Enantiomerically pure cyclopropane building blocks: Synthesis and transformations of 2-iodocyclopropylboronic esters

Article abstract of DOI:10.1002/adsc.200404055

Enantiomerically pure 2-iodocyclopropylboronic esters 6 and 8 have been synthesized from the readily available allylic alcohol 2 via an oxidation-radical decarboxylation sequence. These unique building blocks have been demonstrated to be versatile interme

Full text of DOI:10.1002/adsc.200404055

UPDATES
Enantiomerically Pure Cyclopropane Building Blocks: Synthesis
and Transformations of 2-Iodocyclopropylboronic Esters
Erwin Hohn, Jˆrg Pietruszka*
Institut f¸r Organische Chemie der Universit‰t Stuttgart, Pfaffenwaldring 55, 70569 Stuttgart, Germany
Fax: (þ49)-711-685-4335, e-mail: joerg.pietruszka@po.uni-stuttgart.de
Received: February 24, 2004; Accepted: May 11, 2004
Dedicated to Joe P. Richmond on the occasion of his 60th birthday.
Abstract: Enantiomerically pure 2-iodocyclopropyl-
boronic esters 6 and 8 have been synthesized from
the readily available allylic alcohol 2 via an oxida-
tion-radical decarboxylation sequence. These unique
building blocks have been demonstrated to be versa-
tile intermediates for a consecutive Suzuki-coupling
with aryl-, heteroaryl-, alkenyl-, and cyclopropylbor-
on derivatives (1 example each).
block, we pursued the synthesis of a cyclopropane 3 that
would ultimately allow us to use the synthetic potential
of boron. More importantly, in a first step we should be
able to substitute a suitable group −X× preferentially via a
palladium-catalyzed cross-coupling (1st transformation)
without touching the borolane unit of 3. Only a consec-
utive step (2nd transformation) should lead to its substi-
tution via established reactions. In the present commu-
nication we present the initial results of our search for
such enantiomerically pure 1,2-disubstituted cyclopro-
panes.
Keywords: boron; chiral auxiliaries; cross-coupling;
cyclopropanes; palladium
Results and Discussion
Introduction
Our initial targets were halocyclopropanes 3 (X¼ha-
Despite the fact that the chemistry around the cyclopro- lide). The starting material of our investigation, alcohol
pane moiety is an old field of research, it still is a flour- 2, is readily available in high yield from the silyl-protect-
ishing field with many new aspects and applications con- ed propargyl alcohol 4 via a hydroboration-deprotec-
tinuously being published. Accordingly, cyclopropanes tion-cyclopropanation sequence (Scheme 1).[17,18] Di-
have been the center of interest in a recent thematic is- rect oxidation to carboxylic acid 5 was conveniently ach-
sue of Chemical Reviews.[1] Nevertheless, although some ieved by a ruthenium-catalyzed reaction (yield: 90%).
efforts were directed towards truly general sequences to Next, we focused on the thermal decarboxylation of
enantiomerically pure cyclopropanes, no such protocol the corresponding Barton thiohydroxamic ester[24] in
has been disclosed as yet.[2] The utilization of cyclopro- the presence of iodoform, a sequence that was success-
pylboronic esters could be a promising approach,[3
fully applied (in the presence of bromoform) by Falck
10]
with many transformations of the boron moiety possi- et al. in their synthesis of the oligocyclopropane antibi-
ble. A difficulty used to be the lack of stability of boro-
nates thus preventing the supply of enantiomerically
pure intermediates.[11 15] We recently introduced esters
20]
of the general type 1[16
(as well as higher substitut-
ed[21,22] and cis-configurated[23] derivatives) that proved
to be highly stable, allowing for chromatographic purifi-
cation and separation of the diastereoisomers (Fig-
ure 1). All products were found to be solids which
made them convenient to handle and from the practi-
cal point of view another important issue very easy to
detect due to the chromophore in the auxiliary. In addi-
tion, we proved that a number of envisaged transforma-
tions were not only possible via the boronate, but also se-
lectively in the side chain. In this context, we have shown
in a number of investigations the convenience of alcohol
Figure 1. Flexible use of stable, enantiomerically pure cyclo-
2.[17,18] However, in order to have a truly flexible building propylboronic esters.
Adv. Synth. Catal. 2004, 346, 863 866
DOI: 10.1002/adsc.200404055
¹ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
863

Erwin Hohn, Jˆrg Pietruszka
UPDATES
Scheme 2. Suzuki couplings of iodocyclopropane 6. Condi-
tions: a) 1.5 equivs. 9, 2 equivs. KOt-Bu (1 M in t-BuOH),
0.05 equivs. Pd(PPh3)4, DME, 15 h, 808C.
Scheme 1. Synthesis of iodocyclopropanes 6 and 8. Condi-
tions: a) NaIO4, cat. RuCl3 ¥3 H2O, CCl4/H2O/MeCN, 2 h,
408C (90%); b) 1. 1.2 equivs. 7, cat. DMAP, MeCN/THF,
Et3N, 1 h, rt; 2. cyclohexene, 3 equivs. HCI3, 24 h, 808C
(70% of 6 and 8 as a separable 6:1 mixture).
with phenylboronic acid (9a) (87% of 10a), but also
with heteroarylboronic acids (e.g., 9b: 79% of 10b), alke-
nylboronic acids (e.g., 9c: 65% of 10c), and especially cy-
otic FR-900848.[25,26] We observed low yields for the for- clopropylboronates (e.g., 9d: 67% of 10d). This is only
mation of iodide 6 when we introduced the ester via the the second[30] example for a successful cyclopropane-cy-
acid chloride (33%). Direct esterification using DCC clopropane cross-coupling using a palladium catalyst. In
(dicyclohexylcarbodiimide) proved unsatisfactory as the present case we still have the advantage to be able to
well. Again, not the consecutive radical reaction was further elaborate the bicyclopropane via the intact bor-
problematic, but the formation of side-products during on moiety.[18]
the first step that could not be separated after work-
Although the cis-iodocyclopropane 8 is only the minor
up. The method of choice giving pure products in good product in the radical process (see Scheme 1), it is of im-
overall yield was based on recent work by Garner portance, since cis-cyclopropylboronic esters[23,32] let
et al.[27] The group introduced the −HOTT-reagent× 7 to alone enantiomerically pure representatives[23] have
efficiently synthesize the Barton thiohydroxamic ester. hardly been reported yet. In view of the incomplete as-
The following radical transformation yielded the de- signment of the absolute configuration of most deriva-
sired iodide 6 as well as the cis-cyclopropane 8 as a 6:1 tives,[23] a successful Suzuki Miyaura coupling[33,34] of
mixture in 70% yield. The isomers were readily separat- compound 8 (with known absolute configuration) could
ed by chromatography.
confirm the previous NMR-based results. Fortunately,
We then focused on the transformation of the major the reaction between cis-iodide 8 and phenylboronic
isomer 6 with boron derivatives 9 (Scheme 2). Surpris- acid (9a) not only proceeded more rapidly than with
ingly, despite the fact that iodocyclopropanes are readily the corresponding trans-cyclopropane 6, but also fur-
available (e.g., ref.[28,29]), only a limited number of palla- nished highly pure product 11 in comparable yield
dium-catalyzed cross-couplings have been report- (88%). The comparison of NMR data proved our assign-
ed.[7,18,30,31] We were pleased to find that different palla- ment that was additionally unequivocally supported by
dium sources successfully led to the formation of prod- the first successful X-ray crystallographic analysis of a
uct 10, however, of ultimate importance for a high turn- cis-cyclopropylboronic ester (Scheme 3).
over was a) the absence of oxygen during the reaction
and b) the purity of all reagents catalysts and iodide
6. In our hands, the conditions used by Hildebrand and Conclusion
Marsden[8] were most convenient. We observed a dra-
matic decrease in yield (35 70%) when using only one We have reported a short synthesis of 2-iodocyclopro-
equivalent of boron derivative 9 and as a compromise pylboronic ester 6 (along with minor amounts of cis-de-
between best yield and efficient use of boronic acid/ester rivative 8), a promising new, enantiomerically pure cy-
9, 1.5 equivalents of 9 were introduced. These standard clopropane building block. It was demonstrated that
conditions would allow not only the cross-coupling the iodide could be successfully introduced into palladi-
864
¹ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2004, 346, 863 866

Synthesis and Transformations of 2-Iodocyclopropylboronic Esters
UPDATES
2.2 Hz, 1H, thiophene H), 6.73 (d, J¼2.2 Hz, 1H, thiophene
H), 7.01 (d, J¼5.1 Hz, 1H, thiophene H), 7.25 7.40 (m, 20H,
arom. H); 13C NMR (CDCl3, 125 MHz): d¼5.1 (C-1’), 15.3
(C-3’), 21.9(C-2’), 51.6 (OCH3), 77.1 (C-4, C-5), 83.3 (CPh2
OCH3), 122.0, 122.6, 127.1, 127.2, 127.4, 127.7, 128.1, 128.3,
138.3 (arom. C), 141.2, 141.3 (arom. i-C); anal. calcd. for C37
H35BO4S (586.55 g/mol): C 75.76, H 6.01; found: C 75.49, H
5.93.
2-(2-Hepten-1-yl)cyclopropylboronic ester 10c: Softening
range: 98 1078C; [a]2D1: ꢀ63.5 (c 1.45, CHCl3); IR (film): n¼
3060, 2956, 2932, 2833, 1493, 1446. 1421, 1366, 1320, 1239,
1184, 1075, 1032, 1019, 965, 921, 921, 857 cmꢀ1; MS (EI,
70 eV): m/z (%)¼600 (1) [Mþ], 569 (7) [(M CH3OH)þ],
þ
197 (100) [(Ph2COCH3)þ], 105 (10) [C7H5Oþ], 97 (4) [C7H13
], 77 (6) [C6H5þ]; 1H NMR (CDCl3, 500 MHz): d¼ ꢀ0.47
3
3
3
(ddd, J1’,2’ ¼9.8 Hz, J1’,3’b ¼6.5 Hz, J1’,3’a ¼5.3 Hz, 1H, 1’-H),
3
3
3
0.29 (ddd, J2’, 3’a ¼7.8 Hz, J1’,3’a ¼5.3 Hz, J3’a,3’b ¼3.4 Hz, 1H,
3
3
3
3’-Ha), 0.39 (ddd, J2’,3’b ¼9.8 Hz, J1’,3’b ¼6.5 Hz, J3’a,3’b
¼
3
3.4 Hz, 1H, 3’-Hb), 0.91 (t, J6’’,7’’ ¼7.2 Hz, 3H, 7’’-H), 1.17
1.27 (m, 1H, 2’-H), 1.28 1.36 (m, 6H, 4’’-H, 5’’-H, 6’’-H), 1.95
Scheme 3. Suzuki coupling of iodocyclopropane 8. Condi-
tions: a) 1.5 equivs. 9a, 2 equivs. KOt-Bu (1 M in t-BuOH),
0.05 equivs. Pd(PPh3)4, DME, 15 h, 808C (88%).
3
(m, 2H, 3’’-H), 2.99 (s, 6H, OCH3), 4,79 (dt, J1’’,2’’ ¼15.1 Hz,
3J2’’,3’’ ¼8.5 Hz, 1H, 2’’-H), 5.25 (s, 2H, 4-H, 5-H), 5.51 (dd,
3J4’,5’ ¼15.1 Hz, J3’,4’ ¼6.9 Hz, 1H, 1’’-H), 7.27 7.34 (m, 20H,
3
arom. H); 13C NMR (CDCl3, 125 MHz): d¼1.8 (C-1’), 12.4
(C-7’’), 12.9 (C-3’), 16.7 (C-6’’), 21.0 (C-5’’), 22.1 (C-4’’), 27.2
(C-2’), 31.8 (C-3’’), 51.7 (CPh2OCH3), 77.4 (C-4 and C-5),
83,2 (CPh2OCH3), 127.1, 127.2, 127.4, 127.7, 128.1, 128.3,
(arom. CH), 129.6 (C-1’’), 133.4 (C-2’’), 141.1, 141.3 (arom. i-
C); anal. calcd. for C40H45BO4 (600.59 g/mol): C 79.99, H
7.55; found: C 79.63, H 5.33.
um-catalyzed cross-couplings with boron compounds,
also allowing a cyclopropane-cyclopropane bond forma-
tion. Hence, we tuned the reactivity of the coupling part-
ners by varying the protection group on the boronic acid.
The process should be rather general and readily appli-
cable for the synthesis of enantiomerically pure 1,2-dis-
ubstituted cyclopropanes.
2-(2-Phenylcycloprop-1-yl)cyclopropylboronic ester 10d:
IR (film): n¼3057, 3024, 2937, 2832, 1494, 1445, 1423, 1396,
1350, 1320, 1240, 1184, 1074þ, 1032, 966, 883 cmꢀ1; MS (EI,
þ
ꢀ
70 eV): m/z (%)¼620 (2) [M ], 589 (6) [(M CH3OH) ], 197
(100) [(Ph2COCH3)þ], 105 (10) [C7H5Oþ], 77 (5) [C6H5þ];
1H NMR (CDCl3, 500 MHz): d¼ ꢀ0.66 0.71 (m, 1H, 1’-H),
0.02 0.05 (m, 1H, 3’-Ha), 0.21 0.25 (m, 1H, 3’-Hb), 0.57 0.61
(m, 1H, 1’’-H), 0.63 0.67 (m, 1H, 2’-H), 0.93 0.95 (m, 1H,
3’’-Ha), 0.98 1.04 (m, 1H, 3’’-Hb), 1.46 1.50 (m, 1H, 2’’-H),
2.99 (s, 6H, OCH3), 5.25 (s, 2H, 4-H, 5-H), 7.17 7.34 (m,
25H, arom. H); 13C NMR (CDCl3, 125 MHz): d¼ ꢀ1.9 (C-
1’), 10.2/10.4 (C-3’’), 13.4 (C-3’), 19.7 (C-2’), 21.6 (C-1’’), 25.3/
25.4 (C-2’’), 51.7 (OCH3), 77.5 (C-4, C-5), 83.3 (CPh2OCH3),
125.2, 125.6, 127.1, 127.2, 127.4, 127.7, 128.1, 128.3, 128.7,
129.3 (arom. C), 141.2, 141.3, 143.5 (arom. i-C); anal. calcd.
for C42H41BO4 (620.31 g/mol): C 81.29, H 6.66; found: C
81.11, H 6.48.
Experimental Section
General Procedure for the Suzuki Coupling
Iodocyclopropane 6 (or 8) (1.0 equiv.) was dissolved in 1,2-di-
methoxyethane (DME; 10 mL/mmol 6 or 8, respectively). Af-
ter addition of boron derivative 9 (1.5 equivs.), Pd(PPh3)4
(5 mol %) and KOt-Bu (2 mL/mmol 7 of a 1 M solution in t-
BuOH) the educts were carefully deoxygenated by the freeze
technique. After 15 h at 808C the mixture was diluted with di-
ethyl ether, filtered through Celite, rinsed with diethyl ether;
the solvents were removed under reduced pressure. All crude
products were purified by means of flash column chromatogra-
phy (petroleum ether:ethyl acetate 99:1).
2-Phenylcyclopropylboronic ester 11: Data in full agree-
ment with those published.[23]
2-Phenylcyclopropylboronic ester 10a: Data in full agree-
ment with those published.[16]
2-Thienylcyclopropylboronic ester 10b: Softening range:
93 1018C; [a]2D1: ꢀ124 (c 0.9, CHCl3); IR (film): n¼3075,
3056, 2935, 2836, 1450, 1423, 1360, 1241, 1185, 1071, 963,
755 cmꢀ1; MS (EI, 70 eV): m/z (%)¼586 (3) [Mþ], 555 (9)
X-Ray Crystallographic Data
Crystals of 11 suitable for a crystallographic study were ob-
tained from petroleum ether/diethyl ether at ꢀ208C. X-ray
data were collected on a Siemens P 4 diffractometer with
graphite monochromator in Omega scan modus with Cu-Ka
(l¼1.54178 ä) radiation: C39H37BO4, Mr ¼580.5, colorless,
T¼293, crystal size 0.15ꢁ0.10ꢁ0.10, triclinic, P1, a¼
9.1714(12) ä, b¼9.5155(8) ä, c¼11.0476(8) ä, a¼
72.611(8)8, b¼77.442(8)8, g¼62.110(10)8, V¼809.75(14) ä3,
Z¼1, dcalcd. ¼1.190 g cmꢀ3, m¼0.591 mmꢀ1, F(000)¼308, q
þ
þ
ꢀ
[(M CH3OH) ], 197 (100) [(Ph2COCH3) ], 105 (13) [C7H5
Oþ], 82 (15) [C4H3Sþ], 77 (5) [C6H5þ]; 1H NMR (CDCl3,
3
3
500 MHz): d¼ ꢀ0.18 (ddd, J1’,3’b ¼9.8 Hz, J1’,3’a ¼6.6 Hz,
3
3
3J1’,2’ ¼5.4 Hz, 1H, 1’-H), 0.41 (ddd, J2’, ¼8.0 Hz, J1’,3’a
¼
3a×
3
3
6.6 Hz, J3’a,3’b ¼3.5 Hz, 1H, 3’-Ha), 0.71 (ddd, J1,3’b ¼9.8 Hz,
3J2’,3’b ¼5.1 Hz, J3’a,3’b ¼3.5 Hz, 1H, 3’-Hb), 1.83 (ddd, J2’,3’a
¼
3
3
3
3
8.0 Hz, J1’,2’ ¼5.4 Hz, J2’,3’b ¼5.1 Hz, 1H, 2’-H), 2.99 (s, 6H,
OCH3), 5.24 (s, 2H, 4-H, 5-H), 6.66 (dd, 3J¼5.1 Hz, J¼
Adv. Synth. Catal. 2004, 346, 863 866
asc.wiley-vch.de
¹ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
865

Erwin Hohn, Jˆrg Pietruszka
UPDATES
range 4.21 65.998, 2904 measured/independent reflections,
2299 with [I>3s(I)]. Solved by direct methods and refined
by full-matrix, least-squares on F2 for all data weights to R¼
0.065, Rw ¼0.164, S¼1.073, H atoms riding, max. shift/error
[9] X.-Z. Wang, M.-Z. Deng, J. Chem. Soc. Perkin Trans. 1
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4986 4988.
[12] J. Pietruszka, M. Widenmeyer, Synlett 1997, 977 979.
[13] S.-M. Zhou, M.-Z. Deng, L.-J. Xia, M.-H. Tang, Angew.
Chem. 1998, 110, 3061 3063; Angew. Chem. Int. Ed.
1998, 37, 2845.
[14] J. Pietruszka, T. Wilhelm, A. Witt, Synlett 1999, 1981
1983.
<0.001, residual 1max ¼0.207 äꢀ3
.
Crystallographic data (excluding structure factors) for the
structure(s) reported in this paper have been deposited with
the Cambridge Crystallographic Data Centre as supplementa-
ry publication no. CCDC-230792. Copies of the data can be ob-
tained free of charge on application to CCDC, 12 Union Road,
Cambridge CB21EZ, UK [Fax: int. code þ44(1223)336 033;
E-mail: deposit@ccdc.cam.ac.uk].
[15] J. Pietruszka, A. C. M. Rieche, T. Wilhelm, A. Witt, Adv.
Synth. Catal. 2003, 345, 1273 1286.
[16] J. E. A. Luithle, J. Pietruszka, Liebigs Ann./Recueil 1997,
2297 2302.
Acknowledgements
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4293 4300.
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3219 3229.
We gratefully acknowledge the generous support by the Deut-
sche Forschungsgemeinschaft, the Fonds der Chemischen In-
dustrie, the Landesgraduiertenfˆrderung Baden-W¸rttemberg
(™Graduiertenstipendium∫ for E. H.) and the Otto-Rˆhm-Ge-
d‰chtnisstiftung. Donations from Degussa AG, Bayer AG,
Wacker AG, and Novartis AG were greatly appreciated. We
are indebted to Dr. W. Frey for performing the X-ray analysis
as well as Dr. Joachim E. A. Luithle for preliminary experi-
ments.
¬
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¹ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2004, 346, 863 866