N-heterocyclic carbene-catalyzed hydroacylation of unactivated double bonds

Article abstract of DOI:10.1021/ja906361g

(Chemical Equation Presented) An intramolecular N-heterocyclic carbene (NHC)-catalyzed hydroacylation of unactivated double bonds is reported. Systematic variation of the catalyst structure revealed an N- mesitylthiazolylidene annulated with a seven-membered ring to be especially reactive. This NHC enables a unique C-C bond-forming reaction to afford substituted chroman-4-ones in moderate to excellent yields, even ones containing all-carbon quaternary centers.

Full text of DOI:10.1021/ja906361g

Published on Web 09/17/2009
N-Heterocyclic Carbene-Catalyzed Hydroacylation of Unactivated Double Bonds
Keiichi Hirano, Akkattu T. Biju, Isabel Piel, and Frank Glorius*
Organisch-Chemisches Institut der Westfa¨lischen Wilhelms-UniVersita¨t Mu¨nster, Corrensstrasse 40,
48149 Mu¨nster, Germany
Received July 29, 2009; E-mail: glorius@uni-muenster.de
Table 1. Optimization of the Reaction Conditionsa
N-Heterocyclic carbene (NHC)-catalyzed umpolung reactions of
aldehydes constitute an important class of organocatalysis and have
found a broad range of applications in synthetic organic chemistry.1
The corresponding nucleophilic acyl anion or homoenolate equiva-
lent intermediates can react with various electrophiles, like alde-
hydes,2 ketones,2c,3 imines,4 and activated, polarized CdC double
bonds.5 The latter class of reactions is especially interesting, since
olefins are ubiquitous in organic chemistry. Intriguingly, however,
whereas many transition-metal-catalyzed processes make use of
unactivated olefin substrates, the incorporation of unactivated olefins
in organocatalyzed reactions is very rare. The organocatalyzed
addition of aldehydes, converted to acyl anion equivalents by
umpolung,ontounactivatedolefinssthehydroacylationofolefinsshas
not been previously reported.6 In this Communication, we report
the first NHC-organocatalyzed hydroacylation of unactivated olefins,
namely the first Stetter reaction with unactiVated olefins.
entry
variation of the standard conditionsa
yield of 2a (%)b
1
2
3
4
5
6
7
8
9
none
4 instead of 3
5 instead of 3
6 instead of 3
69
2
21
2
11
34
3
32
69
7 instead of 3
DBU: 20 mol % instead of 40 mol %
TEA instead of DBU
K2CO3 instead of DBU
KOt-Bu instead of DBU
10 mol % of 3, 20 mol % DBU
reaction time: 2 h instead of 1 h
10
11
65
Our study commenced with the optimization of the cyclization
of O-allylated o-vanillin 1a to the corresponding chromanone 2a
(Table 1).7 Among a wide range of NHCs, the carbene generated
by deprotonation with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
from thiazolium salt 38 showed the best reactivity, within 1 h
providing the desired chroman-4-one 2a in 69% yield (based on
GC; entry 1). Other common NHCs generated from 4-7 and other
azolium salts7 reduced the yield dramatically (entries 2-5). The
excess amount of DBU with respect to 3 is essential to achieve
satisfactory yields (entry 6), and a strong base is required to promote
the desired reaction efficiently (entries 7-9). Finally, a longer
reaction time of 2 h improved the isolated yield to 85% (entry 11).
This new method can be applied to a range of substrates with
different substitution patterns of the aromatic ring (Table 2). First,
various electron-donating substituents at the 2-position are well
tolerated (2a-d). In addition, aldehydes bearing halides on the
aromatic ring readily cyclize to afford the corresponding chro-
manones (2e-g). Methylthioether, trimethylsilyl, phenyl, cinnamyl,
and even a strongly electron-withdrawing trifluoromethyl substituent
are all tolerated (2h-l). Furthermore, disubstituted aldehydes with
alkyl as well as halogen and ether substitution undergo the
hydroacylation in good yields (2m-p). The transformations of the
naphthaldehydes 1q,r resulted in smooth product formation in high
yields of up to 95% (2q,r). An even more highly substituted
chromanone 2s is obtained in 77% yield. Finally, the unsubstituted
parent system 1t also works well, providing chromanone 2t.
Moreover, this novel transformation is not limited to chromanone
formation, but instead, a nitrogen tether can successfully replace
the oxygen linkage, giving dihydroquinolinone 2u in 71% yield.
Next, substrates with differently substituted allyl moieties were
tested. The (E)-crotyl-substituted substrate 8a gave only trace
amounts of chromanone 9a (Table 3, entry 1), and the aldehyde
bearing a (Z)-2-pentenyl group gave no substantial amount of the
corresponding product 9c at all (entry 3). Interestingly, these results
indicate that simple alkyl substitution on the terminal carbon of
81 (85)c
a Standard conditions: 1a (0.25 mmol), NHC ·HX (20 mol %), DBU
(40 mol %), 1,4-dioxane (0.5 mL), 120 °C, and 1 h. b GC yield using
mesitylene as an internal standard. c Isolated yield in parentheses.
the allyl group significantly reduces the reactivity of the double
bond. Switching to a phenyl substituent (8b) improved the yield
of the desired product 9b to 25% (entry 2). Intriguingly, however,
slightly electron-withdrawing (Z)-benzyloxymethyl substitution at
the terminal allylic carbon led to a smooth cyclization in 93%
isolated yield (entry 4). The related substrate 8e, with two allylic
ethers, could be transformed into the desired chromanone 9e with
complete chemoselectivity (entry 5). Moreover, a triple bond was
also found to be compatible with this novel cyclization reaction
(entry 6).
The construction of all-carbon quaternary centers9 poses a great
challenge. Gratifyingly, NHC precursor 3 catalyzed the cyclization
of aldehyde substrates 10 to the chromanones 11a-d with newly
formed all-carbon stereocenters in the chromanone ring in excellent
yields (Scheme 1). Electron-donating (11a) and -withdrawing (11b)
substituents, as well as variation at the newly formed quaternary
center (11d), were well tolerated.
Likely, the reaction is initiated by the formation of a Breslow
intermediate.10 In a concerted Conia-ene-type transition state,11 the
enamine could then add to the olefin of the allyl moiety, and at the
same time the negative charge building up on the other end of the
olefin is stabilized by deprotonation of the hydroxyl group.
In conclusion, we have developed a transition-metal-free12 NHC-
organocatalyzed hydroacylation of unactivated double bonds. This
method readily affords biologically and pharmaceutically interesting
9
14190 J. AM. CHEM. SOC. 2009, 131, 14190–14191
10.1021/ja906361g CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Table 2. NHC-Catalyzed Hydroacylation of Unactivated Double
Acknowledgment. We thank Ms. Karin Gottschalk, Dr. Klaus
Bergander, Dr. Sascha Nowak, and Prof. Uwe Karst for support
and Prof. Jeffrey Bode and Prof. Armido Studer for helpful
discussions. Generous financial support by the DFG and fellowships
by the DAAD (K.H.), Alexander von Humboldt Foundation
(A.T.B.), and the International NRW Graduate School of Chemistry
(I.P.) are gratefully acknowledged. The research of F.G. has been
supported by the Alfried Krupp Prize for Young University
Teachers of the Alfried Krupp von Bohlen und Halbach Foundation.
a
Bonds: Variation of the Aromatic Ring
Supporting Information Available: Experimental and characteriza-
tion details. This material is available free of charge via the Internet at
http://pubs.acs.org.
References
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a General conditions: 1 (1.0 mmol), 3 (20 mol %), DBU (40 mol %),
1,4-dioxane (2.0 mL), 120 °C, and 2 h. Given are isolated yields. b 24 h.
c 0.40 mmol scale. d 3 h. e Using 10 mol % of 3, an isolated yield of
91% was obtained. f 0.32 mmol scale. g 6 h. h 0.69 mmol scale, 132 h.
chroman-4-ones and demonstrates an unprecedented reactivity of
the catalytically generated acyl anion equivalent. Efforts to obtain
further insight into the mechanism and the development of an
asymmetric variant are ongoing.
Table 3. Variation of the Allyl Moietya
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681.
entry
R1
R2
product
yield of 9 (%)b
1
2
3
4
5
6
H
H
CH3
Ph
H
H
H
9a
9b
9c
9d
9e
9f
<5
25
(7) See Supporting Information for further details.
CH2CH3
<5
(8) Lebeuf, R.; Hirano, K.; Glorius, F. Org. Lett. 2008, 10, 4243.
(9) Trost, B. M.; Jiang, C. Synthesis 2006, 369.
(10) Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719.
(11) For a recent example and key references on the Conia-ene reaction, see:
Corkey, B. K.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 17168. In our
reaction, the NHC might generate a 1,3-enophile undergoing a concerted
Conia-ene-type reaction. Despite different transition-state geometries of the
Conia-ene and our reaction (six- vs five-membered, respectively), the overall
similarity, including the polarity of the reacting olefins, is striking.
CH2OCH2Ph
CH2OCH2CHdCH2
CH2OCH2C′CCH2CH3
93c
89c
83c
H
a General conditions: 8 (1.0 mmol), 3 (20 mol %), DBU (40 mol %),
1,4-dioxane (2.0 mL), 120 °C, 2 h. b Isolated yield. c 24 h.
Scheme 1. Formation of All-Carbon Quaternary Stereocenters
(12) ICP-OES (inductively coupled plasma optical emission spectrometry)
analyses were performed determining the amount of transition-metal
impurities in the reaction mixture. No significant amounts of any transition-
metal contaminant were detected.7
JA906361G
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J. AM. CHEM. SOC. VOL. 131, NO. 40, 2009 14191