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Published in final edited form as: Chemistry (Basel). 2025 Jun 16;7(3):99. doi: 10.3390/chemistry7030099

Transformation of Linear Alkenyl N-Alkoxy Carbamates into Cyclic Bromo Carbonates

Shyam Sathyamoorthi a,*, Steven P Kelley b
PMCID: PMC12380031  NIHMSID: NIHMS2090777  PMID: 40873694

Abstract

We present a protocol for the facile conversion of linear alkenyl N-alkoxy carbamates into cyclic bromo carbonates. The reaction is operationally simple, uses widely available, inexpensive reagents, and requires no rigorous exclusion of air or moisture. A broad range of functional groups is compatible, and the reaction diastereoselectivities range from good to excellent. The reactions are scalable, and the product carbonates can be further transformed.

Graphical Abstract

graphic file with name nihms-2090777-f0001.jpg

As part of a programmatic focus on exploring the synthetic utility of unusual tethers for olefin functionalization reactions,1–4 we aimed to develop an amino-fluorination of alkenes using N-alkoxycarbamate auxiliaries. We expected that the treatment of 1 with a combination of Selectfluor (a potent oxidant) and CuBr2,5–9 would facilitate formation of an N-centered radical or a nitrenium ion,10, 11 unstable intermediates which would rapidly attack the pendant olefin. Trapping by fluoride anion or fluoride radical would ultimately form an interesting amino-fluoride product (Scheme 1).

Scheme 1.

Scheme 1.

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An unexpected result with Selectfluor and CuBr2 sparks a new investigation.

Of course, none of what we had drawn on paper transpired in the flask. Instead, bromo carbonate 2 was the only isolable product (Scheme 1)! We were very excited by this result, as olefin halofunctionalization with tethered O- or N-nucleophiles is useful for regioselectively and diastereoselectively constructing heterocycles of importance.12–25 In this area, prior art with carbamate tethers has largely focused on iodination reactions,26–37 with comparatively fewer reports on analogous brominations.38–46 There are no reports examining the use of N-alkoxycarbamate tethers for olefin halofunctionalizations; indeed, these unusual auxiliaries are underutilized for organic synthesis in general.11, 47–49 For these reasons, we felt that this serendipitous discovery was worth further exploration.

We hypothesized that the reaction was proceeding through in situ generation of Br+ by the rapid oxidation of Br− by Selectfluor. It seemed reasonable to replace this complicated system with simpler reagents capable of directly delivering Br+. We wished to avoid reaction mixtures containing Br−, which would compete with the carbamate tether for nucleophilic opening of the transient bromonium ion, leading to the formation of undesired, linear dibromide products. Switching to dibromoisocyanuric acid in acetonitrile gave product 2 in a reasonable yield of 57% (Table 1, Entry 1). No improvement was observed when either N-bromosaccharin or 1,3-dibromo-5,5-dimethylhydantoin was used in place of dibromoisocyanuric acid (Table 1, Entries 2 – 3). With N-bromosuccinimide (NBS) in either CH2Cl2 or CH3CN, formation of product 2 markedly worsened (Table 1, Entries 4 – 5). During the replication of these experiments, we noticed some fluctuations in the yield of product 2 based on the bottle of CH3CN used, suggesting that the presence of H2O was affecting the reaction outcome. Indeed, with NBS reactions in CH3CN, adding 2 equivalents of H2O dramatically improved formation of 2 (Table 1, Entries 6 and 8)! 2 equivalents of H2O were sufficient for improved reaction performance; with a large excess (~55 equiv.) of H2O, product yield dropped by 12% (Table 1, Entry 7). Ultimately, the optimal yield of 2 came with the use of 2 equivalents of NBS and 2 equivalents of H2O in CH3CN (Table 1, Entry 9). We recommend using NBS recrystallized from H2O50 as commercial preparations contain unregulated amounts of HBr and Br2, both of which could complicate product formation through undesired side reactions with Br−. All subsequent experiments in this manuscript were performed with recrystallized NBS.

Table 1.

Optimization Experiments.

graphic file with name nihms-2090777-t0002.jpg
Br+ sourcea Additivea Solventb Yieldc
1 DBI (1)d None CH3CN 57%
2 NBSacc (1.5)e None CH3CN 53%
3 DBH (1.5)f None CH3CN 55%
4 NBS (1.5)g None CH2Cl2 20%
5 NBS (1.5) None CH3CN 22%
6 NBS (1.5) H2O (2) CH3CN 72%
7 NBS (1.5) H2O (55) CH3CN 60%
8 NBSh (1.5) H2O (2) CH3CN 70%
9 NBSh (2) H 2 O (2) CH 3 CN 75%
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a

Equivalents are given in parentheses.

b

Reaction concentration = 0.1 M

c

Estimated by 1H NMR integration against an internal standard; relative configuration of product is shown.

d

DBI = dibromoisocyanuric acid [15114-43-9]

e

NBSacc = N-bromosaccharin [35812-01-2]

f

DBH = l,3-dibromo-5,5-dimethyLhydantoin [77-48-5]

g

NBS = N-bromosuccinimide [128-08-5]

h

recrystallized from H2O

Next, we aimed to delineate the effect of the N-alkoxy substituent of the carbamate tether on reaction performance (Scheme 2). We were pleased to see that a variety of alkyl substituents were well tolerated (Scheme 2, Entries 1 – 8). Even carbamate tethers with bulky N-alkoxy groups such as tert-butyl (Scheme 2, Entry 3) and benzyl (Scheme 2, Entry 7) substituents transformed nicely into the desired cyclic carbonate. While product 2 did form with N-OH substrate 10 and with N-OPh substrate 11, the yields were markedly lower (Scheme 2, Entries 9 – 10). With these compounds, analyses of the unpurified reaction mixtures by 1H NMR showed an unusual profile of side products in addition to desired product 2; thus, we hypothesize that competitive bromination of the carbamate tether triggered a variety of undesired reaction pathways.

Scheme 2.

Scheme 2.

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Varying the carbamate tether.

We were pleased that a variety of alkenyl carbamates cyclized productively into carbonates when stirred in acetonitrile with two equivalents of NBS and 2 equivalents of water at ambient temperature (Scheme 3). Cis-disubstituted alkenes, trans-disubstituted alkenes, trisubstituted alkenes, and terminal alkenes were all compatible and gave products in good to excellent yields. Carbamates derived from both allylic and homoallylic alcohols fared well. A crystal structure of product 25 (CCDC 2429439) allowed for assignment of the relative stereochemistry of the two newly formed stereocenters, and the relative stereochemistry of most other products was assigned by analogy. Stereoarrays could also be synthesized in good to excellent diastereoselectivities (Scheme 3, Entries 1, 4, and 10). Our optimized reaction protocol was tolerant of a diverse array of functional groups, including aryl halides (Scheme 3, Entry 2), an aryl pinacol boronate (Scheme 3, Entry 2), alkyl ethers (Scheme 3, Entries 5 and 9), and a Boc-protected amine (Scheme 3, Entry 7).

Scheme 3.

Scheme 3.

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Substrate scope exploration.

A collection of substrates that failed to react as expected is shown in Scheme 4. With (E)-hex-2-en-1-yl methoxycarbamate (Compound 54), an approximately 1:1 mixture of products was observed by 1H NMR analysis of the unpurified reaction mixture. Here, because of the substrate geometry, we hypothesize that both endocyclic and exocyclic bromonium cleavage pathways were feasible, leading to a mixture of 5-membered and 6-membered cyclic carbonate products. Substrates bearing electron-rich aromatic rings (Scheme 4, Compounds 55 and 56) gave complex mixtures of products. Here, we hypothesize that aromatic bromination was a deleterious side pathway. Finally, no productive reaction was observed with styrenyl substrate 57.

Scheme 4.

Scheme 4.

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Interesting and problematic substrates.

The high diastereoselectivity and predictable stereochemical outcome with a variety of test substrates suggests the reaction mechanism depicted in Scheme 5. The reaction of the olefin substrate with NBS leads to formation of a transient bromonium ion.51 This is rapidly ring-opened in an SN2 manner by the carbamate tether’s carbonyl oxygen forming a transient oxime-like intermediate, which is then hydrolyzed during the course of the reaction or the work-up.

Scheme 5.

Scheme 5.

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Mechanistic Hypothesis.

Even with six-fold and twelve-fold increases in scale (Scheme 6A), products formed in reasonable yields. With product 39, which contains a primary alkyl bromide moiety, substitution with sodium azide proceeded at room temperature (Scheme 6B). Unsurprisingly with 2, an analogous transformation required mild heating. In both cases, an excess of sodium azide was required for starting material consumption.

Scheme 6.

Scheme 6.

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(A) Scale up (B) Applications.

In summary, we present a protocol for the facile conversion of linear alkenyl N-alkoxy carbamates into cyclic bromo carbonates. The reaction is operationally simple, uses widely available, inexpensive reagents, and requires no rigorous exclusion of air or moisture. A broad range of functional groups is compatible, and the reaction diastereoselectivities range from good to excellent. The reactions are scalable, and the product carbonates can be further transformed. We expect this work to be well-received by chemists engaged in the stereoselective construction of interesting heterocycles.

Supplementary Material

SI

Additional experimental details include reaction procedures, tabulated characterization, NMR spectra, and X-ray crystallographic tables.

ACKNOWLEDGMENT

This work was supported by National Institutes of Health grants R35GM142499, P20GM113117, and P20GM130448. Justin Douglas and Sarah Neuenswander (KU NMR Lab) are acknowledged for help with structural elucidation. Lawrence Seib and Anita Saraf (KU Mass Spectrometry Facility) are acknowledged for help acquiring HRMS data. We thank Dr. Frederick J. Seidl for many helpful discussions regarding the bromination of olefins.

Data Availability Statement

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

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Associated Data

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

Supplementary Materials

SI
NIHMS2090777-supplement-SI.pdf (6.2MB, pdf)

Data Availability Statement

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

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