Chromium-catalyzed homoaldol equivalent reaction employing a nucleophilic propenyl acetate

Article abstract of DOI:10.1021/ja910057g

A scalable, highly regioselective chromium-catalyzed homoaldol equivalent reaction employing 3-bromopropenyl acetate as a masked homoenolate nucleophile in additions to aromatic, aliphatic, and α,β-unsaturated aldehydes under mild Cr/Mn redox conditions in good to excellent yields is reported. The resulting vinyl acetate-containing adducts are easily hydrolyzed with mild base to provide formal homoaldol adducts, or transformed to other more functionalized products by stereoselective transformations including epoxidation and cyclopropanation.

Full text of DOI:10.1021/ja910057g

Published on Web 05/19/2010
Chromium-Catalyzed Homoaldol Equivalent Reaction Employing a
Nucleophilic Propenyl Acetate
Jun Yong Kang and Brian T. Connell*
Texas A&M UniVersity, Department of Chemistry, P.O. Box 30012, College Station, Texas 77842-3012
Received November 27, 2009; E-mail: connell@chem.tamu.edu
Although the first observation of a presumed homoenolate anion
dates back to 1962,1 the homoenolate retains the status of a synthon,
as there are no known literal examples. Despite the utility that
homoenolate addition reactions hold for C-C bond construction,
as such reactions can be considered to be the polarity reversal of
the venerable conjugate addition reaction, direct homoenolate
formation is of little practical use due to the simultaneous presence
of both nucleophilic and electrophilic sites which undergo rapid
cyclization to the oxyanionic isomers.
presence of an amine base would increase the reactivity of this
system.12 Notably, we observed a significant increase in the yield of
the reaction in the presence of catalytic Et3N, leading to a 99% yield
of regiomerically pure 3a (Table 1, entry 8). Other bases, including
chelating diamines, were less effective.13
Table 2. Scope of Homoaldol Equivalent Reactiona
entry
SM
R
product
yield (%)b
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
99
90
91
82
78
85
75
80
96
70
71
75
99
96
p-MeOC6H4
p-CF3C6H4
o-MeC6H4
o-BrC6H4
PhCHCH
PhCH2
PhCH2CH2
C6H11
p-CH3COC6H4
p-CH3O2CC6H4
p-NCC6H4
p-TBSOC6H4
m, p-(OCH2O)C6H4
Several strategies have emerged to access homoenolate equiva-
lents, including the use of acetal-protected Grignard reagents,2
stoichiometric Li(I),3 Si(IV),4 Ti(IV),5 and Zn(II)6 reagents, as well
as more recent developments in the area of NHC-catalyzed
transformations.7 Separately, chromium-mediated additions of al-
lylic nucleophiles to aldehydes, specifically the Nozaki-Hiyama-
Kishi8 and Takai-Utimoto9 reactions, as well as the catalytic variant
developed by Fu¨rstner,10 are well-studied processes. Here, we report
efficient, catalytic generation of a chromium homoenolate equivalent
and application to highly regioselective intermolecular homoaldol
reactions which proceed under mild reaction conditions.
9
10
11
12
13c
14
a Reactions were performed using 2c (0.64 mmol), aldehydes 1 (0.32
mmol), CrCl3 (0.032 mmol), Mn0 (0.64 mmol), Et3N (0.048 mmol), and
TMSCl (0.64 mmol) in 2 mL of THF at rt for 20 h, quenched with sat.
NaHCO3 and deprotected with TBAF. b Isolated yield. c 24 h reaction.
Table 1. Initial Screening Resultsa
With these catalytic reaction conditions in hand, we explored
the scope of the reaction of various aldehydes with nucleophile
2c. The results are summarized in Table 2. Aromatic, aliphatic,
and R,ꢀ-unsaturated aldehydes undergo clean reaction to provide
the desired products in good to excellent yields after 20 h at room
temperature. It appears that steric effects are more important than
electronic effects in modulating aldehyde reactivity. For instance,
the bulkier o-substituted aldehydes 2-methylbenzaldehyde (1d)
(entry 4) and 2-bromobenzaldehyde (1e) (entry 5) provide somewhat
lower but still acceptable product yields (82% and 78% yields,
respectively) compared to the high yields (approximately 90%)
obtained from the electronically differentiated p-substituted alde-
hydes (p-OMe vs p-CF3) 1b/1c. Potentially reactive functionalities
including ketone (1j), ester (1k), nitrile (1l), and acetal (1n) are
compatible with the desired reaction.
entry reagent
base
yield (%)b entry reagent
base
yield (%)b
1
2
3
4
2a
2a
2b
2b
i-Pr2NEt
Et3N
none
0
0
0
0
5
6
7
8
2b
2c
2c
2c
i-Pr2NEt
none
i-Pr2NEt
Et3N
0
45
90
99
Et3N
a Reactions were performed using nucleophiles (2a, 2b, or 2c, 0.64
mmol), aldehyde 1a (0.32 mmol), CrCl3 (0.032 mmol), Mn0 (0.64
mmol), Et3N (0.048 mmol), and TMSCl (0.64 mmol) in 2 mL of THF at
rt for 20 h and then quenched with sat. NaHCO3 followed by 1 M
TBAF. b Isolated yield.
Previous studies by Lombardo had shown that acetoxyallyl chlorides
are poor nucleophiles in Cr-catalyzed additions to aldehydes,11 so we
chose to employ masked carbonyls 2a and 2b (acetals), and the
presumably more reactive allyl bromide 2c (3-bromopropenyl acetate)
as nucleophiles in additions to benzaldehyde (Table 1). Nucleophiles
2a and 2b were not competent in the reaction (0% yield), but bromide
2c provided the desired product in 45% yield. We surmised that the
In all cases, none of the potential 1,2-oxygenated regioisomeric
product is observed, and none of the trans-vinyl acetate product is
observed. We preliminarily attribute these observations to the
formation of a 5-membered ring chelate between a proximal acetate
and the chromium center as part of a well-established 6-membered
ring transition state arrangement for the C-C bond-forming
reaction. This arrangement correctly rationalizes the product’s cis-
9
7826 J. AM. CHEM. SOC. 2010, 132, 7826–7827
10.1021/ja910057g  2010 American Chemical Society

C O M M U N I C A T I O N S
alkene geometry as well as the observed regiochemistry of the
addition reaction.
with hydroxyl direction. Several other substrates underwent cyclo-
propanation with good yields and diastereoselectivities (Table 4),
again indicating that the proximal acetate does not interfere with
this directed reaction.
Table 4. Hydroxyl-Directed Cyclopropanation of Vinyl Acetatesa
Because of the potential utility of this process for creating chiral
building blocks applicable to total synthesis, we investigated larger-
scale reactions. Upon utilizing 2 mmol of benzaldehyde, we still
were able to isolate a 99% yield of product 3a. On even larger
scales, care must be taken to use Mn0 which has been freshly
washed with HCl to obtain high yields. On 5 or 20 mmol scale,
the isolated yield of product 3a is 90% or 85%, respectively.
entry
SM
R
product
yield (%)b
drc
1
2
3
4
3a
3d
3i
Ph
5a
5d
5i
95
84
88
80
6.6:1
5:1
6:1
o-MeC6H4
C6H11
o-BrC6H4
3e
5e
3.8:1
a All reactions were performed using Et2Zn (1 mmol), CH2I2 (2
mmol), TFA (1 mmol), olefin 3 (0.5 mmol) in CH2Cl2 at 0 °C for 4 h.
b Isolated yield. c dr (syn:anti) was determined by HPLC; see Supporting
Information.
Scheme 1. Hydrolysis and Reduction of Homoaldol Equivalent
Product
In summary, we have reported a scalable, highly regioselective,
catalytic homoaldol equivalent reaction employing 3-bromopropenyl
acetate as a masked homoenolate nucleophile under mild Cr/Mn
redox conditions. This reaction allows rapid access to stereo- and
regiochemically enriched 1,4-oxygenated compounds which can be
further manipulated to a variety of synthetically valuable compounds.
Acknowledgment. The Norman Hackerman Advanced Re-
search Program and the Robert A. Welch Foundation (A-1623) are
acknowledged for support of this research. The reviewers are
thanked for helpful commentary.
We next focused on the manipulation of the homoaldol equivalent
products to demonstrate the value of the proximal hydroxyl and
vinyl acetate groups. Hydrolysis of adduct 3a under mild conditions
(LiOH/MeOH/rt) provides the formal homoaldol product, which
is isolated after spontaneous cyclization to lactol 6 (Scheme 1) in
quantitative yield, as expected.11 Alternatively, reduction of 3a with
NaBH4 in NaOH/H2O provides 1,4-diol 7 in excellent yield (99%).
1
Supporting Information Available: Experimental procedures, H
and 13C NMR spectra of new compounds, and stereochemical proofs.
This material is available free of charge via the Internet at http://
pubs.acs.org.
References
Table 3. Hydroxyl-Directed Epoxidation of Vinyl Acetatesa
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product
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drc
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3e
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4a
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C6H11
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a Reagents: VO(acac)2 (2 mol %), adducts 3 (1 mmol), TBHP (5.5 M
solution) (2 mmol) in CH2Cl2 at rt for 15 h. b Isolated yield. c dr
(syn:anti) was determined by 1H NMR spectroscopy; see Supporting
Information.
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the epoxide/acetal, providing the 1,2,4-oxygenated R-acetoxy-δ-
hydroxy R,ꢀ-epoxide in 82% yield as primarily the syn diastereomer
(dr ) 13:1, entry 1, Table 3). Diastereoselectivity was slightly better
in the case of the bulkier o-substituted alcohol 3e but slightly lower
in the case of the aliphatic alcohol 3i.
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(13) See the Supporting Information for details.
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(CF3CO2ZnCH2I)15 afforded the desired cyclopropane (dr )
6.6:1) in excellent yield (95%) with diastereoselectivity consistent
(15) Lorenz, J. C.; Long, J.; Yang, Z.; Xue, S.; Xie, Y.; Shi, Y. J. Org. Chem.
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