Scalable and Phosphine-Free Conversion of Alcohols to Carbon-Heteroatom Bonds through the Blue Light-Promoted Iodination Reaction

Article abstract of DOI:10.1021/acs.joc.9b03373

One of the fundamental and highly valuable transformations in organic chemistry is the nucleophilic substitution of alcohols. Traditionally, these reactions require strategies that employ stoichiometric hazardous reagents and are associated with difficulty in purification of the by-products. To overcome these challenges, here, we report a simple route toward the diverse conversion of alcohols via an S_N2 pathway, in which blue light-promoted iodination is used to form alkyl iodide intermediates from simple unreactive alcohols. The scope of the process tolerates a range of nucleophiles to construct C-N, C-O, C-S, and C-C bonds. Furthermore, we also demonstrate that this method can be used for the preparation and late-stage functionalization of pharmaceuticals, as highlighted by the syntheses of thiocarlide, butoxycaine, and pramoxine.

Full text of DOI:10.1021/acs.joc.9b03373

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Article
Scalable and Phosphine-Free Conversion of Alcohols to Carbon-
Heteroatom Bonds through Blue-Light Promoted Iodination Reaction
Bin Liu, W. Zachary Elder, and Garret M. Miyake
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03373 • Publication Date (Web): 05 Feb 2020
Downloaded from pubs.acs.org on February 5, 2020
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Scalable and Phosphine-Free Conversion of Alcohols to Carbon-
Heteroatom Bonds through Blue-Light Promoted Iodination
Reaction
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Bin Liu, W. Zachary Elder, and Garret M. Miyake*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, United States.
*e-mail: Garret.Miyake@colostate.edu
TOC Image for
Abstract: One of the fundamental and highly valuable transformations in organic
chemistry is the nucleophilic substitution of alcohols. Traditionally, these reactions require
strategies that employ stoichiometric hazardous reagents and are associated with difficulty
in purification of the biproducts. To overcome these challenges, here we report a simple
route toward the diverse conversion of alcohols via an SN2 pathway, in which blue light
promoted iodination is used to form alkyl iodide intermediates from simple unreactive
alcohols. The scope of the process tolerates a range of nucleophiles to construct C–N, C–
O, C–S, and C-C bonds. Furthermore, we also demonstrate that this method can be used
for the preparation and late stage functionalization of pharmaceuticals, as highlighted by
the synthesis of thiocarlide, butoxycaine, and pramoxine.
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INTRODUCTION
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Alcohols represent one of the most abundant organic molecules among drugs, bioactive
natural products, and synthetic intermediates.1 Therefore, various strategies have been
developed for the conversion of alcohols into a wide range of different functional groups,
such as alkenes, halides, aldehydes, ketones, carboxylic acids, and esters.2 Among them,
nucleophilic substitution reactions of alcohols through a redox combination of a trialkyl or
triarylphosphine and a dialkyl azodicarboxylate (Mitsunobu reaction) (Figure 1a)3 or
combination of triphenylphosphine and an electrophilic halogen source such as
tetrachloromethane (CCl4), tetrabromomethane (CBr4), or I2 (under Appel conditions)4
have been extensively investigated and applied to the synthesis of drugs and natural
products. However, both of these methodologies employ triphenylphosphine as a reductant
which is converted to triphenylphosphine oxide and is difficult to remove. Moreover, for
the Mitsunobu reaction, the high energy and relatively expensive reagent, azodicarboxylate,
is required. The arduous separation of stoichiometric waste by-product, poor atom
economy,5 and the use of a high energy reagent limits the use of the reaction on scale in
process chemistry.6 Although phosphine oxide catalyzed Mitsunobu reactions have been
developed recently,7 the scope of pronucleophiles is limited (Figure 1b). Consequently, the
development of more general and applicable approaches for the transformation of alcohols
has involved continuous efforts in both academia and industry.
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Alkyl halides8 and alkyl sulfonates9 are representative substrates for SN2 reactions that
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can be used in a variety of carbon–carbon and carbon–heteroatom bond-forming
reactions.10 However, preparation of these reagents is traditionally difficult and
stoichiometric waste needs to be separated to facilitate subsequent nucleophilic substitution
reactions. To enable diverse conversion of alcohols, we questioned whether it would be
possible to use in-situ generated alkyl halides from alcohols as an intermediate without
purification and subsequently employ bimolecular nucleophilic substitution (SN2)
reactions to prepare derivatives or analogues in a one-pot reaction.11
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To generate the targeted alkyl halide in-situ, we investigated established procedures for
the visible-light mediated conversion of alcohols to alkyl halides using CBr4 or CHI3
(Figure 1c, d), en route to the targeted construction of carbon-heteroatom bonds in a one-
pot reaction because of the demonstrated good functional group tolerance for the iodination
reaction that proceeded under mild conditions.12 Herein, we report the transformation of
alcohols, through blue-light promoted iodination in a two-step, one-pot reaction. In the
presence of dimethylformamide (DMF) and under blue LED irradiation, alcohols and
iodoform react to yield an alkyl iodide. Subsequent addition of the nucleophile and base to
the reaction mixture containing the alkyl iodide generated the corresponding substitution
products with excellent yields (Figure 1e). This process represents the direct and diverse
conversion of alcohols with a wide range of nucleophiles via an alkyl iodide intermediate,
avoiding the handling of phosphine, use of diethyl azodicarboxylate (DEAD), as well as
the isolation of alkyl halides or alkyl tosylates. We further demonstrate that this mild
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nucleophile substitution procedure can serve as a powerful and general method in the
preparation of medicinally relevant molecules and for the late-stage functionalization of
bioactive compounds.
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Figure 1 Development of nucleophilic substitution reactions of alcohols. a) Mitsunobu reaction. b)
Redox-neutral organocatalytic Mitsunobu reaction. c) Photoredox catalyzed conversion of alcohols to halides.
d) Visible-light driven iodination of alcohols. e) This work: Diverse conversion of alcohols through blue light
promoted iodination reaction. Nu: nucleophile.
RESULTS AND DISCUSSION
Our initial discovery arose from our continuing interest in visible light-driven and
transition metal free chemistry.13 When CBr4 was utilized as the bromide source and 3,7-
di(4-biphenyl) 1-naphthalene-10-phenoxazine as catalyst, the brominated product of 6-
hydroxyhexyl benzoate was produced in 39% yield. Encouragingly, the iodination product
was detected in high yield with blue LED irradiation of a solution containing 6-
hydroxyhexyl benzoate, iodoform and the phenoxazine organic photoredox catalyst in
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DMF. Furthermore, the desired product could also isolated in high yield (90%) in the
absence of the organic photoredox catalyst after 20 h of blue LED irradiation at room
temperature,14 similarly to published reports.12b,c The iodination product was also obtained
in high yield by switching the solvent to N,N’-dimethylacetamide (DMAc) or N-methyl-2-
pyrrolidone (NMP). Without isolation of iodinated products, we investigated potential for
a one-pot nucleophilic substitution using 4-bromobenzoic acid as the pronucleophile.
Encouragingly, the ester product (49) was isolated in 89% yield after heating the reaction
solution after addition of 4-bromobenzoic acid and K2CO3.
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To investigate the generality and robustness of the reaction conditions, we then explored
the scope of suitable alcohols. A variety of alcohols bearing different functional groups
were all competent substrates (Figure 2, 1-11). Secondary alcohol cyclopentanol provided
the ester product in 30% yield (1). Unprotected indole ethanol was tolerated and afforded
the desired product in 23% yield (4). Substrates containing ether functional groups afforded
the corresponding products in excellent yields (5, 6, 8). Primary alcohols bearing alkene
functionalities were esterified in good yields (3, 7) under mild reaction conditions. A
terminal alkyne containing alcohol was transformed to corresponding product in 85% yield
(9). It is noteworthy that a substrate containing a phosphine-sensitive alkyl azide (10) was
compatible with the robust reaction conditions.
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Figure 2 Scope of alcohols. Reaction conditions: alcohol (0.5 mmol), iodoform (1.0 mmol), 4-bromobenzoic
acid (1.0 mmol), K2CO3 (4.0 mmol), DMF (3.0 mL), isolated yields provided.
We then sought to extend the reaction system to develop other synthetically useful
carbon-heteroatom bond-forming processes. Using thiols as pronucleophiles allowed
access to a range of thioether derivatives (Figure 3, 12-24). As shown in Figure 3, diverse
thiophenols were found to be suitable pronucleophiles, including those with nitrogen-
containing heterocycles (13-15, 17-21). These common motifs are ubiquitous in
pharmaceutical molecules. Alkyl thiols were also amenable, as demonstrated by the
formation of thioether products in high yields (22, 23). Moreover, thiobenzoic acid could
also be converted to the corresponding thioester in 78% yield (24). We next investigated
the use of nitrogen nucleophiles (Figure 3). Primary and secondary amines were successful
and provided the corresponding products in good yields (25, 27-30). In addition to amines,
phthalimide can also participate in the nucleophilic substitution reaction under this system
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(26). Azido, nitro and cyano groups were compatible with the reaction, affording the
desired nucleophile substitution product in good yields (31-32).
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Figure 3 C-S and C-N bonds formation. Reaction conditions: 6-hydroxyhexyl benzoate (0.5 mmol),
iodoform (1.0 mmol), pronucleophile (1.0 mmol), K2CO3 (4.0 mmol), DMF (3.0 mL), isolated yields
provided.
In order to investigate the compatibility of this reaction system more thoroughly, the
potential of using phenols and carboxylic acids was also explored (Figure 4). Heterocycles,
including pyridine (35, 36, 40, 46), quinoline (39), coumarin (37), indole (44, 51), furan
(48) and benzo[b]thiophene (50) are tolerated under the reaction conditions. When
indomethacin was subjected to the standard reaction conditions, the deprotection product
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was also isolated in 38% yield. Other functionalities, including bromide (33, 49), nitro (34),
alkenes (42, 43, 47) and protected amine (52) groups, also participate well in the reaction.
Interestingly, biotin (41) is also tolerated and generated the desired product in 84% yield.
Furthermore, we successfully introduced diphenylphosphinic acid (53) to form the
phosphinate product in 60% yield.
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To demonstrate our system’s potential utility, this strategy was applied to the late-stage
diversification of ketoprofen. Under the standard reaction conditions, a variety of
ketoprofen derivatives were efficiently prepared (54-57). Finally, we applied our strategy
to the synthesis of thiocarlide,15 butoxycaine16 and pramoxine (Figure 5).17 Our one-pot
SN2 reactions provide a convenient and atom economical procedure to make aryl ethers in
good yields (58-60), without handling triphenylphosphine or isolating the alkyl halides and
alkyl sulfonates. The key structure of thiocarlide was synthesized by conversion of isoamyl
alcohol to isoamyl iodide, which was reacted with acetaminophen in-situ to produce the
product 58 in 94% yield. This strategy afforded the product in higher yield compared with
the recently reported phosphine oxide catalyzed Mitsunobu reaction.7b Aryl ether product
59 was produced in 96% yield, avoiding the use of a palladium catalyzed C-O cross-
coupling reaction.16 In particular, we scaled up the production of 59 to 50 mmol, although
the yield was reduced to 50%, most likely due to the high concentration of the solution or
poorer irradiation of the larger reaction mixture.
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Figure 4 C-O bond formation. Reaction conditions: 6-hydroxyhexyl benzoate (0.5 mmol), iodoform (1.0
mmol), pronucleophile (1.0 mmol), K2CO3 (4.0 mmol), DMF (3.0 mL), isolated yields provided.
Figure 5 Late-stage diversification of bioactive molecule and active pharmaceutical ingredient
synthesis. a) Late-stage diversification of bioactive molecule. b) Active pharmaceutical ingredient synthesis.
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CONCLUSIONS
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In sum, we have successfully developed a convenient and efficient approach for the
diverse functionalization of alcohols through the direct iodination of alcohols with
iodoform. As the traditional conversion of alcohols requires the isolation of alkyl halides
or alkyl tosylates, this one-pot approach is expected to modernize this transformation by
providing more direct syntheses and access to new products. A simple procedure for both
the iodination and nucleophilic substitution reactions (SN2) in one-pot renders this protocol
highly practical. This transformation has been applied to the late-stage functionalization of
pharmaceutical reagents and the synthesis of thiocarlide, butoxycaine and pramoxine.
Further, the reaction was effectively scaled to employ 50 mmol of starting material.
Considering the operational simplicity, broad functional group compatibility and
scalability of this reaction, we anticipate this transformation will have both academic and
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industrial value.
EXPERIMENT SECTION
General Information. Dimethylformamide (DMF), dimethylacetamide (DMAc) and N-
methyl-2-pyrrolidone (NMP) was purchased from Sigma-Aldrich and sparged with
nitrogen for 15 min at room temperature and stored under nitrogen atmosphere. Hexane-
1,6-diol were purchased from TCI America. CHI3 was purchased from Sigma-Aldrich.
Thiols, phenols, carboxylic acids and amines were purchased from Sigma-Aldrich, TCI
and Alfa Aesar. Organic solutions were concentrated under reduced pressure on a Büchi
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rotary evaporator using a water bath. The visible light source was a 16-inch strip of double-
density blue LEDs, purchased from Creative Lighting Solutions (item no. CL-
FRS5050WPDD-5M-12V-BL), wrapped inside a 400 mL beaker (Figure S1). The distance
from the light source to the irradiation vessel is about 4 cm, no filters are used.
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The 1H and 13C NMR spectra were recorded at 400 MHz for 1H or at 101 MHz for 13C,
respectively. Deuterated solvents were purchased from Cambridge Isotope Laboratories
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(Andover, MA) and used as received. All H NMR experiments are reported in δ units,
parts per million (ppm), and were measured relative to the signals for residual chloroform
(7.26 ppm) in the deuterated solvent. Data for 1H NMR are reported as follows: chemical
shift (δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, p = quintet, m =
multiplet, dd = doublet of doublets, dt = doublet of triplets…etc, br = broad), coupling
constant (Hz) and integration. All 13C NMR spectra are reported in ppm relative to CDCl3
(77.0 ppm). Trimethyoxybenzene was used as an internal standard for NMR yields from
proton analysis for the 6-iodohexyl benzoate formation.
Flash column chromatography was performed by using a 100-150 times weight excess
of flash silica gel 40-63 μm from Aldrich. Fractions were analyzed by TLC using TLC
silica gel F254 250 μm precoated-plates from Merck and permanganate stain was used for
UV-inactive compounds. High resolution mass spectra were obtained via DART-MS on an
Agilent 6210 TOF interfaced to DART 100 source and Aglient 6224 time of flight (TOF)
LC-MS provided by Colorado State University Central Instrument Facility.
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General Procedure forConversion of Alcohols. A 50 mL storage flask was charged
with a stir bar, flame dried under vacuum and back filled with nitrogen three times. The
flask was then charged with 6-hydroxyhexyl benzoate (111.1 mg, 0.5 mmol, 1.0 eq.),
iodoform (397.7 mg, 1.0 mmol, 2.0 eq.), and 3.0 mL DMAc. The reaction mixture was
evacuated and purged with inert gas (N2) three times. The reaction mixture was then placed
into an LED-lined beaker and stirred under compressed air cooling (room temperature).
After the time specified in the reaction schemes, K2CO3 (552.8 mg, 4.0 mmol, 8.0 eq),
pronucleophile (1.0 mmol, 2.0 eq) was added into the reaction mixture, and stirred at 100
oC using oil bath for 20 h. The reaction mixture was washed with water and extracted with
EtOAc. Purification of the crude product by flash chromatography on silica gel using the
indicated solvent system afforded the desired product.
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Synthesis of Drugs
N-(4-(isopentyloxy)phenyl)acetamide1
A 50 mL storage flask was charged with a stir bar, flame dried under vacuum and back
filled with nitrogen three times. The flask was then charged with 3-methylbutan-1-ol (88.2
mg, 1.0 mmol, 1.0 eq.), iodoform (795.5 mg, 2.0 mmol, 2.0 eq.), and 3.0 mL DMAc. The
reaction mixture was evacuated and purged with inert gas (N2) three times. The reaction
mixture was then placed into an LED-lined beaker and stirred under compressed air cooling
(room temperature). After the time specified in the reaction schemes, K2CO3 (552.8 mg,
4.0 mmol, 4.0 eq), pronucleophile (302.3 mg, 1.0 mmol, 2.0 eq) was added into the reaction
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mixture, and stirred at 100 °C for 20 h. The reaction mixture was washed with water and
extracted with EtOAc. Purification by flash chromatography (1:1 EtOAc:hexanes)
provided the title compound (310 mg) in 94% yield.
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4-Butoxyphenol2
A 50 mL storage flask was charged with a stir bar, flame dried under vacuum and back
filled with nitrogen three times. The flask was then charged with butan-1-ol (74.1 mg, 1.0
mmol, 1.0 eq.), iodoform (795.5 mg, 2.0 mmol, 2.0 eq.), and 3.0 mL DMAc. The reaction
mixture was evacuated and purged with inert gas (N2) three times. The reaction mixture
was then placed into an LED-lined beaker and stirred under compressed air cooling (room
temperature). After the time specified in the reaction schemes, K2CO3 (552.8 mg, 4.0 mmol,
4.0 eq), pronucleophile (304.2 mg, 1.0 mmol, 2.0 eq) was added into the reaction mixture,
and stirred at 100 oC for 20 h. The reaction mixture was washed with water and extracted
with EtOAc. Purification by flash chromatography (1:4 EtOAc:hexanes) provided the title
compound (101 mg) in 60% yield.
Methyl 4-butoxybenzoate3
A 50 mL storage flask was charged with a stir bar, flame dried under vacuum and back
filled with nitrogen three times. The flask was then charged with butan-1-ol (74.1 mg, 1.0
mmol, 1.0 eq.), iodoform (795.5 mg, 2.0 mmol, 2.0 eq.), and 3.0 mL DMAc. The reaction
mixture was evacuated and purged with inert gas (N2) three times. The reaction mixture
was then placed into an LED-lined beaker and stirred under compressed air cooling (room
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temperature). After the time specified in the reaction schemes, K2CO3 (552.8 mg, 4.0 mmol,
4.0 eq), pronucleophile (304.3 mg, 1.0 mmol, 2.0 eq) was added into the reaction mixture,
and stirred at 100 oC for 20 h. The reaction mixture was washed with water and extracted
with EtOAc. Purification by flash chromatography (1:9 EtOAc:hexanes) provided the title
compound (200 mg) in 96% yield.
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Multi-Gram Scale Experiment. A250 mL storage flask was charged with a stir bar, flame
dried under vacuum and back filled with nitrogen three times. The flask was then charged
with butan-1-ol (3.7 g, 50.0 mmol, 1.0 eq.), iodoform (39.3 g, 100.0 mmol, 2.0 eq.), and
100.0 mL DMAc. The reaction mixture was evacuated and purged with inert gas (N2) three
times. The reaction mixture was then placed into an LED-lined beaker and stirred under
compressed air cooling (room temperature). After the time specified in the reaction
schemes, K2CO3 (27.6 g, 200.0 mmol, 4.0 eq), pronucleophile (15.2 g, 100.0 mmol, 2.0 eq)
o
was added into the reaction mixture, and stirred at 100 C for 20 h. The reaction mixture
was washed with water and extracted with EtOAc. Purification by flash chromatography
(1:9 EtOAc:hexanes) provided the title compound (5.27 g) in 50% yield.
Cyclopentyl 4-bromobenzoate (1) (41 mg, 30% yield) Physical State: colorless oil; Rf
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= 0.5 (silica gel, 1:10 EtOAc:hexanes); H NMR (400 MHz, CDCl3) δ 7.94 – 7.79 (m,
2H), 7.62 – 7.51 (m, 2H), 5.39 (m, 1H), 2.03 – 1.90 (m, 2H), 1.90 – 1.75 (m, 4H), 1.74 –
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1.60 (m, 2H). C NMR (101 MHz, CDCl3) C{ H} 165.6, 131.6, 131.0, 129.8, 127.7,
78.0, 32.7, 23.8. HRMS (DART) m/z: [M+H]+ calcd. for C12H14BrO2 269.0172, found
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2-(Pyridin-2-yl)ethyl 4-bromobenzoate (2) (59 mg, 38% yield) Physical State:
colorless oil; Rf = 0.5 (silica gel, 1:3 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 8.56
(ddd, J = 4.9, 1.9, 0.9 Hz, 1H), 7.84 – 7.81 (m, 2H), 7.61 (td, J = 7.6, 1.8 Hz, 1H), 7.56 –
7.52 (m, 2H), 7.22 (dt, J = 7.8, 1.1 Hz, 1H), 7.15 (m, 1H), 4.70 (t, J = 6.7 Hz, 2H), 3.24 (t,
J = 6.7 Hz, 2H). 13C NMR (101 MHz, CDCl3) 13C{1H} δ 165.7, 157.9, 149.6, 136.4, 131.6,
131.1, 129.1, 128.0, 123.4, 121.7, 64.4, 37.4. HRMS (DART) m/z: [M+H]+ calcd. for
C14H13BrNO2 306.0124, found 306.0152.
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4-((3aR,7aS)-1,3-dioxo-1,3,3a,4,7,7a-hexahydro-2H-4,7-methanoisoindol-2
yl)benzyl 4-bromobenzoate (3) (150 mg, 66% yield) Physical State: white solid; Rf = 0.5
(silica gel, 1:1 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 7.93 – 7.90 (m, 2H), 7.55
m, 4H), 7.40 – 7.18 (m, 2H), 6.34 (s, 2H), 5.35 (s, 2H), 3.40 (s, 2H), 2.86 (s, 2H), 1.63 (d,
J = 10.0 Hz, 1H), 1.47 (d, J = 10.0 Hz, 1H). 13C NMR (101 MHz, CDCl3) 13C{1H} δ 176.9,
165.5, 137.9, 136.2, 131.8, 131.7, 131.2, 129.0, 128.8, 128.2, 126.5, 66.2, 47.8, 45.8, 42.9.
HRMS (DART) m/z: calcd. [M+H]+ for C23H19BrNO4 452.0492, found 452.0487.
2-(1H-indol-3-yl)ethyl 4-bromobenzoate (4) (79 mg, 23% yield) Physical State:
yellow oil; Rf = 0.5 (silica gel, 1:3 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 8.05
(s, 1H), 7.92 – 7.88 (m, 2H), 7.70 – 7.68 (m, 2H), 7.60 – 7.55 (m, 2H), 7.38 (d, J = 8.1,
1H), 7.25 – 7.21 (m, 1H), 7.16 (ddd, J = 8.0, 7.0, 1.1 Hz, 1H), 7.10 – 7.08 (m, 1H), 4.61 (t,
J = 7.1 Hz, 2H), 3.25 (td, J = 7.1, 0.9 Hz, 2H). 13C NMR (101 MHz, CDCl3) 13C{1H} δ
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165.9, 136.2, 131.6, 131.1, 129.3, 128.0, 127.4, 122.2, 122.0, 119.5, 118.7, 112.0, 111.2,
65.3, 24.8. HRMS (DART) m/z: [M+Na]+ calcd. for C17H14BrNO2Na 366.0100, found
366.0123.
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2-(Phenylthio)ethyl 4-bromobenzoate (5) (159 mg, 94% yield) Physical State: yellow
oil; Rf = 0.5 (silica gel, 1:10 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 7.82 – 7.79
(m, 2H), 7.57 – 7.54 (m, 2H), 7.45 – 7.41 (m, 2H), 7.33 – 7.28 (m, 2H), 7.24 – 7.20 (m,
13
1H), 4.48 (t, J = 6.8 Hz, 2H), 3.28 (t, J = 6.8 Hz, 2H). C NMR (101 MHz, CDCl3) δ
165.6, 135.1, 131.7, 131.2, 130.1, 129.1, 128.8, 128.2, 126.7, 63.9, 32.6. HRMS (DART)
m/z: [M+H]+ calcd. for C15H14BrO2S 336.9892, found 336.9886.
4-(Benzyloxy)butyl 4-bromobenzoate (6) (151 mg, 83% yield) Physical State: white
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solid; Rf = 0.5 (silica gel, 1:10 EtOAc:hexanes); H NMR (400 MHz, CDCl3) δ 7.91 –
7.87 (m, 2H), 7.63 – 7.55 (m, 2H), 7.37 – 7.32 (m, 4H), 7.31 – 7.26 (m, 1H), 4.52 (s, 2H),
4.34 (t, J = 6.5 Hz, 2H), 3.54 (t, J = 6.2 Hz, 2H), 1.90 – 1.86 (m, 2H), 1.79 – 1.85 (m, 2H).
13C NMR (101 MHz, CDCl3) 13C{1H} δ 165.9, 138.4, 131.7, 131.1, 129.3, 128.4, 127.9,
127.6, 127.6, 73.0, 69.7, 65.1, 26.4, 25.6. HRMS (DART) m/z: [M+NH4]+ calcd. for
C18H23BrNO3 380.0856, found 380.0862.
(Z)-Octadec-9-en-1-yl 4-bromobenzoate (7) (201 mg, 88% yield) Physical State:
yellow oil; Rf = 0.5 (silica gel, 1:10 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 7.91
– 7.88 (m, 2H), 7.59 – 7.56 (m, 2H), 5.36 – 5.33 (m, 2H), 4.30 (t, J = 6.7 Hz, 2H), 2.04 –
1.99 (m, 4H), 1.79 – 1.72 (m, 2H), 1.45 – 1.26 (m, 23H), 0.88 (t, J = 6.8 Hz, 3H). 13C NMR
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(101 MHz, CDCl3) C{1H} 165.9, 131.6, 131.1, 130.0, 129.7, 129.4, 127.9, 65.4, 31.9,
29.8, 29.7, 29.6, 29.5, 29.5, 29.4, 29.2, 29.2, 29.2, 28.6, 27.2, 26.0, 22.7, 14.1. HRMS
(DART) m/z: [M+H]+ calcd. for C25H40BrO2 451.2206, found 451.2200.
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Benzo[d][1,3]dioxol-5-ylmethyl 4-bromobenzoate (8) (160 mg, 95% yield) Physical
State: white solid; Rf = 0.5 (silica gel, 1:5 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3)
δ 7.92 – 7.89 (m, 2H), 7.58 – 7.54 (m, 2H), 6.93 – 6.90 (m, 2H), 6.80 (dd, J = 7.7, 0.6 Hz,
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1H), 5.97 (s, 2H), 5.24 (s, 2H). C NMR (101 MHz, CDCl3) C{ H} δ 165.7, 147.8,
147.7, 131.7, 131.2, 129.4, 129.0, 128.1, 122.3, 109.0, 108.3, 101.2, 66.9. HRMS (DART)
m/z: [M+NH4]+ calcd. for C15H15BrNO4 352.0179, found 352.0163.
Hex-5-yn-1-yl 4-bromobenzoate (9) (120 mg, 85% yield) Physical State: colorless oil;
Rf = 0.5 (silica gel, 1:10 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 7.90 – 7.87 (m,
2H), 7.58 – 7.54 (m, 2H), 4.33 (td, J = 6.5, 0.9 Hz, 2H), 2.27 (td, J = 7.0, 2.7, 2H), 1.97 (t,
J = 2.7 Hz, 1H), 1.93 – 1.86 (m, 2H), 1.72 – 1.64 (m, 2H). 13C NMR (101 MHz, CDCl3)
13C{1H} δ 165.8, 131.6, 131.0, 129.2, 127.9, 83.71, 68.8, 64.7, 27.7, 25.0, 18.1. HRMS
(DART) m/z: [M+H]+ calcd. for C13H14BrO2 281.0172, found 281.0175.
6-Azidohexyl 4-bromobenzoate (10) (100 mg, 61% yield) Physical State: colorless oil;
Rf = 0.5 (silica gel, 1:2 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 7.91 – 7.87 (m,
2H), 7.59 – 7.56 (m, 2H), 4.31 (t, J = 6.6 Hz, 2H), 3.27 (t, J = 6.8 Hz, 2H), 1.80 – 1.74 (m,
2H), 1.64 – 1.59 (m, 2H), 1.49 – 1.43 (m, 4H). 13C NMR (101 MHz, CDCl3) 13C{1H} δ
165.9, 131.7, 131.0, 129.3, 127.9, 65.1, 51.3, 28.7, 28.5, 26.4, 25.6. HRMS (DART) m/z:
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[M+NH4]+ calcd. for C13H20BrN4O2 343.0764, found 343.0773.
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((4S,6S)-6-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,2
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dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 4-bromobenzoate (11) (60 mg,
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26% yield) Physical State: colorless oil; Rf = 0.5 (silica gel, 4:1 EtOAc:hexanes); H
NMR (400 MHz, CDCl3) δ 9.69 (s, 1H), 7.90 – 7.88 (m, 2H), 7.59 – 7.57 (m, 2H), 7.27 –
7.25 (m, 1H), 5.69 (d, J = 8.1 Hz, 1H), 5.61 (d, J = 1.7 Hz, 1H), 5.10 (dd, J = 6.4, 1.7 Hz,
1H), 4.95 (dd, J = 6.4, 4.2 Hz, 1H), 4.58 – 4.54 (m, 1H), 4.47 – 4.45 (m, 1H), 1.58 (s, 3H),
1.37 (s, 3H). 13C NMR (101 MHz, CDCl3) 13C{1H} δ 165.4, 163.6, 150.0, 142.7, 131.8,
131.7, 131.2, 131.2, 128.5, 128.4, 114.6, 102.6, 95.6, 85.7, 84.6, 81.2, 64.7, 60.4, 27.1,
25.3, 14.2. HRMS (LC-MS-TOF) m/z: [M+H]+ calcd. for C19H20BrN2O7 467.0448, found
467.0449.
6-((4-Bromophenyl)thio)hexyl benzoate (12) (187 mg, 95% yield) Physical State:
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colorless oil; Rf = 0.5 (silica gel, 1:10 EtOAc:hexanes); H NMR (400 MHz, CDCl3) δ
8.05 – 8.02 (m, 2H), 7.58 – 7.54 (m, 1H), 7.46 – 7.43 (m, 2H), 7.42 – 7.37 (m, 2H), 7.19 –
7.16 (m, 2H), 4.31 (t, J = 6.6 Hz, 2H), 2.90 (t, J = 6.6 Hz, 2H), 1.80 – 1.73 (m, 2H), 1.70
– 1.63 (m, 2H), 1.54 – 1.44 (m, 4H). 13C NMR (101 MHz, CDCl3) 13C{1H} δ 166.6, 136.0,
132.8, 131.8, 130.4, 130.4, 129.5, 128.3, 119.5, 64.8, 33.6, 28.8, 28.6, 28.4, 25.6. HRMS
(DART) m/z: [M+H]+ calcd. for C19H22BrO2S 393.0518, found 393.0516.
6-(Benzo[d]thiazol-2-ylthio)hexyl benzoate (13) (186 mg, 97% yield) Physical State:
yellow oil; Rf = 0.5 (silica gel, 1:3 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 8.05
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– 8.03 (m, 2H), 7.86 (dt, J = 8.0, 1.0 Hz, 1H), 7.74 (dt, J = 8.0, 1.0 Hz, 1H), 7.56 – 7.52
(m, 1H), 7.44 – 7.37 (m, 3H), 7.30 – 7.25 (m, 1H), 4.32 (t, J = 6.6 Hz, 2H), 3.40 – 3.25 (m,
2H), 1.90 – 1.76 (m, 4H), 1.59 – 1.49 (m, 4H). 13C NMR (101 MHz, CDCl3) 13C{1H} δ
167.1, 166.6, 153.3, 135.1, 132.8, 130.3, 129.5, 128.3, 126.0, 124.0, 121.4, 120.9, 64.8,
33.4, 29.1, 28.5, 28.3, 25.5. HRMS (DART) m/z: [M+H]+ calcd. for C20H22NO2S2
372.1086, found 372.1102.
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6-(Pyrimidin-2-ylthio)hexyl benzoate (14) (155 mg, 88% yield) Physical State:
colorless oil; Rf = 0.5 (silica gel, 1:3 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 8.50
(d, J = 4.9 Hz, 2H), 8.06 – 8.03 (m, 2H), 7.57 – 7.53 (m, 1H), 7.46 – 7.41 (m, 2H), 6.94 (t,
J = 4.8 Hz, 1H), 4.32 (t, J = 6.6 Hz, 2H), 3.16 (t, J = 7.2 Hz, 2H), 1.83 – 1.74 (m, 4H), 1.58
– 1.49 (m, 4H). 13C NMR (101 MHz, CDCl3) 13C{1H} δ 172.7, 166.7, 157.2, 132.8, 130.5,
129.5, 128.3, 116.3, 65.0, 30.7, 29.0, 28.6, 28.5, 25.7. HRMS (DART) m/z: [M+H]+ calcd.
for C17H21N2O2S 317.1318, found 317.1340.
6-((4,5-Dihydrothiazol-2-yl)thio)hexyl benzoate (15) (155 mg, 95% yield) Physical
State: colorless oil; Rf = 0.5 (silica gel, 1:3 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3)
δ 8.05 – 8.02 (m, 2H), 7.57 – 7.53 (m, 1H), 7.46 – 7.42 (m, 2H), 4.31 (t, J = 6.6 Hz, 2H),
4.20 (t, J = 8.0 Hz, 2H), 3.37 (t, J = 7.9 Hz, 2H), 3.11 (t, J = 7.2 Hz, 2H), 1.79 – 1.71 (m,
4H), 1.50 – 1.40 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 166.6, 165.7, 132.8, 130.4, 129.5,
128.3, 64.9, 64.3, 35.3, 32.6, 29.2, 28.6, 28.4, 25.6. HRMS (DART) m/z: [M+H]+ calcd.
for C16H22NO2S2 324.1086, found 324.1105.
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6-((4-Methyl-2-oxo-2H-chromen-7-yl)thio)hexyl benzoate (16) (195 mg, 91% yield)
Physical State: yellow oil; Rf = 0.5 (silica gel, 1:3 EtOAc:hexanes); 1H NMR (400 MHz,
CDCl3) δ 8.04 – 8.01 (m, 2H), 7.56 – 7.52 (m, 1H), 7.45 – 7.40 (m, 3H), 7.14 – 7.12 (m,
2H), 6.19 (q, J = 1.2 Hz, 1H), 4.31 (t, J = 6.6 Hz, 2H), 2.99 (t, J = 7.2 Hz, 2H), 2.38 (d, J
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= 1.3 Hz, 3H), 1.80 – 1.70 (m, 5H), 1.60 – 1.48 (m, 4H). C NMR (101 MHz, CDCl3)
13C{1H} δ 166.6, 160.6, 153.8, 152.2, 143.5, 132.8, 130.3, 129.5, 128.3, 124.5, 122.9, 117.0,
113.9, 113.7, 64.8, 32.0, 28.5, 28.5, 28.5, 25.6, 18.5. HRMS (LC-MS-TOF) m/z: [M+H]+
calcd. for C23H25O4S 397.1468, found 397.1485.
6-((1-methyl-1H-imidazol-2-yl)thio)hexyl benzoate (17) (150 mg, 94% yield)
Physical State: colorless oil; Rf = 0.5 (silica gel, 1:1 EtOAc:hexanes); 1H NMR (400 MHz,
CDCl3) δ 8.04 – 8.01 (m, 2H), 7.56 – 7.52 (m, 1H), 7.45 – 7.40 (m, 2H), 7.04 (d, J = 1.3
Hz, 1H), 6.90 (d, J = 1.3 Hz, 1H), 4.29 (t, J = 6.6 Hz, 2H), 3.59 (s, 3H), 3.05 (t, J = 7.2 Hz,
2H), 1.77 – 1.65 (m, 4H), 1.50 – 1.43 (m, 4H). 13C NMR (101 MHz, CDCl3) 13C{1H} δ
166.6, 141.9, 132.8, 130.4, 129.4, 129.2, 128.3, 122.0, 64.8, 34.1, 33.1, 29.6, 28.5, 28.2,
25.6. HRMS (DART) m/z: [M+H]+ calcd. for C17H23N2O2S 319.1475, found 319.1484.
6-((1H-benzo[d]imidazol-2-yl)thio)hexyl benzoate (18) (165 mg, 89% yield) Physical
State: yellow solid; Rf = 0.5 (silica gel, 1:3 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3)
δ 10.75 (s, 1H), 8.05 – 8.02 (m, 2H), 7.56 – 7.51 (m, 2H), 7.45 – 7.40 (m, 2H), 7.20 – 7.16
(m, 2H), 4.28 (t, J = 6.6 Hz, 2H), 3.31 (t, J = 7.3 Hz, 2H), 1.80 – 1.67 (m, 4H), 1.49 – 1.37
(m, 4H). 13C NMR (101 MHz, CDCl3) 13C{1H} δ 166.8, 150.6, 132.9, 130.3, 129.5, 128.3,
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122.2, 64.9, 32.5, 29.4, 28.5, 28.2, 25.5. HRMS (DART) m/z: [M+H]+ calcd. for
C20H23N2O2S 355.1475, found 355.1488.
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6-(Benzo[d]oxazol-2-ylthio)hexyl benzoate (19) (161 mg, 90% yield) Physical State:
white solid; Rf = 0.5 (silica gel, 1:6 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 8.05
– 8.03 (m, 2H), 7.61 – 7.58 (m, 1H), 7.57 – 7.53 (m, 1H), 7.46 – 7.41 (m, 3H), 7.30 – 7.21
(m, 2H), 4.33 (t, J = 6.6 Hz, 2H), 3.3 (t, J = 7.2 Hz, 2H), 1.92 – 1.77 (m, 4H), 1.62 – 1.50
(m, 4H). 13C NMR (101 MHz, CDCl3) 13C{1H} δ 166.6, 165.1, 151.8, 142.0, 132.8, 130.4,
129.5, 128.3, 124.2, 123.8, 118.3, 109.8, 64.9, 32.1, 29.1, 28.6, 28.3, 25.6. HRMS (DART)
m/z: [M+H]+ calcd. for C20H22NO3S 356.1315, found 356.1346.
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6-((4-Aminopyrimidin-2-yl)thio)hexyl benzoate (20) (155 mg, 93% yield) Physical
State: white solid; Rf = 0.5 (silica gel, 1:1 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3)
δ 8.05 – 8.00 (m, 3H), 7.56 – 7.52 (m, 1H), 7.45 – 7.40 (m, 2H), 6.09 (d, J = 5.8 Hz, 1H),
5.05 (s, 2H), 4.31 (t, J = 6.6 Hz, 2H), 3.10 – 3.07 (m, 2H), 1.93 – 1.70 (m, 4H), 1.53 – 1.46
(m, 4H). 13C NMR (101 MHz, CDCl3) 13C{1H} δ 171.5, 166.7, 162.3, 155.9, 132.8, 130.4,
129.5, 128.3, 100.8, 65.0, 30.4, 29.2, 28.5, 28.4, 25.6. HRMS (DART) m/z: [M+H]+ calcd.
for C17H22N3O2S 332.1427, found 332.1459.
6-(Pyridin-2-ylthio)hexyl benzoate (21) (146 mg, 90% yield) Physical State: colorless
oil; Rf = 0.5 (silica gel, 1:6 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 8.41 (dd, J =
5.0, 1.9 Hz, 1H), 8.06 – 8.03 (m, 2H), 7.57 – 7.52 (m, 1H), 7.47 – 7.41 (m, 3H), 7.15 (dt,
J = 8.1, 1.0 Hz, 1H), 6.95 (ddd, J = 7.4, 5.0, 1.1 Hz, 1H), 4.31 (t, J = 6.6 Hz, 2H), 3.18 (t,
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J = 7.2 Hz, 2H), 1.82 – 1.69 (m, 4H), 1.58 – 1.45 (m, 4H). 13C NMR (101 MHz, CDCl3)
δ 166.6, 159.4, 149.4, 135.8, 132.8, 130.4, 129.5, 128.3, 122.2, 119.2, 64.9, 29.9, 29.2,
28.6, 28.5, 25.7. HRMS (DART) m/z: [M+H]+ calcd. for C18H22NO2S 316.1366, found
316.1373.
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6-((Furan-2-ylmethyl)thio)hexyl benzoate (22) Physical State: yellow oil; Rf = 0.5
(silica gel, 1:10 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 8.05 – 8.03 (m, 2H), 7.57
– 7.53 (m, 1H), 7.46 – 7.41 (m, 2H), 7.34 (dd, J = 1.9, 0.9 Hz, 1H), 6.29 (dd, J = 3.2, 1.8
Hz, 1H), 6.17 – 6.15 (m, 1H), 4.31 (t, J = 6.6 Hz, 2H), 3.70 (d, J = 0.7 Hz, 2H), 2.51 (d, J
= 7.2, 2H), 1.79 – 1.74 (m, 2H), 1.61 – 1.57 (m, 2H), 1.48 – 1.42 (m, 4H). 13C NMR (101
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MHz, CDCl3) C{1H} δ 166.6, 151.8, 142.0, 132.8, 130.4, 129.5, 128.3, 110.3, 107.2,
64.9, 31.6, 29.0, 28.6, 28.4, 28.3, 25.6. HRMS (DART) m/z: [M+NH4]+ calcd. for
C18H26NO3S 336.1628, found 336.1645.
6-(Cyclohexylthio)hexyl benzoate (23) (146 mg, 91% yield) Physical State: colorless
oil; Rf = 0.5 (silica gel, 1:15 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 8.05 – 8.03
(m, 2H), 7.57 – 7.53 (m, 1H), 7.46 – 7.41 (m, 2H), 4.31 (t, J = 6.6 Hz, 2H), 2.66 – 2.59 (m,
1H), 2.54 (t, J = 7.2 Hz, 2H), 2.03 – 1.91 (m, 1H), 1.81 – 1.73 (m, 4H), 1.64 – 1.57 (m,
4H), 1.51 – 1.43 (m, 4H), 1.41 – 1.16 (m, 6H). 13C NMR (101 MHz, CDCl3) 13C{1H} δ
166.6, 132.8, 130.5, 129.5, 128.3, 64.9, 43.5, 42.7, 33.7, 33.2, 30.0, 29.9, 28.6, 26.1, 26.0,
25.9, 25.7. HRMS (DART) m/z: [M+NH4]+ calcd. for C19H32NO2S 338.2148, found
338.2178.
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6-(Benzoylthio)hexyl benzoate (24) (134 mg, 78% yield) Physical State: colorless oil;
Rf = 0.5 (silica gel, 1:10 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 8.06 – 8.03 (m,
2H), 7.98 – 7.95 (m, 2H), 7.58 – 7.53 (m, 2H), 7.47 – 7.41 (m, 4H), 4.33 (t, J = 6.6 Hz,
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2H), 3.09 (t, J = 7.2 Hz, 2H), 1.83 – 1.68 (m, 4H), 1.56 –1.46 (m , 4H). C NMR (101
MHz, CDCl3) C{1H} δ 192.0, 166.6, 137.2, 133.2, 132.8, 130.4, 129.5, 128.5, 128.3,
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127.2, 64.9, 29.5, 28.9, 28.6, 28.5, 25.6. HRMS (DART) m/z: [M+NH4]+ calcd. for
C20H26NO3S 360.1628, found 360.1654.
6-(1H-benzo[d]imidazol-1-yl)hexyl benzoate (25) (94 mg, 58% yield) Physical State:
white solid; Rf = 0.5 (silica gel, 3:1 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 8.05
– 8.01 (m, 2H), 7.88 (s, 1H), 7.85 – 7.78 (m, 1H), 7.57 – 7.46 (m, 1H), 7.46 – 7.37 (m, 2H),
7.32 – 7.25 (m, 2H), 4.30 (t, J = 6.5 Hz, 2H), 4.17 (t, J = 7.1 Hz, 2H), 1.95 – 1.88 (m, 2H),
1.79 – 1.72 (m, 2H), 1.53 – 1.39 (m, 4H). 13C NMR (101 MHz, CDCl3) 13C{1H} δ 166.56,
143.9, 142.8, 133.7, 132.9, 130.3, 129.4, 128.3, 122.8, 122.0, 120.4, 109.5, 64.6, 44.9, 29.7,
28.5, 26.5, 25.6. HRMS (DART) m/z: [M+H]+calcd. for C20H23N2O2 323.1754, found
323.1759.
6-(1,3-Dioxoisoindolin-2-yl)hexyl benzoate (26) (116 mg, 66% yield) Physical State:
white solid; Rf = 0.5 (silica gel, 1:3 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 8.04
– 8.01 (m, 2H), 7.83 – 7.80 (m, 2H), 7.71 – 7.68 (m, 2H), 7.56 – 7.51 (m, 1H), 7.44 – 7.40
(m, 2H), 4.29 (t, J = 6.6 Hz, 2H), 3.69 (t, J = 7.2 Hz, 2H), 1.80 – 1.67 (m, 4H), 1.54 – 1.37
(m, 4H). 13C NMR (101 MHz, CDCl3) δ 168.4, 166.6, 133.8, 132.7, 132.1, 130.4, 129.5,
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128.3, 123.1, 64.8, 37.8, 28.6, 28.5, 26.5, 25.6. HRMS (DART) m/z: [M+NH4]+ calcd. for
C21H25N2O4 369.1809, found 369.1826.
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6-(Indolin-1-yl)hexyl benzoate (27) (122 mg, 75% yield) Physical State: colorless oil;
Rf = 0.5 (silica gel, 1:5 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 8.09 – 8.06 (m,
2H), 7.60 – 7.55 (m, 1H), 7.48 – 7.43 (m, 2H), 7.10 –7.05 (m, 2H), 6.67 – 6.63 (m, 1H),
6.47 (dd, J = 7.6, 1.1 Hz, 1H), 4.36 (t, J = 6.6 Hz, 2H), 3.35 (t, J = 8.3 Hz, 2H), 3.08 (t, J
= 7.6 Hz, 2H), 2.97 (t, J = 8.3 Hz, 2H), 1.86 – 1.79 (m, 2H), 1.70 – 1.63 (m, 2H), 1.58 –
1.45 (m, 4H). 13C NMR (101 MHz, CDCl3) 13C{1H} δ 166.6, 152.7, 132.8, 130.4, 129.9,
129.5, 128.3, 127.2, 124.3, 117.2, 106.7, 64.9, 53.0, 49.1, 28.7, 28.5, 27.3, 26.7, 25.9.
HRMS (DART) m/z: [M+H]+ calcd. for C21H26NO2 324,1958, found 324.1987.
6-Morpholinohexyl benzoate (28) (90 mg, 61% yield) Physical State: yellow oil ; Rf
= 0.5 (silica gel, 8:1 DCM:MeOH); 1H NMR (400 MHz, CDCl3) δ 8.05 – 8.01 (m, 2H),
7.57 – 7.52 (m, 1H), 7.45 – 7.41 (m, 2H), 4.31 (t, J = 6.6 Hz, 2H), 3.70 (t, J = 4.5 Hz, 4H),
2.43 – 2.41 (m, 4H), 2.34 – 2.30 (m, 2H), 1.81 – 1.74 (m, 2H), 1.53 – 1.35 (m, 6H). 13C
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NMR (101 MHz, CDCl3) C{1H} δ 166.6, 132.8, 130.4, 129.5, 128.3, 67.0, 64.9, 64.7,
59.0, 53.8, 28.6, 27.1, 26.4, 26.0. HRMS (DART) m/z: [M+H]+ calcd. for C17H26NO3
292.1907, found 292.1933.
6-((4-Iodophenyl)amino)hexyl benzoate (29) (115 mg, 54% yield) Physical State:
yellow solid; Rf = 0.5 (silica gel, 1:3 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 8.06
– 8.03 (m, 2H), 7.58 – 7.54 (m, 1H), 7.46 – 7.39 (m, 4H), 6.38 – 6.36 (m, 2H), 4.33 (t, J =
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6.6 Hz, 2H), 3.66 (s, 1H), 3.10 – 3.06 (m, 2H), 1.81 – 1.77 (m, 2H), 1.65 – 1.60 (m, 2H),
1.51 – 1.45 (m, 4H). 13C NMR (101 MHz, CDCl3) 13C{1H} δ 166.6, 161.1, 147.9, 137.7,
132.8, 130.4, 129.5, 128.3, 114.8, 77.5, 64.82, 43.6, 29.2, 28.6, 26.7, 25.8. HRMS (DART)
m/z: [M+H]+ calcd. for C19H23INO2 424.0768, found 424.0795.
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6-(Methyl(3-phenyl-3-(4-(trifluoromethyl)phenoxy)propyl)amino)hexyl benzoate
(30) (210 mg, 82% yield) Physical State: colorless oil; Rf = 0.5 (silica gel, 8:1
DCM:MeOH); 1H NMR (400 MHz, CDCl3) δ 8.05 – 8.03 (m, 2H), 7.56 – 7.52 (m, 1H),
7.45 – 7.40 (m, 4H), 7.35 – 7.30 (m, 4H), 7.27 – 7.24 (m, 1H), 6.91 – 6.89 (m, 2H), 5.29
(dd, J = 8.4, 4.7 Hz, 1H), 4.29 (t, J = 6.7 Hz, 2H), 2.58 – 2.51 (m, 1H), 2.45 – 2.39 (m, 1H),
2.35 – 2.28 (m, 2H), 2.21 (s, 3H), 2.19 – 2.11 (m, 1 H) 1.96 – 1.92 (m, 1H), 1.75 – 1.68 (m,
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2H), 1.48 – 1.29 (m, 6H). C NMR (101 MHz, CDCl3) C{ H} δ 166.6, 160.7, 141.3,
132.8, 130.5, 129.5, 129.0, 128.7, 128.3, 127.7, 126.68 (q, J = 3.8 Hz), 125.8, 125.7, 125.6,
122.6 (q, J = 32.0 Hz), 115.6, 78.4, 65.0, 57.8, 53.6, 42.2, 36.6, 28.6, 27.3, 27.1, 26.0.
HRMS (LC-MS-TOF) m/z: [M+H]+ calcd. for C30H35F3NO3 514.2564, found 514.2593.
6-Azidohexyl benzoate (31) (120 mg, 96% yield) Physical State: colorless oil; Rf = 0.5
(silica gel, 1:10 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 8.06 – 8.03 (m, 2H), 7.57
– 7.53 (m, 1H), 7.46 – 7.41 (m, 2H), 4.32 (t, J = 6.6 Hz, 2H), 3.27 (t, J = 6.9 Hz, 2H), 1.80
– 1.75 (m, 2H), 1.67 – 1.60 (m, 2H), 1.51 – 1.43 (m, 4H). 13C NMR (101 MHz, CDCl3)
13C{1H} δ 166.6, 132.8, 130.4, 129.5, 128.3, 64.8, 51.3, 28.7, 28.6, 26.4, 25.6. HRMS
(DART) m/z: [M+NH4]+ calcd. for C13H21N4O2 265.1659, found 265.1685.
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6-Cyanohexyl benzoate (32) (60 mg, 52% yield) Physical State: white solid; Rf = 0.5
(silica gel, 1:1 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 8.05 – 8.02 (m, 2H), 7.57
– 7.53 (m, 1H), 7.46 – 7.41 (m, 2H), 4.32 (t, J = 6.5 Hz, 2H), 2.34 (t, J = 7.1 Hz, 2H), 1.82
– 1.75 (m, 2H), 1.72 – 1.65 (m, 2H), 1.56 – 1.46 (m, 4H). 13C NMR (101 MHz, CDCl3)
13C{1H} δ 166.5, 132.8, 130.3, 129.4, 128.3, 119.6, 64.6, 28.4, 28.3, 25.3, 25.2, 17.0.
HRMS (DART) m/z: [M+H]+ calcd. for C14H18NO2 232.1332, found 232.1346.
6-(4-Bromophenoxy)hexyl benzoate (33) (147 mg, 78% yield) Physical State:
colorless oil; Rf = 0.5 (silica gel, 1:8 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 8.06
– 8.03 (m, 2H), 7.58 – 7.54 (m, 1H), 7.46 – 7.41 (m, 2H), 7.39 – 7.32 (m, 2H), 6.78 – 6.74
(m, 2H), 4.34 (t, J = 6.6 Hz, 2H), 3.93 (t, J = 6.4 Hz, 2H), 1.85 – 1.76 (m, 4H), 1.60 – 1.45
(m, 4H). 13C NMR (101 MHz, CDCl3) 13C{1H} δ 166.6, 158.2, 132.8, 132.2, 130.4, 129.5,
128.3, 116.3, 112.6, 68.0, 64.9, 29.0, 28.6, 25.8, 25.7. HRMS (DART) m/z: [M+NH4]+
calcd. for C19H25NBrO3 394.1012, found 394.0996.
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6-(4-Nitrophenoxy)hexyl benzoate (34) (150 mg, 87% yield) Physical State: white
solid; Rf = 0.5 (silica gel, 1:3 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 8.19 – 8.15
(m, 2H), 8.06 – 8.01 (m, 2H), 7.57 – 7.53 (m, 1H), 7.45 – 7.40 (m, 2H), 6.94 – 6.89 (m,
2H), 4.34 (t, J = 6.6 Hz, 2H), 4.05 (t, J = 6.4 Hz, 2H), 1.87 – 1.80 (m, 4H), 1.58 – 1.53 (m,
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4H). C NMR (101 MHz, CDCl3) C{ H} δ 166.6, 164.1, 141.3, 132.8, 130.3, 129.5,
128.3, 125.8, 114.3, 68.6, 64.7, 28.8, 28.6, 25.7, 25.6. HRMS (DART) m/z: [M+NH4]+
calcd. for C19H25N2O5 361.1758, found 361.1756.
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6-((5-Iodopyridin-2-yl)oxy)hexyl benzoate (35) (105 mg, 49% yield) Physical State:
white solid; Rf = 0.3 (silica gel, 1:1 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 8.04
– 8.01 (m, 2H), 7.57 – 7.52 (m, 1H), 7.46 – 7.38 (m, 4H), 6.38 – 6.36 (m, 1H), 4.30 (t, J =
6.5 Hz, 2H), 3.7 (t, J = 7.2 Hz, 2H), 1.81 – 1.71 (m, 4H), 1.53 – 1.37 (m, 4H). 13C NMR
(101 MHz, CDCl3) 13C{1H} δ 166.6, 160.9, 146.6, 142.3, 132.8, 130.3, 129.5, 128.3, 122.9,
64.7, 64.0, 49.8, 29.2, 28.5, 26.2, 25.7. HRMS (DART) m/z: [M+H]+ calcd. for
C18H21INO3 426.0561, found 426.0556.
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6-((5-Bromopyridin-2-yl)oxy)hexyl benzoate (36) (131 mg, 69% yield) Physical
State: yellow oil; Rf = 0.5 (silica gel, 3:1 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3)δ
8.04 – 8.01 (m, 2H), 7.56 – 7.52 (m, 1H), 7.45 – 7.41 (m, 2H), 7.37 – 7.30 (m, 2H), 6.47
(dd, J = 9.6, 0.6 Hz, 1H), 4.30 (t, J = 6.6 Hz, 2H), 3.88 (t, J = 7.2 Hz, 2H), 1.81 – 1.72 (m,
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4H), 1.53 – 1.39 (m, 4H). C NMR (101 MHz, CDCl3) C{ H} δ 166.6, 160.9, 146.6,
142.3, 132.8, 130.3, 129.5, 128.3, 122.9, 64.7, 64.0, 49.8, 29.2, 28.5, 26.2, 25.7. HRMS
(DART) m/z: [M+H]+ calcd. for C18H21BrNO3 378.0699, found 378.0706.
6-((2-Oxo-2H-chromen-7-yl)oxy)hexyl benzoate (37) (137 mg, 74% yield) Physical
State: colorless oil; Rf = 0.5 (silica gel, 1:2 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3)
δ 8.04 – 8.02 (m, 2H), 7.62 (dd, J = 9.5, 0.6 Hz, 1H), 7.57 – 7.52 (m, 1H), 7.45 – 7.40 (m,
2H), 7.34 (d, J = 8.5 Hz, 1H), 6.83 – 6.78 (m, 2H), 6.23 (d, J = 9.5 Hz, 1H), 4.34 (t, J = 6.6
Hz, 2H), 4.01 (t, J = 6.4 Hz, 2H), 1.86 – 1.80 (m, 4H), 1.57 – 1.52 (m, 4H). 13C NMR (101
MHz, CDCl3) δ13C{1H} 166.6, 162.3, 161.2, 155.9, 143.4, 132.8, 130.4, 129.5, 128.7,
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128.3, 112.9, 112.4, 101.3, 68.4, 64.8, 28.8, 28.6, 25.8, 25.7. HRMS (LC-MS-TOF) m/z:
[M+H]+ calcd. for C22H23O5 367.1540, found 367.1556.
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Physical State: white solid; Rf = 0.5 (silica gel, 1:1 EtOAc:hexanes); 1H NMR (400 MHz,
CDCl3) δ 8.10 (d, J = 8.7 Hz, 1H), 8.05 – 8.01 (m, 2H), 7.89 – 7.86 (m, 2H), 7.55 – 7.47
(m, 4H), 7.43 – 7.39 (m, 2H), 6.96 – 6.92 (m, 2H), 6.73 (s, 1H), 4.34 (t, J = 6.6 Hz, 2H),
4.06 (t, J = 6.4 Hz, 2H), 1.89 – 1.80 (m, 4H), 1.59 – 1.54 (m, 4H). 13C NMR (101 MHz,
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CDCl3) C{1H} δ 177.7, 166.5, 163.6, 162.8, 157.9, 132.8, 131.8, 131.3, 130.3, 129.4,
128.9, 128.2, 126.9, 126.0, 117.6, 114.6, 107.4, 100.8, 68.4, 64.7, 28.8, 28.6, 25.7, 25.6.
HRMS (LC-MS-TOF) m/z: [M+H]+ calcd. for C28H27O5 443.1853, found 443.1874.
6-(Quinolin-6-yloxy)hexyl benzoate (39) (140 mg, 80% yield) Physical State: yellow
oil;
Rf = 0.3(silica gel, 1:1 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 8.76 (dd, J = 4.3,
1.7 Hz, 1H), 8.06 – 7.97 (m, 4H), 7.56 – 7.52 (m, 1H), 7.44 – 7.41 (m, 2H), 7.37 – 7.32 (m,
2H), 7.05 (d, J = 2.8 Hz, 1H), 4.35 (t, J = 6.6 Hz, 2H), 4.09 (t, J = 6.4 Hz, 2H), 1.91 – 1.79
(m, 4H), 1.61 – 1.56 (m, 4H). 13C NMR (101 MHz, CDCl3) 13C{1H} δ 166.7, 157.2, 147.8,
144.4, 134.7, 132.8, 132.8, 130.8, 130.4, 129.5, 129.3, 128.3, 122.5, 121.3, 105.8, 68.0,
64.9, 29.0, 28.7, 25.8, 25.8. HRMS (LC-MS-TOF) m/z: [M+Na]+ calcd. for C22H23NO3Na
372.1570, found 372.1587.
6-(Pyridin-4-yloxy)hexyl benzoate (40) (105 mg, 70% yield) Physical State: yellow
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The Journal of Organic Chemistry
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oil;
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Rf = 0.5 (silica gel, 10:1 DMC:MeOH); H NMR (400 MHz, CDCl3) δ 8.05 – 8.02 (m,
2H), 7.59 – 7.55 (m, 1H), 7.47 – 7.42 (m, 2H), 7.29 – 7.25 (m, 2H), 6.39 – 6.35 (m, 2H),
4.32 (t, J = 6.5 Hz, 2H), 3.77 (t, J = 7.2 Hz, 2H), 1.84 – 1.75 (m, 4H), 1.53 – 1.37 (m, 4H).
13C NMR (101 MHz, CDCl3) 13C{1H} δ 178.7, 166.5, 139.5, 132.9, 130.2, 129.4, 128.3,
118.7, 64.5, 56.8, 30.7, 28.4, 25.8, 25.5. HRMS (DART) m/z: [M+H]+ calcd. for
C18H22NO3 300.1594, found 300.1590.
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6-((5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-
yl)pentanoyl)oxy)hexyl benzoate (41) (189 mg, 84% yield) Physical State: yellow solid;
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Rf = 0.5 (silica gel, 10:1 DCM:MeOH); H NMR (400 MHz, CDCl3) δ 8.04 – 8.01 (m,
2H), 7.56 – 7.52 (m, 1H), 7.45 – 7.40 (m, 2H), 5.96 (s, 1H), 5.59 (s, 1H), 4.50 – 4.46 (m,
1H), 4.32 – 4.27 (m, 3H), 4.06 (t, J = 6.6 Hz, 2H), 3.16 – 3.11 m, 1H), 2.88 (dd, J = 12.8,
5.0 Hz, 1H), 2.72 (d, J = 12.8 Hz, 1H), 2.30 (t, J = 7.5 Hz, 2H), 1.81 – 1.61 (m, 8H), 1.49
– 1.38 (m, 6H). 13C NMR (101 MHz, CDCl3) 13C{1H} δ 173.8, 166.7, 163.7, 132.9, 130.4,
129.5, 128.4, 64.9, 64.3, 62.0, 60.1, 55.5, 40.5, 33.9, 28.6, 28.5, 28.4, 28.3, 25.7, 25.6, 24.8.
HRMS (LC-MS-TOF) m/z: [M+H]+calcd. for C23H33N2O5S 449.2105, found 449.2123.
(E)-6-((2-methylbut-2-enoyl)oxy)hexyl benzoate (42) (98 mg, 64% yield) Physical
State: colorless oil; Rf = 0.5 (silica gel, 1:8 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3)
δ 8.05 – 8.02 (m, 2H), 7.57 – 7.53 (m, 1H), 7.46 – 7.41 (m, 2H), 6.85 – 6.82 (m, 1H), 4.32
(t, J = 6.6 Hz, 2H), 4.13 (t, J = 6.6 Hz, 2H), 1.84 – 1.75 (m, 8H), 1.74 – 1.67 (m, 2H), 1.52
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