Hemisquaramide Tweezers as Organocatalysts: Synthesis of Cyclic Carbonates from Epoxides and CO2

Article abstract of DOI:10.1021/acs.orglett.9b00117

Hemisquaramide tweezers, a new family of H-bond donor organocatalysts, are reported. The catalysts could be synthesized within two steps. Among them, H₈-binaphthyl-linked hemisquaramide 7 markedly accelerated the synthesis of cyclic carbonates from epoxides and CO₂. The reactions proceeded well under mild and solvent-free conditions. Kinetic resolution was also achieved at -20 °C (s = 3.0). The adjustable bite angle and orientation of the two NH groups of the catalysts are important for the high activity.

Full text of DOI:10.1021/acs.orglett.9b00117

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Hemisquaramide Tweezers as Organocatalysts: Synthesis of Cyclic
Carbonates from Epoxides and CO2
Kazuto Takaishi,*,†,‡ Takafumi Okuyama,† Shota Kadosaki,† Masanobu Uchiyama,‡,§
and Tadashi Ema*,†
†Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University, Tsushima, Okayama
700-8530, Japan
‡Cluster for Pioneering Research (CPR), Advanced Elements Chemistry Laboratory, RIKEN, Hirosawa, Wako, Saitama 351-0198,
Japan
§Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
S
* Supporting Information
ABSTRACT: Hemisquaramide tweezers, a new family of H-bond donor
organocatalysts, are reported. The catalysts could be synthesized within two
steps. Among them, H8-binaphthyl-linked hemisquaramide 7 markedly
accelerated the synthesis of cyclic carbonates from epoxides and CO2. The
reactions proceeded well under mild and solvent-free conditions. Kinetic
resolution was also achieved at −20 °C (s = 3.0). The adjustable bite angle
and orientation of the two NH groups of the catalysts are important for the
high activity.
under mild conditions.6d Organocatalysts, however, occasion-
ydrogen-bond organocatalysis is widely used in organic
1
2
3
Hsynthesis. Squaramide and thiourea structures with ally require high CO2 pressure and/or high-temperature
conditions. A new family of organocatalysts capable of acting
under mild conditions is required, and its development
presents significant challenges.
two hydrogen-bond-donating NH groups were recently
adopted as catalysts in various reactions. Some of these
catalysts were used for carbon dioxide (CO2) fixation.2a,3e CO2
is a useful C1-building block and is expected to provide an
alternative to petroleum-based chemicals. The development of
CO2 fixation catalysts presents a major challenge in chemistry.4
The synthesis of cyclic carbonates 2 from CO2 and epoxides 1
has received much attention because of the high atom
economy, and cyclic carbonates are useful as raw materials
for polycarbonates and polyurethanes and as intermediates for
various important materials (Scheme 1).5 Various organo-
catalysts have been developed, including squaramides,2a
thioureas,3e aliphatic alcohols,6 aromatic alcohols,7 and
carboxylic acids.8 We have recently reported macrocyclic
amides9 and calixpyrroles10 as organocatalysts. D’Elia and co-
workers have recently reported that phenol acts as a catalyst
In the present work, we first designed and synthesized
binaphthyl-linked squaramides 3 and 4 with four NH groups,
on the grounds that a greater number of NH groups would
provide better activity (Figure 1). We also prepared
binaphthyl-linked hemisquaramide 6 as a synthetic intermedi-
ate of 3 and biphenyl analogue 5 and H8-binaphthyl analogue 7
as control catalysts. To our surprise, hemisquaramides 5−7,
especially 7, exhibited much higher catalytic activities than
those of the related catalysts 3−4 (Figure 1) and thiourea or
selenourea organocatalysts 12−16 (Scheme S1), although each
of the hemisquaramide tweezer catalysts has only two NH
groups. Herein, we report the synthesis, catalytic activity
toward CO2 fixation, and a plausible catalytic mechanism. This
is the first example of hemisquaramide tweezers acting as an
organocatalyst.11
Scheme 1. Synthesis of Cyclic Carbonates from Epoxides
and CO2
Hemisquaramides 5−7 were synthesized in only one or two
steps (Scheme 2). They were prepared by the Zn(OTf)2-
catalyzed reaction12 of diaminobiaryls (2,2′-diaminobiphenyl
(8), BINAM (9), or H8-BINAM (10)) with an excess amount
of diethyl squarate (11). Compounds 8, 9, and 11 are
Received: January 10, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00117
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Optimization of the Catalysts and Cocatalysts
a
entry
cat.
cocat.
yield (%)
1
2
3
4
5
6
7
8
9
(R)-3
(R,R)-4
5
(R)-6
(R)-7
(R)-7
(R)-7
(R)-7
−
TBAI
TBAI
TBAI
TBAI
TBAI
TBAB
TBAC
−
68
22
60
94
>99
84
30
0
TBAI
TBAI
TBAI
7
>99
92
Figure 1. Structures of squaramides 3 and 4 and hemisquaramides 5−
7.
b
10
11
(R)-7
(R)-7
c
a
1
Scheme 2. Synthesis of Hemisquaramides 5−7
Determined by H NMR using mesitylene as an internal standard.
b
c
Room temperature (ca. 20 °C). (R)-7 (2.0 mol %) was used.
Next, the reactions of several epoxides 1b−i were conducted
with the best catalyst 7 and TBAI at 30 °C or a little higher
temperature than the melting point of substrates and/or
products (Scheme 3). Styrene oxides, alkene oxides, glycidyl
a
Scheme 3. Substrate Scope
commercially available, and 10 could be easily obtained by
reducing 9.13 Squaramide 3 was synthesized from 6 and 3,5-
bis(trifluoromethyl)aniline, and 4 was prepared from 2,2′-
bis(aminomethyl)-1,1′-binaphthyl14 and 11 (Scheme S2).
The catalytic activities of 3−7 were examined for styrene
oxide (1a) in the presence of 5.0 mol % catalyst and
nucleophilic cocatalyst, tetrabutylammonium iodide (TBAI), a
CO2 atmosphere (1 atm, balloon), and no solvent at 30 °C for
24 h (Table 1, entries 1−5). Hemisquaramides 5−7, especially
7, gave 2a in high yields (60−99%, entries 3−5). The high
activity of 5−7, which were originally regarded as simple
synthetic intermediates or control catalysts for squaramides,
was totally unexpected. The activities of several related
thioureas15 and selenoureas16 were also explored, but the
yields were much lower than that of 7 (Scheme S1). The
reaction using 7 alone or TBAI alone did not progress
significantly (entries 8 and 9), suggesting that 7 and TBAI
acted cooperatively. The reactions conducted with tetrabuty-
lammonium bromide (TBAB) or tetrabutylammonium chlor-
ide (TBAC) instead of TBAI exhibited lower yields (30−84%,
entries 6 and 7). The smaller halides may be entrapped by
forming hydrogen bonds with the two NH groups of the
catalyst, which reduces the nucleophilicity of the halide
anion.17 In fact, DFT calculations of the complexation energies
for 7, after applying the BSSE correction, were −23.9 kcal/mol
for TBAC, −19.5 kcal/mol for TBAB, and −15.0 kcal/mol for
TBAI (Figure S1).18 Even at room temperature (ca. 20 °C), 7
maintained a high activity (>99%, entry 10). The catalyst
loading could be decreased to 2.0 mol %, which gave over a
90% yield of 2a (entry 11). The catalyst 7 is an unprecedented
hemisquaramide tweezer catalyst showing a high organo-
catalytic activity.
a
b
Isolated yield. 80 °C.
ethers, and other epoxides were converted to the correspond-
ing cyclic carbonates (75−99%), indicating that the catalyst
possessed a broad substrate scope.
The natural population analysis (NPA) reveals that the
charges of NH protons of 5−7 (0.359−0.361) are less positive
than those of 3−4 (0.402−0.431) and thioureas (Table S1).
Therefore, the high activities of the hemisquaramides could
not be explained by the acidity (and number) of the NH
groups. The activity arose from the distance and angle between
the two NH groups, which adapted to the substrate by rotation
of the biaryl axis like tweezers. Moreover, the substrate could
approach the NH groups without restriction due to the acyclic
structures of 5−7 without bulky substituents around the
catalytic sites. The activity of 5−7 may be modulated by the
dihedral angle of the biaryl axis. The biphenyl of 5 can freely
rotate, whereas the binaphthyl of 6 is somewhat restricted, and
the H8-binaphthyl of 7 is highly restricted due to the bulky
cyclohexene rings.19 DFT calculations suggested that the
angular range (within 2.7 kcal/mol from the most stable
conformation) were 45−135° for 5, 60−120° for 6, and 70−
B
DOI: 10.1021/acs.orglett.9b00117
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
115° for 7 (Figure S2).20 The appropriately preorganized
catalyst 7 can bind to the substrate with the least entropy loss.
A plausible catalytic cycle for a model reaction, the 7/TBAI-
catalyzed reaction of ethylene oxide (EO) with CO2, is shown
in Scheme 4, which was supported by DFT calculations.9,10,21
Scheme 4. Proposed Catalytic Cycle of the 7/TBAI-
a
Catalyzed Reaction of an Epoxide with CO2
a
TBA cation omitted for clarity.
The H8-binaphthyl has a tweezers shape. Initially, 7 and EO
form the reactant complex R via two hydrogen bonds between
NH groups of 7 and the oxygen atom of EO, and the epoxide is
activated simultaneously. Next, the epoxide is attacked and
ring-opened by a nucleophile, the I− anion, to form a linear
alkoxide, intermediate I1. Insertion of a CO2 molecule gives a
carbonate anion as intermediate I2. Finally, the intramolecular
SN2 reaction affords the ring-closed product P. 1H NMR
titrations indicated that the NH group of 7 was downfield
shifted upon addition of 1a in CDCl3 at 20 °C, which suggests
activation of the epoxide by hydrogen bonding (Figure S5).
The energy profile for the reaction and the optimized
transition-state structures are shown in Figure 2. The rate-
determining step is the ring-opening step via I1_TS with a
ΔG‡ of 24.0 kcal/mol. Both I1_TS and I2_TS are stabilized by
two NH−O hydrogen bonds (1.69−1.82 Å). Interestingly,
P_TS included only one hydrogen bond between the NH
hydrogen and the carbonate oxygen with an NH−O distance
of 1.83 Å. One of the two hydrogen bonds is cleaved by the
rotation of the N−aryl bond, which enhances the nucleophil-
icity of the carbonate anion. Throughout the reaction, the
dihedral angle of the H8-binaphthyl is changed in a range of
84.1−93.2° (Figure S4). The catalyst can provide the optimum
NH scaffold for stabilizing the substrate, the reaction
intermediates, and the transition states by the rotation of the
N−aryl bond and the biaryl axis, which is an ability specific to
the hemisquaramide tweezers.
Figure 2. (a) Theoretical Gibbs free energy profile for the 7/TBAI-
catalyzed reaction of ethylene oxide with CO2. (b) Transition-state
structures. DFT calculations were performed at the B3LYP/6-31G(d)
level for the H, C, N, and O atoms and at the B3LYP/LanL2DZ level
for the I atom. Distances are shown in Å.
Table 2. Kinetic Resolution of Styrene Oxide (1a)
b
c
% yield (% ee)
a
d
cat.
temp. (°C) time (h)
c
(%)
38
6
56
10
(S)-2a
(R)-1a
s value
(R)-6
(R)-6
(R)-7
(R)-7
30
−20
30
3
72
3
29 (21)
12 (46)
57 (19)
17 (47)
58 (13)
52 (3)
31 (24)
56 (5)
1.7
2.8
1.8
3.0
−20
72
a
b
Conversion calculated from c = ee(2a)/(ee(2a) + ee(1a)). Isolated
yield. Determined by HPLC and GC analyses. Calculated from s =
ln[1 − c(1 + ee(2a))]/ln[1 − c(1−ee(2a))].
c
d
Finally, 1a was kinetically resolved by either (R)-6 or (R)-7
(Table 2). Interestingly, at 30 °C, (R)-6 and (R)-7 gave (S)-2a
preferentially with s values (kS/kR) of 1.7 and 1.8, respectively.
At −20 °C, the s values increased to 2.8 for (R)-6 and 3.0 for
C
DOI: 10.1021/acs.orglett.9b00117
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
̈
2018, 20, 892−895. (e) Fan, Y.; Tiffner, M.; Schorgenhumer, J.;
Robiette, R.; Waser, M.; Kass, S. R. J. Org. Chem. 2018, 83, 9991−
10000.
(R)-7. The kinetic resolution of epoxides using organocatalysts
is very rare,9,22 and the s values of the hemisquaramides are
high for organocatalysts. In contrast, (R)-3 and (R,R)-4
exhibited little or no enantioselectivity (not shown).
(4) For recent reviews, see: (a) Maeda, C.; Miyazaki, Y.; Ema, T.
Catal. Sci. Technol. 2014, 4, 1482−1497. (b) Zhu, Y.; Romain, C.;
Williams, C. K. Nature 2016, 540, 354−362. (c) Borjesson, M.;
In summary, we developed a new family of hemisquaramide
tweezers 5−7 as organocatalysts, which were synthesized
within two steps. Among them, 7 with the H8-binaphthyl
moiety exhibited the highest catalytic activity toward CO2
fixation. Under mild and solvent-free conditions, the reaction
proceeded well. DFT calculations indicated that the two
adjustable NH groups of the catalyst were important for this
activity. The kinetic resolution also proceeded with an s value
of up to 3.0. We are currently investigating the other utility of
this type of organocatalyst, expecting that hemisquaramide
tweezers have a great potential in various organocatalytic
reactions.
̈
Moragas, T.; Gallego, D.; Martin, R. ACS Catal. 2016, 6, 6739−6749.
(d) Sekine, K.; Yamada, T. Chem. Soc. Rev. 2016, 45, 4524−4532.
(e) Wang, S.; Du, G.; Xi, C. Org. Biomol. Chem. 2016, 14, 3666−3676.
(f) Song, Q.-W.; Zhou, Z.-H.; He, L.-N. Green Chem. 2017, 19,
3707−3728. (g) Poland, S. J.; Darensbourg, D. Green Chem. 2017, 19,
4990−5011. (h) Vaitla, J.; Guttormsen, Y.; Mannisto, J. K.; Nova, A.;
Repo, T.; Bayer, A.; Hopmann, K. H. ACS Catal. 2017, 7, 7231−
7244. (i) Li, M. M.-J.; Tsang, S. C. E. Catal. Sci. Technol. 2018, 8,
3450−3464.
(5) For recent reviews, see: (a) Alves, M.; Grignard, B.; Mereau, R.;
Jerome, C.; Tassaing, T.; Detrembleur, C. Catal. Sci. Technol. 2017, 7,
2651−2684. (b) Shaikh, R. R.; Pornpraprom, S.; D’Elia, V. ACS Catal.
2018, 8, 419−450. (c) Huang, K.; Zhang, J.-Y.; Liu, F.; Dai, S. ACS
Catal. 2018, 8, 9079−9102.
ASSOCIATED CONTENT
* Supporting Information
■
S
(6) (a) Song, J.; Zhang, Z.; Han, B.; Hu, S.; Li, W.; Xie, Y. Green
Chem. 2008, 10, 1337−1341. (b) Li, K.; Wu, X.; Gu, Q.; Zhao, X.;
Yuan, M.; Ma, W.; Ni, W.; Hou, Z. RSC Adv. 2017, 7, 14721−14732.
(c) Arayachukiat, S.; Kongtes, C.; Barthel, A.; Vummaleti, S. V. C.;
Poater, A.; Wannakao, S.; Cavallo, L.; D’Elia, V. ACS Sustainable
Chem. Eng. 2017, 5, 6392−6397. (d) Yingcharoen, P.; Kongtes, C.;
Arayachukiat, S.; Suvarnapunya, K.; Vummaleti, S. V. C.; Wannakao,
S.; Cavallo, L.; Poater, A.; D’Elia, V. Adv. Synth. Catal. 2019, 361,
366−373.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00117.
Synthesis, spectra, catalytic activities, and computational
details (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
̀
(7) Jose, T.; Canellas, S.; Pericas, M. A.; Kleij, A. W. Green Chem.
̃
2017, 19, 5488−5493.
(8) (a) Tharun, J.; Mathai, G.; Kathalikkattil, A. C.; Roshan, R.;
Kwak, J.-Y.; Park, D.-W. Green Chem. 2013, 15, 1673−1677. (b) Liu,
N.; Xie, Y.-F.; Wang, C.; Li, S.-J.; Wei, D.; Li, M.; Dai, B. ACS Catal.
2018, 8, 9945−9957.
(9) Ema, T.; Yokoyama, M.; Watanabe, S.; Sasaki, S.; Ota, H.;
Takaishi, K. Org. Lett. 2017, 19, 4070−4073.
(10) Maeda, C.; Sasaki, S.; Takaishi, K.; Ema, T. Catal. Sci. Technol.
2018, 8, 4193−4198.
(11) Diphenylphosphine-tethered monohemisquaramides were
reported as a catalyst for the Morita-Baylis-Hillman reaction, see:
(a) Song, H.-L.; Yuan, K.; Wu, X.-Y. Chem. Commun. 2011, 47,
1012−1014. (b) Zhang, X.; Ma, P.; Zhang, D.; Lei, Y.; Zhang, S.;
Jiang, R.; Chen, W. Org. Biomol. Chem. 2014, 12, 2423−2426.
(12) Rostami, A.; Colin, A.; Li, X. Y.; Chudzinski, M. G.; Lough, A.
L.; Taylor, M. S. J. Org. Chem. 2010, 75, 3983−3992.
(13) (a) Guo, H.; Ding, K. Tetrahedron Lett. 2000, 41, 10061−
10064. (b) Kano, T.; Tanaka, Y.; Osawa, K.; Yurino, T.; Maruoka, K.
J. Org. Chem. 2008, 73, 7387−7389.
(14) Matsumoto, K.; Tomioka, K. Chem. Pharm. Bull. 2001, 49,
1653−1657.
(15) (a) Fleming, E. M.; McCabe, T.; Connon, S. J. Tetrahedron
Lett. 2006, 47, 7037−7042. (b) Zhang, Y.; Liu, Y.-K.; Kang, T.-R.;
Hu, Z.-K.; Chen, Y.-C. J. Am. Chem. Soc. 2008, 130, 2456−2457.
(c) Rampalakos, C.; Wulff, W. D. Adv. Synth. Catal. 2008, 350, 1785−
1790.
*E-mail: takaishi@okayama-u.ac.jp (K.T.)
*E-mail: ema@cc.okayama-u.ac.jp (T.E.)
ORCID
Kazuto Takaishi: 0000-0003-4979-7375
Masanobu Uchiyama: 0000-0001-6385-5944
Tadashi Ema: 0000-0002-2160-6840
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was partly supported by JSPS KAKENHI Grant No.
JP16H01030 in Precisely Designed Catalysts with Customized
Scaffolding. Allotment of computational resources from
HOKUSAI GreatWave (RIKEN) is gratefully acknowledged.
REFERENCES
■
(1) (a) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713−
5743. (b) Pihko, P. M., Ed. Hydrogen Bonding in Organic Synthesis;
Wiley-VCH: Weinheim, Germany, 2009. (c) List, B., Maruoka, K.,
Eds. Asymmetric Organocatalysis, Workbench Edition; Thieme:
Stuttgart, Germany, 2012.
(2) For recent examples, see: (a) Sopena, S.; Martin, E.; Escudero-
̃
(16) Bian, G.; Yang, S.; Huang, H.; Zong, H.; Song, L.; Fan, H.; Sun,
X. Chem. Sci. 2016, 7, 932−938.
́
Adan, E. C.; Kleij, A. W. ACS Catal. 2017, 7, 3532−3539.
(b) Wendlandt, A. E.; Vangal, P.; Jacobsen, E. N. Nature 2018,
556, 447−451. (c) Zhou, J.; Huang, W.-J.; Jiang, G.-F. Org. Lett. 2018,
20, 1158−1161. (d) Roy, T. K.; Parhi, B.; Ghorai, P. Angew. Chem.,
Int. Ed. 2018, 57, 9397−9401. (e) Didaskalou, C.; Kupai, J.; Cseri, L.;
Barabas, J.; Vass, E.; Holtzl, T.; Szekely, G. ACS Catal. 2018, 8,
7430−7438.
(17) (a) Amendola, V.; Bergamaschi, G.; Boiocchi, M.; Fabbrizzi, L.;
Milani, M. Chem. - Eur. J. 2010, 16, 4368−4380. (b) Edwards, S. J.;
Valkenier, H.; Busschaert, N.; Gale, P. A.; Davis, A. P. Angew. Chem.,
Int. Ed. 2015, 54, 4592−4596. (c) Qin, L.; Hartley, A.; Turner, P.;
Elmes, R. B. P.; Jolliffe, K. A. Chem. Sci. 2016, 7, 4563−4572. (d) Li,
Y.; Yang, G.-H.; Shen, Y.-Y.; Xue, X.-S.; Li, X.; Cheng, J.-P. J. Org.
Chem. 2017, 82, 8662−8667.
̈
(3) For recent examples, see: (a) Hayama, N.; Kuramoto, R.; Foldes,
́
T.; Nishibayashi, K.; Kobayashi, Y.; Papai, I.; Takemoto, Y. J. Am.
(18) DFT calculations were performed using Gaussian16, revision
A.03. See Supporting Information for full reference.
(19) (a) Uemura, T.; Zhang, X.; Matsumura, K.; Sayo, N.;
Kumobayashi, H.; Ohta, T.; Nozaki, K.; Takaya, H. J. J. Org. Chem.
Chem. Soc. 2018, 140, 12216−12225. (b) Ni, Y.; Wei, Y.; Ma, D.
Angew. Chem., Int. Ed. 2018, 57, 10207−10211. (c) Laina-Martín, V.;
́
́
Humbrías-Martín, J.; Fernandez-Salas, J. A.; Aleman, J. Chem.
Commun. 2018, 54, 2781−2784. (d) Ding, R.; Wolf, C. Org. Lett.
D
DOI: 10.1021/acs.orglett.9b00117
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
1996, 61, 5510−5516. (b) Wang, B.; Feng, X.; Huang, Y.; Liu, H.;
Cui, X.; Jiang, Y. J. Org. Chem. 2002, 67, 2175−2182.
(20) The dihedral angles of the most stable structures were 102.1°
for 5, 90.9° for 6, and 90.7° for 7 (Figure S3). The differences may
also have affected the catalytic activities.
(21) (a) Ema, T.; Miyazaki, Y.; Shimonishi, J.; Maeda, C.; Hasegawa,
J. J. Am. Chem. Soc. 2014, 136, 15270−15279. (b) Maeda, C.;
Shimonishi, J.; Miyazaki, R.; Hasegawa, J.; Ema, T. Chem. - Eur. J.
2016, 22, 6556−6563.
(22) Liu, S.; Suematsu, N.; Maruoka, K.; Shirakawa, S. Green Chem.
2016, 18, 4611−4615.
E
DOI: 10.1021/acs.orglett.9b00117
Org. Lett. XXXX, XXX, XXX−XXX