Bifunctional N-Heterocylic Carbene-Catalyzed Highly Enantioselective Trans-Cyclopentannulation of Enals and Enones via Homoenolate

Article abstract of DOI:10.1002/cctc.202001513

An efficient and flexible synthesis of a new class of chiral bifunctional NHC catalyst has been reported. These new imidazolylidene NHCs, bearing a (thio)urea function as a hydrogen bond donor promoted efficiently highly diastereoselective trans-cyclopentannulation of enals and enones in moderate to good yields (up to 69 % yield) along with excellent enantioselectivity (up to 96 % ee). This methodology could be applied to a large variety of substrates (30 examples).

Full text of DOI:10.1002/cctc.202001513

The European Society Journal for Catalysis
Supported by
Accepted Article
Title: Bifunctional N-Heterocylic Carbene-Catalyzed Highly
Enantioselective Trans-Cyclopentannulation of Enals and Enones
via Homoenolate
Authors: Chloee BOURNAUD, Zhiwei Jiang, Martial Toffano, and
Giang Vo-Thanh
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10.1002/cctc.202001513
ChemCatChem
FULL PAPER
Bifunctional N-Heterocylic Carbene-Catalyzed Highly
Enantioselective Trans-Cyclopentannulation of Enals and Enones
via Homoenolate
Zhiwei Jiang, Martial Toffano, Giang Vo-Thanh,* and Chloée Bournaud*[a]
[a]
Z. Jiang, Dr. M. Toffano, Prof. G. Vo-Thanh, Dr. C. Bournaud
Institut de Chimie Moléculaire et des Matériaux d’Orsay, CNRS UMR 8182, Université Paris-Saclay
Rue du doyen Georges Poitou, 91405 Orsay Cedex, France
E-mail: chloee.bournaud@universite-paris-saclay.fr; giang.vo-thanh@universite-paris-saclay.fr
Supporting information for this article is given via a link at the end of the document.
Abstract: An efficient and flexible synthesis of a new class of chiral
bifunctional NHC catalyst has been reported. These new
imidazolylidene NHCs, bearing a (thio)urea function as a hydrogen
bond donor promoted efficiently highly diastereoselective trans-
cyclopentannulation of enals and enones in moderate to good yields
(up to 69 % yield) along with excellent enantioselectivity (up to 96 %
ee). This methodology could be applied to a large variety of substrates
(30 examples).
intermediate but it should be noted that only a few chiral
imidazolylidene organocatalyst have been reported so far
delivering poor level of enantioselectivity in most cases.[10] So, the
design and synthesis of chiral imidazolium, precursor to
imidazolylidene NHCs, could extend the range of reactions
catalyzed by chiral NHCs. Moreover, a few triazolylidene,
thiazolylidene and imidazolinylidene (saturated analogue
imidazolylidene) NHC organocatalysts bearing an additional
hydrogen bond donor have been reported in the literature.[11,12]
For example, combination of an hydroxyl group with triazolylidene
is common.[11] Amide was combined with triazolylidene[12c] or
thiazolylidene.[12e-f] Furthermore, thiourea was associated with
triazolylidene [12a-b] or imidazolinylidene[12d] but the results have
been disappointing or still need to be enhanced to have a highly
efficient chiral NHC catalyst.
To the best of our knowledge, the combination of chiral
imidazolium salt precursor to imidazolylidene NHC and a thiourea
function has never been reported so far. In a continuation of our
research on the design and synthesis of chiral bifunctional
organocatalyst[13] starting from inexpensive and commercially
available precursor from the natural chiral pool, we report herein
the synthesis of a new family of chiral bifunctional imidazolylidene
NHC-thioureas (Figure 1) and their application in organocatalyzed
asymmetric trans-cyclopentannulation of enals and chalcones.
Introduction
Nowadays, developing more sustainable chemistry seems to
be essential. Various strategies have therefore been adopted in
order to reduce the environmental impact of chemistry. Chemists
were able to develop catalyzed transformations improving
selectivity while decreasing reaction time and chemical waste.[1]
Among various catalytic systems reported, organocatalysis, using
a small organic molecule under mild reaction conditions, appears
as a very attractive area in modern organic synthesis and is now
considered the third pillar of catalysis, alongside metal catalysis
and biocatalysis. The main advantages of organocatalysis lie in
their tolerance towards many functional groups and therefore
many types of organocatalyst have been described. For example,
N-heterocyclic carbenes (NHCs) are a class of organocatalyst
that have been studied in depth due to their efficiency in forming
C-C and C-X bonds.[2] They are able to trigger non-conventional
reactions thanks to the formation of reactive intermediates, such
as Breslow intermediate, homoenolate intermediate, azolium
enolate, acyl azolium, ,-unsaturated acyl azolium or azolium
dienenolate, generated by nucleophilic addition of the lone pair of
the carbene to an aldehyde or its equivalent.[3] The first racemic
reaction promoted by a thiazolium salt (precursor to NHC) is the
benzoin condensation and dated since 1943 with Ukai[4] while the
first umpolung reaction was described in 1832 by Wöhler and
Figure 1. Design of new chiral bifunctional imidazolylidene-NHC organocatalyst.
Liebig.[5] Since then, research on NHCs has intensified, and Results and Discussion
enantioselective reactions catalyzed by NHCs are now extremely
efficient, thanks to the discovery of Breslow's mechanism,[6] the
Imidazolium scaffolds of the NHC catalyst were prepared in
isolation of the first stable carbene by Bertrand[7] and Arduengo,[8]
and the first example of enantioselective transformation with
triazolium salt precursor.[9] Although there are manifold chiral NHC
one step by mixing commercially available aminoalcohols, mesityl
amines, formaldehyde, glyoxal and acetic acid.[14] Hydroxy-
imidazolium 2a-d were isolated in moderate yields (Scheme 1).
Then amino-imidazolium 3a-d were obtained in three steps
including an activation of the hydroxyl group by a mesylate
followed by a nucleophilic substitution with sodium azide and a
reduction by hydrogen over Pd/C. Amino-imidazolium 3a-d were
engaged in the next step without further purification. Finally,
catalysts
such
as
thiazolylidene,
imidazolylidene,
imidazolinylidene or triazolylidene, the latter is by far the most
used in asymmetric organocatalysis. Moreover, achiral
imidazolylidene derived from imidazolium salt promotes
effectively racemic umpolung reactions involving homoenolate
1
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10.1002/cctc.202001513
ChemCatChem
FULL PAPER
reaction with various iso(thio)cyanates afforded expected
bifunctional NHC precatalyst 4 in good yields.
Scheme 2. Synthesis of 1,3,4-trisubstituted cyclopentenes catalyzed by NHC
via homoenolate intermediate.
We began our study with the cyclopentannulation of 4-
methoxy-cinnamaldehyde 5a and chalcone 6a in THF at 30°C
using 4af as pre-catalyst in the presence of potassium carbonate.
The cyclopentene adduct was isolated in low yield and moderate
ee (Table 1, entry1). It is noteworthy that only the trans
diastereoisomer 7a was observed (dr>25:1). Next, catalyst
screening was studied. All the previously synthesized pre-
catalysts were then evaluated in the same reaction conditions
(Table 1). This screening revealed that thiourea function gave
slightly better yield and enantiomeric excess than urea one
(entries 2 and 4). Moreover 3,5-bis(trifluoromethyl)phenyl derived
thiourea gave the best ee (entries 1-3). Finally, the influence of
chiral scaffold of the pre-catalyst (R group) was evaluated (entries
2, 7-9), the best yield and enantioselectivity were provided by the
pre-catalyst incorporating an iso-butyl substituent (entry 7).
Scheme 1. Synthesis of bifunctional imidazolylidene-NHC organocatalysts.
We were then interested in evaluating the potentiality of these
new pre-catalysts in asymmetric transformations. In particular, we
focused on a reaction for which an achiral imidazolium pre-
catalyst such as 1,3-dimesityl imidazolium chloride (IMes-HCl) is
an efficient pre-catalyst for racemic transformations and for which
the asymmetric version still remained challenging. In 2006,
Nair[10i] described a cyclopentannulation of enals and chalcones
catalyzed by IMes via homoenolate intermediates, leading to the
formation of racemic trans-disubstituted cyclopentenes in good
yields. In 2007, Bode[15] reported the enantioselective cis-
cyclopentannulation of enals and oxoenoate (scheme 2, Eq. 1) in
good yields and high ee. Since these seminal studies, research
groups have been interested in this transformation. For example,
the use of additives (such as Ti(OiPr)4)[16] gave the cis products in
good yields and ee. In 2013, Coquerel and co-workers[12d]
described the use of NHC functionalized hydrogen-bond donors
to promote the formation of trans-cyclopentene in low yield (18%)
and encouraging 78% ee compared to the previously reported
enantioselectivity.[15a] Moreover, saturated carboxylic acid
derivatives were efficiently used instead of enals.[17] It should be
noted that an excess of DBU is needed to generate the
homoenolate intermediate due to the release of nitrophenol
during the reaction. Finally, various Michael acceptors such as
oxindole, benzofuranones and tetrahydroquinolinone were also
investigated to afford cyclopentene fused heterocycles
adducts.[18] Despite these results, formation of trans-cyclopentene
adducts in high yields and enantioselectivity starting from enals
and chalcones via homoenolate intermediate was still unsolved.
In light of this, we envisioned that trans-cyclopentannulation could
be efficiently and stereoselectively promoted by our chiral
bifunctional imidazolylidene-NHC organocatalysts (scheme 2, Eq.
2).
Table 1. Catalyst screening.[a]
Entry
Catalyst
4af
Yield (%)[b]
ee (%)[c]
51
1
2
3
4
5
6
7
8
28
32
36
28
21
45
36
20
4ae
4ag
4ah
4ai
76
25
73
68
4aj
58
4be
4ce
82
50
2
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10.1002/cctc.202001513
ChemCatChem
FULL PAPER
9
4de
34
81
11
12
K2CO3
K2CO3
DIPE
DIPE
catechol[a]
42
50
94
93
Catechol[a,b]
[a] Reaction conditions: 5a (0.28 mmol), 6a (0.2 mmol), cat. (0.04 mmol), K2CO3
(0.08 mmol), THF (2 mL). [b] Yield of isolated product. [c] Determined by chiral
HPLC analysis.
[a] 20 mol% of catechol was used. [b] The reaction was performed at 40 °C. [c]
Yield of isolated product. [d] Determined by chiral HPLC analysis.
With the best pre-catalyst in hand, we explored reaction
conditions to increase the efficiency of this transformation. To
obtain the trans-cyclopentene adduct in high ee, the use of K2CO3
as a base was crucial (Table 2, entries 1-4). Solvent was also
screened. Among the solvents tested, DIPE was found to be the
best to afford the expected product in 43 % yield and 89% ee.
Next, different phenol derivatives were used as additives in this
transformation.[19] The number of hydroxyl group on the benzene
ring was crucial (Table 2, entries 8-10, see Supplementary Part,
Table S3), the catechol amount could be reduced to 20 mol %
(entry 11) and better yield was obtained at 40°C (entry 12). The
increase in yield by using this additive might be explained by the
fact that catechol could assist a proton transfer to generate
homoenolate intermediate[19c] or by the activation of the enone via
the formation of hydrogen bonding.[19d] In summary, using 20
mol% of catalyst 4be, 40 mol% K2CO3 and 20 mol% catechol in
DIPE at 40 °C afforded only the trans-diasteroisomer (> 25:1 dr)
in 50% yield with 93% ee. Optimization of the reaction conditions
allowed us to increase the yield from 36% to 50%. Generally
speaking, although yields remained moderate, starting materials
could be recovered and reused without difficulty. Moreover, it
should be emphasized that this cyclopentannulation is an atom
economy transformation since only carbone dioxide is released.
Besides, the absolute configuration of the product was assigned
as (S,S) in comparison with data reported in the literature.[17a]
With the optimized reaction conditions, we next evaluated the
scope of cycloannulation by varying the enal substrates 5a-l. As
outlined in Scheme 3, (Z) or (E)-cinnamaldehyde afforded the
same trans-cycloadduct 7c with comparable yield and
enantioselectivity likely due to an isomerization during the
formation of the homoenolate intermediate.[20] Enals with
substituents of different electronic nature on phenyl ring could be
tolerated affording the cycloadduct 7a-h in the same range of
enantioselectivity (89-96%) in 41-60% yield. The best result with
60% yield and 93% ee was observed using p-
fluorocinnamaldehyde 5f as substrate. When the phenyl ring was
changed to the naphtyl or furane ring, the reaction also worked
well and the products 7i and 7j were isolated in 43-48% yield and
90-92% ee. The reaction was also compatible with enals bearing
an alkyl chain, producing 7k with 93% ee, albeit in lower yield
(30 %). Furthermore, a styryl-substituted enal underwent the
cycloannulation to yield 7l in 54% yield and with 90% ee.
Table 2. Optimization of the Reaction Conditions.
Entry
Base
Solvent
Additive
(1 equiv)
Yield
(%)[c]
ee (%)[d]
1
2
3
4
5
6
7
8
9
10
K2CO3
DBU
THF
-
36
58
40
50
48
28
43
24
5
82
36
51
46
80
81
89
95
94
89
THF
-
KHMDS
t-BuOK
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
THF
-
THF
-
Et2O
toluene
DIPE
DIPE
DIPE
DIPE
-
-
-
catechol
pyrogallol
phenol
45
Scheme 3. Enal scope. [a] 5 (0.28 mmol), 6a (0.2 mmol), cat. (0.04 mmol),
K2CO3 (0.08 mmol), catechol (0.04 mmol), DIPE (2 mL). [b] Yield of isolated
product. [c] ee determined by chiral HPLC analysis.
3
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10.1002/cctc.202001513
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To broaden the scope of the trans-cycloannulation, enal 5f
was chosen to react with various unsatured ketones or esters 6a-
s (Scheme 4). First, the scope of chalcone derivatives was
examined. Electron-donating and electron-withdrawing aromatic
substituents at either the -position (R2) or the carbonyl (R3) of the
chalcone are well accommodated, trans-cylopentene were
isolated in 41-69% yield and 86-96% ee with the exception of 7fc
(28% yield and 83% ee). This result might be explained by the
presence of a nitro substituent, which could coordinate to the
catalyst, thereby reducing its efficiency. Furthermore,
heteroaromatic or vinylphenyl on the -position or the carbonyl of
the chalcone was also well tolerated, giving the products 7fo-fq
in moderate yield and high enantioselectivity. Finally, the reaction
was conducted with 4-oxoenoate and 4-oxoenone affording
respectively trans-cylclopentene 7fs and 7fr as the major
diastereoisomer but in low yield and enantioselectivity along with
lower diastereoselectivity. The formation of the major trans
diastereoisomer is notable considering the result previously
reported by Bode.[15]
To evaluate the robustness of our catalytic system, the trans-
cyclopentannulation between p-fluorocinnamaldehyde 5f and
chalcone 6a was carried out at 1 mmol scale. After 4 days, only
single trans diastereoismer 7f was isolated in 58% yield with 93%
ee. These results are comparable to those obtained at 0.2 mmol,
demonstrating our catalytic transformation could be conducted at
a larger scale without drop in yield and stereoselectivity.
The proposed catalytic cycle[21] is depicted in Scheme 5. First
NHC reacts with enal 5 to form the Breslow intermediate I, in
which the E-configuration of the enol should be favored due to the
formation of hydrogen bonding with the thiourea function.[12d]
Then, a nucleophilic addition of the Breslow intermediate by its Si
face to the Si face of the enone 6 (see TS) and a subsequent
proton transfer occurs to afford intermediate II. Intramolecular
aldol reaction generates intermediate III which is converted into
lactone IV along with the release of NHC catalyst. Finally, retro-
[2+2] process provides compound 7 with CO2 elimination.
Scheme 5. Proposed catalytic cycle.
The applicability of our precatalyst 4be to other
transformations was then examined (Scheme 6). Thus,
butyrolactones were obtained by annulation between enals and
aldehyde or trifluoroketone via homoenolate intermediate in
satisfactory yields and moderate enantioselectivity. These results
suggest that our new family of catalyst can also be efficient in
Scheme 4. Enone scope. [a] 5f (0.28 mmol), 6 (0.2 mmol), cat. (0.04 mmol),
K2CO3 (0.08 mmol), catechol (0.04 mmol), DIPE (2 mL). [b] Yield of isolated
product. [c] ee determined by chiral HPLC analysis. [d] >25:1 dr except for 7fr
and 7fs.
4
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10.1002/cctc.202001513
ChemCatChem
FULL PAPER
lactonization transformations. Further optimizations on the chiral
skeleton of these catalysts would be necessary to improve the
enantioselectivity of these reactions.
We are grateful to the ‘Chinese Government’ (China Scholarship
Council) for a doctoral fellowship to Z. Jiang, the CNRS (UMR
8182) and the University Paris-Sud/ University Paris Saclay for
financial supports. We also thank Emilie Kolodziej for technical
assistance with the HPLC analysis. This work has benefited from
the facilities and expertise of the Small Molecule Mass
Spectrometry platform of ICSN (Centre de Recherche de Gif -
www.icsn.cnrs-gif.fr)
Keywords: Asymmetric catalysis • cyclopentannulation • N-
heterocyclic carbenes • homoenolate • organocatalysis
[1]
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Commun. 2012, 48, 5396-5409; b) E. Negishi, J. Synth. Org. Chem., Jpn.
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ChemCatChem 2019, 11, 2943-2977; d) C. Jamieson, A. J. B. Watson,
in Catalysis for Sustainability: Goals, Challenges, and Impacts, Chap. 3
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Guillena, D. Alonso, A. Baeza, R. Chinchilla, J. Flores-Ferrandiz, M.
Gomez-Martinez, P. Trillo, Current Organocatalysis 2015, 2, 102-123; f)
P. T. Anastas, J. B. Zimmerman, Green Chem. 2019, 21, 6545-6566; g)
A. Collado, A. Gómez-Suárez, S. P. Nolan in Sustainable Catalysis : With
Non-endangered Metals, Part 2, Chap. 16 (Ed.: M. North), The Royal
Society of Chemistry, London, 2016, pp. 41-90; h) N. V. Tzouras, I. K.
Stamatopoulos, A. T. Papastavrou, A. A. Liori, G. C. Vougioukalakis,
Coord. Chem. Rev. 2017, 343, 25-138; i) R. A. Sheldon, D. Brady,
ChemSusChem 2019, 12, 2859-2881; j) P. Chauhan, S. S. Chimni.
Beilstein J. Org. Chem. 2012, 8, 2132-2141.
Scheme 6. NHC-catalyzed lactonization reaction.
Conclusion
In conclusion, nine new chiral bifunctional NHC catalysts bearing
imidazolylidene and a (thio)urea function could be easily prepared
through an efficient synthesis from chiral amino alcohols in only
five steps (13-44% overall yields). They were successfully used
in enantioselective cylopentannulation processes affording trans
diastereoisomer in moderate to good yields with excellent
diasteroselectivities and enantioselectivities. In addition, trans-
cyclopentenes were obtained starting from of enals and enones
in the presence of catalytic amount of catalyst, base and catechol
in DIPE and the only side product of this reaction is CO2.Moreover,
the efficiency of this methodology was proved by the large scope
of this transformation and its scalability. Further investigations to
expand the utilization of this new class of bifunctional NHC
catalysts are currently on-going in our laboratory.
[2]
For recent selected reviews, see: a) S. Mondal, S. R. Yetra, S. Mukherjee,
A. T. Biju, Acc. Chem. Res. 2019, 52, 425-436; b) S. Mukherjee, A. T.
Biju, Chem. Asian J. 2018, 13, 2333-2349; c) X.-Y. Chen, S. Li, F. Vetica,
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D. W. Lupton, Synlett 2017, 28, 415-424; g) Q. Ren, M. Li, L. Yuan, J.
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Scheidt, Angew. Chem. 2016, 128, 15134-15145; Angew. Chem. Int. Ed.
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O. Niemeier, A. Henseler, Chem. Rev. 2007, 107, 5606-5655.
Experimental Section
General procedure for the synthesis of 7. To an oven-dried 10 mL
Schlenk tube equipped with a magnetic stirring bar was charged with
enone 6 (0.2 mmol, 1.0 equiv.), enal 5 (0.28 mmol, 1.4 equiv.), K2CO3 (11.1
mg, 0.08 mmol, 0.4 equiv.), catechol (4.5 mg, 0.04 mmol, 0.2 equiv.) and
NHC precatalyst 4be (28.1 mg, 0.04 mmol, 0.2 equiv.). This tube was
closed with a septum, evacuated, and back-filled with argon. To this
mixture, at room temperature, was added freshly distilled diisopropyl ether
(2 mL). The reaction mixture was warmed to 40 ℃ and stirred for 72 h
under argon atmosphere. After removing solvent, the residue was directly
subjected to silica gel column chromatography (petroleum ether/ethyl
acetate as eluent, typically 100/1 to 100/1.5) to give desired single trans-
product 7 (unless otherwise noted). All the corresponding racemic samples
for the standard of chiral HPLC spectra were obtained according to the
known procedure by using achiral NHC precatalyst 1,3-dimesityl
imidazolium chloride.[10i]
[3]
For NHC-catalyzed reactions via the Breslow intermediates, see: a) R. S.
Menon, A. T. Biju, V. Nair, Beilstein J. Org. Chem. 2016, 12, 444-461; b)
S. R. Yetra, A. Patra, A. T. Biju, Synthesis 2015, 47, 1357-1378; c) J.
Read de Alaniz, T. Rovis, Synlett 2009, 1189-1207; d) D. Enders, T.
Balensiefer, Acc. Chem. Res. 2004, 37, 534-541. For NHC-catalyzed
reactions via homoenolate equivalents, see: e) R. S. Menon, A. T. Biju,
V. Nair, Chem. Soc. Rev. 2015, 44, 5040-5052; f) V. Nair, R. S. Menon,
A. T. Biju, C. R. Sinu, R. R. Paul, A. Jose, V. Sreekumar, Chem. Soc.
Rev. 2011, 40, 5336-5346; g) V. Nair, S. Vellalath, B. P. Babu, Chem.
Soc. Rev. 2008, 37, 2691-2698; h) K. J. R. Murauski, A. A. Jaworski, K.
A. Scheidt, Chem. Soc. Rev. 2018, 47, 1773-1782. For NHC-catalyzed
reactions via azolium enolates, see: i) X.-Y. Chen, S. Ye, Synlett 2013,
24, 1614-1622; j) H. U. Vora, P. Wheeler, T. Rovis, Adv. Synth. Catal.
2012, 354, 1617-1639; k) J. Douglas, G. Churchill, A. D. Smith, Synthesis
2012, 44, 2295-2309. For NHC-catalyzed reactions via acyl azoliums,
see: l) J. Mahatthananchai. J. W. Bode, Acc. Chem. Res. 2014, 47, 696-
707; m) C. E. I. Knappke, A. Imami, A. Jacobi von Wangelin,
ChemCatChem 2012, 4, 937-941; n) H. U. Vora, T. Rovis, Aldrichimica
For further experimental details including experimental procedures for
preparation of organocatalyst, copies of NMR spectre and HPLC data, see
Supporting Information.
Acknowledgements
5
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10.1002/cctc.202001513
ChemCatChem
FULL PAPER
Acta 2011, 44, 3-11. For NHC-catalyzed reactions via -unsaturated
[15] a) P.-C. Chiang, J. Kaeobamrung, J. W. Bode, J. Am. Chem. Soc. 2007,
129, 3520-3521; b) P.-C. Chiang, M. Rommel, J. W. Bode, J. Am. Chem.
Soc. 2009, 131, 8714-8718.
acyl azolium intermediates, see: o) C. Zhang, J. F. Hooper, D. W. Lupton,
ACS Catal. 2017, 7, 2583-2596; p) S. De Sarkar, A. Biswas, R. C.
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10.1002/cctc.202001513
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New bifunctional chiral NHC catalysts were prepared and proved their efficiency to promote highly diastereoselective trans-
cyclopentannulation in moderate to good yields and excellent enantioselectivity.
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This article is protected by copyright. All rights reserved.