Unconventional Rose Odorants: Serendipitous Discovery and Unique Olfactory Properties of 2,2-Bis(prenyl)-3-oxobutyronitrile and Its Derivatives

Article abstract of DOI:10.1055/s-0037-1610199

2,2-Bis(3-methylbut-2-enyl)-3-oxobutanenitrile [2,2-bis(prenyl)-3-oxobutyronitrile], an unusual bifunctional nitrile odorant with a fruity rosy, green odor was found to exhibit surprising differences in its detection thresholds (0.25 ng/L air for hyperosm

Full text of DOI:10.1055/s-0037-1610199

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
©
Georg Thieme Verlag Stuttgart · New York
2018, 50, A–K
paper
A
en
Synthesis
N. Hauser et al.
Paper
Unconventional Rose Odorants: Serendipitous Discovery and
Unique Olfactory Properties of 2,2-Bis(prenyl)-3-oxobutyronitrile
and Its Derivatives
Nicole Hauser*a
Philip Kraftb
0
0
0
0
0-
0
0
2
4-
8
0
1
5-
3
8
9
Erick M. Carreiraa
0
0
0
0
0-
0
0
3
1-
4
7
2
4-
9
0
X
a
ETH Zürich, Vladimir-Prelog-Weg 3, 8093 Zürich,
Switzerland
nicole.hauser@org.chem.ethz.ch
carreira@org.chem.ethz.ch
Givaudan Fragrances S&T, Ingredients Research,
Überlandstrasse 138, 8600 Dübendorf, Switzerland
philip.kraft@givaudan.com
b
Published as part of the Special Section dedicated to
Scott E. Denmark on the occasion of his 65th birthday
Received: 14.06.2018
Accepted: 14.06.2018
Published online: 26.06.2018
those who first synthesized it by chance at the end of the
1
19th century. Neither is there any striking structural simi-
DOI: 10.1055/s-0037-1610199; Art ID: ss-2018-e0410-op
larity with well-known rose odorants such as 2-phenyl-
ethanol that catches the eye, nor does the condensation
product of benzaldehyde and chloroform in the presence of
a base such as KOH possess any noteworthy olfactory prop-
erties. However, acetylation of the resulting 2,2,2-trichloro-
1-phenylethan-1-ol changes everything, and the effect of 1,
especially in combination with 2-phenylethanol, is most
impressive. Rosacetol (1) first appeared under the name of
Abstract 2,2-Bis(3-methylbut-2-enyl)-3-oxobutanenitrile [2,2-bis(pre-
nyl)-3-oxobutyronitrile], an unusual bifunctional nitrile odorant with a
fruity rosy, green odor was found to exhibit surprising differences in its
detection thresholds (0.25 ng/L air for hyperosmics; 19 ng/L air for hy-
posmics) and perceived odor characters. To investigate this remarkable
phenomenon, 13 derivatives of 2,2-bis(3-methylbut-2-enyl)-3-oxobu-
tanenitrile were synthesized by either monoalkylation of 3-oxo-2-phen-
ylbutanenitrile, or by dialkylation of sodium 1-cyano-2-oxopropan-1-
ide or methyl or ethyl cyanoacetate, or by direct derivatization of 2,2-
bis(3-methylbut-2-enyl)-3-oxobutanenitrile via its vinyl triflate and
Negishi cross coupling. These systematic permutations of the substitu-
tion pattern allowed some insight to be gained into the underlying
structure–odor relationships and the construction of a simple olfacto-
phore model, albeit no final conclusion could be drawn as to whether
the nitrile or carbonyl function acts as the prime osmophore of the bi-
functional compounds. Depending on slight genetic variations and the
corresponding differences in the receptor morphology both can engage
in H-bond interactions with the olfactory receptors, which might ex-
plain the observed largely diverging sensitivities. Methyl 2-cyano-2,2-
bis(3-methylbut-2-enyl)acetate with a uniform odor threshold of 0.38
ng/L air turned out to be the most interesting floral, rosy odorant of
this study, followed by 3-methyl-2,2-bis(3-methylbut-2-enyl)but-3-
enenitrile with only a nitrile function and varying odor thresholds (0.40
ng/L air vs. 125 ng/L air).
‘
Rodindol’ (Flora, Dübendorf/Th. Muhlethaler, Nyon) on the
market around 1909, and due to its attractive price soon
became very popular. Not protected by patents, it was
widely produced and also sold as ‘Rose Crystals’, ‘Rosone’,
‘
‘
Rosetone’, ‘Rosamen’, ‘Rodalin’, ‘Rosatol’, ‘Rosephenone’,
Trichlor-Rose Body’, ‘Trirosol’, or ‘Abracador’, to name only
the most popular.
Rosacetol (1) lends to perfumery compositions a deep
and heavy powdery rose note of outstanding substantivity
and excellent stability, especially in soaps, shampoos, and
shower gels. However, despite its attractive olfactory prop-
erties it is obviously problematic to release such trichlori-
nated compounds into the environment, especially in
aquatic systems, and insecticidal properties have been re-
ported as well.2 Therefore, an intense search for safe re-
placements with similar properties and performance start-
Key words bifunctional compounds, cross coupling, dialkylation, fra-
grance materials, molecular modeling, nitriles, rose odorants, struc-
ture–odor correlation
3
ed in the late 1990s, out of which Peonile (2) and Petalia
4
(
3) emerged as the most successful ones. In addition to the
Serendipity has always been a significant factor behind
innovations, especially those disruptive and surprising. The
most pleasant and powdery floral-green rose odor of
Rosacetol (1) was certainly completely unexpected for
powdery rose note, the additional methyl group of Petalia
(3) introduces an interesting lychee effect which has for in-
stance been made use of in ‘Hermann à mes Côtés me Para-
issait une Ombre’ (Etat Libre d’Orange, 2015) by Quentin
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

B
Synthesis
N. Hauser et al.
Paper
Bisch and ‘Versace pour Femme Dylan Blue’ (Versace, 2017)
by Calice Becker. So additional facets are still in demand, es-
pecially if they attenuate some of the harshness generally
associated with nitrile odorants.5
But not only was the synthesized 2,2-bis(prenyl)-3-
oxobutyronitrile (6) exceptional in being a bifunctional
rose odorant, upon measuring its odor threshold it was ob-
served that there were two distinctly different groups of
panelists in the ratio of 1:2, hyperosmics/hyposmics. While
an odor threshold of 0.25 ng/L air, so very close to Roseace-
tol (1, th 0.23 ng/L air), was determined for the more sensi-
tive group of hyperosmics, the threshold for the hyposmics
was at 19 ng/L air almost two orders of magnitude higher.
The significant quantitative difference in the odor percep-
tion was accompanied by a qualitative one: green, aromatic,
freesia, ivy-type aspects dominate for the hyperosmics,
while the fruity-rosy note prevails for the hyposmics.
A nitrile function offers high stability in functional ap-
5
plications, but besides Peonile (2) and Petalia (3), there are
almost no nitrile rose odorants known. The only exception
6
is Givrosia (4), which with an odor threshold of 9.0 ng/L air
is, however, rather weak and has a prominent woody-
tobacco aspect that compromises the rosy floralcy. Citrow-
7
anil B (5) is a nitrile odorant with a fresh, citrus note, how-
ever accompanied by some less appreciated spicy-herbal
cuminic effect. We were, therefore, very surprised when by
serendipity, the related structure 6, which had been pre-
pared in synthetic efforts towards a complex natural prod-
uct, displayed a nice and substantive fruity rose odor with
green-aromatic facets in front of a transparent freesia back-
ground (Figure 1). As a ketonitrile, compound 6 was bifunc-
tional, and while bifunctional odorants are known in the
lily-of-the-valley family, to the best of our knowledge none
existed in the domain of rose odorants; all the more featur-
ing a nitrile function.
O
ONa
N
NaOMe
NC
CH2Cl2
0 °C → r.t.
7
8
5-methyl-
isoxazole
O
N
Br
Cs2CO3, DMF
°C → r.t.
0
O
N
N
6
O
Scheme 1 Synthesis of 2,2-bis(prenyl)-3-oxobutyronitrile from 5-me-
thylisoxazole
Cl
Cl
Cl
Due to the olfactory reminiscence of 6 to Peonile (2),
ketonitrile 9 was synthesized by alkylation of 3-oxo-2-
phenylbutanenitrile (10) with iodocyclohexane (4 equiv) in
the presence of K CO (4 equiv) in DMSO at r.t. (Scheme
1
2
3
Rosacetol
Peonile
Petalia
rosy, floral-green,
powdery
th 0.23 ng/L air
rosy, floral-green,
powdery
th 0.60 ng/L air
rosy-fruity, lychee,
powdery
th 0.11 ng/L air
2
3
10
2). After stirring at r.t. for 4.5 days, the target compound 9
N
N
O
N
was obtained in a mere 31% yield due to the incomplete
conversion of the starting material and the formation of mi-
nor amounts of O-alkylated product. However, much to our
disappointment, the Peonile analogue 9 turned out to be
very weak to odorless (th 500 ng/L air) with only a vague,
green, rosy, leathery odor.
4
5
6
Givrosia
Citrowanil B
fresh, citrus,
spicy-herbal,
cuminic
2,2-bis(prenyl)-
3-oxobutyronitrile
fruity, rosy, green,
aromatic, freesia
floral, rosy,
woody, tobacco
th 9.0 ng/L air
O
O
N
N
Figure 1 The trichlorinated powdery rose odorant Rosacetol with its
CyI, K2CO3
DMSO, r.t.
3
4
halogen-free replacements Peonile and Petalia, the rosy nitrile Givro-
6
7
sia, the citrus nitrile Citrowanil B, and 2,2-bis(prenyl)-3-oxobutyroni-
trile, the serendipitous discovery of this paper
10
9
vague, green,
rosy, leathery
th 500 ng/L air
The synthesis of 2,2-bis(prenyl)-3-oxobutyronitrile (6)
is delineated in Scheme 1 and commenced with the depro-
tonation of 5-methylisoxazole (7) with sodium methoxide
in CH Cl according to a procedure by Alexakis and co-
Scheme 2 Synthesis of a Peonile-related ketonitrile from 3-oxo-2-
phenylbutanenitrile by α-alkylation
2
2
8
workers. The crude sodium salt of cyanoacetone 8 was ob-
tained in quantitative yield and then bis-prenylated with
prenyl bromide (2.2 equiv) in DMF in the presence of
To investigate the structural parameters of both the ol-
factory characteristics and the strongly diverging sensitivi-
ties towards the unconventional bifunctional rose odorant
6, a detailed structure–odor relationship study was thus
undertaken. First, the importance of the carbonyl function
9
Cs CO (1 equiv) as a base. The corresponding target com-
2
3
pound 6 was isolated in olfactory purity by flash chroma-
tography in 74% yield.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

C
Synthesis
N. Hauser et al.
Paper
of 6 as the principal osmophore was challenged by replac-
ing it with a hydrophobic methylene unit. To this end, a
standard Wittig methylenation with methyltriphenyl-
phosphonium bromide (1.3 equiv) and n-BuLi in THF/hexane
O
N
N
1. LDA, HMPA
. Comins' reagent
OTf
2
THF, –78 °C → r.t.
11
was first performed on 6; yet, as delineated in Scheme 3
this led to the formation of significant amounts of an unde-
sired byproduct along with the desired compound 11. The
6
13
N
Pd(PPh3)4, Me2Zn
THF, 0 °C → r.t.
12
byproduct was identified as the known bis(prenyl)aceto-
nitrile 12, the formation of which can be explained by a
13
retro-Claisen reaction following the attack of the phos-
phorous ylide on the carbonyl group.
11
mild, rosy, citrusy, sweet, sl. dusty
th 0.40 ng/L / th 125 ng/L
O
N
N
N
N
MePPh3Br
n-BuLi
H
Pd(PPh3)2Cl2
Bu3N, HCO2H
H
THF
78 °C → r.t.
DMF, 60 °C
–
14
6
11
1:1.5
12
fruity-rosy, spicy,
pink pepper, chamomile
fatty undertone
Scheme 3 Attempted Wittig methylenation of 2,2-bis(prenyl)-3-
oxobutanenitrile ( H NMR ratio)
1
th 3.8 ng/L air
Scheme 4 Synthesis of the bis-prenylated but-3-enenitriles from 2,2-
bis(prenyl)-3-oxobutyronitrile
Hence, a two-step sequence relying on a Pd-catalyzed
14
Negishi coupling was employed to construct the propen-
-yl moiety via methylation of the corresponding vinyl tri-
2
15
flate 13 (Scheme 4). The latter was obtained from ketoni-
trile 6 in 90% yield by treatment with LDA (1.3 equiv) in the
presence of HMPA (4.2 equiv), followed by the addition of
Comins’ reagent [N-(5-chloro-2-pyridyl)bis(trifluorometh-
in a fruity direction, and with a spicy chamomile–pink pep-
per character above a fatty undertone. The sensitivities of
the panelists towards 14 did not differ, and the threshold
for 14 was concordantly determined at 3.8 ng/L air, so about
10 times weaker as compared to 11 for hyperosmics and
over 30 times more intense for the hyposmics.
Therefore, there did not seem to be much of a steric
component at this position involved in the receptor interac-
tion regarding the hyperosmics. It thus seemed sensible to
keep the ketonitrile functionality and modify the side
chains instead. We first set out to synthesize dibenzylated
ketonitrile 15. As delineated in Scheme 5, the crude cyano-
acetone enolate 8 was treated with benzyl bromide (2
16
anesulfonimide), 1.3 equiv]. The Negishi coupling of 13
with dimethylzinc (2 equiv) in the presence of 5 mol%
Pd(PPh ) smoothly afforded the bis-prenylated nitrile 11 in
3
4
7
4% yield after chromatographic purification. While the
main rose character of 6 remained present in the odor pro-
file of 11, its green facets were replaced by citrusy aspects.
Overall 11 was, however, weaker than 6, but again, there
were marked differences amongst the panelists. The hyper-
osmics (5 panelists) found 11 at 0.40 ng/L air about as
strong as 6 (0.25 ng/L air), while for the smaller group of
hyposmics (3 panelists) 11 was at 125 ng/L air over six
times weaker than the lead structure 6. But since for both
panelist groups 11 smelled similar in character, the nitrile
function seems to be the main osmophore that binds to the
olfactory receptor, certainly so for hyperosmics.
9
equiv) in DMF in the presence of Cs CO (1 equiv) as a base.
2
3
After purification by flash chromatography, the correspond-
ing target compound 15 was obtained as a colorless solid in
67% yield over two steps. Unfortunately, 15 turned out to be
completely odorless, perhaps due to its relatively high mo-
lecular weight (C H ON, 263.34 u) compared to 6, though
18
17
To investigate if the spatial requirement of the propen-
Rosacetol (1, C H O Cl 267.54 u) has about the same. We
10 9 2 3
2
-yl moieties hampered the interaction of the osmophore
next synthesized the diallylated ketonitrile 16 analogously
from crude 8 and allyl bromide (2.2 equiv) as the electro-
phile. The diallylated compound 16 was isolated in 63%
yield over two steps, and lacked the rosy floralcy of our lead
structure 6. There were, however, significant differences in
sensitivity towards 16 among the panelists with odor
thresholds of 6.8 ng/L air for hyperosmics (4 panelists) and
79 ng/L air for the smaller group of hyposmics (3 panelists).
with the receptor, it was then decided to replace it by a
vinyl group. To that end, vinyl triflate 13 was reacted with
formic acid (1.8 equiv) as the hydride source in the pres-
ence of Bu N (2.8 equiv) and 5 mol% Pd(PPh ) Cl as catalyst
in DMF at 60 °C. After purification by flash chromatogra-
phy, 2,2-bis-prenylated but-3-enenitrile 14 was obtained in
3
3
2
2
17
6
5% yield. The main odor note of 14 was again rosy, though
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

D
Synthesis
N. Hauser et al.
Paper
O
possessed the floral-fruity, aromatic odor note of 6 and 17
with additional accents of arnica, tagetes, and osmanthus in
front of a fatty, animalic background. While all panelists
perceived 22 equally well, the odor threshold (th 8.3 ng/L
air) dropped by one order of magnitude compared to 17 (th
0.38 ng/L air).
ONa
N
2
RBr, Cs2CO3
N
DMF, 0 °C → r.t.
R
R
8
15 R = Bn, odorless
1
6 R = CH2CH=CH2
green, metallic, coniferous
th 6.8 / 79 ng/L air
Scheme 5 Synthesis of the dibenzylated and the diallylated ketonitriles
from sodium 1-cyano-2-oxopropan-1-ide
O
N
OEt
O
Br
N
OEt
Cs2CO3, DMF
With these results in hand, we decided to rather modify
the polarity and H-bond acceptor properties of 6.18 One of
the easiest ways to do so was a simple alkylation of cyano-
acetates. In order to be sterically comparable to the methyl
ketone lead 6, the methyl ester 17 was prepared. Methyl
cyanoacetate (18) was bis-prenylated by treatment with
Cs CO (2.2 equiv) and prenyl bromide (2.2 equiv) in DMF
0 °C → r.t.
21
22
floral-fruity, aromatic, arnica
tagetes, osmanthus
fatty, animalic undertone
th 8.3 ng/L
Scheme 7 Bis-prenylation of ethyl cyanoacetate affording the ethyl
ester
2
3
19
(Scheme 6), and cyanoacetate 17 was isolated in 92% yield
by chromatographic purification. As for the vinyl nitrile 14,
neither quantitative nor qualitative perception differences
were observed, and with an odor threshold of 0.38 ng/L air,
cyanoacetate 17 smelled intensely floral-rosy with some
additional reminiscence of linalyl esters and chamomile.
Next, the bis-prenylated aldehyde 19 was prepared by
hydride reduction with NaBH in THF/H O (14:1, 86% yield,
Since the C-2 substituents exert a significant impact
both on the qualitative and the quantitative olfactory prop-
erties, further analogues were synthesized from methyl cy-
anoacetate (18) by treatment with the respective bromides,
as summarized in Scheme 8. Diallylated methyl cyanoace-
tate 23 was obtained in 89% yield in olfactory purity after
flash chromatography. The smell of 23 was very weak (th
500 ng/L air) with only faint metallic green, rosy, fruity,
pear-type aspects.
4
2
20
Scheme 6) and subsequent oxidation of the resulting alco-
21
hol 20 with Dess–Martin periodinane in CH Cl . Aldehyde
2
2
2
22
19 was isolated in 71% yield and found to smell rather weak
Due to the increased sp -character of their carbons,
(
th 25 ng/L air) in a green, chemical direction with some
cyclopropane rings can mimic double bonds. Thus, the 2,2-
bis(cyclopropropylmethyl) derivative 24 was synthesized as
bioisostere23 to 23, employing cyclopropylmethyl bromide
reminiscence to gun powder. The rosy floralcy of 6 and its
fruity character were lost.
(
2.1 equiv). The bis-cyclopropylmethylated cyanoacetate 24
O
N
was obtained in 60% yield as a yellowish oil with a weak
green, chemical odor, though its threshold was with 310
ng/L air slightly lower than that of 23.
OMe
O
Br
N
OMe
Cs2CO3, DMF
0
°C → r.t.
As a bis-demethyl seco-structure to 17, the bis-(Z)-crot-
ylated methyl cyanoacetate 25 was our next target. Dibuty-
nylation of 18 in the presence of Cs CO in DMF afforded the
18
17
floral rosy, linalyl esters,
chamomile
2
3
th 0.38 ng/L
dibut-2-ynylcyanoacetate 26 in 63% after chromatographic
purification. Hydrogenation of 26 in toluene under 1 atm
O
N
N
24
H2 in the presence of 2 mol% Lindlar’s catalyst and 30
OH
H
25
NaBH4
DMP
mol% quinoline yielded 25 as a colorless and, unexpected-
ly, completely odorless liquid (Scheme 8). To finalize the se-
ries, the known26 dipropargylated methyl cyanoacetate 27
was synthesized from methyl cyanoacetate (18) with prop-
argyl bromide using our standard conditions. Methyl 2-cya-
no-2,2-di(prop-2-ynyl)acetate (27) was isolated in 77%
yield by chromatography as a colorless liquid (Scheme 8).
As in 26, we expected the side chains to lack the rotational
barriers that were observed by 1H NMR with the other
products investigated so far. Compound 27 smelled, howev-
er, only weak and vague in a green, rooty direction with a
rubbery lily-of-the-valley connotation for the hyperosmic
(43 ng/L air), while it was completely odorless for the
hyposmic panelists.
THF/H2O
CH2Cl2
20
19
rather weak, green, chemical,
reminiscent of gun powder
th 25 ng/L
Scheme 6 Bis-prenylation of methyl cyanoacetate affording a methyl
ester, and synthesis of an aldehyde via the corresponding alcohol
This made us return to cyanoacetates, and to synthesize
the homologous ethyl ester 22 by employing our standard
bis-prenylation conditions on 21 (Scheme 7). The desired
product 22 was obtained olfactorily pure in 90% yield and
19
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

E
Synthesis
N. Hauser et al.
Paper
O
ketonitriles into account, one would of course expect the
nitrile function of the synthesized odorants to interact
mainly with the olfactory receptor(s), but would this also
be reflected in an olfactophore model?
O
2 RBr, Cs CO3
N
2
N
OMe
OMe DMF, 0 °C → r.t.
R
R
1
8
23 R = CH2CH=CH2, very weak,
metallic-green, rosy
th 500 ng/L
4 R = CH2c-Pr, weak, green,
chemical, th 310 ng/L
6 R = CH2C≡CCH3
7 R = CH2C≡CH, weak, green,
rooty, rubbery, muguet
th 43 ng/L
An olfactophore is basically a ‘super pharmacophore’
comprising the different receptor sites involved in the com-
binatorial coding of a given odor impression, such that the
broad receptive range might not be too much in the way to
gain at least some rudimentary idea about the required
geometry for nitrile rose odorants. Using the activity data
calculated from the measured odor thresholds in Table 1 for
hyperosmics, an olfactophore model was generated with
2
2
2
O
N
O
N
OMe
OMe
H2 (1 atm)
Lindlar's cat.
28
the Discovery Studio 18.1.100.18065 software package. In
order not to overemphasize weak to odorless materials in
the construction of the model, compounds with thresholds
quinoline
PhMe
2
6
25
>
500 ng/L air (15, 25, and 26) were not considered. Also ex-
odorless
odorless
cluded were compound 16 with only green-metallic, but no
Scheme 8 Difunctionalization of methyl cyanoacetate with allyl bromide,
cyclopropylmethyl bromide, and but-2-ynyl and propargyl bromide,
and synthesis of the bis-(Z)-crotylated methyl ester
Besides our original lead structure, the 2,2-bis(prenyl)-
3
-oxobutyronitrile (6, 0.25 ng/L air), of the 14 nitriles syn-
thesized and investigated in this study (Table 1) only the
corresponding methylene derivative 11 (0.4 ng/L air) and
the analogous methyl ester 17 (0.38 ng/L air) possessed
rosy, floral-green odor characteristics and threshold inten-
sities in the range of Rosacetol (1), Peonile (2), and Petalia
(
3). Only the methyl ester 17 was perceived equally strong
by all panelists. Even the ethyl ester 22 was already 20×
weaker in terms of odor threshold. Abstraction of both ter-
minal methyl groups (compound 23) or even the (Z)-config-
ured methyl only (compound 25) of ester 17 led to weak
and vague odors or even complete odorlessness, while the
abstraction of both terminal methyl groups of our lead 6 re-
sulted in an almost 30× higher odor threshold (for com-
pound 16) considering hyperosmics only. Most surprising
was that even Sturm’s isobutenyl–phenyl analogy27 does
not work for ketonitrile 6, as the dibenzyl analogue 15 is
completely odorless. So, the molecular space for this unusu-
al odorant family seems exceptionally narrow.
While the uncommon and pronounced sensitivity dif-
ferences towards compounds 6, 16, and 27 as well as the
broad qualitative perceptive range of the compounds,
varying between rosy, floral-fruity, green-metallic, and aro-
matic make it extremely challenging to conclude anything
about the interactions with the olfactory receptors involved
in this odorant family, it was nevertheless very interesting
to gain some insight if the osmophore, i.e. the group engag-
ing in H-bonding with the odorant receptors, was the ni-
trile or the carbonyl function. Perhaps this bifunctionality
even was the very reason for the sensitivity differences of
the different panelists groups. Taking the low odor thresh-
old of the methylene derivative 11 (0.4 ng/L air) for hyper-
osmics as well as the dipole moments of the synthesized
Figure 2 Olfactophore model for nitrile rose odorants with Petalia (3,
black), Rosacetol (1, dark grey), the ketonitrile lead 6 (light grey), and
the corresponding methyl ester 17 (white) docked into, featuring: 1 hy-
drogen-bond acceptor (HBA) colored green, 2 hydrophobes depicted in
cyan, and 1 double-bond feature in orange. The model has a correlation
of 77.1% (max. fit 7.97, total cost 68.9, RMS 1.87) and was generated
with the Discovery Studio 18.1.100.18065 software package,28 using a
training set comprising of Rosacetol (1), Peonile (2), and Petalia (3) as
well as compounds 6, 9, 11, 14, 17, 19, 22, 23, and 24 (uncert = 3, con-
formational space = 20 kcal/mol).
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

F
Synthesis
N. Hauser et al.
Paper
floral odor character, and 27 for its weak and vague odor
without any rosy aspects. This gave a small training set of
only 12 compounds, consisting of 6 active, 3 moderately ac-
tive, and 3 inactive structures, that did not allow splitting
into test sets. The resulting olfactophore model is depicted
in Figure 2 and has a correlation value of 77.1%, featuring no
excluded volumes. The inactive compounds (9, 23, 24) thus
are not penalized sterically and are still predicted moder-
ately active; yet, enforcing excluded volumes did not im-
prove on the overall correlation. The model should there-
fore be seen in a more illustrating way, though the calculat-
ed picomolar activities are nevertheless given in Table 1.
in this model competing binding poses of similar energy.
Generally, however, the benzene, cyclohexyl, or prenyl moi-
eties are preferentially situated in the two hydrophobic vol-
umes (depicted in cyan). Decisive for the docking pose is
rather the fit into the double-bond feature (orange), which
is situated more closely towards the hydrophobe binding
the trichloromethyl group, thereby indicating a certain po-
larizability of this hydrophobic group. The overall idea of a
triangular constellation of one HBA and two hydrophobes,
one of which flanked by a double-bond feature, is however
quite plausible for these rosy, floral-green odorants, even
though the hydrophobes are not perfectly addressed by
Roseacetol (1, dark grey).
Table 1 Overview of the Threshold Data (Hyperosmics in the Case of
Different Sensitivity Groups)
In the superposition analysis (Figure 3) of Petalia (3,
black), Peonile (2, dark grey), Rosacetol (1, grey), lead struc-
ture 6 (light grey), and its methyl ester analogue 17 (white)
with the MOE 2016.08.02 software29 using an Amber10:
Extended Hückel Theory (EHT) forcefield, the nitrile func-
tions of both 6 and 17 however point away from those of
Petalia (3) and Peonile (2), each pair of compounds 6/17
and 2/3 overlying almost perfectly. Here, the cyano nitro-
gens of the pair 2/3 map with the carbonyl oxygens of com-
pound 1, 6, and 7, which would indicate the carbonyl group
to be the osmophoric group of the lead structure 6 and
methyl ester 17.
a
Compound Odor threshold
Experimental activity Calculatedactivity
[pM] [pM]
[ng/L]
Rosacetol
1)
0.23 (rosy)
0.86 (active)
68 (moderate)
(
Peonile (2)
0.60 (rosy)
0.52 (active)
0.96 (active)
0.63 (active)
3.6 (active)
Petalia (3)
0.11 (rosy)
0.51 (active)
6
9
0.25 (freesia)
500 (vague)
0.40 (rosy)
1.1 (active)
2100 (inactive)
1.8 (active)
41 (moderate)
12 (active)
1
1
1
1
1
1
2
2
2
2
2
1
4
5
6
7
9
2
3
4
5
6
7
3.8 (rosy)
19 (moderate)
not considered
not considered
1.6 (active)
13 (active)
>500 (odorless)
6.8 (green)
0.38 (rosy)
not considered
not considered
3.3 (active)
25 (green)
120 (moderate)
33 (moderate)
2800 (inactive)
1500 (inactive)
not considered
not considered
not considered
2.7 (active)
8.3 (floral)
1.4 (active)
500 (vague)
310 (green)
>500 (odorless)
>500 (odorless)
43 (vague)
32 (moderate)
33 (moderate)
not considered
not considered
not considered
2
a
For the compounds synthesized and considered in the generation of the
model as well as a comparison of the measured experimental activities
[
pM] with the activities calculated by the Discovery Studio software28 for
the olfactophore model in Figure 2.
Figure 3 Multiflexible alignment of Petalia (3, black), Peonile (2, dark
grey), Rosacetol (1, grey), lead structure 6 (light grey), and the corre-
sponding methyl ester 17 (white) with the MOE 2016.08.02 software
package.29 The strain energy induced by this superposition has a value U
Interestingly, the nitrile function is not always bound by
the hydrogen-bond acceptor (HBA, green) feature; in fact,
the cyano and carbonyl function compete for the hydrogen
bond, depending on the overall complementarity to the
binding pocket. Thus, the osmophore of the ketonitrile lead
=
16.4 kcal/mol, its feature overlap as a measure of configurational sim-
ilarity is F = –95.0, while the resulting alignment score of the probabili-
ty-density overlap is S = –78.6.
6
(light grey) is the carbonyl function with the nitrile func-
tion pointing towards the double-bond feature (orange),
while the methyl ester 17 (white) binds via its nitrile func-
tion with the ester methyl group situated in a hydrophobe
In conclusion, it is not clear whether or not the keto-
nitrile lead 6 and the analogous methyl ester 17 bind via the
nitrile function, which the methylene derivative 11 (0.4
ng/L air) certainly must. This can be the reason for the ob-
served sensitivity differences if only the olfactory receptors
responsible for these rose odorants vary very subtly subject
(cyan). Whether this explains why there was no sensitivity
difference for the methyl ester 17 is highly speculative. But
in any case, the bifunctional compounds investigated have
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

G
Synthesis
N. Hauser et al.
Paper
to the respective genome. This could be interesting for fu-
ture receptor studies, but the sensitivity differences of 6
and 17 hamper any commercial utilization of these com-
pounds. So methyl 2-cyano-2,2-bis(3-methylbut-2-enyl)-
acetate (17) is the only viable new floral rosy odorant
emerging from this study. It is available from methyl cyano-
acetate in one step at an attractive cost, but is with an odor
threshold of 0.38 ng/L air only on a par with Rosacetol (1)
and its halogen-free replacer Peonile (2), while slightly infe-
rior to Petalia (3, 0.11 ng/L air). As seen in 23 and 25, both
methyl groups of the isobutenyl tail are important, and
since even the ethyl ester 22 is one order of magnitude
weaker (8.3 ng/L air), the room for improvements seems
largely exhausted. Nevertheless, the unique olfactory prop-
erties of the derivatives of 2,2-bis(prenyl)-3-oxobutyroni-
trile have already demonstrated that there is still ample op-
portunity for surprise in Fragrance Chemistry.
3-methylbut-2-ene (2.3 mL, 20 mmol, 2.2 equiv) were added. The
mixture was stirred at r.t. for 2.5 h, and then it was quenched by the
addition of sat. aq NH Cl soln (20 mL). The aqueous phase was ex-
4
tracted with CH Cl (3 × 30 mL). The combined organic layers were
2
2
washed with water (2 × 30 mL) and brine (30 mL), dried (MgSO ), and
4
concentrated in vacuo. Purification by flash chromatography (silica
gel, hexane/EtOAc, 40:1, R = 0.2) afforded 6 (1.50 g, 74%) as a colorless
f
liquid.
IR (neat): 2986, 2920, 2857, 2236, 1723, 1443, 1379, 1357, 1168,
–1
1018, 841, 799 cm
.
1
H NMR (400 MHz, CDCl ): δ = 5.14 (m, 2 H, 2′-H), 2.55 (dd, J = 14.3,
3
7.7 Hz, 2 H, 1′-H), 2.42 (dd, J = 14.3, 7.5 Hz, 2 H, 1′-H), 2.35 (s, 3 H, 3-
Me), 1.75–1.72 (m, 6 H, 3′-Me(E)), 1.64 (br, s, 6 H, 3′-Me(Z)).
13
C NMR (101 MHz, CDCl ): δ = 203.0 (s, C-3), 137.8 (2 s, C-3′), 121.0
3
(s, C-1), 116.6 (2 d, C-2′), 54.6 (s, C-2), 34.8 (t, C-1′), 29.4 (q, 3-Me),
25.9 (2 q, 3′-Me(E)), 18.1 (2 q, 3′-Me(Z)).
+
HRMS (EI): m/z [M] calcd for C14
H21NO: 219.1618; found: 219.1621.
Odor description (10% DPG, blotter): green, aromatic, freesia, ivy
leaves (hyperosmics); floral, fruity-rosy (hyposmics).
Odor threshold (GC): 0.25 ng/L air (hyperosmics); 19 ng/L air (hypos-
mics).
Analytical TLC was performed on Merck silica gel 60 F254 TLC glass
plates and visualized with 254 nm light and KMnO staining solution,
4
followed by heating. Purification of reaction products was carried out
by flash chromatography using silica gel from SigmaAldrich (60752,
2-Cyclohexyl-3-oxo-2-phenylbutanenitrile (9)
An oven-dried Schlenk flask was charged with K CO (1.70 g, 12.3
mmol, 4 equiv). DMSO (1.80 mL) was added, and the resulting color-
less slurry was vigorously stirred prior to the addition of solid 3-oxo-
2
3
230–400 mesh particle size) or SiliaFlash P60 from Silicycle (230–400
mesh particle size) under 0.3–0.5 bar pressure. Analytical data were
in accordance with previously reported values. Sodium 1-cyano-2-
2
-phenylbutanenitrile (10; 500 mg, 3.08 mmol, 1 equiv) with rinsing
of the vessel walls with additional DMSO (1.80 mL). Iodocyclohexane
1.60 mL, 12.4 mmol, 4 equiv) was added in one portion via syringe.
9
oxopropan-1-ide (8) was prepared following literature precedence.
1
H NMR spectra were recorded on a Bruker AV 400 MHz spectrometer
with the solvent resonance as the reference (CDCl δ = 7.26). C NMR
spectra were recorded with H-decoupling on a Bruker AV 100 MHz
(
13
3
The mixture was stirred for 4.5 d at r.t., and then it was transferred to
a separatory funnel and diluted with EtOAc (10 mL) and water (5 mL).
The phases were separated, and the aqueous layer was extracted with
EtOAc (2 × 10 mL). The combined organic layers were washed with
sat. aq NaHCO soln (2 × 10 mL) and brine (10 mL), dried (MgSO ), and
1
spectrometer with the solvent resonance as the reference (CDCl δ =
3
77.0). Infrared spectra were recorded neat on a Perkin-Elmer Spec-
trum Two FT-IR spectrometer. HRMS data were obtained from the
mass spectrometry service operated by the Laboratory of Organic
Chemistry at the ETHZ on a Micromass (Waters) AutoSpec Ultima for
EI or on a Bruker maXis–ESI-Qq-TOF-MS for ESI, respectively.
3
4
concentrated in vacuo. Purification by column chromatography (silica
gel, hexanes/EtOAc, 19:1, R = 0.3) afforded 9 (230 mg, 31%) as a color-
f
less and odorless oil that solidified upon storage in the freezer.
Olfactory evaluations were performed by an expert perfumer with a
IR (neat): 2931, 2855, 2238, 1725, 1495, 1449, 1357, 1182, 1166, 754,
10% soln of the sample substances in dipropylene glycol (DPG) and
–1
698, 595 cm
.
EtOH on smelling blotters. Odor thresholds were determined by GC–
olfactometry: Different dilutions of the sample substance were inject-
ed into a gas chromatograph in descending order of concentration un-
til the panelist failed to detect the respective substance at the sniffing
port. The reported threshold values are the geometric means of the
individual odor thresholds of 4–5 trained panelists.
1
H NMR (400 MHz, CDCl ): δ = 7.49–7.45 (m, 2 H, 2′-H), 7.43–7.33 (m,
H, 3′-H, 4′-H), 2.45 (tt, J = 10.9, 3.6 Hz, 1 H, 1′′-H), 2.30 (s, 3 H, 3-Me),
.86–1.73 (m, 2 H, 2′′-H, 2′′-H or 3′′-H), 1.73–1.61 (m, 2 H, 2′′-H
3
3
1
and/or 3′′-H), 1.46–1.28 (m, 2 H, 2′′-H, 2′′-H or 3′′-H), 1.26–0.97 (m, 4
H, 2′′-H or 3′′-H, 4′′-H).
13
C NMR (101 MHz, CDCl ): δ = 199.2 (S, C-3), 132.7 (s, C-1′), 129.3 (2
3
Sodium 1-Cyano-2-oxopropan-1-ide (8)8
d, C-2′), 128.7 (d, C-4′), 126.7 (2 d, C-3′), 118.9 (s, C-1), 65.9 (s, C-2),
3.4 (d, C-1′′), 29.8 (t, C-2′′), 28.3 (q, 3-Me), 27.5 (t, C-4′′), 26.1 (t, C-2′′
or C-3′′), 26.0 (t, C-2′′ or C-3′′), 25.8 (t, C-2′′ or C-3′′).
4
5-Methylisoxazole (7; 1.00 mL, 23.3 mmol, 1 equiv) was dissolved in
CH Cl (14 mL), and the resulting soln was immersed in a cooling
2
2
+
HRMS (EI): m/z [M] calcd for C16H19NO: 241.1462; found: 241.1475.
bath. At 0 °C, NaOMe (2.20 mL, 5.4 M, 23.2 mmol, 1 equiv) was added
in one portion. A colorless precipitate started to form, and the mix-
ture was allowed to spontaneously warm to r.t., and stirred overnight.
The solvent was removed in vacuo; the crude residue was washed
Odor description (10% DPG, blotter): vague, green, rosy, leathery.
Odor threshold (GC): 500 ng/L air.
with anhyd Et O and filtered to give a colorless solid (1.20 g, 99%),
which was used without further purification.
2
3
-Methyl-2,2-bis(3-methylbut-2-enyl)but-3-enenitrile (11)
In a cooling bath at 0 °C, Pd(PPh3)4 (7.9 mg, 6.86 μmol, 5 mol%) was
added to a soln of 3-cyano-6-methyl-3-(3-methylbut-2-enyl)hepta-
2
,2-Bis(3-methylbut-2-enyl)-3-oxobutanenitrile (6)
1
,5-dien-2-yl trifluoromethanesulfonate (13; 48 mg, 0.14 mmol, 1
Sodium 1-cyano-2-oxopropan-1-ide (8; 950 mg, 9.04 mmol, 1 equiv)
was dissolved in DMF (40 mL). The resulting soln was placed in a cool-
ing bath and at 0 °C, Cs CO (3.00 g, 9.49 mmol, 1.1 equiv) and 1-bromo-
equiv) in degassed THF (1 mL). The mixture was stirred at this tem-
perature for 5 min, and then Me Zn (0.14 mL, 0.28 mmol, 2 equiv)
2
2
3
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

H
Synthesis
N. Hauser et al.
Paper
was added dropwise, which resulted in complete discoloration of the
yellow mixture. Upon stirring overnight at r.t. the mixture slowly
turned back yellow again. It was then diluted with EtOAc (3 mL) and
separated, and the aqueous layer was extracted with Et O (3 × 10 mL).
The combined organic layers were washed with brine (10 mL), dried
2
(MgSO ), and concentrated in vacuo. Purification by flash chromatog-
4
quenched by the addition of sat. aq NaHCO (2 mL). The aqueous layer
raphy (silica gel, hexanes/EtOAc, 39:1, R = 0.2) furnished 13 (0.43 g,
3
f
was extracted with EtOAc (3 × 3 mL), and the combined organic layers
90%) as a colorless liquid.
were washed with brine (5 mL), dried (MgSO ), and concentrated in
vacuo. Purification by flash chromatography (silica gel, hexane/EtOAc,
4
IR (neat): 2975, 2919, 2864, 1656, 1422, 1211, 1138, 940, 794, 724,
–1
602 cm
.
3
9:1, R = 0.1) afforded 11 (22 mg, 74%) as a colorless liquid.
f
1
H NMR (500 MHz, CDCl ): δ = 5.45 (d, J = 5.0 Hz, 1 H, 4-H), 5.38 (d, J =
3
IR (neat): 2973, 2917, 2237, 1674, 1645, 1446, 1379, 1233, 1112,
5
.0 Hz, 1 H, 4-H), 5.20–5.14 (m, 2 H, 2′-H), 2.54 (dd, J = 14.7, 7.6 Hz, 2
H, 1′-H), 2.44 (dd, J = 14.7, 7.2 Hz, 2 H, 1′-H), 1.79–1.74 (m, 6 H, 3′-
Me(E)), 1.69–1.65 (br. s, 6 H, 3′-Me(Z)).
–1
1
065, 904, 839, 777 cm .
1
H NMR (400 MHz, CDCl ): δ = 5.20–5.18 (m, 1 H, 4-H), 5.16–5.09 (m,
3
2
2
3
H, 2′-H), 5.05–5.03 (m, 1 H, 4-H), 2.46 (dd, J = 14.8, 7.5 Hz, 2 H, 1′-H),
.35–2.27 (m, 2 H, 1′-H), 1.73 (m, 9 H, 3-Me, 3′-Me(E)), 1.64 (br. s, 6 H,
′-Me(Z)).
13
C NMR (126 MHz, CDCl ): δ = 151.2 (s, C-3), 138.2 (2 s, C-3′), 119.2
3
(s, C-1), 118.2 (q, J = 319.8 Hz, C-5), 116.0 (2 d, C-2′), 105.5 (t, C-4),
48.4 (s, C-2), 34.1 (2 t, C-1′), 25.9 (2 q, 3′-Me(E)
), 18.2 (2 q, 3′-Me(Z)).
13
C NMR (101 MHz, CDCl ): δ = 140.7 (s, C-3), 135.8 (2 s, C-3′), 122.4
19
3
F NMR (377 MHz, CDCl ): δ = –74.19.
3
(
s, C-1), 117.9 (2 s, C-2′), 115.1 (t, C-4), 48.8 (s, C-2), 35.1 (2 t, C-1′),
HRMS (EI): m/z [M]+ calcd for C15H20F NO S: 351.1111; found:
3
3
2
5.9 (2 q, 3′-Me(E)), 18.2 (3 q, 3′-Me(Z)), 18.1 (3 q, 3-Me).
HRMS (ESI): m/z [M + H]+ calcd for C15H24N: 218.1903; found:
18.1906.
351.1097.
2
2,2-Bis(3-methylbut-2-enyl)but-3-enenitrile (14)
Odor description (10% DPG, blotter): mild, rosy, citrusy, sweet, sl.
dusty.
Pd(PPh ) Cl (530 mg, 0.754 mmol, 50 mol%) and formic acid (0.10
mL, 2.65 mmol, 1.8 equiv) were added to a soln of 3-cyano-6-methyl-
3-(3-methylbut-2-enyl)hepta-1,5-dien-2-yl trifluoromethanesulfon-
3
2
2
Odor threshold (GC): 0.40 ng/L air (hyperosmics); 125 ng/L air (hy-
posmics).
ate (13; 0.53 g, 1.51 mmol, 1 equiv) and Bu N (1.0 mL, 4.21 mmol, 2.8
3
equiv) in DMF (12 mL). The mixture was stirred at 60 °C for 3 h, and
5-Methyl-2-(3-methylbut-2-enyl)hex-4-enenitrile (12)
then it was allowed to cool to r.t., prior to the addition of Et O (10 mL)
2
and water (5 mL). The organic layer was separated, the aqueous layer
To a soln of methyltriphenylphosphonium bromide (221 mg, 0.606
mmol, 1.3 equiv) in THF (0.93 mL) at –78 °C was added dropwise 1.6
M n-BuLi (0.38 mL, 0.608 mmol, 1.3 equiv). The mixture was stirred
at –78 °C for 10 min and then it was warmed to 0 °C and stirred for a
further 20 min. Then, 2,2-bis(3-methylbut-2-enyl)-3-oxobutane-
nitrile (6; 105 mg, 0.477 mmol, 1 equiv) in THF (0.30 mL) was added
and the mixture was allowed to spontaneously warm to r.t. and
was extracted with Et O (3 × 10 mL). The combined organic layers
2
were washed with water (10 mL) and brine (10 mL), dried (MgSO4),
and concentrated in vacuo. Purification by flash chromatography (sil-
ica gel, 100:0 to 99:1 pentane/Et O, R = 0.20) afforded 14 (0.20 mg,
2
f
6
5%) as a colorless liquid.
IR (neat): 2971, 2916, 2238, 1673, 1640, 1448, 1379, 1111, 986, 926,
–1
stirred overnight. It was diluted with Et O (5 mL) and quenched with
843, 778 cm .
2
brine (5 mL). The aqueous layer was extracted with Et O (2 × 5 mL).
1
2
H NMR (400 MHz, CDCl ): δ = 5.55 (dd, J = 17.1, 10.0 Hz, 1 H, 3-H),
3
The combined organic layers were dried (Na SO ) and concentrated in
2
4
5.43 (dd, J = 17.1, 0.8 Hz, 1 H, 4-H), 5.24 (dd, J = 10.0, 0.8 Hz, 1 H, 4-H),
5
J = 14.4, 7.0 Hz, 2 H, 1′-H), 1.76–1.73 (m, 6 H, 3′-Me(E)), 1.64 (br, s, 6 H,
3
1
vacuo. The crude H NMR revealed the formation of 12 together with
the desired product 11, in ca. 1.5:1 ratio. Purification by flash chro-
matography (silica gel, hexanes/EtOAc, 39:1) afforded clean fractions
of both compounds 11 and 12 for structure assignment.
1
.21–5.14 (m, 2 H, 2′-H), 2.43 (dd, J = 14.4, 7.8 Hz, 2 H, 1′-H), 2.25 (dd,
′-Me(Z)).
13
C NMR (101 MHz, CDCl ): δ = 136.8 (d, C-3), 136.3 (2 s, C-3′), 121.6
3
H NMR (400 MHz, CDCl ): δ = 5.24–5.12 (m, 2 H, 2′-H), 2.55–2.46 (m,
3
(s, C-1), 117.6 (2 d, C-2′), 116.7 (t, C-4), 46.2 (s, C-2), 36.5 (2 t, C-1′),
25.9 (2 q, 3′-Me(E)), 18.2 (2 q, 3′-Me(Z)).
HRMS (ESI): m/z [M + H]+ calcd for C14H22N: 204.1747; found:
1
H, 2-H), 2.40–2.20 (m, 4 H, 1′-H), 1.76–1.71 (m, 6 H, 3′-Me(E)), 1.64
(br. s, 6 H, 3′-Me(Z)).
13
C NMR (101 MHz, CDCl ): δ = 135.8 (2 s, C-3′), 122.3 (s, C-1), 119.2
3
204.1743.
(
2 d, C-2′), 32.4 (d, C-2), 30.2 (2 t, C-1′), 25.8 (2 q, 3′-Me(E)), 17.9 (2 q,
′-Me(Z)).
The spectroscopic data of 12 were identical to those reported in the
Odor description (10% DPG, blotter): fruity-rosy, spicy, pink pepper,
chamomile, fatty undertone.
3
12
Odor threshold (GC): 3.8 ng/L air.
literature.
2
,2-Dibenzyl-3-oxobutanenitrile (15)
3
-Cyano-6-methyl-3-(3-methylbut-2-enyl)hepta-1,5-dien-2-yl Tri-
fluoromethanesulfonate (13)
,2-Bis(3-methylbut-2-enyl)-3-oxobutanenitrile (6; 300 mg, 1.37
At 0 °C in a cooling bath, Cs CO (650 mg, 2.00 mmol, 1.1 equiv) and
BnBr (0.46 mL, 2.00 mmol, 2 equiv) were added to a soln of sodium 1-
cyano-2-oxopropan-1-ide (8; 200 mg, 1.90 mmol, 1 equiv) in DMF
2
3
2
mmol, 1 equiv) and HMPA (1.00 mL, 5.71 mmol, 4.2 equiv) were dis-
solved in THF (8.40 mL). The resulting soln was cooled to –78 °C and
(10 mL). The mixture was stirred for 3 h at r.t., and then it was
quenched by the addition of sat. aq NH Cl soln (15 mL). The aqueous
phase was extracted with Et O (3 × 20 mL), and the combined organic
layers were washed with water (2 × 20 mL) and brine (20 mL), dried
4
0
.2 M LDA (8.70 mL, 1.74 mmol, 1.3 equiv) was added dropwise. The
mixture was stirred for 40 min at –78 °C, prior to the dropwise addi-
tion of N-(5-chloro-2-pyridyl)bis(trifluoromethanesulfonimide)
Comins’ reagent) (700 mg, 96%, 1.71 mmol, 1.3 equiv) in THF (1.5
2
(MgSO ), and concentrated in vacuo. Purification by flash chromatog-
4
(
raphy (silica gel, hexane/EtOAc, 9:1, R = 0.3) afforded 15 (0.34 g, 67%)
as a crystalline, colorless and odorless solid; mp 93.3–93.8 °C.
f
mL) and the removal of the cooling bath. When the reaction had
warmed up to r.t., sat. aq NaHCO (10 mL) was added, the phases were
3
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

I
Synthesis
N. Hauser et al.
Paper
IR (neat): 3033, 2930, 2238, 1721, 1497, 1456, 1358, 1183, 756, 702
Odor threshold (GC): 0.38 ng/L air.
–1
cm
.
1
H NMR (400 MHz, CDCl ): δ = 7.38–7.22 (m, 10 H, Ph-H), 3.27 (d, J =
2-Formyl-2,2-bis(3-methylbut-2-enyl)acetonitrile (19)
3
1
3.3 Hz, 2 H, 1′-H), 3.00 (d, J = 13.3 Hz, 2 H, 1′-H), 1.84 (s, 3 H, 3-Me).
To a soln of 3-hydroxy-2,2-bis(3-methylbut-2-enyl)propanenitrile
(20; 440 mg, 2.12 mmol, 1 equiv) in CH Cl (14 mL) was added Dess–
13
C NMR (101 MHz, CDCl ): δ = 203.5 (s, C-3), 134.1 (2 s, C-2′), 130.1
2
2
3
Martin periodinane (1.80 g, 4.24 mmol, 2 equiv). The mixture was
stirred at r.t. for 2 h, and then it was quenched by the addition of sat.
NaHCO /10% NaHSO soln (1:1, 15 mL). Phases were separated and
(
2
4 d, C-3′), 128.7 (4 d, C-4′), 127.8 (2 d, C-5′), 120.5 (s, C-1), 57.3 (s, C-
), 43.2 (2 t, C-1′), 31.4 (q, 3-Me).
HRMS (ESI): m/z [M + Na]+ calcd for C18H17NNaO: 286.1202; found:
2
3
4
the aqueous layer was extracted with CH Cl (2 × 20 mL). The com-
2
2
86.1204.
bined organic layers were washed with sat. NaHCO soln (2 × 20 mL)
3
and brine (20 mL), dried (MgSO ), and concentrated in vacuo. Purifi-
4
2,2-Diallyl-3-oxobutanenitrile (16)
cation by flash chromatography (silica gel, hexane/EtOAc, 10:1, R =
f
At 0 °C in a cooling bath, Cs CO (1.00 g, 3.06 mmol, 1.1 equiv) and
0.3) afforded 19 (311 mg, 71%) as a colorless liquid.
2
3
allyl bromide (0.50 mL, 5.78 mmol, 2.2 equiv) were added to a soln of
sodium 1-cyano-2-oxopropan-1-ide (8; 300 mg, 2.86 mmol, 1 equiv)
in DMF (14 mL). The mixture was stirred at r.t. for 2.5 h, and then it
IR (neat): 2972, 2917, 2860, 2244, 1735, 1673, 1444, 1379, 839, 776,
–1
713 cm
.
1
H NMR (400 MHz, CDCl ): δ = 9.42 (s, 1 H, 3-H), 5.19–5.12 (m, 2 H, 2′-
was quenched by the addition of sat. aq NH Cl soln (15 mL). The aque-
3
4
H), 2.60–2.44 (m, 4 H, 1′-H), 1.75 (m, 6 H, 3′-Me(E)), 1.65 (br, s, 6 H, 3′-
Me(Z)).
ous phase was extracted with Et O (3 × 20 mL), and the combined or-
2
ganic layers were washed with water (2 × 20 mL) and brine (20 mL),
13
dried (MgSO ), and concentrated in vacuo. Purification by flash chro-
C NMR (101 MHz, CDCl ): δ = 194.8 (d, C-3), 138.2 (2 s, C-3′), 118.7
3
4
matography (silica gel, hexane/EtOAc, 9:1, R = 0.3) afforded 16 (0.29
g, 63%) as a colorless oil.
(s, C-1), 115.7 (2 d, C-2′), 54.2 (s, C-2), 32.1 (2 t, C-1′), 25.9 (2 q, 3′-
Me(E)), 18.2 (2 q, 3′-Me(Z)).
f
+
IR (neat): 3084, 2985, 2922, 2238, 1724, 1643, 1442, 1419, 1361,
HRMS (EI): m/z [M] calcd for C13H19NO: 205.1462; found: 205.1462.
–1
1186, 995, 929, 600 cm .
Odor description (10% DPG, blotter): rather weak, green, chemical,
reminiscent of gun powder.
1
H NMR (400 MHz, CDCl ): δ = 5.83–5.71 (m, 2 H, 2′-H), 5.29–5.17 (m,
3
4
H, 3′-H), 2.59 (ddt, J = 13.8, 7.4, 1.1 Hz, 2 H, 1′-H), 2.45 (ddt, J = 13.8,
Odor threshold (GC): 25 ng/L air.
7.3, 1.1 Hz, 2 H, 1′-H), 2.38 (s, 3 H, 3-Me).
1
3
C NMR (101 MHz, CDCl ): δ = 201.8 (s, C-3), 130.4 (2 d, C-2′), 121.2
3
3-Hydroxy-2,2-bis(3-methylbut-2-enyl)propanenitrile (20)
(2 t, C-3′), 120.0 (s, C-1), 54.0 (s, C-2), 40.1 (2 t, C-1′), 29.4 (q, 3-Me).
NaBH (849 mg, 22.44 mmol, 8 equiv) was added to a soln of methyl
4
+
HRMS (EI): m/z [M – C H O] calcd for C H11N: 120.0808; found:
2-cyano-2,2-bis(3-methylbut-2-enyl)acetate (17; 660 mg, 2.80 mmol,
2
3
8
120.0813.
1 equiv) in THF/H O (14:1, 9 mL). The mixture was stirred at r.t. for
2
9
.5 h, and then it was quenched by the addition of sat. aq NH Cl (8
Odor description (10% DPG, blotter): green, metallic, coniferous, hay.
4
mL) and diluted with EtOAc (4 mL). The aqueous phase was extracted
with Et O (3 × 10 mL). The combined organic layers were washed
with sat. aq NaHCO3 (20 mL) and brine (20 mL), dried (MgSO ), and
Odor threshold (GC): 6.8 ng/L air (hyperosmics); 79 ng/L air (hypos-
mics).
2
4
concentrated in vacuo. Purification of the resulting residue by flash
Methyl 2-Cyano-2,2-bis(3-methylbut-2-enyl)acetate (17)
chromatography (silica gel, hexane/EtOAc, 9:1, R = 0.1) afforded 20
f
At 0 °C in a cooling bath, 1-bromo-3-methylbut-2-ene (5.80 mL, 50.0
mmol, 2.2 equiv) and Cs CO (16.3 g, 50.0 mmol, 2.2 equiv) were add-
(500 mg, 86%) as a colorless liquid which solidified upon storage in
the freezer.
2
3
ed to a soln of methyl 2-cyanoacetate (18; 2.00 mL, 22.8 mmol, 1
equiv) in DMF (100 mL). The mixture was stirred at r.t. for 1.5 h, and
then the solvent was removed in vacuo. The resulting residue was
IR (neat): 3470, 2970, 2916, 2237, 1673, 1444, 1379, 1078, 1050, 842,
–1
779 cm
.
1
H NMR (400 MHz, CDCl ): δ = 5.29–5.19 (m, 2 H, 2′-H), 3.64 (d, J = 6.4
partitioned between sat. aq NaHCO (50 mL) and EtOAc (200 mL), and
3
3
Hz, 2 H, 3-H), 2.35–2.30 (m, 4 H, 1′-H), 1.76 (m, 6 H, 3′-Me(E)), 1.72 (br.
t, J = 6.4 Hz, 1 H, OH), 1.66 (br. s, 6 H, 3′-Me(Z)).
the aqueous phase was extracted with EtOAc (2 × 200 mL). The com-
bined organic layers were washed with brine (3 × 200 mL), dried
13
(
MgSO ), and concentrated in vacuo. Purification of the resulting resi-
C NMR (101 MHz, CDCl ): δ = 136.9 (2 s, C-3′), 122.5 (s, C-1), 117.4
3
4
due by flash chromatography (silica gel, hexane/EtOAc, 95:5, R = 0.2)
afforded 17 (4.93 g, 92%) as a colorless liquid.
(2 d, C-2′), 65.4 (t, C-3), 44.5 (s, C-2), 32.0 (2 t, C-1′), 26.0 (2 q, 3′-
Me(E)), 18.1 (2 q, 3′-Me(Z)).
f
IR (neat): 2917, 1747, 1438, 1379, 1310, 1231, 1068, 840, 795 cm–1
.
HRMS (EI): m/z [M] calcd for C13H21NO: 207.1618; found: 207.1623.
+
1
H NMR (400 MHz, CDCl ): δ = 5.20–5.13 (m, 2 H, 2′-H), 3.78 (s, 3 H, 4-
3
H), 2.64 (dd, J = 14.3, 7.6 Hz, 2 H, 1′-H), 2.55 (dd, J = 14.3, 7.5 Hz, 2 H,
Ethyl 2-Cyano-2,2-bis(3-methylbut-2-enyl)acetate (22)
1′-H), 1.76–1.72 (m, 6 H, 3′-Me(E)), 1.65 (br, s, 6 H, 3′-Me(Z)).
At 0 °C in a cooling bath, 1-bromo-3-methylbut-2-ene (0.72 mL, 6.19
1
3
mmol, 2.2 equiv) and Cs CO (2.02 g, 6.20 mmol, 2.2 equiv) were add-
ed to a soln of ethyl 2-cyanoacetate (21; 0.30 mL, 2.82 mmol, 1 equiv)
in DMF (15 mL). The mixture was stirred at r.t. for 1.5 h, and then it
C NMR (101 MHz, CDCl ): δ = 169.3 (s, C-1), 137.8 (2 s, C-3′), 119.3
2 3
3
(s, C-3), 116.5 (2 d, C-2′), 53.2 (q, C-4), 50.0 (s, C-2), 35.2 (2 t, C-1′),
2
6.0 (2 q, 3′-Me(E)), 18.1 (2 q, 3′-Me(Z)).
was diluted with Et O (15 mL), prior to quenching by the addition of
HRMS (ESI): m/z [M + H]+ calcd for C14H22NO : 236.1645; found:
2
2
2
sat. aq NaHCO3 (10 mL) and water (10 mL). The aqueous phase was
36.1642.
extracted with Et O (3 × 15 mL). The combined organic layers were
2
Odor description (10% DPG, blotter): floral, rosy, linalyl esters, cham-
omile.
washed with water (2 × 15 mL) and brine (15 mL), dried (MgSO ), and
4
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

J
Synthesis
N. Hauser et al.
Paper
13
concentrated in vacuo. Purification of the resulting residue by flash
C NMR (101 MHz, CDCl ): δ = 170.0 (s, C-1), 119.7 (s, C-3), 53.2 (q, C-
3
chromatography (silica gel, hexane/EtOAc, 25:2, R = 0.2) afforded 22
4), 50.4 (s, C-2), 42.2 (2 t, C-1′), 7.1 (2 d, C-2′), 4.3 (2 t, C-3′a), 4.1 (2 t,
C-3′b).
f
(630 mg, 90%) as a colorless liquid.
IR (neat): 2979, 2917, 2243, 1742, 1446, 1379, 1227, 1068 cm–1
.
HRMS (ESI): m/z [M + H]+ calcd for C12H18NO : 208.1332; found:
2
1
208.1328.
H NMR (400 MHz, CDCl ): δ = 5.24–5.17 (m, 2 H, 2′-H), 4.25 (q, J = 7.1
3
Hz, 2 H, 4-H), 2.61 (dd, J = 14.2, 7.7 Hz, 2 H, 2′-H), 2.51 (dd, J = 14.2, 7.3
Hz, 2 H, 2′-H), 1.74 (br, s, 6 H, 3′-Me(E)), 1.67 (br, s, 6 H, 3′-Me(Z)), 1.31
Odor description (10% DPG, blotter): weak, green, chemical.
Odor threshold (GC): 310 ng/L air.
(t, J = 7.1 Hz, 3 H, 5-H).
1
3
C NMR (101 MHz, CDCl ): δ = 168.8 (s, C-1), 137.6 (2 s, C-3′), 119.4
3
Methyl 2,2-Di[(2Z)-but-2-enyl]-2-cyanoacetate (25)
(s, C-3), 116.6 (2 d, C-2′), 62.4 (t, C-4), 50.0 (s, C-2), 35.3 (2 t, C-1′),
Methyl 2,2-di(but-2-ynyl)-2-cyanoacetate (26; 0.32 g, 1.58 mmol, 1
equiv) was dissolved in toluene (16 mL). Lindlar’s catalyst (0.13 g,
0.031 mmol, 5% Pd, 2 mol%) and quinoline (0.05 mL, 0.424 mmol, 0.3
equiv) were added. The flask was evacuated until the solvents started
to bubble and flushed with N2 (3 ×) prior to the evacuation and the
installation of a H2 balloon. The mixture was stirred at r.t. for 2.5 h.
Then, the mixture was filtered through a plug of wet Celite and con-
centrated in vacuo. Purification by flash chromatography (silica gel,
2
5.9 (2 q, 3′-Me(E)), 18.1 (2 q, 3′-Me(Z)), 14.1 (q, C-5).
HRMS (ESI): m/z [M + H]+ calcd for C15H24NO : 250.1802; found:
2
2
50.1806.
Odor description (10% DPG, blotter): floral-fruity, aromatic, arnica,
tagetes, osmanthus, with fatty, animalic undertone.
Odor threshold (GC): 8.3 ng/L air.
hexane/EtOAc, 15:1, R = 0.3) afforded 25 (0.25 g, 1.221 mmol, 78%) as
a colorless and odorless liquid.
f
Methyl 2,2-Diallyl-2-cyanoacetate (23)
At 0 °C in a cooling bath, allyl bromide (0.60 mL, 6.93 mmol, 2.0
equiv) and Cs CO (2.24 g, 6.86 mmol, 2.0 equiv) were added to a soln
IR (neat): 3023, 2957, 2923, 2245, 1745, 1437, 1233, 1211, 711 cm–1
.
2
3
1
H NMR (400 MHz, CDCl ): δ = 5.75 (dqt, J = 11.1, 6.9, 1.4 Hz, 2 H, 3′-
of methyl 2-cyanoacetate (18; 0.30 mL, 3.41 mmol, 1 equiv) in DMF
15 mL). The mixture was stirred at r.t. for 1 h, and then it was diluted
with Et O (15 mL) and quenched by the addition of sat. aq NaHCO (10
3
H), 5.44 (dtq, J = 11.1, 7.6, 1.8 Hz, 2 H, 2′-H), 3.79 (s, 3 H, 4-Me), 2.73–
(
2.66 (m, 2 H, 1′-H), 2.64–2.57 (m, 2 H, 1′-H), 1.69–1.63 (m, 6 H, 4′-H).
2
3
13
mL) and water (10 mL). The aqueous phase was extracted with Et O (3
C NMR (101 MHz, CDCl ): δ = 169.1 (s, C-1), 129.9 (2 d, C-3′), 122.2
2
3
×
1
15 mL). The combined organic layers were washed with water (2 ×
(2 d, C-2′), 118.9 (s, C-3), 53.3 (q, C-4), 49.4 (s, C-2), 33.9 (2 t, C-1′),
13.1 (2 q, C-4′).
5 mL) and brine (15 mL), dried (MgSO ), and concentrated in vacuo.
4
Purification of the resulting residue by flash chromatography (silica
HRMS (ESI): m/z [M]+ calcd for C12H17NO2: 207.1254; found:
207.1248.
gel, hexane/EtOAc, 25:2, R = 0.2) afforded 23 (0.54 g, 89%) as a color-
f
less liquid.
IR (neat): 3085, 2985, 2958, 2247, 1748, 1644, 1440, 1229, 994, 930
Methyl 2,2-Di(but-2-ynyl)-2-cyanoacetate (26)
–1
cm
.
At 0 °C in a cooling bath, 1-bromobut-2-yne (900 mg, 6.77 mmol, 2.1
equiv) and Cs CO (2.26 g, 6.93 mmol, 2.1 equiv) were added to a soln
1
H NMR (400 MHz, CDCl ): δ = 5.88–5.75 (m, 2 H, 2′-H), 5.27–5.25 (m,
3
2
3
2
H, 3′-H), 5.25–5.21 (m, 2 H, 3′-H), 3.80 (s, 3 H, 4-H), 2.65 (ddt, J =
of methyl 2-cyanoacetate (0.29 mL, 3.30 mmol, 1 equiv) in DMF (15
mL). The mixture was stirred at r.t. for 45 min, and then it was diluted
13.8, 7.4, 1.1 Hz, 2 H, 1′-H), 2.55 (ddt, J = 13.8, 7.2, 1.1 Hz, 2 H, 1′-H).
1
3
with Et O (10 mL), prior to quenching the reaction by the addition of
C NMR (101 MHz, CDCl ): δ = 168.5 (s, C-1), 130.4 (2 d, C-2′), 121.1
2
3
sat. aq NaHCO (8 mL) and water (5 mL). The aqueous phase was ex-
(2 t, C-3′), 118.4 (s, C-3), 53.3 (q, C-4), 49.4 (s, C-2), 40.7 (2 t, C-1′).
3
tracted with Et O (3 × 10 mL). The combined organic layers were
+
2
HRMS (EI): m/z [M – C H ] calcd for C H NO : 138.0550; found:
1
3
5
7
8
2
washed with water (20 mL) and brine (20 mL), dried (MgSO ), and
4
38.0551.
concentrated in vacuo. Purification of the resulting residue by flash
Odor description (10% DPG, blotter): very weak, metallic-green, rosy.
Odor threshold (GC): 500 ng/L air.
chromatography (silica gel, hexane/EtOAc, 9:1, R = 0.3) afforded 26
f
(420 mg, 63%) as a colorless and odorless liquid.
IR (neat): 2958, 2924, 2856, 2243, 1750, 1437, 1244, 1217, 1071 cm–1
.
Methyl 2-Cyano-2,2-bis(cyclopropylmethyl)acetate (24)
1
H NMR (400 MHz, CDCl ): δ = 3.86 (s, 3 H, 4-H), 2.84 (q, J = 2.5 Hz, 4
3
At 0 °C in a cooling bath, Cs CO (2.3 g, 6.99 mmol, 2.1 equiv) and cy-
H, 1′-H), 1.81 (t, J = 2.5 Hz, 6 H, 4′-H).
2
3
clopropylmethyl bromide (0.68 mL, 7.01 mmol, 2.1 equiv) were added
to a soln of methyl 2-cyanoacetate (18; 0.30 mL, 3.41 mmol, 1 equiv)
in DMF (15 mL). The mixture was stirred for 1.25 h at r.t., and then it
13
C NMR (101 MHz, CDCl ): δ = 167.3 (s, C-1), 117.9 (s, C-3), 81.1 (2 s,
3
C-2′), 71.2 (2 s, C-3′), 53.9 (q, C-4), 48.4 (s, C-2), 26.3 (2 t, C-1′), 3.6 (2
q, C-4′).
was poured into sat. aq NaHCO soln (20 mL). The aqueous phase was
3
+
HRMS (EI): m/z [M – CH3] calcd for C11H10NO : 188.0706; found:
extracted with Et O (2 × 70 mL), and the combined organic layers
2
2
188.0710.
were washed with water (30 mL) and brine (30 mL), dried (MgSO4),
and concentrated in vacuo. Purification by flash chromatography (sil-
ica gel, hexane/EtOAc, 19:1, R = 0.3) afforded 24 (0.42 g, 60%) as a col-
Methyl 2-Cyano-2,2-di(prop-2-ynyl)acetate (27)
f
orless liquid.
At 0 °C in a cooling bath, propargyl bromide (0.75 mL, 80% in toluene,
IR (neat): 3084, 3007, 2955, 1770, 1746, 1435, 1239 cm–1
.
6.96 mmol, 2.0 equiv) and Cs CO (2.24 g, 6.86 mmol, 2.0 equiv) were
added to a soln of methyl 2-cyanoacetate (18; 0.30 mL, 3.41 mmol, 1
equiv) in DMF (15 mL). The mixture was stirred at r.t. for 1 h, then it
2 3
1
H NMR (400 MHz, CDCl ): δ = 3.84 (s, 3 H, 4-H), 1.89 (dd, J = 14.0, 6.3
3
Hz, 2 H, 1′-H), 1.73 (dd, J = 14.0, 7.7 Hz, 2 H, 1′-H), 0.93–0.82 (m, 2 H,
was diluted with Et O (15 mL), prior to quenching the reaction by the
2
2
(
4
′-H), 0.62–0.54, (m, 2 H, 3′a-H), 0.54–0.45 (m, 2 H, 3′b-H), 0.24
dddd, J = 9.6, 5.0, 5.0, 5.0, 5.0, Hz, 2 H, 3′a-Ha), 0.11 (dddd, J = 9.6, 4.9,
.9, 4.9 Hz, 2 H, 3′b-H).
addition of sat. aq NaHCO3 (10 mL) and water (10 mL). The aqueous
phase was extracted with Et O (3 × 15 mL). The combined organic lay-
2
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

K
Synthesis
N. Hauser et al.
Paper
ers were washed with water (2 × 15 mL) and brine (15 mL), dried
MgSO ), and concentrated in vacuo. Purification of the resulting resi-
(12) Hanson, S. S.; Doni, E.; Traboulsee, K. T.; Coulthard, G.; Murphy,
J. A.; Dyker, C. A. Angew. Chem. Int. Ed. 2015, 54, 11236.
(13) Examples for nucleophile induced retro-Claisen reactions:
(a) Roshchupkina, G. I.; Gatilov, Y. V.; Rybalova, T. V.; Reznikov,
V. A. Eur. J. Org. Chem. 2004, 1765. (b) Xie, F.; Yan, F.; Chen, M.;
Zhang, M. RSC Adv. 2014, 4, 29502. (c) Yang, D.; Zhou, Y.; Xue,
N.; Qu, J. J. Org. Chem. 2013, 78, 4171.
(
4
due by flash chromatography (silica gel, hexane/EtOAc, 4:1, R = 0.3)
f
afforded 27 (0.46 g, 77%) as a colorless liquid.
IR (neat): 3293, 2960, 2254, 2129, 1751, 1438, 1246, 1221, 660 cm–1
.
1
H NMR (400 MHz, CDCl ): δ = 3.89 (s, 3 H, 4-H), 2.95 (d, J = 2.7 Hz, 4
3
H, 1′-H), 2.24 (t, J = 2.7 Hz, 2 H, 3′-H).
(14) Nobel lecture: Negishi, E. Angew. Chem. Int. Ed. 2011, 50, 6738.
13
C NMR (101 MHz, CDCl ): δ = 166.5 (s, C-1), 117.0 (s, C-3), 76.0 (2 s,
(15) (a) Marshall, J. A.; Zou, D. Tetrahedron Lett. 2000, 41, 1347.
(b) Marshall, J. A.; Van Devender, E. A. J. Org. Chem. 2001, 66,
8037. (c) Jung, Y. C.; Yoon, C. H.; Turos, E.; Yoo, K. S.; Jung, K. W.
J. Org. Chem. 2007, 72, 10114. (d) Whelligan, D. K.; Solanki, S.;
Taylor, D.; Thomson, D. W.; Cheung, K.-M. J.; Boxall, K.; Mas-
Droux, C.; Barillari, C.; Burns, S.; Grummitt, C. G.; Collins, I.; van
Montfort, R. L. M.; Aherne, G. W.; Bayliss, R.; Hoelder, S. J. Med.
Chem. 2010, 53, 7682.
3
C-2′), 73.7 (2 d, C-3′), 54.2 (s, C-4), 47.2 (s, C-2), 25.7 (2 t, C-1′).
HRMS (EI): m/z [M – CH3]+ calcd for C H NO : 160.0393; found:
9
6
2
160.0393.
The spectroscopic data of 27 were identical to those reported in the
26
literature.
Odor description (10% DPG, blotter): weak and vague, green, rooty,
rubbery, muguet.
(
16) (a) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299.
(b) Smith, A. B. III.; Fox, R. J.; Vanecko, J. A. Org. Lett. 2005, 7,
3099.
Odor threshold (GC): 43 ng/L air (hyperosmics); odorless (hypos-
mics).
(
17) (a) Leung, G. Y. C.; Li, H.; Toh, Q.-Y.; Ng, A. M.-Y.; Sum, R. J.;
Bandwo, J. E.; Chen, D. Y.-K. Eur. J. Org. Chem. 2011, 183. (b) Hog,
D. T.; Mayer, P.; Trauner, D. J. Org. Chem. 2012, 77, 5838. (c) Hog,
D. T.; Huber, F. M. E.; Jiménez-Osés, G.; Mayer, P.; Houk, K. N.;
Trauner, D. Chem.–Eur. J. 2015, 21, 13646.
Acknowledgment
Sarah S. Eichenberger is acknowledged for her experimental contri-
bution to this work. Thanks are also due to Katarina Grman, Sandro
Dossenbach, Daniel Bieri, and their panelists for the determination of
odor thresholds, and to Dominique Lelievre for the olfactory evalua-
tions.
(
(
18) Gramstad, T. Spectrochim. Acta 1963, 19, 497.
19) Andrews, K. G.; Frampton, C. S.; Spivey, A. C. Acta Crystallogr.,
Sect. C: Cryst. Struct. Commun. 2013, 1207.
(20) De Jesus Cortez, F.; Lapointe, D.; Hamlin, A. M.; Simmons, E. M.;
Sargpong, R. Tetrahedron 2013, 69, 5665.
(21) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
References
(22) (a) Walsh, A. D. Trans. Faraday Soc. 1949, 45, 179; and refer-
ences cited therein. (b) de Meijere, A. Angew. Chem., Int. Ed. Engl.
1979, 18, 809.
(23) (a) Talele, T. T. J. Med. Chem. 2016, 59, 8712. Recent example for
the application of cyclopropanes as olefin isosteres in fragrance
chemistry: (b) Jordi, S.; Kraft, P. Helv. Chim. Acta 2018, 6,
e1800048.
(1) Jozitsch, J. Zh. Russ. Fiz.-Khim. O-va 1897, 29, 111; Chem. Zentr-
albl. 1897, 68, 1015.
(2) Schmidt, T.; Draber, W.; Behrenz, W. DE 2644590, 1978; Chem.
Abstr. 1978, 89, 23992.
(
(
3) Pesaro, M. WO 9716512, 1997; Chem. Abstr. 1997, 127, 23595
4) Flachsmann, F.; Bachmann, J.-P. WO 2006133592, 2006; Chem.
Abstr. 2006, 146, 86956.
(24) Lindlar, H. Helv. Chim. Acta 1952, 35, 446.
(25) Maddess, M. L.; Lautens, M. Org. Lett. 2005, 7, 3557.
(26) (a) Hashmi, A. S. K.; Haeffner, T.; Rudolph, M.; Rominger, F.
Chem.–Eur. J. 2011, 17, 8195. (b) Oediger, H.; Moeller, F. Justus
Liebigs Ann. Chem. 1976, 348.
(27) Sturm, W. Parfuem. Kosmet. 1974, 55, 351.
(28) Discovery Studio, v. 18.1.100.18065, Dassault Systèmes Biovia
Corp., San Diego, CA 92121 USA, 2017. For more information,
see http://accelrys.com/products/collaborative-science/biovia-
discovery-studio/.
(
5) (a) Narula, A. P. S. In Perspectives in Flavor and Fragrance
Research; Kraft, P.; Swift, K. A. D., Eds.; Verlag Helvetica Chimica
Acta: Zürich and Wiley-VCH, Weinheim, 2005; 163. (b) Narula,
A. P. S. Chem. Biodiversity 2004, 1, 1992.
(6) Gonzenbach, H. U.; Ochsner, P. A. EP 0024306, 1981.
(7) Gebauer, H. DE 3328422, 1985; Chem. Abstr. 1985, 103, 53705.
(8) Romanov-Michailidis, F.; Besnard, C.; Alexakis, A. Org. Lett.
2012, 14, 4906.
(
9) Yu, H.; Moore, M. L.; Erhard, K.; Hardwicke, M. A.; Lin, H.;
Luengo, J. I.; McSurdy-Freed, J.; Plant, R.; Qu, J.; Raha, K.;
Rominger, C. M.; Schaber, M. D.; Spengler, M. D.; Rivero, R. A.
ACS Med. Chem. Lett. 2013, 4, 230.
(29) Molecular Operating Environment (MOE), release 2016.08.02,
Chemical Computing Group, Montreal, Quebec, Canada H3A
2R7, 2014. For more information, see http://www.chem-
comp.com/.
(
(
10) Grenning, A. J.; Tunge, J. A. J. Am. Chem. Soc. 2011, 133, 14785.
11) Zhu, S.; Buchwald, S. L. J. Am. Chem. Soc. 2014, 136, 15913.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K