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. 2023 Dec 29;26(1):360–364. doi: 10.1021/acs.orglett.3c04030

Bridge Cross-Coupling of Bicyclo[1.1.0]butanes

Ryan E McNamee 1, Ayan Dasgupta 1, Kirsten E Christensen 1, Edward A Anderson 1,*
PMCID: PMC10789093  PMID: 38156902

Abstract

graphic file with name ol3c04030_0005.jpg

Bicyclo[1.1.0]butanes (BCBs) have gained growing popularity in “strain release” chemistry for the synthesis of four-membered-ring systems and para- and meta-disubstituted arene bioisosteres as well as applications in chemoselective bioconjugation. However, functionalization of the bridge position of BCBs can be challenging due to the inherent strain of the ring system and reactivity of the central C–C bond. Here we report the first late-stage bridge cross-coupling of BCBs, mediated by directed metalation/palladium catalysis.

Bicyclo[1.1.0]butanes (BCBs) (Figure 1a) are a class of highly strained hydrocarbons that have become valuable tools for “strain release” chemistry.1 These reagents possess the impressive ability to react with nucleophiles,2 radicals,3 electrophiles,4 and transition metal catalysts,5 with applications ranging from the synthesis of natural products2d and para-(6) and meta-substituted7 arene bioisosteres to use as cystine-selective bioconjugation agents.2b,8 Access to these building blocks has been streamlined with the recent developments of late-stage bridgehead and bridge metalation protocols that deliver a broad portfolio of BCBs,9 including a convenient one-pot sulfone-based reaction sequence that affords exceptional diversity.10

Figure 1.

Figure 1

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(a) Applications of BCBs in cyclobutane and bioisostere synthesis. (b) Previous work toward the construction of aryl-substituted BCBs. (c) Bridge directed metalation and cross-coupling of BCBs. DMG = directing metalation group.

BCBs that are aryl-substituted at the bridge carbon atoms are attractive targets due to their potential use in accessing arene-functionalized products upon ring opening. Specifically, access to these products would open up new avenues for medicinal chemists in bicyclo[1.1.1]pentane, -[2.1.1]hexane, and -[3.1.1]heptane synthesis for reaching novel chemical space.7b Recent methodologies developed for the synthesis of aryl-substituted BCBs include (1) biocatalytic double diazo–alkyne condensation that introduces two identical endo/exo bridge ester substituents (bridgehead aryl, Figure 1b);11 (2) asymmetric intramolecular diazo insertion into styrenes, catalyzed by rhodium(II) (bridge aryl);2e,12 and (3) bridgehead-directed metalation and cross-coupling (bridgehead aryl).9a The methods outlined in each case address different challenges, such as the latter providing a divergent synthesis of bicyclopentylation reagents, and the asymmetric diazo insertion facilitating a route toward the total synthesis of piperarborenine B.2d However, although intramolecular diazo insertion offers a powerful method for asymmetric bridge-arylated BCB synthesis, it suffers from the drawback of synthetic linearity rather than late-stage diversification.

We previously developed a method that enables late-stage bridge functionalization through directed metalation/electrophilic quench,9b although this tactic did not enable the introduction of aryl and alkenyl substituents. We questioned whether we might be able to extend this approach to bridge cross-coupling by transmetalation of the intermediate organolithium, enabling the rapid delivery of bridge aryl-substituted strain release reagents (Figure 1c). Notably, a similar strategy has been employed in the elegant polyfunctionalization of cubanes.13

Reaction development began by employing three potential BCB organometallic coupling partners, boronic acid 1a, stannane 1b, and organozinc 1c (prepared from metalation of BCB 2a with organolithiums and electrophilic quench (1a/b) or transmetalation to ZnCl2 (1c)), in Suzuki, Stille, and Negishi coupling protocols, respectively (Table 1, entries 1–3). Interestingly, the former two strategies led only to complete decomposition of the starting material with no observable product, while entry 3 returned 2a with no sign of degradation. This was surprising given previous reports on cyclopropylzinc Negishi couplings as well as our own work on BCB bridgehead Negishi reactivity,9a,14 and it was hypothesized that TMEDA might be interfering with the reaction. To our delight, the use of TMEDA-free metalation in the generation of 3a (t-BuLi in THF) and submission to equivalent coupling conditions (Pd(dba)2/2PPh3) achieved cross-coupling in 28% yield (as determined by 1H NMR spectroscopy; entry 4). A screen of 13 phosphine ligands was conducted, with the Buchwald-based ligands producing the highest yields and CyJPhos being optimal (48%; entry 5).15 A temperature and solvent screen identified THF at 65 °C as being crucial for this transformation (entries 6 and 7). Increasing the equivalents of iodobenzene led to a further increase in the yield (60%; entry 8). While a useful result, the conversion could be further enhanced by increasing the catalyst loading to 15 mol %, giving 3a in 71% yield (entry 9). On scale-up, it became apparent that stirring the reaction mixture for 1 h at room temperature was crucial; otherwise, the reaction would fail due to Pd black formation.

Table 1. BCB Cross-Coupling Optimizationa.

graphic file with name ol3c04030_0004.jpg

entry [M] ligand, variation of conditions yield (%)b
1 B(OH)2 (1a) PPh3 0
2 Sn(n-Bu)3 (1b) AsPh3 0
3 ZnCl·LiCl (1c) PPh3, TMEDA (1.1 equiv) 0
4 ZnCl·LiCl (1c) PPh3 28
5 ZnCl·LiCl (1c) CyJPhos 48
6 ZnCl·LiCl (1c) CyJPhos, 20 °C 6
7 ZnCl·LiCl (1c) CyJPhos, DMF/Tol/1,4-dioxanec –d
8 ZnCl·LiCl (1c) CyJPhos, PhI (4.0 equiv) 60
9 ZnCl·LiCl (1c) CyJPhos2 (30 mol %) and Pd(dba)2 (15 mol %)e 71
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a

Reactions were conducted on a 0.1 mmol scale. See the Supporting Information for details of metalation protocols in the synthesis of 1a–1c.

b

Determined by 1H NMR spectroscopic analysis of the crude reaction mixtures using 1,3,6-trimethoxybenzene as an internal standard.

c

Heated at 110 °C.

d

Extensive decomposition was observed in these solvents.

e

Stirred for 1 h at room temperature before heating.

With optimized metalation and cross-coupling conditions in hand, we then examined the scope of the reaction (Scheme 1). A selection of aryl iodides bearing electron-withdrawing and -donating groups at the para position was first investigated. To our delight, these couplings proceeded in good to excellent yields (3a–3e, 60–84%). Reaction efficiency was maintained with ortho-substituted aryl iodide derivatives (3f and 3g). The introduction of biorelevant functionality was also possible, for example, incorporating a galactose-bearing side chain in excellent yield (3h, 91%, 1:1 dr due to the racemic generation of 1c).

Scheme 1. Synthesis of Aryl Bridge-Substituted BCBs.

Scheme 1

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Reaction conditions, unless stated otherwise: 2a or 2b (0.20 mmol, 1.0 equiv); 1. Lithiation: at-BuLi (0.22 mmol, 1.1 equiv, 1.1–1.3 M in pentane, THF, −78 °C, 1.5 h; bs-BuLi (0.22 mmol, 1.1 equiv, 1.1–1.5 M in cyclohexane), THF, −45 °C, 3.0 h; 2. Transmetalation/coupling: ZnCl2 (0.22 mmol, 1.1 equiv), THF, −78 °C (or −45 °C) to rt; Pd(dba)2 (15 mol %), CyJPhos (30 mol %), R–I (0.4 mmol, 2.0 equiv) THF, 1 h, 20 °C; 1 d, 65 °C. cStructure of 3l from single-crystal X-ray diffraction studies (displacement ellipsoids drawn at 50% probability). dThe reaction was conducted on a 1 mmol scale.

Alkenyl iodides were also compatible with the coupling conditions (3i, 64%); however, alkenes bearing an electron-withdrawing group were essential for the product stability. Heterocycle cross-coupling is also highly appealing from a medicinal chemistry stance due to the application of BCBs in para- and meta-arene bioisostere synthesis. We were therefore delighted to find that a representative range of azacycles could be installed in good yields (50–84%), including 2-substituted pyridine (3j), indole (3k), and quinoline (3i). Pleasingly, these conditions could also be applied to BCB 2b, which is more sterically demanding at the bridgehead position (Ph substituent), giving 3m (64%) and 3n (55%). The latter coupling was also carried out on a 1 mmol scale without significant detriment to the yield (51%).

Cross-coupling on other BCBs, such as trimethylsilyl-substituted BCB 2c and trisubstituted BCB 2d would demonstrate the feasibility of constructing more complex derivatives, including a tetrasubstituted product. However, no product was observed when 2c and 2d were subjected to the developed metalation and cross-coupling conditions, with neither undergoing productive metalation with t-BuLi at −78 °C in THF. Fortunately, TMEDA-free conditions for directed lithiation were identified (s-BuLi at −45 °C in THF)15 that could be applied to 2c and 2d. These substrates were then subjected to the cross-coupling conditions and, to our delight, produced silyl-substituted BCB 3o in 45% yield and tetrasubstituted BCB 3p in 65% yield. Resolving the cross-coupling issue of 2c and 2d inspired us to examine sulfone substrates; pleasingly, 4a could be obtained in an excellent yield of 82% with the s-BuLi metalation conditions.

Having successfully demonstrated cross-coupling with trisubstituted BCB 2d, we questioned whether a complementary approach could be established through a second directed bridge metalation after bridge arylation (Scheme 2). BCB 3c was chosen as a candidate, as the bridge arene possesses a para electron-withdrawing group (CF3) that is tolerant of organolithiums. This substrate presents a regioselectivity challenge: the possibility of directed metalation (5a, Scheme 2) or benzylic deprotonation (5b), both of which would provide a useful class of novel BCBs. Surprisingly, when 3c was subjected to the optimized conditions, neither the unsubstituted bridge nor the benzylic bridge underwent lithiation. Instead, s-BuLi was directed to the bridgehead methyl group, which then underwent BCB ring opening to give the corresponding enolate; quenching with allyl bromide afforded polysubstituted exocyclic cyclobutene 6. This observation of this alternative metalation pathway may relate to restricted rotation of the directing group in substrate 3c, which prevents access to the unsubstituted bridge, as observed in the X-ray crystal structure of 3l and 1H NMR spectrum of the bridge aryl-BCB derivatives.15

Scheme 2. Unexpected Fragmentation in the Metalation of Bridge-Arylated BCB 3c.

Scheme 2

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The reaction was run on a 0.12 mmol scale using optimized conditions with allyl bromide (0.6 mmol, 5.0 equiv) quench.

In summary, we have developed a convenient and general late-stage Negishi cross-coupling strategy to access sp2-bridge-substituted BCBs. This approach enables the introduction of arenes, heteroarenes, and alkenes with broad functional group tolerance with respect to the arene: nitro, ester, halide, silyl, nitrile, ether, and acetal groups are all accommodated, which can allow for further manipulation. This approach enables the rapid delivery of new strain release reagents, which we expect to be of use to the wider chemical community for small-ring and bioisostere construction.

Acknowledgments

R.E.M. thanks the EPSRC Centre for Doctoral Training in Synthesis for Biology and Medicine for a studentship (EP/L015838/1) generously supported by AstraZeneca, Diamond Light Source, Defence Science and Technology Laboratory, Evotec, GlaxoSmithKline, Jannsen, Novartis, Pfizer, Syngenta, Takeda, UCB, and Vertex. E.A.A. and A.D.G. thank the EPSRC for support (EP/S013172/1).

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.3c04030.

  • Additional experimental discussion, experimental procedures, and copies of 1H and 13C NMR spectra (PDF)

The authors declare no competing financial interest.

Supplementary Material

ol3c04030_si_001.pdf (9.9MB, pdf)

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ol3c04030_si_001.pdf (9.9MB, pdf)

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

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