β-Chloroaldehydes from Trapping Zirconium Enolates Produced in Asymmetric 1,4-Additions

Article abstract of DOI:10.1021/acs.orglett.8b03520

Zirconium enolates, derived from copper-catalyzed asymmetric conjugate additions, are trapped with the Vilsmeier-Haack reagent. Asymmetric additions generate quaternary carbon centers with high enantioselectivity (generally ?90% ee), and the enolates are converted to unsaturated β-chloroaldehydes (41-57% yields). The reaction tolerates changes to the nucleophile, can be used to form five-, six-, or seven-membered ring products, and is scalable to 5 mmol, and the products are readily elaborated by condensation, cross coupling, and addition reactions.

Full text of DOI:10.1021/acs.orglett.8b03520

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
β‑Chloroaldehydes from Trapping Zirconium Enolates Produced in
Asymmetric 1,4-Additions
Jiao Yu Joseph Wang, Thomas Palacin, and Stephen P. Fletcher*
Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, U.K.
S
* Supporting Information
ABSTRACT: Zirconium enolates, derived from copper-
catalyzed asymmetric conjugate additions, are trapped with
the Vilsmeier−Haack reagent. Asymmetric additions generate
quaternary carbon centers with high enantioselectivity
(generally ∼90% ee), and the enolates are converted to
unsaturated β-chloroaldehydes (41−57% yields). The reaction
tolerates changes to the nucleophile, can be used to form five-, six-, or seven-membered ring products, and is scalable to 5 mmol,
and the products are readily elaborated by condensation, cross coupling, and addition reactions.
substrate dependent,3,8,10−12 and developing new trapping
symmetric conjugate addition (ACA) is a staple of the
Aorganic chemist’s toolkit for C−C bond formation. When methods would facilitate chemists’ ability to rapidly access
complex molecules.
performed in sequence with an electrophilic trapping reaction,
the resulting tandem sequences are particularly powerful1a−d
(Scheme 1, A). As multiple bonds and stereocenters may be
formed in one step, this strategy is frequently used in natural
Our group has developed ACAs that use alkylzirconium
species as nucleophiles. These organometallics are made in situ
from hydrozirconation of alkenes with Cp2ZrHCl, tolerate a
variety of functional groups, and can be generated and used at
convenient temperatures. We have shown that these
alkylzirconium reagents add to a variety of cyclic and acyclic
enones to furnish ACA products bearing tertiary or quaternary
stereocenters in high yield and enantioselectivity.13
product synthesis.2a−f
.
Scheme 1. (A) General Scheme of the Tandem ACA/
Trapping Reaction. (B) Previous Work15 and This Work
The development of tandem ACA/trapping reactions
initiated by organozirconium reagents has been difficult to
realize, and a variety of approaches examined in our laboratory
did not lead to useful results, possibly because of the strength
of the Zr−O bond in the intermediate enolate.14 However,
Nemethova et al. recently demonstrated that a few specialized
electrophiles can be used to trap zirconium enolates (Scheme
1, B).15 In that work, highly electrophilic carbenium ions gave
trapped products in <20% yield.
Here, we report a synthetically useful tandem ACA/trapping
procedure initiated by copper-catalyzed ACA of alkylzirconium
species to form quaternary centers13 followed by trapping of
the intermediate enolate with the Vilsmeier−Haack reagent
(VH) (Table 1, 2).16 Unsaturated β-chloroaldehydes are the
products of this sequence (Scheme 1, B) which (vida infra)
can readily be elaborated in a number of ways. VH is well
known as a strong formylating agent and under certain
conditions behaves as both a formylating and chlorinating
agent.17
Many ACA/trapping reactions are initiated by organo-
metallic nucleophiles such as Grignard, organoaluminum, and
organozinc reagents. The intermediate enolates generated from
these ACAs have been trapped in a variety of ways,1 including
with Mander’s reagent,3 the Heller−Sarpong reagent,4
carbenium ions,5 nitro-olefins,6 and Stork−Jung electrophiles.7
Trapping of intermediate aluminum enolates has been
extensively investigated by Alexakis and co-workers.8,9
Generally, tandem ACA/trapping reactions remain strongly
The use of highly reactive electrophiles was initially
investigated to trap enolates generated in ACAs as shown in
Table 1.13d,e Although α-hydroxy ketone product 8 (R =
CH2OH) could be obtained using formaldehyde 1, and 8 was
Received: November 3, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03520
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Investigation of Electrophiles Used in Zirconium
Enolate Trapping
Scheme 2. ACA Chloroformylation of 3-Substituted Cyclic
Enones*
a
entry
E
product
yield (%)
conditions
1
2
1
1
8, R = CH2OH up to 50 freshly cracked, anhydrous CH2O
8, R = CH2OH
0
35% wt aqueous solution of
CH2O
3
2
9
41
“2” (POCl3, DMF)
a
Isolated yields.
potentially amenable to further functionalization, the yields
were difficult to reliably reproduce, and there is procedural
complexity in generating gaseous anhydrous formaldehyde
(Table 1, entry 1).
We found that the use of VH 2 resulted in the formation of
unsaturated β-chloroaldehyde 9 as opposed to α-functionalized
ketones (Table 1, entry 3). Compound 2 is prepared by simply
mixing phosphorus(V) oxychloride (POCl3) and DMF in a
solvent. The products present multiple functional groups for
further elaboration and are complementary to the α-function-
alized ketones normally obtained in ACA/trapping protocols.
We were unable to successfully trap this enolate with 3−9.
The conditions found to provide the best yield use 20 equiv
of 2 at 60 °C. These conditions furnished the desired
unsaturated β-chloroaldehydes in fair yields and require ∼20
min for complete consumption of the ACA enolate, after which
the reaction should be carefully quenched at 0 °C.
The trapping procedure shows tolerance (Scheme 2) to
aromatic rings (examples 9, 10, 14, and 16), an alkyl silane
(example 11), an alkyl bromide (15), and a benzyl-protected
alcohol (example 16). When tert-butyldimethylsilyl-protected
alcohols were used (examples 13 and 14), free alcohols were
obtained as the major product. For product 13a, formate ester
13b was also obtained.
We performed the reactions on a 5 mmol scale to give 0.79 g
of 9 in 51% yield with 94% ee. In this reaction, less 2 (10
rather than 20 equiv) can be used without adversely affecting
the yield; however, 2 h was required for complete consumption
of the enolate.
The trapping procedure is suitable for the quaternary center
containing enolates to form six-, seven-,13d and five-member-
ed13g ring containing products. The five-membered-ring
example 17 is of particular interest because 1,2,3-trisubstituted
cyclopentanes bearing a quaternary methyl stereocenter are
common in natural products.2a,18
*
Isolated yields. Unless specified otherwise, ACA reactions were
conducted using L1 with MTBE as solvent. ee’s were determined by
HPLC or SFC. ACA reaction conducted using L2, Et2O as solvent,
and TMSCl (5.0 equiv). Asymmetric addition using TBDMS-
protected alcohols. 5 mmol scale to give 0.79 g of 9.
a
b
c
formation of compound 20. Milder conditions19 as reported
by a Genentech process group for the chlorination of
cyclohexanone led to a decreased yield of trapped product
(12%, Scheme 3, B) and mostly simple 1,4-addition product.
Next, different enolates were investigated. Remarkably, use
of the lithium enolate20 gave only 10% yield of dichloride 20
(mostly recovered SM) and no monochloride 21 (Scheme 3,
C, entry 1). Similarly, the zirconium enolate20 (formed via
transmetalation of the lithium enolate with Cp2ZrCl2) gave
48% yield, exclusively of dichloride 20. Treating cyclohexanone
(drawn as the enol) under optimized trapping conditions gave
dichloride 20 in 4% yield (Scheme 3, C, entry 3). Interestingly,
Sandoval’s conditions19 gave exclusively 21 in 71% yield
(Scheme 3, C, entry 4).
Plausible mechanisms for trapping are suggested in Scheme
4. The zirconium enolate 22 may react with 2 to form 23a.
Loss of hydrogen to 23b, followed by chloride addition/
elimination of an O−Zr species, would give iminium 24 and
furnish the β-chloroaldehyde upon hydrolysis. Alternatively, if
25a is formed from reaction with 2, another equivalent of VH
could activate the oxygen via formation of 25b. This species
Experiments to probe the trapping process were performed
(Scheme 3). Treatment of hydroxymethylene cyclohexanone21
19, a simple model for a 1,3-dicarbonyl which might be formed
through formylation, gave doubly chlorinated α,β,δ,γ-unsatu-
rated aldehyde 20 in 76% isolated yield. As no such dienes
were observed in our reactions, it suggests against dicarbonyl
(or tautomeric) intermediates (Scheme 3, A); however as
shown below, other simple model systems also led to
B
DOI: 10.1021/acs.orglett.8b03520
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Selected Experiments for Mechanistic Studies*
Scheme 5. Examples of Functionalized Products and Their
Starting Materials*
*
Unless specified otherwise, yields determined by 1H NMR
a
spectroscopy using Cl(CH2)2Cl as internal standard. Isolated yield.
b
c
Data consistent with literature.17a−c,19 Lithiation and trans-
metalation procedures carried out according to the procedure of
d
e
Evans and co-workers.20 Cyclohexanone was used. Yield based on
*
a
Isolated yields. 5.0 mol % Pd(OAc)2/XPhos, 3.0 eq. K3PO4,
average over two experiments.
b
MeCN/H2O 5 h. at 40 °C. 2-oxopiperazinone/NMM (N-
methylmorpholine) in DMF 5 h. at 115 °C.
Scheme 4. Possible Mechanisms for Chloroformylation
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03520.
All procedures, characterization data, NMR spectra, and
chromatography traces (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: stephen.fletcher@chem.ox.ac.uk.
ORCID
could then undergo substitution with Cl− as above to provide
24.
The products obtained are well-suited for further function-
alization (Scheme 5). The β-chloroaldehydes readily under-
went Suzuki−Miyaura coupling with boronic acids to give
products 26 and 27. Treatment of the products with Grignard
reagents gave 1,2-addition products 28 (71%) and 29 (67%) as
a 1:1 mixture of diastereomers. Unsaturated β-chloroaldehyde
9 was also subjected to condensation with 2-piperazinone in
the presence of N-methylmorpholine to give dihydropyrrolo-
pyrazinone 30.19
Stephen P. Fletcher: 0000-0001-7629-0997
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the EPSRC EP/H003711/1 and the People
Programme (Marie Curie Actions) of the European Union’s
Seventh Framework Programme (FP7/2007−2013) under
REA Grant Agreement 316955 for funding.
In summary, zirconium enolates from ACA reactions to form
quarternary stereocenters were trapped using the Vilsmeier−
Haack reagent in synthetically useful yields and high
enantioselectivity. The method was shown to be scalable and
is tolerant to functional groups. The products from the
reaction were subjected to further derivatization, and
investigations are currently underway to apply this trapping
procedure in complex molecule synthesis.
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