Direct C-arylation of β-enamino esters and ketones with arynes

Article abstract of DOI:10.1021/ol063057k

(Chemical Equation Presented) An efficient, mild, and general method for the C-arylation of β-enamino esters and ketones with arynes has been developed. This methodology provides a facile and direct access to a variety of substituted aromatic β-enamino co

Full text of DOI:10.1021/ol063057k

ORGANIC
LETTERS
2007
Vol. 9, No. 6
1029-1032
Direct C-Arylation of
and Ketones with Arynes
â-Enamino Esters
Yeeman K. Ramtohul* and Anik Chartrand
Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research,
Merck Frosst Canada & Co., Inc., P.O. Box 1005, 16711 Trans Canada Highway,
Kirkland, Quebec, Canada H9H 3L1
yeeman_ramtohul@merck.com
Received December 18, 2006
ABSTRACT
An efficient, mild, and general method for the C-arylation of â-enamino esters and ketones with arynes has been developed. This methodology
provides a facile and direct access to a variety of substituted aromatic
â
-enamino compounds in moderate to excellent yield.
With the development of a mild and general method for the
generation of arynes from ortho-silyl aryltriflates and a
fluoride anion,1 the use of aryne has seen a growing interest
in the field of organic synthesis.2,3 Because of its electro-
philicity, a wide variety of anionic and uncharged nucleo-
philes add readily to arynes which represent a direct approach
to access substituted arenes.2 In most cases, when an
electrophile is tethered to the nucleophile, the initially formed
zwitterion (Figure 1) undergoes a subsequent intramolecular
Typical examples for the insertion of arynes into a
heteroatom-hydrogen bond include amines, sulfonamides,
carbamates, phenols, and carboxylic acids.4 However, when
active methylene compounds such as â-keto esters,5 malonate
esters,6 and R-cyanocarbonyl compounds7 are used as the
nucleophile, the net result is insertion of the aryne between
the R-methylene and the carbonyl group to generate ortho-
disubstituted arenes.
Because amino groups are known to react with benzyne,4,8
we attempted N-arylation of â-enamino esters 2a with the
benzyne precursor ortho-silyl aryltriflate 1 in the presence
of CsF in CH3CN at 80 °C (Table 1, entry 1). Interestingly,
(3) (a) For the application of arynes in total synthesis, see: Tambar, U.
K.; Ebner, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 11752-
11753. (b) Sato, Y.; Tamura, T.; Mori, M. Angew. Chem., Int. Ed. 2004,
43, 2436-2440.
(4) Liu, Z. J.; Larock, R. C. J. Org. Chem. 2006, 71, 3198-3209 and
references therein.
Figure 1. Insertion of benzyne into a nucleophile-electrophile
σ-bond (Nu-E).
(5) Tambar, U. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 5340-
5341.
(6) Yoshida, H.; Watanabe, M.; Ohshita, J.; Kunai, A. Chem. Commun.
2005, 3292-3294.
reaction with the electrophile leading to the formal insertion
of the aryne into the Nu-E σ-bond.
(7) Yoshida, H.; Watanabe, M.; Ohshita, J.; Kunai, A. Tetrahedron Lett.
2005, 46, 6729-6731.
(8) (a) Liu, Z. J.; Larock, R. C. Org. Lett. 2003, 5, 4673-4675. (b) Liu,
Z. J.; Larock, R. C. Org. Lett. 2004, 6, 3739-3741. (c) Liu, Z. J.; Larock,
R. C. J. Am. Chem. Soc. 2005, 127, 13112-13113. (d) Yoshida, H.;
Shirakawa, E.; Honda, Y.; Hiyama, T. Angew. Chem., Int. Ed. 2002, 41,
3247-3249. (e) Yoshida, H.; Minabe, T.; Ohshita, J.; Kunai, A. Chem.
Commun. 2005, 34540-3456. (f) Yoshida, H.; Fukushima, H.; Ohshita, J.;
Kunai, A. J. Am. Chem. Soc. 2006, 128, 11040-11041.
(1) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983, 1211-
1214.
(2) For a review on the nucleophilic coupling with arynes, see: Kessar,
S. V. ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: New York, 1991; Vol. 4, pp 483-515.
10.1021/ol063057k CCC: $37.00
© 2007 American Chemical Society
Published on Web 02/20/2007

Table 1. Optimization of Reaction Conditionsa
Table 2. C-Arylation of â-Enamino Esters with Benzynea
FQ source
(equiv)
triflate temp time yield
entry solvent
(equiv) (°C)
(h)
(%)b
1
2
3
4
5
6
7
8
9
CH3CN CsF (2.5)
CH3CN CsF (2.5)
1.25
1.25
1.25
1.25
1.25
1.25
1.25
1.25
1.5
80
60
50
40
rt
rt
rt
rt
rt
2
4
5
6
7
8
9
2
3
71
86
84
82
87
77
75
64
26
CH3CN CsF (2.5)
CH3CN CsF (2.5)
CH3CN CsF (2.5)
CH3CN CsF (1.5)
CH3CN CsF (1.1)
THF
THF
TBAF (2.5)
KF/18-C-6 (1.5)
a Reaction conditions: 0.4 mmol of the â-enamino ester 2a in 0.2 M
solvent in a sealed vial. b Isolated yield.
no N-arylation product was isolated and instead reaction
occurred at the R-carbon to generate the C-arylation product
3a in 71% yield. Moreover, although an ester group is
present, no insertion of the benzyne into the R-carbon and
carbonyl σ-bond was observed as is the case with â-keto
esters,5 malonate esters,6 and R-cyanocarbonyl compounds.7
â-Enamino esters are interesting motifs as they can be
reduced asymmetrically and transformed into chiral â-amino
acids.9 To the best of our knowledge, no direct intermolecular
arylation of â-enamino esters involving arynes has been
reported, although some examples of arylation employing
transition-metal and radical-mediated reactions have been
published.10 Herein, we report an efficient and facile
intermolecular C-arylation of â-enamino esters and ketones
with arynes under mild conditions.
We first examined the effect of temperature on the
arylation of the â-enamino ester 2a and found that a lower
temperature is more favorable (Table 1, entries 2-5),
although a longer reaction time is needed. However, using
less CsF (entries 6 and 7) lowered the yield slightly and using
other reported sources of fluoride for generating aryne such
as TBAF1 and KF/18-Crown-66 had a deleterious effect on
the yield (entries 8 and 9). Because TBAF and KF/18-
Crown-6 generate benzyne much faster due to the higher
concentration of fluoride anions, it seems that the slow
formation of aryne under the heterogeneous condition of CsF/
CH3CN at room temperature is more conducive for this
reaction. With the optimal conditions set, we began inves-
tigating the substrate scope with a variety of â-enamino esters
2a-h. As shown in Table 2, aromatic and aliphatic substitu-
a Reaction conditions: 1.25 equiv of ortho-silyl aryltriflate 1, 1 equiv
(0.4 mmol) of the â-enamino ester 2, 2.5 equiv of CsF, 0.2 M CH3CN in
a sealed vial at room temperature. b Isolated yield. c Configuration of the
double bond was determined by NOE.
tion on the nitrogen are tolerated in 2a-d. However, when
a γ-ester group is present in 2c and 2d, the yield is moderate
presumably due to the decreased nucleophilicity of the
enamine. Interestingly, a free amino group is well tolerated
in 2e-h and no N-arylation product was observed. In
addition, a furan derivative, which is known to undergo
Diels-Alder cycloaddition with benzyne,11 is tolerated as
well (entry 8), affording mainly the C-arylation product 3h
in good yield. It should be noted that the configuration of
the double bond is retained in the reaction and that only the
Z-isomer was produced as determined by an NOE experiment
for representative compounds.
With the encouraging results obtained, our next approach
was to extend the substrate scope to include â-enamino
ketones. As illustrated in Table 3, â-enamino ketones 4a-j
work as well affording moderate to high yields of the
corresponding arylated â-enamino ketones 5a-j. Function-
alities such as olefin 4c and alcohol 4d are well tolerated,
affording high yields of the desired arylated products 5c and
5d, respectively. Here again, although alkenes2 and hydroxyl4
groups are known to react with benzyne, no reaction with
these functionalities was observed. Of particular interest are
the cyclic â-enamino ketones 4g-j which can be arylated
(9) (a) Hsiao, Y.; Rivera, N. R.; Rosner, T.; Krska, S. W.; Njolito, E.;
Wang, F.; Sun, Y.; Armstrong, J. D.; Grabowski, E. J. J.; Tillyer, R. D.;
Spindler, F.; Malan, C. J. Am. Chem. Soc. 2004, 126, 9918-9919. (b)
Elaridi, J.; Thaqi, A.; Prosser, A.; Jackson, W. R.; Robinson, A. J.
Tetrahedron: Asymmetry 2005, 16, 1309-1319.
(10) (a) Sakamoto, T.; Nagano, T.; Kondo, Y.; Yamanaka, H. Synthesis
1990, 215-218. (b) Majumdar, K. C.; Sarkar, S. Synth. Commun. 2004,
34, 2873-2883. (c) Tseng, C.-M.; Wu, Y.-L.; Chuang, C.-P. Tetrahedron
2004, 60, 12249-12260.
(11) Pena, D.; Cobas, A.; Perez, D.; Guitian, E. Synthesis 2002, 1454-
1458.
1030
Org. Lett., Vol. 9, No. 6, 2007

Table 3. C-Arylation of â-Enamino Ketones with Benzynea
Table 4. C-Arylation of â-Enamino Esters and Ketones with
Substituted Benzynea
a Reaction conditions: 1.25 equiv of ortho-silyl aryltriflate 6, 1 equiv
(0.4 mmol) of the â-enamino ester 2e or ketone 4e, 2.5 equiv of CsF, 0.2
M CH3CN in a sealed vial at room temperature. b Isolated yield.
c Configuration of the double bond was determined by NOE.
ring of 3e and 5e, respectively. In a separate experiment,
the acidic protons of the â-enamino ester 2a and ketone 4e
were exchanged for deuterium by stirring in deuterated
a Reaction conditions: 1.25 equiv of ortho-silyl aryltriflate 1, 1 equiv
(0.4 mmol) of the â-enamino ketone 4, 2.5 equiv of CsF, 0.2 M CH3CN in
a sealed vial at room temperature. b Isolated yield. c Configuration of the
double bond was determined by NOE.
Scheme 1. Deuterium Labeling Experiments
in a similar manner to generate interesting C-arylated
products 5g-j in moderate to high yield.
The C-arylation of the â-enamino esters and ketones could
also be extended to substituted arynes. As depicted in Table
4, arynes with electron-donating group 6a, electron-
withdrawing group 6c, sterically crowded 6d, and bulky
arynes 6e work efficiently to afford good to excellent yields
of the C-arylated products 7a-j.
On the basis of the fact that no insertion of aryne into the
R-carbon and carbonyl σ-bond of the enamines was observed,
we hypothesize that the anion of the initially formed
zwitterionic species is rapidly protonated, presumably via
an intramolecular proton transfer. To further substantiate this
hypothesis, we conducted deuterium labeling experiments.
When the reaction of â-enamino ester 2e and ketone 4e with
ortho-silyl aryltriflate 1 (Scheme 1) was quenched with D2O,
no deuterium incorporation was observed on the benzene
Org. Lett., Vol. 9, No. 6, 2007
1031

methanol to afford the trideuterated substrates 2e-d3 and 4e-
d3, respectively (Scheme 1). Upon treatment of substrates
2e-d3 and 4e-d3 with the benzyne precursor 1, we were
pleased to find that there was quantitative incorporation of
deuterium at the ortho position of the respective products
3e-d and 4e-d. This proves that protonation of the zwitterionic
anion is carried out by the â-enamino substrate and not by
water during quenching.
On the basis of the deuterium labeling results, we propose
two possible mechanistic pathways for the C-arylation of
the â-enamino compounds, a concerted (path A) or a stepwise
(path B) pathway (Scheme 2). The initial step involves
zwitterionic intermediate 12. The iminium group of 12 is
predisposed to transfer its proton to the aryl anion generating
the intermediate 10 which after tautomerization would afford
the desired product 11. In addition, because a fluoride anion
is a weak base, a pathway involving deprotonation of the
N-H proton of 9 to generate the corresponding enamine
anion cannot be ruled out.
In summary, we have developed a mild, efficient, and
general method for the C-arylation of â-enamino esters and
ketones with arynes. The reaction tolerates a variety of
substitutions and functionalities and provides arylated prod-
ucts in moderate to excellent yield. Moreover, functionalities
that are known to react with arynes such as amino, alcohol,
alkene, and furan are well tolerated. This methodology
provides a facile and direct access to a variety of substituted
aromatic â-enamino esters that could potentially be trans-
formed into chiral â-amino acids.9 Further studies on the
substrate scope with other â-enamino compounds are in
progress and will be reported in due course.
Scheme 2. Plausible Mechanisms for the C-Arylation of
â-Enamino Esters and Ketones with Aryne
Acknowledgment. The authors gratefully acknowledge
Chun Sing Li, Cameron Black, and Nicolas Lachance for
their technical support and helpful discussions. We also thank
Dan Sorensen and Laird Trimble (Merck Frosst) for NMR
experiments.
Supporting Information Available: Experimental details
and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
generation of the benzyne 8 in the presence of a fluoride
anion. In path A, the benzyne 8 can react with the â-enamino
carbonyl compound 9 through a concerted aza-ene12 type
reaction to produce the imine intermediate 10 which subse-
quently tautomerizes to the more stable isomer 11. On the
other hand, in path B, the â-enamino carbonyl 9 can undergo
a direct nucleophilic attack on the benzyne 8 to generate the
OL063057K
(12) (a) Borzilleri, R. M.; Weinreb, S. M. Synthesis 1995, 347-360. (b)
Zhang, J.-H.; Wang, M.-X.; Huang, Z.-T. Tetrahedron Lett. 1998, 39, 9237-
9240. (c) For ene reaction of arynes with alkynes, see: Jayanth, T. T.;
Jeganmohan, M.; Cheng, M.-J.; Chu, S.-Y.; Cheng, C.-H. J. Am. Chem.
Soc. 2006, 128, 2232-2233.
1032
Org. Lett., Vol. 9, No. 6, 2007