Amide-Directed C?H Sodiation by a Sodium Hydride/Iodide Composite

Article abstract of DOI:10.1002/anie.201702512

A new protocol for amide-directed ortho and lateral C?H sodiation is enabled by sodium hydride (NaH) in the presence of either sodium iodide (NaI) or lithium iodide (LiI). The transient organosodium intermediates could be transformed into functionalized aromatic compounds.

Full text of DOI:10.1002/anie.201702512

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International Edition: DOI: 10.1002/anie.201702512
German Edition: DOI: 10.1002/ange.201702512
Metalation
Hot Paper
À
Amide-Directed C H Sodiation by a Sodium Hydride/Iodide
Composite
Yinhua Huang+, Guo Hao Chan+, and Shunsuke Chiba*
Dedicated to Professor Teruaki Mukaiyama on the occasion of his 90th birthday
Abstract: A new protocol for amide-directed ortho and lateral
bonds. Subsequent reactions of the resulting organosodium
intermediates with the amide moiety furnished useful aro-
matic building blocks such as arylaldehydes bearing secon-
dary alkyl groups at the ortho-position, 2-indanones, and
polycyclic aromatic hydrocarbons. The discovery and scope/
limitations of these processes are described herein.
À
C H sodiation is enabled by sodium hydride (NaH) in the
presence of either sodium iodide (NaI) or lithium iodide (LiI).
The transient organosodium intermediates could be trans-
formed into functionalized aromatic compounds.
À
D
irected C H metalation of aromatic compounds with
basic metalating reagents is a regioselective way to convert
We recently disclosed that sodium hydride (NaH) could
be endowed with unprecedented hydride donor reactivity by
solvothermal treatment with either NaI or LiI in THF, and the
resulting composites could be used for a series of hydride
reductions.[6] For example, the NaH/iodide composite enabled
hydride reduction of N,N-dimethylamides into aldehydes
(Scheme 2a).[6b] During the course of the study of the hydride
reduction of aliphatic amides by the NaH/NaI system, we
found that the reduction of the a-arylacetamide 1a delivers
3-isopropyl-2-naphthaldehyde (2a) in 64% yield (Sche-
me 2b). In sharp contrast to the reduction of aliphatic
amides shown in Scheme 2a, the reduction of 1a did not
form the corresponding aliphatic aldehyde at all. Notably, no
reaction was observed with only NaH. We assumed that the
NaH/iodide composite bears reasonable Lewis acidity and
À
a relatively inert C H bond into a nucleophilic organometal-
lic species (i.e., ortho metalation for aromatic C(sp ) H
bonds and lateral metalation for benzylic C(sp ) H bonds),
and is one of the most useful and practical methods in the
2
À
3
À
production
of
functionalized
aromatic
chemicals
(Scheme 1).[1,2] Typically, organolithium/magnesium reagents
Scheme 1. Directed ortho- and lateral metalation. DG=directing
group.
and lithium/magnesium amides are employed as the metal-
ating reagents of choice, whereas organo- and inorganic
sodium reagents have rarely been utilized for metalation
because of their instability, inaccessibility, and limited reac-
tivity despite the lower cost of metallic sodium and its
derivatives.[3–5] Herein, we report use of a sodium hydride/
iodide composite to perform either amide-directed sodiation
2
3
À
À
of either ortho C(sp ) H bonds or lateral benzylic C(sp ) H
[*] Dr. Y. Huang,[+] G. H. Chan,[+] Prof. S. Chiba
Division of Chemistry and Biological Chemistry, School of Physical
and Mathematical Sciences, Nanyang Technological University
Singapore 637371 (Singapore)
E-mail: shunsuke@ntu.edu.sg
[+] These authors contributed equally.
Scheme 2. Reactions of aliphatic amides with a NaH/NaI composite.
[a] The reactions were conducted using 0.5 mmol of 1a in THF
(2.5 mL: 0.2m) and yields of isolated 2a are noted above. No reaction
was observed without NaI. THF=tetrahydrofuran.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201702512.
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forms the complex A with the Lewis-basic amide moiety
(Scheme 2c). With a complex-induced proximity effect,[7]
subsequent ortho deprotonation takes place to form the
arylsodium B, which undergoes nucleophilic addition to the
amide carbonyl group to provide the four-membered ring
anionic carbinolamine C. To release the ring strain of C, ring-
lacetamide (1i) provided the corresponding benzaldehyde 2i
in 65% yield, whereas that of a-triphenylacetamide (1j)
afforded the N,N-dimethylbenzamide 2j in 61% yield. The
resulting bulky ortho-diphenylmethyl moiety of 2j might
impede further hydride reduction, by the NaH/iodide com-
posite, of the rearranged amide moiety.
À
opening takes place through C C bond cleavage to generate
Interestingly, the treatment of the a-(2-tolyl)acetamide
1k with the NaH/iodide composite provided the 2-indanone
4k as the sole product (Scheme 4a), in which use of the NaH/
the arylamide D (1,3-carbamoyl migration). Further hydride
reduction of the amide moiety of D results in the formation of
the aldehyde 2a.
This process is a sequence of unprecedented anionic
C-Fries-type rearrangement[8,9] and amide reduction enabled
by the NaH/iodide composite, thus offering concise access to
arylaldehydes bearing secondary alkyl groups at the ortho-
position (2) from readily available a-quaternary a-arylaceta-
mides (1). Thus, we next investigated the scope and limita-
tions of this multistep molecular transformation
(Scheme 3).[10] The substituent R1, either a methoxy or
Scheme 4. Lateral sodiation for the synthesis of 4k. [a] The reactions
were conducted using 0.5 mmol of 1k in THF (2.5 mL: 0.2m) and
yields of isolated 4k are noted above.
LiI system rendered the process faster.[13] Again, NaH alone
was not sufficient for promoting the reaction, thus indicating
the unique reactivity from the NaH/iodide composite. In this
Scheme 3. Substrate scope for the synthesis of arylaldehydes 2 bearing
secondary alkyl groups at the ortho-position. [a] The reactions were
conducted using 0.5 mmol of 1 in THF (2.5 mL: 0.2m) for 14 h and
yields of the isolated products are noted above. [b] 9,10-Dihydrophe-
nanthren-9-ol (3e) was obtained together with the aldehyde 2e from
the reaction of the amide 1e (see the Supporting Information for more
details). [c] The reaction was completed after 18 h to afford the
benzamide 2j in 61% yield instead of the corresponding benzalde-
hyde.
case, the transient NaH/amide complex E, in turn, undergoes
3
À
lateral benzylic C(sp ) H sodiation exclusively to generate
the benzyl sodium F, which cyclizes with the amide moiety to
give the five-membered ring anionic carbinol amine G
(Scheme 4b). Elimination of sodium dimethylamide produces
4k. Further hydride reduction of the carbonyl group could be
prevented by formation of the enolate H by a-deprotonation.
2-Indanones are a privileged scaffold for production of
pharmaceutical drugs based on the 2-aminoindane core.[14] As
the current protocol with the NaH/iodide composite could be
an attractive alternative to synthesizing 2-indanones,[15] the
scope and limitations were explored (Scheme 5).[10] The
method allowed construction of the spirocyclic 2-indanones
4l–n efficiently. Installation of two different alkyl groups
(benzyl and methyl groups) at C1 of 4o was readily
accomplished. Lateral sodiation of the methylene moiety
also worked with the current protocol, thus furnishing 4p and
4q in moderate to good yields. As for the substituent R4 on
the benzene ring, methyl, methoxy, and fluoro groups were
introduced (4r–t), while the yield of 5-fluoro-2-indanone (4t)
was moderate.
phenyl group, on the aryl group was tolerated (2b–e). The
reaction of the meta-phenyl substrate 1d resulted in selective
installation of the formyl group at the sterically less hindered
carbon center of 2d (marked in red). Interestingly, when the
ortho-phenyl substrate 1e was employed, not only the
biarylaldehyde 2e but also the 9,10-dihydrophenanthren-9-
ol 3e were isolated in 54% and 10% yields, respectively.
Formation of 3e might be triggered by remote sodiation[11] at
À
the biaryl C H bond (marked in blue) by the NaH/NaI
composite, and then followed by a sequence of cyclization and
reduction.[12] It is worthy to note that a pyridyl moiety (2 f) is
compatible in the present process. The protocol allowed the
synthesis of benzaldehydes having cyclohexyl (2g) and
tetrahydropyranyl (2h) moieties. The reaction of a-dipheny-
We next attempted construction of a phenanthrene scaf-
fold by a lateral sodiation/cyclization sequence of biaryl
2
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Scheme 5. Substrate scope for the synthesis of 2-indanones 4.
[a] Unless otherwise stated, the reactions were conducted using 0.3–
0.5 mmol of 1 in THF (0.2m) for 2–4 h and yields of isolated 4 were
noted above. [b] NaI (2 equiv) was used instead of LiI and the reaction
was run for 6 h.
amides.[16] For this purpose, use of the N,N-dimethylbenza-
mide 5 was not optimal with the NaH/iodide composite, thus
affording 9-phenanthrenol (6) in only 4% yield (Scheme 6a).
In this case, the major product was a hydride reduction
product, the biarylaldehyde 7 (89% yield). Since we observed
in the previous study that secondary amides could tolerate
such undesired hydride reduction,[6a] the reactions of the
N-methyl biarylamide 8a were tested (Scheme 6b). As
expected, construction of the phenanthrene skeleton pro-
ceeded smoothly, and more fascinatingly, the product distri-
bution could be switched by changing the iodide additive.
Namely, the reaction with the NaH/NaI system predomi-
Scheme 6. Lateral sodiation of biaryl amides. [a] The reactions were
conducted using 0.5 mmol of amide substrates in THF (2.5 mL: 0.2m)
and yields of isolated products were noted above unless otherwise
stated. [b] Yields within the parentheses are determined based on
1H NMR spectroscopy with the aid of an internal standard. [c] The
reactions were conducted using 0.5 mmol of the amides 8 with NaH
(5 equiv) and LiI (3 equiv) in THF (2.5 mL: 0.2m) at 858C for 14 h and
yields of isolated 9 are noted above. Bn=benzyl.
À
nantly provided 6 by C N bond cleavage of the cyclized
anionic carbinolamine intermediate I, whereas use of the
NaH/LiI system delivered N-methyl-9-phenanthrenamine
À
(9a) by C O bond cleavage as the major product. The roles
of the iodide additives to differentiate the major product (6 or
9a) are the subject of ongoing investigations. As construction
of the amino benzene scaffold has rarely been achieved using
the lateral metalation/cyclization strategy,[17,18] the scope and
limitations of the reaction employing the NaH/LiI system was
examined (Scheme 6c). The method allowed installation of
a cleavable benzyl group on the nitrogen atom of the
phenanthrenamine 9b. Synthesis of the N-methyl-9-phenan-
threnamines 9c–f having methyl and methoxy groups were
successfully achieved. Moreover, the present protocol was
applicable to the reaction of the biarylamide 8g, which did not
easily undergo lateral metalation/cyclization sequence by the
conventional method with LDA, because of the hindered
rotation on the biaryl axis.[16] Cyclization under the NaH/LiI
system provided 5-N-methylamino-[4]helicene (9g) together
with 5-hydroxy-[4]helicene (10) in good combined yield
(Scheme 6d).[19]
investigating other possible directing groups to establish
À
versatile protocols for C H sodiation under user-friendly
reaction conditions and procedures.
Acknowledgments
Funding of S.C. for this work was provided by Nanyang
Technological University, Singapore Economic Development
Board (EDB), and Pfizer Asia Pacific Pte. Ltd. G.H.C. thanks
to EDB-Industrial Post-graduate Program (IPP) for the
scholarship support.
This work demonstrates potential use of a NaH/iodide
À
composite for directed C H sodiation. We are currently
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[9] The reactions of 1a with either sec-BuLi or LDA, which are
commonly used to induce the anionic Fries rearrangement, did
not provide the corresponding amide (a protonated form of
intermediate D in Scheme 2) through 1,3-carbamoyl migration
(see the Supporting Information).
[10] The methods in Schemes 3 and 5 have thus far not proven
successful with a-tertiary and a-secondary amides because of the
inherent Brønsted basicity of NaH.
Conflict of interest
The authors declare no conflict of interest.
À
Keywords: amides · arenes · C H activation · metalation ·
sodium hydride
[11] D. Tilly, J.-m. Fu, B.-p. Zhao, M. Alessi, A.-S. Castanet, V.
Snieckus, J. Mortier, Org. Lett. 2010, 12, 68.
[12] X. Tang, A. Studer, Org. Lett. 2016, 18, 4448.
[13] It should be noted that solvothermal treatment of NaH and LiI
induces counterion metathesis to form the NaH/NaI composite,
which is responsible for the present hydride-transfer reactions.
See Ref. [6c].
[14] There are many examples of small-molecule drugs based on the
2-aminoindane core, and they are commonly prepared from 2-
indanones. For reviews, see: a) S. D. Brandt, R. A. Braithwaite,
M. Evans-Brown, A. T. Kicman, in Novel Psychoactive Sub-
stances: Classification, Pharmacology and Toxicology (Eds.: P. I.
Dargan, D. M. Wood), Elsevier, Amsterdam, 2013, pp. 261 – 283;
b) P. D. Sainsbury, A. T. Kicman, R. P. Archer, L. A. King, R. A.
Braithwaite, Drug Test. Analysis 2011, 3, 479.
[15] For reported methods on the synthesis of 2-indanones, see: a) G.
Henrion, T. E. J. Chavas, X. L. Goff, F. Gagosz, Angew. Chem.
Int. Ed. 2013, 52, 6277; Angew. Chem. 2013, 125, 6397; b) J. Zhao,
D. A. Clark, Org. Lett. 2012, 14, 1668; c) D. L. Usanov, H.
Yamamoto, Org. Lett. 2012, 14, 414; d) A. A. Tudjarian, T. G.
Minehan, J. Org. Chem. 2011, 76, 3576; e) A. M. Dalton, Y.
Zhang, C. P. Davie, R. L. Danheiser, Org. Lett. 2002, 4, 2465;
f) K. Nakatani, Tetrahedron Lett. 1987, 28, 165.
[1] For reviews on directed ortho-metalation, see: a) S. Florio, A.
Salomone, Synthesis 2016, 1993; b) D. Tilly, J. Magolan, J.
Mortier, Chem. Eur. J. 2012, 18, 3804; c) B. Haag, M. Mosrin, H.
Ila, V. Malakhov, P. Knochel, Angew. Chem. Int. Ed. 2011, 50,
9794; Angew. Chem. 2011, 123, 9968; d) V. Snieckus, Pure Appl.
Chem. 1990, 62, 2047; e) V. Snieckus, Chem. Rev. 1990, 90, 879;
f) P. Beak, V. Snieckus, Acc. Chem. Res. 1982, 15, 306.
[2] For a review on directed lateral metalation, see: R. D. Clark, A.
Jahangir, Org. React. 1995, 47, 1.
[3] For reviews on the chemistry of organosodium reagents, see:
a) M. Schlosser, Angew. Chem. Int. Ed. Engl. 1964, 3, 362;
Angew. Chem. 1964, 76, 258; b) M. Schlosser, Angew. Chem. Int.
Ed. Engl. 1964, 3, 287; Angew. Chem. 1964, 76, 124; c) R. A.
Benkeser, D. J. Foster, D. M. Sauve, J. F. Nobis, Chem. Rev. 1957,
57, 867.
[4] For reports on use of in situ generated organosodium reagents
for directed ortho sodiation, see: a) J.-M. Becht, A. Gissot, A.
Wagner, C. Mioskowski, Tetrahedron Lett. 2004, 45, 9331; b) A.
Gissot, J.-M. Becht, J. R. Desmurs, V. Pꢀvꢁre, A. Wagner, C.
Mioskowski, Angew. Chem. Int. Ed. 2002, 41, 340; Angew. Chem.
2002, 114, 350.
[5] For reports on directed magnesiation using Na/Mg bimetallic
reagents, see: a) A. J. Martꢂnez-Martꢂnez, A. R. Kennedy, R. E.
Mulvey, C. T. OꢃHara, Science 2014, 346, 834; b) P. C. Andriko-
poulos, D. R. Armstrong, D. V. Graham, E. Hevia, A. R.
Kennedy, R. E. Mulvey, C. T. OꢃHara, C. Talmard, Angew.
Chem. Int. Ed. 2005, 44, 3459; Angew. Chem. 2005, 117, 3525.
[6] a) D. Y. Ong, C. Tejo, K. Xu, H. Hirao, S. Chiba, Angew. Chem.
Int. Ed. 2017, 56, 1840; Angew. Chem. 2017, 129, 1866; b) P. C.
Too, G. H. Chan, Y. L. Tnay, H. Hirao, S. Chiba, Angew. Chem.
Int. Ed. 2016, 55, 3719; Angew. Chem. 2016, 128, 3783; c) Z.
Hong, D. Y. Ong, S. K. Muduli, P. C. Too, G. H. Chan, Y. L. Tnay,
S. Chiba, Y. Nishiyama, H. Hirao, H. S. Soo, Chem. Eur. J. 2016,
22, 7108.
[16] Construction of 9-phenanthrenols was accomplished by the
reactions of biaryl N,N-diethyl amides with LDA. See: J.-M. Fu,
M. J. Sharp, V. Snieckus, Tetrahedron Lett. 1988, 29, 5459.
[17] The reaction of 8a with LDA (2.2 equiv), which is commonly
used to induce the lateral lithiation, provided only small amounts
of the mixture of 6 and 9a (12 and 15% yield, respectively based
1
on H NMR analysis of the crude reaction mixture) with 67%
recovery of 8a (see the Supporting Information).
[18] N-methyl-9-phenanthrenamines are found as the core scaffold of
dioxoaporphine alkaloids. See: a) C. Hoarau, A. Couture, E.
Deniau, P. Grandclaudon, Eur. J. Org. Chem. 2001, 2559; b) C.
Hoarau, A. Couture, E. Deniau, P. Grandclaudon, Synthesis
2001, 1462; c) R. Suau, J. M. Lꢄpez-Romero, R. Rico, F. J.
Alonso, C. Lobo, Tetrahedron 1996, 52, 11307, and references
therein.
[19] The reaction of 8g with the NaH/NaI composite provided 10 as
a the sole product, while the reaction rate was found to be very
slow. For example, treatment of 8g with NaH (8.3 equiv) and
NaI (5 equiv) for 24 h gave 10 in 32% yield along with 60%
recovery of 8g (see the Supporting Information).
[7] a) M. C. Whisler, S. MacNeil, V. Snieckus, P. Beak, Angew.
Chem. Int. Ed. 2004, 43, 2206; Angew. Chem. 2004, 116, 2256;
b) P. Beak, A. I. Meyers, Acc. Chem. Res. 1986, 19, 356.
[8] For selected reports on anionic O- and N-Fries rearrangements,
see: a) J. C. Riggs, K. J. Singh, M. Yun, D. B. Collum, J. Am.
Chem. Soc. 2008, 130, 13709; b) S. L. MacNeil, B. J. Wilson, V.
Snieckus, Org. Lett. 2006, 8, 1133; c) J. P. H. Charmant, A. M.
Dyke, G. C. Lloyd-Jones, Chem. Commun. 2003, 380; d) M. P.
Sibi, V. Snieckus, J. Org. Chem. 1983, 48, 1935.
Manuscript received: March 9, 2017
Final Article published: && &&, &&&&
4
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Communications
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Communications
Metalation
New direction: An amide-directed ortho
À
and lateral C H sodiation is enabled by
Y. Huang, G. H. Chan,
S. Chiba*
sodium hydride (NaH) in the presence of
either sodium iodide (NaI) or lithium
iodide (LiI). The transient organosodium
intermediates could be transformed into
functionalized aromatic compounds.
&&&& — &&&&
À
Amide-Directed C H Sodiation by
a Sodium Hydride/Iodide Composite
Angew. Chem. Int. Ed. 2017, 56, 1 – 5
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5
These are not the final page numbers!