An efficient carbene-catalyzed access to 3,4-dihydrocoumarins

Full text of DOI:10.1021/jo802285r

First, the high chemoselectivity of nucleophilic carbenes can
be utilized for protecting group-free synthesis;6 moreover, the
potential to alter the practice of traditional retrosynthetic analysis
is of particular interest.7
An Efficient Carbene-Catalyzed Access to
3,4-Dihydrocoumarins
Kirsten Zeitler* and Christopher A. Rose
Synthetic approaches to lactone derivatives that rely on the
catalytic generation of activated carboxylates or enols via
N-heterocyclic carbene-catalyzed reactions of R-functionalized
aldehydes3d have witnessed impressive and rapid progress in
the past few years.8,9 In connection with our work on NHC-
mediated umpolung reactions,10 we considered application of
nucleophilic carbenes for a catalytic access to coumarin deriva-
tives. Herein, we disclose that o-hydroxycinnamaldehydes
cyclize efficiently in the presence of triazolin-5-ylidene carbenes
to form dihydrocoumarins or, under oxidative conditions, their
unsaturated counterparts in moderate to high yield.
Institut fu¨r Organische Chemie, UniVersita¨t Regensburg,
UniVersita¨tsstrasse 31, D-93053 Regensburg, Germany
kirsten.zeitler@chemie.uni-regensburg.de
ReceiVed October 10, 2008
Dihydrocoumarins play an important role as flavor and
fragrance compounds and can be prepared efficiently from
o-hydroxycinnamaldehydes in a mild, atom-economic
N-heterocyclic carbene-catalyzed redox lactonization. Cor-
responding coumarins are accessible via a one-pot domino
oxidation lactonization procedure in the presence of oxidants.
FIGURE 1. Dihydrocoumarins and coumarins by carbene-catalyzed
extended umpolung lactonization.
Coumarins and dihydrocoumarins present a large class of
natural products that have attracted considerable interest due
to their various biological activities.11 Moreover, coumarins play
an important role as fluorescent materials and as dyes in laser
technology.11c,12 Hence, several conventional methods13 are
available to prepare coumarin derivatives, but most of these
With respect to an increasing need for efficient and new
catalytic synthetic methods, organocatalysis represents a power-
ful field and has found widespread application over the past
decade.1,2 The rapidly growing interest in N-heterocyclic carbene
(NHC)-catalyzed processes might be attributed to the great
versatility of these organocatalytic transformations3 but is also
associated with the possibilities that arise from the NHC’s
characteristic inversion of the classical reactivity, i.e., umpol-
ung.4
(6) (a) Hoffmann, R. W. Synthesis 2006, 3531–3541. (b) Gademann, K.;
Bonazzi, S. Angew. Chem., Int. Ed. 2007, 46, 5656–5658. For two recent
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(7) Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis; Wiley: New
York, 1995.
(8) (a) For examples of NHC-catalyzed preparation of lactones, see the
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2006, 2418–2439. (b) Wadamoto, M.; Phillips, E. M.; Reynolds, T. E.; Scheidt,
K. A. J. Am. Chem. Soc. 2007, 129, 10098–10099. γ-Butyrolactones: (c) Sohn,
S. S.; Rosen, E. L.; Bode, J. W. J. Am. Chem. Soc. 2004, 126, 14370–14371.
(d) Glorius, F.; Burstein, C. Angew. Chem., Int. Ed. 2004, 43, 6205–6208. (e)
Ye, W.; Cai, G.; Zhuang, Z.; Jia, X.; Zhai, H. Org. Lett. 2005, 7, 3769–3771.
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8, 507–509. (g) Li, Y.; Zhao, Z.-A.; He, H.; You, S.-L. AdV. Synth. Catal. 2008,
350, 1885–1890. δ-Lactones (in combination with Michael reaction): (h) Phillips,
E. M.; Wadamoto, M.; Chan, A.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007,
46, 3107–3110. δ-Lactones (in combination with Aldol reaction): (i) Tora¨ng, J.;
Vanderheiden, S.; Nieger, M.; Bra¨se, S. Eur. J. Org. Chem. 2007, 943–947.
δ-Lactones via hetero-Diels-Alder reaction: (j) He, M.; Uc, G. J.; Bode, J. W.
J. Am. Chem. Soc. 2006, 128, 15088–15089. (k) He, M.; Beahm, B. J.; Bode,
J. W. Org. Lett. 2008, 10, 3817–3820.
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zwitterionic enolates, see: Zhang, Y.-R.; Lv, H.; Zhou, D.; Ye, S. Chem.sEur.
J. 2008, 14, 8473–8476.
(10) (a) Zeitler, K. Org. Lett. 2006, 8, 637–640. (b) Zeitler, K.; Mager, I.
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Prod. Rep. 1997, 14, 465–475. (c) O’Kennedy, R.; Thornes, R. D. Coumarins:
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Vol. 3, pp 799-810. (b) See also references cited in ref 14a.
Inspired by Nature’s ability to perform nucleophilic acylations
within thiamine-dependent enzymes,5 NHC catalysis merges two
important strategic advantages for efficient synthetic methods.
(1) (a) Berkessel, A.; Gro¨ger, H. Asymmetric Organocatalysis; Wiley-VCH:
Weinheim 2005. (b) Dalko, P. I. EnantioselectiVe Organocatalysis; Wiley-VCH:
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(2) For some recent reviews on organocatalysis, see: (a) Dondoni, A.; Massi,
A. Angew. Chem., Int. Ed. 2008, 47, 4638–4660. (b) Special issue on
organocatalysis: Chem. ReV. 2007, 107 (12), 5413-5883. (c) Special issue on
organocatalysis: Acc. Chem. Res. 2004, 37 (8), 487-631. (d) Special issue on
organocatalysis: AdV. Synth. Catal. 2004, 346 (9/10), 1007–1249. (e) Dalko,
P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138–5175. (f) Seayad, J.;
List, B. Org. Biomol. Chem. 2005, 3, 719–724.
(3) For recent reviews on NHC-catalyzed reactions, see: (a) Enders, D.;
Niemeier, O.; Henseler, A. Chem. ReV. 2007, 107, 5606–5655. (b) Zeitler, K.
E. Schering Found. Symp. Proc. 2007, 2, 183–206. (c) Marion, N.; D´ıez-
Gonza´lez, S.; Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 2988–3000. (d)
Zeitler, K. Angew. Chem., Int. Ed. 2005, 44, 7506–7510. (e) Enders, D.;
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Mu¨ller, M.; Sprenger, G. A. In OxidatiVe Stress and Diseases - Thiamine:
Catalytic Mechanisms and Disease States; Jordan, F., Patel, M. S., Eds.; Marcel
Dekker: New York, 2004; pp 77-90.
10.1021/jo802285r CCC: $40.75
Published on Web 01/26/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 1759–1762 1759

traditional approaches suffer from harsh reaction conditions and
are only rarely catalytic.14 Dihydrocoumarins (DHC), which play
an important role as flavor and fragrance compounds in both
food and cosmetics (perfumes), are traditionally prepared by
transition-metal-catalyzed hydrogenations of coumarins or, more
recently, by biotechnological methods.15 Interestingly, despite
the need for metal-free and enviromentally benign routes, only
very few organocatalytic examples have been reported.16
A
synthesis of 3-alkylcoumarins using a “non-innocent” imida-
zolium ionic liquid as (super)stoichiometric mediator was
recently described by Bra¨se and co-workers.8i
FIGURE 2. Evaluated heterazolium carbene precursors.
We assumed that reaction of easy accessible o-hydroxycin-
namaldehydes with NHCs would result in the formation of 3,4-
dihydrocoumarins via an intramolecular redox lactonization
process. For exploratory studies, 2-hydroxycinnamaldehyde 1
was selected as model substrate.17
Systematic evaluation of a variety of triazolium salts revealed
that both the sterically demanding mesityl N-substituent (entry
7, catalyst 7b) and an electron-rich backbone p-methoxyphenyl
substituent (entry 8, catalyst 7c) were important to achieve useful
reaction rates and yields (entry 9, catalyst 7d). Moreover, the
catalyst loading could be reduced to 5 mol %. The importance
of the N-aryl substituents of triazolium salts was highlighted
by Rovis20 only recently, and Bode et al. reported on the striking
differences in reactivity between triazolium and imidazolium
precursors for a number of different NHC-catalyzed processes.21
TABLE 1. Dihydrocoumarin Synthesis with Different
Heterazolium Carbene Precursors
TABLE 2. Optimization of Reaction Conditions: Influence of
Bases and Solvents
entrya
catalyst
mol %
yielda (%)
1b
2c
3
3
4
5
6a
6b
7a
7b
7c
7d
10
10
5
10
10
10
5
no conv
no conv
no conv
41
42
34
53
22
61
4c
5d
6c
7
entrya
base/cocatalyst (mol %)
solvent
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
THF
yieldb (%)
8
9
5
5
1
K3PO4
DMAP
NEt3
20
8
8
51
61
2c
3c
4c
5c
6c
7
a Yield of isolated product after column chromatography. b 20 mol %
of KOtBu was used as base instead of DMAP. c 20 mol % of base was
used. d NEt3 was used instead of DMAP (reaction was significantly
slower with DMAP).
63/88d
no conv
15
Pyridine
Imidazole
PPY
DIPEA
HOBt/DIPEA
DMAP
DMAP
DMAP
20
20
20
20
10/20
20
20
8
56
54
54
44
50
61
8
9
10
11
THF
We started our experimental investigations with a survey of
different heterazolium precatalysts. Notably, thiazolium 3,
benzimidazolium 4, and imidazolium 5 saltssall known as
potent precatalysts for internal redox reactions18sfailed to give
any conversion and proved to be ineffective for the desired ring-
closing transformation.19
CH3CN
tBuOH
EtOAcdegassed
a Reaction conditions: 10 mol % of 7d at 80 °C unless stated
otherwise. b Yield of isolated product after column chromatography. c 5
mol % of catalyst 7d was used. d Determined by 1H NMR analysis of
crude reaction mixture relative to an internal quantitative standard
(octamethylcyclotetrasiloxane). PPY ) 4-pyrrolidinopyridine, HOBt )
hydroxybenzotriazole, DIPEA ) diisopropylethylamine.
(14) For some recent transition-metal-catalyzed reactions, see: (a) Gabriele,
B.; Mancuso, R.; Salerno, G.; Plastina, P. J. Org. Chem. 2008, 73, 756–759. (b)
Kotani, M.; Yamamoto, K.; Oyamada, J.; Fujiwara, Y.; Kitamura, T. Synthesis
2004, 1466–1470. (c) Kadnikov, D. V.; Larock, R. C. Org. Lett. 2000, 2, 3643–
3646. (d) Trost, B. M.; Toste, F. D.; Greenman, K. J. Am. Chem. Soc. 2003,
125, 4518–4526.
(15) (a) Kuhn, W.; Funk, H.-U.; SenftG. (Haarmann & Reimer GmbH)
WO2002018360, 2002. (b) Zhang, Z.; Ma, Y.; Zhao, Y. Synlett 2008, 1091–
1095. (c) Ha¨ser, K.; Wenk, H. H.; Schwab, W. J. Agric. Food Chem. 2006, 54,
6236–6240.
(16) (a) For an elegant phosphine-catalyzed exception, see: Henry, C. E.;
Kwon, O. Org. Lett. 2007, 9, 3069–3072. For the preparation of furo-coumarins
using an enamine approach, see: (b) Rueping, M.; Merino, E.; Sugiono, E. AdV.
Synth. Catal. 2008, 350, 2127–2131. (c) For a concurrent related NHC-catalyzed
access, see: Du, D.; Wang, Z. Eur. J. Org. Chem. 2008, 4949–4954.
(17) Substrates could be prepared in good yields via Wittig olefination of
the corresponding salicylaldehydes and (formylmethylene)triphenylphosphorane:
Bunce, R. A.; Schilling, C. L., III. Tetrahedron 1996, 53, 9477–9486. For a
general procedure, see the Supporting Information.
With the identification of 7d as a suitable catalyst, the reaction
conditions were further optimized. A variety of inorganic and
organic bases were examined (Table 2) and showed comparable
promising results for DMAP (entry 2) and triethylamine (entry
3). A screen of possible acylation cocatalysts (entries 4, 5, 6,
8), as described concurrently by Rovis and Bode in the context
of relay catalysis for amide bond formation,22 did not show a
beneficial effect on further promoting the cyclization reaction.
Remarkably, the reaction can be carried out in various apolar
and polar (Table 2, entries 7 and 9) and even protic solvents
(entry 10) with comparable yields. The use of dry solvents is
(18) (a) Thiazolium: Reynolds, N. T.; Read de Alaniz, J.; Rovis, T. J. Am.
Chem. Soc. 2004, 126, 9518–9519. (b) Chow, K. Y.-K.; Bode, J. W J. Am. Chem.
Soc. 2004, 126, 8126–8127. (c) Benzimidazolium: Chan, A.; Scheidt, K. A. Org.
Lett. 2005, 7, 905–908. Imidazolium, see ref 8c,d.
(19) Application of reaction conditions as reported by Scheidt et al. (ref 18c)
for a related intermolecular reaction did not yield the desired product.
(20) Rovis, T. Chem. Lett. 2008, 37, 2–7.
(21) Struble, J. R.; Kaeobamrung, J.; Bode, J. W. Org. Lett. 2008, 10, 957–
960.
(22) (a) Vora, H. U.; Rovis, T. J. Am. Chem. Soc. 2007, 129, 13796–13797.
(b) Bode, J. W.; Sohn, S. S. J. Am. Chem. Soc. 2007, 129, 13798–13799.
1760 J. Org. Chem. Vol. 74, No. 4, 2009

TABLE 3. Scope of the Reaction
not mandatory; hence, single-distilled technical-grade solvents
can be used. Interestingly, we noticed the formation of small
amounts of the corresponding oxidized coumarin byproduct 2b
(ratio 14:1; Table 2, entry 2), but simple degassing of the
solvents by purging the solvent with argon or via a freeze-
pump-thaw procedure significantly reduced these oxidized side
products (ratio 25:1; Table 2, entry 11, and Scheme 1).
SCHEME 1. Formation of Minor Amounts of Oxidized
1
Coumarin Byproduct (Ratio Determined by H NMR)
A rational for this oxidative pathway of the reaction is
provided by mechanistic considerations (Scheme 2): upon initial
nucleophilic attack of the nucleophilic carbene I to the aldehyde
function, oxidation of the tetrahedral intermediate II is facilitated
by this generation of a transient “benzylic” alcohol. Rapid
oxidation of similar intermediates was observed by Scheidt and
co-workers in the presence of oxidizing reagents.23,24
NMR studies of the reaction progress revealed the straight-
forward, clean transformation of both E- and Z-isomers of the
unsaturated starting material to yield 3,4-dihydrocoumarin 2a
in combination with only minor amounts of the oxidized
coumarin product 2b (ratio >97:3). The yield of the model
reaction was determined to be greater than 88% by quantitative
NMR analysis of the crude reaction mixture relative to OMS
(octamethylcyclotetrasiloxane) as a quantitative internal standard
(entry 3).25 Both NMR experiments underline the efficiency of
this intramolecular redox lactonization. Due to the high volatility
of these fragrance compounds, some product might be sacrificed
during the workup and purification procedures resulting in lower
isolated yields. Consequently, we turned our attention to the
improvement of the procedure for the product isolation, and
we were pleased to find an even simplified “column-free”
purification method that allows for significantly higher isolated
yields (75% vs 63%).
a Reaction conditions: 5 mol % of 7d with 8 mol % of DMAP in
EtOAc at 80 °C. b Yield of isolated product (mixture of A and B) after
optimized aqueous workup procedure. c 8 mol % of NEt3 was used.
d THF was used as solvent.
Using these optimized conditions, we examined the scope of
the new carbene-catalyzed dihydrocoumarin synthesis. A variety
of different substituted o-hydroxycinnamaldehydes are suitable
substrates for the redox lactonization. The reaction is tolerant
to both electron-rich (Table 3, entries 2, 3, 6, 7, and 8) and
electron-poor aldehyde derivatives (entries 4 and 5).
Notably, the electron-rich substrates appeared to be more
prone to the formation of oxidized coumarin side products.
Comparison of the three regioisomeric methoxy-substituted
substrates (Table 3, entries 6-8) with respect to the ratio of
coumarin generation nicely displays its dependency on electronic
effects where the para-derivative (entry 7) proves to be most
easily oxidized. Only the strongly electron-deficient nitro
derivative failed to undergo the cyclization with useful yield
(entry 9), which might be due to the diminished nucleophilicity
of the electron-poor phenolate.
In addition to its robustness with regard to suitable solvents
and reaction conditions, one of the strengths of our catalytic
protocol is also the atom-economic26 preparation of the desired
dihydrocoumarins.
The catalytic cycle is postulated to initiate upon generation
of the carbene I, which undergoes nucleophilic addition to the
o-hydroxycinnamaldehyde 8 (scheme 2) forming the tetrahedral
intermediate II. Deprotonation to furnish homoenolate equiva-
lent IV and subsequent generation of the activated acyl azolium
intermediate VI by tautomerization of the protonated species
V allows for catalyst turnover by intramolecular acylation to
yield the dihydrocoumarin A. Under oxidizing conditions, the
reaction can proceed via an alternative, oxidative pathway (vide
supra and vide infra). Here, the crucial (unsaturated) acyl
(23) (a) For a detailed study of this benzylic activation of aldehyde precursors,
refer to: Maki, B. E.; Scheidt, K. A. Org. Lett. 2008, 10, 4331–4334. For a
MnO2 tandem oxidation approach, see: (b) Maki, B. E.; Chan, A.; Phillips, E. M.;
Scheidt, K. A. Org. Lett. 2007, 9, 371–374. (c) Guin, J; De Sarkar, S.; Grimme,
S.; Studer, A. Angew. Chem., Int. Ed. 2008, 47, 8727–8730.
(24) The residual amount of oxidized byproduct (3%) could be assigned to
an alternative hydride-transfer mechanism. As described by Scheidt et al. in the
context of stereoselective protonation attempts of homoenolates, alternatively,
intermediate III could be formed in a Cannizzaro-type fashion via intermolecular
hydride transfer, but at the cost of the reduction of an equimolar amount of the
starting material. Maki, B. E.; Chan, A.; Scheidt, K. A. Synthesis 2008, 1306–
1315.
(25) For details, see the Supporting Information.
(26) Trost, B. M. Science 1991, 254, 1471–1477.
J. Org. Chem. Vol. 74, No. 4, 2009 1761

SCHEME 2. Postulated Mechanism for the
Carbene-Catalyzed Synthesis of Dihydrocoumarins and
Coumarins
In summary, we have developed a mild, carbene-catalyzed,
atom-economical access to 3,4-dihydrocoumarins that is
virtually insensitive to solvent effects. Additionally, perfor-
mance of the reaction in the presence of oxidizing reagents
allows for the formation of coumarin derivatives in a one-
pot domino oxidation-lactonization sequence starting from
simple o-hydroxycinnamyl alcohols.
Experimental Section
General Procedure for the Preparation of Dihydro-
coumarins from 2-Hydroxycinnamaldehydes. An oven-dried
screw-capped test tube equipped with a magnetic stirring bar was
charged with the corresponding 2-hydroxycinnamaldehyde 8 (0.40
mmol, 1 equiv) and was then dissolved in ethyl acetate. After the
addition of triazolium salt 7d (0.02 mmol, 5 mol %), the vial was
set under a positive pressure of argon. Finally, the indicated
appropriate base (0.032 mmol, 8 mol %) was added, and the reaction
mixture was stirred at 80 °C for 15 h (TLC control).
Workup Procedure A. The reaction mixture was concentrated
under reduced pressure and purified by column chromatography to
yield pure chroman-2-one A.31
Dihydrocoumarin 2a (Table 2, Entry 3). Purification by flash
chromatography (hexanes/EtOAc 7:1) afforded compound 2a as
yellow oil (37 mg, 63%): 1H NMR (300 MHz, CDCl3) δ 7.26-7.10
(m, 2H), 7.10-6.95 (m, 2H), 3.01-2.89 (m, 2H), 2.78-2.69 (m,
2H); 13C NMR (75.5 MHz, CDCl3) δ 168.6, 152.0, 128.3, 128.0,
124.4, 122.6, 117.0, 29.3, 23.7.
SCHEME 3. Domino Reaction for the Preparation of
Coumarins
Acknowledgment. We gratefully acknowledge generous
support by the Fonds der Chemischen Industrie (Liebig fellow-
ship for K. Zeitler) and by the Deutsche Forschungsgemeinschaft
(DFG) as part of the priority program Organocatalysis (SPP
1179).
azolium species III that performs the intramolecular acyl transfer
to produce coumarin derivatives B is generated upon an
oxidation event.24
Taking advantage of the functional group tolerance and the
distinct chemoselectivity of both an allylic oxidation and the
subsequent redox lactonization, coumarins can be accessed in
a simple “one-pot” domino reaction27 starting from o-hydroxy-
cinnamyl alcohols.
Supporting Information Available: Experimental and char-
acterization data for compounds 2 and 9a to 16a and catalyst
7d, including NMR spectra (1H and 13C). This material is
available free of charge via the Internet at http://pubs.acs.org.
JO802285R
(28) (a) Corey, E. J.; Gilman, N. W.; Ganem, B. E. J. Am. Chem. Soc. 1968,
90, 5616–5617. (b) Foot, J. D; Kanno, H.; Giblin, G. M. P.; Taylor, R. J. K.
Synthesis 2003, 1055–1064.
(29) For a recent application of azobenzene as organic oxidizer, see: Noonan,
C.; Baragwanath, L.; Connon, S. J. Tetrahedron Lett. 2008, 49, 4003–4006.
(30) In the presence of bases like DMAP, coumarins can also be formed via
an alternative hemiacetal pathway,27b while solely MnO2 showed only incomplete
conversion suggesting a possible promotion of double-bond isomerization and
consequent acetalization by nucleophilic catalysts.
In the presence of an oxidizing agent, such as excess
MnO2,23b,28,29 the coumarin derivatives can be generated directly
from allyl alcohol precursors.30
(27) For excellent reviews on domino reactions, see: (a) Enders, D.; Grondal,
C.; Hu¨ttl, M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570–1581. (b) Tietze,
L. F. Chem. ReV. 1996, 96, 115–136. (c) Tietze, L. F.; Brasche, G.; Gericke, K.
Domino Reactions in Organic Synthesis; Wiley-VCH: Weinheim, 2006.
(31) For detailed information on the alternative column-free workup procedure
B, see the Supporting Information.
1762 J. Org. Chem. Vol. 74, No. 4, 2009