One-Step, Effective, and Cascade Syntheses of Highly Functionalized Cyclopentenes with High Diastereoselectivity

Article abstract of DOI:10.1021/acs.orglett.8b00510

Tetrabutylammonium fluoride works as an effective organocatalyst for the cycloaddition between phenacylmalononitriles and electron-deficient olefins (having substituent groups of NO₂, CHO, and COR), providing a facile synthetic route to versatile multifunctionalized cyclopentenes having an allylic quaternary carbon center bearing both cyano and carboxamide groups with high yields and high diastereoselectivity. Preliminary studies reveal that these functionalized cyclopentenes are convenient precursors for making α-cyano-functionalized cyclopentadienone oximes.

Full text of DOI:10.1021/acs.orglett.8b00510

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
One-Step, Effective, and Cascade Syntheses of Highly Functionalized
Cyclopentenes with High Diastereoselectivity
Suman Alishetty, Hong-Pin Shih, and Chien-Chung Han*
Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan, ROC
*
S Supporting Information
ABSTRACT: Tetrabutylammonium fluoride works as an effective organo-
catalyst for the cycloaddition between phenacylmalononitriles and electron-
deficient olefins (having substituent groups of NO , CHO, and COR),
2
providing a facile synthetic route to versatile multifunctionalized cyclo-
pentenes having an allylic quaternary carbon center bearing both cyano and
carboxamide groups with high yields and high diastereoselectivity.
Preliminary studies reveal that these functionalized cyclopentenes are
convenient precursors for making α-cyano-functionalized cyclopentadienone
oximes.
ighly functionalized cyclopentenes are valuable structural
functionalized cyclopentenes with high yields and high
diastereoselectivities.
1
,2
H
motifs for many bioactive and medicinal compounds,
3
a
3b
such as (−)-carbovir, trans-α-necrodyl isobutyrate, lauroka-
Previously, we demonstrated that a catalytic amount of TBAF
can work as an effective base to catalyze the C−C bond formation
via Michael addition between active methylene groups (such as
those in malononitrile, nitromethane, etc., as the Michae7l
donors) and a diiminoquinoid ring (as the Michael acceptors).
In those reactions, the fluoride works as an effective base to
activate the Michael donors via the α-H abstraction, forming HF,
which in turn works as an effective acid to activate the Michael
acceptor by protonating its imino group.
3
c
3d
murene A, (−)-lycoposerramine-R, and tetrahydropyranal
cyclopentyl benzylamide (TCB) derivatives (see Supporting
4
Information (SI) Figure S1). TCB derivatives, having a
functionalized cyclopentene core with a preferable allylic
quaternary carbon center with a carboxamide and another
electron-withdrawing group (such as CN, halogen, ester, CF3,
sulfonyl, heterocycles, etc.), may serve as modulators for
4a,b
chemokine receptor activity
and may be useful in the
prevention/treatment of certain immune regulatory disorders.
In this work, we further conceived that the dual functional
organocatalyst TBAF might be useful in promoting a cascade
Michael reaction between a strong Michael acceptor and a dual
functional compound, such as phenacylmalononitrile (1a) that
contains both a Michael donor moiety and a less reactive Michael
acceptor moiety, to form a five-membered carbocyclic ring. Our
first attempt was performed by reacting 1a with 1 equiv of trans-
β-nitrostyrene (2a) at rt in the presence of 5 mol % of TBAF in
THF (entry 1, Table 1). The reaction was completed in 5 h to
form cyclic diastereomers of 3aa (68%, racemate) and 4aa (20%,
2
,2
Furthermore, a series of small amphipathic β -amino acid
5
derivatives having a quaternary carbon center with a
carboxamide and a β-amino group (which was converted from
an α-cyano group via reduction) are found to be a promising new
6a−d
class of anticancer agents. Quite a few strategies
reported for the synthesis of multifunctionalized cyclopentene
CP) derivatives. While, only limited examples have been
have been
(
reported for making functionalized CP containing a quaternary
carbon center with both cyano and carboxamide groups from (a)
a malononitrile, followed by double α-allylation, ring-closure
8
6
e
racemate) and a highly substituted furan 5a (7%) (see the
metathesis, and enzyme-differentiated hydrolysis; (b) a
cyanoesteramide, followed by double α-allylation and then
equation in Table 1). Racemate formation for 3a (as in 3aa and
3ad) and 4a (as in 4ad) compounds was further confirmed by the
single-crystal X-ray crystallography diffraction data (see SI) and
the inability to show net rotation of plane-polarized light by the
respective compounds. As revealed by the structures, the 4-nitro
group is trans to the carboxamide functional group in 3aa but cis
in 4aa. The cis configuration in 4aa allows its carboxamide to be
H-bonded with the nitro groups, which is accountable for the
6f
ring-closure metathesis; and (c) a cyanoesteramide plus an
asymmetric allenoate to undergo a phosphine-catalyzed [4 + 1]
6
g
annulation. However, these methodologies require expensive
6
e,f,i
6g,i
catalysts (e.g., transition metal catalyst,
organocatalyst, and
6
e
6f
enzyme ) or reactive reagent and are only applicable for
6e−g
limited substrate scope.
Furthermore, they only provided the
functional quaternary carbon at the β-position to the vinyl group,
instead of at the desirable allylic position of the CP core.
Therefore, development of viable synthetic methods for making
CPs having an allylic quaternary carbon bearing both cyano and
carboxamide groups is still needed. Herein, we report a facile
one-step and effective synthetic method for making such highly
more downfield NH peak in 4aa (at δ 8.06) compared to that in
2
3aa (at δ 7.58) (see SI Figure S2). The NMR NOE results for 3aa
Received: February 11, 2018
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00510
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Solvent and Base Effects on the Reaction of 1a and 2a
(entry 9, Table 1) still gave the best yield (85%) and the highest
diastereoselectivity (95:5), probably due to its high solubility.
Although TBAC and TBAB contain the same tetrabutylammo-
nium (TBA) cation like TBAF, they however failed to promote
any reaction (entries 13 and 14, Table 1) even up to 24 h. Thus, it
is the fluoride anion and not the TBA cation that is responsible
for the high reactivity and diastereoselectivity. Other stronger
bases like DBU, NEt , and K CO gave essentially no or very
poor diastereoselectivity (Table 1, entries 15−17). Regarding the
case of NaOH (entry 18), its undesired strong basicity led to the
formation of a very complicated product mixture, which
dramatically reduced the isolable yield of 3aa (17%) and made
the isolation of pure 4aa impossible. The above results clearly
indicated that a nonsolvated fluoride anion plays the key roles for
the reactivity and the stereoselectivity for the cycloaddition
between 1a and 2a.
ratio
(3aa/4aa)
3
2
3
a
b
c
entry
base (mol %)
solvent
time (h)
3aa (%)
1
2
3
4
5
6
7
8
TBAF (5)
TBAF (5)
TBAF (5)
TBAF (5)
TBAF (5)
TBAF (5)
TBAF (5)
TBAF (5)
TBAF (100)
KF (100)
CsF (100)
THF
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
1.0
1.0
1.0
1.0
24
76:24
50:50
50:50
60:40
74:26
79:21
91:9
68
MeOH
EtOH
44
42
i-PrOH
n-BuOH
67
60
CH CN
72
3
DMF
87
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
98:2
89
To check the effective substrate scope of the reaction,
systematic studies were performed with TBAF (5 mol %) in
DMSO at rt using either the combination of 1a and different
substituted reactants 2 or the combination of different
substituted reactants 1 and 2a. The results (Scheme 1) revealed
9
95:5
85
d
10
11
12
13
14
15
16
17
18
19
82:18
89:11
83:17
67
d
d
f
79
KHF (100)
62
2
TBAC (100)
TBAB (100)
DBU (30)
trace
trace
43
f
24
Scheme 1. Applicable Substrate Scopes Based on the Electron-
f
a
1.0
1.0
1.0
1.0
24
58:42
50:50
51:49
e
Deficient Nitrostyrenes and Phenacylmalononitriles
Et N (100)
3
37
d
K CO (100)
35
2
3
NaOH (100)
no base
17
ND
a
[
Substrate] = 0.54 M; the yields of byproduct 5a were found to be
b
1
5
−10% in general. Diastereomeric ratio was determined by H NMR
c
of the crude reaction mixture. Isolated yield after column
chromatography; ND (not detected). Bases were partially soluble
in DMSO. Product mixture was too complicated to be correctly
estimated. TBAC (tetrabutylammonium chloride); TBAB (tetrabuty-
d
e
f
lammonium bromide); DBU (1,8-diazabicyclo[5.4.0]undec-7-ene).
and 4aa, as summarized in SI Scheme S1, are also consistent with
their respective steric structures.
To find the optimal reaction conditions and understand the
nature of the diastereoselectivity, model studies using 1a and 2a
with TBAF (5 mol %) were performed in various solvents at
room temperature, and the results are summarized in Table 1
a
b
Reactions were performed on a 0.27 mmol scale. All yields
1
correspond to isolated yields with dr as determined by H NMR of the
crude mixture.
(
entries 1−8). Interestingly, when protic solvents were used,
such as MeOH (ε = 33), EtOH (ε = 25), i-PrOH (ε = 17.9), and
n-BuOH (ε = 17), the diastereoselectivity clearly decreased as the
polarity (i.e., dielectric constant ε) of the protic solvent medium
increased (entries 2−5, Table 1). In the aprotic solvents, such as
THF (ε = 7.8), CH CN (ε = 38), DMF (ε = 37), and DMSO (ε
=
the aprotic solvent increased (entries 1 and 6−8, Table 1). In the
most polar aprotic solvent, such as DMSO (ε = 47), the reaction
gave the best isolated yield of 3aa (89%) with the highest
that the reactions gave, in general, high yields and high
diastereoselectivities, despite the electronic nature of the
substituents on either of the aryl rings. Apparently, the activation
effect of the fluoride is far more important than the electronic
effects of the substituent. Other aryl or vinyl groups, such as
naphthyl, furyl, and 2-bromocyclopentenyl, were also working
well.
This synthetic method is also applicable for multifunctional
nitrostyrene (e.g., 2p) and the conjugation extended nitrostyrene
(e.g., 2q). Likewise, it is also expandable to other electron-
deficient alkene or alkyne systems, such as α,β-unsaturated
ketones (e.g., ynone 2r, cyclopehexenone 2s, 1,4-benzoquinone
2t) and α,β-unsaturated aldehyde (e.g., 4-methylcinnamalde-
hyde, 2u) (Scheme 2). Interestingly, when 1a reacts with ynone
2r, it forms a cyclopentenol (instead of a cyclopentene) with the
concurrent preservation of the dicycano group (see X-ray
crystallography result in SI). The results suggest that the
formation of the carboxamide group and the loss of the hydroxyl
group (which originated from the carbonyl group of 1a) in all
other cases are tightly linked events.
3
47), the diastereoselectivity actually increased as the polarity of
1
diastereoselectivity (98:2; as estimated by H NMR). The
mechanistic implications for these contradicting solvent effects
will be further discussed below. Regarding the base effects, the
studies were conducted using the same reactants (1a and 2a) in
DMSO with various bases (1 equiv) at rt, and the results are
summarized in Table 1 (entries 9−19). As expected, in the
absence of any base, the control experiment (Table 1, entry 19)
failed to promote any reactions. The results clearly indicated that
a fairly high diastereoselectivity of 3aa/4aa (>82:18) can always
be obtained (entries 9−12) as long as a fluoride base was used,
despite their originality (TBAF, KF, CsF, or KHF ), but TBAF
2
B
DOI: 10.1021/acs.orglett.8b00510
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Extended Synthetic Applications with Other
Electron-Deficient Olefins
center (i.e., the γ-carbonyl group) should be active enough to
undergo fast reaction with 2 via a cascade of two consecutive
Michael additions to form a stereospecific cyclopentanol
intermediate 7 (i.e., 4-hydroxy-3-nitro-2,4-diphenylcyclopen-
a
1
tane-1,1-dicarbonitrile), with the nitro and the R groups (both
originated from nitrostyrene 2) being retained in a 1,2-trans
configuration, as expected for a fast concerted cyclization
reaction between the two molecules. In this hypothetical
1
intermediate 7, the R (originated from 2) and R (originated
from 1) would be preferably arranged in a 1,3-trans configuration
due to the need to minimize the steric hindrance interaction as
the nitrostyrene approaches adduct 6 for cyclization. Such a steric
requirement would render the newly formed hydroxy group (still
H-bonded with the fluoride anion) to be trans to the nitro group,
as depicted in 7.
Likewise, the H-bonding with a fluoride would help increase
the acidity of the O−H group in 7, which, in turn, would increase
its ability to activate the nearby cis-cyano group (i.e., the CN trans
to the nitro) via protonation (or H-bonding interaction) to
enable a fast intramolecular nucleophilic addition between the
hydroxy and the cis-cyano group, resulting in a bicyclic
intermediate 9 (2-oxabicyclo[2.2.1]heptan-3-imine). The fast
conversion from the hypothetical intermediate 7 to 9 can be
confirmed by the experimental observations that no cyclo-
pentene or cyclopentanol with the original dicyanomethylene
moiety (the potential products that could be derived from 7) has
ever been observed. It is conceivable that bicyclic intermediate 9
could be easily further activated via protonation at the basic
imino group (most likely by HF) to form a 2-oxabicyclo[2.2.1]-
heptan-3-iminium cation 10, which could then be converted to
the final product 3 via either an E2 elimination pathway
a
Reactions were performed on a 0.27 mmol scale. All yields
1
correspond to isolated yields with dr as determined by H NMR of
the crude mixture.
Based on the above experimental results, a plausible reaction
mechanism is proposed in Scheme 3 to account for the preferable
Scheme 3. Plausible Formation Mechanism for the
Diastereomer 3
a
(
possibly, through the depicted transition state 11 and being
assisted by a fluoride base) or an E1 elimination pathway
(
possibly through a tertiary benzylic cation 12).
When the reaction was carried out with a stronger base (e.g.,
NEt , K CO , and NaOH), the base might have abstracted the α-
3
2
3
H from the malononitrile group of substrate 1 to form a
conventional anionic nucleophile 14 (1,1-dicyano-3-oxo-3-
phenylpropan-1-ide), which might then react with 2 via a
conventional stepwise Michael addition mechanism, leading to a
pair of diastereomers 3 and 4 with poor selectivity (see SI
Scheme S4).
Although more rigorous studies are still needed to finalize the
actual mechanism, the current proposal can help explain the
unusual contradicting solvent effects on the diastereoselectivity.
In aprotic solvents (e.g., DMSO, DMF, CH CN, and THF), the
3
solvents with higher dielectric constants can better polarize the
α-C−H bond, thus facilitating formation of adduct 6 and
increasing the selectivity. In the protic solvents (e.g., n-BuOH, i-
PrOH, EtOH and MeOH), the solvents with higher dielectric
constants would have a stronger solvation interaction with the
fluoride and thus reduce the concentration of adduct 6 and lower
the selectivity.
a
Electron-rich cyclopentene 3 is more stable than the electron-
deficient cyclopentene 13 by 3.2 kcal/mol, according to the gas-phase
DFT calculation at the B3LYP/6-31G(d) level with Gaussian 09 (as
depicted in SI Scheme S2).
formation of diastereomer 3. Apparently, the fluoride anion is the
major activator and the key controller for the diastereoselectivity.
Thus, the activation might be started with the H-bonding
interaction between fluoride and the most acidic and positively
charged H (i.e., the α-H of the malononitrile group). Such H-
bonding interactions could further increase the ionization degree
and the acidity of α-C−H and render it active enough to
coordinate with the γ-carbonyl group, forming a five-membered
ring, adduct 6. Adduct 6 containing both an activated
nucleophilic center (i.e., the α-C) and an activated electrophilic
This mechanistic rationale actually prompts us to check the
H O (which is a protic solvent with the highest dielectric
2
constant) impurity effect. When the same reaction (entry 8,
Table 1) of 1a and 2a was repeated in freshly purchased
anhydrous DMSO (ACS grade; Merck; H O content <0.025%),
2
the diastereoselectivity of 3aa became quantitative (SI Figure
S3b). On the other hand, when the same reaction was carried out
in a cosolvent of DMSO/H O (90/10), the diastereoselectivity
2
disappeared totally (SI Figure S3c). Likewise, when the syntheses
of 3ac, 3ai, 3ag, 3ba, and 3ia were also repeated in anhydrous
C
DOI: 10.1021/acs.orglett.8b00510
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
DMSO solvent, their diastereoselectivities were all clearly
ORCID
increased (SI Table S1). More detailed studies for the H O
impurity effect are underway.
Interestingly, we found that the multifunctionalized cyclo-
pentene 3 can be further easily transformed into a multi-
functionalized cyclopentadienone oxime 19 (Scheme 4), with
2
Chien-Chung Han: 0000-0002-1045-0270
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We acknowledge the financial support from the Ministry of
Science and Technology, Republic of China.
■
Scheme 4. Formation of (Z)-5-(Hydroxyimino)-2,4-
a
diarylcyclopenta-1,3-diene-1-carbonitrile 19
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ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b00510.
Experimental procedures and characterization of products
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graphic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: cchan@mx.nthu.edu.tw.
D
DOI: 10.1021/acs.orglett.8b00510
Org. Lett. XXXX, XXX, XXX−XXX