Synthesis of highly substituted N-hydroxyindoles through 1,5-Addition of carbon nucleophiles to in situ generated unsaturated nitrones

Article abstract of DOI:10.1002/anie.200601808

(Chemical Equation Presented) As easy as 1→2→3: Generation (1→2) and subsequent capture (2→3) of the reactive α,β-unsaturated nitrone species 2 with silyl enol ethers, silanes, and stannanes leads to a facile and direct entry to a variety of highly substi

Full text of DOI:10.1002/anie.200601808

Communications
Synthetic Methods
DOI: 10.1002/anie.200601808
Synthesis of Highly Substituted N-Hydroxyindoles
through 1,5-Addition of Carbon Nucleophiles to
In Situ Generated Unsaturated Nitrones**
K. C. Nicolaou,* Anthony A. Estrada, Sang Hyup Lee,
and Graeme C. Freestone
We recently reported a new method for the construction of
substituted N-hydroxyindoles through trapping of unsatu-
rated nitrones by oxygen, sulfur, and nitrogen nucleophiles.[1]
Substituted N-hydroxyindoles continue to be of considerable
interest to us not only because of our efforts towards the total
synthesis of the thiopeptide antibiotic nocathiacin I,[2] whose
structure contains such a domain, but also due to the growing
interest in their construction as a consequence of the proven
biological properties of this unique structural motif.[3,4]
Intrigued by the preference of phenolic substrates to react
through their carbon, rather than their oxygen, centers,[1] we
investigated the behavior of various carbon nucleophiles in
that process. Herein, we report our findings in this area which
constitute a new method for generating highly substituted N-
hydroxyindoles through carbon–carbon bond formation
involving 1,5-addition[5] to a,b-unsaturated nitrones.
Scheme 1 depicts the transformation involving
a
SnCl2·2H2O-initiated cascade to facilitate conversion of
nitroaromatic a,b-unsaturated ketoesters I into a,b-unsatu-
rated nitrones II, with subsequent trapping of the latter,
rather reactive species by various carbon nucleophiles to
afford N-hydroxyindoles III.[6] To explore this reaction,
nitroaromatic a,b-unsaturated ketoesters 3a–3e were pre-
pared from nitroaromatic systems 1a–1e by a two-step
process via intermediates 2a–2e in good overall yield
(Scheme 2). Bromo-substituted substrate 3a was then
employed in the new process with silyl enol ethers acting as
[*] Prof. Dr. K. C. Nicolaou, A. A. Estrada, Dr. S. H. Lee,
Dr. G. C. Freestone
Department of Chemistry and
The SkaggsInstitute for Chemical Biology
The Scripps Research Institute
10550 North Torrey PinesRoad, La Jolla, CA 92037 (USA)
and
Department of Chemistry and Biochemistry
University of California, San Diego
9500 Gilman Drive, La Jolla, CA 92093 (USA)
Fax: (+1)858-784-2469
E-mail: kcn@scripps.edu
[**] We thank Dr. D. H. Huang, Dr. G. Siuzdak, and Dr. R. Chadha for
NMR spectroscopic, mass spectrometric, and X-ray crystallographic
assistance, respectively. Financial support for this work was
provided by grantsfrom the National Institutesof Health (USA), the
National Science Foundation, and the SkaggsInstitute for Chemical
Biology, and a fellowship from the National Institutes of Health
(USA) to A.A.E.
Supporting information for thisarticle isavailable on the WWW
under http://www.angewandte.org or from the author.
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the same methoxy ether 19. Fur-
ther confirmation of the structure
of product 19 was obtained by X-
ray crystallographic analysis[7] (see
Figure 1a). The employment of
triethylsilane in the reaction
resulted in reduction of the reac-
tive nitrone species, leading to the
Scheme 1. General path for the construction of 3-substituted N-hydroxyindoles( III). Nu=carbon
nucleophile.
3-methyl-substituted
product
(Table 2, entry 7), while allenyl
trimethylsilane furnished an acety-
lenic compound, 21, albeit in low
yield (20%; Table 2, entry 8). Allyl
stannanes (Table 2, entries 9 and
10) also reacted with the nitrone
derived from 3a, leading to the
desired products in varying yields.
Compound 23 was analyzed by X-
ray crystallography[7] (see Fig-
ure 1b).
To demonstrate the validity of
the proposed method and the gen-
erality and scope of the reaction
with regards to the nitroaromatic
substrate, we explored the employ-
Scheme 2. Synthesis of nitro ketoesters 3a–e. Reagentsand conditions: a) NaH (4.0 equiv),
(CO2Me)2 (5.0 equiv), DMF, 08C, 1 h; then 25À8C, 18 h, 2a (60%), 2b (80%), 2c (75%), 2d (85%),
+
=
2e (65%); b) NaH (1.1 equiv), CH2 N Me2Cl (3.0 equiv), THF, 08C, 1 h; then 258C, 12 h, 3a
(80%), 3b (74%), 3c (75%), 3d (98%), 3e (50%). DMF=N,N-dimethylformamide, THF=tetrahy-
drofuran, SEM=2-(trimethylsilyl)ethoxymethyl.
carbon nucleophiles under the reductive conditions provided
by SnCl2·2H2O (2.5 equiv) in DME at 408C. The results from
these experiments are summarized in Table 1. As seen, both
cyclic (Table 1, entries 1–3) and acyclic (Table 1, entries 4–10)
silyl enol ethers enter the reaction with good yields. The
products include N-hydroxyindoles substituted at the 3-
position with carbon chains containing a-substituted ketones
with various groups. These appendages include aliphatic,
aromatic, and heteroaromatic ketone functionalities. Of
particular interest to pharmaceutical research are the
fluoro-substituted compounds, which are also formed in
good yields (Table 1, entries 8–10) under these conditions.
Furthermore, as a result of their chemical properties, these
compounds may serve as viable substrates for further
manipulation. By-product 4 (Table 1 and Table 2) is also
produced in many of these reactions through an intramolec-
ular Michael addition as previously observed and mechanis-
tically rationalized.[1]
ment of substrates 3a–3e in combination with silyl enol ethers
24 and 25. Products 5, 26a–29a, 8, and 26b–29b were formed
in moderate to good yields (see Table 3). Of particular
interest is the survival of the aromatic nitrile functionality
(Table 3, entry 5) under the reductive and nucleophilic
conditions employed—an observation that stands as a testa-
ment to the mild nature of the process. From Table 3 it can
also be seen that the method accommodates various sub-
stitution patterns around the aromatic nuclei, including a
We next tested the possibility of employing silicon- and
tin-activated nucleophiles such as allyl silanes and stannanes
in the N-hydroxyindole-forming reaction. Table 2 summarizes
the results of this investigation, further demonstrating the
power of this method to construct molecular complexity
rapidly and efficiently from simple building blocks. Thus, allyl
trimethylsilanes carrying a variety of structural motifs were
shown to react smoothly with the a,b-unsaturated nitrone
derived from the bromonitroaromatic ketoester 3a to afford
novel N-hydroxyindoles (Table 2, entries 1–4). Interestingly,
when allyl trimethoxysilane was used (Table 2, entry 5), the
methoxy group was transferred to the N-hydroxyindole to
furnish the corresponding methoxy ether 19 (see Supporting
Information) in good yield. In an attempt to complement this
result, methoxytrimethylsilane (Table 2, entry 6) was sub-
jected to the reaction conditions and produced, as expected,
Figure 1. ORTEP drawingsof compounds 19 (a) and 23 (b) drawn at
the 50% probability level (only heteroatom labelsshown).
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Table 1: Synthesis of 3-alkyl-N-hydroxyindolesthrough 1,5-addition of islyl enol ethersto the
a,b-unsaturated nitrone derived from 3a.[a]
Entry
Enol ether
t [h]
Product
Yield
[%][b]
Yield (4)
[%][b]
1
1.5
61
70
66
73
60
17
17
11
10
10
2
3
4
5
1.5
1.2
1.0
1.3
6
7
2.0
1.0
63
68
10
15
8
1.5
75
[c]
9
1.5
1.5
75
63
[c]
[c]
10
[a] Reactionswere carried out on a scale of 0.06–0.10 mmol in anhydrous1,2-dimethoxyethane (DME; concentration: 0.12–0.16 m), and the products
were purified by preparative TLC (silica gel). [b] Yield of isolated product. [c] Trace amounts not isolated.
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Table 2: Synthesis of 3-alkyl-N-hydroxyindoles through 1,5-addition of silanes and stannanes to the a,b-unsaturated nitrone derived from 3a.[a]
Entry
1
Silane/
stannane
t [h]
Product
Yield
[%][b]
Yield (4)
[%][b]
2.5
57
61
20
15
2
3
1.5
3.5
50
57
11
15
4
15
5
6
1.5
2.0
53
50
12
15
7
8
9
3.5
28
50
20
25
16
[c]
15
30
10
4.5
62
14
[a] Reactionswere carried out on a scale of 0.06–0.10 mmol in anhydrousDME (concentration: 0.12–0.16 m), and the productswere purified by
preparative TLC (silica gel). [b] Yield of isolated product. [c] Trace amounts not isolated.
fluorine residue (Table 3, entries 2 and 3), which often
exhibits unique pharmacological properties.
strate that this method may also be applied to more complex
systems where a large excess of the nucleophile may not be
acceptable.
The chemistry described herein expands the repertoire of
carbon–carbon bond-forming reactions and provides facile
and direct entry to a variety of highly substituted N-
hydroxyindoles. The method is expected to find applications
in chemical synthesis in general and in the construction of
Finally, to demonstrate the effect of varying the stoichi-
ometry of the reaction, bromonitroaromatic ketoester 3a and
difluorosilyl enol ether derived from 2,2,2-trifluoroacetophe-
none[8] were subjected to the standard conditions (Table 1,
entry 8), but using 1, 3, 5, or 10 equivalents of the nucleophile.
The results (50, 59, 75, and 74% yield, respectively) demon-
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Communications
Table 3: Synthesis of 3-alkyl-N-hydroxyindolesthrough 1,5-addition of silyl enol ethers 24 and 25 to substituted a,b-unsaturated nitrones IV.[a,b]
Entry
a,b-Unsaturated
nitro ketoester
Product V
Yield
[%][c]
Product VI
Yield
[%][c]
1
61
73
2
3
4
5
44
45
57
43
61
61
46
40
[a] Reactionswere carried out on a scale of 0.06–0.10 mmol in anhydrousDME (concentration: 0.12–0.16 m), and the productswere purified by
preparative TLC (silica gel). [b] In each case, a minor by-product corresponding to compound 4 was formed (see Table 1 and Table 2), but not isolated.
[c] Yield of isolated product.
[3] For selected reviews on N-hydroxyindoles and their derivatives,
see: a) M. Somei, Adv. Heterocycl. Chem. 2002, 82, 101 – 155;
b) M. Somei, Heterocycles 1999, 50, 1157 – 1211; c) R. M. Ache-
son, Adv. Heterocycl. Chem. 1990, 51, 105 – 175.
molecular complexity and diversity for biological and phar-
maceutical purposes in particular.
Received: May 8, 2006
[4] a) M. Belley, E. Sauer, D. Beaudoin, P. Duspara, L. Trimble, P.
DubØ, Tetrahedron Lett. 2006, 47, 159 – 162; b) A. Penoni, G.
Palmisano, G. Broggini, A. Kadowaki, K. M. Nicholas, J. Org.
Chem. 2006, 71, 823 – 825; c) A. Wong, J. T. Kuethe, I. W. Davies,
J. Org. Chem. 2003, 68, 9865 – 9866; d) A. G. Myers, S. B. Herzon,
J. Am. Chem. Soc. 2003, 125, 12080 – 12081; e) S. Katayama, N.
Ae, R. Nagata, J. Org. Chem. 2001, 66, 3474 – 3483; f) Z. Wróbel,
M. Ma¸kosza, Tetrahedron 1997, 53, 5501 – 5514; g) A. Reissert, H.
Heller, Ber. Dtsch. Chem. Ges. 1904, 37, 4364 – 4379.
[5] This type of reaction is sometimes referred to as a 1,4-addition.
[6] For a comprehensive review on nitrones, see: P. Merino, Science
of Synthesis, Vol. 27 (Ed.: A. Padwa), Thieme, New York, 2004,
pp. 511 – 580.
[7] CCDC 603155 (19) and 603156 (23) contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
[8] a) G. K. S. Prakash, J. Hu, G. A. Olah, J. Fluorine Chem. 2001,
112, 357 – 362; b) H. Amii, T. Kobayashi, Y. Hatamoto, K.
Uneyama, Chem. Commun. 1999, 1323 – 1324.
Published online: July 18, 2006
Keywords: N-hydroxyindoles· nitrogen heterocycles· silanes·
.
stannanes · synthetic methods
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