SYNTHETICALLY USEFUL INTERMEDIATES BY DIAZOSULFONE AND SULFONATE C-H INSERTION

Abstract

Intramolecular C-H insertion on diazosulfone and diazosulfonate substrates was used to prepare synthetically useful intermediates from easily available starting materials.

INTRODUCTION

We previously reported a modification of C-H insertion that leads to selective formation of six-membered sulfur containing heterocycles (δ-sultones or thiane-1,1-dioxides, depending on the substrate used).^[1] More reports of this transformation by other research groups have appeared since then.^[2,3] The most notable feature of this reaction is that the usual preference for formation of five-membered rings^[4,5] is overturned in this case, permitting to target different C-H bonds in the molecule for insertion (Scheme 1). Using this reaction, easily available chiral starting materials can be transformed into useful synthetic intermediates. Earlier, we demonstrated the potential of this approach by converting the δ-sultone, obtained from (-)-citronellol by diazosulfonate C-H insertion,^[2] to natural product bakuchiol.^[7] We, thus, set out to explore preparation of other synthetic intermediates from common precursors using this reaction.

Scheme 1.

C-H insertion on diazosulfones and diazosulfonates

RESULTS AND DISCUSSION

We started by exploring the diazosulfonate substrates. That required suitable alcohols substrates. We identified borneol (1a), isomenthol (1c), and 3-methylpentan-1-ol (1b, available from isoleucine^[8]) as such compounds. The alcohols were converted to the corresponding diazosulfonates using our previously developed procedure, with a few modifications (Table 1).^[1] We found it beneficial, as recommended by Du Bois,^[2] to use pyridine instead of triethylamine in the sulfonation step, while use of mesyl azide instead of nosyl azide in diazotransfer step simplified purification. Additionally, the diazosulfone substrates were of particular interest to us. Cyclization of these substrates leads to cyclic sulfones (thiane-1,1-dioxides) that may have even greater synthetic potential. For example, we previously demonstrated facile alkylation of these compounds and rearrangement of the alkylated products. ^[9] The diazosulfone substrates were prepared by a common sequence of an S_N2 substitution of alkyl sulfonates with ethyl mercaptoacetate, followed, without purification, by Oxone oxidation of the intermediate sulfide to sulfone. The obtained sulfones were then subjected to diazotransfer (Table 2). Tosylates of previously obtained 3-methylpentan-1-ol (4a), as well as of 2-methylpentan-1-ol (4b, easily available in chiral form via stereoselective methylation^[10] using Myers chiral auxiliary^[11], or asymmetric hydrogenation of (E)-2-methylpent-2-en-1-ol^[12]), and mesylate of menthol (4c) were thus converted to the corresponding diazosulfones. In case of mesylate of menthol, the S_N2 substitution step required harsher conditions (60 °, and DMSO as a solvent instead of acetone) and proceeded in a lower yield. The latter sulfone can also be more conveniently prepared by a reaction of neomenthylthiol^[13] with ethyl bromoactate, followed by Oxone oxidation. The obtained diazosulfonates (3a-3c) and diazosulfones (6a-6c) were subjected to C-H insertion as previously described.^[1,2] In case of borneol diazosulfonate (3a), unexpectedly, two products were obtained (7a and 7b, Entry 1, Table 3) – resulting from insertion into methyl group as well as into the methylene bridge, of which the former predominated. 3-Methylpentyl and isomenthyl diazosulfonates (3b and 3c) cleanly provided the expected C-H insertion products, as mixtures of diastereomers. C-H insertion on diazosulfones also proceeded readily. Notably, C-H insertion of diazosulfones 6a and 6b proceeded diastereoselectively, providing the trans-3,4- and cis-3,5- dimethyl thiane-1,1-dioxides (10 and 11) in good yields, effectively creating a new stereocenter in 1,2- and 1,3-positions relative to the existing one, respectively (small amounts of other diastereomers appeared to be present in the crude mixture, but were not isolated or identified). The relative stereochemistry of the observed products was confirmed by NOE studies (Figure 1). In case of neomenthyl diazosulfone, 6c, we hoped to direct C-H insertion into a different site than observed on a corresponding menthol diazosulfonate (Scheme 1). However, exclusive insertion into the same C-H site was observed, producing the five membered cyclic sulfone. The reaction was also slower than with other diazosulfones, requiring 5 hours of reflux in dichloromethane to complete, as opposed to 1 hour in other cases. Notably, two diastereomers of the product were observed in the crude reaction mixture by NMR, but only one was isolated, apparently due to equilibration during chromatography (similar equilibration was observed in case of other five membered cyclic sulfones^[6]).

Table 1.

Preparation of diazosulfonates

Entry	R	Yield of 2a-c	Yield of 3a-c
1		90%	75%
2		85%	72%
3		85%	77%

Table 2.

Preparation of diazosulfones

Entry	R,X	Yield of 5a-c	Yield of 6a-c
1		90%	82%
2		85%	80%
3		45%	85%

Table 3.

C-H insertion

Entry	Substrate	Conditions	Product(s)	Yield
1	3a	Rh2(esp)2, DCM rt, 10 h		75% (~9:1)
2	3b	Rh2(esp)2, DCM reflux, 1 h		65%
3	3c	Rh2(OAc)4, DCM reflux, 1 h		85%
4	6a	Rh2(OAc)4, DCM reflux, 1 h		60%
5	6b	Rh2(OAc)4, DCM reflux, 1 h		65%
6	6c	Rh2(OAc)4, DCM reflux, 5 h		90%

Figure 1.

Confirmation of configuration of 10 and 11

CONCLUSION

We thus prepared a series of synthetically useful intermediates from cheap and readily available starting materials using C-H insertion on sulfonyl substrates. Stereoselective formation of new stereocenters was observed in two cases. These intermediates may serve as precursors to natural products. Further studies will be reported in due course.

EXPERIMENTAL

General procedure for C-H insertion

To the suspension of the rhodium catalyst (Rh₂(esp)₂ or Rh₂(OAc)₄) (0.02 mmol) in CH₂Cl₂ (4 ml), a solution of the corresponding diazo compound (1 mmol) in CH₂Cl₂ (2 ml) was added either at rt over a period of 1 h using a syringe pump, or manually over 5 minutes at reflux. Upon completion of the addition, the reaction mixture was stirred at the specified temperature for the specified time (see Table 3). The volatiles were removed under reduced pressure and the crude reaction mixture was purified on silica column (Ethyl Acetate-Hexanes, 0 to 40%).

Sample physical data:

Ethyl (2S,3S,4R)-3,4-dimethylthiane-1,1-dioxide-2-carboxylate (10)

m.p. 99–100 °C. ¹H NMR (500 MHz, CDCl₃): δ 4.32 (dq, J = 7, 2 Hz, 2H), 3.60 (d, J = 12 Hz, 1H), 3.14 (dt, J = 14, 3.5 Hz, 1H), 2.97–3.05 (m, 1H), 2.16–2.26 (m, 1H), 1.94–2.06 (m, 2H), 1.33 (t, J = 7 Hz, 3H), 1.34–1.42 (m, 1H), 1.06 (d, J = 6.5 Hz, 3H), 1.01 (d, J = 6.5 Hz, 3H). ¹³C NMR (125 MHz, CDCl₃): δ 164.0 (C), 71.9 (CH), 62.7 (CH2), 52.2 (CH2), 39.9 (CH), 36.9 (CH), 31.9 (CH2), 19.4 (CH3), 17.8 (CH3), 14.3 (CH3). HRMS (ESI) calcd for C₁₀H₁₉O₄S [M+H]⁺ 235.1004, found 235.0992.