Large-Scale Synthesis and Modifications of Bicyclo[1.1.1]pentane-1,3-dicarboxylic Acid (BCP)

Article abstract of DOI:10.1021/acs.joc.1c00977

In flow photochemical addition of propellane to diacetyl allowed construction of the bicyclo[1.1.1]pentane (BCP) core in a 1 kg scale within 1 day. Haloform reaction of the formed diketone in batch afforded bicyclo[1.1.1]pentane-1,3-dicarboxylic acid in a

Full text of DOI:10.1021/acs.joc.1c00977

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Article
Large-Scale Synthesis and Modifications of Bicyclo[1.1.1]pentane-
1,3-dicarboxylic Acid (BCP)
Vasyl Ripenko, Daniil Vysochyn, Ivan Klymov, Serhii Zhersh, and Pavel K. Mykhailiuk*
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ABSTRACT: In flow photochemical addition of propellane to
diacetyl allowed construction of the bicyclo[1.1.1]pentane (BCP)
core in a 1 kg scale within 1 day. Haloform reaction of the formed
diketone in batch afforded bicyclo[1.1.1]pentane-1,3-dicarboxylic
acid in a multigram amount. Representative gram scale trans-
formations of the diacid were also performed to obtain various BCP-
containing building blocksalcohols, acids, amines, trifluoroborates,
amino acids, etc.for medicinal chemistry.
of carboxylic groups in diacid 1 (Figure 1).11b In recent years,
we received a lot of requests from pharmaceutical companies
on various BCP-containing building blocks. Therefore, we
needed a practical method to rapidly access multigram
quantities of diacid 1.
INTRODUCTION
■
Benzene is the most popular ring in bioactive compounds.1 In
particular, the structure of more than 500 drugs comprises the
motif of benzene.2 However, bioactive compounds with several
phenyl rings often have low solubility in water3 and high
toxicity due to rapid oxidation in vivo into quinones.4 On the
other hand, because of the recently emerged concept Escape
from Flatland,5 today medicinal chemists often replace benzene
rings in bioactive compounds with saturated bioisosteres. Apart
from improving physicochemical propertiesbetter solubility,
lower lipophilicity, and higher metabolic stabilitythis tactic is
also often used to come out of the patented chemical space.6 In
particular, in 2012, Stepan and co-workers substituted the
phenyl fragment in a γ-secretase inhibitor with the
bicyclo[1.1.1]pentyl (BCP) skeleton.7 The obtained analogue
showed higher activity, better solubility, and improved
metabolic stability. Since then, bicyclo[1.1.1]pentyl-containing
derivatives have been playing an important role in medicinal
chemistry.8 They have already been mentioned in more than
200 patents (Figure 1).
The first synthesis of diacid 1 was described in 1982 by
Applequist.12 The authors converted cyclobutanone 2 into the
substituted bicyclo[1.1.0]butane 3 (Scheme 1).13 From that
intermediate, diacid 1 was synthesized in five steps in a 400 mg
amount. In 1988, Michl developed a practical approach to
access diacid 1 (Scheme 1).14,15 The authors performed the
photochemical reaction between propellane (4) and diacetyl
(5) to produce diketone 6 in 58% yield (2 steps from
dibromide 7). The synthesis was performed in batch, and 26 g
of the product was obtained in a single run. The photo-
chemical step was performed with a medium-pressure Hanovia
mercury lamp in a Pyrex vessel. Haloform reaction of 6 gave
the needed diacid 1 in a 25 g scale. In 2014, Booker-Milburn
performed a reaction between propellane (4) and diacetyl (5)
in flow to obtain 52 g of product 6 (Scheme 1).16 Irradiation
Indeed, an increasing demand from pharmaceutical
institutions initiated many academic groups to work on
elaboration of novel synthetic approaches to substituted
bicyclo[1.1.1]pentanes and their analogues.9−11
Despite the huge development in recent years on the
synthesis of bicyclo[1.1.1]pentanes, however, still the most
popular approach to them relies on the stepwise modifications
Special Issue: Enabling Techniques for Organic Syn-
thesis
Received: April 26, 2021
© XXXX The Authors. Published by
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American Chemical Society
A

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Article
Recently, Baumann also developed an elegant photo-
chemical addition of oxalic acid derivatives to propellane in
flow using a medium-pressure mercury lamp with filters.17,18
In our first attempts, we repeated the protocol of Kaszynski
and Michl which allowed preparing diacid 1 in gram
quantities.14,15 However, the need to perform irradiation
with (a) a Hanovia mercury lamp (b) in Pyrex glassware
prevented further scale-up of this method. Herein, therefore
would like to disclose our results and unexpected observations
on the rapid practical synthesis of diacid 1. Our protocol
employs common LED (365 nm) irradiation with no need to
use Pyrex glassware. Because it is still the most popular
precursor to BCP derivatives (Figure 1), we believe that these
results will be interesting to many organic chemists and
medicinal chemists in both industrial and academic institu-
tions.
RESULTS AND DISCUSSION
■
Synthesis and Storage of Propellane (4). Propellane 4
was first reported in 1982 by Wiberg.19 In 1985, Szeimies
developed an alternative synthesis of 4 from dibromide 7,20
and in 1988, Michl optimized it.14 In 1998, Mondanaro and
Dailey further optimized the protocol.21
For the synthesis of propellane, we used the procedure of
Mondanaro and Dailey.21 Previous reports suggested direct use
of propellane after the preparation, because of its extensive
polymerization under contact with air.22 We found that the
solution of propellane (4) in diethyl ether can be stored at −40
°C for several weeks. Titration with thiophenol revealed that,
after 1 month in a fridge, the concentration of 4 in a solution
dropped from 0.75 to 0.60 N. Scheme 2 shows a photo of six 1
Figure 1. Bioactive derivatives of bicyclo[1.1.1]pentane (BCP).
Scheme 1. Approaches to Bicyclo[1.1.1]pentane-1,3-
dicarboxylic Acid (1)
a
Scheme 2. Synthesis of Propellane (4)
a
Photo: six 1 L bottles with a solution of propellane in diethyl ether
stored in a fridge at −40 °C.
L bottles with a solution of propellane that we routinely store
in a fridge. It is very convenient not to prepare propellane
every time, but to keep its stock solution and use when needed.
Indeed, the solution in the bottle must be kept under an argon
atmosphere.
Multigram Photochemical Preparation of Diketone 6.
Initially, we performed photochemical reactions between
propellane (4) and diacetyl (5) in batch following the protocol
of Michl.14 However, the need to use (a) the broad wavelength
mercury lamp and (b) Pyrex glassware somewhat complicated
the practical aspects of the procedure. Out of curiosity,23 we
tried other standard wavelengths420 and 365 nmthat are
compatible with standard chemical glassware and do not
require Pyrex vessels. Under irradiation with 420 nm (blue
LED), the reaction did not proceed. However, irradiation with
365 nm led to smooth formation of product 6 at room
temperature. Performing the reaction in batch, we could easily
was again performed with a medium-pressure Hanovia
mercury lamp in Pyrex glassware.
B
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synthesize 10 g of diketone 6 (Scheme 3). The reaction was
performed in a standard chemical glass flask.
Scheme 5. Multigram Scale Synthesis of Diacid 1 in Batch
a
Scheme 3. Photochemical Synthesis of Diketone 6 in Batch
related building blocks are still being produced from diacid 1.
Having synthesized a significant amount of diacid 1, we would
also like to present here its representative multigram
functionalizations that were performed before on a smaller
scale. Treatment of 1 with SelectFluor (1.2 equiv) in the
presence of a catalytic amount of AgNO3 gave fluorine-
substituted acid 826 in a 54 g scale (Scheme 6), a key
a
Irradiation is performed at 365 nm in a standard chemical glass flask.
Having an optimized batch procedure in hand, we attempted
next the photochemical reaction in flow. The irradiation was
performed at 365 nm.24 A solution of reagents in diethyl ether
was pumped via a fluorinated ethylene propylene pipe (0.5 cm
inner diameter) through a photoelement.25 After some
optimization, we found that the transformation was complete
with a 30 mL/min flow rate (4:5 = 1:1; conc. = 0.7 M, Scheme
4). We used 80% of the nominal LED luminescence power
Scheme 6. Multigram Scale Synthesis of BCP-Containing
Building Blocks 8−13 from Diacid 1
a
Scheme 4. Photochemical Synthesis of Diketone 6 in Flow
intermediate in the synthesis of a 19F NMR label for solid state
peptide studies.10a Activation of the carboxylic group in 8 with
ClCO2Me and reduction with sodium borohydride gave
interesting alcohol 9 in a 10 g amount. Curtius rearrangement
of acid 8, followed by acidic N-Boc deprotection, afforded
fluoro-substitued amine 10 in a 13 g amount. Esterification of
diacid 1 with methanol and monohydrolysis gave valuable
linker 1114 in a 163 g scale. Curtius rearrangement of 11,
followed by alkali hydrolysis of the ester group, gave N-Boc
amino acid 12 in 40 g quantities. It is worth noting that amino
a
Irradiation is performed at 365 nm in a coil.
(total diode power: 670 W). Interestingly, after the photo-
reaction, the original deep yellow color of diacetyl (5) became
almost white, indicating disappearance of the starting material
(Scheme 4: left and right). Using that in flow protocol, we
could easily pump 9 L of the reaction mixture through a
photoelement and produce ca. 1 kg of diketone 6 within 6 h.
Multigram Synthesis of Diacid 1. Multigram synthesis of
diacid 1 from ketone 6 was performed following the protocol
of Michl14 with a slight modification. Previously, authors
purified diketone 6 and then performed the haloform reaction.
We found, however, that a higher yield of diacid 1 could be
obtained by performing the reaction with crude 6 (obtained by
evaporation of the reaction mixture after irradiation). In fact,
performing the reaction in a 6 L flask, we could start from ca.
250 g of crude 6 and synthesize 115−133 g of diacid 1 in a
single run depending on the batch. Repeating the synthesis
four times in total allowed us to synthesize ca. 500 g of diacid 1
(Scheme 5).
̈
acid 12 was previously used by Patzel as a mimetic of γ-
aminobutyric acid (GABA) in peptides.27 Finally, acylation of
N-hydroxyphthalimide with 11, followed by light-mediated
decarboxylative borylation with B2Cat2, addition of pinacol,
and subsequent treatment with potassium fluoride, gave
valuable organotrifluoroborate 13 in a 20 g amount. The
compound was first synthesized by Aggarwal,28 and recently,
VanHeyst, Qi, and co-workers from Merck used it for practical
photoredox cross-couplings of heterocycles.29
In addition, we wanted also to disclose here the synthesis of
hydroxy acid 14, the compound that, in the unprotected form,
was unknown before. There were several attempts before to
access the needed core. In 1982, Applequist and colleagues
Multigram Synthesis of BCP-Containing Building
Blocks. As it was mentioned earlier, most of the medchem-
C
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tried hydrolysis of compound 15 in the presence of silver
nitrate (Scheme 7).12 However, only ring-opened alkene 16
zoic acid (24). Moreover, similar bioisosteric replacement of
phenols was recently validated by Adsool and colleagues.31
CONCLUSION
Scheme 7. Synthesis of BCP-Containing Hydroxy Acid 14
■
Most of the medchem-relevant BCP-containing derivatives are
obtained today from bicyclo[1.1.1]pentane-1,3-dicarboxylic
acid (1) (Figure 1). In this work, we developed its practical
synthesis on a multigram scale. The key step was in flow
photochemical reaction between propellane (4) and diacetyl
(5) under irradiation with 365 nm in flow. Importantly, the
procedure was mercury lamp-free and quartz vessels-free. The
developed protocol allowed for the rapid production of ca. 1 kg
of diketone 6 during 6 h. The target diacid 1 was subsequently
synthesized in a 500 g scale by haloform reaction of the
diketone in batch. Several representative multigram function-
alizations of diacid 1 into medchem-relevant BCP building
blocks were also demonstrated (Schemes 6 and 7). We believe
that, with the robust practical protocol described here,
medicinal chemists worldwide in both industry and academia
could easily now synthesize and use BCP molecules routinely.
EXPERIMENTAL SECTION
■
General Considerations. All chemicals were provided by
Enamine Ltd. (www.enamine.net). All solvents were treated according
to standard methods. All reactions were monitored by thin-layer
chromatography (TLC) and were visualized using UV light. Product
purification was performed using silica gel column chromatography.
TLC characterization was performed with precoated silica gel GF254
(0.2 mm), while column chromatography characterization was
1
performed with silica gel (100−200 mesh). H NMR spectra were
recorded at 400, 500, or 600 MHz (Varian); 19F NMR spectra were
recorded at 376 MHz (Varian); and 13C NMR spectra were recorded
at 100, 126, or 151 MHz (Varian). 1H NMR chemical shifts are
calibrated using residual undeuterated solvents CHCl3 (δ = 7.26
ppm) or DMSO (δ = 2.50 ppm). 13C NMR chemical shifts for 13C
NMR are reported relative to the central CHCl3 (δ = 77.16 ppm) or
DMSO (δ = 39.52 ppm). 19F NMR chemical shifts are calibrated
using CFCl3 as an internal standard. Coupling constants are given in
Hz. High-resolution mass spectra (HRMS) were recorded on an
Agilent LC/MSD TOF mass spectrometer by electrospray ionization
time-of-flight reflectron experiments.
Tricyclo[1.1.1]pentane (Propellane) (4). A dry three-neck
round-bottom flask (6 L) equipped with an overhead stirrer was
charged with 1,1-bis(chloromethyl)-2,2-dibromocyclopropane (7)
(800.0 g, 2.7 mol, 1.0 equiv) in Et2O (2 L). The mixture was cooled
to −78 °C, and MeLi (3 M, 2 L, 6.0 mol, 2.2 equiv) was added
dropwise at the same temperature under argon. The mixture was
stirred for 30 min at −75 °C, then warmed to 0 °C, and stirred for 1.5
h. The mixture was distilled to a 5 L flask and stored under argon. The
mixture was titrated and transferred into 800 mL bottles for storage.
Yield: 3.75 L, 0.1 M of 4, 78%. Titration: propellane was titrated with
thiophenol. A degassed with argon solution of thiophenol (3.00 g) in
Et2O was added to a solution of 4 (10 mL). The mixture was stirred
for 15 min, concentrated, and subjected to 1H NMR. The ratio of the
obtained PhS-BCP-H and remaining PhSH was calculated based on
the proton of the tertiary carbon in propellane at 2.72 ppm (s, 1H)
and the proton in PhSH at 3.44 ppm (s, 1H).
1,1′-(Bicyclo[1.1.1]pentane-1,3-diyl)bis(ethan-1-one) (6). To
a solution of 4 (0.7 M, 8 L, 5.6 mol, 1.0 equiv) was added a degassed
with argon solution of (MeCO2)2 (482.0 g, 5.6 mol, 1.0 equiv) in
Et2O (500 mL). The reaction mixture (9 L) was passed through a
photoreactor during 6 h with a flow rate of ca. 30 mL/min. The
volume of the illuminated area is 160 mL, and that of the
nonilluminated area is 50 mL. The wavelength is 365 nm, and the
LED luminescence power is 80% of the nominal (total diode power:
670 W). The mixture was concentrated under reduced pressure.
Yield: 821.2 g, 5.4 mol, 94%. This product was used in the next step
was isolated in 34% yield, while formation of alcohol 17 was
not observed. Recently, Baran and co-workers developed an
electrochemical synthesis of hindered ethers and alcohols from
carboxylic acids.30 Being involved in this project, we also tried
to expand this methodology onto acid 11. For that, a mixture
of acid 11 and water in acetone was electrolyzed under a
constant current of 10 mA during 3 h (Scheme 7).
Unfortunately, formation of the desired product was not
observed. Under prolonged electrolysis, only slow decom-
position of the starting material took place. Finally, we
undertook the synthesis of compound 14 from diacid 1
(Scheme 7). Alkylation of the latter with an excess of benzyl
bromide smoothly gave diester 18. Selective alkali mono-
hydrolysis afforded acid 19. Acylation of N-hydroxyphthali-
mide (via 20), followed by light-mediated decarboxylative
borylation with B2Cat2 and addition of pinacol, gave
organoboron derivative 21. Reaction with potassium fluoride
provided trifluoroborate 22. The key oxidation with hydrogen
peroxide formed alcohol 23 in 35% yield. Finally, cleavage of
the O−Bn bond by hydrogenation on Pd/C in methanol gave
the desired molecule 14 in a 1 g amount. Compound 14 can be
viewed as the saturated bioisostere of popular 4-hydroxyben-
D
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without additional purification. An analytically pure sample can be
obtained by crystallization of the compound from pentane:diethyl
ether = 2:1. Mp = 69−70 °C. 1H NMR (400 MHz, CDCl3) δ 2.19 (s,
3H), 2.09 (s, 3H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 205.8,
51.9, 43.3, 26.2 ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C9H13O2 153.0916; found 153.0910.
was concentrated under reduced pressure. The solid residue was
washed with MeOtBu (1 L) and dried (under reduced pressure, 1
mmHg at 50 °C in a heating mantle). Yield: 13.5 g, 0.098 mol, 95%,
white solid. 1H NMR (500 MHz, DMSO-d6) δ 9.43 (s, 3H), 2.33 (s,
6H). ppm. 13C{1H} NMR (126 MHz, DMSO-d6) δ 75.6 (d, J = 321
Hz), 54.3 (d, J = 21 Hz), 37.6 (d, J = 72 Hz) ppm. 19F{1H} NMR
(376 MHz, DMSO-d6) δ −166.6 (s) ppm. HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C5H9FN 102.0719; found 102.0715.
Bicyclo[1.1.1]pentane-1,3-dicarboxylic Acid (1). A solution of
NaOH (1 kg, 24.6 mol, 15.0 equiv) in water (3.5 L) was cooled to 20
°C, and Br2 (2 kg, 12.3 mol, 7.5 equiv) was added to the solution
dropwise. The mixture was stirred for 3 h, then cooled to 0 °C, and a
solution of ketone 6 (250.0 g, 1.64 mol, 1.0 equiv) in dioxane (1 L)
was added dropwise. The mixture was stirred overnight and extracted
with CH2Cl2 (3 × 3 L). An aqueous solution was acidified and
extracted with EtOAc (3 × 3 L). The organic layers were
concentrated under reduced pressure. The residue was mashed in
hexane (1 L), then in CH2Cl2 (1 L), and a white precipitate was
filtered off. The aqueous layer was also concentrated and additionally
extracted with EtOAc (2 × 1 L). Yield: 115.5−133.1 g, 0.74−0.85
mol, 45−51% depending on a batch. After four runs, ca. 500 g of the
diacid was obtained. Mp = 169−170 °C. 1H NMR (400 MHz,
DMSO-d6) δ 12.50 (br s, 2H), 2.14 (s, 6H) ppm. 13C{1H} NMR
(126 MHz, DMSO-d6) δ 170.6, 51.8, 37.2 ppm. HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C7H9O4 157.0501; found 157.0508.
3-Fluorobicyclo[1.1.1]pentane-1-carboxylic Acid (8). Com-
pound 1 (155.0 g, 0.99 mol, 1.0 equiv) and AgNO3 (39.0 g, 0.23 mol,
0.2 equiv) were dissolved in distilled water (3 L). The mixture was
degassed with argon (5 times), and Selectfluor (416.0 g, 1.18 mol, 1.2
equiv) was added. The mixture was degassed with argon (2 times)
and heated at 70 °C in an oil bath with a thermocouple for 24 h. The
solution was cooled to room temperature and extracted with MeOtBu
(3 × 1 L). The organic layer was concentrated under reduced
pressure. The solid residue was recrystallized from a mixture of
MeOtBu:pentane = 1:9 to give the title product as a yellow solid. Mp
3-(Methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic
Acid (11). Compound 1 (200.0 g, 1.28 mol, 1.0 equiv) was dissolved
in MeOH (3 L), and SOCl2 (457.0 g, 3.84 mol, 3.0 equiv) was added
dropwise at 20−40 °C. The mixture was stirred at room temperature
overnight and concentrated under reduced pressure. The mixture was
dissolved in a mixture of hexane:MeOtBu = 1:1 (1 L), filtered through
SiO2 (∼500 g), and concentrated. Yield: 196.1 g, 1.06 mol, 83%,
1
white solid, mp 90−91 °C. H NMR (400 MHz, CDCl3) δ 3.68 (s,
3H), 2.31 (s, 3H) ppm. 13C{1H} NMR (151 MHz, CDCl3) δ 170.3,
54.3, 51.9, 45.8, 28.5 ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C9H13O4 185.0814; found 185.0810. The product (196.1 g, 1.06
mol, 1.0 equiv) was dissolved in THF (2 L), and LiOH·H2O (40.0 g,
0.95 mol, 0.9 equiv) was added to the mixture. The mixture was
heated in an oil bath with a thermocouple at 50 °C for 72 h, then
cooled to room temperature, and concentrated under reduced
pressure. The residue was dissolved in water (1 L) and extracted
with MeOtBu (3 × 500 mL). The aqueous layer was acidified with
HCl to pH ∼3−4. The precipitate was filtered off and dried at 1
mmHg over P2O5. Yield: 163.3 g, 0.96 mol, 90%. Yellow solid. Mp =
1
126−127 °C. H NMR (400 MHz, CDCl3) δ 11.15 (br s, 1H), 3.69
(s, 3H), 2.34 (s, 6H) ppm. 13C{1H} NMR (151 MHz, CDCl3) δ
175.2, 169.8, 52.9, 52.1, 37.7, 37.6 ppm. HRMS (ESI-TOF) m/z: [M
+ H]+ calcd for C8H11O4 171.0657; found 171.0655.
3-((tert-Butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-car-
boxylic Acid (12). Compound 11 (40.0 g, 0.23 mol, 1.0 equiv) was
dissolved in tBuOH (1 L). Et3N (28.0 g, 0.27 mol, 1.2 equiv) and
(PhO)2P(O)N3 (70.0 g, 0.25 mol, 1.1 equiv) were added to the
solution. The mixture was heated in an oil bath with a thermocouple
at 85 °C for 24 h, then cooled to room temperature, and concentrated
under reduced pressure. The residue was dissolved in EtOAc (1 L)
and washed with a saturated aqueous solution of NaHCO3 (2 × 400
mL), water (500 mL), and brine (500 mL). The organic layer was
dried over Na2SO4, filtered, and concentrated. The crude product was
purified by column chromatography (gradient, hexane:MeOtBu = 1:9
to 1:1). Yield: 44.0 g, 0.19 mol, 80%, white solid. Mp = 138−139 °C.
1H NMR (400 MHz, CDCl3) δ 5.00 (br s, 1H), 3.67 (s, 3H), 2.27 (s,
1
= 95−97 °C. Yield: 54.0 g, 0.41 mol, 42%. H NMR (400 MHz,
CDCl3) δ 11.05 (br s, 1H), 2.39 (s, 6H) ppm. 13C{1H} NMR (126
MHz, CDCl3) δ 175.5 (d, J = 37 Hz), 74.8 (d, J = 329 Hz), 55.7 (d, J
= 22 Hz), 28.2 (d, J = 48 Hz) ppm. 19F{1H} NMR (376 MHz,
CDCl3) δ −150.3 (s) ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C6H7FO2 130.0430; found 130.0432.
(3-Fluorobicyclo[1.1.1]pentan-1-yl)methanol (9). Compound
8 (13.0 g, 0.100 mol, 1.0 equiv) was dissolved in THF (200 mL). The
solution was degassed with argon and cooled to 0 °C, and BH3·Me2S
(11.7 g, 0.15 mol, 1.5 equiv) was added dropwise. The mixture was
stirred at room temperature overnight, then cooled to 0 °C, and dry
MeOH (100 mL) was added dropwise. The mixture was stirred for 5
h at room temperature and concentrated under reduced pressure. The
residue was distilled at 1 mmHg. Yield: 10.1 g, 0.087 mol, 86%,
colorless oil. 1H NMR (400 MHz, CDCl3) δ 3.82 (s, 2H), 1.99 (d, J =
2.5 Hz, 6H), 1.81 (s, 1H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ
75.9 (d, J = 329 Hz), 60.8 (d, J = 27 Hz), 52.4 (d, J = 21 Hz), 29.3 (d,
J = 41 Hz) ppm. 19F{1H} NMR (376 MHz, CDCl3) δ −145.7 (s)
ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C6H10FO
117.0716; found 117.0712.
6H), 1.43 (s, 9H) ppm. 13C{1H} NMR (151 MHz, CDCl3) δ 169.8,
53.0, 51.9, 37.7 ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C12H20NO4 242.1392; found 242.1399. The product was dissolved in
a mixture of THF and H2O (7:3, 500 mL), and LiOH·H2O (11.5 g,
0.28 mol, 1.5 equiv) was added to the mixture. The mixture was
stirred overnight at room temperature and then concentrated under
reduced pressure. The residue was dissolved in distilled water (500
mL) and extracted with MeOtBu (3 × 500 mL). The aqueous layer
was acidified with citric acid to pH ∼ 6 and extracted with EtOAc (3
× 300 mL). The combined organic layers were dried over Na2SO4,
filtered, and concentrated under reduced pressure. The crude product
was recrystallized from a mixture of hexane:EtOAc = 7:3 (the product
was boiled in hexane and EtOAc was added in portions). Yield: 40.0
3-Fluorobicyclo[1.1.1]pentan-1-amine Hydrochloride (10).
Compound 8 (16.0 g, 0.125 mol, 1.0 equiv) was dissolved in tBuOH
(500 mL). Et3N (15.0 g, 0.150 mol, 1.2 equiv) and (PhO)2P(O)N3
(38.0 g, 0.137 mol, 1.1 equiv) were added to the solution. The
mixture was heated at 85 °C in an oil bath with a thermocouple for 24
h, cooled to room temperature, and concentrated under reduced
pressure. The residue was dissolved in EtOAc (500 mL) and washed
with a sat. solution of NaHCO3 (200 mL), water (250 mL), and brine
(250 mL). The organic layer was dried over Na2SO4, filtered, and
concentrated. The crude product was purified by column chromatog-
raphy (gradient, hexane:MeOtBu = 1:9 to 1:1). Yield: 21.2 g, 0.105
1
g, 0.176 mol, 95%, white solid. Mp = 176−177 °C. H NMR (400
MHz, DMSO-d6) δ 12.37 (br s, 1H), 7.58 (br s, 1H), 2.08 (s, 6H),
1.37 (s, 9H) ppm. 13C{1H} NMR (126 MHz, DMSO-d6) δ 170.9,
154.5, 53.4, 45.1, 28.2 ppm. LCMS (M − H)−: 226. HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C11H18NO4 228.1236; found
228.1239.
Potassium Trifluoro[3-(methoxycarbonyl)bicyclo[1.1.1]-
pentan-1-yl]boranuide (13). Compound 11 (50.0 g, 0.29 mol,
1.0 equiv) was dissolved in CH2Cl2 (1 L), and N-hydroxyphthalimide
(48.0 g, 0.29 mol, 1 equiv), 4-(dimethylamino)pyridine, and DMAP
(3.51 g, 0.029 mol, 0.1 equiv) were added. N,N′-diisopropylcarbo-
diimide, DIC (44.0 g, 0.35 mol, 1.2 equiv), was added to the mixture
dropwise at room temperature. The mixture was stirred at room
1
mol, 83%. H NMR (500 MHz, CDCl3) δ 4.95 (br s, 1H), 2.30 (s,
6H), 1.42 (s, 9H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 154.9,
80.2, 76.8 (d, J = 316 Hz), 55.3 (d, J = 20 Hz), 39.9 (d, J = 72 Hz),
28.5 ppm. 19F{1H} NMR (376 MHz, CDCl3) δ −169.6 (s) ppm. The
total amount of the product was dissolved in 5 M HCl in dioxane
(500 mL) and stirred at room temperature overnight. The mixture
E
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Article
temperature overnight. The mixture was filtered, and a filtrate was
concentrated under reduced pressure. 1H NMR (500 MHz CDCl3) δ
7.86 (dt, J = 7.0, 3.5 Hz, 2H), 7.77 (dd, J = 5.6, 3.1 Hz, 2H), 3.70 (s,
3H), 2.53 (s, 6H) ppm. The crude product (100.1 g, 0.29 mol, 1.0
equiv) and 2,2′-bis(1,3,2-benzodioxaborole), B2Cat2 (83.0 g, 0.35
mol, 1.2 equiv), were dissolved in DMA (3 L). The mixture was
degassed with argon (5 times) then irradiated in flow. Irradiation: blue
LED: 450 nm, spiral volume: 320 mL, flow rate: 10 mL/min,
radiation intensity: 50% of nominal (total diode power: 850 W),
residence time in the spiral: 32 min, temperature on the cooler: −20
°C, the temperature of the reaction mixture at the outlet: 16 °C. After
completion of the reaction, Et3N (88.0 g, 125 mL, 0.87 mol, 3.0
equiv) and pinacol (51.0 g, 0.435 mol, 1.5 equiv) were added to the
reaction mixture, and it was stirred overnight at room temperature.
The mixture was extracted with a mixture hexane:EtOAc = 9:1 (5 ×
500 mL) and concentrated. The residue was extracted with hexane (3
× 500 mL). The combined organic layers were washed with water (2
× 300 mL) and brine (300 mL), dried over Na2SO4, filtered, and
concentrated under reduced pressure. The final product had ca. 85%
purity according to H NMR. Yield 38.2 g, 0.12 mol, 45%. H NMR
(500 MHz, CDCl3) δ 3.64 (s, 3H), 2.14 (s, 6H), 1.24 (s, 12H) ppm.
The obtained crude product (38.2 g, 0.12 mol, 1.0 equiv) was
dissolved in a mixture of MeOH:H2O = 8:2 (400 mL), and KF·HF
(25.0 g, 0.32 mol, 2.5 equiv) was added. The mixture was stirred at
room temperature overnight and then concentrated. The final product
was dried at 1 mmHg over P2O5 during 24 h. The product was
mashed in MeOtBu (3 L), and the precipitate was extracted with
acetone using a Soxhlet extractor for 48 h. Yield: 20.0 g, 67%, white
solid. Mp = 264−265 °C. 1H NMR (400 MHz, DMSO-d6) δ 3.51 (s,
3H), 1.59 (s, 6H) ppm. 13C{1H} NMR (126 MHz, DMSO-d6) δ
170.5, 50.7, 50.4 ppm. 19F{1H} NMR (376 MHz, DMSO-d6) δ
−143.5 (s) ppm. Anal. Calcd for C7H9BF3KO2: C, 36.23; H, 3.91.
Found: C, 36.10; H, 4.05.
200 mL) and 1 M HCl (3 × 200 mL). The organic layer was dried
over Na2SO4, filtered, and concentrated under reduced pressure.
Yield: 36.40 g, 0.039 mol, 93%, white solid. H NMR (500 MHz,
CDCl3) δ 7.99−7.82 (m, 2H), 7.82−7.68 (m, 2H), 7.48−6.99 (m,
5H), 5.15 (s, 2H), 2.57 (s, 6H) ppm. 13C{1H} NMR (151 MHz,
CDCl3) δ 168.3, 164.7, 161.7, 135.6, 134.9, 128.9, 128.7, 128.4, 128.1,
124.0, 77.2, 66.6, 53.7, 38.8, 35.5 ppm. HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C22H18NO6 392.1134; found 392.1130.
1-Benzyl 3-(1,3-Dioxoisoindolin-2-yl) bicyclo[1.1.1]-
pentane-1,3-dicarboxylate (21). A solution of 20 (7.0 g, 0.0179
mol, 1.0 equiv) and 2,2′-bis(1,3,2-benzodioxaborole) (5.0 g, 0.021
mol, 1.2 equiv) in DMA (90 mL) was degassed with argon (5 times)
then irradiated in flow. Irradiation: blue LED: 450 nm, radiation
intensity: 15% of nominal, the temperature of the reaction mixture: 35
°C. After completion of the reaction, Et3N (5.4 g, 00537 mol, 3.0
equiv) and pinacol (3.1 g, 0.026 mol, 1.5 equiv) were added. The
mixture was stirred at room temperature overnight. The mixture was
extracted with a mixture of hexane:EtOAc, 9:1 (2 × 500 mL), and
concentrated under reduced pressure. The residue was extracted with
hexane (3 × 300 mL), and the combined layers were washed with
water (2 × 300 mL) and brine (1 × 300 mL), dried over Na2SO4,
filtered, and concentrated under reduced pressure. The excess of
pinacol was removed by sublimation. Yield: 3.6 g, 0.011 mol, 61%,
white solid. 1H NMR (500 MHz, CDCl3) δ 7.41−7.23 (m, 5H), 5.08
(s, 2H), 2.15 (s, 6H), 1.22 (s, 12H) ppm. 13C{1H} NMR (126 MHz,
CDCl3) δ 169.5, 136.3, 128.6, 128.2, 128.0, 83.7, 65.9, 52.5, 43.1
ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H26BO4
329.1924; found 329.1918.
1
1
1
Potassium (3-((Benzyloxy)carbonyl)bicyclo[1.1.1]pentan-1-
yl)trifluoroborate (22). To a solution of 21 (10.0 g, 0.03 mol, 1.0
equiv) in a mixture of MeOH:H2O = 8:2 (100 mL) was added KF·HF
(5.46 g, 0.07 mol, 2.5 equiv). The mixture was stirred at room
temperature overnight and then concentrated. The final product was
dried at 1 mmHg over P2O5 during 24 h. The product was mashed in
MeOtBu (250 mL), and the precipitate was dissolved in acetone,
decanted, and concentrated under reduced pressure. Yield: 7.30 g,
Dibenzyl Bicyclo[1.1.1]pentane-1,3-dicarboxylate (18). To a
solution of compound 11 (50.00 g, 0.32 mol, 1.0 equiv) and K2CO3
(101.79 g, 0.74 mol, 2.3 equiv) in DMF (500 mL) was added BnBr
(120.41 g, 0.70 mol, 2.2 equiv) at room temperature. The mixture was
stirred overnight and filtered. The filtrate was diluted with water (1 L)
and extracted with tert-butyl methyl ether (3 × 300 mL). The
combined organic layers were washed with water (2 × 600 mL) and
brine (1 × 600 mL), dried over Na2SO4, filtered, and concentrated
under reduced pressure. The crude product was mashed in hexane,
filtered, washed with hexane, and dried. Yield: 97.44 g, 0.29 mol, 91%,
1
0.0237 mol, 79%, white solid. H NMR (500 MHz, DMSO-d6) δ
7.42−7.24 (m, 5H), 5.03 (s, 2H), 1.64 (s, 6H) ppm. 13C{1H} NMR
(126 MHz, DMSO-d6) δ 169.9, 136.6, 128.5, 127.9, 127.7, 64.7, 50.5
ppm. 19F{1H} NMR (376 MHz, DMSO-d6) δ −143.0 (s) ppm. Anal.
Calcd for C13H13BF3KO2: C, 50.67; H, 4.25. Found: C, 50.50; H,
4.35.
Benzyl 3-Hydroxybicyclo[1.1.1]pentane-1-carboxylate (23).
To a solution of KH2PO4 (15.92 g, 0.117 mol, 3.0 equiv) and
compound 22 (12.00 g, 0.039 mol, 1.0 equiv) in a mixture of H2O
(160 mL) and THF (240 mL) was added H2O2 (30%, 44.21 g, 0.390
mol, 10.0 equiv) dropwise at 0 °C. The mixture was stirred at room
temperature overnight. The mixture was diluted with water (400 mL)
and extracted with MeOtBu (2 × 300 mL). The combined organic
layers were washed with water (1 × 500 mL) and a sat. solution of
NaHSO3 (1 × 500 mL). The organic layer was dried over Na2SO4,
filtered, and concentrated under reduced pressure. The residue was
dissolved in a mixture of hexane:MeOtBu, 1:1 (60 mL), filtered
through SiO2, and concentrated under reduced pressure. Yield: 3.0 g,
1
white solid. H NMR (400 MHz, CDCl3) δ 7.41−7.28 (m, 10H),
5.15 (s, 4H), 2.39 (s, 6H) ppm. 13C{1H} NMR (101 MHz, CDCl3) δ
168.7, 135.6, 128.4, 128.1, 127.9, 77.2, 52.7, 37.6 ppm. HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C21H21O4 337.1440; found 337.1445.
3-((Benzyloxy)carbonyl)bicyclo[1.1.1]pentane-1-carboxylic
Acid (19). To a solution of 18 (25.0 g, 0.074 mol, 1.0 equiv) in dry
THF (680 mL) was added LiOH·H2O (2.8 g, 0.067 mol, 0.9 equiv).
The mixture was heated in an oil bath with a thermocouple at 50 °C
for 72 h. The mixture was concentrated under reduced pressure. The
residue was diluted with water (400 mL) and extracted with tert-butyl
methyl ether (2 × 300 mL). The aqueous layer was acidified with 1 M
HCl to pH ∼ 3. The precipitate was filtered, washed with distilled
water (100 mL), and dissolved in EtOAc (400 mL). The solution was
dried over Na2SO4, filtered, and concentrated under reduced pressure.
1
0.0137 mol, 35%, white solid. H NMR (400 MHz, CDCl3) δ 7.39−
7.17 (m, 5H), 5.36 (s, 1H), 5.10 (s, 2H), 2.21 (s, 6H) ppm. 13C{1H}
NMR (101 MHz, CDCl3) δ 170.4, 135.4, 128.3, 128.0, 127.7, 66.3,
61.8, 55.3, 30.3 ppm. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C13H14NaO3 241.0841; found 241.0833.
1
Yield: 15.7 g, 0.0638 mol, 86%, white solid. H NMR (500 MHz,
CDCl3) δ 11.65 (br s, 1H), 7.35 (s, 5H), 5.14 (s, 2H), 2.37 (s, 6H)
ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 174.8, 169.1, 135.5, 128.6,
128.3, 128.0, 77.2, 66.5, 52.8, 37.6, 37.5 ppm. HRMS (ESI-TOF) m/
z: [M + Na]+ calcd for C14H14NaO4 269.0790; found 269.0792.
1-Benzyl 3-(1,3-Dioxoisoindolin-2-yl) bicyclo[1.1.1]-
pentane-1,3-dicarboxylate (20). To a solution of 19 (25.00 g,
0.100 mol, 1.0 equiv), N-hydroxyphthalimide (17.39 g, 0.107 mol,
1.05 equiv), and DMAP (1.22 g, 0.015 mol, 1.05 equiv) was added
DIC (13.45 g, 0.107 mol, 1.05 equiv) dropwise at room temperature.
The mixture was stirred overnight. The mixture was filtered, and the
filtrate was concentrated under reduced pressure. The residue was
dissolved in CH2Cl2 and washed with a sat. solution of Na2CO3 (3 ×
3-Hydroxybicyclo[1.1.1]pentane-1-carboxylic Acid (14). To
a solution of compound 23 (3.0 g, 0.0137 mol, 1.0 equiv) in MeOH
(50 mL) was added 10% Pd/C (0.25 g, 0.00234 mol, 0.1 equiv). The
mixture was hydrogenated under a rubber ball filled with H2 at rt
overnight. Pd/C was filtered out, and the reaction mixture was
concentrated under reduced pressure. Yield: 1.3 g, 0.01 mol, 74%,
1
white solid. Mp = 98−99 °C. H NMR (400 MHz, DMSO-d6) δ
12.25 (br s, 1H), 6.40 (br s, 1H), 1.98 (s, 6H) ppm. 13C{1H} NMR
(126 MHz, DMSO-d6) δ 171.5, 61.7, 54.9, 30.6 ppm. HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C6H9O3 129.0552; found 129.0543.
F
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Sciammetta, N.; Solban, N.; Yu, W.; Sloman, D. L.; Zhou, H.;
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00977.
■
sı
Copies of NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
Pavel K. Mykhailiuk − Enamine Ltd., 02094 Kyiv, Ukraine;
Email: pavel.mykhailiuk@gmail.com
■
Authors
Vasyl Ripenko − Enamine Ltd., 02094 Kyiv, Ukraine
Daniil Vysochyn − Enamine Ltd., 02094 Kyiv, Ukraine
Ivan Klymov − Enamine Ltd., 02094 Kyiv, Ukraine
Serhii Zhersh − Enamine Ltd., 02094 Kyiv, Ukraine
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00977
2017, 139, 17791−17794. (c) Caputo, D. F. J.; Arroniz, C.; Durr, A.
̈
B.; Mousseau, J. J.; Stepan, A. F.; Mansfield, S. J.; Anderson, E. A.
Synthesis and applications of highly functionalized 1-halo-3-
substituted bicyclo[1.1.1]pentanes. Chem. Sci. 2018, 9, 5295−5390.
(d) Shelp, R. A.; Walsh, P. J. Synthesis of BCP Benzylamines from 2-
Azaallyl Anions and [1.1.1]Propellane. Angew. Chem., Int. Ed. 2018,
57, 15857−15861. (e) Makarov, I. S.; Brocklehurst, C. E.;
Karaghiosoff, K.; Koch, G.; Knochel, P. Synthesis of Bicyclo[1.1.1]-
pentane Bioisosteres of Internal Alkynes and para-Disubstituted
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Fadeyi, O. O.; Gallego, G. M.; Mousseau, J. J.; Oliver, R.; Sach, N. W.;
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful to Mrs. I. Sadkova for the help with
the preparation of the manuscript and to Mr. I. Stadniy and
Mr. M. Kucherbaev for the technical assistance with photo-
reactors. This project has received funding from the European
Research Council (ERC) under the European Union’s
Horizon 2020 research and innovation program (grant
agreement No. 101000893 - BENOVELTY).
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H
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