α-Heteroarylation of esters, lactones, amides, and lactams by nucleophilic aromatic substitution

Article abstract of DOI:10.1021/ol060246u

A mild and efficient α-heteroarylation of simple esters and amides was developed via nucleophilic aromatic substitution. The choice of NaHMDS in toluene gave the best results. A tandem α-heteroarylation and hydroxylation protocol using air as the oxidant

Full text of DOI:10.1021/ol060246u

ORGANIC
LETTERS
2006
Vol. 8, No. 7
1447-1450
r
-Heteroarylation of Esters, Lactones,
Amides, and Lactams by Nucleophilic
Aromatic Substitution
Hong C. Shen,* Fa-Xiang Ding, and Steven L. Colletti
Department of Medicinal Chemistry, Merck Research Laboratories, Merck &
Company, Inc., P.O. Box 2000, Rahway, New Jersey 07065-0900
hong_shen@merck.com
Received January 27, 2006
ABSTRACT
A mild and efficient
r-heteroarylation of simple esters and amides was developed via nucleophilic aromatic substitution. The choice of NaHMDS
in toluene gave the best results. A tandem
r-heteroarylation and hydroxylation protocol using air as the oxidant afforded tertiary alcohols in
good yields.
The R-arylation of carbonyl compounds is a useful reaction
to prepare R-aryl acetic acids, esters, and amides which are
common intermediates used in medicinal chemistry. These
compounds are often prepared from one of several classical
reactions that lack functional group compatibility and regio-
specificity.1 The most recent advance of such a reaction can
be exemplified by the pioneering work of the Hartwig2 and
Buchwald3 groups. They utilized the Pd-catalyzed R-arylation
of carbonyl compounds with aryl halides, which are typically
phenyl iodides or bromides. In contrast, heteroaryl halides,
such as chlorides, are rarely utilized by this strategy.4 Thus,
it would be complimentary to develop a general procedure
for R-heteroarylation of carbonyl compounds with hetero-
cyclic halides, some of which are often unreactive toward
Pd-catalyzed R-arylations. The SRN1 approach5,6 usually
suffers from low yields, inconvenient procedures involving
the handling of the ammonia solvent, and photostimulated
conditions or the incompatibility of substrates with strong
bases such as sodium amide. Alternatively, nucleophilic
aromatic substitution (SNAr) (Scheme 1) may present ad-
Scheme 1
vantages. Previous reports of such transformations involving
ester enolates are limited to doubly stabilized enolates such
as malonates,7 malonitriles,7,8 ammonium ylide esters,9 and
R-iminoesters.10 Herein, we report a mild and general
protocol to prepare R-heteroaryl esters or amides using
readily available heterocyclic chlorides and simple ester or
amide enolates. To the best of our knowledge, this is the
(1) March, J. AdVanced Organic Chemistry, 4th ed.; John Wiley &
Sons: New York, 2001; Chapters 10-16.
(2) For a leading reference, see: Jørgensen, M.; Lee, S.; Liu, X.;
Wolkowski, J. P.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 12557-
12565.
(3) For a leading reference, see: Moraki, W. A.; Buchwald, S. L. J.
Am. Chem. Soc. 2001, 123, 7996-8002.
(7) Ujjainwalla, F.; Walsh, T. F. Tetrahedron Lett. 2001, 42, 6441-
6445.
(4) You, J.; Verkade, J. G. Angew. Chem., Int. Ed. 2003, 42, 5051-
5053.
(8) (a) Turner, S. C.; Carroll, W. A.; White, T. K.; Gopalakrishna, M.;
Coghlan, M. J.; Shieh, C.-C.; Zhang, X.-F.; Parihar, A. S.; Buckner, S. A.;
Milicic, I.; Sullivan, J. P. Bioorg. Med. Chem. Lett. 2003, 13, 2003-2007.
(b) Katz, R. B.; Voyle, M. Synthesis 1989, 314-316.
(9) Jonczyk, A.; Kowalkowska, A. Synthesis 2002, 674-680.
(10) Vangelisti, M.; Amin, M.; Pannell, R. European patent. 1422220,
2004.
(5) Van Leeuwen, M.; McKillop, A. J. Chem. Soc., Perkin Trans. 1 1993,
20, 2433-2440.
(6) Carver, D. R.; Greenwood, T. D.; Hubbard, J. S.; Komin, A. P.;
Sachdeva, Y. P.; Wolfe, J. F. J. Org. Chem. 1983, 48, 1180-1185 and
references therein.
10.1021/ol060246u CCC: $33.50
© 2006 American Chemical Society
Published on Web 03/11/2006

first report of a general and practical R-heteroarylation of
simple esters or amides via the SNAr reaction.
Table 1. Effect of Base, Solvent, Temperature, and Reactant
In a medicinal chemistry program, we attempted to
synthesize 2-substituted 1,3,4-thiadiazol-5-ylacetic ester 3.
Instead of adopting a rather lengthy seven-step synthesis to
access 3 as described in the literature,11 we explored the
possibility of a SNAr route. Inspired by a recent publication
on R-arylation of nitriles from Merck process chemists,12 we
applied the similar reaction conditions for a facile synthesis
of R-thiadiazole acetate 3 (Scheme 2). When chlorothia-
Ratio on the Reaction
isolated
T
reaction
yield
entrya
base
(°C)
time/h solvent
of 6 (%)
1: R ) Et
NaHMDS
(0.6 M in
toluene)
0
2
toluene 20 (40% of 7a,
40% of 5)
Scheme 2
2: R ) Et
NaHMDS
-78
0, rt
16
2, 16
toluene 12 (67% of 5)
toluene 36 (10%
bisarylated
3b: R ) tBu NaHMDS
product +
30% of 5)
4: R ) tBu NaHMDS
-78, 0 0.5, 5 toluene 87
5: R ) tBu
6: R ) tBu
7: R ) tBu
8c: R ) tBu NaHMDS
9: R ) tBu NaHMDS
10: R ) tBu LDA
(0.5 M in
NaHMDS
NaHMDS
NaHMDS
0, rt
0, rt
0, rt
0, rt
0, rt
0, rt
2, 16
2, 16
2, 16
2, 16
2, 16
2, 16
dioxane
Et2O
THF
THF
toluene 85
0
51
<5
41
diazole 2 was reacted with ethyl acetate in the presence of
NaHMDS, the desired product 3 was obtained, yet ac-
companied with side product 4 in a 1:1 ratio. The two-
step synthesis rapidly provides 3 from commercially avail-
able aminothiadiazole 1 albeit in low yield. Starting
with this reaction, we aimed at developing a general
and practical approach to access R-heterocyclic esters and
amides.
Using substrate 5 as a model system,13 we systematically
investigated the impact of base, solvent, temperature, and
reactant ratio on the reaction. The reaction condition
optimization is summarized in Table 1. We again discovered
byproduct 7a when ethyl acetate was employed (Table 1,
entry 1). Presumably, the treatment of ethyl acetate with base
generates the enolate, which then undergoes a Claisen
condensation to release ethoxide. The resulting ethoxide
subsequently reacts with 5 to yield aryl ether 7a. We then
attempted the reaction at -78 °C to minimize the formation
of aryl ether 7a. However, overnight reaction at -78 °C gave
low conversion (∼30%) of the starting material with 12%
isolated yield of 6, although the side reaction was indeed
suppressed (Table 1, entry 2). Subsequent warming of the
reaction mixture to 0 °C increased the yield of both 6 and
7a as observed by LC/MS. Thus, it appears to be difficult
to diminish the side reaction via temperature control while
still driving the desirable reaction to completion. By switch-
ing ethyl acetate to tert-butyl acetate, we were pleased to
toluene <5
THF)
11: R ) tBu NaH
(60% in
0, rt
0, rt
0, rt
0, rt
2, 16
2, 16
2, 16
2, 16
toluene 43
toluene 32
toluene 49
toluene 81
mineral oil)
12: R ) tBu TMPLi
(prepared in
situ in THF)
13: R ) tBu KHMDS
(0.5 M in
toluene)
14: R ) tBu LiHMDS
(1 M in
THF)
a Procedure A: under N2 to a solution of 5 (0.25 mmol) and acetate
(0.75 mmol) in 1 mL of solvent was added base (0.75 mmol) at the indicated
temperature. b 0.25 mmol of 5, 0.25 mmol of tert-butyl acetate, and 0.25
mmol of base were used. c To a solution of acetate was added base at 0 °C.
After being stirred for 30 min at 0 °C, to the resulting solution was then
added 5.
see the improved yield (36%) of 6b and no formation of 7b
(Table 1, entry 3). Meanwhile, about a 10% yield of
bisarylated product was detected if the ratio of acetate, base,
and 5 was 1:1:1. If the ratio of ester and base to 5 was
increased to 3:3:1, 87% yield of 6b was obtained and the
bisarylated product was no longer detectable by LC/MS. The
formation of aryl ether was completely eliminated most likely
because of the sluggishness of the Claisen condensation to
generate tert-butoxide. Furthermore, even if tert-butoxide is
ever formed, the steric hindrance would presumably prevent
its substitution with aryl halides. Now, using tert-butyl acetate
as a substrate, we found that solvent plays a significant role
in this reaction. The use of THF, dioxane, or diethyl ether
gave poor yields of the desired product (Table 1, entries
(11) Toyooka, K.; Kasai, T.; Hori, S.; Kawashima, Y.; Shibuya, M.;
Kubota, S. Chem. Pharm. Bull. 1991, 39, 2837-2841.
(12) Klapars, A.; Waldman, J. H.; Campos, K. R.; Jensen, M. S.;
McLaughlin, M.; Chung, J. R. L.; Cvetovich, R. J.; Chen, C. J. Org. Chem.
2005, 70, 10186-10189.
(13) Only 9% yield of the desired product was obtained for the reaction
of ethyl acetate enolate with methyl chlorothiadiazole as recorded in the
literature. Collins, I.; Moyers, C.; Davey, W. B.; Rowley, M.; Bromidge,
F. A.; Quirk, K.; Atack, J. R.; McKerna, R. M.; Thompson, S.-A.; Wafford,
K.; Dawson, G. R.; Pike, A.; Sohal, B.; Tsou, N. N.; Ball, R. G.; Castro,
J. L. J. Med. Chem. 2002, 45, 1887-1900.
1448
Org. Lett., Vol. 8, No. 7, 2006

Table 2. Reaction Scope for Esters and Lactonesa
Table 3. Reaction Scope for Amides and Lactamsa
a Following procedure A described in Table 1 unless otherwise noted.
b 1 equiv of nucleophile, 2 equiv of base, and 1 equiv of chloride were
used. c Procedure B: to the nucleophile (1 equiv) and halide (1 equiv) at 0
°C was added base (2 equiv) under N2. After 2 h at room temperature, the
reaction mixture was exposed to air and stirred for 12 h. d 1 equiv of
nucleophile, 1 equiv of chloride, and 1.2 equiv of base were used.
a Following procedure A described in Table 1 unless otherwise noted.
b 1 equiv of nucleophile, 2 equiv of base, and 1 equiv of chloride were
used. c Follow general procedure B of Table 2. To a nucleophile (1 equiv)
and chloride (1 equiv) at 0 °C was added base (2 equiv) under N2. After 2
h, the reaction mixture was warmed to room temperature and stirred for 12
h before it was exposed to air. d The enolate was formed by treating the
amide (2 equiv) with base (2 equiv) at -78 °C and was stirred for 30 min
prior to the addition of an electrophile (1 equiv) under nitrogen. e After
following d, the reaction mixture was warmed to room temperature over 2
h and then exposed to air.
5-8). The major byproduct observed was the dechlorinated
phenyl thiadiazole. Interestingly, when diethyl ether was
employed, an appreciable amount of 6b was isolated in
contrast to THF and dioxane (Table 1, entry 6). Toluene is
clearly a superior solvent in this reaction, and dechlorination
was not observed despite a small amount of THF present in
the commercial base solution (Table 1, entry 14). To avoid
dechlorination in THF, one modification is to generate the
enolate before the addition of heterocyclic halides (Table 1,
entry 8). This procedure is less convenient than procedure
A but does improve the yield dramatically. The choice of
base also had a profound impact on the reaction. Sodium or
lithium hexamethyldisilazide (Table 1, entries 9 and 14) gave
much higher yields than their potassium counterpart (Table
1, entry 13). The worst case is LDA, which gave a complex
reaction mixture with a trace amount of the desired product
6b (Table 1, entry 10). Lithium tetramethylpiperidine
(LTMP) gave a comparably modest yield as KHMDS (Table
1, entry 12).
We subsequently explored the scope of this reaction as
shown in Tables 2 and 3. Various readily available chloro-
heterocycles including benzothiazole, oxadiazole, benzox-
azole, quinoxaline, pyrazine, isoquinoline, pyridine, pyrid-
azine, and 1,2,4- and 1,3,4-thiadiazoles were employed. The
scope of nucleophiles extends to five- and six-membered
lactones (Table 2, entries 8-10) and lactams (Table 3, entries
3-10). Known to be reactive toward the Pd-catalyzed
R-arylations, the iodophenyl moiety remains intact under the
nucleophilic aromatic substitution conditions (Table 2, entry
3) and offers an opportunity for further cross-coupling
reactions. The formation of quaternary carbon atoms is
possible as shown in entries 8 and 9 of Table 2. It was found
Org. Lett., Vol. 8, No. 7, 2006
1449

that δ-valerolactone 24 reacted more slowly compared to
other substrates and gave a poorer yield of the desired
product (Table 2, entry 10). Substrates such as chloro-
pyrimidines (Table 2, entry 11 and Table 3, entry 11) or
chloroimidazole (Table 3, entry 8) failed to give any
R-arylation product.
and chloroimidazole (Table 3, entry 8) failed to give the
R-arylation product after 12 h. When the reaction was
exposed to air afterward, the hydroxy product 42 was isolated
in good yield indicating that the enolate was indeed formed
and subsequently oxidized by air.
The attempt to establish asymmetric stereoinduction using
Meyers’ auxiliary19 did not give high diastereoselectivity.
This is most likely due to the racemization of the product
(Table 3, entry 9) because the R-proton of the product 44 is
more acidic than that of the starting material 43.
In conclusion, we have developed an efficient and rather
general protocol for the R-heteroarylation of simple esters,
lactones, amides, and lactams by nucleophilic aromatic
substitution. This method provides several desirable features
that are either complementary or improvements to the Pd-
catalyzed reactions. Specifically, heteroaryl chlorides may
be used, which are more commercially available, much more
stable, and/or cheaper than the corresponding bromides or
iodides. Reactions can also be conducted at ambient tem-
perature as opposed to the elevated temperature usually
required by Pd-catalyzed R-arylations. Last, the introduction
of air to the reaction leads to R-hydroxy-R-heteroaryl esters
and amides offering more diversity to this process.
Interestingly, when chlorobenzothiazole 10 was employed
to react with tert-butyl propionate without rigorous exclusion
of air, we observed two products corresponding to the desired
R-benzothiazole ester 14 (49%) and tandem R-arylation and
R-hydroxylation product 15 (39%).14 When we carefully
conducted the reaction under nitrogen, only 14 was obtained
in 91% yield (Table 2, entry 4). On the other hand, if the
reaction mixture was warmed to ambient temperature and
then exposed to air, the hydroxylation product 15 was formed
exclusively (Table 2, entry 5). Thus, this one-pot protocol
provides an inexpensive, convenient, and efficient approach
to access R-hydroxy-R-heteroaryl esters15 compared to the
conventional methods, such as the use of Vedejs’ reagent,16
Rubottom oxidation,17 or Davis oxaziridine.18 Furthermore,
this procedure also applies to amides and lactams, as shown
in entries 4, 6, and 10 in Table 3. The reaction of oxindole
(14) Most likely, the anion is oxidized through a radical aerobic oxidation
mechanism: (a) Nobe, Y.; Arayama, K.; Urabe, H. J. Am. Chem. Soc. 2005,
127, 18006-18007 and references therein. (b) Wasserman, H. H.; Lipshutz,
B. H. Tetrahedron Lett. 1975, 16, 1731-1734. (c) Bailey, E. J.; Barton, D.
H. R.; Elks, J.; Templeton, J. F. J. Chem. Soc. 1962, 1578-1591.
(15) For leading references to the synthesis of R-hydroxy carbonyl
compounds: (a) Krepski, L. R.; Heilmann, S. T.; Rasmussen, J. K.
Tetrahedron Lett. 1983, 24, 4075-4078. (b) Admczyk, M.; Dolence, E.
K.; Watt, D. S.; Reibenspies, J. H.; Anderson, O. P. J. Org. Chem. 1984,
49, 1378-1382.
Acknowledgment. We thank Drs. Artis Klapars,
Cheng-yi Chen, and James R. Tata for helpful discussions.
Supporting Information Available: Representative ex-
perimental procedures and spectroscopic data for new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(16) Vedejs, E.; Engler, D. A.; Telschow, J. E. J. Org. Chem. 1978, 43,
188-196.
(17) Rubottom, M. A.; Vazquez, M. A.; Pelegrina, D. R. Tetrahedron
Lett. 1974, 15, 4319-4322.
OL060246U
(18) Davis, F. A.; Vishwakarma, L. C.; Billmers, J. M.; Finn, J. J. Org.
Chem. 1984, 49, 3241-3243.
(19) Romo, D.; Meyers, A. I. Tetrahedron 1991, 47, 9503-9569.
1450
Org. Lett., Vol. 8, No. 7, 2006