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The organocatalytic desymmetrization of meso-ferrocene anhydride
Accepted Manuscript The organocatalytic desymmetrization of meso-ferrocene anhydride Carolina Valderas, Luis Casarrubios, María C. de la Torre, Miguel A. Sierra PII: DOI: Reference:
S0040-4039(16)31651-3 http://dx.doi.org/10.1016/j.tetlet.2016.12.025 TETL 48437
To appear in:
Tetrahedron Letters
Received Date: Revised Date: Accepted Date:
10 November 2016 5 December 2016 7 December 2016
Please cite this article as: Valderas, C., Casarrubios, L., de la Torre, M.C., Sierra, M.A., The organocatalytic desymmetrization of meso-ferrocene anhydride, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet. 2016.12.025
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Graphical Abstract To create your abstract, type over the instructions in the template box below. Fonts or abstract dimensions should not be changed or altered.
The Organocatalytic Desymmetrization of meso-Ferrocene Anhydride
Leave this area blank for abstract info.
Carolina Valderas,†,‡,§ Luis Casarrubios,†,§ María C. de la Torre*,‡,§ and Miguel A. Sierra*,†,§ EtOH O
Fe
H
N H N
O EtOH
CO 2H CO 2Et
N
OMe
O
H
N
N
H
OMe
Fe
N O
O
98% ee (60% isolated)
1
Tetrahedron Letters
The organocatalytic desymmetrization of meso-ferrocene anhydride Carolina Valderas,a,b,c Luis Casarrubios,a,c María C. de la Torre,*,b,c Miguel A. Sierra*,a,c a
Departamento de Química Orgánica I, Facultad de Química, Universidad Complutense, 28040-Madrid. Spain. [email protected] Instituto de Química Orgánica General, Consejo Superior de Investigaciones Científicas (CSIC), Juan de la Cierva 3, 28006-Madrid, Spain. [email protected] c Centro de Innovación en Química Avanzada (ORFEO-CINQA) b
ARTICLE INFO
ABSTRACT
Article history: Received Received in revised form Accepted Available online
A new and unique organocatalytic process for the desymmetrization of meso ferrocene anhydride has been developed. After optimization with a series of quinine, quinidine and squaramide ligands, the method was effective with a 60% isolated yield and 98% ee. 2009 Elsevier Ltd. All rights reserved.
Keywords: Desymmetrization meso-ferrocenes Organocatalysis Squaramides Chiral Ligands
Introduction Chiral ferrocene derivatives are among the best ligands for asymmetric catalysis due to their thermal stability and high tolerance to a wide range of functional groups, together with the possibility of performing chemistry under atmospheric conditions (oxygen friendly ligands).1 As a consequence, methods to prepare such formidable ligands in enantiopure form have been extensively searched. Preparation of chiral ferrocene derivatives, including chiral-planar ferrocenes, has been also widely studied. Regarding enantiopure chiral-planar ferrocenes, the lithiation of a cyclopentadiene ring of the ferrocene bearing ortho chiral directing groups has been profusely used 2 affording chiral planar ferrocenes maintaining the additional element of asymmetry. Alternatively, enantioselective lithiation of ferrocene using chiral bases efficiently produces planar chiral ferrocenes (Scheme 1). 3 Other approaches, such as kinetic resolution of chiral-planar racemic ferrocenes4 or asymmetric C–H activation,5,2a have also
Scheme 1
The chemical and enzymatic desymmetrization of ferrocene meso-forms has been pursued.6 However, reports concerning the organocatalytic desymmetrization of ferrocene derived mesoforms are, to the best of our knowledge, unknown. Desymmetrization of cyclic anhydrides have been lately a good source of chiral compounds by different methods, including nucleophilic anhydride opening catalyzed by chiral Lewis bases derived from alkaloids (quinine and quinidine). 7 More recently bifunctional catalysts8 with both, a nucleophilic activating group and a hydrogen bond donor position in their structure such as ureas,9 thioureas,10 sulfonamide11 or squaramides,12 have been used for this purpose. Therefore, we devised the possibility of using organocatalysis to effect the desymmetrization of ferrocene anhydrides. Our parent substrate for the development of the desymmetrization process was anhydride 3. The synthesis of this anhydride started with the double esterification of ferrocenecarboxylic acid to ditertbutyl derivative 1.13 An ethereal solution of 1 was bubbled with gaseous HCl to hydrolize both esters. Under these conditions, diacid 2 precipitated in the reaction media and it was isolated in a 97% yield. Diacid 2 was refluxed in acetic anhydride for 2h to produce anhydride 3 in a 67% yield (Scheme 2).
been described.
2
Tetrahedron
Scheme 2 Initial tests for the desymmetrization process of 3 implied the use of 20 mol% of the cinchonidine catalyst. Although several alcohols (methanol, benzyl alcohol, cinnamyl alcohol and allyl alcohol) are used in most studies of asymmetric anhydride openings, our reactions were always performed using absolute ethanol (10 folds excess) as the nucleophile (Scheme 3). A screening of different solvents at room temperature was then performed (Table 1).
while quinine II leads to full conversion the pseudo enantiomer quinidine V leads to decomposition. A reasonable explanation for this result has evaded us. Moreover, to the best of our knowledge entry 8 in Table 1 represents the first example of the asymmetric alcoholysis of a meso-anhydride using a Fu-type catalyst. Figure 1. Optimization of the organocatalyts
Scheme 3 Table 1. Initial Solvent screening. a
Ratio 3:4b
ee(%)c
Et2O
Dec.
–
–
2
THF
Dec.
–
–
3
CH2Cl2
100:0
–
–
4
CHCl3
100:0
–
–
5
Toluene
50:50
14
1S
6
Toluene (0.2M)
0:100
2
-
Entry
Solvent
1
Mayor Isomer
a
Reaction conditions: 1eq. of 3, 10eq. of EtOH, room temperature, 0.02 M, 48 h. b3:4 ratio was determined by 1H NMR of the reaction crudes. c Determined by HPLC (Daicel Chiralpak IA).
As shown in Table 1, ethereal solvents (Et2O or THF) yielded only complex mixtures (entries 1 and 2). With chlorinated solvents such as CH2Cl2 or CHCl3 (entries 3 and 4) unaltered ferrocene anhydride 3 was recovered. Toluene (entry 5) was the best choice as we detected a 50:50 mixture of 3 and 4. Ester 4 was purified by SiO2 chromatography (hexane/AcOEt 1:1) and a sample was analyzed by chiral HPLC (Daicel Chiralpak IA). The resulting 14% ee, despite low, clearly demonstrates that organocatalysis is a usable method for the desymmetrization of organometallic anhydrides by transferring the central chirality to planar chirality. One last test increasing concentration to 0.2M produced total conversion to monoester 4 although with a poorer ee (2%).
Table 2. Organocatalyst screening. Entry
Catalyst (20 mol %)
Ratio 3:4b
ee(%)c
1
quinine (II)
0:100
8
Mayor Isomer 1S
2
quinine-OCOPh (III)
0:100
2
1S
3
quinine-OAc (IV)
0:100
2
1S
4
quinidine (V)
Dec.
–
–
5
cinchonine (VI)
Dec.
–
–
6
(S)-PPY* (VII)
0:100
82
1S
7
(S)-C5Ph5-DMAP (VIII)
Dec.
–
–
8
(R,R-TUC) (IX)
23:77
12
1R
9
squaramide (X)
0:100
79
1R
10
(DHQD)2PHAL (XI)
9:90
7
1S
11
(DHQD)2Pyr (XII)
50:50
8
1S
12
(DHQD)2AQN (XIII)
0:100
58
1R
a
A second screening of organocatalysts was then pursued including alkaloid (II-VI) and ferrocene derivatives (VII-VIII), dimeric catalysts (XI-XIII), bifunctional catalysts such as the thiourea IX and the Rawal’s squaramide X (Figure 1). Toluene was used in all cases as the solvent. Table 2 summarizes the obtained results in these reactions. Quinine derivatives (II-IV) showed total conversion to monoester 4 but the desired ferrocene was obtained in low ee’s (entries 1, 2, 3. Table 2). Catalyst VII raised ee up to 82% while maintains a complete conversion to 4 (entry 6. Table 2). Analogous catalyst VIII only produced decomposition of the starting anhydride (entry 5. Table 2) and the same results were observed in the case of the quinidine (V) and cinchonine (VI) derivatives (entries 4, 5. Table 2). Thiourea IX (entry 8. Table 2) showed both low conversion and ee. Squaramide X underwent total conversion and 79% ee, similar to the results obtained with Fu’s catalyst VII (entry 6. Table 2). It is worthy to note that
a
Reaction conditions: 1eq. of 3, 10eq. of EtOH, room temperature, 0.02 M in toluene, 48 h. b3:4 relationship was determined by 1H NMR of the reaction crudes. cDetermined by HPLC (Daicel Chiralpak IA).
3 Finally, reactions using dimeric catalysts XI-XIII produced conversions ranging from moderate to complete. Nevertheless, the highest obtained ee in these cases was only 58% (entries 10, 11, 12. Table 2). With all the results in hand, our next step was to study the influence of structural modifications in catalyst X in the desymmetrization process. A new set of easily accessible squaramide-based catalysts XIV–XIX14b-d was then synthesized and tested (Figure 2).
Acknowledgments Support for this work under grants (CTQ2013-46459-C2-01-P to MAS, CTQ2013-46459-C2-02-P to MCT, and CTQ201451912-REDC (Programa Redes Consolider) from the MINECO (Spain) is gratefully acknowledged. We thank Prof. Carmen Carreño (UAM)-Madrid for the use of HPLC facilities. References and notes
H O
H F 3C
nN H
N
HN
H
N
N
CF3
n = 0; R = H n = 0; R = OMe n = 1; R = H n = 1; R = OMe
H
R
N O
N XIV XV XVI XVII
N H N
H
R
1.
N
R
O
XVIII XIX
2.
O
3. 4.
R=H R = OMe
5.
Figure 2. Squaramide-based catalysts Table 3 summarizes the obtained results for the desymmetrization of anhydride 3. All the new catalysts produced total conversion of 3 to monoester 4 with ee’s ranging from 79% to 98%. Best results were obtained with squaramide catalyst XIX (entry 6, Table 3). Only this crude, with the higher ee, was submitted to chromatographic purification. Monoester 4 was thus isolated in a 60% yield and 98% ee. Mono ester 4 was dextrorotatory which points to a (1S)-configuration according to the reported chemical correlation of analogous methyl ester with (1S)-(+)--methylferrocenecarboxylic acid.6f Efforts to establish the absolute configuration of compound 4 have been until now fruitless. Table 3. Modified organocatalysts.
6.
7.
8.
Mayor Isomer
Entrya
Squaramide
Ratio 3:4b
ee(%)c
1
XIV
0:100
79
1S
2
XV
0:100
82
1S
10.
3
XVI
0:100
81
1S
11.
4
XVII
0:100
81
1S
5
XVIII
0:100
87
1S
6
XIX
0:100
98
1S
9.
12.
a
Reaction conditions: 1eq. of 3, 10eq. of EtOH, 20 mol % of catalyst, room temperature, 0.02 M in toluene, 48 h. b3:4 ratio was determined by 1H NMR of the reaction crudes. cDetermined by HPLC (Daicel Chiralpak IA).
In summary, the viability of using an organocatalytic procedure in the desymmetrization of meso-form of ferrocene anhydride with a 60% isolated yield and ee of 98% has been demonstrated. Squaramide catalyst XIX was the catalyst of choice yielding the nearly enantiopure monoester 4. Efforts to generalize this organocatalytic desymmetrization to other mesometal-complex anhydrides as well as to understand the mechanism of these reactions are in progress in our laboratories.
13. 14.
(a) Ferrocenes: Ligands, Materials and Biomolecules, Stepnicka, P. (Ed.), Wiley 2008. (b) Ferrocenes: Homogeneous Catalysis, Organic Synthesis, Materials Science Togni, A.; Hayashi, T. (Eds.), Wiley 2008. (a) Schaarschmidt, D.; Lang, H. Organometallics 2013, 32, 5668– 5704 (review in the special issue: Ferrocene - Beauty and Function). (b) Atkinson, R. C. J.; Gibson, V. C.; Long, N. J. Chem. Soc. Rev. 2004, 313–328. Clayden, J. Top. Organomet. Chem. 2003, 5, 251–286. Illustrative recent review: Skrobo, B.; Rolfes, J. D.; Deska, J. Tetrahedron 2016, 72, 1257–1275. Recent examples: (a) Gao, D.-W.; Shi, Y.-C.; Gu, Q.; Zhao, Z.-L.; You, S.-L. J. Am. Chem. Soc. 2013, 135, 86–89. (b) Gao, D.-W.; Yin, Q.; Gu, Q.; You, S.-L. J. Am. Chem. Soc. 2014, 136, 4841– 4844. (a) Yamazaki, Y.; Hosono, K. Tetrahedron Lett. 1988, 29, 5769– 5770. (b) Yamazaki, Y.; Hosono, K. Biotechnol. Lett. 1989, 11, 679–684. (c) Nicolosi, G.; Morrone, R.; Patti, A.; Piattelli, M. Tetrahedron: Asymmetry 1992, 3, 753–758. (d) Duan, W.-L.; Imazaki, Y.; Shintani, R.; Hayashi, T. Tetrahedron 2007, 63, 8529–8536. (e) Buchgraber, P.; Mercier, A.; Yeo, W. C.; Besnard, C.; Kündig, E. P. Organometallics 2011, 30, 6303–6315. (f) Yamazaki, Y.; Hosono, K. Ann. N.Y. Acad. Sci. 1990, 613, 738–746. (a) Atodiresei, I.; Schiffers, I.; Bolm, C. Chem. Rev. 2007, 107, 5683–5712. (b) Bolm, C.; Atodiresei, I.; Schiffers, I. Org. Synth. 2005, 82, 120–125. (c) Rodriguez-Docampo, Z.; Connon, S. J. ChemCatChem 2012, 4, 151–168. (d) Diaz de Villegas, M. D.; Galvez, J. A.; Etayo, P.; Badorrey, R.; Lopez-Ram-de-Viu, P.; Chem. Soc. Rev. 2011, 40, 5564–5587. For a review on desymmetrizations promoted by bifunctional organocatalysts, see: Quintavalla, A.; Cerisoli. A.; Montroni, E. Curr. Organocat. 2014, 1, 107–171. 12(a) Peschiulli, A.; Gun’ko, Y. K.; Connon, S. J. J. Org. Chem. 2008, 73, 2454–2457. (b) Manzano, R.; Andrés, J. M.; Muruzábal, M. D.; Pedrosa, R. J. Org. Chem. 2010, 75, 5417–5420. Rho, S. H.; Oh, S. H.; Lee, J. W.; Chin, J.; Song, C. E. Chem. Commun. 2008, 1208–1210. (a) Oh, S. H.; Rho, S. H.; Lee, J. W.; Lee, J. E.; Youk, S. H. J.; Chin, C. E. Song, Angew. Chem. Int. Ed. 2008, 47, 7872–7875. (b) Park, S. E.; Nam, E. H.; Jang, H. B.; Oh, J. S.; Some, S.; Lee, Y. S.; Song, S. E. Adv. Synth. Catal. 2010, 352, 2211–2217. (a) Schmitt, E.; Schiffers, I.; Bolm, C. Tetrahedron 2010, 66, 6349–6357. (b) Chen, F.; Liu, Z.; Dai, L.; Xiong, F.; He, Q.; Chen, X. Faming Zhuanli Shenqing 2012, CN 102397793 A 20120404. (c) Nam, E. H.; Park, S. E.; Oh, J. S.; Some, S.; Kim, D. Y.; Bae, H. Y.; Song, C. E. Bull. Korean Chem. Soc. 2011, 32, 3127–3129. Stoll, A. H.; Mayer, P.; Knochel, P. Organometallics, 2007, 26, 6694–6697. (a) Pettit, G. R.; Gupta, S. K. J. Chem. Soc (C), 1968, 1208–1213. (b) Malerich, J. P.; Hagihara, K.; Rawal, V. H. J. Am. Chem. Soc. 2008, 130, 14416–14417. (c) Yang, W.; Du, D.-M. Org. Lett. 2010, 12, 5450–5453. (d) Lee, J. W.; Ryu, T. H.; Oh, J. S.; Bae, H. Y.; Jang, H. B.; Song, C. E. Chem. Commun. 2009, 7224–7226.
4
Tetrahedron
Highlights: Organocatalytic desymmetrization of mesoforms of organometallic anhydrides is unknown. Scope of organocatalysts, including Fu, Rawal and different squaramides. Solvent and reaction conditions optimization up to 98% enantiomeric excess. First example of organocatalytic desymmetrization of ferrocene anhydride.
S0040-4039(16)31651-3 http://dx.doi.org/10.1016/j.tetlet.2016.12.025 TETL 48437
To appear in:
Tetrahedron Letters
Received Date: Revised Date: Accepted Date:
10 November 2016 5 December 2016 7 December 2016
Please cite this article as: Valderas, C., Casarrubios, L., de la Torre, M.C., Sierra, M.A., The organocatalytic desymmetrization of meso-ferrocene anhydride, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet. 2016.12.025
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Graphical Abstract To create your abstract, type over the instructions in the template box below. Fonts or abstract dimensions should not be changed or altered.
The Organocatalytic Desymmetrization of meso-Ferrocene Anhydride
Leave this area blank for abstract info.
Carolina Valderas,†,‡,§ Luis Casarrubios,†,§ María C. de la Torre*,‡,§ and Miguel A. Sierra*,†,§ EtOH O
Fe
H
N H N
O EtOH
CO 2H CO 2Et
N
OMe
O
H
N
N
H
OMe
Fe
N O
O
98% ee (60% isolated)
1
Tetrahedron Letters
The organocatalytic desymmetrization of meso-ferrocene anhydride Carolina Valderas,a,b,c Luis Casarrubios,a,c María C. de la Torre,*,b,c Miguel A. Sierra*,a,c a
Departamento de Química Orgánica I, Facultad de Química, Universidad Complutense, 28040-Madrid. Spain. [email protected] Instituto de Química Orgánica General, Consejo Superior de Investigaciones Científicas (CSIC), Juan de la Cierva 3, 28006-Madrid, Spain. [email protected] c Centro de Innovación en Química Avanzada (ORFEO-CINQA) b
ARTICLE INFO
ABSTRACT
Article history: Received Received in revised form Accepted Available online
A new and unique organocatalytic process for the desymmetrization of meso ferrocene anhydride has been developed. After optimization with a series of quinine, quinidine and squaramide ligands, the method was effective with a 60% isolated yield and 98% ee. 2009 Elsevier Ltd. All rights reserved.
Keywords: Desymmetrization meso-ferrocenes Organocatalysis Squaramides Chiral Ligands
Introduction Chiral ferrocene derivatives are among the best ligands for asymmetric catalysis due to their thermal stability and high tolerance to a wide range of functional groups, together with the possibility of performing chemistry under atmospheric conditions (oxygen friendly ligands).1 As a consequence, methods to prepare such formidable ligands in enantiopure form have been extensively searched. Preparation of chiral ferrocene derivatives, including chiral-planar ferrocenes, has been also widely studied. Regarding enantiopure chiral-planar ferrocenes, the lithiation of a cyclopentadiene ring of the ferrocene bearing ortho chiral directing groups has been profusely used 2 affording chiral planar ferrocenes maintaining the additional element of asymmetry. Alternatively, enantioselective lithiation of ferrocene using chiral bases efficiently produces planar chiral ferrocenes (Scheme 1). 3 Other approaches, such as kinetic resolution of chiral-planar racemic ferrocenes4 or asymmetric C–H activation,5,2a have also
Scheme 1
The chemical and enzymatic desymmetrization of ferrocene meso-forms has been pursued.6 However, reports concerning the organocatalytic desymmetrization of ferrocene derived mesoforms are, to the best of our knowledge, unknown. Desymmetrization of cyclic anhydrides have been lately a good source of chiral compounds by different methods, including nucleophilic anhydride opening catalyzed by chiral Lewis bases derived from alkaloids (quinine and quinidine). 7 More recently bifunctional catalysts8 with both, a nucleophilic activating group and a hydrogen bond donor position in their structure such as ureas,9 thioureas,10 sulfonamide11 or squaramides,12 have been used for this purpose. Therefore, we devised the possibility of using organocatalysis to effect the desymmetrization of ferrocene anhydrides. Our parent substrate for the development of the desymmetrization process was anhydride 3. The synthesis of this anhydride started with the double esterification of ferrocenecarboxylic acid to ditertbutyl derivative 1.13 An ethereal solution of 1 was bubbled with gaseous HCl to hydrolize both esters. Under these conditions, diacid 2 precipitated in the reaction media and it was isolated in a 97% yield. Diacid 2 was refluxed in acetic anhydride for 2h to produce anhydride 3 in a 67% yield (Scheme 2).
been described.
2
Tetrahedron
Scheme 2 Initial tests for the desymmetrization process of 3 implied the use of 20 mol% of the cinchonidine catalyst. Although several alcohols (methanol, benzyl alcohol, cinnamyl alcohol and allyl alcohol) are used in most studies of asymmetric anhydride openings, our reactions were always performed using absolute ethanol (10 folds excess) as the nucleophile (Scheme 3). A screening of different solvents at room temperature was then performed (Table 1).
while quinine II leads to full conversion the pseudo enantiomer quinidine V leads to decomposition. A reasonable explanation for this result has evaded us. Moreover, to the best of our knowledge entry 8 in Table 1 represents the first example of the asymmetric alcoholysis of a meso-anhydride using a Fu-type catalyst. Figure 1. Optimization of the organocatalyts
Scheme 3 Table 1. Initial Solvent screening. a
Ratio 3:4b
ee(%)c
Et2O
Dec.
–
–
2
THF
Dec.
–
–
3
CH2Cl2
100:0
–
–
4
CHCl3
100:0
–
–
5
Toluene
50:50
14
1S
6
Toluene (0.2M)
0:100
2
-
Entry
Solvent
1
Mayor Isomer
a
Reaction conditions: 1eq. of 3, 10eq. of EtOH, room temperature, 0.02 M, 48 h. b3:4 ratio was determined by 1H NMR of the reaction crudes. c Determined by HPLC (Daicel Chiralpak IA).
As shown in Table 1, ethereal solvents (Et2O or THF) yielded only complex mixtures (entries 1 and 2). With chlorinated solvents such as CH2Cl2 or CHCl3 (entries 3 and 4) unaltered ferrocene anhydride 3 was recovered. Toluene (entry 5) was the best choice as we detected a 50:50 mixture of 3 and 4. Ester 4 was purified by SiO2 chromatography (hexane/AcOEt 1:1) and a sample was analyzed by chiral HPLC (Daicel Chiralpak IA). The resulting 14% ee, despite low, clearly demonstrates that organocatalysis is a usable method for the desymmetrization of organometallic anhydrides by transferring the central chirality to planar chirality. One last test increasing concentration to 0.2M produced total conversion to monoester 4 although with a poorer ee (2%).
Table 2. Organocatalyst screening. Entry
Catalyst (20 mol %)
Ratio 3:4b
ee(%)c
1
quinine (II)
0:100
8
Mayor Isomer 1S
2
quinine-OCOPh (III)
0:100
2
1S
3
quinine-OAc (IV)
0:100
2
1S
4
quinidine (V)
Dec.
–
–
5
cinchonine (VI)
Dec.
–
–
6
(S)-PPY* (VII)
0:100
82
1S
7
(S)-C5Ph5-DMAP (VIII)
Dec.
–
–
8
(R,R-TUC) (IX)
23:77
12
1R
9
squaramide (X)
0:100
79
1R
10
(DHQD)2PHAL (XI)
9:90
7
1S
11
(DHQD)2Pyr (XII)
50:50
8
1S
12
(DHQD)2AQN (XIII)
0:100
58
1R
a
A second screening of organocatalysts was then pursued including alkaloid (II-VI) and ferrocene derivatives (VII-VIII), dimeric catalysts (XI-XIII), bifunctional catalysts such as the thiourea IX and the Rawal’s squaramide X (Figure 1). Toluene was used in all cases as the solvent. Table 2 summarizes the obtained results in these reactions. Quinine derivatives (II-IV) showed total conversion to monoester 4 but the desired ferrocene was obtained in low ee’s (entries 1, 2, 3. Table 2). Catalyst VII raised ee up to 82% while maintains a complete conversion to 4 (entry 6. Table 2). Analogous catalyst VIII only produced decomposition of the starting anhydride (entry 5. Table 2) and the same results were observed in the case of the quinidine (V) and cinchonine (VI) derivatives (entries 4, 5. Table 2). Thiourea IX (entry 8. Table 2) showed both low conversion and ee. Squaramide X underwent total conversion and 79% ee, similar to the results obtained with Fu’s catalyst VII (entry 6. Table 2). It is worthy to note that
a
Reaction conditions: 1eq. of 3, 10eq. of EtOH, room temperature, 0.02 M in toluene, 48 h. b3:4 relationship was determined by 1H NMR of the reaction crudes. cDetermined by HPLC (Daicel Chiralpak IA).
3 Finally, reactions using dimeric catalysts XI-XIII produced conversions ranging from moderate to complete. Nevertheless, the highest obtained ee in these cases was only 58% (entries 10, 11, 12. Table 2). With all the results in hand, our next step was to study the influence of structural modifications in catalyst X in the desymmetrization process. A new set of easily accessible squaramide-based catalysts XIV–XIX14b-d was then synthesized and tested (Figure 2).
Acknowledgments Support for this work under grants (CTQ2013-46459-C2-01-P to MAS, CTQ2013-46459-C2-02-P to MCT, and CTQ201451912-REDC (Programa Redes Consolider) from the MINECO (Spain) is gratefully acknowledged. We thank Prof. Carmen Carreño (UAM)-Madrid for the use of HPLC facilities. References and notes
H O
H F 3C
nN H
N
HN
H
N
N
CF3
n = 0; R = H n = 0; R = OMe n = 1; R = H n = 1; R = OMe
H
R
N O
N XIV XV XVI XVII
N H N
H
R
1.
N
R
O
XVIII XIX
2.
O
3. 4.
R=H R = OMe
5.
Figure 2. Squaramide-based catalysts Table 3 summarizes the obtained results for the desymmetrization of anhydride 3. All the new catalysts produced total conversion of 3 to monoester 4 with ee’s ranging from 79% to 98%. Best results were obtained with squaramide catalyst XIX (entry 6, Table 3). Only this crude, with the higher ee, was submitted to chromatographic purification. Monoester 4 was thus isolated in a 60% yield and 98% ee. Mono ester 4 was dextrorotatory which points to a (1S)-configuration according to the reported chemical correlation of analogous methyl ester with (1S)-(+)--methylferrocenecarboxylic acid.6f Efforts to establish the absolute configuration of compound 4 have been until now fruitless. Table 3. Modified organocatalysts.
6.
7.
8.
Mayor Isomer
Entrya
Squaramide
Ratio 3:4b
ee(%)c
1
XIV
0:100
79
1S
2
XV
0:100
82
1S
10.
3
XVI
0:100
81
1S
11.
4
XVII
0:100
81
1S
5
XVIII
0:100
87
1S
6
XIX
0:100
98
1S
9.
12.
a
Reaction conditions: 1eq. of 3, 10eq. of EtOH, 20 mol % of catalyst, room temperature, 0.02 M in toluene, 48 h. b3:4 ratio was determined by 1H NMR of the reaction crudes. cDetermined by HPLC (Daicel Chiralpak IA).
In summary, the viability of using an organocatalytic procedure in the desymmetrization of meso-form of ferrocene anhydride with a 60% isolated yield and ee of 98% has been demonstrated. Squaramide catalyst XIX was the catalyst of choice yielding the nearly enantiopure monoester 4. Efforts to generalize this organocatalytic desymmetrization to other mesometal-complex anhydrides as well as to understand the mechanism of these reactions are in progress in our laboratories.
13. 14.
(a) Ferrocenes: Ligands, Materials and Biomolecules, Stepnicka, P. (Ed.), Wiley 2008. (b) Ferrocenes: Homogeneous Catalysis, Organic Synthesis, Materials Science Togni, A.; Hayashi, T. (Eds.), Wiley 2008. (a) Schaarschmidt, D.; Lang, H. Organometallics 2013, 32, 5668– 5704 (review in the special issue: Ferrocene - Beauty and Function). (b) Atkinson, R. C. J.; Gibson, V. C.; Long, N. J. Chem. Soc. Rev. 2004, 313–328. Clayden, J. Top. Organomet. Chem. 2003, 5, 251–286. Illustrative recent review: Skrobo, B.; Rolfes, J. D.; Deska, J. Tetrahedron 2016, 72, 1257–1275. Recent examples: (a) Gao, D.-W.; Shi, Y.-C.; Gu, Q.; Zhao, Z.-L.; You, S.-L. J. Am. Chem. Soc. 2013, 135, 86–89. (b) Gao, D.-W.; Yin, Q.; Gu, Q.; You, S.-L. J. Am. Chem. Soc. 2014, 136, 4841– 4844. (a) Yamazaki, Y.; Hosono, K. Tetrahedron Lett. 1988, 29, 5769– 5770. (b) Yamazaki, Y.; Hosono, K. Biotechnol. Lett. 1989, 11, 679–684. (c) Nicolosi, G.; Morrone, R.; Patti, A.; Piattelli, M. Tetrahedron: Asymmetry 1992, 3, 753–758. (d) Duan, W.-L.; Imazaki, Y.; Shintani, R.; Hayashi, T. Tetrahedron 2007, 63, 8529–8536. (e) Buchgraber, P.; Mercier, A.; Yeo, W. C.; Besnard, C.; Kündig, E. P. Organometallics 2011, 30, 6303–6315. (f) Yamazaki, Y.; Hosono, K. Ann. N.Y. Acad. Sci. 1990, 613, 738–746. (a) Atodiresei, I.; Schiffers, I.; Bolm, C. Chem. Rev. 2007, 107, 5683–5712. (b) Bolm, C.; Atodiresei, I.; Schiffers, I. Org. Synth. 2005, 82, 120–125. (c) Rodriguez-Docampo, Z.; Connon, S. J. ChemCatChem 2012, 4, 151–168. (d) Diaz de Villegas, M. D.; Galvez, J. A.; Etayo, P.; Badorrey, R.; Lopez-Ram-de-Viu, P.; Chem. Soc. Rev. 2011, 40, 5564–5587. For a review on desymmetrizations promoted by bifunctional organocatalysts, see: Quintavalla, A.; Cerisoli. A.; Montroni, E. Curr. Organocat. 2014, 1, 107–171. 12(a) Peschiulli, A.; Gun’ko, Y. K.; Connon, S. J. J. Org. Chem. 2008, 73, 2454–2457. (b) Manzano, R.; Andrés, J. M.; Muruzábal, M. D.; Pedrosa, R. J. Org. Chem. 2010, 75, 5417–5420. Rho, S. H.; Oh, S. H.; Lee, J. W.; Chin, J.; Song, C. E. Chem. Commun. 2008, 1208–1210. (a) Oh, S. H.; Rho, S. H.; Lee, J. W.; Lee, J. E.; Youk, S. H. J.; Chin, C. E. Song, Angew. Chem. Int. Ed. 2008, 47, 7872–7875. (b) Park, S. E.; Nam, E. H.; Jang, H. B.; Oh, J. S.; Some, S.; Lee, Y. S.; Song, S. E. Adv. Synth. Catal. 2010, 352, 2211–2217. (a) Schmitt, E.; Schiffers, I.; Bolm, C. Tetrahedron 2010, 66, 6349–6357. (b) Chen, F.; Liu, Z.; Dai, L.; Xiong, F.; He, Q.; Chen, X. Faming Zhuanli Shenqing 2012, CN 102397793 A 20120404. (c) Nam, E. H.; Park, S. E.; Oh, J. S.; Some, S.; Kim, D. Y.; Bae, H. Y.; Song, C. E. Bull. Korean Chem. Soc. 2011, 32, 3127–3129. Stoll, A. H.; Mayer, P.; Knochel, P. Organometallics, 2007, 26, 6694–6697. (a) Pettit, G. R.; Gupta, S. K. J. Chem. Soc (C), 1968, 1208–1213. (b) Malerich, J. P.; Hagihara, K.; Rawal, V. H. J. Am. Chem. Soc. 2008, 130, 14416–14417. (c) Yang, W.; Du, D.-M. Org. Lett. 2010, 12, 5450–5453. (d) Lee, J. W.; Ryu, T. H.; Oh, J. S.; Bae, H. Y.; Jang, H. B.; Song, C. E. Chem. Commun. 2009, 7224–7226.
4
Tetrahedron
Highlights: Organocatalytic desymmetrization of mesoforms of organometallic anhydrides is unknown. Scope of organocatalysts, including Fu, Rawal and different squaramides. Solvent and reaction conditions optimization up to 98% enantiomeric excess. First example of organocatalytic desymmetrization of ferrocene anhydride.