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Article

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

by
Shyam Sathyamoorthi
1,* and
Steven P. Kelley
2
1
Department of Medicinal Chemistry, University of Kansas, Lawrence, KS 66047, USA
2
Department of Chemistry, University of Missouri—Columbia, Columbia, MO 65211, USA
*
Author to whom correspondence should be addressed.
Chemistry 2025, 7(3), 99; https://doi.org/10.3390/chemistry7030099
Submission received: 12 May 2025 / Revised: 7 June 2025 / Accepted: 11 June 2025 / Published: 16 June 2025
(This article belongs to the Special Issue Oxygen-Containing Heterocyclic Compounds: Recent Advances in Chemistry)
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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 range of functional groups is compatible, and the reaction diastereoselectivities vary from good to excellent. The reactions are scalable, and the resultant carbonates can be further transformed.

1. Introduction

As part of a programmatic focus on exploring the synthetic utility of unusual tethers for olefin functionalization reactions [1,2,3,4], 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 [5,6,7,8,9] would facilitate the formation of an N-centered radical or a nitrenium ion [10,11], unstable intermediates which would rapidly attack the pendant olefin. Trapping by a fluoride anion or fluoride radical would ultimately form an interesting amino-fluoride product (Scheme 1).
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 halo-functionalization with tethered O- or N-nucleophiles is useful for regioselectively and diastereoselectively constructing heterocycles of importance [12,13,14,15,16,17,18,19,20,21,22,23,24,25]. In this area, prior work with carbamate tethers has largely focused on iodination reactions [26,27,28,29,30,31,32,33,34,35,36,37], with comparatively fewer reports on analogous brominations [38,39,40,41,42,43,44,45,46]. There are no reports examining the use of N-alkoxycarbamate tethers for olefin halo-functionalizations; indeed, these unusual auxiliaries are underutilized for organic synthesis in general [11,47,48,49]. For these reasons, we felt that this serendipitous discovery was worth further exploration.

2. Materials and Methods

All reagents were obtained commercially unless otherwise noted. Solvents were purified by passage under 10 psi N2 through activated alumina columns. Infrared (IR) spectra were recorded on a Thermo Scientific™ (Waltham, MA, USA) Nicolet™ (Green Bay, WI, USA) iS™5 FT-IR Spectrometer; data are reported in frequency of absorption (cm−1). 1H NMR spectra were recorded at 400, 500, or 600 MHz. Data are recorded as: chemical shift in ppm referenced internally using residual solvent peaks, multiplicity (s = singlet, br s = broad singlet, d = doublet, t = triplet, q = quartet, m = multiplet or overlap of nonequivalent resonances, qdd = quartet of doublet of doublets, tdt = triplet of doublet of triplets, dtq = doublet of triplet of quartets, qd = quartet of doublets, tdq = triplet of doublet of quartets), coupling constant (Hz), integration. 13C NMR spectra were recorded at 101 or 126 MHz. Exact mass spectra were recorded using an electrospray ion source (ESI) either in positive mode or negative mode and with a time-of-flight (TOF) analyzer on a Waters LCT PremierTM (Charlotte, NC, USA) mass spectrometer and are given in m/z. Thin Layer Chromatography (TLC) was performed on pre-coated glass plates (Merck, Rahway, NJ, USA) and visualized either with a UV lamp (254 nm) or by dipping into a solution of KMnO4–K2CO3 in water followed by heating. Flash chromatography was performed on silica gel (230–400 mesh) or Florisil (60–100 mesh). “Room temperature” refers to an ambient temperature of 23–25 °C.

3. Results and Discussion

We hypothesized that the reaction was proceeding through the 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, the 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 two equivalents of H2O dramatically improved formation of 2 (Table 1, Entries 6 and 8). Two equivalents of H2O were sufficient for an improved reaction performance; with a large excess (~55 equiv.) of H2O, the product yield dropped by 12% (Table 1, Entry 7). Ultimately, the optimal yield of 2 came with the use of two equivalents of NBS and two equivalents of H2O in CH3CN (Table 1, Entry 9). We recommend using NBS recrystallized from H2O [50], 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.
Next, we aimed to delineate the effect of the N-alkoxy substituent of the carbamate tether on the 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 the competitive bromination of the carbamate tether triggered a variety of undesired reaction pathways.
We were pleased that a variety of alkenyl carbamates cyclized productively into carbonates when stirred in acetonitrile with two equivalents of NBS and two equivalents of water at ambient temperature (Table 2). 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 the assignment of the relative stereochemistry of the two newly formed stereocenters, and the relative stereochemistry of most of the other products was assigned by analogy. Stereoarrays could also be synthesized in good to excellent diastereoselectivities (Table 2, Entries 1, 4, and 10). Our optimized reaction protocol was tolerant of a diverse array of functional groups, including aryl halides (Table 2, Entry 2), an aryl pinacol boronate (Table 2, Entry 2), alkyl ethers (Table 2, Entries 5 and 9), and a Boc-protected amine (Table 2, Entry 7).
A collection of substrates that failed to react as expected is shown in Figure 1. With (E)-hex-2-en-1-yl methoxycarbamate (Compound 54), an approximately 1:1 mixture of products was observed with 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 five-membered and six-membered cyclic carbonate products. Substrates bearing electron-rich aromatic rings (Figure 1, 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.
The high diastereoselectivity and predictable stereochemical outcome with a variety of test substrates suggests the reaction mechanism depicted in Scheme 3. The reaction of the olefin substrate with NBS leads to the 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 reaction or the work-up.
Even with six-fold and twelve-fold increases in scale (Scheme 4A), products were formed in reasonable yields. With product 39, which contains a primary alkyl bromide moiety, substitution with sodium azide proceeded at room temperature (Scheme 4B). Unsurprisingly, with 2, an analogous transformation required mild heating. In both cases, an excess of sodium azide was required for starting material consumption.

4. Conclusions

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 range of functional groups is compatible, and the reaction diastereoselectivities vary from good to excellent. The reactions are scalable, and the resultant carbonates can be further transformed. We expect this work to be well-received by chemists engaged in the stereoselective construction of interesting heterocycles.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/chemistry7030099/s1, Additional experimental details include reaction procedures, tabulated characterization, NMR spectra, and X-ray crystallographic tables. References [52,53] are cited in the Supplementary Materials.

Author Contributions

Conceptualization: S.S., Investigation: S.S. and S.P.K., Data Analysis: S.S. and S.P.K., Writing and Editing: S.S. and S.P.K. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the National Institutes of Health grants R35GM142499, P20GM113117, and P20GM130448.

Data Availability Statement

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

Acknowledgments

Justin Douglas and Sarah Neuenswander (KU NMR Lab) are acknowledged for their help with structural elucidation. Lawrence Seib and Anita Saraf (KU Mass Spectrometry Facility) are acknowledged for their help acquiring HRMS data. We thank Frederick J. Seidl for the many helpful discussions regarding the bromination of olefins.

Conflicts of Interest

The authors declare no conflict of interest.

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Chemistry 07 00099 sch001
Scheme 1. An unexpected result with Selectfluor and CuBr2 sparks a new investigation.
Scheme 1. An unexpected result with Selectfluor and CuBr2 sparks a new investigation.
Chemistry 07 00099 sch001
Chemistry 07 00099 sch002
Scheme 2. Varying the carbamate tether.
Scheme 2. Varying the carbamate tether.
Chemistry 07 00099 sch002
Chemistry 07 00099 g001
Figure 1. Interesting and problematic substrates.
Figure 1. Interesting and problematic substrates.
Chemistry 07 00099 g001
Chemistry 07 00099 sch003
Scheme 3. Mechanistic Hypothesis.
Scheme 3. Mechanistic Hypothesis.
Chemistry 07 00099 sch003
Chemistry 07 00099 sch004
Scheme 4. (A) Scale up. (B) Applications.
Scheme 4. (A) Scale up. (B) Applications.
Chemistry 07 00099 sch004
Table 1. Optimization Experiments.
Table 1. Optimization Experiments.
Chemistry 07 00099 i001
Br+ Source aAdditive aSolvent bYield c
1DBI (1) dNoneCH3CN57%
2NBSacc (1.5) eNoneCH3CN53%
3DBH (1.5) fNoneCH3CN55%
4NBS (1.5) gNoneCH2Cl220%
5NBS (1.5)NoneCH3CN22%
6NBS (1.5)H2O (2)CH3CN72%
7NBS (1.5)H2O (55)CH3CN60%
8NBS h (1.5)H2O (2)CH3CN70%
9NBS h (2)H2O (2)CH3CN75%
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 the product is shown. d DBI = dibromoisocyanuric acid [15114-43-9]. e NBSacc = N-bromosaccharin [35812-01-2]. f DBH = 1,3-dibromo-5,5-dimethylhydantoin [77-48-5]. g NBS = N-bromosuccinimide [128-08-5]. h recrystallized from H2O.
Table 2. Substrate scope exploration.
Table 2. Substrate scope exploration.
SubstrateProduct Isolated Yield a
1Chemistry 07 00099 i002Chemistry 07 00099 i003 (#12, #13) b52% c
dr > 20:1
2Chemistry 07 00099 i004Chemistry 07 00099 i005Ar = Ph
                          pCF3OC6H4
                         mCF3C6H4
                    pFC6H4
                     pClC6H4
         [X-ray]pBrC6H4
                          pBpinC6H4
                1-nap		(#14, #15)
(#16, #17)
(#18, #19)
(#20, #21)
(#22, #23)
(#24, #25)
(#26, #27)
(#28, #29)		75%
81%
72%
74%
75%
74%
58%
62%
3Chemistry 07 00099 i006Chemistry 07 00099 i007 (#30, #31)51%
4Chemistry 07 00099 i008Chemistry 07 00099 i009 (#32, #33)83%
dr = 3:1
5Chemistry 07 00099 i010Chemistry 07 00099 i011      R = C2H4OBn
    i-Pr
H		(#34, #35)
(#36, #37)
(#38, #39)		57%
69%
53%
6Chemistry 07 00099 i012Chemistry 07 00099 i013 (#40, #41)46%
7Chemistry 07 00099 i014Chemistry 07 00099 i015X = NBoc
     CH2		(#42, #43)
(#44, #45)		62%
65%
8Chemistry 07 00099 i016Chemistry 07 00099 i017 (#46, #47)70%
9Chemistry 07 00099 i018Chemistry 07 00099 i019 (#48, #49)57%
10Chemistry 07 00099 i020Chemistry 07 00099 i021 (#50, #51)55% c
dr > 20:1
11Chemistry 07 00099 i022Chemistry 07 00099 i023 (#52, #53)70%
a Reaction conditions: NBS (2 equiv.), H2O = (2 equiv.), CH3CN, RT; b (Substrate number, Product number); c Relative stereochemistry assigned by nOe analysis. Note: dr = diastereoselectivity.
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Sathyamoorthi, S.; Kelley, S.P. Transformation of Linear Alkenyl N-Alkoxy Carbamates into Cyclic Bromo Carbonates. Chemistry 2025, 7, 99. https://doi.org/10.3390/chemistry7030099

AMA Style

Sathyamoorthi S, Kelley SP. Transformation of Linear Alkenyl N-Alkoxy Carbamates into Cyclic Bromo Carbonates. Chemistry. 2025; 7(3):99. https://doi.org/10.3390/chemistry7030099

Chicago/Turabian Style

Sathyamoorthi, Shyam, and Steven P. Kelley. 2025. "Transformation of Linear Alkenyl N-Alkoxy Carbamates into Cyclic Bromo Carbonates" Chemistry 7, no. 3: 99. https://doi.org/10.3390/chemistry7030099

APA Style

Sathyamoorthi, S., & Kelley, S. P. (2025). Transformation of Linear Alkenyl N-Alkoxy Carbamates into Cyclic Bromo Carbonates. Chemistry, 7(3), 99. https://doi.org/10.3390/chemistry7030099

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