Influence of a β-Alkoxy Substituent on the C-H Activation Chemistry of Alkyl Ethers

Article abstract of DOI:10.1002/adsc.200303089

C-H activation reactions of 1,2-dimethoxyethane and methyl tert-butyl ether with methyl aryldiazoacetates or styryldiazoacetate catalyzed by Rh ₂(S-DOSP)₄ result in the formation of 2-aryl- or 2-styryl-substituted propanoic acids with asymmetric induction up to 95% ee.

Full text of DOI:10.1002/adsc.200303089

FULL PAPERS
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Influence of a b-Alkoxy Substituent on the C H Activation
Chemistry of Alkyl Ethers
Huw M. L. Davies,* Jaemoon Yang
Department of Chemistry, University at Buffalo, The State University of New York, New York 14260 3000, USA
Fax: ( ‡ 1)-716-645-6547, e-mail: hdavies@acsu.buffalo.edu
Received: May 9, 2003; Accepted: July 3, 2003
À
Abstract: C H activation reactions of 1,2-dimethoxy- induction up to 95% ee.
ethane and methyl tert-butyl ether with methyl
aryldiazoacetates or styryldiazoacetate catalyzed by Keywords: asymmetric catalysis; C H activation;
Rh2(S-DOSP)4 result in the formation of 2-aryl- or 2- C H insertion; carbenoid; diazo compounds; homo-
styryl-substituted propanoic acids with asymmetric geneous catalysis; rhodium
À
À
Introduction
diastereoselective, and regioselective transformations
have been reported. The reactions display subtle
À
The development of practical C H activation methods chemoselectivity due to a delicate balance of steric
is of considerable current interest.[1,2] Such methods and electronic effects. The C H activation is considered
À
could have an immense impact on the functionalization to occur in a concerted non-synchronous manner and
of common hydrocarbon feedstocks and offer novel carbon centers that can stabilize positive charge build-
opportunities and strategies for the synthesis of natural up are very prone to C H activation. The rhodium-
products and pharmaceutical targets. One very effective carbenoid intermediates behave as sterically demanding
catalytic and asymmetric method for C H activation is species and in crowded sites the steric effects can
À
À
À
by means of the C H insertion chemistry of metal dominate over any electronic effects. Consequently,
carbenoid intermediates (Scheme 1).[3] The catalytic numerous examples are known of selective C H
À
À
À
asymmetric intramolecular C H insertion is very well- activation at methyl, methylene and methine C H
established, but until very recently the intermolecular bonds.[3c, d] In general, methine sites tend to be most
version was of limited synthetic utility.[3a, b] The major often favored because such sites display a favorable
difficulty was the high reactivity of the traditional combination of electronic and steric effects.[5]
À
carbenoid intermediates derived from diazoacetate
C H activation is especially favored a to alkoxy or
derivatives. Some progress has been made in taming silyloxy groups because of the electronic stabilization of
this reactivity by the use of very bulky catalysts[4] but the the transition state during the C H activation.
A
[6]
À
major breakthrough in this area came about with the representative example of this is the reaction with
development of donor/acceptor substituted carbe- tetrahydrofuran (Scheme 2).[7] The high preference for
noids.[3c, d] These carbenoids display much greater selec- C H activation a to oxygen is readily seen because the
À
tivity than the traditional carbenoids and enable the optimum conditions used 2 equiv. of tetrahydrofuran at
À
À
intermolecular C H insertion to be a very general C H
À 508C in hexane as solvent without any competing
activation process.[3c, d]
C H insertion into the solvent. Under these conditions,
À
Over the last five years a wide variety of substrates the Rh2(S-DOSP)4-catalyzed reaction of phenyldiazo-
have been shown to be effectively functionalized by acetate gave the C H activation product as a 2.8:1
means of the intermolecular C H activation.
rhodium tetraprolinates such as Rh2(S-DOSP)4 are major diastereomer was formed in 97% ee. An even
exceptional chiral catalysts for these reactions (Fig-
À
[3c, d]
À
Di- mixture of diastereomers in 67% yield, in which the
ure 1). By now a number of highly enantioselective,
À
À
Scheme 1. C H Activation by carbenoid induced C H in-
sertion.
Figure 1. Rh2(S-DOSP)4.
Adv. Synth. Catal. 2003, 345, 1133 1138
DOI: 10.1002/adsc.200303089
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Huw M. L. Davies, Jaemoon Yang
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Scheme 4. C H activation reaction of 1,2-dimethoxyethane.
assigned as (S) based on the predictive model.[8a] Clean
C H activation into a methyl site only occurs when the
À
Scheme 2. C H Activation reactions of tetrahydrofuran and
tetraethoxysilane.
À
rest of the molecule is sterically protected or lacks any
other activated sites.[10] In this case, the result is
indicative that a b-alkoxy susbtituent has a strong
À
deactivating effect on the C H activation reaction.
À
Presumably oxygen b to a C H activation site would
inductively destabilizes the positive charge build up in
À
the transition state.[5]
Scheme 3. Attempted C H activation reaction of 18-crown-6
ether.
The reaction is applicable to a range of aryldiazoace-
À
tates as illustrated in Table 1. In all instances C H
activation only occurs at the methyl site, generating the
À
more impressive example of this chemistry is the C H activation product in 59 76% ee. The reaction of
reaction of phenyldiazoacetate with tetraethoxysilane methyl p-methoxyphenyldiazoacetate (entry 4), which
À
which gave the C H activation product in high enantio- would be expected to generate the least electrophilic
selectivity and diastereoselectivity (Scheme 2).[8a]
carbenoid intermediate was sluggish at room temper-
Having discovered the remarkable selectivity a to ature and was more effective when the reaction was
À
oxygen of the C H activation by the donor/acceptor conducted at 708C. A most notable example is the
substituted carbenoids, my group has been exploring reaction with methyl styryldiazoacetate (entry 6) which
À
avenues for the exploitation of this chemistry for the resulted in the formation of the C H activation product
rapid synthesis of useful target molecules. A reaction in 87% ee. Although carbenoids derived from vinyl-
that appeared especially attractive was the functional- diazoacetates have commonly been less studied in
À
À
ization of crown ethers by means of a C H activation C H activation chemistry than the carbenoids derived
protocol (Scheme 3) because the resulting chiral crown from aryldiazoacetates, in general, vinyldiazoacetates
ethers could have many applications.[9] In any event, the tend to result in the highest levels of asymmetric
attempts at the asymmmetric C H activation of crown- induction.[8a,10b]
ethers were uniformly unsuccessful. Puzzled by the
failure of this apparently straightforward reaction, could be extended further, the reactions using methyl
especially as the crown ether would not be expected to tert-butyl ether (MTBE) were examined.[11] Again, the
be sterically crowded, we have carried out a systematic best results were obtained when MTBE was used as
study to explore the factors that control the reactivity of solvent and the reaction was applicable to a range of
À
À
In order to determine if the methoxy C H activation
À
alkyl ethers towards C H activation. The results of this aryldiazoacetates and a vinyldiazoacetate as summar-
study are described in this paper.
ized in Table 2. The utility of this method is illustrated in
À
Table 1. C H activation of 1,2-dimethoxyethane with various
aryldiazoacetates.
Results and Discussion
A reasonable model substrate to explore the reactivity
of the crown ethers was considered to be 1,2-dimethoxy-
ethane (DME). Even though the oxygen substituent was
expected to make DME a very active substrate towards
À
C H activation, this proved not to be the case and in
order to achieve good yields of C H activation products
À
it was best to use DME as the solvent for the reaction.
Rh2(S-DOSP)4-catalyzed decomposition of p-bromo-
phenyldiazoacetate in DME gave a 72% yield of the
À
À
C H activation product 1a (76% ee), in which the C H
activation had occurred into the methyl site rather than
the methylene site (Scheme 4). The stereochemistry of
the newly generated chiral center was tentatively
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Influence of a b-Alkoxy Substituent on the C H Activation of Alkyl Ethers
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Table 2. C H activation of methyl tert-butyl ether with
various aryldiazoacetates.[a]
À
Scheme 6. Competition study on the C H activation reac-
tions between diethyl ether and methyl tert-butyl ether.
the methyl site in MTBE whereas no reaction was
observed at the methylenesite in DME, is indicativethat
the b-methoxy group has a very negative influence on
À
the C H activation.
The emergence of donor/acceptor-substituted carbe-
noids has been a major factor in enabling the asymmet-
À
ric intermolecular C H activation to become a viable
a 2-step sequence of C H activation followed by acid- synthetic process.[3c, d] We have shown in comparison
induced hydrolysis of the tert-butyl group leading to the studies that the chemoselectivity of the donor/acceptor
formation of a series of methyl tropinate 2b and its aryl substituted carbenoids is very different from that of the
À
derivatives.[12] The tentatively assigned (S) configura- traditional carbenoids lacking the donor group.[14]
A
À
tion for the C H activation products was confirmed for further demonstration of this reactivity difference is
2b, whose optical rotation {[a]D25: À 57.6 (c 0.50, seen in the reaction with crotyl methyl ether. The
acetone) for 79% ee} was in agreement with the reaction with p-bromophenyldiazoacetate led to a clean
literature value for (S)-2b {[a]D23: À 69.8 (c 0.875, C H activation at the methylene site (Scheme 7). A 2:1
À
acetone) for>98% ee}.[12b] In general, the yields were mixture of diastereomers 4a and 4b was formed in 67%
lower for the reactions of MTBE compared to DME but yield, in which the major diastereomer 4a was formed in
the asymmetric induction was higher. Once again, the 56% ee and the minor diastereomer 4b was formed in
À
highest asymmetric induction was obtained with methyl 67% ee. No C H insertion into the methyl group was
styryldiazoacetate (entry 6), which resulted in the observed, indicating that the allylic methylene is highly
À
À
formation of the C H activation product 2f in 95% ee.
activated towards the C H insertion. The low diastereo-
A further evaluation of the influence of the b-alkoxy selectivity in this case compared to the reaction of crotyl
group was conducted by exploring a control reaction silyl ethers[8b] is presumably because the size differ-
with diethyl ether as substrate. Rh2(S-DOSP)4-cata- entiation between the crotyl and methoxy groups is not
lyzed decomposition of methyl p- bromophenyldiazo- sufficient to induce high diastereoselctivity. In contrast,
acetate in ether at room temperature resulted in the the reactions of crotyl methyl ether with ethyl diazo-
formation of 3a/3b as a 3:1 mixture of diastereomers by acetate[15] and dimethyl diazomalonate[16] led to very
1H NMR spectroscopy[13] in 54% yield (Scheme 5). The different results (Scheme 7). No products resulting from
À
À
major diasteromer 3a was formed in 76% ee while the a C H insertion reaction were formed. Instead of C H
minor diasteromer 3b was formed in 83% ee.
Having achieved a successful reaction with diethyl
ether, it was now possible to conduct a competition
reaction between diethyl ether and MTBE. Rh2(S-
DOSP)4-catalyzed reaction of p-bromophenyldiazoace-
tate in a 1:1 mixture of diethyl ether and MTBE resulted
À
in a 7:1 mixture of products favoring C H functional-
ization of diethyl ether (Scheme 6). The demonstration
that the methylene site in diethyl ether is favored over
À
Scheme 7. C H activation reactions of crotyl methyl ether
with different diazo compounds.
À
Scheme 5. C H activation reaction of diethyl ether.
Adv. Synth. Catal. 2003, 345, 1133 1138
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1b: Rf 0.36 (PE:ether, 2:1) [UV, KMnO4]; IR (neat): n ˆ
1739 cmÀ1; 1H NMR (300 MHz, CDCl3): d ˆ 7.31 (m, 5H,
ArH), 4.07 (t, J ˆ 9.3 Hz, 1H, OCH2CH), 3.94 (dd, J ˆ 9.6,
5.1 Hz, 1H, OCH2CH), 3.69 (m, 4H, OCH2CH, CO2CH3), 3.60
(m, 2H, OCH2CH2O), 3.53 3.49 (m, 2H, OCH2CH2O), 3.36 (s,
3 H, OCH3); 13C NMR (75 MHz, CDCl3): d ˆ 172.9, 135.8,
128.7, 128.0, 127.6, 72.9, 71.8, 70.6, 59.0, 52.03, 51.98; HRMS
(EI): calcd. for C13H18O4: 239.1278; found: 239.1277; anal.
calcd.: C 65.53, H 7.61; found: C 65.69 H 7.62; 75% ee by HPLC:
CHIRALCEL OD-H column, 8% 2-propanol in hexanes,
1 mL/min, tR (minor) 6.5 min, tR (major) 7. 1 min; [a]2D5: À 41.5
(c 2.35, CHCl3).
activation, the products were 5 and 6 derived from a
[2,3]-sigmatropic rearrangement of the corresponding
oxonium ylides.
Conclusion
In summary, these studies demonstrate that electronic
À
effects on the C H activation chemoselectivity are very
influential. An alkoxy group at the C H activation site
À
strongly favors the reaction but a b-alkoxy substituent is
1c: Rf 0.24 (PE:ether, 2:1) [UV, KMnO4]; IR (neat): n ˆ
1739 cmÀ1; 1H NMR (300 MHz, CDCl3): d ˆ 7.19 (d, J ˆ
8.1 Hz, 2H, ArH), 7.12 (d, J ˆ 8.4 Hz, 2H, ArH), 4.06 (t, J ˆ
9.6 Hz, 1H, OCH2CH), 3.91 (dd, J ˆ 9.6, 5.1 Hz, 1H,
OCH2CH), 3.68 3.61 (m, 6H, OCH2CH, CO2CH3, OCH2-
2O), 3.53 3.49 (m, 2H, OCH2CH2O), 3.36 (s, 3H, OCH3),
2.32 (s, 3H, ArCH3); 13C NMR (75 MHz, CDCl3): d ˆ 173.0,
137.3, 132.7, 129.4, 127.9, 73.0, 71.8, 70.6, 58.9, 52.0, 51.5, 21.0;
HRMS(EI): calcd. for C 14H21O4: 253.1434; found: 253.1429;
anal. calcd.: C 66.65, H 7.99; found: C 66.88 H 7.99; 67% ee by
HPLC: CHIRALCEL OD-H column, 2% 2-propanol in
hexanes, 1 mL/min, tR (minor) 8.9 min, tR (major) 9.6 min;
[a]2D5: À 37.6 (c 1.82, CHCl3).
strongly deactivating. These effects offer further con-
À
trolling strategies for the chemoselectvity of the C H
activation chemistry of donor/acceptor-substituted rho-
dium carbenoids. Furthermore, these studies again
demonstrate that the donor/acceptor substituted carbe-
À
noids are uniquely suited for the C H activation
chemistry.
Experimental Section
Reactions were performed under an atmosphere of argon.
Methyl aryldiazoacetates[7b] and methyl styryldiazoacetate[17]
were prepared according to the published procedures. 1,2-
Dimethoxyethane (DME), methyl tert-butyl ether (MTBE),
diethyl ether, and hexane were distilled from sodium-benzo-
phenone ketyl prior to use.
1d: Rf 0.27 (PE:ether, 2:1) [UV, KMnO4]; IR (neat): n ˆ
1738, 1513 cmÀ1; 1H NMR (500 MHz, CDCl3): d ˆ 7.23 (d, J ˆ
9.0 Hz, 2H, ArH), 6.85 (d, J ˆ 9.0 Hz, 2H, ArH), 4.04 (t, J ˆ
10.0 Hz, 1H, OCH2CH), 3.91 (dd, J ˆ 9.5, 5.0 Hz, 1H,
OCH2CH), 3.78 (s, 3H, CO2CH3), 3.68 3.60 (m, 6H,
OCH2CH, OCH2CH2O, ArOCH3), 3.55 3.47 (m, 2H, OCH2-
2O), 3.36 (s, 3H, OCH3); 13C NMR (75 MHz, CDCl3): d ˆ 173.2,
159.1, 129.1, 127.8, 114.1, 73.0, 71.8, 70.6, 59.0, 55.2, 52.0, 51.1;
‡
General Procedure for the Rhodium(II)-Catalyzed
Decomposition of Aryldiazoacetates in the Presence
of Alkyl Ethers
LRMS(EI): m/z ˆ 269 [M ‡ H] ; anal. calcd.: C 62.67, H 7.51;
found: C 62.95, H 7.38; 65% ee by HPLC: (R,R)-Whelk-O 1
column, 2% 2-propanol in hexanes, 1 mL/min, tR (major)
9.0 min, tR (minor) 9.6 min; [a]2D5: À 32.77 (c 1.30, CHCl3).
1e: Rf 0.23 (PE:ether, 2:1) [UV, KMnO4]; IR (neat): n ˆ
1736 cmÀ1; 1H NMR (300 MHz, CDCl3): d ˆ 7.80 (m, 4H,
ArH), 7.47 (m, 3H, ArH), 4.23 4.10 (m, 2H, OCH2CH), 3.80
(dd, J ˆ 9.0, 4.5 Hz, 1H, OCH2CH), 3.71 (s, 3H, CO2CH3), 3.60
(m, 2H, OCH2CH2O), 3.58 3.48 (m, 2H, OCH2CH2O), 3.37 (s,
3H, OCH3); 13C NMR (75 MHz, CDCl3): d ˆ 172.9, 133.4,
133.2, 132.7, 128.4, 127.8, 127.6, 127.0, 126.2, 126.0, 72.9, 71.8,
70.7, 58.9, 52.06, 52.03; HRMS(EI): calcd. for C 17H21O4:
289.1434; found 289.1434; anal. calcd.: C 70.81, H 6.99; found C
71.05, H 7.02; 59% ee by HPLC: CHIRALCEL OD-H column,
2% 2-propanol in hexanes, 1 mL/min, tR (minor) 8.9 min, tR
(major) 9.9 min; [a]2D5: À 34.4 (c 1.56, CHCl3).
The procedure for the preparation of 1a is representative. A
solution of methyl p-bromophenyldiazoacetate (128 mg,
0.5 mmol) in hexane (2 mL) was added into a green solution
of Rh2(S-DOSP)4 (9 mg, 1 mol %) in 1,2-dimethoxyethane
(1.5 mL) over 30 min at rt. Stirring continued for another hour
under argon. The reaction mixture was concentrated under
vacuum and the residue was purified by flash chromatography
(silica gel, PE:Et2O, 2:1) to give pure product 1a as an oil; yield:
114 mg (72%).
Deprotection of tert-butyl ethers was achieved by treating
appropriate tert-butyl ethers with MeSO3H (12 equiv.) in
CH2Cl2 at rt for 30 min.
1a: Rf 0.31 (PE:ether, 2:1) [UV, KMnO4]; IR (neat): n ˆ
1739, 1736 cmÀ1; 1H NMR (500 MHz, CDCl3): d ˆ 7.45 (d, J ˆ
8.4 Hz, 2H, ArH), 7.19 (d, J ˆ 8.4 Hz, 2H, ArH), 4.02 (t, J ˆ
9.0 Hz, 1H, OCH2CH), 3.89 (dd, J ˆ 9.0, 5.2 Hz, 1H,
OCH2CH), 3.70 (m, 4H, OCH2CH, CO2CH3), 3.64 3.58 (m,
2H, OCH2CH2O), 3.52 3.38 (m, 2H, OCH2CH2O), 3.35 (s, 3H,
OCH3); 13C NMR (75 MHz, CDCl3): d ˆ 172.4, 134.8, 131.7,
129.8, 121.6, 72.5, 71.7, 70.6, 58.9, 52.1, 51.3; HRMS(EI): calcd.
for C13H17BrO4: 316.0305; found: 316.0310; anal. calcd.: C
49.23, H 5.40; found: C 49.45 H 5.40; 76% ee by HPLC:
CHIRALCEL OD-H column, 8% 2-propanol in hexanes,
1 mL/min, tR (minor) 6.6 min, tR (major) 7. 8 min; [a]2D5: À 30.5
(c 0.39, CHCl3).
1f: Rf 0.19 (PE:ether, 2:1) [UV, KMnO4]; IR (neat): n ˆ
1738 cmÀ1; 1H NMR (300 MHz, CDCl3): d ˆ 7.33 7.18 (m, 5H,
ˆ
ArH), 6.50 (d, J ˆ 15.9 Hz, 1H, CH CH), 6.12 (dd, J ˆ 15.9,
ˆ
8.4 Hz, 1H, CH CH), 3.83 (t, J ˆ 9.0 Hz, 1H, OCH2CH), 3.69
(s, 3H, CO2CH3), 3.66 3.44 (m, 6H, OCH2CH, OCH2CH
OCH2CH2O), 3.33 (s, 3H, OCH3); 13C NMR (75 MHz, CDCl3):
d ˆ 172.8, 136.5, 133.6, 128.5, 127.7, 126.4, 123.7, 72.1, 71.8, 70.6,
59.0, 52.0, 49.9; HRMS(EI): calcd. for C 15H21O4: 265.1434;
found: 265.1434; anal. calcd.: C 68.16, H 7.63; found: C 68.19, H
7.62; 87% ee by HPLC: (R,R)-Whelk-O 1 column, 5% 2-
propanol in hexanes, 1 mL/min, tR (minor) 19.0 min, tR (major)
21.7 min; [a]2D5: À 42.3 (c 2.75, CHCl3).
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Influence of a b-Alkoxy Substituent on the C H Activation of Alkyl Ethers
FULL PAPERS
2a: Rf 0.42 (PE:ether, 2:1) [UV, KMnO4]; IR (neat): n ˆ
1741 cmÀ1; 1H NMR (500 MHz, CDCl3): d ˆ 7.44 (d, J ˆ
8.5 Hz, 2H, ArH), 7.21 (d, J ˆ 8.5 Hz, 2H, ArH), 3.90 (t, J ˆ
8.5 Hz, 1H, OCH2CH), 3.75 (dd, J ˆ 8.5, 5.5 Hz, 1H,
OCH2CH), 3.68 (s, 3H, CO2CH3), 3.51 (dd, J ˆ 8.5, 5.5 Hz,
1H, OCH2CH), 1.14 [s, 9H, C(CH3)3]; 13C NMR (75 MHz,
CDCl3): d ˆ 172.7, 135.4, 131.7, 130.0, 121.5, 73.3, 63.8, 52.1,
52.0, 27.3; HRMS(EI): calcd. for C 14H19BrO3Na: 337.0410;
found: 337.0399; 85% ee for corresponding tert-butyl ether by
HPLC: (R,R)-Whelk-O 1 column, 2% 2-propanol in hexanes,
1 mL/min, tR (minor) 5.3 min, tR (major) 5.8 min; [a]2D5: À 14.0
(c 0.25, CHCl3).
2b: Rf 0.20 (PE:ether, 1:1) [UV, PMA]; IR (neat): n ˆ 3413,
1735 cmÀ1; 1H NMR (400 MHz, CDCl3): d ˆ 7.36 (m, 5H,
ArH), 4.14 (t, J ˆ 9.2 Hz, 1H, OCH2CH), 3.87 (m, 2H,
OCH2CH, OCH2CH), 3.72 (s, 3H, CO2CH3), 2.25 (br m, 1H,
D2O exch, OH); 13C NMR (75 MHz, CDCl3): d ˆ 173.6, 135.6,
128.9, 128.2, 127.8, 64.6π 53.9, 52.2; HRMS(CI): calcd. for
C10H12O3: 181.0859; found: 181.0866; anal. calcd.: C 66.65, H
6.71; found: C 66.44, H 6.74; 79% ee for corresponding tert-
butyl ether by HPLC: CHIRALCEL OD-H column, 3% 2-
propanol in hexanes, 1 mL/min, tR (major) 4.3 min, tR (minor)
4.7 min; [a]2D5: À 57.6 (c 0.50, acetone), À 77.4 (c 0.54, CHCl3),
lit.[12b] {[a]2D3: À 69.8 (c 0.875, acetone) for>98% ee}.
ArH), 7.73 (s, 1H, ArH), 7.49 (m, 2H, ArH), 7.38 (dd, J ˆ 8.8,
1.6 Hz, 1H, ArH), 4.25 (m, 1H, OCH2CH), 4.03 (dd, J ˆ 8.8,
5.6 Hz, 1H, OCH2CH), 3.90 (m, 1H OCH2CH), 3.73 (s, 3H,
CO2CH3), 2.29 (br m, 1H, OH); 13C NMR (75 MHz, CDCl3):
d ˆ 173.6, 133.4, 133.0, 132.8, 128.7, 127.8, 127.7, 127.2, 126.4,
126.2, 125.9, 64.6, 54.0, 52.3; HRMS(EI): calcd. for C 14H14O3:
230.0940; found: 230.0937; anal. calcd.: C 73.03, H 6.13; found:
C 73.25, H 6.26; 76% ee for corresponding tert-butyl ether by
HPLC: CHIRALCEL OD-H column, 3% 2-propanol in
hexanes, 1 mL/min, tR (minor) 4.7 min, tR (major) 5.5 min;
[a]2D5: 69.1 (c 0.39, CHCl3) [product with Rh2(R-DOSP)4].
2f: Rf 0.37 (PE:ether, 9:1) [UV, KMnO4]; IR (neat): n ˆ
1738 cmÀ1; 1H NMR (300 MHz, CDCl3): d ˆ 7.33 7.16 (m, 5H,
ˆ
ArH), 6.50 (d, J ˆ 15.9 Hz, 1H, CH CH), 6.14 (dd, J ˆ 15.9,
ˆ
8.7 Hz, 1H, CH CH), 3.68 (m, 4H, OCH2CH, CO2CH3), 3.48
(dd, J ˆ 6.6, 5.4 Hz, 1H, OCH2CH), 3.42 3.35 (m, 1H,
OCH2CH), 1.13 [s, 9 H, O(CH3)3]; 13C NMR (75 MHz,
CDCl3): d ˆ 173.2, 136.7, 133.3, 128.5, 127.7, 126.4, 124.4,
73.2, 63.3, 51.8, 50.8, 27.4; HRMS(EI): calcd. for C 16H22O3Na:
285.1467; found: 285.1461; anal. calcd.: C 73.25, H 8.45; found:
C 73.25, H 8.46; 76% ee for corresponding tert-butyl ether by
HPLC: CHIRALCEL OD-H column, 3% 2-propanol in
hexanes, 1 mL/min, tR (minor) 4.9 min, tR (major) 5.5 min;
[a]2D5: 30.9 (c 0.39, CHCl3) [product with Rh2(R-DOSP)4].
3a/3b: Rf 0.35 (PE:ether, 9:1) [UV, KMnO4]; IR (neat): n ˆ
1736 cmÀ1; 1H NMR (500 MHz, CDCl3) (a 3:1 mixture of
diastereomers): d ˆ 7.43 (m, 2H, ArH), 7.23 (m, 2H, ArH), 3.94
(m, 1H, CH3CH), 3.67 (s, 3H, CO2CH3), 3.56 3.11 (m, 3H,
OCH2CH3, CHCO2CH3), 1.19 and 0.92 (2d, J ˆ 6.0 Hz, 3H,
CH3CH), 1.17 and 0.96 (2 t, J ˆ 7.0 Hz, 3H, OCH2CH3);
13C NMR (75 MHz, CDCl3) a 3:1 mixture of diastereomers):
d ˆ 173.0, 172.4, 135.5, 135.0, 131.8, 131.3, 130.8, 130.3, 121.8,
121.3, 77.1, 76.4, 65.0, 64.8, 58.7, 57.8, 52.0, 51.9, 18.5, 17.2, 15.5,
2c: Rf 0.27 (PE:ether, 1:1) [UV, PMA]; IR (neat): n ˆ 3436,
1739 cmÀ1; 1H NMR (300 MHz, CDCl3): d ˆ 7.15 (s, 4H, ArH),
4.12 (ddd, J ˆ 11.7, 11.7, 6.0 Hz, 1H, OCH2CH), 3.85 3.76 (m,
2H, OCH2CH, OCH2CH), 3.70 (s, 3H, CO2CH3), 2.33 (s, 3H,
ArCH3); 13C NMR (75 MHz, CDCl3): d ˆ 173.8, 137.5, 132.5,
129.6, 128.0, 64.6, 53.5, 52.2, 21.0; HRMS(EI): calcd. for
C11H15O3 [M ‡ H]: 195.1011; found: 195.1016; anal. calcd.: C
68.02, H 7.27; found: C 67.91, H 7.28; 71% ee for corresponding
tert-butyl ether by HPLC: CHIRALCEL OD-H column, 3% 2-
propanol in hexanes, 1 mL/min, tR (minor) 3.9 min, tR (major)
4.3 min; [a]2D5: 70.8 (c 0.72, CHCl3) [product with Rh2(R-
DOSP)4].
2d: Rf 0.19 (PE:ether, 1:1) [UV, PMA]; IR (neat): n ˆ 3412,
1733, 1513 cmÀ1; 1H NMR (500 MHz, CDCl3): d ˆ 7.19 (d, J ˆ
8.7 Hz, 2H, ArH), 6.88 (d, J ˆ 9.0 Hz, 2H, ArH), 4.10 (dd, J ˆ
12.6, 10.8 Hz, 1H, OCH2CH), 3.79 (m, 5H, OCH2CH,
OCH2CH, ArOCH3), 3.70 (s, 3H, CO2CH3), 2.26 (br m, 1H,
OH); 13C NMR (75 MHz, CDCl3): d ˆ 173.8, 159.2, 129.2,
127.6, 114.3, 64.7, 55.3, 53.0, 52.1; HRMS(EI): calcd. for
C11H14O4Na: 233.0791; found: 233.0784; anal. calcd.: C 62.85, H
6.71; found: C 63.01, H 6.31; 79% ee for corresponding tert-
butyl ether by HPLC: CHIRALCEL OD-H column, 3% 2-
propanol in hexanes, 1 mL/min, tR (minor) 4.7 min, tR (major)
5.5 min; [a]2D5: 71.0 (c 0.555, CHCl3) [product with Rh2(R-
DOSP)4].
2-(3-tert-Butyl-4-methoxyphenyl)-3-hydroxypropionic acid
methyl ester 2d× was also formed (2d:2d× ˆ 3:1) during
deprotection: Rf 0.24 (PE:ether, 1:1) [UV, PMA]; IR (neat):
n ˆ 3421, 1736 cmÀ1; 1H NMR (300 MHz, CDCl3): d ˆ 7.14 (d,
J ˆ 2.1 Hz, 1H, ArH), 7.08 (dd, J ˆ 8.4, 2.1 Hz, 1H, ArH), 6.83
(d, J ˆ 8.4 Hz, 1H, ArH), 4.10 (dd, J ˆ 12.6, 10.8 Hz, 1H,
OCH2CH), 3.80 (m, 5H, OCH2CH, OCH2CH, ArOCH3), 3.71
(s, 3H, CO2CH3), 1.36 [s, 9 H, ArC(CH3)3]; 13C NMR (75 MHz,
CDCl3): d ˆ 174.0, 158.1, 138.7, 126.9, 126.7, 126.3, 111.7, 64.8,
55.0, 53.4, 52.1, 34.8, 29.6; HRMS(EI): calcd. for C 15H22O4Na:
289.1410; found: 289.1410.
‡
15.2; LRMS(EI): m/z ˆ 302 [M ]; anal. calcd.: C 51.84, H 5.69;
found: C 51.76, H 5.55; 83% ee for minor isomer and 76% ee for
major isomer by HPLC: (R,R)-Whelk-O 1 column, 2% 2-
propanol in hexanes, 1 mL/min: minor isomer, tR (minor)
5.7 min, tR (major) 6.3 min: major isomer, tR (major) 6.0 min, tR
(minor) 7.4 min.; [a]2D5: 28.3 (c 1.075, CHCl3).
4a, syn-isomer: Rf 0.48 (hexane:ether, 9:1, Â 2) [UV, PMA];
IR (neat): n ˆ 1737 cmÀ1; 1H NMR (500 MHz, CDCl3): d ˆ 7.4
(d, J ˆ 8.5 Hz, 2H, ArH), 7.25 (d, J ˆ 8.5 Hz, 2H, ArH), 5.74 (m,
ˆ
ˆ
1H, CH CH), 5.30 (ddd, J ˆ 15.5, 8.5, 1.5 Hz, 1H, CH CH),
4.04 (t, J ˆ 8.5 Hz, 1H, CHOCH3), 3.65 (d, J ˆ 8.5 Hz, 1H,
CHCO2CH3), 3.63 (s, 3H, CO2CH3), 3.14 (s, 3H, OCH3), 1.71
(dd, J ˆ 6.0, 1.5 Hz, 3H, CH3CH CH); 13C NMR (125 MHz,
ˆ
CDCl3): d ˆ 171.7, 135.0, 131.6, 131.4, 130.7, 128.3, 121.4, 82.9,
56.9, 56.4, 52.0, 17.7; HRMS(EI): calcd. for C 14H17BrO3:
312.0356; found: 312.0362; 56% ee by HPLC: CHIRALCEL
OD-H column, 2% 2-propanol in hexanes, 1 mL/min, tR
(minor) 7.1 min, tR (major) 8.6 min; [a]2D5: 6.2 (c 4.00, CHCl3).
4b, anti-isomer: Rf 0.36 (hexane:ether, 9:1, Â 2) [UV,
PMA]; IR (neat): n ˆ 1739 cmÀ1; 1H NMR (400 MHz, acetone-
d6): d ˆ 7.43 (d, J ˆ 8.0 Hz, 2H, ArH), 7.23 (d, J ˆ 8.0 Hz, 2H,
ˆ
ˆ
ArH), 5.47 (m, 1H, CH CH), 5.05 (m, 1H, CH CH), 4.02 (t,
J ˆ 9.2 Hz, 1H, CHOCH3), 3.58 (m, 4H, CHCO2CH3,
CO2CH3), 3.15 (s, 3H, OCH3), 1.46 (d, J ˆ 6.4 Hz, 3H,
CH3CH CH); 13C NMR (75 MHz, CDCl3): d ˆ 172.7, 134.4,
ˆ
131.6, 131.5, 130.6, 127.7, 121.6, 83.9, 57.1, 56.5, 52.1, 17.6;
HRMS(EI): calcd. for C 14H17BrO3: 312.0352; found: 312.0356;
anal. calcd.. C 53.69, H 5.47; found: C 54.05, H 5.59; 67% ee by
HPLC: CHIRALPAK AD-RH column, 3% 2-propanol in
2e: Rf 0.18 (PE:ether, 1:1) [UV, PMA]; IR (neat): n ˆ 3523,
1735, 1719 cmÀ1; 1H NMR (300 MHz, CDCl3): d ˆ 7.82 (m, 3H,
Adv. Synth. Catal. 2003, 345, 1133 1138
asc.wiley-vch.de
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1137

Huw M. L. Davies, Jaemoon Yang
FULL PAPERS
hexanes, 1 mL/min, tR (minor) 3.8 min, tR (major) 4.2 min;
[a]2D5: 45.0 (c 1.60, CHCl3).
Org. Chem. 2002, 67, 4352, g) K. L. Tan, R. G. Bergman,
J. A. Ellman, J. Am. Chem. Soc. 2002, 124, 3202; h) H. A.
Zhong, J. A. Labinger, J. E. Bercaw, J. Am. Chem. Soc.
2002, 124, 1378.
5: An inseparable mixture of 5a (syn) and 5b (anti) was
obtained in 39% yield [with Rh2(OAc)4, 5a: 5b ˆ 1:4.12 by
chiral GC] and 17% yield [with Rh2(R-DOSP)4, 5a: 5b ˆ 1:3.76
by chiral GC], respectively. The relative stereochemistry was
assigned based on the literature[15a], but the absolute stereo-
chemistry was not determined.; Rf 0.38 (PE:ether, 9:1) [PMA];
[3] a) M. P. Doyle, M. A. McKervey, T. Ye, in Modern
Catalytic Methods for Organic Synthesis with Diazo
Compounds; Wiley-Interscience, New York, 1998,
pp. 112 162; b) G. Maas, in Topics in Current Chemistry,
Springer-Verlag, New York, 1987, Vol. 137, pp. 75 254;
c) H. M. L. Davies, E. G. Antoulinakis, J. Organomet.
Chem. 2001, 617 618, 45; d) H. M. L. Davies, J. Mol.
Cat. A 2002, 189, 125.
[4] M. M. Diaz-Requejo, T. R. Belderrain, M. C. Nicasio, S.
Trofimenko, P. J. Perez, J. Am. Chem. Soc. 2002, 124, 896.
[5] H. M. L. Davies, Q. Jin, P. Ren, A. Y. Kovalevsky, J. Org.
Chem. 2002, 67, 4165.
[6] P. Wang, J. Adams, J. Am. Chem. Soc. 1994, 116, 3296.
[7] a) H. M. L. Davies, T. Hansen, J. Am. Chem. Soc. 1997,
119, 9075; b) H. M. L. Davies, T. Hansen, M. R. Church-
ill, J. Am. Chem. Soc. 2000, 122, 3063.
[8] a) H. M. L. Davies, E. G. Antoulinakis, Org. Lett. 2000,
2, 4153; b) H. M. L. Davies, E. G. Antoulinakis, T.
Hansen, Org. Lett. 1999, 1, 383.
1
IR (neat). n ˆ 1725 cmÀ1; H NMR (500 MHz, CDCl3): d ˆ
ˆ
ˆ
5.81 (m, 1H, CH CH2), 5.06 (m, 2H, CH CH2), 4.23 (m, 2H,
CO2CH2CH3), 3.63 (d, J ˆ 5.2 Hz, 1H, CHOCH3), 3.40 (s, 3H,
OCH3), 2.64 (m, 1H, CHCH3), 1.30 (t, J ˆ 6.4 Hz, 3H,
CO2CH2CH3), 1.10 and 1.07 (2 d, 3:1, J ˆ 6.4 Hz, 3H,
‡
CHCH3); GC/MS: m/z ˆ 172 [M ]; 17% ee for minor diaster-
eomer (5a, syn) and 10% ee for major (5b, anti) diastereomer
by GC: 30-m chiraldex B-DM column, flow rate 1 mL/min,
808C isothermal, tR (minor diastereomer) 15.9 and 16.3 min, tR
(major diastereomer) 16.6 and 17.3 min; [a]2D5: 0.0 (c 0.60,
CHCl3).
6: The racemic compound is known.[16]; Rf 0.31 (PE:ether,
9:1) [PMA]; IR (neat): n ˆ 1741 cmÀ1; H NMR (400 MHz,
1
ˆ
CDCl3): d ˆ 5.86 (ddd, J ˆ 17.6, 10.4, 8.4 Hz, 1H, CH CH2),
ˆ
5.08 (d, J ˆ 17.6 Hz, 1H, CH CH2), 5.07 (d, J ˆ 10.4 Hz, 1H,
ˆ
CH CH2), 3.797 and 3.794 (2 s, 6H, CO2CH3), 3.49 (s, 3H,
OCH3), 2.99 (q, J ˆ 7.2 Hz, 1H, CHCH3), 1.10 (d, J ˆ 7.2 Hz,
3H, CHCH3); 13C NMR (75 MHz, CDCl3): d ˆ 168.57, 168.52,
137.8, 116.4, 88.1, 55.4, 52.27, 52.19, 44.3, 14.7; HRMS(EI):
calcd. for C9H12O4 [M CH3OH]; 184.0730; found: 184.0737;
0% ee by 1H NMR spectroscopy using europium [tris[3-
(heptafluoropropylhydroxymethylene)-(‡)-camphorate]
[Eu(hfc)3]; [a]D25: À 0.36 (c 3.935, CHCl3).
[9] a) L. R. Sousa, G. D. Y. Sogah, D. H. Hoffman, D. J.
Cram, J. Am. Chem. Soc. 1978, 100, 4569; b) R. J.
Steffeck, Y. Zelechonok, K. H. Gahm, J. Chromatogr.
A, 2002, 947, 301, and references cited therein; c) S.
Kobayashi, T. Hamada, S. Nagayama, K. Manabe, Org.
Lett. 2001, 3, 165.
À
À
[10] For recent examples of C H activation of methyl C H
bonds, see: a) H. M. L. Davies, C. Venkataramani, An-
gew. Chem. Int. Ed. 2002, 41, 2197; b) H. M. L. Davies,
Q. Jin, Tetrahderon: Asymmetry 2003, 14, 941.
Acknowledgements
[11] J. Adams, M.-A. Poupart, L. Grenier, C. Schaller, N.
Ouimet, R. Frenette, Tetrahedron Lett. 1989, 30, 1749.
[12] a) H. Imogai, M. Larcheveque, Tetrahedron: Asymmetry
1997, 8, 965; b) T. M. Baker, G. J. Bodwell, S. G. Davies,
A. J. Edwards, M. R. Metzler, Tetrahedron, 1993, 49,
5635; c) N. C. J. E. Chesters, K. Walker, D. O×Hagan,
H. G. Floss, J. Am. Chem. Soc. 1996, 118, 925; d) R.
Glaser, D. Shiftan, M. Drouin, J. Org. Chem. 1999, 64,
9217.
[13] H. M. L. Davies, P. Ren, Tetrahedron Lett. 2001, 42, 3149.
[14] H. M. L. Davies, L. M. Hodges, J. J. Matasi, T. Hansen,
D. S. Stafford, Tetrahedron Lett. 1998, 39, 4417.
[15] a) M. P. Doyle, V. Bagheri, N. K. Harn, Tetrahedron Lett.
1988, 29, 5119; b) W. Ando, T. Yagihara, S. Kondo, K.
Nakayama, H. Yamata, S. Nakaido, T. Migita, J. Org.
Chem. 1971, 36, 1732; c) M. P. Doyle, W. Hu, J. Org.
Chem. 2000, 65, 8839.
Financial support of this workby the National Science
Foundation (CHE 0092490) is gratefully acknowledged.
References
À
[1] For reviews on other methods for C H activation, see:
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[2] For recent representative examples of C H activation,
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1138
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2003, 345, 1133 1138