Synthesis of enantiomerically pure cyclopropyl trifluoroborates

Article abstract of DOI:10.1055/s-2006-944185

Enantiomerically pure cyclopropylboronic esters were converted to the corresponding trifluoroborates, versatile inter-mediates for a variety of transformations. The new deprotection conditions allowed the utilization of general building blocks for cyclopr

Full text of DOI:10.1055/s-2006-944185

LETTER
1531
Synthesis of Enantiomerically Pure Cyclopropyl Trifluoroborates
E
nantiomericall
r
y
Pure
C
w
yclopropyl Trifluo
i
robora
n
tes Hohn, Jörg Pietruszka,* Gemma Solduga
Institut für Bioorganische Chemie der Heinrich-Heine-Universität Düsseldorf im Forschungszentrum Jülich, Im Stetternicher Forst,
Geb. 15.8, 52426 Jülich, Germany
Fax 49(2461)616196; E-mail: j.pietruszka@fz-juelich.de
Received 19 February 2006
In a current project we were especially interested in
general building blocks for cyclopropyl amines, known
for their diverse physiological properties.4 Compounds 4
would be suitable targets, but previous described depro-
tection modes would obviously not be tolerated. In view
of some recent successful applications of trifluoroborates5
and particularly cyclopropyl trifluoroborates,6 we envis-
aged that the corresponding amines 5 would be a suitable
substitute. In the present communication we wish to re-
port our first results on the successful deprotection of
boronic esters 1 applying the protocol in the synthesis of
trifluoroborates 5.
Abstract: Enantiomerically pure cyclopropylboronic esters were
converted to the corresponding trifluoroborates, versatile inter-
mediates for a variety of transformations. The new deprotection
conditions allowed the utilization of general building blocks for
cyclopropyl amines.
Key words: boron, stereoselectivity, protecting groups, cyclo-
propanes, cross-coupling
Cyclopropylboronic esters in general1 and enantiomeri-
cally pure cis- and trans-substituted2 members of the
family in particular have attracted considerable interest in
recent years. By utilizing the synthetic potential of the
boron moiety, a truly universal building block for cyclo-
propanes could be devised. The highly stable ester 1
proved especially useful (Scheme 1), since a variety of
transformations could be achieved in the side chain ‘R’ in
the presence of the boron group.3 A drawback could be the
rather harsh deprotection conditions: Activation via MeLi
or preferentially LiAlH4 limited the number of functional
groups present in the boronic acid 2; however, alternatives
would have to meet the high standard set by the transfor-
mation observing almost quantitative reisolation of diol 3
in most cases.
The synthesis of the essential boronic ester intermediates
is described in Scheme 2: a three-step, one-pot sequence
utilizing dicyclohexylborane7 allowed the hydroboration
of alkyne 6 to the benzyl-protected (Bn) alkenylboronic
ester 7. Slightly modifying the reported procedure,2c we
could improve the yield (65%). While cyclopropanation
using diazomethane Pd(OAc)2 was high yielding giving
the diastereoisomers 11 and 12 in moderate selectivity,
the procedure proved impractical on large scale. Selectiv-
ity was no object in the project – both diastereoisomers
were needed as intermediates – but large quantities of the
product were important. Under Denmark conditions8 (in
the presence of rac-8)9 the product was isolated in high
yield (92%) as a 1:1 mixture of diastereoisomers that are
readily separable by MPLC. Hydrogenation furnished the
primary alcohols 11 and 12, respectively, in quantitative
yield. When just one of the diastereoisomers is needed, a
good value alternative is preferentially used: the tri-
methylsilyl-protected (TMS) propargylic alcohol 13 was
directly converted to allyl alcohol 14; it was essential to
remove cyclohexanol from the intermediate before cleav-
age of the silyl ether. Cyclopropanation using Denmark’s
conditions yielded either cyclopropane 11 (in the presence
of S,S-8) or its diastereoisomer 12 (in the presence of R,R-
8) preferentially.2b
Ph Ph
a) LiAlH4 or MeLi
b) H3O+
R
O
O
OMe
OMe
B
Ph Ph
1
Ph Ph
R
HO
HO
OH
OH
OMe
OMe
B
Ph Ph
3
2
PG
PG
PG
PG
N
N
OR
Next we focused on the deprotection of the pure diaste-
reoisomers 9 and 10 with KHF2 (Table 1). Utilizing the
original procedure of Vedejs et al.10 (modified by Genêt et
al.11), no conversion of the boronic esters could be detect-
ed. Increasing the reaction temperature (80 °C) and the
equivalents of KHF2 (14 equiv) furnished the desired
product in five days in 70% yield (slightly impure prod-
uct); the equilibrium was reached. Quantitative conver-
sion and isolation of 91% product was achieved with 50
equiv KHF2 in two days. The procedure was further
simplified by omitting aqueous conditions, also slightly
B
BF3K
OR
4
5
Scheme 1 Enantiomerically pure cyclopropylboronic esters 1:
activation and envisaged new general building block for cyclopropyl-
amines 5.
SYNLETT 2006, No. 10, pp 1531–1534
2
1
.0
6
.2
0
0
6
Advanced online publication: 12.06.2006
DOI: 10.1055/s-2006-944185; Art ID: D05306ST
© Georg Thieme Verlag Stuttgart · New York

1532
E. Hohn et al.
LETTER
a) Cy2BH, DME,
0 °C, 1 h,
b) 2 equiv Me3NO,
0 °C, 1 h,
Table 1 Deprotection of Boronic Esters 9 and 10 with KHF2
Ph Ph
BnO
9
10
O
O
OMe
OMe
BnO
B
BnO
BnO
c) 3, r.t., 15 h
Ph Ph
(65%)
BF3K
6
7
BF3K
15
ent-15
a) 0.1 equiv rac-8, 1.1 equiv Et2Zn,
CH2Cl2, 0 °C, 10 min
b) 2 equiv I2, Et2Zn,
CH2Cl2, 0 °C, 15 min
c) 2 equiv CH2I2, 1 equiv Et2Zn,
CH2Cl2, 0 °C, 20 h
NHTs
NHTs
KHF2
(equiv)
Solvent
Time Temp
Turnover
Yield
(%)
(d)
(°C)
r.t.
80
8
7
14
50
50
MeOH–H2O
MeOH–H2O
MeOH–H2O
MeOH
4
–
–
5
ca. 90%
Quant.
Quant.
ca. 70
91
Ph Ph
Ph Ph
BnO
BnO
O
O
O
O
OMe
OMe
OMe
OMe
2
80
B
B
2
80
93
Ph Ph
Ph Ph
9
10
(92%; dr 1:1)
H2, Pd/C (quant.)
As demonstrated previously, these types of intermediates
can be used in the Suzuki–Miyaura cross-coupling reac-
tion, the Matteson homologation and for the formation of
cyclopropanols.
Ph Ph
Ph Ph
HO
HO
O
O
O
O
OMe
OMe
OMe
OMe
B
B
Next, the primary alcohols 11 and 12 were converted to
protected amines (Scheme 4): oxidation3c to the diastereo-
isomeric carboxylic acids 21 and 22 (97% and 90% yield,
respectively) was followed by the formation of the corre-
sponding azides 23 and 24 in 95% yield. Curtius
degradation14 of 23 yielded the amine that was immediate-
ly protected with phthalic anhydride. The crude boronic
ester 25 was obtained in 92% yield and preferentially used
directly for further transformation, since massive loss of
Ph Ph
Ph Ph
11
12
(91%, dr 60:40)
(95%, dr 95:5)
a) 0.1 equiv (R,R)-8, 1.1 equiv Et2Zn,
CH2Cl2, 0 °C, 10 min
same, but
(S,S)-8
b) 2 equiv I2, Et2Zn,
CH2Cl2, 0 °C, 15 min
c) 2 equiv CH2I2, 1 equiv Et2Zn,
CH2Cl2, 0 °C, 20 h
1a) Cy2BH, DME,
0 °C, 1 h,
Ph Ph
HO
b) 2 equiv Me3NO,
0 °C, 1 h
O
O
OMe
OMe
BnO
TMSO
PhBr
B
15
c) 3, r.t., 15 h
2) HCl, EtOH, r.t.,
CH2Cl2, 20 min
(66%)
Ph
5 mol% Pd(PPh3)4,
Ph Ph
16 (66%)
3 equiv K3PO4, 100 °C,
13
14
toluene–H2O (3:1)
BnO
ent-15
2-bromonaphthalene
Scheme 2 Synthesis of key boronic esters 9–12.
increasing the yield (93%). As indicated by 19F NMR
spectroscopy, the crystalline enantiomers 15 and ent-15
were obtained in pure form; inorganic fluorides were ex-
tracted during work-up.12
17 (85%)
a) 2 equiv SiCl4,
BnO
THF, 1 h, r.t.
O
15
As expected, Pd-catalyzed cross-coupling of the function-
alized cyclopropyl trifluoroborates was possible under the
conditions reported by Deng et al.6a The products 16 and
17 were isolated in 66% and 85% yield, respectively
(Scheme 3). However, simple boronic esters are generally
more flexible to employ. Hence, a good protocol to con-
vert the trifluoroborate would be crucial. In our hands, the
Matteson procedure proved to be very reliable even for
cyclopropane derivatives:5c,13 treatment of the trifluoro-
borate ent-15 with SiCl4 in THF furnished dichloride 18
that was not isolated, but directly esterified with
methanol–1,3-propanediol or methanol–pinacol provid-
ing boronic esters 19 (90%) and 20 (quant.), respectively.
BCl2
18
b) MeOH, 10 min
c) 1 equiv 1,3-propanediol,
15 h
b) MeOH, 10 min
c) 1.5 equiv pinacol,
15 h
BnO
BnO
O
B
O
O
B
O
20 (90%)
19 (quant.)
Scheme 3 Transformations of trifluoroborates 15 and ent-15.
Synlett 2006, No. 10, 1531–1534 © Thieme Stuttgart · New York

LETTER
Enantiomerically Pure Cyclopropyl Trifluoroborates
1533
26
25
11
12
3 equiv NaIO4, 5 mol% RuCl3·3 H2O,
97%
90%
82%
50 equiv KHF2, MeOH, 80 °C, 3 d
89%
CCl4–H2O–MeCN, r.t., 12 h
Ph Ph
Ph Ph
O
HO2C
HO2C
O
O
O
BnO
OMe
OMe
OMe
OMe
Phth>N
B
B
HN
BF3K
O
BF3K
27
28
Ph Ph
Ph Ph
21
22
a) 2 equiv SiCl4
1 M in hexane,
THF, r.t., 1 h
a) 1.5 equiv Et3N, THF,
95%
1.5 equiv ClCO2Et, 0 °C, 30 min 95%
b) 50 equiv NaN3, r.t., 30 min
Suzuki-coupling
products
b) 5.7 equiv MeOH,
0 °C, 10 min
87%
Ph Ph
Ph Ph
N3
O
N3
O
c) 1,3-propanediol,
0 °C to r.t., 3.5 h
O
O
O
O
OMe
OMe
OMe
OMe
B
B
Pd(IPh3)4, PhI,
t-BuOK, DME,
Ph Ph
Ph Ph
Phth>N
100 °C, 36 h
23
24
Phth>N
O
O
Ph
(40%)
B
a) 1.2 equiv HCl (37%), toluene,
100 °C, 2 h
1.1 equiv BnOH,
40 °C, toluene
30
29
b) Et3N, pH >7
90%
92%
Scheme 5 Synthesis and transformations of amino group containing
cyclopropyl trifluoroborates.
c) 5.7 equiv phthalic anhydride,
70 °C, 12 h
O
Ph Ph
Ph Ph
BnO
Unfortunately, all attempts to directly obtain Suzuki–
Miyaura cross-coupling products failed; the decreased
reactivity of trifluoroborates in combination with the de-
activating amine group prevented the transmetallation.
Nevertheless, the corresponding 1,3,2-dioxaborinane 29 –
readily available from 28 via the established sequence –
proved to be more reactive: the phenylcyclopropane 30
was obtained in unoptimized 40% yield.
Phth>N
HN
O
O
O
OMe
OMe
OMe
B
B
OMe
O
Ph Ph
Ph Ph
25
26
In summary, enantiomerically pure cyclopropyl tri-
fluoroborates have been utilized for the first time. Highly
stable boronic esters could be deprotected by KHF2 using
a modified protocol from Vedejs. Furthermore, the
sequence could also be applied to aminocyclopropane de-
rivatives, first reported in the present communication.
Thus, a new, general approach to synthesize enantiomeri-
cally pure aminocyclopropanes was provided. An applica-
tion of the method in the synthesis of physiologically
active compounds is currently investigated.
26
Scheme 4 Synthesis of protected cyclopropylamines 25 and 26.
product was observed during purification. When the rear-
rangement was performed in the presence of benzyl alco-
hol, the pure Cbz-protected amine 26 was isolated as
crystalline solid (90%); X-ray analysis confirmed the
configuration of the product.15
Acknowledgment
We gratefully acknowledge the Deutsche Forschungsgemeinschaft,
the Fonds der Chemischen Industrie, the Otto-Röhm-Gedächtnis-
stiftung and the Landesgraduiertenförderung Baden-Württemberg
(‘Graduiertenstipendium’ for E.H.) for the generous support of
our projects. Donations from the Boehringer Ingelheim KG, the
Degussa AG, the Bayer AG, the BASF AG, the Wacker AG, and the
Novartis AG were greatly appreciated. We thank Dr. Wolfgang
Frey for performing the X-ray structure analysis.
Deprotection of boronic esters 25 and 26 was straightfor-
ward with KHF2 in MeOH, yielding crystalline trifluoro-
borates 27 (82%) and 28 (89%), respectively (Scheme 5).
Synlett 2006, No. 10, 1531–1534 © Thieme Stuttgart · New York

1534
E. Hohn et al.
LETTER
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not furnish the product in high selectivity.
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M. R. J. Org. Chem. 1995, 60, 3020.
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(12) Representative Procedure – Synthesis of ent-15.
KHF2 (5.50 g, 70.5 mmol) was placed in a round-bottom
flask (CAUTION: use Teflon vessel) and dissolved in MeOH
(150 mL). The boronic ester 10 (880 mg, 1.41 mmol),
dissolved in a minimum amount of CH2Cl2, was added and
the mixture heated at 80 °C for 2 d. The solvents were
removed under reduced pressure, the remaining colorless
solids transferred on a Büchner funnel and washed with
Et2O. The product was dissolved in MeCN, the solvent
removed under reduced pressure, and the remaining solid
recrystallized from MeCN (10 mL). Yield: 92% (345 mg,
1.29 mmol); [a]D20 –16.4 (c 0.5, DMSO); mp 197 °C. Anal.
Calcd for C11H13BF3KO (268.12): C, 49.27; H, 4.89. Found:
C, 48.82; H, 4.87. 1H NMR (400 MHz, DMSO-d6): d = –0.87
(ddd, 3J1,3a = 9.8 Hz, 3J1,3b = 6.7 Hz, 3J1,2 = 3.4 Hz, 1 H, 1-H),
–0.16 (ddd, 3J3a,1 = 9.8 Hz, 3J3a,2 = 3.3 Hz, 2J3a,3b = 2.9 Hz, 1
H, 3-Ha), 0.09 (ddd, 3J3b,2 = 6.8 Hz, 3J3b,1 = 6.7 Hz,
2J3b,3a = 2.9 Hz, 1 H, 3-Ha), 0.79 (mc, 1 H, 2-H), 3.07 (dd,
2J4a,4b = 10.2 Hz, 3J4a,2 = 7.3 Hz, 1 H, 4-Ha), 3.30 (dd,
2J4b,4a = 10.2 Hz, 3J4b,2 = 6.1 Hz, 1 H, 4-Hb), 4.61 (d,
2J = 12.2 Hz, 1 H, Bn-Ha), 4.68 (d, 2J = 12.2 Hz, 1 H, Bn-
Hb), 7.25–7.34 (m, 5 H, arom.-H) ppm. 13C NMR (100 MHz,
DMSO-d6): d = 6.9 (C-3), 13.6 (C-2), 70.6 (Bn-CH2), 76.4
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F
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Synlett 2006, No. 10, 1531–1534 © Thieme Stuttgart · New York