The rhodium catalyzed three-component reaction of diazoacetates, titanium(IV) alkoxides and aldehydes

Article abstract of DOI:10.1039/b502093j

The rhodium(n)-catalyzed three-component reaction of diazoacetates, titanium alkoxides and aldehydes is shown to give α-alkoxyl-β- hydroxyl acid derivatives; the novel C-C bond formation reaction is proposed to occur through oxonium ylides derived from diazo compounds and titanium alkoxides, and followed by intermolecular trapping by aldehydes. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b502093j

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The rhodium catalyzed three-component reaction of diazoacetates,
titanium(IV) alkoxides and aldehydes{
Chong-Dao Lu,ab Hui Liu,a Zhi-Yong Chen,a Wen-Hao Hu*a and Ai-Qiao Mia
Received (in Cambridge, UK) 10th February 2005, Accepted 22nd March 2005
First published as an Advance Article on the web 6th April 2005
DOI: 10.1039/b502093j
The rhodium(II)-catalyzed three-component reaction of dia-
zoacetates, titanium alkoxides and aldehydes is shown to give
a-alkoxyl-b-hydroxyl acid derivatives; the novel C–C bond
formation reaction is proposed to occur through oxonium
ylides derived from diazo compounds and titanium alkoxides,
and followed by intermolecular trapping by aldehydes.
The transition metal-catalyzed decomposition of diazocarbonyl
compounds is an attractive transformation in organic synthesis.1
Scheme 2 The rhodium-catalyzed three-component reaction of diazoa-
The rhodium-catalyzed reaction in the presence of aldehydes
cetates, titanium(IV) alkoxides and aldehydes.
normally leads to 1,3-dioxolanes2 or epoxides3 from carbonyl ylide
intermediates.4 On the other hand, Lewis acids such as TiCl4,
of titanium(IV) isopropoxide (2a) and p-anisaldehyde (3a).
SnCl4, etc. have been reported to catalyze reactions of diazo
compounds with aldehydes; however, the process afforded
nitrogen-free 3-hydroxyacrylates and b-dicarbonyl products
instead of 1,3-dioxolanes.1,5
Products 4a and 5a were obtained in 69% isolated yield with
68 : 32 diastereomeric ratio (dr) favoring the erythro-stereoisomer
(Table 1, entry 1, R1 5 Ph, R2 5 iPr, R3 5 p-methoxyphenyl).
Epoxide 6a was the main by-product (6a : (4a + 5a) 5 13 : 87)
1
Doyle et al.3a and Davies et al.3b individually reported
stereospecific epoxidation from the dirhodium(II)-catalyzed reac-
tion of aryl- and styryldiazoacetates with aryl/styryl aldehydes. The
reaction occurred through the intramolecular ring closure of a
carbonyl ylide derived from the diazoacetates and the aldehydes
(Scheme 1). It is worth mentioning that the reaction was limited to
aromatic/styryl aldehydes; the use of aliphatic aldehydes gave a
complex mixture. To our surprise, when the reaction was
performed in the presence of both a dirhodium(II) catalyst and a
titanium(IV) alkoxide, three-component coupling occurred to
produce a-alkoxyl-b-hydroxyl esters 4 and 5 in moderate to good
yield (Scheme 2). In this three-component reaction, an alkoxyl
group was transferred from the titanium reagent to the product
4/5. Excellent chemoselectivity and high diastereoselectivity was
obtained with unbranched aliphatic aldehydes. To the best of our
knowledge, this is the first example of a three-component reaction
of diazoacetate, titanium(IV) alkoxide and aldehyde.6
determined by H NMR analysis of the crude reaction mixture.
This novel three-component reaction reported here is essentially
different from the rhodium-catalyzed three-component coupling
reaction of diazoacetate, alcohol and aldehyde (or imine) reported
in ref. 6c, in which the O–H insertion product derived from
diazoacetate and alcohol in the presence of aldehyde was the main
by-product.
Tests carried out with decreasing amounts of titanium reagent
(Table 1, entries 1–3) led to a decrease of the product yield, down
to 45% for 0.25 equiv. of titanium regent. A yield greater than 25%
is indeed indicative that more than one isopropoxy group of
Ti(OiPr)4 is transferred in the reaction.
A control reaction of epoxide 6a with titanium(IV) isopropoxide
(2a) did not result in three-component products, indicating that 4a
and 5a were not formed from the Lewis acid catalyzed ring
opening of the corresponding epoxides (Scheme 3). It was
interesting to find that no decomposition of diazo 1a occurred
with dirhodium acetate catalyst in the presence of 1.1 equiv. of
titanium(IV) isopropoxide (2a) without benzaldehyde in the
The first indication of this reaction occurred in the Rh2(OAc)4-
catalyzed reaction of methyl phenyldiazoacetate (1a) with 1.1 equiv.
Table 1 The three-component reaction of methyl phenyldiazoacetate
(1a) with titanium(IV) isopropoxide (2a) and p-anisaldehyde (3a) with
different ratios of reactants (Scheme 2)a
%Yield
Entry 1a : 2a : 3a/mmol (4a + 5a)b dr (4a : 5a)c (4a + 5a) : 6ac
1
2
3
4
a
1.0 : 1.1 : 1.1
1.0 : 0.5 : 1.1
1.0 : 0.25 : 1.1
1.0 : 0.0 : 1.1
69
58
45
0
68 : 32
66 : 34
57 : 43
N/A
87 : 13
66 : 34
57 : 43
0 : 100
Scheme 1 The catalyzed epoxidation of diazo compounds and
aldehydes.
{ Electronic supplementary information (ESI) available: experimental
details, NMR assignments, analytical data and X-ray structures. See http://
www.rsc.org/suppdata/cc/b5/b502093j/
All reactions were carried out in refluxing CH2Cl2 in the presence
b
of Rh2(OAc)4 (1 mol %). Isolated yields after chromatography.
c
Determined by 1H NMR of crude reaction mixtures.
*huwh@cioc.ac.cn
2624 | Chem. Commun., 2005, 2624–2626
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successfully used to give a moderate yield of 4m/5m in this reaction
(Table 2, entry 14). Attempts to achieve three-component coupling
with other electrophiles such as imines, ketones and a, b-unsatu-
rated ketones were unsuccessful.
Also no obvious principle was found to explain the variable
diastereomeric ratio of 4 : 5. The reaction favors formation of the
erythro diastereomer 4 with a dr as high as 95 : 5 with
butyraldehyde, decreasing to 86 : 14 and 73 : 27 with the more
hindered isobutyraldehyde and pivaldehyde, respectively. The
stereochemistry of stereoisomer 4d was confirmed by its X-ray
structure.8
Scheme 3 Control experiments clarifying the proposed reaction
pathway.
Although the mechanism for the formation of the three-
component products 4 and 5 is unknown, a possible reaction
pathway is proposed. The reaction is likely to proceed through an
aldol-type nucleophilic addition of an oxonium ylide to the
aldehyde, in which the ylide is generated from the carbenoid with
an alkoxyl group of titanium(IV) alkoxide. The titanium reagent
also serves as a Lewis acid to activate the aldehyde in proposed
intermediate 8 (Scheme 4). The reason for the different ratios of 4 :
5 is unclear at this time and deserves further investigation.
In conclusion, we have developed the first example of a three-
component reaction of diazoacetate, titanium(IV) alkoxide and
aldehyde in the presence of dirhodium acetate catalyst.
Titanium(IV) alkoxide plays a dual role as both reagent and
activator. The novel C–O/C–C bond formation reaction gave
reaction. Total recovery of diazo compound 1a was observed in
this case (Scheme 3). In contrast, decomposition of diazoacetate 1a
with dirhodium acetate gave a mixture of 2,3-diphenyl fumarate
and maleate in the absence of 2a.7,8 The three-component reaction
occurred after an aldehyde was added to the unreacted mixture of
1a, 2a, and dirhodium acetate. This may be rationalized by the
aldehyde retrieving reactivity of 1a towards the dirhodium catalyst
by competitive coordination with titanium complex 2a.
The three-component reaction was found to be quite general. In
Table 2, the scope of the reaction with combinations of various
aldehydes and titanium alkoxides was explored. Satisfactory yields
were observed from aromatic aldehydes bearing either electron-
withdrawing or electron-donating groups (entries 1–5).
Unbranched or branched aliphatic aldehydes also gave a good
yield of 4/5 (entries 8–10). An a,b-unsaturated aldehyde was also a
good substrate (entry 7). However, the reaction was dramatically
influenced by the steric effect of the titanium reagents. Better
chemoselectivity was obtained by using less sterically hindered
titanium(IV) alkoxides. A product ratio as high as 96 : 4 for (4 + 5)
: 6 was obtained by using Ti(OEt)4 or Ti(OnPr)4 (entries 11 and
12), and the ratio decreased to 89 : 11 with Ti(OiPr)4 (entry 2). The
use of Ti(OtBu)4 gave only epoxide 6 with no three-component
adducts 4/5 being observed.
The reaction was further expanded to other diazo compounds.
The best result was obtained from the methyl p-methoxyphenyl
diazoacetate, affording 4l/5l in 92% yield and a moderate dr
(Table 2, entry 13). Methyl trans-styryl diazoacetate was also
Scheme 4 Proposed mechanism of formation of a-alkoxyl-b-hydroxyl
acid derivatives.
Table 2 The three-component reaction of diazoacetate with different titanium alkoxides and aldehydes (Scheme 2)a
Entry
R1
R2
R3
Products
%Yield (4 + 5)b
dr (4 : 5)c
(4 + 5) : 6c
1
2
3
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
PMP
(E)-styryl
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
Et
p-MeOPh
Ph
4a + 5a
4b + 5b
4c + 5c
4d + 5d
4d + 5d
4e + 5e
4f + 5f
4g + 5g
4h + 5h
4i + 5i
69
71
71
70
90
78
55
77
72
60
75
75
92
49
68 : 32
75 : 25
80 : 20
83 : 17
85 : 15
75 : 25
53 : 47
95 : 5
86 : 14
73 : 27
60 : 40
66 : 34
81 : 19
61 : 39
87 : 13
89 : 11
93 : 7
n.d.d
p-NO2Ph
o-NO2Ph
o-NO2Ph
2,4-(NO2)2Ph
(E)-styryl
nPr
4
5e
6
n.d.d
99 : 1
62 : 38
n.d.d
7
8
9
iPr
n.d.d
10
11
12
13
14
a
tBu
Ph
n.d.d
4j + 5j
96 : 4
96 : 4
n.d.d
nPr
iPr
iPr
Ph
Ph
Ph
4k + 5k
4l + 5l
4m + 5m
78 : 22
All reactions were carried out in refluxing CH2Cl2 in the presence of Rh2(OAc)4 (1 mol %) with 1 : 2 : 3 5 1.0 : 1.1 : 1.1 mmol unless
otherwise indicated. Isolated yields after chromatography. Determined by 1H NMR of crude reaction mixtures. The data were not
detected. 1 : 2 : 3 5 1.3 : 1.0 : 1.0 mmol.
b
c
d
e
This journal is ß The Royal Society of Chemistry 2005
Chem. Commun., 2005, 2624–2626 | 2625

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S. Muthusamy, Tetrahedron, 2002, 58, 9477; (f) D. M. Hodgson, F. Y. T.
M. Pierad and P. A. Stupple, Chem. Soc. Rev., 2001, 30, 50; (g) A. Padwa
and M. D. Weingarten, Chem. Rev., 1996, 96, 223.
5 (a) C. R. Holmquist and E. J. Roskamp, J. Org. Chem., 1989, 54, 3258;
(b) S. J. Mahmood and M. M. Hossain, J. Org. Chem., 1998, 63, 3333; (c)
S. Kanemasa, T. Kanai, T. Araki and E. Wada, Tetrahedron Lett., 1999,
40, 5055; (d) M. E. Dudley, M. M. Morshed, C. L. Brennan, M. S. Islam,
M. S. Ahmad, M.-R. Atuu, B. Branstetter and M. M. Hossain, J. Org.
Chem., 2004, 69, 7599.
6 For ethereal oxonium ylide chemistry promoted by Ti(OR)4, see: (a)
Y. Sawada, T. Mori and A. Oku, Chem. Commun., 2001, 1086; (b)
Y. Sawada, T. Mori and A. Oku, J. Org. Chem., 2003, 68, 10040; for
alcoholic oxonium ylide chemistry with Ti(OtBu)4 catalyst, see: (c)
C.-D. Lu, H. Liu, Z.-Y. Chen, W.-H. Hu and A.-Q. Mi, Org. Lett., 2005,
7, 83.
7 The dimers were obtained as the only products when the reaction was
performed under Ar. If the reaction was conducted under oxygen, no
trace amount of dimers was detected, the oxidation product methyl
benzoylformate accompanied by other by-products was obtained instead.
For the experimental details and the X-ray structure of dimethyl 2,3-
diphenyl maleate, see ESI.
a-alkoxyl-b-hydroxyl acid derivatives in moderate to good yield
with various aldehydes. Asymmetric induction of this reaction with
a chiral titanium reagent is currently underway in our laboratories.
We thank Prof. Michael P. Doyle from the University of
Maryland for helpful discussions. We are grateful for financial
support from the National Science Foundation of China (Grant
No. 20472080). We thank Prof. Zhong-Yuan Zhou from The
Hong Kong Polytechnic University for X-ray measurements.
Chong-Dao Lu,ab Hui Liu,a Zhi-Yong Chen,a Wen-Hao Hu*a and
Ai-Qiao Mia
aKey Laboratory for Asymmetric Synthesis and Chirotechnology of
Sichuan Province, Chengdu Institute of Organic Chemistry, Chinese
Academy of Sciences, Chengdu 610041, China. E-mail: huwh@cioc.ac.cn
bGraduate School of the Chinese Academy of Sciences, China
Notes and references
˚
1 M. P. Doyle, M. A. McKervey and T. Ye, Modern Catalytic Methods for
Organic Synthesis with Diazo Compounds, Wiley & Sons, New York,
1998.
2 (a) P. de March and R. Huisgen, J. Am. Chem. Soc., 1982, 104, 4952; (b)
M. Alt and G. Maas, Tetrahedron, 1994, 50, 7435; (c) M. P. Doyle,
D. C. Forbes, M. N. Protopopova, S. A. Stanley, M. M. Vasbinder and
K. R. Xavier, J. Org. Chem., 1997, 62, 7210; (d) B. Jiang, X. Zhang and
Z. Luo, Org. Lett., 2002, 4, 2453; (e) C.-D. Lu, Z.-Y. Chen, H. Liu,
W.-H. Hu and A.-Q. Mi, Org. Lett., 2004, 6, 3071.
3 (a) M. P. Doyle, W. Hu and D. J. Timmons, Org. Lett., 2001, 3, 933; (b)
H. M. L. Davies and J. DeMeese, Tetrahedron Lett., 2001, 42, 6803; (c)
S. Muthusamy, C. Gunanathan and M. Nethaji, Synlett, 2004, 639.
4 (a) 1,3-Dipolar Cycloaddition Chemistry, ed. A. Padwa, Wiley-
Interscience, New York, 1984; (b) M. P. Doyle, Chem. Rev., 1986, 86,
919; (c) M. P. Doyle and D. C. Forbes, Chem. Rev., 1998, 98, 911; (d)
A. Padwa and W. H. Pearson, The Chemistry of Heterocyclic
Compounds, Wiley & Sons, New York, 2002, ch. 4; (e) G. Mehta and
8 Crystal data (l 5 0.71073 A, the structure was solved by direct methods
(SHELXL-97) and refined by full-matrix least-squares on F2.): dimethyl
2,3-diphenyl maleate: C18H16O4, M 5 296.31, monoclinic, space group
˚
˚
˚
˚
P21/n, a 5 8.8668(12) A, b 5 8.7122(12) A, c 5 19.668(3) A, a 5 90u,
b 5 94.189(3)u, c 5 90u, V 5 1515.3(4) A , Z 5 4, m 5 0.092 mm
T 5 294(2) K, 13787 reflections collected, 3507 unique (Rint 5 0.0395).
Final GooF 5 1.059, R1 5 0.0476, wR2 5 0.1246, R indices based on
3507 reflections with I . 2s(I), 201 parameters, 0 restraints, CCDC
261327. Compound 4d: C19H21NO6, M 5 359.37, monoclinic, space
3 21
,
˚
˚
˚
group P21/c, a 5 13.289(2) A, b 5 8.1727(12) A, c 5 16.5883(3) A,
3
˚
a 5 90u, b 5 91.999(3)u, c 5 90u, V 5 1800.4(5) A , Z 5 4,
m 5 0.099 mm21, T 5 294(2) K, 16387 reflections collected, 4172 unique
(Rint 5 0.0357). Final GooF 5 1.016, R1 5 0.0399, wR2 5 0.1091, R
indices based on 4172 reflections with I . 2s(I), 241 parameters, 0
restraints, CCDC 261328. See http://www.rsc.org/suppdata/cc/b5/
b502093j/ for crystallographic data in CIF or other electronic
format.
2626 | Chem. Commun., 2005, 2624–2626
This journal is ß The Royal Society of Chemistry 2005