, J.
S.; Mwenda, E. T.; Nguyen, H. M. Angew. Chem. 2014, 126, 3762.
(j) Ghosh, A.; Stanley, L. M. Chem. Commun. 2014, 50, 2765.
(k) Hoffman, T. J.; Carreira, E. M. Angew. Chem., Int. Ed. 2011, 50,
10670.
(17) (a) Muerling, A. Chemica Scripta 1987, 27, 349. (b) Barry, J.;
Kagain, H.-B. Tetrahedron 1971, 27, 4737.
(4) (a) Bendorf, H. D.; Colella, C. M.; Dixon, E. C.; Marchetti, M.;
Matukonis, A. N.; Musselman, J. D.; Tiley, T. A. Tetrahedron Lett.
2002, 43, 7031. (b) Bendorf, H. D.; Ruhl, K. E.; Shurer, A. J.; Shaffer,
D
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