An efficient catalytic chromium-mediated iodocyclopropanation Reaction: Stereoselective synthesis of iodocyclopropanecarboxamides

Article abstract of DOI:10.1002/adsc.201000574

A catalytic chromium-mediated novel synthesis of iodocyclopropanecarboxamides is reported. This reaction can be carried out on aromatic (E)- or (Z)-α,β-unsaturated amides in which the C=C double bond is di- or trisubstituted. This process takes place with

Full text of DOI:10.1002/adsc.201000574

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DOI: 10.1002/adsc.201000574
An Efficient Catalytic Chromium-Mediated
Iodocyclopropanation Reaction: Stereoselective Synthesis of
Iodocyclopropanecarboxamides
Josꢀ M. Concellꢁn,a,c Humberto Rodrꢂguez-Solla,a,* Elena G. Blanco,a
Santiago Garcꢂa-Granda,b and and M. Rosario Dꢂazb
a
Departamento de Quꢂmica Orgꢃnica e Inorgꢃnica, Facultad de Quꢂmica, Universidad de Oviedo, Juliꢃn Claverꢂa 8, 33071
Oviedo, Spain
Fax : (+34)-985-10-2971; e-mail: hrsolla@uniovi.es
Departamento de Quꢂmica Fꢂsica y Analꢂtica, Facultad de Quꢂmica, Universidad de Oviedo, Juliꢃn Claverꢂa 8, 33071
b
Oviedo, Spain
c
Prof. Josꢀ M. Concellꢁn passed away unexpectedly in March 2010
Received: July 21, 2010; Published online: December 30, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000574.
Abstract: A catalytic chromium-mediated novel
synthesis of iodocyclopropanecarboxamides is re-
ported. This reaction can be carried out on aromat-
ic (E)- or (Z)-a,b-unsaturated amides in which the
C=C double bond is di- or trisubstituted. This pro-
cess takes place with total stereospecificity and the
have demonstrated the utility of CrCl2 for the cyclo-
propanation of unsaturated compounds. Unfortunate-
ly, when the iodocyclopropanation of a,b-unsaturated
amides 1 was attempted under the same conditions
described for the halocyclopropanation reaction,[4]
a
1:3 mixture of the corresponding iodocyclopropana-
mide 2 and cyclopropanamide 3, was obtained. These
undesirable results could be explained by assuming
that, after iodocyclopropanation, the reaction of the
excess of CrCl2 with the obtained iodocyclopropana-
mide could afford an organochromium intermediate,
which could be hydrolyzed in the same reaction mix-
ture, giving the corresponding cyclopropanamide 3.[4]
These precedents prompted us to develop a stereo-
selective iodocyclopropanation of a,b-unsaturated
amides using catalytic amounts of CrCl2 rather than
stoichiometric quantities. In addition, this method
could overcome the drawback of the high price of
À
new C I stereogenic center is generated with high
stereoselectivity. Some synthetic applications of the
obtained iodocyclopropanecarboxamides are also
reported. The structures of the iodocyclopropanes
and derivatives were established by X-ray analysis.
Keywords: catalysis; chromium; cyclopropanes; io-
docyclopropanes; iron
Chromium dichloride has become an important re- CrCl2.
agent in synthetic organic chemistry because of its
In this communication we report a stereoselective
versatility in electron transfer reactions. In the last synthesis of iodocyclopropanamides 2 with moderate
years, chromium dichloride has been applied to a to good stereoselectivity and yields (>62%) from
multitude of organic transformations, which generally a,b-unsaturated amides 1 using catalytic amounts of
proceeded with high selectivity.[1] The only drawback CrCl2. As a synthetic application of compounds 2, we
in the use of CrCl2 in organic synthesis is its relatively also described the metalation of 2a with SmI2 and its
high price. Thus, methods to carry out transformations stereoselective addition to aldehydes.
using this salt in catalytic amounts would be desira-
ble.
To carry out transformations with catalytic CrCl2, a
redox system would be necessary to reduce the
In particular, previous contributions by us (the ste- CrACTHNUGTRNEUNG(III) (generated in the reaction) to Cr(II). In this
reospecific cyclopropanation of a,b-unsaturated sense, we attempted the use of Fe for such a purpose
amides,[2] the highly stereoselective tert-butyl- and si- due to its ready availability and low price.[6]
lylcyclopropanation[3] and the chloro- and bromocy-
The initial reactions were performed using iodo-
clopropanation of a,b-unsaturated amides with total form
as
iodomethylation
agent
and
N,N-
or high stereoselectivity[4]) and other[5] laboratories, diethylcinnam
ACTHNUTRGNEUaGN mide 1a as the model substrate. To op-
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49

Josꢀ M. Concellꢁn et al.
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Table 1. Initial studies on the iodocyclopropanation of 1a.
Table 2. Synthesis of Iodocyclopropanecarboxamides 2.
[a]
[a]
R1
2a Ph
R2 N(R3)2 dr
H NEt2 90/10 69
Yield [%][a]
Entry CHI3
CrCl2
Fe[a] T [8C]/t[b]
2a/3a/1a[c]
Entry
2
1
2
3
4
5
1.2
1.2
3.0
1.2
1.2
0.42
0.42
0.42
0.42
0.42
10.0 55/16 h
10.0 reflux/16 h
10.0 55/16 h
2/1/1
4/2/1
2/1/1
2/1/4
1
2
3
4
5
6
7
8
2b
2c Ph
2d Ph
2e p-MeOC6H4
2f o-MeOC6H4
2g p-CF3C6H4
2h o-CF3C6H4
2i p-FC6H4
2j m-HOC6H4
2k Ph
H
Ph NEt2 80/20 67
(i-Pr)2 80/20 61
H
H
H
H
H
H
H
H
NAHCTUNGTERNNUNG
[b]
5.0
55/16 h
–
80/20 71
75/25 70
71/29 68
75/25 66
70/30 67
75/25 63
75/25 62
81/15 73
10.0 sonication/5 h 2/1/-
NEt2
NEt2
NEt2
NEt2
NEt2
NEt2
[a]
[b]
[c]
Equivalents of reagents.
Reaction time.
Ratio of compounds obtained determined by 300 MHz
9
10
11
1H NMR.
Et NEt2
[a]
Yield of the corresponding isolated products 2 based on
timize the iodocyclopropanation reaction, the reac-
tions shown in Table 1 were performed. The best re-
sults were obtained (Table 1, entry 5) sonicating for
5 h a mixture composed of 1 equivalents of cinnama-
mide 1a, 1 equivalent of CHI3, 0.42 equivalent of
CrCl2 and 10 equivalents of Fe.
compounds 1.
From morpholine.
[b]
The structures and relative configurations of iodo-
cyclopropylamides (as depicted in Table 2 and
These reaction conditions were used to generalize Scheme 1) were established by analysis of the
the process. Thus, a solution of 1 equivalent of the un- 1H NMR coupling constants between the cyclopro-
saturated amides 1 and CHI3 (1.0 mmol, 1.0 equiv.) in pane protons of amides 2, by NOE experiments of
THF was added to a suspension of anhydrous CrCl2 compounds 2a, 2b, 2d, 2e, 2h, 2j, 2k and single-crystal
(0.42 mmol, 0.42 equiv.) and Fe powder (10 mmol, X-ray analysis of compounds 2b, and 2d.[7] The NOE
10 equiv.) in THF. After sonication for 5 h, the reac- experiments in compounds 2b and 2d were in agree-
tion mixture was quenched, producing the corre- ment with the X-ray structures. It is important to note
sponding iodocyclopropanamides 2 after purification that the relative configuration of the C=C double
(Table 2). When the reaction was carried out in the bond of the starting amides was conserved during the
absence of CrCl2, no iodocyclopropanation reaction cyclopropanation. The conservation of the C=C ge-
took place and compounds 1 were isolated unaltered. ometry was unambiguously established by performing
Analysis of the results compiled in Table 2 indicates the reaction from the diastereoisomers (E)- and (Z)-
that: a) all iodocyclopropanation reactions took place cinnamamide 1a and 1b (Table 2, entries 1 and 2). No
efficiently (62–73% yield) and with good to high ste-
reoselectivity (diastereoisomers ratio ranging from
70/30 to 90/10); b) the reaction was general from aro-
matic a,b-unsaturated amides, and no important dif-
ferences were observed when the aromatic ring was
substituted with electron-rich or electron-withdrawing
groups. When the iodocyclopropanation was per-
formed, under the same reaction conditions, with ali-
phatic a,b-unsaturated amides, cyclopropanecarboxa-
mides 3 were mainly obtained along with a small
amount of the desired compounds 2 (3/2 ratio 5/1 ap-
proximately).
The diastereoisomeric ratio (dr) of iodocyclo-
propylACHTUNGTRENNUNGamides 2 was determined by GC-MS and/or
300 MHz 1H NMR analysis of the crude reaction
products. These dr values should be analyzed taking
into account that there are three stereogenic centers
in iodocyclopropanamides 2, one of them being gener-
ated during the reaction.
Scheme 1. Mechanistic proposal.
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Adv. Synth. Catal. 2011, 353, 49 – 52

An Efficient Catalytic Chromium-Mediated Iodocyclopropanation Reaction
important differences were observed from these dia-
stereoisomers, and the relative positions of the R1 and
amide groups in 1a and 2a or in 1b and 2b were the
same. The stereogenic centers generated in the halo-
À
À
À
cyclopropanations (CH I, CH Br and CH Cl) were
obtained with the same relative configurations.[4] In
all cases, the iodine atom adopted a trans position
with respect to the carboxamide.
This iodocyclopropanation process could be ex-
plained assuming the initial formation of a chromium-
Scheme 3. Derivatization of 5a for X-ray determination.
ACHTUNGTRENNUNG(III) carbenoid intermediate 4, after the reaction of
2 equivalents of CrCl2 with 1 equivalent of CHI3. This compounds 5 has been possible, treatment of 5a with
anion could react with a,b-unsaturated amides 1 to p-bromobenzoyl chloride, was carried out (Scheme 3).
give the corresponding iodocyclopropane 2, through a Thus, 5a afforded the corresponding ester 7 in nearly
similar mechanism to that proposed by Houk for the quantitative yield, which was utilized to confirm the
addition of carbenoids to olefins.[9]
A coordination of the Cr(III) center with the
structure for 5.
G
These structures were compatible with a metalla-
À
oxygen atom of the amide group could explain the tion reaction of the C I bond performed by SmI2
observed conservation of the C=C geometry.[10] Tenta- with total retention of its configuration. Thus, the ad-
tively, we propose transition state model A depicted dition reaction of the generated anion 6 to the corre-
in Scheme 1, in which the formation of the new ste- sponding aldehyde also took place with total stereose-
reogenic center with total or high stereoselectivity lectivity, since only one diastereoisomer of com-
could be explained based on the steric hindrance be- pounds 5 was observed.[5]
tween the iodine atom and the amide group. To mini-
In conclusion, we have described a novel and effi-
mize the steric hindrances, the iodine atom could cient iodocyclopropanation reaction of a variety of
occupy a trans relative position with respect to the a,b-unsaturated amides 1 under very mild conditions,
amide function. This relative configuration was in promoted by catalytic amounts of CrCl2 to afford 1-
agreement to that observed in the previously reported (2-iodo-3-arylcyclopropyl)amides 2 from moderate to
chloro- or bromocyclopropanation of a,b-unsaturated good stereoselectivity and high yields. The synthetic
amides.[4] Once compound
chromium
to produce more chromium(II).
2
is generated, the applications of compounds 2 were tested by generat-
(III) species are then reduced with iron(0) ing the corresponding organosamarium compound via
treatment of iodocyclopropanecarboxamide 2a with
ACHTUNGTRENNUNG
The obtained iodocyclopropanamides 2 can be ver- SmI2/HMPA. The addition of this intermediate to al-
satile starting materials, due to their high functionali- dehydes afforded compounds 5 with total stereoselec-
ty. To illustrate this synthetic possibility, metallation tivity.
of compound 2a with SmI2 in the presence of HMPA
Studies directed toward fully delineating the factors
at À788C, was carried out.[11] The obtained organosa- involved in the CrCl2-mediated catalytic syntheses
marium 6 was allowed to react with propanal and oc- and the generality of the transformations of iodocy-
tanal and to afford compounds 5a and 5b with total clopropanamides in other valuable compounds are
stereoselectivity[12] (Scheme 2).
currently in progress in our laboratory.
The relative configuration of compounds 5 was un-
ambiguously assigned based on the studies of single-
crystal X-ray diffraction.[13] Since no crystallization of
Experimental Section
Synthesis of Products 2
To a suspension of anhydrous CrCl2 (0.42 mmol, 0.42 equiv.)
and Fe powder (10 mmol, 10 equiv.) in THF (6 mL) was
added the corresponding a,b-unsaturated amide
1
(1.0 mmol, 1.0 equiv.) in THF (3 mL) and CHI3 (1.0 mmol,
1.0 equiv.) in THF (3 mL) at room temperature and under
an inert atmosphere. After sonication for 5 h the reaction
mixture was quenched by the addition of 1.0M aqueous
HCl (5 mL) and extracted with diethyl ether (3ꢅ10 mL).
The combined extracts were washed with saturated NH4Cl
solution and an aqueous sodium thiosulfate solution, dried
over Na2SO4, and concentrated under vacuum. Purification
Scheme 2. Synthetic application of compound 2a.
Adv. Synth. Catal. 2011, 353, 49 – 52
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asc.wiley-vch.de
51

Josꢀ M. Concellꢁn et al.
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by column chromatography on silica gel (hexane/EtOAc
5:1) afforded pure compounds 2.
Solla, C. Mꢀjica, E. G. Blanco, S. Garcꢂa-Granda, M. R.
Dꢂaz, J. Org. Chem. 2008, 73, 3828–3836.
[4] J. M. Concellꢁn, H. Rodrꢂguez-Solla, E. G. Blanco,
M. A. Villa-Garcꢂa, N. Alvaredo, S. Garcꢂa-Granda,
M. R. Dꢂaz, Adv. Synth. Catal. 2009, 351, 2185–2198.
[5] a) K. Takai, S. Toshikawa, A. Inoue, R. Kokumai, M.
Hirano, J. Organomet. Chem. 2007, 692, 520–529; b) K.
Takai, S. Toshikawa, A. Inoue, R. Kokumai, J. Am.
Chem. Soc. 2003, 125, 12990–12991; c) K. Takai, M.
Hirano, S. Toshikawa, Synlett 2004, 1347–1350.
Synthesis of Compounds 5
The synthesis of compounds 5a, 5b was carried on according
the procedure described in ref.[10]
Synthesis of Products 7
To a suspension of 4-bromobenzoyl chloride (0.4 mmol,
1 equiv.) in CH2Cl2 (4 mL) was added theNEt3 (0.8 mmol,
2 equiv.) and a catalytic amount of DMAP (5 mg). The alco-
hol 5a (0.4 mmol, 1 equiv.) was added dropwise with cooling
in a bath of ice-water and under an inert atmosphere. After
stirring of the mixture for 16 h the reaction was quenched
by the addition of H2O and extracted with CH2Cl2 (3ꢅ
5 mL). The combined extracts were washed with HCl
(1.0M), dried over Na2SO4 and concentrated under vacuum.
Purification of the product was carried on by column chro-
matography on silica gel (hexane/EtOAc 5:1).
[6] Some co-reductants have been employed to perform
transformations in which catalytic amounts of CrCl2
were utilized.
[7] CCDC 780481 and CCDC 780482 contain the supple-
mentary crystallographic data for compounds 2b and
2d, respectively. These data can be obtained free of
charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif [or
from the Cambridge Data Center, 12 Union Road,
Cambridge CB2 1EZ, UK; fax (+44)-1223-336-033; or
deposit@ccdc.cam.ac.uk].
[8] a) M. N. Paddon-Row, N. G. Rondan, K. N. Houk, J.
Am. Chem. Soc. 1982, 104, 7162–7166; b) J. Mareda,
N. G. Rondan, K. N. Houk, J. Am. Chem. Soc. 1983,
105, 6997–6999.
Acknowledgements
[9] Other alternative mechanism involving a chromium
carbene complex cannot be discarded. So, synthesis of
2 can be explained assuming a [2+2]addition reaction
of the corresponding chromium alkylidene specie
IHC=Cr followed by a reductive elimination from the
generated chromacyclobutane, see refs.[3b,5b]
We thank the MICINN (CTQ2007-61132 and MAT2006-
01997) and Principado de Asturias (FICYT IB08-028) for fi-
nancial support. E.G.B. thanks the Principado de Asturias
for a predoctoral fellowship.
[10] A similar transition state A (based on steric interac-
tions) has been previously used to justify the synthesis
and stereochemistry of the alkyl-, silyl-, and halo-cyclo-
propanation of a,b-unsaturated amides (see refs.[3,4]).
[11] T. Nagano, J. Motoyoshiya, A. Kakehi, Y. Nishii, Org.
Lett. 2008, 10, 5453–5456.
References
[1] For reviews concerning the synthetic applications of
CrCl2, see: a) A. Fꢆrstner, Chem. Rev. 1999, 99, 991–
1045; b) L. A. Wessjohann, G. Scheid, Synthesis 1999,
1–36; c) P. Cintas, Synthesis 1992, 248–257.
[12] The presence of only one diastereoisomer was estab-
1
[2] J. M. Concellꢁn, H. Rodrꢂguez-Solla, C. Mꢀjica, E. G.
lished by GC-MS, and/or 300 MHz H NMR analysis of
Blanco, Org. Lett. 2007, 9, 2981–2984.
the crude reaction product.
[13] CCDC 780482 contains the supplementary crystallo-
[3] a) J. M. Concellꢁn, H. Rodrꢂguez-Solla, C. Mꢀjica,
E. G. Blanco, S. Garcꢂa-Granda, M. R. Dꢂaz, Org. Lett.
2008, 10, 349–352; b) J. M. Concellꢁn, H. Rodrꢂguez-
graphic data for compound 7. These data can be ob-
tained free of charge, see ref.[7]
.
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Adv. Synth. Catal. 2011, 353, 49 – 52