Bicyclo[1.1.1]pentane-Derived Building Blocks for Click Chemistry

Article abstract of DOI:10.1002/ejoc.201701296

Syntheses of bicyclo[1.1.1]pentane-derived azides and terminal alkynes – interesting substrates for click reactions – are described. With a few exceptions, these compounds were prepared in two or three steps starting from common synthetic intermediates – the corresponding carboxylic acids. The key step in the synthesis of 1-azidobicyclo[1.1.1]pentanes is a copper-catalysed diazo-transfer reaction with imidazole-1-sulfonyl azide. The preparation of bicyclo[1.1.1]pentyl-substituted alkynes relies on a Seyferth–Gilbert homologation with dimethyl 1-diazo-2-oxopropylphosphonate (Ohira–Bestmann reagent). Both types of target compounds were found to be suitable substrates for click reactions, and thus they are promising building blocks for medicinal, combinatorial and bioconjugate chemistry. A practically important side result of this study was a multigram preparation of Boc-monoprotected 1,3-diaminobicyclo[1.1.1]pentane – a representative bicyclic conformationally restricted diamine derivative.

Full text of DOI:10.1002/ejoc.201701296

A Journal of
Accepted Article
Title: Bicyclo[1.1.1]pentane-Derived Building Blocks for Click Chemistry
Authors: Serhii Kokhan, Yevheniia B. Valter, Andriy Tymtsunik, Igor
Komarov, and Oleksandr O Grygorenko
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701296
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10.1002/ejoc.201701296
European Journal of Organic Chemistry
FULL PAPER
Bicyclo[1.1.1]pentane-Derived Building Blocks for Click
Chemistry
Serhii O. Kokhan,[a,b] Yevheniia B. Valter,[b] Andriy V. Tymtsunik,[b,c] Igor V. Komarov,[a,b]
Oleksandr O. Grygorenko*[a,b]
Abstract: Syntheses of bicyclo[1.1.1]pentane-derived azides and
terminal alkynes – interesting substrates for click reactions – are
described. With
a few exceptions, the title compounds were
prepared in two or three steps starting from common synthetic
intermediates – the corresponding carboxylic acids. The key step in
the synthesis of 1-azidobicyclo[1.1.1]pentanes was
a copper-
catalyzed diazo transfer reaction with imidazole-1-sulfonyl azide.
The preparation of bicyclo[1.1.1]pentyl-substituted alkynes relied on
Seyferth – Gilbert homologation with dimethyl 1-diazo-2-oxopropyl-
phosphonate (Ohira – Bestmann reagent). It was shown that target
componds of both types are suitable substrates for click reactions,
therefore they are promising building blocks for medicinal,
combinatorial and bioconjugate chemistry. A practically important
Figure 1. Bicyclo[1.1.1]pentane as an isostere of benzene
Click chemistry is another design concept which has gained
momentum in recent decades. While being initially introduced by
Sharpless as a catch phrase for any powerful, highly reliable,
and selective reaction for the rapid synthesis of useful new
compounds,[10] at the moment this term usually refers to the
copper-catalyzed or strain-promoted reaction of azides and
alkynes to produce 1,2,3-triazoles (Scheme 1).[11,12] The method
allows for the preparation of combinatorial libraries of 1,2,3-
triazoles which are attractive chemotypes for drug
discovery.[13,14] Another important aspect of the click reaction is
its use as a bioorthogonal transformation for bioconjugation.[15–17]
Both these areas can potentially benefit from using
bicyclo[1.1.1]pentane-derived building blocks. In particular,
introducing a bicyclo[1.1.1]pentane motif into the 1,2,3-triazole
ring complies well with recent design concepts of medicinal
chemistry such as lead-oriented synthesis, i. e. shifting towards
side result of this study is
a multigram preparation of Boc-
monoprotected 1,3-diaminobicyclo[1.1.1]pentane – a representative
of bicyclic conformationally restricted diamine derivatives.
Introduction
Bicyclo[1.1.1]pentane derivatives have given rise to
a
considerable interest in recent years. While initially these bicyclic
compounds could be found in purely academic studies as the
products obtained from an unusual hydrocarbon possessing
inverted carbon atoms – [1.1.1]propellane (1) (Figure 1),[1–4]
currently they are attracting more and more attention in various
areas of science as rigid structural elements to link molecular
fragments in a linear fashion.[5–7] 1,3-Disubstituted bicyclo[1.1.1]-
pentane has geometric parameters similar to those of a 1,4-
diphenylene motif[5,8] and is therefore considered as an effective
isosteric replacement for this fragment currently occurring in
drug discovery. Such replacement increases three-dimensio-
nality of the molecules and improves DMPK-related properties
such as solubility, hydrophilicity, and membrane permeability.[8,9]
more
sp3-rich,
three-dimensional,
low-molecular-weight,
hydrophilic compounds as the starting points for drug discovery
projects.[18] On the other hand, bicyclo[1.1.1]pentane can serve
as a rigid but sterically undemanding linear spacer allowing
conjugation of the molecules in a well-defined manner, which
can make the bioconjugate design more controllable.
[a]
[b]
[c]
S. O. Kokhan, I. V. Komarov, O. O. Grygorenko
National Taras Shevchenko University of Kyiv
Volodymyrska Street 64, Kyiv 01601, Ukraine
E-mail: gregor@univ.kiev.ua
S. O. Kokhan, Y. B. Valter A. V. Tymtsunik, I. V. Komarov,
O. O. Grygorenko
Enamine Ltd. (www.enamine.net)
Alexandra Matrosova Street 23, Kyiv 01103, Ukraine
A. V. Tymtsunik
Scheme 1. The click reaction of azides and alkynes.
Herein, we describe an approach to the gram-scale synthesis of
bicyclo[1.1.1]pentane-derived azides (2) and alkynes (3) and
demonstrate their use as substrates for the click reaction (Figure
2). To increase the potential for successful application of 2 and 3
and the products derived from them in medicinal, combinatorial
and bioconjugate chemistry, the focus was made on fluorinated
and bifunctional building blocks. In particular, the following
Faculty of Chemical Technology
National Technical University of Ukraine "Igor Sikorsky Kyiv
Polytechnic Institute"
Prospect Peremogy 37, Kyiv 03056, Ukraine
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201701296
European Journal of Organic Chemistry
FULL PAPER
classes of bicyclo[1.1.1]pentane-derived azides/alkynes were
planned to be made: (a) monofunctional building blocks to be
used as decorating reagents, e. g. to introduce isosteres of tert-
butyl[9] or larger lipophilic groups (R1 = H, Ph) or their fluorinated
analogues (R1 = F, CF3); (b) azides/alkynes with additional
protected functional groups (R1 = CO2Me, NHBoc, NHCBz) to be
used as p-phenylene isosteres or linear linkers (i. e. bifunctional
building blocks), possibly under parallel synthesis conditions.[19]
Sonogashira coupling or silylation) of 1,3-diethynyl[1.1.1]-
bicyclopentane (5); it was prepared in two steps from 1,3-
diacetylbicyclo[1.1.1]pentane (6).[25–30] Apart from that, alkynes 3
and 7 (R1 = H, Cl) were prepared using a similar method.[31]
Results and Discussion
The literature methods for the preparation of azides 2 and
alkynes 3 shown in Scheme 2 have limited substrate scope and
are not applicable to the preparation of functionalized substrates.
Therefore, we have looked for more appropriate key
intermediates which could be used for the synthesis of all the
target building blocks. In the case of azides 2, we have turned
our attention to the method of Goddard-Borger and Stick, who
described imidazole-1-sulfonyl azide hydrochloride (8) as a
convenient shelf-stable diazo transfer reagent for primary
amines (Scheme 3).[32] For the synthesis of alkynes 3, we
envisaged the use of the Ohira – Bestmann reagent (9) which is
known to convert aldehydes into terminal acetylenes.[33] Both
primary amines 10 and aldehydes 11 could be obtained from the
bicyclo[1.1.1]pentane-derived carboxylic acids 12, which are
known and accessible compounds for most of the substituents
R1 planned in this study.[34–39]
Figure 2. The target molecules of this study.
Scheme 3. Our retrosynthetic approach to 2 and 3.
Therefore, our synthesis of 2 and 3 started with preparation of
the carboxylic acids 12g–k following the literature procedures
(Scheme 4). A modified Curtius reaction of 12g–j gave the
known amines 10g–j,[21,39–41] isolated as hydrochlorides in 65–
84% yield (Table 1). For the synthesis of novel monoprotected
diamines 10k,l, carboxylic acid 12k was transformed into
unsymmetrical bis-carbamate 14 (85% yield), which was
deprotected selectively to give either 12k (99% yield) or 12l
(93% yield) (Scheme 5). Finally, amine 10b was prepared as a
hydrochloride using a previously reported reaction sequence
(Scheme 6).[42]
Scheme 2. Syntheses of azides 2 and alkynes 3 reported in the literature.
It should be noted that to date, only a few papers described
syntheses of azides 2; they were prepared via a common
synthetic intermediate 2a (R1 = I).[20,21] In turn, compound 2a was
It should be noted that despite the synthesis of the amine 12k
included nine steps, it was performed successfully on up to 86 g
[22]
obtained by reaction of propellane (1) with IN3
or via 1,3-
diiodopropellane (4)[23,24] (Scheme 2). A number of works
described synthesis and some selective reactions (e. g.
scale. Therefore, this building block,
a representative of
monoprotected bicyclic conformationally restricted diamine deri-
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10.1002/ejoc.201701296
European Journal of Organic Chemistry
FULL PAPER
Scheme 4. Synthesis of carboxylic acids 12.
vatives,[43] can be considered now as readily available for drug
discovery and other areas of potential application. It is a far
more convenient reagent for selective modification than the free
1,3-diaminobicyclo[1.1.1]pentane reported previously.[44,45]
reaction mixture (including extraction and chromatographic
purification) could be used, in the case of 2b, 2h and 2i, the
product was distilled from the crude reaction mixture together
with the solvent. Therefore, the latter volatile azides were
obtained as methanolic solutions which were used in further
transformations without isolation.
Table 1. Synthesis of azides 2
#
1
2
3
4
5
6
7
R1
Amine or salt (yield, %)
10bHCl (see Scheme 7)
10gHCl (65)
Azide (yield, %)
2b (84)[a]
2g (63)
H
Ph
F
10hHCl (79)
2h (67)[a]
2i (76)[a]
2j (78)
Scheme 5. Synthesis of amines 10k and 10l.
CF3
10iHCl (70)
CO2Me
NHBoc
NHCbz
10jHCl (84)
10k (see Scheme 6)
10l (see Scheme 6)
2k (82)
2l (61)
[a] Obtained as a methanolic solution; the yield was calculated from 1H NMR
data.
Scheme 6. Synthesis of amine 10b (as hydrochloride)
For the synthesis of alkynes 3, carboxylic acids 12 were reduced
first to alcohols 15 using the BH3Me2S complex (91–94% yield,
Table 2). In the case of alcohol 15j, this method followed the
literature procedures for its preparation.[7,40] To transform 15 into
aldehydes 11, we have initially used the Dess – Martin reagent;
it was shown, however, that Swern oxidation gave much better
Reactions of amines 10 with imidazole-1-sulfonyl azide
hydrochloride (8) in the presence of CuSO4 and K2CO3 gave the
target azides 2 in 61–84% yields (Table 1). It should be noted
that whereas for azides 2g and 2j–l, standard work-up of the
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10.1002/ejoc.201701296
European Journal of Organic Chemistry
FULL PAPER
yields and purer products. To obtain aldehyde 11i, the shorter
literature method was used (Scheme 7).[46] Compounds 11 were
not purified but subjected to the next step (i. e. the Seyferth –
Gilbert reaction with the Ohira – Bestmann reagent (9)) to give
the target alkynes 3g and 3i–k (43–88% yields over two steps).
The volatile acetylene 3i was obtained as a CH2Cl2 solution.
novel type of the bicyclo[1.1.1]pentane and 1,2,3-triazole
scaffolds combination.
Conclusions
Bicyclo[1.1.1]pentane-derived building blocks are interesting
structural motifs for the click reaction. Both azides 2 and alkynes
3 containing the bicyclo[1.1.1]pentane moiety can be prepared
from common synthetic intermediates – the corresponding
carboxylic acids 12 (although in some cases, alternative
pathways are more convenient). In particular, modified Curtius
rearrangement followed by diazo transfer reaction with
imidazole-1-sulfonyl azide hydrochloride (8) is a convenient
approach to 1-azidobicyclo[1.1.1]pentanes, which are obtained
in 41–69% yields (from 12). Bicyclo[1.1.1]pentyl-substituted
terminal acetylenes 3 are prepared from 12 via reduction with
borane, Swern oxidation, and Seyferth – Gilbert reaction with the
Ohira – Bestmann reagent in 40–80% overall yield. Both 2 and 3
are appropriate substrates for click reactions, which give the
corresponding 1,2,3-triazoles in 59–99% yields. An important
side result of this study is the preparation of Boc-monoprotected
1,3-diaminobicyclo[1.1.1]pentane 10k, which has been
performed on up to 86 g scale. The novel compounds described
herein are promising building blocks for medicinal, combinatorial
and bioconjugate chemistry, which can be used either as
decorating reagents to replace lipophilic side chains or as linkers
and benzene isosteres.
Table 2. Synthesis of alkynes 3
#
1
2
3
4
R1
Alcohol (yield, %)
15g (91)
–
Alkyne (yield, %)
3g (88)
Ph
CF3
3i (50)[a]
CO2Me
NHBoc
15j (92)
3j (43)
15k (94)
3k (55)
[a] Obtained via aldehyde 11i (see Scheme 8); yield from 16, detected by
1H NMR
Experimental Section
General. The solvents were purified according to the standard
procedures.[47] Carboxylic acids 12g[35,39] and 12j,[39] hydrochlorides
10bHCl[42] and 10g–jHCl,[21,39–41] alcohol 15j,[7] and aldehyde 11i[46]
were obtained using the reported procedures (see also the main text). All
other starting materials were purchased from commercial sources.
Melting points were measured on MPA100 OptiMelt automated melting
point system. Analytical TLC was performed using Polychrom SI F254
plates. Column chromatography was performed using Kieselgel Merck 60
(230–400 mesh) as the stationary phase. 1H and 13C NMR spectra were
recorded on a Bruker 170 Avance 500 spectrometer (at 499.9 MHz for
Protons and 124.9 MHz for Carbon-13) and Varian Unity Plus 400
spectrometer (at 400.4 MHz for protons and 100.7 MHz for Carbon-13).
Chemical shifts are reported in ppm downfield from TMS as an internal
standard. Elemental analyses were performed at the Laboratory of
Organic Analysis, Department of Chemistry, National Taras Shevchenko
University of Kyiv. Mass spectra were recorded on an Agilent 1100
LCMSD SL instrument (chemical ionization (APCI), electrospray
ionization (ESI)) and Agilent 5890 Series II 5972 GCMS instrument
(electron impact ionization (EI)).
Scheme 7. Synthesis of adehyde 11i
Figure 3. The products of click reactions with 2 and 3
Benzyl tert-butyl bicyclo[1.1.1]pentane-1,3-diyldicarbamate (14).
Diphenylphosphoroyl azide (67.0 g, 0.244 mol) was added dropwise to a
solution of carboxylic acid 12k (51.5 g, 0.212 mol) and triethylamine
(25.7 g, 35.4 mL, 0.254 mol) in benzene (0.64 L) at rt. The solution was
heated under reflux for 3 h. Then benzyl alcohol (27.5 g, 0.254 mol) was
added dropwise, and the solution was heated at reflux for 24 h. The
mixture was cooled, and t-BuOMe (1.2 L) was added. The solution was
washed with 2 M aq NaOH (400 mL), brine (400 mL), dried with Na2SO4
To demonstrate applicability of the products obtained for the
click chemistry, as well as for characterization purposes in the
case of the volatile substrates, we have performed their click
reactions with methyl propiolate or benzyl azide. The products
17a–e were obtained in 59–95% yields (Figure 3). It should be
noted that unlike 17a–c,[20,21] triazoles 17d and 17e represent a
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10.1002/ejoc.201701296
European Journal of Organic Chemistry
FULL PAPER
and concentrated under reduced pressure. The residue was crystallized
from CH2Cl2 – hexanes to give 14. Yield 60.0 g, 85%. Colorless solid. Mp
157–159 °C. Anal. Calcd. for C18H24N2O4: C, 65.04; H, 7.28; N, 8.43.
Found: C, 65.3; H, 7.67; N, 8.70. MS (CI): 355 (MNa+), 233 (MH+–CO2–
C4H8), 189, 91 (C7H7+). 1H NMR (400 MHz, DMSO) δ = 7.93 (s, 1H), 7.48
(s, 1H), 7.33 (s, 5H), 4.98 (s, 2H), 2.04 (s, 6H), 1.36 (s, 9H) ppm. 13C
NMR (101 MHz, DMSO) δ = 155.5, 155.0, 137.5, 128.8, 128.3, 128.3,
78.2, 65.9, 54.5, 44.9, 44.6, 28.7 ppm.
8.68 mmol (for 10k and 10l)), CuSO45H2O (0.01 g, 0.04 mmol), and
imidazole-1-sulfonyl azide hydrochloride (8) (1.28 g, 6.13 mmol) were
added subsequently at rt. The mixture was stirred until the 1H NMR
showed completion of the reaction (ca. 18-48 h). The mixture was
concentrated under reduced pressure, water (25 mL) was added to the
residue acidified with conc. aq HCl (for 10gHCl and 10jHCl) or 1 M aq
NaHSO4 (for 10k and 10l) to pH = 3, and extracted with EtOAc (350
mL). The combined organic extracts were dried over Na2SO4 and
evaporated to dryness. The residue was purified by column
chromatography to give azide 2.
tert-Butyl (3-aminobicyclo[1.1.1]pent-1-yl)carbamate (10k). To
a
stirred solution of carbamate 14 (145.0 g, 0.436 mol) in MeOH – THF
(1:1, 3.0 L), 10% wt. palladium on charcoal (24.0 g) was added.
Hydrogen gas was bubbled through the mixture at rt until the 1H NMR
showed completion of the reaction (18 – 48 h). The mixture was filtered
and evaporated under reduced pressure to give amine 10m pure enough
for further transformations. An analytical sample could be obtained by
recrystallization from methanol. Yield 86.0 g, 99%. Colorless solid. Mp
118–120 C. Anal. Calcd. for C10H18N2O2: C, 60.58; H, 9.15; N, 14.13.
Found: C, 60.21; H, 9.18; N, 14.48. MS (CI): 199 (MH+), 143 (MH+–C4H8),
126. 1H NMR (500 MHz, DMSO) δ = 4.99 (s, 1H), 2.01 (s, 6H), 1.69 (s,
2H), 1.43 (s, 9H) ppm. 13C NMR (126 MHz, CDCl3) δ = 154.9, 79.4, 55.4,
47.6, 42.7, 28.4 ppm.
1-Azido-3-phenylbicyclo[1.1.1]pentane (2g).[21] Yield 0.60 g, 63%.
Colorless oil. Rf 0.62 (hexanes – EtOAc (19:1)). Anal. Calcd. for
C11H11N3: C, 71.33; H, 5.99; N, 22.69. Found: C, 71.61; H, 5.63; N, 22.73.
MS (EI): 157 (M+–N2), 141, 159, 115, 103, 91, 77, 65, 51, 39. 1H NMR
(500 MHz, CDCl3) δ = 7.33 (t, J=7.3, 2H), 7.29 – 7.18 (m, 3H), 2.29 (s,
6H) ppm. 13C NMR (126 MHz, CDCl3) δ = 138.1, 128.4, 127.1, 126.5,
54.5, 51.0, 37.6 ppm.
Methyl 3-azidobicyclo[1.1.1]pentane-1-carboxylate (2j). Yield 0.73 g,
78%. Colorless oil. Rf 0.55 (hexanes – EtOAc (5:1)). Anal. Calcd. for
C7H9N3O2: C, 50.29; H, 5.43; N, 25.14. Found: C, 50.20; H, 5.57; N,
25.31. MS (EI): 136 (M+–OMe), 124, 108 (M+–CO2Me), 96, 80, 69, 59, 53,
Benzyl (3-aminobicyclo[1.1.1]pent-1-yl)carbamate (10l). To a stirred
solution of carbamate 14 (1.42 g, 4.27 mmol) in MeOH (10 mL), 4 M HCl
in dioxane (10 mL, 40 mmol) was added at 0 C. The mixture was stirred
overnight at rt. Then it was concentrated under reduced pressure. The
residue was treated with 2 M aq NaOH (25 mL) and extracted with t-
BuOMe (325 mL). The organic layer was dried with Na2SO4 and
evaporated under reduced pressure to give amine 10n. Yield 0.92 g,
93%. Colorless solid. Mp 92–94 C. Anal. Calcd. for C13H16N2O2: C,
67.22; H, 6.94; N, 12.06. Found: C, 66.98; H, 6.73; N, 11.83. MS (CI):
233 (MH+), 172, 91 (C7H7+). 1H NMR (400 MHz, CDCl3) δ = 7.31 (s, 5H),
5.47 (s, 1H), 5.05 (s, 2H), 2.03 (s, 6H), 1.69 (s, 2H) ppm. 13C NMR (126
MHz, CDCl3) δ = 155.4, 136.4, 128.5, 128.1, 128.1, 66.4, 55.4, 47.6, 42.8
ppm.
45, 39. 1H NMR (400 MHz, CDCl3) δ = 3.69 (s, 1H), 2.26 (s, 2H) ppm. 13
NMR (126 MHz, CDCl3) δ = 169.2, 54.0, 51.9, 51.1, 33.6 ppm.
C
tert-Butyl (3-azidobicyclo[1.1.1]pent-1-yl)carbamate (2k). Yield 0.27 g,
82%. White solid. Mp 79–80 C. Rf 0.51 (hexanes – EtOAc (4:1)). Anal.
Calcd. for C10H16N4O2: C, 53.56; H, 7.19; N, 24.98. Found: C, 53.95; H,
7.12; N, 24.62. MS (CI): 197 (MH+–N2), 169 (MH+–C4H8), 141 (MH+–N2–
1
C4H8). H NMR (400 MHz, CDCl3) δ = 5.05 (br s, 1H), 2.21 (s, 6H), 1.43
(s, 9H) ppm. 13C NMR (126 MHz, CDCl3) δ = 154.7, 80.0, 54.5, 50.2,
43.4, 28.3 ppm.
Benzyl (3-azidobicyclo[1.1.1]pent-1-yl)carbamate (2l). Yield 0.47 g,
61%. Colorless solid. Mp 64–65 C. Rf 0.45 (hexanes – EtOAc (4:1)).
Anal. Calcd. for C13H14N4O2: C, 60.45; H, 5.46; N, 21.69. Found: C,
60.56; H, 5.08; N, 21.37. MS (CI): 281 (MNa+), 231 (MH+–N2), 158, 91
(C7H7+). 1H NMR (400 MHz, CDCl3) δ = 7.34 (s, 5H), 5.29 (s, 1H), 5.09 (s,
2H), 2.26 (s, 6H) ppm. 13C NMR (126 MHz, CDCl3) δ = 155.2, 136.2,
128.6, 128.2, 128.1, 66.8, 54.6, 50.1, 43.5 ppm.
General procedure for the synthesis of azides 2b, 2h, and 2i. To a
suspension of hydrochloride 10 (8.36 mmol), K2CO3 (3.11 g, 22.6 mmol),
and CuSO45H2O (0.02 g, 0.08 mmol) in methanol (40 mL), imidazole-1-
sulfonyl azide hydrochloride (8) (2.10 g, 10.0 mmol) was added at rt. The
mixture was stirred until the 1H NMR showed completion of the reaction
(12-18 h). Then all the volatiles were transferred into a trap kept at –20
C by careful heating of the reaction mixture in a 60 C bath at ca. 20
mmHg. (CAUTION! Safety shield must be used!) The trap content proved
to be a methanol solution of azide 2 and was used without further
purification.
(3-Phenylbicyclo[1.1.1]pent-1-yl)methanol (15g). Carboxylic acid 12g
(0.50 g, 2.66 mmol) was dissolved in THF (5 mL). The solution was
cooled to 0 C, and BH3Me2S (0.31 mL, 3.10 mmol, 10 M in Me2S) was
added dropwise. The mixture was stirred at 0 C for 1 h and then
overnight at rt. Excess of borane was quenched by careful addition of
MeOH (5 mL), and the mixture was concentrated under reduced
pressure. Saturated aq K2CO3 (20 mL) was added to the residue, and the
mixture was extracted with t-BuOMe (330 mL). The organic phases
were dried over Na2SO4, and evaporated to give alcohol 15g. Yield 0.42
g, 91%. Yellowish oil. Anal. Calcd. for C12H14O: C, 82.72; H, 8.10. Found:
C, 82.88; H, 7.86. MS (CI): 157 (MH+–H2O). 1H NMR (500 MHz, CDCl3) δ
1-Azidobicyclo[1.1.1]pentane (2b). Yield 0.77 g (30.5 g of methanolic
1
solution), 84%. H NMR (400 MHz, CDCl3) δ = 2.26 (s, 1H), 1.73 (s, 6H)
ppm. 13C NMR (101 MHz, CDCl3) δ = 51.7, 30.8, 21.7 ppm.
1-Azido-3-fluorobicyclo[1.1.1]pentane (2h). Yield 0.43 g (16.8 g of
methanolic solution), 67%. 1H NMR (400 MHz, CDCl3) δ = 1.90 (s, 6H)
ppm. 19F NMR (376 MHz, CDCl3) δ = –175.02 ppm.
= 7.53 – 7.02 (m, 5H), 3.72 (s, 2H), 1.96 (s, 6H), 1.37 (br s, 1H) ppm. 13
C
NMR (126 MHz, CDCl3) δ = 141.0, 128.3, 126.6, 126.1, 63.4, 50.7, 42.2,
39.2 ppm.
1-Azido-3-(trifluoromethyl)bicyclo[1.1.1]pentane (2i). Yield 0.43
g
(12.5 g of methanolic solution), 76%. 1H NMR (400 MHz, CDCl3) δ = 2.12
(s, 6H) ppm. 19F NMR (376 MHz, CDCl3) δ = –71.79 ppm.
tert-Butyl (3-(hydroxymethyl)bicyclo[1.1.1]pent-1-yl)carbamate (15k).
Carboxylic acid 12k (10.0 g, 44.0 mmol) was dissolved in Et2O (200 mL).
The solution was cooled to 0 C, and BH3Me2S (5.2 mL, 52 mmol, 10 M
in Me2S) was added dropwise. The mixture was stirred at 0 C for 1 h
and then overnight at rt. Excess of borane was quenched by careful
addition of MeOH (50 mL), and the mixture was concentrated under
General procedure for the synthesis of azides 2g, 2j–l. To a
suspension of amine 10 or hydrochloride 10HCl (5.11 mmol) in methanol
(25 mL), K2CO3 (1.90 g, 13.8 mmol (for 10gHCl and 10jHCl) or 1.19 g,
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10.1002/ejoc.201701296
European Journal of Organic Chemistry
FULL PAPER
reduced pressure. Saturated aq K2CO3 (200 mL) was added to the
residue, and the mixture was extracted with CH2Cl2 (3300 mL). The
organic phases were dried over Na2SO4, and evaporated to give alcohol
15. Yield 8.86 g, 94%. Colorless solid. Mp 134–135 C. Anal. Calcd. for
C11H19NO3: C, 61.95; H, 8.98; N, 6.57. Found: C, 62.23; H, 9.28; N, 6.63.
MS (CI): 236 (MNa+), 158 (MH+–C4H8). 1H NMR (400 MHz, CDCl3) δ =
5.01 (br s, 1H), 3.65 (s, 2H), 1.89 (s, 6H), 1.70 (br s, 1H), 1.40 (s, 9H)
ppm. 13C NMR (101 MHz, CDCl3) δ = 154.9, 79.5, 62.0, 51.2, 46.1, 37.2,
28.4 ppm.
General procedure for the preparation of triazoles 17a–c. To a
methanolic solution of azide 2 (4.13 mmol in 20.0 g of the solution),
methyl propiolate (0.52 g, 6.15 mmol) and Cu(OAc)2 (0.037 g, 0.2 mmol)
were added. The mixture was stirred at rt for 72 h, and the solvent was
evaporated under reduced pressure. The residue was purified by column
chromatography (gradient hexanes – EtOAc (2:1 to 1:1)) to give triazole
17.
Methyl
1-(bicyclo[1.1.1]pent-1-yl)-1H-1,2,3-triazole-4-carboxylate
(17a). Yield 0.65 g, 82%. Colorless solid. Mp 92–93 C. Anal. Calcd. for
C9H11N3O2: C, 55.95; H, 5.74; N, 21.75. Found: C, 55.98; H, 5.67; N,
21.89. MS (CI): 194 (MH+), 162 (MH+–MeOH), 128, 94. 1H NMR (500
MHz, CDCl3) δ = 8.06 (s, 1H), 3.92 (s, 3H), 2.73 (s, 1H), 2.41 (s, 6H) ppm.
13C NMR (126 MHz, CDCl3) δ = 161.3, 139.7, 126.0, 53.3, 52.2, 52.1,
23.5 ppm.
General procedure for the preparation of alkynes 3g and 3i–k. To a
solution of oxalyl chloride (0.94 g, 7.46 mmol) in CH2Cl2 (15 mL) cooled
to −60 C, a solution of DMSO (1.17 g, 14.9 mmol) in CH2Cl2 (3 mL) was
added dropwise. After 15 min, a solution of 15 (5.74 mmol) in CH2Cl2 (5.7
mL) was added. The reaction mixture was stirred at −60 C for 30 min,
and Et3N (4.8 mL, 34.4 mmol) was added dropwise. After 30 min at −60
C, the mixture was warmed to rt. H2O (30 mL) was added, the organic
phase was separated, and the aqueous phase was extracted with CH2Cl2
(30 mL). The combined organic layers were washed with 1 M aq NaHSO4
(50 mL), saturated aq NaCl (50 mL), dried with Na2SO4, filtered, and
concentrated under reduced pressure to give crude 11. Aldehydes 11g
(99%) and 11j (63%)[48] were obtained as colorless oils which were
immediately used in the next step. The crude product 11k was purified by
flash chromatography (toluene – EtOAc (1:1)) (78%). Aldehyde 11i was
prepared from iodide 16 (14.7 g, 15.9 mmol) using the reported
procedure.[46]
Aldehyde 11 (15.9 mmol) was dissolved in MeOH (75 mL), and K2CO3
(6.58 g, 47.7 mmol) and dimethyl 1-diazo-2-oxopropylphosphonate (9)
(4.59 g, 23.9 mmol) were added at rt. The reaction mixture was stirred at
rt overnight, and then H2O (150 mL) and Et2O (75 mL) were added. The
layers were separated, and the aqueous phase was extracted with Et2O
(350 mL). The combined organic extracts were washed with H2O (330
mL), and dried over MgSO4. The solution was concentrated at
atmospheric pressure, and the residue was purified by column
chromatography.
Methyl
1-(3-fluorobicyclo[1.1.1]pent-1-yl)-1H-1,2,3-triazole-4-car-
boxylate (17b). Yield 0.11 g, 59%. Colorless solid. Mp 142–144 C. Anal.
Calcd. for C9H10FN3O2: C, 51.18; H, 4.77; N, 19.90. Found: C, 51.34; H,
4.38; N, 20.07. MS (CI): 212 (MH+), 180 (MH+–MeOH), 128, 100. 1H
NMR (400 MHz, DMSO-d6) δ = 8.74 (s, 1H), 3.55 (s, 3H), 2.21 (s, 1H)
ppm. 13C NMR (126 MHz, DMSO-d6) δ = 160.9, 139.5, 129.8, 76.5 (d,
2
3
1JC,F = 319.2 Hz), 56.7 (d, JC,F=21.4 Hz), 52.4, 44.8 (d, JC,F = 76.0 Hz)
ppm. 19F NMR (376 MHz, CDCl3) δ = –173.73 ppm.
Methyl 1-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)-1H-1,2,3-triazole-
4-carboxylate (17c). Yield 0.50 g, 79%. Colorless solid. Mp 169–171 C.
Anal. Calcd. for C10H10F3N3O2: C, 45.98; H, 3.86; N, 16.09. Found: C,
46.15; H, 4.11; N, 16.06. MS (CI): 262 (MH+), 230 (MH+–MeOH), 128. 1H
NMR (500 MHz, CDCl3) δ = 8.13 (s, 1H), 3.93 (s, 3H), 2.65 (s, 6H) ppm.
1
13C NMR (126 MHz, CDCl3) δ = 160.9, 140.3, 126.3, 122.8 (q, JC,F
=
274 Hz), 52.5, 52.3, 49.4, 34.7 (q, JC,F = 41 Hz) ppm. 19F NMR (376
2
MHz, CDCl3) δ = –71.56 ppm.
General procedure for the preparation of triazoles 17d and 17e. To a
solution of benzyl azide (0.55 mL, 1.1 mmol, 2.0 M in CH2Cl2) alkyne 3
(0.15 g, 1.0 mmol) and Cu(OAc)2 (0.005 g, 0.036 mmol) were added. The
mixture was stirred at rt for 24–72 h, and the solvent was evaporated
under reduced pressure. The residue was purified by column
chromatography (CHCl3 – MeOH (98:2) as eluent) to give triazole 17.
1-Ethynyl-3-phenylbicyclo[1.1.1]pentane (3g). Yield 0.81 g, 88%.
Colorless solid. Mp 33–35 C. Anal. Calcd. for C13H12: C, 92.81; H, 7.19.
Found: C, 92.87; H, 7.53. MS (EI): 167 (M+–H), 152, 141, 128, 115, 103,
91, 77 (C6H5+), 63, 51, 39. 1H NMR 1H NMR (500 MHz, CDCl3) δ = 7.33 –
7.14 (m, 5H), 2.35 (s, 6H), 2.15 (s, 1H) ppm. 13C NMR (126 MHz, CDCl3)
δ = 139.9, 128.3, 126.9, 126.1, 83.4, 68.2, 56.4, 44.1, 27.2 ppm.
Methyl 3-(1-benzyl-1H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pentane-1-car-
boxylate (17d). Yield 0.28 g, 99%. Colorless solid. Mp 110–112 C. Anal.
Calcd. for C16H17N3O2: C, 67.83; H, 6.05; N, 14.83. Found: C, 67.69; H,
5.67; N, 14.73. MS (CI): 284 (MH+), 91 (C7H7+). 1H NMR (400 MHz,
CDCl3) δ = 7.52 – 7.31 (m, 3H), 7.31 – 7.17 (m, 3H), 5.49 (s, 2H), 3.70 (s,
3H), 2.39 (s, 6H) ppm. 13C NMR (126 MHz, CDCl3) δ = 170.0, 146.7,
134.6, 129.1, 128.7, 128.1, 120.7, 54.1, 53.9, 51.6, 38.7, 34.3 ppm.
1-Ethynyl-3-(trifluoromethyl)bicyclo[1.1.1]pentane (3i). Yield 1.27 g
(155 g of CH2Cl2 solution), 50%. (1H NMR (400 MHz, CDCl3) δ = 2.24 (s,
1
6H), 2.15 (s, 1H) ppm. 13C NMR (126 MHz, CDCl3) δ = 122.2 (q, JC,F
=
274.9 Hz), 80.8, 69.2, 52.6, 38.5 (q, JC,F = 38.7 Hz), 27.2 (q, JC,F = 106.6
Hz) ppm. 19F NMR (376 MHz, CDCl3) δ = –73.97 ppm.
Methyl 3-ethynylbicyclo[1.1.1]pentane-1-carboxylate (3j). Yield 0.72 g,
43%. Colorless solid. Mp 65–66 C. Anal. Calcd. for C9H10O2: C, 71.98; H,
6.71. Found: C, 71.67; H, 6.88. MS (EI): 149 (M+–H), 135, 119 (M+–OMe),
107, 91, 77, 65, 59, 51, 39. H NMR (400 MHz, CDCl3) δ = 3.65 (s, 3H),
2.31 (s, 6H), 2.11 (s, 1H) ppm. 13C NMR (126 MHz, CDCl3) δ = 169.5,
tert-Butyl (3-(1-benzyl-1H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pent-1-yl)-
carbamate (17e). Yield 0.28 g, 82%. Colorless solid. Mp 170–171 C.
Anal. Calcd. for C19H24N4O2: C, 67.04; H, 7.11; N, 16.46. Found: C, 66.7;
H, 7.09; N, 16.25. MS (CI): 341 (MH+), 285 (MH+–C4H8). 1H NMR (400
MHz, CDCl3) δ = 7.35 (s, 5H), 7.25 (s, 1H), 5.46 (s, 2H), 5.14 (br s, 1H),
2.31 (s, 6H), 1.43 (s, 9H) ppm. 13C NMR (101 MHz, CDCl3) δ = 154.9,
146.3, 134.7, 129.1, 128.7, 128.1, 120.6, 79.5, 55.1, 54.1, 46.4, 31.5,
28.4 ppm.
1
82.0, 68.7, 55.6, 51.7, 39.5, 28.0 ppm.
tert-Butyl (3-ethynylbicyclo[1.1.1]pent-1-yl)carbamate (3k). Yield 0.8
g, 55%. Colorless solid. Mp 107–108 C. Rf 0.63 (hexanes – EtOAc (4:1))
Anal. Calcd. for C12H17NO2: C, 69.54; H, 8.27; N, 6.76. Found: C, 69.86;
H, 8.43; N, 7.07. MS (EI): 206 (M+–H, <1%), 161, 151 (M+–C4H8), 132,
120, 106, 91, 79, 65, 57 (t-C4H9+), 51, 41. 1H NMR (400 MHz, CDCl3) δ =
5.08 (br s, 1H), 2.26 (s, 6H), 2.14 (s, 1H), 1.41 (s, 9H) ppm. 13C NMR
(126 MHz, CDCl3) δ = 154.7, 81.7, 79.7, 69.4, 56.9, 46.7, 28.4, 25.3 ppm.
Acknowledgements
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10.1002/ejoc.201701296
European Journal of Organic Chemistry
FULL PAPER
The authors thank Prof. Andrey A. Tolmachev for his
encouragement and support and Dr. Sci. Pavel Mykhailiuk for
helpful discussions.
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Entry for the Table of Contents
FULL PAPER
Syntheses of mono- and bifunctional
bicyclo[1.1.1]pentane-derived azides
and terminal alkynes – promising
building blocks for medicinal,
combinatorial and bioconjugate
chemistry – are described. Utility of
the title products as substrates for
the copper-catalyzed click reactions
is also demonstrated.
Click chemistry
Serhii O. Kokhan, Yevheniia B. Valter,
Andriy V. Tymtsunik, Igor V. Komarov,
Oleksandr O. Grygorenko*
Page No. – Page No.
Bicyclo[1.1.1]pentane-derived
building blocks for click chemistry
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