Caveat in the stereochemical outcome of the organocatalytic Diels–Alder reaction in PEG-400

Abstract

The organocatalytic Diels–Alder reaction in non-conventional solvent (PEG-400) has yielded cycloaddition products with diastereoselectivities hitherto not reported in detail using classical reaction conditions.

---

The Diels–Alder reaction, even though nine decades old,¹ continues to be the central organic transformation representative of atom economy and green chemistry. This reaction allows the formation of multiple bonds through a concerted mechanism thus making it an interesting chemical transformation for studying diastereo- and enantioselective versions. The enantioselective versions have seen a leap with the knowledge generated in the field of asymmetric organocatalysis. The first report of LUMO lowering activation under the influence of organocatalysis was reported by McMillan et al.² This pioneering observation was followed by several improvements and variations. Other organocatalysts,³ additives viz. water,⁴ organic⁵ and inorganic acids,⁶ hybrid catalysts⁷ etc. have been successful in value addition to this (4 + 2) cycloaddition reaction. Alternative solvent media involving ionic liquids,⁸ solvent free variant,⁹ ball and mill protocol,¹⁰ microwave reaction¹¹ etc. are other additions to this reaction.

Our research group has been engaged to promote the usefulness of polyethylene glycol (with various molecular weights) for chemical transformations with a sole objective to provide an alternate green solvent to the community.¹² We have observed that gaseous reactions perform better in PEG^12f even though the phases are different. The research group of Collins¹³ has taken advantage of phase separation as a strategy for performing high dilution reactions (intramolecular Glaser–Hay macrocyclisation and azide–alkyne cycloaddition ‘click’ reaction) in PEG and provided some insights into mechanistic aspects of performing reactions in PEG.

Our continued interest in this field of research inspired us to attempt the asymmetric Diels–Alder reaction under the influence of an organocatalyst in PEG-400 as the solvent. These experiments made us observe serendipitously that the Diels–Alder reaction between cinnamaldehyde and cyclopentadiene in PEG-400 as a solvent and TMS-diphenylprolinol as organocatalyst can be controlled to deliver a product of choice, either exo or endo, by addition of a co-catalyst. The acid co-catalyst favours formation of the endo product whereas absence of it leads to the prevail of exo. The details pertaining to this serendipitous and diastereoselective observations are presented here in (Scheme 1).

Scheme 1 Organocatalytic Diels–Alder reaction.

Organocatalytic Diels–Alder reactions have been explored using a wide range of catalysts like McMillan catalyst,² L-proline,² C-2 symmetric bipyrrolidines,^3f oxazoborolidine,^3e sulfonylhydrazines^3d etc. McMillan et al.² were the first to report the use of organocatalysis to obtain exo selective Diels–Alder product. We carried out the same reaction in both methanol–water mixture and PEG-400 to decide if PEG can be used as a solvent for this class of reaction. The methanol–water reaction yielded 56 : 44 ratio of the exo : endo (with 83 and 85% ee respectively² entry 1, Table 1) whereas PEG-400 reaction gave a 58 : 42 mixture of the diastereomers with 83 and 85% ee for exo and endo diastereomers (entry 2). Use of TFA as additive catalyst provided more of exo isomer (71 : 29 exo : endo) with 90% and 73% ee respectively (entry 3, Table 1). Perchloric acid on the other hand yielded the endo isomer in more quantities (23 : 77 exo : endo). In this case, however, enantioselectivity was not observed (entry 4, Table 1). These results encouraged us to explore other organocatalysts in PEG for Diels–Alder reaction.

Table 1 Screening of catalysts and conditions^a

Entry	Catalyst	Additive	Solvent	T (°C)	Yield^b [%]	Exo : endo^c	ee^d [%] exo/endo
a All reactions were performed with 5 mol% of catalysts, 20 mol% of additive, 0.75 mmol of cinnamaldehyde (1), and 2.27 mmol of cyclopentadiene (2) at various temperature in 1 M solvent.b Yields of isolated products as a mixture of exo and endo isomers.c Determined by ^1H NMR.d The ee value was determined by chiral stationary phase HPLC analysis using OJ-H column.e [α]^20D values of product 3 for entries 1–3 were +114.03 (c = 1.35, CHCl3); +96.72 (c = 1.7, CHCl3); +129.93 (c = 2.2, CHCl3), respectively.^5b
1^e	A	—	MeOH : H2O	rt	95	56 : 44	83/85
2^e	A	—	PEG 400	rt	85	58 : 42	83/85
3^e	A	TFA	PEG 400	rt	80	71 : 29	90/73
4	A	HClO4	PEG 400	rt	90	23 : 77	0/0
5	A	HClO4	PEG 400	4	88	24 : 76	1/4
6	B	—	PEG 400	rt	40	63 : 37	23/18
7	B	TFA	PEG 400	rt	60	40 : 60	18/6
8	B	HClO4	PEG 400	rt	65	12 : 88	0/0
9	B	HClO4	PEG 400	4	70	10 : 90	0/0
10	B	HClO4	PEG 400	80	20	67 : 33	0/0
11	B	CH3COOH	PEG 400	4	<10	35 : 65	—
12	B	CSA	PEG 400	4	<10	15 : 85	—
13	B	pTSA	PEG 400	4	<10	17 : 83	—
14	B	HCl	PEG 400	4	<10	22 : 78	—
15	C	—	PEG 400	rt	26	67 : 33	—
16	D	TFA	PEG 400	rt	61	63 : 37	21/17
17	D	HClO4	PEG 400	rt	70	23 : 77	0/0
18	E	TFA	PEG 400	rt	—	n.r	—
19	E	HClO4	PEG 400	4	45	10 : 90	0/0
20	F	HClO4	PEG 400	4	70	19 : 81	0/0
21	E	—	PEG 400	4	—	n.r	—
22	G	—	PEG 400	4	20	51 : 49	20/15
23	G	TFA	PEG 400	4	55	68 : 32	32/28
24	G	HClO4	PEG 400	4	66	15 : 85	9/12

---

Recently Hayashi et al.¹⁴ reported the use of (S)-TMS-diarylprolinol as an exo-selective catalyst for Diels–Alder reaction, where addition of 20 mol% of trifluoroacetic acid as a co-catalyst gave a ratio of exo : endo 85 : 15 with 97% ee for exo. Reaction of cyclopentadiene under normal conditions is mostly endo selective while Lewis acid addition increases the yield of the endo isomer. A reaction, catalyzed by (S)-TMS-diphenylprolinol, between cinnamaldehyde and cyclopentadiene in PEG-400, on the contrary, yielded predominantly exo product (63 : 37, exo : endo, entry 6, Table 1). Addition of Lewis acid dramatically changed the ratio favouring endo formation (TFA, 45 : 55, HClO₄ 17 : 83, exo : endo, entry 7, 8, Table 1). This result surprised us as now we had a mechanism to control the diastereoselectivity of the reaction by addition or otherwise of a co-catalyst. Thus, (S)-diphenylprolinol in presence of acid catalyst gave predominantly endo isomer (entries 7–14). To understand the trend for selectivity, 7 catalysts were screened and the results from these screenings are presented in Table 1. Same set of catalysts on addition of Lewis acids, TFA and HClO₄, gave results which were opposite to ones obtained without co-catalyst. Thus organocatalytic reaction in PEG-400 yielded exo predominently and addition of acid yielded the endo product.

Proline hydrochloride (catalyst C) in PEG 400 without any additive gave exo major (entry 15). (S)-TMS-diarylprolinol (catalyst D) and (S)-diarylprolinol (catalyst F) were also subjected to the same reaction and in case of catalyst D exo was major in presence of TFA and endo formed more with perchloric acid (entries 16, 17). Catalyst F in presence of perchloric acid gave 81% of endo (entry 20).

After studying various organocatalysts, we wished to determine the role of co-catalyst and PEG in the reaction. In this connection, we planned a series of reactions altering one parameter at a time. Thus, the first reaction was carried out in absence of PEG-400, catalyst and co-catalyst (Table 2; entry 1) where cyclopentadiene and cinnamaldehyde were heated to 100 °C which resulted in 50 : 50 ratio of endo : exo isomers without any enantioselectivity. In the next set of reactions, cinnamaldehyde (1) and cyclopentadiene (2) in the presence of MeOH : H₂O, MeOH : H₂O : TFA or MeOH : H₂O : HClO₄ (Table 2; entries 2, 3, 4) didn't provide any product. The reaction of 1 and 2 in PEG-400 in the absence of additive also didn't yield any product (Table 2; entry 5). Use of TFA in PEG (entry 6) also failed to produce required product, but a reaction in PEG–HClO₄ (entry 7) gave 14 : 86 ratio of exo : endo diastereomers without enantioselectivity. These reactions confirmed that PEG and organocatalyst or PEG–HClO₄ combinations result in Diels–Alder adducts.

Table 2 Effect of additive in organocatalytic Diels–Alder reaction^a

Entry	Additive	Solvent	Yield^b [%]	Endo : exo^c	ee^d [%] exo/endo
a Reactions were carried out with 0.75 mmol of cinnamaldehyde (1), and 2.27 mmol of cyclopentadiene (2) with 20 mol% of additive in 1 M solvent.b Yields of isolated products as a mixture of exo and endo isomers.c Determined by ^1H NMR.d The ee value was determined by chiral stationary phase HPLC analysis using OJ-H column.e Reaction carried under neat condition.
1^e	—	—	70	1 : 1	0/0
2	—	MeOH : H2O	—	n.r	—
3	TFA	MeOH : H2O	—	n.r	—
4	HClO4	MeOH : H2O	—	n.r	—
5	—	PEG 400	—	n.r	—
6	TFA	PEG 400	—	n.r	—
7	HClO4	PEG 400	30	14 : 86	0/0

---

We then wanted to explore the role of PEG in controlling the diastereoselectivity of the reaction. The first thought was role of hydroxyl group and to check if that was critical, other alcohols and diols were used replacing PEG (Table 3). Solvents used were methanol, t-butanol, 1,4-butanediol, 1,7-heptanediol, ethyleneglycol and water (Table 3; entries 1–6). Reactions in methanol and water resulted in formation of major exo-isomer whereas endo-isomer was formed in higher quantities in t-butanol and ethyleneglycol. Since the reaction was in acidic medium, the ethyleneglycol reaction yielded the acetal instead of the free aldehyde, as in other cases.¹⁵ The reaction in butanediol and heptanediol yielded very low quantity of the product along with recovery of the starting material.

Table 3 Screening of solvent^a

Entry	Solvent	Yield^b [%]	Exo : endo^c	ee^g [%] exo/endo
a Reactions were carried out with 0.75 mmol of cinnamaldehyde (1), and 2.27 mmol of cyclopentadiene (2) with 5 mol% of catalyst B and 20 mol% of additive in 1 M solvent.b Yields of isolated products as a mixture of exo and endo isomers.c Ratio determined by ^1H NMR.d Ref. 15.e Reaction performed at rt.f No reaction was observed in PEG-900 due its solid state at 4 °C.g The ee value was determined by chiral stationary phase HPLC analysis using OJ-H column.
1	MeOH	95	84 : 16	13/0
2	^tBuOH	26	30 : 70	32/0
3	1,4-Butanediol	<5	—	—
4	1,7-Heptanediol	<5	—	—
5^d	Ethyleneglycol	75	16 : 84	37/0
6^e	H2O	65	68 : 32	56/22
7	PEG-600	60	23 : 77	25/0
8^f	PEG-900	n.r	—	—

---

Based on the solvent screening, PEG-400 was found to be the best solvent to carry out the reaction. To understand the logic behind diastereoselectivity observed, we carried out DSC (differential scanning calorimetry)¹⁶ studies to determine the intermediate phase of the reaction. The glass transition temperature of the mixture indicated the formation of a complex between cinnamaldehyde, pyrrolidine of organocatalyst which is enveloped in PEG 400 and stabilized by perchloric acid. Absence of any of these does not form the intermediate complex. Xu and coworkers¹⁷ have reported the formation of a supramolecular self-assembly between organocatalyst and PEG and we expect a similar complex might be forming in our case (Fig. 1). The complex formed may be due to the salt of the organocatalyst which is inducing the formation of the stabilized complex with PEG-400. The cavity like arrangement of the complex may lead to high facial selectivity resulting the endo-product.

Fig. 1 Expected stabilized complex.

Predominant formation of endo isomer was also confirmed by 1D (¹H and ¹³C) and 2D-(DQFCOSY, NOESY, HSQC and HMBC) NMR experiments. The observed NOE cross peaks between 1-H(9.51 ppm)/6-H(6.09 ppm), 8-H(1.73 ppm)/Ar-H(7.18 ppm), 5-H(6.33 ppm)/3-H(3.01 ppm) and 8-H(1.73 ppm)/2-H(2.89 ppm) protons suggest that endo-3 isomer is the major product in the adduct mixture. Furthermore, the scalar coupling constants ³J_2-H/7-H = 3.51 Hz and ³J_3-H/4-H = 1.68 Hz found in endo-3 support the conclusion that the endo isomer is the major product of a adduct mixture. The configuration of the exo-3 isomer of a mixture was assigned by using the observed NOE cross peaks between 5-H(5.99 ppm)/Ar-H(7.06 ppm), 8-H(1.52 ppm)/3-H(3.64 ppm) and 2-H(2.51 ppm)/6-H(6.25 ppm) protons.¹⁶

The catalyst complex was then further explored for other substrates to verify if it has a wider applicability. Substituted cinnamaldehydes also gave endo major in PEG-400 with perchloric acid (Table 4, entries 1–4). The reaction between cinnamaldehyde and furan did not give any product. Also there was no change in the reaction between acrolein and cyclopentadiene.

Table 4 Substrate exploration^a

Entry	Ar	Yield^b [%]	Exo : endo^c	ee^d [%] endo/exo
a All reactions were performed with 5 mol% of catalyst B, 20 mol% of HClO4, 0.75 mmol of aldehyde and 2.27 mmol of cyclopentadiene at 4 °C in 1 M PEG-400.b Yields of isolated products as a mixture of exo and endo isomers.c Determined by ^1H NMR.d The ee value was determined by chiral stationary phase HPLC analysis using OJ-H column.
1	Ph	65	10 : 90	0/0
2	3-Cl-Ph	62	12 : 88	0/0
3	3-NO2-Ph	56	30 : 70	0/0
4	4-MeOH-Ph	60	14 : 86	13/3

---

The reaction with (S)-TMS-diphenylprolinol showed diastereoselective control with the freedom to choose the additive to decide for the required product, it unfortunately compromised the enantioselectivity of the reaction. After getting good to excellent diastereoselectivity we were expecting the products to exhibit enantioselectivity in equal measures. The reaction with McMillan catalyst in PEG 400 had reasonably good enantioselectivity but the use of perchloric acid resulted in lower ratios. A report by Langlois et al.^6a states that for sulfonylhydrazine catalyzed Diels–Alder reaction, use of perchloric acid resulted in lower chiral induction and by extending the same logic, we felt that other Lewis acids need to be explored to get good diastereo and enantio selectivities. The work in this area is being taken up and results of the same will be reported at a later stage.

The PEG-400 was used as a solvent for reusability of catalyst and additive, the reaction was carried out between cinnamaldehyde and cyclopentadiene for four runs (Table 5).

Table 5 Recyclability of catalyst and additive in PEG-400

a Isolated yield after column chromatography.
Run	1st	2nd	3rd	4th
Yield^a (%)	65	60	52	45

---

Conclusions

Thus, in conclusion, we report a distereo-controlled Diels–Alder reaction in PEG-400 as a solvent where the outcome is determined by addition or otherwise of the co-catalyst. A complex intermediate resulting from enamine enveloped by PEG-400 and stabilized by acid co-catalyst may be a plausible reaction for observed results.

Acknowledgements

The authors thank Council of Scientific and Industrial Research under Department of Science and technology, Government of India for funding XII Five year Plan project (ORIGIN). SC thanks JC Bose Fellowship for research funding. Authors thank Dr Rohit Kumar Rana, Dr Pratyay Basak and Dr Rambabu Chegondi for Scientific discussions.

Notes and references

1. (a) D. A. Evans and J. S. Johnson, in Comprehensive Asymmetric Catalysis, ed. E. N. Jacobson, A. Pfaltz and H. Yamamoto, Springer, New York, 1999, vol. 3, p. 1777; (b) E. J. Corey, Angew. Chem., Int. Ed., 2002, 41, 1650; (c) K. C. Nicolaou, S. A. Snyder, T. Montagnon and G. Vassilikogiannakis, Angew. Chem., Int. Ed., 2002, 41, 1668; (d) Y. Hayashi, in Cycladdition Reactions in Organic Synthesis, ed. S. Kobayashi and K. A. Jorgensen, Wiley-VCH, Weinheim, 2002, ch. 1.
2. K. A. Ahrendt, C. J. Borths and D. W. C. McMillan, J. Am. Chem. Soc., 2000, 122, 4243.
3. (a) M. Lemay and W. W. Ogilvie, Org. Lett., 2005, 7, 4141; (b) Z. Zhu and J. H. Espenson, J. Am. Chem. Soc., 1997, 119, 3507; (c) Y. Wang, X. Xu and W. Pei, Synth. Commun., 2009, 39, 2032; (d) Y. Langlois, A. Petit, P. Remy, M.-C. Scherrmann and C. Kouklovsky, Tetrahedron Lett., 2008, 49, 5576; (e) D. Liu, E. Canales and E. J. Corey, J. Am. Chem. Soc., 2007, 129, 1498; (f) Y. Ma, Y. J. Zhang, S. Jin, Q. Li, C. Li, J. Lee and W. Zhang, Tetrahedron Lett., 2009, 50, 7388.
4. (a) M. Lemay and W. W. Ogilive, Org. Lett., 2005, 7, 4141; (b) Y. Hayashi, S. Samanta, H. Gotoh and H. Ishikawa, Angew. Chem., Int. Ed., 2008, 47, 6634; (c) Z. Zhu and J. H. Espenson, J. Am. Chem. Soc., 1997, 119, 3507.
5. (a) E. J. Corey, T. Shibata and T. W. Lee, J. Am. Chem. Soc., 2002, 124, 3808; (b) K. Ishihara, H. Kurihara, M. Matsumoto and H. Yamamoto, J. Am. Chem. Soc., 1998, 120, 6920.
6. (a) Y. Langlois, A. Petit, P. Remy, M.-C. Scherrmann and C. Kouklovsky, Tetrahedron Lett., 2008, 49, 5576; (b) J. L. Cavill, R. L. Elliott, G. Evans, I. L. Jones, J. A. Platts, A. M. Ruda and N. C. O. Tomkinson, Tetrahedron, 2006, 62, 410; (c) Y. Ma, Y. J. Zhang, S. Jin, Q. Li, C. Li, J. Lee and W. Zhang, Tetrahedron Lett., 2009, 50, 7388; (d) J.-J. Zhao, S.-B. Sun, S.-H. He, Q. Wu and F. Shi, Angew. Chem., Int. Ed., 2015, 54, 5460; (e) Y. Wang, M.-S. Tu, L. Yin, M. Sun and F. Shi, J. Org. Chem., 2015, 80, 3223.
7. (a) S. Guizzetti, M. Benaglia and J. S. Siegel, Chem. Commun., 2012, 48, 3188; (b) N. Haraguchi, Y. Takemura and S. Itsuno, Tetrahedron Lett., 2010, 51, 1205; (c) A. Puglist, M. Benaglia, R. Annunziata, V. Chiroli, R. Porta and A. Gervasini, J. Org. Chem., 2013, 78, 11326; (d) A.-B. Xia, D.-Q. Xu, C. Wu, L. Zhao and Z.-Y. Xu, Chem.–Eur. J., 2012, 18, 1055; (e) Z.-Y. Han, D.-F. Chen, Y.-Y. Wang, R. Guo, P.-S. Wang, C. Wang and L.-Z. Gong, J. Am. Chem. Soc., 2012, 134, 6532.
8. (a) T. Rispens and J. B. F. N. Engberts, J. Org. Chem., 2002, 67, 7369; (b) M. J. Earle, P. B. McCormac and K. R. Seddon, Green Chem., 1999, 1, 23; (c) K. Erfurt, I. Wandzik, K. Walczak, K. Matuszek and A. Chrobok, Green Chem., 2014, 16, 3508; (d) T. Fischer, A. Sethi, T. Welton and J. Woolf, Tetrahedron Lett., 1999, 40, 793.
9. D. Huertas, M. Florscher and V. Gragojlovic, Green Chem., 2009, 11, 91.
10. (a) H. Watanabe and M. Senna, Tetrahedron Lett., 2005, 46, 6815; (b) Z. Zhang, Z. W. Peng, M. F. Hao and J. G. Gao, Synlett, 2010, 2895.
11. (a) G. Shore and M. G. Organ, Chem. Commun., 2008, 838–840; (b) A. M. Sarotti, R. A. Spanevelb and A. G. Suarez, ARKIVOC, 2011, vii, 31; (c) A. M. Sarotti, P. L. Pisano and S. C. Pellegrinet, Org. Biomol. Chem., 2010, 8, 5069.
12. (a) S. Chandrasekhar, C. Narsihmulu, S. S. Sultana and N. Ramakrishna Reddy, Org. Lett., 2002, 4, 4399; (b) S. Chandrasekhar and N. Kiranmai, Tetrahedron Lett., 2010, 51, 4058; (c) A. S. Reddy, R. Chegondi and S. Chandrasekhar, Proc. Natl. Acad. Sci., India, Sect. B, 2015, 81, 1171; (d) S. Chandrasekhar, V. Patro, L. N. Chavan, R. Chegondi and R. Gree, Tetrahedron Lett., 2014, 55, 5932; (e) S. Chandrasekhar, V. Patro, G. P. K. Reddy and R. Gree, Tetrahedron Lett., 2012, 53, 6223; (f) S. Chandrasekhar, S. Jaya Prakash and C. Lohitha Rao, J. Org. Chem., 2006, 71, 2196; (g) S. Chandrasekhar, S. Shameem sultana, Y. Srinivasa Rao and N. Ramakrishna Reddy, Synthesis, 2006, 839; (h) S. Chandrasekhar, N. Ramakrishna Reddy, S. Shameem sultana, C. Narsimhulu and K. V. Reddy, Tetrahedron, 2006, 62, 338; (i) S. Chandrasekhar and N. Kiranmai, Tetrahedron Lett., 2010, 51, 4058; (j) S. Chandrasekhar, N. Kesava Reddy and V. Praveen Kumar, Tetrahedron Lett., 2010, 51, 3623; (k) S. Chandrasekhar, T. Shyamsunder, G. Chandrasekhar and C. Narsihmulu, Synlett, 2004, 522; (l) S. Chandrasekhar, C. Narsihmulu, G. Chandrasekhar and T. Shyamsunder, Tetrahedron Lett., 2004, 45, 2421; (m) S. Chandrasekhar, C. Narsimhulu, S. Shameem sultana and N. Ramakrishna Reddy, Chem. Commun., 2003, 1716; (n) S. Chandrasekhar, C. Narsimhulu, S. Shameem sultana and N. Ramakrishna Reddy, Org. Lett., 2002, 4, 4399.
13. (a) A.-C. Bédard and S. K. Collins, J. Am. Chem. Soc., 2011, 133, 19976; (b) A.-C. Bédard and S. K. Collins, Chem.–Eur. J., 2013, 19, 2108; (c) A.-C. Bédard, S. Regnier and S. K. Collins, Green Chem., 2013, 15, 1962; (d) A.-C. Bédard and S. K. Collins, Org. Lett., 2014, 16, 5286.
14. (a) H. Gotoh and Y. Hayashi, Org. Lett., 2007, 9, 2859; (b) Y. Hayashi, S. Samanta, H. Gotoh and H. Ishikawa, Angew. Chem., Int. Ed., 2008, 47, 6634.
15. The reaction in the presence of ethyleneglycol .
16. For more details see ESI.†.
17. (a) D. Q. Xu, S. P. Luo, Y. F. Wang, A. B. Xia, H. D. Yue, L. P. Wang and Z. Y. Xu, Chem. Commun., 2007, 4393; (b) A.-B. Xia, D.-Q. Xu, C. Wu, L. Zhao and Z.-Y. Xu, Chem.–Eur. J., 2012, 18, 1055.

---

Footnote

† Electronic supplementary information (ESI) available: General experimental procedures, NMR data, DSC data, HPLC data or other electronic format. See DOI: 10.1039/c6ra15035g

---