One-Pot Deoxygenation and Substitution of Alcohols Mediated by Sulfuryl Fluoride

Maxim Epifanov, Jia Yi Mo, Rudy Dubois, Hao Yu, and Glenn M. Sammis*

Article

One-Pot Deoxygenation and Substitution of Alcohols Mediated by

Sulfuryl Fluoride

†

Cite This: J. Org. Chem. 2021, 86, 3768 −3777

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sı Supporting Information

ABSTRACT: Sulfuryl ﬂuoride is a valuable reagent for the one-pot

activation and derivatization of aliphatic alcohols, but the highly reactive

alkyl ﬂuorosulfate intermediates limit both the types of reactions that can

be accessed as well as the scope. Herein, we report the SO F -mediated

alcohol substitution and deoxygenation method that relies on the

conversion of ﬂuorosulfates to alkyl halide intermediates. This strategy

allows the expansion of SO F -mediated one-pot processes to include radical reactions, where the alkyl halides can also be exploited

in the one-pot deoxygenation of primary alcohols under mild conditions (52−95% yield). This strategy can also enhance the scope

of substitutions to nucleophiles that are previously incompatible with one-pot SO F -mediated alcohol activation and enables

substitution of primary and secondary alcohols in 54−95% yield. Chiral secondary alcohols undergo a highly stereospeciﬁc (90−98%

ee) double nucleophilic displacement with an overall retention of conﬁguration.

INTRODUCTION

Scheme 1. Strategies for SO

Nucleophilic Substitution

F -Mediated Alcohol Activation

2 2

■

One-pot synthesis, in which multiple chemical reactions are

carried out in a single reaction vessel, is a powerful strategy as

it leads to higher eﬃciency, minimization of reactor time, and a

decrease in the amount of chemical waste. From Robinson’s

one-pot synthesis of tropinone to recent advances in multistep

catalysis, there has been a long history of the development of

one-pot processes in synthetic organic chemistry. Despite the

depth of research in this area, many simple transformations are

still challenging to perform in a single step. This is exempliﬁed

in one-pot transformations involving aliphatic alcohols.

Alcohol derivatizations, which make up a major proportion

of U.S. pharmaceutical synthetic patents over the past 40

years, are consistently identiﬁed by the industry as one of the

top ﬁve transformations that require better one-pot processes.

While signiﬁcant progress has been made in this area through

the development of novel reagents and catalysts, new versatile

one-pot processes are still essential to meet the breadth of

substrate scope needed for the chemical industry.

Sulfuryl ﬂuoride (SO F ) is a promising candidate for

We hypothesized that we may be able to develop a more

general SO F -mediated one-pot alcohol activation strategy by

ﬁrst converting alkyl ﬂuorosulfate 2 to a reactive intermediate,

which would be more stable than ﬂuorosulfate yet still

suﬃciently reactive to undergo a variety of subsequent

promoting one-pot processes with alcohols as the reaction

byproducts are relatively unreactive and are easy to remove.

Strategically, every one-pot method involving SO F has relied

upon alkyl ﬂuorosulfate intermediate 2 as the key reactive

intermediate (Scheme 1). This has limited the reactions that

can be accessed to substitutions and substitutions combined

Received: October 27, 2020

Published: February 11, 2021

with subsequent oxidations and/or eliminations. Even for

the successful one-pot methods, the high reactivity of

ﬂuorosulfate 2 places signiﬁcant limitations on the scope

with respect to both the alcohol and the nucleophile. A new

approach is needed to increase both the synthetic utility and

generality of these SO F -mediated processes.

2021 American Chemical Society

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J. Org. Chem. 2021, 86, 3768−3777

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Article

transformations (Scheme 1). Alkyl halide 6 was identiﬁed as a

potential candidate as it enables a subsequent radical or ionic

transformation. Alkyl halides are commonly utilized as

intermediates in one-pot transformations, but there were

no examples of using them as the intermediates in one-pot

sulfuryl ﬂuoride-mediated processes.

Scheme 3. Alcohol Scope for the SO F -Mediated Alkyl

2 2

Halide Formation

RESULTS AND DISCUSSION

■

To examine the synthetic utility of sulfuryl ﬂuoride-mediate

one-pot processes beyond nucleophilic substitutions and

oxidations, we began our studies by investigating one-pot

halodeoxygenation followed by dehalogenation, which achieves

a net deoxygenation reaction. Primary alcohols were selected

as they can be challenging to reduce using conventional

Barton−McCombie reactions. Recent one-pot approaches to

primary alcohol deoxygenation include Lewis acid-catalyzed

Reaction conditions: SO F (4.3 equiv; generated according to the

2 2

silane reduction, dehydrogenation followed by Wolﬀ−

procedure described in ref 18) was bubbled through a solution of 1

0.6 mmol), DIPEA or Et N (2.0 equiv), and TBAI (2.0 equiv) in

Kishner reduction, and photoredox catalysis. We began

our investigations into a one-pot deoxygenation reaction by

(

acetonitrile or DMF for ∼5 min; then, the reaction mixture was

allowed to stir at room temperature for an additional 7 min. All

reactions were run on 0.6 mmol scale. Isolated yields are reported.

ﬁrst focusing on the halodeoxygenation step. A brief

exploration found that alkyl chlorides, bromides, and iodides

could be formed cleanly using the respective tetrabutylammo-

18,23

nium halide salt in only 12 min (Scheme 2).

Notably,

Treatment of 3-phenyl-1-propanol with SO F , N,N-

diisopropylethyl-amine (DIPEA), and TBAI for 10 min,

followed by triethylborane and tris(trimethylsilyl)silane

Scheme 2. SO F -Mediated Conversion of Benzylic Alcohols

to Alkyl Halides

(

TTMSS), readily produced dehalogenation product 7i in

0% isolated yield (Scheme 4). Trimethylphenyl substrate 7j

was isolated in a comparable yield. The deoxygenation

Scheme 4. Primary Alcohol Scope for One-Pot Alcohol

deoxygenation

Reaction conditions: SO F (4.3 equiv; generated according to the

procedure described in ref 18) was bubbled through a solution of 1a

(

0.6 mmol), DIPEA (2.0 equiv), and TBAX (2.0 equiv) in DMF for 5

min; then, the reaction mixture was allowed to stir at room

temperature for an additional 7 min. All reactions were run on 0.6

mmol scale. Isolated yields are reported with F NMR yields in

parentheses. Isolated yields were lower than F NMR yields due to

the volatility of these compounds.

when tetrabutylammonium iodide (TBAI) was used as the

halide source, the reaction mixture gradually changed color.

We suspected that this color change could have been caused by

an undesired redox reaction between iodide and SO F .

Control experiments demonstrated that iodine had indeed

been formed but only in minor quantities (<5% of iodide

oxidized in 15 min) suggesting that this redox process is

considerably slower than alkyl iodide formation.

This halogenation protocol was then applied to representa-

tive primary alcohols (Scheme 3). Triﬂuoromethyl benzyl

alcohol was an eﬀective substrate, aﬀording the desired iodide

Reaction conditions: SO F (3.0 equiv; generated according to the

procedure described in ref 18) was bubbled through a solution of

alcohol (1.0 mmol), DIPEA (2.0 equiv), and TBAI (1.1 equiv) in

DMF for 5 min; then, the reaction mixture was allowed to stir at room

(d) in 78% yield. A slight decrease in yield was observed for

electron-rich para-methoxy benzyl alcohol (6e). Phenethyl

iodides 6f and 6g were successfully synthesized in good to

excellent yields, with 10% elimination observed along with 6f

and no elimination observed with 6g. Activated α-keto alcohol

temperature for an additional 7 min. Subsequently, BEt (1 M in

THF, 0.2 equiv) and TTMSS (1.2 equiv) were added, and the

mixture was allowed to stir at room temperature for 30 min to 2 h. All

reactions were run on 1.0 mmol scale. All yields refer to isolated

(

1h) was also an eﬀective substrate, giving 6h in 68% yield.

Using the optimized halogenation procedure, we examined

yields. A second addition of SO₂F₂was carried out; see the

the one-pot deoxygenation of 3-phenyl-1-propanol.

Experimental Section for details.

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protocol also aﬀorded a O-benzyl phenol derivative (7k) and

Scheme 5. Nucleophile Scope for SO F -Mediated Primary

2 2

,5-dimethyl benzoate (7l) in nearly quantitative yields. This

Alcohol Substitution

method was tolerant of nitrogroups and thiophenes (7m),

phthalimides (7n), and Cbz-protected amines (7o). A more

complex substrate, cortexolone, successfully underwent deox-

ygenation to give 7p in 58% yield.

With a new reaction class for one-pot SO F -mediated

transformations established, we then explored if this halide-

intermediate strategy is eﬀective in one-pot substitution

reactions. Substitution reactions make up the majority of

alcohol functionalization reactions in the industry. Classic

methods for one-pot substitution typically use phosphorus-

based reagents whose byproducts are often challenging to

remove. While there are many variants that address some of

the fundamental challenges, none have the scope required by

the industry. Recent attention has focused on reagents that do

not contain phosphorus, such as sulfuryl ﬂuoride, but the scope

of these methods is limited by the high reactivity of the alkyl

ﬂuorosulfate intermediate. Eﬃcient reactivity can be achieved

when the alkyl ﬂuorosulfate intermediate is stabilized, but this

approach limits the alcohol scope to deactivated 1,1-

dihydroﬂuoroalcohols. Primary aliphatic alcohols could be

used in select cases but the nucleophile scope was limited to

reagents that do not readily react with SO F . Of the

successful nucleophiles, only aryl thiols could be used to

displace secondary aliphatic alcohols.

We began our investigations into applying our new sulfuryl

ﬂuoride-mediated strategy in substitution reactions with the

one-pot displacement of 3-phenyl-1-propanol. Using the same

halide formation protocol, followed by adding 2 equiv of

Reaction conditions: alkyl iodide was prepared as described in

Scheme 2 using 2.0 equiv of TBAI (see the Experimental Section);

then, the reaction mixture was degassed with N for 1 min, charged

−

with nucleophile (2.0 equiv; either prepared by reacting the

corresponding nucleophile with NaH or purchased from commercial

sources), and allowed to stir at 80 °C for 1 h. All reactions were run

on 0.6 mmol scale. All yields refer to isolated yields. R = PhCH CH .

sodium di-tert-butyliminodicarboxylate (Na (Boc) N ), af-

forded 8a in 74% isolated yield (Scheme 5). This is a slightly

better yield than what was achieved using 4 equiv of

nucleophiles in our previously developed conditions. Using

The reaction was carried out at room temperature. Decarboxylation

this new protocol with nucleophiles that were competent in

our previous method aﬀorded 8b, 8c, and 8d in 80, 89, and

was a competing pathway at 80 °C; to minimize this, the reaction was

carried out at room temperature.

3% isolated yields, respectively. We next explored nucleo-

philes that were unsuccessful in our previous methodology.

Nitrogen nucleophiles, such as benzimidazole and azide,

provided 8e and 8f in 80 and 84% yields, respectively. The

success of 8f is noteworthy as this protocol prevents the

interaction of SO₂F₂and azide, which can lead to the

Table 1. Reaction Condition Optimization for the SO F -

Mediated Alcohol Conversion to the Corresponding Alkyl

Halide

formation of ﬂuorosulfuryl azide. The scope with respect to

sulfur nucleophiles can be expanded to thiocyanate and

thioacetate to aﬀord 8g and 8h in good yields. Diethyl

malonate and N-hydroxyphthalimide were also eﬀective

nucleophiles, aﬀording 8i and 8j in 54 and 75% yields,

respectively.

halide

source

conv to 6q or

6r (%)

conv to

entry

base

solvent

byproducts (%)

DIPEA

DBU

NEt₃

TBAI

TBAB

DMF

MeCN

A signiﬁcant limitation of previous SO F -mediated

substitution reaction was that only aryl thiols could be used

to displace enantiopure secondary aliphatic alcohols without

deterioration of the enantiomeric excess (ee). Investigations

began with examining the deoxyhalogenation step with

secondary alcohol 1q (Table 1). Under the previously

developed conditions, alkyl halide 6q was formed in 65%

conversion (entry 1), along with 24% conversion to undesired

All reactions were run on 0.6 mmol scale. The ratio of products was

determined by H NMR analysis of the crude reaction mixture after 1

h. See Supporting Information for details about the observed

byproducts.

byproducts. Switching the solvent to acetonitrile led to a

modest improvement in conversion (entry 2), and only 10% of

the starting material was lost to byproduct formation. DBU

was an ineﬀective base for this transformation as only 11% of

TBAB (entry 5), with the latter leading to less byproduct

formation.

With the optimized conditions in hand, we explored the

nucleophile scope for secondary alcohols. Unfortunately, chiral

benzylic alcohols were not successful as poor enantioselectiv-

q was formed along with 33% of products resulting from

elimination (entry 3). The conversion could be increased if

triethylamine was used as a base with either TBAI (entry 4) or

ities were observed using thioacetate. Chiral aliphatic

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alcohols, such as (S)-2-octanol, could be converted to the

corresponding aryl thiol 9a in 63% yield with a net retention of

conﬁguration (Scheme 6). Unlike in our previous report,

ethylene/silicon septa were purchased from Chemglass Life Sciences

LLC. BD Intramedic polyethylene tubing (I.D. 1.57 mm, O.D. 2.08

mm) was used for the reactions. Infrared (IR) spectra were obtained

using a Thermo Nicolet 4700 FT-IR spectrometer or a PerkinElmer

−1

Frontier FT-IR. The spectra are reported in cm . High-resolution

electrospray ionization mass (HRMS-ESI) spectra were recorded on a

Waters, Micromass LCT or Agilent 6550 iFunnel Q-TOF

spectrometer. High-resolution electron ionization (HRMS-EI) spectra

were recorded on a JEOL AccuTOF-GC spectrometer. The

enantiomeric ratio was determined by HPLC analysis using a chiral

column on an Agilent 1290 inﬁnity LC system. Chiral HPLC:

Chiralcel OJ-RH, 4.6 × 150 mm, multi UV−vis detector (210 or 230

nm), at 30 °C, eluent: (acetonitrile/1% formic acid in water), ﬂow

rate: 0.5 mL/min at 57−58 bar. Optical rotations were measured on a

Jasco P-2000 polarimeter. The reported value was the average of ﬁve

Scheme 6. Secondary Alcohol Scope for the One-Pot

Halogenation Substitution

runs. Proton, carbon, and ﬂuorine nuclear magnetic resonance ( H,

C, and F NMR) spectra were obtained using a Bruker AV-300 or

AV-400 spectrometer. Chemical shifts (δ) are reported in parts per

million (ppm) and are referenced to the centerline of CDCl (7.26

ppm H NMR; 77.16 ppm C NMR). F NMR chemical shifts were

referenced to CFCl . Coupling constants (J) are reported in Hz to the

nearest 0.1 Hz. Peak multiplicity is indicated as follows: s (singlet), d

(

doublet), t (triplet), q (quartet), p (pentet), br s (broad singlet), m

multiplet), dd (doublet of doublets), tq (triplet of quartets), and qt

quartet of triplets). Assignment of peaks was done based on the

chemical shifts, multiplicities, and integrals of the peaks. NMR yields

were determined by F NMR using a relaxation delay (or recycle

Reaction conditions: SO F (4.3 equiv; generated according to the

delay) of 40 s to ensure complete relaxation of all ﬂuorine nuclei.

procedure described in ref 18) was bubbled through a solution of 1

0.6 mmol), Et N (2.0 equiv), and TBAB (tetrabutylammonium

bromide, 2.0 equiv) in acetonitrile for 3−5 min; then, the reaction

mixture was allowed to stir at room temperature for 1 h. The mixture

α,α,α-Triﬂuorotoluene (PhCF , δ −63.72 ppm) was used as an

(

internal standard, unless otherwise speciﬁed.

CAUTION: Sulfuryl ﬂuoride is a toxic gas and must always be

handled with care in a well-ventilated fumehood. Excess sulfuryl

ﬂuoride can be quenched by passing it through a basic aqueous

medium.

was degassed with N for 1 min, charged with nucleophile (2.0 equiv),

and allowed to stir at room temperature for 16 h. All reactions were

run on 0.6 mmol scale. All yields refer to isolated yields. The

General Procedure (A) for the SO F -Mediated Reaction of

substitution step was carried out at 40 °C.

Alcohols with Tetrabutylammonium Halides. Two 20 mL vials

equipped with magnetic stir-bars were capped with septum-ﬁtted vial

caps and then connected by a polyethylene tube. Vial A was charged

with SDI (2.6 mmol, 4.3 equiv) and anhydrous KF (7.0 mmol, 11.7

equiv). To vial B were added alcohol (0.6 mmol, 1.0 equiv) and TBAI

thioacetate was also an eﬀective nucleophile, aﬀording 9b in

6% yield and 96% ee. Sodium azide could also be utilized for

the formation of achiral product 9c in 71% yield, as well as

products 9d and 9e in 71% and 83% yield, respectively.

(

1.2 mmol, 2.0 equiv) in MeCN (2.0 mL), followed by DIPEA (1.2

mmol, 2.0 equiv) to aﬀord a homogenous solution. The polyethylene

tube in vial B was immersed into the solution, and then, to vial A was

added triﬂuoroacetic acid (TFA) (1.5 mL) in one portion. Vigorous

CONCLUSIONS

We have demonstrated a new strategy in one-pot, SO F -

■

bubbling of SO

and when the bubbling subsided, vial B was vented via a needle for 1−

min (this triggered more bubbling of SO F through the solution).

F and fuming were observed in vial B for 2−3 min,

2 2

mediated alcohol derivatizations that exploit alkyl halides as

the key reactive intermediates. This strategy was used to

expand the reactions that can be promoted in one-pot sulfuryl

ﬂuoride-mediated processes to radical reactions. We have

demonstrated that the radical dehalogenation of iodide

intermediates can be utilized in the overall two-step, one-pot

deoxygenation of primary alcohols under mild conditions. This

protocol also provides the most general SO F -mediated, one-

The polyethylene tube and needle were then removed, and the

reaction mixture in vial B was allowed to stir at room temperature for

0 min.

Workup and Puriﬁcation. To the reaction mixture were added

H O (20 mL) and Et O (20 mL); the layers were separated; then, the

aqueous layer was extracted with Et O (2 × 10 mL). The combined

organic layers were washed with H O (3 × 20 mL) and brine (40

pot alcohol substitution process developed to date. In

particular, the scope with respect to nucleophiles is now

competitive with phosphorus-based methods. Our SO₂F₂

method also enables substitution of enantiopure alcohols to

provide overall retention of conﬁguration, which is consistent

with two sequential nucleophilic displacements.

mL), then dried over Na SO , and concentrated under reduced

2 4

pressure. The crude product was puriﬁed by ﬂash column

chromatography. Fractions containing the desired product were

combined and concentrated under reduced pressure.

General Procedure (B) for the SO F -Mediated One-Pot

Deoxygenation of Primary Alcohols. Two 20 mL vials equipped

with magnetic stir-bars were capped with septum-ﬁtted vial caps

connected by a polyethylene tube. Vial A was charged with SDI (3

mmol, 3.0 equiv) and anhydrous KF (7.9 mmol, 7.9 equiv). Vial B

was charged with TBAI (1.1 mmol, 1.1 equiv); then, the system was

EXPERIMENTAL SECTION

General Information. All reactions were performed in 20 mL (28

61 mm) glass vials under air atmosphere unless otherwise noted. All

■

evacuated and ﬁlled with N three times. To vial B were then added

chemicals and solvents were purchased from commercial sources and

used as received unless otherwise noted. Sulfuryl diimidazole (SDI)

was either prepared or purchased (Oakwood Product, Inc.) and used

to generate sulfuryl ﬂuoride (SO F ) following a modiﬁed procedure

DIPEA (2 mmol, 2.0 equiv) and primary alcohol (1 mmol, 1.0 equiv)

in dry dimethylformamide (DMF) (2.9 mL). The polyethylene tube

in vial B was immersed into the solution, and then, to vial A was

added TFA (1.6 mL). Vigorous bubbling of SO F and fuming were

2 2

from Org. Lett. 2017, 19, 5244−5247. Screw caps and polytetraﬂuoro-

observed in vial B for a few minutes, and when the bubbling subsided,

771

J. Org. Chem. 2021, 86, 3768−3777

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Article

vial B was vented via a needle for 1−2 min (this triggered more

was isolated via ﬂash column chromatography (1% Et O/petroleum

bubbling of SO F through the solution). The tube and needle were

ether) as a colorless oil (45 mg, 52% yield).The spectroscopic data

match a literature report (Bayguzina, A. R.; Gallyamova, L. I.;

Khalilov, L. M.; Khusnutdinov, R. I. Synthesis of Mono- and

Diﬂuorobenzyl Chlorides by Chlorination of Mono- and Diﬂuor-

then removed, and the mixture in vial B was allowed to stir at room

temperature. The reaction progress was monitored by thin layer

chromatography (TLC), and if unreacted starting materials were

observed after 10 min, second addition of SO F was carried out (see

otoluenes with CCl

Catalysts. J. Fluorine Chem. 2019, 226, 109346). H NMR (300 MHz,

CDCl ): δ 7.37 (dd, J = 8.6, 5.3 Hz, 2H), 7.05 (t, J = 8.7 Hz, 2H),

4.57 (s, 2H). C{ H} NMR (75 MHz, CDCl ): δ 162.8 (d, JC−F =

and t-BuOCl Induced by Iron-Containing

below). Otherwise, to the solution were added Et B (1 M in THF, 0.2

mmol, 0.2 equiv) and TTMSS (1.2 mmol, 1.2 equiv), and the mixture

was left stirring at room temperature under air. The reaction progress

was monitored by TLC and gas chromatography−mass spectrometry.

Once all alkyl iodide had been consumed, TBAF quench, workup, and

puriﬁcation were carried out (see below).

247.5 Hz), 133.5 (d, JC−F = 3.3 Hz), 130.6 (d, JC−F = 8.4 Hz), 115.8

(d, JC−F = 21.8 Hz), 45.6. F NMR (282 MHz, CDCl

(tt, J = 8.9, 4.5 Hz). LRMS-El (m/z): 144.0 [M] .

): δ −113.6

Second Addition of SO F . To reaction vial B was added DIPEA

2 mmol, 2.0 equiv). A new vial A was prepared containing SDI (3

1-(Iodomethyl)-4-(triﬂuoromethyl)benzene (6d). The title com-

pound was prepared on a 0.6 mmol scale following general procedure

A. The product was isolated via ﬂash column chromatography (1%

(

mmol, 3.0 equiv) and anhydrous KF (7.9 mmol, 7.9 equiv) and

Et O/petroleum ether) as an orange solid (134 mg, 78% yield). The

individually evacuated and ﬁlled with N three times. As in the general

spectroscopic data match a literature report (Combe, S. H.; Hosseini,

A.; Song, L.; Hausmann, H.; Schreiner, P. R. Catalytic Halogen Bond

Activation in the Benzylic C−H Bond Iodination with Iodohydan-

procedure, the two vials were connected by a polyethylene tube and

TFA (1.6 mL) was added to vial A. SO F generated bubbles through

the mixture in vial B for a few minutes; then, the vial was vented via a

needle and allowed to stir at room temperature for another 10 min.

TBAF Quench, Workup, and Puriﬁcation. To quench

unreacted TTMSS and silane byproducts, 1 M TBAF in THF was

added dropwise to the reaction mixture until evolution of gas

toins. Org. Lett. 2017, 19, 6156−6159). H NMR (300 MHz,

CDCl ): δ 7.56 (d, J = 8.3 Hz, 2H), 7.48 (d, J = 8.3 Hz, 2H), 4.46 (s,

H). C{ H} NMR (75 MHz, CDCl ): δ 143.5, 130.1 (q, J

2.7 Hz), 129.2, 125.9 (q, J

Hz), 3.4. F NMR (282 MHz, CDCl ): δ −63.1. LRMS-El (m/z):

86.0 [M] .

C−F

= 3.7 Hz), 124.1 (q, J

= 273.2

C−F

(

Me SiF) stopped. The solution was then diluted with 20 mL of 1 M

aqueous HCl and 20 mL of organic solvent (pentanes, hexanes, or

diethyl ether); the layers were separated; then, the aqueous layer was

extracted with 3 × 20 mL of previously used organic solvent. The

combined organics were washed with water (20 mL) and brine (20

mL) and then dried over Na SO and concentrated under reduced

-(Iodomethyl)-4-methoxybenzene (6e). The title compound was

prepared on a 0.6 mmol scale following general procedure A. The

product was isolated via ﬂash column chromatography (5% Et O/

petroleum ether) as a yellow oil (77 mg, 52% yield). The

spectroscopic data match a literature report (Krohn, K.; Steingrover,

K.; Srinivasa Rao, M. Isolation and Synthesis of Chalcones with

pressure. The crude product was puriﬁed by ﬂash column

chromatography. Fractions containing the desired product were

combined and concentrated under reduced pressure. The ﬁnal

product was occasionally contaminated with tetrakis-

Diﬀerent Degrees of Saturation. Phytochemistry 2002, 61, 931−936).

H NMR (300 MHz, CDCl ): δ 7.36−7.26 (m, 2H), 6.85−6.79 (m,

H), 4.48 (s, 2H), 3.80 (s, 3H). C{ H} NMR (75 MHz, CDCl ): δ

(

trimethylsilyloxy)silane Si(OSiMe ) . In such cases, the ﬁnal yield

59.3, 131.5, 130.2, 114.4, 55.5, 6.7. LRMS-El (m/z): 248.0 [M] .

was corrected for this impurity.

-(Benzyloxy)-4-(2-iodoethyl)benzene (6f). The title compound

-Fluoro-4-(iodomethyl)benzene (6a). The title compound was

was prepared on a 0.6 mmol scale following general procedure A. The

prepared on a 0.6 mmol scale following general procedure A using

product was isolated via ﬂash column chromatography (1% Et O/

DMF as the solvent. The crude product was obtained (70%) based on

_q_u_a_n_t_i_t_a_t_i_v_e₁9F NMR using triﬂuorotoluene as the internal standard.

petroleum ether) as an oﬀ-white solid (179 mg, 88% yield). The

spectroscopic data match a literature report (Erdeljac, N.; Kehr, G.;

Ahlqvist, M.; Knerr, L.; Gilmour, R. Exploring Physicochemical Space

via a Bioisostere of the Triﬂuoromethyl and Ethyl Groups (BITE):

Attenuating Lipophilicity in Fluorinated Analogues of Gilenya for

The product was isolated via ﬂash column chromatography (1%

Et O/petroleum ether) as a pale orange solid (100 mg, 70% yield).

The spectroscopic data match a literature report (Artaryan, A.;

Mardyukov, A.; Kulbitski, K.; Avigdori, I.; Nisnevich, G. A.; Schreiner,

P. R.; Gandelman, M. Aliphatic C−H Bond Iodination by a N-

Multiple Sclerosis. Chem. Commun. 2018, 54, 12002−12005). H

NMR (300 MHz, CDCl ): δ 7.48−7.27 (m, 5H), 7.15−7.07 (m, 2H),

Iodoamide and Isolation of an Elusive N-Amidyl Radical. J. Org.

6.97−6.89 (m, 2H), 5.05 (s, 2H), 3.32 (t, J = 8.3 Hz, 2H), 3.12 (t, J =

Chem. 2017, 82, 7093−7100). H NMR (300 MHz, CDCl ): δ 7.36

.8 Hz, 2H). C{ H} NMR (75 MHz, CDCl ): δ 157.9, 137.1, 133.3,

(

dd, J = 8.6, 5.3 Hz, 2H), 6.98 (t, J = 8.6 Hz, 2H), 4.44 (s, 2H).

C{ H} NMR (75 MHz, CDCl ): δ 162.2 (d, J

35.3 (d, J = 3.4 Hz), 130.6 (d, J = 8.4 Hz), 115.9 (d, J

1.7 Hz), 4.7. F NMR (282 MHz, CDCl ): δ −113.8 (t, J = 7.2 Hz).

LRMS-El (m/z): 236.0 [M] .

-(Bromomethyl)-4-ﬂuorobenzene (6b). The title compound was

129.5, 128.7, 128.1, 127.6, 115.1, 70.2, 39.7, 6.4. LRMS-El (m/z):

= 247.7 Hz),

C−F

38.0 [M] .

C−F

-(2-Iodoethyl)-4-nitrobenzene (6g). The title compound was

prepared on a 0.6 mmol scale following general procedure A. The

product was isolated via ﬂash column chromatography (5% Et O/

petroleum ether) as a white solid (115 mg, 69% yield). The

spectroscopic data match a literature report (Ellwood, A. R.; Porter,

M. J. Selective Conversion of Alcohols into Alkyl Iodides Using a

prepared on a 0.6 mmol scale following general procedure A using

tetrabutylammonium bromide as the nucleophile and DMF as the

solvent. The crude product was obtained (87%) based on quantitative

Thioiminium Salt. J. Org. Chem. 2009, 74, 7982−7985). H NMR

F NMR using triﬂuorotoluene as the internal standard. The product

(

300 MHz, CDCl ): δ 8.24−8.15 (m, 2H), 7.42−7.32 (m, 2H),

was isolated via ﬂash column chromatography (1% Et O/petroleum

13 1

3.45−3.33 (m, 2H), 3.35−3.23 (m, 2H). C{ H} NMR (75 MHz,

CDCl ): δ 147.8, 147.1, 129.4, 124.1, 39.6, 3.8. LRMS-El (m/z):

ether) as a colorless oil (75 mg, 66% yield). The spectroscopic data

matched that of an authentic sample (Sigma-Aldrich). H NMR (300

77.0 [M] .

MHz, CDCl ): δ 7.37 (dd, J = 8.6, 5.3 Hz, 2H), 7.03 (t, J = 8.6 Hz,

1-(4-Fluorophenyl)-2-iodoethan-1-one (6h). The title compound

was prepared on a 0.6 mmol scale following general procedure A. The

H), 4.48 (s, 2H). C{ H} NMR (75 MHz, CDCl ): δ 162.7 (d,

^JC−F = 248.0 Hz), 133.8 (d, J

Hz), 115.9 (d, J

= 3.3 Hz), 131.0 (d, J

= 8.4

C−F

product was isolated via ﬂash column chromatography (1% Et O/

= 21.8 Hz), 32.7. F NMR (282 MHz, CDCl ):

petroleum ether) as a pale yellow oil (108 mg, 67% yield). The

spectroscopic data match a literature report (Zhang, J.; Li, S.; Deng,

G.-J.; Gong, H. Metal-Free, Oxidant-Free, and Controllable Graphene

C−F

δ −113.2 (tt, J = 9.0, 5.3 Hz). LRMS-El (m/z): 188.0 [M] .

-(Chloromethyl)-4-ﬂuorobenzene (6c). The title compound was

prepared on a 0.6 mmol scale following general procedure A using

tetrabutylammonium chloride as the nucleophile and DMF as a

solvent. The crude product was obtained (91%) based on quantitative

Oxide Catalyzed Direct Iodination of Arenes and Ketones.

ChemCatChem 2018, 10, 376−380). H NMR (300 MHz, CDCl ):

δ 8.09−7.95 (m, 2H), 7.21−7.08 (m, 2H), 4.33 (s, 2H). C{ H}

F NMR using triﬂuorotoluene as the internal standard. The product

NMR (75 MHz, CDCl ): δ 191.4, 166.1 (d, J = 256.3 Hz), 131.9

3 C−F

772

J. Org. Chem. 2021, 86, 3768−3777

The Journal of Organic Chemistry

Article

d, ³J_C₋_F= 9.4 Hz), 129.9 (d, J

= 3.0 Hz), 116.1 (d, ²J_C₋_F= 22.1

1H), 4.26 (t, J = 6.7 Hz, 2H), 1.79 (sxt, J = 7.2 Hz, 2H), 1.03 (t, J =

(

C−F

Hz), 1.5. F NMR (282 MHz, CDCl ): δ −103.8 (tt, J = 8.4, 5.3 Hz).

7.4 Hz, 3H). C{ H} NMR (75 MHz, CDCl ): δ 167.0, 137.9, 134.4,

−1

LRMS-El (m/z): 264.0 [M] .

130.4, 127.3, 66.4, 22.2, 21.1, 10.5. IR (cm ) (neat): 2968, 2922,

Propylbenzene (7i). The title compound was synthesized on a 1

mmol scale according to general procedure B using pentanes for

extraction. The product was isolated via ﬂash column chromatography

1716, 1609, 1309, 1210. HRMS-EI (m/z): calcd for C H O

([M ]), 192.1150; found, 192.1149.

(5-Nitrothiophen-2-yl)methanol (Precursor to 7m). 5-Nitro-

thiophene-2-carboxaldehyde (10 mmol, 1 equiv) was dissolved in

methanol (32 mL) at 0 °C, and to the resulting solution was added

sodium borohydride (11 mmol, 1.1 equiv). The mixture was warmed

up to room temperature and allowed to stir for 2 h. The mixture was

poured onto ice, acidiﬁed with 1 M aqueous HCl to pH 7, and

extracted with ethyl acetate (5 × 20 mL). The combined organics

were concentrated, and the product was isolated by ﬂash column

chromatography (50% ethyl acetate/hexane to 100% ethyl acetate) as

a brown oil (1.33 g, 84% yield). The spectroscopic data match a

(

100% pentanes) as a clear liquid (85 mg, 60% yield). The product

yield has been corrected for Si(OSiMe ) . The spectroscopic data

match a literature report (Eisch, J. J.; Dutta, S. Carbon−Carbon Bond

Formation in the Surprising Rearrangement of Diorganylzirconium

Dialkoxides: Linear Dimerization of Terminal Oleﬁns. Organometallics

(

005, 24, 3355−3358). H NMR (300 MHz, CDCl ): δ 7.34−7.26

m, 2H), 7.24−7.16 (m, 3H), 2.67−2.56 (m, 2H), 1.68 (sxt, J = 7.4

Hz, 2H), 0.97 (t, J = 7.3 Hz, 3H). C{ H} NMR (75 MHz, CDCl ):

δ 142.8, 128.6, 128.4, 125.7, 38.2, 24.7, 14.0. LRMS-El (m/z): 120.2

[

M ].

literature report (Riviere, P.; Castel, A.; Cosledan, F. Etude de

Nouvelles reactions par transfert monoelectronique: action d’organo-

-Ethyl-1,3,5-trimethylbenzene (7j). The title compound was

synthesized on a 1 mmol scale according to general procedure B using

pentanes for extraction. The product was isolated via ﬂash column

chromatography (hexanes to 10% ethyl acetate/hexanes) as a clear

liquid (125.2 mg, 64% yield). The product yield has been corrected

for Si(OSiMe ) . The spectroscopic data match a literature report

germyllithiums sur le furfureal le thiophenaldehyde et les derives

intres correspondants. Phosphorus, Sulfur Silicon Relat. Elem. 1995,

04, 169−180). H NMR (300 MHz, CDCl ): δ 7.74 (d, J = 4.2 Hz,

H), 6.88 (d, J = 4.2 Hz, 1H), 4.81 (d, J = 1.1 Hz, 2H), 3.67 (br s,

1H). C{ H} NMR (75 MHz, CDCl ): δ 154.4, 150.4, 129.2, 123.5,

0.0. LRMS-ESl (m/z): 158.2 [M-H] .

(

Kondolﬀ, I.; Doucet, H.; Santelli, M. Palladium−Tetraphosphine as

‑

Catalyst Precursor for High-Turnover-Number Negishi Cross-

Coupling of Alkyl- or Phenylzinc Derivatives with Aryl Bromides.

Organometallics 2006, 25, 5219−5222). H NMR (300 MHz,

CDCl ): δ 6.91 (s, 2H), 2.70 (q, J = 7.5 Hz, 2H), 2.37 (s, 6H),

-Methyl-5-nitrothiophene (7m). The title compound was

synthesized on a 1 mmol scale from the corresponding alcohol

preparation of which is described above) according to general

procedure B. The second addition of SO F was performed; TBAF

(

2 2

.33 (s, 3H), 1.18 (t, J = 7.6 Hz, 3H). C{ H} NMR (75 MHz,

quench was skipped, and diethyl ether was used for extraction. The

product was isolated via ﬂash column chromatography (10% ethyl

acetate/hexanes) as a pale brown solid (73 mg, 52% yield). The

spectroscopic data match a literature report (Katritzky, A.; Vakulenko,

A.; Sivapackiam, J.; Draghici, B.; Damavarapu, R. Synthesis of Dinitro-

CDCl ): δ 138.0, 135.8, 134.9, 129.0, 22.4, 20.9, 19.6, 13.6. LRMS-El

(

m/z): 148.2 [M ].

-(Benzyloxy)-4-ethylbenzene (7k). The title compound was

synthesized on a 1 mmol scale according to general procedure B.

The second addition of SO F was performed, and diethyl ether was

Substituted Furans, Thiophenes, and Azoles. Synthesis 2008, 2008,

used for extraction. The product was isolated via ﬂash column

chromatography (5% ethyl acetate/hexanes) as a clear oil (195 mg,

99−706). H NMR (300 MHz, CDCl ): δ 7.75 (d, J = 4.1 Hz, 1H),

.74 (dd, J = 4.1, 1.1 Hz, 1H), 2.54 (d, J = 1.0 Hz, 3H). C{ H}

2% yield). The spectroscopic data match a literature report (Zhu, C.;

NMR (75 MHz, CDCl ): δ 149.6, 149.3, 129.3, 125.6, 16.4. LRMS-El

Yukimura, N.; Yamane, M. Synthesis of Oxygen- and Sulfur-Bridged

Dirhodium Complexes and Their Use As Catalysts in the Chemo-

(

m/z): 143.0 [M ].

-(4-Hydroxybutyl)isoindoline-1,3-dione (Precursor to 7n). 4-

selective Hydrogenation of Alkenes. Organometallics 2010, 29, 2098−

Amino-1-butanol (10 mmol, 1 equiv), phthalimide (20 mmol, 2

equiv), and iron(III) nitrate nonahydrate (0.5 mmol, 0.05 equiv) were

suspended in toluene (10 mL). The resulting reaction mixture was

stirred under reﬂux (heated in an oil bath) for 17 h, then allowed to

cool down, diluted with ethyl acetate (20 mL), and ﬁltered through

Celite. The ﬁltrate was concentrated under reduced pressure, and the

resulting residue was diluted with 3% MeOH/DCM. The undissolved

solid (phthalimide) was ﬁltered oﬀ, and the product was isolated by

ﬂash column chromatography (3 to 5% MeOH/DCM) as a straw-

colored solid (1.69 g, 76% yield). The product yield has been

corrected for MeOH. The spectroscopic data match a literature report

103). H NMR (300 MHz, CDCl ): δ 7.47−7.29 (m, 5H), 7.13 (d, J

8.2 Hz, 2H), 6.92 (d, J = 8.2 Hz, 2H), 5.05 (s, 2H), 2.60 (q, J = 7.6

Hz, 2H), 1.22 (t, J = 7.6 Hz, 3H). C{ H} NMR (75 MHz, CDCl ):

δ 157.0, 137.4, 136.8, 128.8, 128.6, 128.0, 127.6, 114.8, 70.1, 28.1,

6.0. LRMS-El (m/z): 212.2 [M ].

-Hydroxypropyl 3,5-Dimethylbenzoate (Precursor to 7l). A

solution of propane-1,3-diol (45 mmol, 3 equiv) and Et N (30 mmol,

equiv) in dichloromethane (DCM) (75 mL) was cooled down to 0

°C. To the mixture was added 3,5-dimethylbenzoyl chloride (15

mmol, 1 equiv) dropwise over 5 min. The mixture was warmed up to

room temperature and allowed to stir for 17 h. The solution was

transferred to a separatory funnel and diluted with 75 mL of water,

and the layers were separated. The aqueous layer was extracted with

DCM (3 × 50 mL), and the combined organics were washed with

brine (75 mL), dried over Na SO , and concentrated under reduced

(

Wappes, E. A.; Nakafuku, K. M.; Nagib, D. A. Directed β C−H

Amination of Alcohols via Radical Relay Chaperones. J. Am. Chem.

Soc. 2017, 139, 10204−10207). H NMR (300 MHz, CDCl ): δ

s, 1H), 1.83−1.69 (m, 2H), 1.66−1.49 (m, 2H). C{ H} NMR (75

MHz, CDCl ): δ 168.6, 134.0, 132.2, 123.3, 62.3, 37.8, 29.9, 25.2.

LRMS-ESl (m/z): 220.3 [M + H] .

.86−7.77 (m, 2H), 7.73−7.65 (m, 2H), 3.74−3.62 (m, 4H), 1.93 (br

13 1

pressure. The product was isolated via ﬂash column chromatography

(

50% ethyl acetate/hexanes) as a clear oil (1.73 g, 55% yield). H

NMR (300 MHz, CDCl ): δ 7.62 (s, 2H), 7.15 (s, 1H), 4.43 (t, J =

-Butylisoindoline-1,3-dione (7n). The title compound was

synthesized on a 1 mmol scale from the corresponding alcohol

preparation of which is described above) according to general

.2 Hz, 2H), 3.75 (t, J = 6.1 Hz, 2H), 2.89 (br s, 1H), 2.32 (s, 6H),

.98 (p, J = 6.2 Hz, 2H). C{ H} NMR (75 MHz, CDCl ): δ 167.4,

(

38.0, 134.7, 129.9, 127.3, 61.8, 59.0, 31.9, 21.1. HRMS-ESl (m/z):

calcd for C H O Na ([M + Na] ), 231.0997; found, 231.0991.

procedure B with equivalents of SDI, KF, DIPEA, and TBAI doubled.

Diethyl ether was used for extraction, and the product was isolated via

ﬂash column chromatography (8% ethyl acetate/hexanes) as a clear

oil (110 mg, 54% yield). The spectroscopic data match a literature

report (Hsieh, J.-C.; Cheng, C.-H. Nickel-Catalyzed Coupling of

Isocyanates with 1,3-Iodoesters and Halobenzenes: A Novel Method

Propyl 3,5-Dimethylbenzoate (7l). The title compound was

synthesized on a 1 mmol scale from the corresponding alcohol

(

preparation of which is described above) according to general

procedure B. The second addition of SO F was performed with an

additional 0.55 equiv of TBAI added prior to it. Diethyl ether was

used for extraction, and the product was isolated via ﬂash column

chromatography (5% ethyl acetate/hexanes) as a pale yellow solid

for the Synthesis of Imide and Amide Derivatives. Chem. Commun.

2005, 4554). H NMR (300 MHz, CDCl

): δ 7.88−7.79 (m, 2H),

(

195 mg, 95% yield). The product yield has been corrected for

7.74−7.66 (m, 2H), 3.68 (t, J = 7.3 Hz, 2H), 1.72−1.60 (m, 2H),

1.44−1.29 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H). C{ H} NMR (75

13 1

Si(OSiMe ) . H NMR (300 MHz, CDCl ): δ 7.67 (s, 2H), 7.16 (s,

773

J. Org. Chem. 2021, 86, 3768−3777

The Journal of Organic Chemistry

Article

MHz, CDCl ): δ 168.5, 133.9, 132.3, 123.2, 37.9, 30.7, 20.2, 13.7.

LRMS-ESl (m/z): 242.4 [M + K] .

2-((3-Phenylpropyl)thio)benzo[d]thiazole (8c). (3-Iodopropyl)-

benzene was prepared on a 0.6 mmol scale following the general

procedure A using DMF as the solvent. After stirring for 10 min, the

resulting mixture was degassed with nitrogen for 60 s and then was

charged with sodium 2-mercaptobenzothiazole (2.0 equiv). The

reaction mixture was heated in an oil bath to 80 °C for 1 h and then

was worked up as per general procedure A. The product was isolated

Benzyl (R)-(1-Phenylpropan-2-yl)carbamate (7o). The title

compound was synthesized on a 1 mmol scale according to general

procedure B. The second addition of SO F was performed with an

additional 1.1 equiv of TBAI added prior to it. Diethyl ether was used

for extraction, and the product was isolated via ﬂash column

chromatography (5 to 15% ethyl acetate/hexanes) as a white solid

via ﬂash column chromatography (5% Et

(152 mg, 89% yield). The spectroscopic data match a literature report

Yu, Y.; Li, Z.; Jiang, L. A Novel Synthesis of 2-Alkylthiobenzothia-

zoles and 2-Alkylthiobenzoxazoles. Phosphorus, Sulfur Silicon Relat.

O/hexane) as a colorless oil

(

143 mg, 53% yield). H NMR (300 MHz, CDCl ): δ 7.39−7.30 (m,

(

H), 7.29−7.21 (m, 3H), 7.19−7.12 (m, 2H), 5.08 (s, 2H), 4.63−

.53 (br s, 1H), 4.06−3.94 (m, 1H), 2.85 (dd, J = 13.6, 5.7 Hz, 1H),

Elem. 2012, 187, 632−640). H NMR (300 MHz, CDCl ): δ 7.86 (d,

.70 (dd, J = 13.4, 7.2 Hz, 1H), 1.12 (d, J = 6.6 Hz, 3H). C{ H}

J = 8.1 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.41 (td, J = 8.2, 7.8, 1.3 Hz,

1H), 7.34−7.25 (m, 3H), 7.22 (d, J = 7.2 Hz, 3H), 3.36 (t, J = 7.2 Hz,

NMR (75 MHz, CDCl ): δ 155.7, 138.0, 136.8, 129.6, 128.6, 128.5,

−

28.2, 126.6, 66.6, 48.13, 42.9, 20.3. IR (cm ) (neat): 3355, 2971,

H), 2.86−2.77 (m, 2H), 2.17 (p, J = 7.4 Hz, 2H). C{ H} NMR

929, 1688, 1533, 1340, 1249. HRMS-ESI (m/z): calcd for

(75 MHz, CDCl ): δ 167.0, 153.4, 141.0, 135.3, 128.6, 128.6, 126.2,

C H NO ([M + H] ), 270.1494; found, 270.1488.

26.1, 124.3, 121.6, 121.0, 34.8, 33.0, 30.9. LRMS-APCl (m/z): 286.3

(

8R,9S,10R,13S,14S,17R)-17-Acetyl-17-hydroxy-10,13-dimethyl-

[M + H] .

[

,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta-

a]phenanthren-3-one (7p). The title compound was synthesized on

5-Phenyl-2-(phenylsulfonyl)pentanenitrile (8d). (3-Iodopropyl)-

a 1 mmol scale according to general procedure B. The second

addition of SO F was performed with an additional 1.1 equiv of

benzene was prepared on a 0.57 mmol scale following general

procedure A using DMF as a solvent. After stirring for 10 min, the

resulting mixture was degassed with nitrogen for 60 s and then was

added to a solution of (phenylsulfonyl)acetonitrile (2.0 equiv) and

NaH (2.2 equiv) in DMF (1.0 mL) at room temperature. The

solution of (phenylsulfonyl)acetonitrile, NaH, and DMF was prepared

TBAI added prior to it. Diethyl ether was used for extraction, and the

product was isolated via ﬂash column chromatography (10 to 20%

ethyl acetate/DCM) as a white solid (191 mg, 58% yield). The

spectroscopic data match a literature report (Claudel, E.; Arbez-

Gindre, C.; Berl, V.; Lepoittevin, J.-P. An Eﬃcient Hemisynthesis of

0 min prior to the addition. The reaction mixture was heated in an

oil bath to 80 °C for 1 h and then was worked up as per general

procedure A. The product was isolated via ﬂash column

chromatography (20% ethyl acetate/hexane) as a colorless oil (248

mg, 83% yield). The spectroscopic data match a literature report

0- and 21-[ C]-Labeled Cortexolone: A Model for the Study of Skin

Sensitization to Corticosteroids. Synthesis 2009, 2009, 3391−3398).

H NMR (300 MHz, CDCl ): δ 5.73 (br s, 1H), 2.68 (ddd, J = 14.7,

1.4, 2.9 Hz, 1H), 2.51−2.34 (m, 4H), 2.28 (s, 3H), 2.09−1.96 (m,

(

Hirose, D.; Gazvoda, M.; Kosmrlj, J.; Taniguchi, T. Systematic

H), 1.93−1.52 (m, 9H), 1.50−1.33 (m, 3H), 1.19 (s, 3H), 1.15−

Evaluation of 2-Arylazocarboxylates and 2-Arylazocarboxamides as

.93 (m, 2H), 0.77 (s, 3H). C{ H} NMR (75 MHz, CDCl ): δ

Mitsunobu Reagents. J. Org. Chem. 2018, 83, 4712−4729). H NMR

11.7, 199.7, 171.3, 124.0, 89.9, 53.4, 50.1, 48.2, 38.7, 35.8, 35.6, 34.0,

(

300 MHz, CDCl ): δ 8.03−7.93 (m, 2H), 7.83−7.71 (m, 1H),

3.6, 32.9, 32.1, 30.2, 27.9, 24.0, 20.6, 17.5, 15.5. LRMS-ESl (m/z):

7.70−7.58 (m, 2H), 7.33−7.10 (m, 5H), 3.88 (dd, J = 10.1, 4.6 Hz,

53.2 [M + Na] .

H), 2.69 (t, J = 7.3 Hz, 2H), 2.32−2.13 (m, 1H), 2.04−1.89 (m,

tert-Butyl (tert-Butoxycarbonyl)(3-phenylpropyl)carbamate (8a).

H), 1.89−1.71 (m, 1H). C{ H} NMR (101 MHz, CDCl ): δ

(3-Iodopropyl)benzene was prepared on a 0.6 mmol scale following

40.4, 135.7, 135.4, 129.8, 129.7, 128.8, 128.5, 126.5, 114.0, 57.5,

5.1, 28.4, 26.4. LRMS-APCl (m/z): 322.2 [M + Na] .

general procedure A using DMF as a solvent. After stirring for 10 min,

the resulting reaction mixture was degassed with nitrogen for 60 s and

-(3-Phenylpropyl)-1H-benzo[d]imidazole (8e). (3-Iodopropyl)-

then was added to a solution of NHBoc (2.0 equiv) and NaH (2.2

benzene was prepared on a 0.6 mmol scale following general

procedure A using DMF as a solvent. After stirring for 10 min, the

resulting mixture was degassed with nitrogen for 60 s and then was

added to a solution of benzimidazole (2.0 equiv) and NaH (2.2

equiv) in DMF (1.0 mL) at room temperature. The solution of

benzimidazole, NaH, and DMF was prepared 30 min prior to the

addition. The reaction mixture was heated in an oil bath to 80 °C for

equiv) in DMF (1.0 mL) at room temperature. The solution of

NHBoc , NaH, and DMF was prepared 30 min prior to the addition.

The reaction mixture was heated in an oil bath to 80 °C for 1 h and

then was worked up as per general procedure A. The product was

isolated via ﬂash column chromatography (2% ethyl acetate/hexane)

as a colorless oil (148 mg, 74% yield). H NMR (300 MHz, CDCl ):

δ 7.32−7.24 (m, 2H), 7.21−7.14 (m, 3H), 3.67−3.55 (m, 2H), 2.68−

h and then was worked up as per general procedure A. The product

.56 (m, 2H), 1.90 (p, J = 7.7 Hz, 2H), 1.48 (s, 18H). C{ H} NMR

was isolated via ﬂash column chromatography (50% ethyl acetate/

DCM) as a white solid (113 mg, 80% yield). The spectroscopic data

match a literature report (O’Connell, J.; Moriarty, E.; Aldabbagh, F.

Access to Aromatic Ring-Fused Benzimidazoles Using Photochemical

(

101 MHz, CDCl ): δ 152.8, 141.8, 128.5, 128.4, 126.0, 82.3, 46.4,

−

3.4, 30.8, 28.2. IR (cm ) (neat): 2978, 2930, 1694, 1366, 1134.

HRMS-ESI (m/z): calcd for C H NO Na ([M + Na] ), 358.1994;

found, 358.1991.

Substitutions of the Benzimidazol-2-Yl Radical. Synthesis 2012, 44,

-(3-Phenylpropyl)isoindoline-1,3-dione (8b). (3-Iodopropyl)-

371−3377). H NMR (300 MHz, CDCl ): δ 8.03 (s, 1H), 7.90−

benzene was prepared on a 0.6 mmol scale following general

procedure A using DMF as the solvent. After stirring for 10 min, the

resulting mixture was degassed with nitrogen for 60 s and then was

charged with potassium phthalimide (2.0 equiv). The reaction

mixture was heated in an oil bath to 80 °C for 1 h and then was

worked up as per general procedure A. The product was isolated via

ﬂash column chromatography (20% ethyl acetate/hexane) as a white

solid (124 mg, 80% yield). The spectroscopic data match a literature

report (Tsui, G. C.; Menard, F.; Lautens, M. Regioselective

Rhodium(I)-Catalyzed Hydroarylation of Protected Allylic Amines

.79 (m, 1H), 7.40−7.26 (m, 5H), 7.27−7.12 (m, 3H), 4.21 (t, J =

.1 Hz, 2H), 2.68 (t, J = 7.5 Hz, 2H), 2.27 (p, J = 7.4 Hz, 2H).

C{ H} NMR (101 MHz, CDCl ): δ 144.1, 143.1, 140.3, 133.9,

28.8, 128.5, 126.5, 123.0, 122.2, 120.6, 109.8, 44.4, 32.8, 31.1.

LRMS-ESI (m/z): 237.4 [M + H] .

(3-Azidopropyl)benzene (8f). (3-Iodopropyl)benzene was pre-

pared on a 0.6 mmol scale following general procedure A using DMF

as a solvent. After stirring for 10 min, the resulting mixture was

degassed with nitrogen for 60 s and then was charged with sodium

azide (2.0 equiv). The resulting reaction mixture was heated in an oil

bath to 80 °C for 1 h and then was worked up as per general

procedure A to aﬀord the product as a yellow oil (83 mg, 84% yield).

The spectroscopic data match a literature report (Benati, L.;

Bencivenni, G.; Leardini, R.; Nanni, D.; Minozzi, M.; Spagnolo, P.;

Scialpi, R.; Zanardi, G. Reaction of Azides with Dichloroindium

Hydride: Very Mild Production of Amines and Pyrrolidin-2-Imines

with Arylboronic Acids. Org. Lett. 2010, 12, 2456−2459). H NMR

(

300 MHz, CDCl ): δ 7.87−7.77 (m, 2H), 7.75−7.63 (m, 2H),

.29−7.09 (m, 5H), 3.75 (t, J = 7.2 Hz, 2H), 2.73−2.66 (m, 2H),

.04 (p, J = 7.7 Hz, 2H). C{ H} NMR (101 MHz, CDCl ): δ

68.57, 141.18, 134.02, 132.28, 128.52, 128.44, 126.08, 123.32, 37.96,

3.32, 30.02. LRMS-ESI (m/z): 288.3 [M + Na] .

774

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Article

through Possible Indium−Aminyl Radicals. Org. Lett. 2006, 8, 2499−

7.81−7.69 (m, 2H), 7.36−7.26 (m, 4H), 7.23−7.14 (m, 1H), 4.23 (t,

13 1

502). H NMR (400 MHz, CDCl ): δ 7.3−7.3 (m, 2H), 7.2−7.2

J = 6.4 Hz, 2H), 2.93−2.82 (m, 2H), 2.18−2.03 (m, 2H). C{ H}

(

m, 3H), 3.3 (t, J = 6.9 Hz, 2H), 2.7−2.7 (m, 2H), 2.0−1.9 (m, 2H).

NMR (101 MHz, CDCl ): δ 163.8, 141.3, 134.6, 129.1, 128.8, 128.6,

C{ H} NMR (101 MHz, CDCl ): δ 141.0, 128.7, 128.6, 126.3, 50.8,

126.2, 123.7, 77.7, 31.9, 30.1. LRMS-ESI (m/z): 304.3 [M + Na] .

2.9, 30.6. HRMS-EI (m/z): calcd for C H N ([M] ), 161.0953;

(S)-2-(Octan-2-ylthio)benzo[d]thiazole (9a). (R)-2-Bromooctane

was prepared on a 0.6 mmol scale following general procedure A using

tetrabutylammonium bromide as the nucleophile and 4.0 mL of

MeCN. After stirring for 1 h, the resulting mixture was degassed with

nitrogen for 60 s and then was charged with sodium 2-

mercaptobenzothiazole (2.0 equiv). The reaction mixture was stirred

at room temperature overnight and then was worked up as per general

procedure A. The product was isolated via ﬂash column

found, 161.0953.

(3-Thiocyanatopropyl)benzene (8g). (3-Iodopropyl)benzene was

prepared on 0.58 mmol scale following general procedure A using

DMF as a solvent. After stirring for 10 min, the resulting mixture was

degassed with nitrogen for 60 s and then was charged with

ammonium thiocyanate (2.0 equiv). The reaction mixture was heated

in an oil bath to 80 °C for 1 h and then was worked up as per general

procedure A. The product was isolated via ﬂash column

chromatography (4% Et

mg, 63% yield). The spectroscopic data match a literature report

(Hirose, D.; Gazvoda, M.; Kosmrlj, J.; Taniguchi, T. Systematic

O/petroleum ether) as a colorless oil (106

chromatography (10% Et O/pentane) as a yellow oil (88 mg, 85%

yield). The spectroscopic data match a literature report (Kiasat, A. R.;

Fallah-Mehrjardi, M. Polyethylene Glycol: A Cheap and Eﬃcient

Evaluation of 2-Arylazocarboxylates and 2-Arylazocarboxamides as

Medium for the Thiocyanation of Alkyl Halides. Bull. Korean Chem.

Mitsunobu Reagents. J. Org. Chem. 2018, 83, 4712−4729). H NMR

Soc. 2008, 29, 2346−2348). H NMR (300 MHz, CDCl ): δ 7.37−

(300 MHz, CDCl ): δ 7.87 (d, J = 8.1 Hz, 1H), 7.75 (d, J = 8.3 Hz,

.27 (m, 2H), 7.25−7.13 (m, 3H), 2.93 (t, J = 7.2 Hz, 2H), 2.79 (t, J

7.3 Hz, 2H), 2.17 (p, J = 7.2 Hz, 2H). C{ H} NMR (101 MHz,

1H), 7.46−7.36 (m, 1H), 7.32−7.26 (m, 1H), 3.97 (h, J = 6.8 Hz,

1H), 1.90−1.56 (m, 2H), 1.54−1.48 (m, 4H), 1.39−1.18 (m, 7H),

CDCl ): δ 139.9, 128.8, 128.6, 126.6, 112.2, 33.9, 33.2, 31.3. HRMS-

0.91−0.83 (m, 3H). C{ H} NMR (101 MHz, CDCl ): δ 167.3,

EI (m/z): calcd for C H NS ([M] ), 177.0612; found, 177.0610.

153.2, 135.2, 126.2, 124.4, 121.6, 121.0, 44.8, 36.9, 31.8, 29.2, 27.1,

S-(3-Phenylpropyl) Ethanethioate (8h). (3-Iodopropyl)benzene

was prepared on a 0.59 mmol scale following general procedure A

using DMF as a solvent. After stirring for 10 min, the resulting

mixture was degassed with nitrogen for 60 s and then was charged

with potassium thioacetate (2.0 equiv). The reaction mixture was

stirred at room temperature for 1 h and then was worked up as per

general procedure A. The product was isolated via ﬂash column

22.7, 21.6, 14.2. LRMS-ESI (m/z): 280.4 [M + H] . The

enantiomeric ratio was determined by HPLC analysis using a chiral

column to be 95:5, t

= 31.2 (S), 32.6 (R); [α] = −10.8 (c = 1.33,

CHCl ), eluent: (acetonitrile/1% formic acid in water) 65:35.

(S)-(4-Phenylbutan-2-yl) Ethanethioate (9b). (R)-(3-

Bromobutyl)benzene was prepared on a 0.6 mmol scale following

general procedure A using tetrabutylammonium bromide as the

nucleophile and 4.0 mL of MeCN. After stirring for 1 h, the resulting

mixture was degassed with nitrogen for 60 s and then charged with

potassium thioacetate (2.0 equiv). The reaction mixture was stirred at

room temperature overnight and then was worked up as per general

procedure A. The product was isolated via ﬂash column

chromatography (2% ethyl acetate/hexane) as a yellow oil (87 mg,

6% yield). H NMR (300 MHz, CDCl ): δ 7.33−7.26 (m, 2H),

.24−7.13 (m, 3H), 2.89 (t, J = 7.3 Hz, 2H), 2.75−2.63 (m, 2H),

.34 (s, 3H), 1.98−1.82 (m, 2H). C{ H} NMR (101 MHz, CDCl ):

−

δ 196.0, 141.3, 128.6, 128.6, 126.2, 35.0, 31.3, 30.8, 28.7. IR (cm )

neat): 3025, 2934, 2853, 1688, 1502, 1132. HRMS-ESI (m/z): calcd

(

chromatography (2% Et

O/petroleum ether) as a yellow oil (95

mg, 76% yield). H NMR (300 MHz, CDCl ): δ 7.34−7.23 (m, 2H),

7.25−7.13 (m, 3H), 3.60 (h, J = 6.9 Hz, 1H), 2.81−2.60 (m, 2H),

for C H ONaS ([M + Na] ), 217.0663; found, 217.0661.

Diethyl 2-(3-Phenylpropyl)malonate (8i). (3-Iodopropyl)benzene

was prepared on a 0.6 mmol scale following general procedure A using

DMF as a solvent. After stirring for 10 min, the resulting mixture was

degassed with nitrogen for 60 s and then was added to a solution of

diethyl malonate (2.0 equiv) and NaH (2.2 equiv) in DMF (1.0 mL)

at room temperature. The solution of diethyl malonate, NaH, and

DMF was prepared 30 min prior to the addition. The reaction mixture

was stirred at room temperature for 1 h and then was worked up as

per general procedure A. The product was isolated via ﬂash column

chromatography (5% ethyl acetate/hexane) as a colorless oil (91 mg,

2.33 (s, 3H), 1.95−1.80 (m, 2H), 1.35 (d, J = 6.9 Hz, 3H). C{ H}

NMR (75 MHz, CDCl ): δ 196.0, 141.7, 128.5, 128.5, 126.1, 39.4,

38.4, 33.5, 30.9, 21.6. IR (cm ) (neat): 3029, 2927, 2860, 1685,

−

1495, 1111. HRMS-EI (m/z): calcd for C12

found, 208.0925. The enantiomeric ratio was determined by HPLC

analysis using a chiral column to be 98:2, t = 11.458 (R), 12.018 (S);

[α] = −29.4 (c = 1.16, CHCl ), eluent: (acetonitrile/1% formic acid

in water) 65:35.

H16OS ([M] ), 208.0922;

(Azidomethylene)dibenzene (9c). (Bromomethylene)dibenzene

was prepared on a 0.6 mmol scale following general procedure A

using tetrabutylammonium bromide as nucleophile and 4.0 mL of

MeCN. After stirring for 1 h, the resulting mixture was degassed with

nitrogen for 60 s, and then, sodium azide (2.0 equiv) was added. The

reaction mixture was stirred at room temperature overnight and then

was worked up as per general procedure A. The product was isolated

4% yield). The spectroscopic data match a literature report (Ines, B.;

Palomas, D.; Holle, S.; Steinberg, S.; Nicasio, J. A.; Alcarazo, M.

Metal-Free Hydrogenation of Electron-Poor Allenes and Alkenes.

Angew. Chem. Int. Ed. 2012, 51, 12367−12369). H NMR (300 MHz,

CDCl ): δ 7.33−7.22 (m, 2H), 7.24−7.12 (m, 3H), 4.19 (q, J = 7.2

Hz, 4H), 3.34 (t, J = 7.5 Hz, 1H), 2.65 (t, J = 7.7 Hz, 2H), 2.02−1.88

(

m, 2H), 1.66 (p, J = 8.1 Hz, 2H), 1.26 (t, J = 7.1 Hz, 6H). ¹³C{ H}

via ﬂash column chromatography (2% Et O/petroleum ether) as a

NMR (101 MHz, CDCl ): δ 169.6, 141.9, 128.5, 126.0, 61.5, 52.1,

colorless oil (89 mg, 71% yield). The spectroscopic data match a

literature report (Matoba, M.; Kajimoto, T.; Nishide, K.; Node, M.

Preparation and Application of Odorless 1,3-Propanedithiol Reagents.

5.6, 29.3, 28.5, 14.2. LRMS-ESI (m/z): 301.3 [M + Na] .

-(3-Phenylpropoxy)isoindoline-1,3-dione (8j). (3-Iodopropyl)-

benzene was prepared on a 0.58 mmol scale following general

procedure A using DMF as a solvent. After stirring for 10 min, the

resulting mixture was degassed with nitrogen for 60 s and then was

added to a solution of PhthN-OH (2.0 equiv) and NaH (2.2 equiv) in

DMF (1.0 mL) at room temperature. The solution of PhthN-OH,

NaH, and DMF was prepared 30 min prior to the addition. The

reaction mixture was heated in an oil bath to 80 °C for 1 h and then

was worked up as per general procedure A. The product was isolated

via ﬂash column chromatography (20% ethyl acetate/hexane) as a

pale yellow solid (122 mg, 75% yield). The spectroscopic data match

a literature report (Hirose, D.; Taniguchi, T.; Ishibashi, H. Recyclable

Mitsunobu Reagents: Catalytic Mitsunobu Reactions with an Iron

Chem. Pharm. Bull. 2006, 54, 141−146). H NMR (300 MHz,

CDCl ): δ 7.43−7.25 (m, 10H), 5.72 (s, 1H). C{ H} NMR (101

MHz, CDCl ): δ 139.7, 128.9, 128.2, 127.5, 68.7. LRMS-APCI [M −

N + H] : 182.4.

(S)-(3-Azidobutyl)benzene (9d). (R)-(3-Bromobutyl)benzene was

prepared on a 0.6 mmol scale following general procedure A using

tetrabutylammonium bromide as the nucleophile and 4.0 mL of

MeCN. After stirring for 1 h, the resulting mixture was degassed with

nitrogen for 60 s and then was charged with sodium azide (2.0 equiv).

The reaction mixture was stirred at room temperature overnight and

then was worked up as per general procedure A. The product was

isolated via ﬂash column chromatography (4% Et O/petroleum

Catalyst and Atmospheric Oxygen. Angew. Chem. Int. Ed. 2013, 52,

ether) as pale yellow oil (75 mg, 71% yield). The spectroscopic data

match a literature report (Liu, C.; Wang, X.; Li, Z.; Cui, L.; Li, C.

613−4617). H NMR (300 MHz, CDCl ): δ 7.91−7.78 (m, 2H),

775

J. Org. Chem. 2021, 86, 3768−3777

The Journal of Organic Chemistry

Article

Silver-Catalyzed Decarboxylative Radical Azidation of Aliphatic

ACKNOWLEDGMENTS

■

Carboxylic Acids in Aqueous Solution. J. Am. Chem. Soc. 2015, 137,

Financial support for this work was provided by the University

of British Columbia (UBC) and the Natural Sciences and

Engineering Resource Council of Canada (2015-RGPIN-

05856). Student support was provided the NSERC CREATE

Sustainable Synthesis Program (M.E., J.Y.M.) and an NSERC

USRA (H.Y.).

820−9823). H NMR (300 MHz, CDCl ): δ 7.36−7.24 (m, 2H),

.26−7.15 (m, 3H), 3.44 (h, J = 6.5 Hz, 1H), 2.84−2.59 (m, 2H),

.92−1.67 (m, 2H), 1.29 (d, J = 6.5 Hz, 3H). C{ H} NMR (75

MHz, CDCl ): δ 141.4, 128.6, 128.6, 126.2, 57.3, 38.0, 32.5, 19.6.

LRMS-APCI (m/z): 148.3 [M−N + H] . The enantiomeric ratio

was determined by HPLC analysis using a chiral column to be 99:1, t

26.2 (R), 27.3 (S); [α]_D= −53.6 (c = 1.18, CHCl ), eluent:

(acetonitrile/1% formic acid in water) 50:50.

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ASSOCIATED CONTENT

■

sı Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.joc.0c02557.

Selected optimization studies; chiral HPLC chromato-

grams; and H, C and F NMR spectra (PDF)

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AUTHOR INFORMATION

■

Corresponding Author

(b) An, J.; Denton, R. M.; Lambert, T. H.; Nacsa, E. D. The

Glenn M. Sammis − Department of Chemistry, University of

British Columbia, Vancouver, British Columbia V6T 1Z1,

Canada; orcid.org/0000-0002-8204-8571;

Email: gsammis@chem.ubc.ca

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Substitution of the Hydroxyl Group in Stereogenic Alcohols with

Chirality Transfer. J. Am. Chem. Soc. 2015 , 137 , 4646 −4649.

Authors

Maxim Epifanov − Department of Chemistry, University of

British Columbia, Vancouver, British Columbia V6T 1Z1,

Canada

Jia Yi Mo − Department of Chemistry, University of British

Columbia, Vancouver, British Columbia V6T 1Z1, Canada

Rudy Dubois − Department of Chemistry, University of British

Columbia, Vancouver, British Columbia V6T 1Z1, Canada

Hao Yu − Department of Chemistry, University of British

Columbia, Vancouver, British Columbia V6T 1Z1, Canada

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Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.0c02557

Author Contributions

M.E. and J.Y.M. contributed equally to this work.

†

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The authors declare no competing ﬁnancial interest.

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