Microwave-assisted Suzuki-Miyaura couplings on α-iodoenaminones

Article abstract of DOI:10.1016/j.tetlet.2007.10.078

A systematic study of α-iodination and subsequent Suzuki-Miyaura couplings between non-attenuated enaminones and a wide range of aromatic boronic acids is reported. The microwave-assisted variant of this transformation furnished the α-arylenaminones in si

Full text of DOI:10.1016/j.tetlet.2007.10.078

Available online at www.sciencedirect.com
Tetrahedron Letters 48 (2007) 8811–8814
Microwave-assisted Suzuki–Miyaura couplings
on a-iodoenaminones
Xin Wang, Brandon J. Turunen, Matthew W. Leighty and Gunda I. Georg*
Department of Medicinal Chemistry and Center for Methodology and Library Development, University of Kansas,
1251 Wescoe Hall Drive, Lawrence, KS 66045, USA
Received 21 August 2007; revised 13 October 2007; accepted 16 October 2007
Available online 22 October 2007
Abstract—A systematic study of a-iodination and subsequent Suzuki–Miyaura couplings between non-attenuated enaminones and a
wide range of aromatic boronic acids is reported. The microwave-assisted variant of this transformation furnished the a-arylenam-
inones in significantly shorter reaction times and slightly improved yields as compared to conventional heating.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Recently, we reported a new method for the preparation
of mono and bicyclic enaminones.1 This procedure
allows direct access to a variety of substituted, six
membered vinylogous amides. Although compounds
such as these have been studied, it is our view that they
remain underutilized in natural product and chemical
library synthesis.2,3 To increase their synthetic value
we became interested in employing them as coupling
partners in the Suzuki–Miyaura reaction (Fig. 1).4,5
yield under the standard Johnson conditions (Table 1,
condition A).9 Furthermore, the modified Johnson con-
ditions reported by Kim et al. (Method B) proceeded
smoothly on both bicyclic (1–3) and monocyclic (4–6)
systems.10 It is notable that tertiary Z-enaminones
(1–4 and 6) posed no problems despite a report that this
reaction does not proceed on tertiary E-enaminones.6a
In addition, the use of I2 and DMAP also provided
the desired iodinated enaminones in excellent yields
(Method C).6b,11 Furthermore, a tolerance for substitu-
tion adjacent to the ring fused nitrogen (3a) as well
as a secondary vinylogous amide nitrogen (5a) was
demonstrated.
Our strategy relied upon the unique ambident nature
of the enaminone to first function as a nucleophile
(a-iodination) and then as an electrophile (oxidative
insertion). While the a-iodination of unprotected
E-enaminones is well known,6 the same transformation
with unprotected Z-enaminones has only been recently
reported.4,7 Conditions for the a-iodination of enones
first developed by Johnson et al.,8 as well as modifi-
cations thereof,6a,b were investigated on a series of vinyl-
ogous amides, which were prepared according to our
previously reported procedure (Table 1).1 Gratifyingly,
installation of iodine was achieved in near quantitative
With the a-iodoenaminones in hand, we next turned to
their coupling with boronic acids. A survey of the liter-
ature reveals that coupling reactions have been achieved
on a-halo vinylogous amides with success.13 However,
in most cases, the resonance contribution of the enami-
none nitrogen is attenuated via an electron withdrawing
protecting group.12 Without this protecting group the
resonance contribution of the nitrogen is greatly
O
O
O
R4
R4
HO
I
B
Iodination
OH
R1
N
R3
R1
N
R3
R1
N
R3
Coupling
R2
R2
R2
Figure 1. Proposed route to a-aryl enaminones.
*
Corresponding author. Tel.: +1 612 626 6320; fax: +1 612 626 6316; e-mail: georg239@umn.edu
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.10.078

8812
X. Wang et al. / Tetrahedron Letters 48 (2007) 8811–8814
Table 1. a-Iodination of enaminones
Table 2. Optimization of coupling reaction between enaminone 1a and
4-methoxyphenylboronic acida
Enaminone
Conditions
a-Iodoenaminone Yielda (%)
Entry Base
Solvent (s),
Reaction Yieldb
O
O
temperature (ꢁC)
time
(%)
A. pyridine/
CCl4, I2
99
N
1
2
3
4
5
6
7c
CaCO3
DMF/H2O (3/1), 150
Na2CO3 DME/H2O (1/1), 100
Na2CO3 Toluene, 110
20 h
20 h
20 h
0
N
I
B. CH2Cl2, I2,
then NEt3
95
13
23
25
27
65
70
1a
1
Na2CO3 Toluene/EtOH (1/1), 110 20 h
CsF
Ba(OH)2 Dioxane/H2O (3/1), 110
Ba(OH)2 Dioxane/H2O (3/1),
150 MWc
O
O
MeCN/H2O (1/1), 100
14 h
14 h
15 min
B. CH2Cl2, I2,
then NEt3
87
N
N
I
2a
2
C. CH2Cl2,
I2, DMAP
97
a Compound 1a (0.10 mmol) was dissolved in degassed solvent mixture
(0.25–0.5 M) under argon and 4-methoxyphenylboronic acid
(0.17 mmol), base (0.20 mmol) and Pd(PPh3)4 (0.02 mmol) added.
b Isolated yield.
O
O
O
N
N
B. CH2Cl2, I2,
then NEt3
85
88
I
c Carried out employing microwave irradiation (150 ꢁC, 15 min).
Ph
Ph
3a
3
O
I
enhanced. In turn, this electron rich system is less willing
to undergo oxidative insertion, often the rate limiting
step in this coupling process, leading to poor conversion
and low yields.4a This limits the use of Suzuki coupling
reactions in these systems to those that do not contain
tertiary aliphatic substitution. This is unfortunate, given
the common occurrence of this structural feature in
alkaloid natural products.13
N
N
B. CH2Cl2, I2,
then NEt3
Me
Me
Ph
4a
4
O
O
O
Ph
B. CH2Cl2, I2,
then NEt3
85
94
HN
HN
5a
I
5
O
A variety of conditions were explored with enaminone
1a and 4-methoxyphenylboronic acid to determine opti-
mal conditions for coupling (Table 2). In all the cases
Pd(PPh3)4 was employed as the palladium source and
heating was required for conversion. In addition, it
C. CH2Cl2, I2,
DMAP
Ph
N
Ph
N
I
6a
6
a Isolated yield.
Table 3. Cross-coupling of iodoenaminones and arylboronic acidsa
a-Iodoenaminone
Product
Substitution (R1, R2, R3)
Yieldb (%)
1b (H, H, OMe)
1c (H, H, OBn)
1d (H, NO2, H)
1e (Cl, Cl, H)
1f (H, H, H)
1g (H, H, OH)
1h (H, OMe, OMe)
70
71
57
60
65
45
75c
O
O
R1
N
R2
R3
N
I
1a
O
O
N
N
OMe
OMe
N
2b (as shown)
3b (as shown)
72
60
I
2a
O
O
N
OMe
OMe
I
Ph
Ph
3a
4b (H, H, OMe)
4c (H, H, OBn)
4d (H, NO2, H)
4e (Cl, Cl, H)
4f (H, H, H)
4g (H, H, OH)
4h (H, OMe, OMe)
60
71
62
50
55
36
68
O
O
R1
N
R2
R3
N
Me
Me
I
4a

X. Wang et al. / Tetrahedron Letters 48 (2007) 8811–8814
8813
Table 3 (continued)
a-Iodoenaminone
Product
Substitution (R1, R2, R3)
Yieldb (%)
O
O
O
Ph
Ph
HN
OMe
OMe
5b (as shown)
70
HN
I
5a
O
Ph
N
6b (as shown)
69
Ph
N
I
6a
OMe
a Coupling reactions were conducted as in Table 2, entry 7.
b Isolated yields.
c 1 h reaction time.
was critical that the solvent mixtures be carefully deoxy-
genated. The best conditions were obtained when a
mixture of dioxane and water was used as solvent and
Ba(OH)2 employed as base (Table 2, entry 6).14
Although pleased with the results of our optimization,
the reaction times were less than ideal. Microwave irra-
diation has been used to decrease reaction times and in
some cases increase reaction yields.5 Thus microwave
conditions were applied to this system and a dramatic
rate enhancement was noted (Table 2, entry 7, 14–20 h
reduced to 15 min) along with a modest increase in
yield.15
NIH GM076302, and NIH GM069663). B.J.T. was sup-
ported by the Department of Defense Breast Cancer
Predoctoral Fellowship (DAMD17-02-1-0435).
References and notes
1. Turunen, B. J.; Georg, G. I. J. Am. Chem. Soc. 2006, 128,
8702.
2. For recent reviews, see: (a) Negri, G.; Kascheres, C.;
Kascheres, A. J. J. Heterocycl. Chem. 2004, 41, 461; (b)
Elassar, A.-Z. A.; El-Khair, A. A. Tetrahedron 2003, 59,
8463.
3. (a) Michael, J. P.; De Koning, C. B.; Gravestock, D.;
Hosken, G. D.; Howard, A. S.; Jungmann, C. M.; Krause,
R. W. M.; Parsons, A. S.; Pelly, S. C.; Stanbury, T. V.
Pure Appl. Chem. 1999, 71, 979; (b) Comins, D. L. J.
Heterocycl. Chem. 1999, 36, 1491.
4. During the course of our investigation an example of
iodination and Suzuki–Miyaura coupling of an N-ara-
binosyl dehydropiperidinone appeared (a) Kranke, B.;
Kunz, H. Can. J. Chem. 2006, 84, 625; (b) Kranke, B.;
Kunz, H. Org. Biomol. Chem. 2007, 5, 349.
5. (a) Suzuki, A. J. Organomet. Chem. 1999, 576, 147; (b)
Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457; (c)
Fitzmaurice, R. J.; Etheridge, Z. C.; Jumel, E.; Woolfson,
D. N.; Caddick, S. Chem. Commun. 2006, 4814; (d)
Kappe, O. C. Angew. Chem., Int. Ed. 2004, 43, 6250; (e)
Kellogg, R. M. Chemtracts 2004, 17, 451; (f) Song, Y. S.;
Kim, B. T.; Heo, J.-N. Tetrahedron Lett. 2005, 46, 5987;
(g) Song, Y. S.; Lee, Y.-J.; Kim, B. T.; Heo, J.-N.
Tetrahedron Lett. 2006, 47, 7427.
6. (a) Kim, J. M.; Na, J. E.; Kim, J. N. Tetrahedron Lett.
2003, 44, 6317; (b) Ohshima, T.; Xu, Y.; Takita, R.;
Shibasaki, M. Tetrahedron 2004, 60, 9569; (c) Sha, C.-K.;
Shen, C.-Y.; Jean, T.-S.; Chiu, R.-T.; Tseng, W.-H.
Tetrahedron Lett. 1993, 34, 7641; (d) Sha, C.-K.; Santh-
osh, K. C.; Tseng, C.-T.; Lin, C.-T. J. Chem. Soc., Chem.
Commun. 1998, 397; (e) Campos, P. J.; Arranz, J.;
Rodriguez, M. A. Tetrahedron Lett. 1997, 38, 8397; (f)
Matsuo, K.; Ishida, S.; Takuno, Y. Chem. Pharm. Bull.
1994, 42, 1149; (g) Kordik, C. P.; Reitz, A. B. J. Org.
Chem. 1996, 61, 5644; (h) Ramesh, N. G.; Heijne, E. H.;
Klunder, A. J. H.; Zwanenburg, B. Tetrahedron Lett.
1998, 39, 3295; (i) Ramesh, N. G.; Heijne, E. H.; Klunder,
A. J. H.; Zwanenburg, B. Tetrahedron 2002, 58, 1361; (j)
The scope of the reaction was next investigated under
the optimized microwave conditions using the enami-
nones and boronic acid coupling partners shown in
Table 3. In general, electron rich boronic acids partici-
pated well in the coupling reaction while electron poor
coupling partners delivered moderate yields (1b–h and
4b–h). Employing an unprotected phenolic boronic acid
resulted in a poor yield of enaminones 1g and 4g. Both
the 5/6 (1a) and 6/6 (2a and 3a) enaminone systems
couple effectively as do monocyclic enaminones (4a–
6a). It should be pointed out that even the sterically
encumbered substrate 3a underwent coupling under
these conditions. In addition it should be noted that a
free NH was tolerated (5a).
In summary, we have demonstrated a significant
improvement in the technology available for preparing
a-iodoenaminones and coupling them with arylboronic
acids. The use of microwave irradiation proved advanta-
geous in the coupling process. The scope of both the
enaminone and boronic acid partners demonstrated
versatility. Ongoing studies in these labs are directed
toward further method development upon these vinylo-
gous amide scaffolds as well as applications in natural
product and diversity-oriented synthesis (DOS).
Acknowledgments
We thank the National Institutes of Health for their
generous support of our programs (NIH CA90602,

8814
X. Wang et al. / Tetrahedron Letters 48 (2007) 8811–8814
Papoutsis, I.; Spyroudis, S.; Varvoglis, A.; Callies, J. A.;
Zhdankin, V. V. Tetrahedron Lett. 1997, 38, 8401.
7. For an example of a bromodesilylation on an unprotected
enaminone, see: Comins, D. L.; Chen, X.; Morgan, L. A.
J. Org. Chem. 1997, 62, 7435.
8. Johnson, C. R.; Adams, J. P.; Braun, M. P.; Senanayake,
C. B. W.; Wovkulich, P. M.; Uskokovic, M. R. Tetra-
hedron Lett. 1992, 33, 917.
CDCl3) d 1.30–1.57 (m, 3H), 1.69–1.83 (m, 3H), 2.42 (dd,
1H, J = 13.2 Hz), 2.70 (dd, 1H, J = 5.4 Hz), 3.04 (td, 1H,
J = 3 Hz), 3.36–3.43 (m, 2H), 7.34 (s, 1H); 13C NMR
(100 MHz, CDCl3) d 22.91, 25.53, 31.55, 41.94, 53.17,
57,26, 62.71, 159.48, 186.03; IR (neat) 2924, 2853, 1630,
1564, 1461, 1318, 1136 cmÀ1; HRMS (ES+) m/e calcd for
[M+H]+ C9H13INO: 278.0036, found 278.0038.
12. (a) Comins, D. L.; Joseph, S. P.; Chen, X. Tetrahedron
Lett. 1995, 36, 9141; (b) Felpin, F.-X. J. Org. Chem. 2005,
70, 8575.
13. Cordell, G. A. The Alkaloids: Chemistry and Biology;
Elsevier, 2003; Vol. 60.
9. Table 1, method A: 6-Iodo-2,3,8,8a-tetrahydroindolizin-
7(1H)-one (1a). Enaminone 1 (760 mg, 5.54 mmol) was
dissolved in CCl4/pyridine (1:1, 10 mL) and cooled to
0 ꢁC. To this mixture was added iodine (3.52 g, 13.9 mmol)
in CCl4/pyridine (1:1, 2 mL) dropwise. The reaction was
then allowed to warm to rt. After 5 h this solution was
concentrated into a brown oil under reduced pressure and
purified via flash column chromatography (silica gel, 1%
Et3N in EtOAc) to provide 1.45 g of the title compound
(99%) as a yellow solid (mp = 97–98 ꢁC): 1H NMR
(500 MHz, CDCl3) d 1.62–1.72 (m, 1H) 1.90–2.10 (m,
1H), 2.07–2.17 (m, 1H), 2.22–2.23 (m, 1H), 2.43 (dd,
J = 16.2 Hz, 16.2 Hz, 1H), 2.74 (dd, J = 15.9 Hz, 4.7 Hz,
1H), 3.59–3.66 (m, 2H), 3.81–3.93 (m, 1H); 13C NMR
(125 MHz, CDCl3) d 24.6, 32.4, 40.3, 49.8, 58.3, 59.9,
154.7, 185.3; IR (neat) 2970, 2872, 1620, 1559, 1296,
14. Conventional heating method: 6-(3,4-Dimethoxyphenyl)-
2,3,8,8a-tetrahydroindolizin-7(1H)-one (1h). a-Iodoenam-
inone 1a (240 mg, 0.91 mmol) was dissolved in degassed
dioxane:water (3:1, 4 mL). The 3,4-dimethoxyphenyl-
boronic acid (282 mg, 1.55 mmol), barium hydroxide
(345 mg, 1.82 mmol), and Pd(PPh3)4 (210 mg, 0.182
mmol) were added sequentially. This mixture, equipped
with reflux condenser, was heated to 110 ꢁC for 18 h. The
reaction was allowed to cool to rt, concentrated under
reduced pressure, dissolved in CH2Cl2, filtered, dried over
Na2SO4, and purified via flash column chromatography
(silica gel, 1% Et3N in EtOAc) to provide 161 mg of the
title compound (65%) as a yellow oil: 1H NMR (400 MHz,
CDCl3) d 1.65–1.80 (m, 1H) 1.91–2.07 (m, 1H), 2.08–2.18
(m, 1H), 2.26–2.39 (m, 1H), 2.45–2.60 (m, 2H), 3.55–3.63
(m, 2H), 3.83–3.88 (m, 1H), 3.86 (s, 3H), 3.88 (s, 3H),
6.80–6.86 (m, 2H), 7.09 (s, 1H), 7.42 (s, 1H); 13C NMR
(100 MHz, CDCl3) d 24.8, 33.4, 42.7, 50.2, 56.2, 56.3, 58.2,
110.0, 111.5, 112.0, 119.7, 129.0, 130.3, 147.4, 148.9, 149.3,
189.5; IR (neat) 3381, 2935, 2835, 1609, 1514, 1407,
1223 cmÀ1
;
HRMS (ES+) m/e calcd for [M+H]+
C8H11INO: 263.9885, found 263.9886.
10. Iodination Method B: 6-Iodo-2,3,8,8a-tetrahydroindolizin-
7(1H)-one (1a). To a stirred solution of enaminone 1
(137 mg, 1.0 mmol) and iodine (254 mg, 1.0 mmol) in
CH2Cl2 (3 ml) was added Et3N (140 ll, 1.0 mmol) at rt.
After 5 min this solution was concentrated into a brown
oil under reduced pressure then purified via flash chro-
matography (silica gel, 1% Et3N in EtOAc) to provide the
desired a-iodoenaminone 1a (95%).
;
1250 cmÀ1 HRMS (ES+) m/e calcd for [M+H]+
C16H20NO3: 274.1443, found 274.1441.
11. Iodination Method C: 3-Iodo-7,8,9a-tetrahydro-1H-quino-
lizin-2(6H)-one (2a). A solution of I2 in CH2Cl2 (210 mg,
0.83 mmol, 0.05 M) was added dropwise over 20 min to a
solution of enaminone 2 (104 mg, 0.69 mmol) and DMAP
(171 mg, 1.38 mmol) in CH2Cl2 (15 mL) at rt. After stirring
overnight at the same temperature, the reaction mixture
was quenched by the addition of water and extracted with
CH2Cl2 (2·). The combined organic layers were washed
with saturated aq NH4Cl, water, saturated aq Na2S2O3,
water, brine, dried over Na2SO4 and concentrated. The
residue was purified by flash column chromatography
(silica gel, 50% EtOAc in hexanes) to afford iodide 2a
15. Microwave irradiation method: 6-(3,4-Dimethoxyphenyl)-
2,3,8,8a-tetrahydroindolizin-7(1H)-one
(1h).
a-Iodo
enaminone 1a (240 mg, 0.91 mmol) was dissolved in
degassed dioxane:water (3:1, 4 mL). The 3,4-di-
methoxyphenylboronic acid (282 mg, 1.55 mmol), barium
hydroxide (345 mg, 1.82 mmol), and Pd(PPh3)4 (210 mg,
0.182 mmol) were added sequentially. This mixture was
heated under microwave irradiation at 150 ꢁC for 1 h. The
reaction was allowed to cool to rt, concentrated under
reduced pressure, dissolved in CH2Cl2, filtered, dried over
Na2SO4, and purified via flash column chromatography
(silica gel, 1% Et3N in EtOAc) to provide 187 mg of the
title compound (75%).
1
(186 mg, 97%) as a pale yellow oil: H NMR (500 MHz,