Zinc-Mediated Allylation and Benzylation of Phenylazocarboxylic Esters

Article abstract of DOI:10.1021/acs.joc.5b01978

Allylation and benzylation of phenylazocarboxylic tert-butyl esters have been achieved under Barbier-type reaction conditions and in very short reactions times using the corresponding allyl and benzyl bromides or iodides in combination with zinc powder. Whereas all reactions occurred exclusively at the β-nitrogen atom of the azocarboxylic esters, the linkage of allyl units was shown to depend on the substitution pattern at the double bond of the allyl halide. The hydrazines obtained are useful precursors for indoles and indazoles.

Full text of DOI:10.1021/acs.joc.5b01978

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Note
Zinc-mediated allylation and benzylation of phenylazocarboxylic esters
Roman Lasch, and Markus Rolf Heinrich
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01978 • Publication Date (Web): 24 Sep 2015
Downloaded from http://pubs.acs.org on September 26, 2015
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Zinc-mediated allylation and benzylation of phenylazocarboxylic
esters
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Roman Lasch, Markus R. Heinrich*
Department of Chemistry and Pharmacy, Pharmaceutical Chemistry, Friedrich-Alexander-
Universität Erlangen-Nürnberg, Schuhstraße 19, 91052 Erlangen, Germany
markus.heinrich@fau.de
Abstract
Allylation and benzylation of phenylazocarboxylic tert-butyl esters have been achieved under
Barbier-type reaction conditions and in very short reactions times using the corresponding allyl
and benzyl bromides or iodides in combination with zinc powder. Whereas all reactions
occurred exclusively at the β-nitrogen atom of the azocarboxylic esters, the linkage of allyl
units was shown to depend on the substitution pattern at the double bond of the allyl halide.
The hydrazines obtained are useful precursors for indoles or indazoles.
The formation of carbon-nitrogen bonds is mainly achieved by three general strategies:
reactions of nucleophilic organometallic compounds or carbanions with nitrogen-centered
1
2,3
4
electrophiles, transition-metal mediated cross-coupling reactions and C-H aminations, as
well as classical amination reactions proceeding via nucleophilic substitution of electrophilic
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carbon residues with amines, phthalimides or azides. Regarding the organometallic approach,
research has focused on nitrogen-centered electrophiles such as substituted hydroxylamines,6
in which the hydroxyl group was turned into a suitable leaving group, and on additions of
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organometallics to nitro compounds, nitroso compounds and oximes. Nucleophilic additions
to azo compounds preferably occur if the azo compound is suitably activated by ring-strain or
at least one electron-withdrawing group. Only a few reactions have been reported with
azobenzenes10a or diazirines,10b whereas organometallic additions to dialkyl azodicarboxylates
are more frequent.10c-f Over the last decade, nucleophilic additions to unsymmetrical azo
compounds (Scheme 1), such as phenylazosulfones (1)11 and phenylazocarboxylic esters
(
2,3),12-14 have gained more interest. In these transformations, however, mainly aryl and only
1
5
few alkyl residues have so far been coupled to the azo compounds (2). For allylation reactions,
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in particular, there is currently only one example by Yanagisawa (3) who reported the addition
of a geranyl-barium chloride onto tert-butyl phenylazocarboxylate.
Scheme 1. Addition of organometallic reagents to phenylazosulfones and phenylazocarboxylic
esters.
Our interest in the functionalization of phenylazocarboxylic esters by organometallic reagents
was due to recent studies showing that the aromatic core of such reagents is highly activated
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towards nucleophilic aromatic substitution with diverse reagents such as phenols, aromatic and
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aliphatic amines as well as [ F]fluoride. The combination of this aromatic substitution with
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modifications at the azo moiety could in turn allow a quick two-step access to a broad variety
of products. Thereby, it would be particularly useful if the generation of the organometallic
reagent and its addition onto the azocarboxylic ester were feasible under simple reaction
conditions, as they have been reported for Barbier-type reactions19,20 of allyl- and benzylzinc
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reagents with wide range of carbonyl compounds. In case that the nucleophilic addition could
be conducted in short overall reaction times, it might also be applicable in radiosyntheses
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starting from F-labelled phenylazocarboxylic esters.
In this article, we now present the first examples for zinc-mediated allylations and benzylations
of phenylazocarboxylic esters, which are shown to be versatile and exceptionally fast reactions
to access functionalized hydrazines (Scheme 1, (4)).
Against the background that phenylazocarboxylic esters were readily reduced to their
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corresponding hydrazines by metallic zinc powder, we decided to add the benzyl bromide and
zinc powder – after a short mixing time in which no reaction should occur – simultaneously to
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the azocarboxylic ester. A mixture of benzyl bromide (2a) and an equivalent amount of
commercially available zinc powder in tetrahydrofuran was thus stirred for 1 minute before
being added to a solution of phenylazocarboxylic tert-butyl ester (1a) in tetrahydrofuran and
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saturated aqueous ammonium chloride under air (Table 1). As the characteristic orange color
of the phenylazocarboxylate 1a disappeared after a reaction time of only 30 seconds, the
1
reaction was quenched by the addition of water. Analysis of the crude reaction mixture by H-
NMR revealed the formation of the desired adduct 3a in 89% yield and showed no detectable
amounts of the hydrazine resulting from the reduction of 1a. Furthermore, the homo-coupling
of benzyl bromide (2a) during the short premixing phase had indeed not occurred, as no
dibenzyl was found as by-product. After the high yield of hydrazine 3a was confirmed through
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isolation and purification by column chromatography (Table 1, entry 1), we directly turned to
evaluate scope and limitations of the benzylation reaction.
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Table 1. Zinc-mediated benzylation of phenylazocarboxylic tert-butyl esters
entry
azocarboxylate benzyl bromide
hydrazine
1
2
a
1
: R =
2: R =
3 (%)
1
1a: H
2a: H
2a: H
2a: H
2a: H
2a: H
2a: H
2a: H
2a: H
2b: 2-Br
2c: 2-I
3a: 87
3b: 88
3c: 80
3d: 89
3e: 73
3f: 82
3g: 82
3h: 75
2
1b: 4-F
1c: 4-Br
1d: 4-I
3
4
5
1e: 4-CN
1f: 4-OMe
6
7
1g: 2,4-Cl
1h: 4-F, 2-Me
1c: 4-Br
2
8
b
9
3i: 62
b
10
1c: 4-Br
3j: 44
a
b
Yields determined after purification by column chromatography. tert-Butyl 2-(4-bromophenyl)hydrazinecarboxylate detected as by-product
(ca. 20-40%).
Good to high yields were obtained for all combinations of phenylazocarboxylic esters 1a-h with
1
benzyl bromide (2a) (entries 1-8) irrespective of the presence of an electron-withdrawing (R =
1
4
-CN, entry 5) or an electron-donating group (R = 4-OMe, entry 6). Moreover, all types of
2
5
halogen atoms, including iodine, on the aromatic core of the azocarboxylate were tolerated,
and even ortho-substitution, as in azocarboxylates 1g and 1h (entries 7 and 8), did not have
remarkably negative effects on the product formation. The two attempts with the ortho-
substituted benzyl bromides 2b and 2c gave lower yields (entries 9 and 10), which can be
attributed to slower benzylation reactions and a consequently increased reduction of the azo
compound 1c to its corresponding hydrazine.
Further experiments demonstrated that the benzylation reaction can also be performed as a one-
pot procedure in the way that the azocarboxylic ester 1c is added as a solid to a mixture of
benzylbromide 2a and zinc powder in tetrahydrofuran and aqueous ammonium chloride to give
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c in 84% yield. Alternatively, and with an even slightly higher yield of 93%, hydrazine 3c
could be obtained by the addition of zinc powder to 1c and 2a in the usual solvent mixture,
which makes the transformation fully comparable to a Barbier-type reaction.19
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The replacement of benzyl bromide (2a) for 4-chlorobenzyl chloride in a reaction with
azocarboxylate 1d led to no product formation but instead to the complete reduction of the
azocarboxylate, thus indicating that the desired reaction pathway is too slow (c.f. Table 1,
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6
entries 9 and 10). A control experiment with 2-(4-bromophenyl)hydrazinecarboxylic acid tert-
butyl ester and benzyl bromide in the absence of zinc, but under otherwise identical conditions,
ruled out a reaction course in which the azo compound 1 is first reduced to a hydrazine that
does then react with benzyl bromide.
In a second series of experiments we evaluated the transferability of the previously found
reaction conditions to allylation reactions (Table 2). The first attempts in this series indicated
that two equivalents of allyl bromide (4a) or of the more reactive allyl iodide (4b) are not
sufficient to obtain the desired allylation product 5a in good yield. By increasing the amounts
of 4a or 4b and zinc powder to five equivalents, the phenylazocarboxylates 1c-e and 1g then
underwent allylation in good to high yields (entries 3-7). Similar to the benzylation reactions
summarized in Table 2, only the hydrazines arising from reduction of the azocarboxylates 1
were detected as minor by-products. An experiment with the addition of zinc powder to a
mixture of 1d and 4b (c.f. entry 5, Table 2) provided 5b in a yield of 92%, thereby showing
that the Barbier-type order of addition is possible, too.
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Table 2. Zinc-mediated allylation of phenylazocarboxylates.
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entry azocarboxylate allyl halide
hydrazine
1
a
1
: R =
4: X =
4a: Br
4b: I
(equiv.)
5 (%)
b
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1c: 4-Br
1c: 4-Br
1c: 4-Br
1c: 4-Br
1d: 4-I
2
5a: 29
5a: 45
5a: 70
5a: 71
5b: 91
5c: 90
5d: 66
b
2
4a: Br
4b: I
5
5
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5
5
4b: I
1e: 4-CN
1g: 2,4-Cl
4b: I
2
4b: I
a
b
Yields determined after purification by column chromatography. Reactions conducted with reduced amounts of allyl halide (1.0 mmol) and
zinc powder (1.0 mmol).
In widely studied reactions of aldehydes and ketones under aqueous Barbier conditions, using
ammonium chloride and tetrahydrofuran as solvents, allyl zinc reagents preferably react at their
γ-carbon atom,24,27 which can be rationalized by a 6-membered zinc-containing transition
2
8
state. For comparable allylation reactions of azo compounds, only results from a study with
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allylbarium reagents are so far available (c.f. Scheme 1, (3)). As the allylbarium reagent was
thereby found to react with the phenylazocarboxylic ester unselectively at the α- and the γ-
position of the allyl unit, two different mechanisms appear to be possible for azobenzenes in
contrast to the carbonyls. For further insights, we submitted the substituted allyl bromides 6a-
c to the previously developed conditions (Table 3).
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Table 3. Zinc-mediated allylation of phenylazocarboxylates.
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entry azo-
carboxylate
allyl bromide
hydrazines
2
3
4
a
6
: R , R , R =
7:8 (%:%)
1
1
: R =
preferred attack (vs. )
1
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6
7
1c: Br
6a: H, Me, H
6a: H, Me, H
6a: H, Me, H
6b: H, Me, Me
6b: H, Me, Me
6b: H, Me, Me
6c: Me, H, H
7a:8a (0:86)
7b:8b (18:72)
7c:8c (33:65)

1e: CN
1f: OMe
1c: Br


7d:8d (48:32) 
7e:8e (51:36)
1e: CN
1f: OMe
1c: Br
7f:8f (57:9)
7g (44)

-
a
Yields determined after purification by column chromatography.
If only one methyl group is present in γ-position of the allylbromide, as in (E)-2-buten-1-yl
bromide (6a), the addition occurs preferably in γ-position (entries 1-3). This strongly suggests
that 6a, and mostly probably allyl bromide (4a) and allyl iodide (4b), too, react with
phenylazocarboxylic esters 1 via the above mentioned 6-membered transition state, which was
also suggested by Fristrup and Madsen.28b The acceptor- as well as the donor-substituted
1
azocarboxylates 1e and 1f gave lower regioselectivities, which, in case of 1e (R = CN, entry
2) could be due to an increased electrophilicity of the N=N-moiety. In agreement with the
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observations previously made with allylbarium reagents, the γ,γ-disubstituted allylbromide
6b showed C-N bond formation preferably at its -position, whereby the products 7d-f resulting
from the -attack were obtained in nearly the same yield for all three azocarboxylates 1c, 1e
1
and 1f (R = Br, CN, OMe; entries 4-6). The already less pronounced -attack in the reactions
with 6b was found to be especially unfavorable for the donor-substituted azocarboxylate 1f (R1
=
OMe; entry 7). Unexpectedly, a comparably low yield was obtained with 1c and the β-
substituted allylbromide 6c, for which the products resulting from - and γ-attack are identical
(
entry 7). In conclusion, it appears that the introduction of further substituents in γ-position of
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the allyl halide complicates the formation of a 6-membered transition state consisting of the N-
N moiety of the azo compound, the zinc ion, and the allyl unit, and therefore more of the non-
rearranged product 7 resulting from α-attack is obtained.
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Two experiments with azocarboxylate 1c and propargyl bromide (9) demonstrated that the
Barbier-type procedure, in which zinc powder is added to 1c and 9, is clearly superior for
propargylation reactions, as the addition of premixed zinc powder and propargyl bromide 9
gave the desired hydrazine 10 in only 28% yield compared to 61% for the zinc addition
2
9
(Scheme 2). Although the related allenyl hydrazine resulting from a potential γ-attack on 9
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could not be detected, the known instability of comparable compounds could however be an
explanation for the formation of several by-products. Two further reactions with competing
electrophiles demonstrated that the phenylazocarboxylic ester 1c is more reactive towards the
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organozinc reagent formed from 2a than towards pivalyl aldehyde (11), as only hydrazine 3c
was obtained. On the other hand, 1c is less reactive than diethyl azodicarboxylate (12), as
evidenced by the individual yields of 3c (36%) and 13 (99%).
Scheme 2. Propargylation and comparison of reactivity.
The hydrazines 3f and 3j (Table 1) obtained as products were finally used for further
transformations (Scheme 3). In a one-pot procedure, hydrazine 3f was first Boc-deprotected by
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sulfuric acid in methanol and then converted to indole 14 by the addition of cyclohexanone in
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an overall yield of 83%. In another one-pot procedure, the removal of the Boc-group from 3j
by trifluoroacetic acid was combined with a copper-mediated intramolecular amination to give
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indazole 15 in 90% yield. The reductive cleavage of the N-N bond of the hydrazine can be
3
5
performed directly after benzylation of the azo compound without intermediate work-up. For
the purpose of obtaining amine 16 from 1c and 2a, however, additional zinc powder,
trifluoroacetic acid and elevated temperatures over longer reaction times were required in the
second step.
Scheme 3. Synthesis of heterocycles and reductive cleavage of the N-N bond.
In summary, we have shown that tert-butyl phenylazocarboxylic esters can efficiently be
applied in zinc-mediated allylation and benzylation reactions. All reactions turned out to be
robust regarding the order of how the reagents are mixed, whereby the combined addition of
zinc and allyl or benzyl halide to the azocarboxylate gave in most cases – with exception of the
propargylation - similar results as the Barbier-type procedure, in which zinc powder was finally
added to the other reagents In the allylations, benzylations and the propargylation,
functionalization selectively occurred at the β-nitrogen atom of the azocarboxylic esters, which
is adjacent to the aromatic core. Only allyl halides substituted at their C-C double bond gave
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product mixtures, as they were found to undergo C-N bond formation at their - and γ-position
depending on the substitution pattern.
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Experimental Section
1
Solvents and reagents were used as received. H NMR spectra were recorded on 360 and 600
MHz spectrometers using CDCl
3
as solvent referenced to TMS (0.00 ppm) or CDCl
3
13
(
7.26 ppm). C NMR spectra were recorded at 91 or 151 MHz in CDCl
3
(77.0 ppm) as standard.
Chemical shifts are reported in parts per million (ppm). Coupling constants are in Hertz (J Hz).
The following abbreviations are used for the description of signals: s (singlet), d (doublet), t
(
triplet), q (quartet), m (multiplet), bs (broad singlet) and mc (centered multiplet). Mass spectra
were recorded using electron impact (EI) or electron spray ionization (ESI). A sector field mass
analyzer or TOF were used for HRMS measurements.
Analytical TLC was carried out on Merck silica gel plates using short wave (254 nm) UV light,
KMnO
in 300 mL H
For flash column chromatography silica gel (Kieselgel 60, grain size 40 - 63 μm, Merck) was
4
[3.0 g KMnO
4
, 20 g potassium carbonate, 5.0 mL aqueous sodium hydroxide (5% w/w)
2
O] and ninhydrin [200 mg ninhydrin in 100 mL ethanol] to visualize components.
1
8
used. The phenylazocarboxylic esters 1a-h have been previously characterized and were
prepared according to established procedures.
General procedures
General procedure for the N-benzylation of phenylazocarboxylic esters (GP 1)
A solution of the phenylazocarboxylic ester (1.00 mmol) in tetrahydrofuran (3 mL) and
saturated aqueous solution of ammonium chloride (0.5 mL) is treated with a suspension of the
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benzyl bromide (2.00 mmol) and zinc (2.00 mmol) in tetrahydrofuran (1 mL). After complete
consumption of the phenylazocarboxylate, as monitored by TLC, ethyl acetate (20 mL) is added
and the mixture is filtered. The filtrate is washed with water (3 × 15 mL), a saturated aqueous
solution of sodium chloride (20 mL) and dried over sodium sulfate. The solvent is removed
under reduced pressure and the residue is subjected to column chromatography. Note:
Upscaling of the reaction requires external cooling or a slower addition of the reagents due to
considerable generation of heat.
10
11
12
13
14
15
16
17
18
19
20
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23
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49
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53
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55
56
57
58
59
60
General procedure for the N-allylation of phenylazocarboxylic esters (GP 2)
A solution of the phenylazocarboxylic ester (1.00 mmol) in tetrahydrofuran (3 mL) and
saturated aqueous solution of ammonium chloride (0.5 mL) is treated with a suspension of the
allyl bromide/iodide (5.00 mmol) and zinc (5.00 mmol) in tetrahydrofuran (1 mL). After
complete consumption of the phenylazocarboxylate, as monitored by TLC, ethyl acetate
(20 mL) is added and the mixture is filtered. The filtrate is washed with water (3 × 15 mL), a
saturated aqueous solution of sodium chloride (20 mL) and dried over sodium sulfate. The
solvent is removed under reduced pressure and the residue is subjected to column
chromatography. Note: Upscaling of the reaction requires external cooling or a slower addition
of the reagents due to considerable generation of heat.
tert-Butyl 2-benzyl-2-phenylhydrazine carboxylate (3a) is prepared from tert-butyl 2-
phenylazocarboxylate (1a) (242 µmol, 50.0 mg) and benzyl bromide (2a) (484 µmol, 60 µL)
according to general procedure GP 1. The crude product is subjected to column chromatography
(
silica gel, hexane / ethyl acetate = 10:1) to give the title compound 3a as a white solid
(210 µmol, 62.6 mg, 87%): R
f
= 0.4 (hexane / ethyl acetate = 9:1) (UV); mp 97–98 °C; IR
-1
~
1
(
NaCl, cm )  3302, 2986, 1727, 1599, 1501, 1461, 1362, 1250, 1166, 1033, 757, 684; H NMR
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
4
4
4
4
4
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5
5
5
5
5
5
5
6
(
600 MHz, CDCl
3
) δ 1.45 (s, 9 H), 4.73 (bs, 2 H), 6.36 (bs, 1 H), 6.84 (t, J = 7.3 Hz, 1 H), 6.89
1
3
(
d, J = 8.0 Hz, 2 H), 7.27-7.34 (m, 7 H); C NMR (91 MHz, CDCl ) δ 28.3, 56.5, 80.9, 112.9,
3
119.5, 127.4, 128.0, 128.6, 129.2, 137.1, 149.3. (Signal of hydrazine carboxylate missing); MS
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
+
+
(
ESI) m/z 299 [MH ]; HRMS (ESI) calcd for C18
H
22
N
2
O
2
[M + Na ]: 321.1573, found:
3
21.1573. Analytical data is in agreement with those reported in literature ref 35b.
tert-Butyl 2-benzyl-2-(4-fluorophenyl)hydrazine carboxylate (3b) is prepared from tert-
butyl 2-(4-fluorophenyl)azocarboxylate (1b) (1.00 mmol, 224 mg) and benzyl bromide (2a)
(2.00 mmol, 238 µL) according to general procedure GP 1. The crude product is subjected to
column chromatography (silica gel, hexane / ethyl acetate = 9:1) to give the title compound 3b
as a pale brown solid (877 µmol, 278 mg, 88%): R = 0.4 (hexane / ethyl acetate = 9:1) (UV);
f
-1
~
mp 95–96 °C; IR (NaCl, cm )  3313, 2979, 1717, 1508, 1455, 1368, 1228, 1157, 822, 744,
1
696; H NMR (360 MHz, CDCl
3
) δ 1.42 (s, 9 H), 4.67 (bs, 2 H), 6.34 (bs, 1 H), 6.84 (dd,
13
J
HF= 4.4 Hz, J = 9.2 Hz, 2 H), 6.94 (dd, J HF= 8.2 Hz, J = 9.2 Hz, 2 H), 7.27-7.37 (m, 5 H); C
NMR (151 MHz, CDCl ) δ 28.2, 57.0, 81.0, 114.4 (d, JCF = 7.6 Hz) 115.5 (d, JCF = 23.0 Hz),
3
1
27.5, 128.1, 128.6, 136.8, 145.8, 157.0 (d, JCF = 237.4 Hz). (Signal of hydrazine carboxylate
+
+
+
missing); MS (ESI) m/z 317 [MH ]; HRMS (ESI) calcd for C18
H21FN
2
O [M + Na ]: 339.1479,
2
found: 339.1474.
tert-Butyl 2-benzyl-2-(4-bromophenyl)hydrazine carboxylate (3c) is prepared from tert-
butyl 2-(4-bromophenyl)azocarboxylate (1c) (1.00 mmol, 285 mg) and benzyl bromide (2a)
(2.00 mmol, 238 µL) according to general procedure GP 1. The crude product is subjected to
column chromatography (silica gel, hexane / ethyl acetate = 9:1) to give the title compound 3c
as a pale yellow solid (799 µmol, 301 mg, 80%): R = 0.4 (hexane / ethyl acetate = 9:1) (UV);
f
-1
~
mp 96–97 °C; IR (NaCl, cm )  3308, 2979, 1709, 1591, 1491, 1454, 1392, 1368, 1250, 1213,
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1
160, 1080, 999, 815, 755, 733, 699; H NMR (600 MHz, CDCl
3
) δ 1.43 (s, 9 H), 4.68 (bs,
1
3
2
H), 6.38 (bs, 1 H), 6.76 (d, J = 8.1 Hz, 2 H), 7.26-7.35 (m, 7 H); C NMR (91 MHz, CDCl
3
)
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
δ 28.2, 56.4, 81.2, 111.6, 114.6, 127.6, 127.9, 128.7, 131.9, 136.6, 148.4. (Signal of hydrazine
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
81
+
carboxylate missing); MS (ESI) m/z 379 [ Br-MH ]; HRMS (ESI) calcd for C18
H
21BrN
2
O
2
+
+
[
M + Na ]: 399.0679, found: 399.0670.
Barbier-type procedure: A mixture of tert-butyl 2-(4-bromophenyl)azocarboxylate (1c)
175 µmol, 50.0 mg) and benzyl bromide 2a (350 µmol, 42.0 µL) in tetrahydrofuran (2.0 mL)
(
and saturated aqueous ammonium chloride (0.5 mL) is treated with zinc (350 µmol, 23.0 mg)
and stirred vigorously for 30 seconds. Work up is as described above. The solvent is removed
under reduced pressure and the residue is subjected to column chromatography (silica gel,
hexane / ethyl acetate = 9:1) to give compound 3c as a pale yellow solid (167 µmol, 62.9 mg,
9
3%).
Addition of solid phenylazocarboxylate: A mixture of benzyl bromide 2a (350 µmol, 42.0 µL)
and zinc (350 µmol, 23.0 mg) in tetrahydrofuran (2.0 mL) and saturated aqueous ammonium
chloride (0.5 mL) is treated with solid tert-butyl 2-(4-bromophenyl)azocarboxylate (1c)
(
175 µmol, 50.0 mg) and stirred vigorously for 30 seconds. Work up is as described above. The
solvent is removed under reduced pressure and the residue is subjected to column
chromatography (silica gel, hexane / ethyl acetate = 9:1) to give compound 3c as a pale yellow
solid (147 µmol, 55.4 mg, 84%).
tert-Butyl 2-benzyl-2-(4-iodophenyl)hydrazine carboxylate (3d) is prepared from tert-butyl
2-(4-iodophenyl)azocarboxylate (1d) (602 µmol, 200 mg) and benzyl bromide (2a) (1.20 mmol,
1
50 µL) according to general procedure GP 1. The crude product is subjected to column
chromatography (silica gel, hexane / ethyl acetate = 8:1) to give the title compound 3d as a pale
yellow solid (533 µmol, 208 mg, 89%): R = 0.4 (hexane / ethyl acetate = 9:1) (UV); mp 97–
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
-
1
~
9
1
2
8 °C; IR (NaCl, cm )  3311, 2978, 1717, 1587, 1489, 1454, 1392, 1368, 1250, 1159, 1053,
1
028, 10145, 995, 813, 757, 732, 697; H NMR (360 MHz, CDCl
3
) δ 1.44 (s, 9 H), 4.68 (bs,
1
3
H), 6.38 (bs, 1 H), 6.67 (d, J = 8.7 Hz, 2 H), 7.26-7.35 (m, 5 H), 7.49 (d, J = 8.7 Hz, 2 H); C
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
NMR (91 MHz, CDCl
3
) δ 28.2, 56.4, 81.2, 115.1, 127.6, 127.8, 128.7, 136.6, 137.8, 149.1.
+
(
(
Signal of hydrazine carboxylate missing, signal missing); MS (ESI) m/z 425 [MH ]; HRMS
+
+
ESI) calcd for C18
H
21IN
2
O [M + Na ]: 447.0540, found: 447.0536.
2
tert-Butyl 2-benzyl-2-(4-cyanohenyl)hydrazine carboxylate (3e) is prepared from tert-butyl
-(4-cyanophenyl)azocarboxylate (1e) (1.00 mmol, 233 mg) and benzyl bromide (2a)
2.00 mmol, 238 µL) according to general procedure GP 1. The crude product is subjected to
column chromatography (silica gel, hexane / ethyl acetate = 7:1 → 5:1) to give the title
compound 3e as a white solid (732 µmol, 238 mg, 73%): R = 0.3 (hexane / ethyl acetate = 3:1)
2
(
f
-1
~
(
UV); mp 122–123 °C; IR (NaCl, cm )  3302, 2980, 1699, 1604, 1512, 1496, 1455, 1393,
1
1
368, 1352, 1217, 1161, 1029, 1015, 826, 760, 700; H NMR (360 MHz, CDCl
3
) δ 1.45 (s,
9 H), 4.80 (bs, 2 H), 6.47 (bs, 1 H), 6.90 (d, J = 9.1 Hz, 2 H), 7.26-7.39 (m, 5 H), 7.50 (d,
13
J = 9.1 Hz, 2 H); C NMR (91 MHz, CDCl
3
) δ 28.0, 56.0, 81.7, 101.2, 112.2, 119.7, 127.5,
1
27.7, 128.3, 133.4, 135.6, 152.2. (Signal of hydrazine carboxylate missing); MS (ESI) m/z 324
+
+
+
[MH ]; HRMS (ESI) calcd for C19
H
21
N
3
O [M + Na ]: 346.1526, found: 346.1524.
2
tert-Butyl 2-benzyl-2-(4-methoxyhenyl)hydrazine carboxylate (3f) is prepared from tert-
butyl 2-(4-methoxyhenyl)azocarboxylate (1f) (1.00 mmol, 236 mg) and benzyl bromide (2a)
(2.00 mmol, 238 µL) according to general procedure GP 1. The crude product is subjected to
column chromatography (silica gel, hexane / ethyl acetate = 7:1) to give the title compound 3f
as a pale yellow solid (819 µmol, 269 mg, 82%): R = 0.5 (hexane / ethyl acetate = 3:1) (UV);
f
-1
~
mp 81–82 °C; IR (NaCl, cm )  3316, 2978, 1718, 1510, 1454, 1392, 1367, 1245, 1160, 1030,
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8
21; H NMR (360 MHz, CDCl
.80-6.92 (m, 4 H), 7.26-7.33 (m, 5 H); C NMR (91 MHz, CDCl
114.5, 114.9, 127.4, 128.2, 128.5, 137.1, 143.6, 153.5. (Signal of hydrazine carboxylate
3
) δ 1.41 (s, 9 H), 3.75 (s, 3 H), 4.64 (bs, 2 H), 6.28 (bs, 1 H),
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
6
3
) δ 28.2, 55.6, 57.3, 80.7,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
+
+
missing); MS (ESI) m/z 329 [MH ]; HRMS (ESI) calcd for C19
H
24
N
2
O [M + Na ]: 351.1679,
3
found: 351.1675.
tert-Butyl 2-benzyl-2-(2,4-dichorohenyl)hydrazine carboxylate (3g) is prepared from tert-
butyl 2-(2,4-dichlorophenyl)azocarboxylate (1g) (1.00 mmol, 275 mg) and benzyl bromide (2a)
(
2.00 mmol, 238 µL) according to general procedure GP 1. The crude product is subjected to
column chromatography (silica gel, hexane / ethyl acetate = 8:1) to give the title compound 3g
as a white solid (819 µmol, 269 mg, 82%): R = 0.5 (hexane / ethyl acetate = 8:1) (UV); mp
18–119 °C; IR (NaCl, cm )  3312, 2979, 1717, 1699, 1476, 1456, 1392, 1367, 1250, 1159,
f
-1
~
1
1
7
72; H NMR (360 MHz, CDCl
J = 2.4 Hz, J = 8.6 Hz, 1 H), 7.27-7.42 (m, 7 H); C NMR (151 MHz, CDCl
0.7, 123.5, 127.0, 127.7, 128.5, 128.9, 129.0, 129.4, 130.1, 136.5, 145.2. (Signal of hydrazine
3
) δ 1.36 (s, 9 H), 4.62 (bs, 2 H), 6.53 (bs, 1 H), 7.17 (dd,
1
3
3
) δ 28.2, 56.9,
8
3
5
+
carboxylate missing); MS (ESI) m/z 367 [ Cl
2
-MH ]; HRMS (ESI) calcd for C18
H20Cl
2
N
2
O
2
+
+
[
M + Na ]: 389.0794, found: 389.0789.
tert-Butyl 2-benzyl-2-(4-fluoro-2-methylphenyl)hydrazine carboxylate (3h) is prepared
from tert-butyl 2-(4-fluoro-2-methylphenyl)azocarboxylate (1h) (1.00 mmol, 238 mg) and
benzyl bromide (2a) (2.00 mmol, 238 µL) according to general procedure GP 1. The crude
product is subjected to column chromatography (silica gel, hexane / ethyl acetate = 8:1) to give
the title compound 3h as a white solid (747 µmol, 247 mg, 75%): R = 0.3 (hexane / ethyl
f
-1
~
acetate = 9:1) (UV); mp 113–114 °C; IR (NaCl, cm )  2977, 1597, 1497, 1457, 1391, 1366,
1
1
245, 1155, 728, 698; H NMR (600 MHz, CDCl
3
) δ 1.34 (s, 9 H), 2.38 (s, 3 H), 4.41 (bs, 2 H),
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8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
.09 (bs, 1 H), 7.17 (dt, J = 3.0 Hz, J = 8.4 Hz, JHF = 8.4 Hz, 1 H), 6.87 (dd, J = 3.0 Hz,
13
J = 9.3 Hz, 1 H), 6.99-7.34 (m, 6 H); C NMR (91 MHz, CDCl
3
) δ 18.6 (d, JCF = 1.3 Hz), 28.2,
58.8, 80.3, 112.3 (d, JCF = 22.1 Hz), 117.3 (d, JCF = 21.9 Hz), 122.0 (d, JCF = 7.8 Hz), 127.5,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
128.4, 129.2, 135.0 (d, JCF = 7.9 Hz), 136.7, 144.5, 159.5 (d, JCF = 242.6 Hz). (Signal of
+
hydrazine carboxylate missing); MS (ESI) m/z 331 [MH ]; HRMS (ESI) calcd for C19
H23FN
2
O
2
+
+
[M + Na ]: 353.1636, found: 353.1629.
tert-Butyl 2-(4-bromophenyl)-2-(2-bromobenzyl)hydrazine carboxylate (3i) is prepared
from tert-butyl 2-(4-bromophenyl)azocarboxylate (1c) (500 µmol, 143 mg) and 2-bromobenzyl
bromide (2b) (1.00 mmol, 250 mg) according to general procedure GP 1. The crude product is
subjected to column chromatography (silica gel, hexane / ethyl acetate = 8:1) to give the title
compound 3i as a viscous yellow oil (312 µmol, 142 mg, 62%): R = 0.3 (hexane / ethyl
f
-1
~
acetate = 9:1) (UV); ; IR (NaCl, cm )  3303, 2979, 1708, 1590, 1441, 1392, 1368, 1344, 1250,
1
1
6
215, 1158, 1026, 999, 815, 750; H NMR (360 MHz, CDCl
3
) δ 1.43 (s, 9 H), 4.73 (bs, 2 H),
.45 (bs, 1 H), 6.71 (d, J = 9.2 Hz, 2 H), 7.16 (dt, J = 1.8 Hz, J = 7.5 Hz, J = 7.7 Hz, 1 H), 7.24-
1
3
7,41 (m, 4 H), 7.59 (dd, J = 1.2 Hz, J = 7.9 Hz, 1 H); C NMR (91 MHz, CDCl
3
) δ 28.3, 57.5,
8
1.5, 111.8, 114.5, 123.4, 127.7, 129.2, 129.8, 131.9, 133.0, 135.6, 148.0, 154.6; MS (ESI)
8
1
+
81
79
+
+
+
m/z 459 [ Br
2
-MH ], 457 [ Br Br-MH ]; HRMS (ESI) calcd for C18
H20Br
2
N
2
O
2
[M + Na ]:
478.9764, found: 478.9751.
tert-Butyl 2-(4-bromophenyl)-2-(2-iodobenzyl)hydrazine carboxylate (3j) is prepared from
tert-butyl 2-(4-bromophenyl)azocarboxylate (1c) (1.00 mmol, 285 mg) and 2-iodobenzyl
bromide (2c) (2.00 mmol, 540 mg) according to general procedure GP 1. The crude product is
subjected to column chromatography (silica gel, hexane / ethyl acetate = 10:1) to give the title
compound 3j as an orange oil (440 µmol, 221 mg, 44%): R = 0.3 (hexane / ethyl acetate = 9:1)
f
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3
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(
UV); H NMR (360 MHz, CDCl ) δ 1.45 (s, 9 H), 4.68 (bs, 2 H), 6.65 (bs, 1 H), 6.72 (d,
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
J = 8.9 Hz, 2 H), 6.99-7.02 (m, 1 H), 7.29-7.37 (m, 4 H), 7.88 (dd, J = 1.2 Hz, J = 7.9 Hz, 1 H).
Due to low stability of 3j the compound was immediately used for the synthesis of 15.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
tert-Butyl 2-allyl-2-(4-bromophenyl)hydrazine carboxylate (5a) is prepared from tert-butyl
2
-(4-bromophenyl)azocarboxylate (1c) (500 µmol, 140 mg) and allyl iodide (4b) (2.50 mmol,
225 µL) according to general procedure GP 2. The crude product is subjected to column
chromatography (silica gel, hexane / ethyl acetate = 8:1) to give the title compound 5a as a
white solid (356 µmol, 117 mg, 71%): R = 0.2 (hexane / ethyl acetate = 9:1) (UV); mp 105–
f
-1
~
1
06 °C; IR (NaCl, cm )  3295, 2979, 1673, 1644, 1593, 1488, 1393, 1365, 1304, 1288, 1254,
1
1152, 913, 821, 771; H NMR (360 MHz, CDCl
3
) δ 1.39 (s, 9 H), 4.07 (d, J = 5.9 Hz, 2 H),
13
5
.15-5.21 (m, 2 H), 5.82-5.93 (m, 1 H), 6.62 (d, J = 8.9 Hz, 2 H), 7.30 (d, J = 8.9 Hz, 2 H); C
NMR (151 MHz, CDCl ) δ 28.2, 52.4, 81.4, 112.5, 114.6, 118.1, 131.9, 132.7, 146.9, 155.7;
3
7
9
+
+
+
MS (ESI) m/z 327 [ Br-MH ]; HRMS (ESI) calcd for C14
H19BrN
2
O [M + Na ]: 349.0522,
2
found: 349.0516.
tert-Butyl 2-allyl-2-(4-iodophenyl)hydrazine carboxylate (5b) is prepared from tert-butyl 2-
(4-iodophenyl)azocarboxylate (1d) (500 µmol, 166 mg) and allyl iodide (4b) (2.50 mmol,
2
25 µL) according to general procedure GP 2. The crude product is subjected to column
chromatography (silica gel, hexane / ethyl acetate = 10:1) to give the title compound 5b as a
white solid (456 µmol, 171 mg, 91%): R = 0.3 (hexane / ethyl acetate = 9:1) (UV); mp 97–
f
-1
~
98 °C; IR (NaCl, cm )  3312, 2978, 1699, 1592, 1485, 1384, 1367, 1250, 1175, 1150, 998,
1
8
2
16, 771; H NMR (360 MHz, CDCl
3
) δ 1.39 (s, 9 H), 4.07 (d, J = 5.8 Hz, 2 H), 5.15-5.21 (m,
13
H), 5.82-5.93 (m, 1 H), 6.52 (d, J = 8.9 Hz, 2 H), 7.49 (d, J = 8.9 Hz, 2 H); C NMR
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2
2
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(
151 MHz, CDCl
3
) δ 28.2, 52.5, 81.4, 82.1, 115.1, 118.1, 132.7, 137.8, 147.8, 155.7; MS (ESI)
+
+
+
m/z 375 [MH ]; HRMS (ESI) calcd for C14
H19IN
2
O [M + Na ]: 397.0383, found: 397.0376.
2
Barbier-type procedure: A mixture of tert-butyl 2-(4-iodophenyl)azocarboxylate (1d)
151 µmol, 50.0 mg) and allyl iodide 4b (755 µmol, 70.0 µL) in tetrahydrofuran (3.0 mL) and
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
saturated aqueous ammonium chloride (0.5 mL) is treated with zinc (755 µmol, 50.0 mg) and
stirred vigorously for 30 seconds. Work up is as described above. The solvent is removed under
reduced pressure and the residue is subjected to column chromatography (silica gel,
hexane / ethyl acetate = 9:1) to give compound 5b as a white solid (139 µmol, 52.1 mg, 92%).
tert-Butyl 2-allyl-2-(4-cyanophenyl)hydrazine carboxylate (5c) is prepared from tert-butyl
2
2
-(4-iodophenyl)azocarboxylate (1e) (500 µmol, 166 mg) and allyl iodide (4b) (2.50 mmol,
25 µL) according to general procedure GP 2. The crude product is subjected to column
chromatography (silica gel, hexane / ethyl acetate = 10:1) to give the title compound 5c as a
white solid (456 µmol, 171 mg, 91%): R = 0.4 (hexane / ethyl acetate = 3:1) (UV); mp 106–
f
-1
~
1
9
5
07 °C; IR (NaCl, cm )  3310, 2979, 1701, 1596, 1515, 1392, 1368, 1275, 1250, 1170, 1151,
1
25, 831, 762; H NMR (360 MHz, CDCl
3
) δ 1.41 (s, 9 H), 4.09 (bs, 2 H), 5.19-5.24 (m, 2 H),
13
.85-5.92 (m, 1 H), 6.20 (bs, 1 H), 6.75 (d, J = 8.8 Hz, 2 H), 7.51 (d, J = 8.8 Hz, 2 H); C NMR
(151 MHz, CDCl ) δ 28.1, 52.7, 81.4, 81.8, 102.5, 112.4, 118.5, 119.6, 132.2, 133.6, 151.3,
3
+
+
+
1
55.4; MS (ESI) m/z 274 [MH ]; HRMS (ESI) calcd for C15
H
19
N
3
O [M + Na ]: 296.1369,
2
found: 296.1367.
tert-Butyl 2-allyl-2-(2,4-dichlorophenyl)hydrazine carboxylate (5d) is prepared from tert-
butyl 2-(2,4-dichlorophenyl)azocarboxylate (1g) (1.00 mmol, 275 mg) and allyl iodide (4b)
(
5.00 mmol, 450 µL) according to general procedure GP 2. The crude product is subjected to
column chromatography (silica gel, hexane / ethyl acetate = 8:1) to give the title compound 5d
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as a white solid (658 µmol, 209 mg, 66%): R = 0.5 (hexane / ethyl acetate = 9:1) (UV); mp 52–
f
-1
~
5
3 °C; IR (NaCl, cm )  3341, 2979, 1710, 1595, 1577, 1496, 1457, 1368, 1269, 1248, 1152,
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
1
103, 1049, 993, 928, 855, 812, 759; H NMR (360 MHz, CDCl
3
) δ 1.39 (s, 9 H), 4.10 (d,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
J = 5.3 Hz, 2 H), 5.20-5.26 (m, 2 H), 5.86-5.97 (m, 1 H), 6.35 (bs, 1 H), 6.75 (d, J = 8.7 Hz,
13
1
H), 7.13 (dd, J = 2.3 Hz, J = 8.7 Hz, 1 H), 7.27-7.29 (m, 1 H); C NMR (91 MHz, CDCl
3
)
δ 28.1, 52.7, 81.6, 114.0, 118.6, 119.1, 124.8, 127.7, 129.0, 132.5, 142.6, 155.4; MS (ESI)
+
+
+
m/z 317 [MH ]; HRMS (ESI) calcd for C14
H18Cl
2
N
2
O [M + Na ]: 339.0638, found:
2
3
39.06356.
tert-Butyl 2-(4-bromophenyl)-2-(but-3-en-2-yl)hydrazine carboxylate (8a) is prepared from
tert-butyl 2-(4-bromophenyl)azocarboxylate (1c) (500 µmol, 140 mg) and crotyl bromide (6a)
(
2.50 mmol, 260 µL) according to general procedure GP 2. The crude product is subjected to
column chromatography (silica gel, hexane / ethyl acetate = 8:1) to give the title compound 8a
as a white solid (429 µmol, 146 mg, 86%): R
f
= 0.3 (hexane / ethyl acetate = 9:1) (UV); mp
-1
~
1
100–101 °C; IR (NaCl, cm )  3316, 2978, 1701, 1596, 1490, 1368, 1318, 1253, 1164, 820; H
NMR (600 MHz, CDCl
3
) δ 1.28 (d, J = 6.8 Hz, 3 H), 1.37 (s, 9 H), 4.69-4.85 (m, 1 H), 5.10-
5
.19 (m, 2 H), 5.87 (ddd, J = 6.5 Hz, J = 10.4 Hz, J = 17.1 Hz, 1 H), 6.67 (d, J = 8.9 Hz, 2 H),
1
3
7.29 (d, J = 8.9 Hz, 2 H); C NMR (151 MHz, CDCl ) δ 17.3, 28.1, 56.1, 81.4, 112.1, 114.7,
3
81
+
79
+
1
15.8, 131.7, 138.0, 148.2, 155.8; MS (ESI) m/z 343 [ Br-MH ], 341 [ Br-MH ]; HRMS (ESI)
+
+
calcd for C15
H21BrN
2
O [M + Na ]: 363.0679, found: 363.0670.
2
tert-Butyl 2-(4-cyanophenyl)-2-(but-3-en-2-yl)hydrazine carboxylate (8b) and tert-butyl 2-
but-2-en-1-yl)-2-(4-cyanophenyl)hydrazine carboxylate (7b) are prepared from tert-butyl
-(4-cyanophenyl)azocarboxylate (1e) (500 µmol, 117 mg) and croytl bromide (6a)
(
2
(
2.50 mmol, 260 µL) according to general procedure GP 2. The crude product is subjected to
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column chromatography (silica gel, hexane / ethyl acetate = 6:1) to give compound 8b
(
360 µmol, 103 mg, 72%) and 7b (90.0 µmol, 25.9 mg, 18%) as white solids. Tert-butyl 2-(4-
cyanophenyl)-2-(but-3-en-2-yl)hydrazine carboxylate (8b): R
f
= 0.4 (hexane / ethyl
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
acetate = 9:1) (UV); H NMR (600 MHz, CDCl
3
) δ 1.29 (mc, 3 H), 1.39 (s, 9 H), 4.84 (bs, 1 H),
5
2
.08-5.33 (m, 2 H), 5.86 (ddd, J = 6.4 Hz, J = 10.4 Hz, J = 17.1 Hz, 1 H), 6.81 (d, J = 8.6 Hz,
1
3
H), 7.49 (d, J = 8.6 Hz, 2 H); C NMR (151 MHz, CDCl
3
) δ 17.8, 28.1, 55.4, 81.9, 112.4,
112.7, 116.1, 119.7, 133.5, 137.4, 152.8. (Signal of hydrazine carboxylate missing); MS (ESI)
8
1
+
79
+
+
+
m/z 343 [ Br-MH ], 341 [ Br-MH ]; HRMS (ESI) calcd for C16
H
21
N
3
O
2
[M + Na ]:
3
10.1526, found: 310.1522. Tert-butyl 2-(but-2-en-1-yl)-2-(4-cyanophenyl)hydrazine
1
carboxylate (7b): R
f
= 0.4 (hexane / ethyl acetate = 9:1) (UV); H NMR (600 MHz, CDCl )
3
δ 1.49 (s, 9 ), 1.74 (d, J = 6.4 Hz, 3 H), 3.83-4.32 (m, 2 H), 5.48-5.57 (m, 1 H), 5.78-6.10 (m,
81
+
79
+
1
H), 6.86 (mc, 2 H), 7.51 (mc, 2 H); MS (ESI) m/z 343 [ Br-MH ], 341 [ Br-MH ]; HRMS
+
+
(
ESI) calcd for C16
H
21
N
3
O [M + Na ]: 310.1526, found: 310.1522.
2
tert-Butyl 2-(4-methoxyphenyl)-2-(but-3-en-2-yl)hydrazine carboxylate (8c) and tert-butyl
-(but-2-en-1-yl)-2-(4-methoxyphenyl)hydrazine carboxylate (7c) are prepared from tert-
2
butyl 2-(4-methoxyphenyl)azocarboxylate (1f) (500 µmol, 118 mg) and croytl bromide (6a)
(2.50 mmol, 260 µL) according to general procedure GP 2. The crude product is subjected to
column chromatography (silica gel, hexane / ethyl acetate = 6:1) to give compound 8c
(
325 µmol, 95.9 mg, 65%) and 7c (165 µmol, 48.2 mg, 33%) as highly viscous oils. Tert-butyl
-(4-methoxyphenyl)-2-(but-3-en-2-yl)hydrazine carboxylate (8c): R = 0.5 (hexane / ethyl
2
f
-1
~
acetate = 6:1) (UV); IR (NaCl, cm )  3322, 2978, 1697, 1510, 1456, 1367, 1316, 1240, 1164,
1
1
107, 1038, 825; H NMR (360 MHz, CDCl
3
) δ 1.29 (d, J = 6.8 Hz, 3 H), 1.35 (s, 9 H), 3.74
(
(
s, 3 H), 4.76 (mc, 1 H), 5.07-5.11 (m, 1 H), 5.13-5-18 (m, 1 H), 5.86-5.95 (m, 1 H), 6.71-6.78
1
3
m, 4 H); C NMR (91 MHz, CDCl ) δ 17.5, 28.2, 55.6, 56.2, 81.0, 114.3, 114.4, 115.4, 138.5,
3
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+
+
+
1
43.5, 153.5, 156.3; MS (ESI) m/z 293 [MH ]; HRMS (ESI) calcd for C16
H
24
N
2
O [M + Na ]:
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
15.1679, found: 315.1683. Tert-butyl 2-(but-2-en-1-yl)-2-(4-methoxyphenyl)-hydrazine
-1
~
carboxylate (7c): R
f
= 0.4 (hexane / ethyl acetate = 6:1) (UV); IR (NaCl, cm )  3306, 2979,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
1717, 1510, 1456, 1367, 1244, 1161, 1040, 822; H NMR (360 MHz, CDCl
3
) δ 1.44 (s, 9 H),
1.68-1.72 (m, 3 H), 3.75 (s, 3 H), 3.89-4.14 (m, 2 H), 5.47-5.59 (m, 1 H), 5.65-5.77 (m, 1 H),
13
6
.20 (bs, NH), 6.79-6.89 (m, 4 H); C NMR (151 MHz, CDCl
3
) δ 17.8, 28.3, 55.5, 55.6, 80.6,
+
114.3, 114.4, 115.2, 125.2, 130.3, 143.5, 153.5; MS (ESI) m/z 293 [MH ]; HRMS (ESI) calcd
+
+
for C16
H
24
N
2
O [M + Na ]: 315.1679, found: 315.1678.
3
tert-Butyl 2-(4-bromophenyl)-2-(2-methylbut-3-en-2-yl)hydrazine carboxylate (8d) and
tert-butyl 2-(4-bromophenyl)-2-(3-methylbut-2-en-1-yl)hydrazine carboxylate (7d) are
prepared from tert-butyl 2-(4-bromophenyl)azocarboxylate (1c) (500 µmol, 142 mg) and 3,3-
dimethylallyl bromide (6b) (2.50 mmol, 288 µL) according to general procedure GP 2. The
crude product is subjected to column chromatography (silica gel, hexane / ethyl acetate = 9:1)
to give the title compounds 8d (160 µmol, 56.8 mg, 32%) and 7d (240 µmol, 85.3 mg, 48%) as
a pale yellow oils. Tert-butyl 2-(4-bromophenyl)-2-(2-methylbut-3-en-2-yl)hydrazine
-1
~
carboxylate (8d): R
f
= 0.3 (hexane / ethyl acetate = 9:1) (UV); IR (NaCl, cm )  3332, 2979,
1
1
699, 1596, 1489, 1456, 1368, 1339, 1289, 1255, 1164, 1073, 818, 772; H NMR (600 MHz,
CDCl ) δ 1.34 (s, 9 H), 1.44 (s, 3 H), 1.51 (s, 3 H), 5.01 (dd, J = 0.7 Hz, J = 10.8 Hz, 1 H), 5.06
3
(
dd, J = 0.7 Hz, J = 17.5 Hz, 1 H), 6.19 (dd, J = 10.8 Hz, J = 17.5 Hz, 1 H), 6.68 (d, J = 8.9 Hz,
1
3
2
H), 7.30 (d, J = 8.9 Hz, 2 H); C NMR (91 MHz, CDCl
3
) δ 26.7, 27.0, 28.2, 62.8, 81.5, 110.5,
8
1
+
111.9, 114.3, 131.8, 144.7, 148.8, 155.9; MS (ESI) m/z 358 [ Br-MH ]; HRMS (ESI) calcd for
+
+
C
16
H23BrN
2
O
2
[M + Na ]: 377.0835, found: 377.0827. Tert-butyl 2-(4-bromophenyl)-2-(3-
methylbut-2-en-1-yl)hydrazine carboxylate (7d): R = 0.3 (hexane / ethyl acetate = 9:1) (UV);
f
1H NMR (600 MHz, CDCl
) δ 1.47 (s, 9 H), 1.71 (s, 3 H), 1.75 (s, 3 H), 4.05 (bs, 2 H), 5.24
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2
2
2
2
2
2
2
3
3
3
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3
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3
3
3
3
4
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4
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5
5
5
5
5
5
6
13
(
mc, 1 H), 6.75 (d, J = 8.5 Hz, 2 H), 7.31 (d, J = 8.5 Hz, 2 H); C NMR (151 MHz, CDCl
3
)
δ 17.9, 25.8, 28.2, 62.8, 81.5, 110.4, 111.9, 114.3, 137.8, 144.7, 148.8, 155.9; MS (ESI) m/z 358
8
1
+
+
+
[ Br-MH ]; HRMS (ESI) calcd for C16
H23BrN
2
O [M + Na ]: 377.0835, found: 377.0827.
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
tert-Butyl 2-(4-cyanophenyl)-2-(2-methylbut-3-en-2-yl)hydrazine carboxylate (8e) and
tert-butyl 2-(4-cyanophenyl)-2-(3-methylbut-2-en-1-yl)hydrazine carboxylate (7e) are
prepared from tert-butyl 2-(4-cyanophenyl)azocarboxylate (1e) (500 µmol, 116 mg) and 3,3-
dimethylallyl bromide (6b) (2.50 mmol, 288 µL) according to general procedure GP 2. The
crude product is subjected to column chromatography (silica gel, hexane / ethyl acetate = 2:1)
to give an inseparable mixture of the title compounds 8e and 7e with a total yield of (435 µmol,
1
131 mg, 87%) as a pale yellow oil. The ratio of the two isomers is determined by H NMR.
Tert-butyl 2-(4-cyanophenyl)-2-(2-methylbut-3-en-2-yl)hydrazine carboxylate (8e): R = 0.2
f
1
(
hexane / ethyl acetate = 6:1) (UV); H NMR (600 MHz, CDCl
3
) δ 1.35 (s, 9 H), 1.44 (s, 3 H),
1.51 (s, 3 H), 5.03 (d, J = 10.8 Hz, 1 H), 5.08 (d, J = 17.4 Hz, 1 H), 6.16 (dd, J = 10.8 Hz,
J = 17.4 Hz, 1 H), 6.79 (d, J = 8.8 Hz, 2 H), 7.49 (d, J = 8.8 Hz, 2 H). Tert-butyl 2-(4-
cyanophenyl)-2-(3-methylbut-2-en-1-yl)hydrazine carboxylate (7e): R = 0.2 (hexane / ethyl
f
1
acetate = 6:1) (UV); H NMR (600 MHz, CDCl
3
) δ 1.48 (s, 9 H), 1.72 (s, 3 H), 1.77 (s, 3 H),
13
4
.13 (bs, 2 H), 5.22-5.26 (m, 1 H), 6.85 (d, J = 8.8 Hz, 2 H), 7.49 (d, J = 8.8 Hz, 2 H); C NMR
(
151 MHz, CDCl , mixture of 8e and 7e) δ 25.6, 25.7, 26.8, 28.0, 28.1, 63.0, 81.6, 81.9, 100.9,
3
1
02.3, 110.9, 112.3, 112.3, 112.3, 117.5, 119.6, 119.9, 133.4, 133.5, 133.5, 133.5, 144.0, 152.1,
+
1
53.1, 155.5, one signal missing due to overlap; MS (ESI) m/z 302.2 [MH ]; HRMS (ESI) calcd
+
+
for C17
H
23
N
3
O [M + Na ]: 324.1682, found: 324.1688.
2
tert-Butyl 2-(4-methoxyphenyl)-2-(2-methylbut-3-en-2-yl)hydrazine carboxylate (8f) and
tert-butyl 2-(4-methoxyphenyl)-2-(3-methylbut-2-en-1-yl)hydrazine carboxylate (7f) are
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prepared tert-butyl 2-(4-methoxyphenyl)azocarboxylate (1f) (500 µmol, 118 mg) and 3,3-
dimethylallyl bromide (6b) (2.50 mmol, 288 µL) according to general procedure GP 2. The
crude product is subjected to column chromatography (silica gel, hexane / ethyl acetate = 5:1)
to give the title compounds 8f (45.0 µmol, 13.8 mg, 9%) and 7f (285 µmol, 87.3 mg, 57%) as
a pale yellow oils. Tert-butyl 2-(4-methoxyphenyl)-2-(2-methylbut-3-en-2-yl)hydrazine
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
-1
~
carboxylate (8f): R
f
= 0.3 (hexane / ethyl acetate = 9:1) (UV); IR (NaCl, cm )  3332, 2977,
1
1699, 1510, 1456, 1367, 1332, 1240, 1163, 1078, 1036, 825; H NMR (600 MHz, CDCl
3
) δ 1.34
(
s, 9 H), 1.46 (s, 3 H), 1.52 (s, 3 H), 3.76 (3 H), 5.01 (dd, J = 0.8 Hz, J = 10.8 Hz, 1 H), 5.06
dd, J = 0.8 Hz, J = 17.5 Hz, 1 H), 6.19 (dd, J = 10.8 Hz, J = 17.5 Hz, 1 H), 6.74 (d, J = 9.1 Hz,
(
1
3
2
8
H), 6.80 (d, J = 9.1 Hz, 2 H); C NMR (151 MHz, CDCl
3
) δ 25.7, 27.1, 28.2, 55.7, 62.6,
+
1.1, 110.0, 113.9
,
114.5, 143.5, 145.2, 153.8, 156.2; MS (ESI) m/z 307 [MH ]; HRMS (ESI)
+
+
calcd for C17H
26
N
2
O [M + Na ]: 329.1836, found: 329.1840. Tert-butyl 2-(4-methoxyphenyl)-
3
2
-(3-methylbut-2-en-1-yl)hydrazine carboxylate (7f): R
f
= 0.3 (hexane / ethyl acetate = 9:1)
-1
~
1
(
UV); IR (NaCl, cm )  3311, 2977, 1717, 1510, 1456, 1367, 1245, 1161, 1036, 822; H NMR
(600 MHz, CDCl
3
) δ 1.45 (s, 9 H), 1.70 (s, 3 H), 1.74 (s, 3 H), 3.75 (3 H), 4.02 (bs, 2 H), 5.26
13
(
mc, 1 H), 6.21 (bs, NH), 6.80-6.90 (m, 4 H); C NMR (91 MHz, CDCl
3
) δ 18.0 (CH ), 25.9,
3
28.3, 50.9, 55.7, 80.5, 114.5, 115.3, 118.5, 137.3, 143.6, 153.5. (Signal of hydrazine carboxylate
+
+
+
missing); MS (ESI) m/z 307 [MH ]; HRMS (ESI) calcd for C17
H
26
N
2
O [M + Na ]: 329.1836,
3
found: 329.1834.
tert-Butyl 2-(4-bromophenyl)-2-(2-methylallyl)hydrazine carboxylate (7g) is prepared from
tert-butyl 2-(4-bromophenyl)azocarboxylate (1c) (500 µmol, 143 mg) and 3-bromo-2-
methylpropene (6c) (2.50 mmol, 252 µL) according to general procedure GP 2. The crude
product is subjected to column chromatography (silica gel, hexane / ethyl acetate = 5:1) to give
the title compound 7g as a pale brown solid (219 µmol, 74.9 mg, 44%): R = 0.4 (hexane / ethyl
f
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9
1
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2
2
2
2
2
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3
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5
5
5
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5
5
5
6
-
1
~
acetate = 9:1) (UV); mp 105–106 °C; IR (NaCl, cm )  3304, 2977, 1696, 1595, 1488, 1456,
1
1
435, 1392, 1367, 1289, 1253, 1164, 1132, 1073, 900, 856, 819, 767; H NMR (600 MHz,
CDCl
3
) δ 1.42 (s, 9 H), 1.76 (s, 3 H), 4.03 (bs, 2 H), 4.79 (mc, 1 H), 4.92 (mc, 1 H), 6.62 (d,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
J = 8.8 Hz, 2 H), 7.32 (d, J = 8.8 Hz, 2 H); C NMR (151 MHz, CDCl
3
) δ 20.3, 28.2, 55.2,
81
+
8
1.4, 112.5, 112.8, 114.6, 132.0, 140.6, 146.6, 155.9; MS (ESI) m/z 343 [ Br-MH ]; HRMS
+
+
(
ESI) calcd for C15
H21BrN
2
O [M + Na ]: 363.0679, found: 363.0675.
2
Description of experiments (Scheme 2)
Propargylation: tert-butyl 2-(4-bromophenyl)-2-(prop-2-yn-1-yl)hydrazine carboxylate
(10) is prepared from tert-butyl 2-(4-bromophenyl)azocarboxylate (1c) (500 µmol, 142 mg) and
propargyl bromide, 80% in toluene (2.50 mmol) 9 according to general procedure GP 2 for
allylation reactions. The crude product is subjected to column chromatography (silica gel,
hexane / ethyl acetate = 6:1) to give the title compound 10 (140 µmol, 45.7 mg, 28%) as a
-1
~
yellow oil: R
f
= 0.4 (hexane / ethyl acetate = 3:1) (UV); IR (NaCl, cm )  3300, 2979, 1701,
1
1
697, 1594, 1489, 1426, 1368, 1249, 1162, 1133, 1073, 851, 821, 635; H NMR (600 MHz,
CDCl ) δ 1.41 (s, 9 H), 2.27 (s 1 H), 4.28 (bs, 2 H), 6.00 (bs, NH), 6.69 (d, J = 8.9 Hz, 2 H),
3
1
3
7.31 (d, J = 8.9 Hz, 2 H); C NMR (151 MHz, CDCl ) δ 28.1, 72.2, 78.6, 82.3, 112.7, 114.8,
3
79
+
1
31.9, 146.6, 155.3. One signal missing; MS (ESI) m/z 325.2 [ Br-MH ]; HRMS (ESI) calcd
+
+
for C15
H23BrN
2
O [M + Na ]: 365.0835, found: 365.0836.
2
Propargylation (Barbier-type procedure): tert-butyl 2-(4-bromophenyl)-2-(prop-2-yn-1-
yl)hydrazine carboxylate (10). A mixture of tert-butyl 2-(4-bromophenyl)azocarboxylate (1c)
(
175 µmol, 50.0 mg) and propargyl bromide, 80% in toluene (1.75 mmol) 9 in tetrahydrofuran
(3.0 mL) and saturated aqueous ammonium chloride (0.5 mL) is treated with zinc (875 µmol,
5
7.2 mg) and stirred vigorously for 4 minutes. Work up is as described above. The solvent is
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8
9
removed under reduced pressure and the residue is subjected to column chromatography (silica
gel, hexane / ethyl acetate = 6:1) to give compound 10 as a pale yellow oil (107 µmol, 35.0 mg,
61%).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Competition experiment with pivaldehyde:
A
mixture of tert-butyl 2-(4-
bromophenyl)azocarboxylate (1c) (105 µmol, 30.0 mg) and pivaldehyde 11 (105 µmol,
11.0 µL) in tetrahydrofuran (2.0 mL) and saturated aqueous ammonium chloride (0.5 mL) is
treated with a suspension of benzyl bromide (2a) (263 µmol, 31.2 µL) and zinc (263 µmol,
1
7.0 mg) in tetrahydrofuran (0.5 mL). After stirring for one minute the reaction mixture is
diluted with water (5 mL) and extracted with dichloromethane (3 × 15 mL). The combined
organic phases are washed with a saturated aqueous solution of sodium chloride (5 mL) and
dried over sodium sulfate. The solvent is removed under reduced pressure and the residue is
subjected to column chromatography (silica gel, hexane / ethyl acetate = 9:1) to give 3c as a
pale yellow solid (83.2 µmol, 31.4 mg, 79%).
Competition experiment with diethyl azodicarboxylate: A mixture of tert-butyl 2-(4-
bromophenyl)azocarboxylate (1c) (175 µmol, 50.0 mg) and diethyl azodicarboxylate 12
(
175 µmol, 52 µL, 40% in toluene) in tetrahydrofuran (2.0 mL) and saturated aqueous
ammonium chloride (0.5 mL) is treated with a suspension of benzyl bromide (2a) (438 µmol,
2.0 µL) and zinc (438 µmol, 29.0 mg) in tetrahydrofuran (0.5 mL). After stirring for one
5
minute the reaction mixture is diluted with water (5 mL) and extracted with dichloromethane
(3 × 15 mL). The combined organic phases are washed with a saturated aqueous solution of
sodium chloride (5 mL) and dried over sodium sulfate. The solvent is removed under reduced
pressure. The yields of 3c (63.0 µmol, 36%) and 13 (174 µmol, 99%) were determined with an
internal standard 1,3,5-trimethoxybenzene. Diethyl 1-benzylhydrazine-1,2-dicarboxylate (13):
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7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
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5
5
5
5
5
5
5
5
5
5
6
1
R
f
= 0.3 (hexane / ethyl acetate = 9:1) (UV); H NMR (360 MHz, CDCl
3
) δ 1.27 (m, 6 H), 4.20
(
m, 4 H), 4.69 (bs, 2 H), 7.26-7.40 (m, 5 H). Analytical data is in agreement with those reported
in literature ref 36.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
9
-Benzyl-6-methoxy-2,3,4,9-tetrahydro-1H-carbazole (14). A solution of tert-butyl 2-
benzyl-2-(4-methoxyphenyl)hydrazine carboxylate (3f) (305 µmol, 100 mg) in methanol
1.8 mL) is treated with one droplet of concentrated sulfuric acid and stirred for 45 minutes at
0 °C. After complete consumption of 3f, as monitored by TLC, cyclohexanone (763 µmol,
80.0 µL) is added and the reaction is stirred for four hours. The mixture is diluted with water
4.0 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phases are washed
(
5
(
with a saturated aqueous solution of sodium chloride (10 mL) and dried over sodium sulfate.
The solvent is removed under reduced pressure and the residue is subjected to column
chromatography (silica gel, hexane / ethyl acetate = 12:1) to give the title compound 14 as a
white solid (253 µmol, 73.7 mg, 83%): R = 0.5 (hexane / ethyl acetate = 9:1) (UV); mp 87–
f
-1
~
8
1
1
6
8 °C; IR (NaCl, cm )  2933, 2834, 1622, 1585, 1481, 1453, 1426, 1356, 1309, 1291, 1260,
1
223, 1167, 1149, 1054, 1030, 883, 793, 752, 731, 695; H NMR (600 MHz, CDCl
3
) δ 1.84-
.92 (m, 4 H), 2.62 (t, J = 6.1 Hz, 2 H), 2.73 (t, J = 6.0 Hz, 2 H), 3.85 (s, 3 H), 5.21 (s, 2 H),
.75 (dd, J = 2.4 Hz, J = 8.8 Hz, 1 H), 6.97 (d, J = 2.4 Hz, 1 H), 6.98-6.99 (m, 2 H), 7.07 (d,
13
J = 8.8 Hz, 1 H), 7.19-7.27 (m, 4 H); C NMR (151 MHz, CDCl
3
) δ 21.2, 22.2, 23.2, 46.3,
5
6.0, 100.3, 109.5, 109.6, 110.3, 126.1, 127.1, 127.7, 128.6, 131.8, 136.3, 138.4, 153.8; MS
+
+
+
(ESI) m/z 292 [MH ], HRMS (ESI) calcd for C20H21NO [M + Na ]: 314.1515, found:
3
14.1516.
2
-(4-Bromophenyl)-2H-indazole (15). tert-Butyl 2-(2-iodobenzyl)-2-(4-bromophenyl)-
hydrazine carboxylate (3j) (100 µmol, 50.0 mg) is treated with trifluoroacetic acid (100 µmol,
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7.0 µL) in dioxane (2 mL) and stirred for 30 minutes at 60 °C in a pressure tube. Cesium
carbonate (300 µmol, 98.0 mg) and copper(I) iodide (10.0 µmol, 19.0 mg) are added and the
reaction is heated to 110 °C and stirred for 36 hours. The mixture is diluted with water (5 mL)
and extracted with ethyl acetate (3 × 20 mL). The combined organic phases are washed with a
saturated aqueous solution of sodium chloride (5 mL) and dried over sodium sulfate. The
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
solvent is removed under reduced pressure to obtain 15 as a yellow solid (89.7 µmol, 24.5 mg,
1
9
0%): R
f
= 0.5 (hexane / ethyl acetate = 9:1) (UV); H NMR (600 MHz, CDCl
3
) δ 7.13 (ddd,
J = 0.8 Hz, J = 6.6 Hz, J = 8.5 Hz, 1 H), 7.34 (ddd, J = 1.1 Hz, J = 6.6 Hz, J = 8.8 Hz, 1 H),
7
1
.66 (d, J = 8.9 Hz, 2 H), 7.71 (td, J = 1.1 Hz, J = 8.5 Hz, 1 H), 7.78 (qd, J = 1.0 Hz, J = 8.8 Hz,
1
H), 7.82 (d, J = 8.9 Hz, 2 H), 8.40 (d, J = 1.0 Hz, 1 H). H NMR spectrum is in agreement
with those reported in literature ref 37.
N-Benzyl-4-bromoaniline (16) is prepared from tert-butyl 2-(4-bromophenyl)azocarboxylate
(
1c) (500 µmol, 142 mg) and benzyl bromide (2a) (1.00 mmol, 170 µL) according to general
procedure GP 1. The reaction is stirred for two minutes followed by the addition of zinc
5.00 mmol, 325 mg) and trifluoroacetic acid (1.0 mL). The reaction is heated to reflux
(
overnight. After four hours additional zinc (5.00 mmol, 325 mg) is added. After cooling to room
temperature, the reaction is extracted with ethyl acetate (3 × 25 mL). The combined organic
phases are washed with a saturated aqueous solution of sodium chloride (10 mL) and dried over
sodium sulfate. The solvent is removed under reduced pressure and the residue is subjected to
column chromatography (silica gel, hexane / ethyl acetate = 7:1) to give the title compound 16
1
as a yellow oil (310 µmol, 81.3 mg, 62%): R
f
= 0.4 (hexane / ethyl acetate = 6:1) (UV); H
NMR (600 MHz, CDCl ) δ 4.31 (s, 2 H), 6.52 (d, J = 9.0 Hz, 2 H), 7.22 (d, J = 9.0 Hz, 2 H),
3
1
7.27-7.36 (m, 5 H). H NMR spectrum is in agreement with those reported in literature ref 38.
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Acknowledgments
The authors would like to thank the Deutsche Forschungsgemeinschaft (DFG) for financial
support of this project within the grants HE5413/3-3 and GRK1910/B3.
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Supporting Information
1
13
Copies of H and C-NMR spectra of all new compounds 3a-3j, 5a-5d, 7b-7g, 8a-8f and 14.
This material is available free of charge via the Internet at http://pubs.acs.org.
References and footnotes
(1)
For review articles, see: (a) Erdik, E.; Ay, M. Chem. Rev. 1989, 89, 1947. (b) Olson, D.
E. Mini-Reviews in Organic Chemistry 2011, 8, 341.
(
2)
For review articles, see: (a) Aubin, Y.; Fischmeister, C.; Thomas, C. M.; Renaud, J.-L.
Chem. Soc. Rev. 2010, 39, 4130. (b) Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev.
2
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Buchwald, S. L. Angew. Chem. Int. Ed. 2008, 47, 6338. (e) Bariwal, J.; Van der Eycken,
E. Chem. Soc. Rev. 2013, 42, 9283.
(
3)
For recent examples, see: (a) Fors, B. P.; Watson, D. A.; Biscoe, M. R.; Buchwald, S. L.
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Stradiotto, M. J. Org. Chem. 2012, 77, 1056. (c) Wong, S. M.; Choy, P. Y.; Yuen, O. Y.;
So, C. M.; Kwong, F. Y. Org. Synth. 2015, 92, 195. (d) Zhang, Y.; Lavigne, G.; César,
V. J. Org. Chem. 2015, 80, 7666. (e) Bhattacharya, P.; Senapati, K.; Chattopadhyay, K.;
Mandal, S. M.; Basak, A. RSC. Adv. 2015, 5, 61562. (f) Wang, Y.; Liang, H.; Chen, C.;
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(
4)
5)
(a) Shin, K.; Kim, H.; Chang, S. Acc. Chem. Res. 2015, 48, 1040. (b) Intrieri, D.; Zardi,
P.; Caselli, A.; Gallo, E. Chem. Comm. 2014, 50, 11440. (c) Mahy, J.-P.; Ciesielski, J.;
Dauban, P. Angew. Chem. Int. Ed. 2014, 53, 6862.
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5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
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4
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5
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5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
(a) Ahmad, N. M. in Name Reactions for Functional Group Transformations, Eds. Li,
J. J.; Corey, E. J. Wiley: New York 2007, 438. (b) Ragnarsson, U.; Grehn, L. Acc. Chem.
Res. 1991, 24, 285. (c) Gibson, M. S.; Bradshaw, R. W. Angew. Chem. Int. Ed.
1
968, 7, 919.
(6)
(7)
(a) Genêt, J. P.; Mallart, S.; Greck, C.; Piveteau, E. Tetrahedron Lett. 1991, 32, 2362.
(
b) McDonald, S. L.; Wang, Q. Synlett 2014, 25, 2233. (c) Greck, C.; Bischoff, L.;
Ferreira, F.; Genêt, J. P. J. Org. Chem. 1995, 60, 7010. (d) See also ref. 1a
(a) Liu, K.-M.; Zhang, F.; Duan, X.-F. Eur. J. Org. Chem. 2013, 6152. (b) Sapountzis,
I.; Knochel, P. J. Am. Chem. Soc. 2002, 124, 9390. (c) Barboni, L.; Bartoli, G.;
Marcantoni, E.; Petrini, M. J. Chem. Soc. Perkin Trans. 1 1990, 2133. (d) Bartoli, G.;
Marcantoni, E.; Petrini, M. J. Org. Chem. 1992, 57, 5835. (e) Bartoli, G.; Palmieri, G.
Tetrahedron Lett. 1989, 30, 2129. (f) Okazaki, R.; Inagaki, Y.; Inamoto, N. J. C. S. Chem.
Comm. 1974, 415. (g) Wieland, H. Ber. Dtsch. Chem. Ges. 1903, 36, 2315. (h) H.
Gilman, McCracken, R. J. Am. Chem. Soc. 1927, 49, 1052. (i) Koebrich, G.; Buck, P.
Chem. Ber. 1970, 103, 1412.
(8)
(9)
(a) Kopp, F.; Sapountzis, I.; Knochel, P. Synlett 2003, 6, 885. (b) Momoyama, N.;
Yamamoto, H. Angew. Chem. Int. Ed. 2002, 41, 2986. (c) Momoyama, N.; Yamamoto,
H. Org. Lett. 2002, 4, 3579.
(a) Kitamura, M.; Suga, T.; Chiba, S.; Narasaka, K. Org. Lett. 2004, 6, 4619. (b) Erdik,
E.; Daskapan, T. J. Chem. Soc., Perkin Trans. 1 1999, 3139. (c) Erdik, E.; Daskapan, T.
Synth. Comm. 1999, 29, 3989. (d) Erdik. E.; Ömür, O. Appl. Organomet. Chem. 2005,
1
9, 887.
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