Traceless Isoprenylation of Aldehydes via N-Boc-N-(1,1-dimethylallyl)hydrazones

Article abstract of DOI:10.1002/ejoc.202000382

A short isoprenylation protocol starting from non-conjugated N-Boc-N-(1,1-dimethylallyl)hydrazones was developed utilising Thomson's traceless bond construction. This type of [3,3]-sigmatropic rearrangement is catalysed by the Br?nsted acid triflimide and liberates only gaseous by-products. The required N-Boc-N-allylhydrazine precursor is available in three steps starting from a known diazene using biocatalytic aldol addition and Tebbe olefination as key steps. Allylhydrazones are prepared via condensation with appropriate aldehydes. Scope and limitations of the [3,3]-sigmatropic rearrangements are analysed.

Full text of DOI:10.1002/ejoc.202000382

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Traceless isoprenylation of aldehydes via N-Boc-N-(1,1-
dimethylallyl)hydrazones
Authors: Desirée Heerdegen, Julia Junker, Sebastian Dittrich, Peter
Mayer, and Franz Bracher
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000382
Link to VoR: https://doi.org/10.1002/ejoc.202000382
0
1/2020

European Journal of Organic Chemistry
10.1002/ejoc.202000382
FULL PAPER
Traceless isoprenylation of aldehydes via N-Boc-N-(1,1-
dimethylallyl)hydrazones
[a]
[a]
[a]
[b]
[a]
Desirée Heerdegen, Julia Junker, Sebastian Dittrich, Peter Mayer, and Franz Bracher*
[
a]
Desirée Heerdegen, Julia Junker, Dr. Sebastian Dittrich, Prof. Dr. Franz Bracher
Department of Pharmacy - Center for Drug Research
Ludwig-Maximilians University
Butenandtstr. 5-13, 81377 Munich, Germany
Franz.Bracher@cup.uni-muenchen.de
https://bracher.cup.uni-muenchen.de/
Dr. Peter Mayer
[
b]
Department of Chemistry
Ludwig-Maximilians University
Butenandtstr. 5-13, 81377 Munich, Germany
Supporting information for this article is given via a link at the end of the document.
Abstract:
A
short isoprenylation protocol starting from non-
isoprenyl function is a common structural element in terpenoid
biomolecules and natural secondary metabolites.[6] The natural
isoprene building block in terpenoid biosynthesis is dimethylallyl
conjugated N-Boc-N-(1,1-dimethylallyl)hydrazones was developed
utilising Thomson’s traceless bond construction. This type of [3,3]-
sigmatropic rearrangement is catalysed by the Brønsted acid triflimide
and liberates only gaseous by-products. The required N-Boc-N-
allylhydrazine precursor is available in three steps starting from a
known diazene using biocatalytic aldol addition and Tebbe olefination
as key steps. Allylhydrazones are prepared via condensation with
appropriate aldehydes. Scope and limitations of the [3,3]-sigmatropic
rearrangements are analysed.
[
7],[8]
pyrophosphate (DMAPP).
Steroids like cholesterol as a
[
9]
[10]
membrane component , pigments like β-carotene, or cortisone
or progesterone to name a few hormones,[11] are naturally
occurring terpenoid derivatives, derived from DMAPP.
Introduction
The [3,3]-sigmatropic rearrangement is a common but impressive
tool for the formation of new C-C-bonds in synthetic chemistry.[1]
In 1973 Stevens showed that N-allylhydrazones undergo such a
2
rearrangement under release of N as well, but due to very harsh
reaction conditions (300 °C) and low yields, this reaction was
limited in its applicability.[2] For several decades, synthetic
chemists did not see any real benefit of this unique rearrangement,
until 2010, when Thomson and co-workers published the
traceless bond construction (TBC), an improved variant of
Stevens’ [3,3]-sigmatropic rearrangement, working with N-Boc-N-
allylhydrazones (A, Scheme 1a) and catalytic amounts of the
[3]
2
Brønsted superacid triflimide (HNTf ). It was now possible to
lower the temperature of the rearrangement to 125 °C and the
yields of the products could be increased. This pioneering work of
Thomson allowed the synthesis of various 1,2-disubstituted
olefins (B) and one 1,1-disubstituted olefin (Scheme 1a). Mono-
substituted olefins could not be obtained by this way. Later our
group extended the scope to the synthesis of 1,1-disubstituted
olefins (D, Scheme 1b), bearing an isopropyl group in 1-position,
which resulted in a methylene branched end, a motif which is
found in the side chains of steroidal natural products, e.g.
episterol.[4] In the same year we reported the synthesis of terminal
vinylsilanes (F, Scheme 1c) using TBC, which opened a new
route to diversely substituted olefins.[5]
Scheme 1. a) Original TBC by Thomson and co-workers.[3] b) Extension of the
[
4]
TBC to the synthesis of 1,1-disubstituted olefins bearing an isopropyl group.
c) TBC yielding terminal vinylsilanes.[ d) Introduction of an isoprenyl group via
5]
TBC developed in this work.
In this work we present a protocol for the introduction of an
isopentenyl (isoprenyl) residue to aldehydes (Scheme 1d). The
At the biological level, protein prenyltransferases attach terpenoid
residues like farnesyl (C15) or geranylgeranyl (C20) groups to
1
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European Journal of Organic Chemistry
10.1002/ejoc.202000382
FULL PAPER
1
cysteinyl residues of proteins in posttranslational modifications.
Due to the introduction of this hydrophobic group, the proteins can
anchor in biomembranes resulting in altered biological
activities.[ In synthetic chemistry, organometallic building blocks
like 3-methyl-2-butenylmagnesium chloride are commonly used
for the introduction of an isoprenyl group.[13] Utilising inverse
reactivities, 3,3-dimethylallyl bromide can be applied as an
electrophilic isoprenyl building block,[14] as exemplified by the total
syntheses of natural products, e.g. (±)-eldanolide[15] and (±)-
fumagillin.[16] Besides direct isoprenylation, eliminations can lead
to the isoprenyl function by forming the thermodynamically most
stable double bond, e.g. from tertiary alcohols by dehydration.[17]
An intramolecular isoprenylation, in which the group is
constructed during a rearrangement, is to the best of our
knowledge, not described in literature yet.
ratio could be improved to 91:9 (determined retrospectively by H
NMR spectroscopy) of the desired aldehyde 6a and its
regioisomer 6b. Methylenation of the aldehyde function of 6a/6b
gave the olefins 7a and 7b. Different methods like Wittig,[27]
Nysted-Takai[28] and Tebbe[29] olefination were tested, whereby
the first two methods did not result in any product. Under Tebbe
conditions the desired terminal olefin 7a and its regioisomer 7b
were obtained in an acceptable yield of 48% as an inseparable
mixture.
12]
A further centrepiece of this work is the synthesis of the required,
hitherto unknown, N-Boc-N-(1,1-dimethylallyl)hydrazine building
block (G, Scheme 1d), bearing two geminal methyl groups in α-
position to the hydrazine moiety to receive the desired
isoprenylated products (I, Scheme 1d) via N-Boc-N-
allylhydrazones (H, Scheme 1d). In our previous investigations
leading to 1,1-disubstituted olefins,[4] undesired subsequent acid-
catalysed isomerisations of the formed olefinic double bond[18]
were observed, which led occasionally to isomeric mixtures of
product alkenes. In the present case this is not expected to
happen, since the resulting trisubstituted olefin should be the
thermodynamically most stable isomer. An additional benefit of
the two geminal methyl groups in precursor G is on the one hand
that product I cannot be formed as mixture of E/Z isomers and on
the other hand it is expected to facilitate the rearrangement due
to the Thorpe-Ingold effect (gem-dimethyl effect).[19] As a result,
less drastic reaction temperatures and shortened reaction times
may be employable.[20]
Scheme 2. Route A leading to an equimolar mixture of 8a/8b starting from silyl
enolether 3. Route B provides 8a, contaminated with 9% of isomer 6b starting
from aldehyde 4. *The ratios of the isomers were determined retrospectively by
NMR spectroscopy of the product 8a/8b. The X-ray crystal structure of the
desired isomer 8a is shown on the left. Diazene 2 was synthesised according to
literature.[
Results and Discussion
The
synthesis
of
the
required
N-Boc-N-(1,1-
dimethylallyl)hydrazine building block 8a (Scheme 2; G in
Scheme 1d) started with the two-step synthesis of known N-Troc-
N-Boc-protected diazene 2.[21] Conversion into aldehyde 6a was
performed on two different routes. Route A used commercially
available silyl enol ether 3, which was activated by LiOTf and
TBAF. The idea was to achieve a controlled O-Si-bond cleavage
in 3 by slow addition of the fluoride source. Simultaneously, the
presence of significant amounts of lithium ions should lead to an
immediate formation of the lithium enolate. However, the addition
of 3 to 2 did not proceed in a regioselective manner, and a 50:50
mixture of the isomeric aldehydes 6a and its regioisomer 6b was
obtained. It is noteworthy, that the regioselectivity of this reaction
could not be measured in this step, hence, it was determined
retrospectively after conversion into 8a/8b after the last step. Both
isomers showed identical chromatographic behaviour and no
distinct signals enabling quantification of the ratio of regioisomers
could be observed by NMR spectroscopy until reaching 8a/8b.
Because of the lack of regioselectivity, an alternative approach to
intermediate 6a utilising organocatalysis[22],[23] was worked out
21]
Chemoselective reductive Troc cleavage with zinc powder gave a
still inseparable mixture of the desired olefin 8a and its
constitutional isomer 8b in excellent yield. However, at this stage
NMR spectroscopy enabled determination of the ratio of isomers
(
route A 50:50, route B 91:9). The structure of the desired N-Boc-
N-allylhydrazine 8a was unambiguously confirmed by X-ray
crystal structure analysis (see Supporting Information). The
enriched isomeric mixture of building block 8a and 8b could be
used for the next step without further purification, since
exclusively 8a undergoes condensation with the employed
aldehydes to give the N-Boc-N-allylhydrazones 9, whereas the
isomer 8b remains unreacted. Scheme 3 shows the prepared
allylhydrazones 9a-q. Aliphatic (9a-d, 9f, 9g, 9p), allylic (9h, 9q)
and aromatic (9i-9o) and ester-bearing (9e) allylhydrazones were
synthesised by reacting the appropriate aldehydes with building
block mixture 8a/b in ethanol (yields 33-95%). Especially non-
conjugated allylhydrazones slowly decomposed during the
purification process, which is reflected in the yields. Before we
studied the capability of our N-Boc-N-allylhydrazine building block
(
route B). For this Aldol-type reaction with isobutyraldehyde (4),
three catalysts were explored: L-proline,[24] L-phenylalanine,[25]
and Ley’s (S)-5-(pyrrolidin-2-yl)-1H-tetrazole (5).[21],[26] Tetrazole
catalyst 5 gave the best result with 68% yield and the isomeric
8
a, we identified the optimum reaction conditions for the
2
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European Journal of Organic Chemistry
10.1002/ejoc.202000382
FULL PAPER
rearrangement utilising cyclohexanecarboxaldehyde-derived
hydrazone 9g as a model compound. Overall, 33 test reactions
were performed with variations of temperature (23 to 125 °C), time
sigmatropic rearrangement providing the appropriate olefins 10a-
c in 20-21% isolated yields. The poor yields are in part due to the
high volatility of the olefinic products, as demonstrated by an
increased yield (25%) of 10g on a larger scale (3 mmol). The
rearrangement product 10d of isobutyraldehyde-derived N-
allylhydrazone 9d could be detected by GC/MS, but could not be
isolated due to its very high volatility (b.p. 135-136 °C ). Ester
9e did not undergo rearrangement to the corresponding olefin and
only the Boc-deprotected allylhydrazone was found.
(
15 to 75 min) and solvents (THF and diglyme) (see Supporting
Information). Significant rearrangement was only accomplished at
temperatures of 75 °C and above. Besides HNTf (pK -12.0,
measured in DCE),[30] triflic acid (TfOH, pK
-11.3, measured in
DCE)[30] and trifluoroacetic acid (TFA, pK 0.23)[31] were tested.
All in all, the hitherto used conditions of Thomson[3] (HNTf
2
a
[32]
a
a
2
,
diglyme, 125 °C) gave the best results for this conversion, closely
followed by the rearrangement with triflic acid in diglyme at 125 °C,
which would be
2
a rewarding alternative to HNTf , which
decomposes immediately in air and requires extremely dry
reaction conditions. As the main side product, and even right at
the beginning of the reaction, the corresponding Boc-deprotected
allylhydrazone was observed, a compound which does not
undergo the rearrangement. This is in accordance with the
observations of Thomson and could not be prevented.[3] This
prompted us to further investigate an alternative carbamate
residue, which might be less prone to premature acidic cleavage.
We prepared the ethyl carbamate analogue S5a of 8a starting
from ethyl carbazate on a route analogous to route B shown in
Scheme 2 (for details, see Supporting Information). Two N-Boc-
N-allylhydrazones S6g and S6i derived thereof were subjected to
the previously determined best reaction conditions for
2
rearrangement (HNTf , diglyme, 125 °C), but though the starting
Scheme 4. Successful rearrangements of N-Boc-N-allyhydrazones using the
standard conditions of the TBC. The reactions were performed at least in a 0.5
mmol scale. Isolated yields are given.
materials were fully consumed, none of the expected
rearrangement products could be identified by GC/MS analysis.
Consequently, the Boc group cannot be replaced in this protocol
by the smaller ethoxycarbonyl group.
N-Allylhydrazones derived from cycloalkane carboxaldehydes (9f,
9
g) underwent rearrangement to olefins 10f and 10g with a yield
of 20% for both compounds (Scheme 4). In contrast,
allylhydrazone 9h derived from an a,b-unsaturated aldehyde did
not undergo rearrangement and again only Boc-deprotected
allylhydrazone was isolated. The attempted rearrangements of
variously substituted arylidene hydrazones failed as well (9i-m).
During the purification process of the attempted rearrangements
of 9i and 9j crystalline solids were obtained, which were identified
as the symmetric bis-hydrazones 12a/b (Scheme 5).
Scheme 5. Attempted rearrangements of allylhydrazones 9i and 9j leading to
deprotected allylhydrazons 11a/b and bis-hydrazones 12a/b.
Obviously, acid-mediated removal of both the Boc and the
dimethylallyl residue took place in these experiments. Next to
those, once again Boc-deprotected allylhydrazones 11a/b were
formed. Introduction of both electron-donating (methoxy
compound 9l) and electron-withdrawing groups (nitro compound
9m) did not lead to successful rearrangements, and the same
holds for hydrazones derived from heteroaromatic aldehydes
Scheme 3. N-Boc-N-allylhydrazones 9a-q prepared via condensation reaction
between N-Boc-N-allylhydrazine 8a and appropriate aldehydes. The yields refer
to the content of N-Boc-N-allylhydrazine 8a in the applied 8a/8b mixture.
(
thiophene 9n and pyridine 9o). After these experiments it
became evident which type of allylhydrazones would undergo the
attempted acid-catalysed rearrangement. Non-conjugated
allylhydrazones, like aliphatic systems 9a-d, 9f, and 9g form the
Scheme 4 shows the following rearrangement of substrates 9.
The allylhydrazones 9a-c derived from n-alkanals underwent
3
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European Journal of Organic Chemistry
10.1002/ejoc.202000382
FULL PAPER
corresponding olefins, in contrast to allylhydrazones conjugated
with aryl or ester groups, which do not show any rearrangement.
The following experiments supported this assumption: Non-
conjugated N-allylhydrazone 9p derived from phenylpropanal
showed a successful rearrangement with 19% yield, whereas its
cinnamaldehyde-derived congener (9q) did not give the desired
alkene 10q and only Boc-deprotected allylhydrazone was
obtained. Thomson also reported on problems during the
development of methods for hydrazone rearrangements, but with
instrument. For detection a Smiths Detection DuraSamp IR II Diamond
ATR sensor was used. The absorption bands are reported in wave
-
1
numbers (cm ). High resolution mass spectra (HRMS) were recorded on
a Jeol Mstation 700 (Fa. Jeol, Peabody, USA) or JMS GCmate II Jeol
instrument for electron impact ionisation (EI) equipped with a quadrupole
doublet based lens system. Thermo Finnigan LTQ FT (Fa. Thermo
Electron Corporation, Bremen, Germany) was used for electrospray
ionization (ESI) equipped with an ion trap. Melting points were measured
with a Büchi apparatus B-540 (Büchi, Flawill, Switzerland) and are
reported in °C and are not corrected. Gas chromatography (GC) was
performed on a Varian 3800 gas chromatograph coupled to a Saturn 2200
ion trap from Varian (Darmstadt, Germany). The autosampler was from
CTC Analytics (Zwingen, Switzerland) and the split/splitless injector was a
Varian 1177 (Darmstadt, Germany). Instrument control and data analysis
were carried out with Varian Workstation 6.9 SP1 software (Darmstadt,
Germany). A Varian VF-5-ms capillary column of 30 m length, 0.25 mm i.d.
and 0.25 µm film thickness (Darmstadt, Germany) was used at a constant
flow rate of 1.4 mL/min. Carrier gas was helium 99.999% from Air Liquide
(Düsseldorf, Germany). The inlet temperature was kept at 300 °C and
injection volume was 1 µL with splitless time 1.0 min. The initial column
temperature was 50 °C and was held for 1.0 min. Then the temperature
was ramped up to 250 °C with 50 °C/min. Then the products were eluted
at a rate of 5 °C/min until 310 °C (hold time 3 min). Total run time was 20
min. Transfer line temperature was 300 °C and the ion trap temperature
was 150 °C. The ion trap was operated with electron ionization (EI) at 70
eV in scan mode (m/z 50 - 650) with a solvent delay of 6.3 min.
systems,[3],[33]
aliphatic
which resulted in unidentified
decomposition products. However, the rearrangement of aryl
substituted allylhydrazones worked well in his setup. Boc-
deprotected allylhydrazones were observed in every reaction as
by-products by GC/MS analysis, but no rearrangement takes
place with these deprotected forms under our conditions. The
deprotection reaction outcompetes the rearrangement and is a
possible reason for the observed yields. This finding validates
computational studies towards the mechanism of the triflimide-
catalysed [3,3]-sigmatropic rearrangement by Gutierrez et al.
indicating that conversion of deprotected allylhydrazones does
not proceed well or not at all.[34]
Conclusion
Crystallography. All X-ray intensity data were measured on a Bruker D8
Venture TXS system equipped with
a multilayer mirror optics
In summary, we present
a unique method for traceless
monochromator and a Mo Kα rotating-anode X-ray tube (λ = 0.71073 Å).
The data collections were performed at 103 K. The frames were integrated
with the Bruker SAINT Software package[35]. Data were corrected for
absorption effects using the Multi-Scan method (SADABS)[36]
structures were solved and refined using the Bruker SHELXTL Software
Package[37]. All C-bound hydrogen atoms were calculated in positions
isoprenylation of aliphatic aldehydes via triflimide-catalysed [3,3]-
sigmatropic rearrangement of N-Boc-N-allylhydrazones. The
central N-Boc-N-allylhydrazine building block 8a is available in
four steps utilising organocatalysis and Tebbe methylenation.
This method opens a new route to isoprenyl compounds. This
novel protocol is compromised by poor yields in the final step and
its limitation to non-conjugated systems. Nevertheless, it
broadens the scope of Stevens-type traceless bond constructions
and represents the first example of a TBC for the introduction of
an isoprenyl group into readily available aliphatic aldehydes.
Therefore, this work extends the repertoire of methods for the total
synthesis of isoprenoid natural products.
. The
having ideal geometry riding on their parent atoms. The data have been
deposited with the Cambridge Crystallographic Data Centre (CCDC) and
can
be
obtained
free
of
charge
from:
https://www.ccdc.cam.ac.uk/structures/. The deposition number for
compound 8a is CCDC 1907495.
Synthesis of Compounds.
Diazene 2 was synthesised according to a literature protocol[21] in two
steps and a total yield of 81%.
Experimental Section
1
-(tert-Butyl)
yl)hydrazine-1,2-dicarboxylate (6a) and 2-(tert-Butyl) 1-(2,2,2-
trichloroethyl) 1-(2-methyl-1-oxopropan-2-yl)hydrazine-1,2-
dicarboxylate (6b). Route A: A suspension of LiOTf (875 mg, 5.61 mmol,
2-(2,2,2-trichloroethyl)
1-(2-methyl-1-oxopropan-2-
General information. All reactions were carried out in oven-dried Schlenk
flasks equipped with a septum and a magnetic stirring bar which were
evacuated and back filled with dry nitrogen. Solvents were dried according
to standard methods by distillation over drying agents. Thin layer
chromatography (TLC) was performed using polyester sheets polygram
1.52 eq) in dry CHCl
3
(20 mL) was cooled to - 50 °C. A solution of diazene
(10 mL), 2-methyl-1-
2
(1.70 g, 5.56 mmol, 1.5 eq) in CHCl
3
SIL G/UV254 covered with SiO
from Macherey-Nagel. Spots were visualized with
ammonium molybdate) solution followed by heating. Flash column
chromatography was performed using SiO 60 (0.040–0.063 mm, 230–
00 mesh ASTM) from Merck. For chromatography distilled solvents were
used. NMR spectra were recorded on JNM-Eclipse 400 (400 MHz), JNM-
Eclipse 500 (500 MHz), Avance III HD 400 MHz Bruker Biospin (400 MHz)
and Avance III HD 500 MHz Bruker Biospin (500 MHz) with CryoProbe™
Prodigy. Chemical shifts δ are reported as δ values in ppm relative to the
deuterated solvent peak. The chemical shifts are reported in parts per
million [ppm] and refer to the δ scala. Coupling constants J are indicated
in hertz [Hz]. For the characterization of the observed signal multiplicities
the following abbreviations were applied: s (singlet), d (doublet), dd
2
(layer thickness 0.2 mm, 40 x 80 mm)
(
(
trimethylsilyloxy)-1-propen (3) (533 mg, 3.70 mmol, 1.0 eq) in CHCl
10 mL) was added, followed by TBAF (1M in THF, 3.7 mL, 3.7 mmol, 1.0
3
a
CAM (ceric
eq). The resulting reaction mixture was allowed to warm to room
temperature and stirred for 16 h. The reaction was stopped with aq. sat.
NH
2
4
4
Cl solution (10 mL) and the layers were separated. The organic layer
4
solution (10 mL), dried over MgSO ,
was washed with aq. sat. NaHCO
3
filtered and the solvent was removed in vacuo. The title compound was
purified by flash column chromatography (hexanes/EtOAc 8:1). An
inseparable mixture of aldehydes 6a/6b (911 mg, 2.43 mmol, 66%) were
obtained as a colourless solid in an isomeric mixture of 50:50 (determined
1
retrospectively via H NMR). Route B: Diazene 2 (690 mg, 2.26 mmol, 1.0
eq) and (S)-5-(pyrrolidin-2-yl)-1H-tetrazole (5) (31.4 mg, 0.226 mmol, 10
mol %) were dissolved in dry methylene chloride (15 mL) and the solution
was cooled to 0 °C. Isobutyraldehyde (4) (0.25 mL, 2.71 mmol, 1.2 eq) was
added slowly and the reaction mixture was allowed to warm to room
temperature. After completion of the reaction, the solvent was removed in
(
(
4
doublet of doublet), dt (doublet of triplet), t (triplet), q (quartet), quint
quintet), m (multiplet), br (broad). Infrared spectra were recorded from
000-650 cm-1 on
a PERKIN ELMER Spectrum BX-59343 FT-IR
4
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European Journal of Organic Chemistry
10.1002/ejoc.202000382
FULL PAPER
vacuo and the product was purified by flash column chromatography
the solvent was removed in vacuo and the crude product was purified by
flash column chromatography. Isolated yields are correlated to the amount
of 8a in the isomeric mixture 8a/8b.
(hexanes/EtOAc 8:1). An inseparable mixture of aldehydes 6a/6b (580 mg,
1
.53 mmol, 68%) were obtained as a colourless solid in an isomeric
mixture of 91:9 (determined retrospectively via 1H NMR): R
= 0.17
f
1
(hexanes/EtOAc 8:1); m.p. 128 – 129 °C; H NMR (500 MHz, chloroform-
tert-Butyl
carboxylate (9a). Mixture of allylhydrazines 8a/8b (250 mg, 1.75 mmol ≙
.59 mmol of isomer 8a) and octanal (0.298 mL, 1.75 mmol) gave N-Boc-
1-(2-methylbut-3-en-2-yl)-2-octylidenehydrazine-1-
d) δ/ppm = 9.49 (s, 1H), 6.70 (s, 1H), 4.93 – 4.51 (m, 2H), 1.44 (s, 9H),
1
1
3
1
7
.36 (s, 3H), 1.29 (s, 3H); 13C NMR (101 MHz, chloroform-d δ/ppm = 198.1,
55.4, 154.3, 94.9, 84.3, 75.2, 67.4, 28.2, 20.5; IR (ATR) ṽ/cm-1 = 3255,
013, 2980, 2936, 1771, 1723, 1694, 1528, 1457, 1391, 1380, 1365, 1358,
287, 1254, 1220, 1161, 1108, 1054, 992, 945, 916, 882, 858, 834, 817,
1
N-allylhydrazone 9a (178 mg, 0.576 mmol, 36% referred to isomer 8a) as
1
colourless oil via GP1: R
f
= 0.58 (hexanes/EtOAc 9:1); H NMR (400 MHz,
chloroform-d) δ/ppm = 7.71 (t, JH,H = 5.6 Hz, 1H), 6.11 (dd, 3JH,H = 17.5,
0.8 Hz, 1H), 5.07 – 4.86 (m, 2H), 2.35 (td, 3JH,H = 5.6 Hz, 2H), 1.59 – 1.50
m, 2H), 1.42 (s, 9H), 1.39 (s, 6H), 1.34 – 1.24 (m, 8H), 0.87 (m, 3H); 13C
3
99, 763, 750, 724, 709, 658; HRMS (ESI): m/z calcd for C12
H
18Cl
3
N
O
2 5
1
(
-
[M-H] 375.0287, found: 375.0287.
NMR (101 MHz, chloroform-d) δ/ppm = 169.5, 154.3, 146.3, 109.4, 80.9,
61.7, 33.0, 31.9, 29.5, 29.2, 28.6, 26.7, 26.2, 22.8, 14.3; IR (ATR) ṽ/cm-1
= 3084, 3004, 2972, 2958, 2927, 2857, 1698, 1641, 1455, 1412, 1391,
1
-(tert-Butyl)
2-(2,2,2-trichloroethyl)
1-(2-methylbut-3-en-2-
yl)hydrazine-1,2-di-carboxylate (7a) and 2-(tert-Butyl) 1-(2,2,2-
trichloroethyl) 1-(2-methylbut-3-en-2-yl)hydrazine-1,2-dicarboxylate
1366, 1302, 1244, 1157, 1101, 1003, 991, 901, 855, 757, 724, 686; HRMS
+
(7b). The isomeric mixture of aldehydes 6a/6b (569 mg, 1.51 mmol, 1.0
(ESI): m/z calcd for C18
H
35
N
O
2 2
[M+H] 311.2693, found: 311.2694.
eq) and pyridine (0.22 mL, 2.7 mmol, 1.8 eq) were added to a flame dried
flask and the mixture was blended to a gel via ultrasound bath. The
suspension was cooled to -80 °C and Tebbe reagent (0.5M in toluene, 3.92
mL, 1.96 mmol, 1.3 eq) was added carefully by adding it along the flask.
The reaction mixture was allowed to warm to 0 °C and stirred 48 h. The
tert-Butyl
carboxylate (9b). Mixture of allylhydrazines 8a/8b (404 mg, 2.02 mmol ≙
.83 mmol of isomer 8a) and nonanal (0.346 mL, 2.02 mmol) gave N-Boc-
1-(2-methylbut-3-en-2-yl)-2-nonylidenehydrazine-1-
1
N-allylhydrazone 9b (284 mg, 0.877 mmol, 48% referred to isomer 8a) as
reaction was quenched with a saturated aqueous NaHCO
at -80 °C and extracted with methylene chloride (3 x 10 mL). The combined
organic layers were dried over MgSO , filtered and the solvent was
removed in vacuo. Purification by flash column chromatography
hexanes/EtOAc 9:1) gave an inseparable mixture of olefines 7a/7b (270
3
solution (6 mL)
1
colourless oil via GP1: R
f
= 0.58 (hexanes/EtOAc 9:1); H NMR (500 MHz,
chloroform-d) δ/ppm = 7.71 (t, JH,H = 5.6 Hz, 1H), 6.11 (dd, 3JH,H = 17.5,
0.8 Hz, 1H), 5.05 – 4.89 (m, 2H), 2.34 (td, 3JH,H = 5.6 Hz, 2H), 1.55 (m,
H), 1.42 (s, 9H), 1.39 (s, 6H), 1.36 – 1.21 (m, 10H), 0.89 – 0.85 (m, 3H);
C NMR (101 MHz, chloroform-d) δ/ppm = 169.4, 154.3, 146.3, 109.4,
0.9, 61.7, 33.0, 31.9, 29.5, 29.4, 29.3, 28.5, 26.7, 26.2, 22.8, 14.2; IR
ATR) ṽ/cm-1 = 3086, 2972, 2956, 2926, 2856, 1698, 1640, 1455, 1412,
3
4
1
2
(
13
mg, 0.719 mmol, 48%) as a colourless solid in an isomeric mixture of 91:9
8
(
1
(
determined retrospectively via H NMR): R
f
= 0.29 (hexanes/EtOAc 9:1);
1
m.p. 103 – 104 °C; H NMR (500 MHz, chloroform-d) δ/ppm = 6.68 (s, 1H),
1
390, 1366, 1302, 1244, 1157, 1100, 1003, 992, 900, 874, 857, 783, 756,
6
3
.10 (dd, 3JH,H = 17.4, 11.0 Hz, 1H), 5.08 (d, 3JH,H = 17.1 Hz, 1H), 5.00 (d,
+
723, 687, 599; HRMS (ESI): m/z calcd for C19
H
37
N
O
2 2
[M+H] 325.2849,
2
J
H,H = 10.9 Hz, 1H), 4.87 (d, 2JH,H = 11.5 Hz, 1H), 4.68 (d, JH,H = 11.8 Hz,
found: 325.2849.
1
H), 1.50 (s, 3H), 1.44 (s, 9H), 1.42 (s, 3H); 13C NMR (126 MHz,
chloroform-d) δ/ppm = 155.4, 154.5, 144.6, 111.2, 95.2, 82.1, 75.1, 62.9,
tert-Butyl
2-decylidene-1-(2-methylbut-3-en-2-yl)hydrazine-1-
2
1
1
8.4, 26.6, 26.4; IR (ATR) ṽ/cm-1 = 3323, 2924, 2854, 1733, 1706, 1644,
carboxylate (9c). Mixture of allylhydrazines 8a/8b (115 mg, 0.574 mmol
0.522 mmol of isomer 8a) and decanal (0.108 mL, 0.574 mmol) gave N-
522, 1456, 1414, 1386, 1359, 1274, 1253, 1233, 1156, 1101, 1078, 1044,
≙
011, 990, 967, 922, 907, 851, 815, 759, 741, 724, 688; HRMS (ESI): m/z
Boc-N-allylhydrazone 9c (56 mg, 0.17 mmol, 33% referred to isomer 8a)
as colourless oil via GP1: R
MHz, chloroform-d) δ/ppm = 7.71 (t, JH,H = 5.6 Hz, 1H), 6.11 (dd, JH,H
-
calcd for C13
H
20 4
O N
2
Cl
3
[M-H] 373.0494, found: 373.0499.
1
f
= 0.56 (hexanes/EtOAc 9:1). H NMR (500
3
3
=
tert-Butyl 1-(2-methylbut-3-en-2-yl)hydrazine-1-carboxylate (8a) and
tert-Butyl 2-(2-methylbut-3-en-2-yl)hydrazine-1-carboxylate (8b). The
mixture of olefins 7a/7b (95.6 mg, 0.254 mmol, 1.0 eq) was dissolved in a
mixture of ethanol (0.3 mL), water (0.3 mL) and acetic acid (0.3 mL). Zinc
powder (582 mg, 8.91 mmol, 35.0 eq) was added and the reaction mixture
was stirred for 10 minutes at room temperature. After filtration of the
reaction mixture, the filtrate was extracted with methylene chloride (3 x 3
mL) and the residue was extracted. The combined organic layers were
7.5, 10.8 Hz, 1H), 5.01 (dd, 3JH,H = 17.5, 2JH,H = 0.7 Hz, 1H), 4.92 (dd, J
1
3
H,H = 10.8, 2JH,H = 0.7 Hz, 1H), 2.35 (td, 3JH,H = 5.6 Hz, 2H), 1.57 – 1.54
m, 2H), 1.42 (s, 9H), 1.39 (s, 6H), 1.26 (m, 12H), 0.89 – 0.86 (m, 3H). 13C
NMR (126 MHz, chloroform-d) δ/ppm = 169.5, 154.3, 146.3, 109.4, 80.9,
1.7, 33.0, 32.0, 29.6, 29.5, 29.5, 29.4, 28.6, 26.7, 26.2, 22.8, 14.3. IR
ATR) ṽ/cm-1 = 2924, 2853, 1696, 1458, 1407, 1368, 1310, 1245, 1158,
J
(
6
(
1
101, 990, 903, 852, 754, 719, 665. HRMS (ESI): m/z calcd for C20
H
39
N
O
2 2
+
[M+H] 339.3006; found: 339.3011.
washed was saturated aqueous NaHCO
3
solution (5 mL) and the organic
layer was dried over MgSO , filtered and the solvent was removed in vacuo.
The product was used without purification. 8a/8b (57 mg, 0.28 mmol,
4
tert-Butyl
methylpropylidene)hydrazine-1-carboxylate (9d). Mixture of olefins
a/8b (519 mg, 2.59 mmol 2.36 mmol of isomer 8a) and
isobutyraldehyde (0.237 mL, 2.59 mmol) gave N-Boc-N-allylhydrazone 9d
1-(2-methylbut-3-en-2-yl)-2-(2-
quantitative) was obtained as a colourless oil in an isomeric mixture of
8
≙
1
91:9: R
f
= 0.15 (hexanes/EtOAc 8:2); H NMR (8a) (400 MHz, DMSO-d
6
)
3
3
δ/ppm = 6.00 (dd, JH,H = 17.5, 10.7 Hz, 1H), 4.87 (dd, JH,H = 17.5, 10.8,
H), 4.24 (s, 2H), 1.38 (s, 9H), 1.33 (s, 6H); 13C NMR (8a) (126 MHz,
DMSO-d
) δ/ppm = 156.4, 146.2, 108.8, 79.3, 60.6, 28.1, 26.5; 1H NMR
8b) (500 MHz, DMSO-d H,H = 17.6,
) δ/ppm = 7.95 (s, 1H), 5.81 (dd, 3
0.8 Hz, 1H), 5.08 – 4.92 (m, 2H), 4.07 (s, 1H), 1.38 (s, 9H), 1.03 (s, 6H);
) δ/ppm = 155.6, 145.0, 112.2, 78.1,
7.8, 28.2, 24.8; IR (ATR) ṽ/cm-1 = 3334, 2977, 2932, 1679, 1477, 1455,
(
R
262 mg, 1.03 mmol, 44% referred to isomer 8a) as colourless oil via GP1:
2
1
f
= 0.55 (hexanes/EtOAc 9:1); H NMR (400 MHz, chloroform-d) δ/ppm =
6
.61 (d, 3 H,H = 5.9 Hz, 1H), 6.11 (dd, 3
J JH,H = 17.6, 10.8 Hz, 1H), 5.03 –
7
4
1
1
3
1
(
6
J
.90 (m, 2H), 2.66 – 2.56 (m, 1H), 1.42 (s, 9H), 1.39 (s, 6H), 1.13 (s, 3H),
.12 (s, 3H). 13C NMR (101 MHz, chloroform-d) δ/ppm = 173.2, 154.1,
46.3, 109.4, 80.9, 61.9, 32.2, 28.6, 26.6, 19.6. IR (ATR) ṽ/cm-1 = 3086,
1
1
3C NMR (8b) (126 MHz, DMSO-d
6
5
1
008, 2973, 2930, 2872, 1698, 1641, 1456, 1412, 1390, 1366, 1304, 1289,
412, 1365, 1249, 1163, 1101, 1005, 994, 948, 907, 868, 766, 724, 687;
244, 1156, 1092, 1058, 992, 970, 902, 879, 856, 756, 686, 599, 588.
+
HRMS (ESI): m/z calcd for C10
H
21
N
O
2 2
[M+H] 201.1597, found: 201.1597.
+
HRMS (ESI): m/z calcd for C14
H
27
N
O
2 2
[M+H] 255.2067; found: 255.2066.
General procedure
dimethylallyl)hydrazones 9a–q:
1
(GP1) for the synthesis of N-Boc-N-(1,1-
tert-Butyl
2-(2-ethoxy-2-oxoethylidene)-1-(2-methylbut-3-en-2-
yl)hydrazine-1-carboxylate (9e). Mixture of olefins 8a/8b (200 mg, 0.990
mmol, ≙ 0.901 mmol of isomer 8a) and ethyl glyoxalate solution (~ 50% in
toluene, 0.198 mL, 0.990 mmol) gave N-Boc-N-allylhydrazone 9e (108 mg,
The mixture of N-(1,1-dimethylallyl)hydrazines 8a/8b (1.0 eq) was
dissolved in absolute EtOH and the appropriate aldehyde (1.0 eq) was
added. The reaction mixture was stirred at room temperature for 15 h, then
0.380 mmol, 42% referred to isomer 8a) as colourless oil via GP1: R
f
=
1
0.44 (hexanes/EtOAc 9:1); H NMR (400 MHz, chloroform-d) δ/ppm = 8.41
5
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.202000382
FULL PAPER
(
s, 1H), 6.05 (dd, 3JH,H = 17.5, 10.8 Hz, 1H), 5.07 – 4.93 (m, 2H), 4.26 (q,
J
referred to isomer 8a) as colourless oil via GP1: R
f
= 0.64 (hexanes/EtOAc
3
H,H = 7.1 Hz, 2H), 1.52 (s, 6H), 1.48 (s, 9H), 1.31 (t, 3JH,H = 7.1 Hz, 3H);
1
3
9:1); H NMR (500 MHz, chloroform-d) δ/ppm = 8.68 (s, 1H), 7.56 (d, JH,H
= 8.4 Hz, 2H), 7.50 (d, 3JH,H = 8.3 Hz, 2H), 6.14 (dd, 3JH,H = 17.5, 10.8 Hz,
1H), 5.07 – 4.92 (m, 2H), 1.51 (s, 6H), 1.47 (s, 9H); 13C NMR (126 MHz,
chloroform-d) δ/ppm = 153.9, 153.5, 146.3, 134.7, 131.9, 128.9, 124.1,
109.6, 82.1, 63.9, 28.5, 27.3; IR (ATR) ṽ/cm-1 = 3086, 2979, 2932, 1696,
1643, 1591, 1564, 1487, 1455, 1412, 1392,1367, 1289, 1244, 1148, 1115,
1
3
C NMR (101 MHz, chloroform-d) δ/ppm = 164.9, 151.9, 145.5, 135.7,
10.6, 83.6, 65.9, 60.9, 28.3, 27.7, 14.4; IR (ATR) ṽ/cm-1 = 1742, 1708,
585, 1477, 1456, 1369, 1339, 1288, 1242, 1206, 1181, 1148 , 1113, 1093,
1
1
1
044, 911, 848, 798, 759, 744, 576; HRMS (EI): m/z calcd for C
9
H
16
N
O
2 2
+
[M-Boc]˙ 184.1206, found: 184.1205.
1
6
3
098, 1069, 1044, 1009, 992, 953, 929, 901, 856, 819, 786, 752, 708, 691,
2 2
67; HRMS (ESI): m/z calcd for C17H24BrN O
[M+H]+ 367.1015; found:
tert-Butyl
2-(cyclopentylmethylene)-1-(2-methylbut-3-en-2-
67.1026.
yl)hydrazine-1-carboxylate (9f) Mixture of olefins 8a/8b. (430 mg, 2.15
mmol ≙ 1.96 mmol of isomer 8a) and cyclopentane carboxaldehyde
(
0.229 mL, 2.15 mmol) gave N-Boc-N-allylhydrazone 9f (245 mg, 0.874
tert-Butyl 2-(4-(dimethylamino)benzylidene)-1-(2-methylbut-3-en-2-
yl)hydrazine-1-carboxylate (9k). Mixture of olefins 8a/8b (100 mg, 0.499
mmol ≙ 0.454 mmol of isomer 8a) and 4-dimethylaminobenzaldehyde
(74.5 mg, 0.499 mmol) gave N-Boc-N-allylhydrazone 9k (143 mg, 0.431
mmol, 45% referred to isomer 8a) as colourless oil via GP1: R
(
3
f
= 0.57
1
hexanes/EtOAc 9:1); H NMR (400 MHz, chloroform-d) δ/ppm = 7.62 (d,
H,H = 6.8 Hz, 1H), 6.11 (dd, 3
JH,H = 17.5, 10.8 Hz, 1H), 5.08 – 4.82 (m,
J
2
9
1
1
H), 2.87 – 2.71 (m, 1H), 1.95 – 1.79 (m, 2H), 1.73 – 1.54 (m, 6H), 1.42 (s,
H), 1.38 (s, 6H); 13C NMR (101 MHz, chloroform-d) δ/ppm = 172.6, 154.2,
46.2, 109.4, 80.8, 61.8, 42.9, 30.3, 28.6, 28.5, 26.6, 25.7; IR (ATR) ṽ/cm-
f
mmol, 95% referred to isomer 8a) as white crystalline solid via GP1: R =
0.35 (hexanes/EtOAc 9:1); m.p. = 73 – 75 °C; 1H NMR (400 MHz,
chloroform-d) δ/ppm = 8.30 (s, 1H), 7.61 (d, 3JH,H = 8.9 Hz, 2H), 6.69 (d,
3JH,H = 8.9 Hz, 2H), 6.19 (dd, 3
JH,H = 17.5, 10.8 Hz, 1H), 5.08 – 4.90 (m,
2H), 3.01 (s, 6H), 1.47 (s, 6H), 1.44 (s, 9H); 13C NMR (101 MHz,
chloroform-d) δ/ppm = 162.4, 154.2, 152.2, 146.6, 129.4, 122.4, 111.8,
=
3084, 2968, 2956, 2869, 1697, 1639, 1476, 1454, 1412, 1390, 1366,
1304, 1244, 1156, 1101, 1061, 1003, 992, 900, 877, 856, 783, 757, 687;
+
HRMS (ESI): m/z calcd for C16
H
29
N
O
2 2
[M+H] 281.2224; found: 281.2225.
1
1
8
3
09.2, 80.9, 62.6, 40.4, 28.6, 26.9; IR (ATR) ṽ/cm-1 = 2976, 2930, 1693,
616, 1601, 1528, 1477, 1455, 1363, 1300, 1237, 1155, 1100, 1060, 894,
[M+H]+
30 3 2
59, 816, 755, 731; HRMS (ESI): m/z calcd for C19H N O
tert-Butyl
2-(cyclohexylmethylene)-1-(2-methylbut-3-en-2-
yl)hydrazine-1-carboxylate (9g). Mixture of olefins 8a/8b (91.6 mg, 0.686
mmol ≙ 0.624 mmol of isomer 8a) and cyclohexanecarboxaldehyde
32.2333, found: 332.2333.
(55.4 µL, 0.686 mmol) gave N-Boc-N-allylhydrazone 9f (63.3 mg, 0.215
mmol, 34% referred to isomer 8a) as colourless oil via GP1: R
f
= 0.64
tert-Butyl
2-(4-methoxybenzylidene)-1-(2-methylbut-3-en-2-
1
(
3
hexanes/EtOAc 9:1); H NMR (500 MHz, chloroform-d) δ/ppm = 7.58 (d,
J
yl)hydrazine-1-carboxylate (9l). Mixture of olefins 8a/8b (150 mg, 0.749
mmol ≙ 0.682 mmol of isomer 8a) and 4-anisaldehyde (102 mg, 91.1 µL,
0.749 mmol) gave N-Boc-N-allylhydrazone 9l (151 mg, 0.475 mmol, 70%
H,H = 6.0 Hz, 1H), 6.11 (dd, 3JH,H = 17.5, 10.8 Hz, 1H), 5.01 (dd, 3JH,H
=
1
2
1
7.5, 2JH,H = 0.9 Hz, 1H), 4.92 (dd, 3JH,H = 10.8, 2JH,H = 0.9 Hz, 1H), 2.42 –
.25 (m, 1H), 1.89 – 1.80 (m, 2H), 1.80 – 1.73 (m, 2H), 1.70 – 1.64 (m, 1H),
.41 (s, 9H), 1.39 (s, 6H), 1.35 – 1.28 (m, 4H), 1.27 – 1.18 (m, 1H). 13C
referred to isomer 8a) as colourless oil via GP1: R
f
= 0.42 (hexanes/EtOAc
1
3
9:1); H NMR (400 MHz, chloroform-d) δ/ppm = 8.48 (s, 1H), 7.66 (d, JH,H
= 8.8 Hz, 2H), 6.91 (d, 3JH,H = 8.9 Hz, 2H), 6.17 (dd, 3JH,H = 17.5, 10.8 Hz,
1H), 5.08 – 4.92 (m, 2H), 3.84 (s, 3H), 1.49 (s, 6H), 1.45 (s, 9H); 13C NMR
(101 MHz, chloroform-d) δ/ppm = 161.5, 159.0, 153.9, 146.5, 129.3, 127.8,
114.1, 109.3, 81.4, 63.1, 55.5, 28.6, 27.0; IR (ATR) ṽ/cm-1 = 2975, 2932,
NMR (101MHz, chloroform-d) δ/ppm = 172.6, 154.3, 146.3, 109.4, 80.8,
6
1
1.8, 41.5, 29.9, 28.6, 26.7, 26.1, 25.5; IR (ATR) ṽ/cm-1 = 2929, 2854, 1709,
366, 1308, 1244, 1160; HRMS (ESI): m/z calcd for C17
H
31
N
2 2
O : 295.2380
+
[M+H] , found: 295.2385.
1
8
3
693, 1606, 1512, 1456, 1366, 1293, 1245, 1150, 1104, 1031, 900, 859,
+
31, 75; HRMS (ESI): m/z calcd for C18
H
27
N
O
2 3
[M+H] 319.2016; found:
tert-Butyl
2-(cyclohex-1-en-1-ylmethylene)-1-(2-methylbut-3-en-2-
19.2015.
yl)hydrazine-1-carboxylate (9h). Mixture of olefins 8a/8b (200 mg, 0.999
mmol ≙ 0.909 mmol of isomer 8a) and 1-cyclohexene-1-carboxaldehyde
(
0
0
0.114 mL, 0.990 mmol) gave N-Boc-N-allylhydrazone 9h (135 mg,
tert-Butyl 1-(2-methylbut-3-en-2-yl)-2-(4-nitrobenzylidene)hydrazine-
1-carboxylate (9m). Mixture of olefins 8a/8b (250 mg, 1.25 mmol ≙ 1.14
mmol of isomer 8a) and 4-nitrobenzaldehyde (0.126 mL, 1.25 mmol) gave
N-Boc-N-allylhydrazone 9m (233 mg, 0.698 mmol, 61% referred to isomer
.460 mmol, 51% referred to isomer 8a) as colourless oil via GP1: R
.52 (hexanes/EtOAc 9:1); H NMR (400 MHz, chloroform-d) δ/ppm = 7.99
f
=
1
(s, 1H), 6.18 – 6.05 (m, 2H), 5.05 – 4.85 (m, 2H), 2.37 – 2.12 (m, 4H), 1.70
–
1.61 (m, 4H), 1.43 (s, 9H), 1.41 (s, 6H); 13C NMR (101 MHz, chloroform-
8a) as yellow solid via GP1: R
f
= 0.51 (hexanes/EtOAc 9:1); m.p. = 67 –
1
d) δ/ppm = 163.9, 153.9, 146.6, 138.2, 136.3, 109.1, 81.2, 62.7, 28.6, 26.9,
2
1
69 °C; H NMR (400 MHz, chloroform-d) δ/ppm = 9.02 (s, 1H), 8.24 – 8.19
(m, 2H), 7.82 – 7.75 (m, 2H), 6.12 (dd, J = 17.5, 10.8 Hz, 1H), 5.10 – 4.93
(m, 2H), 1.56 (s, 6H), 1.50 (s, 9H); 13C NMR (101 MHz, chloroform-d)
δ/ppm = 152.9, 148.1, 147.7, 145.9, 142.7, 127.6, 124.0, 110.1, 82.9, 65.0,
6.3, 23.4, 22.5, 22.1; IR (ATR) ṽ/cm-1 =2976, 2931, 2859, 1697, 1639,
596, 1366, 1291, 1243, 1152, 1107, 902, 881, 754, 699; HRMS (ESI):
+
m/z calcd for C17
H
29
N
O
2 2
[M+H] 293.2224; found: 293.2223.
2
1
8.5, 27.6; IR (ATR) ṽ/cm-1 = 1699, 1598, 1572, 1518, 1368, 1343, 1286,
246, 1146, 1107, 907, 849, 832, 729, 692, 647; HRMS (EI): m/z calcd for
tert-Butyl
2-benzylidene-1-(2-methylbut-3-en-2-yl)hydrazine-1-
+
C
17
H
23
N
O
3 4
[M]˙ 333.1683; found: 333.1710.
carboxylate (9i). Mixture of olefins 8a/8b (580 mg, 2.90 mmol ≙ 2.64
mmol of isomer 8a) and benzaldehyde (0.294 mL, 2.90 mmol) gave N-Boc-
N-allylhydrazone 9i (312 mg, 1.08 mmol, 41% referred to isomer 8a) as
tert-Butyl
ylmethylene)hydrazine-1-carboxylate (9n). Mixture of olefins 8a/8b (150
mg, 0.749 mmol 0.681 mmol of isomer 8a) and 2-
thiophenecarboxaldehyde (70 µL, 0.749 mmol) gave N-Boc-N-
allylhydrazone 9n (104 mg, 0.352 mmol, 52% referred to isomer 8a) as
1-(2-methylbut-3-en-2-yl)-2-(thiophen-2-
1
colourless oil via GP1: R
f
= 0.64 (hexanes/EtOAc 9:1); H NMR (400 MHz,
chloroform-d) δ/ppm = 8.65 (s, 1H), 7.74 – 7.68 (m, 2H), 7.43 – 7.34 (m,
≙
3
3
1
1
H), 6.17 (dd, JH,H = 17.5, 10.8 Hz, 1H), 5.11 – 4.90 (m, 2H,), 1.52 (s, 6H),
.47 (s, 9H); 13C NMR (101 MHz, chloroform-d) δ/ppm = 157.1, 153.6,
46.4, 135.4, 130.2, 128.7, 127.7, 109.4, 81.8, 63.6, 28.5, 27.2; IR (ATR)
ṽ/cm- = 3083, 3062, 2976, 2932, 1697, 1642, 1574, 1476, 1449, 1412,
1
light yellow oil via GP1: R
f
= 0.60 (hexanes/EtOAc 9:1); H NMR (400 MHz,
1
chloroform-d) δ/ppm = 8.85 – 8.83 (m, 1H), 7.32 (dt, 3JH,H = 5.0, 1.0 Hz,
1H), 7.24 (dd, JH,H = 3.6, 1.2 Hz, 1H), 7.04 (dd, 3
3
J
H,H = 5.1, 3.6 Hz, 1H),
1
391, 1366, 1289, 1243, 1149, 1109, 1071, 992, 947, 898, 856, 784, 753,
+
3
692, 659, 563; HRMS (ESI): m/z calcd for C17
H
25
N
O
2 2
[M+H] 289.1910,
6.14 (dd, JH,H = 17.5, 10.8 Hz, 1H), 5.08 – 4.91 (m, 2H), 1.49 (s, 6H), 1.47
(s, 9H); 13C NMR (101 MHz, chloroform-d) δ/ppm = 153.6, 150.2, 146.3,
40.9, 129.7, 127.9, 127.4, 109.5, 81.9, 63.7, 28.5, 27.2; IR (ATR) ṽ/cm-1
2985, 2938, 1742, 1708, 1585, 1369, 128, 1242, 1181, 1148, 1113, 1093,
044, 911, 848, 759, 744, 576; HRMS (EI): m/z calcd for C15
found: 289.1909.
1
=
1
tert-Butyl
2-(4-bromobenzylidene)-1-(2-methylbut-3-en-2-
H
22
N
2 2
O S
yl)hydrazine-1-carboxylate (9j). Mixture of olefins 8a/8b (243 mg, 1.21
mmol ≙ 1.10 mmol of isomer 8a) and 4-bromobenzaldehyde (224 mg,
+
[M]˙ 294.1396; found: 294.1392.
1.21 mmol) gave N-Boc-N-allylhydrazone 9j (356 mg, 0.971 mmol, 88%
6
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European Journal of Organic Chemistry
10.1002/ejoc.202000382
FULL PAPER
tert-Butyl
1-(2-methylbut-3-en-2-yl)-2-(pyridin-4-
2-Methyltridec-2-ene (10b). Allylhydrazone 9b (162 mg, 0.500 mmol) and
ylmethylene)hydrazine-1-carboxylate (9o). Mixture of olefins 8a/8b (350
mg, 1.75 mmol ≙ 1.59 mmol of isomer 8a) and 4-pyridinecarboxaldehyde
HNTf
2
(14 mg, 0.050 mmol) gave olefin 10b (19 mg, 0.10 mmol, 21%) as
1
colourless oil via GP2: R
chloroform-d) δ/ppm = 5.12 (tdt, 3JH,H = 7.2, 1.5 Hz, 1H), 1.96 (q, 3
6.8 Hz, 2H), 1.69 (d, 3JH,H = 1.4 Hz, 3H), 1.60 (d, JH,H = 1.3 Hz, 3H), 1.26
(s, 16H), 0.93 – 0.83 (m, 3H); 13C NMR (101 MHz, chloroform-d) δ/ppm =
131.3, 125.1, 32.1, 30.1, 29.8, 29.8, 29.8, 29.5, 29.5, 28.2, 25.9, 22.9, 17.8,
14.3; IR (ATR) ṽ/cm-1 = 2955, 2922, 2853, 1456, 1376, 1094, 984, 886,
832, 721, 593, 556; HRMS (EI): m/z calcd for C14
196.2183.
f
= 0.88 (pentane/Et
2
O 9:1); H NMR (400 MHz,
(0.165 mL, 1.75 mmol) gave N-Boc-N-allylhydrazone 9o (342 mg, 1.18
J
H,H
=
3
mmol, 74% referred to isomer 8a) as light yellow oil via GP1: R
f
= 0.12
1
(
hexanes/EtOAc 9:1); H NMR (400 MHz, chloroform-d) δ/ppm = 8.90 (s,
1
=
H), 8.65 – 8.55 (m, 2H), 7.50 (dd, 3JH,H = 6.1, 0.4 Hz, 2H), 6.11 (dd, 3JH,H
17.5, 10.8 Hz, 1H), 5.11 – 4.90 (m, 2H), 1.54 (s, 6H), 1.49 (s, 9H); 13C
+
NMR (101 MHz, chloroform-d) δ/ppm = 152.9, 150.3, 147.7, 146.0, 143.8,
H
28 [M]˙ 196.2185, found:
1
1
21.1, 109.9, 82.8, 64.9, 28.5, 27.6; IR (ATR) ṽ/cm-1 = 2977, 2933, 1698,
590, 1367, 1287, 1246, 1147, 989, 903, 859, 814, 755, 732, 656; HRMS
+
(
ESI): m/z calcd for C16
H
24
N
O
3 2
[M+H] 290.1863; found: 290.1862.
2-Methyltetradec-2-ene (10c). Allylhydrazone 9c (169 mg, 0.500 mmol)
and HNTf
2
(14 mg, 0.050 mmol) gave olefin 10c (21 mg, 0.099 mmol, 20%)
= 0.98 (pentane); 1H NMR (400 MHz,
tert-Butyl
1-(2-methylbut-3-en-2-yl)-2-(3-
as colourless oil via GP2: R
chloroform-d) δ/ppm = 5.12 (ddt, 3JH,H = 7.1 Hz, 1H), 1.96 (q, 3
JH,H = 6.9
f
phenylpropylidene)hydrazine-1-carboxylate (9p). Mixture of olefins
a/8b (237 mg, 1.18 mmol 1.07 mmol of isomer 8a) and 3-
phenylpropionaldehyde (0.157 mL, 1.18 mmol) gave N-Boc-N-
8
≙
Hz, 2H), 1.69 (s, 3H), 1.60 (s, 3H), 1.26 (br, 18H), 0.88 (t, 3JH,H = 6.8 Hz,
3H); 13C NMR (101 MHz, chloroform-d) δ/ppm = 131.3, 125.1, 34.3, 32.1,
30.1, 29.9, 29.8, 29.8, 29.5, 28.2, 25.9, 22.9, 22.5, 17.8, 14.3; IR (ATR)
allylhydrazone 9p (141 mg, 0.446 mmol, 42% referred to isomer 8a) as
1
ṽ/cm-1 = 2958, 2921, 2850, 1461, 1372, 1260, 1090, 1022, 881, 806, 723;
colourless oil via GP1: R
DMSO-d
f
= 0.46 (hexanes/EtOAc 9:1); H NMR (400 MHz,
) δ/ppm = 7.75 (t, 3JH,H = 5.3 Hz, 1H), 7.31 – 7.22 (m, 4H), 7.18
HRMS (EI): m/z calcd for C15
H
30 [M]˙ 210.2342; found: 210.2347.
+
6
(
1
m, 1H), 5.99 (dd, 3JH,H = 17.5, 10.8 Hz, 1H), 4.94 (dd, 3JH,H = 17.5, 2JH,H
=
.1 Hz, 1H), 4.86 (dd, JH,H = 10.8, 2JH,H = 1.1 Hz, 1H), 2.83 (t, 3JH,H = 7.3
3
(
4-Methylpent-3-en-1-yl)cyclopentane (10f). Allylhydrazone 9f (140 mg,
Hz, 2H), 2.59 (ddd, JH,H = 7.3, 5.3 Hz, 2H),1.36 (s, 9H), 1.25 (s, 6H); 13C
3
0
.500 mmol) and HNTf
2
(14 mg, 0.050 mmol) gave olefin 10f (15 mg,
NMR (101 MHz, DMSO-d
6
) δ/ppm = 166.7, 153.2, 145.7, 140.9, 128.3,
1
0.099 mmol, 20%) as colourless oil via GP2: R
f
= 0.95 (pentane); H NMR
1
2
8
3
28.3, 125.9, 109.4, 80.1, 61.1, 33.9, 31.3, 27.9, 26.4; IR (ATR) ṽ/cm-1
=
(
500 MHz, chloroform-d) δ/ppm = 5.15 – 5.10 (m, 1H), 2.01 – 1.95 (m, 2H),
979, 2929, 1693, 1639, 1455, 1264, 1303, 1241, 1155, 1101, 903, 870,
56, 748; HRMS (ESI): m/z calcd for C19
17.2229.
.77 – 1.73 (m, 2H), 1.69 (d, 3JH,H = 1.4 Hz, 3H), 1.60 (d, 3
1
3
0
3
JH,H = 1.2 Hz,
+
H
29
N
O
2 2
[M+H] 317.2224; found:
H), 1.52 – 1.46 (m, 2H), 1.34 – 1.30 (m, 2H), 1.11 – 1.05 (m, 2H), 0.91 –
.86 (m, 3H); 13C NMR (126 MHz, chloroform-d) δ/ppm = 131.1, 125.2,
9.9, 36.6, 32.8, 27.4, 25.9, 25.4, 17.8; IR (ATR) ṽ/cm-1 = 2983, 2950, 2922,
tert-Butyl
1-(2-methylbut-3-en-2-yl)-2-((E)-3-
2857, 1452, 1376, 1105, 985, 907, 830, 735, 650, 574, 560; HRMS (EI):
+
phenylallylidene)hydrazine-1-carboxylate (9q). Mixture of olefins 8a/8b
m/z calcd for C11
H
20 [M]˙ 152.1559, found: 152.1558.
(
(
250 mg, 1.25 mmol ≙ 1.13 mmol of isomer 8a) and cinnamaldehyde
0.157 mL, 1.25 mmol) gave N-Boc-N-allylhydrazone 9q (228 mg,
(
4-Methylpent-3-en-1-yl)cyclohexane (10g). Allylhydrazone 9g (147 mg,
0
.725 mmol, 64% referred to isomer 8a) as yellow oil via GP1: R
f
= 0.56
0
0
.500 mmol) and HNTf
.10 mmol, 20%) as colourless oil via GP2. (4-Methylpent-3-en-1-
). Allylhydrazone 9g (127 mg, 0.433
(37 mg, 0.13 mmol) gave olefin 10g (18 mg, 0.11 mmol,
2%) as colourless oil via GP2. (4-Methylpent-3-en-1-yl)cyclohexane
10g, 3.00 mmol scale). Allylhydrazone 9g (822 mg, 3.00 mmol) and
2
(14 mg, 0.050 mmol) gave olefin 10g (17 mg,
1
(
hexanes/EtOAc 9:1); H NMR (500 MHz, chloroform-d) δ/ppm = 8.33 (dd,
3
J
H,H = 7.2, 1.5 Hz, 1H), 7.49 – 7.47 (m, 2H), 7.38 – 7.33 (m, 2H), 7.32 –
.28 (m, 1H), 6.96 – 6.93 (m, 2H), 6.14 (dd, 3
H,H = 17.5, 10.8 Hz, 1H),
.07 – 4.92 (m, 2H), 1.47 (s, 6H), 1.46 (s, 9H); 13C NMR (101 MHz,
yl)cyclohexane (10g, 30 mol% HNTf
mmol) and HNTf
2
2
7
5
J
2
chloroform-d) δ/ppm = 161.7, 153.7, 146.2, 140.5, 136.2, 128.9, 128.9,
(
1
1
27.2, 126.0, 109.5, 81.6, 62.9, 28.5, 26.9; IR (ATR) ṽ/cm-1 = 1694, 1449,
366, 1289, 1243, 1148, 1109, 1051, 973, 906, 879, 850, 749, 689; HRMS
HNTf
2
(84 mg, 0.30 mmol) gave olefin 10g (129 mg, 0.759 mmol, 25%) as
1
colourless oil via GP2: R
f
= 0.91 (pentane); H NMR (500 MHz, chloroform-
+
(
ESI): m/z calcd for C19
H
27
N
O
2 2
[M+H] 315.2067; found: 315.2066.
d) δ/ppm = 5.15 – 5.00 (m, 1H), 2.03 – 1.91 (m, 2H), 1.75 – 1.57 (m, 11H),
.25 – 1.15 (m, 6H), 0.92 – 0.83 (m, 2H); 13C NMR (126 MHz, chloroform-
1
General procedure for the synthesis of olefins via [3,3]-sigmatropic
rearrangement (GP2):
d) δ/ppm = 131.1, 125.3, 37.8, 37.5, 33.5, 26.9, 26.6, 25.9, 25.5, 17.8; IR
(ATR) ṽ/cm- = 2923, 2852, 1694, 1448, 1376; HRMS (EI): m/z calcd for
1
+
C
12
H
22 [M]˙ 166.1722, found: 166.1720.
In an oven dried two-necked Schlenk flask HNTf
in dry diglyme (1 mL). solution of the appropriate N-Boc-N-
allylhydrazone 9 (1.0 eq) in dry diglyme (2 mL + 1 mL rinse) was added at
room temperature. The reaction mixture was fitted with a N flashed reflux
condenser and immediately heated to 125 °C in a pre-heated oil bath. After
completion of the rearrangement detected by TLC (75 min), the reaction
was immediately cooled to room temperature via water bath and then
2
(10 mol %) was dissolved
A
(6-Methylhept-5-en-1-yl)benzene (10p). Allylhydrazone 9p (217 mg,
0.686 mmol) and HNTf
0.13 mmol, 19%) as colourless oil via GP2: R
(400 MHz, methylene chloride-d
2
(14 mg, 0.068 mmol) gave olefin 10p (25 mg,
1
2
f
= 0.48 (pentane); H NMR
2
) δ/ppm = 7.29 – 7.23 (m, 2H), 7.20 – 7.13
(m, 3H), 5.12 (tdt, 3JH,H = 7.2, 1.5 Hz, 1H), 2.60 (t, 3JH,H = 7.7 Hz, 2H), 2.01
(q, 3JH,H = 7.3 Hz, 2H), 1.68 (d, 3JH,H = 1.4 Hz, 3H), 1.64 – 1.58 (m, 5H),
quenched with a sat. aq. NaHCO
3
solution (4 mL). Pentane (10 mL) was
1.41 – 1.33 (m, 2H); 13C NMR (101 MHz, methylene chloride-d
2
) δ/ppm =
added and the organic layer was washed with at least 100 mL water. The
solvent was removed in vacuo (30 °C, max. 700 mbar) and the crude
product was purified by flash column chromatography.
143.6, 131.8, 128.9, 128.7, 126.1, 125.2, 36.4, 31.8, 30.1, 28.4, 25.9, 17.9;
IR (ATR) ṽ/cm-1 = 3026, 2922, 2853, 1602, 1494, 1451, 1378, 1108, 1079,
+
1029, 741, 698, 571; HRMS (EI): m/z calcd for C14
H
20 [M]˙ 188.1565;
found: 188.1565.
2-Methyldodec-2-ene (10a). Allylhydrazone 9a (155 mg, 0.500 mmol) and
HNTf
2
(14 mg, 0.050 mmol) gave olefin 10a (18 mg, 0.099 mmol, 20%) as
Keywords: hydrazones • isoprenylation • sigmatropic
rearrangement • traceless bond construction • triflimide
1
colourless oil via GP2: R
d) δ/ppm = 5.15 – 5.08 (m, 1H), 1.96 (q, JH,H = 7.1 Hz, 2H), 1.69 (d, 3JH,H
f
= 0.94 (pentane); H NMR (400 MHz, chloroform-
3
=
2
3
=
1.4 Hz, 3H), 1.60 (d, 3JH,H = 1.3 Hz, 3H), 1.26 (s, 14H), 0.88 (t, 3
.9 Hz, 3H). 13C NMR (101 MHz, chloroform-d) δ/ppm = 131.3, 125.1, 32.1,
0.1, 29.8, 29.8, 29.5, 29.5, 28.2, 25.9, 22.9, 17.8, 14.3. IR (ATR) ṽ/cm-1
H,H
J =
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m/z calcd for C13
H
26 [M]˙ 182.2029, found: 182.2027.
7
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.202000382
FULL PAPER
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European Journal of Organic Chemistry
10.1002/ejoc.202000382
FULL PAPER
Entry for the Table of Contents
Key Topic: traceless isoprenylation
A traceless isoprenylation method of non-conjugated aldehydes is reported. Synthesis of the required N-Boc-N-(1,1-
dimethylallyl)hydrazine precursor, as well as the N-Boc-N-allylhydrazones are described. Optimisation reactions for the
rearrangement were performed and the scope of the rearrangement was studied.
9
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