First evidence for the formation of a geminal dizinc carbenoid: A highly stereoselective synthesis of 1,2,3-Substituted cyclopropanes

Article abstract of DOI:10.1021/ja017230d

Significant amounts of novel gem-dizinc carbenoids (RZnCHIZnR) are formed when diethylzinc is mixed with iodoform in CH₂Cl₂ at 0 °C. This reagent was shown to be effective in the cyclopropanation of butenediol derivatives to generate

Full text of DOI:10.1021/ja017230d

Published on Web 12/19/2001
First Evidence for the Formation of a Geminal Dizinc Carbenoid: A Highly
Stereoselective Synthesis of 1,2,3-Substituted Cyclopropanes
Andre´ B. Charette,* Alexandre Gagnon, and Jean-Franc¸ois Fournier
De´partement de Chimie, UniVersite´ de Montre´al, P.O. Box 6128, Station Downtown,
Montre´al, Que´bec, Canada H3C 3J7
Received October 4, 2001; Revised Manuscript Received November 14, 2001
Scheme 1
1,2,3-Substituted cyclopropanes are found widely in natural
products and biologically active molecules.1 Our interest in
developing enantioselective methods for their synthesis using zinc
carbenoids prompted us to look at novel organometallic species
for their formation. We recently reported one approach to 1,2,3-
substituted cyclopropanes which involved using substituted 1,1-
diiodoalkanes as precursors to substituted zinc carbenoids (eq 1).2
Scheme 2
High levels of diastereo- and enantiocontrol were achieved in these
olefination reaction7 but there is no precedence thus far of a dizinc
reactions and in all the cases, an anti relationship was obtained
analogue of this reagent. Theoretically, the dizinc reagent could
between the R2 group and the hydroxymethyl substituent. An
be prepared by the reaction between iodoform and diethylzinc and
intriguing complementary approach to the other diastereomeric
our initial efforts were focused toward obtaining evidence that this
cyclopropane 2 would involve generating a syn-cyclopropylzinc 3
species could be formed.8
(M ) ZnR), which could then directly be used as the nucleophilic
Our initial control experiments involving the mixing of iodoform
partner in subsequent reactions with electrophiles (Scheme 1).
and diethylzinc under various reaction conditions and stoichiom-
Cyclopropylzinc derivatives have been prepared by using various
etries are shown in Scheme 2. A first alkyl exchange process
procedures3 including the cyclopropanation of an alkenylzinc.4
between CHI3 and Et2Zn would lead to zinc carbenoid 5 (R ) Et).
However, this approach has not yet been extended to the synthesis
In principle, this reagent can either undergo a second alkyl group
of 1,2,3-substituted cyclopropane. The basic strategy reported in
exchange with Et2Zn to generate the gem-dizinc carbenoid 6 (R )
this communication involves the expedient synthesis of a cyclo-
Et) or it can decompose to generate zinc carbenoid 7 (R ) Et).9
propylzinc unit in a cyclopropanation reaction involving a novel
Alternatively, 7 can react further with CHI3 to generate the zinc
gem-dimetallic carbenoid reagent 4 (M ) ZnR). In principle, these
carbenoid 5 (R ) I). To obtain evidence for the formation of the
unprecedented reagents should be amenable to directed processes
gem-dizinc carbenoid 6, the reagents were mixed and aliquots were
since either Lewis acidic zinc atom of the gem-dizinc carbenoid
quenched with D2O. The presence of a gem-dizinc carbenoid 6
could interact with a proximal basic group. It is widely accepted
would lead to the formation of CD2HI whereas the presence of the
that directed electrophilic cyclopropanation reactions occur through
monozinc carbenoid 5 would produce CDHI2. GC/MS analysis
complexation of the metal carbenoid with a proximal basic group
revealed that upon mixing equimolar amounts of Et2Zn and CHI3
(A).5 However, it is anticipated that the stereochemical outcome
in (CH2Cl)2, at 0 °C and in the absence of a complexing ligand, a
of a directed reaction involving a gem-dizinc carbenoid should be
rapid consumption of iodoform was observed within 5 min. Its
governed by complexation of the zinc center that is not involved
subsequent quench with D2O indicated that the main species present
in the electrophilic carbenoid delivery (B). As a result, the reaction
was the zinc carbenoid 5 as evidenced by the amount of CDHI2
between these reagents and an allylic alcohol or ether would be
formed (Table 1, entry 1). More importantly, significant quantities
predicted to lead to the syn-diastereomer 3.
of CHD2I were also detected, thus confirming that the gem-dizinc
carbenoid 6 was also present. The same experiment carried out this
time with 1 equiv of a complexing ligand produced similar results
but with a slightly higher yield (entry 2). When the stoichiometry
between the reactants was increased to 2:1 (Et2Zn:CHI3), the amount
of the gem-dizinc reagent 6 surpassed that of 5 as evidenced by
Our initial efforts were directed toward the demonstration that
the formation of these novel gem-dizinc reagents was possible.
Although gem-dimetallic compounds have become quite common
reagents in the synthetic organic chemist’s arsenal,6 the related gem-
dimetallic carbenoids are still elusive species. Such a reagent (when
M ) Cr) has been postulated to be the reactive species in the Takai
the amount of deuterated material obtained (entry 3). However, the
low yield indicated that the carbenoids rapidly decomposed under
these conditions and its confirmation was obtained by the detection
of 1-iodopropane by GC/MS (via 7 in Scheme 2). Finally, 6 was
also formed in substantial quantities when EtZnI was used instead
of Et2Zn (entry 4). Consequently, the data in Table 1 indicate that
9
386 VOL. 124, NO. 3, 2002 J. AM. CHEM. SOC.
10.1021/ja017230d CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Trapping Experiments of Zinc Carbenoid Reagents 5
and 6
Scheme 3
a The diether was used as a stabilizing ligand. b Percent determined by
the following: [[CHI3] + [CHDI2] + [CHD2]]/[CHI3] × 100. Heptane was
used as the internal standard. A small percentage means that 5 and 6 have
decomposed before the quench. c The reagents were mixed without any
complexing agent. d EtZnI was used in place of Et2Zn.
substituted cyclopropanes. The study of the scope of this new
reagent is underway and will be reported in due course.
gem-dizinc reagent 6 can be formed under a variety of conditions
but the zinc carbenoid 5 is also present. The next issues were to
determine whether reagent 6 could react preferentially over 5 in a
cyclopropanation process and whether it was possible to trap the
resulting cyclopropylzinc with electrophiles. After surveying a
number of allylic alcohols and their protected derivatives, we found
that protected 2-butene-1,4-diols were ideal candidates to test the
synthetic potential of the gem-dizinc carbenoid reagents and to
evaluate the stereochemical outcome of the reactions. After
extensive experimentation, we found that the optimal reaction
conditions consisted of mixing 2 equiv of Et2Zn and CHI3 with
the allylic ether at 0 °C.10 The cyclopropanation was rapid (<15
min) and a subsequent addition of the electrophile (5 equiv)
produced the corresponding cyclopropane in excellent yields.11,12
Iodo- (11), bromo- (12), and phenylseleno-substituted (13) cyclo-
propanes can be prepared very efficiently by using this very simple
procedure. The NMR analysis of the crude reaction also revealed
that in all the cases, the syn diastereomer was formed exclusively
(>99:1).13 As expected, based on literature background, the resulting
cyclopropylzinc 9 was not sufficiently reactive to give the addition
product with allyl or acyl halides. In those cases, transmetalation
with CuCN‚2LiCl followed by the addition of the electrophile
proved to be effective.14,15 We have also shown that this reagent
reacts with other allylic ethers or alcohols and that the stereochem-
ical outcome is highly dependent upon the nature of the proximal
directing group (eqs 2-4). For example, benzyl ethers 16 and 22
Acknowledgment. This work was supported by the E. W. R.
Steacie Fund, NSERC, Merck Frosst Canada, Boehringer Ingelheim,
FCAR (Que´bec), and the Universite´ de Montre´al. A.G. and J.-F.F.
are grateful to NSERC (PGF A and B) and FCAR for postgraduate
scholarship.
Supporting Information Available: Experimental procedures and
spectral data of selected compounds (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
References
(1) (a) Small Ring Compounds in Organic Synthesis VI; de Meijere, A., Ed.;
Springer: Berlin, 2000; Vol. 207. (b) Houblen-Weyl, Methods of Organic
Chemistry; Thieme: Stuttgart, 1997; Vol. E 17c.
(2) Charette, A. B.; Lemay, J. Angew. Chem., Int. Ed. Engl. 1997, 36, 1090-
1092.
(3) (a) Piers, E.; Jean, M.; Marrs, P. S. Tetrahedron Lett. 1987, 28, 5075-
5078. (b) Be´ruben, D.; Marek, I.; Labaudinie`re, L.; Normant, J. F.
Tetrahedron Lett. 1993, 34, 2303-2306. (c) Be´ruben, D.; Marek, I.;
Normant, J. F.; Platzer, N. Tetrahedron Lett. 1993, 34, 7575-7578. (d)
Nakamura, M.; Arai, M.; Nakamura, E. J. Am. Chem. Soc. 1995, 117,
1179-1180. (e) Be´ruben, D.; Marek, I.; Normant, J. F.; Platzer, N. J.
Org. Chem. 1995, 60, 2488-2501. (f) Martin, S. F.; Dwyer, M. P.
Tetrahedron Lett. 1998, 39, 1521-1524.
(4) Yachi, K.; Shinokubo, H.; Oshima, K. Angew. Chem., Int. Ed. Engl. 1998,
37, 2515-2517.
(5) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93, 1307-
1370 and references therein.
(6) (a) Marek, I.; Normant, J. F. Chem. ReV. 1996, 96, 3241-3267. (b)
Normant, J. F. Acc. Chem. Res. 2001, 34, 640-644. (c) Matsubara, S.;
Oshima, K.; Utimoto, K. J. Organomet. Chem. 2001, 617, 39-46 and
references therein.
(7) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108, 7408-
7410.
(8) Literature reports of low yields (<60%) of iodocyclopropanes are possible
when an alkene is treated with diethylzinc and iodoform: (a) Nishimura,
J.; Furukawa, J. Chem. Commun. 1971, 1375-1376. (b) Miyano, S.;
Hashimoto, H. Bull. Chem. Soc. Jpn. 1974, 47, 1500-1503.
(9) This is the main pathway of decomposition of zinc carbenoids, see:
Charette, A. B.; Marcoux, J. F. J. Am. Chem. Soc. 1996, 118, 4539-
4549.
(10) No additive was used in this case since the substrate can stabilize the
carbenoids.
(11) The formation of cyclopropylzinc 9 from iodide 11 under the reaction
conditions was ruled out by showing that 11 was stable when treated with
Et2Zn and CHI3.
(12) When D2O was used as electrophile, <5% of the iodo-substituted
cyclopropane was observed, which indicates that gem-dizinc carbenoid 6
is substantially more reactive than carbenoid 5.
were converted to the deuteriocyclopropanes 18 and 23 in 71%
and 49% yield, respectively. Interestingly, when one of the benzyl
ether groups was replaced by a triisopropylsilyl group, deuterium
incorporation occurred exclusively syn to the best directing group
(eq 2). Conversely, the monoprotected butenediol 20 afforded the
cyclopropylzinc syn to the alkoxide, showing the versatility and
the flexibility of this approach (eq 3).
(13) The relative configurations of all the compounds were determined by nOe
experiments.
(14) (a) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem.
1988, 53, 2390-2392. (b) Knochel, P.; Singer, R. D. Chem. ReV. 1993,
93, 2117-2188. (c) Nakamura, E.; Aoki, S.; Sekiya, K.; Oshino, H.;
Kuwajima, I. J. Am. Chem. Soc. 1987, 109, 8056-8066.
(15) Pd- or Ni-catalyzed cross coupling reactions are also possible: (a) Piers,
E.; Coish, P. D. G. Synthesis 2001, 251-261. (b) de Lang, R.-J.;
Brandsma, L. Synth. Commun. 1998, 28, 225-232.
In summary, we have reported the synthesis and reactivity of a
novel gem-dizinc carbenoid which provides an expedient access to
JA017230D
9
J. AM. CHEM. SOC. VOL. 124, NO. 3, 2002 387