Synthesis of Bicyclo[1.1.1]pentane Bioisosteres of Internal Alkynes and para-Disubstituted Benzenes from [1.1.1]Propellane

Article abstract of DOI:10.1002/anie.201706799

We report a general preparation of arylated bicyclo[1.1.1]pentanes through the opening of [1.1.1]propellane with various arylmagnesium halides. After transmetalation with ZnCl₂ and Negishi cross-coupling with aryl and heteroaryl halides, bis-arylated bicyclo[1.1.1]pentanes are obtained. These bis-arylated bicyclo[1.1.1]pentanes may be considered as bioisosteres of internal alkynes. Bioisosteres of tazarotene and the metabotropic glutamate receptor 5 (mGluR5) antagonist 2-methyl-6-(phenylethynyl)pyridine were prepared and their physicochemical properties were evaluated.

Full text of DOI:10.1002/anie.201706799

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Accepted Article
Title: Convenient Preparation of Bicyclo[1.1.1]pentane Bioisosteres
of Internal Alkynes and para-Disubstituted Benzenes using
[1.1.1]Propellane
Authors: Ilya S. Makarov, Cara E. Brocklehurst, Konstantin
Karaghiosoff, Guido Koch, and Paul Knochel
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201706799
Angew. Chem. 10.1002/ange.201706799
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10.1002/anie.201706799
Angewandte Chemie International Edition
COMMUNICATION
Convenient Preparation of Bicyclo[1.1.1]pentane Bioisosteres of
Internal Alkynes and para-Disubstituted Benzenes using
[1.1.1]Propellane
Ilya S. Makarov,[a] Cara E. Brocklehurst,[b] Konstantin Karaghiosoff,[a] Guido Koch,[b] and Paul
Knochel*[a]
Abstract: We report
a
general preparation of arylated
bicyclo[1.1.1]pentanes by the opening of [1.1.1]propellane with
various arylmagnesium halides. After transmetalation with ZnCl2 and
a Negishi cross-coupling with aryl and heteroaryl halides, bis-arylated
CO2Et
N
N
Me
bicyclo[1.1.1]pentanes
are
obtained.
These
bis-arylated
1
2
S
bicyclo[1.1.1]pentanes may be considered as bioisosteres of internal
alkynes. Bioisosteres of tazarotene and the metabotropic glutamate
receptor 5 (mGluR5) antagonist 2-methyl-6-(phenylethynyl)pyridine
have been prepared and their physicochemical properties have been
evaluated.
CO2Et
N
N
Me
3
4
S
Figure 1. Alkyne-containing drug tazarotene (1) and drug-candidate MPEP (2)
and their BCP-analogues 3 and 4.
The preparation of pharmaceuticals with optimal physicochemical
properties can be challenging using only standard building blocks
such as aryl or heteroaryl groups. Bioisosteric replacement
represents an important approach for improving various
physicochemical properties of drugs and drug candidates in
medicinal chemistry.[1] The bicyclo[1.1.1]pentyl (BCP) moiety was
proposed to be used as a bioisostere of a para-substituted
benzene ring because both of these fragments share similar
geometrical characteristics such as the dihedral angle and the
distance between the substituents. It was demonstrated that such
a replacement significantly improved the physicochemical profile,
e.g. aqueous solubility, membrane permeability, in vitro metabolic
stability, of an mGlu1 receptor antagonist,[2a] a γ-secretase
inhibitor[2b], an LpPLA2 inhibitor[2c] as well as several drug
candidates.[2d] The BCP-moiety was also studied as a potential
isosteric replacement for a tert-butyl group.[3] As an extension of
these concepts, we envisioned that the BCP-unit may also act as
a bioisostere of an alkynyl group. Specifically, we envisaged
changing the alkynyl moiety in pharmaceuticals tazarotene (1)[4a]
(used for treatment of psoriasis, acne, sun damaged skin) as well
as the metabotropic glutamate receptor 5 (mGluR5) antagonist 2-
methyl-6-(phenylethynyl)-pyridine MPEP (2)[4b,c] with a BCP-unit
in order to investigate the pharmacokinetics and physicochemical
properties of the BCP-analogues 3 and 4 (Figure 1).
The introduction of the BCP-moiety in an organic target
molecule is a synthetic challenge and difficult to realize in a
predictable way.[5] Bunker et al have shown that the synthesis of
1-BCP-amine can be achieved by hydrohydrozination of
[1.1.1]propellane.[6a] More recently, Baran reported a method for
the synthesis of amino-BCP-derivatives by a nucleophilic opening
of [1.1.1]propellane (5) by turbo-amides.[6b,c] In pioneering work,
de Meijere has prepared a range of alkyl-substituted BCP-iodides
using a radical opening of 5 by primary or secondary alkyl iodides.
The further conversion of these iodides to magnesium reagents
allows the Kumada cross-couplings with various aryl and
heteroaryl halides.[7a] Unfortunately, attempts to prepare aryl-
substituted BCP-iodides proceeded in only 10-21% yields.
Alternatively, de Meijere and Szeimies demonstrated that the
direct opening of 5 with arylmagnesium reagents is possible and
produces the corresponding BCP-magnesium species after
reaction times of 3-7 days.[7] The long reaction time and variable
yields precluded applications of the pharmaceutical analogues.
Herein, we report an alternative method for adding a broad range
of arylmagnesium halides ArMgX of type 6 to [1.1.1]propellane (5)
within 45 min to 3 h (instead of 3-7 days) leading to the BCP-
Grignard reagents of type 7 and show that after a transmetalation
with ZnCl2 and a Negishi cross-coupling with various aryl or
heteroaryl halides (Ar’X) the desired bis-arylated BCPs 8 are
obtained in good yields (Scheme 1). We also have also prepared
bioisosteres of pharmaceutical targets such as tazarotene (1) and
mGluR5 antagonist MPEP (2).
[a]
[b]
Dr. I. S. Makarov, Prof. Dr. K. Karaghiosoff, Prof. Dr. P. Knochel
Ludwig-Maximilians-Universität München, Department Chemie
Butenandtstrasse 5-13, Haus F, 81377 München (Germany)
E-mail: paul.knochel@cup.uni-muenchen.de
Dr. C. E. Brocklehurst, Dr. G. Koch
MgX
Ar'
1) ZnCl2
ArMgX (6)
2) Ar'X, Pd(0)
Global Discovery Chemistry
5
7
Ar
Ar
8
Novartis Institutes for BioMedical Research
141 Klybeckstrasse, 4057 Basel, Switzerland
Scheme 1. Preparation of bis-arylated BCPs 8 by opening [1.1.1]propellane
with various arylmagnesium halides followed by transmetalation with ZnCl2 and
a Negishi cross-coupling.
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201706799
Angewandte Chemie International Edition
COMMUNICATION
Preliminary experiments showed that the reaction conditions
used for the addition of arylmagnesium halides (ArMgX, 6) to 5
are key for the success of this addition. [1.1.1]Propellane (5) was
prepared using an improvement of a previous method.[8] We found
that the treatment of the readily available tetrahalide (9)[8] in Et2O
with 2 equiv. of PhLi in Bu2O (instead of MeLi) followed by the
distillation of the reaction mixture produced a 0.6–0.7 M solution
of 5 in Et2O free of any organic halides which proved to be
essential for the next step.[9] In first optimization experiments, a
solution of 4-propylphenylmagnesium bromide (6a, 1.1 equiv.) in
ether[10] was mixed with a solution of 5 (1 equiv.) in a sealed tube
and heated at 50 °C for 18 h producing after aqueous workup the
BCP-derivative 10a in 42% yield as determined by GC-analysis
using an internal standard (Table 1, entry 1). The use of a THF
solution of 6a led to a yield decrease (26%, entry 2). Increasing
the reaction temperature to 70 °C had a dramatic effect and the
product 10a was now obtained in 91% GC-yield (entry 3). Addition
of TMEDA (1 equiv. relative to 6a) did not have a positive effect
on the reaction yield (entry 4). Increasing the reaction temperature
even higher to 90 or 100 °C showed that the BCP-magnesium
intermediate 7a was not stable at such elevated temperatures for
a prolonged period of time (entries 5 and 6). However, shortening
the reaction time to 45 min proved to be beneficial and 10a was
obtained in 65% yield (entry 7). Finally, by using a larger excess
of 6a (2 equiv.), the BCP-derivative (10a) was obtained in an
excellent yield of 92% after 45 min at 100 °C (entry 8).[11]
leading to the corresponding ethyl esters 11b–i in 60–92% yields
(Scheme 2). Arylmagnesium halides with electron-donating
substituents provided the corresponding BCP-esters 11 in higher
yields (11c–e, 74–92% yields) in comparison with those Grignard
reagents bearing the electron-withdrawing substituents (11f–i,
47–61% yields). An ortho-substituent on the Grignard reagent did
not hamper the reaction and an o-tolylmagnesium bromide (6i)
provided the BCP-ester (11i) in a comparable yield as the reagent
without a methyl group 6h (60 vs 61% yields). Notably, more
sensitive Grignard reagents such as an alkynyl-substituted
arylmagnesium bromide 6j and 3-thienylmagnesium bromide (6k)
gave the corresponding esters 11j and 11k in 84% yield.
ArMgX (6)
(2 equiv)
MgX
CO2Et
ClCOOEt (4 equiv)
-78 °C to rt, 30 min
ether, 100 °C
45 min to 3 h
5
Ar
7
Ar
11
CO2Et
CO2Et
CO2Et
Me
Me3Si
11b, 89%
11c, 92%
11d, 74%[a]
CO2Et
CO2Et
CO2Et
11e, 78%
11f, 60%
11g, 47%
MeO
Cl
F
CO2Et
CO2Et
Me
11h, 61%
11i, 60%
F3CO
F3CO
Table 1. Optimization of the reaction of [1.1.1]propellane (5) with
4-propylphenylmagnesium bromide (6a).
CO2Et
CO2Et
TMS
S
11j, 84%
11k, 84%
PhLi (2 equiv)
Br Br
Et2O/Bu2O
4-PrC6H4MgBr (6a)
Cl
-45 to 0 °C, 2.5 h
in ether
Scheme 2. Preparation of ethyl 3-(hetero)arylbicyclo[1.1.1]pentyl carboxylates
11. Yields of isolated products relative to 5 are shown. [a] The reaction time of
5 with 6c was 3 h.
then
distillation
then H2O
Cl
Pr
9
5
10a
Yield [%][b]
Amount of
Reaction
time
Entry
T [°C]
6a [equiv.][a]
This new transformation also provided a convenient access to
1,3-bisarylated BCP-derivatives of type 12 (Scheme 3). The BCP-
intermediate obtained initially by reacting [1.1.1]propellane (5)
with aryl Grignard reagents 7 was converted to the zincated BCP-
species by transmetalation with ZnCl2 and was further coupled
with various aryl and heteroaryl halides under Negishi cross-
1
2
3
4
5
6
7
8
50
1.1
1.1
1.1
1.1
1.1
1.1
1.1
2
18 h
42
50
18 h
26[c]
91
70
18 h
70
18 h
78[d]
77
[12]
coupling conditions. PdCl2(dppf)·CH2Cl2 (2 mol%, dppf = 1,1'-
bis(diphenylphosphino)ferrocene) was found to be the best
catalyst allowing to use aryl iodides as well as heteroaryl
bromides and chlorides as electrophiles in the Negishi cross-
coupling. Aryl iodides with electron-donating or electron-
withdrawing groups reacted smoothly at 40 °C giving the
corresponding 1,3-bisarylated bicyclo[1.1.1]pentanes (12cc, de,
df, ef) in 55–62% yields after 1 h. Increasing the cross-coupling
temperature to 65 °C made it possible to use heteroaryl bromides
and chlorides as electrophiles providing BCPs bearing various
heterocyclic ring systems in 49–91% yields (12aj, ba, bb, cd, eh,
eg, fi, gb, gj, hj). Noteworthy, under the reaction conditions such
sensitive groups as a nitrile or an ester are tolerated (12bb, df, ef,
gb). The cross-coupling with an aryl iodide bearing a methyl group
in the ortho-position required the more demanding conditions and
provided 12ji in 43% yield after 24 h at 65 °C.
90
18 h
100
100
100
18 h
40
45 min
45 min
65
92
[a] Relative to 5. [b] Determined by GC using undecane as an internal
standard. [c] Using solution of 6a in THF instead of Et2O. [d] TMEDA (1.1
equiv.) was added.
These addition conditions proved to be very convenient and
allowed for the first time for a reliable access to a various arylated
BCP-derivatives of type 7. We have treated 5 with various
arylmagnesium bromides of type 6 and quenched the resulting
BCP-magnesium intermediates (7) with ethyl chloroformate
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10.1002/anie.201706799
Angewandte Chemie International Edition
COMMUNICATION
ArMgX (6)
(2 equiv)
MgX
Ar'
MgBr
1) ZnCl2, THF
ether, 100 °C
45 min to 3 h
2) Ar'X (2.1 equiv)
2% PdCl2(dppf)·CH2Cl2
40 or 65 °C, 1 to 18 h
MgBr
5
Ar
7
Ar
1) ZnCl2, THF
CO2Et
12
S
(6i, 2 equiv.)
CO2Et
ether, 100 °C, 6 h
N
5
7i
S
2)
(2.1 equiv)
Cl
N
N
N
Me
2% PdCl2(dppf), 65 °C, 3 h
CO2Et
12bb, X = Cl, 67%
12aj, X = Br, 71%
12ba, X = Br, 71%
nPr
N
CF3
OMe
N
N
3, 40%
S
Me
Me
TMS
PhMgBr (6b)
(2 equiv.)
MgBr
1) ZnCl2, THF
12cd, X = Br, 91%
12cc, X = I, 55%
12de, X = I, 57%
N
Me
ether, 100 °C
45 min
5
Ph
7b
N
4
2)
(2.1 equiv)
Me
2% PdCl2(dppf), 65 °C, 3 h
Br
N
71% - 0.3 mmol scale
69% - 5 mmol scale
CN
N
CN
TMS
Scheme 4. Preparation of the BCP-analogues 3 and 4 of tazarotene (1) and
MPEP (2). Yields of isolated products relative to 5 are shown.
12df, X = I, 56% MeO
12ef, X = I, 62%
12eg, X = Cl, 71%
MeO
N
N
N
Physicochemical properties of the BCP-analogues 3 and 4
were compared with their acetylenic counterparts 1 and 2 (Table
2). It was found that the replacement of a triple bond in 1 with a
BCP-moiety slightly increases the basicity and almost does not
change the non-specific binding as measured by the
chromatographic hydrophobicity index on immobilized artificial
membranes, CHI(IAM).[13] The melting point of 3 is 64 °C higher
than of 1 which indicates a better crystal packing for 3. The
difference in the properties of 2 and 4 is larger relative to 1 and 3.
The BCP-analogue 4 is 1.8 units of pKa more basic than 2 and
has a higher CHI(IAM). However, when 4 was compared with its
para-substituted phenyl analogue 2-([1,1'-biphenyl]-4-yl)-6-
methylpyridine 13, the non-specific binding was found to be lower
for 4 than for 13 which is in line with the previous findings.[2d]
MeO
12eh, X = Br, 68% Cl
12fi, X = Br, 49%
F
12gj, X = Cl, 61%
CO2Et
CO2Et
N
N
S
12gb, X = Cl, 61%
12ki, X = I, 61%
F3CO
12hj, X = Br, 58%
F
OCF3
TMS
TMS
OMe
Me
12jj, X = I, 76%
12ji, X = I, 47%
Scheme 3. Preparation of 1,3-diarylbicyclo[1.1.1]pentanes through the opening
of 5 with arylmagnesium bromides followed by a Negishi cross-coupling with
aryl and heteroaryl halides. Yields of isolated products relative to 5 are shown.
Cross-coupling temperature for X = I: 40 °C, X = Cl and Br: 65 °C.
Table 2. Physicochemical properties of compounds 1–4.
Compound
mp[a] [°C]
pKa[b]
CHI(IAM)
We also applied this new methodology for the synthesis of the
BCP-analogues of the bioactive compounds 3 and 4 (Scheme 4).
Thus, the standard [1.1.1]propellane opening-transmetalation-
Negishi cross-coupling sequence provided compound 3 in 40%
yield. The reaction of 5 with arylmagnesium reagent 7i required a
prolonged reaction time of 6 h due to a low solubility of 7i in Et2O.
In the preparation of analog 4, the BCP-intermediate 7b was
obtained in almost quantitative yield after 45 min and after a
transmetalation with ZnCl2, a Negishi cross-coupling provided the
desired product in 71% overall yield on a 0.3 mmol scale and 69%
yield on a 5 mmol scale. These experiments demonstrate that the
proposed methodology can be applied for the synthesis of bis-
arylated BCPs on larger scale.
1
103.4
167.7
n.d.[c,d]
n.d.[c,d]
116
2.1
3.0
4.2
6.0
5.2
52.9
53.1
29.1
44.6
50.4
3
2
4
13
[a] – melting point, [b] – pKa of conjugated acid, [c] – liquid at rt, [d] – n.d. – not
determined.
In conclusion, we have reported a general preparation of
arylated
bicyclo[1.1.1]pentanes
by
the
opening
of
[1.1.1]propellane with various arylmagnesium halides. After
transmetalation with ZnCl2 and Negishi cross-coupling with aryl
and heteroaryl halides, we have obtained bis-arylated
bicyclo[1.1.1]pentanes which may be considered as bioisosteres
of disubstituted alkynes such as tazarotene and the metabotropic
glutamate receptor
5 antagonist 2-methyl-6-(phenylethynyl)-
pyridine MPEP. Potentially, these BCPs can also be bioisosteres
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10.1002/anie.201706799
Angewandte Chemie International Edition
COMMUNICATION
Lett. 2017, 8, 43; d) Y. P. Auberson, C. Brocklehurst, M. Furegati, T. C.
Fessard, G. Koch, A. Decker, L. La Vecchia, E. Briard, ChemMedChem
2017, 12, 590.
of para-substituted benzene rings and therefore these bis-
arylated BCPs are promising targets for obtaining
pharmaceuticals with the appropriate physicochemical properties.
[3]
[4]
M. V. Westphal, B. T. Wolfstädter, J.-M. Plancher, J. Gatfield, E. M.
Carreira, ChemMedChem 2015, 10, 461.
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Pagano, D. Rüegg, S. Litschig, N. Stoehr, C. Stierlin, M. Heinrich, P.
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J. Flor, F. Gasparini, R. Kuhn, J. Biol. Chem. 2000, 275, 33750. c) P. M.
Lea IV, A. I. Faden, CNS Drug Rev. 2006, 12, 149.
Experimental Section
Representative procedure for the preparation of bis-arylated BCPs.
Preparation of 2-methyl-6-(3-phenylbicyclo[1.1.1]pentan-1-yl)pyridine
(12ba). Safety note: extreme care should be taken when working with
glassware under pressure. All reactions were conducted in properly
equipped fume-hoods behind a blast shield. In an Ace pressure vial
(10 mL), PhMgBr (6b) in Et2O (0.8 mL, 1 mmol) was mixed with undecane
(40 mg, 0.256 mmol). A solution of [1.1.1]propellane (5) in Et2O (0.8 mL,
0.5 mmol) was added, the vial was sealed with a screw cap and was placed
in an oil bath (T = 100 °C). After 45 min, the vial was removed from the
bath and cooled to 0 °C. Then, a solution of ZnCl2 in THF (1.1 mL, 1.1
mmol) was added to give a white suspension and the mixture was stirred
at 0 °C for 5 min. PdCl2(dppf)·CH2Cl2 (7.3 mg, 10 µmol) and 2-bromo-6-
methylpyridine (179 mg, 1.04 mmol) were added, the vial was sealed and
was placed in an oil bath (T = 65 °C). After 90 min, GC-analysis showed
complete conversion of the zinc intermediate, the vial was cooled to 0 °C
and a sat. solution of NH4Cl (2 mL) was added. The aqueous layer was
extracted with ether (3 × 15 mL), all organic fractions were combined,
washed with brine, dried over MgSO4 and concentrated. The crude mixture
was purified by silica gel column chromatography (eluent: i-hexane:EtOAc
15:1) to give 12ba (83 mg, 0.353 mmol, 71% yield) as a white solid.
[5]
[6]
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M. D. Levin, P. Kaszynski, J. Michl, Chem. Rev. 2000, 100, 169. c) A. M.
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a) K. D. Bunker, N. W. Sach, Q. Huang, P. F. Richardson, Org. Lett. 2011,
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[8]
[9]
K. R. Mondanaro, W. P. Dailey, Org. Synth. 1998, 75, 98.
Keywords: magnesium • small ring systems • bioisostere •
The yield of 5 was estimated to be approx. 70% by using 1H NMR
analysis. See Supporting Information for the detailed procedure.
nitrogen heterocycles • arenes
[10] All Grignard reagents were prepared from aryl bromides by magnesium
insertion in ether (0 °C, 3 h).
[1]
[2]
N. Brown, R. Mannhold, Bioisosteres in Medicinal Chemistry, Wiley-VCH,
Weinheim, 2012.
[11] In order to simplify the reaction setup, the addition of 6a to 5 was
attempted in a microwave reactor under the conditions from entry 8,
however, the yield of 10a was lower.
a) G. Costantino, K. Maltoni, M. Marinozzi, E. Camaioni, L. Prezeau, J.
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54, 722.
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10.1002/anie.201706799
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COMMUNICATION
COMMUNICATION
Ilya S. Makarov, Cara E. Brocklehurst,
Konstantin Karaghiosoff, Guido Koch,
Paul Knochel*
Page No. – Page No.
Convenient Preparation of
Bicyclo[1.1.1]pentane Bioisosteres of
Internal Alkynes and para-
Disubstituted Benzenes using
[1.1.1]Propellane
CO2Et
MgBr
MgBr
1) ZnCl2,THF
CO2Et
N
S
ether, 100 °C, 6 h
S
2)
Cl
N
40%
S
2% PdCl2(dppf), 65 °C, 3 h
BCPs have the right profile! The opening of [1.1.1]propellane with various
arylmagnesium halides proceeds smoothly in sealed tubes providing
bicyclo[1.1.1]pentylmagnesium (BCP-magnesium) derivatives which after
transmetalation with ZnCl2 undergo Negishi cross-coupling with various aryl and
heteroaryl halides providing bis-arylated BCPs which represent a useful class of
bioisosteres of alkynes or 1,4-disubstituted arenes.
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