Practical Preparation of Cyclopropenone 1,3-Propanediol Ketal

Article abstract of DOI:10.1055/s-0039-1690830

Cyclopropenone 1,3-propanediol ketal is an increasingly versatile building block for the introduction of various C ₃ and dioxaspiro units due to the emergence of numerous methodologies for the application of strained hydrocarbons. This Practical Synthetic Procedure gives an updated synthesis for a basic ketal of cyclopropenone with lowered solvent toxicity and a detailed step-by-step guide for the safe production of potassium amide in liquid ammonia and for its application in the synthesis of the cyclopropene ring.

Full text of DOI:10.1055/s-0039-1690830

SYNTHESIS
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© Georg
Thieme Ver-
lag Stuttgart
· New York
, 202052, A–D
A
F. F. Mulks et al.
PSP
Synthesis
Practical Preparation of Cyclopropenone 1,3-Propanediol Ketal
Florian F. Mulks*1
Robin Heckershoff
Marc Zimmer
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PSP
condensation
condensation
Δ
O
O
O
O
O
+
HO
OH
A. Stephen K. Hashmi
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0
0
2-6
7
2
0-8
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Cl
Cl
p-TsOH
Toluene
82%
KNH2, NH3
63%
Cl
Cl
Organisch-Chemisches Institut, Ruprecht-Karls Universität Heidelberg,
Im Neuenheimer Feld 271, 69120 Heidelberg, Germany
florian.mulks@dcb.unibe.ch
simple C3 and dioxaspirooctene building block
detailed step-by-step guide for 10 g scale synthesis
Received: 01.01.2020
Accepted after revision: 28.01.2020
Published online: 24.02.2020
1 with freshly prepared potassium amide and deliver an
easily reproducible step-by-step guide for this endeavour
(Scheme 1).
DOI: 10.1055/s-0039-1690830; Art ID: ss-2020-t0001-psp
Abstract Cyclopropenone 1,3-propanediol ketal is an increasingly ver-
satile building block for the introduction of various C3 and dioxaspiro
units due to the emergence of numerous methodologies for the appli-
cation of strained hydrocarbons. This Practical Synthetic Procedure
gives an updated synthesis for a basic ketal of cyclopropenone with low-
ered solvent toxicity and a detailed step-by-step guide for the safe pro-
duction of potassium amide in liquid ammonia and for its application in
the synthesis of the cyclopropene ring.
Δ
O
O
O
HO
OH
O
O
Cl
Cl
p-TsOH
Toluene
KNH2, NH3
Cl
Cl
1
2
Scheme 1 Updated synthetic route for cyclopropenone 1,3-propane-
diol ketal (2)
Key words acetals, bicyclic compounds, carbocycles, condensation,
cyclization, elimination, ring closure
Due to aromatic stabilization via the zwitterionic meso-
meric structure, cyclopropenones are surprisingly stable.
Without further functionalization, they are, however, low-
boiling and thus inconvenient for synthetic procedures.
Their high-boiling ketal surrogates have attracted synthetic
attention for their use as building blocks and for their ap-
pearance in natural products.
Cyclopropenone 1,3-propanediol ketal (2) is a versatile
building block that has seen various applications in recent
years due to ring-strain-release reactions emerging to be-
come standard synthetic tools in preparative chemistry
(Scheme 2). The -system can be employed to induce cat-
ionic ring-opening analogues to the thermal generation of
vinyl carbenes that cyclopropenes can undergo. This ap-
proach has been used to access allyl cationic vinylgold(I)
species 3.5 Furthermore, the strain-induced CH acidity of
the vinylic protons in cyclopropenone 1,3-propanediol ke-
tal can be used to lithiate these positions with lithium di-
isopropylamide (LDA) granting access to a variety of func-
tionalizations, as exemplary shown in the 1-aurated cyclo-
propenone complexes 4.6 These examples showcase the
liberation of the cyclopropenone 3-oxo domain by hydroly-
sis of the ketal. Complexes 4 can also undergo cationic ring-
opening reactions with gold(I) complexes.7
Early synthetic procedures for higher boiling ketals of
cyclopropenone employ a stepwise procedure from ketals
of 1-bromo-3-chloroacetone.2 Potassium amide was used
therein to generate the cyclopropene ring on the pre-
formed ketal. Not long thereafter, in an article focusing on
neopentyl glycol ketals, it was reported that the use of 1-
bromo-3-chloroacetone is unnecessary.3 1,3-Dichloroace-
tone is obtained in the chemical industry by direct chlori-
nation of acetone, together with monochloroacetone, 1,1-
dichloroacetone, and higher chlorinated acetone derivatives
such as 1,1,3-trichloroacetone.4 On a molar basis, 1,3-di-
chloroacetone is 125 times less expensive as a reactant than
1 mole of 1-bromo-3-chloro-2,2-dimethoxypropane. For
these reasons, we have established an updated procedure
that avoids the use of the solvent carcinogen benzene with-
out losses in performance in the Dean–Stark condensation
to produce the ketal 2,2-bis(chloromethyl)-1,3-dioxane (1)
in increased yield (79–84%). The dichloroacetone ketal can
be easily purified by recrystallization from diethyl ether.
We demonstrate a very inexpensive way to synthesize cy-
clopropenone 1,3-propanediol ketal (2, 54–71% yield) from
© 2020. Thieme. All rights reserved. Synthesis 2020, A–D
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
F. F. Mulks et al.
PSP
Synthesis
equipped with a 10 mL Dean–Stark apparatus and a condenser. The
resulting solution was stirred and heated (bath temperature 150 °C)
for 24 h.
1) LDA
2) LAuCl
O
O
O
R3PAuNTf2
3) hydrolysis
AuL
4
AuPR3
a: 64% L = IPr
b: 73% L = IPr*
O
O
3
via
O
O
Li
2
O
O
R
6
7
O
HSiMe2Ph
or HGeEt3
O
+
O
[Pt]
5
O
a: 75% R = SiMe2Ph
b: 56% R = GeEt3
57%
50:50 6/7
Scheme 2 Reaction with cationic gold complexes (3), substitution at a
lithiated center (4), hydrometalation (5), and Diels–Alder reaction (6, 7)
Group 10 metals can even be employed to catalyze reac-
tions on cyclopropenone ketals, without decomposing the
ring system. With PtCl2, for example, hydrosilylation and
hydrogermanation reactions give 5a in 75% yield and 5b in
56% yield, respectively.8 Cyclopropenone ketals can also be
employed in Diels–Alder reactions, to give a large variety of
products, for example 6 and 7.9 The application of these re-
actions and, even more so, achieving a comprehensive un-
derstanding of them have not ceased to attract further in-
vestigation.10
Figure 1 Experimental setup for the synthesis of 2,2-bis(chlorometh-
yl)-1,3-dioxane (1)
The boiling point significantly rises over the course of the reaction.
Lower temperatures do not ensure vigorous boiling until full conver-
sion is reached. The reaction can be easily followed by observing the
volume of the formed water in the Dean–Stark apparatus (3.62 mL of
reaction water are expected).
1,3-Dichloroacetone (purity ≥95%) was purchased from Sigma-
Aldrich. The brownish-gray solid was purified by dissolving it (50.0 g,
394 mmol) in dichloromethane (500 mL) and filtering the solution
over Celite (50.0 g) on a porosity 3 glass filter frit. A black residue re-
mained on the filter. Removal of the solvent under reduced pressure
at 40 °C utilizing a rotary evaporator gave the colorless solid (48.0 g,
378 mmol, 96%). The following materials were employed as pur-
chased from Sigma-Aldrich. Potassium in mineral oil: trace metals ba-
sis ≥98%, 1,3-propanediol: ≥98%, p-toluenesulfonic acid monohy-
drate: ≥98%, iron(III) chloride: ≥97%. The following materials were
employed as purchased from Riedel-de Haën: toluene: ≥99.5%, diethyl
ether: ≥99.5%, acetone: ≥99.5%, ammonium chloride: ≥99.5%. NMR
spectra were recorded on a Bruker Avance III 300 spectrometer. FT-IR
spectra were recorded on a Bruker Vector 22 FT-IR spectrophotome-
ter with an ATR unit. Elemental analyses were performed on a vario
MICRO cube analyzer.
The solution was allowed to cool to room temperature and the vola-
tiles were removed under reduced pressure at 40 °C utilizing a rotary
evaporator. The pressure was gradually reduced, until no further sol-
vent was collected for 15 min at 15 mbar. The crude product was
transferred to a 250 mL, one-necked, round-bottomed flask. The ma-
terial was dissolved in diethyl ether (150 mL) at 40 °C and recrystal-
lized by cooling to –21 °C for 24 h in a freezer. The mother liquor was
collected in another 250 mL, one-necked, round-bottomed flask by
decantation and recrystallized from diethyl ether (80 mL) following
the same procedure as above. The crystals were combined in one of
the two flasks. 2,2-Bis(chloromethyl)-1,3-dioxane was obtained as a
colorless solid; yield: 28.8–30.6 g (79–84%).
Quantitative 1H NMR purity (300 MHz, CDCl3, p-dinitrobenzene):
>99%.
IR (ATR): 2990, 2967, 2939, 2896, 2851, 1748, 1541, 1472, 1435, 1427,
1380, 1330, 1302, 1258, 1246, 1216, 1158, 1129, 1100, 1047, 1027,
950, 933, 889, 859, 821, 779, 762, 729, 650 cm–1
.
2,2-Bis(chloryomethyl)-1,3-dioxane (1)
[CAS Reg. No. 69245-14-3]
1H NMR (300 MHz, CDCl3):  = 3.96 (t, J = 1.78 Hz, 4 H, OCH2), 3.79 (s,
4 H, ClCH2), 1.79 (quin, J = 1.78 Hz, 2 H, (CH2)2CH2).
The experimental setup is shown in Figure 1.
13C NMR (75 MHz, CDCl3):  = 97.7 (s, 1 C, O2C), 60.7 (t, 2 C, OCH2),
42.3 (t, 2 C, ClCH2), 24.6 (t, 1 C, (CH2)2CH2).
A 100 mL, one-necked, round-bottomed flask with a magnetic stir-
ring bar (cylindric shape, 15 × 6 mm, PTFE covered) was charged with
1,3-dichloroacetone (25.0 g, 197 mmol, 1.00 equiv), toluene (50 mL),
1,3-propanediol (16.5 g, 217 mmol, 1.10 equiv), and p-toluenesulfon-
ic acid monohydrate (749 mg, 3.94 mmol, 2.0 mol%). The flask was
Anal. Calcd for C6H10Cl2O2: C, 38.95; H, 5.45; Cl, 38.32; O, 17.29.
Found: C, 38.94; H, 5.43.
Analytical data match the literature.3a
© 2014. Thieme. All rights reserved. Synthesis 2014, 2020, A–D

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F. F. Mulks et al.
PSP
Synthesis
Cyclopropenone 1,3-Propanediol Ketal (2)
[CAS Reg. No. 60935-21-9]
SAFETY: 1) We strongly encourage the use of an additional safety
shield and full face, hand, arm, and body protection during work with
liquid ammonia. While ignition or spontaneous evaporation of am-
monia are not expected under the operating conditions, such risks
can never fully be eliminated when working with condensed flamma-
ble gases. 2) Acetone will ignite on contact with potassium. Special
care is advised.
The experimental setup is shown in Figure 2.
A 1000 mL, four-necked, round-bottomed flask (with a 400 mL filling
height of the flask marked prior to the experiment) was equipped
with a Quickfit joint with a low-temperature thermometer, a gas inlet
connected to ammonia, an empty acetone–dry ice condenser, an
empty 500 mL pressure-equalizing dropping funnel, and a magnetic
stirring bar (dumbbell shape, 35 × 8 mm, PTFE covered). The proce-
dure was most effective with the gas inlet tube pointing at the cooled
flask surface. Alternatively, we also carried out the condensation by
utilizing a septum and a cannula to connect the ammonia stream, and
observed the same result. The top of the dropping funnel was
equipped with a gas inlet connected to nitrogen. The outlet of the
condenser was connected to a gas bubbler leading to the back of the
fume hood through a wash bottle filled with potassium hydroxide
pellets. The flask was purged with nitrogen for 30 min before the ace-
tone–dry ice condenser was charged. The flask was cooled with an ac-
etone–dry ice bath (–78 °C) and a low stream of dry ammonia was
opened. Commercial dry ammonia (Air Liquide) was used (anhydrous,
≥99.98%) without further purification. The nitrogen stream was set to
a very low stream. Nitrogen and ammonia can be switched off to
check the corresponding gas streams with the gas bubbler. Ca. 400 mL
of dry ammonia was condensed, measured by the filling height mark-
ing. The ammonia gas flow was switched off and a slow flow of nitro-
gen was switched on. The ammonia inlet was removed to charge the
flask with pieces of potassium and with catalytic amounts of iron(III)
chloride to catalyze the reduction of ammonia by potassium under
hydrogen evolution. (ATTENTION: Acetone will ignite on contact with
potassium. Special care is advised in the next step.) A piece of potassi-
um (0.5 g) was added under vigorous stirring, and the solution turned
dark blue. (Note: Potassium was employed due to potassium amide
having 103 times better solubility in liquid ammonia over sodium am-
ide, potentially avoiding stirring problems.) The neck was closed with
a stopper in between addition steps. Iron(III) chloride (110 mg,
678 μmol, 0.5 mol%) was added, and the solution turned dark gray.
The cooling bath was removed from the fume hood, replaced with a
glass bowl, and the mixture was allowed to warm to reflux (ca.
–33 °C). Over 30 min, the remainder of the potassium metal (total of
15.3 g, 391 mmol, 2.90 equiv) was added in 0.5 g pieces. After every
piece, the solution turned dark blue for about 5 min.
Figure 2 Experimental setup for the synthesis of cyclopropenone 1,3-
propanediol ketal (2), after removal of the cooling bath (note the rec-
ommended safety shield).
–50 °C. The reaction mixture was stirred at –50 to –60 °C for 3 h. The
solution turned olive over this period. Afterwards, the stopper was re-
moved and ammonium chloride (30.0 g, 561 mmol, 4.16 equiv) was
added with a spatula over 30 min. The dropping funnel was replaced
with a new, clean, 500 mL scaled dropping funnel charged with anhy-
drous diethyl ether (350 mL) and the cooling bath was removed. The
stopper on the 1000 mL flask was replaced with an internal ther-
mometer. The condenser was not charged with dry ice anymore and
the ammonia was allowed to evaporate overnight (8 h), while its vol-
ume was replaced with diethyl ether, maintaining a slow flow from
the dropping funnel. The flow was observed for 10–15 min and ad-
justed with the scale of the dropping funnel to achieve a flow that
would empty the 350 mL of diethyl ether within 90 min (~4 mL/min).
The internal thermometer was used to monitor the reaction until it
reached room temperature, before the reaction was left alone for the
remaining time. The resulting brown suspension was filtered over a
coarse glass frit (porosity 1) by suction. The inorganic remains on the
filter were then washed with anhydrous diethyl ether (3 × 25 mL).
The combined ethereal filtrate and washes were concentrated with a
rotary evaporator under reduced pressure (80–100 mbar, 30 °C) until
no more evaporation was visible on the condenser (1 h). The residue
was then transferred to a 50 mL, round-bottomed flask with a pipet.
Anhydrous diethyl ether (3 × 3 mL) can be used to dissolve the residue
for transfer to the 50 mL flask. In this case, the solvent needs to be re-
moved from the 50 mL flask under reduced pressure on a rotary evap-
orator (same conditions as before) for about 30 min.
A separate 250 mL, two-necked, round-bottomed flask was charged
with 2,2-bis(chloromethyl)-1,3-dioxane (1; 25.0 g, 135 mmol, 1.00
equiv). The flask was then purged through a gas inlet with nitrogen
for 30 min prior to the addition of anhydrous diethyl ether (200 mL)
to dissolve the solid. The 500 mL dropping funnel on the 1000 mL
flask was charged with the solution through a glass funnel. 20–
30 min after the addition of potassium and iron(III) chloride, a dark
gray suspension was observed. The acetone–dry ice cooling bath was
allowed to warm and was then set to –50 °C by adding a sufficient
amount of dry ice. The cooling bath was then placed under the flask
again, replacing the glass bowl. The solution of 2,2-bis(chloromethyl)-
1,3-dioxane was added to the freshly generated solution of potassium
amide over 15 min while the bath temperature was maintained at
The flask was fitted with a short-path distillation head with water-
cooling, and the product was distilled (10–1 mbar, 30 °C) into 25 mL,
one-necked, round-bottomed flask receivers, which were cooled to
–78 °C with an acetone–dry ice cooling bath. The flask was exchanged
with a clean, new flask when the desired fraction evaporated at
>29 °C distillation head temperature. (Note: Careful temperature
monitoring is advised. When present, impurities might show boiling
© 2014. Thieme. All rights reserved. Synthesis 2014, 2020, A–D

D
F. F. Mulks et al.
PSP
Synthesis
points only separated by a few °C in both directions.) Cyclopropenone
1,3-propanediol ketal was obtained as a colorless liquid; yield: 8.2–
10.7 g (73.1–96.5 mmol, 54–71%); bp 29–31 °C/10–1 mbar. The prod-
uct is labile towards hydrolysis; storage under argon or nitrogen in a
standard freezer is recommended.
Primary Data
for this article are available online at https://doi.org/10.1055/s-0039-
1690830 and can be cited using the following DOI: 10.4125/pd0115th.
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References
Quantitative 1H NMR purity (300 MHz, CDCl3, 1,3,5-trimethoxyben-
zene): >96%.
(1) New address: F. F. Mulks, Departement für Chemie und Bioche-
mie, Universität Bern, Freiestrasse 3, 3012 Bern, Switzerland.
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IR (ATR): 3120, 3092, 2960, 2926, 2856, 2717, 1836, 1724, 1597, 1473,
1459, 1431, 1366, 1345, 1297, 1271, 1244, 1215, 1172, 1152, 1081,
1021, 960, 927, 906, 862, 733, 694, 648, 612 cm–1
.
1H NMR (300 MHz, CDCl3):  = 7.85 (s, 2 H, CH), 4.02 (t, J = 5.5 Hz, 4 H,
OCH2), 1.85 (quin, J = 5.5 Hz, 2 H, (CH2)2CH2).
13C NMR (75 MHz, CDCl3):  = 125.8 (d, 2 C, CH), 81.3 (s, 1 C, O2C), 66.5
(t, 2 C, OCH2), 26.1 (t, 1 C, (CH2)2CH2).
(4) Szmant, H. H. Organic Building Blocks of the Chemical Industry;
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Analytical data match the literature.2,3
Note: Novel isolation procedures for the viscous and moisture-sensi-
tive product promise to further increase the yield. Decomposition
over the course of the careful evaporation of ammonia, rotary evapo-
ration, and distillation cause fluctuations and losses in the isolated
yield, alongside adhesion to the distillation apparatus.
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690830.
S
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orti
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gInformati
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© 2014. Thieme. All rights reserved. Synthesis 2014, 2020, A–D