Stereoselective Synthesis of cis- or trans-3,5-Disubstituted Pyrazolidines via Pd-Catalyzed Carboamination Reactions. Use of Allylic Strain to Control Product Stereochemistry Through N-Substituent Manipulation

Abstract

The stereoselective synthesis of either trans- or cis-3,5-disubstituted pyrazolidines is accomplished via Pd-catalyzed carboamination reactions of unsaturated hydrazine derivatives. The products are obtained in good yield with up to >20:1 diastereoselectivity. Stereocontrol is achieved by modulating the degree of allylic strain in the transition state for syn-aminopalladation through a simple modification of the substrate N²-substituent. The pyrazolidine products can be further transformed to 3,5-disubstituted pyrazolines via deprotection/oxidation, or to substituted 1,3-diamines via N-N bond cleavage.

Introduction

Pd-catalyzed reactions of γ-hydroxy- and γ-aminoalkenes with aryl bromides are efficient and convergent methods for the stereoselective construction of substituted oxygen- and nitrogen heterocycles.^1,2 However, despite the utility of these transformations, their stereochemical outcome is substrate-controlled, and it has not been possible to overcome inherent bias for formation of either cis-or trans- disubstituted products in a series. For example, secondary alcohol substrates always afford trans-2,5-disubstituted tetrahydrofurans via syn-oxypalladation through cyclic transition states with pseudoequatorial orientation of the R-group (Scheme 1).2a,b In contrast, reactions of analogous N-Boc or N-aryl amine substrates provide cis-2,5-disubstituted pyrrolidines via syn-heteropalladation with the R-group in a pseudoaxial position to minimize developing A^(1,3)-strain.^2c,d

Scheme 1.

2,5-Disubstituted Heterocycle Stereochemistry

The model shown in Scheme 1 suggests that product stereochemistry in Pd-catalyzed carboamination reactions could be controlled through variation of N-substituents to maximize or minimize A^(1,3)-strain, which would allow the synthesis of either stereoisomer of a heterocyclic target with only minor substrate modification. Although the impact of A^(1,3)-strain on stereoselective reactions is welldocumented,³ manipulation of A^(1,3)-strain to allow for selective generation of two different product stereoisomers from closely related substrates is rare,⁴ and has not been demonstrated in Pd-catalysis.

N-Butenyl hydrazines were initially selected as substrates for our studies on the effect of A^(1,3)-strain on product stereochemistry in Pd-catalyzed carboamination reactions, as the N² substituent of these compounds can be varied with minimal electronic perturbation to the cyclizing N¹-atom. As shown in Scheme 2, it seemed that trans-3,5-disubstituted pyrazolidines could be prepared from hydrazine substrates bearing formally sp²-hybridized N²-atoms with π-accepting substituents, such as aryl groups or carbamates. These compounds should react via transition state 2 in which the C4 R-group is oriented in a pseudoaxial position to avoid unfavorable A^(1,3)-strain between the sp²N-Ar group and the R-substituent that is present in transition state 1. In contrast, we believed that selective synthesis of cis-3,5-disubstituted pyrazolidines could be accomplished through cyclizations of substrates lacking an N^2- substituent, which should occur via transition state 4 with the R-group in a pseudoequatorial position.

Scheme 2.

Transition States for Pyrazolidine Synthesis

In addition to the fundamental significance of investigations on the effects of allylic strain in the reactions described above, the pyrazolidine products of these transformations are potentially useful precursors to biologically active molecules.^5a,6 The N-N bond of pyrazolidines can also be cleaved under reducing conditions to afford synthetically useful 1,3-diamines,^5c,d and pyrazolidines can be oxidized to afford pyrazolines^7,8 or pyrazoles,^9,10 which are also of utility in medicinal chemistry applications.

In this Article we demonstrate the validity and application of this concept in Pd-catalyzed carboamination reactions, which provide a new stereoselective route to both 3,5-cis- and 3,5-trans disubstituted pyrazolidines from simple precursors.⁵ These are the first examples of the synthesis of pyrazolidine derivatives via Pd-catalyzed carboamination reactions between aryl/alkenyl halides and alkenes bearing pendant heteroatoms. Moreover, the transformations described herein are the first to illustrate that allylic strain interactions can be manipulated through a simple substrate modification (N²-protection vs. no N²-protection) to allow for control of relative stereochemistry in Pd-catalyzed reactions.

Results and Discussion

Stereoselective Synthesis of Disubstituted Pyrazolidines: Proof of Concept

In order to test the hypothesis outline above, we elected to initially examine Pd-catalyzed carboamination reactions of 4-bromobiphenyl with N²-butenylhydrazine derivatives 5 and 7. These substrates were prepared from butyraldehyde in two steps via condensation with the appropriate hydrazine, followed by addition of allylmagnesium bromide. After some optimization, we found that treatment of 5 with 4-bromobiphenyl and NaOtBu in the presence of catalytic amounts of Pd₂(dba)₃ and dppe¹¹ afforded trans-3,5-disubstituted pyrazolidine 6 with 9:1 dr. Upon purification 6 was obtained in 78% yield with >20:1 dr (eq 1). Although the Pd₂(dba)₃/dppe catalyst was not effective in the analogous reaction of 7,¹² use of a Pd(OAc)₂/dpe-phos catalyst provided satisfactory results, and led to the generation of cis-3,5-disubstituted pyrazolidine 8 with 6:1 dr. After column chromatography, 8 was obtained in 72% yield with 10:1 dr (eq 2). These results clearly demonstrate that product stereochemistry can be reversed by varying the degree of allylic strain in the transition state through a very simple modification of the substrate N²-substituent.

Stereoselective Synthesis of trans-3,5-Disubsititued Pyrazolidines

Having demonstrated that the stereoselective synthesis of trans-3,5-disubstituted pyrazolidines can be achieved using N²-arylated substrates such as 5, we proceeded to examine the scope of these transformations. As shown in Table 1, the coupling reactions can be conducted with a variety of electron-rich, -neutral, and -poor aryl bromides, and a number of functional groups are tolerated. Several substrates bearing aryl or unbranched alkyl substituents at C4 (9-11) were successfully transformed to trans-3,5-disubstituted pyrazolidines 12-16 in moderate to good yield. Good to excellent levels of diastereoselectivity are obtained,¹³ and pyrazolidines bearing differentially substituted nitrogen atoms (N¹-Boc, N²-PMP) can be prepared in a straightforward manner. Curiously, although the coupling of 4-bromobiphenyl with hydrazine 5 proceeded with good diastereoselectivity (9:1 dr, eq 1), use of α-bromostyrene as an electrophilic coupling partner with this substrate (entry 6) led to the formation of 17 with only 2:1 dr. However, partial separation of diastereomers was achieved during purification, and 17 was isolated in 70% yield as a 10:1 mixture of stereoisomers. The origin of the diminished diastereoselectivity in this reaction is not clear, although this effect has been previously observed in related Pd-catalyzed carboamination reactions of N-allylureas.¹⁴

Table 1.

Synthesis of trans-3,5-Disubstituted-N²-Aryl Pyrazolidines^a

Entry	Substrate	R	Ar	R1	Product	Yield(%)b	drc
1	9	Ph	Ph	p-PhC(O)Ph	12	74	20:1 (11:1)
2d	10	C3H7	PMP	o-MePh	13	61	>20:1 (10:1)
3	10	C3H7	PMP	p-tBuPh	14	55	>20:1 (8:1)
4	10	C3H7	PMP	p-CNPh	15	63	>20:1 (>20:1)
5e	11	(CH2)4CH(OMe)2	Ph	p-CF3Ph	16	64	>20:1 (>20:1)
6f	5	C3H7	Ph	α-styryl	17	70	10:1 (2:1)

^aConditions: 1.0 equiv hydrazine, 1.7 equiv ArBr, 1.7 equiv NaOtBu, 2 mol % Pd(OAc)₂, 2 mol % dppe, toluene (0.25 M), 90 °C, 3-12 h.

^bIsolated yield, average of two or more experiments.

^cDiastereomeric ratios are reported for the isolated products. Diastereomeric ratios in parentheses were observed in crude reaction mixtures.

^dThe reaction was conducted using Pd₂(dba)₃ as precatalyst.

^eThe reaction was conducted with 4 mol % P(2-furyl)₃ in place of dppe.

^fThe reaction was conducted with 4 mol % Dpephos in place of dppe.

The presence of a Boc-group on N¹ was essential for the stereoselective preparation of trans-3,5-disubstituted N²-aryl pyrazolidines. As shown in eq 3, the carboamination of 1,2-diphenylhydrazine-derived substrate 18 with 4-bromo-tert-butylbenzene proceeded with only 2:1 diastereoselectivity.¹⁵ Efforts to carry out the Pd-catalyzed carboamination reactions of 20, which lacks an N¹ substituent, did not generate pyrazolidines, but instead afforded pyrazolines 21-22 in synthetically useful yields (eq 4).¹⁶

The hypothesis outlined above in Scheme 2 suggests that replacement of the N²-aryl substituent on the substrate with other π-accepting groups should also allow for the construction of trans-3,5-disubstituted pyrazolidines. Therefore, in order to examine the effect of the N²-substituent on both reactivity and stereoselectivity, we prepared several butenylhydrazine derivatives bearing N²-carbonyl functionality. Our initial attempts to employ substrates analogous to 5 but with N²-Ac or Bz groups were unsuccessful, and led to the formation of complex mixtures of products. However, we were gratified to discover that the Pd/BINAP-catalyzed carboamination of 4-bromobiphenyl with 23, which contains Boc-groups on both N¹ and N², provided the desired pyrazolidine 25 in moderate yield (52%), but with >20:1 diastereoselectivity (Table 2, entry 1).¹⁷ The modest yield in this reaction was due to competing Heck arylation of 23. Interestingly, coupling reactions of 23 with electron-poor aryl bromides were much cleaner, and afforded pyrazolidines 26-27 in good yield with excellent dr (entries 2-3). However, efforts to employ alkenyl bromides as coupling partners in carboamination reactions of 23 failed to generate the desired pyrazolidine products; competing Heck alkenylation of the substrates was observed. Coupling reactions of aryl bromides with the C4-phenyl substituted substrate 24 provided similar results as were obtained in transformations of 23 (entries 4-5).

Table 2.

Synthesis of trans-3,5-Disubstituted-N²-Boc Pyrazolidines^a

Entry	Substrate	R	Ar	Product	Yield(%)b	drc
1	23	C3H7	p-PhPh	25	52	>20:1 (>20:1)
2	23	C3H7	p-PhC(O)Ph	26	78	>20:1 (>20:1)
3	23	C3H7	m-CF3Ph	27	81	>20:1 (>20:1)
4	24	Ph	2-naphthyl	28	55	>20:1 (>20:1)
5	24	Ph	m-MeOPh	29	47	>20:1 (>20:1)

^aConditions: 1.0 equiv of substrate, 1.7 equiv of ArBr, 1.7 equiv of NaOtBu, 2 mol % Pd(OAc)₂, 2 mol % BINAP, toluene (0.25 M), 110 °C. Reactions were complete in 12-14 h; reaction times have not been minimized.

^bIsolated yield (average of two or more experiments).

^cDiastereomeric ratios are reported for the isolated products. Diastereomeric ratios in parentheses were observed in crude reaction mixtures.

Stereoselective Synthesis of cis-3,5-Disubsititued Pyrazolidines and 3,3,5-Trisubstituted Pyrazolidines

In order to explore the scope of carboamination reactions of N-butenylhydrazine derivatives lacking N²-substituents, several substrates were prepared and treated with various aryl or alkenyl bromides. These transformations proceeded with moderate to good yields and diastereoselectivities for several different substrate combinations (Table 3). Both aryl and alkenyl halides can be employed as coupling partners, although reactions involving alkenyl halides proceeded with somewhat lower yields and diastereoselectivities. The reactions were effective with both aldehyde-derived substrates (7 and 30, entries 1-5) and ketone-derived substrates (31-34, entries 6-9). Substrates 33-34 bearing two different substituents at C4 were converted to trisubstituted pyrazolidines 42-43 with moderate to good stereocontrol (entries 8-9).

Table 3.

Synthesis of trans-Disubstituted and -Trisubstituted Pyrazolidines^a

Entry	Substrate	RS	RL	R1	Product	Yield(%)b	drc
1	7	H	C3H7	p-ClPh	35	70	>20:1 (7:1)
2d	7	H	C3H7	β-styryl	36	54	5:1 (5:1)
3	30	H	Ph	m-MePh	37	66	13:1 (10:1)
4	30	H	Ph	p-tBuO2CPh	38	55	>20:1 (>20:1)
5d	30	H	Ph	α-styryl	39	63	11:1 (8:1)
6d	31	Me	Me	p-tBuO2CPh	40	80	-
7d	32	(CH2)5		N-(Bn)-5-indolyl	41	56	-
8	33	Me	Ph	p-PhPh	42	83	6:1 (6:1)
9	34	Me	tBu	6-MeO-2-naphthyl	43	73	>20:1 (12:1)

^aConditions: 1.0 equiv hydrazine, 1.2 equiv ArBr, 1.2 equiv NaOtBu, 2 mol % Pd(OAc)₂, 2 mol % Dpe-phos, toluene (0.25 M), 70 °C, 4-12 h.

^bIsolated yield, average of two or more experiments.

^cDiastereomeric ratios are reported for the isolated products. Diastereomeric ratios in parentheses were observed in crude reaction mixtures.

^dThe reaction was conducted using 1.2 equiv ArBr and 1.2 equiv of NaOtBu at 70 °C.

Transformations of Pyrazolidine Products

In order to further illustrate the synthetic utility of the pyrazolidine-forming reactions described above, we have briefly examined transformations of the pyrazolidine products into other useful compounds such as 1,3-diamines and pyrazolines. Our initial attempts to cleave the N-N bond of the pyrazolidine products, using a number of different conditions, were unsuccessful. However, we were gratified to find that N-N bond cleavage of cis-3,5-disubstituted pyrazolidine 8 could be achieved after benzoylation of the unprotected nitrogen atom. As shown in Scheme 3, treatment of 8 with benzoyl chloride and pyridine provided 44 in 77% yield. The doubly protected pyrazolidine was then converted to syn-1,3-diamine 45 in 92% yield by treatment with SmI₂.¹⁸

Scheme 3.

Syn-1,3-Diamine Synthesis

Conversion of trans-1,3-disubstituted pyrazolidine 14 to a 1,3-diamine required exchange of the N-Boc substituent for a trifluoroacyl group. However, standard conditions for cleavage of N-Boc groups led to complex mixtures of products, and competing oxidation of the deprotected pyrazolidine was also observed. After considerable experimentation we found that treatment of 14 with HCl/dioxane followed by addition of pyridine and trifluoroacetic anhydride generated 46 in a modest 38% yield. Fortunately, the N-N bond cleavage of 46 proceeded smoothly using conditions identical to those employed for the conversion of 44 to 45, and the anti-1,3-diamine 47 was obtained in 90% yield (Scheme 4).

Scheme 4.

Anti-1,3-Diamine Synthesis

The selective conversion of trans-3,5-disubstituted pyrazolidine 15 to 3,5-disubstituted pyrazolines 48 and 49 was easily accomplished as shown in Scheme 5. Treatment of 15 with CAN led to cleavage of the N-PMP group with concomitant oxidation to pyrazoline 48 in 75% yield. Alternatively, use of microwave irradiation to remove the N-Boc group from 15 also led to facile oxidation, and provided 49 in 55% yield.

Scheme 5.

Synthesis of 3,5-Disubstituted Pyrazolines

Summary and Conclusion

In summary, we have developed a new stereoselective synthesis of cis- and trans-disubstituted pyrazolidines from N-butenyl hydrazine derivatives. The products are generated with good to excellent diastereoselectivity and chemical yield, and can be transformed to synthetically useful pyrazolines or 1,3-diamines via oxidation or reduction. These are the first examples of the use of hydrazine-derived substrates in Pd-catalyzed alkene carboamination reactions with aryl/alkenyl halides, and represent a significant extension of carboamination methodology. Importantly, these experiments also demonstrate that allylic strain interactions can be manipulated through a simple substrate modification (N²-protection vs. no N²-protection) to allow for control of relative stereochemistry in Pd-catalyzed reactions. Further studies to extend this concept to other heterocyclic systems are currently underway.

Experimental

Pd-Catalyzed Synthesis oftrans-3,5-Disubstituted Pyrazolidines: General Procedure

A flame-dried Schlenk tube equipped with a magnetic stirbar was cooled under a stream of nitrogen and charged with either Pd₂(dba)₃ (1 mol % complex, 2 mol % Pd) or Pd(OAc)₂ (2 mol % complex, 2 mol % Pd), dppe (2 mol %), sodium tert-butoxide (1.7 equiv), and the aryl bromide (1.7 equiv). The Schlenk tube was purged with nitrogen and the hydrazine substrate (1.0 equiv) was added as a solution in toluene (4 mL solvent/ mmol substrate). The resulting mixture was heated to 90 °C until the starting material was consumed as judged by ¹H NMR analysis. The reaction mixture was cooled to rt and treated with saturated aqueous ammonium chloride (2 mL) and ethyl acetate (5 mL). The layers were separated, the aqueous layer was extracted with ethyl acetate (2 × 5 mL), and the combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel.

(±)-(3R,5R)-tert-Butyl-5-(biphenyl-4-yl-methyl)-2-phenyl-3-propylpyrazolidine-1-carboxylate (6)

The reaction of 50 mg (0.16 mmol) of 5 with 4-bromobiphenyl (65 mg, 0.28 mmol) was conducted for 18 h at 90 °C according to the general procedure using a catalyst composed of Pd₂(dba)₃ (1.5 mg, 0.002 mmol, 1 mol %) and dppe (1.3 mg, 0.003 mmol, 2 mol %). This procedure afforded 59 mg (79%) of the title compound as a yellow oil. ¹H NMR analysis of the crude reaction mixture indicated the product was formed as a 9:1 mixture of diastereomers; the isolated product was obtained with >20:1 dr following purification. Data are for the major diastereomer. ¹H NMR (500 MHz, CDCl₃) δ 7.57-7.56 (d, J = 8.0 Hz, 2 H), 7.51-7.49 (d, J = 8.0 Hz, 2 H), 7.44-7.41 (t, J = 8.0 Hz, 2 H), 7.34-7.31 (t, J = 7.5 Hz, 1 H), 7.27-7.24 (m, 4 H), 6.97-6.96 (d, J = 8.0 Hz, 2 H), 6.91-6.88 (t, J = 7.0 Hz, 1 H), 4.41-4.36 (m, 1 H), 3.93-3.90 (m, 1 H), 3.44 (dd, J = 4.5, 12.5 Hz, 1 H), 2.56-2.51 (m, 1 H), 1.92-1.88 (m, 1 H), 1.84-1.81 (m, 1 H), 1.60-1.58 (m, 1 H), 1.47-1.42 (s, 9 H), 1.33-1.27 (m, 1 H), 1.27-1.25 (s, 2 H), 0.97-0.94 (t, J = 7.0 Hz, 3 H); ¹³C NMR (125 MHz, CDCl₃) δ 151.6, 141.2, 139.5, 138.2, 129.7, 129.0, 128.8, 127.4, 127.2, 127.0, 120.5, 114.7, 80.7, 64.9, 60.5, 42.4, 37.3, 36.2, 28.6, 20.2, 14.3 (one carbon signal is absent due to incidental equivalence); IR (film) 2963, 1696 cm^-1. MS (ESI) 457.2855 (457.2855 calcd for C₃₀H₃₆N₂O₂, M + H⁺

Pd-Catalyzed Synthesis ofcis-3,5-Disubstituted Pyrazolidines: General Procedure

A flame-dried Schlenk tube equipped with a magnetic stirbar was cooled under a stream of nitrogen and charged with Pd(OAc)₂ (2 mol % complex, 2 mol % Pd), dpe-phos (2 mol %), sodium tert-butoxide (1.2 equiv), and the aryl bromide (1.2 equiv). The Schlenk tube was purged with nitrogen and the hydrazine substrate (1.0 equiv) was added as a solution in toluene (4 mL solvent/mmol substrate). The resulting mixture was heated to 70 °C until the starting material was consumed as judged by ¹H NMR analysis. The reaction mixture was cooled to rt and treated with saturated aqueous ammonium chloride (2 mL) and ethyl acetate (5 mL). The layers were separated, the aqueous layer was extracted with ethyl acetate (2 × 5 mL), and the combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel.

(±)-(3R,5S)-tert-Butyl-5-(biphenyl-4-yl-methyl)-3-propylpyrazolidine-1-carboxylate (8)

The reaction of 57 mg (0.25 mmol) of 7 with 4-bromobiphenyl (70 mg, 0.30 mmol) was conduced for 12 h at 70 °C according to the general procedure using a catalyst composed of Pd(OAc)₂ (1.1 mg, 0.005 mmol, 2 mol %) and dpe-phos (2.7 mg, 0.005 mmol, 2 mol %). This procedure afforded 70 mg (74%) of the title compound as a yellow oil. ¹H NMR analysis of the crude reaction mixture indicated the product was formed as a 6:1 mixture of diastereomers; the isolated product was obtained with 10:1 dr following purification. Data are for the major diastereomer. ¹H NMR (500 MHz, CDCl₃) 7.59-7.57 (m, 2 H), 7.53-7.52 (m, 2 H), 7.45 (m, 2 H), 7.35-7.32 (m, 1 H), 7.27-7.24 (m, 2H), 4.26-4.24 (m, 1 H), 3.42 (s, br, 1 H), 3.14 (dd, J = 4.0, 8.0 Hz, 1 H), 3.02-2.99 (m, 1 H), 2.79 (dd, J = 5.5, 8.0 Hz, 1 H), 2.32-2.27 (m, 1 H), 1.59-1.54 (m, 1 H), 1.51 (s, 9 H), 1.36-1.29 (m, 3 H), 1.23-1.17 (m, 1 H), 0.89 (t, J = 7.5 Hz, 3 H); ¹³C NMR (125 MHz, CDCl₃) δ 155.2, 140.8, 139.2, 137.2, 130.0, 128.8, 127.1, 127.0, 126.9, 80.2, 60.4, 59.6, 40.6, 34.4, 32.2, 28.5, 20.0, 14.2; IR (film) 3234, 2963, 2360, 1714 cm^-1. MS (ESI) 403.2346 (403.2361 calcd for C₂₄H₃₂N₂O₂, M + Na⁺)