Tertiary amine mediated tandem cross-rauhut-currier/acetalization reactions: Access to functionalized

Article abstract of DOI:10.1002/anie.200905091

Γ-Proton transfer furnished the highly selective title reaction in which cyclic bhaloenals 1 react with b,g-unsaturated aketoesters 2 to generate functionalized spiro-3,4-dihydro-2H-pyrans 3 having an a-quaternary carbon center and an adjacent vinyl halid

Full text of DOI:10.1002/anie.200905091

Angewandte
Chemie
DOI: 10.1002/anie.200905091
Tandem Reactions
Tertiary Amine Mediated Tandem Cross-Rauhut–Currier/
Acetalization Reactions: Access to Functionalized Spiro-3,4-
Dihydropyrans**
Weijun Yao, Yihua Wu, Gang Wang, Yiping Zhang, and Cheng Ma*
Continuing development in synthetic organic chemistry relies
on discovering new, high yielding, and selective reactions. The
Rauhut–Currier (RC) reaction (also known as the vinylogous
Morita–Baylis–Hillman reaction), involving the coupling of
one active alkene/latent enolate to a Michael acceptor,
À
provides a unique method to create a new C C bond between
the a-position of one activated alkene and the b-position of a
second alkene under the influence of a nucleophilic catalyst.[1]
Whereas significant progress has recently been made with the
intramolecular RC reaction as well as in the enatioselective
Scheme 1. Convergent access to substituted 3,4-dihydro-2H-pyrans (1).
variants,[2] the intermolecular RC reaction remains a chal-
lenge because of the lack of selectivity in cross-coupling
reactions involving different activated alkenes.[3] In contrast,
the products of an RC reaction, which are electron-deficient
alkenes as well, are susceptible to polymerization. Notably,
some RC reactions have been successfully incorporated into
tandem or cascade processes to give access to structurally
complex molecules.[4] Conceptually, these pioneering studies
expanded the synthetic application of the RC reaction, even
though substrates were limited to a,b-unsaturated ketones.
Substituted 3,4-dihydropyrans (1) are very useful precur-
sors for the synthesis of carbohydrates and natural products.[5]
A common way to access 1 is, for example, by an inverse-
electron-demand hetero-Diels–Alder reaction between elec-
tron-rich alkenes with a,b-unsaturated carbonyl compounds
(Scheme 1, path a).[6] Very recently, Rueping et al. and
Jørgensen and co-workers independently reported an enatio-
selective domino Michael addition/cyclization of a 1,3-cyclo-
alkanedione with an a,b-enal using a chiral secondary amine
to afford bicyclic 1 (Scheme 1, path b).[7] Despite the myriad
of approaches afforded by these reactions, few synthetic
methods that produce quaternary carbon-containing spirocy-
clic structures by using nucleophilic promoters exist.[8] Herein
we report an unprecedented tertiary amine mediated highly
selective synthesis of spiro-3,4-dihydro-2H-pyrans from cyclic
b-halo-a,b-unsaturated aldehydes (2) and b,g-unsaturated
a-keto ester (3) by a tandem cross-RC/acetalization reaction
process (Scheme 1, path c).
Given their functionality, which offers a useful starting
point for additional transformations, bromoenal 2a and
enone ester 3a were reacted in presence of a Lewis base to
explore the possibility of a cross-coupling.[9] We were pleased
to discover that such a transformation could indeed be
accomplished upon treatment with DBU in toluene, and more
interestingly, a mixture of two anomers of hemiacetal 4a,
bearing a tethered vinyl bromide group and a spirocycle, was
furnished in 36% yield (Table 1, entry 1).[10,11] The oxidation
of this mixture with pyridinium chlorochromate (PCC) gave
trans-lactone 5a as a single diastereomer (Scheme 2). These
results confirm: 1) the enolate can be generated from 2a
in situ to conduct a Michael addition; 2) g-proton transfer
leads to the formation of 4a; and 3) the formation of the two
carbon stereogenic centers is completely diastereoselective.
Moreover, DBN also gave the product in a lower yield,
whereas other nuclophilic tertiary amines such as DABCO,
quinidine, DMAP, as well as the stronger base TMG, only
afforded trace amounts of 4a (Table 1, entries 2–6). In
addition, (nBu)3P did not efficiently promote this reaction
(Table 1, entry 7). Evidently, not only the basicity but also the
nucleophility of DBU played a significant role in this tandem
procedure.[12,13]
Encouraged by these results, we additionally optimized
the reaction conditions using DBU as the Lewis base. Solvent
screening (Table 1, entries 1 and 8–12) revealed that toluene
was the most ideal as it led to the best result. A decrease in the
reaction temperature to 08C improved the yield of product 4a
to 54% although an extended reaction time was required
(Table 1, entry 13); whereas an additional lowering of the
reaction temperature to À208C (Table 1, entry 14) caused a
drop in the product yield to 45% after a reaction time of
16 hours. Upon changing the amount of DBU to 1.5 equiv-
[*] W. Yao, Y. Wu, G. Wang, Y. Zhang, Prof. C. Ma
Department of Chemistry
Zhejiang University
20 Yugu Road, Hangzhou 310027 (China)
Fax: (+86)571-8795-3375
E-mail: mcorg@zju.edu.cn
[**] We are grateful to the National Natural Science Foundation of China
(Grant Nos. 20672096 and 20772106) for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200905091.
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Table 1: Optimization of the coupling reaction of 2a and 3a.[a]
alents at 08C, the optimal balance of the reaction rate and
yield was obtained (Table 1, entry 16). When 0.5 equivalents
or 3.0 equivalents of DBU was used instead, the yield of 4a
fell to 43% (08C, 12 h) and 52% (À208C, 3.5 h), respectively
(Table 1, entries 15 and 17).
Next, the cross-RC/acetalization of 2a with a variety of
enones 3 under the optimized reactions conditions were
investigated. As shown in Table 2, the electron-rich or
electron-poor aryl-substituted substrates 3a–f clearly under-
went cross-cyclization in moderate to good yields. Electron-
poor substrates underwent conversion more quickly than
their electron-rich counterparts, albeit with a slightly lower
yield[14] (Table 2, entries 3, 5, versus 6). Moreover, the size of
ester substitutent (R2) of 3 had little effect on the tandem
process, as 3b (R2 = ethyl) gave 4b in almost similar yield to
that of 4a from 3a (R2 = methyl; Table 2, entries 1 and 2).
Entry
Lewis base (equiv)
Solvent
T [oC]
t [h]
Yield [%][b]
1
2
3
4
5
6
7
8
DBU (1.0)
DBN (1.0)
DABCO (1.0)
quinidine (1.0)
DMAP(1.0)
TMG (1.0)
(nBu)3P (1.0)
DBU (1.0)
DBU (1.0)
DBU (1.0)
DBU (1.0)
DBU (1.0)
DBU (1.0)
DBU (1.0)
DBU (0.5)
DBU (1.5)
DBU (3.0)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DMF
CH3CN
CH2Cl2
THF
tBuOH
toluene
toluene
toluene
toluene
toluene
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
0
1
1
12
12
12
2
12
1
1
1
1
1
8
36
27
trace
trace
trace
trace
trace
trace
trace
21
18
11
54
45
9
10
11
12
13
14
15
16
17
Table 3: Substrate scope of the tandem coupling of enals 2 and enones
3.[a]
À20
16
12
3
0
43
64
52
Entry
2
3
t [h][d] 4, Yield [%][e] 5, Yield [%][f]
0
À20
3.5
[a] Reaction conditions: 2a (0.75 mmol, 1.5 equiv), 3a (0.5 mmol,
1.0 equiv), and Lewis base in solvent (5.0 mL). [b] Yield of isolated
product.
DBU=1,8-diazabicyclo[5.4.0]undec-7-ene,
DBN=1,5-
1
2
2b
2b
3a
3
4
4i, 65
4j, 62
5i, 87
diazabicyclo[4.3.0]non-5-ene, DABCO=1,4-diazabicyclo[2.2.2]octane,
DMAP=4-dimethylaminopyridine, TMG=1,1,3,3-tetramethylguanidine.
3i[b]
5j (R1 =4-ClC6H4), 92
3
4
2b
2c
3j[c]
5
4k, 51
4l, 59
5k, 83
5l, 89
Scheme 2. Conversion of 4a into 5a.
3a
4.5
Table 2: Tandem coupling reaction of 2a with enones 3 and the oxidation
of product 4 into lactones 5.[a]
5
2d
3a
3a
2.5
4m, 91
5m, 85
5n, 72
Entry
3
R1
R2 t [h][b] 4,Yield [%][c] 5,Yield [%][d]
1
2
3
4
5
6
7
8
3a Ph
3b Ph
Me
Et 2.5
Me 1.5
Me
Et
Et
3
4a, 64
4b, 66
4c, 55
4d, 63
4e, 55
4 f, 51
4g, 48[e]
4h, 45
5a, 91
5b, 95
5c, 91
5d, 96
5e, 92
5 f, 85
5g, 81
5h, 65
6
7
2e
2 f
3
4n, 42
3c 4-FC6H4
3d 4-CH3C6H4
3e 3-NO2C6H4
3 f 4-CH3OC6H4
3g N-tosyl-indol-3-yl Et
3h 2-furyl
3
1
6
5
3a 24
4o, n.r.
5o, n.r.
Et 4.5
[a] Reaction conditions: a) 2 (0.75 mmol),
3
(0.5 mmol.), DBU
(0.75 mmol), 08C, toluene (5.0 mL); b) PCC (1.5 equiv), CH2Cl2, reflux.
[b] 3i: R1 =4-ClC6H4, R2 =Me. [c] 3j: R1 =2-thienyl, R2 =Et. See reaction
equation in Table 2 for structure, Tos=4-toluenesulfonyl. [d] Time for
consuming 3. [e] Yield of the mixture of two anomers after flash
chromatography. [f] Yield of isolated product. n.r.=no reaction.
[a] Reaction conditions: 1. 2a (0.75 mmol),
3
(0.5 mmol.), DBU
(0.75 mmol), 08C, toluene (5.0 mL); 2. PCC (1.5 equiv), reflux, CH2Cl2.
[b] Time for consuming 3. [c] Yield of the mixture of two anomers after
flash chromatography. [d] Yield of isolated product. [e] Reaction was run
in CH2Cl2. tosyl=4-toluenemethanesulfonyl.
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Heteroaromatic compounds 3, including a
furan and an indole, were also successfully
employed in this reaction. Nevertheless,
the product 4g was obtained in 48% yield
when using CH2Cl2 as the solvent; 3g
displayed poor solubility in toluene.
Whereas the tandem reaction of the
five-membered and heteroatom-substi-
tuted six-membered enals 2b–e proceeded
smoothly to produce the expected hemi-
acetals of 4, the seven-membered enal 2 f
did not undergo reaction under the reac-
tion conditions (Table 3). Notably, the
oxygen-containing enal 2d completed the
reaction within 2.5 hours and furnished 4m
in excellent yield, and N-tosyl-protected
enal 2e only gave 4n in 42% (Table 3,
entries 5 and 6). These results can be
rationalized by steric and electronic effect
considerations: an electron-withdrawing
oxygen atom could enhance the acidity of
the g proton and thereby promote the
reaction of 2d; in contrast, a bulky tosyl
group may lead to an unfavorable confor-
mation for the corresponding transforma-
tion of 2e.
Scheme 3. Asymmetric tandem coupling of 2a with 3k. Reaction conditions: a) DBU,
toluene, 2.5 h, 74%; b) PCC, CH2Cl2, 7.5 h, 78%.
Preliminary studies on an asymmetric
variant of this tandem reaction was tested
with (À)-menthyl ester 3k and enal 2a as
the substrates under the previous opti-
mized reaction conditions (Scheme 3).
Although 3k underwent coupling to give
4p in 74% yield after 2.5 hours, 5p (product isolated after
oxidation with PCC) was obtained with poor diastereoselec-
Scheme 4. Possible mechanism for the tertiary amine mediated cross-Rauhut–Currier/
acetalization of 2 and 3. NR3 =DBU, R1 =aryl, R2 =alkyl, X=Br, Cl.
Experimental Section
Representative procedure (Table 2, entry 1): DBU (114 mg,
0.75 mmol) was added to a solution of cyclic b-bromo-enal 2a
(142 mg, 0.75 mmol) and b,g-unsaturated a-keto ester 3a (95 mg,
0.5 mmol) in 5 mL of anhydrous toluene at 08C under N2 atmosphere.
The reaction mixture was stirred at this temperature for 3 h until
complete consumption of 3a (as observed by TLC methods). The
reaction was quenched with 5 mL of saturated aqueous NaHCO3 and
extracted with EtOAc (10 mL ꢀ 3). After washing with 10 mL of
brine, the organic phase was dried over MgSO4 and concentrated
under reduced pressure. The residue was purified by column
chromatography (n-hexane/EtOAc 5:1) to afford compound 4a:
121 mg, 64%; colorless oil; ratio of the two anomers of 4a = 93:7
(from 1H NMR analysis); 1H NMR (400 MHz, CDCl3, TMS, major
anomer) d = 7.31–7.25 (m, 5H), 6.42 (dd, J = 2.8 Hz, 1H), 6.29 (d, J =
2.4 Hz, 1H), 5.48 (d, J = 3.2 Hz, 1H), 4.38–4.36 (m, 2H), 3.86 (s, 3H),
1.98–1.90 (m, 1H), 1.88–1.82 (m, 1H), 1.63–1.60 (m, 2H), 0.02–
(À0.09) ppm (m, 1H); 13C NMR (100 MHz, CDCl3, TMS, major
anomer) d = 162.5, 142.1, 138.7, 136.7, 128.8, 128.1, 127.3, 126.0, 114.6,
99.1, 52.5, 45.6, 45.2, 27.2, 2.5, 17.8 ppm; IR (film): n˜ = 3481, 2951,
2871, 1731, 1652, 1440, 1287, 1277 cmÀ1; HRMS (ESI): calculated for
C18H19BrO4Na [M + Na]+ 401.0359, found 401.0353.
1
tivity (d.r. 56:45) as determined by H NMR analysis.
Although detailed mechanistic studies have not been
undertaken, a plausible mechanism for the tertiary amine
mediated tandem cross-Rauhut–Currier/acetalization reac-
tion is illustrated in Scheme 4. Conjugate addition of DBU to
enal 2 provides enolate I, which could be stabilized by
resonance as proposed for MBH reactions.[15] Subsequent
intermolecular Michael addition onto enone 3 affords zwit-
terionic intermediate II.[16] This newly formed enolate under-
goes intramolecular acetalization with the tethered aldehyde
rendering spirocyclic alkoxide III instead of protonation as in
classic RC reaction. Finally, g-proton transfer ensues, directly
or assisted by DBU, yielding hemiacetal 4 with regeneration
of the amine catalyst.
In summary, we have presented an efficient, tertiary
amine mediated cross-Rauhut–Currier/acetalization of cyclic
b-haloenals and b,g-unsaturated a-ketoesters. The tertiary
amine serves not only as a nucleophilic promoter to conduct a
cross-RC reaction but probably also as a mediator of g-proton
transfer. Significantly, functionalized spiro-3,4-dihydro-2H-
pyran derivatives with an a quaternary carbon center and an
adjacent vinyl bromide group in skeleton are easily assembled
from simple substrates by this method. Experiments designed
to explore the scopes, limitations, and asymmetric variants of
this reaction are ongoing and will be reported in due course.
Received: September 11, 2009
Published online: November 24, 2009
Keywords: cross-coupling · cyclization · Lewis bases ·
.
Michael addition · tandem reactions
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