Modular Synthesis of Alkenyl Sulfamates and β-Ketosulfonamides via Sulfur(VI) Fluoride Exchange (SuFEx) Click Chemistry and Photomediated 1,3-Rearrangement

Photomediated 1,3-Rearrangement

Letter

Modular Synthesis of Alkenyl Sulfamates and β‑Ketosulfonamides

via Sulfur(VI) Fluoride Exchange (SuFEx) Click Chemistry and

†

Felipe Cesar Sousa e Silva, Katarzyna Doktor, and Quentin Michaudel*

Cite This: Org. Lett. 2021, 23, 5271 −5276

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sı Supporting Information

ABSTRACT: Herein, we report a synthesis of medicinally relevant β-

ketosulfonamides via a photomediated 1,3-rearrangement of alkenyl sulfamates.

This protocol tolerates a wide array of sensitive functional groups including

alkenes, alkynes, and nitrogen-based heterocycles. Additionally, this work

provides a general approach toward alkenyl sulfamates via a two-step

Sulfur(VI) Fluoride Exchange (SuFEx) sequence capitalizing on SO F as a

linchpin to eﬃciently couple readily available ketones and amines without a

large excess of either partner.

ulfur(VI)-containing functional groups such as sulfona-

mides, sulfamides, and sulfamates are becoming increas-

ingly prevalent in pharmacophores. Sulfonamides alone were

present in 25% of all sulfur-containing drugs approved by the

US FDA through 2016 and, as a result, are one of the most

widespread functional groups in active pharmaceutical

ingredients. Sulfonamides are also ubiquitous in agro-

chemicals. While the introduction of aryl sulfonamides can

be eﬃciently achieved via the intermediacy of aryl sulfonyl

chlorides prepared by electrophilic aromatic substitution,

Suzuki−Miyaura cross-coupling, or C−H thianthrenation,

their alkyl counterparts are typically more challenging to

access. Among these, β-ketosulfonamides are particularly

valuable as precursors for a variety of bioactive molecules.

Interestingly, alkenyl sulfamates, which are constitutional

isomers of β-ketosulfonamides, are a virtually unexplored

class of compounds; the properties and potential bioactivity of

these molecules, which are structurally related to common

alkenyl (vinyl) triﬂates, remain unknown. Herein, we report

the eﬃcient and modular synthesis of β-ketosulfonamides

through a photomediated 1,3-rearrangement of alkenyl

sulfamates readily obtained via Sulfur(VI) Fluoride Exchange

Figure 1. (a) Prior syntheses of β-ketosulfonamides. (b) Synthesis of

β-ketosulfonamides from alkenyl sulfamates through photomediated

(

SuFEx) click chemistry.

Typical syntheses of β-ketosulfonamides rely on a polar

1,3-rearrangement.

disconnection between a silyl enol ether, or an enamine,

and a sulfamoyl chloride reagent (Figure 1a). This approach

requires the multistep preparation of highly reactive sulfamoyl

chloride reagents that are generally sensitive to moisture and

Received: June 8, 2021

Published: June 20, 2021

challenging to purify. Additionally, only monoalkylated₈

sulfamoyl chloride derivatives were shown to be compatible

and the propensity of the S−Cl bond to undergo homolytic

,5b

cleavage might lead to side reactions. The reverse strategy,

which relies on the Claisen condensation of deprotonated

2021 American Chemical Society

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Org. Lett. 2021, 23, 5271−5276

Organic Letters

isolation of alkenyl sulfamates.

Letter

sulfonamide and an ester, remains rare. In 2019, Wang and

co-workers reported the transformation of silyl enol ethers into

β-ketosulfonamides via a radical process catalyzed by a Ru

(1) was selected as a test substrate to develop the desired

synthetic sequence. Following deprotonation of 1 with lithium

diisopropylamide (LDA) in THF at −78 °C and trapping of

the resulting enolate with SO F , alkenyl ﬂuorosulfonate 2 was

photocatalyst (Figure 1a). Despite being an elegant

departure from the traditional polar disconnection, this

approach still suﬀers from the use of sulfamoyl chloride

derivatives and requires a large excess of the silyl enol ether (5

equiv), thereby hampering large-scale applications with

advanced coupling partners. Following our investigation of

isolated in 84% yield. However, these conditions led to lower

yields with more sensitive substrates (Table S2 ), which

prompted us to screen alternative bases. Potassium tert-

butoxide was found to aﬀord 2 in 90% yield (Figure 2), which

compares favorably to the 75% yield reported by Sharpless and

the synthesis of sulfamides via SuFEx, we hypothesized that

co-workers using LiHMDS. These optimized conditions

sulfuryl ﬂuoride (SO F ) could serve as a linchpin to access a

broad array of β-ketosulfonamides from simple ketones and

amines. Engaging an alkenyl ﬂuorosulfonate (obtained from

allowed the eﬃcient preparation of a broad array of alkenyl

ﬂuorosulfonates while circumventing the use of corrosive

14a

reagents, such as ﬂuorosulfonic acid. The next challenge was

the preparation of alkenyl sulfamates through the second step

of the SuFEx coupling. These compounds are exceedingly rare

in the literature and only a few alkenyl sulfamates have been

the reaction of an enolate with SO F ) with a variety of amines

should allow the rapid formation of alkenyl sulfamates.

Subsequent 1,3-rearrangement should deliver the desired β-

ketosulfonamides (Figure 1b). This sequence merges polar and

radical approaches and would provide a modular and eﬃcient

route to these desirable intermediates while presenting the

opportunity to explore uncharted chemical space through the

previously isolated. Ball, am Ende, and co-workers recently

demonstrated that Lewis acidic calcium triﬂimide (Ca(NTf ) )

selectively activates a variety of sulfonyl ﬂuoride derivatives

17,18

toward clean ﬂuoride exchange with nucleophilic amines.

Ca(NTf₂)₂presumably coordinates to both Lewis basic

oxygens of the sulfonyl group, thereby allowing for eﬃcient

SuFEx reaction. These conditions delivered alkenyl sulfamate 3

in 98% yield (Figure 2). With optimized SuFEx conditions in

hand, diverse ketones and amines were coupled to form a

variety of alkenyl sulfamates (Figure 3). High-to-excellent

yields over two steps were obtained with a range of aliphatic

and aromatic amines, including primary (4, 6, and 9) and

secondary amines (3, 5, 7, and 8). The mild conditions of the

second step allowed the incorporation of 5-methylhex-4-en-1-

amine, allylamine, and propargyl amine to sulfamates 10−12.

Halogenated benzyl amines were successfully coupled to form

13 and 14 in 69% and 56% yield, respectively. Finally, L-proline

derivative S5 proved a competent amine in this reaction, which

proceeded with minimal racemization (<3%). The scope of the

ketone partner was subsequently explored. α -Tetralone and

Figure 2. Design of a synthesis of alkenyl sulfamates via SuFEx

chemistry.

Aryl ﬂuorosulfonates are known alternatives to aryl triﬂates

in Pd-catalyzed cross-coupling reactions, but only a handful

of alkenyl ﬂuorosulfonates have been reported thus far,

thereby precluding exploration of their reactivity. α -Tetralone

Figure 3. Scope of Alkenyl Sulfamates. The sequence was performed with 0.15 mmol of ketone substrate. All yields are isolated. Deviations from

general conditions: MeCN (step 2); LDA (step 1); Et O (step 1); DCM at 0 °C (step 1).

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Org. Lett. 2021, 23, 5271−5276

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ketones was subsequently conducted. High yields were

Letter

Table 1. Optimization of the Photomediated 1,3-

Rearrangement

(Table S3). Delightfully, irradiation with visible light led to the

formation of β-ketosulfonamide 29 (Figure 4 ). Optimization of

the photochemical 1,3-rearrangement (Table S4) allowed the

isolation of 29 in 99% yield using blue LEDs (456 nm) and a

:1 mixture of DMSO/H O (Figure 4). Unfortunately, N-

dialkylated alkenyl sulfamates such as 3 did not undergo the

1,3-rearrangement under these conditions (Table 1, entry 1).

We hypothesized that using a photosensitizer might encourage

the photochemical activation of recalcitrant substrates. While

the addition of eosin B to the otherwise identical reaction

conditions did not provide any desired product (Table 1, entry

2), adding 9-ﬂuorenone led to the formation of 28 in 50% yield

entry

deviation from the initial conditions

yield

None

N.R.

50%

70%

95%

Addition of eosin B (1 mol %)

9-Fluorenone (1 mol %) instead of eosin B

Ir(ppy) (1 mol %) instead of 9-ﬂuorenone

Ir(ppy) (1 mol %) and reaction time = 48 h

(Table 1, entry 3). Ir(ppy) , another commonly used

photosensitizer, aﬀorded the desired product in 70% yield

(Table 1, entry 4). Increasing the reaction time to 48 h

resulted in an improvement of the yield to 95% (Table 1, entry

Ir(ppy) (1 mol %), no degassing, and reaction time = 6 h 97%

No Ir(ppy) , no degassing

28%

N.R.

same as entry 6 but in the dark

5). Surprisingly, when no eﬀort was made to remove O via

Reactions were performed with 0.036 mmol of 3. N.R. = No

reaction. Yields were calculated by NMR using 1,4-dimethoxyben-

“freeze-pump-thaw” degassing, the reaction reached comple-

tion in only 6 h with 97% yield (Table 1, entry 6). In the

zene as internal standard.

presence of air but without photocatalyst, a 28% yield was

observed (Table 1, entry 7), which supports the nonspectator

role played by O in the reaction process. Full recovery of 3

was observed when the reaction was carried out in the absence

of light (Table 1, entry 8).

acetophenone derivatives adorned with electron-rich and

electron-poor substituents were coupled in moderate yields

(

16−20). A variety of heterocycle-containing sulfamates were

synthesized including drug-like pyridine (21−24) and pyrazine

5 congeners. Impressively, aliphatic ketones such as tert-

The scope of this intriguing photochemical 1,3-rearrange-

ment was explored using the optimized conditions and a

variety of alkenyl sulfamates (Figure 4). All alkenyl sulfamates

derived from tetralone (29 to 41) underwent rearrangement in

good to quantitative yields. Importantly, alkene (35 and 36)

and alkyne (37) functional groups were tolerated in this

photochemical reaction. Alkenyl sulfamate 15 synthesized from

L-proline aﬀorded 40 as a 1:2 mixture of diastereomers after

rearrangement. Similarly, moderate diastereoselectivity was

observed in the synthesis of 31 (1:1.4 dr). Investigation of the

reactivity of alkenyl sulfamates prepared from a variety of

butylcyclohexanone and the natural product (S)-carvone were

successfully transformed into sulfamates 26 and 27.

Alkenyl sulfamates were puriﬁed through standard column

chromatography. No decomposition was observed under

ambient conditions for several months, and sulfamate 3 did

not hydrolyze in acidic or basic aqueous media at room

temperature. Investigation of the ﬁnal step en route to β-

ketosulfonamides was initiated with N-benzyl alkenyl sulfamate

. Attempts to trigger the 1,3-rearrangement thermally or in

the presence of Brønsted or Lewis acids led to poor yields

Figure 4. Scope of β-ketosulfonamides. The reaction was performed with 0.15 mmol of substrate. All yields are isolated. No photocatalyst was

used. (Ir[dF(CF )ppy] (dtbpy))PF instead of Ir(ppy) .

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Org. Lett. 2021, 23, 5271−5276

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material as determined by NOESY experiments (Figure 5 a).

Letter

obtained for acetophenone derivatives including ﬂuorinated

compounds 43 and 44 and dimethyl analog 45. Pyridine-

containing sulfamates (46−49) and pyrazine 50 were all

isolated in great yields as well, which bodes well for

applications in drug discovery. Interestingly, aliphatic sulfa-

mates 26 and 27 were impervious to the 1,3-rearrangement.

The high stability of these compounds suggests that aliphatic

alkenyl sulfamates may prove to be a useful motif in medicinal

chemistry. Additionally, this sequence can be coupled to the

venerable CuAAC click reaction to rapidly build structural

presence of a radical initiator. However, attempts to induce

the 1,3-rearrangement of 7 with AIBN only led to low yields

(see SI ). While the exact role of O remains puzzling, reactive

oxygen species have been shown to serve as radical initiators in

other photochemical transformations. A postulated chain

mechanism consistent with experimental data and literature

precedent is summarized in Figure 5b. Homolytic fragmenta-

tion of alkenyl sulfamate I in the reaction conditions likely

leads to the formation of a small amount of α-ketonyl radical II

and sulfamoyl radical III. Addition of III into the double bond

of IV is subsequently proposed to take place, followed by

regeneration of sulfamoyl radical III and concomitant

formation of β-ketosulfonamide V.

complexity from readily available building blocks. For

example, S13 was synthesized in 94% yield from 37 under

typical CuAAC conditions (see SI ).

A few experiments were devised to investigate the 1,3-

rearrangement. A crossover experiment with sulfamates 3 and

In summary, we have developed a modular and eﬃcient

synthesis of β-ketosulfonamides through a photomediated 1,3-

rearrangement of alkenyl sulfamates accessed via SuFEx click

chemistry. The SuFEx process allows the preparation of a

broad array of alkenyl sulfamates in good-to-excellent yields by

coupling various amines and ketones. Both SuFEx steps and

the subsequent 1,3-rearrangement were shown to tolerate a

range of functional groups, including alkenes and alkynes, and

are therefore promising for the design of medicinally relevant

molecules with sulfur(VI) linkages. The mild conditions and

nonexcess amounts of coupling partners are clear advantages

over prior methods. Initial experiments suggest that the

photochemical rearrangement follows a radical chain mecha-

nism triggered by initial generation of a sulfamoyl radical

through homolytic cleavage. The presence of oxygen was

found to be beneﬁcial to the rearrangement, which should

facilitate the large-scale implementation of this reaction.

2 led to the formation of four products (Figure S6), which

supports a nonconcerted transfer of the sulfamoyl group.

Addition of TEMPO to the reaction mixture inhibited the

rearrangement (see SI ), which suggests a radical pathway as

postulated for the 1,3-rearrangement of alkenyl tosylates,

rather than an anionic process. Since the reaction takes place

without photocatalyst, Ir(ppy)₃is believed to act as a

photosensitizer that facilitates the homolytic cleavage of the

S−O bond via energy transfer, which is in line with the report

of Li and co-workers on the photochemical rearrangement of

alkenyl tosylates. However, further studies are necessary to

rule out a mechanism that relies on single electron transfer.

Finally, a radical clock experiment was performed using

23b

cyclopropyl derivative 53. Irradiation of 53 in the presence

of (Ir[dF(CF )ppy] (dtbpy))PF led to the formation of

rearranged product 54, as well as partially isomerized starting

ASSOCIATED CONTENT

sı Supporting Information

■

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.orglett.1c01907.

Detailed experimental procedures and spectroscopic

characterization (PDF )

Accession Codes

CCDC 2083388−2083389 contain the supplementary crys-

tallographic data for this paper. These data can be obtained

free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by

emailing data_request@ccdc.cam.ac.uk, or by contacting The

Cambridge Crystallographic Data Centre, 12 Union Road,

Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

AUTHOR INFORMATION

■

Corresponding Author

Quentin Michaudel − Department of Chemistry, Texas A&M

University, College Station, Texas 77843, United States;

orcid.org/0000-0002-1791-9174 ;

Email: quentin.michaudel@chem.tamu.edu

Figure 5. (a) Radical clock-experiment. (b) Postulated mechanism.

Authors

Felipe Cesar Sousa e Silva − Department of Chemistry, Texas

A&M University, College Station, Texas 77843, United

States

Katarzyna Doktor − Department of Chemistry, Texas A&M

University, College Station, Texas 77843, United States

The cyclopropyl ring was left intact during the rearrangement,

which suggests that a chain propagation reaction involving

attack of a sulfur-centered radical into the double bond is more

likely than a radical−radical recombination. A similar chain

mechanism has been put forward for the rearrangement of

stilbenyl tosylate derivatives at high temperatures in the

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.orglett.1c01907

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Org. Lett. 2021, 23, 5271−5276

Organic Letters

Reactions with N -Carbonylsulfamoyl Chloride. Angew. Chem., Int. Ed.

Letter

Author Contributions

†_F_._C_._S_._S_._a_n_d_K_._D_._c_o_n_t_r_i_b_u_t_e_d_e_q_u_a_l_l_y_t_o_t_h_i_s_s_t_u_d_y_.

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sulfamoyl chlorides. J. Org. Chem. 1976 , 41 , 4028−4029. (b) Graf, R.

Engl. 1968 , 7 , 172 −182. (c) Wei β , G.; Schulze, G. Herstellung und

Reaktionen von N -Monoalkyl-amidosulfonylchloriden. Liebigs Ann.

Notes

The authors declare no competing ﬁnancial interest.

969, 729, 40−51. (d) Guo, C.; Dong, L.; Hou, X.; Vanderpool, D.

L.; Villafranca, J. E. International Patent WO 2001040185 A1, June 7,

2001.

ACKNOWLEDGMENTS

■

This work was supported by Texas A&M University, and used

the NMR and X-ray facilities in the Department of Chemistry.

The authors acknowledge the Welch Foundation (A-2004-

(11) (a) Vannada, J.; Bennett, E. M.; Wilson, D. J.; Boshoff, H. I.;

Barry, C. E.; Aldrich, C. C. Design, Synthesis, and Biological

Evaluation of β -Ketosulfonamide Adenylation Inhibitors as Potential

Antitubercular Agents. Org. Lett. 2006, 8, 4707−4710. (b) Soley, J.;

Chiu, E.; Chung, R.; Green, J.; Hein, J. E.; Taylor, S. D. Synthesis of

β -Ketosulfonamides Derived from Amino Acids and Their Con-

version to β -Keto-α ,α -difluorosulfonamides via Electrophilic Fluori-

nation. J. Org. Chem. 2017, 82, 11157−11165.

0190330) for ﬁnancial support. This work was also supported

by the National Institute of General Medical Sciences at the

National Institutes of Health under Award Number

R35GM138079. The authors acknowledge Dr. Michael

Crockett (Texas A&M University) for technical assistance.

(12) Kulow, R. W.; Wu, J. W.; Kim, C.; Michaudel, Q. Synthesis of

unsymmetrical sulfamides and polysulfamides via SuFEx click

chemistry. Chem. Sci. 2020, 11, 7807 −7812.

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