Ethyl 6-Hydroxyfulvene-1-Carboxylate: A Reagent Discriminating Primary Amines from Secondary Amines

Article abstract of DOI:10.1021/acs.joc.8b01046

A highly chemo-selective reaction was observed when ethyl 6-hydroxyfulvene-1-carboxylate 1 was treated with different nucleophiles such as primary amines, secondary amines, alcohols, and thiols. Among them, only primary amines are reactive toward 1 to afford the condensation products 3, which exhibit good stability under both weakly acidic and basic conditions. The condensation process proved to be reversible between different primary amines. On the basis of this observation, the chemical selectivity of typical primary aromatic amines was evaluated quantitatively by determining equilibrium constants of the condensation reactions with aniline as a reference. Moreover, the primary amines of 3 can be readily released upon treatment with aqueous ammonia, making 6-hydroxyfulvene-1-carboxylate 1 a promising protecting reagent for primary amines.

Full text of DOI:10.1021/acs.joc.8b01046

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Article
Ethyl 6-Hydroxyfulvene-1-Carboxylate: A Reagent
Discriminating Primary Amines from Secondary Amines
Sen Yang, Dengfu Lu, Yuequan Zhu, Mei Shi, Fan Luo, and Yuefa Gong
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01046 • Publication Date (Web): 31 May 2018
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Ethyl 6-Hydroxyfulvene-1-Carboxylate: A Reagent
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Discriminating Primary Amines from Secondary Amines
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Sen Yang, Dengfu Lu, Yuequan Zhu, Mei Shi, Fan Luo*, Yuefa Gong*
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School of Chemistry and Chemical Engineering, Huazhong University of Science and
Technology, 1037 Luoyu Road, Wuhan 430074, China
gongyf@hust.edu.cn; luofan16@hust.edu.cn
RECEIVED DATE (to be automatically inserted after your manuscript is
accepted if required according to the journal that you are submitting your paper
to)
* To whom correspondence should be addressed. Phone: +86 027 87543232. Fax:
+86 027 87543632.
ABSTRACT
A highly chemoꢀselective reaction was observed when ethyl 6ꢀhydroxyfulveneꢀ1ꢀ
carboxylate 1 was treated with different nucleophiles such as primary amines,
secondary amines, alcohols and thiols. Among them, only primary amines are reactive
toward 1 to afford the condensation products 3, which exhibit good stability under
both weakly acidic and basic conditions. The condensation process proved to be
reversible between different primary amines. Based on this observation, chemical
selectivity of typical primary aromatic amines was evaluated quantitatively by
determining equilibrium constants of the condensation reactions with aniline as a
reference. Moreover, the primary amines of 3 can be readily released upon treated
with aqueous ammonia, making 6ꢀhydroxyfulveneꢀ1ꢀcarboxylate 1 a promising
protecting reagent for primary amines.
Keywords: Ethyl 6-hydroxyfulvene-1-carboxylate; Amination; Selective
protection of primary amine; Chemical selectivity
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INTRODUCTION
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Development of chemoꢀselective reactions always play important role in organic
synthesis.1 Due to the structural similarity, primary amines usually show similar
nucleophilic reactivity to secondary amines. Although, some works published
previously were concerned with chemoꢀselective protection or isolation of primary
amine in the presence of secondary amine in organic synthesis.2ꢀ6 For example,
trifluoroacetyl is an important primary amine protecting group.4 However, as the
trifluoroacetamide is easily hydrolyzed in basic solution, trifluoroacetylation is not a
practical protecting strategy when the protected compounds need to be subsequently
reacted in basic media. On the other hand, as another primary amine protecting
group,5b the Nꢀtrityl group is easily removed under acidic condition or through
hydrogenolysis. Thus, finding ideal protecting methods of primary amines from
secondary amines with high chemoꢀselectivity is still kept very attractive in organic
synthesis. Moreover, to our knowledge, few work reported hitherto was concerned
with the differentiation of chemical property of various primary amines.4bꢀd
Fulvene derivatives, which exhibit intriguing chemical properties, are significant
organic compounds usually being treated as synthetic building blocks.7 They are not
only widely used in the synthesis of various kinds of functional materials,8 but also
recognized as privileged scaffolds, which can be found in many natural products and
pharmaceuticals.9 Our group has established a method to synthesize a series of novel
6ꢀhydroxyfluvenes in the past years.10 Recently, we found these fulvenes derivatives
exhibit unique chemical properties toward amines in comparison to other fulvenes
previously reported, mainly due to the ketoꢀenol tautomerism of the hydroxyl group
on C6 and a potential intramolecular hydrogen bonding.
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SCHEME 1. Selective Amination of 6-Hydroxyfulvene with Primary Amines
They can react with primary amines with excellent selectivity in the presence of
secondary amines, alcohols or even mercaptans. This is the first example referred to
6ꢀhydroxyfulvenes to discriminate primary and secondary amines. The remarkable
selectivity encouraged us to explore whether it can be an ideal protecting group for
different structural primary amines. Moreover, although the basicity of amines is
already wellꢀestablished, their relative reactivity is not always consistent with their
basicity. Pioneering works had been done for measuring the nucleophilicity of amines
by their reaction with carbocation species.11 In this work, we try to develop a way to
evaluate the chemical selectivity of substituted anilines quantitatively through their
reactions with ethyl 6ꢀhydroxyfulveneꢀ1ꢀcarboxylate (Scheme 1).
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RESULTS AND DISCUSSION
In the beginning, the reaction of ethyl 6ꢀhydroxyfulveneꢀ1ꢀcarboxylate 1 with
piperidine was performed in ethanol at reflux temperature, and no any detectable
product was observed. The same thing happened when the mixture of substrate 1 and
diꢀnꢀbutylamine was heated under the conditions (Table 1, entries 1ꢀ2). In contrast, an
amination product 3a was generated in 85% isolated yield (Table 1, entry 3) when
nꢀbutylamine, a common primary amine, was treated instead of diꢀnꢀbutylamine under
the same reaction conditions, and the structure of 3a was characterized and confirmed
by 1H and 13C NMR, and HRMS (see supporting information). For further research on
their specific reaction behavior, both nꢀbutylamine and diꢀnꢀbutylamine were taken
into reaction with substrate 1. As a consequence, the primary amine condensation
product 3a was obtained exclusively in 85% yield (Table 1, entry 4). To our delight,
the exceptional selectivity of 1 towards a primary amine also applies in the presence
of other nucleophiles such as phenol or 4ꢀchlorothiophenol (Table 1, entries 5 and 6).
When substrates 2b and 2c possessing both NH and NH2 groups were assessed, the
anticipated primary amine condensation product 3b and 3c were isolated in 76% and
95% yield, respectively (Table 1, entries 7, 8). Substrate 2d, 3ꢀaminopropanol, is also
compatible and gave the desired Nꢀattacked product 3d in 90% yield (Table 1, entry
9). Subsequently, a mixture of equal amount of oꢀchloroaniline and pꢀchloroaniline is
tested for the reaction with 1, and a competitive amination underwent smoothly,
which gave 71% yield of 3e from pꢀchloroaniline and 17% yield of product from
oꢀchloroaniline (Table 1, entry 10).
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TABLE 1. Selective Amination of 6-Hydroxyfulvene 1 with Nucleophiles a
Entry
1
NuH
Products
Yieldb
n.d.
2
3
n.d.
85%
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3a
85%c
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3a
3a
84%d
85%e
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76%
95%
9
90%
10
71%f
a Reactions were carried out with 0.2 mmol of each of the reactants in 2 mL ethanol under
refluxing condition. Isolated yields, n.d.=not detected. the product from 1 and
b
c
d
e
diꢀnꢀbutylamine was not detected. No product from 1 and phenol. No detected product
f
from 1 and pꢀchlorothiophenol. 17% yield of product from oꢀchloroaniline was
determined by 1H NMR.
Next, a variety of primary amines were investigated under the above conditions.
The observed results are summarized in Table 2. Initially, aliphatic amines were
tested. Simple methylamine gave the corresponding product 3g in excellent yield. In
contrast, the reaction of lauryl amine and octadecylamine with long alkyl chains
underwent slowly and provided 3h and 3i in moderate yields, respectively.
Benzylamine worked smoothly, delivering the desired product 3j in high yield of 93%.
There was a little bit of decline in the yield of 3k isolated from the reaction of
optically active (R)ꢀ1ꢀmethylbenzylamine. From the above observations, we realized
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that the increase of steric hindrance of alkyl amines disfavored the amination reaction
to some extent.
Amines with other functional group were also studied. Glycine ethyl ester worked
smoothly, providing the expected product 3l in excellent yield of 99%. When ethyl
(S)ꢀalaninate hydrochloride was used for the reaction, product 3m was formed in a
relatively lower yield of 81% due to its bigger steric hindrance.
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Successively, some representative aromatic amines were chosen and tested under
the same conditions. Aniline gave the product 3n in 86% yield. pꢀAnisidine with an
electronꢀdonating group provided 95% yield of amination product 3o, whereas
pꢀchloroaniline with an electronꢀwithdrawing group gave 78% of 3e. In addition,
1ꢀNaphthalenamine gave a lower yield of 3p compared to aniline mainly owing to its
bigger steric hindrance. Apparently, the electronic property of aromatic amine has a
considerable effect on the reaction rate and yield.
TABLE 2. Amination of Ethyl 6-Hydroxyfulvene-1-carboxylate 1 with Various
Primary Amines a, b
aReactions were carried out with 0.2 mmol of each of the reactants in 2 mL ethanol under
b
c
refluxing condition. Isolated yield; Ethyl (S)ꢀalaninate hydrochloride was added in the reaction
first and then treated with one equivalent of triethylamine.
The chemical stability of amination product was then tested using 3a as the model.
In fact, 3a was quite stable when it was treated with aqueous solution of potassium
carbonate or acetic acid under reflux (Scheme 2).
SCHEME 2. Estimation of the Chemical Stability of Amination Products 3
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Based on the experimental results mentioned above, a possible mechanism is
proposed as shown in Scheme 3. The reaction between primary amine and ethyl
6ꢀhydroxyfulveneꢀ1ꢀcarboxylate proceeded via nucleophilic addition and then
dehydration reaction to give the product 3. The lacking of intramolecular hydrogen
bond and the increasing steric hindrance during dehydration could account for the
difficulty for the formation of amination product from secondary amine and substrate
1 (Scheme 3). This clearly indicates that the formation of intramolecular hydrogen
bonding should be the crucial factor for stabilizing the product 3 and for
discriminating primary and secondary amines.
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SCHEME 3. A Proposed Mechanism for Selective Amination
As mentioned above, we supposed that the additionꢀelimination sequence between
ethyl 6ꢀhydroxyꢀfulveneꢀ1ꢀcarboxylate 1 and amines would be a reversible process.
Thus, a control reaction was performed to prove whether the reactions between the
amination products 3 and other primary amines would be in an equilibrium too, in
which the product 3n, isolated and purified by silica gel column chromatography, was
treated with one equivalent of pꢀanisidine 2o in ethanol at reflux temperature. After 12
hours, 3o was collected in 80% yield, and meanwhile almost an equal amount of
aniline was recovered. This positive evidence demonstrates that the compound 3 is
still reactive towards electronꢀrich primary amines.
This result enabled us to further assess the chemical selectivity of different primary
amines by determining the equilibrium constant K of the reaction with ethyl
6ꢀhydroxyfulveneꢀ1ꢀcarboxylate 1 (Scheme 4). The magnitude of the equilibrium
constant, K, denotes the chemical selectivity of primary aromatic amines in the
condensation reaction quantitatively. Firstly, it is necessary to establish a reliable
method for determination of the equilibrium constant K. For this purpose, aniline and
pꢀchloroaniline were chosen as the examples, and 0.1 mmol of 1 was treated with 0.1
mmol of aniline (2n) or 0.1 mmol of pꢀchloroaniline (2e), respectively, under the
1
above reaction conditions. The crude products were analyzed by H NMR. We found
the chemical shifts (δ) of methyl groups at C4 and C6 sites of ethyl
6ꢀhydroxyfulveneꢀ1ꢀcarboxylate 1 are 2.653 and 2.676, respectively, very close to
each other. However, their differences in chemical shifts (2.587 and 2.780) are
apparently amplified after amination with aniline (3n). Similar change in chemical
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shifts (2.575 and 2.762) was also observed in the case of pꢀchloroaniline (3e). So, we
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can determine the concentration of each of the amination products, and find at which
time the reactions reached their equilibria by means of H NMR (see supporting
information). When the reactions got their equilibria, the equilibrium constants KH
and KpꢀCl (eq 1) are calculated to be 975 and 321, respectively, and the ratio between
KpꢀCl and KH is equal to 0.329. Obviously, KR (pꢀCl) < 1 means that pꢀchloroaniline is
less selective than aniline.
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SCHEME 4. Chemical Selectivity Evaluation of Substituted Anilines
Me
Me
Y
NH2
O
K
1
N
Y
(1)
+ H2O
H
Ph
CO2Et
2n Y = H
2e Y = p-Cl
3n Y = H
3e Y = p-Cl
Competitive reactions:
1
KR
KR
(2)
(3)
2e, 2r or 2o
2n
2r
+
3n
3r
+
+
3e, 3r or 3o + H2O
3o
1
+ 2o
2o Y = p-MeO
+ H2O
2r Y = p-Me
3r Y = p-Me 3o Y = p-MeO
[3e] [2n]
[2e] [3n]
Kp-Cl
KH
[3e]
[3n] [H2O]
[1] [2n]
[H2O]
KH
=
KR (p-Cl) =
Kp-Cl
=
=
[1] [2e]
Next, we wondered if the ratio KR between KpꢀCl and KH is well consistent with that
determined in a competitive reaction system. Thus, a competitive reaction was
conducted by mixing 0.1 mmol of pꢀchloroaniline, 0.1 mmol of aniline and 0.1 mmol
of 1 in 2ml ethanol under reflux. It is clear that the competitive reaction system
comprises two equilibrium reactions with equilibrium constants KH and KpꢀCl. When
the two competitive reactions got in equilibrium, the equilibrium constant ratio KR(pꢀCl)
for pꢀchloroaniline and aniline can also be measured (eq 2, Scheme 4), and is equal to
0.329. The same results observed respectively in individual reaction (eq 1) and
competitive reaction (eq 2) indicate that the KR value is acceptable. Further
experiment was performed to assess substituent effect of anilines on the chemical
selectivity. In the same manner, KR(pꢀMe) and KR(pꢀMeO) are measured to be 3.433 and
7.904, respectively (eq 2). The calculated ratio of KR(pꢀMeO) to KR(pꢀMe) is 2.302. In
comparison, the ratio of KR(pꢀMeO) to KR(pꢀMe) determined in the competitive reaction
system with pꢀtoluidine (2p) and 4ꢀmethoxyaniline (2i) is equal to 2.290 (eq 3).
Obviously, All the above results clearly demonstrate that it is applicable to evaluate
the chemical selectivity of various anilines through this equilibrium method.
With the preliminary results in hand, we start to study the chemical selectivity of a
variety of primary anilines by the competitive reaction system using aniline as the
reference. In order to investigate the effect of the substrate concentrations on the
competitive reactions, we carried out the experiments using different molar ratios of 1
to anilines. One is that the same amount (0.1 mmol) of 1 and two amines were
employed, and the other is that 0.1 mmol of 1 and 0.2 mmol of each of the two
aromatic amines were used. According to the above method, we determined the
1
concentration of each of the compounds by H NMR when the reactions got their
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equilibria, and calculated the KR of the reactions for these two cases, respectively. All
the results are listed in Table 3. The small deviation for KR determined in the two
reaction system indicates that the molar ratio of 1 to anilines has little effect on the
measured results. The average of KR for some typical primary anilines was then
calculated and listed in Table 3.
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Table 3. Determination of KR for Various Substituted Anilines
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Me
Me
NH2
Me
Me
KR
Y
O
O
NH2
Ph
Ph
1
N
N
EtOH
reflux
H
H
Ph
Ph
CO2Et
CO2Et
Y
a
b
c
Entry
Amine
KR (1eq.)
KR (2eq.)
KR
1
1
1
1
2
3
0.090
0.111
1.152
0.120
0.329
0.117
0.286
0.530
1.754
3.433
0.724
7.904
0.096
0.109
1.118
0.133
0.345
0.124
0.297
0.527
1.699
3.432
0.752
7.950
0.093
0.110
1.135
0.127
0.337
0.121
0.292
0.529
1.727
3.433
0.738
7.927
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14
0.434
0.441
0.438
a
Reactions were carried out with 0.1 mmol 1 and 0.1 mmol aniline and 0.1 mmol
substituted anilines in 2ml ethanol under refluxing condition. Reactions were carried out
b
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with 0.1 mmol 1 and 0.2 mmol aniline and 0.2 mmol substituted anilines in 2ml ethanol
under refluxing condition. c The average value of KR (1eq.) and KR (2eq.)
.
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Obviously, the properties of the substituent at the ring of anilines have a significant
effect on their chemical selectivity in the above condensation reactions. Among the
three isomers of fluoroaniline, pꢀfluoroaniline shows a slightly higher selectivity than
that of aniline 2n, whereas mꢀfluoroaniline and oꢀfluoroaniline have much lower
selectivity (entries 1ꢀ4). pꢀchloroaniline and pꢀbromoaniline also exhibit better
selectivity than their meta isomers, whereas all of them show inferior selectivity in
comparison with aniline (entries 5ꢀ8). The relative selectivity for toluidines and
aniline is in the following order: pꢀtoluidine > mꢀtoluidine > aniline > oꢀtoluidine
(entries 9ꢀ11). A significant difference in the selectivity was observed in the cases of
pꢀanisidine and mꢀanisidine (entries 12ꢀ13). Naphthalenꢀ1ꢀamine is also less selective
in comparison to aniline (entry 14).
From the above observations, we can conclude that para isomers have the much
higher selectivity than their meta counterparts, suggesting that the electronꢀdonating
conjugative effect of the substituents plays a great role on the chemical selectivity of
primary anilines. Moreover, the lowest reactivity of ortho isomers demonstrated the
remarkable influence of the steric hindrance of the substituents on the reaction. In the
case of oꢀfluoroaniline, the electronꢀwithdrawing inductive effect of fluoro group also
seems to be considerable.
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In order to understand the relationship of the chemical selectivity and the reactivity
of substituted anilines, we determined the conversion rate of fulvene 1 during the
reaction with four typical primary aromatic amines by means of 1H NMR
spectroscopy. Figure 1 depicted the curves of conversion ratios versus time for the
amination reactions.
100%
80%
60%
pꢀCH3OC6H4NH2
C6H5NH2
40%
pꢀClC6H4NH2
oꢀFC6H4NH2
20%
0%
0
2
4
6
t (h)
8
10
12
Figure 1. Change curve of conversion ratio of fulvene 1with time
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Obviously, the property of substituents at primary anilines has a marked effect on
both the reaction rate and the conversion ratio of the equilibrium reactions. The
reaction rates of both pꢀchloroaniline and oꢀfluoroaniline decrease with the
introduction of electronꢀwithdrawing pꢀchloro or oꢀfluoro groups at benzene ring of
aniline. Among the four anilines, the reaction of pꢀanisidine with an electronꢀdonating
methoxy group shows a highest reaction rate. Similarly, the conversion ratio of
pꢀanisidine was also the highest, and the magnitude order in conversion ratio is the
same to that in reaction rate, namely, pꢀanisidine> aniline> pꢀchloroaniline>
oꢀfluoroaniline. In addition, all the four reversible reactions could reach their
equilibria within 8 hours, despite of the different initial reaction rates.
The kinetics of the above reactions are calculated from the determined conversion
rates. The secondꢀorder model is expressed in Equation 4, where c and c0 (mol•Lꢀ1)
represent the concentration of 6ꢀhydroxyfulveve at time t (h) and initial concentration,
respectively, and k (molꢀ1•L•hꢀ1) is the rate constant. When we plot the reciprocal
concentration of 6ꢀhydroxyfulveve versus the reaction time (eq 4), a good correlation
was observed with correlation coefficient R2> 0.99, demonstrating that the
condensation reaction follows a secondꢀorder reaction kinetics well in the first hour.
The calculated reaction rate constants and correlation coefficients R2 for the four
typical anilines are given in Table 4. Obviously, the relative order in chemical
selectivity is consistent with the reaction rate for the primary anilines.
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c0
= kc0t +1
(4)
c
Table 4. The rate constants and correlation coefficients for the reactions
c0(mol·dmꢀ3)
0.05
k(molꢀ1·dm3·hꢀ1)
35.96
R2
Amines
C6H5NH2
0.991
0.991
0.992
0.994
pꢀClC6H4PhNH2
pꢀCH3OC6H4NH2
oꢀFC6H4NH2
0.05
32.66
0.05
45.80
0.05
15.32
Since the amination product 3 can undergo the reversible exchange reaction with
other primary amines, we continue to estimate the possibility of using these fulvenes
as protecting reagents of amino group. First, the recovery of primary amines was tried
by the treatment of 3n with 3 equivalents of aqueous ammonia, a cheap and
commercially available reagent, in ethanol under reflux. Consequently, 3n was almost
quantitatively converted into 6ꢀaminofulvene 3q and aniline (Scheme 5). Additionally,
aliphatic amination products require excess aqueous ammonia to release aliphatic
amines. For example, Lꢀalanine condensed product 3m was refluxed with 10
equivalents of aqueous ammonia solution to furnish 6ꢀaminofulvene 3q in 93% yield.
A representative successful example is the highly selective protection of amino group
of (S)ꢀpyrrolidinꢀ2ꢀylmethanamine, a typical molecule containing both NH2 group and
NH group. Its amination product 3c underwent highly selective acylation reaction
with benzoyl chloride under mild condition to give acylation product 4c in 96% yield.
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The Nꢀbenzoylated product of (S)ꢀpyrrolidinꢀ2ꢀylmethanamine was easily obtained by
treatment of 4c with 15 equivalents of aqueous ammonia. Thus, we believed that ethyl
6ꢀhydroxyfulveneꢀ1ꢀcarboxylate would be a potentially useful and highly selective
reagent for protecting intramolecular amino group from other functional groups, and
the protecting group can be removed by commercially available aqueous ammonia.
Although selective protection of primary amines of linear tetraamines was presented
in the work reported previously,5b where addition of equivalent amount of trityl
chloride was necessary and the undesired tritylation of secondary amine can not be
completely prevented. The apparent advantage for our 6ꢀhydroxyfulvene reagent lies
in its exclusive protection of primary amine, despite of its molar ratio to the amine.
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SCHEME 5. Deprotection of Condensation Products with Aqueous Ammonia
CONCLUSION
In conclusion, we claim that ethyl 6ꢀhydroxyfulveneꢀ1ꢀcarboxylate is a useful reagent
for highly selective amination with primary amines, and this method can be used to
discriminate primary amines from secondary amines, alcohols, thiols, and even
different primary amines. Moreover, the condensation reaction of ethyl
6ꢀhydroxyfulveneꢀ1ꢀcarboxylate can be also applied to assess the chemical selectivity
of different primary anilines quantitatively by a competitive reaction system. In
addition, the highly selective amination, the stability of the amination product towards
weak acid and base, and facile removal of protecting group provide a new strategy for
the chemoselective protection of primary amines over secondary amines and other
functional groups.
EXPERIMENTAL SECTION
General Information. Solvents and reagents were employed without further
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purification as commercially available unless otherwise noted. Progress of reactions
was monitored by TLC analysis using silica gel 60 Å Fꢀ254 thin layer plates. Flash
column chromatography was performed on silica gel 60 Å, 10−40 ꢀm. Melting points
1
were measured on a MeltꢀTemp apparatus and uncorrected. H NMR spectra were
recorded in CDCl3 on a Bruker AMꢀ400 spectrometer (400 MHz or 600MHz) with
1
TMS as internal standard. H NMR splitting patterns are indicated as follows: a,
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apparent; br, broad; s, singlet; d, doublet; t, triplet; q, quartet; doublet of doublets (dd);
m, multiplet. 13C NMR spectra were taken on a Bruker AMꢀ400 (101 MHz)
spectrometer. HRMS was measured on a TOFꢀQ mass spectrometer equipped with an
EI source.
General procedure for Preparation of ethyl 6-hydroxyfulvene-1-carboxylate 1.
Acetylacetone 4 mmol was added to a solution of ethyl αꢀchlorocycloproꢀ
panecarboxylate (2 mmol), Cs2CO3 (4 mmol) in DMF (20 mL). The solution was then
o
stirred at 80 C. After completion of reaction as indicated by TLC, the reaction
solution was cooled to room temperature. Then, 1 mol/L HCl (aq) solution was added
to neutralize reaction solution. The mixture was extracted with CH2Cl2 three times,
and the combined extract was washed with brine, dried over anhydrous sodium sulfate,
and concentrated under reduced pressure. The residue was purified by flash
chromatography on silica gel to afford the desired products 1. (see Zhu, Y. Q.; Zhang,
M.; Yuan, H. L.; Gong, Y. F. Org. Biomol. Chem., 2014, 12, 8828ꢀ8831.)
General procedure for selective amination of 1. 6ꢀhydroxyfulvene derivative 1
(0.2mmol) was added to a solution of amines 2 (0.2 mmol) in 2 mL of ethanol under
reflux condition. The reaction progress was monitored by TLC. After completion, the
reaction mixture was cooled to room temperature, concentrated in vacuo, and then the
residue was purified by silica gel column chromatography to give the amination
products 3.
Ethyl(Z)-3-benzoyl-5-(1-(butylamino)ethylidene)-4-methylcyclopenta-1,3-diene-1
-carboxylate (3a). Yellow solid (60mg, 85%), mp: 139ꢀ141 °C; PE/EA = 5/1 as eluent;
1H NMR (400 MHz, CDCl3) δ 13.29 (s, 1H), 7.82 – 7.75 (m, 2H), 7.52 – 7.37 (m, 4H),
4.22 (q, J = 7.2 Hz, 2H), 3.50 (td, J = 7.2, 5.2 Hz, 2H), 2.75 (s, 3H), 2.57 (s, 3H), 1.77
(dt, J = 14.8, 7.6 Hz, 2H), 1.58 – 1.42 (m, 2H), 1.28 (t, J = 7.2 Hz, 3H), 0.99 (t, J =
7.2Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 193.4, 169.2, 169.1, 142.7, 141.6, 134.4,
130.8, 129.5, 127.8, 127.6, 118.5, 112.9, 60.5, 44.9, 30.9, 20.2, 18.8, 17.9, 14.4, 13.7.
HRMSꢀEI (m/z): calcd for C22H28NO3 [M+H]+: 354.2064, found: 354.2059.
Ethyl(Z)-3-benzoyl-4-methyl-5-(1-((3-(methylamino)propyl)amino)ethylidene)c-
yclopenta-1,3-diene-1-carboxylate (3b). Yellow solid (56mg, 76%), mp: 95ꢀ97 °C;
1
CH3OH/CH2Cl2 = 10/1 as eluent; H NMR (400 MHz, CDCl3) δ 7.80 – 7.75 (m,
2H), 7.51 – 7.46 (m, 1H), 7.45 – 7.40 (m, 2H), 7.38 (s, 1H), 4.20 (q, J = 7.2Hz, 2H),
3.62 (t, J = 7.2 Hz, 2H), 2.78 (t, J = 6.4Hz, 2H), 2.73 (s, 3H), 2.57 (s, 3H), 2.47 (s,
3H), 2.08 – 1.93 (m, 2H), 1.27 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ
193.4, 169.6, 169.0, 142.7, 141.5, 134.5, 130.8, 129.5, 127.9, 127.7, 118.7, 113.0,
60.5, 48.7, 42.9, 36.1, 29.7, 28.5, 18.9, 17.9, 14.4. HRMSꢀEI (m/z): calcd for
C22H29N2O3 [M+H]+: 369.2173, found: 369.2169.
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Ethyl(S,Z)-3-benzoyl-4-methyl-5-(1-((pyrrolidin-2-ylmethyl)amino)ethylidene)cy-
clopenta-1,3-diene-1-carboxylate (3c). Yellow solid (72mg, 95%), mp: 137ꢀ139 °C;
CH3OH/CH2Cl2 = 10/1 as eluent; 1H NMR (600 MHz, CDCl3) δ 7.80 – 7.76 (m, 2H),
7.50 – 7.47 (m, 1H), 7.44 – 7.41 (m, 2H), 7.39 (s, 1H), 4.21 (q, J = 7.2 Hz, 2H), 3.56
– 3.50 (m, 2H), 3.49 – 3.44 (m, 1H), 3.01 (t, J = 6.6 Hz, 2H), 2.74 (s, 3H), 2.58 (s,
3H), 2.10 – 2.00 (m, 1H), 1.91ꢀ1.83 (m, 1H), 1.82 – 1.74 (m, 1H), 1.55ꢀ1.46 (m, 1H),
1.28 (t, J = 7.2 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 193.4, 169.5, 169.1, 142.9,
141.5, 134.6, 130.8, 129.5, 127.8, 127.7, 118.7, 113.1, 60.5, 57.0, 51.0, 46.8, 29.6,
25.5, 19.2, 17.9, 14.4. HRMSꢀEI (m/z): calcd for C23H29N2O3 [M+H]+: 381.2173,
found: 381.2165.
Ethyl(Z)-3-benzoyl-5-(1-((3-hydroxypropyl)amino)ethylidene)-4-methylcyclopen-
ta-1,3-diene-1-carboxylate (3d). Yellow solid (64mg, 90%), mp: 147ꢀ149 °C;
CH3OH/CH2Cl2 = 30/1 as eluent; 1H NMR (400 MHz, CDCl3) δ 13.23 (s, 1H), 7.80 –
7.73 (m, 2H), 7.54 – 7.45 (m, 1H), 7.47 – 7.38 (m, 2H), 7.39 (s, 1H), 4.20 (q, J = 7.2
Hz, 2H), 3.79 (t, J = 5.6 Hz, 2H), 3.65 (dd, J = 12.4, 6.8 Hz, 2H), 2.71 (s, 3H), 2.54
(s, 3H), 2.05 – 1.97 (m, 2H), 1.27 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ
193.6, 169.7, 169.1, 142.8, 141.5, 134.6, 130.9, 129.5, 127.9, 118.7, 113.0, 60.5, 59.3,
41.8, 31.4, 18.8, 17.9, 14.4. HRMSꢀEI (m/z): calcd for C21H26NO4 [M+H]+: 356.1856,
found: 356.1846.
Ethyl(Z)-3-benzoyl-5-(1-((4-chlorophenyl)amino)ethylidene)-4-methylcyclopenta-
1,3-diene-1-carboxylate (3e). Bright yellow solid (58mg, 71%); mp: 167ꢀ169 °C;
PE/EA = 10/1 as eluent; 1H NMR (400 MHz, CDCl3) δ 15.00 (s, 1H), 7.82 – 7.79 (m,
2H), 7.55 – 7.50 (m, 2H), 7.49 – 7.41 (m, 4H), 7.22 – 7.16 (m, 2H), 4.25 (q, J = 7.2
Hz, 2H), 2.76 (s, 3H), 2.58 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ 193.5, 169.4, 166.3, 145.4, 141.0, 136.2, 136.0, 133.4, 131.2, 129.8, 129.5,
129.3, 128.0, 126.8, 119.5, 113.6, 60.9, 20.7, 18.1, 14.4. HRMSꢀEI (m/z): calcd for
C24H23ClNO3 [M+H]+: 408.1361, found: 408.1352.
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Ethyl(Z)-3-benzoyl-4-methyl-5-(1-(methylamino)ethylidene)cyclopenta-1,3-dien-
o
e-1-carboxylate (3g). Yellow solid (58mg, 93%), mp: 181ꢀ183 C; PE/EA = 3/1 as
eluent; 1H NMR (400 MHz, CDCl3) δ 13.28 (s, 1H), 7.83 – 7.73 (m, 2H), 7.52 –7.39
(m, 4H), 4.21 (q, J = 7.2 Hz, 2H), 3.21 (d, J = 4.8 Hz, 3H), 2.75 (s, 3H), 2.56 (s, 3H),
1.29 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 193.4, 170.3, 169.2, 142.8,
141.5, 134.6, 130.8, 129.5, 127.9, 127.8, 118.5, 112.9, 60.5, 31.2, 18.6, 17.9, 14.4.
HRMSꢀEI (m/z): calcd for C19H22NO3 [M+H]+: 312.1594, found: 312.1582.
Ethyl(Z)-3-benzoyl-5-(1-(dodecylamino)ethylidene)-4-methylcyclopenta-1,3-dien
o
e-1-carboxylate (3h). Yellow solid (71mg, 76%), mp: 69ꢀ71 C; PE/EA = 4/1 as
eluent; 1H NMR (400 MHz, CDCl3) δ 13.30 (s, 1H), 7.83 – 7.75 (m, 2H), 7.52 – 7.47
(m, 1H), 7.46 – 7.38 (m, 3H), 4.22 (q, J = 7.2 Hz, 2H), 3.50 (q, J = 7.2 Hz, 2H), 2.76
(s, 3H), 2.57 (s, 3H), 1.77 (p, J = 7.2 Hz, 2H), 1.50 – 1.41 (m, 2H), 1.33 – 1.20 (m,
19H), 0.88 (t, J = 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 193.4, 169.1, 169.1,
142.7, 141.6, 134.4, 130.7, 129.5, 127.8, 127.6, 118.5, 112.9, 60.4, 45.2, 31.9, 29.6,
29.5, 29.5, 29.4, 29.2, 28.9, 26.9, 22.7, 18.8, 17.9, 14.4, 14.1. HRMSꢀEI (m/z): calcd
for C30H44NO3 [M+H]+: 466.3316, found: 466.3311.
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Ethyl(Z)-3-benzoyl-4-methyl-5-(1-(octadecylamino)ethylidene)cyclopenta-1,3-di-
o
ene-1-carboxylate (3i). Yellow solid (65mg, 59%), mp: 52ꢀ54 C; PE/EA = 4/1 as
eluent; 1H NMR (400 MHz, CDCl3) δ 13.30 (s, 1H), 7.81 – 7.77 (m, 2H), 7.52 – 7.47
(m, 1H), 7.46 – 7.39 (m, 3H), 4.22 (q, J = 7.2 Hz, 2H), 3.50 (q, J = 7.2 Hz, 2H), 2.76
(s, 3H), 2.57 (s, 3H), 1.83 – 1.73 (m, 2H), 1.50 – 1.41 (m, 2H), 1.39 – 1.20 (m, 31H),
0.88 (t, J = 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 193.4, 169.1, 169.1, 142.7,
141.6, 134.4, 130.7, 129.5, 127.8, 127.7, 118.5, 112.9, 60.4, 45.2, 31.9, 29.7, 29.7,
29.6, 29.6, 29.5, 29.4, 29.2, 28.9, 26.9, 22.7, 18.8, 17.9, 14.4, 14.1. HRMSꢀEI (m/z):
calcd for C36H56NO3 [M+H]+: 550.4255, found: 550.4267.
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Ethyl(Z)-3-benzoyl-5-(1-(benzylamino)ethylidene)-4-methylcyclopenta-1,3-diene-
1-carboxylate (3j). Yellow solid (72mg, 93%), mp: 175ꢀ178 °C; PE/EA = 5/1 as
eluent; 1H NMR (400 MHz, CDCl3) δ 13.75 (s, 1H), 7.84 – 7.78 (m, 2H), 7.54 – 7.48
(m, 1H), 7.47 – 7.36 (m, 5H), 7.33 (t, J = 7.2 Hz, 3H), 4.75 (d, J = 6.0 Hz, 2H), 4.22
(q, J = 7.2 Hz, 2H), 2.74 (s, 3H), 2.55 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H). 13C NMR (101
MHz, CDCl3) δ 193.4, 169.7, 169.1, 143.5, 141.4, 135.8, 134.9, 130.9, 129.5, 129.1,
128.2, 128.1, 127.9, 127.1, 118.7, 113.4, 60.6, 48.3, 19.0, 18.0, 14.4. HRMSꢀEI (m/z):
calcd for C25H26NO3 [M+H]+: 388.1907, found: 388.1911.
Ethyl(R,Z)-3-benzoyl-4-methyl-5-(1-((1-phenylethyl)amino)ethylidene)cyclopent-
a-1,3-diene-1-carboxylate (3k). Bright yellow solid (69mg, 86%), mp: 58ꢀ60 °C;
PE/EA = 5/1 as eluent; 1H NMR (600 MHz, CDCl3) δ 13.73 (d, J = 4.8 Hz, 1H), 7.82
– 7.79 (m, 2H), 7.53 – 7.48 (m, 1H), 7.47 – 7.42 (m, 3H), 7.41 – 7.36 (m, 2H), 7.35 –
7.28 (m, 3H), 4.93 (p, J = 6.6 Hz, 1H), 4.28 (q, J = 7.2 Hz, 2H), 2.70 (s, 3H), 2.45 (s,
3H), 1.76 (d, J = 6.6 Hz, 3H), 1.32 (t, J = 7.2 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ
193.4, 169.1, 168.8, 143.4, 142.5, 141.4, 134.7, 130.9, 129.5, 129.2, 128.0, 127.9,
125.8, 118.7, 113.3, 60.6, 55.5, 23.8, 19.6, 18.0, 14.5. HRMSꢀEI (m/z): calcd for
C26H28NO3 [M+H]+: 402.2064, found: 402.2061.
Ethyl(Z)-3-benzoyl-5-(1-((2-ethoxy-2-oxoethyl)amino)ethylidene)-4-methylcyclo-
penta-1,3-diene-1-carboxylate (3l). Yellow solid (76mg, 99%), mp: 148ꢀ150 °C;
PE/EA = 4/1 as eluent; 1H NMR (400 MHz, CDCl3) δ 13.46 (s, 1H), 7.82 – 7.75 (m,
2H), 7.53 – 7.47 (m, 1H), 7.48 – 7.39 (m, 3H), 4.32 – 4.17 (m, 6H), 2.73 (s, 3H), 2.51
(s, 3H), 1.35 – 1.26 (m, 6H). 13C NMR (101 MHz, CDCl3) δ 193.5, 169.5, 169.0,
167.6, 144.3, 141.2, 135.3, 131.0, 129.5, 128.7, 127.9, 118.8, 113.9, 62.2, 60.6, 46.0,
19.0, 18.2, 14.4, 14.2. HRMSꢀEI (m/z): calcd for C22H26NO5 [M+H]+: 384.1805,
found: 384.1809.
Ethyl(S,Z)-3-benzoyl-5-(1-((1-ethoxy-1-oxopropan-2-yl)amino)ethylidene)-4-met-
hylcyclopenta-1,3-diene-1-carboxylate (3m). Yellow solid (64mg, 81%), mp:
1
126ꢀ127 °C; PE/EA = 4/1 as eluent; H NMR (400 MHz, CDCl3) δ 13.49 (d, J = 6.8
Hz, 1H), 7.83 – 7.75 (m, 2H), 7.53 – 7.47 (m, 1H), 7.44 (m, 3H), 4.50 (p, J = 7.2 Hz,
1H), 4.24 (m, 4H), 2.74 (s, 3H), 2.53 (s, 3H), 1.71 (d, J = 7.2 Hz, 3H), 1.29 (m, 6H).
13C NMR (101 MHz, CDCl3) δ 193.5, 170.8, 168.9, 168.3, 144.1, 141.3, 135.1, 130.9,
129.5, 128.5, 127.9, 118.6, 113.8, 62.1, 60.6, 53.3, 19.1, 18.2, 17.9, 14.4, 14.1.
HRMSꢀEI (m/z): calcd for C23H28NO5 [M+H]+: 398.1962, found: 398.1956.
Ethyl(Z)-3-benzoyl-4-methyl-5-(1-(phenylamino)ethylidene)cyclopenta-1,3-dien-
e-1-carboxylate (3n). Bright yellow solid (64mg, 86%), mp: 183ꢀ184 °C; PE/EA =
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10/1 as eluent; 1H NMR (400 MHz, CDCl3) δ 15.03 (s, 1H), 7.84 – 7.79 (m, 2H), 7.55
– 7.42 (m, 6H), 7.36 (t, J = 7.6 Hz, 1H), 7.27 – 7.22 (m, 2H), 4.25 (q, J = 7.2 Hz, 2H),
2.78 (s, 3H), 2.59 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ
193.5, 169.4, 166.8, 145.1, 141.2, 137.4, 135.9, 131.1, 129.6, 129.6, 128.9, 128.0,
127.7, 125.5, 119.4, 113.5, 60.8, 20.8, 18.1, 14.4. HRMSꢀEI (m/z): calcd for
C24H24NO3 [M+H]+: 374.1751, found: 374.1748.
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Ethyl(Z)-3-benzoyl-5-(1-((4-methoxyphenyl)amino)ethylidene)-4-methylcyclope-
nta-1,3-diene-1-carboxylate (3o). Bright yellow solid (80mg, 99%), mp: 152ꢀ154 °C;
PE/EA = 10/1 as eluent; 1H NMR (400 MHz, CDCl3) δ 14.89 (s, 1H), 7.85 – 7.78 (m,
2H), 7.55 – 7.48 (m, 2H), 7.48 – 7.42 (m, 2H), 7.19 – 7.12 (m, 2H), 7.02 – 6.93 (m,
2H), 4.25 (q, J = 7.2 Hz, 2H), 3.85 (s, 3H), 2.78 (s, 3H), 2.56 (s, 3H), 1.30 (t, J = 7.2
Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 193.5, 169.4, 167.3, 159.0, 144.7, 141.3,
135.6, 131.0, 130.1, 129.6, 128.6, 127.9, 126.7, 119.2, 114.8, 113.3, 60.8, 55.6, 20.7,
18.0, 14.4. HRMSꢀEI (m/z): calcd for C25H26NO4 [M+H]+: 404.1856, found:
404.1860.
Ethyl(Z)-3-benzoyl-4-methyl-5-(1-(naphthalen-1-ylamino)ethylidene)cyclopenta-
1,3-diene-1-carboxylate (3p). Dark yellow solid (69mg, 81%), mp: 135ꢀ137 °C;
PE/EA = 10/1 as eluent; 1H NMR (400 MHz, CDCl3) δ 15.22 (s, 1H), 8.00 – 7.91 (m,
3H), 7.90 – 7.84 (m, 2H), 7.65 – 7.45 (m, 7H), 7.37 (d, J = 7.2 Hz, 1H), 4.27 (q, J =
13
7.2 Hz, 2H), 2.82 (s, 3H), 2.48 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H). C NMR (101 MHz,
CDCl3) δ 193.6, 169.5, 168.7, 145.2, 141.2, 135.9, 134.4, 133.9, 131.2, 129.6, 129.6,
129.0, 128.8, 128.6, 128.0, 127.6, 127.1, 125.4, 124.2, 122.6, 119.0, 113.7, 60.9, 20.8,
18.1, 14.4. HRMSꢀEI (m/z): calcd for C28H26NO3 [M+H]+: 424.1907, found:
424.1911.
Ethyl(Z)-3-benzoyl-5-(1-((2-fluorophenyl)amino)ethylidene)-4-methylcyclopenta-
1,3-diene-1-carboxylate (o-3r). Yellow solid, mp: 145ꢀ146 °C; PE/EA = 10/1 as
eluent; 1H NMR (400 MHz, CDCl3) δ 14.85 (s, 1H), 7.85 – 7.79 (m, 2H), 7.56 – 7.50
(m, 2H), 7.50 – 7.42 (m, 2H), 7.42 – 7.34 (m, 1H), 7.33– 7.27 (m, 2H), 7.25 – 7.18
(m, 1H), 4.26 (q, J = 7.2 Hz, 2H), 2.78 (s, 3H), 2.53 (d, J = 2.4 Hz, 3H), 1.31 (t, J =
7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 193.6, 169.4, 167.7, 158.1, 155.6, 145.7,
141.0, 136.2, 131.2, 129.6, 129.6, 129.3, 128.0, 127.8, 125.6, 125.4, 125.0, 125.0,
119.2, 116.9, 116.8, 113.9, 60.9, 20.3, 20.3, 18.2, 14.4. HRMSꢀEI (m/z): calcd for
C24H23FNO3 [M+H]+: 392.1656, found: 392.1649.
Ethyl(Z)-3-benzoyl-5-(1-((3-fluorophenyl)amino)ethylidene)-4-methylcyclopenta-
1,3-diene-1-carboxylate (m-3r). Yellow solid, mp: 170ꢀ172 °C; PE/EA = 10/1 as
eluent; 1H NMR (400 MHz, CDCl3) δ 15.05 (s, 1H), 7.84 – 7.77 (m, 2H), 7.56 – 7.49
(m, 2H), 7.49 – 7.42 (m, 3H), 7.11 – 7.03 (m, 2H), 7.02 – 6.97 (m, 1H), 4.26 (q, J =
13
7.2 Hz, 2H), 2.77 (s, 3H), 2.61 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H). C NMR (101 MHz,
CDCl3) δ 193.5, 169.4, 166.2, 164.2, 161.8, 145.6, 141.0, 139.0, 138.9, 136.3, 131.2,
130.9, 130.8, 129.6, 129.4, 128.0, 121.3, 121.3, 119.5, 114.7, 114.5, 113.7, 113.1,
112.9, 61.0, 20.7, 18.2, 14.4. HRMSꢀEI (m/z): calcd for C24H23FNO3 [M+H]+:
392.1656, found: 392.1647.
Ethyl(Z)-3-benzoyl-5-(1-((4-fluorophenyl)amino)ethylidene)-4-methylcyclopenta-
1,3-diene-1-carboxylate (p-3r). Yellow solid, mp: 166ꢀ168 °C; PE/EA = 10/1 as
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eluent; 1H NMR (400 MHz, CDCl3) δ 14.95 (s, 1H), 7.84 – 7.78 (m, 2H), 7.56 – 7.49
(m, 2H), 7.49 – 7.42 (m, 2H), 7.25 – 7.20 (m, 2H), 7.20 – 7.13 (m, 2H), 4.25 (q, J =
13
7.2 Hz, 2H), 2.77 (s, 3H), 2.56 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H). C NMR (101 MHz,
CDCl3) δ 201.1, 167.3, 165.6, 160.2, 141.6, 136.9, 132.9, 132.6, 131.7, 130.4, 129.5,
129.4, 128.7, 127.8, 126.3, 122.1, 119.4, 118.4, 118.2, 52.6, 52.5, 17.9. HRMSꢀEI
(m/z): calcd for C24H23FNO3 [M+H]+: 392.1656, found: 392.1659.
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Ethyl(Z)-3-benzoyl-5-(1-((3-chlorophenyl)amino)ethylidene)-4-methylcyclopenta-
1,3-diene-1-carboxylate (3s). Yellow solid, mp:156ꢀ158 °C; PE/EA = 10/1 as eluent;
1H NMR (400 MHz, CDCl3) δ 14.95 (s, 1H), 7.77 – 7.69 (m, 2H), 7.49 – 7.42 (m,
2H), 7.41 – 7.30(m, 3H), 7.29 – 7.23(m, 1H), 7.23 – 7.16 (m, 1H), 7.07 (d, J = 7.6 Hz,
13
1H), 4.18 (q, J = 7.2 Hz, 2H), 2.68 (s, 3H), 2.52 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H). C
NMR (101 MHz, CDCl3) δ 193.5, 169.4, 166.1, 145.6, 141.0, 138.7, 136.3, 135.3,
131.2, 130.6, 129.5, 129.4, 128.0, 127.7, 125.7, 123.8, 119.5, 113.7, 61.0, 20.7, 18.2,
14.4. HRMSꢀEI (m/z): calcd for C24H23ClNO3 [M+H]+: 408.1361, found: 408.1358.
Ethyl(Z)-3-benzoyl-5-(1-((3-bromophenyl)amino)ethylidene)-4-methylcyclopenta
-1,3-diene-1-carboxylate (m-3t). Yellow solid, mp: 173ꢀ175 °C; PE/EA = 10/1 as
eluent; 1H NMR (400 MHz, CDCl3) δ 15.03 (s, 1H), 7.84 – 7.79 (m, 2H), 7.56 – 7.41
(m, 6H), 7.35 (t, J = 8.0 Hz, 1H), 7.22 – 7.17 (m, 1H), 4.26 (q, J = 7.2 Hz, 2H), 2.76
(s, 3H), 2.60 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 193.5,
169.4, 166.1, 145.7, 141.0, 138.9, 136.3, 131.2, 130.8, 130.7, 129.5, 129.4, 128.6,
128.0, 124.3, 123.1, 119.5, 113.7, 61.0, 20.7, 18.2, 14.4. HRMSꢀEI (m/z): calcd for
C24H23BrNO3 [M+H]+: 452.0856, found: 452.0851.
Ethyl(Z)-3-benzoyl-5-(1-((4-bromophenyl)amino)ethylidene)-4-methylcyclopenta
-1,3-diene-1-carboxylate (p-3t). Yellow solid, mp: 159ꢀ161 °C; PE/EA = 10/1 as
eluent; 1H NMR (400 MHz, CDCl3) δ 14.99 (s, 1H), 7.84 – 7.77 (m, 2H), 7.62 – 7.57
(m, 2H), 7.55 – 7.49 (m, 2H), 7.49 – 7.42 (m, 2H), 7.13 (d, J = 8.4 Hz, 2H), 4.25 (q, J
= 7.2 Hz, 2H), 2.76 (s, 3H), 2.58 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H). 13C NMR (101
MHz, CDCl3) δ 193.5, 169.4, 166.1, 145.5, 141.0, 136.6, 136.2, 132.8, 131.2, 129.5,
129.3, 128.0, 127.1, 121.3, 119.6, 60.9, 20.7, 18.1, 14.4. HRMSꢀEI (m/z): calcd for
C24H23BrNO3 [M+H]+: 452.0856, found: 452.0849.
Ethyl(Z)-3-benzoyl-4-methyl-5-(1-(o-tolylamino)ethylidene)cyclopenta-1,3-diene-
1
1-carboxylate (o-3u). Yellow solid, mp: 156ꢀ157 °C; PE/EA = 10/1 as eluent; H
NMR (400 MHz, CDCl3) δ 14.83 (s, 1H), 7.88 – 7.78 (m, 2H), 7.56 – 7.50 (m, 2H),
7.49 – 7.42 (m, 2H), 7.37 – 7.28 (m, 3H), 7.15 – 7.08 (m, 1H), 4.25 (q, J = 7.2 Hz,
13
2H), 2.79 (s, 3H), 2.47 (s, 3H), 2.33 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H). C NMR (101
MHz, CDCl3) δ 193.5, 169.3, 168.0, 144.9, 141.2, 136.4, 135.6, 134.5, 131.3, 131.1,
129.6, 128.7, 128.4, 127.9, 127.0, 126.8, 118.7, 113.5, 60.8, 20.4, 18.1, 14.4.
HRMSꢀEI (m/z): calcd for C25H26NO3 [M+H]+: 388.1907, found: 388.1901.
Ethyl(Z)-3-benzoyl-4-methyl-5-(1-(m-tolylamino)ethylidene)cyclopenta-1,3-diene
1
-1-carboxylate (m-3u). Yellow solid, mp: 157ꢀ158 °C; PE/EA = 10/1 as eluent; H
NMR (400 MHz, CDCl3) δ 14.97 (s, 1H), 7.82 (dd, J = 7.6, 1.6 Hz, 2H), 7.56 – 7.42
(m, 4H), 7.35 (t, J = 8.0 Hz, 1H), 7.18 (d, J = 7.6 Hz, 1H), 7.09 – 7.01 (m, 2H), 4.26
(q, J = 7.2 Hz, 2H), 2.79 (s, 3H), 2.59 (s, 3H), 2.42 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H).
13C NMR (101 MHz, CDCl3) δ 193.5, 169.4, 166.9, 145.0, 141.2, 139.8, 137.3, 135.8,
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131.1, 129.6, 129.4, 128.8, 128.5, 127.9, 126.0, 122.6, 119.3, 113.4, 60.8, 21.4, 20.8,
18.1, 14.4. HRMSꢀEI (m/z): calcd for C25H26NO3 [M+H]+: 388.1907, found:
388.1903.
Ethyl(Z)-3-benzoyl-4-methyl-5-(1-(p-tolylamino)ethylidene)cyclopenta-1,3-diene-
1
1-carboxylate
(
p-3u
)
. Yellow solid, mp: 136ꢀ138 °C; PE/EA = 10/1 as eluent; H
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NMR (400 MHz, CDCl3) δ 14.95 (s, 1H), 7.85 – 7.77 (m, 2H), 7.54 – 7.48 (m, 2H),
7.48 – 7.42 (m, 2H), 7.26 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 4.25 (q, J = 7.2
Hz, 2H), 2.78 (s, 3H), 2.58 (s, 3H), 2.40 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H). 13C NMR
(101 MHz, CDCl3) δ 193.5, 169.4, 167.0, 144.8, 141.3, 137.8, 135.7, 134.8, 131.0,
130.2, 129.6, 128.7, 127.9, 125.3, 119.3, 113.3, 60.8, 21.1, 20.8, 18.1, 14.4. HRMSꢀEI
(m/z): calcd for C25H26NO3 [M+H]+: 388.1907, found: 388.1900.
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Ethyl(Z)-3-benzoyl-5-(1-((3-methoxyphenyl)amino)ethylidene)-4-methylcyclopen
ta-1,3-diene-1-carboxylate (3v). Yellow solid, mp: 165ꢀ166 °C; PE/EA = 10/1 as
eluent; 1H NMR (400 MHz, CDCl3) δ 14.99 (s,1H), 7.84 – 7.78 (m, 2H), 7.55 – 7.49
(m, 2H), 7.49 – 7.42 (m, 2H), 7.37 (t, J = 8.0 Hz, 1H), 6.91 (dd, J = 8.4, 2.4 Hz, 1H),
6.83 (dd, J = 7.6, 2.0 Hz, 1H), 6.78 (t, J = 2.4 Hz, 1H), 4.26 (q, J = 7.2 Hz, 2H), 3.85
(s, 3H), 2.78 (s, 3H), 2.60 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ 193.5, 169.4, 166.9, 160.5, 145.1, 141.2, 138.5, 135.8, 131.1, 130.4, 129.5,
128.9, 127.9, 119.3, 117.8, 113.4, 113.2, 111.5, 60.8, 55.5, 20.8, 18.1, 14.4. HRMSꢀEI
(m/z): calcd for C25H26NO4 [M+H]+: 404.1856, found: 404.1846.
Determinination of the equilibrium reaction times. Ethyl 6ꢀhydroxyfulveneꢀ1ꢀ
carboxylate 1 (0.1mmol) was added into a solution of substituted anilines (0.1mmol)
in 2 mL of ethanol and stirred under refluxing condition for a period. The reaction
was worked up with 1 mol/L HCl (aq) solution. The mixture was extracted with
CH2Cl2 three times, and washed with brine. The combined extract was dried over
anhydrous sodium sulfate and concentrated under reduced pressure. The conversion
1
of fulvene 1 and the yield of amination product 3 were measured by means of H
NMR. When the reaction time was prolonged to 8ꢀ12 hours, the conversion of fulvene
1 almost remained constant (table S1 see supporting information), indicating the
reaction got equilibrium. The equilibrium constants for the equation given in Scheme
S1 were calculated.
The competitive reaction was conducted in the same procedure mentioned above,
and fulvene 1 (0.1mmol), aniline (0.1mmol) and pꢀchloroaniline (0.1mmol) was
mixed in 2 mL of ethanol and stirred under refluxing condition. The yields for the
amination products 3k and 3e were calculated based on the amount of fulvene 1.
The kinetic study: Fulvene 1 (0.1mmol) and aniline (0.1mmol) was mixed in 2 mL
of ethanol and stirred under refluxing condition for a specified period. The conversion
of fulvene 1 and the yield of amination product 3k at different reaction times were
measured by means of 1H NMR (Table S2 see supporting information). We found that
the reaction follows a secondꢀorder reaction kinetics well in the first hour.
The secondꢀ order reaction kinetics equation is c0/c = kc0t + 1. The calculated data
c0/c for fulvene 1 and the corresponding reaction time were listed in Table S3 (see
supporting information). The plot c0/c of conversion ratio of fulvene 1 versus the
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corresponding reaction time was depicted in Figure S1(see supporting information).
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Procedure for deprotecting of 3 or 4. Amination product 3n (0.2 mmol) was added
to 3 equiv. of aqueous ammonia in 2 mL of ethanol and stirred under refluxing
condition for 12 h. The reaction was followed by TLC. After completed, the reaction
mixture was cooled to room temperature, the solvent evaporated in vacuo, and then
the residue was purified by silica gel column chromatography to give the
6ꢀaminofulvene 3q. The same procedure was followed for the deprotection of 3m or
4c using 10 equiv. and 15 equiv. of aqueous ammonia, respectively.
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Ethyl(Z)-5-(1-aminoethylidene)-3-benzoyl-4-methylcyclopenta-1,3-diene-1-carb-
1
oxylate (3q). Yellow solid, mp: 158ꢀ159 °C; PE/EA = 10/1 as eluent; H NMR (400
MHz, CDCl3) δ 12.75 (s, 1H), 7.83 – 7.76 (m, 2H), 7.55 – 7.40 (m, 4H), 7.04 (s, 1H),
4.22 (q, J = 7.2 Hz, 2H), 2.72 (s, 3H), 2.61 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H). 13C NMR
(101 MHz, CDCl3) δ 193.9, 169.1, 168.5, 145.1, 141.1, 135.6, 131.2, 129.5, 128.5,
128.0, 116.7, 114.4, 60.5, 25.8, 17.4, 14.4. HRMSꢀEI (m/z): calcd for C18H20NO3
[M+H]+: 298.1438, found: 298.1416.
Ethyl(S,Z)-3-benzoyl-5-(1-(((1-benzoylpyrrolidin-2-yl)methyl)amino)ethylidene)-4
-methylcyclopenta-1,3-diene-1-carboxylate(4c). Yellow solid (46mg, 96%), mp: 49ꢀ
1
ꢀ50 °C; PE/ Acetone = 3/1 as eluent; H NMR (600 MHz, CDCl3) δ 13.43 (t, J = 6.0
Hz, 1H), 7.82 – 7.77 (m, 2H), 7.63 – 7.59 (m, 2H), 7.51 – 7.47 (m, 1H), 7.46 – 7.39
(m, 6H), 4.46 (qd, J = 7.8, 3.0 Hz, 1H), 4.25 (q, J = 7.2 Hz, 2H), 4.04 (ddd, J = 13.8,
6.6, 3.0 Hz, 1H), 3.93 (dt, J = 13.2, 6.0 Hz, 1H), 3.61 (td, J = 10.2, 6.6 Hz, 1H), 3.50
(ddd, J = 10.8, 7.2, 3.6 Hz, 1H), 2.76 (s, 3H), 2.69 (s, 3H), 2.25 (h, J = 7.2 Hz, 1H),
2.07 – 1.91 (m, 2H), 1.86 – 1.75 (m, 1H), 1.31 (t, J = 7.2 Hz, 3H). 13C NMR (101
MHz, CDCl3) δ 193.4, 171.1, 170.3, 169.1, 143.5, 141.4, 136.4, 134.8, 130.9, 130.5,
129.5, 128.3, 128.1, 127.9, 127.5, 118.8, 113.0, 60.6, 57.0, 51.0, 46.2, 28.7, 25.2, 19.0,
18.2, 14.5. HRMSꢀEI (m/z): calcd for C30H33N2O4 [M+H]+: 485.2435, found:
485.2413.
Supporting Information Available: The NMR spectra for all the new compounds
are available free of charge via the Internet at http://pubs.acs.org
Acknowledgements
This work was supported by grants from National Natural Science Foundation of
China (no. 21472053, 21172082). The Analysis and Testing Centre of Huazhong
University of Science and Technology is acknowledged for characterization of the
new compounds.
References
1. (a) Afewerki, S.; Córdova A. Combinations of Aminocatalysts and Metal
Catalysts: A Powerful Cooperative Approach in Selective Organic Synthesis. Chem.
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2
3
4
5
6
7
8
9
Rev. 2016, 116, 13512ꢀ13570. (b) Vasseur, A.; Bruffaerts, J.; Marek I. Remote
functionalization through alkene isomerization. Nature Chemistry, 2016, 8, 209ꢀ219.
2. (a) Kellam, B.; Bycroft, B. W.; Chan, W. C.; Chhabra, S. R. Solid phase
strategies: Applications of 2ꢀacetylꢀ4ꢀnitroindaneꢀ1,3ꢀdione as a selective protecting
group for primary amines. Tetrahedron, 1998, 54, 6817ꢀ6832; (b) Siaugue, J. M.;
Dioury, F. S.; Sylvestre, I.; FavreꢀReÂguillon, A.; Foos, J.; Madicc, C.; Guyb, A.
Regioselective synthesis of Nꢀfunctionalized 12ꢀmembered azapyridinomacrocycles
bearing trialkylcarboxylic acid side chains. Tetrahedron, 2001, 57, 4713ꢀ4718.
3. Prugh, J. D.; Birchenough, L. A.; Eghertson, M. S. A Simple Method of
Protecting a Secondary Amine with Tert Butyloxycarbonyl (Boc) in the Presence of a
Primary Amine. Synth. Commun. 1992, 22, 2357ꢀ2360.
4. (a) O’Sullivan, M. C.; Dalrymple, D. M. A oneꢀstep procedure for the selective
trifluoroacetylation of primary amino groups of polyamines. Tetrahedron Lett. 1995,
36, 3451ꢀ3452; (b) Xu, D. Q; Prasad, K.; Repic, O.; Blacklock, T. J. Ethyl
trifluoroacetate: a powerful reagent for differentiating amino groups. Tetrahedron Lett.
1995, 36, 7357ꢀ7360. (c) Brotzel, F.; Chu, Y. C.; Mayr H. Nucleophilicities of
Primary and Secondary Amines in Water. J. Org. Chem., 2007, 72, 3679ꢀ3688. (d)
Kanzian, T.; Nigst,T. A.; Maier, A.; Pichl, S.; Mayr H. Nucleophilic Reactivities of
Primary and Secondary Amines in Acetonitrile. Eur. J. Org. Chem., 2009, 6379–6385.
5. (a) Xu, D.; Mattner, P. G.; Prasad, K.; Repic, O.; Blacklock, T. J. An expeditious
synthesis of a biscyclam with an aromatic linker. Tetrahedron Lett. 1996, 37,
5301ꢀ5304; (b) Krakowiak, K. E.; Bradshaw, J. S. Selective Protection of the Primary
Amine Functions of Linear Tetraamines Using the Trityl Group. Synth. Commun.
1998, 28, 3451ꢀ3459.
6. (a) Laduron, F.; Tamborowski, V.; Moens, L.; Horva´th, A.; Smaele, D. D.; Leurs,
S. Efficient and Scalable Method for the Selective Alkylation and Acylation of
Secondary Amines in the Presence of Primary Amines. Organic Process Research &
Development, 2005, 9, 102ꢀ104. (b) Guoxiang Ma; Amitabh Jha. A Practical Guide
for BufferꢀAssisted Isolation and Purification of Primary, Secondary, and Tertiary
Amine Derivatives from Their Mixture. Org. Process. Res. Dev., 2005, 9, 847ꢀ852.
7. (a) Nair, V.; Jayan, C. N.; Radhakrishnan, K. V.; Anilkumar, G.; Rath, N. P. [4+2]
Cycloaddition reactions of coumarin quinone methide with pentafulvenes: facile
synthesis of novel polycyclic pyran derivatives. Tetrahedron, 2001, 57, 5807ꢀ5813; (b)
Lash, T. D.; Colby, D. A.; Idate, A. S.; Davis, R. N. Fulvene Dialdehyde Strategy for
adjꢀDicarbaporphyrinoid Synthesis:ꢁ Preparation of a 22ꢀCarbaazuliporphyrin. J. Am.
Chem. Soc., 2007, 129, 13800ꢀ13801; (c) Devendar, B.; Wu, C. P.; Chen, C. Y.; Chen,
H. C.; Chang, C. H.; Ku, C. K.; Tsai, C. Y.; Ku, C. Y. Synthesis, characterization and
applications of densely functionalized pyridazines and fulveneꢀtype compounds
containing azulene moiety. Tetrahedron, 2013, 69, 4953.
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27
28
29
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42
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44
45
46
47
48
49
50
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53
54
55
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57
58
59
60
8. (a) Kondo, K.; Goda, H.; Takemoto, K.; Aso, H.; Sasaki, T.; Kawakami, K.;
Yoshida, H.; Yoshida, J. Microꢀ and macroꢀscopic secondꢀorder nonꢀlinear optical
properties of fulvene compounds. J. Mater. Chem., 1992, 2, 1097ꢀ1102; (b) Dong, Y.;
Geng, Y.; Ma, J.; Huang, R. Organometallic Silver(I) Coordination Polymers and
Supramolecular Complexes Based on Novel Multidentate Thiopheneꢀ and
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BenzenenitrileꢀContaining Symmetric and Unsymmetric Fulvene Ligands.
Organometallics, 2006, 25, 447ꢀ462.
9. (a) Strohfeldt, K.; Tacke, M. Bioorganometallic fulveneꢀderived titanocene
antiꢀcancer drugs. Chem. Soc. Rev., 2008, 37, 1174ꢀ1187; (b) Tanasova, M.; Sturla, S.
J. Chemistry and Biology of Acylfulvenes: SesquiterpeneꢀDerived Antitumor Agents.
Chem. Rev., 2012, 112, 3578ꢀ3610; (c) Siegel, D. S.; Piizzi, G.; Piersanti, G.;
Movassaghi, M. Enantioselective Total Synthesis of (−)ꢀAcylfulvene and
(−)ꢀIrofulven. J. Org. Chem., 2009, 74, 9292ꢀ9304.
10. Zhu, Y. Q.; Zhang, M.; Yuan, H. L.; Gong, Y. F. Synthesis of functionalized
fulvenes: [3+2] annulation of ethyl αꢀchlorocyclopropaneformates with
1,3ꢀdicarbonyl compounds. Org. Biomol. Chem., 2014, 12, 8828ꢀ8831.
11. (a) Nigst, T. A.; Antipova A.; Mayr H. Nucleophilic Reactivities of Hydrazines
and Amines: The Futile Search for the αꢀEffect in Hydrazine Reactivities J. Org.
Chem. 2012, 77, 8142ꢀ8155. (b) Stredl, N.; Antipova A.; Mayr H. Suppression of
CommonꢀIon Return by Amines: A Method to Measure Rates of Fast SN1 Reactions J.
Org. Chem. 2009, 74, 7328ꢀ7334.
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