Grignard reagent acceleration of the intramolecular diels-alder reaction of furans with unactivated alkynes: Towards structurally complex oxabicyclic alkenes

Article abstract of DOI:10.1002/chem.201102028

Chelate to accelerate: A cascade reaction of ortho-(alkynyl)phenyl furanyl ketones with Grignard reagents, involving an interesting intramolecular Diels-Alder reaction of furans with unactivated alkynes, is described (see scheme). DFT calculations and exp

Full text of DOI:10.1002/chem.201102028

DOI: 10.1002/chem.201102028
Grignard Reagent Acceleration of the Intramolecular Diels–Alder Reaction
of Furans with Unactivated Alkynes: Towards Structurally Complex
Oxabicyclic Alkenes
Yifeng Chen, Lu Wang, Yuanhong Liu,* and Yuxue Li*[a]
Diels–Alder reactions are among the most useful pericy-
clic reactions for the construction of six-membered rings
with up to four stereogenic centers, in which the regio- and
stereochemistry is well controlled and based on well-defined
rules.[1] In particular, the intramolecular Diels–Alder reac-
tions of furans as dienes with various p bonds have received
considerable attention[2] due to their notable success in the
total synthesis of various natural products.[3] Moreover, the
oxanorbornenes or oxanorbornadienes generated by this
chemistry are valuable synthetic intermediates because they
can undergo facile ring-opening reactions to create highly
substituted ring systems.[4] However, due to the aromaticity
of furan rings, it is sometimes difficult to achieve this type
of Diels–Alder reaction. Alkynes may be employed as dien-
ophiles in these reactions, although, to the best of our
knowledge, only activated alkynes containing at least one
electron-withdrawing group or terminal alkynes have so far
been found to react well with furans.[5,6] Terminal alkynes
usually undergo the cycloaddition through an isomeric
allene species.[7] Therefore, the intramolecular Diels–Alder
reactions of furans with unactivated alkynes as the dieno-
phile partner remains a great challenge.
In 1979, Mukaiyama et al. reported that the intramolecu-
lar Diels–Alder reaction of furans with acrylamides could be
accelerated through internal coordination of a magnesium
salt.[8a] It was assumed that the metal behaves as a weak
Lewis acid to activate the dienophiles.[8] A “temporary cova-
lent connection” strategy involving C-M-O linkers (M=Si,
Mg, B, Al, or Zn) has also been employed to promote the
Diels–Alder reaction of dienes with olefins.[9] The metals
can serve as a temporary tether to bring together the two re-
action partners, facilitating the cycloaddition reaction. How-
ever, there is no efficient method for the Diels–Alder reac-
tion of furans with unactivated alkynes. Herein, we describe
our investigation of the cascade Grignard addition/Diels–
Alder reaction of ortho-(alkynyl)phenyl furanyl ketones
containing an unactivated alkyne moiety, leading to synthet-
ically useful 7-oxabicycloACTHUNRGTNE[NUG 2.2.1]hepta-2,5-diene derivatives
with high efficiency and excellent diastereoselectivity
(Scheme 1). DFT calculations reveal that the alkoxide group
may activate the adjacent furan ring by increasing the
energy level of the highest energy occupied orbital of the
furan fragment (the HOMOdiene of the Diels–Alder reaction)
and facilitating the second step of the reaction.
Scheme 1. The intramolecular Diels–Alder reaction of furans with unacti-
vated alkynes.
During the course of our studies into the gold-catalyzed
furan/yne cyclization reaction,[5b,c] we occasionally found
that the reaction of furan-2-yl[2-(phenylethynyl)phenyl]me-
thanone 1a with a Grignard reagent afforded oxabicycle 3a
in a one-pot procedure. The optimization results for this re-
action are summarized in Table 1. It was found that the ad-
Table 1. The optimization studies for the cascade Grignard addition/
Diels–Alder reaction.
Entry
MeMgBr
[equiv]
Solvent
T
t
Yield of 2a
Yield of 3a
G
[oC]
[h]
[%][a]
[%][a]
1
3
3
2
1
3
3
THF
THF
THF
THF
THF
toluene
RT
80
80
80
80
80
1
3
3
28
24
24
96
–
–
–
–
–
2[b]
3[b]
4[b]
5[c]
6[b]
89
86
53
50
[a] Y. Chen, L. Wang, Prof. Dr. Y. Liu, Prof. Dr. Y. Li
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
[d]
–
–
345 Lingling Lu, Shanghai 200032 (P.R. China)
Fax : (+86)021-64166128
E-mail: yhliu@mail.sioc.ac.cn
[a] Isolated yield. All reactions were carried out by addition of Grignard
reagents at 08C, followed by warming to the indicated temperature.
[b] In a sealed tube. [c] The reaction mixture was heated at reflux by
using an internal reflux condenser. [d] Compound 4a was obtained in
75% yield.
liyuxue@sioc.ac.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102028.
12582
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Chem. Eur. J. 2011, 17, 12582 – 12586

COMMUNICATION
Table 2. The formation of 7-oxabicyclo
AHCTUNGTRENNUNG
ACHUTNGTRENNUG[2.2.1]hepta-2,5-diene derivACHTUNGTRENNUNGa-
dition of MeMgBr (3 equiv) to 1a in THF at room tempera-
ture resulted in the formation of tertiary alcohol 2a in 96%
yield (Table 1, entry 1). To our delight, heating the reaction
mixture at 808C for 3 h in a sealed tube provided Diels–
Alder cycloadduct 3a in 89% yield as a single diastereomer
(Table 1, entry 2). The use of two equivalents of MeMgBr
afforded a comparable isolated yield of 86%, although de-
creasing the amount of Grignard reagent to one equivalent
resulted in a lower yield of 53% even after a prolonged re-
action time (Table 1, entries 3 and 4). It should be noted
that under the normal conditions used for heating at reflux,
that is, without the use of a sealed tube, the desired product
3a was obtained in only a 50% yield, along with some by-
products (Table 1, entry 5). These results indicate that in
this case the presence of a higher pressure in the sealed
system has a marked effect on the reaction process. To our
surprise, if the reaction was carried out in toluene (Table 1,
entry 6), the initially formed oxabicycle is gradually convert-
ed into a new product, phenol 4a,[10] in good yield (see
below).
tives.[a]
Product
t
Yield Product
t
Yield
[h] [%][b]
[h] [%][b]
3a
3b
3
2
89
3i
3j
2
5
81
81
79[c]
3c
7
64[c,d]
3k
3
64[c]
Encouraged by these results, we next examined the scope
of this cascade sequence in terms of Grignard reagents and
alkyne substituents (Table 2). In all cases, oxabicycles 3
were obtained as a single cis isomer, in which the hydroxyl
group is oriented cis with respect to the oxygen bridge. The
structure and stereochemical assignment of oxabicycles 3
were unambiguously confirmed by X-ray crystal-structure
analysis of 3e[11] and by use of the 2D NOESY spectrum of
3a. The cis diastereoselectivity observed in these cycloaddi-
tion reactions can be attributed to chelation of the alkoxide
and furanyl oxygen atoms with the magnesium center, as
shown in intermediate 5 (Table 2), which would bridge both
groups and thus hold them on the same side during the cy-
cloaddition process. We first investigated the effect of vari-
ous Grignard reagents. Aromatic Grignard reagents, such as
phenyl- or p-chlorophenylmagnesium bromide, could be
used in this reaction, giving oxabicycles 3b and c in 79 and
64% yields, respectively. Allyl and ethynylmagnesium bro-
mides proved to be quite efficient in inducing this cascade
reaction, leading to 3d–f in 74–85% yields. Next, we exam-
ined the effect of the alkynyl substituent (R1). Indeed, aryl,
alkyl, and alkenyl substitutions were all accommodated and
Diels–Alder cycloadducts 3a–o were obtained in good to
high yields of 61–90%. Functionalities like -MeO, -Cl, and
-CF3 groups on the aromatic ring (3 f–i) were especially well
tolerated during the reaction. Modification of the parent
phenyl ring by introducing synthetically valuable fluoro, me-
thoxy, or methylenedioxy groups was also well tolerated by
this cyclization process, and good to high yields were ach-
ieved in these cases (3l–o). In the cases of 3c, g, and o, to
minimize the formation of byproducts, the reactions were
performed by first stirring the reaction mixture at room
temperature for 1 h and then at 808C under normal condi-
tions of heating to reflux.
3d 10 79
3l
2
2
90
61
3e
3 f
3
2
85
74
3m
3n
3o
2
3
89
3g 22 90[c,d]
87[c,d]
3h
2
88
[a] Unless otherwise noted, all of the reactions were carried out by addi-
tion of Grignard reagents (3 equiv) at 08C, followed by heating at 808C
in a sealed tube. [Substrate]=0.1m. [b] Isolated yield. [c] Two equivalents
of the Grignard reagent were used. [d] These reactions were carried out
by addition of Grignard reagents at 08C, stirring at room temperature for
1 h and then at 808C with an internal reflux condenser.
phenyl-2-ol products 4b and
c
in 69–82% yields
(Scheme 2).[11] These products are presumably derived by an
intramolecular Diels–Alder reaction followed by fragmenta-
tion of the oxabridge in the presence of an excess of the
Grignard reagent leading to the observed product.
Interestingly, if ketone 1j, containing a methyl group on
the furan ring, was subjected to the cyclization conditions,
the reaction proceeded efficiently to afford ring-opened bi-
To demonstrate the utility of oxabicycles 3 as synthetic
building blocks, we investigated the ring-opening reaction of
Chem. Eur. J. 2011, 17, 12582 – 12586
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12583

Y. Liu, Y. Li et al.
Scheme 4. The Diels–Alder reactions of 2a in the presence and absence
of a Grignard reagent.
Grignard regents, density functional theory (DFT)[19] studies
were performed at the M06/(6-311G** and 6-311+G**)
level with THF as the solvent[20,21] by using the Gaussian 09
program.[22]
Scheme 2. The formation of biphenyl-2-ol derivatives.
Initially, the Diels–Alder reaction of tertiary alcohol 2a
without Grignard regents was explored. As shown in
Figure 1, compound 2a has two conformers, 2a-a and 2a-b,
for which 2a-a is slightly more stable (1.7 kcalmolÀ1). The
concerted transition states were located in this calculation,
and the stepwise mechanism was excluded by a relaxed po-
tential energy surface (PES) scan.[21] The transition state 2a-
a-TS-trans is only 0.8 kcalmolÀ1 more stable than 2a-b-TS-
cis, indicating that the reaction will lead to a mixture of cis-
and trans-products, with the trans-product being more favor-
able. These results are consistent with our experimental ob-
servations (Scheme 4).
3a with aryl iodides in the presence of organometallic re-
agents[4a] (Scheme 3). Cheng and co-workers have previously
shown that this type of coupling reaction can be achieved by
using a catalytic amount of a PdII complex, giving rise to cis-
dihydronaphthol derivatives.[12] Gratifyingly, we found that
these reactions proceeded smoothly under modified reaction
conditions involving the use of a [PdCl2ACHTUNRGTNEUNG(PPh3)2]/Zn/ZnCl2/
Et3N catalyst system, giving aromatized derivatives 7a–c in
good yields (52–70%).[11]
Based on the model structures shown in Figure 1, the
structures containing a chelated magnesium atom were cal-
culated (Figure 2). In these structures, one BrÀ ion and two
THF solvent molecules are coordinated with each magnesi-
um center. The results show that for 2a-Mg, the cis transi-
tion state 2a-b-Mg-TS-cis is 4.5 kcalmolÀ1 more favorable
than the trans transition state 2a-a-Mg-TS-trans, and conse-
quently the cis compound becomes the sole product of this
reaction. It seems that coordination of magnesium with the
furan oxygen atom in 2a-b-Mg-TS-cis causes the stabiliza-
Scheme 3. The transformation of the oxabicycles.
To improve our understanding of the reaction mechanism,
tertiary alcohol 2a was prepared. The cycloaddition reaction
of 2a occurred smoothly in the presence of MeMgBr
(2 equiv) to generate exclusively the cis-oxabicycle 3a, as
observed in the tandem process, within 2 h.[13] In marked
contrast, in the absence of the Grignard reagent, heating a
sample of 2a at 808C for 44 h provided a mixture of cis- and
trans-diastereomers of 3a, with the trans-product being fa-
vored. In addition, a 40% yield of 2a was recovered
(Scheme 4). These results show the importance of the anion-
ic oxygen atom, not only for rate acceleration, but also to
direct the stereochemical course of the reaction. The struc-
ture of the trans isomer was also determined by X-ray crys-
tallography of trans-3e.[14]
It is known that Diels–Alder reactions can be accelerated
by, for example, Lewis acids,[15] substitution effects (gem-dia-
lkyl effect),[16] metal complexes,[8,17] or the formation of an
anionic species.[18] To rationalize the increased reactivity and
stereoselectivity of this Diels–Alder reaction when using
Figure 1. The optimized structures of reactant 2a and the transition states
2a-a-TS-trans and 2a-b-TS-cis of the Diels–Alder reaction. Structures
2a-a and 2a-b are the two conformers of 2a. Selected bond lengths are
given in ꢁ and the relative free energies in the solvent (DGsol; 353.15 K)
are given in kcalmolÀ1
.
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Chem. Eur. J. 2011, 17, 12582 – 12586

Intramolecular Diels–Alder Reactions of Furans
COMMUNICATION
Table 3. The HOMOdiene and LUMOdienophile of 2a-a (depicted by using
an isodensity of 0.04 au). The energy levels and energy gap (DEgap) of the
HOMOdiene and LUMOdienophile for 2a-a, 2a-b, 2a-a’, 2a-a-Mg, and 2a-b-
Mg are listed.
HOMOdiene
[eV]
LUMOdienophile DEgap NBO[a] charges
[eV] [eV] on
the furan frag-
ment
2a-a
2a-b
2a-a’
2a-a-
Mg
À6.59 HOMOÀ1 À1.46 LUMO 5.12
À6.56 HOMOÀ1 À1.45 LUMO 5.11
À5.68 HOMOÀ2 À0.95 LUMO 4.73
+0.003
À0.001
À0.092
À0.027
À6.11 HOMO
À1.31 LUMO 4.80
2a-b-
Mg
À6.28 HOMOÀ1 À1.28 LUMO 4.99
À0.015
[a] NBO=natural bond orbital.
Figure 2. The optimized structures of reactant 2a-Mg and the transition
states 2a-a-Mg-TS-trans and 2a-b-Mg-TS-cis of the Diels–Alder reaction.
Structures 2a-a-Mg and 2a-b-Mg are the two conformers of 2a-Mg. Se-
lected bond lengths are given in ꢁ and the relative free energies in the
ever, this charge changes to negative and the magnitude in-
creases to À0.092 in 2a-a’ and drops to À0.027 in 2a-a-Mg,
owing to the coordination with Mg. These results indicate
that the oxygen anion increases the energy of the Ap orbital
and the total negative charge of the furan fragment. Thus,
the system is activated by the electron-donating alkoxide
group on the furan ring.
solvent (DGsol; 353.15 K) are given in kcalmolÀ1
.
tion and accounts for the change in selectivity. Thus, the cis
selectivity originates from cis coordination of magnesium
with the hydroxyl and furan oxygen atoms.
Compared with 2a, the reaction energy barrier for 2a-Mg
dropped from 30.2 kcalmolÀ1 to 28.1 kcalmolÀ1. In the
Diels–Alder reaction, the energy separation between the
HOMOdiene and LUMOdienophile is crucial to reactivity. Rate
acceleration would be expected by either increasing the
energy of the HOMOdiene or decreasing the energy of the
LUMOdienophile. An inspection of the molecular orbitals in
2a-a (Table 3) shows that HOMOÀ1 mainly corresponds to
the highest occupied orbital of the furan fragment (the Ap
orbital of the furan ring, the HOMOdiene in Diels–Alder re-
actions), and the LUMO mainly corresponds to the lowest
unoccupied orbital of the alkyne unit (the LUMOdienophile).[21]
The data in Table 3 show that the energy of the HOMOdiene
in 2a-a-Mg and 2a-b-Mg is increased by 0.48 and 0.31 eV,
respectively, compared with that of 2a-a. Consequently, the
energy separation, DEgap, between the HOMOdiene and LU-
MOdienophile is decreased by 0.32 (7.4) and 0.13 eV (3.0 kcal
molÀ1), respectively.
To determine why the energy of the HOMOdiene is in-
creased, the ionic deprotonated model structure of 2a-a,
2a-a’ (1-(furan-2-yl)-1-[2-(phenylethynyl)phenyl]ethanolate),
was also calculated. The energy of the Ap molecular orbital
of the furan fragment in 2a-a’ is dramatically increased to
À5.68 eV. However, if the ionic oxygen atom coordinates
with magnesium (2a-a-Mg), the energy of this orbital is de-
creased rapidly to À6.11 eV, but is still much higher than
that of 2a-a (À6.59 eV). The total NBO charge on the furan
fragment in 2a-a is positive and very small (+0.003). How-
In conclusion, we have described a cascade reaction of
ortho-(alkynyl)phenyl furanyl ketones with Grignard re-
agents leading to 7-oxabicycloACTHNUTRGENUGN[2.2.1]hepta-2,5-diene deriva-
tives with excellent diastereoselectivity. An interesting
aspect of this cascade reaction is the intramolecular Diels–
Alder reaction of furans with unactivated alkynes. DFT cal-
culations and experimental results suggest that the forma-
tion of a chelated magnesium alkoxide plays an important
role in accelerating the reaction rate, as well as in determin-
ing the stereoselectivity of the Diels–Alder reaction. We
speculate that the acceleration effect of association of neigh-
boring alkoxides with furan rings might be applicable to the
Diels–Alder reactions of other related systems.
Experimental Section
Typical procedure for the intramolecular Diels–Alder reaction of ortho-
(alkynyl)phenyl furanyl ketones: MeMgBr (0.3 mL, 0.9 mmol, 3.0m in
Et2O) was added to a solution of furan-2-yl[2-(phenylethynyl)phenyl]me-
thanone (1a, 81.7 mg, 0.3 mmol) in THF (3.0 mL) at 08C and then the
ice bath was removed. The flask was sealed and immersed in an oil bath
at 808C. After stirring for 3 h, the mixture was cooled, quenched with sa-
turated ammonium chloride solution, extracted with diethyl ether, and
dried over anhydrous Na2SO4. The crude product was purified by column
chromatography on silica gel (petroleum/ethyl acetate, 2.5:1) to afford
oxabicyclic alkene 3a (76.8 mg, 89%) as
a
yellow foam. 1H NMR
(300 MHz, CDCl3, Me4Si): d=1.91 (s, 3H), 3.04 (brs, 1H), 5.94 (s, 1H),
7.02 (d, J=5.4 Hz, 1H), 7.28–7.49 (m, 8H), 7.57–7.60 (m, 1H), 7.72–
7.75 ppm (m, 1H); 13C NMR (75.5 MHz, CDCl3, Me4Si): d=23.12, 73.35,
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Y. Liu, Y. Li et al.
89.47, 104.67, 123.53, 124.59, 125.82, 127.72, 128.67, 129.21, 129.69, 132.63,
134.40, 140.59, 143.82, 144.83, 150.76, 153.76 ppm; HRMS (EI): m/z calcd
for C20H16O2: 288.1150; found: 288.1153.
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[10] We also carried out the reaction of 3a with 2 equivalents of
MeMgBr, for which it was found that 4a was obtained in 83% yield
after heating the mixture at 808C for 24 h in toluene.
[11] CCDC-826771 (3e), 826773 (4c, ethanol adduct), 826774 (7c, ether
adduct), and 826772 (trans-3e) contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
We thank the National Natural Science Foundation of China (grant num-
bers: 20872163, 20732008, 20821002, and 20872168), the Chinese Acade-
my of Science, and the Major State Basic Research Development Pro-
gram (grant number 2011CB808700) for financial support.
[12] J. P. Duan, C. H. Cheng, Organometallics 1995, 14, 1608.
[13] The reaction of 1 equivalent of MeMgBr with 2a at 808C for 2 h
gave 3a (cis/trans, 24:1) in 77% yield. For details, see the Supporting
Information.
Keywords: alkynes
reactions · furans · Grignard reaction · stereoselectivity
·
Diels–Alder reaction
·
domino
[14] The compound trans-3e was obtained by heating the corresponding
alcohol 2b at 808C for 120 h. For details, see the Supporting Infor-
mation.
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Received: July 1, 2011
Published online: September 29, 2011
12586
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Chem. Eur. J. 2011, 17, 12582 – 12586