Three-component reaction of aryl diazoacetates, alcohols, and aldehydes (or imines): Evidence of alcoholic oxonium ylide intermediates

Article abstract of DOI:10.1021/ol0478483

(Chemical Equation Presented) The Rh(II)-catalyzed three-component reaction of aryl diazoacetates, alcohols and aldehydes was explored, which provided evidence of alcoholic oxonium ylide formation for O-H insertion. A new C-C bond formation reaction where alcoholic oxonium ylides were trapped by electron-deficient aryl aldehydes (or imines) was realized.

Full text of DOI:10.1021/ol0478483

ORGANIC
LETTERS
2005
Vol. 7, No. 1
83-86
Three-Component Reaction of Aryl
Diazoacetates, Alcohols, and Aldehydes
(or Imines): Evidence of Alcoholic
Oxonium Ylide Intermediates
Chong-Dao Lu, Hui Liu, Zhi-Yong Chen, Wen-Hao Hu,* and Ai-Qiao Mi
Key Laboratory for Asymmetric Synthesis and Chirotechnology of Sichuan ProVince,
Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu
610041, and Graduate School of Chinese Academy of Sciences, Beijing, China
huwh@cioc.ac.cn
Received October 19, 2004
ABSTRACT
The Rh(II)-catalyzed three-component reaction of aryl diazoacetates, alcohols and aldehydes was explored, which provided evidence of alcoholic
oxonium ylide formation for O H insertion. A new C C bond formation reaction where alcoholic oxonium ylides were trapped by electron-
deficient aryl aldehydes (or imines) was realized.
−
−
Oxygen-hydrogen insertion by catalytic reactions of diazo
compounds has drawn a great deal of interest because of its
ability to provide a direct entry to C-O bond formation.1
However, the mechanism of this reaction is not fully
understood. The suggestion has been made that the insertion
occurs stepwise via initial oxonium ylide formation followed
by a rapid 1,2-hydrogen shift (Scheme 1, 4/5 to 6).2 Yet
experimental evidence to support this mechanism is lacking.
There is a recent report on the electronic effects of Rh(II)
carbene O-H insertion, where the Hammett correlation data
support a concerted reaction pathway that is similar to the
well-established C-H insertion.3 We report here evidence
Scheme 1. Possible C-C Bond Formation Reaction of
Alcoholic Oxonium Ylides
(1) For reviews, see: (a) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern
Catalytic Methods for Organic Synthesis with Diazo Compounds; Wiley &
Sons: New York, 1998; Chapter 8. (b) Ye, T.; Mckervey, M. A. Chem.
ReV. 1994, 94, 1091.
(2) (a) Cox, G. G.; Moody, C. J.; Austin, D. J.; Padwa, A. Tetrahedron
1993, 49, 5109. (b) Miller, D. J.; Moody, C. J. Tetrahedron 1995, 51, 10811.
(c) Moody, C. J.; Miller, D. J. Tetrahedron 1998, 54, 2257. (d) Doyle, M.
P.; Yan, M. Tetrahedron Lett. 2002, 43, 5929.
for the stepwise ylide-mediated reaction pathway rather than
the concerted insertion.
(3) Qu, Z.; Shi, W.; Wang, J. J. Org. Chem. 2004, 69, 217.
10.1021/ol0478483 CCC: $30.25
© 2005 American Chemical Society
Published on Web 12/09/2004

Our experimental system is the rhodium(II)-catalyzed
three-component reaction of methyl phenyl diazoacetate with
alcohols in the presence of aldehydes/imines. We have
previously shown that ammonium ylides generated from
diazo compounds and arylamines underwent aldol-type
nucleophilic addition reactions.4 We hypothesized that an
alcoholic oxonium ylide,5 similar to an ammonium ylide,
generated in situ from a diazo compound and an alcohol may
be trapped similarly by an electrophile such as an aldehyde
or imine (Scheme 1). The stepwise mechanism can be
demonstrated by showing a correlation of the degree of
oxonium ylide trapping with the generation of product 6 by
1,2-hydrogen shift (O-H insertion). The chemoselectivity
of this reaction can be systematically studied by changing
the alcohols, aldehydes, and diazo compounds.
Methyl phenyl diazoacetate (1a, Ar1 ) Ph) and benzyl
alcohol (2a, R1 ) Bn) were found to react with p-nitro-
benzaldehyde (3a, Ar2 ) p-NO2Ph) to generate the desired
three-component products 7a + 8a in 70% yield with 43:57
dr (7a:8a) favoring the erythro-isomer (Scheme 2, Table 1,
Figure 1. ORTEP representation of the crystal structure of 7j.
(6a:7a+8a). There was no formation of epoxide from reac-
tion of 1a with p-nitrobenzaldehyde (3a) in this case. In
contrast, 6a was the only product in the absence of aldehyde
3a, and epoxidation with 3a was the only reaction in the
absence of alcohol 2a.6 Furthermore, control experiments
indicated that the formation of 7a/8a is neither from a ring
opening reaction of the epoxide (from 3a) with alcohol 2a
nor from the O-H insertion product 6a with aldehyde 3a
(Scheme 3).
Scheme 2
The reaction chemoselectivity was found to be dependent
on electronic and steric features of the alcohol used. Electron-
rich and less hindered alcohols favored the alcoholic oxonium
ylide formation, and the oxonium ylide derived from
electron-rich alcohols favored the three-component product.
Examples are (1) p-methoxybenzyl alcohol gave higher yield
and better selectivity than benzyl alcohol, favoring the three-
entry 1). The stereochemistry of isomers 7 was confirmed
by the analogue 7j, which was assigned with the single-
crystal X-ray structure (Figure 1). The O-H insertion prod-
uct 6a (Ar1 ) Ph, R1 ) Bn) was formed in a 13:87 ratio
Table 1. Three-Component Reaction of Aryl Diazoacetate, Alcohols, and Aldehydes (Scheme 2)a
entry
Ar1
R1
Ar2
products
yieldb (%)
dr (7:8)c
7+8:6c
1d
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Bn
PMB
H
Me
tBu
PMB
PMB
PMB
PMB
Bn
Bn
Bn
Bn
PMB
PMB
p-NO2Ph
p-NO2Ph
p-NO2Ph
p-NO2Ph
2,4-(NO2)2Ph
p-NO2Ph
o-NO2Ph
p-CF3Ph
p-CNPh
p-MeOPh
2,4-(NO2)2Ph
p-NO2Ph
p-NO2Ph
p-CF3Ph
p-CF3Ph
7a + 8a
7b + 8b
7c + 8c
7d + 8d
7e + 8e
7b + 8b
7f + 8f
7g + 8g
7h + 8h
7i + 8i
7j + 8j
7k + 8k
7l + 8l
7g + 8g
7g + 8g
70
83
65
48
18
76
47
56
51
56
78
87
50
64
40
43:57
42:58
50:50
41:59
88:12
38:62
67:33
35:65
29:71
33:67
82:18
38:62
56:44
32:68
26:74
87:13
95:5
92:8
71:29f
g
2d
3d,e
4d
5d
6h
97:3
7h
64:36
62:38
57:43
77:23
89:11
92:8
69:31
71:29
46:54
8h
9h
10d,i
11d
12d
13d
14h,j
15h,k
PMP
trans-styryl
Ph
Ph
a All reactions were carried out in refluxing CH2Cl2 in the presence of Rh2(OAc)4 (1 mol %) with Ar1dPh unless otherwise indicated. b Isolated yields
1
after chromatography. c Determined by H NMR of crude reaction mixtures. d 1:2:3 ) 1.0:1.1:1.1 mmol. e Performed at 40 °C in THF. f 7+8:6:epoxide )
64:26:10. g No formation of 6. h 1:2:3 ) 1.3:1.0:1.5 mmol. i 1.1 mmol of Ti(OtBu)4 was used. j Rh2(tfa)4 as catalyst. k Rh2(S-DOSP)4 as catalyst.
84
Org. Lett., Vol. 7, No. 1, 2005

three-component product due to reduced eletrophilicity. We
anticipated that adding additional Lewis acid would promote
the reaction by activating the aldehyde. In fact, Ti(OtBu)4
was found to be the choice among Lewis acids including
Ti(OiPr)4, TiCl4, and BF3‚Et2O. The three-component product
was obtained in 56% isolated yield with p-anisaldehyde in
the presence of 1.1 equiv of Ti(OtBu)4 (Table 1, entry 10),7
suggesting a stepwise reaction pathway for the three-
component reaction, (1) alcoholic oxonium ylide formation
and (2) nucleophilic attack of the ylide to an aldehyde. It is
worthwhile to note that water serves as an “active alcohol”
to afford a three-component product R,â-dihydroxyl esters
(7c + 8c) in moderate yield (Table 1, entry 3).
Scheme 3
component formation (Table 1, entry 2 vs entry 1); (2)
whereas methanol gave moderate yield of the three-
component products along with O-H insertion and epoxi-
dation (Table 1, entry 4), the epoxide of p-nitrobenzaldehyde6
The oxonium ylide was also successfully trapped with
imines. When aryl imines 9 were employed, the reactions
yielded highly substituted R-alkoxy-â-alkylamino esters
(Scheme 4) in moderate to good yields, and with improved
t
was the major product with bulky BuOH accompanying a
lower yield of three-component products 7/8 (Table 1, entry
5). Electron-deficient phenols such as phenol, p-methoxy-
phenol, and p-nitrophenol led to only epoxide formation.
Scheme 4
Reaction of methyl p-methoxyphenyl diazoacetate, a more
electron-rich diazo compound than methyl phenyl diazo-
acetate, with benzyl alcohol and p-nitrobenzaldehyde gave
a three-component product in 87% isolated yield along with
a small amount of O-H insertion (Table 1, entry 12). This
is in agreement with the rationale that electron-rich alcoholic
oxonium ylides favor the three-component reaction. Different
aldehydes were tested for the trapping. Electron-deficient aryl
aldehydes gave the desired three-component products in
moderate to good yields (Table 1, entries 6-9). Electron-
rich aromatic aldehydes such as p-anisaldehyde gave no
diastereoselectivities favoring erythro-isomers. Hydrolysis of
the isomers of esters 10c + 11c gave the corresponding
amino acids, and the major isomer 12c of amino acids was
crystallized as a pure diastereomer. We determined the
stereochemistry of 10c through the X-ray crystal structure
of 12c (Figure 2). This process was demonstrated to build
(4) Wang, Y.; Zhu, Y.; Chen, Z.; Mi, A.; Hu, W.; Doyle, M. P. Org.
Lett. 2003, 5, 3923.
(5) For reviews, see: (a) Padwa, A.; Hornbuckle, S. Chem. ReV. 1991,
91, 263. (b) Padwa, A.; Weingarten, M. D. Chem. ReV. 1996, 96, 223. (c)
Li, A.-H.; Dai, L.-X.; Aggarwal, V. K. Chem. ReV. 1997, 97, 2341. (d)
Hodgson, D. M.; Pierad. F. Y. T. M.; Stupple, P. A. Chem. Soc. ReV. 2001,
30, 50. For sulfonium ylides, see: (e) Corey, E. J.; Chaykovsky, M. J. Am.
Chem. Soc. 1962, 84, 867. (f) Corey, E. J.; Chaykovsky, M. J. Am. Chem.
Soc. 1962, 84, 3782. (g) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc.
1965, 87, 1353. (h) Li, A.-H.; Dai, L.-X.; Aggarwal, V. K. Chem. ReV.
1997, 97, 2341. (i) Aggarwal, V. K. Synlett 1998, 329. (j) Aggarwal, V.
K.; Alonso, E.; Fang, G.; Ferrara, M.; Hynd, G.; Porcelloni, M. Angew.
Chem., Int. Ed. 2001, 40, 1433. (k) Aggarwal, V. K.; Harvey, J. N.;
Richardson, J. J. Am. Chem. Soc. 2002, 124, 5747. (l) Aggarwal, V. K.;
Alonso, E.; Bae, I.; Hynd, G.; Lydon, K. M.; Palmer, M. J.; Patel, M.;
Porcelloni, M.; Richardson, J. Stenson, R. A.; Studley, J. R.; Vasse, J.-L.;
Winn, C. L. J. Am. Chem. Soc. 2003, 125, 10926. (m) Aggarwal, V. K.;
Winn, C. L. Acc. Chem. Res. 2004, 37, 611. Ethereal oxonium ylides. For
[1,2] rearrangement, see: (n) Eberlein, T. H.; West, F. G.; Tester, R. W. J.
Org. Chem. 1992, 57, 3479. (o) West, F. G.; Naidu, B. N.; Tester, R. W.
J. Org. Chem. 1994, 59, 6892. (p) Marmsater, F. P.; West, F. G.; J. Am.
Chem. Soc. 2001, 123, 5144. (q) Marmsater, F. P.; Vanecko, J. A. West, F.
G. Tetrahedron 2002, 58, 2027. (r) Marmsater, F. P.; Murphy, G. K.; West,
F. G. J. Am. Chem. Soc. 2003, 125, 14724. For [2,3] rearrangement, see:
(s) Clark, J. S. Tetrahedron Lett. 1992, 33, 6193. (t) Clark, J. S.; Dossetter,
A. G.; Blake, A. J.; Li, W.-S.; Whittingham, W. G. Chem. Commun. 1999,
749. (u) Clark, J. S.; Bate, A. L.; Grinter, T. Chem. Commun. 2001, 459.
(v) Clark, J. S.; Whitlock, G.; Jiang, S.; Onyia, N. Chem. Commun. 2003,
2578. (w) Clark, J. S.; Fessard, T. S.; Wilson, C. Org. Lett. 2004, 6, 1773.
For C-C bond formation, see: (x) Sawada, Y.; Mori, T.; Oku, A. Chem.
Commun. 2001, 1086. (y) Sawada, Y.; Mori, T.; Oku, A. J. Org. Chem.
2003, 68, 10040.
Figure 2. ORTEP representation of the crystal structure of 12c.
(6) (a) Doyle, M. P.; Hu, W.; Timmons, D. J. Org. Lett. 2001, 3, 933.
(b) Davies, H. M. L.; DeMeese, J. Tetrahedron Lett. 2001, 42, 6803. (c)
Lu, C.-D.; Chen, Z.-Y.; Liu, H.; Hu, W.-H.; Mi, A.-Q. Org. Lett. 2004, 6,
3071.
highly substituted R-alkoxy-â-amino acid 12c in large scale.
Greater than 16 g of 12c was prepared from this atom-
efficient three-component reaction.
Org. Lett., Vol. 7, No. 1, 2005
85

To address if the oxonium ylide intermediate was metal-
associated 4 or metal-free 5 (Scheme 1), several Rh(II)
catalysts bearing different ligands including Rh2(tfa)4,
Rh2(S-DOSP)4, Rh2(cap)4, and Rh2(S-nttl)4 were employed
(Table 1, entries 8, 14, 15 and Table 2, entries 1, 5-8).8
Rh2(S-DOSP)4 (Table 1, entry 14 vs entry 15). Because
electron-withdrawing ligands on Rh(II) retard the O-H
insertions,2,9 there may be more opportunity for nucleophile
attack on aldehydes. Changes in diastereoselectivity were
also observed in some cases (Table 1, entry 8 vs entry 15,
dr from 35:65 to 26:74 and Table 2, entry 1 vs entry 7, dr
from 85:15 to 68:32). The catalyst dependence of chemose-
lectivity and diastereoselectivity support the rationale that
alcoholic oxonium ylide intermediates are metal-associated.
Unfortunately, racemic products were obtained by using
Rh2(S-DOSP)4 and Rh2(S-nttl)4.
In conclusion, we report here the first example of Rh(II)-
catalyzed three-component reactions of aryl diazoacetates,
alcohols, and aldehydes/imines. Our data suggests that the
reaction occurs through a metal-associated alcoholic oxonium
ylide intermediate and is followed by a nucleophilic addition
to an electrophile, providing evidence of alcoholic oxonium
ylide formation for O-H insertion. This work provides a
convenient route to R,â-dihydroxy acid and R-hydroxy-â-
amino acid derivatives that are important compounds in
organic and medicinal chemistry.
Table 2. Three-Component Reaction of Aryl Diazoacetate,
Alcohols, and Imines (Scheme 4)a
entry Ar1
R1
Bn
PMB Ph
Ar2
products
yieldb (%) dr (10:11)c
1
2
3
Ph
Ph
Ph
Ph
10a + 11a
10b + 11b
70
74
62
57
79
65
81
29
85:15
82:18
79:21
81:19
80:20
82:18
68:32
77:23
PMB PMP 10c + 11c
4
PMP Bn
Ph
Ph
Ph
Ph
Ph
10d + 11d
10a + 11a
10a + 11a
10a + 11a
10a + 11a
5d
6e
7f
8g
Ph
Ph
Ph
Ph
Bn
Bn
Bn
Bn
a All reactions were carried out in refluxing CH2Cl2 in the presence of
Rh2(OAc)4 (1 mol %) with 1:2:9 ) 1.0:1.1:1.1 mmol.. b Isolated yield after
purification. c Ratios were determined by 1H NMR analysis of crude reaction
mixtures. d Rh2(S-DOSP)4 as catalyst. e Rh2(S-nttl)4 as catalyst. f Rh2(tfa)4
as catalyst. g Rh2(cap)4 as catalyst.
Acknowledgment. We thank Prof. Michael P. Doyle
from the University of Maryland for helpful discussions. We
thank Prof. Kai-Bei Yu from Chengdu Institute of Organic
Chemistry and Prof. Zhong-Yuan Zhou from The Hong Kong
Polytechnic University for X-ray measurements. We are
grateful for financial support from the National Science
Foundation of China (Grant no. 20472080).
Significant changes in both chemoselectivity and diastereo-
selectivity were observed with the catalysts. For example,
Rh2(tfa)4 gave a higher yield of the three-component products
and suppressed the O-H insertion product better than
Supporting Information Available: Experimental pro-
cedures and characterization data of all new compounds and
X-ray crystallographic data of 7j and 12c in CIF format. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(7) It is notable that no reaction occurs in the absence of catalyst
Rh2(OAc)4.
(8) Rh2(tfa)4 ) rhodium trifluroacetate; Rh2(S-DOSP)4 ) dirhodium
tetrakis(S-(N-dodecylbenzenesulfonyl) prolinate); Rh2(cap)4 ) rhodium
caprolactam; Rh2(S-nttl)4 ) dirhodium tetrakis(S-(N-1,8-naphthoyl) tert-
leucinate).
(9) Cox, G. G.; Miller, D. J.; Moody, C. J.; Sie, E.-R. H. B.; Kulagowski,
J. J. Tetrahedron 1994, 50, 3195.
OL0478483
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