Organocatalytic enantioselective substitution of MBH carbonates by 2-fluoromalonates

Article abstract of DOI:10.1016/j.tetlet.2012.05.121

The enantioselective fluoromalonate addition to Morita-Baylis-Hillman carbonates is presented. The reaction is simply catalyzed by β-isocupreidine affording the final fluorinated products in good yields and enantioselectivities.

Full text of DOI:10.1016/j.tetlet.2012.05.121

Tetrahedron Letters 53 (2012) 4124–4129
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Organocatalytic enantioselective substitution of MBH carbonates by
2-fluoromalonates
Bing Wang a,b, Xavier Companyó b, Jing Li a, Albert Moyano b, Ramon Rios b,c,
⇑
a State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 30007, PR China
b Department de Química Orgànica, Universitat de Barcelona, Martí i Franqués, 1-11 08028 Barcelona, Spain
c Catalan Institution for Research and Advanced Studies (ICREA), Passeig Lluís Companys 23, 08018 Barcelona, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The enantioselective fluoromalonate addition to Morita–Baylis–Hillman carbonates is presented. The
reaction is simply catalyzed by b-isocupreidine affording the final fluorinated products in good yields
and enantioselectivities.
Received 24 April 2012
Revised 23 May 2012
Accepted 25 May 2012
Available online 31 May 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Organocatalysis
MBH carbonates
Lewis base
Fluorine
Enantioselective
The asymmetric synthesis of fluorine-containing molecules1 is
one of the most important fields in organic chemistry. The unique
properties of fluorinated molecules have attracted a lot of interest
in the field of organic synthesis due to their wide use in both
medicinal chemistry and material science.2 Whereas organofluori-
nated compounds are primarily used in studies of biochemical and
metabolic processes,3 strategic fluorination is commonly employed
in medicinal chemistry to improve the metabolic properties and
bioavailability of drug candidates.4
In the realm of organocatalysis5 several procedures have been
developed for the enantioselective synthesis of fluorinated mole-
cules starting from carbonyl compounds. These include a-fluorina-
X
(DHQD)2AQN
OBoc
PhO2S
Ar
SO2Ph
COOMe
PhO2S
SO2Ph
(20 mol%)
COOMe
(eq. 1)
+
Ar
Toluene, r.t.
X
(X=H, F)
up to 90% yield
up to 99% ee
Ph
Ph
OTMS
N
H
O
O
O
O
F
(20 mol%)
(eq. 2)
+
EtO
OEt
R
O
EtO
OEt
1 equiv. AcOEt
CH2Cl2, r.t.
F
O
R
up to 78% yield
up to 96% ee
Scheme 1. Organocatalytic methodologies developed in our research group.
⇑
Corresponding author. Tel.: +34 934021245; fax: +34 933397878.
E-mail address: rios.ramon@icrea.cat (R. Rios).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.121

B. Wang et al. / Tetrahedron Letters 53 (2012) 4124–4129
4125
Table 1
Catalyst screeninga
O
O
O
F
O
O
20 mol% Catalyst
Solvent, r.t.
O
O
EtO
OEt
EtO
OEt
COOMe
COOMe
F
1a
2
3a
Entry
Catalyst
b-ICPD (I)
Quinine (II)
Cinchonine (III)
(DHQD)2PHAL (IV)
(DHQ)2PHAL (V)
(DHQD)2AQN (VI)
(DHQ)2AQN (VII)
(R,R)-TUC (VIII)
(DHQD)2PYR (IX)
b-ICPD (I)
b-ICPD (I)
b-ICPD (I)
b-ICPD (I)
b-ICPD (I)
b-ICPD (I)
b-ICPD (I)
(DHQD)2PHAL (IV)
Solvent
Conv. (14 h)b
eec
1
2
3
4
5
6
7
8
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CF3-Toluene
Xylene
CH2Cl2
TBME
AcOEt
Toluene
Toluene
Toluene
80%
60%
Traces
16%
Traces
31%
23%
traces
16%
92%
85%
Full
60%
90%
95%
40%
15%
75%
77%
80%
ꢀ81%
50%
23%
ꢀ9%
ND
49%
77%
81%
71%
75%
73%
70%
80%
ꢀ74%
9
10
11
12
13
14
15d
16e
17f
a
Experimental conditions15: In a small flask, 1a (1.2 equiv), 2 (1 equiv), and catalyst (20 mol %) were added in 0.5 mL of solvent: the reaction mixture was stirred for 14 h
and then analyzed by NMR.
b
Determined by 1H NMR of the crude reaction.
Determined by chiral HPLC.
The reaction was carried out at 50 °C.
The reaction was carried out at 0 °C.
c
d
e
f
1 equiv of FeCl2 was used as additive.
Table 2
Substrate screeninga
O
O
F
OPG
O
O
EtO
OEt
β-ICPD
COOR
EtO
OEt
COO R
toluene, r.t.
F
1a-e
2
3a
Entry
R
PG
Solvent
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
Me
Et
Boc
Boc
Boc
Boc
Ac
Toluene
Toluene
Toluene
Toluene
Toluene
Xylene
80
75
90
82
80
61
85
75
60
90
3
50
87
81
tBu
Ph
Me
tBu
Me
Boc
Boc
Xylene
a
b
c
Experimental conditions: In a small flask, 1a (1.2 equiv), 2 (1 equiv), and catalyst (20 mol %) were added in 0.5 mL of solvent.
Isolated yield.
ee determined by chiral HPLC analysis.
tion,6
others.
a
-trifluoromethylation,7 and b-methylfluorination,8 among
tertiary amine-catalyzed reaction of racemic MBH carbonates with
fluoromalonates could provide a facile stereo controlled route to
chiral fluoroderivatives.
Very recently, the use of Morita–Baylis–Hillman (MBH) carbon-
ates as electrophiles for highly enantioselective organocatalytic
reactions has attracted much attention.9 Tan and co-workers,10
Shibata and co-workers,11 and our research group12 have been
developing the addition of methylenesulfones or fluorometh-
yl(bisphenylsulfones) to MBH carbonates with excellent results
(Scheme 1; Eq. 1).
Spurred on by the excellent results obtained in the addition of
fluoromalonates to enals13 (Scheme 1; Eq. 2), and given our previ-
ous experience on organocatalysis,14 we envisioned that the chiral
In our preliminary experiments, we investigated the reaction of
MBH carbonate 1a with 2-fluorodiethylmalonate 2 in the presence
of different chiral organic Lewis bases. As depicted in Table 1,
b-isocupreidine (I) (bꢀICPD, Table 1; entry 1) was found to be
the most active catalyst in toluene solution, giving 80% conversion
to the expected product within 14 h and with good enantioselec-
tivity. Quinine (II) demonstrated similar results in terms of enanti-
oselectivity but with lower conversion (entry 2; Table 1).
Cinchonine (III), (DHQD)2PHAL (IV), (DHQ)2PHAL (V), (DHQD)2AQN

4126
B. Wang et al. / Tetrahedron Letters 53 (2012) 4124–4129
O
O
O
F
O
O
EtO
OEt
O
O
20 mol% β-ICPD
COOR2
COOR2
EtO
OEt
+
R1
R1
F
Toluene or xylene, r.t.,
4 days
1a-k
2
3a-l
OH
O
N
N
β-ICPD
O
O
O
O
O
O
F
F
F
EtO
OEt
COOtBu
EtO
OEt
COOMe
EtO
OEt
COO Me
NC
3a:
3b:
3c:
83% yield, 45% ee
73% yield, 81% ee
80% yield, 90% ee
O
O
O
O
O
O
F
F
F
EtO
OEt
COOtBu
EtO
OEt
EtO
OEt
COOtBu
COOMe
NC
F3C
F3C
3d:
3e:
3f:
88% yield, 77% ee
92% yield, 60% ee
85% yield, 64% ee
O
O
O
O
O
O
F
F
F
EtO
OEt
EtO
OEt
EtO
OEt
COOMe
COOtBu
COOMe
MeO
Cl
Cl
3g:
3h:
3i:
81% yield, 73% ee
77% yield, 60% ee
80% yield, 82% ee
O
O
O
O
O
O
F
F
F
EtO
OEt
EtO
OEt
EtO
OEt
COOtBu
COOtBu
COOMe
F
F
MeO
3j:
3k:
3l:
76% yield, 77% ee
76% yield, 88% ee
72% yield, 63% ee
O
O
O
O
F
F
O
O
F
EtO
OEt
COOtBu
EtO
OEt
EtO
OEt
COOtBu
COOMe
Br
3m: 75% yield, 59% ee
3n: 83% yield, 32% ee
3o: 85% yield, 40% ee
Scheme 2. Reaction scope (Experimental conditions: In a small flask, 1 (1.2 equiv), 2a (1 equiv), and B-ICPD (20 mol %) were added in 0.5 mL of toluene (methyl acrylate
derivatives) or xylene (tert-butyl acrylate derivatives).15 Isolated yields after flash chromatography. ee determined by chiral HPLC analysis).
(VI), (DHQ)2AQN (VII), (DHQD)2PYR (IX), and Takemoto catalysts
(TUC) (VIII) gave both low conversions and enantioselectivities
(entries 3–9; Table 1). Further optimization of the reaction condi-
tions with regard to the solvent showed that xylenes (isomer mix-
ture) afforded the best enantioselectivity while maintaining a good
conversion (entry 11; Table 1). Trifluoromethyl benzene, CH2Cl2,
and AcOEt all gave excellent conversions but with slightly lower
enantioselectivities than xylene (entries 10, 12 and 14; Table 1).
TBME resulted in both low conversion and enantioselectivity
(entry 13; Table 1). Raising the temperature increased conversion

B. Wang et al. / Tetrahedron Letters 53 (2012) 4124–4129
4127
O
O
O
O
F
F
H2, 10 mol% Pd/C (10% w/w)
AcOEt, r.t., 2-3 days
EtO
OEt
EtO
OEt
COOR2
COOR2
R1
R1
Me
4a,b,d,f,o
3a,b,d,f,o
O
O
O
O
O
O
F
F
F
EtO
OEt
COOtBu
EtO
OEt
EtO
OEt
COOtBu
COOMe
Me
Me
Me
F3C
4a: 91% yield, >25:1 d.r.
4b: 82% yield, >25:1 d.r.
4f: 96% yield, 8:1 d.r.
O
O
O
O
F
F
EtO
OEt
EtO
OEt
H2, 10 mol% Pd/C (10% w/w)
AcOEt, r.t., 3 days
CO OMe
COOMe
(eq. 1)
Me
3o
4o:84% yield, >25:1 d.r.
O
O
O
O
F
F
EtO
OEt
COOtBu
EtO
OEt
CO OtBu
H2, 10 mol% Pd/C (10% w/w)
AcOEt, r.t., 3 days
(eq. 2)
Me
Me
NC
3d
4d:74% yield, 10:1 d.r.
Scheme 3. Catalytic hydrogenation of 3.
but diminished its enantioselectivity. On the other hand, at 0 °C,
the reaction renders the final product in low conversion but
reasonable ee (entry 16; Table 1). The addition of a mild Lewis acid
such as FeCl2 did not improve the outcome of the reaction (entry
17; Table 1).
Based on these results, we found that the optimal conditions for
this reaction are to use xylene as the solvent at room temperature
with b-ICPD as the catalyst.
After determining the optimum conditions, we proceeded to
study the scope of the reaction in terms of the ester moiety of
the MBH carbonate. As shown in Table 2, the ee was strongly influ-
enced by the nature of the ester. When we used ethyl acrylate
derivative (1b) the ee decreased to 60%. The best result was
achieved when using tert-butyl acrylate derivative (1c) in toluene,
achieving 90% yield and 90% ee (entry 3; Table 2). However, when
phenyl acrylate derivative 1d was used, the product obtained was
almost racemic (entry 4; Table 2). Finally, we studied the reaction
using an alternative leaving group such as acetyl. Unfortunately,
this reaction afforded 3a in good yield but with low enantioselec-
tivity (entry 5; Table 2).
Next, we studied the scope of the reaction using different sub-
stituents on the aryl ring of the MBH carbonate. As shown in
Scheme 2, the reaction gave good yields for all of the substituents
tested, but the enantioselectivity of the reaction is strongly depen-
dent of the nature of the substituent. When electron withdrawing
groups such as 4-CN or 4-CF3 (3c–f) was used, the ee decreased
substantially. Electron-donating groups such as 4-OMe, 4-Cl, or
4-F gave yields similar to those obtained with the unsubstituted
phenyl 3a, albeit with slightly lower enantioselectivities (3g–l).
Finally, when bulky aryl substituents such as 2-bromophenyl or
1-naphthyl were used, the enantioselectivities of the resulting
compounds (3m–o) dropped dramatically.
We then decided to further extend the applicability of the
reaction by derivatization of compounds 3. The reduction of the
double bond was achieved by treatment of compounds 4 with
Pd over H2, affording the hydrogenated products in excellent
yields and moderate to excellent (>25:1 dr) diastereoselectivities
(Scheme 3). Remarkably, when compounds 3o and 3d were trea-
ted in the reaction conditions the over-reduced products 4o and
4d were obtained in excellent yields and diastereoselectivities
(Scheme 3).
The absolute configuration of adducts was ascertained by chem-
ical correlation (Scheme 4). Following the procedure developed by
Hiemstra,16 we prepared the enantioenriched compound 5a, with
an (R) absolute configuration. After fluorination of the malonate
moiety by sequential treatment with sodium hydride and Select-
fluorÒ we obtained compound 3a, .that exhibited an optical rota-
tion (½a 2D5
ꢀ50.6 (c = 0.8 g/100 mL, CHCl3, 61% ee) of the same
ꢁ
sign than that of compound 3a, obtained by our methodology with
b-ICPD as the catalyst (½a D25
ꢀ65.6 (c = 0.8 g/100 mL, CHCl3 81% ee).
ꢁ
This indicates that the absolute configuration of this compound is
also (R) (Scheme 4).

4128
B. Wang et al. / Tetrahedron Letters 53 (2012) 4124–4129
O
O
OBoc
-ICPD
(20 mol%)
O
O
β
EtO
OEt
COOMe
COOMe
+
EtO
OEt
Toluene, r.t.
[ref XX]
1a
2b
5a (61% ee)
1/ NaH, DMF, 0ºC to r.t, 1h
2/ 1.5 equiv Select-F,
MeCN, 70ºC, 14h
O
O
F
EtO
OEt
COOMe
3a 61% ee
[α]D20= -50.6 ( CHCl3; c=0.8 g/100mL )
Scheme 4. Determination of the absolute configuration of 3a.
Kansy, M.; Kuhn, B.; Müller, K.; Obst-Sander, U.; Stahl, M. ChemBioChem 2004,
5, 637–643.
To summarize, we have described a practical, inexpensive, and
powerful organocatalytic alternative to organometallic allylic sub-
stitution. We have achieved asymmetric fluoromalonate addition
to MBH carbonates with excellent yields and good enantioselectiv-
ities. Moreover, we have demonstrated the broad applicability of
this method. Mechanistic studies and synthetic applications of this
new methodology, as well as the discovery of new reactions based
on this concept are currently ongoing in our laboratories.
5. For a concise review on the organocatalytic synthesis of fluorinated compounds
see: Valero, G.; Companyó, X.; Rios, R. Chem. Eur. J. 2011, 17, 2018–2037.
6. (a) Enders, D.; Huttl, M. R. M. Synlett 2005, 991–993; (b) Steiner, D. D.; Mase,
N., ; Barbas, C. F., III Angew. Chem., Int. Ed. 2005, 44, 3706–3710; (c) Beeson, T.
D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 8826–8828. For a nice
tandem reaction with a-fluorination see:; (d) Appayee, C.; Brenner-Moyer, S. E.
Org. Lett. 2010, 12, 3356–3359.
7. Nagib, D. A.; Scott, M. E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131,
10875–10877.
8. (a) Alba, A.-N.; Companyó, X.; Moyano, A.; Rios, R. Chem. Eur. J. 2009, 15, 7035–
7038; (b) Zhang, S.; Zhang, Y.; Ji, Y.; Wang, W. Chem. Commun. 2009, 4886–
4888; (c) Ullah, F.; Zhao, G.-L.; Deiana, L.; Zhu, M.; Dziedzic, P.; Ibrahem, I.;
Hammar, P.; Sun, J.; Cordova, A. Chem. Eur. J. 2009, 15, 10013–10017; (d)
Furukawa, T.; Shibata, N.; Mizuta, S.; Nakamura, S.; Toru, T.; Shiro, M. Angew.
Chem., Int. Ed. 2008, 47, 8051–8054.
9. For an example of malonate addition to MBH carbonates catalyzed by b-ICN
see: Du, Y.; Han, X.; Lu, X. Tetrahedron Lett. 2004, 45, 4967–4971.
10. Yang, W.; Wei, X.; Pan, Y.; Lee, R.; Zhu, B.; Liu, H.; Yan, L.; Huang, K.-W.; Jiang,
Z.; Tan, C.-H. Chem. Eur. J. 2011, 17, 8066–8070.
Acknowledgments
We thank the Spanish Ministry of Science and Innovation (MIC-
INN) for financial support (Project AYA2009-13920-C02-02). X.C.
thanks MICINN for a predoctoral fellowship. B.W. is grateful to Chi-
na Scholarship Council for a fellowship.
11. (a) Furukawa, T.; Kawazoe, J.; Zhang, W.; Nishimine, T.; Tokunaga, E.;
Matsumoto, T.; Shiro, M.; Shibata, N. Angew. Chem., Int. Ed. 2011, 50, 9684–
Supplementary data
9688; For
a similar reaction leading to the trifluoromethylation of MBH
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.05.
121.
carbonates see: (b) Furukawa, T.; Nishimine, T.; Tokunaga, E.; Hasegawa, K.;
Shiro, M.; Shibata, N. Org. Lett. 2011, 13, 3972–3975.
12. (a) Companyó, X.; Valero, G.; Ceban, V.; Calvet, T.; Font-Bardia, M.; Moyano, A.;
Rios, R. Org. Biomol. Chem. 2011, 9, 7986–7989. For
a review about the
organocatalytic methodologies of MBH carbonates see: (b) Rios, R. Catal. Sci.
Technol. 2012, 2, 267–278.
13. Companyó, X.; Hejnová, M.; Kamlar, M.; Vesely´, J.; Moyano, A.; Rios, R.
Tetrahedron Lett. 2009, 50, 5021–5024.
References and notes
1. For an excellent review of stereogenic formation of fluorinated compounds,
see: Cahard, D.; Xu, X.; Couve-Bonnaire, S.; Pannecoucke, X. Chem. Soc. Rev.
2010, 39, 558–568.
14. (a) Valero, G.; Balaguer, A.-N.; Moyano, A.; Rios, R. Tetrahedron Lett. 2008, 49,
6559–6562; (b) Companyó, X.; Valero, G.; Crovetto, L.; Moyano, A.; Rios, R.
Chem. Eur. J. 2009, 15, 6564–6568; (c) Companyó, X.; Balaguer, A.-N.; Cárdenas,
F.; Moyano, A.; Rios, R. Eur. J. Org. Chem. 2009, 3075–3080; (d) Alba, A.-N. R.;
Companyó, X.; Valero, G.; Moyano, A.; Rios, R. Chem. Eur. J. 2010, 16, 5354–
5361; (e) Alba, A.-N. R.; Valero, G.; Calvet, T.; Font-Bardia, M.; Moyano, A.; Rios,
R. Chem. Eur. J. 2010, 16, 9884–9889; (f) Companyó, X.; Zea, A.; Alba, A.-N. R.;
Mazzanti, A.; Moyano, A.; Rios, R. Chem. Commun. 2010, 46, 6953–6955; (g)
Valero, G.; Schimer, J.; Cisarova, I.; Vesely, J.; Moyano, A.; Rios, R. Tetrahedron
Lett. 2009, 50, 1943–1946; (h) Alba, A. N.; Companyo, X.; Moyano, A.; Rios, R.
Chem. Eur. J. 2009, 15, 11095–11099.
2. (a) Kirsh, P. Modern Fluoroorganic Chemistry; Wiley-VCH: Weinheim, Germany,
2004; (b) Smart, B. E. J. Fluorine Chem. 2001, 109, 3–11; (c) Soloshonok, V. A.
Enantiocontrolled Synthesis of Fluoroorganic Compounds: Stereochemical
Challenges and Biomedical Targets; Wiley-VCH: Chichester, UK, 1999; (d)
Banks, R. E.; Smart, J. C. Organofluorine Chemistry: Principles and Commercial
Applications; Plenum: New York, 1994; (e) Filler, R.; Kobayashi, Y.; Yagupol’skii,
L. M. Organofluorine Compounds in Medicinal Chemistry and Biomedical
Applications; Elsevier: Amsterdam, 1993; (f) Hiyama, T. Organofluorine
Compounds: Chemistry and Applications; Springer: Berlin, 2000.
15. General Procedure: In a small vial, MBH carbonate 1a–e (0.25 mmol, 1 equiv), 2-
3. (a) O’Hagan, D. Chem. Soc. Rev. 2008, 37, 308–319; (b) Prakash, G. K. S.; Hu, J.
Acc. Chem. Res. 2007, 40, 921–930.
fluoromalonate 2, (67 mg, 0.375 mmol, 1.5 equiv), and catalyst
I (8 mg,
0.025 mmol, 10 mol %) in 1 mL of toluene were stirred at room temperature
overnight. The crude mixture was monitored by 1H NMR and after completion
the crude was purified by column chromatography, affording compound 3. 1,1-
diethyl 3-methyl 1-fluoro-2-phenylbut-3-ene-1,1,3-tricarboxylate (3a): 1H NMR
(400 MHz, CDCl3) d 7.31–7.28(m, 2H), 7.24–7.20(m, 2H), 6.37–6.37(m, 1H),
4. (a) Miller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881–1888; (b) Purser,
S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320–330;
(c) Isanbor, C.; O’Hagan, D. J. J. Fluorine Chem. 2006, 127, 303–319; (d) Begué, J.
–P.; Bonnet-Delpon, D. J. Fluorine Chem. 2006, 127, 992–1012; (e) Kirk, J. J.
Fluorine Chem. 2006, 127, 1012–1029; (f) Böhm, H. –J.; Banner, D.; Bendels, S.;

B. Wang et al. / Tetrahedron Letters 53 (2012) 4124–4129
4129
6.17(m, 1H), 5.08 (d, JH–F = 35.2 Hz, 1H), 4.24–4.22 (m, 2H), 4.03–4.02(m, 2H),
3.63(s, 3H), 1.24–1.22(t, J = 7.1 Hz, 3H), 1.03–1.02(t, J = 7.1 Hz, 3H). 13C NMR
(100 MHz, CDCl3) d 166.2, 165.2, 164.9, 164.8, 164.5, 138.1, 138.1, 134.9, 129.8,
129.8, 128.2, 127.8, 127.02, 126.9, 98.0, 95.9, 62.9, 62.7, 52.2, 49.0, 48.8, 13.8,
13.7; 19F NMR (376 MHz, CDCl3) d ꢀ174.1 (d, J = 35.4 Hz). HRMS (ESI) calcd. for
½ ꢁ ꢀ65.6 (CHCl3; c = 0.8 g/100 mL) determined by HPLC (Daicel Chiralpak IA,
a 2D0
i-PrOH/Hexane = 5/95), UV 254 nm, flow rate 0.8 mL/min, major 9.7 min,
minor 10.9 min.
16. Van Steenis, S. D. J. V. C.; Marcelli, T.; Lutz, M.; Spek, A. L.; van, H.; Hiemstra, M.
J. H. Adv. Synth. Catal. 2007, 349, 281–286.
C
18H25FNO6 (M+NH4)+, 370.1666 found 370.1665. Enantiomeric excess: 81%,