Mechanochemical Grinding Diels-Alder Reaction: Highly Efficient and Rapid Access to Bi-, Tri-, and Tetracyclic Systems

Article abstract of DOI:10.1055/s-0036-1558970

Grinding of various electron-deficient dienophiles with diverse dienes in a pestle and mortar for 1-15 minutes afforded the corresponding Diels-Alder adducts in quantitative yields under catalyst-free and solvent-free conditions, without the necessity for

Full text of DOI:10.1055/s-0036-1558970

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–E
letter
A
J. Agarwal et al.
Letter
Synlett
Mechanochemical Grinding Diels–Alder Reaction: Highly Efficient
and Rapid Access to Bi-, Tri-, and Tetracyclic Systems
Jyoti Agarwal
Ph
Ph
O
O
H
Rashmi Rani
Ph
Rama Krishna Peddinti*
N
R
N
R
O
O
(CN)n
(CN)n
O
H
O
O
Department of Chemistry, Indian Institute of Technology
Roorkee, Roorkee-247667, Uttarakhand, India
rkpedfcy@iitr.ac.in
Ph
Ph
O
H
Ph
(CN)n
ramakpeddinti@gmail.com
N
R
catalyst-free
solvent-free
1–5 min grinding, r.t.
19 examples
H
O
chromatography-free
100% yield
Received: 07.01.2017
Accepted after revision: 22.02.2017
Published online: 15.03.2017
almost all examples suffered from very low to low yields of
the corresponding products and required elevated tempera-
tures. Zang et al. described a reaction between cyclopenta-
diene and various N-arylmaleimides in a ball-mill appara-
tus;24 however, when they attempted to simplify the meth-
odology by carrying out the reaction of cyclopentadiene
with N-tosylmaleimide through hand grinding, they ob-
tained only a 54% yield of the product.
DOI: 10.1055/s-0036-1558970; Art ID: st-2017-d0017-l
Abstract Grinding of various electron-deficient dienophiles with di-
verse dienes in a pestle and mortar for 1–15 minutes afforded the cor-
responding Diels–Alder adducts in quantitative yields under catalyst-
free and solvent-free conditions, without the necessity for any purifica-
tion steps.
In continuation of our efforts on green approaches in or-
ganic synthesis,25,26 we report a practical and operationally
simple method for performing Diels–Alder reactions that
involves manual grinding of two reactants in a pestle and
mortar without a catalyst at ambient temperature; more-
over, the method requires no purification steps. In some
cases, we compared neat grinding with liquid-assisted
grinding (LAG) in terms of yield and reaction time.
Key words solvent-free reaction, Diels–Alder reaction, cycloaddition,
polycyclic compounds, green chemistry
Mechanochemical grinding reactions have drawn atten-
tion from scientists in the areas of organic chemistry, su-
pramolecular chemistry, materials science, and (co)crystal
engineering for their ability to produce a range of materi-
als,1 and such methods have been applied to the prepara-
tion of molecular semiconductors,2 pharmaceuticals,3 and
optical materials.4 The method involves a reaction between
several solid reactants or between solid and liquid reac-
tants by grinding in the absence of a solvent, and this as-
pect has inspired the development of ever-more efficient
and versatile mechanochemical methodologies.5–7
The Diels–Alder reaction is one of the most significant
and widely used protocols for carbon–carbon, carbon–het-
eroatom, or heteroatom–heteroatom bond-forming reac-
tions to produce cyclic compounds in synthetic organic
chemistry,8 and is widely employed for the synthesis of nat-
ural products, pharmaceutically important molecules, and
related compounds.9–11 The most common methods to ac-
celerate such reactions involve the use of various Lewis acid
catalysts in solvents such as THF, toluene, or ionic liquids, or
performing the reaction at elevated temperatures.12–22
Reports on solvent-free Diels–Alder reactions have ap-
peared sporadically in the literature.22 For example, Huertas
and co-workers reported neat Diels–Alder reactions,23 but
As a model reactant, we chose 1,3-diphenyl-2-benzofu-
ran (1) as the diene because the new double bond of the
Diels–Alder adduct would be part of the aromatic ring,
making the reaction irreversible. Consequently, the cy-
cloaddition reaction of benzofuran 1 with N-phenylma-
leimide (3a) as the dienophile was tested by using both
neat grinding and liquid-assisted grinding techniques
(Scheme 1). Initially, the reaction was performed by mixing
equimolar amounts of the two solid reactants in a pestle
and mortar, and then grinding vigorously without using
any additional liquid (Method A).27 Although the reaction
went to completion in 15 minutes, manual grinding re-
quired a good deal of effort (Table 1, entry 1). When the re-
action mixture was wetted with 2–3 drops of ethyl acetate,
the reaction was complete within two minutes, and it gave
the corresponding tetracyclic product 5a in quantitative
yield (Method B)28 (entry 2). Therefore, the LAG methodolo-
gy accelerated the reaction and, most significantly, the pu-
rity of the product was good enough to permit spectroscop-
ic analysis.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

B
J. Agarwal et al.
Letter
Synlett
Ph
O
Ph
O
O
H
H
5a–d
7a–d
N
R
O
grinding
1–5 min
1
Ph
O
Ph
H
+
or
N
R
O
quantitative yield
O
N
R
3
R = H, Br, Cl, OMe
H
2
O
Scheme 1 Diels–Alder reactions of 1,3-diphenyl-2-benzofuran or cyclopentadiene with various N-arylmaleimides
Table 1 Diels–Alder Reactions of 1,3-Diphenyl-2-benzofuran or Cyclo-
pentadiene with Various Dienophiles
arene moiety of the maleimide derivative (Table 1, entries
3–10). For example, the reaction of N-(4-methoxyphe-
nyl)maleimide (3d) with benzofuran 1 did not reach com-
pletion after 30 minutes of neat grinding, and afforded the
product in only 75% yield. However, by using the LAG proto-
col, complete conversion of the reactants was achieved in
five minutes, giving product 5d in quantitative yield. It is
noteworthy that the success of such protocols relies on the
fact that the reactants are consumed completely to afford
the desired products; the presence of even small amounts
of unreacted starting materials or byproducts would result
in the need for purification steps. Consequently, in almost
all the above examples, the LAG protocol was found to be
optimal for achieving complete conversion of the reactants.
Another observation was that the progress of each of the re-
actions of diene 1 with dienophiles 3a–e could be followed
visually, because the initially yellow-colored reaction mix-
ture was transformed into a white product on completion
of the reaction.
Entry Dienophile
X
Cycloadduct Methoda Time Yieldb
(min) (%)
Ph
O
Ph
O
O
H
+
X
X
O
H
Ph
O
3,4
O
Ph
1
1
2
3a
3b
3c
3d
3e
4
NPh
5a
5b
5c
A
B
15
1
98
quant
3
4
N(C6H4-4-Br)
N(C6H4-4-Cl)
A
B
20
2
95
quant
5
6
A
B
20
2
94
quant
7
8
N(C6H4-4-OMe) 5d
A
B
30
5
75
quant
9
10
NBn
O
5e
6
A
B
25
2
quant
quant
The reaction of 1 with maleic anhydride (4) with neat
grinding provided adduct 6 in 90% yield in 30 minutes (Ta-
ble 1, entry 11). However, when this reaction was per-
formed by using the LAG protocol (Method B), it proceeded
smoothly to give 6 in quantitative yield in only two minutes
(entry 12).
11
12
A
B
30
2
90
quant
O
O
H
X
+
X
H
O
O
We next chose cyclopenta-1,3-diene (2) as the diene.
Freshly distilled cyclopenta-1,3-diene was added to the sol-
id yellow imide 3a in a mortar, and the resulting mixture
was ground for one to two minutes. During this period, the
initially pasty yellow reaction mixture became a white sol-
id, indicating complete conversion of the reactants into the
tricyclic Diels–Alder adduct 7a, which was obtained in
quantitative yield (Table 1, entry 13). No cyclopentadiene
dimer or any other byproduct was formed. The resultant
product was pure enough for standard spectroscopic analy-
sis.
2
3
13
14
15
16
17
3a
3b
3c
3d
3e
NPh
7a
7b
7c
A
A
A
A
A
1
3
3
5
2
quant
quant
quant
quant
quant
N(C6H4-4-Br)
N(C6H4-4-Cl)
N(C6H4-4-OMe) 7d
NBn 7e
a Method A: The reaction was carried out by grinding the two reactants (1
mmol each) for the time shown in the table. Method B: The reaction was car-
ried out by grinding the two reactants (1 mmol each) in the presence of 2–3
drops of EtOAc for the time shown in the table.
b Yield of pure isolated product.
These results encouraged us to study the reactions of
other N-phenylmaleimide derivatives 3b–d and 3e with cy-
clopentadiene 2 by using the same hand-grinding method.
Gratifyingly, all the reactions furnished the corresponding
product 7b–e in quantitative yield within minutes (Table 1,
entries 14–16). As before, the rate of the reaction was af-
fected by the substituents on the arene moiety of the ma-
Encouraged by these results, we tested the reactions of
other N-substituted maleimides 3b–e with benzofuran 1
using both protocols. Although all the reactions gave the
corresponding products 5b–e in quantitative yields, the
rate of the reaction was affected by the substituents on the
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

C
J. Agarwal et al.
Letter
Synlett
leimide; for instance, the reaction between diene 2 and N-
(4-methoxyphenyl)maleimide (3d) required five minutes of
grinding for complete conversion of reactants into the ad-
duct 7d, whereas the reaction of 4-halo-substituted N-aryl-
maleimides 3b and 3c took less time to give the corre-
sponding adducts 7b and 7c in quantitative yield.
To test further the generality of this methodology, we
then extended our Diels–Alder protocol to various dienes
and dienophiles. Nitrile group containing dienophiles, such
as tetracyanoethylene (11) and fumaronitrile (12), were
tested with diene 1. Gratifyingly, these reactions also
reached completion rapidly to afford the tricyclic products
15 and 16, respectively (Table 2, entries 1 and 2). Further-
more, when 1,3-diphenyl-2-benzofuran (1a) was treated
with a stoichiometric amount of a dialkyl acetylenedicar-
boxylate 13 or 14, the green-colored reaction mixture was
transformed into a white solid within minutes to provide
the pure product 17 or 18, respectively, in quantitative yield
(entries 3 and 4). The reaction of cyclopentadiene (2) or
methylcyclopentadiene (8) with the highly electron-defi-
cient dienophile tetracyanoethylene (11) was complete
within one minute and gave the bicyclic product 19 or 20,
respectively, in quantitative yield (entries 5 and 6). The re-
actions of less-reactive dienes such as cyclohexa-1,3-diene
(9) or anthracene 10 with tetracyanoethylene (11) success-
fully also gave the corresponding Diels–Alder products 21
and 22, respectively, in quantitative yield within minutes
(entries 7 and 8). However, when we attempted the cy-
cloaddition reaction of cyclopentadiene with alkynedioates
13 and 14, disappointingly, no reaction was observed.
In conclusion, a very simple, highly efficient, catalyst-
free approach has been developed for promoting the Diels–
Alder reaction of various dienes with dienophiles. The
method provides the products within minutes in near-
quantitative yields and without the formation of any by-
products.
Table 2 Diels–Alder Reactions of Various Dienes and Electron-Deficient Dienophiles under Green Conditions
Entry Diene
Dienophile
Cycloadduct
Methoda
Time (min) Yielda (%)
Ph
O
Ph
CN
CN
NC
NC
CN
CN
CN
1
11
12
15
16
B
1
4
quant
O
CN
Ph
Ph
Ph
1
CN
H
CN
H
2
1
1
B
quantc
O
CN
NC
Ph
Ph
CO2R
CO2R
CO2R
3
4
13, R = Me
14, R = Et
17, R = Me
18, R = Et
A
A
2
2
quant
quant
O
CO2R
Ph
CN
CN
NC
NC
CN
CN
5
6
2, R = H
8, R = Me
19, R = H
20, R = Me
A
A
1
1
quant
quant
11
11
R
R
CN
CN
NC
NC
CN
CN
CN
CN
CN
CN
7
8
21
22
A
A
3
2
quant
quant
9
CN
CN
CN
CN
NC
NC
CN
CN
11
10
a Method A: The reaction was carried out by grinding the two reactants (1 mmol each) for the time shown in the table. Method B: The reaction was carried out by
grinding the two reactants (1 mmol each) in the presence of 2–3 drops of EtOAc for the time shown in the table.
b Yield of pure isolated product.
c Combined yield of a 1:1 mixture of diastereomers. The structure of only one diastereomer is shown.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

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Acknowledgements
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Drug Develop. Res. 2011, 3, 34.
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Practical Methods; Wiley: Chichester, 2009. (b) Cycloaddition
Reactions in Organic Synthesis; Kobayashi, S.; Jørgensen, K. A.,
Eds.; Wiley-VCH: Weinheim, 2002.
J.A. thanks UGC, New Delhi, and R.R. thanks MHRD for the awards of
their research fellowships.
Supporting Information
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Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1558970.
S
u
p
p
ortiInfogrmoaitn
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p
p
ortioInfgrmoaitn
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A mixture of the diene (1 mmol) and the dienophile (1 mmol)
was subjected to hand grinding with a pestle and mortar for the
time shown in Tables 1 and 2 to afford the corresponding prod-
ucts in quantitative yield. In the reactions of cyclopentadiene,
1.2 equiv of the diene was used. In most cases, product forma-
tion was observed by the change in color; with aryl maleimides,
the yellow color of the initial reaction mixture changed to
white, whereas with 1,3-diphenyl-2-benzofuran, the color of
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

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J. Agarwal et al.
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Synlett
the mixture changed almost immediately from fluorescent
green to white.
2-(4-Bromophenyl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoi-
soindole-1,3-dione (7b)
δ = 6.69 (s, 2 H), 3.55 (s, 2 H), 2.24 (d, J = 9.5 Hz, 2 H), 1.62 (d,
J = 9.5 Hz, 2 H). 13C NMR (125 MHz, CDCl3): δ = 133.1, 111.7,
111.3, 107.9, 42.8, 39.1, 18.8.
(28) Method B: Liquid-Assisted Grinding; General Procedure
A mixture of the appropriate diene (1 mmol), dienophile (1
mmol), and EtOAc (2–3 drops) was subjected to hand grinding
with a pestle in a mortar for the time shown in Tables 1 and 2.
Almost immediately, the color of the mixture changed from fluo-
rescent-green or yellow to white. The EtOAc was removed under
vacuum to afford the pure solid product in quantitative yield.
2-(4-Bromophenyl)-4,9-diphenyl-3a,4,9,9a-tetrahydro-1H-
4,9-epoxybenzo[f]isoindole-1,3-dione (5b)
White solid; yield: 317 mg (quant); mp 156 °C. 1H NMR (500
MHz, CDCl3): δ = 7.55 (dt, J = 2.5, 9.0 Hz, 2 H), 7.04 (dt, J = 2.5,
9.5 Hz, 2 H), 6.25 (t, J = 1.5 Hz, 2 H), 3.53–3.47 (m, 2 H), 3.43 (q,
J = 1.5 Hz, 2 H), 1.79 (d, J = 9.0 Hz, 1 H), 1.61 (d, J = 9.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 176.3, 134.5, 132.1, 130.7, 128.1,
122.2, 52.1, 45.7, 45.4.
2-(4-Methoxyphenyl)-3a,4,7,7a-tetrahydro-1H-4,7-metha-
noisoindole-1,3-dione (7d)
White solid; yield: 170 mg (quant); mp 269 °C. 1H NMR (500
MHz, CDCl3): δ = 7.04 (d, J = 8.0 Hz, 2 H), 6.93 (d, J = 8.0 Hz, 2 H),
6.25 (s, 2 H), 3.80 (s, 3 H), 3.50 (s, 2 H), 3.41 (s, 2 H), 1.78 (d,
J = 8.5 Hz, 1 H), 1.60 (d, J = 8.0 Hz, 1 H). 13C NMR (125 MHz,
CDCl3): δ = 177.1, 159.4, 134.5, 127.8, 124.4, 114.4, 55.4, 52.2,
45.6, 45.4.
White solid; yield: 521 mg (quant); mp 242 °C. 1H NMR (500
MHz, CDCl3): δ = 8.05 (d, J = 7.5 Hz, 4 H), 7.54 (t, J = 7.5 Hz, 4 H),
7.47 (d, J = 7.0 Hz, 2 H), 7.28–7.22 (m, 4 H), 7.05 (dd, J = 3.0, 5.0
Hz, 2 H), 6.43 (d, J = 8.5 Hz, 2 H), 4.26 (s, 2 H). 13C NMR (125
MHz, CDCl3): δ = 173.0, 144.0, 136.2, 132.1, 130.1, 128.8, 128.7,
128.3, 127.9, 127.1, 122.7, 120.8, 90.6, 54.3.
Diethyl
2,3-dicarboxylate (18)
1,4-Diphenyl-1,4-dihydro-1,4-epoxynaphthalene-
2-(4-Methoxyphenyl)-4,9-diphenyl-3a,4,9,9a-tetrahydro-
1H-4,9-epoxybenzo[f]isoindole-1,3-dione (5d)
White solid; yield: 440 mg (quant); mp 115 °C. 1H NMR (500
MHz, CDCl3): δ = 7.79 (d, J = 7.0 Hz, 4 H), 7.56 (dd, J = 3.0, 5.0 Hz,
2 H), 7.52–7.43 (m, 6 H), 7.18 (dd, J = 3.0, 5.0 Hz, 2 H), 4.23–4.12
(m, 4 H), 1.17 (t, J = 7.0 Hz, 6 H). 13C NMR (125 MHz, CDCl3):
δ = 163.6, 153.7, 149.2, 133.2, 129.0, 128.4, 128.1, 125.9, 122.1,
94.0, 61.3, 13.8.
Bicyclo[2.2.1]hept-5-ene-2,2,3,3-tetracarbonitrile (19)
White solid; yield: 194 mg (quant); mp 217 °C. 1H NMR (500
MHz, CDCl3): δ = 6.52 (s, 2 H), 4.06 (s, 2 H), 2.25 (s, 2 H). 13C
NMR (125 MHz, CDCl3): δ = 133.6, 111.9, 111.7, 110.9, 110.4,
107.9, 55.9, 46.7, 46.4.
White solid; yield: 473 mg (quant); mp 209 °C. 1H NMR (500
MHz, CDCl3): δ = 8.07 (d, J = 8.0 Hz, 4 H), 7.53 (t, J = 7.5 Hz, 4 H),
7.46 (t, J = 7.0 Hz, 2 H), 7.29–7.22 (m, 2 H), 7.06 (dd, J = 3.0, 5.0
Hz, 2 H), 6.79 (d, J = 8.5 Hz, 2 H), 6.42 (d, J = 9.0 Hz, 2 H), 4.24 (s,
2 H), 3.75 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ = 173.5, 159.5,
144.1, 136.3, 128.6, 128.5, 128.1, 127.5, 127.1, 123.7, 120.8,
114.2, 90.5, 55.3, 54.2.
1,4-Diphenyl-1,2,3,4-tetrahydro-1,4-epoxynaphthalene-2,3-
dicarbonitrile (16)
White solid; yield: 378 mg (quant). 1H NMR (500 MHz, CDCl3):
δ = 7.84–7.79 (m, 2 H), 7.69–7.62 (m, 2 H), 7.60–7.59 (m, 6 H),
7.32–7.29 (m, 3 H), 7.15 (d, J = 7.0 Hz, 1 H), 3.87 (d, J = 4.5 Hz, 1
H), 3.54 (d, J = 4.0 Hz, 1 H). 13C NMR (125 MHz, CDCl3):
δ = 144.1, 142.8, 134.1, 133.3, 129.6, 129.2, 129.1, 129.0, 125.8,
125.5, 121.8, 119.7, 117.1, 117.0, 90.7, 44.4, 43.0.
Bicyclo[2.2.2]oct-5-ene-2,2,3,3-tetracarbonitrile (21)
White solid; yield: 208 mg (quant). 1H NMR (500 MHz, CDCl3):
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E