N-Allyl-N-Sulfonyl Ynamides as Synthetic Precursors to Amidines and Vinylogous Amidines. An Unexpected N-to-C 1,3-Sulfonyl Shift in Nitrile Synthesis

Abstract

A detailed study of amidine synthesis from N-allyl-N-sulfonyl ynamides is described here. Mechanistically, this is a fascinating reaction consisting of diverging pathways that could lead to deallylation or allyl transfer depending upon the oxidation state of palladium catalysts, the nucleophilicity of amines, and the nature of the ligands. It essentially constitutes a Pd(0)-catalyzed aza-Claisen rearrangement of N-allyl ynamides, which can also be accomplished thermally. An observation of N-to-C 1,3-sulfonyl shift was made when examining these aza-Claisen rearrangements thermally. This represents a useful approach to nitrile synthesis. While attempts to render this 1,3-sulfonyl shift stereoselective failed, we uncovered another set of tandem sigmatropic rearrangements, leading to vinyl imidate formation. Collectively, this work showcases the rich array of chemistry one can discover using these ynamides.

Introduction

Amidines^1,2 represent a prolific functional group in medicinal chemistry and an important pharmacophore in drug discovery.^3–6 One notable example is the DNA and RNA binding di-amidine Diminazene, which is found in drugs like Azidin, Berenil, or Pirocide to treat the parasitic protozoan that causes Trypanosoniasis for which African sleeping sickness and Chagas disease are a form.⁷ There are several different variations of amidines depending on the substituents on the nitrogen or the sp²-amidinyl carbon^1,2 [Figure 1]. Aliphatic and aromatic amidines are generally prepared in a very similar manner, frequently from amides, nitriles, and thioamides with a nitrogen nucleophile.^1,2,8 The Pinner reaction and modified Pinner transformations,^9,10 which employ nitriles and go through an imidate, are the most common protocols for synthesizing amidines. However, this method is not good for hindered nitriles and it cannot be used for the synthesis of tertiary amidines. Consequently, amides and thioamides are frequently used.^1,2 Activation of the mono-substituted amide by chlorinating agents or alkylation of the alkoxy group can yield amidines when the resulting compound is reacted with an amine. Thioamides can more directly yield an amidine by simply reacting it with an amine and a mercury salt to act as a sulfide scavenger [Figure 1]. Whitby¹¹ recently reported an interesting usage of isonitrile for accessing amidines by reacting with aryl or allyl bromides and an amine using a palladium catalyst. Lastly, there has been extensive development in constructing amidines through decomposing N-sulfonyl triazoles [not shown here].^12–15

Figure 1.

Amidines and Their General Preparation.

We recently found that ynamides^16–18 could serve as excellent precursors for synthesizing amidines via a Pd(0)-catalyzed N-to-C allyl transfer.¹⁹ As shown in Scheme 1, the oxidative addition [O.A.] of N-allyl-ynamides 1 would lead to novel ynamido-π-allyl complexes 2a and ketenimino-π-allyl complexes 2b. The subsequent formation of amidines 4 would occur in the presence of an amine either through trapping of ketenimines 3, which is derived from 2b via reductive elimination [R.E.]; or through π-allyl complex 5, which is a result of the amine addition to complexes 2b prior to R. E. We also found that while amidines 4 represent a successful N-to-C allyl transfer, the reaction did not always lead to transfer of the allyl group. Instead, a diverging pathway would lead to amidines 6 that could be prepared with concomitant de-allylation depending upon the amine and the nature of the palladium catalyst and ligands. Although it is quite reasonable to presume that this de-allylation could have occurred through amine attacking the palladium π-allyl complexes 2b, it could also be envisioned from keteniminium intermediate 7 generated from 1 with the Pd(II) species serving as a π-Lewis acid. We recognized that not only does this signify a de novo transformation of ynamides with an invaluable opportunity to study ynamido-metal complexes,^{12–16,20,21} but also an excellent method for synthesizing amidines especially given that ynamides are now synthetic readily available substrates.^22–24 We report here details of our investigation in developing this amidine synthesis.

Scheme 1.

Amidine Formation from N-Allyl-Ynamides.

Results and Discussion

1. Deallylative Amidine Formation

We made our initial discovery of the deallylation of ynamides when treating N-allyl-ynamide 8a with 5 mol% of PdCl₂(PPh₃)₂ with an original intent to hydroaminate the alkyne [Scheme 2]. Instead, we found that amidine 9 was formed in high yield when using 10.0 equiv of H₂N-t-Bu, and that the allyl group was missing. Intriguingly, when lowering the amount of the amine to 3.0 equiv, the allyl resonances visibly reappeared in the proton NMR and no longer on the nitrogen atom but on the formerly the β-carbon of the ynamide after isolating 10 in 37% yield. We recognized this unexpected transformation represents an excellent protocol for synthesizing amidines, and to avoid complication with the allyl group issue, we initially focused on deallylation via using 5.0 equiv of the amine. The generality and the effectiveness of this amidine synthesis could be thoroughly captured in Table 1 through using a wide range of primary amines, and demonstrated in Table 2 via employing a diverse array of secondary amines as well as varying the N-allyl-ynamide substitutions. It is noteworthy that based on NOE experiments, these amidines adopt an E-geometry with respect to the C=N bond.¹⁹

Scheme 2.

Amidine Formation with Pd(II) Catalyst.

Table 1.

Deallylative Primary Amidine Formation.

entry	amines [5.0 equiv]a	amidine products	yield [%]b
1		11 12	87
2			92
3		13 14 15	50
4			71
5			22
6		16	30
7		17 18	≥95
8			≥95

^aAll entries utilized ynamide 8a except in entry 8, Ph-substituted ynamide 8b was used. All reactions employed 5.0 mol % PdCl₂(PPh₃)₂, 1.0 equiv K₂CO₃, THF [conc = 0.05 M], 80 °C, 5–8 h.

^bIsolated yields.

Table 2.

Secondary Amidine Formation.

entry	ynamides	aminesa	amidine products	yield [%]b
1	8a 8c 8d 8e		19: R = TIPS 20: R = t-Bu 21: R = (CH2)3OTBS 22: R = 2-MeO-Ph	≥95
2				≥95
3				92
4				37
5	8f		23	39
6	8a 8b 8g		24: R = TIPS 25: R = Ph 26: R = n-hex	≥95
7				≥95
8				≥95
9	8g		27	70
10	8a		28	≥95
11			29	77
12			30a: n = 1 30b: n = 2 30c: n = 3	≥95
13				≥95
14				≥95
15			31	91
16			32	≥95
17			33a: R = CH3 33b: R = Ph	≥95
18				≥95
19			34	≥95
20			35	82

^aAll reactions utilized 5.0 equiv of the amine, 5.0 mol % PdCl₂(PPh₃)₂, and 1.0 equiv K₂CO₃; and were run in THF [conc = 0.05 M] at 80 °C over 5–8 h.

^bIsolated yields.

2. Deallylation Mechanism and Allyl Transfer

While this is an interesting amidine synthesis, we were fascinated by its possible mechanism. Because of their basicity, polarity, and/or volatility, the respective allyl amine byproducts [R₂N-CH₂CH=CH₂] from deallylation were difficult to isolate. Nevertheless, as shown in Scheme 3, a mechanistically revealing experiment involved the use of piperizine, which led to the N-allylated amine 36 in 63% yield. Consequently, deallylation could be either a Pd(0)- or Pd(II)-catalyzed process. The former would require oxidative addition of Pd(0) to N-allyl ynamide 8a, leading to 5 through an N-to-C allyl transfer from ynamido-palladium π–allyl complex 2a; while the latter would involve a palladium(II)-substituted keteniminium ion 7 with Pd(II) serving to activate the alkynyl motif. Deallylation could take place either in an intramolecular manner as shown in 5; or an intermolecular manner as shown in 7. Although attempts were made, these reactions were too fast to allow NMR studies to be revealing of possible ynamido-π-allyl complexes even at 25 °C. Only the starting ynamide, silyl-ketenimine such as 3 and respective amidine product [if the reaction was run in the presence of an amine] were clearly in display spectroscopically.

Scheme 3.

Two Possible Deallylation Pathways.

While both pathways could be operative for the deallylation, we suspected that suppression of the Pd(II)-catalyzed pathway through directly using a Pd(0) source could lead to suppression of the deallylation.²⁵ As shown in Table 3, this predictive assessment turned out to be true. While most Pd(II) sources led to predominantly the deallylation when using 3.0 equiv of c-hex-NH₂, Pd(PPh₃)₄ gave exclusively the allyl transferred amidine 37 [entry 6]. This preservation of the allyl group turned to be general for a number of primary amines, as evident from amidine products 38a–c.

Table 3.

Dependence of Deallylation on Palladium Species.

	entry	Pd(II) or Pd(0) cat	time [h]	yield [%]a	12	37
	1	PdCl2(PPh3)2	2		63	24
	2	PdCl2(dppe)	48		30	<5
	3	PdCl2(dppf)	24		95	0
	4	PdCl2	20		66	16
	5	Pd(OAc)2	20		65	8
	6	Pd(PPh3)4	3		0	≥95

^aAll are isolated yields.

However, the use of Pd(PPh₃)₄ was not sufficient especially in the case of secondary amines such as pyrrolidine or piperidine, which are more nucleophilic than primary amines, leading to exclusively deallylation.²⁶ The nature of the ligand also mattered. Those that favored reductive elimination such as xantphos^27,28 allowed the isolation of a range of different allyl transferred amidines such as 39 and 40a–e [Scheme 4]. X-phos²⁹ was also examined and was comparable in terms of yield of allylated amidines, but xantphos allowed shorted reaction times.¹⁹

Scheme 4.

The Use of Xantphos Ligand.

Furthermore, we found that enamines or vinylogous amides could also be used as nucleophiles under these conditions for allyl transfers. As shown in Table 4, vinylogous amidines 45 and 46 [entries 1 and 2] as well as 47 and 51 [entries 3 and 7] could be accessed utilizing enamine 41 and vinylogous amide 42, respectively. For reasons unknown to us at this moment, the allyl group did not transfer for vinylogous amidines 48 and 49 [entries 4 and 5], and primary vinylogous amides such as 43 did not work well [entry 6]. Nevertheless, a general trend for the dichotomy of deallylation versus N-to-C allyl transfer could be summarized as shown in Figure 2. Deallylation is favored when using excess of amine, or Pd(II) sources, and/or more nucleophilic secondary amines whereas N-to-C allyl transfer is favored with less nucleophilic primary amines, Pd(0) sources, and/or R.E. favoring ligands such as xantphos.

Table 4.

Vinylogous Amidine Synthesis.

entry	ynamides	enaminesa	vinylogous amidines	yield [%]b
1	8a: R = Ts 8h: R = MBS	41	45 46	52c
2				71d
3	8f	42	47	58e
4	8d	41	48	54f
5	8i	41	49	57g
6	8j	43	50	--
7		42	51	62h

^aUnless otherwise noted, all reactions utilized 3.0 equiv of the enamine, 5.0 mol% Pd₂(dba)₃, and 10.0 mol% of xantphos; and were run in THF [conc = 0.05 M].

^bIsolated yields.

^c2 h at 70°C.

^d2 h at 50 °C with 1.5 equiv of K₂CO₃.

^e12 h at 70°C with 1.5 equiv of 42; 2.0 mol % Pd₂(dba)₃; and 4.0 mol% of xantphos.

^f30 min at 50 °C.

^g2 h at RT.

^h2 h at 75 °C with 1.5 equiv of K₂CO₃ and 1.5 equiv of 44.

Figure 2.

A Dichotomy of Deallylation and Allyl Transfer.

3. Aza-Claisen Rearrangement and 1,3-Sulfonyl Shift

Our efforts described above allowed us to recognize that these reactions in essence are aza-Claisen rearrangements^30–32 promoted by palladium catalysts. In fact, aza-Claisen rearrangements could be carried out thermally without any metal catalysts. As shown in Scheme 5, a non-palladium involved pathway would entail an aza-Claisen transition state [see A], leading to allyl-ketenimine intermediate B. Trapping of B would then lead to many products, and in the case of an alcohol, imidates could be accessed.^33,34

Scheme 5.

Thermal Aza-Claisen Rearrangment.

Trapping of the allyl-ketenimine intermediate such as 55 with an external amine could also lead to allyl-transferred amidine 39. This indeed is true not only in the case of 39 but is also highly effective as shown in Table 5 in giving a wide range of amidines 56–60 in good yields.³⁵ However, this pathway requires much higher temperature and longer reaction time. When carried out at 65 °C to 80 °C in THF, the reaction was sluggish and slow,³⁶ thereby suggesting that the palladium catalyst was indeed promoting these transformations.

Table 5.

Amidine Synthesis via Aza-Claisen Rearrangement.

entry	ynamides	aminesa	amidine products	yield [%]b
1	8b		56	94
2	8d		57	58
3	8k		58	77
4	8a		59	≥95
5	8f		60	93

^aAll reactions utilized 3.0 equiv of the amine and were run in toluene [concn = 0.05 M] at 110 °C over 24 h except it was 48 h for entry 4.

^bIsolated yields.

It was during this study that we observed an interesting N-to-C 1,3-sulfonyl shift.³⁷ As shown in Scheme 6, when using ynamides not substituted with TIPS at the terminal position, we observed the formation of quaternary nitriles 61 in the absence of an amine. This observation suggested that allyl ketenimines 3 in which R ≠ TIPS had undergone a N-to-C 1,3-sulfonyl shift; whereas this was not the case when R = TIPS. Silyl ketenimines such as 55 were sufficiently stable^38,39 and could be trapped subsequently.

Scheme 6.

An Unexpected N-to-C 1,3-Sulfonyl Shift.

This nitrile formation is very general including a number of different sulfonyl groups as demonstrated in Table 6 [see entries 1–4]. While the 1,3-sulfonyl shift tolerated various substitutions [entries 5 and 6], again when using 8a containing the TIPS substitution [entry 7], the 1,3-sulfonyl shift only took place only when in conjunction with desilylation. It is also noteworthy that given results in Table 5, the N-to-C 1,3-sulfonyl shift most likely took place after the aza-Claisen rearrangement. In addition, monitoring the thermal aza-Claisen rearrangement of ynamide 8b using proton NMR did not reveal any respective ketenimine, thereby suggesting that the 1,3-sulfonyl shift was very fast at 110 °C.

Table 6.

Tandem Aza-Claisen - 1,3-Sulfonyl Shift

entry	ynamides	nitriles	yielda,b
1	8b: R = Ts 8i: R = 4-MeO-Ph 8j: R = 4-NO2-Ph 8l: R = Me	62 63 64 65	48
2			53
3			53
4			64
5	8m	66	57
6	8d	67	45
7	8a	68	57

^aConditions: Toluene, 110 °C, and 14 h.

^bIsolated yields.

We then attempted to extend this interesting 1,3-sulfonyl shift because the formation of tertiary nitriles holds significant merit in synthesis.⁴⁰ As shown in Scheme 7, we envisioned that using ynamide 69 containing a propargylic stereocenter could lead to a stereoselective 1,3-sulfonyl shift to give 70 or 70′. The level of selectivity would depend upon conformational preference of allyl-ketenimine intermediate 72 and 72′, and in this case, the conformer 72′ could be more preferred given the A^1,2-strain present in 72. This preference could lead to a facial selective 1,3-sulfonyl shift to give 70′. In addition, we could vary the P group so that it could lead to the conformational situation shown in 73′ in which anchiomeric assistance could take place, again leading to possible facial selective 1,3-sulfonyl shift.

Scheme 7.

Diastereoselective N-to-C 1,3-Sulfonyl Shift.

Unfortunately, after examining a number of such ynamides [69a–d], the best ratio was 2:1 using 69c [entry 3 in Table 7]. Most intriguingly, when exploring ynamide 69e [P = N-dimethyl carbamoyl] and 69d [P = Piv] with hope of the aforementioned anchiomeric assistance, we obtained α,β-unsaturated imidates 79 and 81, respectively. The double bond geometry was assured using NOE experiments. In addition, when we went back to crude proton NMR of the reaction using 69b in which P = Ac, we also saw ~10% of the respective imidate. Intriguingly, no nitrile was found in the case of 69e, due to the increased electron density in the carbamate. The isolation of these imidates implied a sequence of tandem sigmatropic rearrangement: an aza-Claisen followed by another [3,3]-sigmatropic rearrangement through the respective allyl-ketenimine intermediates 78 and 80.

Table 7.

Possible Diasteoselective 1,3-Sulfonyl Shift.

entry	ynamidesa	nitriles	yieldb	dr
1	(±)-69a: P = TIPS (±)-69b: P = Ac	74 75	91	1.5:1
2			50c	1.3:1
3	(±)-69c: P = TIPS (±)-69d: P = Piv	76 77	≥95	2.0:1
4			69c	1.5:1

^aConditions: Toluene, 110 °C, and 2–4 h.

^bIsolated yields.

^cSee Scheme 8.

CONCLUSION

We have described here a detailed study of amidine synthesis from N-allyl-N-sulfonyl ynamides. Mechanistically, this is a fascinating reaction consisting of diverging pathways that could lead to deallylation or allyl transfer depending upon the oxidation state of palladium catalysts, the nucleophilicity of amines, and the nature of the ligands. It essentially constitutes a Pd(0)-catalyzed aza-Claisen rearrangement of N-allyl ynamides, which can also be accomplished thermally. An observation of N-to-C 1,3-sulfonyl shift was made when examining these aza-Claisen rearrangements thermally, thereby representing a useful approach to nitrile synthesis. While attempts to render this 1,3-sulfonyl shift stereoselective failed, we uncovered another set of tandem sigmatropic arrangements, leading to vinyl imidate formation, and thereby suggesting rich chemistry one can develop using these ynamides.

EXPERIMENTAL SECTION

General Procedure for the Preparation of Des-Allyl Amidines from N-allyl Ynamides

To a flame dried screw-cap vial was added ynamide 8a (117.0 mg, 0.300 mmol), PdCl₂(PPh₃)₂ (10.5 mg, 0.015 mmol), THF (6 mL), and tert-butyl amine (158.0 μL, 1.50 mmol), then sealed under a dry nitrogen atmosphere and heated to 80 °C for 2 h. After the reaction was judged to be complete by TLC, the solvent was removed in vacuo and the resulting crude residue was purified via silica gel flash column chromatography (isocratic eluent: 6:1 hexane/EtOAc) to afford amidine 9 as a white solid (119.0 mg, 0.282 mmol, 94%).

9: Rf = 0.27 [4:1 hexanes:EtOAc]; white solid; mp = 134 – 135 °C; ¹H NMR (400 MHz, CDCl₃) δ 1.11 (d, 18H, J = 8.8 Hz), 1.28 (sept, 3H, J = 8.8 Hz), 1.31 (s, 9H), 2.39 (s, 3H), 2.45 (s, 2H), 4.91 (brs, 1H), 7.25 (d, 2H, J = 10.0 Hz), 7.79 (d, 2H, J = 10.0 Hz); ¹³C NMR (100 MHz, CDCl₃) δ 11.5, 18.7, 18.8, 21.6, 28.7, 53.4, 126.3, 129.2, 141.7, 141.8, 167.1; IR (film) cm⁻¹ 3328m, 2942m, 2867m, 1570m, 1530s, 1341m; mass spectrum (ESI): m/e (% relative intensity) 447 (100) (M+Na)⁺, 425 (40) (M+H)⁺; HRMS (ESI) m/e calcd for C₂₂H₄₀N₂O₂SSiNa 447.2472, found 447.2476.

11 (87%): Rf = 0.31 [4:1 hexanes:EtOAc]; white solid; mp = 73 – 76 °C; ¹H NMR (400 MHz, CDCl₃) (showing as two rotamers in 2.3:1 ratio) major rotamer δ 0.96 (d, 18H, J = 6.0 Hz), 0.96 – 1.02 (m, 1H), 1.10 (s, 3H), 1.20 – 1.35 (m, 2H), 1.35 – 1.50 (m, 2H), 1.60 (pent, 2H, J = 7.2 Hz), 1.85 (s, 2H), 2.39 (s, 3H), 3.27 (t, 2H, J = 7.2 Hz), 7.22 (d, 2H, J = 8.0 Hz), 7.76 (d, 2H, J = 8.0 Hz), 8.28 (brs, 1H); ¹³C NMR (100 MHz, CDCl₃) major rotamer δ 11.7, 13.9, 18.0, 18.7, 20.1, 21.7, 31.8, 44.6, 126.5, 129.1, 140.4, 142.4, 169.7; IR (film) cm⁻¹ 3322m, 2942m, 2869m, 1532s, 1465m; mass spectrum (APCI): m/e (% relative intensity) 425 (50) (M+H)⁺; HRMS (ESI) m/e calcd for C₂₂H₄₀N₂O₂SSiH 425.2653, found 425.2640.

13 (41%): Rf = 0.20 [4:1 hexanes:EtOAc]; white solid; mp = 84 – 87 °C; ¹H NMR (400 MHz, CDCl₃) δ 0.86 (d, 18H, J = 6.4 Hz), 0.90 (sept, 3H, J = 6.4 Hz), 1.88 (s, 2H), 2.42 (s, 3H), 3.82 (s, 3H), 6.90 (d, 2H, J = 8.8 Hz), 7.08 (d, 2H, J = 8.8 Hz), 7.26 (d, 2H, J = 8.0 Hz), 7.83 (d, 2H, J = 8.0 Hz), 9.80 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 11.5, 18.3, 18.6, 21.7, 55.8, 114.8, 126.6, 128.2, 129.2, 130.3, 140.1, 142.7, 159.1, 169.3; IR (film) cm⁻¹ 3272m, 2943m, 2869m, 1610m, 1573s, 1513m; mass spectrum (ESI): m/e (% relative intensity) 497 (100) (M+Na)⁺, 475 (40) (M+H)⁺; HRMS (ESI) m/e calcd for C₂₅H₃₈N₂O₃SSiNa 497.2265, found 497.2258.

14 (22%): Rf = 0.31 [4:1 hexanes:EtOAc]; white solid; mp = 125 – 128 °C; ¹H NMR (500 MHz, CDCl₃) δ 0.85 (d, 18H, J = 6.0 Hz), 0.85 – 0.95 (m, 3H), 1.94 (s, 2H), 2.42 (s, 3H), 7.17 (d, 2H, J = 7.5 Hz), 7.27 (d, 2H, J = 8.0 Hz), 7.31 (t, 1H, J = 7.5 Hz), 7.40 (t, 2H, J = 7.5 Hz), 7.84 (d, 2H, J = 8.0 Hz), 9.96 (s, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 11.5, 18.4, 18.6, 21.8, 126.7, 126.8, 127.9, 129.3, 129.7, 137.6, 140.0,142.8, 168.9; IR (film) cm⁻¹ 3338w, 2962m, 2867m, 1608m, 1569m, 1527s, 1441m; mass spectrum (ESI): m/e (% relative intensity) 467 (100) (M+Na)⁺, 445 (35) (M+H)⁺; HRMS (ESI) m/e calcd for C₂₄H₃₆N₂O₂SSiNa 467.2159, found 467.2173.

15 (22%): Rf = 0.30 [4:1 hexanes:EtOAc]; white solid; mp = 147 – 150 °C; ¹H NMR (400 MHz, CDCl₃) δ 0.87 (s, 18H), 0.90 – 1.20 (m, 3H), 1.90 (brs, 2H), 2.42 (s, 3H), 7.05 – 7.17 (m, 2H), 7.27 (d, 2H, J = 8.0 Hz), 7.32 – 7.42 (m, 2H), 7.81 (d, 2H, J = 8.0 Hz), 9.91 (brs, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 11.6, 18.6, 21.7, 29.9, 126.6, 128.1, 129.3, 129.9, 133.7, 136.2, 139.7, 142.9, 168.7; IR (film) cm⁻¹ 3314m, 2943m, 2867m, 1600m, 1569s, 1517s, 1493s; mass spectrum (ESI): m/e (% relative intensity) 501 (100) (M+Na)⁺, 479 (45) (M+H)⁺; HRMS (ESI) m/e calcd for C₂₄H₃₅ClN₂O₂SSiNa 501.1770, found 501.1766.

16 (30%): Rf = 0.33 [4:1 hexanes:EtOAc]; white solid; mp = 74 – 76 °C; ¹H NMR (500 MHz, CDCl₃) δ 0.87 (d, 18H, J = 7.0 Hz), 0.94 – 0.98 (m, 3H), 1.82 (s, 2H), 2.26 (s, 3H), 2.42 (s, 3H), 7.10 – 7.17 (m, 1H), 7.20 – 7.26 (m, 3H), 7.27 (d, 2H, J = 8.5 Hz), 7.84 (d, 2H, J = 8.5 Hz), 9.79 (brs, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 11.6, 18.2, 18.2, 18.6, 21.8, 126.7, 127.1, 127.5, 128.2, 129.3, 131.5, 134.7, 136.3, 140.0, 142.7, 169.2; IR (film) cm⁻¹ 3256m, 2941m, 2866m, 1566s, 1461m; 1369m, mass spectrum (ESI): m/e (% relative intensity) 481 (100) (M+Na)⁺, 459 (35) (M+H)⁺; HRMS (ESI) m/e calcd for C₂₅H₃₈N₂O₂SSi 481.2316, found 481.2306.

17 (≥95%): Rf = 0.19 [4:1 hexanes:EtOAc], colorless oil; ¹H NMR (500 MHz, CDCl₃) [showing as two rotamers in a 3:2 ratio] major rotamer δ 0.97 (d, 18H, J = 6.5 Hz), 1.02 (sept, 3H, J = 6.5 Hz), 2.41 (s, 2H), 2.52 (s, 3H), 4.48 (d, 2H, J = 6.0 Hz), 7.24 (d, 2H, J = 7.0 Hz), 7.39 – 7.19 (m, 5H), 7.77 (d, 2H, J = 8.0 Hz), 8.65 (s, 1H); ¹³C NMR (125 MHz, CDCl₃) major rotamer δ 11.7, 18.3, 18.7, 21.7, 48.5, 126.6, 127.2, 128.4, 129.2, 129.3, 136.3, 140.2, 142.6, 170.0; IR (film) cm⁻¹ 3326brs, 2942m, 2866m, 1537s, 1496m, 1270m; mass spectrum (APCI): m/e (% relative intensity) 459 (100) (M+H)⁺; HRMS (ESI) m/e calcd for C₂₅H₃₈N₂O₂SSiH 459.2496, found 459.2506.

19 (≥95%): Rf = 0.36 [2:1 hexanes:EtOAc]; white solid; mp = 143 – 145 °C; ¹H NMR (300 MHz, CDCl₃) δ 1.15 (d, 18H, J = 7.5 Hz), 1.38 (sept, 3H, J = 7.5 Hz), 2.40 (s, 3H), 2.70 (s, 2h), 3.57 (brs, 2H), 3.69 (brs, 6H), 7.25 (d, 2H, J = 8.1 Hz), 7.80 (d, 2H, J = 8.1 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 12.3, 16.3, 18.9, 21.6, 44.1, 47.1, 66.4, 77.6, 126.1, 129.2, 141.7, 142.1, 168.7; IR (film) cm⁻¹ 2966m, 2945m, 2868m, 1519s, 1444m, 1271s, 1089s; mass spectrum (APCI): m/e (% relative intensity) 439 (100) (M+H)⁺; HRMS (ESI) m/e calcd for C₂₂H₃₈N₂O₃SSiNa 461.2265, found 461.2275.

20 (≥95%): Rf = 0.28 [1:1 hexanes:EtOAc]; white solid; mp = 125 – 132 °C; ¹H NMR (400 MHz, CDCl₃) δ 1.16 (s, 9H), 2.39 (s, 3H), 3.09 (s, 2H), 3.66 (brs, 8H), 7.23 (d, 2H, J = 8.4 Hz), 7.78 (d, 2H, J = 8.4 Hz); ¹³C NMR (100 MHz, CDCl₃) δ 21.6, 31.0, 31.4, 39.9, 66.8, 126.1, 129.3, 141.9, 142.3, 165.8 [missing one sp³ carbon due to overlap]; IR (film) cm⁻¹ 2960w, 2868w, 1599s, 1459m, 1398m, 1293s, 1141m, 1065s; mass spectrum (APCI): m/e (% relative intensity) 339 (100) (M+H)⁺; HRMS (ESI) m/e calcd for C₁₇H₂₆N₂O₃SNa 361.1556, found 361.1574.

21 (92%): Rf = 0.36 [1:1 hexanes:EtOAc]; brown oil; ¹H NMR (400 MHz, CDCl₃) δ 0.04 (s, 6H), 0.88 (s, 9H), 1.57 – 1.72 (m, 4H), 2.40 (s, 3H), 2.93 – 2.98 (m, 2H), 3.51 – 3.53 (m, 2H), 3.62 – 3.72 (m, 8H), 7.25 (d, 2H, J = 8.4 Hz), 7.81 (d, 2H, J = 8.4 Hz); ¹³C NMR (100 MHz, CDCl₃) δ −5.2, 14.3, 18.4, 21.2, 21.6, 23.5, 26.1, 30.4, 32.3, 60.5, 62.1, 66.5, 126.4, 128.6, 129.3, 132.3, 142.1; IR (film) cm⁻¹ 3058m, 2929m, 2856m, 1536s, 1438m, 1388w, 1359w, 1268s, 1143s, 1117s, 1087s; mass spectrum (APCI): m/e (% relative intensity) 455 (100) (M+H)⁺; HRMS (ESI) m/e calcd for C₂₂H₃₈N₂O₄SSiNa 477.2214, found 477.2222.

22 (37%): Rf = 0.21 [1:1 hexanes:EtOAc]; yellow foam; mp = 54 – 60 °C; ¹H NMR (400 MHz, CDCl₃) δ 2.37 (s, 3H), 3.24 (t, 2H, J = 4.8 Hz), 3.33 (t, 2H, J = 4.8 Hz), 3.63 (t, 2H, J = 5.2 Hz), 3.81 (t, 2H, J = 5.2 Hz), 3.83 (s, 3H), 4.35 (s, 2H), 6.84 (d, 1H, J = 8.0 Hz), 6.85 (td, 1H, J = 1.2, 7.6 Hz), 7.04 (dd, 1H, J = 1.2, 7.6 Hz), 7.20 (d, 2H, J = 8.0 Hz), 7.21 – 7.23 (m, 1H), 7.80 (d, 2H, J = 8.0 Hz); ¹³C NMR (125 MHz, CDCl₃) δ 21.7, 30.4, 45.2, 46.9, 55.7, 66.5, 66.5, 110.6, 121.2, 122.5, 126.7, 128.5, 128.7, 129.3, 141.1, 142.2, 156.1, 166.4; IR (film) cm⁻¹ 2966w, 2858w, 1540s, 1463m, 1271s, 1069s, 998s; mass spectrum (APCI): m/e (% relative intensity) 389 (100) (M+H)⁺; HRMS (ESI) m/e calcd for C₂₀H₂₄N₂O₄SH 389.1530, found 389.1523.

23 (39%): Rf = 0.50 [1:1 hexanes:EtOAc]; pale yellow solid; mp = 159 – 161 °C; ¹H NMR (400 MHz, CDCl₃) δ 1.15 (d, 18H, J = 7.2 Hz), 1.37 (sept, 3H, J = 7.2 Hz), 2.71 (s, 2H), 3.53 (brs, 2H), 3.65 (brs, 2H), 3.68 (brs, 2H), 3.73 (brs, 2H), 8.08 (d, 2H, J = 9.2 Hz), 8.29 (d, 2H, J = 9.2 Hz); ¹³C NMR (100 MHz, CDCl₃) δ 12.3, 17.0, 18.9, 45.5, 47.3, 66.4, 124.1, 127.4, 149.4, 150.4, 169.2; IR (film) cm⁻¹ 2983w, 2360w, 1740s, 1526m, 1444m, 1374m, 1242s, 1047s; mass spectrum (APCI): m/e (% relative intensity) 470 (100) (M+H)⁺; HRMS (ESI) m/e calcd for C₂₁H₃₅N₃O₅SSiH 470.2140, found 470.2150.

24 (≥95%): Rf = 0.32 [4:1 hexanes:EtOAc]; white solid; mp = 129 – 130 °C; ¹H NMR (500 MHz, CDCl₃) δ 1.08 (t, 3H, J = 7.5 Hz), 1.18 (d, 18H, J = 7.5 Hz), 1.19 (t, 3H, J = 7.0 Hz), 1.39 (sept, 3H, J = 7.5 Hz), 2.36 (s, 3H), 2.62 (s, 2H), 3.32 (q, 2H, J = 7.0 Hz) 3.42 (q, 2H, J = 7.0 Hz), 7.20 (d, 2H, J = 8.0 Hz), 7.79 (d, 2H, J = 8.0 Hz); ¹³C NMR (125 MHz, CDCl₃) δ 12.3, 12.4, 13.6, 16.4, 18.9, 21.5, 43.5, 43.6, 125.9, 129.0, 141.2, 142.7, 167.7; IR (film) cm⁻¹ 2941s, 2868m, 2361w, 1548s, 1469s, 1362m, 1261m, 1395s; mass spectrum (APCI): m/e (% relative intensity) 425 (100) (M+H)⁺; HRMS (ESI) m/e calcd for C₂₂H₄₀N₂O₂SSiNa 447.2472, found 447.2479.

25 (≥95%): Rf = 0.29 [2:1 hexanes:EtOAc]; pale yellow oil; ¹H NMR (300 MHz, CDCl₃) δ 0.94 (t, 3H, J = 7.2 Hz), 1.16 (t, 3H, J = 7.2 Hz), 2.36 (s, 3H), 3.20 (q, 2H, J = 7.2 Hz), 3.50 (q, 2H, J = 7.2 Hz), 4.38 (s, 2H), 7.09 – 7.27 (m, 7H), 7.76 (d, 2H, J = 8.1 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 12.0, 13.5, 21.5, 36.6, 43.3, 43.4, 126.2, 126.7, 127.8, 128.8, 129.0, 134.3, 141.4, 141.6, 164.5; IR (film) cm⁻¹ 2978w, 2937w, 2359w, 1650w, 1549s, 1475m, 1274m, 1143m; mass spectrum (APCI): m/e (% relative intensity) 345 (100) (M+H)⁺; HRMS (ESI) m/e calcd for C₁₉H₂₄N₂O₂SNa 367.1451, found 367.1438.

26 (≥95%): Rf = 0.09 [4:1 hexanes:EtOAc]; waxy white solid; mp = 30 – 31 °C; ¹H NMR (500 MHz, CDCl₃) δ 0.88 (t, 3H, J = 7.0 Hz), 1.10 (t, 3H, J = 7.0 Hz), 1.22 (t, 3H, J = 7.0 Hz), 1.24 – 1.32 (m, 6H), 1.35 – 1.40 (m, 2H), 1.58 – 1.63 (m, 2H), 2.39 (s, 3H), 2.81 – 2.86 (m, 2H), 3.34 (q, 2H, J = 7.0 Hz), 3.44 (q, 2H, J = 7.0 Hz), 7.23 (d, 2H, J = 7.5 Hz), 7.82 (d, 2H, J = 7.5 Hz); ¹³C NMR (125 MHz, CDCl₃) δ 12.3, 14.2, 14.4, 21.6, 22.7, 27.6, 29.0, 30.1, 31.1, 31.8, 43.3, 126.2, 129.1, 141.6, 142.1, 167.8; IR (film) cm⁻¹ 2920m, 2855m, 1550s, 1474s, 1453s, 1434s; mass spectrum (ESI): m/e (% relative intensity) 375 (100) (M+Na)⁺, 353 (30) (M+H)⁺; HRMS (ESI) m/e calcd for C₁₉H₃₂N₂O₂SNa 375.2077, found 375.2075.

27 (70%): Rf = 0.68 [1:1 hexanes:EtOAc]; yellow solid; mp = 78 – 80 °C; ¹H NMR (400 MHz, CDCl₃) δ 0.89 (t, 3H, J = 8.0 Hz), 1.22 – 1.49 (m, 20H), 1.56 – 1.68 (m, 2H), 2.39 (s, 3H), 2.85 – 2.89 (m, 2H), 3.51 (brs, 1H), 4.03 (sept, 1H, J = 6.4 Hz), 7.24 (d, 2H, J = 8.0 Hz), 7.81 (d, 2H, J = 8.0 Hz); ¹³C NMR (100 MHz, CDCl₃) δ 14.3, 20.3, 20.9, 21.6, 22.8, 27.5, 29.1, 30.0, 31.9, 33.0, 48.1, 50.1, 126.3, 129.2, 141.6, 142.2, 166.7; IR (film) cm⁻¹ 3479w, 2970w, 2932w, 1539s, 1494m, 1449m, 1267m, 1086s; mass spectrum (APCI): m/e (% relative intensity) 381 (100) (M+H)⁺; HRMS (ESI) m/e calcd for C₂₁H₃₆N₂O₂SH 381.2570, found 381.2561.

28 (≥95%): Rf = 0.45 [4:1 hexanes:EtOAc]; brown solid; mp = 182 – 184 °C; ¹H NMR (400 MHz, CDCl₃) δ 1.15 (d, 18H, J = 7.2 Hz), 1.46 (sept, 3H, J = 7.2 Hz), 2.39 (s, 3H), 2.84 (brs, 2H), 3.14 (t, 2H, J = 8.4 Hz), 4.11 (t, 2H, J = 8.4 Hz), 7.00 (td, 1H, J = 0.8, 7.2 Hz), 7.06 (t, 1H, J = 7.2 Hz), 7.17 (d, 1H, J = 7.2 Hz), 7.25 (dd, 2H, J = 0.4, 8.8 Hz), 7.85 (d, 2H, J = 8.8 Hz), 8.07, (brs, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 12.8, 19.0, 20.1, 21.7, 27.7, 50.4, 119.8, 124.8, 124.8, 126.5, 127.7, 129.3, 132.9, 141.6, 141.8, 142.6, 166.3; IR (film) cm⁻¹ 3055w, 2941w, 2867w, 1541m, 1481m, 1265s, 1143m, 1089m; mass spectrum (APCI): m/e (% relative intensity) 471 (100) (M+H)⁺; HRMS (ESI) m/e calcd for C₂₆H₃₈N₂O₂SSiNa 493.2316, found 493.2340.

29 (77%): Rf = 0.67 [1:1 hexanes:EtOAc]; white solid; mp = 89 – 90 °C; ¹H NMR (400 MHz, CDCl₃) [showing as two rotamers in 1.7:1 ratio] major rotamer δ 1.13 (d, 18H, J = 7.6 Hz), 1.40 (sept, 3H, J = 7.6 Hz), 2.37 (s, 3H), 2.75 (s, 2H), 3.01 (s, 3H), 4.68 (s, 2H), 7.06 – 7.11 (m, 3H), 7.17 (d, 2H, J = 8.4 Hz), 7.22 – 7.26 (m, 2H), 7.74 (d, 2H, J = 8.4 Hz); ¹³C NMR (125 MHz, CDCl₃) major rotamer δ 12.6, 17.0, 18.9, 21.6, 36.9, 54.2, 126.2, 127.8, 128.5, 128.7, 129.1, 136.1, 141.4, 142.3, 169.4; IR (film) cm⁻¹ 3060w, 2944m, 2867m, 2362w, 1530s, 1454m, 1266s, 1142s, 1088s, 1017m; mass spectrum (APCI): m/e (% relative intensity) 473 (100) (M+H)⁺; HRMS (ESI) m/e calcd for C₂₆H₄₀N₂O₂SSiH 473.2653, found 473.2676.

30a (≥95%): Rf = 0.30 [3:1 hexanes:EtOAc]; white solid; mp = 161 – 163 °0C; ¹H NMR (300 MHz, CDCl₃) δ 1.15 (d, 18H, J = 7.2 Hz), 1.41 (sept, 3H, J = 7.2 Hz), 1.87 (quint, 2H, J = 6.6 Hz), 1.98 (quint, 2H, J = 6.6 Hz), 2.40 (s, 3H), 2.63 (s, 2H), 3.51 (q, 4H, J = 8.7 Hz), 7.23 (d, 2H, J = 8.4 Hz), 7.85 (d, 2H, J = 8.4 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 12.6 18.3, 18.9, 21.5, 24.4, 26.1, 48.3, 49.0, 126.1, 129.0, 141.3, 142.7, 167.2; IR (film) cm⁻¹ 2945w, 2868m, 1530s, 1463m, 1421m, 1337w, 1268m, 1139m, 1089s; mass spectrum (APCI): m/e (% relative intensity) 423 (100) (M+H)⁺; HRMS (ESI) m/e calcd for C₂₂H₃₈N₂O₂SSiNa 445.2316, found 445.2329.

30b (≥95%): Rf = 0.28 [4:1 hexanes:EtOAc]; white solid; mp = 121 – 122 °C; ¹H NMR (300 MHz, CDCl₃) δ 1.15 (d, 18H, J = 7.5 Hz), 1.39 (sept, 3H, J = 7.5 Hz), 1.54 (brs, 2H), 1.64 (brs, 4H), 2.39 (s, 3H), 2.69 (s, 2H), 3.45 (brs, 2H), 3.70 (brs, 2H), 7.28 (d, 2H, J = 8.4 Hz), 7.80 (d, 2H, J = 8.4 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 12.3, 16.5, 18.9, 21.5, 24.3, 25.5, 26.4, 46.3, 48.1, 126.0, 129.0, 141.3, 142.7, 167.9; IR (film) cm⁻¹ 2943m, 2867m, 1526s, 1468m, 1445m, 1271m, 1144s, 1089s; mass spectrum (APCI): m/e (% relative intensity) 437 (100) (M+H)⁺; HRMS (ESI) m/e calcd for C₂₃H₄₀N₂O₂SSiNa 459.2472, found 459.2461.

30c (≥95%): Rf = 0.34 [4:1 hexanes:EtOAc]; white solid; mp = 150 – 152 °C; ¹H NMR (300 MHz, CDCl₃) δ 1.15 (d, 18H, J = 7.2 Hz), 1.39 – 1.73 (m, 11H), 2.40 (s, 3H), 2.68 (s, 2H), 3.49 (t, 2H, J = 6.0 Hz), 3.61 (t, 2H, J = 6.0 Hz), 7.23 (d, 2H, J = 7.8 Hz), 7.81 (d, 2H, J = 8.1 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 12.4, 16.4, 18.9, 21.5, 26.3, 26.4, 26.7, 29.0, 50.0, 50.1, 125.9, 129.0, 141.2, 142.6, 168.4; IR (film) cm⁻¹ 2939m, 2866m, 1533s, 1473m, 1370w, 1271m, 1143m, 1089m; mass spectrum (APCI): m/e (% relative intensity) 451 (100) (M+H)⁺; HRMS (ESI) m/e calcd for C₂₄H₄₂N₂O₂SSiNa 473.2629, found 473.2643.

31 (91%): Rf = 0.64 [1:1 hexanes:EtOAc]; pale solid; mp = 92 – 96 °C; ¹H NMR (400 MHz, CDCl₃) [showing as two rotamers in a 2.0:1 ratio] major rotamer δ 1.10 – 1.24 (m, 21H), 1.33 – 1.40 (m, 3H), 1.86 – 2.04 (m, 4H), 2.36 (s, 3H), 2.43 (d, 1H, J = 12.4 Hz), 2.73 (d, 1H, J = 12.4 Hz), 3.41 – 3.53 (m, 2H), 4.27 – 4.30 (m, 1H), 7.20 (d, 2H, J = 8.4 Hz), 7.79 (d, 2H, J = 8.4 Hz); ¹³C NMR (100 MHz, CDCl₃) major rotamer δ 12.7, 18.4, 19.0, 19.0, 21.6, 23.8, 31.8, 48.6, 55.8, 126.1, 129.1, 141.3, 142.7, 166.9; IR (film) cm⁻¹ 2972m, 2868m, 2839m, 2361m, 1781w, 1738s, 1517s, 1461m, 1240s; mass spectrum (APCI): m/e (% relative intensity) 437 (100) (M+H)⁺; HRMS (ESI) m/e calcd for C₂₃H₄₀N₂O₂SSiNa 459.2472, found 459.2471.

32 (≥95%): Rf = 0.80 [1:1 hexanes:EtOAc]; [α]_D²³ = − 63.5 (c 0.43, dichloromethane); pale yellow oil; ¹H NMR (400 MHz, CDCl₃) δ 1.13 – 1.16 (m, 18H), 1.40 (sept, 3H, J = 6.8 Hz), 1.92 – 1.99 (m, 2H), 2.09 – 2.16 (m, 2H), 2.39 (s, 3H), 2.43 (d, 1H, J = 12.4 Hz), 2.95 (d, 1H, J = 12.4 Hz), 3.34 (s, 3H), 3.59 – 3.60 (m, 1H), 3.66 – 3.72 (m, 1H), 4.45 (dd, 1H, J = 4.0, 8.4 Hz), 7.21 (d, 2H, J = 8.4 Hz), 7.74 (d, 2H, J = 8.4 Hz); ¹³C NMR (100 MHz, CDCl₃) δ 12.6, 18.0, 19.0, 21.6, 24.8, 29.5, 48.7, 52.0, 61.5, 126.4, 129.0, 141.6, 142.0, 167.6, 172.3; IR (film) cm⁻¹ 3058w, 2949m, 2871m, 2364w, 1747s, 1519s, 1459m, 1367w, 1267s, 1142m; mass spectrum (APCI): m/e (% relative intensity) 481 (100) (M+H)⁺; HRMS (ESI) m/e calcd for C₂₉H₄₀N₂O₄SSiNa 503.2370, found 503.2348.

33a (≥95%): Rf = 0.46 [95:5 CH₂Cl₂:MeOH]; pale yellow oil; ¹H NMR (300 MHz, CDCl₃) δ 1.15 (d, 18H, J = 7.5 Hz), 1.38 (sept, 3H, J = 7.5 Hz), 2.30 (s, 3H), 2.39 (brs, 4H), 2.40 (s, 3H), 2.70 (s, 2H), 3.51 (brs, 2H), 3.74 (brs, 2H), 7.24 (d, 2H, J = 8.4 Hz), 7.81 (d, 2H, J = 8.4 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 12.2, 16.5, 18.9, 21.6, 44.8, 45.9, 46.6, 54.4, 54.9, 77.2, 128.6, 133.2, 141.5, 142.3, 168.4; IR (film) cm⁻¹ 2943m, 2868m, 2796m, 1525s, 1452m, 1363w, 1271m, 1143m, 1092m; mass spectrum (APCI): m/e (% relative intensity) 452 (100) (M+H)⁺; HRMS (ESI) m/e calcd for C₂₃H₄₁N₃O₂SSiH 452.2672, found 452.2668.

33b (≥95%): Rf = 0.50 [2:1 hexanes:EtOAc]; white solid; mp = 126 – 127 °C; ¹H NMR (300 MHz, CDCl₃) δ 1.19 (d, 18H, J = 7.2 Hz), 1.43 (sept, 3H, J = 7.2 Hz), 2.42 (s, 3H), 2.77 (s, 2H), 3.17 (brs, 2H), 3.24 (brs, 2H), 3.71 (brs, 2H), 3.92 (brs, 2H), 6.92 – 6.98 (m, 3H), 7.26 – 7.35 (m, 4H), 7.85 (d, 2H, J = 8.1 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 12.0, 16.2, 18.6, 21.3, 44.4, 46.3, 48.5, 49.2, 116.3, 120.6, 125.9, 128.9, 129.2, 141.4, 141.9, 150.3, 168.3; IR (film) cm⁻¹ 3029w, 2945m, 2868m, 1600m, 1525s, 1453m, 1277m, 1143m, 1091m; mass spectrum (APCI): m/e (% relative intensity) 514 (100) (M+H)⁺; HRMS (ESI) m/e calcd for C₂₈H₄₃N₃O₂SSiNa 536.2738, found 536.2737.

34 (≥95%): Rf = 0.59 [1:1 hexanes:EtOAc]; yellow solid; mp = 125 – 126 °C; ¹H NMR (400 MHz, CDCl₃) δ 1.12 (d, 18H, J = 7.2 Hz), 1.10 – 1.20 (m, 6H), 1.34 (sept, 3H, J = 7.2 Hz), 2.28 – 2.31 (m, 1H), 2.37 (s, 3H), 2.62 – 2.74 (m, 2H), 3.47 – 3.68 (m, 3H), 3.37 (sept, 1H, J = 4.8 Hz), 4.62 (d, 1H, J = 13.2 Hz), 7.20 (d, 2H, J = 7.6 Hz), 7.75 (d, 2H, J = 7.6 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 12.3, 12.4, 16.5, 18.9, 19.0, 21.6, 71.6, 126.1, 129.2, 141.7, 142.2, 168.4; IR (film) cm⁻¹ 2973m, 2870m, 1523s, 1463m, 1271m, 1148s, 1093s; mass spectrum (APCI): m/e (% relative intensity) 467 (100) (M+H)⁺; HRMS (ESI) m/e calcd for C₂₄H₄₂N₂O₃SSiH 467.2758, found 467.2747.

35 (82%): Rf = 0.64 [1:1 hexanes:EtOAc]; brown oil; ¹H NMR (400 MHz, CDCl₃) δ 0.91 (d, 18H, J = 7.6 Hz), 1.18 (sept, 3H, J = 7.6 Hz), 2.42 (s, 3H), 2.73 (s, 2H), 3.27 (s, 3H), 3.82 (s, 3H), 6.92 (d, 2H, J = 8.4 Hz), 7.12 (d, 2H, J = 8.4 Hz), 7.25 (d, 2H, J = 7.6 Hz), 7.88 (d, 2H, J = 7.6 Hz); ¹³C NMR (100 MHz, CDCl₃) δ 12.2, 17.3, 18.6, 18.8, 21.6, 55.9, 113.8, 115.1, 115.2, 126.2, 128.9, 129.2, 141.6, 159.3, 169.9; IR (film) cm⁻¹ 2945m, 2868m, 2252w, 1608m, 1509s, 1463m, 1406m; mass spectrum (APCI): m/e (% relative intensity) 498 (100) (M+H)⁺; HRMS (ESI) m/e calcd for C₂₆H₄₀N₂O₃SSiNa 511.2421, found 511.2411.

General Procedure for the Preparation of α-Allyl Amidines from Secondary Amines using Pd₂(dba)₃ and Xantphos.³

To a flame-dried vial filled with nitrogen was added Pd₂(dba)₃ (8.90 mg, 0.010 mmol), xantphos (11.2 mg, 0.020 mmol), and anhyd THF (4 mL). The resulting solution was stirred at rt for 10 min. Subsequently, a respective ynamide (79.0 mg, 0.20 mmol), K₂CO₃ (27.8 mg, 0.20 mmol), and pyrollidine (49.0 μL, 0.60 mmol) were added. The reaction mixture was stirred under nitrogen at 65 °C for 6 h. The progress of the reaction was monitored by TLC. After complete consumption of the starting ynamide, the crude reaction mixture was filtered through Celite^™ and concentrated in vacuo. Purification of the crude residue via silica gel flash column chromatography [isocratic eluent: 5:1 hexanes/EtOAc] afforded amidine 39 (95.0 mg, 0.20 mmol, ≥95%).

39: Rf = 0.22 [5:1 hexanes:EtOAc]; white solid; mp 75 – 76 °C; ¹H NMR (400 MHz, CDCl3) delta; 0.98 (d, 18H, J = 6.0 Hz), 1.16 (m, 3H), 1.76 – 1.82 (m, 1H), 1.92 – 2.08 (m, 3H), 2.17 – 2.22 (m, 1H), 2.26 – 2.29 (m, 1H), 2.38 (s, 3H), 2.44 – 2.52 (m, 1H), 3.56 (q, 1H, J = 8.0 Hz), 3.68 (td, 1H, J = 2.4, 8.0 Hz), 4.22 (brs, 2H), 4.97 (d, 1H, J = 10.8 Hz), 5.02 (d, 1H, J = 17.6 Hz), 5.81 (m, 1H), 7.20 (d, 2H, J = 8.4 Hz), 7.78 (d, 2H, J = 8.4 Hz); ¹³C NMR (125 MHz, CDCl3) δ 11.5, 19.1, 21.5, 25.4, 25.8, 35.8, 35.9, 51.8, 53.2, 116.0, 126.1, 128.8, 137.8, 140.9, 143.2, 167.1; IR (neat) cm⁻¹ 2924ms, 2863m, 1547s, 1414s, 1274s, 1139s; mass spectrum (APCI): m/e (% relative intensity) 463 (100) (M+H)⁺. HRMS (ESI) m/e calcd for C₂₅H₄₂N₂O₂SSiNa 485.2628, found 486.2630.

General Procedure for the Preparation of Vinylogous Amidines

To a flame dried screw-cap vial was added ynamide 8a (75.0 mg, 0.192 mmol), Pd₂(dba)₃ (8.8 mg, 0.0096 mmol), xantphos (11.1 mg, 0.019 mmol), THF (2.0 mL), and enamine 41 (77.0 μL, 0.576 mmol), then sealed under a dry nitrogen atmosphere and heated to 70 °C for 2 h. After the reaction was judged to be complete by TLC, the solvent was removed in vacuo and the resulting crude residue was purified via silica gel flash column chromatography (isocratic eluent: 1:1 hexane/EtOAc + 5% NEt₃ buffer) to afford the vinylogous amidine 45 as an orange solid (52.4 mg, 0.099 mmol, 52%).

45: Rf = 0.23 [1:1 hexanes:EtOAc]; orange solid, mp = 95 – 97 °C; ¹H NMR (400 MHz, CDCl₃) [spectrum complicated by rotamers] δ 1.07 (d, 9H, J = 6.4 Hz), 1.11 (d, 9H, J = 5.2 Hz), 1.10 – 1.20 (m, 3H), 1.83 – 1.90 (m, 2H), 1.90 – 2.01 (m, 3H), 2.01 – 2.15 (m, 2H), 2.25 – 2.35 (m, 1H), 2.34 (s, 3H), 2.50 (d, 1H, J = 11.2 Hz), 2.57 – 2.72 (m, 2H), 2.80 (t, 1H, J = 4.8 Hz), 2.85 – 2.92 (m, 1H), 3.18 (brs, 2H), 3.89 (brs, 2H), 4.66 (d, 1H, J = 18.8 Hz), 4.67 (d, 1H, J = 9.2 Hz), 5.51 – 5.62 (m, 1H), 7.14 (d, 2H, J = 8.4 Hz), 7.76 (d, 2H, J = 8.4 Hz); ¹³C NMR (125 MHz, CDCl₃) δ 12.3, 19.3, 19.4, 21.6, 21.7, 25.4, 29.9, 35.2, 36.2, 40.4, 53.0, 111.4, 113.6, 126.0, 128.7, 131.1, 140.0, 140.2, 143.7, 148.1; IR (film) cm⁻¹ 2944m, 2865m, 1736m, 1579m, 1469s, 1445s, 1342m; mass spectrum (ESI): m/e (% relative intensity) 529 (100) (M+H)⁺; HRMS (ESI) m/e calcd for C₃₀H₄₈N₂O₂SSiH 529.3279, found 529.3269.

46 (71%): Rf = 0.18 [1:1 hexanes:EtOAc], orange oil; ¹H NMR (400 MHz, CDCl₃) [spectrum complicated by rotamers] δ 1.05 (d, 9H, J = 6.4 Hz), 1.09 (d, 9H, J = 5.2 Hz), 1.09 – 1.15 (m, 3H), 1.70 – 2.10 (m, 9H), 2.32 (brs, 1H), 2.48 (d, 1H, J = 11.2 Hz), 2.57 – 2.70 (m, 2H), 2.76 (brs, 1H), 2.80 – 2.90 (m, 1H), 3.13 (brs, 2H), 3.80 (s, 3H), 3.83 (brs, 2H), 4.63 (d, 1H, J = 5.6 Hz), 4.65 (d, 1H, J = 10.8 Hz), 5.48 – 5.60 (m, 1H), 6.81 (d, 2H, J = 8.8 Hz), 7.79 (d, 2H, J = 8.8 Hz); ¹³C NMR (100 MHz, CDCl₃) δ 12.3, 19.3, 19.4, 21.7, 25.4, 35.1, 36.2, 40.3, 52.9, 55.5, 113.2, 113.6,127.9, 139.0, 139.8, 139.9, 160.9 [missing two sp² signals due to rotamers]; IR (film) cm⁻¹ 2943m, 2866m, 1596m, 1590m, 1468s, 1249s; mass spectrum (APCI): m/e (% relative intensity) 545 (100) (M+H)⁺; HRMS (ESI) m/e calcd for C₃₀H₄₈N₂O₃SSiH 545.3228, found 545.3240.

47 (58%): Rf = 0.12 [1:2 hexanes:EtOAc]; orange solid, mp = 69 – 72 °C; ¹H NMR (500 MHz, CDCl₃) δ 1.98 (pent, 2H, J = 6.5 Hz), 2.02 (brs, 4H), 2.32 (t, 2H, J = 8.5 Hz), 2.34 (t, 2H, J = 8.5 Hz), 2.71 (t, 2H, J = 6.5 Hz), 3.07 (t, 2H, J = 6.5 Hz), 3.30 – 3.55 (m, 4H), 4.92 (dq, 1H, J = 1.5, 10.0 Hz), 5.00 (dq, 1H, J = 1.5, 17.0 Hz), 5.81 (ddt, 1H, J = 6.5, 10.5, 17.0 Hz), 8.30 (d, 2H, J = 9.0 Hz), 8.05 (d, 2H, J = 9.0 Hz); ¹³C NMR (125 MHz, CDCl₃) δ 19.3, 25.3, 31.2, 32.1, 38.1, 41.8, 52.5, 109.7, 115.2, 124.1, 128.0, 137.7, 148.6, 149.7, 169.5, 186.5, 193.0; IR (film) cm⁻¹ 3062m, 2954m, 2877m, 1634m, 1608m, 1527s, 1436s, 1349s; mass spectrum (ESI): m/e (% relative intensity) 454 (100) (M+Na)⁺, 432 (15) (M+H)⁺; HRMS (ESI) m/e calcd for C₂₁H₂₅N₃O₅SNa 454.1408, found 454.1402.

48 (54%): Rf = 0.14 [1:1 hexanes:EtOAc]; orange solid; mp = 104 – 107 °C; ¹H NMR (500 MHz, CDCl₃) δ 0.00 (s, 6H), 0.84 (s, 9H), 1.22 (s, 2H), 1.51 – 1.56 (m, 4H), 1.71 – 1.79 (m, 6H), 2.35 (s, 3H), 2.57 (t, 2H, J = 7.5 Hz), 2.61 (t, 2H, J = 7.5 Hz), 2.75 – 2.78 (m, 2H), 3.32 (t, 4H, J = 6.5 Hz), 3.55 (t, 2H, J = 6.5 Hz), 7.19 (d, 2H, J = 8.0 Hz), 7.78 (d, 2H, J = 8.0 Hz); ¹³C NMR (125 MHz, CDCl₃) δ –5.1, 18.5, 21.3, 21.6, 25.0, 25.6, 26.2, 32.8, 33.3, 36.6, 37.1, 53.8, 62.9, 107.0, 126.8, 129.2, 141.6, 142.4, 165.8, 176.9; IR (film) cm⁻¹ 2928m, 2855m, 1569s, 1470s, 1416s; mass spectrum (ESI): m/e (% relative intensity) 505 (100) (M+H)⁺; HRMS (ESI) m/e calcd for C₂₇H₄₄N₂O₃SSiH 505.2915, found 505.2894.

49 (57%): Rf = 0.17 [1:2 hexanes:EtOAc]; orange solid; mp = 79 – 83 °C; ¹H NMR (500 MHz, CDCl₃) δ 1.69 (pent, 2H, J = 7.5 Hz), 1.82 – 1.85 (m, 4H), 2.40 (t, 2H, J = 7.5 Hz), 2.53 (t, 2H, J = 7.5 Hz), 3.43 (t, 4H, J = 7.5 Hz), 3.81 (s, 3H), 4.24 (s, 2H), 6.85 (d, 2H, J = 9.0 Hz), 7.13 – 7.22 (m, 5H), 7.84 (d, 2H, J = 9.0 Hz); ¹³C NMR (125 MHz, CDCl₃) δ 21.2, 25.6, 32.8, 36.4, 42.6, 53.8, 55.7, 108.2, 113.7, 126.1, 128.4, 128.7, 129.2, 137.0, 137.6, 161.9, 166.9, 172.6; IR (film) cm⁻¹ 2953m, 2870m, 1665m, 1594m, 1494m, 1412s; mass spectrum (ESI): m/e (% relative intensity) 425 (100) (M+H)⁺; HRMS (ESI) m/e calcd for C₂₄H₂₈N₂O₃SH 425.1894, found 425.1897.

51 (62%): Rf = 0.15 [1:1 hexanes:EtOAc]; yellow solid; mp = 177 – 179 °C; ¹H NMR (500 MHz, d₈-toluene, 90 °C) spectrum not resolved due to rotamers δ 1.00 – 1.30 (m, 8H), 1.30 – 1.60 (m, 6H), 1.75 – 1.85 (m, 2H), 1.95 – 2.10 (m, 2H), 2.32 (brs, 4H), 2.55 – 2.62 (m, 3H), 2.83 (brs, 6H), 3.05 – 3.13 (m, 1H), 3.31 (brs, 1H), 3.79 (dd, 1H, J = 6.5, 15.0 Hz), 4.65 – 4.75 (m, 2H), 4.76 – 4.85 (m, 2H), 5.52 (brs, 1H), 5.60 – 5.65 (m, 1H), 6.80 – 7.20 (m, 10H), 7.40 (brs, 2H), 7.52 (d, 2H, J = 7.5 Hz), 7.65 (d, 2H, J = 6.5 Hz), 7.65 – 7.80 (m, 2H). ¹³C NMR (125 MHz, CDCl₃) could not obtain spectrum due to rotamers; IR (film) cm⁻¹ 2970m, 2924w, 1738s, 1621m, 1527s, 1432s, 1350s; mass spectrum (APCI): m/e (% relative intensity) 508 (100) (M+H)⁺; HRMS (ESI) m/e calcd for C₂₇H₂₉N₃O₅SH 508.1901, found 508.1900.

General Procedure for the Preparation of α-Allyl Amidines via Thermal Aza-Claisen Rearrangement

To a flame dried screw-cap vial was added ynamide 8b (62.0 mg, 0.20 mmol), cyclohexylamine (69 μL, 0.60 mmol) and anhyd toluene (2.0 mL). The vial was flushed with nitrogen and heated to 110 °C overnight. When the reaction was judged to be complete by TLC, removal of the solvent in vacuo followed by purification via silica gel flash column chromatography (isocratic eluent: 5:1 hexanes/EtOAc) afforded the amidine 56 (77.4 mg, 0.19 mmol, 94% yield).

56: Rf = 0.33 [5:1 hexanes:EtOAc]; white solid; mp = 106 – 108 °C; ¹H NMR (400 MHz, CDCl₃) [showing as two rotamers in 2.5:1 ratio] major rotamer δ 0.80 – 1.40 (m, 6H), 1.40 – 1.70 (m, 3H), 1.70 – 1.95 (m, 2H), 2.41 (s, 3H), 2.82 (pent, 1H, J = 7.2 Hz), 3.47 (brs, 1H), 3.64 (t, 1H, J = 7.2 Hz), 4.89 (d, 1H, J = 11.2 Hz), 4.93 (d, 1H, J = 19.2 Hz), 5.55 – 5.68 (m, 1H), 7.21 (brs, 5H), 7.25 (d, 2H, J = 7.6 Hz), 7.78 (d, 2H, J = 8.4 Hz), 8.34 (d, 1H, J = 8.4 Hz); ¹³C NMR (125 MHz, CDCl₃) major rotamer δ 21.7, 24.6, 24.7, 25.1, 33.3, 34.3, 39.3, 48.7, 52.6, 117.3, 126.5, 127.7, 128.0, 129.0, 129.3, 135.7, 139.5, 140.0, 142.7, 166.9; IR (film) cm⁻¹ 3320brs, 2933m, 2856m, 1532s, 1451m; mass spectrum (ESI): m/e (% relative intensity) 844 (30) (2M+Na+H), 433 (100) (M+Na)⁺; HRMS (ESI) m/e calcd for C₄₈H₆₀N₄O₄S₂Na (2M+Na) 843.3949, found 843.3962.

60 (93%): Rf = 0.12 [4:1 hexanes:EtOAc]; colorless oil; ¹H NMR (400 MHz, CDCl₃) δ 1.03 (s, 18H), 1.15 – 1.30 (m, 3H), 2.18 – 2.32 (m, 2H), 2.32 – 2.61 (m, 1H), 3.45 – 4.20 (m, 8H), 4.99 (d, 1H, J = 16.8 Hz), 5.00 (d, 1H, J = 10.0 Hz), 5.65 – 5.85 (m, 1H), 8.06 (d, 2H, J = 9.2 Hz), 8.30 (d, 2H, J = 9.2 Hz); ¹³C NMR (125 MHz, CDCl₃) δ 11.6, 19.1, 34.0, 35.0, 51.6, 66.7, 116.7, 123.9, 127.3, 137.2, 149.2, 150.6 170.7; IR (film) cm⁻¹2947m, 2869m, 1640w, 1529s, 1425m, 1350m; mass spectrum (ESI): m/e (% relative intensity) 532 (100) (M+Na)⁺; HRMS (ESI) m/e calcd for C₂₄H₃₉N₃O₅SSiNa 532.2272, found 532.2264.

General Procedure for the Preparation of Nitriles and Unsaturated Imidates via Tandem Thermal Rearrangements

To a flame dried screw-cap vial was added ynamide 8i (100.0 mg, 0.306 mmol) and anhyd toluene (2.5 mL). The vial was flushed with nitrogen and heated to 110 °C overnight. When the reaction was judged to be complete by TLC, removal of the solvent in vacuo followed by purification via silica gel flash column chromatography (isocratic eluent: 10:1 hexanes/EtOAc) afforded the nitrile 63 (52.7 mg, 0.161 mmol, 53% yield).

63: Rf = 0.32 [4:1 hexanes:EtOAc]; waxy white solid; mp = 50 – 53 °C; ¹H NMR (400 MHz, CDCl₃) δ 3.32 (dd, 1H, J = 7.2, 14.0 Hz), 3.45 (dd, 1H, J = 6.8, 14.0 Hz), 3.85 (s, 3H), 5.18 (dd, 1H, J = 1.2, 10.0 Hz), 5.30 (dd, 1H, J = 1.2, 16.8 Hz), 5.55 (dddd, 1H, J = 6.8, 7.2, 10.0, 16.8 Hz), 6.84 (d, 2H, J = 9.2 Hz), 7.33 – 7.35 (m, 2H), 7.38 – 7.41 (m, 3H), 7.44 (d, 2H, J = 9.2 Hz); ¹³C NMR (100 MHz, CDCl₃) δ 36.1, 56.0, 72.2, 114.2, 116.6, 122.2, 125.1, 128.8, 128.9, 129.0, 129.3, 130.2, 133.2, 164.9; IR (film) cm⁻¹ 2946m, 2843m, 2238w, 1641s, 1592s, 1495s, 1365s; mass spectrum (ESI): m/e (% relative intensity 350 (100) (M+Na)⁺; HRMS (ESI) m/e calcd for C₁₈H₁₇NO₃SNa 350.0822, found 350.0818.

64 (53%): Rf = 0.21 [4:1 hexanes:EtOAc]; yellow solid; mp = 125 – 128 °C; ¹H NMR (400 MHz, CDCl₃) δ 3.39 (dd, 1H, J = 7.2, 14.0 Hz,), 3.49 (dd, 1H, J = 6.4, 14.0 Hz), 5.24 (d, 1H, J = 10.0 Hz), 5.35 (d, 1H, J = 16.8 Hz), 5.60 – 5.50 (m, 1H), 7.44 – 7.34 (m, 5H), 7.71 (d, 2H, J = 8.4 Hz), 8.22 (d, 2H, J = 8.4 Hz); ¹³C NMR (100 MHz, CDCl₃) δ 35.7, 72.6, 115.8, 123.1, 123.9, 127.8, 128.4, 128.9, 129.4, 130.9, 132.3, 139.5, 151.6; IR (film) cm⁻¹ 3104m, 2932m, 2850m, 2240w, 1606m, 1530s, 1450m; mass spectrum (ESI): m/e (% relative intensity) 365 (100) (M+Na)⁺; HRMS (ESI) m/e calcd for C₁₇H₁₄N₂O₄SNa 365.0566, found 365.0559.

65 (64%): Rf = 0.22 [4:1 hexanes:EtOAc]; white solid; mp = 48 – 50 °C; ¹H NMR (400 MHz, CDCl₃) δ 2.83 (s, 3H), 3.28 – 3.30 (m, 3H), 5.22 (dd, 1H, J = 1.2, 10.0 Hz), 5.31 (dd, 1H, J = 1.2, 16.8 Hz), 5.55 (ddt, 1H, J = 7.2, 10.0, 16.8 Hz), 7.48 – 7.53 (m, 3H), 7.69 – 7.73 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 35.9, 37.1, 70.8, 116.1, 122.8, 128.4, 128.7, 128.7, 129.7, 130.8; IR (film) cm⁻¹ 3008m, 2930m, 2241w, 1642m, 1599m, 1450s; mass spectrum (ESI): m/e (% relative intensity) 258 (100) (M+Na)⁺; HRMS (ESI) m/e calcd for C₁₂H₁₃NO₂SNa 258.0559, found 258.0552.

74 (91%, 1.5:1 dr): Rf = 0.41 [6:1 hexanes:EtOAc], colorless oil; ¹H NMR (400 MHz, CDCl₃) major isomer δ 1.06 (s, 18H), 1.05 – 1.08 (m, 3H), 1.50 (d, 3H, J = 6.0 Hz), 2.48 (s, 3H), 2.82 – 3.00 (m, 2H), 4.50 (q, 1H, J = 6.0 Hz), 5.12 – 5.22 (m, 1H), 5.28 (dd, 1H, J = 1.2, 17.6 Hz), 5.90 (ddtd, 1H, J = 1.2, 7.2, 10.0, 17.2 Hz), 7.41 (d, 2H, J = 8.4 Hz), 7.90 (d, 2H, J = 8.4 Hz); minor isomer δ 0.98 – 1.02 (m, 21H), 1.60 (d, 3H, J = 6.4 Hz), 2.48 (s, 3H), 2.82 – 3.00 (m, 2H), 4.73 (q, 1H, J = 6.4 Hz), 5.12 – 5.22 (m, 2H), 5.68 – 5.78 (m, 1H), 7.38 (d, 2H, J = 8.4 Hz), 7.90 (d, 2H, J = 8.4 Hz); ¹³C NMR (125 MHz, CDCl₃) both isomers δ 12.9, 13.1, 18.2, 18.3, 18.3, 18.4, 19.2, 21.6, 22.0, 22.0, 34.8, 69.5, 71.9, 116.4, 116.7, 120.3, 121.0, 130.0, 130.1, 130.6, 131.0, 131.1, 131.3, 132.5, 133.7, 146.4, 146.8; IR (film) cm⁻¹ 2945m, 2868m, 2256w, 1596m, 1493m, 1330m; mass spectrum (ESI): m/e (% relative intensity) 458 (100) (M+Na)⁺; HRMS (ESI) m/e calcd for C₂₃H₃₇NO₃SSiNa 458.2156, found 458.2171.

75 (50%, 1.3:1 dr): Rf = 0.18 [4:1 hexanes:EtOAc]; colorless oil; ¹H NMR (400 MHz, CDCl₃) major diastereomer δ 1.47 (d, 3H, J = 6.4 Hz), 1.90 (s, 3H), 2.49 (s, 3H), 2.81 – 3.04 (m, 2H), 5.25 – 5.30 (m, 2H), 5.46 (q, 1H, J = 6.4 Hz), 5.85 – 5.98 (m, 1H), 7.42 (d, 2H, J = 8.4 Hz), 7.89 (d, 2H, J = 8.4 Hz); minor diastereomer δ 1.50 (d, 3H, J = 6.4 Hz), 1.97 (s, 3H), 2.49 (s, 3H), 2.81 – 3.04 (m, 2H), 5.25 – 5.30 (m, 2H), 5.46 (q, 1H, J = 6.4 Hz), 5.85 – 5.98 (m, 1H), 7.43 (d, 2H, J = 8.4 Hz), 7.91 (d, 2H, J = 8.4 Hz); ¹³C NMR (125 MHz, CDCl₃) both diastereomers δ 16.6, 17.8, 21.0, 21.1, 22.1, 31.8, 34.3, 34.7, 68.6, 69.3, 71.6, 115.4, 121.7, 121.7, 129.8, 130.0, 130.2, 130.3, 130.8, 131.2, 132.4, 133.2, 147.0, 147.1, 169.1, 169.2 [missing one sp² carbon from minor]; IR (film) cm⁻¹ 2923m, 2243w, 1752s, 1642m, 1597m, 1374, 1335s; mass spectrum (ESI): m/e (% relative intensity) 344 (100) (M+Na)⁺; HRMS (ESI) m/e calcd for C₁₆H₁₉NO₄SNa 344.0927, found 344.0914.

76 (≥95%, 2.0:1 dr): Rf = 0.23 [8:1 hexanes:EtOAc]; colorless oil; ¹H NMR (500 MHz, CDCl₃) major diastereomer δ 0.99 (s, 18H), 1.02 (s, 3H), 2.40 (s, 3H), 3.08 (ddd, 1H, J = 1.0, 7.0, 15.0 Hz), 3.18 (ddd, 1H, J = 1.0, 7.0, 15.0 Hz), 5.13 (d, 1H, J = 9.0 Hz), 5.16 (d, 1H, J = 16.0 Hz), 5.54 (s, 1H), 5.74 (ddt, 1H, J = 7.0, 9.0, 16.0 Hz), 7.21 (d, 2H, J = 8.0 Hz), 7.25 – 7.30 (m, 2H), 7.34 – 7.37 (m, 1H), 7.50 (d, 2H, J = 7.0 Hz), 7.63 (d, 2H, J = 8.0 Hz); minor diastereomer δ 0.99 (s, 18H), 1.02 (s, 3H), 2.44 (ddd, 1H, J =1.0, 6.5, 15.5 Hz), 2.45 (s, 3H), 2.64 (ddd, 1H, J = 1.0, 6.5, 15.5 Hz), 4.81 (d, 1H, J = 17.0 Hz), 4.93 (d, 1H, J = 10.0 Hz); 5.45 (ddt, 1H, J = 6.5, 10.0, 17.0 Hz), 5.81 (s, 1H), 7.25 – 7.30 (m, 2H), 7.31 (d, 2H, J = 8.0 Hz), 7.34 – 7.37 (m, 1H), 7.54 – 7.59 (m, 2H), 7.89 (d, 2H, J = 8.0 Hz); ¹³C NMR (125 MHz, CDCl₃) both diastereomers δ 13.02, 13.12, 18.19, 18.23, 21.95, 22.02, 34.99, 35.38, 72.86, 72.87, 75.50, 75.66, 116.02, 120.06, 120.84, 128.29, 129.14, 129.24, 129.26, 129.43, 129.56, 129.62, 129.65, 129.89, 130.52, 130.89, 130.93, 131.25, 131.31, 133.47, 138.58, 145.94 [missing two sp² signals from minor]; IR (film) cm⁻¹ 2945m, 2893m, 2867m, 2240w, 1639w, 1596m, 1494m, 1365m; mass spectrum (ESI): m/e (% relative intensity) 520 (100) (M+Na)⁺; HRMS (ESI) m/e calcd for C₂₈H₃₉NO₃SSiNa 520.2313, found 520.2322.

77-major (69% for both, 1.5:1 dr): Rf = 0.28 [6:1 hexanes:EtOAc]; colorless oil; ¹H NMR (500 MHz, CDCl₃) δ 1.04 (s, 9H), 2.38 (dd, 1H, J = 7.0, 15.5 Hz), 2.48 (s, 3H), 2.64 (dd, 1H, J = 7.0, 15.5 Hz), 4.76 (dd, 1H, J = 1.5, 17.0), 4.93 (dd, 1H, J = 1.5, 10.0 Hz), 5.27 (ddt, 1H, J = 7.0, 10.0, 17.0 Hz), 6.30 (s, 1H), 7.35 – 7.38 (m, 3H), 7.41 (d, 2H, J = 8.5 Hz), 7.46 – 7.49 (m, 2H), 7.93 (d, 2H, J = 8.5 Hz); ¹³C NMR (125 MHz, CDCl₃) δ 22.0, 26.8, 36.1, 38.9, 69.8, 73.6, 114.9, 120.8, 128.5, 129.1, 129.2, 130.1, 130.3, 131.1, 133.3, 134.8, 146.9, 176.0; IR (film) cm⁻¹ 3068w, 2974m, 2934m, 2873w, 2242w, 1739s, 1595m, 1494m, 1336s; mass spectrum (ESI): m/e (% relative intensity) 448 (100) (M+Na)⁺; HRMS (ESI) m/e calcd for C₂₄H₂₇NO₄SNa 448.1553, found 448.1558.

77-minor: Rf = 0.35 [6:1 hexanes:EtOAc]; colorless oil; ¹H NMR (500 MHz, CDCl₃) δ 1.27 (s, 9H), 2.46 (s, 3H), 3.03 (dd, 1H, J = 7.0, 15.0 Hz), 3.16 (dd, 1H, J = 7.0, 15.0 Hz), 5.22 (d, 1H, J = 9.0 Hz), 5.23 (d, 1H, J = 17.5 Hz), 5.81 – 5.84 (m, 1H), 6.22 (s, 1H), 7.30 – 7.37 (m, 7H), 7.75 (d, 2H, J = 8.5 Hz); ¹³C NMR (125 MHz, CDCl₃) δ 22.1, 27.2, 34.7, 39.2, 70.0, 73.0, 115.4, 121.5, 128.5, 128.7, 129.8, 130.4, 131.2, 132.2, 134.4, 146.7, 175.8; IR (film) cm⁻¹ 3069w, 2978m, 2937m, 2874w, 2244w, 1746s, 1597m, 1495m, 1338s; mass spectrum (ESI): m/e (% relative intensity) 448 (100) (M+Na)⁺; HRMS (ESI) m/e calcd for C₂₄H₂₇NO₄SNa 448.1553, found 448.1566.

79 (74%): Rf = 0.28 [2:1 hexanes:EtOAc]; white solid; mp = 80 – 84 °C; ¹H NMR (400 MHz, CDCl₃) δ 1.70 (d, 3H, J = 7.2 Hz), 2.43 (s, 3H), 2.93 (d, 2H, J = 6.4 Hz), 3.18 (s, 6H), 4.92 (dq, 1H, J = 2.0, 10.2 Hz), 4.95 (dq, 1H, J = 2.0, 16.8 Hz), 5.64 (ddt, 1H, J = 6.4, 10.2, 16.8 Hz), 6.06 (q, 1H, J = 7.2 Hz), 7.31 (d, 2H, J = 8.4 Hz), 7.98 (d, 2H, J = 8.4 Hz); ¹³C NMR (100 MHz, CDCl₃) δ 14.2, 22.0, 32.3, 116.4, 129.4, 129.6, 133.4, 134.1, 134.3, 136.3, 145.3, 169.0 [missing NMe₂ carbon signal]; IR (film) cm⁻¹ 2927m, 2251w, 1703s, 1641m, 1598m, 1495m, 1448m, 1359s; mass spectrum (ESI): m/e (% relative intensity) 373 (100) (M+Na)⁺; HRMS (ESI) m/e calcd for C₁₇H₂₂N₂O₄SNa 373.1193, found 373.1188. mass spectrum (ESI): m/e (% relative intensity) 373 (100) (M+Na)⁺; HRMS (ESI) m/e calcd for C₁₇H₂₂N₂O₄SNa 373.1193, found 373.1188.

81 (30%): Rf = 0.41 [6:1 hexanes:EtOAc]; white solid; mp = 65 – 67 °C; ¹H NMR (400 MHz, CDCl₃) δ 1.46 (s, 9H), 2.43 (s, 3H), 3.28 (d, 2H, J = 5.6 Hz), 5.08 (d, 1H, J = 10.4 Hz), 5.11 (d, 1H, J = 17.2 Hz), 5.89 (ddt, 1H, J = 5.6, 10.4, 17.2 Hz), 7.31 (d, 2H, J = 8.4 Hz), 7.40 (s, 6H), 7.54 (s, 1H), 7.85 (d, 2H, J = 8.4 Hz); ¹³C NMR (125 MHz, CDCl₃) δ 21.9, 27.4, 32.2, 39.9, 116.9, 127.4, 128.9, 129.6, 130.0, 130.0, 132.2, 134.4, 134.9, 138.3, 143.7, 144.0, 162.1, 174.4; IR (film) cm⁻¹ 2966m, 1765s, 1740s, 1601s, 1481m, 1326s; mass spectrum (ESI): m/e (% relative intensity) 448 (100) (M+Na)⁺; HRMS (ESI) m/e calcd for C₂₄H₂₇NO₄SNa 448.1553, found 448.1543.

Scheme 8.

A Tandem Sigmatropic Rearrangement.