Spectroscopic characterization of (diiodomethyl)zinc iodide: Application to the stereoselective synthesis and functionalization of iodocyclopropanes

Article abstract of DOI:10.1039/c7cc04348a

Herein is described an improved synthetic route to enantio- and diastereoenriched iodocyclopropylmethanols using (diiodomethyl)zinc iodide etherate as the active species. The products obtained by this methodology were successfully functionalized by Suzuki-Miyaura cross-coupling reactions. A Buchwald-type palladium precatalyst allowed access to highly substituted and stereo-enriched cyclopropanes without requiring a protecting group.

Full text of DOI:10.1039/c7cc04348a

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Spectroscopic Characterization of Diiodomethylzinc Iodide:
Application to the Stereoselective Synthesis and Functionalization
of Iodocyclopropanes.
Received 00th January 20xx,
Accepted 00th January 20xx
Emmanuelle M. D. Allouche,† Sylvain Taillemaud† and André B. Charette*
DOI: 10.1039/x0xx00000x
www.rsc.org/
a) Previous Stereoselective Iodocyclopropanation6
Herein is described an improved synthetic route to enantio- and
diastereoenriched iodocyclopropylmethanols using
i) CHI3 (4.4 equiv)
ii) Et2Zn (2.2 equiv)
iii) substrate, 1 (1.1 equiv)
R1
I
19 examples
R2
OH
R3
R2
(diiodomethyl)zinc iodide etherate as the active species. The
products obtained by this methodology were successfully
OH
up to 81% yield
4:1 to 20:1 dr
up to 99% ee
CH2Cl2, rt, 15-24 h
R1
R3
b) Previous Suzuki-Miyaura Cross-Coupling of Iodocyclopropanes9a
functionalized by Suzuki-Miyaura cross-coupling reactions.
A
Pd(OAc)2 (10 mol %)
PPh3 (50 mol %)
R1-B(OH)2 or R1-BO2Cat (1.5 equiv)
Buchwald-type palladium precatalyst allowed access to highly
substituted and stereo-enriched cyclopropanes without requiring
a protecting group.
K2CO3 (3.0 equiv)
I
R1
13 examples
Bu4NCl (2.0 equiv)
up to 85% yield
only disubstituted cyclopropanes
OBn
OBn
DMF/H2O (4:1) [0.025M]
90 °C, 4-20 h
The cyclopropane moiety is present in a large number of
bioactive molecules,1 having recently being ranked as the 10th
most commonly used cyclic scaffold for the elaboration of new
drugs.2 The introduction of such crucial motifs in various
structures is, therefore, of interest. One way to achieve this
goal would be the palladium-catalyzed Suzuki-Miyaura cross-
coupling of iodocyclopropanes with various boronic acids, as
this reaction is one of the most used reactions in the
pharmaceutical industry for the formation of carbon-carbon
bonds.3,4,5 Recently, our group reported the first
enantioselective synthesis of such iodocyclopropanes starting
from allylic alcohols using diethylzinc and iodoform as
reagents.6,7 Although this methodology delivers the desired
iodocyclopropanes in good yields and moderate to excellent
stereoselectivities, it suffers from the large amount of
iodoform needed (Scheme 1a). Following our work on the
bromocyclopropanation reaction,8 in which only 1.3
equivalents of diethylzinc and 2.6 equivalents of bromoform
were needed for the reaction, we investigated whether we
could develop a more atom-economical iodocyclopropanation
to minimize the amount of reagents needed for the optimal
preparation of the (diiodomethyl)zinc carbenoid (Scheme 1a).
c) This work: Improved Iodocyclopropanation and Suzuki-Miyaura Cross-Coupling
i) ZnI2•4 Et2O (1.5 equiv)
ii) Et2Zn (1.5 equiv)
iii) CHI3 (3.0 equiv)
iv) substrate, 1 (1.1 equiv)
2 (2.5 mol %)
KOt-Bu (3.5 equiv)
(Het)Ar-B(OH)2 (1.5 equiv)
(Het)Ar
R3
R2
R1
I
R2
OH
OH
R3
R2
OH
R1
R1
CH2Cl2, 0 °C to rt , 14 h
tert-amyl alcohol [0.1M]
60 °C, 15 h
R3
11 examples
16 examples
Via I2HC-Zn-I•2 Et2
O
up to 82% yield
5:1 to 20:1 dr
up to 99% ee
up to 84% yield
no epimerization
air-stable reagents
Me2NOC
CONMe2
NH2
O
O
B
Pd
P(t-Bu)2Me
Bu
1
OMs
2
Scheme 1 a) and b) Previously developed methodologies and c) This work.
In this communication, we report the first spectroscopic
characterization of (diiodomethyl)zinc iodide and its
application to the iodocyclopropanation reaction as well as the
first set of conditions allowing the Suzuki-Miyaura cross-
coupling of 1,2,3-substituted iodocyclopropanes that do not
required an initial protection of the primary alcohol (Scheme
1b).9,10,11,12
We began our investigations by monitoring the preparation of
1
the active carbenoid by H NMR to insure that it was formed
under optimal conditions. Ethylzinc iodide etherate was
formed by mixing zinc iodide, diethylzinc and diethyl ether in a
1:1:2 molar ratio in CD2Cl2.Upon cannulation of this mixture
over a suspension of CHI3 in CD2Cl2 at 0 °C and stirring for 20
minutes, we were delighted to observe a new signal at 4.21
ppm, attributed to the carbenoid (Figure 1a). This intermediate
was formed in 75% yield and was fully characterized by 1H, 13C
and HSQC experiments.13 Although this carbenoid is stable at
0 °C, it rapidly degrades even at room temperature.
Centre in Green Chemistry and Catalysis, Department of Chemistry, Université de
Montréal, P.O. Box 6128, Station Downtown, Montréal, Québec, Canada H3C 3J7.
† These authors contributed equally.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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weakly donating methyl group on the phenyl ring of the
substrate has a negligible effect both on the yield and the
stereoselectivities of the reaction. Steric bulk around the
alkene drastically improved the diastereochemical outcome
(
4c). Electron-poor alkenes, such as 3d, afford the desired
product in a lower yield. This lack of reactivity can be
attributed to the substrate’s poor nucleophilicity. Alkyl and
halogen substituents on the phenyl group are well tolerated,
as depicted by compounds 4b and 4e. The electron-rich
product 4f was obtained in a slightly lower yield but good
conversion. In this case, the degradation of 4f, possibly by a
ring-opening pathway, is the cause of the diminished product
recovery. Non-aromatic alkenes, lacking the stabilizing effect
of conjugation, generally gave slightly diminished yields and
disatereoselectivities (4g, 4i, 4j). cis-Disubstituted alkene 3h
gave the lowest yield, likely due to a steric clash with the
dioxaborolane auxiliary. Finally, the addition of a third aliphatic
substituent gem to the hydroxymethyl increased the
diastereoselectivity, which was also compatible under these
conditions (4k). It is noteworthy that, in almost all examples,
the desired products were obtained in a similar or improved
yield compared to the previously described methodology.6
Our group previously described the first Suzuki cross-coupling
Figure
1 a mixture 1:1:2:2 ZnI2/Et2Zn/CHI3/Et2O in CD2Cl2.
a) 1H NMR spectra of
of
iodocyclopropanes
using
palladium(II)
carbonate
acetate,
and
Triphenylmethane used as internal standard. b) 1H NMR spectra of the previous
triphenylphosphine,
potassium
mixture quenched with aqueous 1N HCl.
tetrabutylammonium chloride in a mixture of DMF and water
(Scheme 1b).9a
Quenching the reaction mixture with 1N HCl triggered the
disappearance of this signal and the appearance of
diiodomethane at 3.90 ppm (Figure 1b). This protocol led to an
effective monoiodocyclopropanation of cinnamyl alcohol to
generate iodocyclopropane 4a. After optimization,13 4a was
obtained in 75% yield and with 10:1 dr and 98% ee using only
1.5 equivalents of diethylzinc and 3.0 equivalents of iodoform.
These conditions were effective to cyclopropanate a wide
range of allylic alcohols producing various iodocyclopropanes
in good to excellent yields and high enantiomeric excesses
(Scheme 2). As illustrated by compound 4b, the presence of a
Under those conditions, only one example involving a trans-2-
iodocyclopropylmethanol was described. When they were
applied to a 1,2,3-substituted iodocyclopropane, the starting
material was completely consumed, but none of the Suzuki
products could be isolated (Scheme 3a). It appears that the
initial oxidative addition process took place, yet the
cyclopropylpalladium readily decomposed prior to undergoing
transmetalation.
i) EtZnI•2 Et2O (3.0 equiv)
Me2NOC
CONMe2
ii) CHI3 (3.0 equiv)
R1
I
iii) substrate, 1 (1.1 equiv)
O
O
R2
OH
R3
R2
B
OH
CH2Cl2, 0 °C to rt, 14 h
R1
R3
Bu
3a-k
4a-k
1
I
I
I
I
I
I
OH
OH
OH
OH
OH
OH
Ph
4-MeC6H4
Mes
4-CF3C6H4
4-ClC6H4
4-MeOC6H4
4a
4b
4c
4d
4e
4f
75%
10:1 dr
98% ee
73%
9:1 dr
96% ee
82%
> 20:1 dr
99% ee
64%
11:1 dr
98% ee
78%
13:1 dr
99% ee
67%
10:1 dr
99% ee
I
I
I
I
I
OH
OH
OH
OH
OH
n-Pr
n-Pr
Cy
Ph
Ph
Me
4g
4h
4i
4j
4k
65%
6:1 dr
94% ee
50%
3:1 dr
>99% ee
56%
5:1 dr
95% ee
61%
4:1 dr
96% ee
64%
15:1 dr
92% ee
Scheme 2 Scope of the improved stereoselective iodocyclopropanation. 0.5 mmol scale. Yields of the isolated major diastereomer. Diastereomeric ratios determined by 1H NMR on
the crude mixture. Enantiomeric excess verified by chiral SFC.
2 | J. Name., 2012, 00, 1-3
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With our more efficient synthesis of enantioenriched and
highly substituted iodocyclopropanes in hand, we decided to
develop conditions for the Suzuki cross-coupling reaction that
would not only be applicable to a broader range of substituted
iodocyclopropanes, but also would allow the coupling of
unprotected cyclopropylmethanol derivatives.
a) Attempt Using Our Previous Conditions
Pd(OAc)2 (10 mol %)
O
PPh3 (50 mol %)
4-MeO-C6H4B(OH)2 (1.5 equiv)
K2CO3 (3.0 equiv)
I
Bu4NCl (2.0 equiv)
DMF/H2O (4:1) [0.025M]
90 °C, 18 h
OH
OH
Ph
Ph
Over the past decades, a lot of efforts have been invested to
promote the development of more efficient, user-friendlier
and milder reaction conditions for the cross-coupling of both
sp2 and sp3 centers.11 Notably, Fu described a protocol for the
effective Suzuki coupling of primary alkyl bromides in tert-amyl
alcohol.14 Applying Fu’s conditions at 60 °C instead of room
temperature, we observed the formation of the desired
product in 85% yield by 1H NMR with no trace of epimerization
(Scheme 3b). Despite an extensive screening of ligands, bases
and solvents, those conditions proved to be the most
effective.13 Although suitable, the source of the Pd(II) catalyst
could affect the reproducibility of the results, as studied by
Colacot.15 On the other hand, Buchwald’s precatalysts are
known to be air- and moisture-stable and very powerful
sources of palladium(0).16 Therefore, the Buchwald’s third
generation precatalyst using the di-tert-butylmethylphosphine
ligand was synthesized.17 After optimization,13 80% of the
desired product 5j was isolated when iodocyclopropane 4j was
treated with 1.5 equivalents of 4-methoxyphenylboronic acid,
0%
b) Attempts Using Fu's Conditions
O
Pd(OAc)2 (5 mol %)
P(t-Bu)2Me.HBF4 (10 mol %)
KOt-Bu (3.0 equiv)
4-MeO-C6H4B(OH)2 (2.0 equiv)
I
OH
OH
Ph
tert-amyl alcohol [0.2M]
T °C, 16 h
Ph
T °C = rt
0%
T °C = 60 °C
85%
Scheme 3 Initial trials of Suzuki Cross-Coupling using a) our previous conditions and b)
adapted conditions from the Fu group.
This lower efficiency may be the result of one of the
cyclopropylpalladium(II) intermediates undergoing ring-
opening due to the propensity of aromatic rings to stabilize
electronic charges at the benzylic position. Iodocyclopropanes
bearing strongly electron-donating or -withdrawing groups on
the aryl substituent (i.e. 4d to 4f) were not compatible with
the coupling conditions. Alkyl substituted iodocyclopropanes
could be smoothly converted into the coupling products (5g to
5j). The attempted coupling of more sterically hindered
iodocyclopropanes (4c and 4k) led to the degradation of the
starting materials, and only traces of the desired products
were observed.
2.5 mol % of precatalyst
2 and 3.5 equivalents of potassium
tert-butoxide in tert-amyl alcohol at 60 °C for 15 hours. The
scope of the reaction was then investigated using various
iodocyclopropanes and boronic acids (Scheme 4). It can be
noted that an aromatic substitution on the iodocyclopropane
moiety is well tolerated under those conditions, although the
corresponding products are obtained in modest yields (5a, 5b).
2 (2.5 mol %)
KOt-Bu (3.5 equiv)
R4-B(OH)2 (1.5 equiv)
I
R4
NH2
R3
R2
R3
OH
OH
Pd
P(t-Bu)2Me
R1
R2
R1
tert-amyl alcohol [0.1M]
OMs
4a-k
5a-k
6a-j
60 °C, 15 h
2
Iodocyclopropane moiety
4-MeOC6H4
4-MeOC6H4
OH
4-MeOC6H4
OH
4-MeOC6H4
OH
4-MeOC6H4
4-MeOC6H4
OH
OH
OH
Ph
4-MeC6H4
n-Pr
n-Pr
Cy
Ph
5a
5b
5g
5h
5i
5j
52%
38%
74%
39%
64%
80%
Boronic acid moiety
Ph
4-MeC6H4
OH
Mes
3-MeOC6H4
4-CF3C6H4
OH
3-CF3C6H4
OH
OH
OH
OH
Ph
Ph
Ph
Ph
Ph
Ph
6a
6b
79%
3-pyr
6c
6d
6e
6f
75%
74%
65%
84%
72%
3-thienyl
3-furyl
Me
OH
OH
OH
OH
Ph
Ph
Ph
Ph
6g
6h
6i
6j
82%
79%
34%
36%*
Scheme 4 Scope of the newly developed Suzuki-Miyaura cross-coupling of iodocyclopropanes. 0.3-0.4 mmol scale. *1H NMR yield on the crude mixture, triphenylmethane used as
internal standard.
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(c) S. R. Goudreau and A. B. Charette, J. Am. Chem. Soc.,
2009, 131, 15633-15635. (d) É. Lévesque, S. R. Goudreau and
A. B. Charette, Org. Lett., 2014, 16, 1490-1493.
(a) L.-P. B. Beaulieu, L. E. Zimmer and A. B. Charette, Chem.
Eur. J., 2009, 15, 11829-11832. (b) L.-P. B. Beaulieu, L. E.
Zimmer, A. Gagnon and A. B. Charette, Chem. Eur. J., 2012,
18, 14784-14791.
For other stereoselective syntheses of iodocyclopropanes,
see: (a) H. Y. Kim, A. E. Lurain, P. García-García, P. J. Carroll
and P. J. Walsh, J. Am. Chem. Soc., 2005, 127, 13138-13139.
(b) H. Y. Kim, L. Salvi, P. J. Carroll and P. J. Walsh, J. Am.
Chem. Soc., 2009, 131, 954-962. (c) J. M. Concellón, H.
Rodríguez-Solla, E. G. Blanco, S. García-Granda, Díaz and M.
Rosario, Adv. Synth. Catal., 2011, 353, 49-52.
The nature of the boronic acid component was then surveyed.
Phenylboronic and p-tolyl boronic acids gave the desired
compounds 6a and 6b in good yields. Mesitylboronic acid was
also successfully coupled (6c), showing high tolerance to steric
hindrance on the boronic acid partner. The reaction seems
unaffected by electronic effects, as both electron-rich and
electron-poor arylboronic acids were viable coupling partners
6
7
(5j, 6d, 6e and 6f). Interestingly, heteroaryl boronic acids, such
as 3-pyridyl and 3-thienylboronic acids, provided access to
compounds 6g and 6h in good yields. Unfortunately, 3-
furanylboronic acid gave a lower yield (6i). Finally, using an
alkylboronic acid as methylboronic acid (6j) gave an observed
low yield by 1H NMR and was not separable from the
dehalogenated cyclopropyl by-product. It is noteworthy that
no epimerization was observed by 1H NMR on the
cyclopropane in any of the described examples.
8
9
S. Taillemaud, N. Diercxsens, A. Gagnon and A. B. Charette,
Angew. Chem., Int. Ed., 2015, 54, 14108-14112.
For previous examples of Suzuki-Miyaura cross-coupling
reactions on disubstituted iodocyclopropanes, see: (a) A. B.
Charette and A. Giroux, J. Org. Chem., 1996, 61, 8718-8719.
(b) A. B. Charette and R. P. De Freitas-Gil, Tetrahedron Lett.,
1997, 38, 2809-2812. (c) S. F. Martin and M. P. Dwyer,
Tetrahedron Lett., 1998, 39, 1521-1524. (d) E. Hohn and J.
Pietruszka, Adv. Synth. Catal., 2004, 346, 863-866.
In conclusion, two synthetic methodologies were developed in
this study. First, we devised an improved and more economical
stereoselective iodocyclopropanation reaction for allylic
alcohols, of which the active species has been characterized
and its formation optimized. The highly substituted products
obtained by this methodology were then successfully engaged
in stereospecific Suzuki-Miyaura cross-coupling reactions
thanks to the development of new conditions using bench-
stable and easy-to-handle reagents.
10 For a selected example of nickel-catalyzed Suzuki-Miyaura
cross-coupling of tertiary iodocyclopropanes, see: K. Yotsuji,
N. Hoshiya, T. Kobayashi, H. Fukuda, H. Abe, M. Arisawa and
S. Shuto, Adv. Synth. Catal., 2015, 357, 1022-1028.
11 For recent reviews and reports on palladium-catalyzed cross-
coupling reactions, see: (a) A. Suzuki, Chem. Commun., 2005,
4759-4763. (b) R. Martin and S. L. Buchwald, Acc. Chem. Res.,
2008, 41, 1461-1473. (c) G. C. Fu, Acc. Chem. Res., 2008, 41
1555-1564.
,
This work was supported through funding from the Natural
Science and Engineering
Discovery Grant RGPIN-06438, the Canada Foundation
Innovation Leaders Opportunity Funds 227346, the Canada
Research Chair Program CRC-227346, the FRQNT Team Grant
ꢀ
Research Council of Canada (NSERC)
12 For other examples of palladium-catalyzed functionalization
of iodocyclopropanes, see: (a) B. de Carné-Carnavalet, A.
Archambeau, C. Meyer, J. Cossy, B. Folléas, J.-L. Brayer and
J.-P. Demoute, Org. Lett., 2011, 13, 956-959. (b) X. Wu, C.
ꢀ
for
ꢀ
Lei, G. Yue and J. Zhou, Angew. Chem., Int. Ed., 2015, 54
9601-9605.
13 See ESI for more details.
,
PR-190452, the FRQNT Centre in Green Chemistry and
Catalysis (CGCC) Strategic Cluster RS-171310, and Université
de Montréal. E.M.D.A and S.T. are grateful to Université de
Montréal for postgraduate scholarships.
14 (a) J. H. Kirchhoff, M. R. Netherton, I. D. Hills and G. C. Fu, J.
Am. Chem. Soc., 2002, 124, 13662-13663. (b) I. D. Hills, M. R.
Netherton and G. C. Fu, Angew. Chem., Int. Ed., 2003, 42
5749-5752.
,
15 (a) W. A. Carole, J. Bradley, M. Sarwar and T. J. Colacot, Org.
Lett., 2015, 17, 5472-5475. (b) W. A. Carole and T. J. Colacot,
Chem. Eur. J., 2016, 22, 7686-7695.
16 (a) M. R. Biscoe, B. P. Fors and S. L. Buchwald, J. Am. Chem.
Soc., 2008, 130, 6686-6687. (b) T. Kinzel, Y. Zhang and S. L.
Buchwald, J. Am. Chem. Soc., 2010, 132, 14073-14075. (c) N.
C. Bruno and S. L. Buchwald, Org. Lett., 2013, 15, 2876-2879.
(d) N. C. Bruno, M. T. Tudge and S. L. Buchwald, Chem. Sci.,
Notes and references
1
2
3
4
For a recent review, see: T. T. Talele, J. Med. Chem., 2016,
59, 8712-8756.
R. D. Taylor, M. MacCoss and A. D. G. Lawson, J. Med. Chem.,
2014, 57, 5845-5859.
For the seminal publication, see: N. Miyaura, K. Yamada and
A. Suzuki, Tetrahedron Lett., 1979, 20, 3437-3440.
(a) C. C. C. Johansson Seechurn, M. O. Kitching, T. J. Colacot
and V. Snieckus, Angew. Chem., Int. Ed., 2012, 51, 5062-
5085. (b) P. G. Gildner and T. J. Colacot, Organometallics,
2015, 34, 5497-5508.
2013, 4, 916-920. (e) WO 2013184198 A1, 2013. (f) N. C.
Bruno, N. Niljianskul and S. L. Buchwald, J. Org. Chem., 2014,
79, 4161-4166. For a recent review on 2-aminobiphenyl
palladacycles, see: (g) A. Bruneau, M. Roche, M. Alami and S.
Messaoudi, ACS Cat., 2015, 5, 1386-1396.
17 Structure confirmed by X-Ray analysis. See ESI for more
details.
5
For other examples concerning the synthesis of highly
substituted cyclopropanes, see: (a) X. Liu and J. M. Fox, J.
Am. Chem. Soc., 2006, 128, 5600-5601. (b) L. E. Zimmer and
A. B. Charette, J. Am. Chem. Soc., 2009, 131, 15624-15626.
This journal is © The Royal Society of Chemistry 20xx
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DOI: 10.1039/C7CC04348A
(Het)Ar
I
R1
I
I
R2
OH
R3
R3
R2
OH
OH
IZn
• 2 Et2O
Pd•P(t-Bu)2Me
R2
R1
R1
R3
New Suzuki-Miyaura conditions;
Easy to handle, air stable reagents;
Highly substituted products
More efficient stereoselective
iodocyclopropanation
Herein are described more efficient methodologies for the synthesis of highly substituted
cyclopropanes as well as the first characterization of a diiodomethylzinc carbenoid.