Main

Small-ring bridged bicyclic organic molecules have become valuable frameworks in modern drug design1,2. The rigidity of these motifs results in well-defined positioning of their substituents in three-dimensional (3D) chemical space, with additional benefits to physicochemical properties such as solubility and metabolic stability arising from their increased sp3 character3 compared to traditional drug fragments such as aromatic rings4,5. In certain cases, these bicyclic systems have been specifically designed to mimic the geometries of arenes. For instance, bridgehead-disubstituted bicyclo[1.1.1]pentanes (BCPs, Fig. 1a) and bicyclo[3.1.1]heptanes (BCHeps) have been shown to act as bioisosteres for para- and meta-substituted benzenes, respectively, due to the equivalent exit vectors of their bridgehead substituents compared to their aromatic counterparts. Key examples include the BCP analogue of the γ-secretase inhibitor avagacestat6, and the BCHep analogue of the anticancer agent sonidegib7. These motifs are most readily accessed by ring-opening reactions of [1.1.1]- and [3.1.1]propellanes (1)7,8,9, where under radical or anionic conditions, cleavage of the central C–C bond enables the installation of a range of substituents at the bridgehead positions10,11,12. Over the past decade, more than 20,000 BCPs have been forged from [1.1.1]propellane alone (Fig. 1a), underlining the importance of propellanes in organic and medicinal chemistry13.

Fig. 1: Bridged bicyclic hydrocarbons as bioisosteres of benzene rings, and heterocyclic analogues based on the bicyclo[3.1.1]heptane framework.
figure 1

a, Carbocyclic [n.1.1]propellanes 1 are versatile precursors for the synthesis of bicyclo[n.1.1]alkanes such as BCPs and BCHeps, which serve as bioisosteres for disubstituted benzene rings in drug design. The importance of [n.1.1]propellanes is illustrated by the rapid growth in BCPs reported in the Reaxys database over the last 15 years, almost all of which originate from [1.1.1]propellane. b, Existing routes to 3-azabicyclo[3.1.1]heptanes based on three-atom insertions into BCBs necessarily introduce specific substitution patterns, as highlighted in maroon. Ring-opening of spirocyclic oxetanes provides an alternative route but again results in specific product substituents. c, The 3-hetero[3.1.1]propellanes 3–5 can be accessed on a gram scale in five to seven synthetic steps from 2,3-dibromopropene and diazomalonate. These propellanes offer an attractive entry to a wide variety of bridgehead substituted 3-hetero-BCHeps that exhibit superior physicochemical profiles compared to carbocyclic BCHeps.

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One drawback of the BCHep scaffold compared to its BCP relative is its higher lipophilicity, which derives from the inclusion of two additional methylene (CH2) groups in its six-membered ring. This results in similar calculated values for the logarithm of the octanol/water partition coefficient (clogP) for BCHeps compared to the analogous aromatic compounds7, limiting the performance of these motifs in drug candidates. A solution to this problem is the introduction of a heteroatom into the bicyclo[3.1.1]heptane framework, which in the case of oxa-BCHeps has been shown to enhance physicochemical properties compared to their carbocyclic parents14,15,16. Furthermore, aza-BCHeps have been proposed as bioisosteres for pyridines, which are commonplace heteroaromatic rings14, and other structures such as oxa- and thia-BCHeps represent an unexplored chemical space in drug design. As such, rapid and diversifying entries to hetero-BCHeps are highly desirable.

Existing approaches to these valuable heterocyclic frameworks have limitations. For example, routes to 3-azacyclic analogues (3-aza-BCHeps, Fig. 1b) have been reported through the stepwise insertion of heteroatom-containing three-atom motifs such as azomethine ylids17, isocyanides18 and vinyl azides19 into the inter-bridgehead bond of bicyclo[1.1.0]butanes (BCBs)20,21. Although successfully generating the 3-aza-BCHep scaffold, these methods display limited diversity in the functionalities that can be introduced at the 3-aza-BCHep bridgehead positions. This is due to restrictions in BCB preparation and stability, and indeed the subsequent insertion reaction pathways, necessitating a predetermined electron-withdrawing group and an aromatic ring (or proton) on the BCB bridgehead atoms (highlighted in maroon). These reactions also install specific substituents on their three-atom bridges in addition to the heteroatom itself, which may not be desired for a given application. An alternative strategy, described by Mykhailiuk and colleagues14,15 and Ryabchuk and colleagues16, involves the ring-opening/cyclization of an amine- or hydroxy-functionalized spirocyclic cyclobutane-oxetane 2, which invariably positions a hydroxymethyl group at one of the bridgehead carbon atoms. Despite a handful of related scaffolds being accessible (albeit also with limitations in substituent scope)19,22,23,24,25,26,27,28, no single method offers unified access to a family of hetero-BCHeps in a manner that enables late-stage bridgehead substituent diversification. This is an important goal, as many hetero-BCHeps have no analogy in heteroaromatic chemical space (for example, oxa- and thia-scaffolds), and therefore offer many opportunities in drug design.

Heteropropellanes (3–5, Fig. 1c) would be highly appealing as alternative precursors to hetero-BCHeps. However, despite more than 50 years of research into propellane chemistry13, hetero[n.1.1]propellanes have so far eluded synthesis. The physical and chemical properties of these strained heteropropellanes are therefore entirely uncharted, and comparison with well-established carbocyclic analogues is an exciting prospect. Furthermore, given the importance of the carbocyclic [1.1.1] and [3.1.1]propellanes in drug design, the availability of such structures would probably be of great utility in medicinal and biological chemistry research. Here we describe a general, scalable strategy for the synthesis of hetero[3.1.1]propellanes 3–5, members of a ‘small ring’ heteropropellane family that have not previously succumbed to chemical synthesis. We show that these molecules can exhibit marked stability compared to their carbocyclic analogues, and are conveniently isolated without recourse to distillation, as has typically been required for carbocyclic propellanes. We also disclose their ring-opening functionalization using a variety of radical-based methods, which offers access to valuable 3-hetero-BCHeps, including the late-stage functionalization of biologically relevant molecules.

Results

Heteropropellane synthesis

Our work began with the development of a viable route to 3-oxa[3.1.1]propellane (Fig. 2). After exploring a number of potential strategies (Supplementary Section 2), we identified a route that began with a rhodium-catalysed cyclopropanation of 2,3-dibromopropene with dimethyl diazomalonate (6). This cyclopropanation benefited from use of the bulky triphenylacetate (TPA)-ligated rhodium catalyst, and could be performed on a decagram scale at just 0.05 mol% catalyst loading (68% yield). Reduction of the resulting cyclopropane diester 7 proceeded optimally using diisobutylaluminum hydride (DIBALH), and direct treatment of the product diol 8 with potassium hydroxide effected cyclization of the alcohol syn to the bromomethyl group to form tetrahydrofuran (THF) 9 (83% over two steps). The residual alcohol in 9 was then converted to the corresponding bromide 10 under Appel-type conditions (74%). With this 3-oxa[3.1.1]propellane precursor in hand, we explored lithiation of the bridgehead bromide, a reaction that in this oxacyclic system carries a risk of β-elimination of the THF ring. We were therefore delighted to observe that on treatment of 10 with 1 equiv. of methyllithium in diethyl ether, cyclization proceeded smoothly at room temperature, affording a solution that consisted solely of the targeted 3-oxa[3.1.1]propellane 3 and bromomethane, along with lithium bromide (the latter as a fine precipitate). Purifications of carbocyclic propellanes typically involve co-distillation of the propellane from the reaction mixture with a solvent of similar boiling point. Pleasingly, we found that the reaction mixture was of sufficient purity that this was not necessary, and a solution of 3 in Et2O could be conveniently obtained by the simple addition of NaHCO3 (to quench any residual MeLi), followed by filtration through celite and partial concentration to remove bromomethane. This solution contained traces of LiBr, which did not affect subsequent reactivity, but could be removed if desired by co-distillation with dibutyl ether (Supplementary Section 5). Importantly, this route could be executed on a multigram scale (for example, reaction of 5 g of 10 afforded 3 in 74% yield). In a similar manner to carbocyclic propellanes, we found that ethereal solutions of 3-oxa[3.1.1]propellane could be stored in the dark at −20 °C under an inert atmosphere, and were stable for several months without degradation.

Fig. 2: Scalable synthesis of 3-hetero-BCHeps.
figure 2

Synthetic routes to 3-oxa-, 3-thia- and 3-aza[3.1.1]propellanes (3–5) initiate with rhodium-catalysed cyclopropanation of 2,3-dibromopropene with diazomalonate. The structure of 3-aza[3.1.1]propellane 5 was determined using single-crystal X-ray diffraction (CCDC 2412510, displacement ellipsoids drawn at 50%).

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With 3-oxa[3.1.1]propellane in hand, we questioned whether we could leverage this synthetic route to access other heterocyclic [3.1.1]propellanes. We first addressed the synthesis of 3-thia[3.1.1]propellane by intercepting diol 8 with potassium thioacetate, whereby substitution of the bromomethyl group afforded thioester 11 (54% over two steps). After some investigation, we found that bromination of this diol offered the optimal means to convert the two alcohols into suitable leaving groups for propellane synthesis, with NBS/PPh3 delivering dibromide 12 in 58% yield. Hydrolysis of the thioester (KOH) triggered cyclization to the tetrahydrothiophene 13 (95%), treatment of which with methyllithium effected lithiation of the bridgehead bromide, followed by cyclization to 3-thia[3.1.1]propellane 4 in 68% yield, which could also be isolated as a solution in diethyl ether.

The synthesis of 3-aza[3.1.1]propellane brings opportunities to functionalize the propellane framework with an additional substituent on the heteroatom. To establish the synthesis, we first considered an N-tosyl group, which we anticipated would prove tolerant of the synthetic route. In the event, we were able to identify a suitable path to the 3-aza[3.1.1]propellane 5 from cyclopropanation product 7. Reaction of 7 with sodium azide (to give 14, 96%), followed by Staudinger reduction using tri-n-butylphosphine, afforded the lactam ester 15 (61%). A screening of various reducing agents revealed that Red-Al was uniquely effective for reduction of the lactam ester to the corresponding pyrrolidine alcohol; direct N-tosylation gave the pyrrolidine sulfonamide 16 (40% over two steps). Following bromination of the residual alcohol (17, 92%), reaction with MeLi gave 3-N-Ts-[3.1.1]propellane 5 as a solution in THF. Remarkably, diffusion of an ether/pentane mixture into this solution afforded crystals of 5, which, unlike carbocyclic propellanes, did not undergo spontaneous polymerization to a BCHep-staffane. Although not stable for a prolonged period, this enabled determination of the single-crystal X-ray structure, providing insight into the geometry of this small-ring propellane (Fig. 2; details are provided in Supplementary Section 7 and a further discussion of propellane stability in Supplementary Section 6). It is possible that the unexpected stability of this propellane can be ascribed to the inductive electron-withdrawing effect of the sulfonamide nitrogen atom, which renders the inter-bridgehead bond less electron-rich, reducing the usual destabilizing Pauli repulsion with adjacent C–C bonds29.

Heteropropellane reactivity

With a selection of hetero[3.1.1]propellanes in hand, their reactivity was explored under a range of radical ring-opening conditions (Table 1). The atom transfer radical addition (ATRA) of carbon–halogen bonds across propellanes is one of the most versatile methods for ring-opening30,31,32, and we were able to generate a range of oxa- and aza-BCHeps using either triethylborane as initiator31, or iridium photocatalysis32. This included the formation of iodo-hetero-BCHeps by the addition of electron-deficient (18a–d) and electron-rich (18e,f) alkyl radicals. In the former case, comparable yields were obtained for the addition of an acetyl radical to both oxa- and aza[3.1.1]propellanes (3 and 5), and for the latter, reaction with 3 proved superior. The addition of a benzyl radical (18g) and both unsaturated (pyridyl) and saturated (piperidine and azetidine) radicals on nitrogen heterocycles (18h–j), as well as C–Br bonds, also proved successful (18k–n). We further achieved the addition of heteroatom-centred radicals: an N-substituted oxa-BCHep (18o) was prepared by radical fragmentation of an iodomethyl aziridine33, and halosulfonylation of 3-oxa[3.1.1]propellane was also achieved in good yields (18p,q)34. Treatment of 3-oxa- or 3-aza[3.1.1]propellane with iodine afforded a mixture of diiodo-BCHep (18r,s) and the corresponding [2]staffanes (18r′,s′) where, interestingly, the proportion of staffane was higher for the aza-BCHep; these adducts represent stable potential propellane precursors (see below). We also found that other radical addition methods could be applied, such as the addition of an α-amino radical via organophotoredox catalysis (18t)35, and a range of chalcogen-substituted BCHeps (18u–z) were prepared by direct addition of the chalcogen or dichalcogen to the propellane36,37,38. We were able to demonstrate the wider potential of these heteropropellanes by the synthesis of pharmaceutically relevant compounds, including the cysteine-substituted oxa-BCHep 18aa, galactopyranose derivative 18ab, and pretilachlor derivative 18ac. Finally, product 18ad is an interesting example of a compound containing both a carbocyclic and heterocyclic BCHep.

Table 1 Ring-opening reactions of hetero[3.1.1]propellanesa
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These reactions revealed differences in behaviour between the various hetero[3.1.1]propellanes. In general, 3-aza[3.1.1]propellane5was found to be less susceptible to ring-opening than 3-oxa[3.1.1]propellane 3; while reacting efficiently with electron-deficient radicals, ring-opening of 5 with electron-rich species was less facile (c.f.18e versus18f), reflecting its greater stability (in some reactions, unreacted5could be observed in the crude reaction mixture). Reactions of 3-thia[3.1.1]propellane were limited to those with very efficient propagation steps, as bridgehead thia-BCHep radicals were otherwise found to be prone to fragmentation of the ring before interception with a halogen or hydrogen atom source—a process not previously witnessed in radical-based propellane chemistry. In these cases, increasing the concentration of the thiol substrate was found to improve yields due to rapid capture of the bridgehead radical (Supplementary Section 3 provides additional details for unsuccessful substrates, and Supplementary Section 5 provides details of thia-BCHep fragmentation).

While the dibromides10,13 and17 provide a convenient means to access the hetero[3.1.1]propellanes, we questioned whether diiodo-hetero-BCHeps might also be suitable precursors39,40. To validate this hypothesis, we treated the mixtures of diiodo-hetero-BCHep and staffane dimer obtained from iodination of 3-oxa[3.1.1]propellane (18r/r′) or 3-aza[3.1.1]propellane (18s/s′) with methyllithium (Fig. 3a), and found, in both cases, that the corresponding propellanes3 and 5 were successfully reformed in excellent yields (100% and 83%, respectively). The presumed lithiated BCHep intermediates in this transformation carry the risk of β-elimination of the heteroatom; however, the only products observed were the propellanes. It is also notable that the hetero-staffane is equally susceptible to this fragmentation, despite the associated cost of C–C bond cleavage and presumed increase in ring strain. We are not aware of any precedent for such staffane fragmentation processes. Importantly, these experiments validate dihalides such as 18r/s as alternative precursors to hetero[3.1.1]propellanes.

Fig. 3: Further aspects of heteropropellane chemistry.
figure 3

a, Re-formation of propellanes from diiodo hetero-BCHeps and hetero-[2]staffanes. b, Examples of 3-aza[3.1.1]propellanes with alternative groups on the nitrogen, which are installed at the penultimate step of propellane synthesis. c, Application of 3-oxa[3.1.1]propellane to the synthesis of oxa-BCHep-sonidegib (22). d, Detosylation of aza-BCHep 18ac. TMEDA, N,N,N’N’-tetramethylethylenediamine; HATU, hexafluorophosphate azabenzotriazole tetramethyl uronium.

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The preparation of bridge-substituted all-carbocyclic propellanes is very challenging, and it typically requires low-yielding and lengthy multistep sequences41,42. We were therefore pleased to find that variation of the exocyclic substituent on the nitrogen atom of 3-aza[3.1.1]propellanes is substantially easier, and can be achieved at a relatively late stage of the synthesis. Specifically (Fig. 3b), detosylation of the immediate aza-propellane precursor 17 using HBr and phenol, followed by reaction with a sulfonyl chloride, afforded quinoline, thiophene and bis-sulfonamide propellane precursors 20a–c. We found that these compounds underwent smooth conversion to the corresponding propellanes 21a–c in excellent yields on treatment with methyllithium (70–99%). Particularly notable is the highly efficient synthesis of the ‘double’ propellane 21c, in which two ring-closing events are required. Generally, we observed that propellane formation proceeds optimally with electron-withdrawing substituents on the nitrogen atom, especially sulfonamides (details are provided in Supplementary Section 4), which opens up the possibility for further exploration of the scope of this substituent.

We were able to demonstrate the potential utility of these heterocyclic propellanes through a synthesis of the oxa-BCHep analogue of the anticancer drug sonidegib (22, Fig. 3c), which has been shown in previous work to display improved solubility and other physicochemical properties compared to the parent compound15,16. We found that ATRA adduct 18e underwent iron-catalysed Kumada cross-coupling with p-trifluoromethoxy phenylmagnesium bromide43, affording product 23 (49%). Elaboration of this product to the drug analogue was achieved by hydrolysis of the pivalate ester in 23, then oxidation to acid 24 (46%); amide bond formation with amine 25 afforded oxa-BCHep sonidegib 22 (refs. 15,16) in 70% yield. Notably, our propellane-based strategy offers opportunities for late-stage variation of both the aromatic and amide parts of the drug analogue. Finally, to enhance opportunities for diversification of the N-sulfonyl propellane-derived 3-aza-BCHeps, we explored removal of the N-tosyl group resident in many of these products. After deiodination of aza-BCHep 18ac (to intermediate 26, Fig. 3d), we showed that detosylation could be effected under mild conditions (Mg, MeOH) to afford amine 27 in good yield (79%).

Discussion

Heterocyclic small-ring propellanes are now accessible via a concise, unified synthetic strategy that can be performed on a multigram scale. The synthesis hinges on an efficient rhodium-catalysed cyclopropanation of 2,3-dibromopropene that can be performed on a multidecagram scale due to the very low catalyst loading that is possible. This transformation establishes the first of the two cyclopropane rings in the heteropropellane target, and is followed by construction of the heterocyclic ring before the key formation of the second cyclopropane via metalation/cyclization. Crucially, the heteropropellanes can be directly isolated without need for distillation, and are found to be substantially more stable than their [3.1.1]propellane carbocyclic relative. These molecules display behaviour distinct from that of the latter well-known propellane, and are shown to offer direct access to valuable bridged heterocyclic small-ring building blocks that are of high interest in contemporary drug design via a range of radical ring-opening processes.

Methods

Dimethyl 2-diazomalonate (6)

To a solution of dimethyl malonate (17.3 ml, 151 mmol, 1.0 equiv.) and 4-acetamidobenzenesulfonyl azide (40.0 g, 167 mmol, 1.1 equiv.) in dry MeCN (150 ml) at 0 °C was added 1,8-diazabicycloundec-7-ene (24.9 ml, 167 mmol, 1.1 equiv.) dropwise over 30 min, keeping the internal temperature below 20 °C. The mixture was then warmed to room temperature (r.t.) and stirred for 3 h. NH4Cl sat. (20 ml) was added, then the solvent was removed under reduced pressure. Water (400 ml) was added and the mixture was extracted with Et2O (3 × 400 ml), then the combined organic layers were washed with brine (600 ml), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The mixture was filtered through a silica plug and eluted with a 4:1 mixture of hexane/EtOAc until all of the yellow substance was removed from the silica. Concentration under reduced pressure gave the product (20.6 g, 130 mmol, 86%) as a yellow oil. For safety reasons, to avoid isolation of neat diazo compound, the product is not concentrated until completely free of solvent, but is taken forward to the next step with ~10% residual solvent remaining. The proportion of product in the isolated mixture was determined by NMR spectroscopy.

Dimethyl 2-bromo-2-(bromomethyl)cyclopropane-1,1-dicarboxylate (7)

To a solution of rhodium(II) triphenylacetate dimer (93.8 mg, 65.1 µmol, 0.050 mol%) in dry CH2Cl2 (100 ml) was added 2,3-dibromoprop-1-ene (25.5 ml, 80%, 208 mmol, 1.6 equiv.). A solution of dimethyl 2-diazomalonate 6 (20.6 g, 130 mmol, 1.0 equiv.) in dry CH2Cl2 (20.0 ml) was added via a syringe pump over 8 h at r.t. then the mixture was stirred at r.t. for an additional 8 h. The solvent was removed under reduced pressure, then purification by column chromatography (SiO2, pentane/Et2O 19:1 → 8:2) gave the product (29.1 g, 88.2 mmol, 68%) as a colourless oil.

(5-Bromo-3-oxabicyclo[3.1.0]hexan-1-yl)methanol (9)

To a solution of 7 (15.0 g, 46.0 mmol, 1.0 equiv.) in dry THF (150 ml) at −78 °C was added DIBALH (200 ml, 1.0 M solution in hexanes, 200 mmol, 4.3 equiv.). The mixture was stirred at −78 °C for 2.5 h, allowed to warm slowly to r.t. and stirred for an additional 30 min. The mixture was cooled to 0 °C, and Rochelle’s salt (250 ml, aq. sat.) was added slowly. The cloudy mixture was stirred at r.t. for 5 h until it became clear. THF was removed under reduced pressure, then the aqueous layer was extracted with EtOAc (3 × 200 ml). The combined organic layers were washed with brine (300 ml), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to afford (2-bromo-2-(bromomethyl)cyclopropane-1,1-diyl)dimethanol (8).

The crude product 8 from the first step was dissolved in MeOH (100 ml) and added to a solution of KOH (4.50 g, 80.0 mmol, 1.8 equiv.) in MeOH (150 ml). The mixture was heated to 60 °C for 1 h, then the solvent was removed under reduced pressure. Water (100 ml) was added and the mixture was extracted with Et2O (3 × 100 ml). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give product 9 (7.40 g, 38.0 mmol, 84%) as a yellow oil, which required no further purification.

(2-Bromo-2-(bromomethyl)cyclopropane-1,1-diyl)dimethanol (8)

To a solution of 7 (6.69 g, 20.3 mmol, 1.0 equiv.) in dry THF (50.0 ml) at −78 °C was added DIBALH (83.1 ml, 1.0 M solution in hexanes). The mixture was stirred at −78 °C for 2 h, then stirred at 0 °C for a further 1 h. Rochelle’s salt (100 ml, aq. sat.) was added, and the cloudy mixture was stirred at r.t. for 3 h until it became clear. THF was removed under reduced pressure, then the aqueous layer was extracted with EtOAc (3 × 100 ml). The combined organic layers were washed with brine (100 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Trituration from a 7:3 mixture of pentane:Et2O gave the product (2.59 g, 9.45 mmol, 47%) as a white amorphous solid, which was collected by filtration.

1-Bromo-5-(bromomethyl)-3-oxabicyclo[3.1.0]hexane (10)

To a solution of 9 (7.59 g, 39.3 mmol, 1.0 equiv.) in dry CH2Cl2 (100 ml), was added N-bromosuccinimide (NBS; 8.40 g, 47.2 mmol, 1.2 equiv.). PPh3 (12.4 g, 47.2 mmol, 1.2 equiv.) was then added in portions at 0 °C, and the mixture was stirred at r.t. for 1 h. Pentane (150 ml) was added to the reaction mixture and stirred for 10 min at r.t. The mixture was filtered through a celite pad, and the filtrate was concentrated. Purification by column chromatography (SiO2, pentane/Et2O 19:1) gave the product (7.43 g, 29.0 mmol, 74%) as a pale yellow oil. This compound is relatively volatile and must be concentrated carefully with pressure not lower than 250 mbar. However, we have not observed any stability issues with the storage of this propellane precursor over a period of several months.

3-Oxa[3.1.1]propellane (3)

To a stirred solution of 10 (5.03 g, 15.7 mmol, 1.0 equiv.) in dry Et2O (80 ml) at r.t. was added MeLi (12.1 ml, 1.3 M in Et2O, 15.7 mmol, 1.0 equiv.). The mixture was stirred at r.t. for 4 h, then NaHCO3 (1.32 g, 15.7 mmol, 1.0 equiv.) was added. The mixture was cooled to 0 °C, then passed through a celite pad and eluted with Et2O (100 ml). The mixture was partially concentrated under reduced pressure to give the product as a solution in Et2O (72.0 ml, 0.16 M, 11.7 mmol, 74%), which was stored in an amber glass bottle with an AcroSeal under N2 at −20 °C (caution: during the partial concentration process, bromomethane will be released). The concentration was determined by integrating the 1H NMR peak at 2.51 ppm relative to the Et2O peaks. The solution of product contains a white precipitate, presumed to be LiBr, which does not affect subsequent reactions. It is recommended to store the propellane solution in the freezer (−20 °C) at <0.5 M concentration, under which conditions it is stable for a period of (at least) several weeks to months.

The propellane 3 can also be isolated by distillation according to the following procedure. To a stirred solution of 10 (1.02 g, 3.19 mmol, 1.0 equiv.) in dry Et2O (16 ml) at r.t. was added MeLi (2.45 ml, 1.3 M in Et2O, 3.19 mmol, 1.0 equiv.). The mixture was stirred at r.t. for 4 h, then NaHCO3 (268 mg, 3.19 mmol, 1.0 equiv.) was added. nBu2O (30 ml) was added and the mixture was distilled using a rotary evaporator (30 °C water bath) with a dry-ice cold finger condenser and a receiving flask immersed in an acetone/dry-ice bath. The Et2O fraction containing bromomethane was removed by slowly decreasing the pressure to 150 mbar and this fraction was discarded. The nBu2O fraction containing 3-oxa[3.1.1]propellane was then distilled by slowly decreasing the pressure to <10 mbar. This gave the product as a solution in nBu2O (27.0 ml, 0.065 M, 1.76 mmol, 55%), which was stored in an amber bottle with an AcroSeal under N2 at −20 °C. The concentration was determined by integrating the 1H NMR peak at 2.42 ppm relative to the Et2O peaks.

3-Thia[3.1.1]propellane (4)

To a stirred solution of 13 (0.961 g, 3.53 mmol, 1.0 equiv.) in dry Et2O (18 ml) at r.t. was added MeLi (2.72 ml, 1.3 M in Et2O, 3.53 mmol, 1.0 equiv.). The mixture was stirred at r.t. for 4 h, then NaHCO3 (297 mg, 3.53 mmol, 1.0 equiv.) was added. The mixture was cooled to 0 °C, then passed through a celite pad and eluted with Et2O (50 ml). The mixture was partially concentrated under reduced pressure to give the product as a solution in Et2O (18.5 ml, 0.13 M, 2.41 mmol, 68%), which was stored in an amber glass bottle with an AcroSeal under N2 at −20 °C. The concentration was determined by integrating the 1H NMR peak at 2.79 ppm relative to the Et2O peaks. It is recommended to store the propellane solution in the freezer (−20 °C) at <0.5 M concentration, under which conditions it is stable for a period of (at least) several weeks to months.

3-(N-tosyl)aza[3.1.1]propellane (5)

To a stirred solution of 17 (2.00 g, 4.89 mmol, 1.0 equiv.) in dry THF (40 ml) at −78 °C was added MeLi (3.76 ml, 1.3 M in Et2O, 4.89 mmol, 1.0 equiv.). The mixture was stirred at −78 °C for 10 min then at r.t. for 1 h. NaHCO3 (411 mg, 4.89 mmol, 1.0 equiv.) was added, then the mixture was cooled to 0 °C, passed through a celite pad and eluted with THF (100 ml). The mixture was partially concentrated under reduced pressure to give the product as a solution in THF (26.0 ml, 0.18 M, 4.79 mmol, 98%), which was stored in an amber glass bottle with an AcroSeal under N2 at −20 °C. The concentration was determined by integrating the 1H NMR peak at 3.17 ppm relative to the THF peaks. It is recommended to store the propellane solution in the freezer (−20 °C) at <0.5 M concentration, under which conditions it is stable for a period of (at least) several weeks to months.