Catalytic addition methods for the synthesis of functionalized diazoacetoacetates and application to the construction of highly substituted cyclobutanones

Article abstract of DOI:10.1021/ol052003s

(Chemical Equation Presented) Methyl 3-(trialkylsilanyloxy)-2-diazo-3- butenoate undergoes Lewis acid-catalyzed Mukaiyama aldol addition with aromatic and aliphatic aldehydes in the presence of low catalytic amounts of Lewis acids in nearly quantitative y

Full text of DOI:10.1021/ol052003s

ORGANIC
LETTERS
2005
Vol. 7, No. 23
5171-5174
Catalytic Addition Methods for the
Synthesis of Functionalized
Diazoacetoacetates and Application to
the Construction of Highly Substituted
Cyclobutanones
Michael P. Doyle,* Kousik Kundu, and Albert E. Russell
Department of Chemistry and Biochemistry, UniVersity of Maryland, College Park,
Maryland 20742
mdoyle3@umd.edu
Received August 18, 2005
ABSTRACT
Methyl 3-(trialkylsilanyloxy)-2-diazo-3-butenoate undergoes Lewis acid-catalyzed Mukaiyama aldol addition with aromatic and aliphatic aldehydes
in the presence of low catalytic amounts of Lewis acids in nearly quantitative yields. Scandium(III) triflate is the preferred catalyst and,
notably, addition proceeds without decomposition of the diazo moiety. Diazoacetoacetate products from reactions with aromatic aldehydes
undergo rhodium(II)-catalyzed ring closure to cyclobutanones with high diastereocontrol. Examples of complimentary Mannich-type addition
reactions with imines are reported.
Diazoacetoacetates are widely used in catalytic metal carbene
reactions.1,2 Generally prepared by alcohol condensation with
diketene or its surrogate,3,4 followed by diazo transfer,5
diazoacetoacetates exhibit higher thermal and acid stability
than do their diazoacetate counterparts, and they often offer
greater reaction control in transformations following diazo
decomposition.1,6 Catalytic reactions of diazoacetoacetates
involving addition, insertion, and association (ylide-derived
processes) that produce cyclopropanes, cycloalkanone struc-
tures, and â-lactams are well documented.1,2,7 Chemical
modifications with diazocarbonyl compounds have been of
long-standing interest,1 and both acid and base promoted
aldol reactions have been developed for this purpose.
However, these reactions generally result in the loss of the
diazo functionality.8 Although earlier studies have shown that
(1) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds: From Cyclopropanes to
Ylides; John Wiley & Sons: New York, 1998.
(2) Reviews: (a) Merlic, C. A.; Zechman, A. L. Synthesis 2003, 1137-
1156. (b) Davies, H. M. L.; Antoulinakis, E. G. Org. React. 2001, 57,
1-326. (c) Hodgson, D. M.; Pierard, F. Y. T. M.; Stupple, P. A. Chem.
Soc. ReV. 2001, 30, 50-61. (d) Doyle, M. P. In Catalytic Asymmetric
Synthesis, 2nd ed.; Ojima, I., Ed.; John Wiley & Sons: New York, 2000.
(e) Doyle, M. P.; Forbes, D. C. Chem. ReV. 1998, 98, 911-935. (f)
Khlebnikov, A. F.; Novikov, M. S.; Kostikov, R. R. AdV. Heterocycl. Chem.
1996, 65, 93-233. (g) Padwa, A.; Austin, D. J. Angew. Chem., Int. Ed.
Engl. 1994, 33, 1797-1815.
(3) (a) Padwa, A.; Austin, D. J.; Price, A. T.; Semones, M. A.; Doyle,
M. P.; Protopopova, M. N.; Winchester, W. R.; Tran. A. J. Am. Chem.
Soc. 1993, 115, 8669-8680. (b) Doyle, M. P.; Westrum, L. J.; Wolthuis,
W. N. E.; See, M. M.; Boone, W. P.; Bagheri, V.; Pearson M. M. J. Am.
Chem. Soc. 1993, 115, 958-964.
(4) Clemens, R. J.; Hyatt, J. A. J. Org. Chem. 1985, 50, 2431-2435.
(5) Regitz, M.; Maas, G. Diazo Compounds; Properties and Synthesis;
Academic Press: Orlando, FL, 1986.
(6) Doyle, M. P. In ComprehensiVe Organometallic Chemistry II;
Hegedus, L. S., Ed.; Pergammon Press: New York, 1995; Vol. 12, Chapter
5.2.
(7) (a) Davis, F. A.; Wu, Y.; Xu, H.; Zhang, J. Org. Lett. 2004, 6, 4523-
4525. (b) Davis, F. A.; Fang, T.; Goswami, R. Org. Lett. 2002, 4, 1599-
1602. (c) Taber, D. F.; Malcolm, S. C. J. Org. Chem. 2001, 66, 944-953.
(d) Hughes, C. C.; Kennedy-Smith, J. J.; Trauner, D. Org. Lett. 2003, 5,
4113-4115.
(8) Holmquist, C. R.; Roskamp, E. J. J. Org. Chem. 1989, 54, 3258-
3260.
10.1021/ol052003s CCC: $30.25
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Published on Web 10/12/2005

condensation of ethyl diazoacetate with aldehydes and
ketones can occur with retention of the diazo group,9-11 only
recently have methods involving Lewis acids been used to
couple diazoacetates with aldehydes. Boron12 and titanium-
(IV)13 enolates of diazoacetoacetates have been reported to
undergo condensation with aldehydes, but stoichiometric
amounts of the Lewis acids were required to achieve full
conversion, and these reactions occurred at -78 °C. We now
report that the use of lanthanide triflates, especially scandium-
(III) triflate, in low catalytic amounts is highly effective for
Mukaiyama aldol addition reactions of methyl 3-(tert-
butyldimethylsilanoxy)-2-diazobut-3-enoate (2)14 with both
aliphatic and aromatic aldehydes at room temperature (eq
1, Scheme 1), and that the same catalysts promote Mannich
we evaluated the potential of this methodology with a
selection of Lewis acids. In addition to achieving high
product yields, our criteria included the use of catalyst
loadings below 5 mol % and to have reactions occur at or
near room temperature. Our survey using the TBDMS
derivative 2 and benzaldehyde identified the lanthanide(III)
triflates as the most promising, and efforts were undertaken
to determine the breadth of application. As indicated in Table
1, nearly quantitative yields of aldol addition reaction
Table 1. Lewis Acid-Catalyzed Mukaiyama Aldol Addition
Reactions of 2 with Representative Aldehydesa
Scheme 1
yield (%) of 3b
aldehyde
R
Sc(OTf)3
La(OTf)3
Cu(OTf)2
1a
1b
1c
1d
1e
1f
1g
1h
1i
4-MeOC6H4
4-MeC6H4
Phc
98
97
93
98
94
0
89
93
91
94
92
90
89
90
91
82
77
76
76
4-ClC6H4
4-CF3 C6H4
d
4-NO2C6H4
trans-â-styryl
BnOCH2
0
88
93
0
72
COOEt
n-heptyl
n-propyle
1j
1k
93
a Aldehyde (1.5 mmol) was added to a solution of vinyldiazoacetate 2
(2.2 mmol) and metal triflate (2.0 mol %) in CH2Cl2 (3 mL) and stirred at
room temperature for 10 h. b Yield of isolated 3 following column
chromatography. c Use of 1.0 mol % catalyst gave 90% yield of 3c and
use of 0.1 mol % catalyst gave 3c in only 5% yield after 10 h. d Unreacted
aldehyde and 2 were the only materials recovered after 10 h. e Isolated yield
for the deprotected Mukaiyama aldol adduct (see the Suppoting Information).
addition of 2 with imines (eq 2, Scheme 1). In both sets of
transformations the diazo functionality is retained, and
product yields are nearly quantitative.
Catalytic Mukaiyama aldol addition reactions of aldehydes
with silyl enol ethers have been achieved by using a broad
selection of catalysts.15 Using the same methodology as with
TMS-vinyl ethers,15,16 but with the acid-sensitive diazo
functionality of silyl enol ethers of methyl diazoacetoacetate,
products (eq 3) were obtained with both aliphatic and
aromatic aldehydes, and scandium(III) triflate was the
catalyst of choice. In all cases the diazo functionality was
found to remain intact throughout the reaction and during
workup.
Scandium(III), lanthanum(III), ytterbium(III), and copper-
(II) triflates were all effective under conditions of low catalyst
loading (1-2 mol %) for addition reactions performed
between 2 and representative aldehydes (Table 1).17 Reac-
tions were generally complete within 10 h at room temper-
(9) (a) Wenkert, E.; McPherson, C. A. J. Am. Chem. Soc. 1972, 94,
8084-8090. (b) Sa, M. M.; Silveira, G. P.; Bortoluzzi, A. J.; Padwa, A.
Tetrahedron 2003, 59, 5441-5447. (c) Jiang, N.; Wang, J. Tetrahedron
Lett. 2002, 43, 1285-1287.
(10) Kanemasa, S.; Araki, T.; Kanai, T.; Wada, E. Tetrahedron Lett.
1999, 40, 5059-5062.
(11) Moody, C. J.; Morfitt, C. N. Synthesis 1998, 1039-1042.
(12) (a) Calter, M. A.; Sugathapala, P. M.; Zhu, C. Tetrahedron Lett.
1997, 38, 3837-3840. (b) Calter, M. A.; Zhu, C. J. Org. Chem. 1999, 64,
1415-1419.
(13) Deng, G.; Tian, X.; Qu, Z.; Wang, J. Angew. Chem., Int. Ed. 2002,
41, 2773-2776.
(14) Davies, H. M. L.; Ahmed, G.; Churchill, M. R. J. Am. Chem. Soc.
1996, 118, 10774-10780.
(15) (a) Mukaiyama, T. Angew. Chem. 1977, 89, 858-866. (b) Mu-
kaiyama, T. Aldrichim. Acta 1996, 29, 59-76. (c) Mahrwald, R. Chem.
ReV. 1999, 99, 1095-1120. (d) Carreira, E. M. In ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer-Verlag: Berlin, Germany, 1999; Chapter 29. (e) Mukaiyama, T.
Angew. Chem., Int. Ed. 2004, 43, 5590-5614. (f) Gro¨ger, H.; Vogl, E. M.;
Shibasaki, M. Chem. Eur. J. 1998, 4, 1137-1141.
(16) Lanthanide complexes: (a) Kobayashi, S.; Manabe, K. Acc. Chem.
Res. 2002, 35, 209-211. (b) Ishikawa, S.; Hamada, T.; Manabe, K.;
Kobayashi, S. J. Am. Chem. Soc. 2004, 126, 12236-12237.
(17) Typical Mukaiyama aldol addition procedure: To a dry 5-mL round-
bottomed flask fitted with a septum was added anhydrous scandium(III)
triflate (14 mg, 0.030 mmol) and 3.0 mL of anhydrous dichloromethane.
Vinyldiazoacetate 2 (564 mg, 2.20 mmol) was then added dropwise over 5
min, using a 1 mL syringe, followed by aldehyde (1.50 mmol). The reaction
mixture was stirred at room temperature for 10 h, during which time the
color of the solution changed from orrange to pale yellow. (The reactions
with 1a and 1c were found to be incomplete after 6 h.) The product was
isolated by flash column chromatography on silica gel, eluting with 9:1
hexane/ethyl acetate.
5172
Org. Lett., Vol. 7, No. 23, 2005

ature, but those catalyzed by Yb(OTf)3 were sluggish under
these same conditions.18 The only exception to the generality
of this process among the aldehydes that were employed is
p-nitrobenzaldehyde, which did not participate in reactions
with 2 and any member of this catalyst selection. That this
is exceptional is indicated by results with 4-R,R,R-trifluo-
rotolualdehyde, which produced the addition product 3e with
very high conversions despite the presence of the strongly
electron-withdrawing trifluoromethyl group. With copper-
(II) triflate, the yields of condensation products 3 were
comparably low due to, we believe, slow decomposition of
the diazo moiety of 2 and/or 3. Reactions performed with
the TMS analogue of 2 underwent condensation at a faster
rate than 2 to give comparable yields of TMS-3. However,
the TBDMS protective group provided greater stability in 2
and to the condensation products, and they were easier to
handle than those with TMS protection.
The potential of this addition process for synthetic
transformations achieved through diazo decomposition was
explored by reactions performed with rhodium acetate. Diazo
decomposition of the Mukaiyama aldol adducts 3b-d in the
presence of 1.0 mol % rhodium(II) acetate led to the
formation of highly substituted cyclobutanones (eq 4) in high
yields and with high diastereoselectivity (Table 2).
Scheme 2
groups on the same face of the cyclobutanone ring of the
major isomer 4.
These surprisingly clean reactions did not form products
from either formal aromatic substitution or aromatic cy-
cloaddition,1 nor was carbon-hydrogen insertion into the
benzylic position observed. Instead, this method provides a
straightforward synthesis of highly substituted cyclobu-
tanones via the oxonium ylide pathway described in Scheme
3. The synthesis of highly substituted cyclobutanes with
Scheme 3
Table 2. Cyclobutanone Formation by Rhodium
Acetate-Catalyzed Diazo Decomposition of 3a
multiple stereogenic centers is considered to be a challenging
task,20 and to our knowledge there has only been one prior
report of cyclobutanone formation through oxonium ylides.21
Extension of the aldol addition reaction methodology to
reactions of 2 with benzylideneanilines (eq 5) produced the
results that are reported in Table 3.
Reactions were performed at room temperature with an
equivalent amount of imine and 2. Results with scandium-
(III) triflate at 2.0 mol % were optimum and are reported.
As expected with the results from Mukaiyama aldol addition
reactions with 2 (Table 1), the diazo functionality was
retained in these Mannich reactions. The TBDMS protective
group comes off nitrogen upon passing the reaction mixture
through a short plug of silica gel to remove catalyst.
Curiously, the basic nature of reactant and product in this
transformation does not change the catalytic loading relative
to that used for reactions with aldehydes. This previously
yield, %b
4 + 5
adduct
Ar
4:5c
3b
3c
3d
4-Me-C6H4
Ph
4-Cl-C6H4
84
80
84
12:1
10:1
10:1
a The Mukaiyama aldol adduct (1.0 mmol) in CH2Cl2 (2 mL) was added
via a syringe pump over 5 h to a refluxing solution of Rh2(OAc)4 (1.0 mol
%) in 2 mL of CH2Cl2. b Isolated yield of 4 + 5. c Determined by integration
of the characteristic 1H NMR signals of 4 (δ 3.37 ppm) and 5 (δ 3.39 ppm).
Experiments to determine the relative stereochemistry of
substituents in 4b directly were inconclussive. However,
reduction of 4b by lithium aluminum hydride19 produced a
diol (6b) from which nOe experiments provided evidence
for the relative stereochemistry reported in Table 2 (Scheme
2). These experiments place the carbomethoxy and the aryl
(18) Under similar conditions, use of 2 mol % of Yb(OTf)3 produced
77% 3a, 77% 3b, 75% 3c, and 72% 3d.
(19) Ramnauth, J.; Lee-Ruff, E. Can. J. Chem. 2001, 79, 114-120.
(20) Lee-Ruff, E.; Mladenova, G. Chem. ReV. 2003, 103, 1449-1483.
(21) Roskamp, E. J.; Johnson, C. J. Am. Chem. Soc. 1986, 108, 6062-
6063.
Org. Lett., Vol. 7, No. 23, 2005
5173

analogues of 8 undergo highly selective intramolecular Ns
H insertion catalyzed by Rh2(OAc)4.7a
Table 3. Lewis Acid-Catalyzed Mannich Addition of
Benzylideneanilines to 2a
In summary, we have developed efficient Mukaiyama aldol
and Mannich addition reactions of readily accessible diazo-
containing silyl enol ether with aldehydes and imines using
low catalytic amounts of commercially available Lewis acids.
The synthetic utility of the Mukaiyama aldol adduct has
been demonstrated with the highly diastereoselective, facile
rhodium(II) acetate-catalyzed syntheses of highly substituted
cyclobutanones. Work is continuing to develop the full
synthetic potential of this methodology.
imine
Ar
Ar′
yield (%) of 8b
7a
7b
7c
7d
4-MeOC6H4
4-ClC6H4
Ph
4-NO2C6H4
Ph
4-NO2C6H4
Ph
95
90
93
88
Acknowledgment. We gratefully acknowledge the fi-
nancial support provided by the National Institutes of Health
(GM46503) and the National Science Foundation. We are
grateful to Julia C. Allbutt and Claire L. Oswald for preparing
vinyldiazoacetate 2.
Ph
a
Imine (1.5 mmol) in CH2Cl2 (1 mL) was added to a solution of
vinyldiazoacetate 2 (2.2 mmol) and scandium(III) triflate (2.0 mol %) in
CH2Cl2 (2 mL) then stirred at room temperature for 10 h. b Yield of isolated
8 following column chromatography.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
unreported Mannich-type addition methodology to form
substituted diazoacetoacetates directly may be a viable
alternative to the approach of effecting diazo transfer to the
amine-substituted acetoacetate.7a,b Davis has reported that
OL052003S
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Org. Lett., Vol. 7, No. 23, 2005