Catalytic Staudinger Reduction at Room Temperature

Article abstract of DOI:10.1021/acs.joc.9b00831

We report an efficient catalytic Staudinger reduction at room temperature that enables the preparation of a structurally diverse set of amines from azides in excellent yields. The reaction is based on the use of catalytic amounts of triphenylphosphine as a phosphine source and diphenyldisiloxane as a reducing agent. Our catalytic Staudinger reduction exhibits a high chemoselectivity, as exemplified by reduction of azides over other common functionalities, including nitriles, alkenes, alkynes, esters, and ketones.

Full text of DOI:10.1021/acs.joc.9b00831

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Note
Catalytic Staudinger Reduction at Room Temperature
Danny C Lenstra, Joris J. Wolf, and Jasmin Mecinovic
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00831 • Publication Date (Web): 03 May 2019
Downloaded from http://pubs.acs.org on May 3, 2019
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Catalytic Staudinger Reduction at Room Temperature
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Danny C. Lenstra,† Joris J. Wolf,† and Jasmin Mecinovi憇*
† Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525 AJ,
Nijmegen, The Netherlands
‡ Department of Physics, Chemistry and Pharmacy, University of Southern Denmark,
Campusvej 55, 5230 Odense, Denmark
ABSTRACT: We report an efficient catalytic Staudinger reduction at room temperature that
enables the preparation of a structurally diverse set of amines from azides in excellent yields.
The reaction is based on the use of catalytic amounts of triphenylphosphine as a phosphine
source, and diphenyldisiloxane as a reducing agent. Our catalytic Staudinger reduction exhibits
a high chemoselectivity, as exemplified by reduction azides over other common functionalities,
including nitriles, alkenes, alkynes, esters, and ketones.
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The Staudinger reduction (also known as the Staudinger reaction), a phosphine-mediated
conversion of organic azides to amines, presents an important synthetic method in the repertoire
of chemical reactions that transformed organic chemistry in the past century (Scheme 1a). Since
its first report in 1919 by Staudinger and Meyer,1 the Staudinger reduction has found a
widespread use in chemistry, ranging from synthetic organic chemistry and material science to
medicinal chemistry and chemical biology.2 Only recently, two organocatalytic versions of the
Staudinger reduction have been developed, both at elevated temperatures (Scheme 1b).3 Along
with recent advances in development of other phosphine-catalyzed reactions, including the
Wittig,4 Appel,5 and Mitsunobu6 reactions, the Staudinger ligation,7 and several other
transformations,8 we are currently lacking efficient catalytic methods that are carried out at
room temperature. Here we report the development of the first efficient catalytic Staudinger
reaction at room temperature.
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Redox-driven organophosphorus catalysis typically relies on efficient
hydrosilane-based in situ reduction of phosphine oxides (P(V)) to the corresponding phosphines
(P(III)).9 For instance, phenylsilane was used as a reducing agent in the catalytic Staudinger
ligation, Staudinger reduction, (Aza-)Wittig, and Mitsunobu reaction. Other frequently used
silanes include diphenylsilane,4c diethoxymethylsilane,8c tetramethyldisiloxane (TMDS),10 and
poly(methylhydrosiloxane) (PMHS).3a Even though these reactive silanes have been
successfully applied as reducing agents in various organophosphorus-catalyzed reactions, the
major drawback is high temperature (typically >100 °C) required for reduction of phosphine
oxide to phosphine.11 Recently, a few methods for the reduction of phosphine oxides to
phosphines at room temperature have been reported. Li et al. developed an iodine-catalyzed
reduction in the presence of phosphites.12 Aldrich and co-workers found that phosphine oxides
can be efficiently reduced in the presence of diphenyldisiloxane ((PhSiH2)2O,
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DPDS)/bis(4-nitrophenyl) phosphate.13 A third method utilizes pinacol borane, HBpin, as a
reducing agent, however, the scope is limited to secondary phosphine oxides.14
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Scheme 1. (a) Classic Staudinger reduction; (b) Organophosphorus-catalyzed Staudinger
reduction in the presence of hydrosilane-based reducing agents
We hypothesized that DPDS alone has an ability to reduce at room temperature the
iminophosphorane intermediate (unlike the more stable phosphine oxide) that is formed during
the catalytic cycle of the Staudinger reduction (Scheme 1b). We started our investigations by
testing whether DPDS is a good reducing agent for the catalytic Staudinger reaction, under
conditions similar to our previously reported PMHS-mediated reaction.3a For this purpose, 4-
nitrophenethyl azide (0.5 mmol) was reacted with catalytic amounts of Ph3P (10 mol%) and
diphenyldisiloxane (DPDS, 1.5 equiv) at room temperature (22 °C) for 24 hours in various
organic solvents (Table 1, entries 1–4). The amount of 4-nitrophenetylamine formed was
determined by 1H NMR spectroscopy, using 1,3,5-trimethoxybenzene as an internal standard.
We were pleased to find that the reaction proceeded very well in toluene, as 96% of
4-nitrophenethylamine was formed from 4-nitrophenethyl azide (Table 1, entry 1). The reaction
also works perfectly well in ethereal solvents such as dioxane (98%), THF (99%), and
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cyclopentyl methyl ether (CPME, >99% NMR yield). From these ethereal solvents, we were
particularly interested in using CPME because it is an environmentally friendly alternative to
THF and dioxane.15 Besides being a sustainable solvent produced from bio-mass, the use of
CPME is also safer compared to THF as it resists peroxide formation (i.e. no stabilizers are
required).16
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Table 1. Optimization of the catalytic Staudinger
reduction at room temperaturea
1) Ph3P, Si-H
solvent, room temp.
N3
NH2
2) H2O (10 equiv)
O2N
O2N
Entry Phosphorus
(equiv)
Silane
(equiv)
Solvent Yield
(%)b
1
2
3
4
Ph3P (0.1)
Ph3P (0.1)
Ph3P (0.1)
Ph3P (0.1)
Ph3P (0.05)
Ph3P (0.02)
Ph3P (0.1)
Ph3P (0.1)
Ph3P (0.05)
Ph3P (0.05)
Ph3P (0.1)
Ph3P (0.1)
Ph3P (0.1)
Ph3P (0.1)
Ph3P (0.1)
-
DPDS (1.5)
DPDS (1.5)
DPDS (1.5)
DPDS (1.5)
DPDS (1.5)
DPDS (1.5)
DPDS (1.5)
DPDS (1.5)
DPDS (1.5)
DPDS (1.5)
DPDS (1.1)
DPDS (0.6)
PMHS (1.5)
Toluene 96
Dioxane 98
THF
99
>99
80
27
97
44
98
>99
79
60
10
12
4
CPMEc
CPME
CPME
CPME
CPME
CPME
CPME
CPME
CPME
CPME
5
6
7d
8e
9f
10g
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17
18
PhSiH3 (1.5) CPME
Ph2SiH2 (1.5) CPME
DPDS (1.5)
-
CPME
CPME
CPME
0
8
0
Ph3P (0.1)
Ph3PO (0.1)
DPDS (1.5)
a4-nitrophenethyl azide (0.5 mmol), DPDS (1.5 equiv),
Ph3P (0.1 equiv), solvent (2.0 mL, 0.25 M), 24 h, rt.
bNMR yield, using 1,3,5-trimethoxybenzene as an
internal standard. ccyclopentyl methyl ether (CPME). d20
h reaction time. e8 h reaction time. f4 h at 60 °C. g30 min
at 106 °C.
We then investigated whether we could lower the amount of Ph3P and found that with
5 mol% of Ph3P the reaction still proceeds very well, affording 80% of 4-nitrophenethylamine
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(Table 1, entry 5). When 2 mol% of Ph3P was used, however, we observed only 27% of the
amine product after 24 hours (Table 1, entry 6). A slight decrease in yield of 4-nitrophenethyl
amine was observed when the reaction proceeded for 20 hours with 10 mol% Ph3P (97%),
whereas only 44% of amine was obtained after 8 hours (Table 1, entries 7 and 8). We observed
that the model reaction proceeded much faster, even in the presence of lower amounts (5 mol%)
of Ph3P, at elevated temperatures: in the presence of 5 mol% Ph3P the reaction took 4 hours for
completion at 60 °C (Table 1, entry 9). Remarkably, a full conversion of 4-nitrophenetyl azide
to 4-nitrophenethylamine was observed with 5 mol% Ph3P in only 30 minutes at 106 °C (with
2 mol% Ph3P in 1 h), highlighting that our newly reported method is far more efficient when
compared to the PMHS-based method developed recently (Table 1, entry 10).3a More details
on the catalytic Staudinger reduction at room temperature and elevated temperatures can be
found in Figures S1 and S2 in Supporting Information. DPDS contains 4 Si-H bonds, thus
employing 1.5 equiv of DPDS corresponds to 6 equiv of Si-H. To investigate whether the Si-H
excess is required for efficient Staudinger reduction, we examined reactions in the presence of
1.1 (4.4 Si-H) and 0.6 (2.4 Si-H) equiv of DPDS, respectively: we found that decreased amounts
of DPDS led to somewhat lower yields (79 and 60%, respectively) (Table 1, entries 11 and 12).
Having shown that a combination of Ph3P and DPDS enables an efficient catalytic
Staudinger reduction at room temperature (Table 1, entry 4), we carried out several important
control experiments. Notably, other silane reagents that are commonly used in
organophosphorus catalysis, such as poly(methylhydrosiloxane), phenylsilane, and
diphenylsilane, are not amenable to the room temperature organophosphorus-catalyzed
Staudinger reduction under our conditions (Table 1, entries 13–15). The model reaction in the
absence of Ph3P did not yield detectable amounts of 4-nitrophenethylamine, demonstrating that
the reaction is phosphine-catalyzed (Table 1, entry 16). In the absence of DPDS, the Staudinger
reduction gave 8% of the amine product; in this case, the small amount of amine was produced
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via classic Staudinger reduction in the presence of 10 mol% Ph3P (Table 1, entry 17). In line
with the findings of Aldrich and co-workers13 that triphenylphosphine oxide is not reduced by
DPDS at room temperature without bis(4-nitrophenyl) phosphate additive, we observed no
Staudinger reduction in a reaction in which catalytic amounts of triphenylphosphine oxide were
used instead of triphenylphosphine (Table 1, entry 18).
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With the optimized conditions in hand, we set out to explore the scope of the room
temperature organophosphorus-catalyzed Staudinger reduction. The reduction of various
substituted phenethyl azides afforded the corresponding amines in very good to excellent
isolated yields (Scheme 2, 1–4); the amine products were obtained as hydrochloride salts upon
precipitation with 4M HCl (in dioxane), thus making the reaction operationally very simple. It
is worth noting that for compounds 1 and 3 we did not observe reduction of the nitro group.
The reaction proceeds very well for the reduction of benzyl azide as benzylamine was obtained
quantitatively (Scheme 2, 5). Notably, a gram scale (1.3 gram, 10 mmol) reduction of benzyl
azide to benzylamine was also carried out; benzylamine was obtained in excellent 94% isolated
yield. Furthermore, various mono- and disubstituted benzylic azides were found to be excellent
substrates for this transformation with yields in the range of 87–99% (Scheme 2, 6–14).
Thioether 15 was also obtained with an excellent 99% isolated yield. In contrast to our
previously reported PMHS-mediated method,3a the room temperature organophosphorus-
catalyzed Staudinger reduction works very well for aryl azides, as p-fluoroaniline 16 and
p-toluidine 17 were both obtained in quantitative (>99%) isolated yield. Furthermore, 2-
fluoroethyl azide was reduced to afford 88% of 2-fluoroethylamine (Scheme 2, 18).
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Scheme 2. Substrate scope for the catalytic
Staudinger reduction at room temperature.
1) Ph3P (10 mol%),
(PhSiH2)2O (1.5 equiv), CPME, rt, 24h
R
N3
R
NH2.HCl
2) H2O (10 equiv)
3) 4.0 M HCl in dioxane
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NH2.HCl
NH2.HCl
NH2.HCl
NH2.HCl
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O2N
NO2
Cl
1 99%a
2 90%
3 >99%
4 90%
CF3
F3C
NH2.HCl
NH2.HCl
NH2.HCl
NH2.HCl
I
5 99%
6 88%
7 87%
8 99%
Cl
NH2.HCl
NH2.HCl
NH2.HCl
NH2.HCl
F
Br
F
F
Cl
10 96%
9 >99%
11 98%
12 99%
NH2.HCl
S
O
NH2.HCl
NH2.HCl
NH2.HCl
F
O
13 87%
14 93%
15 99%
16 >99%
NH2.HCl
NH2.HCl
N
NH2.HCl
F
NH2.HCl
N
F
H3C
17 >99%
18 88%
19 99%
20 99%
NH2.HCl
H
NH2.HCl
N
S
N
NH2.HCl
S
Cl
N
NH2.HCl
S
21 54%
22 97%
23 82%
24 74%
NH2HCl
NH2.HCl
NH2.HCl
NH2.HCl
N
Bn
O
N
28 NR
26 37%
27 NR
25 99%
aisolated yield.
Next, the substrate scope of the reaction with respect to heteroaromatic azides was
investigated. The catalytic reduction of pyridines 19 and 20 proceeded very well (99% yield),
whereas tryptamine 21 was obtained in a moderate yield (54%). The reaction with
benzothiophene-derived azide also underwent nearly quantitative conversion (97%) to the
corresponding amine 22. In addition, thiazole 23 and benzothiazole 24 were formed with good
yields of 82% and 74%, respectively. Furthermore, an azide containing a functionalized
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oxadiazole ring was efficiently converted to the corresponding amine 25 with 99% isolated
yield.
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The reaction scope for secondary and tertiary organic azides was also evaluated. It was
found that the reaction is less efficient for secondary azides. 2-Amino-1-phenylpropane 26 was
obtained in moderate 37% isolated yield, whereas the reduction of 2-azidoindane did not yield
detectable amounts of the amine product (Scheme 2, 27). In addition, when we attempted a
catalytic Staudinger reduction on sterically demanding 1-azidoadamantane, no amine product
was obtained, implying that steric effects play an important role in the efficient reduction
(Scheme 2, 28).
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Having shown that the catalytic Staudinger reduction proceeds very efficiently for a
large panel of primary azides, we explored the scope of the room temperature catalytic
Staudinger reduction for azides bearing functional groups that are prone to reduction (Scheme
3). We found that the reaction is highly chemoselective for reduction of azides to amines in the
presence of various common functional groups, which would be reduced under catalytic
hydrogenation conditions.17 Notably, under our reaction conditions, we did not observe any
reduction of the nitrile (29, 99%), alkene (30–32, 55–99%), alkyne (33, 93%), benzyl ether (34,
76%), and benzyl carbamate (35, 85%) functionalities. As an alternative to the Staudinger
reaction, the reduction of organic azides can also be achieved in the presence of metal hydride
reagents.18 Unfortunately, these reagents, such as lithium aluminium hydride, also reduce many
other functional groups, including esters, ketones, carboxylic acids, and amides.19 We were very
pleased to find that these carbonyl-containing functional groups remained unaffected under our
conditions using Ph3P and DPDS; in all cases the azide was selectively reduced and the desired
amines were obtained in very good to excellent isolated yields in the range of 71–99% (Scheme
3, 36–41). It is worth noting that a combination of reduction-sensitive functional groups is also
tolerated well, as exemplified by the chemoselective reduction of an azide bearing both alkene
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and ester functionalities (42 in 76% yield). Furthermore, sulfone containing amine 43 was
obtained with virtually quantitative yield (>99%). A chemoselective reduction of azide to amine
also proceeds in the presence of alcohol (44, 82%). We also attempted to carry out
chemoselective reduction of 4-formylbenzyl azide, however, we found that no amine product
was obtained.
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Scheme 3. Extended substrate scope highlighting
the chemoselective nature of the catalytic
Staudinger reduction.
aisolated yield.
To investigate the mechanism of the room temperature catalytic Staudinger reduction,
we carried out various experiments and followed these by NMR spectroscopy. We started by
confirming that DPDS does not reduce 4-nitrophenetyl azide in the absence of Ph3P in 24 hours
at room temperature, confirming that no product was formed in an optimization experiment
(Table 1, entry 16, Figure S3). Importantly, in agreement with the control experiment (Table 1,
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entry 18), H and P NMR data showed that Ph3PO does not catalyze the conversion of 4-
nitrophenetyl azide to 4-nitrophenetylamine in the presence of DPDS, hence excluding the
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Figure 1. Time-course of the room temperature organophosphorus-catalyzed Staudinger reduction performed in toluene-d8
followed by in situ 31P NMR spectroscopy. 31P NMR spectra of aPh3P (δ -5.22 ppm); bpreactivation: Ph3P mixed with
4-nitrophenethyl azide but absence of DPDS showing formation of iminophosphorane (Ph3P=N-R, δ 6.35 ppm);
d
e
cpostactivation: 4 h after initiation of the reaction with DPDS; 24 h reaction time, before quenching; after quenching of the
reaction in D2O.
possibility that the catalytic Staudinger reduction proceeds via the Ph3PO-mediated pathway
(Figure S4). Finally, we monitored the catalytic Staudinger reaction by in situ 31P NMR
spectroscopy (Figure 1). The iminophosphorane (Ph3P=N-R, δ 6.35 ppm) was formed
immediately upon pre-mixing of 4-nitrophenethyl azide and 10 mol% of Ph3P (but before the
addition of DPDS), and persisted until the reaction was complete. Eventually, Ph3P (δ -5.22
ppm) was reformed, whereas only traces of Ph3PO (δ 25.98 ppm) were present from the start
of the reaction. In contrast, in the stoichiometric reaction at room temperature, Ph3P was rapidly
consumed to form the iminophosphorane, which was hydrolyzed by water over time to
exclusively form Ph3PO and the amine product: no reformation of Ph3P was observed (Figure
S5). Furthermore, NMR analyses reveal that many different intermediates are present before
quenching of the reaction: i) all nitrogen that is present in the reaction is either in the form of
the silylamine species or has already formed the amine product, and ii) multiple hydrides per
molecule of DPDS participate in the reaction, as different R3SiH, R2SiH2 and RSiH3 species
are formed (Figures S6-S8). Taken together, these observations lead to the conclusion that the
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room temperature catalytic Staudinger reduction proceeds via the DPDS-mediated P=N
reduction pathway (Scheme 1b).
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In summary, we have developed the first efficient organophosphorus-catalyzed
Staudinger reduction that proceeds at room temperature. The catalytic Staudinger reduction,
which is based on the presence of Ph3P as a phosphine source and DPDS as a silane source,
provides a structurally diverse panel of amines in excellent isolated yields (up to 99%). We
demonstrate that the catalytic Staudinger reduction displays a broad substrate scope, and is very
tolerant to functional groups that are prone to reduction, as exemplified by chemoselective
reduction of azide to amine in the presence of alkenes, alkyne, ester, carboxylic acid, ketone,
amide, nitro, nitrile, benzyl ether, carbamate, and sulfone functionalities.
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EXPERIMENTAL SECTION
General experimental. All chemicals and solvents were obtained from commercial suppliers
and used without further purification. 4-Azidotoluene solution in MTBE (CAS 2101-86-2), 1-
Azido-4-fluorobenzene solution in MTBE (CAS 3296-02-4), and 1-azidoadamantane
(CAS 24886-73-5) were purchased from Sigma-Aldrich. Phenylsilane (CAS 694-53-1), copper
chloride (CAS 7447-39-4), copper iodide (CAS 7681-65-4) and 1-azido-2-fluoroethane
(CAS 894792-94-0) were purchased from Fluorochem. Reactions were carried out with
constant magnetic stirring under atmospheric conditions. The reaction progress was monitored
using thin-layer chromatography (TLC) in the indicated solvent mixture on EMD Silica Gel 60
F254 glass plates. Visualisation of the developed plates was performed under UV light (254 nm)
and/or staining with ninhydrin or KMnO4.
Nuclear magnetic spectroscopy (NMR) data were recorded at ambient temperature on a Bruker
Avance III 400 (400 MHz), or Bruker Avance III 500 (500 MHz, equipped with a Prodigy
cryoprobe) spectrometer in the indicated solvents. 1H NMR chemical shifts are reported as δ in
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units of parts per million (ppm) relative to the internal standard tetramethylsilane (TMS, δ = 0
ppm). 13C{1H} NMR shifts are reported as δ in units of parts per million (ppm) and the spectra
were internally referenced to the residual solvent signal (CHCl3 δ = 77.0 ppm, MeOH δ = 49.0
ppm). 31P NMR shifts are reported as δ in units of ppm with respect to Ph3P (δ -5.2 ppm).7c
Multiplicities are given as: s (singlet), bs (broad singlet), d (doublet), t (triplet), q (quartet), hept
(heptet), m (multiplet), app. (apparent). Coupling constants are reported as J-values in Hertz
(Hz). Infrared spectra (IR-ATR, cm-1) were recorded on a Bruker Tensor 27. Mass spectra (MS,
m/z) were recorded on a LCQ Advantage MAX (Finnigan) mass spectrometer. High resolution
mass spectra (HRMS, ESI+) were recorded on a JEOL AccuTOF CS JMS-T100CS mass
spectrometer.
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4-Nitrophenethyl azide, phenethyl azide, 2-nitrophenethyl azide, 3-chlorophenethyl azide,
benzyl azide, 4-bromo-2-fluorobenzyl azide, 3,4-(methylenedioxy)benzyl azide (piperonyl
azide),
1-(azidomethyl)naphthalene,
(2-azidoethyl)
phenyl
sulfide,
2-fluoro-3-
(azidomethyl)pyridine, 3-(2-azidoethyl) indole, 5-(azidomethyl) thiazole, 1-phenyl-2-
azidopropane, 1-azidoindane, 3-cyanobenzyl azide, cinnamyl azide, 4-benzyloxybenzyl azide,
methyl 4-(azidomethyl) benzoate, methyl 6-(azidomethyl) nicotinate, 4-benzoylbenzyl azide,
4-acetamidobenzyl azide, 4-(methylsulfonyl)benzyl azide, and 4-(hydroxymethyl)benzyl azide
were synthesized as previously described.3a
General procedure I (GPI) for the synthesis of azides from alkyl halides. To a 20 mL
mixture of acetone and water (4:1) were subsequently added alkyl halide (4 mmol, 0.2 M final
concentration, 1.0 equiv) and NaN3 (4.8 mmol, 1.2 equiv). The mixture was stirred at room
temperature (22 °C, alkyl bromides) or 60 °C (alkyl chlorides) until TLC analysis showed the
reaction was complete (typically overnight). After this, brine (50 mL) was added and the
product was extracted with Et2O (3x20 mL). The combined organic layer was dried over
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MgSO4, and filtered. After evaporation of the solvent, 1H NMR was taken and if necessary the
crude azide was purified by flash column chromatography.
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4-Iodobenzyl azide (770 mg, 99% isolated yield, pale yellow oil) was synthesized according to
GPI starting from 4-iodobenzyl bromide (890 mg, 4.0 mmol). Rf = 0.50 (EtOAc/n-heptane =
1:9); 1H NMR (500 MHz, CDCl3) δ 7.74 (d, J = 8.3 Hz, 1H), 7.09 (d, J = 8.3 Hz, 1H), 4.32 (s,
1H); 13C{1H} NMR (126 MHz, CDCl3) δ 138.0, 135.0, 130.0, 93.9, 54.2. Data are in
accordance to that previously reported.20
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3-(Trifluoromethyl)benzyl azide (699 mg, 87% isolated yield, pale yellow oil) was synthesized
according to GPI starting from 3-(trifluoromethyl)benzyl chloride (778 mg, 4.0 mmol). Rf =
1
0.60 (EtOAc/n-heptane = 1:9); H NMR (400 MHz, CDCl3) δ 7.65 – 7.56 (m, 2H), 7.54 – 7.50
(m, 2H), 4.44 (s, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 136.5, 131.3 (q, J = 1.2 Hz), 131.2
(q, J = 32.3 Hz), 129.4, 125.1 (q, J = 3.7 Hz), 124.8 (q, J = 3.9 Hz), δ 123.9 (q, J = 272.4 Hz),
54.17; 19F NMR (377 MHz, CDCl3) δ -62.8. Data are in accordance to that previously
reported.21
2-(Trifluoromethyl)benzyl azide (526 mg, 87% isolated yield, colorless oil) was synthesized
according to GPI starting from (trifluoromethyl)benzyl bromide (717 mg, 3.0 mmol). Rf = 0.60
1
(EtOAc/n-heptane = 1:9); H NMR (500 MHz, CDCl3) δ 7.72 (d, J = 7.8 Hz, 1H), 7.64 – 7.57
(m, 2H), 7.48 (t, J = 7.5 Hz, 1H), 4.60 (s, 2H); 13C{1H} NMR (126 MHz, CDCl3) δ 133.9 (q, J
= 1.7 Hz), 132.3, 130.3, 128.3 (q, J = 30.6 Hz), 128.3, 126.2 (q, J = 5.6 Hz), 124.1 (q, J = 273.8
Hz), 51.1 (q, J = 2.5 Hz). Data are in accordance to that previously reported.22
4-Isopropylbenzyl azide (425 mg, 61% isolated yield, colorless oil) was synthesized according
to GPI starting from 4-isopropylbenzyl chloride (675 mg, 4.0 mmol). Rf = 0.65 (EtOAc/n-
1
heptane = 1:9); H NMR (400 MHz, CDCl3) δ 7.24 (s, 4H), 4.30 (s, 2H), 2.92 (hept, J = 6.9
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Hz, 1H), 1.25 (d, J = 6.9 Hz, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 149.1, 132.7, 128.3,
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126.9, 54.7, 33.9, 23.9. Data are in accordance to that previously reported.23
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2,6-Dichlorobenzyl azide (799 mg, 99% isolated yield, pale yellow oil) was synthesized
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according to GPI starting from 2,6-dichlorobenzyl chloride (782 mg, 4.0 mmol). Rf = 0.60
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(EtOAc/n-heptane = 1:9); H NMR (400 MHz, CDCl3) δ 7.41 – 7.33 (m, 2H), 7.27 – 7.23 (m,
1H), 4.68 (s, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 136.4, 131.5, 130.3, 128.6, 49.2. Data
are in accordance to that previously reported.23
3,4-Difluorobenzyl azide (454 mg, 90% isolated yield, colorless oil) was synthesized according
to GPI starting from 3,4-difluorobenzyl chloride (487.7 mg, 3.0 mmol). Rf = 0.45 (EtOAc/n-
1
heptane = 1:9); H NMR (500 MHz, CDCl3) δ 7.23 – 7.14 (m, 2H), 7.09 – 7.04 (m, 1H), 4.34
(s, 2H); 13C{1H} NMR (126 MHz, CDCl3) δ 150.4 (dd, J = 249.6, 12.9 Hz), 150.2 (dd, J =
249.2, 12.6 Hz), 132.4 (dd, J = 3.9, 1.4 Hz), 124.1 (dd, J = 6.5, 3.7 Hz), 117.4 (dd, J = 63.8,
17.6 Hz), 65.2 (d, J = 0.9 Hz). Data are in accordance to that previously reported.24
3-(Azidomethyl)pyridine (204 mg, 38% isolated yield, colorless oil) was synthesized according
to GPI starting from 3-(chloromethyl)pyridine (656 mg, 4.0 mmol). The crude azide was
purified by flash column chromatography using 30-50% EtOAc in n-heptane. Rf = 0.30
1
(EtOAc/n-heptane = 1:1); H NMR (400 MHz, CDCl3) δ 8.65 – 8.51 (m, 2H), 7.73 – 7.62 (m,
1H), 7.34 (ddd, J = 7.8, 4.9, 0.9 Hz, 1H), 4.40 (s, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ
149.8, 149.4, 135.7, 131.1, 123.7, 52.2. Data are in accordance to that previously reported.25
3-(Azidomethyl)-5-chlorobenzo[b]thiophene (636 mg, 95% isolated yield, light yellow solid)
was synthesized according to GPI starting from 3-(bromomethyl)-5-chlorobenzo[b]thiophene
1
(784 mg, 3.0 mmol). Rf = 0.60 (EtOAc/n-heptane = 1:4); H NMR (400 MHz, CDCl3) δ 7.81
– 7.76 (m, 2H), 7.51 – 7.47 (m, 1H), 7.36 (ddd, J = 8.6, 2.0, 0.5 Hz, 1H), 4.54 (d, J = 0.8 Hz,
2H); 13C{1H} NMR (101 MHz, CDCl3) δ 138.8, 138.7, 131.0, 129.8, 127.5, 125.4, 123.9, 121.5,
48.5.
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2-(Azidomethyl)benzo[d]thiazole (680 mg, 89% isolated yield, pale green oil) was synthesized
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according to GPI starting from 2-(chloromethyl)benzo[d]thiazole (735 mg, 4.0 mmol). Rf =
1
0.70 (EtOAc/n-heptane = 1:1); H NMR (400 MHz, CDCl3) δ 8.06 – 8.01 (m, 1H), 7.93 – 7.89
9
(m, 1H), 7.55 – 7.48 (m, 1H), 7.45 – 7.40 (m, 1H), 4.80 (s, 2H). 13C{1H} NMR (126 MHz,
CDCl3) δ 165.8, 153.1, 135.2, 126.4, 125.6, 123.3, 121.8, 52.1. Data are in accordance to that
previously reported.26
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5-(Azidomethyl)-3-benzyl-1,2,4-oxadiazole (604 mg, 94% isolated yield, pale yellow oil) was
synthesized according to GPI starting from 5-(chloromethyl)-3-benzyl-1,2,4-oxadiazole (626
1
mg, 3.0 mmol). Rf = 0.20 (EtOAc/n-heptane = 1:9); H NMR (400 MHz, CDCl3) δ 7.38 – 7.26
(m, 5H), 4.52 (s, 2H), 4.10 (s, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 174.0, 169.9, 135.0,
129.0, 128.8, 127.3, 45.1, 32.3.
4-Vinylbenzyl azide (636 mg, 99% isolated yield, pale yellow oil) was synthesized according to
1
GPI starting from 4-vinylbenzyl chloride (610 mg, 4.0 mmol). Rf = 0.55 (100% n-heptane); H
NMR (400 MHz, CDCl3) δ 7.42 (d, J = 8.1 Hz, 2H), 7.28 (d, J = 8.1 Hz, 2H), 6.72 (dd, J =
17.6, 10.9 Hz, 1H), 5.77 (dd, J = 17.6, 0.8 Hz, 1H), 5.28 (dd, J = 10.9, 0.8 Hz, 1H), 4.32 (s,
2H); 13C{1H} NMR (101 MHz, CDCl3) δ 137.7, 136.2, 134.8, 128.5, 126.6, 114.5, 54.6. Data
are in accordance to that previously reported.27
4-(Azidomethyl)benzaldehyde (416 mg, 84% isolated yield, yellow oil): To a stirred solution of
4-(azidomethyl)benzyl alcohol (500 mg, 3.06 mmol) in DCM (15 mL) was added pyridinium
chlorochromate (1.12 g, 5.21 mmol, 1.7 equiv). The reaction was left to stir at room temperature
for 1 hour. Subsequently, the reaction mixture was filtered over a pad of silica gel on a fritted
funnel. The solvent was removed in vacuo to afford the desired azide without further
purification. Rf = 0.75 (EtOAc/n-heptane = 1:1); 1H NMR (400 MHz, CDCl3) δ 10.03 (s, 1H),
7.91 (d, J = 8.2 Hz, 2H), 7.50 (d, J = 8.2 Hz, 1H), 4.46 (s, 2H); 13C{1H} NMR (101 MHz,
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CDCl3) δ 191.6, 142.1, 136.2, 130.2, 128.5, 54.3. Data are in accordance to that previously
reported.27
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4-Ethynylbenzyl azide (108 mg, 55% isolated yield, colorless oil): To a stirred solution of
4-(azidomethyl)benzaldehyde (200 mg, 1.25 mmol) and K2CO3 (343 mg, 2.5 mmol, 1.5 equiv)
in MeOH (20 mL) was added dimethyl (1-diazo-2-oxopropyl)phosphonate solution (Bestmann-
Ohira reagent, 1.3 equiv) at room temperature. The reaction mixture was left to stir at room
temperature overnight, after which it was quenched by the addition of sat. aq. NaHCO3 (10
mL). The crude mixture was concentrated in vacuo in order to remove the MeOH.
Subsequently, the solution was diluted with EtOAc (10 mL), washed with water (2 x 10 mL),
brine (1 x 10 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude
alkyne was purified by flash column chromatography (0-5% EtOAc in n-heptane). Rf = 0.50
(EtOAc/n-heptane = 1:4); 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 8.2 Hz, 2H), 7.28 (d, J =
8.2 Hz, 2H), 4.35 (s, 2H), 3.10 (s, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 136.1, 132.6, 128.1,
122.2, 83.1, 54.4. Data are in accordance to that previously reported.28
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Benzyl (2-azidoethyl)carbamate (515 mg, 78% isolated yield, colorless oil) was synthesized
according to GPI starting from benzyl (2-chloroethyl)carbamate (641 mg, 3.0 mmol). Rf = 0.30
1
(EtOAc/n-heptane = 1:4); H NMR (400 MHz, CDCl3) δ 7.43 – 7.27 (m, 5H), 5.12 (s, 2H),
5.04 (bs, 1H), 3.45 (t, J = 5.5 Hz, 2H), 3.38 (t, J = 5.5 Hz, 2H); 13C{1H} NMR (101 MHz,
CDCl3) δ 156.2, 136.3, 128.6, 128.2, 128.1, 67.0, 51.2, 40.5. Data are in accordance to that
previously reported.29
3-(Azidomethyl)benzoic acid (495 mg, 93% isolated yield, off-white solid) was synthesized
according to GPI starting from 3-(chloromethyl)benzoic acid (512 mg, 3.0 mmol). Rf = 0.30
1
(EtOAc/n-heptane = 1:1); H NMR (400 MHz, CDCl3) δ 8.14 – 8.06 (m, 2H), 7.59 (dt, J = 7.7,
1.6 Hz, 1H), 7.52 (td, J = 7.7, 0.6 Hz, 1H), 4.44 (s, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ
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171.6, 136.1, 133.4, 130.1, 129.9, 129.8, 129.1, 54.3. Data are in accordance to that previously
reported.30
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Methyl (E)-3-(4-(azidomethyl)phenyl)acrylate (650 mg, >99% isolated yield, pale yellow oil)
was synthesized according to GPI starting from methyl (E)-3-(4-(bromomethyl)phenyl)acrylate
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(765 mg, 4.0 mmol). Rf = 0.30 (EtOAc/n-heptane = 1:9); H NMR (500 MHz, CDCl3) δ 7.71
(d, J = 16.0 Hz, 1H), 7.56 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.2 Hz, 2H), 6.48 (d, J = 16.0 Hz,
1H), 4.39 (s, 2H), 3.84 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 167.3, 144.0, 137.6, 134.4,
128.6, 128.5, 118.4, 54.4, 51.8.
General procedure II (GPII) for the synthesis of azides from alcohols.31 In a dried reaction
flask under a protected atmosphere, the respective alcohol (1.0 equiv) was dissolved in dry
DCM to obtain a 0.1 M solution. The mixture was cooled to -30 °C followed by the addition of
triethylamine (1.5 equiv) and methanesulfonyl chloride (1.3 equiv). The reaction mixture was
allowed to stir at -30 °C for 5 hours after which it was allowed to warm to room temperature.
After additional stirring at room temperature for 30 minutes the solvent was removed in vacuo.
The obtained solid was redissolved in anhydrous dimethylformamide (DMF, 0.1 M) followed
by the addition of NaN3 (2.0 equiv). The reaction was left to stir at room temperature for 20 h.
The reaction mixture was diluted by the addition of water (50 mL) and extracted with Et2O
(3x20 mL). The combined organic layers were washed with brine (1x50 mL), dried over
MgSO4, and filtered. The solvent was removed in vacuo, and the crude azide was purified by
flash column chromatography.
(E)-(3-Azidoprop-1-ene-1,3-diyl)dibenzene (541 mg, 58% isolated yield, colorless oil) was
synthesized according to GPII starting from (E)-1,3-diphenylprop-2-en-1-ol (841.1 mg, 4.0
mmol). The crude azide was purified by flash column chromatography using 1% EtOAc in n-
1
heptane. Rf = 0.60 (EtOAc/n-heptane = 1:4); H NMR (400 MHz, CDCl3) δ 7.44 – 7.23 (m,
10H), 6.72 (dd, J = 15.7, 1.4 Hz, 1H), 6.29 (dd, J = 15.7, 7.2 Hz, 1H), 5.21 (dd, J = 7.2, 1.4 Hz,
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1H). 13C{1H} NMR (101 MHz, CDCl3) δ 138.6, 135.9, 133.0, 128.8, 128.6, 128.3, 128.2, 127.1,
126.9, 126.7, 67.2. Data are in accordance to that previously reported.32
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Ethyl (S)-2-azido-4-phenylbutanoate (213 mg, 23% isolated yield, colorless oil) was
synthesized according to GPII. Rf = 0.65 (EtOAc/n-heptane = 3:7); 1H NMR (500 MHz,
CDCl3) δ 7.33 – 7.27 (m, 2H), 7.23 – 7.17 (m, 3H), 4.23 (q, J = 7.1 Hz, 2H), 3.81 (dd, J = 8.9,
5.0 Hz, 1H), 2.84 – 2.64 (m, 2H), 2.21 – 2.11 (m, 1H), 2.10 – 2.01 (m, 1H), 1.30 (t, J = 7.1 Hz,
3H); 13C{1H} NMR (126 MHz, CDCl3) δ 170.4, 140.1, 128.6, 128.5, 126.4, 61.8, 61.2, 32.9,
31.8, 14.2. Data are in accordance to that previously reported.3a
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General procedure for the catalytic Staudinger reduction. Azide (0.25 or 0.5 mmol, 1.0
equiv) and diphenyldisiloxane (DPDS, 1.5 equiv) were combined in a glass vial containing a
magnetic stir bar. The mixture was dissolved in CPME (0.25 M final conc.) and to this Ph3P
(0.1 equiv) was added. Gas evolves from the reaction immediately. The reaction was left to stir
at room temperature (22 °C) for 24 h, after which it was quenched by the addition of water
(10 equiv). The mixture was allowed to stir until gas stopped evolving, subsequently, the
mixture was diluted two times with Et2O. The desired amine was obtained as the corresponding
hydrochloride salt by precipitation with 0.5 mL of 4.0 M HCl in dioxane.
4-Nitrophenethylamine hydrochloride (Compound 1, 105 mg, 99% isolated yield, off-white
solid) was synthesized according to GPIII starting from 4-nitrophenethyl azide (96 mg, 0.5
mmol). 1H NMR (400 MHz, CD3OD) δ 8.26 (d, J = 8.7 Hz, 2H), 7.58 (d, J = 8.7 Hz, 2H), 3.29
(t, J = 7.8 Hz, 2H), 3.14 (t, J = 7.8 Hz, 2H); 13C{1H} NMR (101 MHz, CD3OD) δ 149.5, 146.6,
131.9, 125.8, 42.1, 35.0; MS (ESI) m/z 167.3 [M+H]+. Data are in accordance to that previously
reported.3a
Phenethylamine hydrochloride (Compound 2, 72 mg, 90% isolated yield, white solid) was
synthesized according to GPIII starting from phenethyl azide (74 mg, 0.5 mmol). 1H NMR (400
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MHz, CD3OD) δ 7.41 – 7.35 (m, 2H), 7.34 – 7.27 (m, 3H), 3.20 (t, J = 8.3 Hz, 2H), 2.97 (t, J =
8.3 Hz, 2H); 13C{1H} NMR (101 MHz, CD3OD) δ 138.8, 130.9, 130.6, 129.2, 42.8, 35.4; MS
(ESI) m/z 122.3 [M+H]+. Data are in accordance to that previously reported.3a
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2-Nitrophenethylamine hydrochloride (Compound 3, 104 mg, >99% isolated yield, off-white
solid) was synthesized according to GPIII starting from 2-nitrophenethyl azide (97.09 mg, 0.5
mmol). 1H NMR (400 MHz, CD3OD) δ 7.52 – 7.47 (m, 2H), 7.41 – 7.35 (m, 2H), 7.32 – 7.27
(m, 1H), 3.27 (t, J = 7.0 Hz, 2H), 3.13 (t, J = 7.0 Hz, 2H); 13C{1H} NMR (101 MHz, CD3OD)
δ 151.7, 135.8, 134.6, 133.7, 130.8, 127.1, 42.0, 32.8; MS (ESI) m/z 167.3 [M+H]+. Data are
in accordance to that previously reported.3a
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3-Chlorophenethylamine hydrochloride (Compound 4, 43.1 mg, 90% isolated yield, white
solid) was synthesized according to GPIII starting from 3-chlorophenethyl azide (45.4 mg, 0.25
mmol). 1H NMR (400 MHz, CD3OD) δ 7.42 – 7.33 (m, 1H), 7.36 – 7.22 (m, 1H), 3.22 (t, J =
7.8 Hz, 1H), 3.00 (dd, J = 8.7, 6.8 Hz, 1H); 13C{1H} NMR (101 MHz, CD3OD) δ 141.1, 136.6,
132.4, 130.8, 129.3, 129.1, 42.5, 35.0; MS (ESI) m/z 156.2 [M+H]+. Data are in accordance to
that previously reported.3a
Benzylamine hydrochloride (Compound 5, 90 mg, 93% isolated yield, white solid) was
synthesized according to GPIII starting from benzyl azide (91 mg, 0.5 mmol). 1H NMR (400
MHz, CD3OD) δ 7.54 – 7.40 (m, 4H), 4.15 (s, 2H);13C{1H} NMR (101 MHz, CD3OD) δ 134.4,
130.1, 130.1, 130.1, 44.3; MS (ESI) m/z 107.9 [M+H]+. Data are in accordance to that
previously reported.3a
4-Iodobenzylamine hydrochloride (Compound 6, 59.0 mg, 88% isolated yield, white solid) was
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synthesized according to GPIII starting from 4-iodobenzyl azide (64.8 mg, 0.25 mmol). H
NMR (400 MHz, CD3OD) δ 7.83 (d, J = 8.5 Hz, 2H), 7.28 (d, J = 8.5 Hz, 2H), 4.11 (s, 2H);
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13C{1H} NMR (126 MHz, CD3OD) δ 138.0, 132.7, 130.7, 94.3, 42.4; MS (ESI) m/z 233.8
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[M+H]+. Data are in accordance to that previously reported.33
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3-(Trifluoromethyl)benzylamine hydrochloride (Compound 7, 41.0 mg, 78% isolated yield,
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white solid) was synthesized according to GPIII starting from 3-(trifluoromethyl)benzyl azide
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(50.3 mg, 0.25 mmol). H NMR (400 MHz, CD3OD) δ 7.90 – 7.84 (m, 1H), 7.82 – 7.74 (m,
2H), 7.72 – 7.64 (m, 1H), 4.26 (s, 2H); 13C{1H} NMR (101 MHz, CD3OD) δ 134.4, 132.6 (q, J
= 1.3 Hz), 131.0 (q, J = 32.6 Hz), 129.7, 125.5 (dq, J = 4.0, 0.6 Hz), 124.0 (q, J = 271.7 Hz),
42.3; 19F NMR (377 MHz, CD3OD) δ -64.2; MS (ESI) m/z 175.9 [M+H]+. Data are in
accordance to that previously reported.34
2-(Trifluoromethyl)benzylamine hydrochloride (Compound 8, 52.0 mg, 99% isolated yield,
white solid) was synthesized according to GPIII starting from 2-(trifluoromethyl)benzyl azide
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(50.3 mg, 0.25 mmol). H NMR (500 MHz, CD3OD) δ 7.85 (d, J = 7.8 Hz, 1H), 7.82 – 7.72
(m, 2H), 7.69 – 7.63 (m, 1H), 4.35 (s, 2H); 13C{1H} NMR (126 MHz, CD3OD) δ 132.9, 131.0,
130.8, 129.44, 128.5 (q, J = 30.5 Hz), 126.3 (q, J = 5.6 Hz), 124.2 (q, J = 272.9 Hz), 39.3 (q, J
= 2.9 Hz); F NMR (377 MHz, CD3OD) δ -60.54; MS (ESI) m/z 175.9 [M+H]+. Data are in
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accordance to that previously reported.34
4-Isopropylbenzylamine hydrochloride (Compound 9,46.1 mg, >99% isolated yield, white
solid) was synthesized according to GPIII starting from4-isopropylbenzyl azide (43.8 mg, 0.25
mmol). 1H NMR (400 MHz, CD3OD) δ 7.42 (d, J = 8.1 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 4.11
(s, 2H), 2.95 (hept, J = 6.9 Hz, 1H), 1.26 (d, J = 6.9 Hz, 6H); 13C{1H} NMR (101 MHz, CD3OD)
δ 150.0, 130.4, 128.7, 126.8, 42.7, 33.8, 22.9; MS (ESI) m/z 149.8 [M+H]+. Data are in
accordance to that previously reported.35
2,6-Dichlorobenzylamine hydrochloride (Compound 10, 60.0 mg, 96% isolated yield, white
solid) was synthesized according to GPIII starting from 2,6-dichlorobenzyl azide (50.5 mg, 0.25
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mmol). H NMR (400 MHz, CD3OD) δ 7.60 – 7.53 (m, 1H), 7.48 (dd, J = 9.1, 7.0 Hz, 1H),
4.50 (s, 2H); 13C{1H} NMR (101 MHz, CD3OD) δ 136.3, 131.8, 129.0, 128.7, 37.9;
MS (ESI) m/z 175.9 [M+H]+. Data are in accordance to that previously reported.36
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3,4-Difluorobenzylamine hydrochloride (Compound 11, 44.0 mg, 98% isolated yield, white
solid) was synthesized according to GPIII starting from 3,4-difluorobenzyl azide (42.3 mg, 0.25
mmol). 1H NMR (500 MHz, CD3OD) δ 7.49 (ddd, J = 11.2, 7.6, 1.8 Hz, 1H), 7.45 – 7.28 (m,
2H), 4.16 (s, 2H); 13C{1H} NMR (126 MHz, CD3OD) δ 150.6 (dd, J = 248.6, 12.2 Hz), 150.2
(dd, J = 247.5, 12.4 Hz), 130.4 (dd, J = 6.1, 4.0 Hz), 125.8 (dd, J = 6.8, 3.7 Hz), 118.1 (d, J =
18.5 Hz), 117.7 (d, J = 17.7 Hz), 41.9; 19F NMR (377 MHz, CD3OD) δ -139.2 (d, J = 20.7 Hz),
-139.8 (d, J = 20.7 Hz); IR (cm-1) 2975, 1526, 1290, 826, 773; MS (ESI) m/z 143.9 [M+H]+;
HRMS (ESI) found m/z 144.0640 [M+H]+, calcd for C7H8F2N+ m/z 144.0619.
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4-Bromo-2-fluorobenzylamine hydrochloride (Compound 12, 127 mg, 99% isolated yield, off-
white solid) was synthesized according to GPIII starting from 4-bromo-2-fluorobenzyl azide
(155 mg, 0.5 mmol). 1H NMR (400 MHz, CD3OD) δ 7.59 – 7.44 (m, 3H), 4.20 (d, J = 1.2 Hz,
2H); 13C{1H} NMR (101 MHz, CD3OD) δ 163.2 (d, J = 252.0 Hz), 134.6 (d, J = 3.7 Hz), 130.3
(d, J = 3.7 Hz), 125.9 (d, J = 9.8 Hz), 121.8 (d, J = 15.0 Hz), 121.4 (d, J = 24.9 Hz), 38.4 (d, J
= 4.1 Hz); 19F NMR (377 MHz, CD3OD) δ -116.0; MS (ESI) m/z 204.2 [M+H]+. Data are in
accordance to that previously reported.3a
3,4-(Methylenedioxy)benzylamine (piperonylamine) hydrochloride (Compound 13, 82 mg,
87% isolated yield, off-white solid) was synthesized according to GPIII starting from piperonyl
azide (89 mg, 0.5 mmol). 1H NMR (400 MHz, CD3OD) δ 7.00 – 6.95 (m, 2H), 6.92 – 6.88 (m,
1H), 6.02 (s, 2H), 4.05 (s, 2H); 13C{1H} NMR (101 MHz, CD3OD) δ 150.7, 150.6, 128.8, 125.0,
111.1, 110.5, 103.8, 45.1; MS (ESI) m/z 152.1 [M+H]+. Data are in accordance to that
previously reported.3a
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1-Naphthylmethylamine hydrochloride (Compound 14, 90 mg, 93% isolated yield, off-white
solid) was synthesized according to GPIII starting from 1-(azidomethyl)naphthalene (91 mg,
0.5 mmol). 1H NMR (400 MHz, CD3OD) δ 8.15 (dq, J = 8.4, 1.0 Hz, 1H), 8.06 – 7.97 (m, 2H),
7.74 – 7.54 (m, 4H), 4.67 (s, 2H); 13C{1H} NMR (101 MHz, CD3OD) δ 136.3, 133.2, 132.0,
131.1, 131.0, 129.7, 129.2, 128.4, 127.4, 124.5, 42.2; MS (ESI) m/z 157.9 [M+H]+. Data are in
accordance to that previously reported.3a
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(2-Aminoethyl) phenyl sulfide hydrochloride (Compound 15, 100 mg, 99% isolated yield, off-
white solid) was synthesized according to GPIII starting from (2-azidoethyl) phenyl sulfide (89
mg, 0.5 mmol). 1H NMR (400 MHz, CD3OD) δ 7.54 – 7.46 (m, 2H), 7.42 – 7.35 (m, 2H), 7.32
13
– 7.27 (m, 1H), 3.27 (t, J = 7.0 Hz, 2H), 3.13 (t, J = 7.0 Hz, 2H); C{1H} NMR (101 MHz,
CD3OD) δ 133.6, 130.2, 129.1, 127.0, 38.4, 30.6;MS (ESI) m/z 154.3 [M+H]+. Data are in
accordance to that previously reported.3a
4-Fluoroaniline hydrochloride (Compound 16, 92 mg, >99% isolated yield, off-white solid)
was synthesized according to GPIII starting from 1-azido-4-fluorobenzene (84 mg, 0.6 mmol,
0.5M in MTBE). 1H NMR (400 MHz, CD3OD) δ 7.55 (dd, J = 9.0, 4.5 Hz, 2H), 7.31 (dd, J =
9.0, 8.3 Hz, 2H); 13C{1H} NMR (101 MHz, CD3OD) δ 164.7 (d, J = 247.3 Hz), 128.8 (d, J =
3.2 Hz), 127.3 (d, J = 8.9 Hz), 118.8 (d, J = 23.8 Hz). 19F NMR (377 MHz, CD3OD) δ -114.25;
MS (ESI) m/z 112.3 [M+H]+. Data are in accordance to that previously reported.37
p-Toluidine hydrochloride (Compound 17, 89 mg, >99% isolated yield, yellow solid) was
synthesized according to GPIII starting from 1-azido-4-methylbenzene (82 mg, 0.6 mmol, 0.5M
in MTBE). 1H NMR (400 MHz, CD3OD) δ 7.37 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H),
2.42 (s, 2H); 13C{1H} NMR (101 MHz, CD3OD) δ 141.5, 132.6, 130.1, 124.7, 21.8; MS (ESI)
m/z 108.3 [M+H]+. Data are in accordance to that previously reported.38
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2-Fluoroethylamine hydrochloride (Compound 18, 44 mg, 88% isolated yield, white solid) was
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synthesized according to GPIII starting from 1-azido-2-fluoroethane ( 45 mg, 0.5 mmol). H
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NMR (400 MHz, CD3OD) δ 4.82 – 4.78 (m, 1H), 4.70 – 4.67 (m, 1H), 3.37 (t, J = 4.7 Hz, 1H),
3.30 (t, J = 4.7 Hz, 1H); 13C{1H} NMR (101 MHz, CD3OD) δ 82.1 (d, J = 167.2 Hz), 42.1 (d,
J = 20.0 Hz); 19F NMR (377 MHz, CD3OD) δ -228.13; MS (ESI): m/z 64.2 [M+H]+. Data are
in accordance to that previously reported.3a
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3-(Aminomethyl)pyridine hydrochloride (Compound 19, 35.9 mg, 99% isolated yield, white
solid) was synthesized according to GPIII starting from 3-(azidomethyl)pyridine (33.5 mg, 0.25
mmol). 1H NMR (400 MHz, CD3OD) δ 9.16 – 9.10 (d, J = 2.0 Hz, 1H), 8.99 (dt, J = 5.8, 1.0
Hz, 1H), 8.89 – 8.81 (m, 1H), 8.24 (ddd, J = 8.1, 5.8, 1.0 Hz, 1H), 4.50 (s, 2H); 13C{1H} NMR
(101 MHz, CD3OD) δ 147.5, 142.4, 142.1, 133.8, 127.5, 39.4; MS (ESI) m/z 109.1 [M+H]+.
Data are in accordance to that previously reported.39
2-Fluoro-3-(aminomethyl)pyridine hydrochloride (Compound 20, 97 mg, 99% isolated yield,
off-white solid) was synthesized according to GPIII starting from 2-fluoro-3-
(azidomethyl)pyridine (85 mg, 0.5 mmol). 1H NMR (400 MHz, CD3OD) δ 8.32 (ddd, J = 5.0,
1.9, 1.1 Hz, 1H), 8.10 (ddd, J = 9.6, 7.5, 1.9 Hz, 1H), 7.45 (ddd, J = 7.5, 5.0, 1.9 Hz, 1H), 4.26
(s, 2H); 13C{1H} NMR (101 MHz, CD3OD) δ 163.8 (d, J = 239.2 Hz), 150.6 (d, J = 14.4 Hz),
144.7 (d, J = 4.1 Hz), 124.4 (d, J = 4.4 Hz), 117.7 (d, J = 30.0 Hz), 38.7; 19F NMR (377 MHz,
CD3OD) δ -73.58; MS (ESI) m/z 127.0 [M+H]+. Data are in accordance to that previously
reported.3a
3-(2-Aminoethyl)indole hydrochloride (Compound 21, 53mg, 54% isolated yield, grey solid)
was synthesized according to GPIII starting from 3-(2-azidoethyl) indole (93 mg, 0.5 mmol).
1H NMR (400 MHz, CD3OD) δ 7.57 (dt, J = 8.1, 1.0 Hz, 1H), 7.38 (dt, J = 8.1, 0.9 Hz, 1H),
7.18 (bs, 1H), 7.16 – 7.10 (m, 1H), 7.08 – 7.02 (m, 1H), 3.24 (t, J = 7.3 Hz, 2H), 3.13 (t, J =
7.3 Hz, 1H); 13C{1H} NMR (101 MHz, CD3OD) δ 138.4, 128.2, 124.3, 122.8, 120.0, 118.9,
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112.6, 110.2, 41.3, 24.5; MS (ESI) m/z 161.22 [M+H]+. Data are in accordance to that
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previously reported.3a
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3-(Aminomethyl)-5-chlorobenzo[d]thiazole hydrochloride (Compound 22, 56.6 mg, 97%
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isolated yield, off-white solid) was synthesized according to GPIII starting from 3-
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(azidomethyl)-5-chlorobenzo[d]thiazole (55.9 mg, 0.25 mmol). H NMR (400 MHz, CD3OD)
δ 8.03 (d, J = 2.0 Hz, 1H), 7.96 (d, J = 8.6 Hz, 1H), 7.92 (s, 1H), 7.45 (dd, J = 8.6, 2.0 Hz, 1H),
4.43 (s, 2H); 13C{1H} NMR (126 MHz, CD3OD) δ 138.7, 138.5, 130.9, 129.7, 127.4, 125.1,
123.9, 120.9, 35.7; IR (cm-1) 2965, 1588, 1427, 1151, 1079, 783 ; MS (ESI) m/z 197.8 [M+H]+;
HRMS (ESI) found m/z 198.0158 [M+H]+, calcd for C9H9ClNS+ m/z 198.0139.
5-(Aminomethyl)thiazole hydrochloride (Compound 23, 67 mg, 82% isolated yield, white solid)
was synthesized according to GPIII starting from 5-(azidomethyl)thiazole (61 mg, 0.43 mmol).
1H NMR (400 MHz, CD3OD) δ 9.75 (s, 1H), 8.36 (d, J = 1.0 Hz, 1H), 4.58 (s, 2H); 13C{1H}
NMR (101 MHz, CD3OD) δ 160.9, 142.0, 134.8, 36.6; MS (ESI) m/z 115.0 [M+H]+. Data are
in accordance to that previously reported.3a
2-(Aminomethyl)benzo[d]thiazole hydrochloride (Compound 24, 37.0 mg, 74% isolated yield,
light brown solid) was synthesized according to GPIII starting from 2-
(azidomethyl)benzo[d]thiazole (47.6 mg, 0.25 mmol). 1H NMR (400 MHz, CD3OD) δ 8.11 –
8.02 (m, 2H), 7.58 (ddd, J = 8.2, 7.2, 1.3 Hz, 1H), 7.50 (ddd, J = 8.4, 7.2, 1.3 Hz, 1H), 4.67 (s,
2H); 13C{1H} NMR (101 MHz, CD3OD) δ 162.3, 152.3, 135.3, 126.4, 125.7, 122.8, 121.7,
40.3; MS (ESI) m/z 164.9 [M+H]+. Data are in accordance to that previously reported.40
(3-Benzyl-1,2,4-oxadiazol-5-yl)methanamine hydrochloride (Compound 25, 55.6 mg, 99%
isolated yield, off-white solid) was synthesized according to GPIII starting from 5-
(azidomethyl)-3-benzyl-1,2,4-oxadiazole (53.8 mg, 0.25 mmol). 1H NMR (500 MHz, CD3OD)
δ 7.38 – 7.21 (m, 5H), 4.52 (s, 2H), 4.14 (s, 2H); 13C{1H} NMR (126 MHz, CD3OD) δ 174.3,
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171.2, 136.7, 130.1, 129.7, 128.2, 36.1, 32.7; IR (cm-1) 2933, 1600, 717, 695; MS (ESI) m/z
189.9 [M+H]+; HRMS (ESI) found m/z 190.0978 [M+H]+, calcd for C10H12N3O+ m/z 190.0975.
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1-Phenyl-2-aminopropane hydrochloride (Compound 26, 32 mg, 37% isolated yield, off-white
solid) was synthesized according to GPIII starting from 1-phenyl-2-azidopropane (80 mg, 0.5
mmol). 1H NMR (400 MHz, CD3OD) δ 7.42 – 7.35 (m, 2H), 7.34 – 7.27 (m, 3H), 3.56 (dt, J =
8.1, 6.3 Hz, 1H), 3.05 (dd, J = 13.5, 6.3 Hz, 1H), 2.84 (dd, J = 13.5, 8.1 Hz, 1H), 1.29 (d, J =
6.3 Hz, 3H); 13C{1H} NMR (101 MHz, CD3OD) δ 138.3, 131.2, 130.8, 129.2, 51.2, 42.6, 19.1;
MS (ESI) m/z 136.3 [M+H]+. Data are in accordance to that previously reported.3a
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3-Cyanobenzylamine hydrochloride (Compound 29, 88 mg, >99% isolated yield, white solid)
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was synthesized according to GPIII starting from 3-cyanobenzyl azide (80 mg, 0.5 mmol). H
NMR (400 MHz, CD3OD) δ 7.97 (t, J = 1.5 Hz, 1H), 7.90 (dt, J = 7.8, 1.5 Hz, 1H), 7.82 (dt, J
= 7.8, 1.5 Hz, 1H), 7.69 (t, J = 7.8 Hz, 1H), 4.29 (s, 2H); 13C{1H} NMR (101 MHz, CD3OD) δ
136.9, 135.9, 134.7, 134.6, 132.2, 120.0, 114.8, 44.3; MS (ESI) m/z 133.3 [M+H]+. Data are in
accordance to that previously reported.3a
Cinnamyl amine hydrochloride (Compound 30, 85 mg, 99% isolated yield, off-white solid) was
synthesized according to GPIII starting from cinnamyl azide (80 mg, 0.5 mmol). 1H NMR (400
MHz, CD3OD) δ 7.51 – 7.47 (m, 2H), 7.42 – 7.29 (m, 3H), 6.85 (d, J = 15.9 Hz, 1H), 6.33 (dt,
J = 15.9, 6.9 Hz, 1H), 3.75 (d, J = 6.9 Hz, 2H); 13C{1H} NMR (101 MHz, CD3OD) δ 138.7,
138.0, 130.7, 130.5, 128.6, 122.0, 43.4; MS (ESI) m/z 134.2 [M+H]+. Data are in accordance to
that previously reported.3a
4-Vinylbenzylamine hydrochloride (Compound 31, 41.4 mg, 98% isolated yield, off-white
solid) was synthesized according to GPIII starting from 4-vinylbenzyl azide (39.8 mg, 0.25
mmol). 1H NMR (400 MHz, CD3OD) δ 7.53 (d, J = 8.3 Hz, 2H), 7.45 (d, J = 8.3 Hz, 2H), 6.78
(dd, J = 17.6, 10.9 Hz, 1H), 5.86 (dd, J = 17.6, 0.9 Hz, 1H), 5.31 (dd, J = 10.9, 0.9 Hz, 1H),
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4.13 (s, 2H); 13C{1H} NMR (101 MHz, CD3OD) δ 138.5, 135.9, 132.4, 128.9, 126.5, 113.9,
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42.7; MS (ESI) m/z 133.8 [M+H]+. Data are in accordance to that previously reported.41
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(E)-1,3-Diphenyl-2-propene-1-amine hydrochloride (Compound 32, 33.5 mg, 55% isolated
yield, white solid) was synthesized according to GPIII starting from (E)-1,3-diphenyl-2-
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propene-1-azide (58.8 mg, 0.25 mmol). H NMR (400 MHz, CD3OD) δ7.60 – 7.40 (m, 7H),
7.38 – 7.25 (m, 3H), 6.82 (d, J = 15.9 Hz, 1H), 6.54 (dd, J = 15.9, 7.6 Hz, 1H), 5.16 (d, J = 7.6
Hz, 1H); 13C{1H} NMR (101 MHz, CD3OD) δ 136.5, 135.5, 134.8, 129.1, 128.9, 128.4, 128.4,
127.0, 126.5, 124.2, 56.9; MS (ESI) m/z 210.2 [M+H]+. Data are in accordance to that
previously reported.42
4-Ethynylbenzylamine hydrochloride (Compound 33, 39.0 mg, 93% isolated yield, white solid)
was synthesized according to GPIII starting from 4-ethynylbenzyl azide (39.3 mg, 0.25 mmol).
1H NMR (400 MHz, CD3OD) δ 7.56 (d, J = 8.6 Hz, 2H), 7.49 (d, J = 8.6 Hz, 2H), 4.16 (s, 2H),
3.61 (s, 1H); 13C{1H} NMR (101 MHz, CD3OD) δ 133.6, 132.3, 128.8, 123.3, 82.2, 78.6, 42.6;
MS (ESI) m/z 131.8 [M+H]+. Data are in accordance to that previously reported.43
4-Benzyloxybenzylamine hydrochloride (Compound 34, 95 mg, 76% isolated yield, off-white
solid) was synthesized according to GPIII starting from 4-benzyloxybenzyl azide (120 mg, 0.5
mmol). 1H NMR (400 MHz, CD3OD) δ 7.47 – 7.29 (m, 7H), 7.08 (d, J = 8.7 Hz, 1H), 5.13 (s,
2H), 4.07 (s, 2H); 13C{1H} NMR (101 MHz, CD3OD) δ 161.6, 139.2, 132.5, 130.4, 129.8,
129.4, 127.4, 117.4, 71.8, 44.7; MS (ESI) m/z 214.1 [M+H]+. Data are in accordance to that
previously reported.3a
Benzyl (2-aminoethyl)carbamate hydrochloride (Compound 35, 49.3 mg, 85% isolated yield,
off-white solid) was synthesized according to GPIII starting from benzyl (2-
1
azidoethyl)carbamate (55.1 mg, 0.25 mmol). H NMR (400 MHz, CD3OD) δ 7.45 – 7.23 (m,
5H), 5.12 (s, 2H), 3.44 (t, J = 5.9 Hz, 2H), 3.09 (t, J = 5.9 Hz, 2H); 13C{1H} NMR (126 MHz,
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CD3OD) δ 157.9, 136.6, 128.1, 127.7, 127.6, 66.5, 39.7, 38.1; MS (ESI) m/z 194.9 [M+H]+.
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Data are in accordance to that previously reported.44
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Ethyl (S)-2-amino-4-phenylbutanoate hydrochloride (Compound 36, 47.8 mg, 78% isolated
yield, white solid) was synthesized according to GPIII starting from ethyl (S)-2-azido-4-
phenylbutanoate (58.3 mg, 0.25 mmol). 1H NMR (400 MHz, CD3OD) δ 7.41 – 7.13 (m, 5H),
4.31 (q, J = 7.1 Hz, 2H), 4.07 (t, J = 6.3 Hz, 1H), 2.92 – 2.69 (m, 2H), 2.36 – 2.11 (m, 1H), 1.35
(t, J = 7.1 Hz, 2H); 13C{1H} NMR (101 MHz, CD3OD) δ 169.0, 139.7, 128.3, 128.1, 126.2,
62.3, 52.2, 32.1, 30.6, 13.1; MS (ESI) m/z 208.0 [M+H]+. Data are in accordance to that
previously reported.3a
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Methyl (4-aminomethyl)benzoate hydrochloride (Compound 37, 100 mg, 99% isolated yield,
white solid) was synthesized according to GPIII starting from methyl (4-azidomethyl)benzoate
(95 mg, 0.5 mmol). 1H NMR (400 MHz, CD3OD) δ 8.16 – 8.08 (m, 2H), 7.66 – 7.58 (m, 2H),
4.24 (s, 2H), 3.95 (s, 3H); 13C{1H} NMR (101 MHz, CD3OD) δ 168.7, 140.4, 132.9, 132.1,
131.0, 53.7, 44.7; MS (ESI) m/z 165.9 [M+H]+. Data are in accordance to that previously
reported.3a
Methyl 6-(aminomethyl)nicotinate hydrochloride (Compound 38, 117 mg, 99% isolated yield,
off-white solid) was synthesized according to GPIII starting from methyl 6-
(azidomethyl)nicotinate (95 mg, 0.5 mmol). 1H NMR (400 MHz, CD3OD) δ 9.25 (dd, J = 2.1,
0.8 Hz, 1H), 8.52 (dd, J = 8.2, 2.1 Hz, 1H), 7.73 (dd, J = 8.2, 0.8 Hz, 1H), 4.47 (s, 2H), 4.00 (s,
3H); 13C{1H} NMR (101 MHz, CD3OD) δ 167.1, 158.1, 151.4, 141.2, 128.6, 124.8, 54.0, 44.5;
MS (ESI) m/z 167.1 [M+H]+. Data are in accordance to that previously reported.3a
4-Benzoylbenzylamine hydrochloride (Compound 39, 122 mg, 99% isolated yield, off-white
solid) was synthesized according to GPIII starting from 4-benzoylbenzyl azide (119 mg, 0.50
mmol). 1H NMR (400 MHz, CD3OD) δ 7.90 – 7.85 (m, 2H), 7.83 – 7.78 (m, 2H), 7.73 – 7.65
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(m, 3H), 7.58 (dddd, J = 8.4, 6.6, 1.5, 0.9 Hz, 2H), 4.28 (s, 2H), 3.38 (s, 1H); 13C{1H} NMR
(126 MHz, CD3OD) δ 196.3, 138.0, 137.5, 137.1, 132.7, 130.2, 129.6, 128.7, 128.2, 42.5; MS
(ESI) m/z 212.0 [M+H]+. Data are in accordance to that previously reported.3a
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3-(Aminomethyl)benzoic acid hydrochloride (Compound 40, 38.5 mg, 82% isolated yield,
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white solid) was synthesized according to GPIII starting from 3-(azidomethyl)benzoic acid
1
(44.3 mg, 0.25 mmol). H NMR (400 MHz, CD3OD) δ 8.18 (t, J = 1.5 Hz, 1H), 8.09 (dt, J =
7.7, 1.5 Hz, 1H), 7.75 (dt, J = 7.7, 1.5 Hz, 1H), 7.59 (t, J = 7.7 Hz, 1H), 4.23 (s, 2H); 13C{1H}
NMR (126 MHz, CD3OD) δ 167.6, 133.5, 133.2, 131.5, 130.0, 129.9, 129.0, 42.6;
MS (ESI) m/z 151.9 [M+H]+. Data are in accordance to that previously reported.45
4-Acetamidobenzylamine hydrochloride (Compound 41, 84 mg, 71% isolated yield, light
yellow solid) was synthesized according to GPIII starting from 4-acetamidobenzyl azide (94
mg, 0.50 mmol). 1H NMR (400 MHz, CD3OD) δ 7.72 – 7.64 (m, 2H), 7.48 – 7.40 (m, 2H), 4.11
(s, 2H), 2.17 (s, 3H); 13C{1H} NMR (101 MHz, CD3OD) δ 172.7, 141.7, 131.5, 130.6, 122.3,
44.8, 24.7; MS (ESI) m/z 164.0 [M+H]+. Data are in accordance to that previously reported.3a
Methyl (E)-3-(4-(aminomethyl)phenyl)acrylate hydrochloride (Compound 42, 43.1 mg, 76%
isolated yield, off-white solid) was synthesized according to GPIII starting from methyl
(E)-3-(4-(azidomethyl)phenyl)acrylate (54.3 mg, 0.25 mmol). 1H NMR (400 MHz, CD3OD) δ
7.76 – 7.69 (m, 3H), 7.56 – 7.52 (m, 2H), 6.61 (d, J = 16.1 Hz, 1H), 4.18 (s, 2H), 3.81 (s, 3H);
13C{1H} NMR (126 MHz, CD3OD) δ 167.4, 143.7, 135.1, 135.1, 129.2, 128.5, 118.5, 50.9,
42.5; IR (cm-1) 2928, 1714, 1640, 1313, 1167, 982, 905; MS (ESI) m/z 191.8[M+H]+; HRMS
+
(ESI) found m/z 192.1027 [M+H]+, calcd for C11H14NO2 m/z 192.1025.
4-(Methylsulfonyl)benzyl amine hydrochloride (Compound 43, 115 mg, 99% isolated yield,
white solid) was synthesized according to GPIII starting from 4-(methylsulfonyl)benzyl azide
1
(107 mg, 0.5 mmol). H NMR (400 MHz, CD3OD) δ 8.11 – 8.03 (m, 2H), 7.80 – 7.72 (m, 2H),
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4.29 (s, 2H), 3.17 (s, 3H); 13C{1H} NMR (101 MHz, CD3OD) δ 143.8, 141.3, 131.9, 130.1,
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45.1, 44.5. MS (ESI) m/z 185.9 [M+H]+. Data are in accordance to that previously reported.3a
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(4-Hydroxymethyl)benzyl amine hydrochloride (Compound 44, 35.4 mg, 82% isolated yield,
white solid) was synthesized according to GPIII starting from 4-(hydroxymethyl)benzyl azide
(40.8 mg, 0.25 mmol). 1H NMR (400 MHz, CD3OD) δ 7.52 – 7.41 (m, 4H), 4.65 (s, 2H), 4.14
(s, 2H); 13C{1H} NMR (126 MHz, CD3OD) δ 142.6, 131.8, 128.7, 127.2, 63.2, 42.7;
MS (ESI) m/z 137.9 [M+H]+. Data are in accordance to that previously reported.3a
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Diphenyldisiloxane ((PhSiH2)2O, DPDS) was synthesized as previously described.46 1H NMR
(400 MHz, CDCl3) δ 7.64 – 7.60 (m, 4H), 7.49 – 7.44 (m, 2H), 7.43 – 7.38 (m, 4H), 5.15 (s,
4H); 13C{1H} NMR (101 MHz, CDCl3) δ 134.4, 134.0, 130.9, 128.5; 29Si NMR (80 MHz,
CDCl3) δ -25.3.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
Supplementary figures, 1H and 13C{1H} NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
* E-mail: mecinovic@sdu.dk
ORCID
Jasmin Mecinović: 0000-0002-5559-3822
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