The Direct Conversion of α-Hydroxyketones to Alkynes

Article abstract of DOI:10.1021/acs.joc.8b02941

Alkynes are highly important functional groups in organic chemistry, both as part of target structures and as versatile synthetic intermediates. In this study, a protocol for the direct conversion of α-hydroxyketones to alkynes is reported. In combination with the variety of synthetic methods that generate the required starting materials by forming the central C-C bond, it enables a highly versatile fragment coupling approach toward alkynes. A broad scope for this novel transformation is shown alongside mechanistic insights. Furthermore, the utility of our protocol is demonstrated through its application in concert with varied α-hydroxyketone syntheses, giving access to a broad spectrum of alkynes.

Full text of DOI:10.1021/acs.joc.8b02941

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Article
The Direct Conversion of #-Hydroxyketones to Alkynes
Francesca Ghiringhelli, Lukas Nattmann, Sabine Bognar, and Manuel van Gemmeren
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02941 • Publication Date (Web): 19 Dec 2018
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The Journal of Organic Chemistry
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The Direct Conversion of α-Hydroxyketones to Alkynes
Francesca Ghiringhelli,[a] Lukas Nattmann,[a] Sabine Bognar,[a] Manuel van Gemmeren[a],[b]*
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[a] Westfälische Wilhelms-Universität Münster, Corrensstraße 40, 48149 Münster, Germany. [b] Max-Planck-Institute for
Chemical Energy Conversion, Stiftstraße 34-36, 45470 Mülheim an der Ruhr, Germany.
Acyloins, Alkynes, Synthetic methods, Triple bond formation
ABSTRACT: Alkynes are highly important functional groups in organic chemistry, both as part of target structures and as versatile
synthetic intermediates. In this study, a protocol for the direct conversion of α-hydroxyketones to alkynes is reported. In combination
with the variety of synthetic methods that generate the required starting materials by forming the central C–C bond, it enables a highly
versatile fragment coupling approach towards alkynes. A broad scope for this novel transformation is shown alongside mechanistic
insights. Furthermore, the utility of our protocol is demonstrated through its application in concert with varied α-hydroxyketone
syntheses, giving access to a broad spectrum of alkynes.
through different approaches, we wondered if it would be
possible to generate this species from benzoin 2a by treatment
INTRODUCTION
The alkyne group arguably ranks amongst the most important
with tosylhydrazine and
a
suitable carbonate-derived
functional groups in organic chemistry.1 Accordingly, a variety
of methods exists to prepare internal alkynes,2 the synthesis of
which is at the center of this work (Scheme 1A). The most
common approaches can be divided into syntheses that start
from preformed alkyne precursors and syntheses that build up
this motif de novo. Notably, the majority of these methods, with
the alkyne metathesis as a notable exception,3 do not involve
the formation of the central C−C-bond, but rather forge the
neighboring bond,4 or do not involve a C−C-bond formation at
all. The latter is for example the case for methods based on the
di-functionalization/double elimination starting from olefins,2
or for fragmentation based approaches.5 Based on the
realization that methods forming the central C−C-bond are
scarce, we wondered, whether a protocol could be devised that,
analogously to olefination reactions, would enable the
formation of internal alkynes from two separate fragments. Our
attention was drawn to the fragmentation of tosylhydrazones
bearing an α-leaving group.6 Such reactions have the inherent
advantage that no regioselectivity issues arise, which would for
example be expected in the dehydration of ketones with two
aliphatic substituents,7 but the respective protocols typically
require harsh conditions and activated starting materials that
have to be accessed over several synthetic steps. In contrast, the
simple α-hydroxy ketone or acyloin moiety can be accessed
conveniently through a variety of established C–C bond-
forming protocols.8 We concluded that, if we could develop a
direct conversion of acyloins into alkynes, a highly flexible
two-step approach for the fragment coupling synthesis of
internal alkynes would result.6e,h, 9 We furthermore
hypothesized that achieving this target reaction would require
us to couple the alkyne formation to the formation of highly
stabilized species, in order to assure an overall favorable
energetic profile. Indeed, the groups of Rosenblum,10 Wilson,11
and Anselme12 have reported the formation of tolane 1a from
substrate 3, which proceeds through the base induced formation
of intermediate 4 and a subsequent thermal fragmentation
leading to nitrogen and carbon dioxide as byproducts (Scheme
1B). Although in these studies substrate 3 was synthesized
electrophile such as carbonyl diimidazole (CDI).13
Scheme 1. Common approaches towards internal alkynes
(A) and concept for the direct conversion of acyloins to
alkynes developed in this work (B).
No Formation of Central C-C Bond
Formation of Central C-C Bond
• Sonogashira reaction/alkylation
H
• Alkyne metathesis
R2
H/Me
+
R2
+
R1
R1
LG
Me/H
From preformed alkynes
• Ketone dehydration
This work: Acyloins as precursors
•
R2
FG
R2
O
LG
O
R1
R2
R2
R2
OH
R1
R1
R1
R1
FG
1
2
• Fragmentation of Ts-hydrazones with
-leaving groups
Many fragment coupling syntheses:
• Acyloin condensation
• Benzoin condensation
• Stoichiometric umpolung
• NHC-catalysis
Ts
HN
N
R2
LG
R1
• Biocatalysis
• ...
A
Ts
HN
B
Ts
N
O
CDI
NH2
N
O
CO2
N2
base

O
N
Ph
Ph
OH
2a
N
Ph
O
O
Ph
Ph
in situ?
Ph
Ph
Ph
3
4
1a
RESULTS AND DISCUSSION
We thus began our studies towards the development of suitable
reaction conditions. After separately optimizing the formation
of the hydrazone and the subsequent reaction with CDI, in both
cases limiting ourselves to conditions that would be compatible
with the respective other reaction step, we could indeed develop
reaction conditions that enable the formation of tolane 1a from
benzoin 2a (Scheme 2, for details on the optimization studies,
see the Supporting Information). The optimized protocol
involves the formation of the tosylhydrazone at room
temperature, catalyzed by diphenylphosphate and with
magnesiumsulfate monohydrate as a drying agent, followed by
the addition of CDI and heating to 100 °C.
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Scheme 2. Scope of the direct conversion of α-
hydroxyketones to alkynes.
settings, we became interested in obtaining further data
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regarding the functional group tolerance. Towards this goal, we
applied the additive based robustness screen developed by
Glorius et al., which provides information on the influence of
varied functional groups in cases where the respective
functional group is sterically and electronically independent of
the reactive center and is thus complementary to the explicitly
studied scope.15 The results of the robustness screen show that
most of the representative functional groups tested exerted
either no, or a very limited detrimental effect on the reaction
itself, free amines and to a lesser extent alcohols being the
notable exceptions (see the Supporting Information for a
detailed documentation of the robustness screen). Similarly, the
majority of additives remained intact under our reaction
conditions. Overall, these results indicate that the present
protocol for the conversion of acyloins to alkynes has a broad
functional group tolerance and will therefore likely be
applicable in complex synthetic settings.
TsNH-NH2 (1.2 equiv.), (PhO)2P(=O)OH (10 mol%)
MgSO4·H2O (1.8 equiv.), t-amyl-OH (0.2 M), rt, 6-12 h;
O
R2
R2
OH
R1
R1
then CDI (2.2 equiv.), 100 °C, 12 h
2
1
• Symmetric aromatic alkynes
O
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O
1a
1b
1c
, 55%
, 70%
(65% on gram scale)
, 71%
Br
Cl
Cl
Cl
COOMe
Br
MeOOC
1d
1e
1f
, 53%
, 61%
, 64%
O
O
During the course of our optimization studies, we made a
number of observations, which indicated that our reaction does
not proceed through the initially targeted intermediate 3. This
prompted us to study the reaction mechanism in more detail,
ultimately leading to the mechanistic proposal shown in
Scheme 3.
O
MeOOC
Cl
1g
1h
1i
, 52%
, 65%
, 50%
• Non-symmetric aromatic alkynes
I
Scheme 3. Mechanistic considerations.
Hal
Cl
TsHN
Hal
O
N
5
5
•
•
formed E-selectively
can be isolated and used as
1j,
1k
Hal = Br:
Hal = Cl:
63%
, 67%
TsNH-NH2
– H2O
Cl
OH
OH
Ph
1l
1m
, 67%
, 65%
Ph
Ph
starting material in next step
Ph
2a
• Aliphatic alkynes
• Robustness screen
5
Product yield
Additive recovery
15
CDI, r.t.
15
R
R
TsHN
N
N
N
N
1n,
1o
R = Cy:
R = n-Pr:
52%
, 49%
, 53%
O
N
• Intermediate proposed
based on literature analogies
Ph
R = (CH2)2Ph 1p
N
Ph
O
0
0
HN
100%
100%
yield
yield
6
• Color change (yellow) and
CO2 evolution almost instantly
after CDI addition
– CO2
– imidazole
We began to explore the scope of the reaction using acyloin
starting materials that are either commercially available or
could easily be accessed through an NCH-catalyzed benzoin
condensation from the corresponding aldehydes.14 Tolane 1a
was obtained in 70% yield, and the method was shown to be
scalable, giving 1a in 65% yield, when the reaction was
conducted on a gram scale. The protocol proved to be applicable
to substrates bearing both electron donating (1b,c) and electron-
TsHN
N
N
Ph

N
7
•
isolated and characterized
Ph
Ph
after CDI addition at r.t.
• Isolated reacts to
further reagents
Ph
7
1a
without
1a
7
During the separate optimization of the reaction steps, we could
confirm the formation of tosylhydrazone 5, which was isolated
as a single stereoisomer. Importantly, the isolated (E)-
tosylhydrazone 5 could be employed in the subsequent part of
the reaction without the need for the acid additive and drying
agent used under the optimized conditions, thus proving that
these components are irrelevant for the remainder of the
reaction. When tosylhydrazone 5 was treated with CDI at room
temperature, the almost instantaneous evolution of a gas
(identified as CO2 based on the stoichiometry of the reaction)
and a yellowish coloration of the reaction mixture were
observed. When this step was performed in different solvents
during the optimization studies, the precipitation of a colorless
compound was observed in some cases, which could be
identified as the imidazole adduct 7. Based on the known
reactivity between alcohols and CDI,16 we propose the initial
withdrawing
(1d-g)
substituents.
Furthermore,
the
heteroaromatic product 1h could be obtained from furoin in
good yield. Similarly, we could also apply our method for the
synthesis of unsymmetrically substituted alkynes 1i-m. It is
particularly noteworthy that both symmetric and non-
symmetric alkynes bearing halide substituents could be
accessed. These substituents provide a handle for further
functionalization and, at the same time, render the
corresponding products challenging targets for other methods
such as the Sonogashira reaction, especially in the case of
bromine (1d, 1j) and iodine (1l) substituents. Finally, we could
show that our method is also suited for the synthesis of alkynes
bearing aliphatic substituents (1n-p). In order to guide the
possible application of our protocol in more complex synthetic
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The Journal of Organic Chemistry
formation of an intermediate 6, which then extrudes CO2 to give proves to be problematic, the use of the other isomer serves as
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7
8
imidazole adduct 7. Two features of this process are remarkable
and suggest the non-innocence of the neighboring
tosylhydrazone functionality: Firstly, the reaction occurs in tert-
amyl alcohol as a solvent, i.e. in the presence of a large excess
of competing OH-groups. Here, the hydrazone lone pair likely
acts as an internal base to increase the reactivity of the OH-
group in the substrate, thereby allowing it to outcompete the
solvent in the reaction with CDI. Secondly, the extrusion of CO2
from alkyl alcohol/CDI-derived carbamates typically requires
very high temperatures, but an accelerating neighboring group
effect (e.g. by amines) has been described in the literature.16
Thus, although the precise mode of action remains unclear, we
propose an active participation of the tosylhydrazone moiety as
an explanation for the unusual ease with which CO2 is released.
We could next confirm that the isolated imidazole adduct 7
reacts to product 1a upon heating in tert-amyl alcohol, proving
that none of the remaining species in the reaction mixture is
required for this step. We concluded that the formation of 1a
either proceeds through an unimolecular thermal fragmentation
or with base assistance (where a second molecule of substrate 7
or the imidazole formed through the process could act as base),
leading to the overall formation of imidazole, nitrogen, p-
toluenesulfinic acid, and product 1a.6a,b,d-i
a strategy to address this challenge. In particular, we
encountered a side reaction when attempting to use substrate 2r
bearing a benzyl-substituent on the OH-side of the α-
hydroxyketone (Scheme 4B). Instead of the expected product
1r, we obtained heterocycle 10 in 53% yield, which is
presumably formed by imidazole elimination from the
intermediate analogous to 7, giving a stabilized, chalcone-
derived tosylhydrazone, which can subsequently cyclize to give
heterocycle 10. Based on this proposed mode of formation, we
predicted that it should be possible to obtain the desired product
1r by using the regioisomeric starting material 2r′ (Scheme 4C).
Indeed, using this starting material, product 1r was obtained in
68% yield using our standard protocol.
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As indicated in Scheme 4, different synthetic approaches can
prove useful to access starting materials with the required
substitution pattern. We thus wanted to probe the ability of our
method to serve as part of a highly flexible fragment coupling
two-step synthesis of internal alkynes. To this end, we
combined our protocol with several well-established syntheses
of α hydroxyketones, which together give access to a broad
spectrum of substitution patterns on the acyloins 2 and
consequently the alkynes 1 obtained in the second step (Scheme
5).
A notable feature of our protocol is that for non-symmetric
acyloins the two regioisomers are expected to converge into a
single product. This is particularly relevant in light of the fact
that many cross-acyloin or cross-benzoin reactions deliver
mixtures of regioisomers. For example, the NHC-catalyzed
cross-benzoin reaction of 4-chlorobenzaldehyde (8a) and
isobutyraldehyde (8b) gave the benzoin product with a high
selectivity for the crossed product, but the two regioisomers. 2q
and 2q′ were formed in close to equal amounts (Scheme 4A).
As expected, we could convert this mixture into a single product
1q using our protocol.
Scheme 5. Synthetic utility of our protocol: Applications in
concert with different syntheses of α-hydroxyketones.
O
OH
A. The traditional acyloin condensation
O
O
Na, TMS-Cl
then pTsOH
standard
MeO
OMe
conditions
11
12
2s
1s
, 52%
, 68%
B. Crossed-selective acyloin condensation: Synthesis of an unsymmetrical dialkylacetylene
O
O
7
Scheme 4. Convergence from mixtures of isomeric
substrates (A) and use of regioisomeric starting materials as
a strategy to address side reactions (B/C).
OH
O
O
2t
Li
standard
7
OH
(4-t-Bu-C6H4)2
conditions
7
7
O
O
13a
1t
, 53%
2t'
2t 2t'
A
O
O
82%,
:
= 1:1.1
H
C. Crossed-selective acyloin condensation: Application to a natural product derivative
OH
Cl
Cl
2q
8a
+
O
NHC-catalyzed
cross-benzoin
standard
O
O
Ph
OH
conditions
O
Li
H
H
OH
H
Cl
(4-t-Bu-C6H4)2
H
H
BzO
O
Cl
8b
2q'
1q
, 53%
H
H
H
H
AcO
HO
2q 2q'
:
60%,
= 1:0.9
H
H
13b
2u
, 39%
B
O
standard
Ph
conditions
H
OH
Ph
standard
N
HN
TMPMgCl • LiCl
8c
+
Ph
Ph
Ph
conditions
Ph
acidic
deprotection
NC
Ph
O
H
H
OTMS
9
2r
10
, 53%
,72%
H
H
HO
H
C
1u
, 38%
(47% NMR-yield)
O
N
O
BnMgBr
D. Stoichiometric Stork-Hünig-type Umpolung
standard
Ph
Ph
Ph
Ph
O
OH
O
conditions
Ph
O
OH
,82%
standard
TMPMgCl • LiCl
OTMS
CN
+
11
2r'
1r
, 68%
H
conditions
Ph
acidic
OH
deprotection
In contrast to this generally occurring convergence, we have
observed that in some cases, where one of the two regioisomers
9
8d
2v
1v
, 50%
, 74%
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We began by synthesizing the 13-membered cyclic substrate 2s Hz) and integration). For the spectra of regioisomeric mixtures
1
from di-ester 12 though a traditional acyloin condensation with
Na/TMS-Cl,8b,e which could subsequently be converted to the
corresponding cyclic alkyne 1s (Scheme 5A). In order to obtain
crossed acyloin products, we turned our attention to the method
developed by Donohoe and co-workers, which achieves the
desired selectivities through an intramolecularisation.17 Using
this method, we could access the substrates 2t and 2t′ from the
di-ester 13a, which as expected converged into a single alkyne
1t when we exposed the mixture to our reaction conditions
(Scheme 5B). In an analogous approach, we could demonstrate
the incorporation of a natural product scaffold by subjecting the
Litocholic acid-derived di-ester 13b to the conditions
developed by Donohoe et al. As expected based on the literature,
substrate 2u was obtained as a single regioisomer and could
subsequently be converted to the desired natural product-
derived alkyne 1u (Scheme 5C). Finally, we combined our
protocol with a substrate synthesis based on a Stork-Hünig-type
stoichiometric umpolung (Scheme 5D). Accordingly, we could
obtain substrate 2v, which is out of reach for typical NHC-
catalyzed protocols, by reacting the silylated cyanohydrin 9
with pivaldehyde 8d and could further convert it to alkyne 1v
using our protocol. a
signals clearly assigned to a particular regioisomer are labelled
with a superscript at the integration. The number of protons in
such cases refers to the number of protons of the respective
isomer. The absence of such an index indicates that the signals
of all observed regioisomers overlap, the integration given
corresponds to the number of protons in each isomer. All
spectra were processed using the MestReNova program. High
resolution mass spectra (HRMS) were recorded on a Bruker
Daltonics MicroTof or on a Thermo-Fisher Scientific Orbitrap
LTQ XL spectrometer using electron spray ionization (ESI).
Infrared Spectroscopy (IR) Infrared spectra were recorded neat
on a Shimadzu FTIR 8400S or a Varian Associates FTIR 3100
Excalibur spectrometer. The wave numbers (ν) of recorded IR-
signals are quoted in cm-1. GC-FID analyses were performed
using an Agilent Technologies 7890B setup equipped with an
HP5 column (30 m, 0.32 mm × 0.25 μm). GC-MS spectra were
recorded on an Agilent Technologies 7890A GC-system with
an Agilent 5975C VL MSD or an Agilent 5975 inert Mass
Selective Detector (EI) and an HP-5MS column (30 m, 0.32 mm
× 0.25 μm). The major signals are quoted in m/z with the relative
intensity in parentheses.
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General Procedure 1 for the Synthesis of Symmetric
Acyloins:14a DBU (0.4 equiv.) was added to a solution of
aldehyde (1 equiv.) and 1,3-dimethyl-1H-benzo[d]imidazol-3-
ium iodide (5 mol%) in dioxane or THF (0.4M). The mixture
was refluxed for 3 h, allowed to cool to room temperature, and
concentrated under reduced pressure. H2O (0.4M) was added to
the residue and the mixture was extracted with EtOAc (3 ×).
The combined organic phases were dried over MgSO4, filtered,
the solvent was evaporated under reduced pressure, and the
crude reaction mixture purified by flash column
chromatography (pentane/EtOAc = 8:2).
General Procedure 2 for the Synthesis of Non-Symmetric
Acyloins:14b 3-mesityl-4,5-dimethylthiazol-3-ium perchlorate
(10 mol%) and Et3N (20 mol%) were added to a solution of
aldehyde 1 (1 equiv.) and aldehyde 2 (1 equiv.) in dry THF
(1.7M). The resulting reaction mixture was stirred at 60 °C for
22 h, allowed to cool to room temperature, adsorbed on silica,
and purified by flash column chromatography (pentane/EtOAc
= 8:2).
General Procedure 3 for the Synthesis of Non-Symmetric
Acyloins via Stork-Hünig-Type Umpolung:18 TMPMgCl
·LiCl (1 M in THF, 1.3 equiv.) was added to a solution of 2-
phenyl-2-((trimethylsilyl)oxy)acetonitrile (1.0 equiv.) in THF
(0.25 M) at −20 °C and stirred for 2 h at this temperature. The
reaction mixture was cooled to −78 °C and the corresponding
aldehyde (1.2 equiv.) was added dropwise. The resulting
mixture was stirred overnight while letting it warm to room
temperature and quenched with sat. aq. NH4Cl solution. The
aqueous phase was extracted with EtOAc (3 ×) and the
combined organic layers were washed with H2O (3 ×), dried
over Na2SO4, filtered, and concentrated under reduced pressure.
The crude OTMS-ether was dissolved in MeOH (0.5 M) and aq.
HCl (1 M, 1.0 equiv.) was added. The mixture was stirred at
room temperature overnight and extracted with EtOAc (3 ×).
The combined organic layers were washed with sat. aq.
NaHCO3, H2O and, brine, dried over Na2SO4, and filtered. The
crude product was concentrated at reduced pressure and
purified by flash column chromatography (pentane/EtOAc =
9:1).
CONCLUSION
In conclusion, we have developed a direct protocol for the
conversion of α-hydroxyketones to alkynes that, in combination
with the multitude of C-C bond-forming syntheses of these
starting materials, constitutes a highly versatile approach to
alkynes. Unlike in most established methods for alkyne
synthesis, the central C-C bond is formed de novo and the
protocol utilizes simple laboratory reagents exclusively, such
that it can be carried out easily in a typical synthetic organic
chemistry lab. We could demonstrate a broad scope and the
applicability in concert with different substrate syntheses as
well as provide substantial insights into the mechanism of the
reaction. Our method provides a novel way of retrosynthetically
analyzing alkynes (α hydroxyketones as retrons), which is
complementary to established approaches and will thus likely
prove to be a valuable new tool in the many areas of chemistry
where alkynes play an important role as target molecules and
synthetic intermediates.
EXPERIMENTAL SECTION
General Information. Unless otherwise noted, all reactions
were carried out in oven-dried glassware and under a dry argon
atmosphere. Analytical thin layer chromatography (TLC) was
performed on silica gel 60 F254 aluminum plates (Merck).
Visualization was achieved by exposure to ultraviolet light (254
nm, 366 nm) and/or by staining. Flash column chromatography
was performed on silica gel (35-70 μm mesh, 60A, Acros) with
1
a positive argon overpressure. H- and 13C-NMR-spectra were
recorded at room temperature on a Bruker Avance II 300 MHz,
Bruker Avance II 400 MHz, Agilent DD2 500 or Agilent DD2
600 spectrometer. Chemical shifts (δ) are reported in ppm
relative to tetramethylsilane (TMS) using the residual solvent
peaks for calibration (CDCl3: δH = 7.26 ppm, δC = 77.16 ppm).
NMR-data are reported as follows: chemical shift (multiplicity
[s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet,
sept = septet, m = multiplet, br = broad], coupling constants (J,
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2-hydroxy-1,2-di-p-tolylethan-1-one (2b):19 Following the
formylbenzoate (328 mg, 2.00 mmol, 1.0 equiv.) as aldehyde
1
2
3
4
5
6
7
8
General Procedure 1 with 4-methylbenzaldehyde (240 mg, 2.00
mmol) as aldehyde component in dioxane the target compound
2b was obtained as a colorless solid (204 mg, 85%): 1H-NMR
(CDCl3, 400 MHz): δ = 7.82 (d, J = 6.7 Hz, 2H), 7.26 – 7.16
(m, 4H), 7.12 (d, J = 7.7 Hz, 2H), 5.89 (s, 1H), 4.55 (s, 1H),
2.35 (s, 3H), 2.29 (s, 3H) ppm; 13C{1H}-NMR (CDCl3, 101
MHz): δ = 198.7, 145.0, 138.5, 136.5, 131.1, 130.2, 129.9,
129.8, 129.5, 129.4, 127.8, 75.9, 21.9, 21.3 ppm.
components the target compound 2i was obtained as a yellow
1
solid (168 mg, 56%): H-NMR (CDCl3, 400 MHz): δ = 7.99
(dm, J = 8.4 Hz, 2H), 7.88 (dm, J = 9.0 Hz, 2H), 7.42 (dm, J =
8.4 Hz, 2H), 6.87 (dm, J = 9.0 Hz, 2H), 5.93 (d, J = 5.4 Hz,
1H), 4.71 (d, J = 5.8 Hz, 1H), 3.88 (s, 3H), 3.82 (s, 3H) ppm;
13C{1H}-NMR (CDCl3, 101 MHz): δ 196.7, 166.7, 164.4, 144.4,
131.7, 130.5, 127.9, 126.1, 114.2, 75.4, 55.7, 52.3 ppm; HRMS
(ESI+) m/z calcd. for C17H16O5Na+ [M + Na]+ 323.0895, found
323.0894; IR: (cm-1) = 3441, 1720, 1667, 1597, 1281, 1257,
1173, 972, 609.
2-hydroxy-1,2-bis(4-methoxyphenyl)ethan-1-one(2c):20
9
Following
the
General
Procedure
1
with
4-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
methoxybenzaldehyde (272 mg, 2.00 mmol) as aldehyde
component in THF the target compound 2c was obtained as a
colorless solid (190 mg, 70%): 1H-NMR (CDCl3, 400 MHz): δ
= 7.92 (d, J = 7.9 Hz, 2H), 7.27 (d, J = 8.9 Hz, 2H), 6.87 (m,
4H), 5.87 (s, 1H), 4.60 (s, 1H), 3.84 (s, 3H), 3.77 (s, 3H) ppm;
13C{1H}-NMR (CDCl3, 101 MHz): δ = 197.5, 164.1, 159.8,
132.0, 131.7, 129.1, 126.4, 114.6, 114.0, 75.4, 55.6, 55.4 ppm.
2-(2-bromophenyl)-1-(4-bromophenyl)-2-hydroxyethan-1-
one (2j):22 Following the General Procedure 2 with 4-
bromobenzaldehyde (370 mg, 2.00 mmol) and 2-
bromobenzaldehyde (370 mg, 2.00 mmol, 1.0 equiv.) as
aldehyde components the target compound 2j was obtained as
a yellow solid (237 mg, 64%): 1H-NMR (CDCl3, 400 MHz): δ
= 7.78 (d, J = 8.6 Hz, 2H), 7.62 (dm, J = 7.9 Hz, 1H), 7.55 (d,
J = 8.6 Hz, 2H), 7.23 (ddm, J = 7.6, 7.6 Hz, 1H), 7.15 (ddm, J
= 7.9, 7.6 Hz, 1H), 7.05 (dm, J = 7.6 Hz, 1H), 6.31 (s, 1H), 4.44
(br s, 1H) ppm; 13C{1H}-NMR (CDCl3, 101 MHz): δ = 197.9,
138.1, 133.8, 132.2, 131.9, 130.5, 130.4, 129.5, 129.2, 128.5,
124.2, 75.4 ppm.
2-(2-chlorophenyl)-1-(4-chlorophenyl)-2-hydroxyethan-1-
one (2k):14b Following the General Procedure 2 with 4-
chlorobenzaldehyde (281 mg, 2.00 mmol) and 2-
chlorobenzaldehyde (281 mg, 2.00 mmol, 1.0 equiv.) as
aldehyde components the target compound 2k was obtained as
a yellow solid (196 mg, 70%): 1H-NMR (CDCl3, 400 MHz): δ
= 7.85 (dm, J = 8.7 Hz, 2H), 7.42 (dd, J = 7.9, 1.4 Hz, 1H),
7.37 (dm, J = 8.7 Hz, 2H), 7.23 (ddd, J = 7.9, 7.4, 1.9 Hz, 1H),
7.18 (ddd, J = 7.6, 7.4, 1.4 Hz, 1H), 7.10 (dd, J = 7.6, 1.9 Hz,
1H), 6.33 (s, 1H), 4.52 (br s, 1H) ppm; 13C{1H}-NMR (CDCl3,
101 MHz): δ = 197.8, 140.8, 136.5, 133.7, 131.6, 130.5, 130.3,
129.3, 127.9, 73.0 ppm.
1,2-bis(4-bromophenyl)-2-hydroxyethan-1-one
(2d):20
Following the General Procedure 1 with 4-bromobenzaldehyde
(370 mg, 2.00 mmol) as aldehyde component in THF the target
compound 2d was obtained as a pale yellow solid (240 mg,
1
65%): H-NMR (CDCl3, 400 MHz): δ = 7.74 (d, J = 7.1 Hz,
2H), 7.55 (d, J = 7.1 Hz, 2H), 7.46 (d, J = 6.8 Hz, 2H), 7.18 (d,
J = 6.8 Hz, 2H), 5.86 (s, 1H), 4.49 (s, 1H) ppm; 13C{1H}-NMR
(CDCl3, 101 MHz): δ = 197.6, 137.6, 132.4, 132.2, 131.9, 130.5,
129.6, 129.4, 123.0, 75.5 ppm.
1,2-bis(4-chlorophenyl)-2-hydroxyethan-1-one(2e):20
Following the General Procedure 1 with 4-chlorobenzaldehyde
(281 mg, 2.00 mmol) as aldehyde component in THF the target
compound 2e was obtained as a yellow solid (216 mg, 77%):
1H-NMR (CDCl3, 400 MHz): δ = 7.69 (d, J = 7.0 Hz, 2H), 7.25
(d, J = 7.0 Hz, 2H), 7.17 (d, J = 8.7 Hz, 2H), 7.12 (d, J = 8.7
Hz, 2H), 5.75 (s, 1H), 4.37 (s, 1H) ppm; 13C{1H}-NMR (CDCl3,
101 MHz): δ = 197.6, 140.9, 137.3, 134.9, 131.7, 130.6, 129.6,
129.3, 129.2, 75.6 ppm.
2-hydroxy-2-(4-iodophenyl)-1-phenylethan-1-one
(2l):
Dimethyl 4,4'-(1-hydroxy-2-oxoethane-1,2-diyl)dibenzoate
(2f):21 Following the General Procedure 1 with methyl 4-
formylbenzoate (328 mg, 2.00 mmol) as aldehyde component
in dioxane the target compound 2f was obtained as a yellow
solid (223 mg, 68%): 1H-NMR (CDCl3, 400 MHz): δ = 8.03 (d,
J = 6.9 Hz, 2H), 7.96 (d, J = 6.7 Hz, 2H), 7.91 (d, J = 6.9 Hz,
2H), 7.39 (d, J = 6.7 Hz, 2H), 6.01 (s, 1H), 4.57 (s, 1H), 3.90
(s, 3H), 3.86 (s, 3H) ppm; 13C{1H}-NMR (CDCl3, 101 MHz): δ
= 198.3, 166.5, 165.9, 143.1, 136.7, 134.8, 130.6, 130.5, 130.0,
129.0, 127.8, 76.3, 52.7, 52.3 ppm.
Following the General Procedure 3 with 4-iodobenzaldehyde
(278 mg, 1.20 mmol, 1.2 equiv.) as aldehyde component, the
target compound 2l was obtained as a colorless solid (270 mg,
1
80%): H-NMR (CDCl3, 300 MHz): δ = 7.92 – 7.85 (m, 2H),
7.65 (d, J = 8.3 Hz, 2H), 7.59 – 7.51 (m, 1H), 7.46 – 7.37 (m,
2H), 7.08 (d, J = 8.3 Hz, 2H), 5.90 (d, J = 6.0 Hz, 1H), 4.55 (d,
J = 6.0 Hz, 1H) ppm; 13C{1H}-NMR (CDCl3, 75 MHz): δ =
198.6, 138.8, 138.4, 134.3, 133.3, 129.7, 129.2, 129.0, 94.7,
75.7 ppm; HRMS (ESI+) m/z calcd. for C13H24O2Na+ [M + Na]+
235.1674, found 235.1676; IR: (cm-1) = 3472, 3379, 1682, 1450,
1249, 1180, 1080, 972, 802, 702.
2-(2-Chlorophenyl)-1-(3-chlorophenyl)-2-hydroxyethanone
(2m):14b Following the General Procedure 2 with methyl 2-
chlorobenzaldehyde (281 mg, 2.00 mmol) and 3-
chlorobenzaldehyde (281 mg, 2.00 mmol, 1.0 equiv.) as
aldehyde components the target compound 2m was obtained as
a yellow solid (210 mg, 71%): 1H-NMR (CDCl3, 400 MHz): δ
= 7.94 (dd, J = 1.9, 1.9 Hz, 1H), 7.75 (ddd, J = 7.8, 1.3, 1.3 Hz,
1H), 7.50 (ddd, J = 8.0, 2.0, 1.0 Hz, 1H), 7.43 (dd, J = 7.8, 1.6
Hz, 1H), 7.34 (dd, J = 7.9, 7.9 Hz, 1H), 7.25 (ddd, J = 7.7, 7.6,
1.9 Hz, 1H), 7.20 (ddd, J = 7.6, 7.5, 1.4 Hz, 1H), 7.11 (dd, J =
7.5, 1.9 Hz, 1H), 6.34 (s, 1H), 4.45 (s, 1H) ppm; 13C{1H}-NMR
(CDCl3, 101 MHz): δ = 197.9, 136.3, 135.3, 134.9, 134.2, 133.7,
130.6, 130.4, 130.2, 129.3, 129.0, 128.0, 127.0, 73.2 ppm.
1,2-bis(3-chlorophenyl)-2-hydoxyethan-1-one
Following the General Procedure with methyl 3-
(2g):19
1
chlorobenzaldehyde (281 mg, 2.00 mmol) as aldehyde
component in THF the target compound 2g was obtained as a
yellow solid (185 mg, 66%): 1H-NMR (CDCl3, 400 MHz): δ =
7.90 (dd, J = 1.9, 1.9 Hz, 1H), 7.73 (ddd, J = 7.9, 1.4, 1.4 Hz,
1H), 7.52 (ddd, J = 8.0, 2.1, 1.0 Hz, 1H), 7.36 (dd, J = 7.9, 7.9
Hz, 1H), 7.33-7.30 (m, 1H), 7.27–7.25 (m, 2H), 7.21–7.18 (m,
1H), 5.87 (d, J = 4.5 Hz, 1H), 4.45 (d, J = 5.8 Hz, 1H) ppm;
13C{1H}-NMR (CDCl3, 101 MHz): δ = 197.5, 140.4, 135.4,
135.3, 134.9, 134.3, 130.7, 130.3, 129.2, 128.0, 127.3, 126.0,
75.8 ppm.
Methyl
4-(1-hydroxy-2-(4-methoxyphenyl)-2-
oxoethyl)benzoate (2i): Following the General Procedure 2 with
4-methoxybenzaldehyde (272 mg, 2.00 mmol) and 4-
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1,2-dicyclohexyl-2-hydroxyethan-1-one (2n):17 Following the
mL) at 0 °C. The resulting mixture was stirred for 1.5 h at 0 °C
1
2
3
4
5
6
7
8
General Procedure 1 with cyclohexanecarbaldehyde (224 mg,
2.00 mmol) as aldehyde component in dioxane the target
compound 2n was obtained as a colorless solid (145 mg, 65%):
1H-NMR (CDCl3, 400 MHz): δ = 4.15 (d, J = 2.4 Hz, 1H), 3.36
(br s, 1H), 2.54 (m, 1H), 1.87 – 1.59 (m, 10H), 1.57 – 1.40 (m,
2H), 1.38 – 1.00 (m, 9H) ppm; 13C{1H}-NMR (CDCl3, 101
MHz): δ = 215.5, 79.4, 46.3, 41.2, 30.5, 30.2, 27.3, 26.7, 26.1,
26.0, 26.0, 25.8, 25.6, 25.3 ppm.
and then allowed to warm to room temperature while stirring
overnight. Sat. aq. NH4Cl solution (5 mL) was added, the
phases were separated, and the organic layer was washed with
aq. HCl (1 M, 5 mL) and H2O (2 × 5 mL). The crude product
was dried over Na2SO4, filtered, concentrated under reduced
pressure, and purified by flash column chromatography
(pentane/EtOAc = 10:1). The target compound 2r´ was
obtained as a colorless solid (37 mg, 82 %): 1H NMR (CDCl3,
300 MHz): δ = 7.38 – 7.28 (m, 3H), 7.28 – 7.13 (m, 5H), 6.94
(dd, J = 7.4, 1.9 Hz, 2H), 5.12 (d, J = 4.5 Hz, 1H), 4.18 (d, J =
4.5 Hz, 1H), 3.58 (s, 2H) ppm; 13C{1H}-NMR (CDCl3, 75
MHz): δ = 207.1, 137.7, 133.0, 129.5, 129.3, 129.1, 128.8,
127.9, 127.4, 79.3, 44.7 ppm.; HRMS (ESI+): m/z calcd. for
C15H14O2Na+ [M + Na]+ 249.0886, found 249.0895; IR: (cm-1)
= 3418, 3387, 1705, 1381, 1335, 1226, 1126, 1273, 1042, 748,
694, 602, 586, 556.
2-hydroxycyclotridecan-1-one (2s): In analogy to a procedure
by Hisanaga et al.,25 a suspension of sodium (92.2 mg, 4.00
mmol, 4 equiv.) in toluene (2.00 mL) was heated at 110°C until
all the sodium melted. The resulting suspension was allowed to
cool to room temperature and trimethylsilyl chloride (507 µL,
4.00 mmol, 4 equiv.) was added dropwise, followed by the
addition of a solution of tridecanedioic acid dimethyl ester (273
mg, 1.00 mmol) in toluene (0.500 mL). The reaction mixture
was heated to 110 °C and stirred at this temperature for 1 h (the
reaction color turned purple). The reaction mixture was allowed
to cool to room temperature, the unreacted sodium was removed
by filtration and quenched with isopropanol. The filtrate was
extracted with EtOAc (3 × 20 mL) and the combined organic
layers were dried over MgSO4, filtered, and concentrated under
reduced pressure. The crude product was dissolved in THF (5
mL) and p-toluenesulfonic acid (688 mg, 4.00 mmol, 4 equiv.)
was added. The reaction mixture was stirred at room
temperature for 1 h. The mixture was diluted with water (10
mL) and extracted with EtOAc (3 × 20 mL). The combined
organic layers were dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude product was
purified by flash column chromatography (pentane/EtOAc =
9:1) and the target compound 2s was obtained as a colorless
solid (144 mg, 68%): 1H-NMR (CDCl3, 300 MHz): δ = 4.28 (t,
J = 4.6 Hz, 1H), 3.44 (s, 1H), 2.79–2.68 (m, 1H), 2.36–2.26 (m,
1H), 2.06–1.82 (m, 2H), 1.80–1.69 (m, 1H), 1.58–1.16 (m,
17H) ppm; 13C{1H}-NMR (CDCl3, 75 MHz): δ = 213.0, 76.4,
36.9, 32.8, 27.0, 26.5, 26.3, 25.3, 25.2, 25.1, 24.8, 21.9, 21.1
ppm; HRMS (ESI+) m/z calcd. for C13H24O2Na+ [M + Na]+
235.1674, found 235.1676; IR: (cm-1) = 3356, 2931, 1712, 1450,
1064, 1033, 702, 648.
4-hydroxy-1,6-diphenylhexan-3-one
(2p):23
3-mesityl-
9
5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazol-3-ium perchlorate
(74.8 mg, 0.200 mmol, 10 mol%) and Et3N (55.0 µL, 0.400
mmol, 20 mol%) were added to a solution of 3-phenylpropanal
(268 mg, 2.00 mmol) in dry THF (1.2 mL). The resulting
reaction mixture was stirred at 60 °C for 22 h, cooled to room
temperature, adsorbed on silica, and purified by flash column
chromatography (pentane/EtOAc = 8:2). The target compound
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
2p was obtained as a yellow oil (188 mg, 70%): H-NMR
(CDCl3, 400 MHz): δ = 7.39 – 7.36 (m, 4H), 7.32 – 7.24 (m,
6H), 4.21 (d, J = 5.0 Hz, 1H), 3.64 (s, 1H), 3.03 – 2.99 (m, 2H),
2.91 – 2.73 (m, 4H), 2.23 – 2.15 (m, 1H), 1.92 – 1.83 (m, 1H)
ppm; 13C{1H}-NMR (CDCl3, 101 MHz): δ = 211.3, 141.1,
140.5, 128.7, 128.6, 128.4, 126.5, 126.3, 75.9, 39.7, 35.5, 31.2,
29.6 ppm.
1-(4-chlorophenyl)-2-hydroxy-3-methylbutan-1-one + 1-(4-
chlorophenyl)-1-hydroxy-3-methylbutan-2one (2q+2q´):14b 3-
mesityl-5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazol-3-ium
perchlorate (74.8 mg, 0.200 mmol, 10 mol%) and Et3N (165 µL,
1.20 mmol, 60 mol%) were added to a mixture of 4-
chlorobenzaldehyde
(281
mg,
2.00
mmol)
and
isobutyraldehyde (547 µL, 6.00 mmol, 3 equiv.) and the
resulting mixture was dissolved in dry ethanol (1.5 mL). The
resulting reaction mixture was stirred at 60 °C for 22 h, allowed
to cool to room temperature, adsorbed on silica, and purified by
flash column chromatography (pentane/EtOAc = 8:2) The
mixture of the target compounds 2q and 2q´ was obtained as a
yellow solid (254 mg, 60%): 1H-NMR (CDCl3, 400 MHz): δ =
7.84 (d, J = 8.6 Hz, 2Hq), 7.47 (d, J = 8.6 Hz, 2Hq), 7.35 (d, J
= 8.5 Hz, 2Hq´), 7.25 (d, J = 8.5 Hz, 2Hq´), 5.19 (s, 1Hq´), 4.93
(s, 1Hq), 4.39 (s, 1Hq´), 3.55 (s, 1Hq), 2.68 (qq, J = 6.9, 6.9 Hz,
1Hq´), 2.09 (qqd, J = 6.8, 6.8, 2.5 Hz, 1Hq), 1.16 (d, J = 6.8
Hz, 3Hq), 1.13 (d, J = 6.9 Hz, 3Hq´), 0.84 (d, J = 6.9 Hz, 3Hq´),
0.65 (d, J = 6.8 Hz, 3Hq) ppm; 13C{1H}-NMR (CDCl3, 101
MHz): δ = 213.1, 201.2, 140.5, 136.6, 134.8, 132.5, 130.0,
129.4, 129.3, 129.0, 128.9, 127.3, 77.7, 77.4, 36.1, 32.8, 20.2,
19.5, 18.1, 14.5 ppm.
2-hydroxy-1,3-diphenylpropan-1-one (2r):24 Following the
General Procedure 3 with phenylacetaldehyde (0.30 mL, 2.6
mmol, 1.3 eq.) as aldehyde component, the target compound 2r
was obtained as a colorless solid (0.33 g, 72%).1H NMR (CDCl3,
400 MHz): δ = 7.92 (d, J = 8.1 Hz, 2H), 7.63 (dd, J = 7.4, 7.4
Hz, 1H), 7.51, (dd, J = 7.3, 7.3 Hz, 2H), 7.30 – 7.17 (m, 3H),
7.11 (d, J = 7.3 Hz, 2H), 5.33 (d, J = 4.4 Hz, 1H), 3.69 (d, J =
6.5 Hz, 1H), 3.19 (dd, J = 14.1, 3.8 Hz, 1H), 2.89 (dd, J = 14.1,
6.9 Hz, 1H) ppm. 13C{1H}-NMR (CDCl3, 101 MHz): δ = 201.2,
136.6, 134.2, 134.0, 129.6, 129.1, 128.8, 128.5, 127.0, 73.9,
42.1 ppm.
1-cyclohexyl-2-hydroxydecan-1-one
+
1-cyclohexyl-1-
hydroxydecan-2-one (2t+2t´): In an oven-dried Schlenk flask
lithium (120 mg, 20.0 mmol, 20 equiv.) was added to a solution
of 4,4 ′‐di‐tert‐butylbiphenyl (DBB) (532 mg, 2.00 mmol, 2.0
equiv.) in THF (20 mL) at 0 °C. The resulting teal-blue coloured
Li/DBB solution was stirred at this temperature for 2 h and was
then cooled to –78 °C.
(nonanoyloxy)bicyclo[2.2.1]heptan-2-yl
A
solution of (rac)-3-
cyclohexane-
carboxylate (13a) (378 mg, 1.00 mmol) in THF (5 mL) was
slowly added to the stirred solution of Li/DBB at –78 °C. After
the addition was completed, the reaction mixture was stirred at
–78 °C for 2 h and was quenched by dropwise addition of a
saturated aqueous solution of NH4Cl (5 mL). The reaction
1-hydroxy-1,3-diphenylpropan-2-one (2r´): Freshly prepared
benzyl magnesium bromide (approx. 1 M in Et2O, 1.2 mL, 1.2
mmol, 6.0 equiv.) was added dropwise to a solution of the
Weinreb amide 11 (0.04 g, 0.20 mmol, 1.0 equiv.) in Et2O (2
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The Journal of Organic Chemistry
mixture was allowed to warm to ambient temperature and was (m, 1H), 7.54 – 7.41 (m, 2H), 4.83 (dd, J = 8.1, 5.1 Hz, 1H),
1
2
3
4
5
6
7
8
transferred via cannula into brine (The remaining Li was
quenched by slow addition of isopropanol.). The solution was
extracted with diethyl ether (3 × 20 mL) and the combined
organic layers were dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude product was
purified by flash column chromatography (pentane/EtOAc =
9:1) and the mixture of the target compounds 2t+2t´ (1:1.1) was
3.50 (dd, J = 8.1, 5.0 Hz, 1H), 0.87 (d, J = 5.1 Hz, 9H) ppm;
13C{1H}-NMR (CDCl3, 75 MHz): δ = 204.3, 137.6, 133.7,
128.8, 128.6, 79.4, 36.5, 26.8 ppm; HRMS (ESI+) m/z calcd.
for C12H16O2Na+ [M + Na]+ 215.1043, found 215.1049; IR: (cm-
1) = 2963, 2253, 1677, 1280, 1226, 1180, 979, 602.
General Procedure 4 for the Synthesis of Alkynes: In a 10
mL Schlenk tube attached to the Ar line, acyloin (0.20 mmol,
1.0 equiv.), diphenylphosphate (5.0 mg, 20 µmol, 0.1 equiv.),
and MgSO4·H2O (50 mg, 0.36 mmol, 1.8 equiv.) were dissolved
in t-amyl-OH (1.0 mL) and tosylhydrazine (44 mg, 0.24 mmol,
1.2 equiv.) was added. The reaction mixture was stirred at room
temperature overnight. After the consumption of the acyloin
was confirmed by TLC analysis, 1,1'-carbonyldiimidazole (72
mg, 0.44 mmol, 2.2 equiv.) was added (immediately after the
addition the reaction turned yellow/orange and CO2 evolution
was observed), the resulting mixture was heated to 100 °C in an
aluminum block and stirred at this temperature for 9 h. The
reaction mixture was allowed to cool to room temperature, the
solvent was evaporated under reduced pressure, and the crude
product was adsorbed onto silica and purified by flash column
chromatography (pentane).
General Procedure 5 for the Synthesis of Alkynes: In a 10
mL Schlenk tube attached to the Ar line, acyloin (0.20 mmol,
1.0 equiv.), diphenylphosphate (5.0 mg, 20 µmol, 0.1 equiv.),
and MgSO4·H2O (50 mg, 0.36 mmol, 1.8 equiv.) were dissolved
in t amyl-OH (1.0 mL) and tosylhydrazine (44 mg, 0.24 mmol,
1.2 equiv.) was added. The reaction mixture was stirred at room
temperature overnight. After the consumption of the acyloin
was confirmed by TLC analysis, 1,1'-carbonyldiimidazole (72
mg, 0.44 mmol, 2.2 equiv.) was added (immediately after the
addition the reaction turned yellow/orange and CO2 evolution
was observed). The resulting mixture was heated to 100 °C in
an aluminum block and stirred at this temperature for 24 h. The
reaction mixture was allowed to cool to room temperature, the
solvent was evaporated under reduced pressure, and the crude
product was adsorbed onto silica and purified by flash column
chromatography (pentane/Et2O = 8:2).
1
obtained as a colorless oil (208 mg, 82%): H-NMR (CDCl3,
600 MHz): δ = 4.28 (ddd, J = 7.4, 5.2, 3.5 Hz, 1Ht), 4.02 (dd, J
= 5.1, 2.5 Hz, 1Ht´), 3.48 (d, J = 5.2 Hz, 1Ht), 3.40 (d, J = 5.1
Hz, 1Ht´), 2.54 (tt, J = 11.4, 3.5 Hz, 1Ht), 2.44 (td, J = 7.4, 2.8
Hz, 2Ht´), 1.85 – 1.75, 1.75 – 1.58, 1.55 – 1.41, 1.36 – 1.21,
1.21 – 1.08 (5m, 24Ht +23Ht´), 0.87 (2t, J = 7.1, 0.8 Hz,
3Ht+3Ht´) ppm; 13C{1H}-NMR (CDCl3, 151 MHz): δ = 215.5,
212.6, 80.9, 75.1, 46.1, 41.5, 38.4, 33.9, 32.0, 31.9, 30.3, 30.0,
29.6, 29.6, 29.4, 29.4, 29.3, 29.2, 27.6, 26.7, 26.2, 26.0, 26.0,
25.8, 25.3, 25.3, 25.3, 23.8, 22.8, 22.8, 14.2, 14.2 ppm; HRMS
(ESI+) m/z calcd. for C16H30O2Na+ [M + Na]+ 277.2143, found
277.2138; IR: (cm-1) = 3480, 2924, 2854, 1705, 1450, 1365,
1119, 1065, 955, 725.
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(5R)-1-hydroxy-5-((3R,5R,8R,9S,10S,13R,14S,17R)-3-
hydroxy-10,13-dimethylhexadecahydro-1H-
cyclopenta[a]phenanthren-17-yl)-1-phenylhexan-2-one
(2u):In an oven-dried Schlenk flask lithium (120 mg, 20.0
mmol, 20 equiv.) was added to a solution of 4,4
′
‐di‐tert‐butylbiphenyl (DBB) (532 mg, 2.00 mmol, 2.0 equiv.)
in THF (20 mL) at 0 °C. The resulting teal-blue colored Li/DBB
solution was stirred at this temperature for 2 h and was then
cooled to –78 °C. A solution of 13b (632 mg, 1.00 mmol) in
THF (5 mL) was slowly added to the stirred solution of the
Li/DBB at –78 °C. After the addition was completed, the
reaction mixture was stirred at –78 °C overnight and was
quenched by dropwise addition of a saturated aqueous solution
of NH4Cl (5 mL). The reaction mixture was allowed to warm to
ambient temperature and was transferred via cannula into brine.
The solution was extracted with diethyl ether (3 × 20 mL) and
the combined organic layers were dried over MgSO4, filtered,
and concentrated under reduced pressure. The crude product
was purified by flash column chromatography (pentane/EtOAc
= 7:3) and the target compound 2u was obtained as a colorless
solid (181 mg, 39%): 1H-NMR (CDCl3, 400 MHz): δ = 7.34 –
7.21 (m, 5H), 5.03 (d, J = 6.59 Hz, 1H), 4.36 (s, 1H), 3.54 (dt,
J = 11.08, 5.99 Hz, 1H), 2.31 – 2.11 (m, 2H), 1.92 – 1.39 (m,
12H), 1.36 – 0.80 (m, 24H), 0.71 (d, J = 6.53 Hz, 1H), 0.61 (d,
J = 6.02 Hz, 1H), 0.51 (d, J = 11.39 Hz, 3H) ppm; 13C{1H}-
NMR (CDCl3, 101 MHz): δ = 210.3, 210.2, 138.2, 138.2, 129.0,
128.7, 127.5, 127.5, 79.9, 79.7, 71.8, 56.5, 56.5, 56.0, 55.9, 42.8,
42.2, 42.1, 40.5, 40.2, 36.5, 35.9, 35.4, 35.3, 34.9, 34.8, 34.6,
30.6, 30.1, 30.0, 28.2, 28.1, 27.3, 26.5, 24.2, 24.2, 23.4, 20.9,
18.4, 18.2, 12.1, 12.1 ppm (presence of two diastereomers,
similar results were observed by Donohoe and coworkers for
analogous compounds17); HRMS (ESI+) m/z calcd. for
C31H46O3Na+ [M + Na]+ 489.3345, found 489.3344; IR: (cm-1)
= 33945, 2932, 2862, 2337, 2252, 1713, 1450, 1373, 1033, 856,
648, 609.
General Procedure 6 for the Synthesis of Alkynes: In a 10
mL Schlenk tube, acyloin (0.20 mmol, 1.0 equiv.),
diphenylphosphate (5.0 mg, 20 µmol, 0.1 equiv.), and
MgSO4·H2O (50 mg, 0.36 mmol, 1.8 equiv.) were dissolved in
t-amyl-OH (1.0 mL) and tosylhydrazine (44 mg, 0.24 mmol, 1.2
equiv.) was added. The reaction mixture was stirred at room
temperature overnight. After the consumption of the acyloin
was confirmed by TLC analysis, 1,1'-carbonyldiimidazole (72
mg, 0.44 mmol, 2.2 equiv.) was added (immediately after the
addition the reaction turned yellow/orange and CO2 evolution
was observed) and the reaction vessel was tightly sealed. The
resulting mixture was heated to 100 °C in an aluminum block,
stirred for 4 h, allowed to cool to room temperature, and the
pressure was released. The flask was re-sealed, the reaction
mixture was heated to 100 °C, and stirred at this temperature for
32 h. The reaction mixture was allowed to cool to room
temperature, the solvent was evaporated under reduced pressure,
and the crude product was adsorbed onto silica and purified by
flash column chromatography (pentane).
2-hydroxy-3,3-dimethyl-1-phenylbutan-1-one
(2v):
1,2-diphenylacetylene (1a):26 Following the General
Procedure 4 with benzoin (2a) (42.6 mg, 0.200 mmol) as
acyloin component, the target compound 1a was obtained as a
colorless solid (24.9 mg, 70%): 1H-NMR (CDCl3, 300 MHz): δ
Following the General Procedure 3 with pivaldehyde (0.56 mL,
5.2 mmol, 1.3 equiv.) as aldehyde component, the target
compound 2v was obtained as a colorless oil (0.57 g, 74 %): 1H
NMR (CDCl3, 300 MHz): δ = 7.90 – 7.83 (m, 2H), 7.63 – 7.54
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= 7.50 – 7.47 (m, 4H), 7.29 – 7.24 (m, 6H) ppm; 13C{1H}-NMR 3H) ppm; 13C{1H}-NMR (CDCl3, 101 MHz): δ = 166.8, 160.2,
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7
8
(CDCl3, 75 MHz): δ = 131.7, 128.5, 128.4, 123.4, 89.5 ppm.
1,2-di-p-tolylacetylene (1b):26 Following the General
Procedure 4 with 2-hydroxy-1,2-di-p-tolylethan-1-one (2b)
(48.3 mg, 0.200 mmol) as acyloin component, the target
compound 1b was obtained as a colorless solid (30.5 mg,
71%):1H-NMR (CDCl3, 400 MHz): δ = 7.43 (d, J = 8.1, 4H),
7.16 (d, J = 8.1, 4H), 2.37 (s, 6 H) ppm;13C{1H}-NMR (CDCl3,
101 MHz): δ = 138.3, 131.6, 129.2, 120.5, 89.0, 21.7 ppm.
1,2-bis(4-methoxyphenyl)ethyne (1c):26 Following the
133.4, 131.4, 129.6, 129.3, 128.5, 114.9, 114.2, 92.7, 87.7, 55.5,
52.4 ppm.
1-bromo-2-((4-bromophenyl)ethynyl)benzene
(1j):28
Following the General Procedure 4 with 2-(2-bromophenyl)-1-
(4-bromophenyl)-2-hydroxyethan-1-one (2j) (74.0 mg, 0.200
mmol) as acyloin, the target compound 1j was obtained as a
colorless solid (42.3 mg, 63%): 1H-NMR (CDCl3, 400 MHz): δ
= 7.62 (dd, J = 8.0, 1.2 Hz, 1H), 7.55 (dd, J = 7.7, 1.7 Hz, 1H),
7.50 (dm, J = 8.6 Hz, 2H), 7.44 (dm, J = 8.6 Hz, 2H), 7.30 (ddd,
J = 7.7, 7.7, 1.2 Hz, 1H), 7.20 (ddd, J = 8.0, 7.7, 1.7 Hz, 1H)
ppm; 13C{1H}-NMR (CDCl3, 101 MHz): δ =133.2, 133.1, 132.5,
131.7, 129.7, 127.1, 125.6, 125.1, 123.0, 121.9, 92.8, 89.1 ppm.
9
General
Procedure
5
with
2-hydroxy-1,2-bis(4-
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methoxyphenyl)ethan-1-one (2c) (54.4 mg, 0.200 mmol) as
acyloin, the target compound 1c was obtained as a colorless
solid (26.2 mg, 55%): 1H-NMR (CDCl3, 400 MHz): δ = 7.45 (d,
J = 8.9 Hz, 4H), 6.87 (d, J = 8.9 Hz, 4H), 3.83 (s, 6H) ppm;
13C{1H}-NMR (CDCl3, 101 MHz): δ = 159.4, 132.9, 115.7,
114.0, 88.0, 55.3 ppm.
1-chloro-2-((4-chlorophenyl)ethynyl)benzene
(1k):
Following the General Procedure 4 with 2-(2-chlorophenyl)-1-
(4-chlorophenyl)-2-hydroxyethan-1-one (2k) (56.2 mg, 0.200
mmol) as acyloin, the target compound 1k was obtained as a
colorless solid (33.0 mg, 67%): 1H-NMR (CDCl3, 400 MHz): δ
= 7.57 – 7.53 (m, 1H), 7.50 (dm, J = 8.5 Hz, 2H), 7.45 – 7.42
(m, 1H), 7.34 (dm, J = 8.5 Hz, 2H), 7.30 – 7.20 (m, 2H) ppm;
13C{1H}-NMR (CDCl3, 101 MHz): δ = 136.1, 134.8, 133.3,
133.1, 129.6, 129.5, 128.9, 126.6, 123.0, 121.5, 93.5, 87.2 ppm;
HRMS (pAPCI) m/z calcd. for C14H8Cl2+ [M]+ 245.9998, found
245.9993; IR: (cm-1) = 2322, 2222, 1489, 1088, 1057, 826, 748.
1-iodo-4-(phenylethynyl)benzene (1l):29 Following the
General Procedure 9 with 2-hydroxy-2-(4-iodophenyl)-1-
phenylethan-1-one (2l) (67.6 mg, 0.200 mmol) as acyloin, the
target compound 1l was obtained as a colorless solid (40.0 mg,
1,2-bis(4-bromophenyl)ethyne (1d):26 Following the General
Procedure 4 with 1,2-bis(4-bromophenyl)-2-hydroxyethan-1-
one (2d) (74.0 mg, 0.200 mmol) as acyloin, the target
compound 1d was obtained as a colorless solid (40.8 mg, 61%):
1H-NMR (CDCl3, 300 MHz): δ = 7.49 (d, J = 8.5, 4H), 7.38 (d,
J = 8.5, 4H) ppm; 13C{1H}-NMR (CDCl3, 75 MHz): δ = 133.1,
131.8, 122.9, 122.0, 89.6 ppm.
1,2-bis(4-chlorophenyl)ethyne (1e):26 Following the General
Procedure 4 with 1,2-bis(4-chlorophenyl)-2-hydroxyethan-1-
one (2e) (56.2 mg, 0.200 mmol) as acyloin, the target compound
1e was obtained as a colorless solid (31.6 mg, 64%): 1H-NMR
(CDCl3, 300 MHz): δ = 7.45 (d, J = 8.6, 4H), 7.33 (d, J = 8.6,
4H) ppm; 13C{1H}-NMR (CDCl3, 75 MHz): δ = 134.7, 132.9,
128.9, 121.6, 89.3 ppm.
1
65%): H-NMR (CDCl3, 300 MHz): δ = 7.69 (d, J = 8.4 Hz,
2H), 7.61 – 7.46 (m, 2H), 7.40 – 7.32 (m, 3H), 7.26 (d, J = 8.4
Hz, 2H) ppm; 13C{1H}-NMR (CDCl3, 75 MHz): δ = 137.5,
133.1, 131.6, 128.6, 128.4, 122.9, 122.8, 94.1, 90.8, 88.5 ppm.
Dimethyl 4,4'-(ethyne-1,2-diyl)dibenzoate (1f):26 Following
the General Procedure 5 with 4,4'-(1-hydroxy-2-oxoethane-1,2-
diyl)dibenzoate (2f) (65.6 mg, 0.200 mmol) as acyloin, the
target compound 1f was obtained as a colorless solid (31.1 mg,
1-chloro-2-((3-chlorophenyl)ethynyl)benzene
(1m):30
Following the General Procedure 7 with 2-(2-chlorophenyl)-1-
(3-chlorophenyl)-2-hydroxyethan-1-one (2m) (56.2 mg, 0.200
mmol) as acyloin, the target compound 1m was obtained as a
colorless solid (33.0 mg, 67%): 1H-NMR (CDCl3, 300 MHz): δ
= 7.56 – 7.53 (m, 2H), 7.46 – 7.40 (m, 2H), 7.35 – 7.21 (m, 4H)
ppm; 13C{1H}-NMR (CDCl3, 75 MHz): δ = 136.1, 134.3, 133.3,
131.6, 129.9, 129.7, 129.7, 129.4, 128.9, 126.5, 124.6, 122.8,
93.0, 87.3 ppm.
1
53%): H-NMR (CDCl3, 300 MHz): δ = 8.04 (d, J = 8.5 Hz,
4H), 7.60 (d, J = 8.5 Hz, 4H), 3.93 (s, 6H) ppm; 13C{1H}-NMR
(CDCl3, 75 MHz): δ = 166.6, 131.8, 130.2, 130.1, 129.7, 127.5,
126.8, 91.5, 52.4 ppm.
1,2-bis(3-chlorophenyl)ethyne (1g): 26 Following the General
Procedure 4 with 1,2-bis(3-chlorophenyl)-2-hydroxyethan-1-
one (2g) (56.2 mg, 0.200 mmol) as acyloin, the target
compound 1g was obtained as a colorless solid (32.1 mg, 65%):
1H-NMR (CDCl3, 400 MHz): δ = 7.52 (t, J = 1.8 Hz, 2H), 7.40
(dt, J = 7.1, 1.7 Hz, 2H), 7.36 – 7.25 (m, 4H) ppm; 13C{1H}-
NMR (CDCl3, 101 MHz): δ = 134.4, 131.6, 129.9, 129.8, 129.0,
124.6, 89.2 ppm.
1,2-dicyclohexylethyne (1n):31 Following the General
Procedure 9 with 1,2-dicyclohexyl-2-hydroxyethan-1-one (2n)
(44.9 mg, 0.200 mmol) as acyloin, the target compound 1n was
1
obtained as a colorless oil (19.7 mg, 52%): H-NMR (CDCl3,
300 MHz): δ = 2.37 – 2.29 (m, 2H), 1.78 – 1.64 (m, 8H), 1.50
– 1.23 (m, 12H) ppm; 13C{1H}-NMR (CDCl3, 75 MHz): δ =
84.7, 33.4, 29.2, 26.2, 25.0 ppm; GC-MS (EI) m/z (%) = 190.1
(18), 119.0 (20), 105.0 (29), 93.0 (63), 91.0 (89), 79.0 (100),
77.0 (44), 67.0 (69), 55.0 (37), 41.0 (57), 39.0 (26).
1,2-di(furan-2-yl)ethyne (1h):27 Following the General
Procedure 5 with furoin (2h) (38.4 mg, 0.200 mmol) as acyloin,
the target compound 1h was obtained as a colorless solid (15.8
mg, 50%): 1H-NMR (CDCl3, 400 MHz): δ = 7.44 (dd, J = 1.9,
0.7 Hz, 2H), 6.71 (dd, J = 3.4, 0.7Hz, 2H), 6.43 (dd, J = 3.4,
1.9 Hz, 2H) ppm; 13C{1H}-NMR (CDCl3, 101 MHz): δ = 144.4,
136.6, 116.6, 111.3, 83.4 ppm.
Oct-4-yne (1o):6 Following the General Procedure 6 with
butyroin (2o) (28.8 mg, 0.200 mmol) as acyloin, the target
compound 1o was obtained as a colorless oil (10.8 mg, 49%):
1H-NMR (CDCl3, 400 MHz): δ = 2.12 (t, J = 7.2 Hz, 4H), 1.50
(qt, J = 7.2, 7.2 Hz, 4H), 0.96 (t, J = 7.2 Hz, 6H) ppm; 13C{1H}-
NMR (CDCl3, 101 MHz): δ = 80.2, 22.6, 20.8, 13.5 ppm.
1,6-diphenylhex-3-yne (1p):32 Following the General
Procedure 6 with 4-hydroxy-1,6-diphenylhexan-3-one (2p)
(53.6 mg, 0.200 mmol) as acyloin, the target compound 1p was
Methyl
4-((4-methoxyphenyl)ethynyl)benzoate
(1i):26
Following the General Procedure 5 with methyl 4-(1-hydroxy-
2-(4-methoxyphenyl)-2-oxoethyl)benzoate (2i) (60.0 mg, 0.200
mmol) as acyloin, the target compound 1i was obtained as a
colorless solid (27.6 mg, 52%): 1H-NMR (CDCl3, 400 MHz): δ
= 8.01 (d, J = 8.6 Hz, 2H), 7.56 (d, J = 8.6 Hz, 2H), 7.48 (d, J
= 8.9 Hz, 2H), 6.89 (d, J = 8.9 Hz, 2H), 3.92 (s, 3H), 3.84 (s,
1
obtained as a colorless oil (24.8 mg, 53%): H-NMR (CDCl3,
300 MHz): δ 7.33 – 7.25 (m, 4H), 7.25 – 7.17 (m, 6H), 2.79 (t,
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J = 7.5 Hz, 4H), 2.44 (t, J = 7.5 Hz, 4H) ppm; 13C{1H}-NMR
(CDCl3, 75 MHz): δ = 141.0, 128.5, 128.3, 126.2, 80.3, 35.5,
21.0 ppm.
product was adsorbed onto silica and purified by flash column
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chromatography (pentane/EtOAc = 8:2). The target compound
1u was obtained as a colorless solid (32.8 mg, 38%, since the
isolation of this compound proved to be challenging an NMR-
yield was determined and found to be 47%): 1H-NMR (CDCl3,
400 MHz): δ = 7.42 – 7.36 (m, 2H), 7.28 – 7.26 (m, 3H), 3.69
– 3.56 (m, 1H), 2.51 – 2.39 (m, 1H), 2.38 – 2.25 (m, 1H), 2.03
– 1.94 (m, 1H), 1.93 – 1.72 (m, 4H), 1.70 – 1.50 (m, 5H), 1.46
– 1.03 (m, 17H), 1.00 – 0.89 (m, 6H), 0.68 – 0.63 (m, 3H) ppm;
13C{1H}-NMR (CDCl3, 101 MHz): δ = 131.6, 128.3, 127.6,
124.3, 91.0, 80.5, 72.0, 56.7, 56.2, 43.0, 42.3, 40.6, 40.3, 36.6,
36.0, 35.5, 35.5, 35.2, 34.7, 30.7, 28.4, 27.4, 26.6, 24.4, 23.5,
21.0, 18.5, 16.7, 12.2 ppm; HRMS (ESI+) m/z calcd. for
C31H44ONa+ [M + Na]+ 455.3290, found 455.3294; IR: (cm-1) =
2924, 2862, 2238, 1697, 1450, 1374, 1033, 910, 756, 733, 563:
(3,3-dimethylbut-1-yn-1-yl)benzene (1v):35 Following the
1-chloro-4-(3-methylbut-1-yn-1-yl)benzene (1q): Following
the General Procedure 6 with a 1:0.87 mixture of 1-(4-
chlorophenyl)-2-hydroxy-3-methylbutan-1-one and 1-(4-
chlorophenyl)-1-hydroxy-3-methylbutan-2-one (2q+2q´) (42.4
mg, 0.200 mmol) as acyloin, the target compound 1q was
1
obtained as a pale yellow solid (19.3 mg, 53%): H-NMR
(CDCl3, 300 MHz): δ = 7.35 (d, J = 8.6 Hz, 2H), 7.28 (d, J =
8.6 Hz, 2H), 2.79 (sept, J = 6.9 Hz, 1H), 1.29 (d, J = 6.9 Hz,
6H) ppm; 13C{1H}-NMR (CDCl3, 75 MHz): δ = 133.5, 132.9,
128.6, 122.7, 96.9, 78.8, 23.1, 21.3 ppm; HRMS (pAPCI) m/z
calcd. for C11H10Cl [M–H]+ 177.0466, found 177.0466; IR: (cm-
1) = 2986, 2931, 2376, 2222, 1489, 1280, 1087, 1010, 710.
Prop-1-yne-1,3-diyldibenzene (1r):33 Following the General
Procedure 6 with 1-hydroxy-1,3-diphenylpropan-2-one (2r´)
(45.2 mg, 0.200 mmol) as acyloin, the target compound 1r was
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General Procedure
6
with 2-hydroxy-3,3-dimethyl-1-
phenylbutan-1-one (2v) (39.5 mg, 0.200 mmol) as acyloin, the
target compound 1v was obtained as a colorless oil (19.5 mg,
1
obtained as a colorless oil (26.1 mg, 68%): H-NMR (CDCl3,
1
500 MHz): δ = 7.46 (dd, J = 6.5, 3.3 Hz, 2H), 7.44 – 7.41 (m,
2H), 7.35 (dd, J = 7.6, 7.6 Hz, 2H), 7.30 (dd, J = 4.9, 2.0 Hz,
3H), 7.28 – 7.24 (m, 1H), 3.85 (s, 2H) ppm; 13C{1H}-NMR
(CDCl3, 126 MHz): δ = 136.9, 131.8, 128.7, 128.4, 128.1, 128.0,
126.8, 123.8, 87.7, 82.8, 25.9 ppm.
50%): H NMR (CDCl3, 300 MHz): δ = 7.32 – 7.23 (m, 2H),
7.21 – 7.10 (m, 3H), 1.22 (s, 9H) ppm; 13C{1H}-NMR (CDCl3,
75 MHz): δ = 131.7, 128.3, 127.5, 124.2, 98.7, 79.1, 31.2, 28.1
ppm.
(E)-N'-(2-hydroxy-1,2-diphenylethylidene)-4-
Cyclotridecyne (1s):34 Following the General Procedure 6
with 2-hydroxycyclotridecan-1-one (2s) (42.4 mg, 0.200 mmol)
as acyloin, the target compound 1s was obtained as a colorless
methylbenzenesulfonohydrazide (5).Benzoin 2a (0.42 g, 2.0
mmol) was stirred in MeOH (2.0 mL) and tosylhydrazine (4.5
g, 24 mmol, 1.2 equiv.) was added. The slurry was stirred
overnight at rt. After filtration, the solid was washed with
MeOH (20 mL) several times until the filtrate was colorless.
The colorless solid was dried under reduced pressure (0.59 g,
1
oil (18.5 mg, 52%): H-NMR (CDCl3, 500 MHz): δ = 2.20 –
2.15 (m, 4H), 1.52 – 1.44 (m, 8H), 1.44 – 1.34 (m, 10H) ppm;
13C{1H}-NMR (CDCl3, 126 MHz): δ = 81.3, 27.7, 26.4, 25.9,
25.6, 25.5, 18.8 ppm.
1
81%): H-NMR (500 MHz, CDCl3): δ = 7.81 (d, J = 8.0 Hz,
Dec-1-yn-1-ylcyclohexane (1t): Following the General
Procedure 9 with 1-cyclohexyl-2-hydroxydecan-1-one (2t)
(50.8 mg, 0.200 mmol) as acyloin, the target compound 1t was
2H), 7.51 (s, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.35 (t, J = 7.4 Hz,
1H), 7.31 (t, J = 7.6 Hz, 2H), 7.23 – 7.13 (m, 3H), 6.97 (d, J =
7.2 Hz, 2H), 6.72 (d, J = 7.2 Hz, 2H), 5.35 (d, J = 5.1 Hz, 1H),
4.10 (d, J = 5.1 Hz, 1H), 2.49 (s, 3H) ppm;13C{1H}-NMR (126
MHz, CDCl3): δ = 157.4, 144.5, 139.0, 134.9, 130.3, 129.9,
129.6, 129.5, 128.3, 128.1, 127.9, 127.4, 127.0, 76.2, 21.7 ppm;
HRMS (ESI+) m/z calcd. for C21H20N2O3SNa+ [M + Na]+
403.1087, found 403.1108.
1
obtained as a colorless oil (23.2 mg, 53%): H-NMR (CDCl3,
400 MHz): δ = 2.36 – 2.28 (m, 1H), 2.15 (td, J = 7.04, 2.24 Hz,
2H), 1.83 – 1.64 (m, 4H), 1.53 – 1.45 (m, 3H), 1.42 – 1.34 (m,
3H), 1.33 – 1.23 (m, 12H), 0.91 – 0.80 (m, 3H) ppm; 13C{1H}-
NMR (CDCl3, 101 MHz): δ = 84.8, 80.3, 33.4, 32.0, 29.9, 29.4,
29.4, 29.3, 29.3, 29.0, 26.1, 25.1, 22.8, 18.9, 14.3 ppm; HRMS
(pAPCI) m/z calcd. for C16H28 [M]+ 220.2191, found 220.2186;
IR: (cm-1) = 2924, 2854, 1450, 1373, 1157, 748, 570, 555.
(3R,5R,8R,9S,10S,13R,14S,17R)-10,13-dimethyl-17-((R)-6-
phenylhex-5-yn-2-yl)hexadecahydro-1H-
IR: (cm-1) = 3518, 3187, 1420, 1335, 1173, 772, 634.
(E)-N'-(2-(1H-imidazol-1-yl)-1,2-diphenylethylidene)-4-
methylbenzenesulfonohydrazide (7). The hydrazone 5 (1.14 g,
3.00 mmol) was stirred in toluene (0.500 mL) and CDI (0.400
g, 3.00 mmol, 1 equiv.) was added. The reaction mixture turned
yellow and gas evolution (CO2) was observed. The mixture was
stirred at room temperature for 12 h. The reaction mixture was
filtered and the filtrate was dried under reduce pressure. The
product was obtained as a colorless solid without further
cyclopenta[a]phenanthren-3-ol (1u): In a 10 mL Schlenk tube
attached
to
the
Ar
line,
(5R)-1-hydroxy-5-
((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-
dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-
1-phenylhexan-2-one (2u) (93.3 mg, 0.200 mmol),
diphenylphosphate (5.0 mg, 20 µmol, 0.1 equiv.), and
MgSO4·H2O (50 mg, 0.36 mmol, 1.8 equiv.) were dissolved in
t-amyl-OH (2.0 mL) and tosylhydrazine (44 mg, 0.24 mmol, 1.2
equiv.) was added. The reaction mixture was stirred at room
temperature for 30 h. After the consumption of the acyloin was
confirmed by TLC analysis, 1,1'-carbonyldiimidazole (90 mg,
0.55 mmol, 2.75 equiv.) was added (immediately after the
addition the reaction turned yellow/orange and CO2 evolution
was observed). The resulting mixture was heated to 100 °C in
an aluminum block and stirred at this temperature for 30 h. The
reaction mixture was allowed to cool to room temperature, the
solvent was evaporated under reduced pressure, and the crude
1
purification (0.864 g, 67%): H-NMR (500 MHz, DMSO-d6):
δ = 7.60 (t, J = 1.2 Hz, 1H), 7.42 (d, J = 8.3 Hz, 2H), 7.40 –
7.35 (m, 5H), 7.32 (m, 1H), 7.31 (m, 2H), 7.28 (d, J = 8.0 Hz,
2H), 7.23 – 7.19 (m, 2H), 7.04 (t, J = 1.3 Hz, 1H), 6.89 (t, J =
1.1 Hz, 1H), 6.67 (s, 1H), 2.39 (s, 3H) ppm; 13C{1H}-NMR (126
MHz, DMSO-d6): δ = 152.6, 143.1, 137.1, 136.9, 135.5, 132.2,
129.6, 129.1, 128.6, 128.6, 128.3, 128.3 127.8, 127.8, 127.7,
119.4, 63.8, 21.0 ppm; HRMS (ESI+) m/z calcd. for
C24H23N4O2S+ [M + H]+ 431.1536, found 431.1548; IR: (cm-1)
= 1343, 1227, 1165, 1073, 918, 818, 650.
2-phenyl-2-((trimethylsilyl)oxy)acetonitrile
(9):36
Benzaldehyde (0.81 mL, 8.0 mmol, 1.0 equiv.) was added
dropwise to a solution of ZnI2 (tip of a spatula) in
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trimethylsilylcyanide (1.1 mL, 8.8 mmol, 1.1 equiv.) at room
temperature. The resulting reaction mixture was stirred for 5 h
at 100 °C. The reaction mixture was allowed to cool to room
temperature and directly purified by flash column
chromatography (pentane/EtOAc = 9:1). The product 9 was
= 9.5:0.5) and the target compound 13a was obtained as a
yellow oil (559 mg, 74%): H-NMR (CDCl3, 300 MHz): δ =
1
1
2
3
4
5
6
7
8
4.70 – 4.64 (m, 2H), 2.28 – 2.17 (m, 5H), 1.91 – 1.68 (m, 5H),
1.67 – 1.47 (m, 5H), 1.43 – 1.34 (m, 2H), 1.34 – 1.10 (m, 16H),
0.91 – 0.80 (m, 3H) ppm; 13C{1H}-NMR (CDCl3, 75 MHz): δ
= 175.1, 173.0, 76.6, 76.3, 43.3, 41.3, 41.2, 34.3, 33.6, 31.9,
29.4, 29.3, 29.2, 29.1, 29.1, 25.9, 25.5, 25.0, 24.5, 24.4, 22.7,
14.2 ppm; HRMS (ESI+) m/z calcd. for C23H38O4Na+ [M + Na]+
401.2668, found 401.2667; IR: (cm-1) = 2924, 2854, 1735, 1450,
1311, 1249, 1165, 1049, 732, 563.
1
obtained as a light yellow oil (1.4 g, 85%): H NMR (CDCl3,
300 MHz): δ = 7.51 – 7.45 (m, 2H), 7.45 – 7.38 (m, 3H), 5.50
(s, 1H), 0.24 (s, 9H) ppm; 13C{1H}-NMR (CDCl3, 75 MHz): δ
= 136.4, 129.5, 129.1, 126.5, 119.3, 63.8, −0.1 ppm.
3,5-diphenyl-1H-pyrazole (10):37 Following the General
Procedure 6 with 2-hydroxy-1,3-diphenylpropan-1-one (2r)
(45.2 mg, 0.200 mmol) as acyloin, the target compound 10 was
obtained as a colorless solid (23.3 mg, 53%): 1H-NMR (CDCl3,
500 MHz): δ = 7.72 (dd, J = 5.2, 3.3 Hz, 4H), 7.40 – 7.35 (m,
4H), 7.33 (ddd, J = 4.8, 2.0, 1.9 Hz, 2H), 6.83 (s, 1H) ppm;
13C{1H}-NMR (CDCl3, 126 MHz): δ = 129.0, 128.3, 125.8,
100.2 ppm.
9
(rac)-3-(((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-acetoxy-
10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-
17-yl)pentanoyl)oxy)bicyclo[2.2.1]heptan-2-yl benzoate (13b):
A solution of benzoyl chloride (232 µL, 2.00 mmol, 2 equiv.)
in dichloromethane (2.00 mL) was added to a solution of 14b
(528 mg, 1.00 mmol), DMAP (12.2 mg, 0.100 mmol, 1 mol%),
and pyridine (178 µL, 2.20 mmol, 2.2 equiv.) in
dichloromethane (7.5 mL). The reaction mixture was stirred
overnight and was quenched with a saturated aqueous solution
of sodium bicarbonate (15 mL). The resulting mixture was
extracted with dichloromethane (3 × 10 mL) and the combined
organic layers were dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude product was
purified by flash column chromatography (pentane/EtOAc =
9:1) and the target compound 13b was obtained as a colorless
solid (379 mg, 60%): 1H-NMR (CDCl3, 400 MHz): δ = 7.98 (d,
J = 7.71 Hz, 2H), 7.52 (t, J = 7.48 Hz, 1H), 7.39 (t, J = 7.63
Hz, 2H), 4.95 (d, J = 5.98 Hz, 1H), 4.81 (d, J = 5.92 Hz, 1H),
4.68 (tt, J = 10.92, 4.79 Hz, 1H), 2.38 (s, 1H), 2.28 (s, 1H), 2.20
– 1.93 (m, 6H), 1.90 – 1.74 (m, 4H), 1.69 – 0.77 (m, 30H), 0.73
– 0.63 (m, 3H), 0.52 (d, J = 5.61 Hz, 3H) ppm; 13C{1H}-NMR
(CDCl3, 101 MHz): δ = 173.3, 173.2, 170.7, 165.7, 133.0, 130.5,
129.7, 128.5, 77.6, 76.5, 76.5, 74.5, 56.6, 56.0, 55.9, 42.8, 42.1,
41.3, 41.3, 40.6, 40.3, 40.3, 35.9, 35.3, 35.3, 35.2, 34.7, 33.9,
32.4, 31.3, 31.2, 30.9, 30.8, 28.1, 27.2, 26.8, 26.5, 24.6, 24.4,
24.3, 23.5, 21.6, 21.0, 18.3, 12.2 ppm (presence of two
diastereomers, similar results were observed by Donohoe and
coworkers for analogous compounds17); HRMS (ESI+) m/z
calcd. for C40H56O6Na+ [M + Na]+ 655.3975, found 655.3948;
IR: (cm-1) = 2947, 1720, 1273, 1250, 1172, 1118, 1026, 648,
570.
(rac)-3-hydroxybicyclo[2.2.1]heptan-2-yl nonanoate (14a):A
solution of nonanoyl chloride (352 mg, 2.00 mmol) in
dichloromethane (10.0 mL) was added to a solution of
bicyclo[2.2.1]heptane-2,3-diol (384 mg, 3.00 mmol, 1.5 equiv.)
in dichloromethane (15.0 mL) at 0 °C over 1 h. The reaction
mixture was stirred overnight and during this time allowed to
slowly warm to room temperature. The reaction was quenched
by addition of a saturated aqueous solution of sodium
bicarbonate (25 mL). The resulting mixture was extracted with
dichloromethane (3 × 20 mL) and the combined organic layers
were dried over MgSO4, filtered, and concentrated under
reduced pressure. The crude product was purified by flash
column chromatography (pentane/EtOAc = 9:1) and the target
compound 14a was obtained as a yellow oil (428 mg, 80%): 1H-
NMR (CDCl3, 300 MHz): δ = 4.55 (dd, J = 5.96, 1.73 Hz, 1H),
3.84 (d, J = 6.19 Hz, 1H), 2.34 (t, J = 7.58 Hz, 2H), 2.26 – 2.16
(m, 2H), 2.02 (s, 1H), 1.79 (dt, J = 10.37, 1.97 Hz, 1H), 1.70 –
1.57 (m, 2H), 1.55 – 1.45 (m, 2H), 1.30 – 1.22 (m, 10H), 1.20 –
1.10 (m, 3H), 0.91 – 0.84 (m, 3H) ppm; 13C{1H}-NMR (CDCl3,
75 MHz): δ = 174.0, 78.2, 75.8, 43.4, 40.9, 34.5, 32.8, 31.9,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-hydroxy-N-methoxy-N-methyl-2-phenylacetamide (11):38
SOCl2 (0.80 mL, 11 mmol, 1.1 equiv.) was added dropwise to a
solution of mandelic acid (1.5 g, 10 mmol, 1.0 equiv.) in dry
MeOH (20 mL) at 0 °C, stirred for 45 min at this temperature,
allowed to warm to room temperature, and stirred for an
additional 90 min. The reaction was quenched by addition of sat.
aq. NaHCO3 solution (15 mL) and extracted with CH2Cl2 (3 ×
10 mL). The combined organic layers were dried over Na2SO4,
filtered, and concentrated under reduced pressure. The resulting
2-hydroxy-2-phenylacetyl chloride was directly used in the
following step. AlMe3 (2 M in toluene, 6.0 mL, 12 mmol, 2.0
equiv.) was added dropwise to
a solution of N,O
Dimethylhydroxylamine hydrochloride (1.2 g, 12 mmol, 2.0
equiv.) in toluene (12 mL) at 0 °C, stirred at this temperature
for 1 h, allowed to warm to room temperature, and stirred for an
additional 2 h. The reaction mixture was cooled to 0 °C and a
solution of 2-hydroxy-2-phenylacetyl chloride (6.0 mmol, 1.0
equiv.) in toluene (6 mL) was added dropwise. The resulting
mixture was stirred overnight while being allowed to slowly
warm to room temperature. The reaction mixture was again
cooled to 0 °C and aq. HCl (1 M, 6 mL) was added dropwise at
this temperature. The crude mixture was extracted with EtOAc
(3 × 7 mL), dried over Na2SO4, filtered, concentrated under
reduced pressure, and purified by flash column chromatography
(pentane/EtOAc = 3:1). The target compound 11 was obtained
as a colorless solid (0.83 g, 71%): 1H NMR (CDCl3, 500 MHz):
δ = 7.39 – 7.32 (m, 4H), 7.32 – 7.28 (m, 1H), 5.34 (d, J = 5.8
Hz, 1H), 4.28 (d, J = 6.4 Hz, 1H), 3.21 (s, 6 H) ppm; 13C{1H}-
NMR (CDCl3, 126 MHz): δ = 173.7, 139.8, 128.8, 128.4, 127.7,
71.7, 60.8, 32.8 ppm.
(rac)-3-(nonanoyloxy)bicyclo[2.2.1]heptan-2-yl
cyclohexanecarboxylate
(13a):
A
solution
of
cyclohexanecarbonyl chloride (584 mg, 4.00 mmol, 2 equiv.) in
dichloromethane (5.00 mL) was added to a solution of (rac)-3-
hydroxybicyclo[2.2.1]heptan-2-yl nonanoate (14a) (536 mg,
2.00 mmol), DMAP (24.4 mg, 0.200 mmol, 1 mol%), and
pyridine (355 µL, 4.40 mmol, 2.2 equiv.) in dichloromethane
(12.0 mL). The reaction mixture was stirred at room
temperature overnight and was quenched with a saturated
aqueous solution of sodium bicarbonate (25 mL). The resulting
mixture was extracted with dichloromethane (3 × 20 mL) and
the combined organic layers were dried over MgSO4, filtered,
and concentrated under reduced pressure. The crude product
was purified by flash column chromatography (pentane/EtOAc
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The Journal of Organic Chemistry
1,1'-carbonyldiimidazole (2.01 g, 12.3 mmol, 2.2 equiv.) was
29.3, 29.3, 29.2, 25.2, 24.6, 24.5, 22.8, 14.2 ppm; HRMS
(ESI+) m/z calcd. for C16H28O3Na+ [M + Na]+ 291.1936, found
291.1940; IR: (cm-1) = 3341, 2862, 1712, 1450, 1373, 1033, 648.
(rac)-3-hydroxybicyclo[2.2.1]heptan-2-yl(4R)-4-
added (immediately after the addition the reaction turned
yellow/ orange and CO2 evolution was observed) and the
resulting mixture was heated to 100 °C in an oil bath and stirred
at this temperature for 12 h. The reaction mixture was allowed
to cool to room temperature, the solvent was evaporated under
reduced pressure, the crude product was directly adsorbed onto
silica, and purified by flash column chromatography (pentane).
The target compound 1a was obtained as a colorless solid (647
mg, 65%)
1
2
3
4
5
6
7
8
((3R,5R,8R,9S,10S,13R,14S,17R)-3-acetoxy-10,13-
dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-
yl)pentanoate
(3R,5R,8R,9S,10S,13R,14S,17R)-17-((R)-5-chloro-5-
oxopentan-2-yl)-10,13-dimethylhexadecahydro-1H-
(14b):
A
solution
of
cyclopenta[a]phenanthren-3-yl acetate (872 mg, 2.00 mmol) in
dichloromethane (10 mL) was added to a solution of
bicyclo[2.2.1]heptane-2,3-diol (384 mg, 3.00 mmol, 1.5 equiv.)
in dichloromethane (15 mL) at 0 °C over 1 h. The reaction
mixture was stirred overnight and allowed to slowly warm to
room temperature during this time. The reaction was quenched
by addition of a saturated aqueous solution of sodium
bicarbonate (25 mL). The resulting mixture was extracted with
dichloromethane (3 × 20 mL) and the combined organic layers
were dried over MgSO4, filtered, and concentrated under
reduced pressure. The crude product was purified by flash
column chromatography (pentane/EtOAc = 9:1) and the target
compound 14b was obtained as a colorless solid (739 mg, 70%):
1H-NMR (CDCl3, 400 MHz): δ = 4.74 – 4.64 (m, 1H), 4.52 (d,
J = 5.92 Hz, 1H), 3.82 (d, J = 5.90 Hz, 1H), 2.42 – 2.31 (m,
1H), 2.30 – 2.22 (m, 3H), 2.19 (d, J = 13.95 Hz, 1H), 2.09 (s,
3H), 2.00 (s, 1H), 1.86 – 1.73 (m, 6H), 1.71 – 1.60 (m, 1H), 1.56
– 0.96 (m, 24H), 0.90 – 0.88 (m, 6H), 0.62 (s, 3H) ppm;
13C{1H}-NMR (CDCl3, MHz): δ = 174.3, 174.2, 170.7, 78.2,
78.1, 75.7, 75.7, 74.5, 56.6, 56.1, 43.4, 42.8, 42.0, 40.8, 40.5,
40.2, 35.9, 35.4, 35.4, 35.1, 34.7, 32.8, 32.3, 31.3, 31.3, 31.1,
31.1, 28.3, 27.1, 26.7, 26.4, 24.6, 24.5, 24.3, 23.4, 21.5, 20.9,
18.4, 12.1 ppm (39 Signals, due to the presence of two
inseparable diastereomers, similar results were observed by
Donohoe and coworkers for analogous compounds17); HRMS
(ESI+) m/z calcd. for C33H52O5Na+ [M + Na]+ 551.3712, found
551.3709; IR: (cm-1) = 2939, 2870, 1720, 1242, 1165, 1026, 648.
9
10
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15
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17
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ASSOCIATED CONTENT
Supporting Information. Preparative procedures and analytical
data. This material is available free of charge via the Internet at
http://pubs.acs.org.”
AUTHOR INFORMATION
Corresponding Author
*mvangemmeren@uni-muenster.de.
ACKNOWLEDGMENT
We gratefully acknowledge financial support from the DFG
(Project: GE 2945/1-1), Max Planck Society (Otto Hahn Award to
M.v.G.), FCI (Liebig Fellowship to M.v.G.), Studienstiftung des
deutschen Volkes (Fellowship to F.G.), and WWU Münster. We
thank the members of our NMR and MS departments for their
excellent service. Furthermore, we are indebted to Prof. F. Glorius
for his generous support.
REFERENCES
(1)
(a) Modern Acetylene Chemistry; Wiley-VCH Verlag
GmbH: Weinheim, 1995; (b) Acetylene Chemistry: Chemistry,
Biology, and Material Science; Wiley-VCH Verlag GmbH & Co.
KGaA: Weinheim, 2005.
(2)
Larock, R. C. Comprehensive Organic Transformations: A
Bicyclo[2.2.1]heptane-2,3-diol (15):17
A
solution of
guide to Functional Group Preparations; 2nd ed.; Wiley-VCH:
Weinheim, 1999.
potassium permanganate (KMnO4) (2.4 g, 15 mmol, 1.5 equiv.)
and sodium hydroxide (0.52 g, 13 mmol, 1.3 equiv.) in water
(50 mL) was added to a solution of norbornene (1.0 g, 10 mmol)
in tert-butanol (40 mL) and water (10 mL) at 0 °C. The reaction
mixture was stirred for 1 h and was quenched with a saturated
aqueous solution of sodium metabisulphite (Na2S2O5) until the
solution turned colorless (40 mL). The mixture was filtered and
the tert-butanol was removed under reduced pressure. The
remaining aqueous phase was extracted with EtOAc (4 × 30
mL) and the combined organic layers were dried over MgSO4,
filtered, and concentrated under reduced pressure. The resulting
product (15) was used in the following reaction without further
(3)
Wiley-VCH Verlag GmbH & Co. KGaA: 2015, p 445.
(4) (a) Sonogashira, K. Palladium ‐Catalyzed Alkynylation:
Fürstner, A. Alkyne metathesis. In Handbook of Metathesis;
Sonogashira Alkyne Synthesis. In Handbook of Organopalladium
Chemistry for Organic Synthesis; John Wiley & Sons, Inc.: 2003, p
493; (b) Le Vaillant, F.; Courant, T.; Waser, J. Room-temperature
decarboxylative alkynylation of carboxylic acids using photoredox
catalysis and EBX reagents. Angew. Chem. Int. Ed. 2015, 54, 11200;
(c) Yang, J.; Zhang, J.; Qi, L.; Hu, C.; Chen, Y. Visible-light-induced
chemoselective reductive decarboxylative alkynylation under
biomolecule-compatible conditions. Chem. Commun. 2015, 51, 5275;
(d) Huang, L.; Olivares, A. M.; Weix, D. J. Reductive decarboxylative
alkynylation of N-hydroxyphthalimide esters with bromoalkynes.
Angew. Chem. 2017, 129, 12063; (e) Smith, J. M.; Qin, T.; Merchant,
R. R.; Edwards, J. T.; Malins, L. R.; Liu, Z.; Che, G.; Shen, Z.; Shaw,
S. A.; Eastgate, M. D.; Baran, P. S. Decarboxylative alkynylation
Angew. Chem. Int. Ed. 2017, 56, 11906.
1
purification (0.90 g, 70%): H-NMR (CDCl3, 300 MHz): δ =
3.64 (d, J = 1.66 Hz, 2H), 3.50 (s, 2H), 2.11 – 2.09 (m, 2H),
1.72 (dt, J = 10.37, 1.94 Hz, 1H), 1.46 – 1.41 (m, 2H), 1.09 –
1.00 (m, 3H) ppm; 13C{1H}-NMR (CDCl3, 75 MHz): δ = 74.8,
43.1, 31.7, 24.6 ppm.
Large scale synthesis of 1,2-diphenylethyne (1a): In a 100 mL
flask, benzoin (2a) (1.20 g, 5.60 mmol), diphenylphosphate
(140 mg, 0.560 mmol, 0.1 equiv.), and MgSO4·H2O (1.40 g,
10.1 mmol, 1.8 equiv.) were dissolved in t-amyl-OH (40 mL)
and tosylhydrazine (1.23 g, 6.72 mmol, 1.2 equiv.) was added.
The reaction mixture was stirred at room temperature for 36 h.
After the consumption of the acyloin was confirmed by TLC,
(5)
For example, see: Deng, J.; Wu, J.; Tian, H.; Bao, J.; Shi, Y.;
Tian, W.; Gui, J. Alkynes from furans: A general fragmentation method
applied to the synthesis of the proposed structure of Aglatomin B.
Angew. Chem. Int. Ed. 2018, 57, 3617-3621 and references cited
therein.
(6)
(a) Iwadare, T.; Adachi, I.; Hayashi, M.; Matsunaga, A.;
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acetate and benzoin benzoate with alkali. Tetrahedron Lett. 1969, 10,
4447; (b) Wieland, P. Über ein neues verfahren zur herstellung von.
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acetylenverbindungen. Vorläufige mitteilung. Helv. Chim. Acta 1970,
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organocatalysis: Synthesis, investigation and application in cross ‐
benzoin condensation. Eur. J. Org. Chem. 2011, 2011, 5475.
53, 171; (c) Bauer, D. P.; Macomber, R. S. A new route to acetylenes
J. Org. Chem. 1976, 41, 2640; (d) Kano, S.; Yokomatsu, T.; Ono, T.;
Hibino, S.; Shibuya, S. A new synthesis of phenylalkynes from the p-
Toluene-sulfonylhydrazone of α-methylthioacetophenone. Synthesis
1978, 305; (e) Kano, S.; Yokomatsu, T.; Shibuya, S. New synthetic
design for formation of carbon-carbon triple bonds. J. Org. Chem.
1978, 43, 4366; (f) Feldman, K. S.; Weinreb, C. K.; Youngs, W. J.;
Bradshaw, J. D. Preparation and some subsequent transformations of
tetraethynylmethane. J. Am. Chem. Soc. 1994, 116, 9019; (g) Iwadare,
T.; Ichinohe, Y.; Orito, K. Decomposition of tosylhydrazones of
benzoin, benzoin acetate, and benzoin benzoate with alkali and metal
complex hydrides. Can. J. Chem. 1996, 74, 227; (h) Katritzky, A. R.;
Wang, J.; Karodia, N.; Li, J. A novel transformation of esters to alkynes
with 1-substituted benzotriazoles. J. Org. Chem. 1997, 62, 4142; (i)
Gaber, A. E.-A. M.; Mohamed, O. S.; Aly, M. M. Thermal
rearrangement of some benzoin arylsulfonylhydrazone derivatives. J.
Anal. Appl. Pyrolysis 2005, 73, 53.
1
2
3
4
5
6
7
8
(15)
(a) Collins, K. D.; Glorius, F. A robustness screen for the
9
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• Wide scope/functional group tolerance
• No transition metal catalysis
• Simple reagents/protocol
• Starting matierials easily available
from fragment coupling:
O
FG
R2
R2
R1
R2
OH
R1
R1
FG
-
-
-
Acyloin/benzoin condensation
NHC catalysis
...
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