Pathways in the Degradation of Geminal Diazides

Article abstract of DOI:10.1021/acs.joc.7b01019

The degradation of geminal diazides is described. We show that diazido acetates are converted into tetrazoles through the treatment with bases. The reaction of dichloro ketones with azide anions provides acyl azides, through in situ formation of diazido ketones. We present experimental and theoretical evidence that both fragmentations may involve the generation of acyl cyanide intermediates. The controlled degradation of terminal alkynes into amides (by loss of one carbon) or ureas (by loss of two carbons) is also shown.

Full text of DOI:10.1021/acs.joc.7b01019

Note
pubs.acs.org/joc
Pathways in the Degradation of Geminal Diazides
Kristina Holzschneider,† Andreas P. Haring,† Alexander Haack,‡ Daniel J. Corey,§ Thorsten Benter,‡
̈
and Stefan F. Kirsch*,†
‡
†Organic Chemistry and Physical and Theoretical Chemistry, Bergische Universitat Wuppertal, Gaußstr. 20, 42119 Wuppertal,
Germany
̈
§Department of Chemistry, University of Michigan-Flint, 303 E. Kearsley St., Flint, Michigan 48502, United States
S
* Supporting Information
ABSTRACT: The degradation of geminal diazides is described. We show that diazido
acetates are converted into tetrazoles through the treatment with bases. The reaction of
dichloro ketones with azide anions provides acyl azides, through in situ formation of
diazido ketones. We present experimental and theoretical evidence that both
fragmentations may involve the generation of acyl cyanide intermediates. The
controlled degradation of terminal alkynes into amides (by loss of one carbon) or ureas
(by loss of two carbons) is also shown.
diazido acetate leaving group 4. In the presence of base
eminal diazides are a largely disregarded class of
1
Gcompounds. Despite an inspiring report by Forster and additives, however, it was found that the diazido acetate 4 was
co-workers as early as in 1908,2 only a small number of further
rapidly converted, and azide functionalities have vanished
completely after, for example, basic workup conditions.8a When
studying the related acylation of amine 2 with diazido
compounds derived from 1,3-diketones (e.g., 5), the proposed
diazido leaving group 6 was never detected; instead, a second
acyl transfer onto the amine was observed leading to the overall
formation of both amides 3 and 7.8b Since little is known about
the possible degradation pathways of geminal diazides,4a−g we
then began to carefully investigate the fate of the two diazido
species A and B. These diazido compounds are potentially
hazardous,9 and gaining knowledge on their reactivity and in
particular on their controlled degradation is important when
new methods with diazido intermediates are envisioned. The
results presented in this work show how the reactive diazido
compounds can be used to create challenging structural entities,
such as tetrazoles and acyl azides, through novel pathways.
Finally, we demonstrate that the diazide degradation can be
applied to the question of how to manipulate terminal alkynes,
and a novel sequence is presented that results in the controlled
dismounting of the alkyne through scission of either a one-
carbon or a two-carbon unit.
reports described the synthesis of geminal diazides,3 and even
less studies focused on their reactivities.4,5 We recently
launched a research program that aims to unveil new reactions
with geminal diazides,6 and we also started to reinvestigate
previously reported reactions in a systematic way.7 In the
course of this program, it became apparent that geminal
diazides derived from 1,3-dicarbonyls are powerful acylating
agents that allow for the acylation of primary amines (Scheme
1).8 Since we unequivocally observed the stoichiometric
1
evolution of tert-butyl 2,2-diazidoacetate (4) using H NMR
spectroscopy when diazido acylacetate 1 reacted with primary
amine 2 to give amide 3, this acyl transfer reaction was believed
to be a classical substitution: The attack of the substituting
amine at the carbonyl carbon is followed by elimination of the
Scheme 1. Diazido-Containing Compounds in the Acylation
of Amines
Our studies began again with diazido ester 4, derived from
the conversion of diazido acylacetate 1 with benzylamine
(Scheme 2). The diazido ester 4 was readily isolated by
submitting the crude reaction mixture directly onto silica for
purification through flash chromatography (in up to 70% yield).
The single other compound, besides the amide main product 3,
was the carbamate 8, a compound that was formed in
surprisingly inconsistent yields nevertheless, it was possible to
isolate the carbamate 8 in up to 20% yield when a 2-fold excess
of benzylamine was employed (see Scheme 2a). Since the
Received: April 27, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.7b01019
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The Journal of Organic Chemistry
Note
Scheme 2. Carbamate Formation from Diazido Ester 4
Scheme 4. Proposed Mechanism for the Reactivity of
Diazido Esters A
quantitative carbamate formation was observed with a greater
excess of benzylamine and significantly lengthened reaction
times (see Scheme 2b), we currently believe that the carbamate
8 is formed through the slow reaction of the diazido ester 4
with benzylamine, a rational that is fully supported by the direct
reaction of isolated diazide 4 with benzylamine, resulting in
unequivocal carbamate formation (see Scheme 2c).
It is important to note that NMR spectroscopy showed that
diazidomethane, the formal remainder of the mass, was not
formed in the course of the conversion of diazido ester 4 into
carbamate 8. Instead, the NMR data suggested the existence of
a compound with a tetrazole unit that occurred to a markedly
higher extent when less nucleophilic amine bases (e.g.,
cyclohexylamine) were employed, rather than benzylamine.
This tetrazole-containing compound was, according to crude
NMR data, exclusively formed when diazido ester 4 was treated
with stronger bases such as DBU or NEt3; however, its isolation
failed, mainly for purification reasons. Therefore, the related
diazido esters 9 and 11 were employed, and they readily yielded
the expected tetrazoles 10 and 12 when treated with NEt3 at
room temperature in benzene (Scheme 3). It was possible to
carbamate F is formed with nucleophilic amines through
classical substitution, 1,3-dipolar cycloaddition with the azide
anion results in the tetrazole E. Related tetrazole formations by
cycloadditions were intensively studied by others,12 including
with calculations.12d We also observed complete and clean
conversion into tetrazole 12 when stirring ethyl cyanoformate
and triethylammonium azide13 at room temperature in benzene
for 20 h. Unfortunately, we lack clear experimental evidence for
the in situ formation of cyanide intermediate D;14 our NMR
studies remain inconclusive in this regard. However, the
proposed pathways via D are supported by three findings: (i)
Calculations on the B3LYP15/6-311+G(2d,p)16 level of theory
including empirical dispersion17 carried out with the Gaussian
09 program strongly suggest that, on the singlet surface, there is
a concerted reaction pathway from the anion 1C to the
Scheme 3. Tetrazole Formation from Diazido Esters 9 and
11
1
cyanoformate D (path a). The corresponding transition state
lies only 0.28 eV (27 kJ/mol) above the energy of the anion,
hence a fast conversion is plausible (for further information
including graphics, see SI). Along the calculated pathway, the
loss of N2 is directly followed by cleavage of the C−N3 bond
under formation of the cyanide and azide anion. Neither the
−
nitrene anion (only N2 loss) nor the carbene (only N3 loss)
were found to be stable intermediates in a singlet state.
However, the lowest triplet surface is close to the singlet surface
3
and shows a minimum corresponding to a triplet anion C. Its
geometry is similar to the one of the singlet transition state and
exhibits a bending of one azide group with an elongated N−N
3
distance. On the triplet surface, the anion C can decompose
cleanly isolate the ammonium salt (e.g., 10) or, upon
acidification with 1 N HCl, the neutral tetrazole (e.g., 12).10
Tetrazole 12 can also be isolated without the need for handling
the geminal diazide 11 in a direct way; to this end, the dichloro
compound 11* was treated with a mixture of NaN3 and NEt3 at
room temperature to give the tetrazole 12 in 87% yield.11
We conclude that subtle variations in basicity and
nucleophilicity result in the formation of the tetrazole and
the carbamate products, respectively, with bases favoring
tetrazole formation and nucleophiles favoring carbamate
formation. It was, at least in our hands, not possible to convert
the tetrazoles into the carbamates through treatment with
amines. The reactivity of diazido esters of type A is summarized
in Scheme 4. We speculate that, in the presence of bases,
deprotonation leads to the initial formation of anion C, a
species that rapidly collapses into cyanoformate D. While the
via a small barrier (0.15 eV) forming a stable triplet nitrene
3
−
anion N (through loss of N2, path b). Also the carbene (N3
loss) is stable on the triplet surface, but high in energy (2.38 eV
above the triplet anion 3C). Because of the similarities in energy
and geometry around the N−N distance of 1.4 Å, an
intersystem crossing from the singlet to the triplet surface is
at least plausible, and the triplet decomposition pathway via 3N
cannot be ruled out completely. (ii) A crossover experiment
where a mixture of ethyl-containing diazide 11 and methyl
cyanoformate was treated with triethylamine produced a
mixture of the two tetrazoles, ethyl and methyl 1H-tetrazole-
5-carboxylate, in a ratio close to 1:1 (as analyzed by LCMS).
Accordingly, a pathway through the imino anion N followed by
direct cyclization to the tetrazole appears to be less likely;18 the
cyanoformate D is the reasonable intermediate. (iii) The
treatment of the related diazido amide 13 with benzylamine 2
B
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Note
gave the expected amide 3 and an unseparable mixture of
diazide 15 (13C NMR: δ = 164.5, 71.5, 37.0, 36.3 ppm) and
cyanide 14 (13C NMR: δ = 145.0, 110.6, 38.0, 34.5 ppm).8b
To further elucidate the reactivity of the diazido ketones of
type B with amines, we tried to isolate the required 2,2-diazido
ketones such as, for example, 6; unfortunately, all our attempts
were not successful. Instead, acyl azides were found as the
exclusive products when the corresponding 2,2-dichloro
ketones were treated with an excess of azide anions. For
example, dichloro compound 16a was converted with sodium
azide in DMF at 0 °C to give acyl azide 17a in 75% isolated
yield (Scheme 5). In analogy to the reactivity of the diazido
Table 1. Degradation of Terminal Alkynes
a
substrate 22
yield (%)
b
c
d
entry
R1
no.
16
18
21
1
2
3
4
5
6
7
C6H5
b
c
d
e
f
71
64
86
93
88
83
87
75
85
42
47
27
43
41
30
31
3−Cl-C6H4
4-MeO-C6H4
4-Me-C6H4
4−F-C6H4
3-thienyl
e
80
e
Scheme 5. Reaction Pathways of Dichloro Ketone 16a with
Azides
64
80
54
58
g
h
n-hexyl
a
b
Isolated yield after chromatography. Conditions: Oxone (2.0 equiv),
c
KCl (2.0 equiv), MeCN/H2O, rt. Conditions: NaN3 (4.0 equiv),
BnNH2 (1.2 equiv), Pr2NEt (1.2 equiv), DMF, 0 °C. Conditions:
Oxone (2.0 equiv), KCl (2.0 equiv), NaN3 (3.5 equiv), BnNH2 (1.2
d
i
e
equiv), MeCN/H2O. Conditions: NCS (2.2 equiv), FeCl3·6H2O
(0.05 equiv), THF/H2O, 80 °C.23
azide anions, the 2,2-dichloro ketone 16a is converted into
azide 19a, a compound that was isolated in pure form (Scheme
5). As shown before by Bols and co-workers,22 azides such as
19a can be hydrolyzed to yield amines (e.g., 19a → 20a with
NaOH) or reacted to ureas with amines (e.g., 19a → 21a with
benzylamine). Futhermore, the oxyhalogenation of terminal
alkyne 22a was coupled with the degradation triggered by
diazido intermediates and Curtius rearrangement. To this end,
the alkyne 22a was treated with oxone, KCl, and NaN3 in
aqueous acetonitrile at 65 °C, and the azide 19a was obtained
in acceptable 45% yield. In the presence of amine additives
(e.g., 2), it became now feasible to directly convert the terminal
alkyne 22a into the urea 21a; the method of choice simply used
the amine, oxone, KCl, and NaN3 in aqueous acetonitrile at 65
°C (Method B). We applied this powerful method for alkyne
degradation to a number of alkynes, summarized in Table 1.
The method is capable of the removal of a two-carbon alkyne
functionality from the precursor molecules 22 attaching a
nitrogen atom at R1 in return in moderate yields. Despite the
fact that geminal diazides should be considered hazardous, the
degradation methods A and B discussed above are reasonably
safe and convenient, and the reactive diazido species B are
generated in situ from dichloro precursor molecules under the
present conditions. We are not aware of alternative synthesis
strategies for the rapid and controlled degradation of terminal
alkynes, and therefore our methods appear to fill a gap in
contemporary synthetic chemistry.
In conclusion, we have shown how geminal diazides undergo
degradation, most likely through initial cyanide formation.
When the degradation leads to possible cyanoformate
intermediates, it was found that azide addition may finally
provide tetrazole products, while amine nucleophiles may
create carbamate products. On the other hand, the clean
degradation of geminal diazido compounds to acyl azides was
also studied, a reaction that provides access to new scaffolds
including amides and ureas. We believe that this deeper
understanding of the diazide fragmentation pathways paves the
way toward the development of new methods for the
esters discussed above, we currently believe that, under the
reaction conditions, the diazido ketone B is generated in situ,
followed by rapid fragmentation to cyanide G. We have shown
before that acyl cyanides interconvert into acyl azides in the
presence of azide anions.8b Acyl azide 17a reacts smoothly with
benzylamine (2) to provide amide 18a, as expected. We point
out that a one-pot protocol for the direct transformation of
dichloro ketone 16a into amide 18a is also possible. Through
treatment of ketone 16a with sodium azide, benzylamine, and
diisopropylethylamine in DMF at 0 °C, amide 18a was
obtained in 92% yield (Method A). As shown in Table 1, a
range of dichloro ketones 16 were effectively converted into
amides using this experimentally simple method. Yields were
high in all cases, and various aromatic and aliphatic groups R1
attached to the carbonyl were well tolerated. We note that a
straightforward way to access the required dichloro starting
materials 16 is to use the method developed by Madabhushi
and co-workers19 where terminal alkynes are treated with oxone
and KCl. This highly reliable method, in combination with our
amide-forming fragmentation of the dichloro ketones (Method
A), represents a general approach to degrade terminal alkynes
through the controlled removal of a one-carbon unit.
Since acyl azides20 are prone to thermal decomposition
producing isocyanates through Curtius rearrangement,21 we
demonstrated that, at elevated temperatures with an excess of
C
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Note
flash-chromatography on silica gel furnished the corresponding urea
21.
reorganization and cleavage of the carbon frameworks of
organic molecules.
2,2-Dichloro-1-(4-pentylphenyl)ethan-1-one (16a). According to
the general procedure A using (0.50 g, 2.82 mmol, 1.0 equiv) 1-
ethynyl-4-pentylbenzene (22a), 2,2-dichloro-1-(4-pentylphenyl)ethan-
1-one (0.48 g, 1.86 mmol, 66%) (16a) was obtained after
chromatography (PE:Et2O 95:5 → 9:1) as yellow oil. TLC: Rf =
EXPERIMENTAL SECTION
■
General Remarks. The commercial reagents and solvents were
used as purchased. TLC was conducted with precoated glass-backed
plates (silica gel 60 F254) and visualized by exposure to UV light (254
nm) or stained with ceric ammonium molybdate (CAM), basic
potassium permanganate (KMnO4), and subsequent heating. Flash
column chromatography was performed on silica gel (40−60 μm), the
eluent used is reported in the respective experiments. Abbreviations of
solvents are as followed: PE: petroleum ether, EA: ethyl acetate, DCM:
dichloromethane, MeOH: methanol, iPrOH: isopropanol. IR spectra
were measured using ATR technique in the range of 400−4000 cm−1.
1H NMR spectra were recorded with 400 or 600 MHz instruments,
13C NMR spectra at 101 or 151 MHz. Chemical shifts are reported in
1
0.57 (PE:EA 8:2) [UV, KMnO4]. H NMR (400 MHz, CDCl3) δ
[ppm] = 8.04−7.97 (m, 2 H), 7.35−7.29 (m, 2 H), 6.68 (s, 1 H),
2.75−2.64 (m, 2H), 1.73−1.57 (m, 2H), 1.41−1.26 (m, 4H), 0.90 (t, J
= 7.0 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ [ppm] = 185.7, 150.9,
130.0, 129.1, 129.1, 67.9, 36.2, 31.5, 30.7, 22.6, 14.1. The analytical
data are in agreement with previously reported ones.19
2,2-Dichloro-1-phenylethan-1-one (16b). According to the general
procedure A using (1.00 g, 9.79 mmol, 1.0 equiv) phenylacetylene
(22b), 2,2-dichloro-1-phenylethan-1-one (1.31 g, 6.94 mmol, 71%)
(16b) was obtained after chromatography (PE:Et2O 95:5 → 9:1) as
1
colorless oil. TLC: Rf = 0.51 (PE:EA 8:2) [UV, KMnO4]. H NMR
ppm relative to the solvent signal, coupling constants J in Hz.
Multiplicities were defined by standard abbreviations. Low-resolution
mass spectra (LRMS) were recorded using a LC/MS-combination
(ESI). High-resolution mass spectra (HRMS) were obtained using ESI
ionization (positive) on a Bruker micrOTOF.
(400 MHz, CDCl3) δ [ppm] = 8.12−8.06 (m, 2H), 7.69−7.62 (m,
1H), 7.56−7.48 (m, 2H), 6.69 (s, 1H). 13C NMR (101 MHz, CDCl3)
δ [ppm] = 186.0, 134.7, 131.5, 129.9 129.1, 67.9. The analytical data
are in agreement with previously reported ones.19
2,2-Dichloro-1-(3-chlorophenyl)ethan-1-one (16c). According to
the general procedure A using (0.10 g, 0.73 mmol, 1.0 equiv) 1-chloro-
3-ethynylbenzene (22c), 2,2-dichloro-1-(3-chlorophenyl)ethan-1-one
(0.10 g, 0.47 mmol, 64%) (16c) was obtained after chromatography
(PE:Et2O 95:5 → 9:1) as colorless oil. TLC: Rf = 0.66 (PE:EA 8:2)
Caution! Geminal diazides are potentially hazardous and should be
handled with care. The scale of reactions involving the use or isolation
of diazido compounds was typically limited to a maximum of 0.5
mmol; additional protective gear was used with larger scales. The oily
diazides were dissolved in appropriate solvents when transferred with
pipettes. The heating bath of the rotary evaporator was set to 40 °C.
General Procedures. General Procedure A for the Synthesis of
2,2-Dichloro Ketones 16. The alkyne 22 (1.0 equiv) was dissolved in
ACN (0.4 M), and oxone (2.0 equiv) and KCl (2.0 equiv) were
subsequently added. Then, water (0.8 M) was added dropwise, and the
reaction mixture was stirred at 40 °C until completion of the reaction
(as monitored by TLC). The mixture was diluted with water and
extracted with diethyl ether. The combined organic layers were washed
with brine, dried over anhydrous Na2SO4, and concentrated under
reduced pressure. Purification by flash-chromatography on silica gel
furnished the corresponding 2,2-dichloro ketone 16.
General Procedure B for the Synthesis of 2,2-Dichloro Ketones
16. The alkyne 22 (1.0 equiv), NCS (2.2 equiv) and FeCl3·6 H2O
(0.05 equiv) were dissolved in THF (2.5 M) under nitrogen
atmosphere, and water (0.5 M) was added. The reaction temperature
was raised to 80 °C, and the mixture was stirred for 3 h. The reaction
mixture was cooled to rt, quenched with aqueous saturated NaHCO3
solution, and extracted with diethyl ether. The combined organic
layers were washed with brine, dried over Na2SO4, and concentrated
under reduced pressure. Purification by flash chromatography on silica
gel furnished the corresponding 2,2-dichloro ketone 16.
1
[UV, KMnO4]. H NMR (400 MHz, CDCl3) δ [ppm] = 8.06 (t, J =
1.8 Hz, 1H), 7.98 (ddd, J = 7.9, 1.7, 1.1 Hz, 1H), 7.62 (ddd, J = 8.0,
2.1, 1.0 Hz, 1H), 7.47 (t, J = 7.9 Hz, 1H), 6.60 (s, 1H). 13C NMR (101
MHz, CDCl3) δ [ppm] = 184.9, 135.44, 134.6, 132.9, 130.3, 129.9,
127.9, 67.8. The analytical data are in agreement with previously
reported ones.23
2,2-Dichloro-1-(4-methoxyphenyl)ethan-1-one (16d). According
to the general procedure B using (0.15 g, 1.10 mmol, 1.0 equiv) 1-
ethynyl-4-methoxybenzene (22d), 2,2-dichloro-1-(4-methoxyphenyl)-
ethan-1-one (0.19 g, 0.89 mmol, 80%) (16d) was obtained after
chromatography (PE:EA 95:5 → 9:1) as colorless oil. TLC: Rf = 0.49
(PE:EA 8:2) [UV, KMnO4]. 1H NMR (400 MHz, CDCl3) δ [ppm] =
8.12−8.03 (m, 2H), 7.02−6.94 (m, 2H), 6.64 (s, 1H), 3.90 (s, 3H).13C
NMR (101 MHz, CDCl3) δ [ppm] = 184.7, 164.8, 132.4, 124.1, 114.4,
68.0, 55.8. The analytical data are in agreement with previously
reported ones.24
2,2-Dichloro-1-(p-tolyl)ethan-1-one (16e). According to the
general procedure A using (0.50 g, 4.22 mmol, 1.0 equiv) 1-ethynyl-
4-methlbenzene (22e), 2,2-dichloro-1-(p-tolyl)ethan-1-one (0.58 g,
2.83 mmol, 67%) (16e) was obtained after chromatography (PE:Et2O
95:5 → 9:1) as colorless oil. TLC: Rf = 0.62 (PE:EA 8:2) [UV,
KMnO4]. 1H NMR (400 MHz, CDCl3) δ [ppm] = 7.98 (d, J = 8.2 Hz,
2H), 7.31 (d, J = 8.4 Hz, 2H), 6.67 (s, 1H), 2.44 (s, 3H).13C NMR
(101 MHz, CDCl3) δ [ppm] = 185.7, 145.9, 129.9, 129.8, 128.9, 67.9,
21.9.The analytical data are in agreement with previously reported
ones.19
General Procedure C for the Synthesis of Amides 18. The 2,2-
dichloro ketone 16 (1.0 equiv) was dissolved in DMF (1.0 M), and the
mixture was cooled to −5 °C. NaN3 (4.0 equiv) was added, and the
reaction mixture was stirred for 16 h at 0 °C. Then benzylamine (1.2
equiv) and DIPEA (1.2 equiv) were added, and the resulting mixture
was stirred for additional 20 h at rt. The mixture was diluted with
water and extracted with ethyl acetate. The combined organic layers
were washed with brine, dried over anhydrous Na2SO4, and
concentrated under reduced pressure. Purification by flash chromatog-
raphy on silica gel furnished the corresponding amide 18.
2,2-Dichloro-1-(4-fluorophenyl)ethan-1-one (16f). According to
the general procedure A using (0.50 g, 4.08 mmol, 1.0 equiv) 1-
ethynyl-4-fluorobenzene (22f), 2,2-dichloro-1-(4-fluorophenyl)ethan-
1-one (0.69 g, 3.33 mmol, 82%) (16f) was obtained after
chromatography (PE:Et2O 95:5 → 9:1) as colorless oil. TLC: Rf =
1
0.56 (PE:EA 8:2) [UV, KMnO4]. H NMR (400 MHz, CDCl3) δ
[ppm] = 8.20−8.10 (m, 2H), 7.23−7.15 (m, 2H), 6.61 (s, 1H). 13C
NMR (101 MHz, CDCl3) δ [ppm] = 184.7, 167.9, 165.3, 132.9 (d, J =
9.6 Hz), 127.7 (d, J = 3.1 Hz), 116.4 (d, J = 22.1 Hz), 67.9. The
analytical data are in agreement with previously reported ones.24
2,2-Dichloro-1-(thiophen-3-yl)ethan-1-one (16g). According to
the general procedure B using (0.20 g, 1.78 mmol, 1.0 equiv) 3-
ethynylthiophene (22g), 2,2-dichloro-1-(thiophen-3-yl)ethan-1-one
(0.19 g, 0.96 mmol, 54%) (16g) was obtained after chromatography
(PE:Et2O 95:5 → 9:1) as colorless oil. TLC: Rf = 0.52 (PE:EA 8:2)
General Procedure D for the Synthesis of Ureas 21. The alkyne 22
(1.0 equiv) was dissolved in ACN (0.4 M), and oxone (2.0 equiv) and
KCl (2.0 equiv) were added. Then, water (0.8 M) was added
dropwise, and the reaction mixture was stirred at 40 °C until
completion of the reaction (as monitored by TLC). NaN3 (3.5 equiv)
was added, and the reaction mixture was heated to 65 °C and stirred
for 16 h. Then the mixture was cooled to rt, benzylamine (1.2 equiv)
was added, and the mixture was stirred for additional 20 h at rt. The
mixture was diluted with water and extracted with ethyl acetate. The
combined organic layers were washed with brine, dried over anhydrous
Na2SO4, and concentrated under reduced pressure. Purification by
1
[UV]. H NMR (400 MHz, CDCl3) δ [ppm] = 8.38 (dd, J = 2.9, 1.3
Hz, 1H), 7.67 (dd, J = 5.2, 1.3 Hz, 1H), 7.38 (dd, J = 5.2, 2.9 Hz, 1H),
D
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Note
6.43 (s, 1H). 13C NMR (101 MHz, CDCl3) δ [ppm] = 180.7, 135.6,
127.7, 127.1, 44.2, 21.6. The analytical data are in agreement with
previously reported ones.26
135.1, 128.1, 126.9, 68.7. IR (ATR): v [cm−1] = 3107, 3003, 2926,
̃
1687, 1506, 1411, 1223, 1203, 819, 714, 615. LRMS (EI): [m/z] 194
(1) [M-H+], 131 (7), 111 (100), 83 (25). HRMS (ESI-TOF) m/z: [M
+ H]+ calcd for C6H5Cl2OS 194.9438; found 194.9433.
N-Benzyl-4-fluorobenzamide (18f). According to the general
procedure C using 2,2-dichloro-1-(4-fluorophenylethan-1-one (0.30
g, 1.45 mmol, 1.0 equiv) (16f), N-benzyl-4-fluorobenzamide (0.29 mg,
1.26 mmol, 87%) (18f) was obtained after chromatography (PE:EA
1,1-Dichlorooctan-2-one (16h). According to the general proce-
dure A using (0.50 g, 4.45 mmol, 1.0 equiv) oct-1-yne (22h), 1,1-
dichlorooctan-2-one (0.51 g, 2.59 mmol, 58%) (16h) was obtained
after chromatography (PE:Et2O 95:5) as colorless oil. TLC: Rf = 0.54
(PE:EA 8:2) [KMnO4]. 1H NMR (400 MHz, CDCl3) δ [ppm] = 5.80
(s, 1H), 2.80 (t, J = 7.3 Hz, 2H), 1.73−1.60 (m, 2H), 1.40−1.24 (m,
6H), 0.94−0.85 (m, 3H). 13C NMR (101 MHz, CDCl3) δ [ppm] =
197.5, 70.1, 35.1, 31.6, 28.7, 23.9, 22.6, 14.1. The analytical data are in
agreement with previously reported ones.19
1
8:2 → 6:4) as white solid. TLC: Rf = 0.61 (PE:EA 1:1) [UV]. H
NMR (400 MHz, CDCl3) δ [ppm] = 7.88−7.73 (m, 2H), 7.40−7.27
(m, 5H), 7.16−7.05 (m, 2H), 6.39 (s, 1H), 4.63 (d, J = 5.7 Hz, 2H).
13C NMR (101 MHz, CDCl3) δ [ppm] = 166.42, 164.9 (d, J = 252
Hz), 138.2, 130.7 (d, J = 3.2 Hz), 129.4 (d, J = 8.9 Hz), 128.9, 128.1,
127.9, 115.8 (d, J = 21.9 Hz), 44.4. The analytical data are in
agreement with previously reported ones.27
N-Benzylthiophene-3-carboxamide (18g). According to the
general procedure C using 2,2-dichloro-1-(thiophen-3-yl)ethan-1-one
(0.25 g, 1.28 mmol, 1.0 equiv) (16g), N-benzylthiophene-3-
carboxamide (0.21 mg, 0.96 mmol, 75%) (18g) was obtained after
chromatography (DCM:MeOH 99:1) as white solid. TLC: Rf = 0.34
N-Benzyl-4-pentylbenzamide (18a). According to the general
procedure C using 2,2-dichloro-1-(4-pentylphenyl)ethan-1-one (0.23
g, 0.89 mmol, 1.0 equiv) (16a), N-benzyl-4-pentylbenzamide (0.23 g,
0.82 mmol, 92%) (18a) was obtained after chromatography
(DCM:MeOH 99:1) as white solid. TLC: Rf = 0.50 (DCM:MeOH
1
(DCM:MeOH 99:1) [UV]. H NMR (400 MHz, CDCl3) δ [ppm] =
1
99:1) [UV]. H NMR (400 MHz, CDCl3) δ [ppm] = 7.74−7.67 (m,
7.88−7.86 (m, 1H), 7.39 (dd, J = 5.1, 1.3 Hz, 1H), 7.35−7.30 (m,
6H), 6.46 (s, 1H), 4.59 (d, J = 5.8 Hz, 2H). 13C NMR (101 MHz,
CDCl3) δ [ppm] = 163.1, 138.4, 137.5, 128.9, 128.5, 128.0, 127.7,
126.6, 126.2, 43.9. The analytical data are in agreement with previously
reported ones.26
2H), 7.38−7.32 (m, 4H), 7.32−7.27 (m, 1H), 7.23 (d, J = 8.4 Hz,
2H), 6.36 (s, 1H), 4.65 (d, J = 5.7 Hz, 2H), 2.71−2.59 (m, 2H), 1.67−
1.57 (m, 3H), 1.39−1.25 (m, 4H), 0.89 (t, J = 6.9 Hz, 3H). 13C NMR
(101 MHz, CDCl3) δ [ppm] = 167.4, 147.1, 138.5, 131.9, 128.9, 128.7,
128.1, 127.7, 127.1, 44.2, 35.9, 31.5, 31.0, 22.6, 14.1. IR (ATR): v
[cm−1] = 3317, 3066, 3059, 3027, 2950, 2925, 2854, 1638, 1609, 1548,
1312, 854. LRMS (ESI): [m/z] 282 (34) [M + H+]. HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C19H23NNaO: 304.1672; found
304.1670.
̃
N-Benzylheptanamide (18h). According to the general procedure
C using 1,1-dichlorooctan-2-one (0.20 g, 1.01 mmol, 1.0 equiv) (16h),
N-benzylheptanamide (0.19 mg, 0.87 mmol, 85%) (18h) was obtained
after chromatography (PE:EA 8:2 → 1:1) as white solid. TLC: Rf =
1
0.42 (PE:EA 1:1) [UV]. H NMR (400 MHz, CDCl3) δ [ppm] =
N-Benzylbenzamide (18b). According to the general procedure C
using 2,2-dichloro-1-phenylethan-1-one (0.50 g, 2.64 mmol, 1.0 equiv)
(16b), N-benzylbenzamide (0.48 g, 2.27 mmol, 86%) (18b) was
obtained after chromatography (DCM:MeOH 99:1) as white solid.
7.36−7.30 (m, 2H), 7.30−7.24 (m, 3H), 5.76 (s, 1H), 4.43 (d, J = 5.7
Hz, 2H), 2.25−2.16 (m, 2H), 1.70−1.60 (m, 2H), 1.38−1.23 (m, 6H),
0.88 (t, J = 6.9 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ [ppm] =
173.1, 138.6, 128.8, 127.9, 127.6, 43.7, 36.95, 31.7, 29.1, 25.9, 22.6,
14.1. The analytical data are in agreement with previously reported
ones.28
1
TLC: Rf = 0.42 (DCM:MeOH 99:1) [UV]. H NMR (400 MHz,
CDCl3) δ [ppm] = 7.83−7.75 (m, 2H), 7.53−7.47 (m, 1H), 7.46−
7.39 (m, 2H), 7.35 (d, J = 4.4 Hz, 4H), 7.33−7.27 (m, 1H), 6.50 (s,
1H), 4.64 (d, J = 5.7 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ [ppm]
= 167.5, 138.3, 134.5, 131.7, 128.9, 128.7, 128.0, 127.8, 127.1, 44.3.
The analytical data are in agreement with previously reported ones.25
N-Benzyl-3-chlorobenzamide (18c). According to the general
procedure C using 2,2-dichloro-1-(3-chlorophenylethan-1-one (73
mg, 0.33 mmol, 1.0 equiv) (16c), N-benzyl-3-chlorobenzamide (75
mg, 0.31 mmol, 93%) (18c) was obtained after chromatography
(DCM:MeOH 99:1) as white solid. TLC: Rf = 0.60 (DCM:MeOH
1-Benzyl-3-(4-pentylphenyl)urea (21a). According to the general
procedure D using (0.20 g, 1.13 mmol, 1.0 equiv) 1-ethynyl-4-
pentylbenzene (22a), 1-benzyl-3-(4-pentylphenyl)urea (0.13 g, 0.45
mmol, 40%) (21a) was obtained after chromatography (DCM:MeOH
99:1) as white solid. TLC: Rf = 0.32 (DCM:MeOH 99:1) [UV,
1
KMnO4]. H NMR (400 MHz, CDCl3) δ [ppm] = 7.33−7.19 (m,
5H), 7.16−7.11 (m, 2H), 7.09−7.04 (m, 2H), 6.68 (s, 1H), 5.37 (t, J =
5.6 Hz, 1H), 4.36 (d, J = 5.8 Hz, 2H), 2.58−2.49 (m, 2H), 1.57 (dt, J =
15.1, 7.6 Hz, 2H), 1.38−1.24 (m, 4H), 0.88 (t, J = 6.9 Hz, 3H). 13C
NMR (101 MHz, CDCl3) δ [ppm] = 156.0, 139.4, 138.9, 135.5, 129.3,
128.6, 127.4, 127.3, 122.3, 44.3, 35.2, 31.4, 31.1, 22.5, 13.9. IR (ATR):
1
99:1) [UV]. H NMR (600 MHz, CDCl3) δ [ppm] = 7.78 (t, J = 1.8
Hz, 1H), 7.68−7.63 (m, 1H), 7.49−7.45 (m, 1H), 7.39−7.28 (m, 6H),
6.44 (s, 1H), 4.63 (d, J = 5.7 Hz, 2H). 13C NMR (151 MHz, CDCl3) δ
[ppm] = 166.2, 138.0, 136.3, 134.9, 131.7, 130.1, 129.0, 128.1, 127.9,
127.5, 125.2, 44.4. The analytical data are in agreement with previously
reported ones.20c
v [cm−1] = 3311, 3028, 2959, 2928, 2872, 2849, 1632, 1589, 1557,
̃
1523, 1453, 1231, 696, 651, 529. LRMS (ESI): [m/z] 297 (100) [M +
H+]. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C19H24N2NaO:
319.1781; found 319.1784.
N-Benzyl-4-methoxybenzamide (18d). According to the general
procedure C using 2,2-dichloro-1-(4-methoxyphenylethan-1-one (0.15
g, 0.68 mmol, 1.0 equiv) (16d), N-benzyl-4-methoxybenzamide (0.15
mg, 0.61 mmol, 88%) (18d) was obtained after chromatography
(DCM:MeOH 99:1) as white solid. TLC: Rf = 0.33 (DCM:MeOH
1-Benzyl-3-phenylurea (21b). According to the general procedure
D using (1.00 g, 9.79 mmol, 1.0 equiv) phenylacetylene (22b), 1-
benzyl-3-phenylurea (0.92 mg, 4.07 mmol, 42%) (21b) was obtained
after chromatography (DCM:MeOH 99:1) as white solid. TLC: Rf =
0.39 (DCM:MeOH 99:1) [UV]. 1H NMR (400 MHz, CDCl3) δ
[ppm] = 8.52 (s, 1H), 7.44−7.37 (m, 2H), 7.37−7.28 (m, 4H), 7.28−
7.18 (m, 3H), 6.89 (m, 1H), 6.59 (t, J = 5.9 Hz, 1H), 4.30 (d, J = 5.9
Hz, 2H). 13C NMR (101 MHz, CDCl3) δ [ppm] = 155.2, 140.4,
140.3, 128.6, 128.3, 127.1, 126.7, 121.1, 117.7, 42.7. The analytical data
are in agreement with previously reported ones.29
1
99:1) [UV]. H NMR (600 MHz, CDCl3) δ [ppm] = 7.81−7.72 (m,
2H), 7.38−7.32 (m, 4H), 7.33−7.27 (m, 1H), 6.96−6.86 (m, 2H),
6.40 (s, 1H), 4.62 (d, J = 5.7 Hz, 2H), 3.84 (s, 3H). 13C NMR (151
MHz, CDCl3) δ [ppm] = 166.9, 162.4, 138.6, 128.9, 128.9, 128.0,
127.7, 126.8, 113.9, 55.5, 44.2. The analytical data are in agreement
with previously reported ones.26
1-Benzyl-3-(3-chlorophenyl)urea (21c). According to the general
procedure D using (0.27 g, 1.90 mmol, 1.0 equiv) 1-chloro-3-
ethynylbenzene (22c), 1-benzyl-3-(3-chlorophenyl)urea (0.23 g, 0.88
mmol, 47%) (21c) was obtained after chromatography (DCM →
DCM:MeOH 99:1) as white solid. TLC: Rf = 0.34 (DCM:MeOH
N-Benzyl-4-methylbenzamide (18e). According to the general
procedure C using 2,2-dichloro-1-(4-methylphenylethan-1-one (0.30
g, 1.48 mmol, 1.0 equiv) (16e), N-benzyl-4-methylbenzamide (0.28
mg, 1.22 mmol, 83%) (18e) was obtained after chromatography
(PE:EA 8:2 → 6:4) as white solid. TLC: Rf = 0.62 (PE:EA 1:1) [UV].
1H NMR (400 MHz, CDCl3) δ [ppm] = 7.72−7.65 (m, 2H), 7.39−
7.33 (m, 4H), 7.33−7.27 (m, 1H), 7.22 (dd, J = 8.5, 0.6 Hz, 2H), 6.40
(s, 1H), 4.64 (d, J = 5.7 Hz, 2H), 2.39 (s, 3H). 13C NMR (151 MHz,
CDCl3) δ [ppm] = 167.4, 142.1, 138.5, 131.7, 129.4, 128.9, 128.1,
1
99:1) [UV]. H NMR (400 MHz, DMSO) δ [ppm] = 8.77 (s, 1H),
7.68 (t, J = 2.0 Hz, 1H), 7.38−7.27 (m, 4H), 7.26−7.16 (m, 3H), 6.93
(ddd, J = 7.5, 2.0, 1.4 Hz, 1H), 6.70 (t, J = 5.9 Hz, 1H), 4.30 (d, J = 5.9
Hz, 2H). 13C NMR (101 MHz, DMSO) δ [ppm] = 154.9, 141.9,
E
DOI: 10.1021/acs.joc.7b01019
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
140.1, 133.1, 130.2, 128.3, 127.1, 126.7, 120.6, 117.0, 116.0, 42.7. The
analytical data are in agreement with previously reported ones.30
1-Benzyl-3-(4-methoxyphenyl)urea (21d). According to the
general procedure D using (1.04 g, 7.63 mmol, 1.0 equiv) 1-ethynyl-
4-methoxybenzene (22d), 1-benzyl-3-(4-methoxyphenyl)urea (0.52
mg, 2.04 mmol, 27%) (21d) was obtained after chromatography
(DCM → DCM:MeOH 99:1) as white solid. TLC: Rf = 0.38 (PE:EA
g, 1.46 mmol, 70%) (4) as colorless oil. 3: TLC: Rf = 0.31
(DCM:MeOH 95:5) [KMnO4]. 1H NMR (400 MHz, CDCl3) δ
[ppm] = 7.39−7.16 (m, 5H), 6.20 (br. s., 1H), 4.37 (d, J = 5.6 Hz,
2H), 1.97 (s, 3H). 13C NMR (101 MHz, CDCl3) δ [ppm] = 170.1,
138.4, 128.7, 127.9, 127.5, 43.7, 23.2. The analytical data are in
agreement with previously reported ones.34 4: TLC: Rf = 0.60 (PE:EA
9:1) [KMnO4]. 1H NMR (400 MHz, CDCl3) δ [ppm] = 4.71 (s, 1H),
1.54 (s, 9H). 13C NMR (101 MHz, CDCl3) δ [ppm] = 164.0, 85.1,
73.9, 27.9. The analytical data are in agreement with previously
reported ones. 8: TLC: Rf = 0.75 (PE:EA 7:3) [KMnO4]. H NMR
(400 MHz, CDCl3) δ [ppm] = 7.40−7.19 (m, 5H), 4.90 (s, 1H), 4.31
(d, J = 5.5, 2H), 1.47 (s, 9H). 13C NMR (101 MHz, CDCl3) δ [ppm]
= 156.0, 139.1, 128.7, 127.6, 127.4, 79.6, 44.8, 28.5. The analytical data
are in agreement with previously reported ones.35
1
1:1) [UV]. H NMR (400 MHz, DMSO) δ [ppm] = 8.35 (s, 1H),
7.34−7.27 (m, 7H), 6.85−6.81 (m, 2H), 6.48 (t, J = 5.9 Hz, 1H), 4.29
(d, J = 5.9 Hz, 2H), 3.71 (s, 3H).13C NMR (101 MHz, DMSO) δ
[ppm] = 155.4, 153.9, 140.5, 133.6, 128.2, 127.1, 126.6, 119.9, 113.9,
55.1, 42.8. The analytical data are in agreement with previously
reported ones.29
8
1
1-Benzyl-3-(4-methylphenyl)urea (21e). According to the general
procedure D using (1.02 g, 8.61 mmol, 1.0 equiv) 1-ethynyl-4-
methylbenzene (22e), 1-benzyl-3-(4-methylphenyl)urea (0.90 mg,
3.73 mmol, 43%) (21e) was obtained after chromatography (DCM →
DCM:MeOH 99:1) as white solid. TLC: Rf = 0.22 (DCM:MeOH
N-Benzylacetamide (3) and tert-Butyl Benzylcarbamate (8). tert-
Butyl 2,2-diazido-3-oxobutanoate (50 mg, 0.21 mmol, 1.0 equiv) (1)
was dissolved in benzene (1 mL), and benzylamine (90 mg, 0.83
mmol, 2.4 equiv) in benzene (1 mL) was added. The reaction mixture
was stirred for 60 h at rt. Evaporation of the solvent under reduced
pressure and flash chromatography on silica gel (EA:PE 1:9 →
EA:iPrOH 8:2) gave N-benzylacetamide (27 mg, 0.18 mmol, 87%) (3)
and tert-butyl benzylcarbamate (39 mg, 0.19 mmol, 90%) (8) as white
1
99:1) [UV]. H NMR (400 MHz, DMSO) δ [ppm] = 8.39 (s, 1H),
7.39−7.19 (m, 7H), 7.02 (d, J = 8.2 Hz, 2H), 6.52 (t, J = 5.9 Hz, 1H),
4.29 (d, J = 5.9 Hz, 2H), 2.21 (s, 3H). 13C NMR (101 MHz, CDCl3) δ
[ppm] = 155.2, 140.4, 137.8, 129.7, 128.9, 128.2, 127.1, 126.6, 117.7,
42.7, 20.2. The analytical data are in agreement with previously
reported ones.31
1
solids. 3: TLC: Rf = 0.31 (DCM:MeOH 95:5) [KMnO4]. H NMR
(400 MHz, CDCl3) δ [ppm] = 7.39−7.16 (m, 5H), 6.20 (br. s., 1H),
4.37 (d, J = 5.6 Hz, 2H), 1.97 (s, 3H). 13C NMR (101 MHz, CDCl3) δ
[ppm] = 170.1, 138.4, 128.7, 127.9, 127.5, 43.7, 23.2. The analytical
data are in agreement with previously reported ones.33 8: TLC: Rf =
0.75 (PE:EA 7:3) [KMnO4]. 1H NMR (400 MHz, CDCl3) δ [ppm] =
7.40−7.19 (m, 5H), 4.90 (s, 1H), 4.31 (d, J = 5.5, 2H), 1.47 (s, 9H).
13C NMR (101 MHz, CDCl3) δ [ppm] = 156.0, 139.1, 128.7, 127.6,
127.4, 79.6, 44.8, 28.5. The analytical data are in agreement with
previously reported ones.35
1-Benzyl-3-(4-fluorophenyl)urea (21f). According to the general
procedure D using (0.51 g, 4.18 mmol, 1.0 equiv) 1-ethynyl-4-
fluorobenzene (22f), 1-benzyl-3-(4-fluorophenyl)urea (0.42 mg, 1.72
mmol, 41%) (21f) was obtained after chromatography (DCM →
DCM:MeOH 99:1) as white solid. TLC: Rf = 0.31 (DCM:MeOH
1
99:1) [UV]. H NMR (600 MHz, DMSO) δ [ppm] = 8.56 (s, 1H),
7.43−7.39 (m, 2H), 7.35−7.28 (m, 4H), 7.26−7.22 (m, 1H), 7.08−
7.03 (m, 2H), 6.58 (t, J = 5.9 Hz, 1H), 4.29 (d, J = 6.0 Hz, 2H). 13C
NMR (151 MHz, CDCl3) δ [ppm] = 156.9 (d, J = 237.1 Hz), 155.2,
140.3, 136.8, 128.2, 127.1, 126.7, 119.3 (d, J = 7.6 Hz), 115.0 (d, J =
22.1 Hz), 42.7. The analytical data are in agreement with previously
reported ones.32
1-Benzyl-3-(thiophen-3-yl)urea (21g). According to the general
procedure D using (0.50 g, 4.44 mmol, 1.0 equiv) 3-ethynylthiophene
(22g), 1-benzyl-3-(thiophen-3-yl)urea (0.31 mg, 1.33 mmol, 30%)
(21g) was obtained after chromatography (DCM:MeOH 99:1) as
white solid. TLC: Rf = 0.37 (DCM:MeOH 99:1) [UV]. 1H NMR (600
MHz, DMSO) δ [ppm] = 8.81 (s, 1H), 7.36 (dd, J = 5.1, 3.2 Hz, 1H),
7.35−7.27 (m, 4H), 7.26−7.22 (m, 1H), 7.18 (dd, J = 3.2, 1.4 Hz,
1H), 6.99 (dd, J = 5.1, 1.4 Hz, 1H), 6.56 (t, J = 6.0 Hz, 1H), 4.30 (d, J
= 6.0 Hz, 2H).13C NMR (151 MHz, CDCl3) δ [ppm] = 155.0, 140.4,
138.1, 128.2, 127.0, 126.6, 124.2, 121.1, 104.5, 42.8. IR (ATR): v
[cm−1] = 3322, 3296, 3152, 3101, 3023, 2915, 2867, 1688, 1631, 1584,
153, 1260, 1222, 761, 743, 503. LRMS (ESI): [m/z] 233 (100) [M +
H+]. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C12H12N2NaOS:
255.0563; found 255.0563.
tert-Butyl Benzylcarbamate (8). tert-Butyl 2,2-diazidoacetate (50
mg, 0.25 mmol, 1.0 equiv) (1) was dissolved in benzene (1.5 mL), and
benzylamine (164 mg, 1.51 mmol, 6.0 equiv) in benzene (1 mL) was
added. The reaction mixture was stirred for 3 d at rt. Evaporation of
the solvent under reduced pressure and flash-chromatography on silica
gel (EA:PE 1:9 → EA:iPrOH 8:2) gave tert-butyl benzylcarbamate (39
mg, 0.19 mmol, 75%) (8) as white solid. TLC: Rf = 0.75 (PE:EA 7:3)
1
[KMnO4]. H NMR (400 MHz, CDCl3) δ [ppm] = 7.40−7.19 (m,
5H), 4.90 (s, 1H), 4.31 (d, J = 5.5, 2H), 1.47 (s, 9H). 13C NMR (101
MHz, CDCl3) δ [ppm] = 156.0, 139.1, 128.7, 127.6, 127.4, 79.6, 44.8,
28.5. The analytical data are in agreement with previously reported
ones.35
2,4,6-Trimethylbenzyl 2,2-Diazidoacetate (9). 2,4,6-Trimethylben-
zyl2,2-diazido-5-(4-methoxyphenyl)-3-oxopentanoate (80 mg, 0.18
mmol, 1.0 equiv) was dissolved in THF (1.0 mL, 0.1 M). Benzylamine
(22 mg, 0.20 mmol, 1.1 equiv) in THF (1.0 mL) was added, and the
reaction mixture was stirred at rt for 17 h, before concentrated under
reduced pressure. Purification by flash-chromatography (PE:EA 95:5
→1:1) on silica gel furnished 2,4,6-trimethylbenzyl 2,2-diazidoacetate
(35 mg, 0.13 mmol, 40%) (9) as white solid. TLC: Rf = 0.81 (PE:EA
̃
1-Benzyl-3-hexylurea (21h). According to the general procedure D
using (0.50 g, 4.45 mmol, 1.0 equiv) oct-1-yne (22h), 1-benzyl-3-
hexylurea (0.32 mg, 1.36 mmol, 31%) (21h) was obtained after
chromatography (PE:EA 7:3 → 3:7) as white solid. TLC: Rf = 0.42
1
1:1) [UV, CAM]. H NMR (400 MHz, C6D6) δ [ppm] = 6.65 (s,
2H), 5.03 (s, 2H), 4.04 (s, 1H), 2.16 (s, 6H), 2.04 (s, 3H).13C NMR
1
(101 MHz, C6D6) δ [ppm] = 165.3, 139.1, 138.4, 129.5, 128.2, 73.6,
(PE:EA 1:1) [UV]. H NMR (600 MHz, CDCl3) δ [ppm] = 7.34−
63.4, 20.9, 19.4. IR (ATR): v [cm−1] = 3007, 2918, 2865, 2107, 1736,
̃
7.27 (m, 2H), 7.26−7.17 (m, 3H), 6.24 (t, J = 5.8 Hz, 1H), 5.88 (t, J =
5.6 Hz, 1H), 4.19 (d, J = 6.0 Hz, 2H), 2.99 (dd, J = 12.8, 6.8 Hz, 2H),
1.39−1.33 (m, 2H), 1.31−1.21 (m, 6H), 0.86 (t, J = 7.0 Hz, 3H). 13C
NMR (151 MHz, CDCl3) δ [ppm] = 158.0, 140.9, 128.1, 126.9, 126.4,
42.8, 30.9, 29.9, 26.0, 21.9, 13.8. The analytical data are in agreement
with previously reported ones.33
1456, 1312, 1243, 1192, 997, 859, 553. LRMS (ESI): [m/z] 297 (6)
[M + Na+]. As direct HRMS was not possible, 2,4,6-trimethylbenzyl
2,2-diazidoacetate (9) was converted into its bistriazole derivative 9′:
2,4,6-Trimethylbenzyl 2,2-diazidoacetate (30 mg, 0.11 mmol, 1.0
equiv) (9) was dissolved in DMF (0.7 mL, 0.15 M), (+)-sodium L-
ascorbate (22 mg, 0.11 mmol, 1.0 equiv), CuSO4·5H2O (27 mg, 0.11
mmol, 1.0 equiv), and phenylacetylene (34 mg, 0.33 mmol, 3.0 equiv)
were added, and the reaction mixture was stirred for 3 d at rt. The
mixture was chromatographed over silica gel (PE:EA 9:1 →1:1) to
give 2,4,6-trimethylbenzyl 2,2-bis(4-phenyl-1H-1,2,3-triazol-1-yl)-
acetate (45 mg, 0.09 mmol, 86%) (9′) as white solid. TLC: Rf =
0.18 (PE:EA 8:2) [UV]. 1H NMR (400 MHz, CDCl3) δ [ppm] = 8.19
(s, 2H), 7.85−7.77 (m, 4H), 7.70 (s, 1H), 7.47−7.39 (m, 4H), 7.39−
7.32 (m, 2H), 6.84 (s, 2H), 5.47 (s, 2H), 2.27 (s, 6H), 2.25 (s, 3H).
N-Benzylacetamide (3), tert-Butyl 2,2-Diazidoacetate (4), and
tert-Butyl Benzylcarbamate (8). tert-Butyl 2,2-diazido-3-oxobutanoate
(0.50 g, 2.08 mmol, 1.0 equiv) (1) was dissolved in benzene (5 mL),
and benzylamine (0.54 g, 5.00 mmol, 2.4 equiv) in benzene (5 mL)
was added. The reaction mixture was stirred for 26 h at rt. Evaporation
of the solvent under reduced pressure and flash chromatography on
silica gel (EA:PE 1:9 → EA:iPrOH 8:2) gave N-benzylacetamide (0.28
g, 1.86 mmol, 90%) (3) and tert-butyl benzylcarbamate (88 mg, 0.42
mmol, 20%) (8) as white solids and tert-butyl 2,2-diazidoacetate (0.29
F
DOI: 10.1021/acs.joc.7b01019
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
13C NMR (101 MHz, CDCl3) δ [ppm] = 162.3, 149.0, 139.6, 138.7,
4.52 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H). 13C NMR (151
MHz, CDCl3) δ [ppm] = 156.7, 151.6, 63.8, 14.0. The analytical data
are in agreement with previously reported ones.36
129.6, 129.4, 129.1, 128.9, 127.0, 126.1, 120.3, 70.9, 65.2, 21.2, 19.5. IR
(ATR): v [cm−1] = 3126, 3084, 2963, 2921, 2853, 1768, 1614, 1426,
̃
1244, 828, 745. LRMS (ESI): [m/z] 479 (57) [M + H+]. HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C28H26N6NaO2: 501.2009; found
501.2009.
Ethyl 1H-Tetrazole-5-carboxylate (12). Ethyl dichloroacetate (0.10
g, 0.63 mmol, 1.0 equiv) (11*) was dissolved in DMF (0.63 mL, 1.0
M). NaN3 (164 mg, 2.52 mmol, 4.0 equiv) and triethylamine (0.19 g,
1.89 mmol, 3.0 equiv) were added, and the reaction mixture was
stirred at rt for 3 d. Aqueous HCl (1.0 M) was added (until pH < 7),
and the mixture was extracted with EA. The combined organic phase
was washed with brine, dried over Na2SO4, and concentrated under
reduced pressure. Ethyl 1H-tetrazole-5-carboxylate (78 mg, 0.55
Triethylammonium 5-(((2,4,6-trimethylbenzyl)oxy)carbonyl)-
tetrazol-1-ide (10). 2,4,6-Trimethylbenzyl 2,2-diazidoacetate (0.11 g,
0.42 mmol, 1.0 equiv) (9) was dissolved in benzene (0.85 mL, 0.5 M).
Triethylamine (0.13 g, 1.25 mmol, 3.0 equiv) was added, and the
reaction mixture was stirred at rt for 3 d. The white precipitate was
filtered, washed with benzene, and dried under vacuum to obtain
triethylammonium 5-(((2,4,6-trimethylbenzyl)oxy)carbonyl)tetrazol-
1
mmol, 87%) (12) was isolated as white solid. H NMR (600 MHz,
CDCl3) δ [ppm] = 15.07 (s, 1H), 4.52 (q, J = 7.1 Hz, 2H), 1.38 (t, J =
7.1 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ [ppm] = 156.7, 151.6,
63.8, 14.0. The analytical data are in agreement with previously
reported ones.36
1
1-ide (0.13 g, 0.38 mmol, 91%) (10). H NMR (400 MHz, DMSO)
δ [ppm] = 9.00 (s, 1H), 6.89 (s, 2H), 5.28 (s, 2H), 3.09 (q, J = 7.3 Hz,
6H), 2.33 (s, 6H), 2.23 (s, 3H), 1.17 (t, J = 7.3 Hz, 9H). 13C NMR
(101 MHz, DMSO) δ [ppm] = 161.6, 154.9, 137.8, 137.5, 129.4,
128.6, 60.1, 45.8, 20.6, 19.1, 8.6. For further analytics, the salt 10 was
converted into the free 2,4,6-trimethylbenzyl 1H-tetrazole-5-carbox-
ylate (10′): Triethylammonium 5-(((2,4,6-trimethylbenzyl)oxy)-
carbonyl)tetrazol-1-ide (0.13 g, 0.38 mmol, 1.0 equiv) (10) was
dissolved in water. Aqueous HCl (1.0 M) was added (until pH < 7),
and the mixture was extracted with EA. The combined organic phase
was washed with brine, dried over Na2SO4, and concentrated under
reduced pressure. 2,4,6-Trimethylbenzyl 1H-tetrazole-5-carboxylate
(88 mg, 0.36 mmol, 86%) (10′) as white solid. 1H NMR (600
MHz, CDCl3) δ [ppm] = 6.77 (s, 2H), 5.47 (s, 2H), 2.29 (s, 6H), 2.22
(s, 3H). 13C NMR (151 MHz, CDCl3) δ [ppm] = 156.4, 151.1, 139.5,
N-Benzylacetamide (3), Dimethylcarbamoyl Cyanide (14), and
2,2-Diazido-N,N-dimethylacetamide (15). 2,2-Diazido-N,N-dimethyl-
3-oxobutanamide (50 mg, 0.24 mmol, 1.0 equiv) (13) was dissolved in
benzene (1.2 mL, 0.1 M) under nitrogen. Benzylamine (56 mg, 0.52
mmol, 2.2 equiv) (2) in benzene (1.2 mL) was added, and the reaction
mixture was stirred at room temperature for 20 h. Evaporation of the
solvent under reduced pressure and flash-chromatography on silica gel
(PE:EtOAc 9:1 → EA:iPrOH:MeOH 5:4:1) gave a 2:1 mixture of
dimethylcarbamoyl cyanide (7 mg, 0.07 mmol, 29%) (14) and 2,2-
diazido-N,N-dimethylacetamide (6 mg, 0.04 mmol, 15%) (15) as
colorless oil and N-benzylacetamide (26 mg, 0.17 mmol, 74%) (3) as
white solid. 14: TLC: Rf = 0.55 (PE:EtOAc 1:1) [KMnO4]. 1H NMR
(400 MHz, CDCl3) δ [ppm] = 3.29 (s, 3H), 3.01 (s, 3H). 13C NMR
(101 MHz, CDCl3) δ [ppm] = 144.9, 110.6, 38.0, 34.5. The analytical
data are in agreement with previously reported ones.37 15: TLC: Rf =
0.55 (PE:EtOAc 1:1) [KMnO4]. 1H NMR (400 MHz, CDCl3) δ
[ppm] = 5.01 (s, 1H), 3.06 (s, 3H), 3.02 (s, 3H). 13C NMR (101
MHz, CDCl3) δ [ppm] = 164.5, 71.5, 37.0, 36.3. 3: TLC: Rf = 0.27
138.4, 129.3, 127.0, 63.9, 21.1, 19.5. IR (ATR): v [cm−1] = 3101, 2919,
̃
2731, 2253, 1741, 1613, 1200, 906, 852, 762. LRMS (ESI): [m/z] 269
(51) [M + Na+]. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C12H14N4NaO2: 269.1009; found 269.1007.
Ethyl 2,2-Diazidoacetate (11). Ethyl 2,2-diazido-3-oxobutanoate
(0.35 g, 1.64 mmol, 1.0 equiv) was dissolved in THF (10 mL, 0.1 M).
Benzylamine (0.20 g, 1.80 mmol, 1.1 equiv) in THF (6.0 mL) was
added, and the reaction mixture was stirred at rt for 18 h, before
concentrated under reduced pressure. Purification by flash chromatog-
raphy (PE:EA 95:5) on silica gel furnished ethyl 2,2-diazidoacetate
(0.15 g, 0.88 mmol, 54%) (11) as colorless oil. TLC: Rf = 0.59 (PE:EA
8:2) [KMnO4]. 1H NMR (400 MHz, CDCl3) δ [ppm] = 4.85 (s, 1H),
4.33 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H). 13C NMR (101
1
(DCM:MeOH 95:3) [Cl2]. H NMR (400 MHz, CDCl3) δ [ppm] =
7.42−7.27 (m, 5 H), 5.75 (br. s., 1 H), 4.43 (d, J = 5.6 Hz, 2 H), 2.02
(s, 3 H). 13C NMR (101 MHz, CDCl3) δ [ppm] = 170.0, 138.4, 128.9,
128.0, 127.7, 44.0, 23.4. The analytical data are in agreement with
previously reported ones.34
4-Pentylbenzoyl Azide (17a). 2,2-Dichloro-1-(4-pentylphenyl)-
ethan-1-one (0.20 g, 0.77 mmol, 1.0 equiv) (16a) was dissolved in
DMF (1.0 mL, 1.0 M) and cooled to −5 °C. NaN3 (0.20 g, 3.09 mmol,
4.0 equiv) was added, and the reaction mixture was stirred at 0 °C for
16 h. Water was added, and the mixture was extracted with
dichloromethane. The combined organic layers were washed with
brine, dried over Na2SO4, and concentrated under reduced pressure.
Purification by flash chromatography on silica gel (PE:EA 98:2) gave
4-pentylbenzoyl azide (0.13 g, 0.58 mmol, 75%) (17a) as yellow solid.
MHz, CDCl ) δ [ppm] = 165.2, 73.6, 63.3, 14.1. IR (ATR): v [cm−1]
̃
3
= 2987, 2102, 1749, 1394, 1189, 1020, 915, 555. As direct HRMS and
LRMS was not possible, ethyl 2,2-diazidoacetate (11) was converted
into its bistriazole derivative 11′: Ethyl 2,2-diazidoacetate (30 mg, 0.18
mmol, 1.0 equiv) (11) was dissolved in DMF (1.2 mL, 0.15 M),
(+)-sodium L-ascorbate (35 mg, 0.18 mmol, 1.0 equiv), CuSO4·5H2O
(44 mg, 0.18 mmol, 1.0 equiv), and phenylacetylene (54 mg, 0.53
mmol, 3.0 equiv) were added, and the reaction mixture was stirred for
20 h at rt. The mixture was chromatographed over silica gel (PE:EA
9:1 → 6:4) to give ethyl 2,2-bis(4-phenyl-1H-1,2,3-triazol-1-yl)acetate
(59 mg, 0.16 mmol, 89%) (11′) as white solid. TLC: Rf = 0.43 (PE:EA
1:1) [UV, KMnO4]. 1H NMR (400 MHz, CDCl3) δ [ppm] = 8.35 (s,
2H), 7.89−7.82 (m, 5H), 7.46−7.39 (m, 4H), 7.38−7.32 (m, 2H),
4.42 (q, J = 7.1 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H). 13C NMR (101
MHz, CDCl3) δ [ppm] = 162.3, 148.9, 129.6, 129.1, 128.9, 126.1,
1
TLC: Rf = 0.63 (PE:EA 9:1) [UV]. H NMR (400 MHz, CDCl3) δ
[ppm] = 77.98−7.90 (m, 2H), 7.29−7.23 (m, 2H), 2.71−2.62 (m,
2H), 1.69−1.57 (m, 2H), 1.41−1.23 (m, 4H), 0.89 (t, J = 7.0 Hz, 3H).
13C NMR (101 MHz, CDCl3) δ [ppm] = 172.5, 150.5, 129.7, 128.9,
128.3, 36.2, 31.5, 30.8, 22.6, 14.1. IR (ATR): v [cm−1] = 2957, 2929,
̃
2858, 2350, 2130, 1689, 1602, 1236, 1174, 984, 648. LRMS (EI): [m/
z] 189 (14) [M − N2]+, 132 (100), 77 (13).
N-Benzyl-4-pentylbenzamide (18a). 4-Pentylbenzoyl azide (65 mg,
0.30 mmol, 1.0 equiv) was dissolved in THF (0.3 mL, 1.0 M), and
benzylamine (38 mg, 0.38 mmol, 1.2 equiv), and DIPEA (47 mg, 0.38
mmol, 1.2 equiv) were added. The reaction mixture was stirred for 20
h at rt. Concentration under reduced pressure and purification with
flash chromatography (DCM:MeOH 99:1) gave N-benzyl-4-pentyl-
benzamide (78 mg, 0.82 mmol, 92%) (18a) as white solid. TLC: Rf =
0.50 (DCM:MeOH 99:1) [UV]. 1H NMR (400 MHz, CDCl3) δ
[ppm] = 7.74−7.67 (m, 2H), 7.38−7.32 (m, 4H), 7.32−7.27 (m, 1H),
7.23 (d, J = 8.4 Hz, 2H), 6.36 (s, 1H), 4.65 (d, J = 5.7 Hz, 2H), 2.71−
2.59 (m, 2H), 1.67−1.57 (m, 3H), 1.39−1.25 (m, 4H), 0.89 (t, J = 6.9
Hz, 3H). 13C NMR (101 MHz, CDCl3) δ [ppm] = 167.4, 147.1,
138.5, 131.9, 128.9, 128.7, 128.1, 127.7, 127.1, 44.2, 35.9, 31.5, 31.0,
120.6, 70.9, 64.7, 13.9. IR (ATR): v [cm−1] = 3130, 3102, 2981, 2969,
̃
1760, 1457, 1427, 1371, 1282, 1209, 1019, 820, 763, 692. LRMS
(ESI): [m/z] 375 (100) [M + H+]. HRMS (ESI-TOF) m/z: [M +
Na]+ calcd for C20H18N6NaO2: 397.1383; found 397.1384.
Ethyl 1H-tetrazole-5-carboxylate (12). Ethyl 2,2-diazidoacetate
(0.15 g, 0.88 mmol, 1.0 equiv) (11) was dissolved in benzene (1.8 mL,
0.5 M). Triethylamine (0.27 g, 2.63 mmol, 3.0 equiv) was added and
the reaction mixture was stirred at rt for 3 d. The white precipitation
was filtered, washed with benzene and dissolved in water. Aqueous
HCl (1.0 M) was added (until pH < 7) and the mixture was extracted
with EA. The combined organic phase was washed with brine, dried
over Na2SO4 and concentrated under reduced pressure. Ethyl 1H-
tetrazole-5-carboxylate (0.11 g, 0.79 mmol, 90%) (12) was isolated as
22.6, 14.1. IR (ATR): v [cm−1] = 3317, 3066, 3059, 3027, 2950, 2925,
̃
1
white solid. H NMR (600 MHz, CDCl3) δ [ppm] = 15.07 (s, 1H),
2854, 1638, 1609, 1548, 1312, 854. LRMS (ESI): [m/z] 282 (34) [M
G
DOI: 10.1021/acs.joc.7b01019
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
+ H+]. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C19H23NNaO:
304.1672; found 304.1670.
H+]. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C19H24N2NaO:
319.1781; found 319.1784.
(4-Pentylphenyl)carbamoyl Azide (19a). 2,2-Dichloro-1-(4-
pentylphenyl)ethan-1-one (0.10 g, 0.39 mmol, 1.0 equiv) (16a) was
dissolved in acetonitrile (1.0 mL) and water (0.5 mL), and NaN3 (88
mg, 1.35 mmol, 3.5 equiv) was added. The reaction mixture was stirred
at 65 °C for 16 h. Water was added, and the mixture was extracted
with EA. The combined organic layers were washed with brine, dried
over Na2SO4, and concentrated under reduced pressure. Purification
by flash chromatography on silica gel (PE:EA 95:5) gave (4-
pentylphenyl)carbamoyl azide (27 mg, 0.12 mmol, 30%) (19a) as
yellow solid. TLC: Rf = 0.56 (PE:EA 8:2) [UV, CAM]. 1H NMR (400
MHz, CDCl3) δ [ppm] = 7.33 (d, J = 8.1 Hz, 2H), 7.14 (d, J = 8.4 Hz,
2H), 6.79 (s, 1H), 2.63−2.52 (m, 2H), 1.67−1.53 (m, 2H), 1.40−1.24
(m, 4H), 0.89 (t, J = 7.0 Hz, 3H).13C NMR (101 MHz, CDCl3) δ
[ppm] = 154.0, 139.7, 134.6, 129.2, 119.5, 35.4, 31.6, 31.3, 22.7, 14.1.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.7b01019.
■
S
1H and 13C NMR spectra of selected examples, data on
the crossover experiment and computational details
(PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: sfkirsch@uni-wuppertal.de.
ORCID
Stefan F. Kirsch: 0000-0003-2628-8703
Notes
■
IR (ATR): v [cm−1] = 3316, 2953, 2926, 2858, 2139, 1680, 1543,
̃
1241, 684, 521. LRMS (ESI): [m/z] 233 (37) [M + H+]. HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C12H16N4NaO: 255.1216; found
255.1215.
(4-Pentylphenyl)carbamoyl azide (19a). 1-Ethynyl-4-pentylben-
zene (100 mg, 0.56 mmol, 1.0 equiv) (22a) was dissolved in
acetonitrile (2.0 mL), and oxone (0.35 g, 1.13 mmol, 2.0 equiv) and
KCl (84 mg, 1.13 mmol, 2.0 equiv) were added. Next, water (1.0 mL)
was added, and the reaction mixture was stirred for 8 h at rt. NaN3
(109 mg, 1.69 mmol, 3.0 equiv) was added, and the mixture was
stirred for additional 16 h at 65 °C. Water was added, and the mixture
was extracted with Et2O. The combined organic layers were washed
with brine, dried over Na2SO4, and concentrated under reduced
pressure. Purification by flash-chromatography on silica gel (PE:EA
95:5) gave (4-pentylphenyl)carbamoyl azide (59 mg, 0.25 mmol, 45%)
The authors declare no competing financial interest.
REFERENCES
■
(1) (a) Haring, A. P.; Kirsch, S. F. Molecules 2015, 20, 20042.
̈
(b) Brase, S.; Banert, K. Organic azides: Syntheses and Applications;
̈
John Wiley: Chichester, U.K., 2010. (c) Brase, S.; Gil, C.; Knepper, K.;
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Zimmermann, V. Angew. Chem., Int. Ed. 2005, 44, 5188. (d) Banert, K.
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(2) Forster, M. O.; Fierz, H. E.; Joshua, W. P. J. Chem. Soc., Trans.
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(3) Recent examples: (a) Kirchmeyer, S.; Mertens, A.; Olah, G. A.
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Am. Chem. Soc. 1975, 97, 6181. (c) Moriarty, R. M.; Bailey, B. R., III;
Prakash, I. J. Org. Chem. 1985, 50, 3710. (d) Ogilvie, W.; Rank, W.
Can. J. Chem. 1987, 65, 166. (e) Moriarty, R. M.; Kliegman, J. M. J.
Am. Chem. Soc. 1967, 89, 5959. (f) Barash, L.; Wasserman, E.; Yager,
W. A. J. Am. Chem. Soc. 1967, 89, 3931. (g) Ranaweera, R. A. A. U.;
Sankaranarayanan, J.; Casey, L.; Ault, B. S.; Gudmundsdottir, A. D. J.
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B.; Sharpless, K. B.; Fokin, V. V. Angew. Chem., Int. Ed. 2009, 48, 8018.
(5) Selected applications: (a) Gilbert, E. E. J. Energ. Mater. 1987, 5,
77. (b) Suzuki, H.; Hwang, Y. S.; Nakaya, C.; Matano, Y. Synthesis
1993, 1993, 1218. (c) Dong, G.-X.; Li, J.-S.; Chan, T.-H. J. Chem. Soc.,
Chem. Commun. 1995, 1725.
1
(19a) as yellow solid. TLC: Rf = 0.56 (PE:EA 8:2) [UV, CAM]. H
NMR (400 MHz, CDCl3) δ [ppm] = 7.33 (d, J = 8.1 Hz, 2H), 7.14 (d,
J = 8.4 Hz, 2H), 6.79 (s, 1H), 2.63−2.52 (m, 2H), 1.67−1.53 (m, 2H),
1.40−1.24 (m, 4H), 0.89 (t, J = 7.0 Hz, 3H).13C NMR (101 MHz,
CDCl3) δ [ppm] = 154.0, 139.7, 134.6, 129.2, 119.5, 35.4, 31.6, 31.3,
22.7, 14.1. IR (ATR): v [cm−1] = 3316, 2953, 2926, 2858, 2139, 1680,
̃
1543, 1241, 684, 521. LRMS (ESI): [m/z] 233 (37) [M+H+]. HRMS
(ESI-TOF) m/z: [M + Na]+ calcd for C12H16N4NaO: 255.1216; found
255.1215.
4-Pentylaniline (20a). (4-Pentylphenyl)carbamoyl azide (0.12 g,
0.50 mmol, 1.0 equiv) (19a) was dissolved in dioxane (1.0 mL, 0.5 M),
and aqueous NaOH (1.0 mL, 2.0 M) was added. The reaction mixture
was stirred for 0.5 h at rt, before aqueous HCl (1.0 mL, 1.0 M) was
added, and the reaction was stirred for additional 0.5 h. The mixture
was diluted with aqueous NaOH and extracted with diethyl ether. The
combined organic layers were washed with brine, dried over Na2SO4,
and concentrated under reduced pressure. 4-Pentylaniline (74 mg,
1
0.45 mmol, 91%) (20a) was obtained as orange oil. H NMR (400
MHz, CDCl3) δ [ppm] = 7.05−6.94 (m, 2H), 6.69−6.60 (m, 2H),
3.62−3.27 (m, 2H), 2.56−2.47 (m, 2H), 1.65−1.53 (m, 2H), 1.40−
1.26 (m, 4H), 0.91 (t, J = 7.0 Hz, 3H). 13C NMR (101 MHz, CDCl3)
δ [ppm] = 144.1, 133.2, 129.2, 115.3, 35.2, 31.6, 22.6, 14.1. The
analytical data are in agreement with previously reported ones.38
1-Benzyl-3-(4-pentylphenyl)urea (21a). (4-Pentylphenyl)-
carbamoyl azide (0.25 g, 1.08 mmol, 1.0 equiv) (19a) was dissolved
in THF (2.0 mL), and benzylamine (0.14 g, 1.29 mmol, 1.2 equiv) and
DIPEA (0.17 g, 1.29 mmol, 1.2 equiv) were added. The reaction
mixture was stirred for 18 h at rt. Concentration under reduced
pressure and purification with flash-chromatography (DCM:MeOH
99:1) gave 1-benzyl-3-(4-pentylphenyl)urea (0.24 g, 0.81 mmol, 76%)
(21a) as white solid. TLC: Rf = 0.32 (DCM:MeOH 99:1) [UV,
(6) (a) Harschneck, T.; Hummel, S.; Kirsch, S. F.; Klahn, P. Chem. -
Eur. J. 2012, 18, 1187. (b) Klahn, P.; Erhardt, H.; Kotthaus, A.; Kirsch,
S. F. Angew. Chem., Int. Ed. 2014, 53, 7913. (c) Erhardt, H.; Haring, A.
̈
P.; Kotthaus, A.; Roggel, M.; Tong, M. L.; Biallas, P.; Jubermann, M.;
̈
Mohr, F.; Kirsch, S. F. J. Org. Chem. 2015, 80, 12460. (d) Erhardt, H.;
Mohr, F.; Kirsch, S. F. Chem. Commun. 2016, 52, 545.
(7) (a) Ehrhardt, H.; Mohr, F.; Kirsch, S. F. Eur. J. Org. Chem. 2016,
2016, 5629. (b) Ehrhardt, H.; Kunz, K. A.; Kirsch, S. F. Org. Lett. 2017,
19, 178.
(8) (a) Haring, A. P.; Biallas, P.; Kirsch, S. F. Eur. J. Org. Chem. 2017,
̈
2017, 1526. (b) Biallas, P.; Haring, A. P.; Kirsch, S. F. Org. Biomol.
̈
Chem. 2017, 15, 3184.
1
(9) Conrow, R. E.; Dean, W. D. Org. Process Res. Dev. 2008, 12, 1285.
(10) Recent tetrazole syntheses: (a) Zarganes-Tzitzikas, T.; Patil, P.;
KMnO4]. H NMR (400 MHz, CDCl3) δ [ppm] = 7.33−7.19 (m,
5H), 7.16−7.11 (m, 2H), 7.09−7.04 (m, 2H), 6.68 (s, 1H), 5.37 (t, J =
5.6 Hz, 1H), 4.36 (d, J = 5.8 Hz, 2H), 2.58−2.49 (m, 2H), 1.57 (dt, J =
15.1, 7.6 Hz, 2H), 1.38−1.24 (m, 4H), 0.88 (t, J = 6.9 Hz, 3H). 13C
NMR (101 MHz, CDCl3) δ [ppm] = 156.0, 139.4, 138.9, 135.5, 129.3,
128.6, 127.4, 127.3, 122.3, 44.3, 35.2, 31.4, 31.1, 22.5, 13.9. IR (ATR):
Khoury, K.; Herdtweck, E.; Domling, A. Eur. J. Org. Chem. 2015, 2015,
̈
51. (b) Shmatova, O. I.; Nenajdenko, V. G. J. Org. Chem. 2013, 78,
9214. (c) Imai, T.; Harigae, R.; Moriyama, K.; Togo, H. J. Org. Chem.
2016, 81, 3975.
v [cm−1] = 3311, 3028, 2959, 2928, 2872, 2849, 1632, 1589, 1557,
(11) Diazido compound 11 was isolated in 47% yield through the
reaction of 11* with NaN3 (4 equiv) in DMF at rt.
̃
1523, 1453, 1231, 696, 651, 529. LRMS (ESI): [m/z] 297 (100) [M +
H
DOI: 10.1021/acs.joc.7b01019
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
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I
DOI: 10.1021/acs.joc.7b01019
J. Org. Chem. XXXX, XXX, XXX−XXX