Palladium and copper catalyzed cyclizations of hydrazine derived Ugi products: Facile synthesis of substituted indazolones and hydroxytriazafluorendiones

Article abstract of DOI:10.1016/j.tetlet.2012.02.095

Indazolones are medicinally relevant targets. Herein we disclose an improved synthesis to N'-(acetamido-2-yl)-substituted indazolones with four points of diversity introduced by Ugi-[M]-amination and -amidation. The ring closure can be achieved by either conventional palladium catalysis or with a ligandless copper protocol. When α-unbranched isocyanides were employed the sole cyclization products of the copper catalyzed reactions are the hitherto undescribed 2-hydroxy-3H-3,4a,9a-triaza-fluorene-4,9-diones.

Full text of DOI:10.1016/j.tetlet.2012.02.095

Tetrahedron Letters 53 (2012) 2298–2301
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium and copper catalyzed cyclizations of hydrazine derived
Ugi products: facile synthesis of substituted indazolones
and hydroxytriazafluorendiones
Sebastian J. Welsch a,b, , Cédric Kalinski a, Michael Umkehrer a, Günther Ross a, Jürgen Kolb a,
⇑
Christoph Burdack a, Ludger A. Wessjohann b
a Priaxon AG, Gmunder Str. 37-37a, 81379 München, Germany
b Leibniz-Institut für Pflanzenbiochemie, Weinberg 3, 06120 Halle (Saale), Germany
a r t i c l e i n f o
a b s t r a c t
Indazolones are medicinally relevant targets. Herein we disclose an improved synthesis to N0-(acetamido-2-yl)-
substituted indazolones with four points of diversity introduced by Ugi-[M]-amination and -amidation. The ring
closure can be achieved by either conventional palladium catalysis or with a ligandless copper protocol. When
Article history:
Received 28 October 2011
Revised 16 February 2012
Accepted 21 February 2012
Available online 28 February 2012
a-unbranched isocyanides were employed the sole cyclization products of the copper catalyzed reactions are
the hitherto undescribed 2-hydroxy-3H-3,4a,9a-triaza-fluorene-4,9-diones.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Multicomponent reactions
Heterocycles
Palladium catalysis
Copper catalysis
Triazines
Indazolones
Ugi reaction
Hydroxytriazafluorendione
Multicomponent reactions (MCRs) are a powerful tool to pro-
vide compound libraries for high-throughput screening and hit
finding.1,2 Especially the Ugi-reaction has generated much interest
due to its synthetic potential and its capacity to generate highly di-
verse products of medicinal relevance, that is, heterocycles and
compounds with peptide like moieties. In order to further enhance
the diversity a plethora of different methods have been used for
postmodification of multi-component reaction products.3
Indazolone derivatives have attracted increasing attention due
to their promising pharmacological properties,4,5 including anti-
inflammatory,6 antiallergic,7 antipsychotic,8 hypolipidemic9 and
cytostatic10 activities. A variety of synthetic routes have been re-
ported,4,11 but all of these require multiple steps and in some cases
the use of dangerous intermediates. The only multicomponent reac-
tion based synthesis following the UDC (Ugi-deprotection-cycliza-
tion) strategy has been published by Tempest et al. (Scheme 1).12
It consists of an Ugi reaction (U-4CR) with Boc-protected hydrazine
as amine component and 2-fluoro-5-nitrobenzoic acid as acid com-
ponent, followed by Boc removal of the Ugi product and subsequent
nucleophilic aromatic substitution (U-4CR-SNAr, Scheme 1). The
major drawback of this sequence is the need for the strong acceptor
in the cyclization step to work which restricts the diversity of the
product space accessible with readily available starting materials
considerably. Furthermore the nitro group is among those function-
alities medicinal chemistry to avoid.13
Herein we want to report an improved protocol obviating the
aforementioned problems. It comprises an Ugi reaction of a pro-
tected hydrazine (2, R2 = Boc or Bn) and an o-bromo- or o-iodoben-
zoic acid (1), an oxo compound (3, ketone or aldehyde) and an
isocyanide (4, R5) followed by a transition metal catalyzed cycliza-
tion (Scheme 2). Such cyclizations, especially palladium-mediated
ones, have been successfully employed for MCR postmodifications
on numerous occasions.14
In a preliminary experiment equimolar amounts of Boc-pro-
tected hydrazine, isobutyraldehyde, o-bromobenzoic acid and
tert-butyl isocyanide were stirred in methanol (1 M) at room tem-
perature. The reaction went smoothly and the Ugi product 5a was
isolated with 94% yield (Scheme 3, entry 1). Subsequent deprotec-
tion with 20% trifluoroacetic acid in dichloromethane yielded the
free hydrazide 6a which was subjected to varied cyclization condi-
tions selected from procedures reported in literature.15–17 Entries
1–3 in Table 1 show results of a starting catalyst (ligand) variation.
Only the Pd2dba3/P(tBu)3 system gave complete conversion and
⇑
Corresponding author. Tel.: +49 (0) 89 4521308 13; fax: +49 (0) 89 4521308 22.
E-mail address: welsch@priaxon.de (S.J. Welsch).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.02.095

S. J. Welsch et al. / Tetrahedron Letters 53 (2012) 2298–2301
2299
R
O
F
O
R
O
H
H
N
O2N
O2N
N
SNAr
U-4CR
N
R'
OH
N
R'
NH
O
HN
O
O2N
F
Boc
Scheme 1. Indazolone synthesis via Ugi-SNAr-strategy12 (R = substituents derived from aldehyde (R) or isocyanide (R0) starting materials).
O
R3 R4
O
O
R3 R4
R3
H
H
OH
Br/I
R1
NH2
HN
N
N
R5
N
HN
R5
U-4CR
[Pd or Cu]
CN
N
R5
R1
R1
O
R4
R2
N
O
O
R2/H
R2
Br/I
2
3
4
5
7
1
R2=Boc, Bn
Scheme 2. Indazolone synthesis via Ugi reaction and palladium or copper catalysed amidation/amination.
O
R3
R4
R3 R4
R3 R4
O
X
O
O
H
3
H
N
N
R5
N
R5
TFA
PG = Boc
CN
N
HN
Ugi reaction
OH
R5
R1
R1
R1
+
O
NH2
O
4
X
Br
PG
NH2
5a-g (X=Br)
5a'-n' (X=I)
6a-f
PG = Boc
HN
1
R4=H
PG
R5=alpha
unbranched
[Cu]
2
[Cu], 80 °C
or
[Pd], dppf, 110 °C
[Pd] , P(tBu)3,
110 °C
[Cu]
rt
80 °C
R3 R4
R3 R4
O
O
R3
O
PG=Boc
H
H
R5=alpha
N
R2 = Boc
TFA
R5
OH
R5
N
N
unbranched
R5
N
R1
N
R1
R1
H+ or 40 °C
N
O
N
O
N
N
H
PG
7a,f,h,i
Scheme 3. General reaction scheme.
O
8a-c,e-g
9k-n
Table 1
Screening of catalysts and conditions for the Pd-catalyzed cyclization of 5a/6a to indazolone 8a
Entry
Catalyst
Base
s.m.
HPLC yielda
1
2
3
4
5
6
5 mol % Pd(PPh3)4
1.4 equiv NatOBu, 1.6 equiv K2CO3
1.4 equiv NatOBu
6a
6a
6a
5a
5a
5a
59%
3.5 mol % Pd(OAc)2, 5 mol % dppf
10 mol % Pd2dba3, 5 mol % P(tBu)3
5 mol % Pd2dba3, 6 mol % BINAP
2 mol % Pd2dba3, 10% xantphos
2 mol % Pd2dba3, 10 mol % dppf
40%
2 equiv NatOBu 2 equiv K2CO3
2 equiv NaOPh 2 equiv Cs2CO3
2 equiv Cs2CO3
82%b
64%
>99%
>99%
2 equiv NatOBu
All reactions were performed in anhydrous toluene under nitrogen at 110 °C.
a
254 nm.
b
Isolated yield after chromatography: 71% (see Table 2).
yielded the desired indazolone 8a without side products (isolated
yield 71%).
the nitrogen again. Therefore N0-protected 5a was directly sub-
jected to the above cyclization conditions (cf. Table 1, entry 3)
but gave only traces of 8a with the majority of the starting material
unchanged. In a control experiment without palladium we ob-
served a slow deprotection of 5a producing 6a indicating that only
after thermal cleavage of the Boc group a cyclization of the free
amine occurs. As the current catalytic system was obviously
unsuitable for our purpose, different ligands and conditions were
tested17 (Table 1, entries 4–6). Both xantphos/Cs2CO3 (entry 5)
This catalytic system (entry 3) was used to synthesize com-
pounds 7g and 8a–f (vi), but it turned out that other conditions
would allow the direct, one step conversion of the Ugi products
to the desired cyclization products 8 without a dedicated deprotec-
tion step. If alternatively cyclization conditions could be found that
leave the protecting group in place, this would retain the possibil-
ity to further elaborate the products without having to re-protect

2300
S. J. Welsch et al. / Tetrahedron Letters 53 (2012) 2298–2301
Table 2
[Pd]-cyclizations: X = Br, 10 mol % Pd2dba3, 5 mol % PtBu3, 2 equiv NaOtBu, 2 equiv Cs2CO3, dry toluene, 110 °C, overnight
Entry
R
PG
R3, R4
R5
Ugi-4CR
DeBoc-Ugi
Product (isolated yield)
1
2
3
4
5
6
7
H
H
H
H
Boc
Boc
Boc
Boc
Boc
Boc
Bn
iPr, H
iPr, H
iPr, H
–(CH2)5–
iPr, H
iPr, H
iPr, H
tBu
5a
5b
5c
5d
5e
5f
94%
64%
86%
36%
70%
79%
11%
6a
6b
6c
6d
6e
6f
51%
61%
34%
Degr.
83%
69%
8a
8b
8c
—
8e
8f
71%
20%
16%
4-Cl-Ph
4-MeO-Bn
tBu
5-NO2-
5-MeO-
H
tBu
52%
25%
77%
tBu
tBu
5g
n.a.
7g
Table 3
[Cu]-cyclizations: X = I, PG = Boc; 5 mol % CuI, 2 equiv Cs2CO3, dry DMF
Entry
R1
R3, R4
R5
Ugi-4CR
Cyclization conditions
Product (isolated yield)
1
2
3
4
5
6
7
8
H
H
iPr, H
iPr, H
iPr, H
Me,Me
iPr, H
iPr, H
iPr, H
iPr, H
iPr, H
iPr, H
iPr, H
iPr, H
iPr, H
iPr, H
iPr, H
iPr, H
tBu
5a0
5a0
5f0
73%
73%
95%
73%
90%
82%
91%
73%
73%
77%
95%
90%
82%
91%
77%
48%
A
B
A
A
A
A
A
C
D
C
C
C
C
C
C
C
7a
7a
7f
7h
7i
7k0
9l
8a
8a
8e
8f
8j
9k
9l
93%
95%a
12%
77%
67%
Degr.
57%
55%
59%
99%
38%
Degr.
75%
55%
82%
61%
tBu
5-MeO
H
H
H
H
H
H
5-NO2
tBu
tBu
5h0
5i0
Ph
CH2CH2OMe
5k0
5l0
Bn
tBu
5a0
5a0
5e0
5f0
9
tBu
10
11
12
13
14
15
16
tBu
5-MeO
tBu
H
H
H
H
H
Ph
5i0
CH2CH2OMe
Bn
4-MeO-Bn
4-F3C-Bn
5k0
5l0
5m0
5n0
9m
9n
Conditions: A: rt; B: rt, 10 mol % 1,10-phenanthrolin; C: 80 °C; D: 80 °C, 10 mol % 1,10-phenanthrolin.
a
HPLC yield (254 nm).
and dppf/NaOtBu (entry 6) led to a clean and complete conversion
of 5a to 8a with intrinsic deprotection but the latter one was con-
siderably faster (36 and 14 h, respectively).
be purified with care, for example, on basic aluminum oxide. Treat-
ment of 7a and 7h with 20% TFA in dichloromethane gave the free
indazolone in 46% and 62% yield, respectively.
With this catalytic system (Table 1, entry 3) we examined the
scope and versatility of this sequence (Table 2). The Ugi products
were obtained in moderate to good yields. The cyclization works
for both electron deficient and electron rich benzoic acids but the
yield of the latter suffers from increased side product formation
(Table 2, entries 1, 5, 6). Besides aliphatic aldehydes ketones can
be easily employed in the Ugi reaction but the deprotected bisa-
mide 6d degraded during final purification on silica (Table 2, entry
4, cf. Table 3, entry 4). The use of different isocyanides was some-
what hindered by incomplete conversions during the cyclization
(Table 2, entry 2, 3). N0-Alkyl substituted hydrazides are also suit-
able substrates, but the liberation of the free base from the benzyl-
hydrazine dihydrochloride salt proved to be difficult. Among the
bases tested (triethylamine, sodium hydroxide, potassium carbon-
ate) only sodium hydroxide used in situ gave some amounts of 5g
(entry 7). Liberation prior the Ugi reaction failed as well as the use
of potassium carbonate and triethylamine in situ.
Phenylic isocyanides worked fine (Table 3, entry 5) but alkyl
isocyanides lead to different results: reaction monitoring via
HPLC/MS showed a clear conversion also for benzyl isocyanides
and 2-methoxyethyl isocyanide to the desired Boc-protected ind-
azolones but these proved to be instable at elevated temperatures.
While 7k degraded already upon heating to 40 °C to several differ-
ent products (including deprotected indazolone and hydroxytri-
azafluorendione, vide infra), 7l was converted to a new product
which we identified by HPLC/MS and NMR as hydroxytriazafluo-
rendione 9l. The same reaction took place when we tried to cleave
the Boc-group in situ with 20% TFA.
Intrigued by this unusual behavior of the Boc-group we started
to investigate cyclizations at higher temperature. Subjecting 1a0 to
previous cyclization conditions at 80 °C led directly to the free
indazolone 8a irrespective of the presence of 1,10-phenanthroline
(Table 3, entries 8 and 9). Reaction monitoring showed that ther-
mal Boc cleavage occurs at a much lower rate than cyclization
and that the rate of the latter is strongly dependent on the substit-
uents at the benzoic acid residue: while the reaction of the nitro
substituted substrate is finished within a few minutes even at rt,
reactions of electron rich aryliodide moieties require several hours
at elevated temperatures to achieve complete conversions (entries
10 and 11). In the same order increasing amounts of different,
inseparable dimers of the free indazolone were formed which were
in the case of 8f the main product.
Finally we were interested if palladium could be substituted by
the cheaper copper which is also a well-known catalyst of amide
arylations.18,19 Stirring 5a0 (the apostrophe denotes the use of ary-
liodides instead of bromides) in anhydrous DMF under a nitrogen
atmosphere with 5 mol % copper iodide, 10 mol % 1,10-phenan-
throline and 2 equiv of cesium carbonate20 for half an hour re-
sulted in
a complete and clean conversion of the starting
material. Surprisingly no ligand seems to be required for this cycli-
zation: a control reaction without 1,10-phenanthroline performed
similar and gave 93% of the still Boc-protected product 7a along
with 4% deprotected 8a within half an hour. The reaction tolerates
both aldehydes and ketones but Ugi products of the latter have a
tendency to degrade (hydrolyze?) on silica and therefore have to
When more nucleophilic and sterically less hindered (unsubsti-
tuted
a-carbon) isocyanides were employed, the aforementioned
hydroxytriazafluorendiones were formed in a clean reaction and
isolated as the sole products (entries 13–15). Apparently Boc-
group acts as intramolecular acylation source annealing a third

S. J. Welsch et al. / Tetrahedron Letters 53 (2012) 2298–2301
2301
Umkehrer, M.; Ross, G.; Kolb, J.; Burdack, C.; Hiller, W. Tetrahedron Lett. 2006,
47, 3423–3426; (g) Ribelin, T. P.; Judd, A. S.; Akritopoulou-Zanze, I.; Henry, R.
F.; Cross, J. L.; Whittern, D. N.; Djuric, S. W. Org. Lett. 2007, 9, 5119–5122; (h)
Dai, W. M.; Shi, J.; Wu, J. Synlett 2008, 2716–2720; (i) Riva, R.; Banfi, L.; Basso,
A.; Cerulli, V.; Guanti, G.; Pani, M. J. Org. Chem. 2010, 5134–5143; (j) Salcedo,
A.; Neuville, L.; Zhu, J. J. Org. Chem. 2008, 73, 3600–3603; (k) Oble, J.; El Kaim,
L.; Gizzi, M.; Grimaud, L. Heterocycles 2007, 73, 503–517.
cycle by an attack of the secondary amide nitrogen originating
from the isocyanide building block initially.
In summary we have developed an improved two-step synthe-
sis for indazolones with an additional point of diversity (a total of
four), increased yield and broadened substrate range. It is based on
an Ugi reaction and subsequent palladium or copper catalyzed
intramolecular coupling. The cyclizing coupling can be applied to
both Boc protected, alkyl substituted and free hydrazides. In case
of 1-Boc-protectedindazolones with 2-carboxamidomethyl substi-
tuent (5k0–n0), a spontaneous second cyclization to triazoles gives
the hitherto undescribed 2-hydroxy-3H-3,4a,9a-triaza-fluorene-
4,9-diones as sole products.
15. Zhu, Y.; Kiryu, Y.; Katayama, H. TetrahedronLett. 2002, 43, 3577–3580.
16. Margolis, B. J.; Swidorski, J. J.; Rogers, B. N. J. Org. Chem. 2003, 68, 644–647.
17. Muci, A. R.; Buchwald, S. L. In Topics in current Chemistry; Springer-Verlag:
Berlin, Heidelberg, 2002; Vol. 219,
18. Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108, 3054–3131.
19. Tanimori, S.; Ozaki, Y.; Iesaki, Y.; Kirihata, M. Synlett 2008, 1973–1976.
20. Wolter, M.; Klapars, A.; Buchwald, S. L. Org. Lett. 2001, 3, 3803–3805
Typical procedure for the synthesis of 5a0:
To 292 mg (4 mmol) of isobutyraldehyde in 4 ml of MeOH, 530 mg (4 mmol)of
tert-butylcarbazatare added and the mixture is stirred at rt for 2 h. Then
1011 mg (4 mmol)of o-iodobenzoic acid and 339 mg (4 mmol)of tert-
butylisocyanidare added and the reaction mixture is stirred overnight at rt.
After evaporation of the solvent the crude product is purified by column
chromatography on silica gel (chloroform/methanol = 99.5/0.5?90/10,
Rf = 0.20 [chloroform/methanol = 99.5/0.5]) to yield 1.52 g of the title
compound (white solid, 73%).1H NMR (400 MHz, CDCl3) d 7.88 (s, 1H), 7.73
(d, J = 7.8 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.34–7.29 (m, 1H), 7.02 (t, J = 7.4 Hz,
1H), 6.47 (s, 1H), 4.75 (d, J = 10.3 Hz, 1H), 2.16–2.03 (m, 1H), 1.32 (s, 9H), 1.24–
1.14 (m, 12H), 1.02 (d, J = 6.6 Hz, 3H).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2012.02.095.
References and notes
Typical procedure for the synthesis of 7a:
1. Ugi, I.; Dömling, A.; Werner, B. Res. Adv. Inorg. Chem. 2000, 1, 91–106.
2. Hulme, C. In Multicomponent Reactions; Zhu, J., Bienaymé, H., Eds.; Wiley-VCH,
2005; pp 311–312.
3. (a) Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3168–3210; (b) Dömling,
A. Chem. Rev. 2006, 106, 17–89; (c) Kalinski, C.; Umkehrer, M.; Weber, L.; Kolb,
J.; Burdack, C.; Ross, G. Mol. Div. 2010, 14, 513–522; (d) Wessjohann, L. A.;
Rhoden, C. R. B.; Rivera, D. G.; Vercillo, O. E. Top. Heterocycl. Chem. 2010, 23,
199–226.
4. Dou, G.; Shi, D. J. Comb. Chem. 2009, 11, 1073–1077. and Refs. 7–16 cited
therein.
5. Dolle, R. E.; Le Bourdonnec, B.; Worm, K.; Morales, G. A.; Thomas, C. J.; Zhang,
W. J. Comb. Chem. 2010, 12, 765–806.
6. Abouzid, K. A. M.; EI-Abhar, H. S. Arch. Pharm. Res. 2003, 26, 1–8; (b) Tse, E.;
Butner, L.; Huang, Y.; Hall, I. H. Arch. Pharm. Med. Chem. 1996, 329, 35–40.
7. Bruneau, P. A. R. European Patent EP355970, 1990.
8. Norman, M. H.; Rigdon, G. C.; Navas, F., III; Cooper, B. R. J. Med. Chem. 1994, 37,
2552–2563.
9. Wyrick, S. D.; Voorstad, P. J.; Cocolas, G.; Hall, I. H. J. Med. Chem. 1984, 27, 768–
772.
10. Hall, I. H.; Wong, O. T.; Hall, E. S.; Chen, L. K. Anticancer Drugs 1993, 4, 389–393.
11. Correa, A.; Tellitu, I.; Dominguez, E.; San Martin, R. Tetrahedron 2006, 62,
11100–11105.
In a dry Schlenk tube filled with nitrogen, 41.9 mg (77.3
are dissolved in 0.5 ml of abs. DMF together with 1.4 mg (7.7
CuI and 28.3 mg (85.0 mol, 1.1 equiv)of Cs2CO3 and stirred at rt until reaction
l
mol, 1 equiv)of 5a0
mol, 10 mol %)of
l
l
is completed (HPLC). Then the reaction mixture is filtered through celite,
stripped of its solvent and purified by column chromatography on silica (ethyl
acetate/hexane = 1/4, Rf = 0.45) to yield 28.1 mg of the title compound (white
solid, 93 %).1H NMR (400 MHz, CDCl3) d 8.31 (s, 1H), 7.87 (dd, J = 8.1, 3.0 Hz,
2H), 7.68–7.62 (m, 1H), 7.36 (t, J = 7.5 Hz, 1H), 4.00 (d, J = 11.3 Hz, 1H), 2.96–
2.83 (m, 1H), 1.64 (s, 9H), 1.38 (s, 9H), 1.05 (d, J = 6.7 Hz, 3H), 0.64 (d, J = 6.5 Hz,
3H).
Typical procedure for the synthesis of 8a:
In a dry pressure tube filled with nitrogen 158 mg (0.43 mmol, 1 equiv) of 6a
are dissolved in 5 ml of abs. Toluene together with 39.9 mg (43
lmol,
10 mol %) of Pd2dba3, 4.6 mg (21
l
mol, 5 mol %) of PtBu, 84.3 mg (0.85 mmol,
2 equiv) of NaOtBu and 118 mg (0.85 mmol, 2 equiv) of K2CO3 and stirred for
18 h at 110 °C. Then the reaction mixture is filtered through celite, stripped of
its solvent and purified by column chromatography on silica (ethyl acetate/
hexane = 1/1?9/1, Rf = 0.26 [ethyl acetate/hexane = 1/1]) to yield 87.3 mg of a
brown solid (71%).1H NMR (400 MHz, CDCl3) d 9.03 (s, 1H), 7.79 (d, J = 7.8 Hz,
1H), 7.50 (t, J = 7.4 Hz, 1H), 7.23 (d, J = 8.2 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 5.11
(d, 2 rotamers: J = 9.8, 4.2 Hz, 1H), 2.61–2.47 (m, 1H), 1.38 (s, 9H), 1.10 (d,
J = 6.7 Hz, 3H), 0.83 (d, J = 6.6 Hz, 3H).
12. Tempest, P.; Ma, V.; Kelly, M. G.; Jones, W.; Hulme, C. Tetrahedron Lett. 2001, 42,
4963–4968.
Typical procedure for the synthesis of 9m:
In a dry Schlenk tube filled with nitrogen 202 mg (0.34 mmol, 1 equiv) of 5m0
are dissolved in 3 ml abs. DMF together with 3.7 mg (0.017 mmol, 5 mol %) of
CuI and 128 mg (0.38 mmol, 1.1 equiv) of Cs2CO3 and stirred for 15 h at 80 °C.
Then the reaction mixture is filtered through celite, stripped of its solvent and
purified by column chromatography on silica (ethyl acetate/hexane = 1/2,
Rf = 0.25) to yield 107 mg (82 %).1H NMR (400 MHz, DMSO-d6) d 7.88 (d, J = 7.3
Hz, 1H), 7.71–7.62 (m, 2H), 7.37–7.31 (m, 1H), 7.23 (d, J = 8.7 Hz, 2H), 6.88 (d,
J = 8.7 Hz, 2H), 4.62 (d, J = 15.0 Hz, 1H), 4.57 (d, J = 15.0 Hz, 1H), 3.69 (s, 3H),
2.18–2.06 (m, 1H), 0.85 (d, J = 6.8 Hz, 3H), 0.62 (d, J = 6.9 Hz, 3H).
13. Lemke, T. L. In Review of Organic Functional Groups: Introduction to Medicinal
Organic Chemistry, 4th ed.; Lippincott Williams & Wilkins, 2003.
14. (a) Welsch, S. J.; Umkehrer, M.; Ross, G.; Kolb, J.; Burdack, C.; Wessjohann, L. A.
Tetrahedron Lett. 2011, 52, 6295–6297; (b) Kalinski, C.; Umkehrer, M.; Schmidt,
J.; Ross, G.; Kolb, J.; Burdack, C.; Hiller, W.; Hoffmann, S. D. Tetrahedron Lett.
2006, 47, 4683–4686; (c) Umkehrer, M.; Kalinski, C.; Kolb, J.; Burdack, C.
Tetrahedron Lett. 2006, 47, 2391–2393; (d) Gracias, V.; Moore, J. D.; Djuric, S. W.
Tetrahedron Lett. 2004, 45, 417–420; (e) Xiang, Z.; Luo, T.; Lu, K.; Cui, J.; Shi, X.;
Fathi, R.; Chen, J.; Yang, Z. Org. Lett. 2004, 6, 3155–3158; (f) Kalinski, C.;