Mechanochemical Diels-Alder cycloaddition reactions for straightforward synthesis of endo-norbornene derivatives

Article abstract of DOI:10.1055/s-0030-1259030

Under mechanochemical milling conditions, Diels-Alder cycloaddition of cyclopentadiene with maleic anhydride and maleimide derivatives proceeded very smoothly, affording endo-norbornenes exclusively in quantitative yield. All the transformations were accomplished at room temperature without using any catalyst or organic solvent, thus the workup and purification procedure is very simple. Control experiments on traditional and other tentative conditions were also investigated. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1259030

LETTER
2895
Mechanochemical Diels–Alder Cycloaddition Reactions for Straightforward
Synthesis of endo-Norbornene Derivatives
M
echanochemic
e
al Synthesis of
e
Z
ndo-Norbornen
h
e
s
ang,* Zhi-Wei Peng, Ming-Feng Hao, Jian-Gang Gao
School of Biochemical Engineering, Anhui Polytechnic University, Wuhu, Anhui 241000, P. R. of China
Fax +86(553)2871254; E-mail: zzhang@ahpu.edu.cn
Received 16 August 2010
O
Abstract: Under mechanochemical milling conditions, Diels–
neat, r.t.
Alder cycloaddition of cyclopentadiene with maleic anhydride and
maleimide derivatives proceeded very smoothly, affording endo-
norbornenes exclusively in quantitative yield. All the transforma-
tions were accomplished at room temperature without using any
catalyst or organic solvent, thus the workup and purification proce-
dure is very simple. Control experiments on traditional and other
tentative conditions were also investigated.
O
+
X
MM400, 30 min
X
O
O
3
1
2
X = O or NR
Scheme 1
Key words: norbornenes, mechanochemical milling, solvent-free,
cyclopentadiene, Diels–Alder reaction
conditions without using any catalyst or solvent
(Scheme 1).
In a typical procedure, cyclopentadiene 1 (5.2 mmol, 0.44
mL, freshly distilled maintaining the head temperature be-
low 45 °C) and maleic anhydride or maleimide deriva-
tives 2 (5.0 mmol), together with a stainless ball of 7.0
mm in diameter, were introduced into a stainless jar (25
mL). The same mixture was also introduced into a second
parallel jar. The two reaction vessels were sealed with
screw caps, fixed on the vibration arms of a ball-milling
apparatus (Retsch MM400 mixer mill, Retsch GmbH,
Haan, Germany), and were vibrated vigorously at a rate of
1800 rpm (30 Hz) at room temperature for 30 minutes.
TLC analysis on the resulting mixtures demonstrated that
reactions in all cases proceeded completely and only the
desired products 3 were generated, which were obtained
just by washing with about 5 mL hexane to remove the
slightly excessive cyclopentadiene. The results are sum-
marized in Table 1.
Norbornene and its derivatives, which carry a double
bond inducing significant ring strain and thus significant
reactivity, can be utilized to make pharmaceutical inter-
mediates, pesticide compounds, specialty fragrances, and
in organic synthesis.1 They are also employed as impor-
tant monomers in ring-opening metathesis polymeriza-
tions (ROMP) for the synthesis of various
polynorbornenes with high glass-transition temperatures,
high light harvesting and liquid crystal properties, high
optical clarity, and so on.2,3 Norbornene moiety is normal-
ly constructed via Diels–Alder cycloaddition reaction,
which represents the favorite protocol to synthesize six-
membered carbo- or heterocycles.4–6 In fact, different sol-
vents, catalysts, and reaction conditions have proved to be
robust for this kind of transformation.4–7 However, current
methods often involve the use of toxic solvents, relatively
expensive or harmful catalysts, long reaction time or te-
dious purification workup procedures. To circumvent
these problems, one of the best methods is to carry out this
kind of reaction under solvent-free or uncatalyzed condi-
tions, which has the advantages of reduced pollution, low
cost, and simplicity in process and handling.8,9 Other than
traditional solvent-free conditions, mechanical ball-mill-
ing technique has recently contributed significantly to
promote various organic transformations.10,11
As shown in Table 1, the cycloaddition reactions gave
products 3 in remarkably high yields, which are almost
quantitative. Generally, the efficiency would not be af-
fected by various substituents at the X position, including
O, aliphatically and aromatically substituted N. This
means that a large variety of norbornene derivatives could
be synthesized by this method. Furthermore, this protocol
does not require the use of any organic solvent during the
reaction process and only an excess of 4% molar equiva-
lent of cyclopentadiene is enough to promote the reaction.
In fact, the resulted crude products in most cases can even
be directly used for normal IR and 1H NMR analysis. As
anticipated, all cycloadducts were formed exclusively in
In light of the great successes of mechanochemistry in or-
ganic synthesis and with a view to the above reasons for
the synthesis of norbornene derivatives, we are inspired to
perform Diels–Alder cycloaddition reactions of cyclopen-
tadiene with maleic anhydride and maleimide derivatives
promoted by mechanical milling technique. Herein, we
wish to report the results of this transformation under neat
1
endo conformation according to H NMR analysis. We
have attempted to further decrease the usage amount of
cyclopentadiene even up to 1.0 equivalent, but the product
turned out to be contaminated by a trace amount of unre-
acted 2 as indicated by 1H NMR analysis on these cases.
SYNLETT 2010, No. 19, pp 2895–2898
x
x
.x
x
.2
0
1
0
Advanced online publication: 10.11.2010
DOI: 10.1055/s-0030-1259030; Art ID: W12810ST
© Georg Thieme Verlag Stuttgart · New York
To contrast with traditional methods, we also prepared
these norbornene derivatives by carrying out the cycload-

2896
Z. Zhang et al.
LETTER
dition reactions in THF–hexane as the following: to a stir- gy caused by local high pressure, friction, shear strain, etc.
ring mixture containing maleic anhydride or maleimide could also greatly enforce the reaction to a great extent.19
derivatives 2 (50 mmol), THF (30 mL), and hexane (70
mL) was added a solution of cyclopentadiene 1 (15 mL,
180 mmol) and hexane (50 mL) under nitrogen, and the
resulting reaction mixture was kept stirring at room tem-
perature overnight. After removal of most solvent, the res-
idue was diluted with hexane, and the white precipitate
To further investigate the effect of reaction conditions
(solvent, vibration frequency, reaction temperature, and
time) on the chemoselectivity, we performed some control
experiments on cycloaddition of N-4-tosylmaleimide (2g,
5.0 mmol) with cyclopentadiene (1, 5.2 mmol) under var-
ious conditions (Scheme 2). The results are summarized
was collected by filtration to afford the crude product,
in Table 2.
which was further purified via crystallization from ethyl
From Table 2 it can be seen that this kind of cycloaddition
acetate–hexane (v/v = 1:1). The isolated yields from this
reactions took place readily. Both solvent-added and neat
condition were also summarized in Table 1, from which
conditions could promote this transformation to a certain
we could see that these compounds were also practically
extent just in 30 minutes at room temperature (entry 1, 7,
synthesized in moderate to good yield (ca. 80–90%), and
1H NMR analysis also suggested exclusive endo selectiv-
H
ity. In fact, TLC analysis on reactant 2 showed that these
H
reactions also proceeded completely, but this method in-
O
volves the use of largely excessive cyclopentadiene (3.6
equiv), anhydrous organic solvents, relatively long reac-
N
O
tion time, and tedious work up procedure. Whereas the
present mechanochemical (MM400) conditions exhibits
the main advantages of milder conditions, higher yield
(90–98%), shorter reaction time (30 min), only 4% excess
of cyclopentadiene, and fairly easy operation. We also
employed the same usage amount of cyclopentadiene
(1.04 equiv) as that under MM400 neat conditions. But in
most cases, the reactant 2 was not completely reacted,
which contaminated the crude product and made column
chromatography necessary for effective purification. The
corresponding isolated yield is moderate (65–78%) as
shown in Table 1. The reasons for the high efficiency of
the current mechanochemical solvent-free conditions may
be due to an enhanced second-order reaction rate resulting
from ultimately high concentrations of reactants in the ab-
sence of solvent. Furthermore, the high mechanical ener-
3g
+
O
1
+
N
O
O
H
H
N
3g'
+
O
2g
4
Scheme 2
Table 1 Results of Cycloaddition of Cyclopentadiene with Maleic Anhydride and Maleimide Derivatives under MM400 Neat Conditions and
in THF–Hexane (1:4 v/v)
Compound 2a
Product 3b
Yield (%)c
Yield (%)d Yield (%)e Mp (°C)
X
O
N
N
N
N
N
N
N
N
2a
2b
2c
2d
2e
2f
–
3a
3b
3c
3d
3e
3f
94
98
90
92
94
95
93
96
92
89
87
78
89
90
79
84
88
85
77
74
65
76
78
68
76
73
75
163–165 (lit.14 164–165)
186–187 (lit.15 187)
156–157 (lit.16 157–158)
142–143 (lit.17 144)
156–157 (lit.18 153–155)
191–192
H
c-Hex
Ph
4-BrC6H4
4-F3CC6H4
4-MeC6H4
4-MeOC6H4
4-EtOOCC6H4
2g
2h
2i
3g
3h
3i
157–158 (lit.17 157)
170–172 (lit.18 172–173)
133–134
a Compounds 2c–i were prepared according to reported method.12,
b Characterized by mp, IR, 1H NMR, 13C NMR, and HRMS analysis.13,
c Isolated yield combined from two parallel runs via MM400 ball miller.
d Isolated yield from reactions carried out in THF–hexane (1:4 v/v) overnight at r.t. (1/2 = 3.6:1).
e Isolated yield from reactions carried out in THF–hexane (1:4 v/v) overnight at r.t. (1/2 = 1.04:1).
Synlett 2010, No. 19, 2895–2898 © Thieme Stuttgart · New York

LETTER
Mechanochemical Synthesis of endo-Norbornene Derivatives
2897
and 9). Under solvent-added or hand-grinding conditions,
it was not easy to make the reaction proceed to completion
unless prolonged reaction time was employed (entry 2, 3,
and 8). However, it is well known that cyclopentadiene
dimerizes easily and rapidly to dicyclopentadiene even at
room temperature. Therefore, too long reaction time in
these cases led to dimerization of unreacted cyclopentadi-
ene into the corresponding dimer 4, thus high product
yield was difficult to achieve. It appeared that elevating
the reaction temperature may be an alternative to avoid
this problem. As a result, higher reaction temperature (re-
fluxing) was employed in order to induce rapid conver-
sion of the reactant, but the reaction chemoselectivity was
somewhat decreased (entry 4). In addition, 1H NMR anal-
ysis on the resulting mixture under these conditions
showed that the endo product 3g was contaminated with
minor thermally more stable exo side products 3g¢. When
neat hexane was used as the solvent, the transformation
was very slow (entry 5). In the presence of THF as sol-
vent, the reaction could be promoted to some extent (entry
6 vs. entry 1). This can be easily understood from the fact
that the solubility of reactant 2g in hexane is very poor but
higher in THF. Based on the results of these control exper-
iments, we could deduce that the best way was to perform
this reaction under neat conditions at room temperature
Table 2 Results of Control Experiments on Cycloaddition of Cyclo-
pentadiene with N-4-Tosylmaleimide under Different Conditions
Entry Solvent
Temp Time
Products
(°C)
(h)
0.5
3
distribution (%)a
1
2
3
4
5
6
7
8
9
THF–hexaneb
20
3g (48)
THF–hexaneb
THF–hexaneb
THF–hexaneb
hexane
20
3g (62) + 4 (trace)
20
overnight 3g (88) + 4 (trace)
reflux 0.5
3g (83) + 3g¢ (6)d
3g (14)
20
20
20
20
20
20
20
<5f
0.5
0.5
0.5c
3c
THF
3g (59)
–/hand grinding
–/hand grinding
–/MM400 (10 Hz)
3g (54)
3g (80) + 4 (7)
3g (62)
0.5
0.5
0.5
0.5
10 –/MM400 (20 Hz)
11 –/MM400 (30 Hz)
12 –/MM400 (30 Hz)
a Based on HPLC analysis.
3g (78)
3g (>99)e
3g (>99)e
b THF–hexane (1:4 v/v; 25 mL).
within a short reaction time. We then carried out this reac- c Including several standing intermission (about 5 min each).
d Based on 1H NMR analysis on the resulted crude mixture.
tion under different vibration frequencies for further in-
vestigations. It was found that the vibration frequency of
the applied vibration mill had a significant effect on the
reaction process and conversion (entries 9–11). General-
ly, higher vibration frequency accelerated the reaction
process. It is easy to understand that the faster the mill vi-
brates the higher the mechanical energy, and therefore the
higher local pressure applied to the reaction system. Fur-
thermore, when a mill vibrates at higher speed, it may be
advantageous for the diffusion process to promote ho-
mogenization and thus beneficial for the ongoing reac-
tion.19 Considering the very exothermic nature of the
Diels–Alder reaction, a relatively low temperature (<5 °C,
entry 12) was employed, giving almost the same result as
that at 20 °C (entry 11). This means that the high efficien-
cy of mechanical milling promoted reactions cannot be
simply ascribed to the simultaneously generated heat en-
ergy.
e The excessive cyclopentadiene was subtracted.
f Keeping the mixer mill in a ice-cooling box [80 cm × 80 cm × 50 cm]
and the temperature was detected by a thermometer around 3–5 °C).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We are grateful for the financial support from National Natural Sci-
ence Foundation of China (20902002).
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In conclusion, we have developed a powerful method for
the synthesis of various norbornene derivatives via the Di-
els–Alder reaction of cyclopentadiene with maleic anhy-
dride and maleimide derivatives, in which a novel
solvent-free technique – mechanical ball milling – was
employed to promote this transformation efficiently at
room temperature without using any solvent or catalyst.
Under these mild conditions, the endo-norbornenes were
exclusively formed in quantitative yields within 30 min-
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LETTER
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Hz, 2 H), 3.41–3.49 (m, 2 H), 6.24 (s, 2 H), 7.02 (d, J = 8.8
Hz, 2 H), 7.53 (d, J = 8.8 Hz, 2 H). 13C NMR (100 MHz,
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134.6, 176.4. HRMS (FAB+): m/z calcd for C15H12BrNO2
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Synlett 2010, No. 19, 2895–2898 © Thieme Stuttgart · New York