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. Author manuscript; available in PMC: 2014 Jan 1.
Published in final edited form as: Synthesis (Stuttg). 2013 May 15;45(13):1749–1758. doi: 10.1055/s-0033-1338476

A Convenient Synthesis of γ–Amino-Ynamides via Additions of Lithiated Ynamides to Aryl Imines. Observation of an Aza-Meyer-Schuster Rearrangement.†

Rui Qi a, Xiao-Na Wang b, Kyle A DeKorver c,✉, Yu Tang a,✉, Chao-Chao Wang a, Qian Li a, Hui Li a, Ming-Can Lv a, Qing Yu a, Richard P Hsung b,✉
PMCID: PMC3748967  NIHMSID: NIHMS466066  PMID: 23976795

Abstract

Efforts in developing an expeditious and convenient method for synthesizing γ–amino-ynamides via nucleophilic addition of lithiated ynamides to aryl imines are described. This work also features an aza-variant of a Meyer-Schuster rearrangement of γ–amino-ynamides and the synthetic utility of γ–amino-ynamides in an intramolecular ketenimine-[2 + 2] cycloaddition.

Keywords: Lithiated ynamides, γ–amino-ynamides, aryl imine addition, azetene, aza-Meyer-Schuster rearrangement

Introduction

We have been involved with the chemistry of ynamides for the last 17 years, and this burgeoning field has attracted an immense amount of attention from the synthetic community in recent years.1-4 Consequently, new and improved protocols for synthetizing ynamides3 and structural relatives of ynamides5,6 have continued to appear in the literature.3e Recently, when we employed γ–amino-ynamides 1 [see Scheme 1] to develop N-tethered intramolecular transformations for constructing N-heterocycles,7 we recognized that this class of ynamides is not trivial to make.

Scheme 1.

Scheme 1

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Possible Approaches to γ–Amino-Ynamides.

The existing copper-catalyzed protocols,1,2,5 albeit attractive, may not be suitable to directly couple amides with N-unprotected propargyl amines 3 [see retrosynthetic cleavage a].8 On the other hand, with N-protected propargyl amines 5, it would constitute an encumbered process in addition to the fact that the penultimate deprotection step could still pose problems to the stability of ynamides. The most direct access would be retrosynthetic pathway b in which the metallated ynamide 7 could be added to a nitrogen source in the form of an imine. While metallated ynamides have been added to a number of electrophiles,9 to the best of our knowledge, it is not known in adding to imines.1 Inspired by Poisson's recent account10 on additions of lithiated ynol-ethers to imines,11 we explored this potentially expeditious method. We wish to report here a general and convenient protocol for synthesizing γ–amino-ynamides.

Results and Discussions

Deprotonation of ynamides 8 with 1.5 equiv LHMDS in THF at –50 °C followed by the addition of various imines turned out to be a highly efficient protocol. A diverse array of N-sulfonyl or N-carbamoyl-γ–amino-ynamides 9-15 could be accessed in good yields through this simple method [Table 1]. Ynamide precursors could be those of oxazolidinone-substituted [entries 1-6], sulfonyl-substituted [entries 7-14], or even phosphoryl-substituted12 [entry 15]. Ketimines were also suitable substrates [entries 5 and 13], while aldimines could include electron withdrawing [entry 11] or donating [entries 4 and 12] sulfonyl systems.

Table 1.

Lithiated Ynamide Additions to Aryl Imines.

graphic file with name nihms-466066-f0006.jpg
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What intrigued us was that some of these γ–amino-ynamides did not overtly stable to silica gel column chromatography and appeared to rearrange cleanly to another compound especially in the presence of acid. Upon further examination, we found that ynamide 12a could rearrange to α,β–unsaturated amidine 16 when treated with 5 mol% of HNTf2 at rt [Scheme 2]. The assignment of amidine 16 was confirmed through its single-crystal X-ray structure [Figure 1]. Two possible mechanistic pathways could be proposed to account for this rearrangement. Pathway-a features an acid promoted γ–elimination followed by re-association of the departed amide with the allenylidine iminium ion 17. Pathway-b favors an intramolecular non-dissociative possibility through pericyclic ring-opening of an azetene intermediate 19.13

Scheme 2.

Scheme 2

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An Acid Promoted Rearrangement of 12a.

Figure 1.

Figure 1

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X-ray Structure of Vinyl Amidine 16.

To further delineate these two possibilities, we carried out the following crossover experiments [Scheme 3]. After treating a mixture of γ–amino-ynamides 12a and 12z with a ratio of either 4:1 [Reaction-A] or 1:4 [Reaction-B] with 5 mol% HNTf2, we examined closely the crude reaction mixture and all fractions resulting from purifications of both reactions. We did not find possible crossover products 16az and 16za in either reaction using 1H-NMR, and ynamides 12a and 12z in both reactions appeared to yield only their respective rearranged products 16a and 16z. The presence of products 16az and 16za would have implied pathway-a being operative.

Scheme 3.

Scheme 3

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A Crossover Experiment.

To be more precise, we scanned the crude mixture from incomplete reactions using LCMS, and impressively, we did not find fractions with the mass that would correlate to either 16az or 16za [see red arrows in Figure 2, which indicate where 16az and 16za would be respectively when co-injected with the crude mixtures from Reaction A and B]. It is noteworthy that rearrangement of 12a appears to be much faster than that 12z. These results suggest pathway-b that would involve the formation of azetene 19 and pericyclic ring-opening. Related ring-opening through oxetenes14,15 is quite well-known, and the current rearrangement essentially constitutes an aza-variant of Meyer-Schuster rearrangements.16

Figure 2.

Figure 2

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LC-Traces from LCMS of Crossover Experiments A and B.

While this rearrangement is of interest both synthetically and mechanistically, and that this has become an ongoing project of another focus, we demonstrate here how these γ–amino-ynamides can be utilized in further transformations. As shown in Scheme 4, the γ–amino group in 9a could be readily N-allylated using Mitsunobu conditions, leading to ynamide 20 in 60% yield. This N-allylation proved to quite general for a number of γ–amino-ynamides such as 12a, 14, and 15 to give N-allylated products 21-23, respectively. An immediate application is a Pd(0)-catalyzed aza-Claisen rearrangement17-19 in tandem with ketenimine-[2 + 2] cycloaddition,20-23 leading to either a rare crossed cycloadduct 24 from ynamide 22, or fused cycloadduct 25 from ynamide23 in a highly stereoselective manner [Scheme 5].7

Scheme 4.

Scheme 4

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N-Allylations of γ–Amino-Ynamides.

Scheme 5.

Scheme 5

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Application of γ–Amino-Ynamides in [2 + 2].

Conclusion

We have described here our efforts in developing an expeditious and convenient method for synthesizing γ–amino-ynamides via nucleophilic addition of lithiated ynamides to aryl imines. In this study, we also uncovered an aza-variant of a Meyer-Schuster rearrangement of γ–amino-ynamides and demonstrated the usefulness of these γ–amino-ynamides in designing intramolecular transformation.

Experimental Section

General Procedure for Additions to Aryl Imines

To a solution of ynamide in freshly distilled THF (concn = 0.1 M) at –50 °C was added LHMDS (1.5 equiv, 1.0 M solution in THF) dropwise via syringe. The reaction was allowed to stir at –50 °C for 1 h to ensure complete deprotonation. Then a solution of imine (1.5 equiv, 1.5 M in freshly distilled THF) was added via 10 min. After 1 h, H2O (5 mL) was added and the reaction was allowed to warm to room temperature and diluted with EtOAc. The organic phase was separated and the aqueous phase extracted twice with EtOAc. The combined organic phases were washed with sat aq NaCl, dried over Na2SO4, and concentrated in vacuo. The resulting crude product was purified through silica gel flash column chromatography (gradient eluent: EtOAc in petroleum ether) to give corresponding γ–amino-ynamides.

γ–Amino-Ynamide (9a)

(68%, 0.16 g); Rf = 0.46 [2:3 hexanes/EtOAc]; white solid; mp = 147-149 °C.

IR (KBr): 1415 (m), 1475 (m), 1492 (w), 1597 (w), 1761 (s), 1928 (w), 2268 (m), 2912 (w), 2972 (w), 3062 (w), 3086 (w), 3263 (brs).

1H NMR (400 MHz, CDCl3): δ = 2.43 (s, 3H), 3.64–3.73 (ddd, 2H, J = 8.0 Hz), 4.39 (dd, 2H, J = 8.0 Hz), 4.92 (d, 1H, J = 8.4 Hz), 5.48 (d, 1H, J = 8.4 Hz), 7.29–7.34 (m, 5H), 7.47 (d, 2H, J = 6.8 Hz), 7.80 (d, 2H, J = 8.4 Hz).

13C NMR (100 MHz, DMSO-d6): δ = 21.4, 46.7, 48.9, 64.0, 68.2, 77.0, 127.3, 127.6, 128.4, 128.9, 129.8, 138.80, 138.82, 143.06, 156.14.

MS (ESI): m/z (% relative intensity) 763 (100) (2M+Na)+.

HRMS (ESI): m/z calcd for C19H18N2O4SK+: 409.0987; found 409.0668.

γ–Amino-Ynamide (9b)

(80%, 0.18 g); Rf = 0.41 [2:3 hexanes/EtOAc]; light yellow solid; mp = 155-157 °C. IR (KBr): 1386 (w), 1423 (s), 1445 (w), 1477 (m), 1497 (w), 1597 (w), 1747 (s), 2274 (m), 2860 (w), 2910 (w), 1373 (w), 1984 (w), 3205 (brs).

1H NMR (400 MHz, CDCl3): δ = 2.42 (s, 3H), 3.73 (dd, 2H, J = 8.0 Hz), 4.39 (t, 2H, J = 8.0 Hz), 5.16 (d, 1H, J = 8.0 Hz), 5.52 (d, 1H, J = 8.0 Hz), 6.26 (d, 1H, J = 3.2 Hz), 6.36 (d, 1H, J = 3.2 Hz), 7.28 (s, 1H) ,7.30 (d, 2H, J = 6.8 Hz), 7.77 (d, 2H, J = 8.4 Hz).

13C NMR (100 MHz, DMSO-d6): δ = 21.5, 43.7, 46.4, 63.1, 66.5, 75.3, 108.6, 110.5, 127.4, 129.5, 137.4, 143.1, 143.5, 149.2, 155.6.

MS (ESI): m/z (% relative intensity) 743 (100) (2M+Na)+.

HRMS (ESI): m/z calcd for C17H16N2O5SNa+: 383.0780; found 383.0833.

γ–Amino-Ynamide (9c)

(81%, 0.26 g); Rf = 0.33 [2:3 hexanes/EtOAc]; white solid; mp = 199-201 °C.

IR (KBr): 1367 (s), 1408 (m), 1435 (w), 1454 (m), 1478 (m), 1566 (w), 1598 (w), 1731 (s), 1782 (s), 2270 (w), 2355 (w) 2914 (w), 2986 (w), 3246 (brs).

1H NMR (400 MHz, CDCl3): δ = 2.66 (s, 9 H), 2.24 (s, 3 H ), 3.59–3.71 (ddd, 2 H, J = 8.0 Hz), 4.38 (dd, 2 H, J = 8.0 Hz), 4.93 (d, 1H, J = 8.8 Hz), 5.59 (d, 1H, J = 8.8 Hz), 7.21–7.24 (m, 3 H), 7.30–7.33 (t, 1 H, J = 8.0 Hz ), 7.68 (d, 1 H, J = 8.0 ), 7.71 (s, 1H ), 7.80 (d, 2H, J = 8.0 Hz) 8.10 (d, 1 H, J = 8.0 Hz).

13C NMR (100 MHz, DMSO-d6): δ = 21.4, 28.1, 42.0, 46.5, 64.1, 67.5, 76.0, 84.5, 115.2, 118.4, 120.5, 123.2, 125.0, 125.2, 127.35, 128.0, 129.7, 135.7, 138.6, 143.1, 149.3, 156.3.

MS (ESI): m/z (% relative intensity) 1041 (100) (2M+Na)+.

HRMS (ESI): m/z calcd for C26H27N3O6SNa+: 532.1621; found 532.1829.

γ–Amino-Ynamide (9d)

(72%, 0.18 g); Rf = 0.26 [2:3 hexanes/EtOAc]; white solid; mp = 148-150 °C.

IR (KBr): 1421 (m), 1477 (m), 1499 (m), 1579 (m), 1596 (m), 1757 (s), 2260 (m), 2848 (w), 2916 (w), 2974 (w), 3032 (w), 3080 (w), 3010 (w), 3292 (brs).

1H NMR (400 MHz, CDCl3): δ = 3.66–3.70 (ddd, 2H, J = 8.0 Hz), 3.88 (s, 3 H ), 4.38 (dd, 2 H, J = 8.0 Hz ), 4.98 (d, 1 H, J = 8.8 Hz ), 5.46 (d, 1 H, J = 6.8 Hz ), 6.99 (d, 2 H, J = 8.8 Hz ) 7.29–7.34 (m, 3 H ), 7.48 (d, 2H, J = 8 Hz), 7.85 (d, 2H, J = 8.8 Hz ).

13C NMR (100 MHz, DMSO-d6): δ = 46.5, 48.9, 56.1, 64.0, 68.4, 77.0, 114.5, 127.6, 128.3, 128.8, 129.4, 133.4, 138.9, 156.0, 162.6.

MS (ESI): m/z (% relative intensity) 795 (100) (2M+Na)+.

HRMS (ESI): m/z calcd for C19H18N2O5SNa+: 409.0936; found 409.1123.

γ–Amino-Ynamide (10)

(73%, 0.15 g); Rf = 0.30 [7:3 hexanes/EtOAc]; white solid; mp = 183-185 °C.

IR (KBr): 1421 (m), 1449 (w), 1479 (w), 1599 (w), 1632 (w), 1767 (s), 2266 (m), 2320 (w), 2378 (w), 2878 (w), 2920 (w), 2938 (w), 3059 (w), 3165 (s), 3440 (brs).

1H NMR (400 MHz, CDCl3): δ = 2.41 (s, 3H), 3.78 (t, 2H, J = 8.0 Hz), 4.40 (t, 2H, J = 8.0 Hz), 5.38 (s, 1H), 7.19 (d, 2H, J = 4.0 Hz), 7.24–7.33 (m, 6 H), 7.50 (d, 4H, J = 8.0 Hz), 7.61 (d, 2H, J = 8.0 Hz ).

13C NMR (100 MHz, DMSO-d6): δ = 21.4, 46.4, 62.7, 64.1, 70.5, 79.9, 127.2, 127.4, 127.8, 128.4, 129.3, 140.4, 142.6, 143.8, 156.1.

MS (ESI): m/z (% relative intensity) 915 (100) (2M+Na)+.

HRMS (ESI): m/z calcd forC25H22N2O4SK+: 485.1300; found 485.1325.

γ–Amino-Ynamide (11)

(61%, 0.26 g); Rf = 0.56 [2:3 hexanes/EtOAc]; white solid; mp = 102-104 °C.

IR (KBr): 1377 (w), 1421 (m), 1454 (w), 1475 (w), 1493 (w), 1526 (s), 1687 (s), 1773 (s), 2262 (m), 2330 (w), 2360 (w), 2920 (w), 3033 (w), 3057 (w), 3309 (brs).

1H NMR (400 MHz, CDCl3): δ = 2.91 (t, 2H, J = 8.0 Hz), 4.44 (t, 2H, J = 8.0 Hz), 5.14 (dd, 2H, J = 12.0, 16.0 Hz), 5.30 (d, 1H, J = 8.8 Hz), 5.85 (d, 1H, J = 8.8 Hz), 7.29–7.38 (m, 6H),7.52 (d, 2H, J = 7.2 Hz).

13C NMR (100 MHz, DMSO-d6): δ = 46.5, 46.9, 64.1, 66.2, 69.6, 75.6, 127.3, 128.2, 128.3, 128.3, 128.8, 128.9, 137.3, 140.0, 155.9, 156.5.

MS (ESI): m/z (% relative intensity) 723 (38) (2M+Na)+.

HRMS (ESI): m/z calcd for C20H18N2O4K+: 389.1267; found 389.1141.

γ–Amino-Ynamide (12a)

(84%, 0.61 g); Rf = 0.28 [2:3 hexanes/EtOAc]; white solid; mp = 158-160 °C.

IR (KBr): 1362 (s), 1400 (w), 1427 (m), 1450 (m), 1492 (m), 1597 (m), 1917 (w), 1964 (w), 2249 (m), 2367 (w), 2837 (w), 2871 (w), 2922 (w), 3070 (w), 3275 (brs).

1H NMR (400 MHz, CDCl3): δ = 2.37 (s, 3H), 2.43 (s, 3H), 4.29 (dd, 2H, J = 13.6, 20.8 Hz), 4.72 (d, 1H, J = 8.4 Hz), 5.34 (d, 1H, J = 8.4 Hz), 7.12 (d, 2H, J = 6.8 Hz), 7.18–7.20 (m, 5H), 7.22–7.26 (m, 4H), 7.29–7.33 (m, 3H), 7.60 (d, 2H, J = 8.4 Hz), 7.68 (d, 2H, J = 8.4 Hz).

13C NMR (100 MHz, DMSO-d6): δ = 21.4, 21.6, 48.8, 55.2, 68.7, 79.4, 127.1, 127.6, 127.9, 128.3, 128.6, 128.7, 128.7, 128.9, 129.7, 130.5, 134.4, 135.2, 138.9, 139.2, 142.8, 145.4.

MS (ESI): m/z (% relative intensity) 1111 (100) (2M+Na)+.

HRMS (ESI): m/z calcd for C30H28N2O4S2K+: 583.1490; found 583.1080.

γ–Amino-Ynamide (12b)

(67%, 0.35 g); Rf = 0.20 [7:3 hexanes/EtOAc]; white solid; mp = 116-117 °C.

IR (KBr): 1367 (s), 1420 (w), 1440 (m), 1498 (m), 1529 (w), 1660 (w), 1732 (w), 1801 (w), 1917 (w), 2247 (m), 2368 (w), 2723 (w), 2877 (w), 3032 (w), 3120w (brs).

1H NMR (400 MHz, CDCl3): δ = 2.35 (s, 3H), 2.42 (s, 3H), 4.30 (dd, 2H, J = 21.6, 14.0 Hz), 5.06 (d, 1H, J = 8.5 Hz), 5.38 (d, 1H, J = 8.5 Hz), 6.09 (d, 1H, J = 3.2 Hz), 6.20 ( t, 1H, J = 2.9 Hz), 7.16 ( m, 4H), 7.26 (m, 6H), 7.63 (d, 2H, J = 8.2 Hz), 7.67 (d, 2H, J = 8.2 Hz).

13C NMR (100 MHz, CDCl3): δ = 21.5, 21.7, 43.7, 55.2, 66.7, 78.9, 108.3, 110.4, 127.2, 127.7, 128.4, 128.6, 128.7, 129.6, 129.8, 134.1, 134.5, 137.4, 142.9, 143.5, 144.9, 149.8.

MS (ESI): m/z (% relative intensity) 1091 (100) (2M+Na)+.

HRMS (ESI): m/z calcd for C28H26N2O5S2K+: 573.1283; found 573.1393.

γ–Amino-Ynamide (12c)

(79%, 0.19 g); Rf = 0.27 [4:1 hexanes/EtOAc]; white solid; mp = 143-145 °C.

IR (KBr): 1082 (m), 1159 (s), 1370 (s), 1454 (m), 1597 (w), 1735 (s), 2254 (m), 2981 (w), 3252 (s).

1H NMR (400 MHz, CDCl3): δ = 1.66 (s, 9H), 2.30 (s, 3H), 2.41 (s, 3H), 4.17 (d, 1H, J = 14.4 Hz), 4.37 (d, 1H, J = 14.4 Hz), 5.03 (d, 1H, J = 8.8 Hz), 5.60 (d, 1H, J = 8.4 Hz), 7.06–7.11 (m, 4H), 7.15–7.21 (m, 3H), 7.23– 7.27 (m, 3H), 7.29–7.34 (m, 2H), 7.55 (d, 1H, J = 4.4 Hz), 7.60 (d, 2H, J = 8 Hz), 7.64–7.66 (m, 3H).

13C NMR (100 MHz, CDCl3): δ = 21.4, 21.6, 28.1, 42.7, 55.1, 67.7, 79.0, 84.0, 115.1, 117.5, 119.7, 122.8, 124.7, 124.9, 127.2, 127.4, 127.5, 128.3, 128.4, 128.5, 129.3, 129.7, 134.2, 134.6, 135.9, 137.2, 143.3, 144.7, 149.3.

MS (ESI): m/z (% relative intensity) 1389 (100) (2M+Na)+.

HRMS (ESI): m/z calcd for C37H37N3O6S2K+: 722.2124; found 722.2424.

γ–Amino-Ynamide (12d)

(78%, 0.16 g); Rf = 0.38 [7:3 hexanes/EtOAc]; white solid; mp = 141-143 °C.

IR (KBr): 1167 (s), 1348 (s), 1529 (s), 1597 (w), 2248 (m), 3275 (s).

1H NMR (400 MHz, CDCl3): δ = 2.45 (s, 3H), 4.32 (s, 2H), 5.33 (d, 1H, J = 8.0 Hz), 5.47 (d, 1H, J = 8.0 Hz), 7.15 (d, 2H), 7.20–7.27 (m, 6H), 7.29–7.33 (m, 4H), 7.64 (d, 2H, J = 8.4 Hz), 7.90 (d, 2H, J = 8.8 Hz), 8.15 (d, 2H, J = 8.8 Hz).

13C NMR (100 MHz, DMSO-d6): δ = 21.6, 49.8, 55.0, 68.0, 80.4, 124.1, 127.2, 127.5, 128.2, 128.5, 128.6, 128.7, 129.9, 133.9, 134.3, 137.1, 145.0, 146.1, 149.8 (2 carbon peaks missing due to overlap).

MS (ESI): m/z (% relative intensity) 1173 (100) (2M+Na)+.

HRMS (ESI): m/z calcd for C29H25N3O6S2Na+: 598.0987; found 598.1057.

γ–Amino-Ynamide (12e)

(70%, 0.12 g); Rf = 0.30 [7:3 hexanes/EtOAc]; white solid; mp = 150-152 °C.

IR (KBr): 1367 (s), 1404 (w), 1435 (m), 1495 (s), 1579 (s), 1597 (s), 1801 (w), 1895 (w), 1951 (w), 1969 (w), 2032 (w), 2250 (s), 2585 (w), 2844 (w), 2947 (w), 3014 (w), 3032 (w), 3105 (w), 3226 (brs).

1H NMR (400 MHz, CDCl3): δ = 2.45 (s, 3H), 3.83 (s, 3H), 4.34 (dd, 2H, J = 13.6, 24.4 Hz), 4.85 (d, 1H, J = 8.4 Hz), 5.35 (d, 1H, J = 8.4 Hz), 6.89 (d, 2 H, J = 8.8 Hz), 7.15 (d, 2H, J = 6.4 Hz), 7.20–7.33 (m, 10H), 7.63 (d, 2H, J = 8.0 Hz), 7.75 (d, 2H, J = 8.8 Hz).

13C NMR (100 MHz, CDCl3): δ = 21.6, 49.4, 55.1, 55.5, 68.5, 79.9, 114.1, 127.1, 127.6, 128.2, 128.4, 128.5, 128.5, 128.7, 129.3, 129.7, 131.9, 134.1, 134.5, 137.7, 144.8, 162.8.

MS (ESI): m/z (% relative intensity) 583 (100) (M+ Na)+.

HRMS (ESI): m/z calcd for C30H28N2O5S2Na+: 583.1440; found 583.1829.

γ–Amino-Ynamide (12z)

(76%, 0.12 g); Rf = 0.24 [7:3 hexanes/EtOAc]; white solid; mp = 152-154 °C.

IR (KBr): 1360 (s), 1463 (w), 1496 (m), 1556 (s), 1576 (s), 1610 (s), 2830 (w), 3021 (w), 3445 (brs).

1H NMR (400 MHz, CDCl3): δ = 2.38 (s, 3H), 3.74 (s, 3H), 4.35 (dd, 2H, J = 13.8, 34.2 Hz), 4.91(d, 1H, J = 8.4 Hz ), 5.48 (d, 1H, J = 8.4 Hz ), 6.79 (d, 2H, J = 9.0 Hz), 7.14 (d, 2H, J = 7.8 Hz), 7.17 (d, 2H, J = 7.8 Hz) 7.24– 7.31 (m, 4H), 7.46–7.49 (m, 2H), 7.60 (d, 2H, J = 7.8 Hz).

13C NMR (100 MHz, CDCl3): δ = 21.6, 49.7, 55.2, 55.5, 68.6, 80.3, 114.1, 125.0, 126.2, 126.3, 126.4, 127.6, 127.6, 128.2, 128.4, 128.5, 128.6, 128.7, 129.4, 129.8, 131.9, 133.0, 133.0, 134.2, 134.5, 135.1, 144.8, 162.8.

MS (ESI): m/z (% relative intensity) 611.2 (100) (M+ H)+.

HRMS (ESI): m/z calcd for C34H30N2O5S2Na+: 633.1596; found 633.1487.

γ–Amino-Ynamide (13)

(65%, 0.13 g); Rf = 0.25 [10:3 hexanes/EtOAc]; white solid; mp = 147-149 °C.

IR (KBr): 1367 (s), 1400 (m), 1438 (m), 1452 (s), 1493 (m), 1594 (m), 1649 (w), 1762 (w), 1803 (w), 1818 (w), 1936 (w), 2256 (s), 2322 (w), 2956 (w), 3034 (w), 3089 (w), 3208 (brs).

1H NMR (400 MHz, CDCl3): δ = 2.41 (s, 3H), 2.44 (s, 3H), 4.35 (s, 2H), 5.14 (s, 1H), 7.09 (d, 2H, J = 8.0 Hz), 7.15–7.30 (m, 17H), 7.39 (d, 2H, J = 8.0 Hz), 7.71 (d, 2H, J = 8.0 Hz).

13C NMR (100 MHz, DMSO-d6): δ = 21.4, 21.5, 54.8, 62.7, 71.3, 82.2, 127.0, 127.2, 127.7, 127.9, 128.2, 128.6, 128.8, 128.9, 129.2, 130.49, 134.5, 135.0, 140.4, 142.3, 143.6, 145.4.

MS (ESI): m/z (% relative intensity) 1263 (100) (2M+Na)+.

HRMS (ESI): m/z calcd for C36H32N2O4S2K+: 659.1803; found 659.2013.

γ–Amino-Ynamide (14)

(74%, 0.31 g); Rf = 0.22 [3:1 hexanes/EtOAc]; white solid; mp = 123–124 °C.

IR (film): 2961 (m), 2922 (m), 2248 (m), 1738 (m), 1597 (m), 1365 cm-1 (s).

1H NMR (400 MHz, CDCl3): δ = 2.39 (s, 3H), 2.43 (s, 3H), 3.72 (ddt, 1H, J = 1.2, 6.4, 14.8 Hz), 3.78 (ddt, 1H, J = 1.2, 6.4, 14.8 Hz), 4.98 (d, 1H, J = 8.4 Hz, 1H), 5.10 (dq, 1H, J = 1.2, 16.8 Hz), 5.12 (dq, 1H, J = 1.2, 10.4 Hz), 5.41 (d, 1H, J = 8.4 Hz), 5.52 (ddt, 1H, J = 6.4, 10.4, 16.8 Hz), 7.22 (dd, 2H, J = 0.8, 8.4 Hz), 7.26 (dd, 2H, J = 0.8, 8.4 Hz), 7.28–7.34 (m, 3H), 7.39–7.41 (m, 2H), 7.63 (d, 2H, J = 8.4 Hz), 7.71 (d, 2H, J = 8.4 Hz).

13C NMR (125 MHz, CDCl3): δ = 21.6, 21.8, 49.6, 54.0, 68.1, 79.7, 120.1, 127.4, 127.4, 127.8, 128.4, 128.7, 129.7, 129.9, 130.7, 134.6, 137.7, 137.9, 143.5, 145.0.

MS (ESI): m/z (% relative intensity) 495 (100) (M+H)+.

HRMS (ESI): m/z calcd for C26H27N2O4S2 [M+H]+: 495.1407; found 495.1427.

γ–Amino-Ynamide (15)

(48%, 0.65 g); Rf = 0.23 [1:1 hexanes/EtOAc]; white solid; mp = 137–138 °C.

IR (film): 3143 (brm), 2968 (m), 2934 (m), 2888 (m), 2251 (m), 1454 (m), 1325 (s), 1273 cm-1 (s).

1H NMR (500 MHz, CDCl3): δ = 0.84 (s, 3H), 1.01 (s, 3H), 2.38 (s, 3H), 3.60–3.69 (m, 2H), 3.94–4.02 (m, 4H), 5.15 (d, 1H, J = 9.5 Hz), 5.18 (d, 1H, J = 16.0 Hz), 5.35 (s, 1H), 5.67–5.75 (m, 1H), 6.22 (brs, 1H), 7.20–7.26 (m, 5H), 7.38–7.40 (m, 2H), 7.73 (d, 2H, J = 8.5 Hz).

13C NMR (125 MHz, CDCl3): δ = 20.4, 20.9, 21.2, 31.7 (d, J = 6.8 Hz), 49.1, 52.8 (d, J = 5.8 Hz), 62.6 (d, J = 5.8 Hz), 78.0 (d, J = 6.8 Hz), 81.5 (d, J = 4.8 Hz), 118.5, 126.0, 126.8 (d, J = 4.9 Hz), 127.7, 128.1, 129.1, 131.9, 137.6, 138.2, 142.8.

31P NMR (202 MHz, CDCl3) δ = –1.31.

MS (ESI): m/z (% relative intensity) 489 (100) (M+H)+.

HRMS (ESI): m/z calcd for C24H30N2O5PS [M+H]+: 489.1608; found 489.1600.

General Procedure for the Rearrangement

To a 0.05 M solution of ynamide in anhyd CH2Cl2 was added HNTf2 (0.05 equiv) at rt. The resulting solution was stirred at rt and the reaction progress was monitored using TLC analysis. When the starting material was completely consumed, the reaction mixture was quenched with Et3N. Removal of the solvent in vacuo led to a crude material that was purified using silica gel flash column chromatography (gradient eluent: EtOAc in hexane).

Rearranged Product (16a)

(78%, 0.14 g); Rf = 0.59 [7:3 hexanes/EtOAc]; white solid; mp = 156-157 °C.

IR (KBr): 1346 (m), 1380 (w), 1399 (w), 1446 (w), 1495 (w), 1512 (w), 1558 (m), 1576 (m), 1612 (m), 1705 (m), 1747 (w), 2928 (w), 2964 (w), 3030 (w), 3064 (w), 3443 (brs).

1H NMR (400 MHz, CDCl3): δ = 2.39 (s, 6H), 4.93 (s, 2H), 7.03–7.16 (m, 5H), 7.18–7.24 (m, 6H), 7.38–7.43 (m, 5H), 7.46 (d, 2H, J = 8.4 Hz), 7.51 (d, 2H, J = 8.4 Hz).

13C NMR (100 MHz, DMSO-d6): δ = 21.5, 21.6, 52.0, 119.4, 127.0, 127.8, 128.2, 128.3, 128.4, 128.6, 128.9, 129.2, 129.6, 130.6, 134.3, 135.4, 135.7, 138.5, 143.1, 144.7, 145.0, 164.1.

MS (APCI): m/z (% relative intensity) 545.32 (100) (M+H)+.

HRMS (ESI): m/z calcd for C30H28N2O4S2K+: 583.1490; found 583.1641.

Rearranged Product (16z)

(65%, 0.060 g); Rf = 0.33 [7:3 hexanes/EtOAc]; yellow solid; mp = 139–140 °C.

IR (KBr): 1364 (s), 1429 (m), 1454 (m), 1496 (s), 1557 (m), 1596 (s), 2252 (m), 2843 (w), 2914 (w), 3062 (w), 3219 (s).

1H NMR (600 MHz, CDCl3): δ = 2.39 (s, 3H), 3.80 (s, 3H), 4.95 (s, 2H), 6.81 (d, 2H, J = 12.0 Hz), 7.14 (d, 2H, J = 12.0 Hz), 7.20–7.26 (m, 7H), 7.49–7.58 (m, 7H), 7.80 (s, 1H), 7.84 (t, 3H, J = 6.0 Hz)

13C NMR (150 MHz, CDCl3): δ = 21.6, 52.1, 55.6, 100.0, 113.7, 119.5, 123.6, 126.8, 127.5, 127.8, 128,2, 128.4, 128.6, 128.7, 128.8, 129.1, 129.6, 130.5, 131.8, 133.2, 133.3, 134.4, 135.3, 135.8, 145.01, 145.02, 162.7, 164.0

MS (ESI): m/z (% relative intensity) 611.2 (100) (M+K)+.

HRMS (ESI): m/z calcd for C34H30N2O5S2Na+: 633.1596; found 633.1490.

Rearranged Product (16az)

(72%, 0.24 g); Rf = 0.39 [7:3 hexanes/EtOAc]; yellow solid; mp = 149–151 °C.

IR (KBr): 1361 (s), 1322 (m), 1496 (m), 1556 (s), 1577 (s), 1595 (s), 1610 (s), 2841 (w), 2935 (w), 2960 (w), 3033 (w), 3062 (w).

1H NMR (600 MHz, CDCl3): δ =2.39 (s, 3H), 3.82 (s, 3H), 4.95 (s, 2H), 6.81 (d, 2H, J = 8.5 Hz), 7.02 (d, 1H, J = 16.2 Hz), 7.11-7.14 (m, 3H), 7.18–7.25 (m, 5H), 7.38 (m, 5H), 7.48 (d, 2H, J = 7.8 Hz), 7.56 (d, 2H, J = 8.4 Hz)

13C NMR (150 MHz, CDCl3): δ = 21.6, 52.0, 55.6, 113.7, 119.4, 127.8, 128.2, 128.3, 128.3, 128.6, 128.9, 129.1, 129.6, 130.6, 133.2, 134.3, 135.3, 135.7, 144.6, 145.0, 162.7, 164.0.

MS (ESI): m/z (% relative intensity) 561 (100) (M +H)+.

HRMS (ESI): m/z calcd for C30H28N2O5S2Na+: 583.1440; found 583.1332.

Rearranged Product (16za)

(57%, 0.19 g); Rf = 0.54 [7:3 hexanes/EtOAc]; yellow solid; mp = 178–179 °C.

IR (KBr): 1361 (s), 1454 (w), 1496 (w), 1593 (m), 3028 (w), 3260 (w).

1H NMR (600 MHz, CDCl3): δ = 2.38 (s, 6H), 4.95 (s, 2H), 7.14 (d, 2H, J = 7.8 Hz), 7.16 (d, 2H, J = 7.2 Hz), 7.21-7.26 (m, 7H), 7.48 (d, 2H, J = 8.4 Hz), 7.52 (d, 4H, J = 7.8 Hz), 7.57 (d, 1H, J = 8.4 Hz), 7.80 (s, 1H), 7.85 (m, 3H).

13C NMR (150 MHz, CDCl3): δ = 21.5, 21.6, 52.1, 119.5, 123.6, 125.6, 126.8, 127.0, 127.5, 127.8, 128.2, 128.4, 128.6, 128.7, 128.8, 129.2, 129.6, 130.5, 131.8, 133.2, 134.4, 135.3, 135.7, 138.5, 143.1, 145.0, 145.2, 164.2.

MS (ESI): m/z (% relative intensity) 595 (100) (M +H)+.

HRMS (ESI): m/z calcd for C34H30N2O4S2Na+: 617.1647; found 617.1535.

N-Allylations of γ–Amino-Ynamide. A Representative Procedure using Ynamide 14

To a flame-dried screw-cap vial were charged with γ–amino-ynamide 14 (125.0 mg, 0.25 mmol), cinnamyl alcohol (36.9 mg, 0.275 mmol), PPh3 (72.1 mg, 0.275 mmol) and THF (0.8 mL). The solution was stirred for 5 min at rt before being cooled to 0 °C, and DIAD (51.0 μL, 0.275 mmol) was added dropwise. After which, the cooling bath was removed and the reaction mixture was allowed to warm to rt. The reaction was monitored using TLC and when the starting material was consumed after 15 h, the solvent was removed in vacuo. The crude residue was purified through silica gel flash column chromatography (isocratic eluent: 4:1 hexanes/EtOAc + 2% NEt3 [to buffer the column]) to afford ynamide 22 as a mixture with DIAD being the byproduct. Ynamide 22 (67.0 mg, 0.11 mmol, 44%) could be recrystallized cleanly from the mixture with benzene:hexane.

N-Allylated Ynamides (20)

(60%, 0.18 g); Rf = 0.22 [7:3 hexanes/EtOAc]; white solid; mp = 129–130 °C.

IR (film): 1368 (w), 1417 (m), 1424 (m), 1441 (w), 1473 (m), 1493 (m), 1599 (w), 1789 (s), 2250 (m), 2924 (w), 2986 (w), 3038 (w), 3432 (brs).

1H NMR (600 MHz, CDCl3): δ = 2.42 (s, 3H), 3.56 (dq, 2H, J = 8.4, 26.4 Hz), 3.81 (d, 2H, J = 6.6 Hz), 4.29–4.33 (m, 2H), 5.70 (dt, 1H, J = 6.6, 22.8 Hz), 6.14 (d, 1H, J = 15.6 Hz), 6.29 (s, 1H), 7.02 (d, 2H, J = 7.2 Hz), 7.15 (t, 1H, J = 7.2 Hz), 7.20 (t, 2H, J = 7.2 Hz), 7.24– 7.26 (m, 1H), 7.30–7.32 (m, 4H), 7.59 (d, 2H, J = 7.8 Hz), 7.85 (d, 2H, J = 8.4 Hz).

13C NMR (125 MHz, CDCl3): δ = 21.5, 46.4, 47.4, 53.4, 63.0, 66.5, 78.4, 125.7, 126.3, 127.4, 127.9, 128.2, 128.3, 128.5, 129.6, 132.7, 136.2, 136.6, 136.9, 143.4, 155.7 (1 carbon missing due to overlap).

MS (APCI): m/z (% relative intensity) 487 (100) (M+H)+.

HRMS (ESI): m/z calcd for C28H26N2O4SNa+: 509.1613; found 509.1950.

N-Allylated Ynamides (21)

(37%, 0.17 g); Rf = 0.54 [7:3 hexanes/EtOAc]; white solid; mp = 125–126 °C.

IR (film): 1363 (m), 1399 (w), 1427 (w), 1454 (m), 1490 (m), 1592 (m), 2245 (m), 2857 (w), 2921 (w), 3028 (w), 3064 (w), 3438 (brs).

1H NMR (600 MHz, CDCl3): δ = 2.33 (s, 3H), 2.38 (s, 3H), 3.56 (dd, 1H, J = 7.2, 15 Hz), 3.72 (dd, 1H, J = 5.4, 15 Hz), 4.36 (dd, 2H, J = 14.4, 39 Hz), 5.51–5.56 (m, 1H), 5.98 (d, 1H, J = 15.6 Hz), 6.22 (s, 1H), 6.90 (d, 2H, J = 6 Hz), 7.10 (d, 2H, J = 7.2 Hz), 7.16–7.23 (m, 12H), 7.26–7.29 (m, 3H), 7.64 (d, 2H, J = 8.4 Hz), 7.75 (d, 2H,J = 7.2 Hz)

13C NMR (125 MHz, CDCl3): δ = 21.5, 21.6, 47.4, 53.6, 55.2, 66.3, 81.6, 125.6, 126.4, 127.4, 127.7, 127.8, 128.0, 128.1, 128.3, 128.4, 128.5, 128.7, 129.7, 129.9, 132.4, 134.3, 134.7, 136.6, 136.96, 136.97, 143.4, 144.9 (1 carbon peak missing due to overlap).

MS (APCI): m/z (% relative intensity) 661 (100) (M+H)+.

HRMS (ESI): m/z calcd for C39H36N2O4S2Na+: 683.8441; found 683.1985.

N-Allylated Ynamides (22)

(44%, 0.070 g); Rf = 0.38 [2:1 hexanes/EtOAc]; white solid; mp = 80–81 °C.

IR (film): 2961 (m), 2922 (m), 2248 (m), 1738 (m), 1597 (m), 1365 cm-1 (s).

1H NMR (500 MHz, CDCl3): δ = 2.38 (s, 6H), 3.77 (ddd, 1H, J = 1.0, 8.0, 15.5 Hz), 3.82 (ddt, 2H, J = 1.5, 3.0, 6.0 Hz), 3.88 (ddd, 1H, J = 1.0, 6.0, 15.5 Hz), 5.11 (dq, 1H, J = 1.0, 11.0 Hz), 5.11 (dq, 1H, J = 1.0, 17.5 Hz), 5.53 (ddt, 1H, J = 6.0, 11.0, 17.5 Hz), 5.60 (ddd, 1H, J = 6.0, 8.0, 16.0 Hz), 6.13 (d, 1H, J = 16.0 Hz), 6.26 (s, 1H), 6.94 (dd, 2H, J = 1.5, 7.5 Hz), 7.14–7.20 (m, 2H), 7.22–7.30 (m, 7H), 7.54 (dd, 2H, J = 1.0, 7.0 Hz), 7.68 (d, 2H, J = 8.5 Hz), 7.78 (d, 2H, J = 8.5 Hz).

13C NMR (125 MHz, CDCl3): δ = 21.7, 21.8, 47.7, 53.7, 54.1, 65.9, 81.4, 120.0, 125.7, 126.5, 127.6, 127.8, 127.9, 128.28, 128.34, 128.4, 128.5, 129.8, 130.0, 130.9, 132.7, 134.9, 136.7, 137.1, 137.2, 143.5, 145.1.

MS (ESI): m/z (% relative intensity) 495 (60) (M–C9H10+H), 611 (30) (M+H)+.

HRMS (ESI): Attempted but not stable enough for an accurate mass.

N-Allylated Ynamides (23)

(57%, 0.31 g); Rf = 0.32 [Et2O]; colorless oil.

IR (film): 2974 (m), 2891 (m), 2249 (m), 1453 (m), 1331 (s), 1281 cm-1 (s).

1H NMR (500 MHz, CDCl3): δ = 1.04 (s, 3H), 1.08 (s, 3H), 1.31 (s, 3H), 2.44 (s, 3H), 3.57–3.79 (m, 4H), 4.01–4.09 (m, 2H), 4.12–4.19 (m, 2H), 4.57 (d, 2H, J = 47.0 Hz), 5.20 (d, 1H, J = 10.0 Hz), 5.21 (d, 1H, J = 17.0 Hz), 5.72–5.78 (m, 1H), 6.19 (d, 1H, J = 3.0 Hz), 7.26–7.34 (m, 5H), 7.52–7.54 (m, 2H), 7.77 (d, 2H, J = 8.0 Hz).

13C NMR (126 MHz, CDCl3): δ = 19.4, 21.1 (d, J = 2.4 Hz), 21.4, 32.1 (d, J = 6.8 Hz), 51.2, 53.0 (d, J = 5.8 Hz), 54.1 (d, J = 1.4 Hz), 59.5 (d, J = 5.8 Hz), 77.8 (d, J = 7.2 Hz), 77.9 (d, J = 6.7 Hz), 83.7 (d, J = 5.3 Hz), 113.8, 118.7, 127.7, 127.8, 127.9, 128.5, 129.4, 132.2 (d, J = 2.0 Hz), 136.1, 137.0 (d, J = 1.0 Hz), 140.9, 143.3.

31P NMR (202 MHz, CDCl3) δ = –0.75.

MS (APCI): m/z (% relative intensity) 543 (57) (M+H)+.

HRMS (ESI): m/z calcd for C28H39N3O5PS [M+NH4]+: 560.2343; found 560.2337.

General Procedure for [2 + 2] Cycloadditions

To a flame-dried screw-cap vial were added ynamide 23 (54.4 mg, 0.10 mmol), Pd(PPh3)4 (5.80 mg, 0.0050 mmol), and toluene (1 mL; concn = 0.1 M for ynamide). The vial was sealed under N2 and heated to 70 °C. After 2 h, TLC analysis showed complete consumption of the starting ynamide and the solvent was removed in vacuo. The crude residue was purified through silica gel flash column chromatography (isocratic eluent: 1:1 hexanes/EtOAc) to afford cycloadduct 25 (46.3 mg, 0.085 mmol) in 85% yield.

[2 + 2] Cycloadduct (24)

(95%, 0.060 g); Rf = 0.40 [2:1 hexanes/EtOAc]; white solid; mp = 114–115 °C.

IR (film): 3032 (w), 2930 (m), 2852 (m), 1727 (m), 1660 (s), 1597 (m), 1453 (m), 1327 cm-1 (s).

1H NMR (500 MHz, CDCl3): δ = 1.76 (dd, 1H, J = 9.0, 15.5 Hz), 1.84 (ddt, 1H, J = 2.0, 5.0, 15.5 Hz), 2.03 (s, 1H), 2.37 (s, 3H), 2.45 (s, 3H), 3.62 (s, 1H), 4.21 (s, 1H), 4.21 (d, 1H, J = 15.5 Hz), 4.62 (dd, 1H, J = 5.5, 11.0 Hz), 4.76 (dd, 1H, J = 1.0, 17.0 Hz), 5.07 (d, 1H, J = 10.0 Hz), 5.48 (dddd, 1H, J = 5.0, 9.0, 10.0, 17.0 Hz), 5.72 (s, 1H), 6.88 (d, 2H, J = 7.0 Hz), 7.03 (t, 2H, J = 8.0 Hz), 7.07–7.09 (m, 4H), 7.16 (t, 1H, J = 7.5 Hz), 7.21–7.23 (m, 5H), 7.33 (d, 2H, J = 8.0 Hz), 7.83 (d, 2H, J = 8.0 Hz).

13C NMR (100 MHz, CDCl3): δ = 21.6, 21.8, 30.7, 45.9, 53.1, 54.0, 66.1, 72.2, 120.1, 127.0, 127.7, 127.8, 127.9, 128.1, 128.5, 128.6, 128.9, 129.5, 129.8, 130.8, 136.2, 136.4, 136.6, 137.0, 143.3, 144.7, 193.5.

MS (ESI): m/z (% relative intensity) 611 (100) (M+H)+.

HRMS (ESI): m/z calcd for C35H35N2O4S2 [M+H]+: 611.2038; found 611.2047.

[2 + 2] Cycloadduct (25)

(85%, 0.050 g); Rf = 0.15 [1:1 hexanes/EtOAc]; colorless oil.

IR (film): 2966 (m), 2933 (m), 2879 (m), 1702 (s), 1340 (s), 1287 cm-1 (s).

1H NMR (500 MHz, CDCl3): δ = 0.95 (s, 3H), 1.37 (s, 3H), 1.45 (s, 3H), 2.02–2.06 (m, 1H), 2.13–2.18 (m, 1H), 2.29 (s, 3H), 3.28 (t, 2H, J = 2.5 Hz), 3.38 (d, 1H, J = 10.5 Hz), 3.83 (d, 1H, J = 10.5 Hz), 3.98 (dd, 2H, J = 10.5, 21.0 Hz), 4.39 (dd, 1H, J = 4.0, 10.0 Hz), 4.59 (dd, 1H, J = 1.5, 17.0 Hz), 4.90 (dd, 1H, J = 1.0, 10.0 Hz), 5.24 (s, 1H), 5.65–5.73 (m, 1H), 6.95 (t, 4H, J = 8.0 Hz), 7.10–7.15 (m, 4H), 7.21 (d, 1H, J = 7.5 Hz).

13C NMR (125 MHz, CDCl3): δ = 19.8, 20.3, 21.4, 22.2, 32.4 (d, J = 6.2 Hz), 32.5, 43.6, 53.2 (d, J = 16.2 Hz), 59.8, 70.4 (d, J = 27.4 Hz), 71.6 (d, J = 2.4 Hz), 77.8 (d, J = 7.2 Hz), 78.2 (d, J = 6.7 Hz), 118.7, 126.8, 128.0, 128.3, 128.8, 129.0, 131.7, 135.4, 135.7, 142.7, 200.4 (d, J = 9.6 Hz).

31P NMR (202 MHz, CDCl3) δ = –3.02.

MS (APCI): m/z (% relative intensity) 543 (100) (M+H)+.

HRMS (ESI): m/z calcd for C28H36N2O5PS [M+H]+: 543.2078; found 543.2062.

Acknowledgment

RPH thanks NIH [GM066055] for funding. KAD thanks the American Chemical Society for a Division of Medical Chemistry Pre-Doctoral Fellowship. YT thank Natural Science Foundation of China for generous funding [No. 21172169 and No.21172168]. Service from The Instrumentation Center at School of Pharmaceutical Science and Technology of Tianjin University is greatly appreciated.

Footnotes

†

With the deepest respect and admiration, authors wish to dedicate this paper to Professor Scott E. Denmark on a very special occasion in celebrating his 60th Birthday.

References

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