A dehydrogenative diels-alder reaction of prenyl derivatives with 2,3-dichloro-5,6-dicyanobenzoquinone

Article abstract of DOI:10.1002/adsc.201401038

An efficient dehydrogenative Diels-Alder (DHDA) reaction of prenyl derivatives with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) has been developed under mild conditions, leading to a series of cyclohexene derivatives with good to excellent yields and excellent diastereoselectivity.

Full text of DOI:10.1002/adsc.201401038

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DOI: 10.1002/adsc.201401038
A Dehydrogenative Diels–Alder Reaction of Prenyl Derivatives
with 2,3-Dichloro-5,6-dicyanobenzoquinone
Hong-Xia Feng,a Yuan-Yuan Wang,a Jie Chen,a,* and Ling Zhoua,*
a
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, Department of
Chemistry & Materials Science, Northwest University, Xiꢀan 710069, Peopleꢀs Republic of China
E-mail: chmchenj@nwu.edu.cn or zhoul@nwu.edu.cn
Received: October 31, 2014; Revised: January 19, 2015; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201401038.
Abstract: An efficient dehydrogenative Diels–
Alder (DHDA) reaction of prenyl derivatives with
2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) has
been developed under mild conditions, leading to
a series of cyclohexene derivatives with good to ex-
cellent yields and excellent diastereoselectivity.
As a powerful oxidizing reagent in organic chemis-
try, DDQ has been proven to be useful for a wide
range of reactions,[6] such as oxidation of hydroaro-
matic compounds,[7a] steroid derivatives (ketones, pyr-
razoles, lactones, etc.),[7b] alcohols,[7c] phenols,[7d] allylic
and benzylic ethers,[7e] and heterocyclic compounds.[7f]
Additionally, 1,4-benzoquinones are good dienophiles
for the DA reaction.[8] Inspired by allylic oxidation re-
actions with DDQ,[7e,9] we envisage that the oxidation
of a prenyl motif by DDQ would generate an allylic
carbocation intermediate, then elimination of a proton
and rearrangement would form an isoprene motif.[10]
Finally, a DA reaction of the isoprene derivative and
Keywords: C–H activation; cycloaddition; dehydro-
genation; diastereoselectivity; oxidation
The Diels–Alder (DA) reaction is one of the most DDQ would yield a DHDA reaction product.
fundamental and synthetically useful reactions in or- To test this hypothesis, we examined the reaction
ganic chemistry. In which a diene is combined with using prenyl ether 1a and DDQ in a ratio of 1:1.1 in
a dienophile to form a cyclohexene derivatives, and DCM at room temperature, to our delight, the desired
two new C–C bonds and several new stereocenters DHDA reaction product 2a was obtained in 40%
may be generated in a single step.[1] Studies on the yield as a single diastereomer (Table 1, entry 1). In-
DA reaction have a long history, many remarkable creasing the amount of DDQ gave a significant in-
endeavors have been made to develop various DA re- crease in yield, and 2a was obtained in 94% yield
actions.[2] However, one limitation of the reaction is when a slightly excess of DDQ was employed
that the diene component is usually unavailable and (Table 1, entry 3). However, other 1,4-benzoquinones
needs to be prepared. As a consequence, a dehydro- (BQ) such as 2,6-Me2BQ, BQ, or 2,3,5,6-Cl4BQ all re-
genative Diels–Alder (DHDA) reaction strategy has turned no desired products; the starting materials
been emerged.[3] This contains two variations: one is were recovered (Table 1, entries 7-9), indicating that
that a DA reaction takes place followed by a dehydro- the dehydrogenative step didnꢀt occur under these
genation (usually aromatization);[4] the other is that conditions. When an excess amount of other strong
a dehydrogenative reaction takes place prior to a DA dienophiles, such as maleic anhydride, N-phenylmale-
reaction.[5] The latter one is more challenging and po- imide, and tetracyanoethylene, were employed togeth-
tential useful, because a C–H bond oxidation reaction er with DDQ for this reaction, unfortunately, no cross
is involved to prepare a diene in situ, and the newly DHDA reaction products, resulting from the reaction
generated stereocenters of the DA reaction product with these dienophiles, were detected. 2a, resulting
are remained. Recently, the White group developed from the reaction with DDQ was the only product ob-
an efficient Pd-catalyzed DHDA reaction with termi- tained.[11] The reason may be due to DDQ is the
nal alkenes.[5a] As this is an efficient method to realize strongest dienophile among them. Indeed, the suc-
DA reactions, it is high desirable to discover new var- cessful DA reaction of these dienophiles with iso-
iants of this type reaction. Here we report an efficient, prene, without DDQ, confirm this point.[11] With sol-
metal-free DHDA reaction of prenyl derivatives with vents other than DCM, the yields clearly diminished
2,3-dichloro-5,6-dicyanobenzoquinone (DDQ).
(Table 1, entries 4-6).
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Hong-Xia Feng et al.
Table 1. Optimization of the reaction conditions.[a]
Table 2. DHDA reaction of DDQ with prenyl derivatives.[a]
Entry Substrate R
n
Time [h] Yield [%][b]
Entry oxidant (equiv)
Solvent Time [h] Yield [%][b]
1
1a C6H5O
0
0
0
0
0
0
0
0
0
0
0
0
0
1
1
1
2
2
0
48
48
36
48
48
60
48
60
60
48
60
60
48
48
60
60
60
48
48
95[c]
90
92
81
72
NR
85
60
70
88
2
3
4
5
6
7
8
1b 4-CH3-C6H4O
1c 4-CH3O-C6H4O
1d 4-Cl-C6H4O
1e 4-Br-C6H4O
1 f 4-NO2-C6H4O
1g 3-CH3-C6H4O
1h 3-Cl-C6H4O
1
2
3
4
DDQ (1.1)
DDQ (2.5)
DDQ (2.1)
DDQ (2.1)
DDQ (2.1)
DDQ (2.1)
2,6-Me2BQ (2.1)
BQ (2.1)
DCM
DCM
DCM
ACN
48
48
48
48
40
82
94
15
5
toluene 48
32
6
THF
DCM
DCM
60
60
60
60
60
5
7[c]
8
NR
NR
NR
NR
9
1i
3-Br-C6H4O
10
11
12
13
14
15
16
17
18
19
20
1j 2-CH3-C6H4O
1k 2-Cl-C6H4O
9
2,3,5,6-Cl4BQ (2.1) DCM
2,3,5,6-Cl4BQ (2.1) DCE
10[d]
61
77
80
84
1l
2-Br-C6H4O
[a]
Reactions were carried out with compound 1a
(0.2 mmol) and oxidant (equiv) in solvent (2.0 mL) at r.t.
Isolated yield.
BQ=1,4-benzoquinone.
The reaction temperature is 908C.
1m C6H5
1n C6H5O
1o 4-CH3O-C6H4O
1p 4-NO2-C6H4O
1q 4-NO2-C6H4O
1r TsO
[b]
[c]
[d]
67
NR
96
56[d]
53
1s BnO
1t 2,3-dimethyl-2-butene 48
58
Having established the optimal reaction conditions,
[a]
Reactions were carried out with compound 1a-t
we then first carried out the reaction between DDQ
and a variety of prenyl ethers to test the scalability
and generality. A 10-fold increase in scale resulted in
little change in the yield (Table 2, entry 1 vs Table 1,
entry 3). Substrates with electron-rich substituents at
the para-position of the phenyl ring gave the corre-
sponding products in good yields (Table 2, entries 2
and 3). However, substrates with electron-deficient
(0.20 mmol) and DDQ (0.42 mmol) in DCM (2.0 mL) at
r.t.
[b]
[c]
[d]
Isolated yield.
2.0 mmol scale.
trans:cis=8.5:1, determined by H NMR analysis.
1
substituents at the para position returned clearly de- substrate for this DHDA reaction (Table 2, entry 18),
creased yields (Table 2, entries 4, 5), and the strong offering excellent handle for further synthetic manip-
electron-deficient 4-nitro substituted 1 f resulted in no ulations. Prenyl benzyl ether returned the desired
reaction (Table 2, entry 6). The negative effects of the product 3s in 53% yield, indicating the encouraging
electron-deficient substrates on the yields could result level of chemoselectivity (Table 2, entry 19). Surpris-
from the electron-deficient allylic protons being less ingly, simple alkene substrate 2,3-dimethyl-2-butene
reactive toward oxidation. Similar phenomena were also gave in the desired DHDA product with moder-
observed when the reactions were conducted with ate yield (Table 2, entry 20).
substrates containing various substituents at the 3- or
2-position of the phenyl ring (Table 2, entries 7–12).
Encouraged by these results, prenyl derivatives con-
taining nitrogen functional groups were also exam-
Next, we examined an all-carbon containing sub- ined. A substrate containing N-benzyl and N-tosyl
strate 1m for this DHDA reaction; as expected, the groups resulted in the desired DHDA product in
desired cycloaddition product 2m was obtained as 93% yield with exclusive trans selectivity (Table 3,
a single isomer in 80% yield (Table 2, entry 13). Ad- entry 1). A similar result was observed when the
ditionally, substrates with one more carbon in the benzyl group was substituted by a p-methoxybenzyl
chain lead to similar results as above mentioned (PMB) group (Table 3, entry 2).[12] Other sulfonyl
(Table 2, entries 14–16). There is no longer an elec- groups containing several functional groups such as
tron withdrawing effect for the allylic proton when nitro, alkoxy, and halo could be well tolerated, and
a longer carbon chain is employed (Table 2, entry 17). the desired DHDA products were obtained with ex-
Notably, all these products were obtained with excel- cellent yields (Table 3, entries 3-5). The structures and
lent trans selectivity. Prenyl tosylate is also a suitable stereoselectivity were confirmed by NMR and X-ray
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A Dehydrogenative Diels–Alder Reaction
Table 3. Selective DHDA reaction of DDQ with prenyl de-
rivatives.[a]
Entry Substrate R1
R2
Time [h] Yield [%][b]
Scheme 1. Proposed mechanism.
1
2
3
4
5
6
7
3a 4-CH3-C6H4SO2 Bn
20
96
93
87
92
96
95
0[c]
3b 4-CH3-C6H4SO2 PMB 20
3c 4-NO2-C6H4SO2 PMB 20
3d 4-CH3O-C6H4SO2 PMB 20
3e 4-Br-C6H4SO2
3 f 4-NO2-C6H4SO2 C6H5 20
3g C6H5 PMB 10
PMB 20
[a]
Reactions were carried out with compound 3a-g
(0.20 mmol) and DDQ (0.42 mmol) in DCM (2.0 mL) at
r.t.
Isolated yield.
4-Methoxybenzaldehyde was obtained in 81% yield.
[b]
[c]
Scheme 2. Reaction of DDQ with isoprene and 1u.
crystal analysis (4c, Figure 1).[13] A substrate with N-
sulfonyl and N-phenyl groups also gave excellent re-
sults (Table 3, entry 6). However, a substrate with N-
phenyl and N-PMB groups returned no desired
DHDA product; in contrast, 4-methoxybenzaldehyde
was formed by deprotection of the PMB group
(Table 3, entry 7).[12]
A proposed mechanism for this DHDA reaction is
depicted in Scheme 1. Initially, a transfer of hydride
ion to DDQ occurs, resulting in the formation of an
allylic carboncation intermediate and DDHQ. Subse-
Scheme 3. Synthesis of 5.
quent deprotonation and rearrangement to an iso- the DA reaction of DDQ with the isoprene inter-
prene intermediate, which undergoes a DA reaction mediates is too faster to be trapped. Indeed, treat-
with DDQ leads to the cycloaddition product. Nota- ment of 1.1 equiv of DDQ with isoprene in DCM at
bly, most of the reactions need a long reaction time, room temperature for 2 min, the desired DA reaction
and the desired isoprene intermediates were not sepa- product was obtained in quantitative yield
rated during the process. The reason may be because (Scheme 2). Meanwhile, reaction of isoprene precur-
sor 1u with 2.1 equiv of DDQ for 48 h gave 2u only
in 16% yield. These results indicate the first dehydro-
genation step is the rate determine step in this
DHDA reaction.
In summary, we have developed an efficient
DHDA reaction of prenyl derivatives with DDQ. A
series of DDQ adduct cyclic product were prepared
with good to excellent yields and excellent diastereo-
selectivity. Which are potential building blocks for
further transformations (e. g. Scheme 3).[14] The scope
of the protocol is large, and the substrates can be flex-
ibly varied. Control experiments indicate that the de-
hydrogenation step is the rate determine step of this
reaction. Further investigations to better understand-
ing the mechanism and to extend the scope and appli-
Figure 1. X-ray structure of 4c.
cation of this DHDA reaction are underway.
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Hong-Xia Feng et al.
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Experimental Section
General Procedure for the DHDA Reaction of DDQ
with Prenyl Derivatives (Table 2)
A solution of prenyl substrate (0.20 mmol, 1.0 equiv) and
DDQ (94 mg, 0.42 mmol, 2.1 equiv) in DCM (2.0 mL) was
stirred at room temperature for 48–60 h. TLC revealed the
absence of starting material. The reaction mixture was
quenched by saturated NaHCO3 solution (2.0 mL) and ex-
tracted with EtOAc (3ꢂ5.0 mL). The combined extracts
were dried with anhydrous Na2SO4, filtered and concentrat-
ed under reduced pressure. The residue was purified by
flash column chromatography (petroleum ether, EtOAc) to
yield the corresponding product.
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Acknowledgements
We thank the National Natural Science Foundation of China
(NSFC-21203148, 21302151), Science and Technology De-
partment of Shaanxi Province (2013 JQ2012), Education De-
partment of Shaanxi Province (2013 JK0644), the New
Teachersꢀ Fund for Doctor Stations (20126101120010), the
Scientific Research Foundation for the Returned Overseas
Chinese Scholars, Ministry of Education, and the Northwest
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6 A Dehydrogenative Diels–Alder Reaction of Prenyl
Derivatives with 2,3-Dichloro-5,6-dicyanobenzoquinone
Adv. Synth. Catal. 2015, 357, 1 – 6
Hong-Xia Feng, Yuan-Yuan Wang, Jie Chen,* Ling Zhou*
6
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