Phosphine-catalyzed synthesis of 1,3-dioxan-4-ylidenes

Article abstract of DOI:10.1021/ol050203y

(Chemical Equation Presented) A phosphine-catalyzed reaction of an allenoate with aldehydes furnished (2,6-diaryl-[1,3]dioxan-4-ylidene)-acetates 4 in excellent to moderate yields with complete diastereoselectivity and high E/Z-selectivities. Upon removal of the acetal functionality in this domino reaction product 4, δ-hydroxy-β-ketoester 11 was obtained. The reported vinylphosphonium-based approach provides a new way to achieve a synthesis of δ-hydroxy-β-ketoesters that differs from the classical dianion-based approach.

Full text of DOI:10.1021/ol050203y

ORGANIC
LETTERS
2005
Vol. 7, No. 7
1387-1390
Phosphine-Catalyzed Synthesis of
1,3-Dioxan-4-ylidenes
Xue-Feng Zhu, Christopher E. Henry, Jay Wang, Travis Dudding,† and
Ohyun Kwon*
Department of Chemistry and Biochemistry, UniVersity of California, Los Angeles,
607 Charles E. Young DriVe East, Los Angeles, California 90095-1569
ohyun@chem.ucla.edu
Received January 31, 2005
ABSTRACT
A phosphine-catalyzed reaction of an allenoate with aldehydes furnished (2,6-diaryl-[1,3]dioxan-4-ylidene)-acetates 4 in excellent to moderate
yields with complete diastereoselectivity and high E/Z-selectivities. Upon removal of the acetal functionality in this domino reaction product
4,
δ
-hydroxy-â-ketoester 11 was obtained. The reported vinylphosphonium-based approach provides a new way to achieve a synthesis of
δ
-hydroxy-
â
-ketoesters that differs from the classical dianion-based approach.
Catalysis employing phosphines and amines as nucleophilic
triggers has emerged as a rapidly growing area of synthetic
organic chemistry. In particular, phosphine catalysis of
allenoates and butynoates has proven to be useful for the
development of new annulation reactions providing various
carbo- and heterocycles.1 Despite the abundance of coupling
reactions between allenes and various electrophiles under
nucleophilic catalysis, there exist no reports on phosphine-
catalyzed reactions between allenes and aldehydes. As part
of a program focused on the development of organic
phosphine-mediated annulation reactions to form hetero-
cycles,2 we report herein the first phosphine-catalyzed
reaction of aldehydes with allenoates to produce 2,6-
disubstituted-1,3-dioxan-4-ylidene-acetates.
In an effort to expand the synthetic scope of previously
reported phosphine catalyzed [3 + 2] cycloadditions, we
explored the reactivity of allenoates with aldehydes.3 On the
basis of the reaction of N-tosylimines to form dihydropyr-
roles4 we expected to obtain dihydrofuran adducts. Contrary
to our expectations, dioxanylidenes 3E and 3Z5 were obtained
in 74% yield with exclusive cis-diastereoselectivity and high
E/Z-selectivity (E/Z ) 8:1) upon mixing ethyl allenoate (1a)
with 4-pyridinecarboxaldehyde (2a) in the presence of 20
† Current address: Department of Chemistry, Brock University, St.
Catharines, Ontario L2S 3A1, Canada.
(1) For a review, see: (a) Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res.
2001, 34, 535 and references therein. (b) Jung, C.-K.; Wang, J.-C.; Krische,
M. J. J. Am. Chem. Soc. 2004, 126, 4118. (c) Wang, J.-C.; Krische, M. J.
Angew. Chem., Int. Ed. 2003, 42, 5855. (d) Wang, J.-C.; Ng, S.-S.; Krische,
M. J. J. Am. Chem. Soc. 2003, 125, 3682. (e) Du, Y.; Lu, X. J. Org. Chem.
2003, 68, 6463. (f) Kuroda, H.; Tomita, I.; Endo, T. Org. Lett. 2003, 5,
129. (g) Du, Y.; Lu, X.; Yu, Y. J. Org. Chem. 2002, 67, 8901. (h) Lu, C.;
Lu, X. Org. Lett. 2002, 4, 4677. (i) Lu, B.; Davis, R.; Joshi, B.; Reynolds,
D. W. J. Org. Chem. 2002, 67, 4595. (j) Ung, A. T.; Schafer, K.; Lindsay,
K. B.; Pyne, S. T.; Amornraksa, K.; Wouters, R.; Van der Linden, I.;
Biesmans, I.; Lesage, A. S. J.; Skelton, B. W.; White, A. H. J. Org. Chem.
2002, 67, 227. (k) Kumar, K.; Kapoor, R.; Kapur, A.; Ishar, M. P. S. Org.
Lett. 2000, 2, 2023. (l) Kumar, K.; Kapur, A.; Ishar, M. P. S. Org. Lett.
2000, 2, 787. (m) Trost, B. M.; Dake, G. R. J. Am. Chem. Soc. 1997, 119,
7595.
(2) Zhu, X.-F.; Lan, J.; Kwon, O. J. Am. Chem. Soc. 2003, 125,
4716.
(3) Reaction of ethyl 2,3-butadienoate with aldehydes in the presence
of DABCO gave the normal Baylis-Hillman adducts. See: Tsuboi, S.;
Kuroda, H.; Takatsuka, S.; Fukawa, T.; Sakai, T.; Utaka, M. J. Org. Chem.
1993, 58, 5952.
(4) Xu, Z.; Lu, X. Tetrahedron Lett. 1997, 38, 3461.
(5) The connectivity and relative stereochemistry of these compounds
were confirmed by X-ray crystallographic analysis. Crystallographic data
for 3-E and 3-Z have been deposited with the Cambridge Crystallographic
Data Centre as supplementary numbers CCDC 250757 and 250758. CCDC
250757 and 250758 contain the supplementary crystallographic data for
this paper. These data can be obtained online free of charge (or from the
Cambridge Crystallographic Data Center, 12, Union Road, Cambridge CB2
1EZ, U.K..; fax: (+44) 1223-336-033; or deposit@ccdc.cam.ac.uk).
10.1021/ol050203y CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/04/2005

Table 1. Effect of Alkyl Group of Allenoates 1 on Formation
of ([1,3]Dioxan-4-ylidene)-acetates 3a
Table 2. Synthesis of Isopropyl
(2,6-Diaryl-[1,3]dioxan-4-ylidene)-acetates 4 from Isopropyl
2,3-Butadienoate and Aldehydesa
entry
R
3
yield (%)b E/Z ratioc
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1-naphthyl (1b)
phenyl (1c)
2,2,2-trifluoroethyl (1d)
2-fluoroethyl (1e)
benzyl (1f)
methyl (1g)
ethyl (1a)
isobutyl (1h)
neopentyl (1i)
2-trimethylsilylethyl (1j) 3j
isopropyl (1k)
trimethylsilylmethyl (1l) 3l
isopropyl (1k)
tert-butyl (1m)
3b
3c
3d
3e
3f
3g
3a
3h
3i
0
tr
0
n/a
n/a
n/a
7:1
n/a
8:1
9:1
8:1
8:1
8:1
8:1
8:1
8:1
10:1
entry
R
product
yield (%)b
E/Z ratioc
1
2
3
4
5d
6
7
8
9
10
11
12
13
14
15
16
17
4-pyridyl (2a)
3-pyridyl (2c)
2-pyridyl (2d)
4-CF3C6H4 (2e)
3-CF3C6H4 (2f)
2-CF3C6H4 (2g)
4-NO2C6H4 (2h)
3-NO2C6H4 (2i)
4-CNC6H4 (2j)
3-CNC6H4 (2k)
3-ClC6H4 (2b)
2-ClC6H4 (2l)
3-FC6H4 (2m)
Ph (2n)
4a
4c
4d
4e
4f
4g
4h
4i
99
96
47
99
90
65
84
97
99
98
87
64
77
54e
47
tr
8:1
9:1
4:1
7:1
8:1
6:1
8:1
7:1
7:1
7:1
8:1
8:1
14:1
only Ef
only Ef
n/a
22
34
50
37
68
68
71
72
75
87d
63
4j
3k
4k
3k
4l
4m
4n
4o
4p
4q
3k
3m
a See Supporting Information for experimental procedure. b Isolated
yields. c E/Z stereoisomer ratio determined on the basis of isolated yields.
d 10 equiv of 3-chlorobenzaldehyde was used.
3-MeOC6H4 (2o)
4-MeC6H4 (2p)
n-propyl (2q)
0
n/a
a See Experimental Section for experimental procedure. b Isolated yields.
c E/Z stereoisomer ratio determined on the basis of isolated yields. d 95%
of excess aldehyde was recovered. e 3 equiv Na2CO3 was added. f No minor
isomer was isolated.
mol % tributylphosphine in benzene at room temperature
[eq 1].
leaving ample room for improvement (37%, Table 1, entry
7). Electron-deficient alkyl or aryl groups proved detrimental
to the reaction (Table 1, entries 1-4). This observation stands
in contrast with the enhanced reactivity of acrylates bearing
electron-deficient alkyl or aryl groups in the Baylis-Hillman
reaction.8 Use of sterically demanding and electron-rich
substituents led to improved product yields (Table 1, entries
8-14). An exception to this general trend was observed for
the benzyl and methyl groups (Table 1, entries 5 and 6).
Extreme steric hindrance appeared to diminish product
formation only to a small extent (Table 1, entry 14). From
these results we speculate that steric factors are less important
and product formation is governed by the allenoate electron
density. Despite the optimal chemical yields obtained with
trimethylsilylmethyl allenoate (Table 1, entry 12), we elected
to use the more economical isopropyl allenoate for further
studies. The use of a larger excess of aldehyde (10 equiv)
led to a moderate increase in product yields (Table 1, entry
13). When an excess of allenoates was used, a mixture of
oligomeric products that contained more than 1 equiv of
allenoate formed.
Though the reaction remained exclusively cis-stereose-
lective as well as highly E-selective for a variety of aromatic
aldehydes, the product yields decreased significantly when
more electron-rich aromatic aldehydes were used. For
example, using the conditions in eq 1, 3-chlorobenzaldehyde
and benzaldehyde provided 28% and no product, respec-
tively. To expand the practical use of this transformation,
optimized experimental conditions were developed. Trim-
ethylphosphine provided the highest product yields among
many commercially available phosphines.6 Solvent studies
demonstrated that a variety of common organic solvents
afforded higher product yields than benzene.6 Among them,
chloroform was the best solvent, providing 3 in 94% yield
with an improved E/Z ratio (9:1).
The yield of the reaction was augmented dramatically by
tuning the electronic and steric properties of the alkoxy group
of the allenoate (Table 1).7 3-Chlorobenzaldehyde was
employed as a probe electrophile since it provided enough
product to be isolated when reacted with ethyl allenoate while
Using conditions optimized for the formation of 3k, we
prepared various dioxanylidenes (Table 2). Pyridyl aldehydes
as well as benzaldehydes bearing electron-withdrawing
(8) For examples, see: (a) Perlmutter, P.; Puniani, E.; Westman, G.
Tetrahedron Lett. 1996, 37, 1715. (b) Iwabuchi, Y.; Nakatani, M.;
Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc. 1999, 121, 10219. (c)
Lee, W.; Yang, K.; Chen, K. Chem. Commun. 2001, 1612.
(6) For detailed information, see Supporting Information.
(7) For the preparation of alkyl allenoates 1, see Supporting Information.
1388
Org. Lett., Vol. 7, No. 7, 2005

Scheme 1. Mechanistic Proposal for Formation of
1,3-Dioxan-4-ylidene 3
Table 3. Synthesis of δ-Hydroxy-â-ketoesters 11 via
Acid-Mediated Hydrolysis of ([1,3]Dioxan-4-ylidene)-acetates 4a
entry
Ar
Ph (4n)
E/Z isomer product yield (%)b,c
1
2
3
4
5
6
7
8
E
E
E
E
Z
E
Z
E
11a
11b
11c
11d
11d
11e
11e
11f
97
96
87
88
88
82
85
89
3-ClC6H4 (3k)
4-CNC6H4 (4j)
3-CNC6H4 (4k)
3-CNC6H4 (4k)
4-NO2C6H4 (4h)
4-NO2C6H4 (4h)
3-NO2C6H4 (4i)
a See Supporting Information for experimental procedure. b Isolated
yields. c Yields not optimized.
groups afforded the desired dioxanylidenes in 77-99% yield
(Table 2, entries 1-13), with the exception of ortho-
substituted benzaldehydes (Table 2, entries 3, 6, and 12).
The less reactive electron-rich benzaldehydes afforded
moderate reaction yields (Table 2, entries 14 and 15). In the
case of p-tolualdehyde only trace amounts of products were
detected in the 1H NMR of the crude reaction mixtures (Table
2, entry 16). Butyraldehyde was recalcitrant to the reaction
conditions (Table 2, entry 17). The reaction was completely
diastereoselective. Only 2,6-cis-disubstituted-1,3-dioxan-4-
ylidenes were obtained for all substrates tested. The E/Z-
selectivity remained in the range of >20:1 to 7:1, with the
exception of 2-pyridinecarboxaldehyde (4:1, Table 2, entry
3) and 2-trifluoromethylbenzaldehyde (6:1, Table 2, entry
6).
When dihydrofuran 5 was independently synthesized9 and
subjected to the optimized reaction conditions, no trace of
dioxanylidene 3k was detected, and dihydrofuran 5 was
recovered in 98% yield [eq 2]. This excludes the possibility
that the expected dihydrofuran 5 is an intermediate en route
to the final dioxanylidene product.
about the final zwitterionic intermediate 10, which dissociates
to 1,3-dioxan-4-ylidene 3 and trimethylphosphine. The
cyclization step (9 f 10) is similar to Evans’ base-catalyzed
intramolecular conjugate addition of hemiacetal alkoxides,
derived from δ-hydroxy-R,â-unsaturated esters to form
benzylidene acetals of â,δ-dihydroxy esters.11 The overall
reaction is reminiscent of the three-component coupling of
2 equiv of aldehyde and one acrylate to form 5-methylene-
1,3-dioxan-4-ones from the attempted Baylis-Hillman reac-
tion.12
The distinctive reactivity pattern exhibited by zwitterionic
intermediate 6 T 7 with aldehydes adds to the increasing
examples of divergent reaction pathways in nucleophilic
catalysis of allenoates.1 Recently, Shi13 and Miller14 reported
that different reaction pathways were taken when amines
were employed as catalysts instead of phosphines in nucleo-
philic catalysis of allenoates; however, the formation of
dioxanylidene is the first example in which vinylphospho-
nium zwitterions add to an electrophile exclusively at the
γ-carbon of allenoate 1.15
The synthetic utility of this reaction is further demonstrated
by acid-mediated hydrolysis of the dioxane acetal. When
dioxanylidenes 4 were treated with 1 equiv of HCl, δ-hy-
droxy-â-ketoesters 11 were obtained in 82-97% yield (Table
3).16 Accordingly, allenoate can be viewed as a masked
precursor for the acetoacetate unit. The classical process to
synthesize δ-hydroxy-â-ketoesters, referred to as the Weiler
alkylation, involves γ-alkylation through the dianions of
acetoacetates.17 Generation of dianions requires use of a
stoichiometric amount of two strong bases, sodium hydride
Based on this observation, we rationalize that the formation
of 3 arises through the γ-addition of the vinylphosphonium
salt 6 T 7 to an aldehyde to form 8 (Scheme 1). Adduct 8
incorporates another equivalent of aldehyde to produce 9.
The allowed 6-exo cyclization10 of intermediate 9 brings
(11) Evans, D. A.; Gauchet-Prunet, J. A. J. Org. Chem. 1993, 58, 2446.
(12) For examples, see: (a) Drewes, S. E.; Emslie, N. D.; Karodia, N.;
Khan, A. A. Chem. Ber. 1990, 123, 1447. (b) Brzezinski, L. J.; Rafel, S.;
Leahy, J. W. J. Am. Chem. Soc. 1997, 119, 4317. (c) Reference 8.
(13) Zhao, G.; Huang, J.; Shi, M. Org. Lett. 2003, 5, 4737.
(14) Evans, C. A.; Miller, S. J. J. Am. Chem. Soc. 2003, 125, 12394.
(15) A substituent at R-carbon of allenoates can deflect the inherent
reactivity pattern of nonsubstituted allenoates. For an example, see ref 2.
(16) It is noteworthy that both the E- and Z-isomer provide one
δ-hydroxy-â-ketoester.
(9) For the synthesis of dihydrofuran 5, see: (a) Kolsaker, P.; Jørgensen,
T.; Wøien Larsen, G. Tetrahedron 1974, 30, 3393. (b) Hudlicky, T.;
Fleming, A.; Lovelace, T. C. Tetrahedron 1989, 45, 3021.
(10) (a) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734. (b)
Baldwin, J. E.; Cutting, J.; Dupont, W.; Kruse, L.; Silberman, L.; Thomas,
R. C. J. Chem. Soc., Chem. Commun. 1976, 736.
Org. Lett., Vol. 7, No. 7, 2005
1389

(NaH) and n-butyllithium (n-BuLi). Our approach, which
consists of a combination of neutral phosphine catalysis and
acid hydrolysis, provides an alternative for the construction
of ubiquitous δ-hydroxy-â-ketoesters. The resulting δ-hy-
droxy-â-ketoesters are recurrent subunits in polyketide
antitumor antibiotics.18
To summarize, our effort to expand the repertoire of
phosphine-catalyzed annulations has led us to the discovery
of a reaction of allenoates with aldehydes to form (2,6-diaryl-
[1,3]dioxan-4-ylidene)-acetates in excellent to moderate
yields with complete diastereoselectivity and high E/Z-
selectivities. Our vinylphosphonium-based approach provides
a synthesis of δ-hydroxy-â-ketoesters, differing from the
classical dianion-based approaches. Future efforts will focus
on examining the synthetic potential of allenoates bearing
diverse substituents at the R- and γ-carbons, as well as
performing the annulation in an enantioselective manner.19
Acknowledgment. This research was supported by
UCLA (Seed Grant) and Amgen, Inc. (Young Investigator’s
Award to O.K.). We thank Dr. Saeed Khan for the X-ray
analysis.
Supporting Information Available: Representative ex-
perimental procedures and spectral data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(17) (a) Huckin, S. N.; Weiler, L. J. Am. Chem. Soc. 1974, 96, 1082.
(b) Caine, D. In ComprehensiVe Organic Synthesis; Trost, B. M.; Fleming,
I., Eds.; Pergamon Press: Oxford, 1991; Vol. 3, Chapter 1.1.
(18) Macrolide Antibiotics. Chemistry, Biology, and Practice; Omura,
S., Ed.; Academic Press: Orlando, FL, 1984.
OL050203Y
(19) Zhu, G.; Chen, Z.; Jiang, Q.; Xiao, D.; Cao, P.; Zhang, X. J. Am.
Chem. Soc. 1997, 119, 3836.
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Org. Lett., Vol. 7, No. 7, 2005