Direct displacement of alkoxy groups of vinylogous esters by grignard reagents

Article abstract of DOI:10.1021/jo102537n

The direct displacement of alkoxy groups from the β position of aromatic and unsaturated esters and ketones is described. The reaction is chemo- and regioselective, displaying wide substrate scope.

Full text of DOI:10.1021/jo102537n

NOTE
pubs.acs.org/joc
Direct Displacement of Alkoxy Groups of Vinylogous
Esters by Grignard Reagents
Anthony J. Brockway, Marcos Gonzꢀalez-Lꢀopez, James C. Fettinger, and Jared T. Shaw*
Department of Chemistry, One Shields Ave, University of California, Davis, California 95616, United States
S Supporting Information
b
ABSTRACT: The direct displacement of alkoxy groups from the
β position of aromatic and unsaturated esters and ketones is
described. The reaction is chemo- and regioselective, displaying
wide substrate scope.
he creation of carbonꢀcarbon bonds at sp2-hybridized
T
carbon centers is dominated by transition metal-catalyzed
cross-coupling reactions. In most cases, an organometallic cou-
pling partner reacts with an aryl or vinyl halide or triflate in the
presence of a palladium or nickel catalyst.1 Although these
transformations are a mainstay of organic synthesis, complemen-
tary reactivity in the form of direct displacement reactions are
useful in cases where orthogonal reactivity enables selective
functionalization of a synthetic intermediate.
The direct, i.e. catalyst-free, displacement of aryl alkoxy groups
has been used in the synthesis of substituted aromatic rings. An
early example is found in the displacement of an o-methoxy
group from a hindered naphthophenone (Figure 1).2 This
reaction was later applied to aromatic esters3 and to the
auxiliary-controlled synthesis of biaryl bonds using a naphthyl
ether derived from menthol.4 One dramatic example of displace-
ment of a methoxy group on an unhindered ester has been
reported to proceed in high yield, which was tentatively attrib-
uted to the presence of an activating o-cyano group.5 Displace-
ment of o-methoxy groups from extremely hindered benzoate
esters was also demonstrated.6 A more general synthetic strategy
was realized by replacing carbonyl groups with oxazolines to
serve as carboxylic acid equivalents that avoided any potential
carbonyl addition.7 This reaction was subsequently extended to
naphthalenes,8 rendered asymmetric with chiral oxazolines,9 and
used as a key bond construction in the assembly of natural
products.10
Figure 1. Displacement of methoxy groups from naphthyl ketones and
esters.
We recently observed that iodinated naphthopyranone 1
(Scheme 1) exhibited remarkably selective reactions with i-
PrMgCl. Almost exclusive displacement of the methoxy group
at the 10-position was observed, with no observable addition to
the lactone ring. On the basis of this result, we initiated a
systematic study of this displacement reaction. Herein we report
the capabilities of this reaction using a variety of substrates,
including nonaromatic vinylogous esters and unhindered
ketones.
seen in Table 1, the displacement of alkoxy groups adjacent to
esters in naphthyl esters is affected by the steric demand of both
the Grignard reagent and the alkyl group of the ether. Although
displacement of methoxy groups is efficient for aryl as well as
primary and secondary organomagnesium compounds, this
reaction fails completely for t-BuMgCl. A similar trend was
A series of 1-alkoxy-2-naphthoic methyl esters was examined
in displacement reactions with a variety of Grignard reagents. As
Received: December 21, 2010
Published: March 29, 2011
r
2011 American Chemical Society
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|

The Journal of Organic Chemistry
NOTE
Scheme 1. Displacement of a Methoxy Group in the
Presence of a Lactone and an Aryl Iodide
Table 1. Influence of Steric Demand of the Alkoxy Substitu-
ent (R1) and Grignard Reagent (R2) on the Yield of Dis-
placement Product
entry
substrate (R1)
R2 MgX
product
yield, %
1
2
5a (CH3)
5b (n-Bu)
5c (Bn)
5d (i-Pr)a
5a (CH3)
5b (n-Bu)
5c (Bn)
5d (i-Pr)a
5a (CH3)
5b (n-Bu)
5c (Bn)
5d (i-Pr)a
5a (CH3)
5b (n-Bu)
5c (Bn)
n-BuMgCl
n-BuMgCl
n-BuMgCl
n-BuMgCl
i-BuMgCl
i-BuMgCl
i-BuMgCl
i-BuMgCl
PhMgBr
6a
6a
6a
6a
6b
6b
6b
6b
6c
6c
6c
6c
6d
6d
6d
6d
90
80
58
35
70
63
53
33
70
66
49
25
78
71
50
30
3
4
5
6
7
8
9
10
11
12
13
14
15
16
PhMgBr
PhMgBr
PhMgBr
i-PrMgCl
i-PrMgCl
i-PrMgCl
i-PrMgCl
5d(i-Pr)a
a Heated to reflux for 3 h.
observed for n-butyl ethers and the efficiency of displacement
drops off for benzyl ethers. Finally, isopropyl ethers are not
displaced under temperatures ranging from ꢀ78 °C to room
temperature but can be displaced in modest yields upon refluxing
in dichloromethane (DCM).
Scheme 2. Comparison of Alkyl Ether and Tosylate Reac-
tivity toward Displacement
The displacement reaction is unique to organomagnesium
compounds, possibly due to the activating effect of a transiently
formed magnesium chelate. Addition of n-butyllithium to 5a or
n-butylzinc chloride provided the displacement product in poor
yields (20% and 15% respectively). In addition, competition
between displacement of a methoxy group and a toluenesulfo-
nate favored displacement of the methoxy group completely
(Scheme 2). A one-to-one mixture of propyl ester 7 and allyl
ester 8 was treated with 1 equiv of n-butyl magnesium chloride.
Although a tosylate is ostensibly a much better leaving group, the
reduced Lewis basicity of this group would be expected to form a
much less stable chelate complex with magnesium, resulting in
less activation of the sp2 carbon center toward nucleophilic
attack. A subsequent experiment revealed complete selectivity
pairing between Grignard reagents and alkoxy groups and a
similar relationship between organomagnesium cuprates and
naphthyl tosylates.
High yields of displacement product are observed in the
reaction of methyl 3-methoxy-2-naphthoate 12. This reaction
requires the disruption of all of the naphthalene aromaticity to
proceed. In contrast, no reaction is observed with methyl
2-methoxybenzoate (not shown), demonstrating that the activa-
tion energy for this process is prohibitively high. The analogous
reaction of the corresponding oxazoline requires high tempera-
ture and long reaction times.7a
reaction of substrate 14, in which methoxy groups at both
positions can be displaced. Although no reaction is observed
in THF, the reaction in dichloromethane proceeded readily
at ꢀ78 °C with preferential attack at the 1 position. As
expected, higher reactivity was observed in DCM, when
compared to THF, due to the decreased solvation of the
Grignard reagent.
The displacement reaction is regioselective (Scheme 3). A
competition experiment between 5a and 12 indicated that attack
at the 1 position was favored. This trend is also observed in the
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The Journal of Organic Chemistry
NOTE
Scheme 3. Regioselectivity in the Displacement of Alkoxides
with Grignard Reagents
placement of the alkyl or aryl group cis to the ester. Analogous
cyclic substrates react with a range of efficiency. A fused
5-membered-ring ester 23 is totally unreactive
toward n-BuMgCl, even in refluxing THF or CH2Cl2 (eq 4).
6-Membered-ring ester 24 undergoes smooth displacement
(eq 5). These results are consistent with the increased bond
angle and the weaker chelate structure that can be formed
between magnesium and the β-alkoxy carbonyl.
In summary, we have demonstrated that direct displacement
of alkoxy groups from aromatic and R,β-unsaturated esters and
ketones is an efficient CꢀC bond-forming process. Although
ketones are generally viewed as incompatible with the high
nucleophilicity of Grignard reagents, we have shown that the
displacement reaction is facile at temperatures below which the
ester or ketone products will undergo addition. This process
enables the CꢀC bond formation with normally unreactive
alkoxy groups and minimal use of protecting groups.
Table 2. Comparison of Carbonyl Reactivity toward Alkoxide
Displacement
’ EXPERIMENTAL SECTION
General Procedure 1: Displacement of Alkyl Ethers by
Grignard Reagents. To a cooled solution (ꢀ78 °C) of alkyl ether
(1.00 mmol) in THF or DCM (5 mL) was added a solution of i-PrMgCl
in THF (2.0 M, 0.5 mL). The reaction was monitored until complete by
TLC and quenched with saturated ammonium chloride (5 mL). The
resulting layers were separated, and the aqueous layer was extracted with
2 ꢁ 10 mL of EtOAc. The combined organic layers were washed with
20 mL of brine, dried (MgSO4), and concentrated in vacuo to afford the
crude displacement product. The product was purified by flash chro-
matography to afford pure displacement product.
entry substrate (R1) R2 ratio of 19:20 isolated yield, % (product)
1
2
3
4
5
18a
18b
18c
18b
18c
n-Bu
n-Bu
n-Bu
i-Pr
>95:<5
27:73
85 (19a)
66 (20b)
85 (20c)
61 (20d)a
90 (20e)
<5:>95
<5:>95
<5:>95
i-Pr
General Procedure 2: Displacement of Alkyl Ethers by
Grignard Reagents. To a cooled solution (ꢀ78 °C) of alkyl ether
(1.00 mmol) in THF or DCM (5 mL) was added a solution of i-PrMgCl
in THF (2.0 M, 0.5 mL). The solution was allowed to warm to rt and
then heated at reflux for 3 h. The reaction was monitored until complete
by TLC and quenched with saturated ammonium chloride (5 mL). The
resulting layers were separated, and the aqueous layer was extracted with
2 ꢁ 10 mL of EtOAc. The combined organic layers were washed with
20 mL of brine, dried (MgSO4), and concentrated in vacuo to afford the
crude displacement product. The product was purified by flash chro-
matography to afford pure displacement product.
4b: According to general procedure 1, 3 (0.030 g 0.104 mmol) was
reacted with a solution of PhMgBr in THF (1.0 M, 0.10 mL) to afford a crude
yellow solid. The solid was purified by flash chromatography (10:90 EtOAc/
hexanes) to yield the product 4b as a white solid (0.027 g, 77%). 1H NMR
(300 MHz, CDCl3) δ7.52 (s, 1H), 7.33 (d, J=7.2Hz, 3H), 7.19(dd, J=2.0,
7.4 Hz, 2H), 6.72 (d, J = 2.4 Hz, 1H), 6.36 (d, J = 2.4 Hz, 1H), 4.48 ꢀ 4.43
a The corresponding secondary alcohol, resulting from carbonyl reduc-
tion, was isolated in 20% yield.
The displacement reaction works well with alkyl ketones
(Table 2). Methyl ketone 18b reacts with a significant preference
for methoxy group displacement when treated with either i-PrMgCl
or n-BuMgCl. n-Butyl ketone 18c reacts with complete selectivity for
methoxy group displacement and none of the alcohol product 20c
can be observed by GCMS. Although related reactions of hindered
aromatic ketones have been observed, this is the first example of an n-
alkyl ketone undergoing alkoxy group displacement.
Nonaromatic carbonyl compounds are also substrates for
displacement. Z-Ethyl 3-methoxycinnamate 21 reacts with n-
BuMgCl with high yield to give a 50:50 mixture of alkene isomers
(eq 3). This result indicates that the collapse of the presumed β-
alkoxy enolate intermediate proceeds with little preference for
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NOTE
(m, 2H), 3.93 (s, 3H), 3.32 (s, 3H), 3.15 (t, J = 5.7 Hz, 2H); 13C NMR (101
MHz, CDCl3) δ 163.8, 160.7, 159.9, 144.9, 142.9, 138.5, 136.5, 128.2, 126.7,
126.2, 124.5, 120.9, 120.3, 99.8, 98.4, 66.7, 55.7, 55.6, 30.2; HRMS (ESI) m/z
calcd for C21H18O4Na (M þ Na)þ 357.1103, found 357.1111; IR (thin film)
3095, 2910, 1715, 1595 cmꢀ1; mp 185ꢀ186 °C.
by the National Institutes of Health (R56AI80931-01 and
R01AI080931-01). M.G.L. thanks the Fundaciꢀon Ramon Areces
for a postdoctoral fellowship and A.J.B. acknowledges support in
the form of a Bradford Borge Graduate Research Fellowship
from UC Davis.
9: Double Labeling Experiment. An equimolar amount of 7
(0.030 g, 0.079 mmol) and 8 (0.019 g, 0.079 mmol) was dissolved in
0.5 mL of THF and the solution was cooled to ꢀ78 °C. To this solution
was added a 1.5 M solution of n-BuMgCl in THF (0.052 mL, 0.079
mmol). The reaction was stirred for 10 min and was then quenched with
saturated ammonium chloride (5 mL). The resulting layers were
separated, and the aqueous layer was extracted with 2 ꢁ 10 mL of
EtOAc. The combined organic layers were washed with 10 mL of brine,
dried (MgSO4), and concentrated in vacuo to afford a crude oil. GCMS and
NMR analysis showed only methoxy displacement and no observable
evidence of tosylate displacement. The crude product was purified by flash
chromatography (20:80 EtOAc/hexanes) to afford 9 (0.020 g, 95%) as a
colorless oil. 1H NMR (300 MHz, CDCl3) δ8.14ꢀ8.09(m, 1H), 7.80ꢀ7.43
(m, 5H), 4.25 (t, J = 6.7 Hz, 2H), 3.36ꢀ3.2 (m, 2H), 1.81ꢀ1.60 (m, 2H),
1.53ꢀ1.40 (m, 4H), 0.99 (t, J = 7.4 Hz, 3H), 0.92 (t, J = 7.3 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 169.1, 141.985, 135.2, 132.3, 128.9, 128.1, 127.3,
126.7, 126.4, 126.2, 125.5, 67.0 33.9, 29.6, 23.6, 22.4, 14.2, 10.9; HRMS (ESI)
m/z calcd for C18H23O2 (M þ H)þ 271.1693, found 271.1690; IR (thin
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film) 3070, 2937, 2880, 1715, 1595 cmꢀ1
.
Competition Experiment. An equimolar amount of 5a (0.10 g,
0.462 mmol) and 11 (0.10 g, 0.462 mmol) was dissolved in 2 mL of THF
and the solution was cooled to ꢀ78 °C. To this solution was added a
2.0 M solution of i-PrMgCl in THF (0.23 mL, 0.462 mmol). The reaction
was stirred for 10 min and was then quenched with saturated ammonium
chloride (5 mL). The resulting layers were separated, and the aqueous layer
was extracted with 2 ꢁ 10 mL of EtOAc. The combined organic layers were
washed with 10 mL of brine, dried (MgSO4), and concentrated in vacuo to
afford a crude oil. NMR analysis showed only displacement at the
1-position. The crude product was purified by flash chromatography
(20:80 EtOAc/hexanes) to afford 6d (0.079 g, 75%) as the only product.
20e: According to general procedure 1, 18c (0.035 g, 0.1457 mmol)
was reacted with a solution of i-PrMgCl in THF (2.0 M, 0.073 mL) to
afford a crude oil. The oil was purified by flash chromatography (10:90
EtOAc/hexanes) to yield the product 20e as a colorless oil (0.033 g,
90%). 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 8.0 Hz, 1H), 7.77 (d,
J = 8.3 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.53ꢀ7.34 (m, 2H), 7.16 (d, J =
8.5 Hz, 1H), 3.60ꢀ3.42 (m, 1H), 2.81 (t, J = 7.4 Hz, 2H), 1.71ꢀ1.59 (m,
2H), 1.50 (d, J = 7.2 Hz, 6H), 1.35 (dd, J = 7.4, 14.8 Hz, 2H), 0.88 (t, J =
7.3 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 210.0, 140.9, 139.3, 134.9,
131.8, 129.4, 127.1, 126.4, 126.3, 126.1, 123.0, 44.4, 31.6, 26.5, 22.9, 22.6,
14.2; HRMS (ESI) m/z calcd for C18H23O (M þ H)þ 255.1743, found
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255.1742; IR (thin film) 3095, 2959, 2865, 1687 cmꢀ1
.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures, spec-
b
tra (1H NMR, 13C NMR, NMR) for all new compounds, and a
CIF file for 4b. This material is available free of charge via the
Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: shaw@chem.ucdavis.edu.
’ ACKNOWLEDGMENT
This research was supported by the Petroleum Research
Fund (administered by the American Chemical Society) and
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