Silica-Supported Oligomeric Benzyl Phosphate (Si-OBP) and Triazole Phosphate (Si-OTP) Alkylating Reagents

Article abstract of DOI:10.1021/acs.joc.5b01456

The syntheses of silica-supported oligomeric benzyl phosphates (Si-OBP_n) and triazole phosphates (Si-OTP_n) using ring-opening metathesis polymerization (ROMP) for use as efficient alkylating reagents is reported. Ease of synthesis and grafting onto the surface of norbornenyl-tagged (Nb-tagged) silica particles has been demonstrated for benzyl phosphate and triazole phosphate monomers. It is shown that these silica polymer hybrid reagents, Si-OBP_n and Si-OTP_n, can be used to carry out alkylation reactions with an array of different nucleophiles to afford the corresponding benzylated and (triazolyl)methylated products in good yield and high purity.

Full text of DOI:10.1021/acs.joc.5b01456

Article
pubs.acs.org/joc
Silica-Supported Oligomeric Benzyl Phosphate (Si-OBP) and Triazole
Phosphate (Si-OTP) Alkylating Reagents
Pradip K. Maity,†,‡ Saqib Faisal,†,‡ Alan Rolfe,†,‡ Diana Stoianova,§ and Paul R. Hanson*,†,‡
†Department of Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, Kansas 66045-7582, United States
‡The University of Kansas Center for Chemical Methodologies and Library Development (KU-CMLD), 2034-Becker Drive, Delbert
M. Shankel Structural Biology Center, Lawrence, Kansas 66047, United States
§Materia, Inc., 60 North San Gabriel Boulevard, Pasadena, California 91107, United States
S
* Supporting Information
ABSTRACT: The syntheses of silica-supported oligomeric benzyl phosphates (Si-OBPn) and triazole phosphates (Si-OTPn)
using ring-opening metathesis polymerization (ROMP) for use as efficient alkylating reagents is reported. Ease of synthesis and
grafting onto the surface of norbornenyl-tagged (Nb-tagged) silica particles has been demonstrated for benzyl phosphate and
triazole phosphate monomers. It is shown that these silica polymer hybrid reagents, Si-OBPn and Si-OTPn, can be used to carry
out alkylation reactions with an array of different nucleophiles to afford the corresponding benzylated and (triazolyl)methylated
products in good yield and high purity.
Janda-gels, and microporous resins,3 there is still a need for
additional materials that can deliver the performance of
solution-phase reagents with the ease of removal (via filtration,
INTRODUCTION
■
The need to rapidly synthesize a wide variety of small
molecules in the desired quantities with high purities and
precipitation, extraction, etc.) afforded by their immobilization.
We have previously examined a variety of soluble, high-load,
oligomeric reagents and scavengers derived through the use of
ring-opening methathesis polymerization (ROMP) of function-
alized norbornene and 7-oxanorbornene monomers.17 These
materials, known as ROMPgels, build on the pioneering efforts
of Barrett,18 Buchmeiser,19 Bolm,20 and others,21 and they have
effectively been used to mediate a number of chemical
reactions. However, while these ROMPgel materials have the
advantage of behaving equivalently to traditional homogeneous
reagents and catalysts, they are generally removed from
solution via precipitation, which can limit their use in
pharmaceutical applications.
As a result, inspired by the seminal work of Buchmeister and
co-workers,22 efforts were focused on the synthesis and study of
a number of hybrid materials that graft several of the ROMPgel
materials onto the surface of silica particles.23 Through this
grafting process, the resulting immobilized ROMP reagents can
be removed from solution by simple filtration, thus eliminating
the precipitation step. In this fashion, silica-supported
ROMPgel acid chloride, dichlorotriazine, and triphenylphos-
phine reagents were generated with properties nearly identical
yields is an important challenge facing drug discovery and
developmental chemistry.1 To help address this need,
immobilized reagents and scavengers have been developed to
provide ease of synthesis and to eliminate time-consuming
chromatographic separation protocols. These reagents have
found frequent use in the arena of facilitated synthesis and
high-throughput chemistry,2,3 as well as in the scale-up of
advanced pharmaceutical intermediates.4 Given the large range
of chemistries and conditions in which they need to be
employed as reagents, scavengers, or catalysts, the field has seen
a number of new innovations regarding immobilized poly-
styrene resins,5 silicas,6 soluble polyethylene glycol (PEG)
polymers,7 and monolith8 and fluorous-tagged compounds9 to
remove impurities or excess reagents from reaction mixtures.
Some of the more recent developments reported include silica-
supported isocyanide ligands for scavenging ruthenium,10
mesocellular silica-supported boronic acids as direct amidation
catalysts,11 silica-supported rhodium catalysts,12 N-heterocyclic
carbenes,13 palladium and copper(I) catalysts,14 phosphines,15
and prolinol as well as TADDOLs.16 However, for all of their
advantages immobilized reagents are often limited by several
factors, including (i) low load levels, (ii) heterogeneous
reaction kinetics and nonsurface diffusion-controlled processes,
(iii) immobilized reagent swelling, and (iv) poor solvent
tolerance. While some of these issues have been addressed
through the development of technologies such as microgels,
Received: June 26, 2015
© XXXX American Chemical Society
A
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to those of the equivalent soluble ROMPgel oligomeric
reagents.23
using a modification of the procedure reported by Buchme-
iser.28 The activated silica 1 (60 Å, 20 μm) was tagged with
commercially available norbornene silyl reagent [(MeO)3Si−
(CH2)2−Nb (2)] followed by capping with trimethoxymethyl-
silane and dimethoxydimethylsilane to afford the norbornene-
functionalized silica (Si−Nb) 3 (Scheme 1). It was observed
that the use of (MeO)3Si−(CH2)2−Nb (2) dramatically
increased the norbornene load of Si−Nb (3), compared to 5-
(bicycloheptenyl)-triethoxysilane [Nb−Si(OEt)3], which was
previously used for silica tagging.23 By this optimized method,
we prepared norbornene-functionalized silica 3 (Si−Nb) on
gram scale with a 0.4 mmol/g loading (determined by a
modified bromine titration method).29 With this Si-tagged
nanoparticle (3) in hand, a metathesis catalyst-armed surface-
initiated polymerization was established using the C848
[Grubbs second generation catalyst, G-II]30 (20 mol %,
based on Si−Nb load) in CH2Cl2 and toluene as solvents,
followed by addition of the Nb-tagged benzyl phosphate
monomer 4 to rapidly generate the desired hybrid material 5a,
silica oligomeric benzyl phosphate (Si-OBPn). The benzyl
phosphate monomer 4 was itself easily synthesized in good
yield and purity according to previously reported methods.24a
Norbornene exo-diol 6 was reacted with POCl3 and Et3N in the
presence of catalytic DMAP to generate the Nb-tagged
monochlorophosphate compound 7 in moderate yields as a
white solid (Scheme 1). This material was then reacted with
benzyl alcohol in NMI, and CH2Cl2 at room temperature to
yield 4. The scale-up synthesis of the monomeric reagent, as
well as Si-OBPn, have been carried out on gram scale as stable,
free-flowing powders. The SEM images of Si-OBPn and Si-
OTPn silica hybrid materials demonstrate the grafting of the
corresponding monomer on the silica surface and inherent
morphology of hybrid materials (Figure 1).
We herein describe our efforts to expand the family
oligomeric materials that have been grafted onto silica to
include ROMP-derived oligomeric benzyl phosphate (OBPn)
and triazole phosphate (OTPn), which we previously reported
as soluble alkylating reagents that were used in facilitated library
generation.24 Benzylation and triazolation are useful diversifi-
cation reactions in medicinal chemistry, high-throughput
chemistry, and diversity-oriented synthesis (DOS).25 The
benzylation of amines and alcohols also serves as one of the
most utilized protecting group strategies in organic synthesis
due to its easy incorporation and removal.26 While these uses
have spurred development of a number of alternative
approaches to benzylation27 and triazolation, we believe the
generation of the analogous silica-oligomeric benzyl phosphate
(Si-OBPn) and triazole phosphate (Si-OTPn) reagents could
find efficient, safe, and cost-effective applications in chemical
synthesis and library production. Key advantages of these
reagents, include (i) their stability at room temperature (ii)
safety in handling when compared to commercially available
benzyl bromides or iodides, and (iii) ease of purification via
simple filtration through Celite.
RESULTS AND DISCUSSION
Initial efforts centered on the synthesis of the silica-grafted
oligomeric benzyl phosphate reagent, as outlined in Scheme 1,
■
Scheme 1. Synthesis of Silica-Supported Oligomeric Benzyl
Phosphate (Si-OBPn)
The utilization of silica oligomeric benzyl phosphate 5a (Si-
OBPn) for benzylation with various N-, O-, S- nucleophiles,
including anilines, amines, phenols, thiols, and sulfonamides
(Table 1), was next examined. The reactions were carried out
in a sealed pressure tube with different nucleophiles (1 equiv),
Si-OBPn (1.5 equiv), Cs2CO3 (3.0 equiv), and NaI (0.2 equiv)
in THF at 80 °C (oil bath temperature) to yield the products
after simple filtration via Celite-SPE to remove the Si-
phosphate byproduct. The corresponding benzylated analogs
(8a−8h) were isolated in excellent purities (>90%, determined
by LC-MS) and yields. We have screened wide varieties of
nucleophiles for benzylation. Initially, a variety of amines and
phenols (Table 1, entries 1−4) were utilized and then extended
to thiophenols and sulfonamides (Table 1, entries 5−8) to yield
(>90%) the benzylated products.
With these results in hand, an expanded set of Si-OBPn
derivatives were next examined (Figure 2). These high load
reagents (5b−5d) were synthesized in an analogous fashion to
Figure 1. SEM images of Si−Nb (left), Si-OBPn (middle), and Si-OTPn (right).
B
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Table 1. Benzylation of N-, O-, and S-Nucleophiles Utilizing
Si-OBPn
Table 2. Benzylation of N-, O-, and S-Nucleophiles Utilizing
Various Si-OBPn Analogs
entry
Si-OBPn
nucleophile
Pdt
yield (%)
1
2
3
4
5
6
5b
5b
5c
5c
5d
5d
2,4-Cl-PhOH
2,4,6-Cl-PhSH
2,4-Cl-PhOH
2,4,6-Cl-PhSH
2,4-Cl-PhOH
2,4,6-Cl-PhSH
8i
98
94
96
95
98
94
8j
8k
8l
8m
8n
containing compounds. Silica-immobilized oligomeric triazole
phosphate 10a (Si-OTPn) was synthesized via grafting of the
Nb-tagged benzyl triazole phosphate monomer 9 onto the
surface of norbornene-functionalized silica (Si−Nb) 3 through
the same protocol discussed for the synthesis of Si-OBPn in
Scheme 1. The product, 10a (Si-OTPn), was isolated as a free-
flowing solid in high-load (1.15 mmol/g) (Scheme 2). The
triazole phosphate monomer 9 was synthesized in good yield
and purity according to previously reported methods.24
Phosphorylation of propargyl alcohol with Nb-tagged phos-
phonyl chloride 7, followed by a “Click”-capture event of the
corresponding azide, yields the desired monomer 9 in an
efficient fashion (Scheme 2). The triazole phosphate monomer
and silica oligomeric triazole phosphate reagents (Si-OTPn)
have been synthesized on gram scale as stable, free-flowing
solids.
With Si-OTPn 10a in hand, the hybrid material was evaluated
for (triazolyl)methylation on various nucleophiles including
amines, phenols, thiophenols, and sulfonamides in good yields
and high purity with chromatography-free purification. The
reaction was carried out in a pressure tube with different
nucleophiles (1 equiv), Si-OTPn (1.5 equiv), Cs2CO3 (3.0
equiv), and NaI (0.2 equiv) in DMF at 90 °C for overnight.
The reaction mixture was diluted with EtOAc and filtered
through a pad of Celite to give the corresponding (triazolyl)-
methylated products. Optimal results were achieved in DMF
compared to THF. A variety of N-, O-, S-nucleophiles were
utilized for nucleophilic substitution reactions with the Si-OTPn
triazolating reagent giving the (triazolyl)methylated products
(11a−11g) in excellent yield and high purity (>85%,
determined by LC-MS) (Table 3). In all cases, similar results
(Table 3) were obtained as compared to Si-OBPn in THF in
Table 1.
the Si-OBPn reagent in Scheme 1 and were also obtained on
gram scales as free-flowing powders. Utilization of these
reagents in substitution reactions with O- and S-nucleophiles
were next carried out to afford benzylated products (8i−8n) in
good yields (>90%) and excellent purity after Celite-SPE
filtration (Table 2). Diversification of the Si-OBPn reagents via
substituting electron-withdrawing groups, as well as electron-
donating groups, on the aryl moiety were next examined, and in
all cases, analogous results to Table 1 were obtained (see Table
2).
Attention was next placed on the gram-scale generation of
silica oligomeric triazole phosphate hybrid reagents (Si-OTPn).
Triazoles and their derivatives have demonstrated a wide
variety of biological activity, with many reports focusing on
antifungal activity.31 We previously reported soluble oligomeric
triazole phosphates to construct a wide array of triazole-
Building on these results, the project was expanded to the
synthesis of additional variants of Si-OTPn hybrid reagents
(10b−10d, Figure 3) on gram scales as free-flowing powders in
an analogous fashion to the Si-OTPn reagent in Scheme 2.
Figure 2. Various silica-supported oligomeric benzyl phosphate (Si-OBPn) analogs.
C
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Scheme 2. Synthesis of Silica-Supported Oligomeric Triazole Phosphate (Si-OTPn)
Table 3. Triazolation Utilizing Si-OTPn with O-, N-, and S-Nucleophiles
These Si-OTPn hybrid reagents were utilized for (triazolyl)-
methylation of O- and S-nucleophiles. In all cases, (triazolyl)-
methylated products (11h−11m) were isolated in excellent
yield and high purity after passing through a Celite SPE (Table
4).
load, hybrid Si-ROMP benzylating and (triazolyl)methylating
reagents. A metathesis catalyst-armed surface (CAS)-initiated
polymerization was key to functionalization of units off the
silica particle surface. With this technology, we developed Si-
immobilized oligomeric benzyl phosphate (Si-OBPn) as a
benzylating reagent and triazole phosphate (Si-OTPn) as a
(triazolyl)methylating reagent on gram scale as stable, free-
In conclusion, the combination of Nb-tagged silica particles
and functionalized Nb-tagged monomers efficiently yields high-
D
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Figure 3. Various silica-supported oligomeric triazole phosphate (Si-OTPn) analogs.
was added (50 equiv w/r to cat. G-II) in CH2Cl2 and toluene to the
reaction mixture and heated at 45 °C for overnight. The reaction
mixture was cooled to room temperature and EVE was added, with
stirring for an additional 1 h at room temperature. The reaction
mixture was filtered and washed with a mixture of toluene/CH2Cl2
(1:1) and dried via high vacuo pump.
Table 4. Triazolation of N-, O-, and S-Nucleophiles Utilizing
Various Si-OTPn Analogs
Procedure A: General Procedure for Different Nucleophilic
Substitution with Si-OBPn. In a sealed pressure tube was added Si-
OBPn 5a (1.5 equiv), followed by addition of sodium iodide (0.2
equiv), Cs2CO3 (3.0 equiv), and solvent THF (0.2 M). The mixture
was stirred rapidly, and then nucleophiles were added. The reaction
was sealed under argon and heated to 80 °C with stirring for 12 h.
After such time, the reaction was cooled to rt and the crude mixture
was filtered via a Celite-packed SPE and rinsed several times with a
mixture of hexanes/EtOAc (1:2). The resulting eluent was
concentrated in vacuo to yield the benzylated products in good to
excellent yields and purities.
entry
Si-OTPn
nucleophile (R5−XH)
Pdt
yield (%)
1
2
3
4
5
6
10b, R4 = 4-MePh
10b, R4 = 4-MePh
10c, R4 = 4-OMePh
10c, R4 = 4-OMePh
10d, R4 = cyclohexyl
10d, R4 = cyclohexyl
4-Br-PhOH
11h
11i
85
87
89
86
86
88
2,4,6-Cl-PhSH
4-Br-PhOH
11j
2,4,6-Cl-PhSH
4-Br-PhOH
11k
11l
2,4,6-Cl-PhSH
11m
Procedure B: General Procedure for Different Nucleophilic
Substitution with Si-OTPn. In a pressure tube was added Si-OTPn
10a (1.5 equiv), followed by addition of NaI (0.2 equiv), Cs2CO3 (3.0
equiv), and solvent DMF (0.2 M). The nucleophile was added, and the
resulting mixture was stirred rapidly. The reaction was sealed under
argon and heated to 90 °C w/stirring for (12−14 h), after which time
DMF was removed in vacuo. The crude mixture was filtered via Celite-
SPE and rinsed with EtOAc. The resulting eluent was then
concentrated in vacuo to yield the products in good to excellent
yields and purities.
flowing powders in all cases, utilizing ROMP of Nb-tagged
phosphate monomers. SEM imaging was utilized to demon-
strate the successful grafting of the corresponding oligomer and
the inherent morphology of the hybrid materials. Utilization of
these reagents for representative small molecule synthesis,
under purification free protocols, was demonstrated to afford
corresponding products in excellent yield and with high purity.
Since benzylation is a key transformation in many synthetic
processes, we are currently working on expanding the scope of
nucleophiles (i.e., alcohols, bis-nucleophilic, etc.), as well as the
scale on which these transformations can be carried out.
1-(Benzyloxy)-4-(tert-butyl)benzene (8c). Utilizing general
procedure A, 8c (18.5 mg, 0.077 mmol, 97%) was isolated as a
white solid. MP: 65 °C; FTIR (neat): 3056, 3024, 2960, 2866, 1610,
1
1512, 1456, 1242, 1182, 1024 cm−1; H NMR (400 MHz, CDCl3): δ
7.46−7.43 (m, 2H), 7.42−7.38 (m, 2H), 7.36−7.30 (m, 3H), 6.92−
6.96 (m, 2H), 5.06 (s, 2H), 1.33 (s, 9H); 13C NMR (126 MHz,
CDCl3): δ 156.6, 143.7, 137.3, 128.5 (2C), 127.9, 127.5 (2C), 126.2
(2C), 114.2 (2C), 70.0, 34.1, 31.4 (3C); GC-MS (EI+) calculated for
C17H20O 240.15; found 240.1 (M+ 7), 91.0 (100).32a
1-(Benzyloxy)-2,4-dichlorobenzene (8d). Utilizing general
procedure A, 8d (30 mg, 0.119 mmol, 98%) was isolated as a thick
liquid. FTIR (neat): 3031, 2931, 2835, 1597, 1481, 1452, 1382, 1290,
1249, 1060 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.47−7.44 (m, 2H),
7.43−7.38 (m, 3H), 7.37−7.33 (m, 1H), 7.18 (dd, J = 2.6, 8.7 Hz,
1H), 6.90 (d, J = 8.9 Hz, 1H), 5.16 (s, 2H); 13C NMR (126 MHz,
CDCl3): δ 153.0, 136.1, 130.1, 128.7 (2C), 128.1, 127.5, 127.1 (2C),
126.0, 124.1, 114.8, 71.2; GC-MS (EI+) C13H10Cl2O calculated 252.01;
found 251.9 (M+ 4), 91.0 (100).32b
Benzyl(2,4,6-trichlorophenyl)sulfane (8e). Utilizing general
procedure A, 8e (21 mg, 0.07 mmol, 98%) was isolated as a yellow
solid. MP: 112 °C; FTIR (neat): 3087, 2935, 2850, 1583, 1454, 1321,
1116, 1054 cm−1. 1H NMR (400 MHz, CDCl3): δ 7.47 (s, 1H), 7.37−
7.33 (m, 4H), 7.32−7.39 (m, 2H), 4.15 (s, 2H); 13C NMR (126 MHz,
CDCl3): δ 136.3, 135.3, 132.0, 131.3, 130.6, 130.0, 129.5, 128.9 (2C),
128.8 (2C), 127.8, 37.6; GC-MS (EI+) C13H9Cl3S calculated 301.95;
found 301.9 (32), 169 (7), 91.0 (100).
Benzyl(3,4-dimethoxyphenyl)sulfane (8f). Utilizing general
procedure A, 8f (22 mg, 0.085 mmol, 98%) was isolated as a thick
liquid. FTIR (neat): 2933, 2833, 1595, 1504, 1251, 1228, 1135, 1026
cm−1. 1H NMR (400 MHz, CDCl3): δ 7.31−7.19 (m, 5H), 6.95 (dd, J
= 8.3, 2.2 Hz, 1H), 6.0−6.74 (m, 2H), 4.02 (s, 2H), 3.88 (s, 3H), 3.75
(s, 3H); 13C NMR (126 MHz, CDCl3): δ 148.7 (2C), 138.2, 129.0
(2C), 128.4 (2C), 127.0, 126.2, 125.3, 115.9, 111.3, 55.9, 55.8, 41.2;
EXPERIMENTAL SECTION
■
General Information. All reactions were carried out under an
argon atmosphere. Stirring was achieved with oven-dried magnetic stir
bars. Et2O and CH2Cl2 were purified by passage through the Solv-Tek
purification system employing activated Al2O3 (Pangborn, A. B.;
Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J. Safe and
Convenient Procedure for Solvent Purification. Organometallics 1996,
15, 1518−1520). CHCl3 was passed through basic alumina and dried
over molecular sieves. Et3N was purified by passage through basic
alumina or distilled over CaH2 and stored over KOH. For Celite-SPE,
6 mL empty cartridges were used. All the solvents for routine isolation
of products and chromatography were reagent grade. Flash
chromatography was performed using silica gel (300−400 mesh)
with the indicated solvents. Melting points were recorded on an
Electrothermal digital melting point apparatus and were uncorrected.
IR spectra were recorded on a spectrophotometer using KBr optics.
1H NMR and 13C NMR spectra were recorded on 400 or 500 MHz
(1H NMR) and 100 or 125 MHz (13C NMR) spectrometers using
CDCl3 as the solvent and TMS as the internal standard. The 1H NMR
data are reported as the chemical shift in parts per million, multiplicity
(s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), coupling
constant in hertz, and number of protons. High-resolution mass
spectra were obtained using a high-resolution ESI-TOF mass
spectrometer.
General Procedure for Silica Oligomeric Benzyl Phosphate
(Si-OBPn) and Triazole Phosphate (Si-OTPn). Si−Nb (load ∼0.4
mmol/g, 1 equiv) was heated with C848 (G-II, 0.2 equiv) at 45 °C in
dichloromethane for 2 h under argon. The OBP or OTP monomer
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GC-MS (EI+) C15H16O2S calculated 260.09; found 260.0 (32), 169
(30), 91.0 (100).
161.0 (2C), 152.9, 138.5, 130.0, 127.5, 126.1, 124.0, 114.8, 104.7 (2C),
99.8, 70.9, 55.3 (2C). GC-MS (EI+). C15H13Cl3O2S, calculated 312.03;
found 312.0 (M+, 3), 151.1 (100).
N-Benzyl-4-bromo-N-butyl-2-fluorobenzenesulfonamide
(8g). Utilizing general procedure A, 8g (24 mg, 0.060 mmol, 99%) was
isolated as a thick liquid. FTIR (neat): 3089, 3025, 2958, 2931, 1589,
1472, 1456, 1396, 1344, 1161, 1135 cm−1. 1H NMR (500 MHz,
CDCl3): δ 7.79 (t, J = 7.70 Hz, 1H), 7.43−7.38 (m, 2H), 7.34−7.28
(m, 5H), 4.47 (s, 2H), 3.19 (t, J = 7.60 Hz, 2H), 1.35−1.29 (m, 2H),
1.16−1.11 (m, 2H), 0.76 (t, J = 7.45 Hz, 3H). 13C NMR (126 MHz,
CDCl3): δ 158.44 (1JC−F = 259 Hz), 136.1, 131.8, 128.6 (2C), 128.2
(2C), 128.0, 127.8 (3C), 120.7 (2J = 25.0 Hz), 51.4, 47.3, 29.7, 19.7,
13.5. GC-MS (EI+) C17H19BrFNO2S calculated 399.3; found 399.0
(M+ 3), 401.2 (M+2 2), 355.8 (60), 357.8 (60), 91 (100).
(3,5-Dimethoxybenzyl)(2,4,6-trichlorophenyl)sulfane (8n).
Utilizing general procedure A, 8n (20 mg, 0.055 mmol, 94%) was
isolated as a white solid. MP: 84 °C; FTIR (neat): 2956, 2931, 2830,
1610, 1596, 1454, 1431, 1323, 1205, 1157, 1158 cm−1; 1H NMR (500
MHz, CDCl3): δ 7.46 (s, 1H), 7.30 (s, 1H), 6.51 (d, J = 2.25 Hz, 2H),
6.38 (t, J = 2.3, Hz 1H), 4.08 (s, 2H), 3.79 (s, 6H). 13C NMR (126
MHz, CDCl3): δ 160.1 (2C), 137.5, 136.3, 131.9, 131.3, 130.6, 130.0,
129.4, 106.9 (2C), 99.8, 55.4 (2C), 37.8. GC-MS (EI+).
C15H13Cl3O2S, calculated 361.97 found 361.9 (M+, 3), 151.1 (100).
1-Benzyl-4-((3-chlorophenoxy)methyl)-1H-1,2,3-triazole
(11a). Utilizing general procedure B, 1-benzyl-4-((3-chlorophenoxy)-
methyl)-1H-1,2,3-triazole 11a (50 mg, 0.167 mmol, 91%) was isolated
as a white solid. MP: 96 °C; FTIR (neat): 2960, 2358, 1610, 1511,
1463, 1250, 1184, 1031 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.53 (s,
1H), 7.43−7.35 (m, 3H), 7.29 (dd, J = 4.8, 2.8 Hz, 2H), 7.20 (t, J = 8.1
Hz, 1H), 6.98−6.93 (m, 2H), 6.89−6.84 (m, 1H), 5.55 (s, 2H), 5.17
(s, 2H). 13C NMR (126 MHz, CDCl3): δ 158.9, 144.1, 134.9, 134.4,
130.3, 129.2 (2C), 128.9, 128.2 (2C), 122.7, 121.5, 115.4, 113.1, 62.2,
54.3. HRMS calculated for C16H15ClN3O (M+H)+ 300.0904; found
300.0906 (TOF MS ES+).
1-Benzyl-4-((naphthalen-1-yloxy)methyl)-1H-1,2,3-triazole
(11b). Utilizing general procedure B, 11b (53 mg, 0.168 mmol, 90%)
was isolated as a light brown solid. MP: 94 °C; FTIR (neat): 3409,
2918, 1583, 1458, 1390, 1267, 1238, 1155, 1095 cm−1; 1H NMR (400
MHz, CDCl3): δ 8.23 (d, J = 8.1 Hz, 1H), 7.82 (d, J = 7.6 Hz, 1H),
7.62 (s, 1H), 7.54−7.44 (m, 3H), 7.43−7.36 (m, 4H), 7.34−7.25 (m,
2H), 6.98 (d, J = 7.6 Hz, 1H), 5.57 (s, 2H), 5.41 (s, 2H). 13C NMR
(126 MHz, CDCl3): δ 153.9, 144.8, 134.5, 129.2 (2C), 128.8, 128.1
(2C), 127.5, 126.5, 125.8, 125.6, 125.3, 122.6, 122.0, 120.9, 105.4,
62.5, 54.3. HRMS calculated for C20H18N3O (M+H)+ 316.1450; found
316.1427 (TOF MS ES+).
(S)-2,3-Dibenzyl-7-bromo-3,4-dihydro-2H-benzo[b][1,4,5]-
oxathiazepine 1,1-Dioxide (8h). Utilizing general procedure A, 8h
(30 mg, 0.066 mmol, 97%) was isolated as a white solid. MP: 170 °C;
FTIR (neat): 3026, 2921, 2852, 1595, 1552, 1325, 1153, 700 cm−1. 1H
NMR (500 MHz, CDCl3): δ 7.74 (d, J = 8.5 Hz, 1H), 7.33−7.28 (m,
4H), 7.25−7.19 (m, 5H), 7.17 (d, J = 1.8 Hz, 1H), 6.92 (d, J = 7.5 Hz,
2H), 4.85 (t, J = 12.0 Hz, 1H), 4.40 (d, J = 14.3 Hz, 1H), 4.26 (dd, J =
4.5, 13.42 Hz, 1H), 4.09 (d, J = 14.6 Hz, 1H), 3.85 (m, 1H), 2.93 (m,
2H). 13C NMR (126 MHz, CDCl3): δ 156.1, 137.4, 135.2, 129.8,
130.8, 129.0 (2), 128.7 (2), 128.6 (2), 128.1 (2), 127.1 (2), 126.7,
126.4, 124.4, 73.7, 62.4, 55.2, 37.9. HRMS calculated for
C22H20BrNO3SNa (M+Na)+ 480.0245; found 480.0258 (TOF MS).
1-((4-Bromobenzyl)oxy)-2,4-dichlorobenzene (8i). Utilizing
general procedure A, 8i (29 mg, 0.088 mmol, 98%) was isolated as
a yellow solid. MP: 87 °C; FTIR (neat) 3070, 2923, 2866, 1585, 1571,
1
1480, 1456, 1290, 1262, 1103 cm−1. H NMR (500 MHz, CDCl3): δ
7.52−7.54 (m, J = 8.4 Hz, 2H), 7.40 (d, J = 2.7 Hz, 1H), 7.32−7.34
(m, 2H), 7.15−7.18 (dd, J = 8.6, 2.4 Hz, 1H), 6.85 (d, J = 8.8, 1H),
5.10 (s, 2H). 13C NMR (126 MHz, CDCl3): δ 152.7, 135.0, 131.8
(2C), 130.1, 128.7 (2C), 127.5, 126.3, 124.1, 122.1, 114.7, 70.3. GC-
MS (EI+) C13H9BrCl2O calculated 329.92; found 331.9 (M+2, 2), 169
(100), 90 (25).32b
1-Benzyl-4-(pyrrolidin-1-ylmethyl)-1H-1,2,3-triazole (11c).
Utilizing general procedure B, 11c (48 mg, 0.198 mmol, 84%) was
isolated as a light brown thick liquid. FTIR (neat): 3307, 2923, 1581,
1448, 1420, 1396, 1238, 1215, 1121, 1008 cm−1; 1H NMR (400 MHz,
CDCl3): δ 7.59 (s, 1H), 7.41−7.33 (m, 3H), 7.30−7.26 (m, 2H), 5.52
(s, 2H), 3.87 (s, 2H), 2.74−2.67 (m, 4H), 1.89−1.81 (m, 4H). 13C
NMR (126 MHz, CDCl3): δ 144.6, 134.6, 129.1 (2C), 128.7, 128.1
(2C), 122.9, 54.2, 53.9 (2C), 50.5, 23.4 (2C). HRMS calculated for
C14H19N4 (M+H)+ 243.1610; found 243.1631 (TOF MS ES+).
1-Benzyl-4-(((2,4,6-trichlorophenyl)thio)methyl)-1H-1,2,3-
triazole (11e). Utilizing general procedure B, 11e (63 mg, 0.164
mmol, 92%) was isolated as a white solid. MP: 137 °C; FTIR (neat):
(4-Bromobenzyl)(2,4,6-trichlorophenyl)sulfane (8j). Utilizing
general procedure A, 8j (25 mg, 0.066 mmol, 94%) was isolated as a
white solid. MP: 54 °C; FTIR (neat) 2923, 1590, 1487, 1452, 1433,
1
1323, 1116, 1058, 1012 cm−1. H NMR (500 MHz, CDCl3): δ 7.44−
7.47 (m, 3H), 7.27 (s, 1H), 7.20−7.22 (m, 2H), 4.08 (s, 2H). 13C
NMR (126 MHz, CDCl3): δ 135.6, 134.5, 132.4, 131.9 (2C), 131.4,
130.7, 130.5 (2C), 130.4, 129.9, 121.7, 37.1. GC-MS (EI+)
C13H8Cl3BrS calculated 379.86; found 379.8 (M+ 5), 381.8 (M+2,
7), 169 (100), 90 (25).
2,4-Dichloro-1-((4-fluorobenzyl)oxy)benzene (8k). Utilizing
general procedure A, 8k (24 mg, 0.088 mmol, 96%) is isolated as a
thick liquid. FTIR (neat) 2931, 1604, 1510, 1483, 1379, 1226, 1060,
1
3369, 2923, 1699, 1456, 1433, 1363, 1242, 1116, 1049, 721 cm−1; H
1
823, 730 cm−1. H NMR (500 MHz, CDCl3): δ 7.41−7.45 (m, 2H),
NMR (400 MHz, CDCl3): δ 7.44 (s, 1H), 7.41−7.34 (m, 5H), 7.24−
7.20 (m, 2H), 5.52 (s, 2H), 4.25 (s, 2H). 13C NMR (126 MHz,
CDCl3): δ 143.8, 135.1, 134.4, 132.3, 131.5, 130.7, 130.6, 130.0, 129.2
(2C), 128.9, 128.0 (2C), 122.1, 54.3, 27.8. HRMS calculated for
C16H13Cl3N3S (M+H)+ 383.9896; found 383.9912 (TOF MS ES+).
1-Benzyl-4-(((3,4-dimethoxyphenyl)thio)methyl)-1H-1,2,3-
triazole (11f). Utilizing general procedure B, 11f (53 mg, 0.155
mmol, 94%) was isolated as a white solid. MP: 101 °C; FTIR (neat):
2952, 1581, 1502, 1438, 1253, 1228, 1135, 1024 cm−1; 1H NMR (400
MHz, CDCl3): δ 7.58−7.32 (m, 3H), 7.20 (dd, J = 6.7, 2.7 Hz, 2H),
7.17 (s, 1H), 6.89 (dt, J = 5.1, 2.1 Hz, 2H), 6.72 (d, J = 8.2 Hz, 1H),
5.47 (s, 2H), 4.14 (s, 2H), 3.86 (s, 3H), 3.79 (s, 3H). 13C NMR (126
MHz, CDCl3): δ 149.0, 148.7, 145.5, 134.6, 129.1 (2C), 128.7, 127.9
(2C), 125.7, 124.8, 121.9, 115.2, 111.4, 55.9, 55.9, 54.1, 30.8. HRMS
calculated for C18H19N3O2S (M+Na)+ 364.1096; found 364.1063
(TOF MS ES+).
7.40 (d, J = 2.5 Hz, 1H), 7.15−7.18 (dd, J = 8.6, 2.5 Hz, 1H), 7.07−
7.11 (m, 2H), 6.88 (d, J = 7.5, 1H), 5.10 (s, 2H). 13C NMR (126
MHz, CDCl3): δ 162.5 (1JC−F = 246.5 Hz) 152.8, 131.8, 130.1, 129.1
(3J = 8.4 Hz, 2), 127.5, 126.6, 124.2, 115.6 (2J = 21.6 Hz, 2) 114.9,
70.5. GC-MS (EI+) C13H9Cl2FO calculated 270.00; found 269.9 (M+,
2), 109 (100).
4-Fluorobenzyl)(2,4,6-trichlorophenyl)sulfane (8l). Utilizing
general procedure A, 8l (21 mg, 0.065 mmol, 95%) was isolated as
a thick liquid. FTIR (neat) 2933, 1600, 1505, 1433, 1323, 1228, 1116,
1058, 837 cm−1. 1H NMR (500 MHz, CDCl3): δ 7.49 (s, 1H), 7.31−
7.34 (m, 2H), 7.29 (s, 1H), 7.01−7.05 (m, 2H), 4.13 (s, 2H). 13C
NMR (126 MHz, CDCl3): δ 163.3, (1JC−F = 247.5 Hz) 135.8, 132.3,
131.3, 131.1 (4JC−F = 3.6 Hz), 130.7, 130.5 (3J = 8.5 Hz, 2) 130.4,
129.9, 115.7 (2J = 22.3 Hz, 2), 36.9. GC-MS (EI+). C13H8Cl3FS
calculated 319.94; found 319.9 (M+, 5), 109 (100).
2,4-Dichloro-1-((3,5-dimethoxybenzyl)oxy)benzene (8m).
Utilizing general procedure A, 8m (28 mg, 0.089 mmol, 98%) was
isolated as a yellow solid. MP: 55 °C; FTIR (neat): 2935, 2825, 1598,
N-((1-Benzyl-1H-1,2,3-triazol-4-yl)methyl)-2-bromo-N-
isopropylbenzenesulfonamide (11g). Utilizing general procedure
B, 11g (47 mg, 0.104 mmol, 89%) was isolated as a colorless thick
liquid. FTIR (neat): 3134, 2923, 2846, 1703, 1604, 1487, 1456, 1411,
1328, 1220, 1049 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.14 (dd, J =
7.8, 1.8 Hz, 1H), 7.70, (dd, J = 7.7, 1.4 Hz, 1H), 7.65 (s, 1H), 7.48−
7.32 (m, 5H), 7.27−7.20 (m, 2H), 5.52 (d, J = 5.1 Hz, 2H), 4.71 (s,
1
1483, 1456, 1292, 1157, 1060 cm−1; H NMR (500 MHz, CDCl3): δ
7.38 (d, J = 2.5 Hz, 1H), 7.14−7.16 (dd, J = 8.7, 2.4 Hz, 1H), 6.88−
6.85 (d, J = 7.8 Hz, 1H), 6.60 (d, J = 2.2 Hz, 2H), 6.42 (t, J = 2.5 Hz,
1H), 5.09 (s, 1H), 3.80 (s, 6H); 13C NMR (126 MHz, CDCl3): δ
F
DOI: 10.1021/acs.joc.5b01456
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
2H), 4.03−3.82 (m, 1H), 1.09 (d, J = 6.8 Hz, 6H). 13C NMR (126
MHz, CDCl3): δ 147.1, 139.3, 135.6, 134.7, 133.5, 132.5, 129.1 (2C),
128.7, 127.9 (2C), 127.5, 123.6, 120.3, 54.2, 49.9, 38.6, 21.1 (2C).
HRMS calculated for C19H21BrN4NaO2S (M+H)+ 471.0466; found
471.0478 (TOF MS ES+).
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b01456.
■
S
4-((4-Bromophenoxy)methyl)-1-(4-methylbenzyl)-1H-1,2,3-
triazole (11h). Utilizing general procedure B, 11h (52 mg, 0.145
mmol, 85%) was isolated as a white solid. MP: 103 °C; FTIR (neat):
Experimental details and NMR spectral data for new
compounds (PDF)
1
3087, 2920, 1589, 1490, 1384, 1282, 1242, 1022, 825, 757 cm−1. H
AUTHOR INFORMATION
Corresponding Author
*E-mail: phanson@ku.edu.
NMR (400 MHz, CDCl3): δ 7.49 (s, 1H), 7.37 (d, J = 8.8 Hz, 2H),
7.19 (m, 4H), 6.85 (d, J = 8.8 Hz, 2H), 5.49 (s, 1H), 5.14 (s, 1H), 2.36
(s, 1H). 13C NMR (126 MHz, CDCl3): δ 157.3, 144.1, 138.8, 132.3
(2C), 131.3, 129.8 (2C), 128.2 (2C), 122.6, 116.6 (2C), 113.5, 62.2,
54.1, 21.2. HRMS calculated for C17H17BrN3O (M+H)+ 358.0555;
found 358.0558 (TOF MS ES+).
1-(4-Methylbenzyl)-4-(((2,4,6-trichlorophenyl)thio)methyl)-
1H-1,2,3-triazole (11i). Utilizing general procedure B, 11i (48 mg,
0.120 mmol, 87%) was isolated as a white solid. MP: 136 °C; FTIR
(neat): 3083, 2920, 1515, 1434, 1323, 1151, 1116, 1058, 871 cm−1. 1H
NMR (400 MHz, CDCl3): δ 7.43 (s, 1H), 7.38 (s, 1H), 7.31 (s, 1H),
7.18 (d, J = 7.9 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 5.45 (s, 2H), 4.23
(s, 2H), 2.36 (s, 3H). 13C NMR (126 MHz, CDCl3): δ 143.7, 138.2,
135.1, 132.3, 131.5, 131.3, 130.7, 130.5, 130.0, 129.8 (2C), 128.0 (2C),
122.0, 54.1, 27.9, 21.2. HRMS calculated for C17H15Cl3N3S (M+H)+
398.0052; found 398.0063 (TOF MS ES+).
4-((4-Bromophenoxy)methyl)-1-(4-methoxybenzyl)-1H-
1,2,3-triazole (11j). Utilizing general procedure B, 11j (67 mg, 0.179
mmol, 89%) was isolated as a white solid. MP: 98 °C; FTIR (neat):
3137, 2933, 1612, 1514, 1487, 1461, 1247, 1176, 1049, 1031, 821
cm−1. 1H NMR (400 MHz, CDCl3): δ 7.48 (s, 1H), 7.36 (dd, J = 9.6,
2.5 Hz, 2H), 7.23 (d, J = 8.6 Hz, 2H), 6.91 (d, J = 8.6 Hz, 2H), 6.85
(d, J = 8.9 Hz, 2H), 5.47 (s, 2H), 5.14 (s, 2H), 3.82 (s, 3H). 13C NMR
(126 MHz, CDCl3): δ 160.0, 157.3, 144.1, 132.3 (2C), 129.8 (2C),
126.3, 122.4, 116.6 (2C), 114.5 (2C), 113.5, 62.2, 55.4, 53.9. HRMS
calculated for C17H16BrN3NaO2 (M+Na)+ 396.0324; found 396.0331
(TOF MS ES+).
■
Notes
The authors declare the following competing financial
interest(s): P.R.H. is on the Scientific Advisory Board of
Materia, Inc.
ACKNOWLEDGMENTS
■
This research was made possible by the National Institute of
General Medical Sciences [NIH STTR R42 GM097896] and
NIH Center for Chemical Methodologies and Library
Development at the University of Kansas (P50 GM069663).
The authors thank Justin Douglas and Sarah Neuenswander in
the University of Kansas NMR Laboratory. We acknowledge
Dr. Prem Thapa and Ms. Heather Shinogle for carrying out
SEM analysis (KU). We thank Materia Inc. for providing the
metathesis catalyst. We also thank Dr. Patrick Kearney for
helpful discussions and proofing the manuscript.
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1
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4-((4-Bromophenoxy)methyl)-1-(cyclohexylmethyl)-1H-
1,2,3-triazole (11l). Utilizing general procedure B, 11l (52 mg, 0.148
mmol, 86%) was isolated as a white solid. FTIR (neat): 2921, 2852,
1488, 1446, 1384, 1244, 1224, 1112, 1054 cm−1; MP: 90 °C; 1H NMR
(400 MHz, CDCl3): 7.54 (s, 1H), 7.41−7.35 (ddd, J = 10.2, 3.4, 2.2,
2H), 6.91−6.85 (ddd, J = 10.2, 3.4, 2.2, 2H), 5.19 (s, 2H), 4.18 (d, J =
7.2 Hz, 2H), 1.94−1.83 (m, 1H), 1.76−1.61 (m, 5H), 1.29−1.14 (m,
3H), 1.04−0.94 (m, 2H). 13C NMR (126 MHz, CDCl3): δ 157.3,
143.5, 132.3, 123.1, 116.7, 113.5, 62.3, 56.6, 38.7, 30.5 (2C), 26.0, 25.5
(2C). HRMS calculated for C16H21BrN3O (M+H)+ 350.0868; found
350.0870 (TOF MS ES+).
1-(Cyclohexylmethyl)-4-(((2,4,6-trichlorophenyl)thio)-
methyl)-1H-1,2,3-triazole (11m). Utilizing general procedure B,
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1H NMR (500 MHz, CDCl3): δ 7.46 (s, 1H), 7.39 (d, J = 5.3 Hz, 2H),
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