Asymmetric synthesis of homoallylic amines via 1,2-addition of Grignard reagent to aliphatic N-phosphonyl hemiaminal

Tetrahedron Letters 57 (2016) 619–622

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Asymmetric synthesis of homoallylic amines via 1,2-addition of Grignard reagent to aliphatic N-phosphonyl hemiaminal Shuo Qiao a,b, Suresh Pindi a, Preston T. Spigener b, Bo Jiang b,c, Guigen Li a,b,⇑ a

Institute of Chemistry & BioMedical Sciences, Nanjing University, Nanjing 210093, PR China Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409-1061, USA c School of Chemistry and Chemical Engineering, Jiangsu Normal University, Xuzhou 221116, Jiangsu, PR China b

a r t i c l e

i n f o

Article history: Received 19 November 2015 Revised 21 December 2015 Accepted 26 December 2015 Available online 29 December 2015 Keywords: Alkylated homoallylic amines N-Phosphonyl amides 1,2-Nucleophilic addition N-Phosphonyl imines Group-assisted-purification (GAP)

a b s t r a c t A general method for asymmetric synthesis of alkylated homoallylic amines was developed via a one-pot three-component reaction of easily available N-phosphonyl amides, aliphatic aldehydes, and allylic Grignard reagents. As anticipated the reaction proceeds through six-membered chelation controlled mechanism, allowing 1,2-nucleophilic addition to directly give chiral homoallylic amines with high yields and excellent diastereoselectivity. Ó 2016 Published by Elsevier Ltd.

Introduction Isolation and purification are challenging issues in organic chemistry. Current purification techniques used in synthetic organic chemistry and chemical production have many shortcomings including waste generation, pollution, energy, and consumption of manpower as well as time.1 Among them, both chromatography and recrystallization are well-known purification methods, but require a tremendous amount of silica gel and solvents in laboratories and pharmaceutical industries, thereby suffering from costly process and complex work-ups along with toxic solvents.2 To address these common issues, our group developed ‘group assisted purification (GAP)’ that can avoid traditional purification methods such as chromatography and recrystallization.3 We eliminated these steps by purposely introducing well functionalized groups in starting materials or newly generated groups in precursors and products. So it is the first of its kind that combines the attributes of reagent/ reaction/separation/purification (chemical and physical concepts). On the other hand, asymmetric 1,2-addition of chiral imines is one of the most practical methods to make homoallylic amines. These amines are important intermediates of compounds having bioactivities and pharmaceutical value.4 In our previous reports, ⇑ Corresponding author. E-mail address: [email protected] (G. Li). http://dx.doi.org/10.1016/j.tetlet.2015.12.106 0040-4039/Ó 2016 Published by Elsevier Ltd.

several phosphinyl and phosphonyl auxiliary groups were designed and applied in nucleophilic addition reactions resulting in high overall yields and excellent distereoselectivity.5 Specifically, we can isolate the desired product with GAP technique from non-polar solvents. For instance, asymmetric 1,2-addition of allylmagnesium bromide to aromatic N-phosphonyl imines gave homoallylic amines with excellent yield and high diastereoselectivity (Scheme 1a).6 Unluckily, aliphatic counterparts were not applied in this asymmetric 1,2-addition owing to aliphatic N-phosphonyl imine is difficult to obtain and it is unstable in silica gel or in the presence of moisture.7 Therefore, the development of a new method for the synthesis of alkylated homoallylic amines is necessary because of its significance in organic chemistry. Recently, Kuduk et al. used aliphatic aldehydes to subject with (S)-tert-butanesulfinamide in the presence of Ti(OEt)4 to afford sulfinamino acetals, which generated in situ imines and underwent addition with Grignard reagents to form amine derivatives.8 Enlightened by this method and our projects on N-phosphonyl imine chemistry,5 we reason that treatment of our preformed phosphonyl amide and aliphatic aldehydes in the presence of Ti (OiPr)4 could generate in situ hemiaminals 3, followed by the reaction of allylmagnesium bromide without isolation, therefore converting into the desired alkylated homoallylic amines in a one-pot manner. With this notion in hand, we attempted the feasibility of this designed reaction. Fortunately, the reaction worked well, providing the desired aliphatic N-phosphonyl amines. Herein,

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reaction temperatures is unfavorable to form hemiaminals 3a (entries 2 and 3). With presence of molecule sieves (MS), the reaction generated a 75% yield of 5a accompanied with a 23% yield of 3a (entry 4). Exchanging toluene with DCM at room temperature, the reaction delivered 3a in a 65% yield (entry 5). Increased loading of 2.0 equiv of Ti(OiPr)4 resulted in 92% yield by 31P NMR (entry 6). To get a better yield of allylation and facilitate the reaction procedure, we considered to perform the one-pot reaction for the synthesis of aliphatic N-phosphonyl amines using toluene as a solvent at 50 °C with the presence of molecule sieves (MS), which gave access to the best total yield of mixed aldimines and hemiaminals (entry 4), because both aldimines and hemiaminals can be served as good substrates for the nucleophilic addition reactions with allylmagnesium bromide. Interestingly, the one-pot reaction led to the aliphatic N-phosphonyl amines 4a in a 91% yield (Scheme 2, 4a). With acceptable conditions in hand, we next explored the reaction scope by using different aliphatic aldehydes including i-Bu, i-Pr, Et, n-Bu, Cy, phenylethyl, and homoallylic groups. Delightedly, all these substrates were successfully engaged in these reactions, transforming into the corresponding densely functionalized N-phosphonyl amines in excellent yields and high enantioselectivity. Alternatively, the long-chain counterpart such as undecanal was also applicable in this nucleophilic addition, delivering the corresponding products with potentially industrial application (Scheme 2, 4i). Diphenylated N-phosphonyl amines were further examined under the standard conditions, which were converted into the products 4j and 4k, respectively. To our knowledge, Ti (OiPr)4-mediated three-component reaction of aliphatic aldehydes, N-phosphonyl amides, and allylmagnesium bromide in an one-pot pattern has not been reported.9 With previously reported procedure for aromatic substrates,6 up to 99:1 enantioselectivity and almost quantitative conversion were achieved. Notably, the rate of charging allylmagnesium bromide is very important to control the reaction purity so it can be purified with GAP. Otherwise the enamine can form as a byproduct, which cannot be easily removed by any purification method. Owing to the aliphatic substrates being hydrophobic, the nonpolar hexane dissolves the products along with any impurities. However, after completion of the reaction, we were able to precipitate the target product from acetone/water mixture, and get the desired product as pure compound with simple filtration, which accommodates the GAP techniques. Interestingly, the dr values also increased slightly after GAP than the crude product. The stereoselective structure of product 4a was confirmed by X-ray analysis (Scheme 2).10

MgBr N

N

i-Pr

P

O

i-Pr

i-Pr

THF, -78 o C

N

N

N

(a)

i-Pr

P NH

O Ar

Ar

Our previous report R

R

R

O i-Pr

N

N P

i-Pr

i-Pr

H Toluene, 4A MS 50 °C, 24 h

R1

NH2

O

Ti(OiPr)4

+

i-Pr

i-Pr

(b)

NH

i-PrO

R1

R

N

N P

BrMg

i-Pr

-78o C

NH

O

GAP Chemistry

N P

3 (Not Isolated)

R

This work

N O

2

1

R

one-pot strategy

1

R

4 Scheme 1. Nuleophilic reactions with GAP technique.

we would like to report this result using a one-pot method for the synthesis of chiral phosphonyl amines by the GAP technique. Results and discussion In a previous report,6 we tried to synthesize aliphatic phosphonyl imine with TiCl4 as Lewis acid and Et3N as acid scavenger in dichloromethane. Conversions were moderate (60–70%) according to 31P NMR without any other impurities. However, the salt generated from the reaction along with phosphonyl amide made it difficult to be purified. Also, purification with chromatography decomposes imines to amides, so we had to turn our attention to other methods. Kuduk et al. have reported Ti(OEt)4-mediated reaction between aliphatic aldehydes and (S)-tert-butanesulfinamide to afford sulfinamino acetals.8 Considering this successful case, we planned to synthesize hemiaminals 3 using Ti(OiPr)4. The different conditions were tested with phosphonyl amide and butaldehyde, and we found that this reaction in toluene at room temperature gave aldimines, hemiaminals, and enamines as a mixture, which were confirmed by 31P NMR (Table 1, entry 1). However, the following purification by chromatography generated hemiaminals 3a in a 35% chemical yield accompanied with the decomposition of imine. Increasing Table 1 Different conditions in the condensation of phosphonyl amide and butaldehyde

O i-Pr

N

N P

+ i-Pr

c

N

i-Pr +

P O

2a

i-Pr

NH

N

i-Pr

N O

5a

Solvent

Additive (equiv)

T (°C)

Time (h)

1 2 3 4c 5 6

Toluene Toluene Toluene Toluene DCM DCM

Ti(OiPr)4 Ti(OiPr)4 Ti(OiPr)4 Ti(OiPr)4 Ti(OiPr)4 Ti(OiPr)4

rt 50 85 50 rt rt

16 16 32 16 16 16

Yield based on 31P NMR. Isolated yield by chromatography. The use of molecule sieves (50 mg).

i-Pr +

N

N P

i-Pr

NH

n-Pr

3a

Entry

(1.0) (1.0) (1.0) (1.0) (1.0) (2.0)

N P

O

n-Pr

i-PrO

1

a

N

i-Pr

NH2

O

b

Ti(OiPr)4 H Solvent, additive

n-Pr

6a Yielda (%) 3a

5a

6a

43 (35)b 0 0 23 65 92 (75)b

25 75 0 75 15 0

8 25 99 0 0 0

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S. Qiao et al. / Tetrahedron Letters 57 (2016) 619–622

R O N

N

i-Pr

+

i-Pr

P

N NH

n-Pr

N

R BrMg

i-Pr

P

R

i-PrO

N

R1

i-Pr

i-Pr

P NH

O

4

N

N NH

4c (92%, 90:10 dr)

(85%, 99:1 dr)b

(87%, 95:5 dr)b

a

N

N

N

i-Pr

i-Pr

P NH

O

N P

i-Pr

4d (94%, 89:11 dr) (90%, 94:6 dr)b

NH

O

( )8

Ph

i-Pr

Ph

Ph

N

N

i-Pr

i-Pr

P

b

(88%, 95:5 dr)

N

N

i-Pr

P NH

i-Bu

i-Pr

4k (86%, 88:12 dr)c

c 4h (91%, 88:12 dr)a 4i (67%, 98:2 dr)a 4j (88%, 91:9 dr) (77%, 97:3 dr)d (78%, 91:9 dr)b (49%, 99:1 dr)b

4g (92%, 90:10 dr)a

Ph

O

NH

O

Cy

4e (90%, 92:8 dr)a 4f (87%, 93:7 dr)a (85%, 99:1 dr)b (79%, 99:1 dr)b

a

Ph

i-Pr N P N i-Pr NH O

Bu

Et

(88%, 99:1 dr)b

i-Pr

i-Pr N P N i-Pr NH O

i-Pr

P O

4b (92%, 98:2 dr)a

one-pot

R1

i-Pr

a

i-Pr N P N i-Pr NH O

i-Pr N P N i-Pr NH O

-78oC

NH

O

N

i-Pr

i-Bu

4a (91%, 95:5 dr)

N

3 (Not Isolated)

i-Pr N P N i-Pr NH O

i-Pr

P O

i-Pr

2

1

N

Ti(OiPr)4 H Toluene, 4Å MS 50 °C, 24h

R1

NH2

O

i-Pr

R

R

R

X-ray structure 4a

(78%, 89:11 dr)d

Scheme 2. One-pot synthesis of chiral homoallylic amines. Reaction conditions: The mixture of imine and hemiaminal was dissolved in dry THF and cooled down to 78 °C, the allylic magnesium bromide was charged at rate of 0.1 ml/min, quenched with NH4Cl solution after 6 h at 78 °C. aYield based on 31P NMR of reaction mixture. bIsolated yield from GAP procedure. cDetermined by 31P NMR of analytically pure material. dIsolated yield from chromatography.

O i-Pr

N

N

i-Pr

P

Ti(OiPr)4 (2.0 eq)

+ R1

DCM, rt, 24h

H

i-Pr

N NH

2

i-Pr N P N i-Pr O NH

R1

i-PrO

1

i-Pr

P O

NH2

O

N

3

i-Pr N P N i-Pr NH O

THF

+ R2MgBr

-41 oC

R1

R1

i-PrO

i-Pr

N P O i-PrO

N i-Pr NH n-Pr

3a (75%)

i-Pr

N

N

i-Pr

P O i-PrO

NH i-Bu

3b (95%)

i-Pr

N P O i-PrO

N i-Pr NH

i-Pr

Scheme 3. Reaction of aliphatic aldehyde with chiral N-phosphonyl amides. a Isolated yield by column chromatography.

After successfully synthesizing chiral homoallylic amines 4, we attempted to further evaluate the reaction scope using phenyl lithium, benzylmagnesium bromide, and phenylmagnesium bromide as organometallic components under the same conditions. Unfortunately, these reactions stumbled and gave poor yields with complex mixtures, which might be caused by Ti(OiPr)4. To solve this problem we synthesize the hemiaminals 3a–3c in 75–96% yields under the optimized conditions (Table 1, entry 6 and Scheme 3) and employed them as precursors for next step. Based on the findings of Plobeck and Powell with N-sulfininyl imines,11 we found the best condition to be the reaction with purified N-phosphinyl hemiaminals 3 in THF at 41 °C. However, the reactions with these organometallic reagents resulted in products 7 with low diastereoselectivity, except for 7f with benzyl magnesiumbromide (Scheme 4). From the X-ray analysis of product 7f, we found the primary configuration of the above reaction to be (R, R, S) (Fig. 1). According to the resulting chirality and studies from Hua’s and co-workers,13 two proposed mechanisms for the formation of products 4 and 7 are shown in Scheme 5. The phosphonyl hemiaminal 3 converts into to the phosphonyl imine 5 via

N

i-Pr N P N i-Pr NH O

i-Pr

P NH

O

i-Pr

3c (96%)

N

n-Pr

R2 7

3

i-Bu

Ph

N

i-Pr

N NH

i-Pr

Ph

i-Pr N P N i-Pr NH O

i-Pr

P O

n-Pr

Ph

7a (91%, 53:47 dr)a 7b (92%, 52:48 dr)a 7c (92%, 68:32 dr)a (90%, 50:50 dr)b

i-Pr

N

N

i-Pr

P NH

O i-Bu

(83%, 56:44 dr)b

(88%, 65:35 dr)b

i-Pr N P N i-Pr NH O i-Pr

Bn

N

i-Pr

N

Ph

Bn

i-Pr N P N i-Pr NH O

i-Pr

P O

NH

i-Bu

Bn

7e (72%, 75:25 dr)a 7f (92%, 85:15 dr)a 7g (99%, 67:33 dr)a (66%, 63:37 dr)b (84%, 89:11 dr)b (88%, 68:32 dr)b

i-Pr N P N i-Pr O NH

THF

+ PhLi

o

-78 C

i-Pr N P N i-Pr O NH Ph 7

3

i-Pr N P N i-Pr O NH n-Pr

Me

7h (38%, 45:55 dr)a (trace)b

R1

R1

i-PrO

Bn

7d (91%, 48:52 dr)a (80%, 51:49 dr)b

Ph

7a (90%, 42:58 dr)a

i-Pr

N

N

i-Pr

P O i-Bu

NH Ph

7b (81%, 40:60 dr)a

i-Pr N P N i-Pr NH O i-Pr

Ph

7c (73%, 37:63 dr)a

Scheme 4. Addition of other organometallic reagents to N-phosphonyl hemiaminal. a Yield based on 31PNMR of reaction mixture. bIsolated yield from GAP procedure.

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S. Qiao et al. / Tetrahedron Letters 57 (2016) 619–622

high diastereoselectivity through a one-pot, three-component reaction of easily available chiral N-phosphonyl amides, aliphatic aldehydes, and allylmagnesium bromide. With the use of organometallic reagents such as PhLi, PhMgBr, and BnMgBr, we were able to achieve the synthesis of alkylated N-phosphonyl amides with good to excellent yields, albeit with relatively low diastereoselectivity. The reason for fair diastereoselectivity of other organometallic reagents is due to a difference in the mechanism. In future studies we will focus on modifying N-phosphonyl imines or hemiaminals. Acknowledgments We gratefully acknowledge NIH (R33DA031860), the Robert A. Welch Foundation (D-1361), NSFC (No. 21332005, P. R. China), for financial support. We thank Dr. David Purkiss for assistance with the NMR spectroscopic analysis and Daniel Unruh for the crystal structure analysis.

Figure 1. XRD for 7f.12

R1 H

Mg N MgBr

i-Pr N P N i-Pr O NH

i-Pr H N P O N i-Pr H

i-Pr N O

P

N i-Pr

i-PrO

4

A N i-Pr i-Pr N P O N 5 R1

NH R1

3

RMgBr

i-Pr

or RLi

i-Pr

N i-Pr P R1 N O M H

N

B

N

N

i-Pr

P O

NH R1

R

7

R

Scheme 5. Proposed different reaction mechanisms of organometallic reagents.

H N P N O N

Grubbs 2nd 40 oC, DCM

N H N P N O

N

N

Cl Ru Cy3 P

4i (0.01M, dr=91:9)

8 (yield:89%, dr=99:1)

References and notes

R1

Ph Cl Grubbs 2nd Catalyst

Scheme 6. Ring-closing metathesis of substrate 4i.

elimination of hydrogen attached N-atom and isopropyl groups under basic condition. Then, the allylation of N-phosphonyl imine 5 occurs through a six-membered coordinated transition state from the less bulky face accompanied with migration of double bond of the allylic group to generate the final (S)-phosphonyl amide. On the contrary, with other organometallic reagents such as PhLi, PhMgBr, and BnMgBr, the S configuration comes from the attacking of the carbon attached to the metal onto the Si face of the imine. The coordination between the oxygen and the metal could be used in another type of six-membered transition states. Clearly from this pattern we can see the prochiral center is far from the steric group on the auxiliary that controls the selectivity. This could explain its relatively low diastereoselectivity. To further expand the utility of this reaction, the reaction of the resultant 4i, derived from allylation of 3i, via ring-closing metathesis by employing Grubbs catalyst 2nd generation, was conducted, affording a cyclic product 8 in 89% yield (Scheme 6). We found the purification of the special cyclohexenyl amine could be applied to GAP technique with increase of the diastereoselectivity. Conclusion In conclusion, we have developed a practical and versatile protocol toward chiral homoallylic amides in excellent yields and

1. (a) Trost, B. M. Science 1991, 254, 1471; (b) Schreiber, S. L. Science 1964, 2000, 287; (c) Tietze, L. F.; Brasche, G.; Gericke, K. Domino Reactions in Organic Synthesis; Wiley-VCH: Weinheim, 2006; (d) Tietze, L. F. Domino ReactionConcepts for Organic Synthesis; Wiley-VCH: Weinheim, 2014; (e) Padwa, A. Chem. Soc. Rev. 2009, 38, 3072. 2. (a) Anderson, N. G. Process Research and Development-A Gide for Organic Chemists, 2nd ed.; Academic Press, 2012; (b) Lee, S.; Robinson, G. Process Development: Fine Chemicals from Grams to Kilograms, 1st ed.; Oxford University Press, 1995. 3. An, G.; Seifert, C.; Li, G. Org. Biomol. Chem. 2015, 13, 1600. 4. (a) Bloch, R. Chem. Rev. 1998, 98, 1407; (b) Ding, H.; Friestad, G. K. Synthesis 2005, 2815; (c) Davis, F. A. J. Org. Chem. 2006, 71, 8993. 5. (a) Sun, H.; Li, G. Tetrahedron Lett. 2010, 51, 4403; (b) Xiong, Y.; Mei, H.; Xie, C.; Han, J.; Li, G.; Pan, Y. RSC Adv. 2013, 3, 15820; (c) Han, J. L.; Ai, T.; Nguyen, T.; Li, G. Chem. Biol. Drug Des. 2008, 72, 120; (d) Han, J. L.; Ai, T.; Li, G. Synthesis 2008, 2519; (e) Kattamuri, P. V.; Ai, T.; Pindi, S.; Sun, Y. W.; Gu, P.; Shi, M.; Li, G. J. Org. Chem. 2011, 76, 2792; (f) Xie, J. B.; Luo, J.; Li, G. Beilstein J. Org. Chem. 2014, 10, 746. 6. Kattuboina, A.; Kaur, P.; Nguyen, T.; Li, G. Tetrahedron Lett. 2008, 49, 3722. 7. (a) Vijay, N. W.; Rashmi, R. M.; Ahson, J. S.; Thomas, C. N. Eur. J. Org. Chem. 2007, 959; (b) Liu, G. C.; Derek, A. C.; Timothy, D. O.; Tony, P. T.; Jonathan, A. E. J. Org. Chem. 1999, 64, 1278. 8. Kuduk, S. D.; Marco, C. N. Di; Pitzenberger, S. M.; Tsou, N. Tetrahedron Lett. 2006, 47, 2377. 9. Truong, V. L.; Dion, I. Org. Lett. 2007, 9, 683. 10. Single crystal X-ray diffraction data were collected on A Bruker Apex II threecircle X-ray diffractometer for unit cell determination and data collection. The sample was optically centered with the aid of a video camera to insure that no translations were observed as the crystal was rotated through all positions. The detector was set at 6.0 cm from the crystal. X-ray radiation was produced from a Mo sealed X-ray tube (Ka = 0.71073 Å, with a potential of 50 kV and a current of 30 mA) and filtered with a graphite monochromator. A unit cell collection was then carried out and after comparison with known unit cells a sphere of data was collected. Omega scans were carried out with a 60 s/frame exposure time and a rotation of 0.5° per frame. After data collection the crystal was measured for size, morphology, and colour. These values are reported in supporting information. Crystal data for 4a: C23H40N3O, M = 405.55, Monoclinic, P2(1), a = 5.7012(7), b = 16.1680(19) Å, c = 12.5835(15) Å, V = 1158.8(2) Å3, Z = 2, qcalcd = 1.162 mg/cm3, 12288 reflections measured, 5449 unique (Rint = 0.0513), R1 = 0.0517, wR2 = 0.1190 for 5449 observed reflections. 11. Plobeck, N.; Powell, D. Tetrahedron: Asymmetry 2002, 13, 303. 12. Single Crystal data for 7f: C23H40N3O, M = 405.55, Monoclinic, P2(1), a = 5.7012 (7), b = 16.1680(19) Å, c = 12.5835(15) Å, V = 1158.8(2) Å3, Z = 2, qcalcd = 1.162 mg/cm3, 12288 reflections measured, 5449 unique (Rint = 0.0513), R1 = 0.0517, wR2 = 0.1190 for 5449 observed reflections. 13. Hua, D. H.; Miao, S. W.; Iguchi, S. J. Org. Chem. 1991, 56, 4. All new compounds reported here are racemic and characterized on the basis of spectroscopic data (31P, 1H, 13C NMR). Spectral data for a key compound 4a are as follows: 1H NMR (CDCl3 400 MHz): d 5.80–5.73 (m, 1H), 5.09–5.04 (m, 2H), 3.52–3.50 (m, 2H), 3.23–3.22 (m, 1H), 2.96–2.90 (m, 1H), 2.74 (t, 1H), 2.35–2.19 (m, 2H), 2.08–1.99 (m, 3H), 1.75 (d, 2H), 1.32–1.15 (m, 19H), 0.89– 0.88 (m, 3H) 13C NMR (CDCl3 100 MHz): d 134.6, 117.7, 60.1, 59.0, 50.7, 44.2, 43.8, 39.8, 38.2, 31.6, 31.3, 31.2, 24.4, 23.8, 23.7, 20.0, 19.8, 18.6, 14.3 31P NMR (CDCl3 162 MHz): d 24.3.