Ylide hydrolysis in tandem reactions: A highly Z/E-selective access to 3-alkylidene dihydrobenzofurans and related analogues

Article abstract of DOI:10.1021/ol401240z

An efficient synthetic approach to benzoheterocycles has been developed based on the hydrolysis of key ylide intermediates in a tandem reaction, upon which a variety of 3-alkylidene dihydrobenzofurans and related benzoheterocyclic products can be obtained

Full text of DOI:10.1021/ol401240z

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Ylide Hydrolysis in Tandem Reactions:
A Highly Z/E‑Selective Access to
3‑Alkylidene Dihydrobenzofurans and
Related Analogues
Jian-Bo Zhu, Peng Wang, Saihu Liao,* and Yong Tang*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032,
P. R. China
shliao@sioc.ac.cn; tangy@mail.sioc.ac.cn
Received May 3, 2013
ABSTRACT
An efficient synthetic approach to benzoheterocycles has been developed based on the hydrolysis of key ylide intermediates in a tandem reaction,
upon which a variety of 3-alkylidene dihydrobenzofurans and related benzoheterocyclic products can be obtained in high yields with excellent Z/E
selectivity.
In the over 100-year history of phosphorus ylide chemistry,
a variety of phosphorus ylide based reactions have been
developed and have found widespread applications in
organic synthesis, especially in the synthesis of naturally
occurring products and pharmaceutics.1 However, ylide
hydrolysis, although frequently encountered in ylide
reactions, is normally regarded as a side reaction that is
usually avoided.2 Its synthetic potential is far less explored
and greatly underestimated. The reactions employing
ylide hydrolysis have only sporadically appeared in the
literature.1,3 During our recent study on ylide-initiated
Michael additionꢀcyclization reactions (YIMACRs),4 we
speculated that the integration of an ylide hydrolysis step
in a tandem reaction to intercept the phosphonium inter-
mediates might enable some new transformations and can
be potentially useful. Hydrolysis of the betaine intermediate
to cleave the CꢀP bond will realize, in principle, a formal
reactivity umpolung of the alkyl halides (Scheme 1a), which
is different from typical phosphorus ylide reactions such as
the Wittig reaction and small ring formation reactions
where the phosphines act more like an “RHC” unit carrier.
Based on this approach, recently we successfully developed
an efficient nonmetal mediated direct coupling of alkyl
halides with electron-deficient alkenes for the synthesis
of chromans and analogues.5 As a continuous effort, we
wish to report here the application of ylide hydrolysis to a
(1) Kolodiazhnyi, O. I. Phosphorus Ylides: Chemistry and Application
in Organic Synthesis; Wiley-VCH: New York, 1999.
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(2) For mechanistic studies, see: (a) Corfield, J. R.; Death, N. J.;
Trippett, S. J. Chem. Soc. C 1971, 1930–1933. (b) Schnell, A.; Tebby,
J. C. J. Chem. Soc., Perkin Trans. 1 1977, 1883–1886.
(3) (a) Taylor, E. C.; Martin, S. F. J. Am. Chem. Soc. 1974, 96, 8095–
8102. (b) Schwarz, M.; Oliver, J. E.; Sonnet, P. E. J. Org. Chem. 1975, 40,
2410–2411. (c) Zaragoza, F. J. Org. Chem. 2002, 67, 4963–4964. (d) Lee,
K. Y.; Na, J. E.; Lee, M. J.; Kim, J. N. Tetrahedron Lett. 2004, 45, 5977–
5981. (e) El-Dahshan, A.; Ahsanullah; Rademann, J. Biopolymers 2010,
94, 220–228. (f) Duvvuru, D.; Retailleau, P.; Betzer, J.-F.; Marinetti, A.
Eur. J. Org. Chem. 2012, 897–900.
(4) For reviews, see: (a) Sun, X.-L.; Tang, Y. Acc. Chem. Res. 2008,
41, 937–948. (b) Tang, Y.; Ye, S.; Sun, X.-L. Synlett 2005, 18, 2720–2730.
For selected examples, see: (c) Ye, L.-W.; Sun, X.-L.; Wang, Q.-G.;
Tang, Y. Angew. Chem., Int. Ed. 2007, 46, 5951–5954. (d) Wang, Q.-G.;
Deng, X.-M.; Zhu, B.-H.; Ye, L.-W.; Sun, X.-L.; Li, C.-Y.; Zhu, C.-Y.;
Shen, Q.; Tang, Y. J. Am. Chem. Soc. 2008, 130, 5408–5409. (e) Han, X.;
Ye, L.-W.; Sun, X.-L.; Tang, Y. J. Org. Chem. 2009, 74, 3394–3397. (f)
Wang, Q.-G.; Sun, X.-L.; Zheng, J.-C.; Tang, Y. Chin. J. Chem. 2010, 28,
1618–1622.
(5) Zhu, J.-B.; Wang, P.; Liao, S.; Tang, Y. Chem. Commun. 2013, 49,
4570–4572.
r
10.1021/ol401240z
XXXX American Chemical Society

conjugate addition/hydrolysis tandem reaction of allylic
ylides and the development of a new and highly Z/E
selective synthetic route for 3-alkylidene 2,3-dihydroben-
zofurans and related benzoheterocycles (Scheme 1b).
Table 2. Reaction Scopea
Scheme 1. Ylide Hydrolysis and Reaction Design
A key issue in the reaction design is the competing
hydrolysis of the starting material. We envisioned that
suchaside reactioncouldbe regulated bychoosing suitable
reaction conditions (base, solvent, etc.) to ensure the first
conjugate addition is faster than the hydrolysis of the
starting phosphonium salt 1a (Table 1). We initiated our
study with the screening of bases under typical reaction
conditions for base-catalyzed hydrolysis of phosphorus
ylides. As shown in Table 1, carbonates proved to be more
Table 1. Reaction Optimizationa
entry
base
solvent
yield (%)b
1
Na2CO3
K2CO3
Cs2CO3
NaOH
t-BuOK
NaH
DME
25
69
51
27
<5
<5
<5
51
48
74
80
2
2
DME
3
DME
a Reaction conditions: 1 (0.4 mmol), K2CO3 (1.2 mmol), H2O
(1 mmol), in i-PrOAc (8 mL). b Determined by 1H NMR of crude
product. c Isolated yield. d 1p (0.2 mmol), K2CO3 (0.6 mmol), H2O
(8 mmol), in i-PrOAc (4 mL), at 25 °C, 24 h.
4
DME
5
DME
6
DME
7
DMAP
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DME
8
DCE
9
DMF
suitable than stronger bases such as NaOH and t-BuOK
(entries 1ꢀ6), and K2CO3 gave the optimal result. Organic
base DMAP failed to deliver the desired product 2a (entry7).
To our delight, the yield with K2CO3 can be further increased
to 80% by using i-PrOAc as a solvent (entry 11). On the
other hand, an elevated temperature seems critical to this
reaction; reaction at room temperature furnished the desired
product in 2% yield only (entry 12 vs 11). The E/Z ratios
10
11
12c
13d
MeOAc
i-PrOAc
i-PrOAc
i-PrOAc
92
a Reaction conditions: 1a (0.4 mmol), base (0.92 mmol), solvent
(4 mL). b Isolated yield. c At room temperature. d K2CO3 (1.2 mmol),
H2O (1 mmol), in i-PrOAc (8 mL), 12 h.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 2. Proposed Pathways for the Z or E Product Formation
in all these entries were determined to be around 95/5 by
1H NMR analysis. To our delight, adding 2.5 equiv of water
significantly accelerated the reaction and further increased
the yield to 92% (entry 13).5
current reaction provides a novel and highly Z/E selective
approach to these compounds.7
As described above, an interesting phenomenon that
was observed is the opposite Z/E selectivity between
dihydrofuran and dihydrothiophene products, which also
existed between the five- and six-membered cycles (entry 2
vs 15). To rationalize the reversal in the Z/E selectivity,
two pathways as shown in Scheme 2 were proposed. In
pathway I, the initial Michael addition product 4 first
underwent a proton transfer or a double bond shift via
protonation/deprotonation to generate ylide intermediate
5 and 50, which was then hydrolyzed to give the product 2.
The predominance of Z-product could be attributed to the
repulsion between C4ꢀH and the phosphonium moiety in
50. On the other hand, the Michael adduct 4 would undergo
a retro-Michael reaction to afford 6, followed by deproto-
nation, hydrolysis of ylide 7, and an intramolecular
conjugate addition, to give (E)-2 as the major product
(Path II). The E-dihydrobenzofuran products (entries
1ꢀ12) should be produced mainly through Pathway II,
as a result of fast β-elimination of 4 due to the strained
Under the optimized reaction conditions, the reaction
scope was investigated next and the results are tabulated in
Table 2. The reactions proceeded quite well with various
substrates, giving the desired 3-alkylidene 2,3-dihydroben-
zofurans generally in high yields and high E-selectivities.
The ester groups slightly influenced the yield (entries 1ꢀ3).
Substrates with electron-withdrawing or -donating substi-
tuents on the aryl can all be smoothly converted to the
desired 2,3-dihydrobenzofurans in high yields (entries 4ꢀ9).
The current reaction also tolerates a variety of substitution
patterns well on the benzene ring (entries 4ꢀ9). Notably,
2,3-dihydrobenzofurans with a C2 quaternary center are
also accessible using the corresponding 3,3-disubstituted ac-
rylates as the substrate (entries 10ꢀ11). In all cases, excellent
E-selectivities (E/Z > 92/8) were observed (entries 1ꢀ12).
To our delight, the current transformation can be suc-
cessfully extended to the synthesis of dihydrobenzothio-
phene 2n (entries 14), and even to six-membered hetero-
cycles such as chromans and tetrahydroquinolines (entries
15ꢀ16). It is worth mentioning that 2p was obtained in
high yield with perfect E-selectivity at room temperature,
while at 80°C ∼13% ofthe intramolecular Wittig product6
was isolated which was generated by the olefination reac-
tion of the ylide intermediate with the carbonyl group of
the ester (entry 16). Accordingly, a diverse range of five-
and six-memberedbenzoheteocyclesare accessible, andthe
dihydrofuran ring8 and the strong Oꢀ Pþ interaction1,9
3 3 3
in intermediate 7. In fact, at room temperature and with
the addition of 20 equiv of H2O, the elimination product 3
(X = OH) can be isolated in 90% yield as the sole
geometricisomer, and subjecting 3 to the standardreaction
(7) (a) Le Strat, F.; Harrowven, D. C.; Maddaluno, J. J. Org. Chem.
ꢀ
2005, 70, 489–498. (b) Fressigne, C.; Girard, A.-L.; Durandetti, M.;
Maddaluno, J. Angew. Chem., Int. Ed. 2008, 47, 891–893. (c) Durandetti,
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M.; Hardou, L.; Clement, M.; Maddaluno, J. Chem. Commun. 2009,
4753–2755. (d) Okamoto, R.; Okazaki, E.; Noguchi, K.; Tanaka, K.
Org. Lett. 2011, 13, 4894–4897. (e) Durandetti, M.; Hardou, L.;
Lhermet, R.; Rouen, M.; Maddaluno, J. Chem.;Eur. J. 2011, 17,
12773–12783.
(6) At 80 °C, the intramolecular Wittig product was isolated in 13%
yield:
(8) Katritzky, A. R.; Ramsden, C. A.; Joule, J.; Zhdankin, V. V.
Handbook of Heterocyclic Chemistry, 3rd ed.; Elsevier: 2010, p 132.
(9) (a) He, R.; Wang, X.; Hashimoto, T.; Maruoka, K. Angew.
Chem., Int. Ed. 2008, 47, 9466–9468. (b) Werner, T. Adv. Synth. Catal.
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Org. Lett., Vol. XX, No. XX, XXXX
C

CAr > C3), the retro-Michael reaction issue would not be
present and products 2o and 2p were produced along Path I;
thus the E-selection should mainly result from the steric
interaction in 5 (X = OCH2 or N(Ts)CH2) in these cases.
The products are useful synthetic intermediates and can
be readily converted to benzofuran and benzofuran-3-one
derivatives.7,10 As illustrated in Scheme 3, 2baromatized to
3-ethylbenzofuran9 smoothlyinthepresenceofa catalytic
amount of TsOH. Ozonolysis can cleave the double bond
to give benzofuran-3-one 10, while treatment of 2b with
m-CPBA in chloroform converted 2b into 11 in 82% yield.
In conclusion, ylide hydrolysis has been successfully
integrated in a conjugate addition-initiated tandem reac-
tion, providing a new and highly Z/E selective approach
for the syntheses of a range of 3-alkylidene dihydrobenzo-
furans and related benzoheterocyclic compounds. Two
reaction pathways were proposed to account for the sub-
strate-dependent Z/E selectivity, and key intermediates
were trapped and characterized. The strategy that discon-
tinues a tandem reaction by intercepting ylide inter-
mediates with hydrolysis would find more applications in
developing new transformations. Application of the cur-
rent method and further exploration of ylide hydrolysis in
tandem reactions are ongoing in our laboratory.
Scheme 3. Selected Conversions of the Product 2b
conditions delivered adduct 2b in 94% yield with a >99:1
E/Z ratio; this is consistent with Path II. In addition, we
prepared the phosphonium salt of intermediate 6 which
can also be converted to 2b with the same Z/E selectivity
under the same conditions. In contrast, in the case of the
predominant formation of Z-configured dihydroben-
zothiophene 2n, the proton-transfer pathway should be
more favored over the retro-Michaelroute probably due to
the much less strained8 dihydrothienyl cycle (entry 14). It is
noteworthy that the different inductive effect of O and S
could be another factor that enhances this selectivity
by changing the relative rate of proton transfer or the
deprotonation (from 4 to 5). Whereas, for the E-configured
six-membered product formation (entries 15 and 16, when
X = OCH2 or N(Ts)CH2, the priority of C3 has changed:
Acknowledgment. We are grateful for the financial
support from the National Natural Sciences Foundation
of China (Nos. 21121062, 20932008, and 21272248), the
Major StateBasic ResearchDevelopmentProgram (Grant
No. 2009CB825300), and the Chinese Academy of Sciences.
Supporting Information Available. Experimentaldetails,
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The authors declare no competing financial interest.
D
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