Tetrahedron Letters

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A new pyrrolidine-derived atropisomeric amino alcohol as a highly efﬁcient chiral ligand for the asymmetric addition of diethylzinc to aldehydes

Ferenc Faiglâ,b, Zsuzsa Erdélyiâ, Szilvia Deákâ, Miklós Nyerges^c, Béla Mátravölgyi^b,^⇑

aDepartment of Organic Chemistry and Technology, Budapest University of Technology and Economics, Budafoki út 8., H-1111 Budapest, Hungary

bMTA-BME Organic Chemical Technology Research Group, Hungarian Academy of Sciences, Budafoki út 8., H-1111 Budapest, Hungary

cServier Research Institute of Medicinal Chemistry, Záhony u. 7., H-1031 Budapest, Hungary

a r t i c l e i n f o

Article history:

Received 2 August 2014 Revised 6 October 2014 Accepted 16 October 2014 Available online 23 October 2014

Keywords:

Chiral ligand Amino alcohol Enantioselective addition Axial chirality

Asymmetric catalysis

a b s t r a c t

A highly efﬁcient pyrrolidine-derived atropisomeric amino alcohol, (Sa)-1-[2-diphenylhydroxymethyl-6- (triﬂuoromethyl)phenyl]-2-(1-pyrrolido)methyl-1H-pyrrole, has been synthesized as a chiral ligand for the enantioselective addition of diethylzinc to some prochiral aldehydes to afford (S)-alcohols. The conversion rates were close to quantitative with good to excellent enantiomeric excesses (up to 95%ee).

The asymmetric addition of organozinc reagents to aldehydes is an important synthetic method for the formation of optically active secondary alcohols.¹Since the pioneering work of Oguni and Omi,² significant efforts have been devoted to the development of more selective and efficient catalytic systems for this synthetically useful transformation. Despite the excellent results that have been obtained by using diverse ligand structures (amino alcohols,³diols,⁴ diamines,⁵ amino thiols⁶), the design and development of novel backbones and efficient chiral ligands remains an important challenge in organic chemistry. Chiral amino alcohols have proved to be highly efficient ligand structures for the addition of diethylzinc to prochiral aldehydes, providing enantioenriched secondary alcohols. For this purpose, a variety ofb-amino alcohols have been developed.^7–11Comparatively,c- andd-amino alcohols have been less studied thanb-amino alcohols, even though satisfactory results were achieved with the former ligands.^12,13Martinez and co-work- ers studied the catalytic activity of norbornane-derivedc-amino alcohols in the addition of dialkylzincs to aldehydes and presented a qualitative empirical explanation for the observed moderate enantioselectivity imposed by these amino alcohols.¹⁴ Peng also described detailed investigations of chiral homoprolinol analogs (c-amino alcohols) as catalytic ligands for diethylzinc addition to

aldehydes, but only moderate to satisfactory enantioselectivities (6–82% ee) were achieved.¹⁵ Despite the widespread application of axially chiral ligands in asymmetric synthesis,^16,17only a few examples of amino alcohols with a 1,1⁰-biaryl backbone have been reported for the addition of organozincs to aldehydes.^18–21

Recently, the ﬁrst synthesis and application of a new atropisomeric amino alcohol ligand (1) (Scheme 1) were reported by our group.²² The new ligand1 showed outstanding catalytic activity and good chiral induction in the addition of diethylzinc to benzaldehyde (97% yield, 86% ee) despite there being a six-atom-long chain between the amino and hydroxyl groups within the molecule.

Based on this observation, we became interested in the development of a more efﬁcient ligand possessing a 1-arylpyrrole

⇑ Corresponding author. Tel.: +36 1 463 5389; fax: +36 1 463 3648.

E-mail address:bmatravolgyi@mail.bme.hu(B. Mátravölgyi).

N F₃C

(Sa)-1²² NH OH PhPh

N F₃C

(Sa)-2 N

OH Ph Ph Pyrrolidine-derived

ligand Target structure

Scheme 1.Strategy to improve the structure of the atropisomeric chiral ligand (Sa)-1²²for the efﬁcient asymmetric addition of organozinc to aldehydes.

Tetrahedron Letters 55 (2014) 6891–6894

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backbone and the study of its catalytic behavior in enantioselective alkylations. Pyrrolidine-derived compounds have achieved significant success in the field of asymmetric catalysis as a result of the five-membered ring skeleton, which presents a certain degree of rigidity. If there are additional bulky substituents close to the het- eroatom, this chiral system could provide a transition state having a well-defined chiral environment. Consequently, more efficient control is attained in the enantioselective transformations.⁷ We envisaged that this relatively rigid cyclic dialkylamino moiety might increase the asymmetric induction ability of our 1-arylpyrrole-based catalyst. Herein, we report on the development of the synthesis of (Sa)-2 and the application of this new compound as an efficient chiral ligand in the asymmetric addition of diethylzinc to different aldehydes.

The new pyrrolidine-derived chiral ligand (Sa)-2was prepared from carboxylic acid (Sa)-3²²as shown in Scheme 2. In the ﬁrst step, (Sa)-3was converted into (Sa)-4via an acid chloride, which was treated with pyrrolidine in toluene to afford the corresponding amide in excellent yield (99%). The triarylcarbinol moiety of (Sa)-5 was evolved by addition of an organometallic reagent. Finally, compound (Sa)-5was transformed into the desired amino alcohol (Sa)-2by reduction of the amide group applying borane tetrahydro- furan complex as the reducing agent. After decomposition of the borane substrate complex, the crude product was recrystallized from hexane to give the pure amino alcohol (Sa)-2in good yield (82%). The enantiomeric purity of the fully characterized (Sa)-2 was determined by HPLC analysis.²³ With the desired ligand in hand, optimum reaction conditions for the enantioselective addition of diethylzinc to benzaldehyde (as test reactant) were determined in the presence of different catalytic amounts of (Sa)-2, as shown inTable 1.

The reactions were monitored by GC and were stopped when aldehyde 6 had been consumed completely. Our initial experiments were focused on studying the inﬂuence of the amount of the ligand at 0°C. The best asymmetric effect was achieved by applying 5 mol % of ligand (S_a)-2 (Table 1, entry 2); using only 1 mol % resulted in a lower enantiomeric excess (93%?86%ee).

When the reaction was run at room temperature, the addition was complete in a shorter time (4 h) but in terms of the stereose- lectivity fell short of the best result (Table 1, entry 4).

Thus, the optimum conditions were found to be 5 mol % of (Sa)- 2at 0°C for 18 h. Using these conditions, we observed complete conversion of benzaldehyde into the desired alcohol in excellent enantiomeric purity (93%ee). This efﬁciency is signiﬁcantly higher than the best result achieved earlier in the presence of ligand (Sa)- 1²²(86%ee). Having established optimum conditions, we reacted a series of aldehydes bearing different substituents. The addition of diethylzinc to the aldehydes was conducted with 5 mol % of ligand (S_a)-2.³⁵As highlighted inTable 2, high yields and enantioselectivities (up to 95%ee) were achieved.

The substituents on the benzene ring of the benzaldehyde derivatives (Table 2, entries 1–13) did not inﬂuence signiﬁcantly the rate of the reaction and theeevalues of the products were uniformly high. Since the yields were determined after isolation

of the products, small deviations might be caused by preparative manipulations. The enantiomeric purities of the products were between 90% and 95%, except in the case of 2-bromobenzaldehyde (Table 1, entry 9), in which theeedropped to 88%, possibly due to the bulkiness and greater polarizability of the bromine atom

N COO H COOCH₃ F₃C

(Sa)-3 ee99%

N

COOCH₃ F₃C

(Sa)-4 O

N

a,b c N

F₃C

(Sa) -5 O

N HO

P h P h

N F₃C

(Sa)-2 ee99%

N OH Ph Ph d

Scheme 2.Synthesis of ligand (Sa)-2; (a) SOCl2, toluene, 80°C, 2 h, (b) pyrrolidine, toluene, 0°C, 99%, (c) PhLi, THF,75°C?rt, 85%, (d) BH3THF, THF, 60°C, 48 h; MeOH, NaOH, 50°C, 5 d, 82%.

Table 1

The reactions were performed using 3 mol equiv of ZnEt2in hexane O

H

OH

6 7

chiral ligand (Sa)-2 hexane

Zn Et₂

Entry (Sa)-2(mol %) Temp (°C) Time (h) Yield^a(%) ee^b,c(%)

1 10 0 8 96 92 (S)

2 5 0 16 93 94 (S)

3 1 0 48 69 86 (S)

4 5 rt 4 92 89 (S)

aIsolated yields.

bDetermined by GC analysis using a Supelcob-DEX 120 chiral capillary column.

cAbsolute conﬁguration was assigned by comparison of the direction of optical rotation of the samples with literature data.²⁴

Table 2

The reactions were performed using 3 mol equiv of ZnEt2

R O

H R

OH 5 mol% (Sa)-2

hexane, 0 °C, 16 h

8 9

ZnEt₂

Entry R Yield^a(%) ee^b(%) Conﬁg.^c

1 Ph 92 94 (S)

2 2-MeC6H4 93 94 (S)

3 3-MeC6H4 94 93 (S)

4 4-MeC6H4 96 92 (S)

5 2-MeOC6H4 93 93 (S)

6 3-MeOC6H4 92 93 (S)

7 4-MeOC6H4 88 92 (S)

8 3-BnO,4-MeOC6H3 94 95^d (S)^e

9 2-BrC6H4 91 88 (S)

10 2-ClC6H4 92 90 (S)

11 2-FC6H4 90 93 (S)

12 3-FC6H4 95 92 (S)

13 4-FC6H4 91 93 (S)

14 1-Naphth 93 90 (S)

15 2-Naphth 92 90 (S)

16 PhACH@CH 91 63^d (S)

aIsolated yields.

bDetermined by GC analysis using a Supelcob-DEX 120 chiral capillary column.

cAbsolute conﬁgurations of the alcohols were assigned by comparison of the direction of optical rotation of the samples with literature data.^24–34

dDetermined by HPLC analysis using a Phenomonex Lux Cellulose-1 chiral column. The reaction was carried out in toluene.

eAbsolute conﬁguration of the alcohol was assumed based on the stereochem- istry of the reaction.

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compared to chlorine and ﬂuorine atoms as well as a methyl group.

Very good enantiomeric excesses were observed in the reactions of both naphthaldehydes (Table 2, entries 14 and 15). Cinnamalde- hyde also reacted smoothly with diethylzinc in the presence of (Sa)-2 to form (S)-1-phenyl-1-penten-3-ol with moderate ee (Table 2, entry 16).

On the basis of the experimental results, we assumed that the addition of diethylzinc to aldehydes using ligand (Sa)-2 would proceed via a plausible transition intermediate 14c (Scheme 3).

(Sa)-2 forms a nine-membered cyclic adduct (Sa)-10 with an ethylzinc moiety. This adduct is stable and rigid enough to accept a diethylzinc molecule via the oxygen atom of the metallocyclic catalyst (11,Scheme 3) in such a way that after coordination of benzaldehyde, an ethyl group from the diethylzinc molecule can attack the Si-face of the carbonyl group (13, Scheme 3). Proper orientations of the two organometallic species and the aldehyde in 14c are determined by the axial chirality of the ligand (Sa)-2 as follows. Within the ligand, the relative positions of the N

Zn N

O

CF3 O Zn

H

N

Zn N

O

CF3 O Zn

H N

Zn N

O

CF3 Zn

O

H

N

Zn N

O

CF3 O Zn

H N

Zn N

O

CF3 Zn

N

Zn N

O

CF3

N

Zn N

O

CF3 Zn

O H

N

Zn N

O

CF3 O

H Zn

Shielding effects of the pyrrolidine and phenyl groups determine the coordination ofZnEt₂

+ ZnEt₂ + PhCHO

+ PhCHO

N

Zn N

O

CF3 O Zn

H

N

Zn N

O

CF3 Zn

O H

H₂O

+

Re-face Si-face

Si-face Re-face

3 % OH

(R)-7

97 % OH

(S)-7

(S)-7 (R)-7

(Sa)-10

(Sa)-10 16

15

14b 14c 14d

14a

13 11

12

Scheme 3.Visualization of a plausible transition complex14cin the formation of (S)-7.

F. Faigl et al. / Tetrahedron Letters 55 (2014) 6891–6894 6893

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diphenyl-hydroxymethyl group (depicted in blue inScheme 3) and the pyrrolidinomethyl group (highlighted in red inScheme 3) are determined by the conﬁguration of the molecule. Therefore (Sa)- 10can accept a diethylzinc molecule from one side only (the other sides of the electron donor oxygen atom are shadowed by the two phenyl groups, the triﬂuorophenyl group, the pyrrolidinomethyl, and ethylzinc moiety of the ligand). Thus, the structure of complex 11is determined by the axial chirality of (Sa)-2. After complexation of an aromatic aldehyde, the orientation of the diethylzinc molecule within 13 should suit two requirements: an ethyl group should be in a parallel position with the C@O group for the addition reaction, and the other ethyl group should not cause a repulsive steric interaction within the complex molecule (14a–d). There are two structures (14aand14d) among the four possible transition states, which are unfavored, because of steric hindrance (des- ignated by arrows inScheme 3). There is only one repulsive steric interaction between an ethyl group and an aromatic ring in14b from which the minor enantiomer (R)-7 might be formed. The most favorable arrangement seems to be14cin whichSi-face addition results in the formation of15, which dissociates to form the catalyst (Sa)-10and the alcoholate16. From this latter compound, after hydrolysis, (S)-7is isolated in high yield andee.

In conclusion, the novel pyrrolidine-derived ligand (S_a)-2, which is based on the atropisomeric 1-arylpyrrole skeleton, can be readily prepared from optically active3, in three steps, with a high 69%

overall yield. The new ligand forms a more efﬁcient catalyst system with diethylzinc than compound (Sa)-1. Using 5 mol % of ligand (Sa)-2, the asymmetric addition is complete within 16 h under mild conditions (0°C) and affords excellent enantioselectivities (up to 95% ee). Investigation of a variety of substituted benzaldehydes and naphthaldehydes showed that the substituent on the aldehyde practically had no detrimental effect on the yields and theeevalues of the products. Therefore, we have demonstrated that the new atropisomeric 1-phenylpyrrole skeleton containing a 1,6-amino alcohol function can be used as a highly efﬁcient ligand for diethylzinc additions to a range of aldehydes.

Acknowledgments

We gratefully acknowledge the Hungarian Scientific Research Fund (OTKA K 104528) and the Richter Gedeon Talentum Founda- tion for their financial support. This work is also connected to the scientific program of the ‘Development of quality-oriented and harmonized R+D+I strategy and functional model at BME’ project, supported by the New Széchenyi Plan (Project ID: TÁMOP-4.2.1/

B-09/1/KMR-2010-0002).

Supplementary data

Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.1 0.101.

References and notes

1. Piu, L.; Yu, H. B.Chem. Rev.2001,101, 757–824.

2. Oguni, N.; Omi, T.Tetrahedron Lett.1984,25, 2823–2824.

3. Kitamura, M.; Okada, S.; Suga, S.; Noyori, R.J. Am. Chem. Soc.1989,111, 4028–

4036.

4. Roudeau, R.; Pardo, D. G.; Cossy, J.Tetrahedron2006,62, 2388–2394.

5. (a) Serra, M. E. S.; Murtinho, D.; Gonsalves, A. M. d’A. RAppl. Organomet. Chem.

2008,22, 488–493;(b) Martins, J. E. D.; Wills, M.Tetrahedron: Asymmetry2008, 19, 1250–1255.

6. Kang, J.; Lee, W. J.; Kim, J. I.J. Chem. Soc., Chem. Commun.1994, 2009–2010.

7. Soai, K.; Niwa, S.Chem. Rev.1992,92, 833–856.

8. Wu, Z. L.; Wu, H. L.; Wu, P. Y.; Uang, B. J.Tetrahedron: Asymmetry2009,20, 1556–1560.

9. Pisani, L.; Superchi, S.Tetrahedron: Asymmetry2008,19, 1784–1789.

10. Harada, A.; Fujiwara, Y.; Katagiri, T.Tetrahedron: Asymmetry2008,19, 1210–

1214.

11. Tasgin, D. I.; Unaleroglu, C.Appl. Organomet. Chem.2010,24, 33–37.

12. Sanchez-Carnerero, E. M.; Engel, C. T.; Maroto, B. L.; Cerero, S. M.Tetrahedron:

Asymmetry2009,20, 2655–2657.

13. Olsson, C.; Helgesson, S.; Frejd, T.Tetrahedron: Asymmetry2008,19, 1484–

1493.

14. Martinez, A. G.; Vilar, E. T.; Fraile, A. G.; Cerero, S. M.; Maroto, B. L.Tetrahedron 2005,61, 3055–3064.

15. Liu, C.-L.; Wei, C.-Y.; Wang, S.-W.; Peng, Y.-G.Chirality2011,23, 921–928.

16. Ohkuma, T.; Kurono, N. in Privileged Chiral Ligands and Catalysts, Zhon, Q.-L., Wiley-VCH, Weinheim, 2011, ch. 1, pp. 1–54.

17. Shibasaki, M.; Matsunaga, S. in Privileged Chiral Ligands and Catalysts, Zhon, Q.-L., Wiley-VCH, Weinheim, 2011, ch. 8, pp. 295–332.

18. Vyskocil, S.; Jaracz, S.; Smrcina, M.; Sticha, M.; Hanus, V.; Polasek, M.;

Kocovsky, P.J. Org. Chem.1998,63, 7727–7737.

19. Bringmann, G.; Breuning, M.Tetrahedron: Asymmetry1998,9, 667–679.

20. Ko, D.-H.; Kim, K.-H.; Ha, D.-C.Org. Lett.2002,4, 3759–3762.

21. Superchi, S.; Mecca, T.; Giorgio, E.; Rosini, C.Tetrahedron: Asymmetry2001,12, 1235–1239.

22. Faigl, F.; Mátravölgyi, B.; Szöll}osy, Á.; Czugler, M.; Tárkányi, G.; Vékey, K.;

Kubinyi, M.Chirality2012,24, 532–542.

23. (Sa)-1-[2-Diphenylhydroxymethyl-6-(triﬂuoromethyl)-phenyl]-2-(1- pyrrolidino)methyl-1H-pyrrole ((Sa)-2): white solid (99%ee). Mp: 76–78°C. IR (KBr,mmax): 3087, 2973, 2824, 1480, 1450, 1315, 1165, 1136, 719, 700 cm¹.¹H NMR (500 MHz, CDCl3)d8.34 (br s, 1H), 7.74 (d,J= 7.8 Hz, 1H), 7.39 (t, J= 8.0 Hz, 1H), 7.28–7.23 (m, 6H), 7.21 (d,J= 8.1 Hz, 1H), 7.10 (d,J= 6.8 Hz, 4H), 6.14–6.04 (m, 1H), 5.83 (t,J= 3.1 Hz, 1H), 5.50 (s, 1H), 3.44 (d,J= 13.8 Hz, 1H), 3.14 (d,J= 13.8 Hz, 1H), 2.75–2.64 (m, 2H), 2.39–2.29 (m, 2H), 1.85–1.72 (m, 4H). ¹³C NMR (75 MHz, CDCl3) d 149.54, 148.85, 146.20, 137.09 (d, J= 1.4 Hz), 135.35, 131.18, 130.98 (q, J= 29.7 Hz), 128.01, 127.80, 127.56, 127.46, 127.41, 126.85, 126.71, 126.36 (q, J= 5.5 Hz), 125.18, 123.00 (q, J= 274.6 Hz), 108.42, 106.02, 81.12, 53.91, 50.99, 23.34.¹⁹F NMR (282 MHz, CDCl3)d 60.89 (s). ½a²⁵_D +94 (c 0.65; CHCl3). HRMS (ESI) m/z calcd for C29H28F3N2O (M+H)⁺: 477.2154, found 477.2157.eewas determined by HPLC analysis using a chiral stationary phase, Phenomenex Lux Amylose-2 column (5lm, 2504.6 mm), eluent hexane/EtOH = 98.5/1.5, 0.5 mL/min, UV detector 222 nm, 15°C, retention time for (S)-4: 9.5 min, for (R)-4: 11.7 min.

24. Lutz, C.; Knochel, P.J. Org. Chem.1987,62, 7895–7898.

25. Vastila, P.; Pastor, I. M.; Adolfsson, H.J. Org. Chem.2005,70, 2921–2929.

26. Salvi, N. A.; Chattopadhyay, S.Tetrahedron: Asymmetry2008,19, 1992–1997.

27. Huang, J.; Ianni, J. C.; Antoline, J. E.; Hsung, R. P.; Kozlowski, M. C.Org. Lett.

2006,8, 1565–1568.

28. Qi, G.; Judeh, Z. M. A.Tetrahedron: Asymmetry2010,21, 429–436.

29. Seebach, D.; Beck, A. K.; Schmidt, B.; Wang, Y. M.Tetrahedron1994,50, 4363–

4384.

30. Zhong, J.; Guo, H.; Wang, M.; Yin, M.; Wang, M.Tetrahedron: Asymmetry2007, 18, 734–741.

31. Dai, W.-M.; Zhua, H.-J.; Haob, X.-J.Tetrahedron: Asymmetry2000,11, 2315–

2337.

32. Cakici, M.; Catir, M.; Karaguba, S.; Ulukanli, S.; Kilic, H.Tetrahedron: Asymmetry 2011,22, 300–308.

33. Osorio-Planes, L.; Rodríguez-Escrich, C.; Pericás, M. A.Org. Lett.2012,14, 1816–

1819.

34. Rodríguez-Escrich, S.; Reddy, K. S.; Jimeno, C.; Colet, G.; Rodríguez-Escrich, C.;

Solá, L.; Vidal-Ferran, A.; Pericás, M. A.J. Org. Chem.2008,73, 5340–5353.

35. General procedure for the addition of diethylzinc to aldehydes:Ligand (Sa)-2 (0.095 mmol, 4.5 mg, 99%ee) was dissolved in a solution of diethylzinc (1 M in hexane, 0.6 mmol, 0.6 mL) under a nitrogen atmosphere. The mixture was stirred for 1 h at room temperature then cooled to 0°C. Freshly distilled aldehyde (0.2 mmol) was added to the mixture. The colour of the resulting mixture turned to a distinctive yellow. After stirring for 16 h, the mixture changed to colourless indicating the completion of the reaction. The reaction was quenched by the addition of saturated aqueous NH4Cl (5 mL) and extracted with toluene (35 mL). The combined organic layers were dried over anhydrous Na2SO4, and evaporated under reduced pressure. Puriﬁcation of the residue by column chromatography (EtOAc in hexane) afforded the corresponding alcohol. Theeewas determined by GC or HPLC analysis using a chiral column.

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Racemization-free synthesis of atropisomeric 1-phenylpyrrole based diamines using diphenylphosphoryl azide

Ferenc Faigl^a,b, Zsuzsa Erdélyi^a, Miklós Nyerges^c, Béla Mátravölgyi^b,^⇑

aDepartment of Organic Chemistry and Technology, Budapest University of Technology and Economics, H-1111 Budapest, Budafoki út 8., Hungary

bMTA-BME Organic Chemical Technology Research Group, Hungarian Academy of Sciences, H-1111 Budapest, Budafoki út 8., Hungary

cServier Research Institute of Medicinal Chemistry, H-1031 Budapest, Záhony u. 7., Hungary

a r t i c l e i n f o

Article history:

Received 7 May 2015 Accepted 3 June 2015 Available online 22 June 2015

a b s t r a c t

An efﬁcient, highly stereoconservative synthesis has been developed for the preparation of aniline derived 1-arylpyrrole-2-carboxamide atropisomers using diphenylphosphoryl azide (DPPA). The classical azide synthesis, involving reaction with active acylating agents prepared from axially chiral benzoic acid derivatives, showed signiﬁcant racemization caused by intramolecular tricyclic isoimidium salt formation. In order to avoid the ring closure reaction, the azide synthesis was carried out with DPPA in a stereoconservative manner, and Curtius rearrangement followed by hydrolysis resulted in enantiopure products. The application of the novel racemisation-free synthetic method of axially chiral anilines from atropisomeric benzoic acid derivatives is demonstrated by the preparation of secondary as well as tertiary amines containing 2-(2-substituted-1H-pyrrole-1-yl)aniline type diamines.

1. Introduction

1-Phenylpyrrole backbone containing compounds are known as important building blocks for biologically active compounds.^1–4Optically active 1-phenylpyrrole derivatives have also been used as chiral reagents⁵ and resolving agents.⁶ Recently, successful applications of 1-phenylpyrrole derived amino alcohols as highly efﬁcient ligands in asymmetric transformations have been published.^7–10 An enantiopure amine can be prepared by resolution of the racemic mixture, although it is usually more convenient to synthesize the individual enantiomer from an enantiomerically pure key intermediate.¹¹ The synthesis of the dicarboxylic acid intermediate of numerous enantiopure atropisomeric 1-phenylpyrrole derived amino alcohols was elaborated upon several years ago in our laboratory¹² via o,

a-dimetalated species.¹³ Thus, racemic 1-[2-carboxy-6-(trifluoromethyl)phenyl]-1H-pyrrole-2-carboxylic acid¹¹ was prepared by dimetallation of 1-[2-(trifluoromethyl)phenyl]-1H-pyrrole with Schlosser’s base¹⁴ followed by dry ice addition. The single atropisomers of 1-[2-carboxy-6-(trifluoromethyl)phenyl]-1H-pyrrole-2-carboxylic acid were prepared via diastereomeric salt formation in pure form.⁶ However, the development of an efficient resolution for a new racemate is usually laborious. In

the case of the widely used binaphthalene derived amino alcohol NOBIN, both methods (resolution and synthesis from optically active precursors) were published.^15,16 The synthetic method was used as the aromatic amine was prepared by Curtius reaction from enantiopure carboxylic acid and proved to be a highly stereoconvergent process.¹⁶Other axially chiral aromatic amines were also synthesized using this method preserving the optical activities.^17,18Diphenylphosphoryl azide (DPPA) is also a suitable reagent for modified Curtius reactions.^18–25 In addition, DPPA proved to be highly efficient for racemization-free peptide synthesis,²⁶ azidation of alcohols,²⁷ decarbonylation of aldehydes,²⁸ and the synthesis of oxazoles²⁹and thiol esters³⁰. Optically active amino alcohols are of great scientific interest;^31,32the diamines and their derivatives are also widely used as excellent bifunctional ligands and organocatalysts.^33–37 Moreover, recent advances in primary amine catalysed asymmetric transformations demonstrate the exceptional usefulness and versatility of primary amines in enantioselective synthesis.³⁸Therefore, the design and development of novel amine type chiral scaffolds is a major challenge in organic synthesis.

Herein, the ﬁrst racemization-free synthesis of the primary amino group containing diamine-type axially chiral 1-phenylpyr- roles is described. The comparison of the classical and the modiﬁed Curtius reactions is shown to demonstrate the functional sensitivity of the transformation. In addition, novel bifunctional primary/secondary and primary/tertiary diamines with an atropisomeric structural scaffold are presented.

⇑Corresponding author. Tel.: +36 1 463 3652; fax: +36 1 463 4648.

E-mail address:bmatravolgyi@mail.bme.hu(B. Mátravölgyi).

Tetrahedron:Asymmetry26 (2015) 738–745

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2. Results and discussion

The atropisomeric biaryl type anilines (Ra)-3 were prepared from the readily available amido esters (Sa)-1 as shown in Scheme 1. The optically active amido esters (Sa)-1 were synthesized according to recently reported methods by our group.^6,11 After the selective hydrolysis of the ester group, we studied the transformation of the carboxylic acid function into an amino group by employing azide formation followed by Curtius rearrangement and hydrolysis (Scheme 1). Primary (Sa)-1a, secondary (Sa)-1g as well as tertiary (Sa)-1b–f1-arylpyrrole-2-carboxamide derivatives were tested in these reactions.

Complete hydrolysis of (Sa)-1a–gesters was achieved over 1–

7 days at ambient temperature depending on theN-substituents of the amide moiety. High yields and excellent chemoselectivities were achieved in all cases. With the desired enantiopure benzoic acid derivatives in hand (Sa)-2a–g, we next focused on the synthesis of (Ra)-3cusing known classical methods: the formation of an activated acyl group followed by the reaction with sodium azide and Curtius rearrangement. Acylating functions were formed using thionyl chloride, oxalyl chloride or methyl chloroformate. At this stage our target compound was a new azide derivative, however we wanted to investigate the stereochemical stability of the atropisomeric intermediate. Therefore the reaction mixtures were quenched with methanol. The well known and fully characterized (Sa)-1cester was obtained from each activated acyl group containing derivatives. Enantiomeric compositions of these products were monitored by HPLC.¹¹Very small ee values or even racemic compositions were measured (Scheme 2). The stereochemical stability of the enantiomers of a rotationally hindered biaryl depends on several factors,^39,40one of which are the relative steric positions of the substituents which hinder the free rotation of the two aryl groups around the aryl–aryl connecting bond. In biphenyl derivatives, these groups are situated closer to the neighbouring benzene ring than in the case of 1-phenyl-1H-pyrrole derivatives because of the different bond angles of the six membered and ﬁve membered rings. Interconversions of the individual conformers of 1-phenyl-

1H-pyrrole skeleton containing atropisomers could be observed at elevated temperatures^11,41 or during intramolecular reactions of the repulsive functions, when the intermediate or the product had a low rotational barrier.^11,41Recently, we have reported the successful synthesis of optically active 1-phenyl-1H-pyrrole based amino alcohols, where the amide intermediates (e.g., (Sa)-4, Scheme 2) were produced from an ester group containing analogue (Sa)-5using thionyl chloride without any racemization.⁷

The mechanism of the racemisation is shown inScheme 3. The formed highly active acylating agents (S_a)-6react with the pyrrole connected amide group (supported by the steric proximity) in an intramolecular reaction to give a cyclic isoimidium salt7. The cyclic intermediate should have a low rotatory barrier (comparable to the literature data of similar compounds),^11,41and racemization easily occurs. The seven membered ring opens selectively in the reaction with methanol into racemic1cas the sole product, due to the electron withdrawing CF3group and the electron donating pyrrole ring caused by the high electron density difference between the iminium carbon and the carbonyl carbon nuclei.

Based on these results, further experiments were carried out to test a reagent, which provide a racemisation-free process. A well-established method to synthesize acyl azides is the use of DPPA (diphenylphosphoryl azide).²⁰ The carboxylic acid reacts with DPPA in the presence of base (triethylamine) to give an acyl azide directly, which thermally undergoes a Curtius rearrangement accompanied with expulsion of nitrogen. The formed isocyanate (Ra)-8 could be reacted with nucleophiles, such as alcohol or water (Scheme 4). However, the isocyanate could also react in the reaction mixture with the starting carboxylic acid giving possibilities for the formation of side products.²⁰ Therefore (to reduce side reactions) the reactions are usually performed in tert-butyl alcohol. DPPA is inert for tert-butyl alcohol and the formed isocyanate is transformed intotert-butyl carbamate instantaneously. In our case, by using a slight excess of DPPA in tert-butyl alcohol, the reaction gave the desired product in 65% yield.

N COOH F3C

O X

ee99% ee0-16%

1) SOCl2or (COCl)2 N

COOMe F3C

O NEt2

or ClCOOMe 2) MeOH

N COOMe

F3C

NMe2

O 1) SOCl2

2) HNMe2

(aq) ee99%

no racemization X = NEt2 racemization

(Sa)-2c

(Sa)-4 ⁷ 1c

X = OMe (Sa)-5

Scheme 2.Inﬂuence of the lateral substituents on the stereochemical stability of atropisomeric benzoic acid derivatives during their transformation into ‘regioisomeric’

products (Sa)-4⁷and1c.

N

COOCH3

F3C

O NR¹R²

(Sa)-1a-g ee99% (Sa)-2a-g

i) ii), iii)

(Ra)-3a-g N

COOH F3C

O NR¹R²

N NH2

F3C

O NR¹R²

Scheme 1.Synthesis of anilines (Ra)-3a–g. Reagents and conditions: (i) NaOH, MeOH–H2O, rt, 1–7 days, (ii) azide formation followed by Curtius rearrangement, (iii) hydrolysis; R¹= R²: H (a); Me (b); Et (c); Bu (d); pyrrolidinyl (e); R¹: Me, R²: (S)-

a-Me-Bn (f); R¹: H, R²: Bn (g). N

F3C

O NEt2

(Sa)-6 ee99%

N F3C

O NEt2

7 O

X N

COOMe F3C

O NEt2

1c ee0%

X O

low rotatory barrier racemization MeOH

Scheme 3.Supposed mechanism of the racemisation of (Sa)-6(X = Cl, OCOOMe).

F. Faigl et al. / Tetrahedron:Asymmetry26 (2015) 738–745 739

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However, increasing the molar ratio of DPPA led to higher yield.

By performing the reaction with 2 equiv of reagent, the product (Ra)-9cwas isolated in 73% yield after puriﬁcation (Table 1, entry 2). In the second step, the tert-butyl carbamate was converted under mild acidic conditions into the amine (R_a)-3c (83% yield, Scheme 4,Table 1, entry 2). This way the amido amine (Ra)-3c was prepared in satisfactory (61%) overall yield in two steps.

These promising results encouraged us to carry out a one-pot synthesis (route B) and compare the efficiencies of the two routes (A and B). We found that aqueous hydrolysis after completion of the Curtius rearrangement provided better results than those obtained from the two separate reactions (route A). Under the optimum conditions 2 equiv of DPPA were used for the formation of the isocyanate and its reaction with water afforded the amido amine (Ra)-3c(Scheme 4). Isolation of the pure product was easy and efficient (85% yield,Table 1, entry 3) by using column chromatography. To extend the scope of the one-pot synthesis and at the same time investigate the stereochemical stability of the model compounds during the multistep chemical transformation, other derivatives were also tested. In the case of the primary amide (Sa)-2a, the formation of side-products was observed only. The secondary amide (Sa)-2g proved to be suitable for this reaction sequence, but the moderate yield (42%,Table 1, entry 10) indicates the formation of side products. Tertiary amide groups were found to be well tolerated functions in the reaction with DPPA. As highlighted in Table 1, compounds (Sa)-2b–fwere transformed into the corresponding anilines with good preparative yields (entries 4, 6–9). Finally, diamines were prepared by reduction of the amido amines (Ra)-3b–gusing a borane complex to avoid defluorination of the trifluoromethyl group.¹¹Subsequent decomposition of the

formed borane-amine complexes afforded products (Ra)-10b–gin pure form (Scheme 5,Table 2).

The efficiency of the stereoconvergent synthesis of aniline-type diamines can be evaluated only if the enantiomeric purities of the products are taken into consideration. The large specific optical rotatory powers of the amido amines (Ra)-3b–g (obtained by Curtius rearrangement using DPPA followed by hydrolysis) indi- cated high enantiopurities in all cases (Table 2). However, by the reduction of the chromophore carbonyl groups, the specific optical rotational power of the product diamines radically decreased, as expected. Therefore, additional HPLC measurements on a chiral column were carried out to investigate any racemization during the whole transformation of the studied acids into diamines.

HPLC measurements showed that the enantiomeric composition of the obtained diamine type atropisomers remained unchanged, all compounds (Ra)-10b–gwere essentially pure (eeP99%).

3. Conclusions

On the basis of the experimental data we have concluded that the classical transformation of the free carboxylic acid function of optically active 1-(2-carboxy-6-triﬂuoromethylphenyl)-1H-pyrrole-2-carboxamides into an azide group via the acid chloride, or (Sa)-2a-g

DPPA, Et3N

(Ra)-8a-g N

COOH F3C

O NR¹R²

N NCO F3C

O NR¹R²

tBuOH (Ra)-9c

N NH F3C

O NR¹R²

O O

(Ra)-3a-g N

NH2

F3C

O NR¹R²

H2O

HCl, H2O A

B reflux, -N2

solvent

Scheme 4.Synthesis of anilines (Ra)-3a–gin two steps (‘A’) or in one-pot (‘B’).

Table 1

Synthesis of anilines (Ra)-3a–gin two steps (‘A’) or in one-pot (‘B’)^a

Entry Acid Synthesis way^a DPPA^b(equiv) Yield of (Ra)-3^c(%)

1 (Sa)-2c A 1.2 54 (65)^d

2 (Sa)-2c A 2 61 (73)^d

3 (Sa)-2c B 2 85

4 (Sa)-2a B 2 Trace

5 (Sa)-2b B 2 58

6 (Sa)-2d B 2 77

7 (Sa)-2e B 2 68

8 (Sa)-2f B 2 79

9 (Sa)-2g B 2 42

aSolvent for ‘A’ wastert-butyl alcohol, for ‘B’ was toluene.

b Diphenylphosphoryl azide.

c Isolated yields.

d Yield in the brackets related to thetert-butyl carbamate (Ra)-9cwhich was hydrolyzed to amine in 83% yield.

(Ra)-3b-g N

NH2

F3C

O NR¹R²

1) BH3SMe2

toluene, 60 °C 2) hydrolysis

(Ra)-10b-g N

NH2

F3C

NR¹R²

Scheme 5.Synthesis of diamines (Ra)-10b–g.

Table 2

Yields of diamines (Ra)-10b–gand the speciﬁc rotations of (Ra)-3b–gand (Ra)-10b–g Entry R¹,R² [a]D25of

(Ra)-3^a

Yield of (Ra)-10^b(%)

[a]D25of (Ra)-10^a

ee of (Ra)-10^c(%)

1 b 271.1 51 68.7 P99

2 c 292.3 64 75.1 P99

3 d 355.6 45 32.1 P99

4 e 184.4 62 50.0 P99

5 f 512.3 56 58.1 P99

6 g 123.5 47 29.9 P99

aAll of the speciﬁc rotations were determined in CHCl3solutions.

bIsolated yields.

cEe values were determined by HPLC measurements using chiral column (details are given in Section4).

740 F. Faigl et al. / Tetrahedron:Asymmetry26 (2015) 738–745