Dehydrogenative [4 + 2] cycloaddition of formamides with alkynes through double c-h activation

Article abstract of DOI:10.1021/ja1102037

Formamides having 1-arylalkyl groups on nitrogen undergo an unprecedented dehydrogenative [4 + 2] cycloaddition reaction with alkynes via nickel/AlMe ₃ cooperative catalysis to give highly substituted dihydropyridone derivatives in good yields. Notably, the transformation proceeds through double functionalization of C(sp²)-H and C(sp³)-H bonds in the formamides.

Full text of DOI:10.1021/ja1102037

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Dehydrogenative [4 þ 2] Cycloaddition of Formamides with Alkynes
through Double C-H Activation
Yoshiaki Nakao,* Eiji Morita, Hiroaki Idei, and Tamejiro Hiyama*,†
Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan
S Supporting Information
b
Scheme 1. Strategies for Metallacycle Formation through
C-H Activation
ABSTRACT: Formamides having 1-arylalkyl groups on
nitrogen undergo an unprecedented dehydrogenative [4 þ 2]
cycloaddition reaction with alkynes via nickel/AlMe3 co-
operative catalysis to give highly substituted dihydropyridone
derivatives in good yields. Notably, the transformation pro-
ceeds through double functionalization of C(sp2)-H and
C(sp3)-H bonds in the formamides.
ycloaddition reactions represent one of the most important
C
class of transformations in organic synthesis. A diverse range
of ring structures can be constructed by these transformations in
a single operation starting with two or more compounds.1 A
number of transition-metal complexes have been investigated
as mediators or catalysts for cycloaddition reactions,2 many of
which provide cyclic molecules that are inaccessible by
classical concerted cycloaddition reactions such as the
Diels-Alder reaction. A key common feature of transition-
metal-mediated cycloaddition reactions is a metallacycle
intermediate, which is typically formed through the reaction
of a metal center with unsaturated C-C or C-heteroatom
bonds. Recent studies have shown that the key metallacycle
intermediates can also be formed through metalation of
unreactive C-H bonds. For example, the reaction of reactive
C-halogen, O-H, or N-H bonds at a metal center followed
by that of unreactive C-H bonds in an intramolecular
manner leads to a metallacycle species (Scheme 1).3 Subsequent
reactions with unsaturated compounds give cycloadducts, allowing
direct functionalization of C-H bonds to afford synthetically useful
cyclic products. Ultimately, the metallacycle intermediates could
also be generated by sequential activation of two C-H bonds.
Cycloaddition reactions involving such double C-H functionaliza-
tion allow the use of less-oxidized starting materials and thus should
be of great synthetic potential in terms of atom4 and redox
economy.5 Only a limited number of examples that proceed
through activation of C(sp2)-H bonds have been reported,6
whereas no precedents involving unreactive C(sp3)-H
functionalization7 are available.8 We report herein the oxidative
cycloaddition reaction of N,N-bis(1-arylalkyl)formamides with
alkynes via functionalization of formyl C(sp2)-H and alkyl
C(sp3)-H bonds. A catalytic cycle involving oxidative addition
of the formyl C(sp2)-H bond followed by hydronickelation of the
alkyne and intramolecular C(sp3)-H activation by the resultant
alkenyl group bound to the nickel center to form a key nickelacycle
intermediate is proposed.
We recently reported that the C(sp2)-H bond of various
formamides can be functionalized by cooperative nickel/Lewis
acid (LA) catalysis to allow hydrocarbamoylation of unsaturated
compounds.9 The reaction of (R,R)-N,N-bis(1-pheny-
lethyl)formamide [(R,R)-1a] having over 99% enantiomeric
excess (ee) with 4-octyne (2a) in the presence of bis(1,5-
cyclooctadiene)nickel [Ni(cod)2, 1 mol %], tri(tert-butyl)pho-
sphine [P(t-Bu)3, 4 mol %], and trimethylaluminum (AlMe3, 20
mol %) in toluene at 80 °C for 21 h (conditions similar to those
for the hydrocarbamoylation reaction9) gave the expected R,β-
unsaturated amide 4aa in only 4% yield, and dihydropyridone
3aa was obtained instead in 91% yield (Table 1, entry 1). Use of
P(t-Bu)3 as a ligand was crucial: use of PCy3 resulted in ∼10%
yield of 3aa, and other ligands gave not even trace amounts of the
products. The ee value for 3aa was found to be over 99%,
showing that no loss of the stereochemical information in (R,R)-
1a was observed under the reaction conditions. Lack of either of
the catalyst components resulted in no formation of 3aa and 4aa.
The reaction of 7-tetradecyne (2b) gave a stereoisomeric mixture
of tetradec-7-ene (70% yield) and the corresponding cycload-
duct 3ab (entry 2), suggesting that excess alkyne serves as a
hydrogen acceptor. (E)-Tetradec-7-ene was formed gradually
under the reaction conditions, probably through isomerization of
the initially formed (Z)-alkene on the basis of the reaction profile
monitored by GC. Formamides with other bulky N-substituents
[e.g., N,N-diisopropylformamide9 and N-isopropyl-N-(1-phen-
ylethyl)formamide] resulted in either preferential hydrocarba-
moylation of alkynes or no reaction. Curiously, meso-1a showed a
lower reaction rate and gave the corresponding adduct in 66%
yield under identical conditions after 21 h (entry 3). Therefore,
two 1-phenylethyl groups having the same configuration are
crucial for this transformation, presumably because they allow a
Received: November 19, 2010
Published: February 22, 2011
r
2011 American Chemical Society
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|

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Table 1. Dehydrogenative [4 þ 2] Cycloaddition of Forma-
mides with Alkynes Catalyzed by Ni/AlMe3
Figure 1. Molecular structure of 3ac.
Scheme 2. Reactions of Deuterated 1a with 2f
conformation suitable for the C(sp3)-H functionalization. The
reaction of (R,R)-1a with diphenylacetylene (2c) exclusively
gave cycloadduct 3ac in 79% yield (entry 4), whose structure was
unambiguously confirmed by X-ray crystallography (Figure 1).
Alkynes having sterically biased substituents also reacted with
racemic 1a (entries 5-9). Whereas modest regioselectivity was
observed with alkynes 2d, 2e, and 2g, 4,4-dimethylpent-2-yne
(2f) and phenyl(trimethylsilyl)acetylene (2h) gave a single
cycloadduct. Generally, a smaller substituent was introduced at
the R-position of the carbonyl in 3, except for 3ad and 3ah. The
attempted cycloaddition reactions with terminal alkynes were
futile because of rapid tri- and/or oligomerization of the alkynes.
Both electron-donating and -withdrawing groups on the phenyl
ring of 1a were tolerated, giving the corresponding adducts 3ba
and 3ca in good yields (entries 10 and 11). On the other hand,
the reaction of 1-naphthyl variant 1d with 2a was sluggish,
presumably as a result of steric repulsion induced by the aryl
group (entry 12). (R*,R*)-N,N-Bis(1-phenylpropyl)formamide
(1e) also gave six-membered-ring product 3ea through functio-
nalization of its methylene C(sp3)-H bond rather than the
terminal methyl group (entry 13). Notably, the C(sp3)-H bond
functionalization took place highly diastereoselectively.
a Isolated yields based on 1. b Estimated by GC and/or 1H NMR analysis
of the crude products. c >99% ee as estimated by chiral HPLC. d Tetra-
dec-7-ene (E/Z = 19:81) was also isolated in 70% yield. e Meso isomer of
f
1a. 4.4 mmol was used. g The reaction was run at 100 °C. h Slow
addition over 1 h (2g) or 5 h (2h). i 6.6 mmol was used. j (R*,R*)-N,N-
bis(1-phenylpropyl)formamide. k Diastereoselectivity = 96:4.
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COMMUNICATION
Scheme 3. Plausible Catalytic Cycle
functionalization of the C(sp3)-H bond may be rate-determin-
ing. Highly electron-donating, bulky P(t-Bu)3 may facilitate both
of the C-H activation steps in terms of electron density and steric
environment of the nickel center.
In conclusion, we have demonstrated that N,N-bis(1-arylalk-
yl)formamides undergo an unprecedented dehydrogenative [4
þ 2] cycloaddition reaction with alkynes via nickel/AlMe3
cooperative catalysis through double functionalization of other-
wise unreactive C(sp2)-H and C(sp3)-H bonds to give highly
substituted dihydropyridone derivatives, which can serve as
versatile synthetic precursors for nitrogen-containing six-mem-
bered heterocycles.12 Current efforts are being directed toward
understanding in detail the reaction mechanisms for the two C-
H activation steps and further development of this class of novel
cycloaddition reactions.
’ ASSOCIATED CONTENT
S
Supporting Information. Detailed experimental proce-
b
dures, spectroscopic and analytical data, and crystallographic data
(CIF). This material is available free of charge via the Internet at
http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
yoshiakinakao@npc05.mbox.media.kyoto-u.ac.jp; thiyama@kc.
chuo-u.ac.jp
Some additional experiments were performed to gain mechan-
istic insights into the present cycloaddition reaction. First, the
reaction of isolated hydrocarbamoylation product 4aa under the
reaction conditions gave no trace amount of 3aa, suggesting that
the present cycloaddition reaction is independent of the hydro-
carbamoylation. Second, the reaction of 1a-d, which was deuter-
ated at the formyl C-H bond, with 2f in C6D6 showed the
formation of 3af and 4af-d as well as (Z)-3-deuterio-4,4-
dimethyl-2-pentene10 by 1H NMR analysis of the crude product
(Scheme 2). On the other hand, the identical reaction using 1a-d6
labeled on both methyl groups of 1a gave 3af-d5, 4af-d6, and (Z)-
2-deuterio-4,4-dimethyl-2-pentene10 (Scheme 2). These results
indicate that hydrogenation of the alkyne takes place in a manner
distinct from simple addition of free H2 across alkynes, which
would have led to the formation of identically deuterated (Z)-
4,4-dimethyl-2-pentene.
Present Addresses
†Research & Development Initiative, Chuo University, Bunkyo-
ku, Tokyo 112-8551, Japan.
’ ACKNOWLEDGMENT
We thank Professor Masaki Shimizu for X-ray crystallographic
analysis. This work was financially supported by Grants-in-Aid
for Scientific Research (S) (21225005 to T.H.) and Scientific
Research on Innovative Areas “Molecular Activation Directed
toward Straightforward Synthesis” (22105003 to Y.N.) from
JSPS and MEXT, respectively.
’ REFERENCES
On the basis of these observations, the following catalytic cycle is
proposed (Scheme 3). The formamide coordinated to AlMe3 at
the carbonyl oxygen interacts with an electron-rich nickel(0)
species through η2-coordination to give A, which undergoes
oxidative addition of the formyl C-H bond to give B. Coordina-
tion followed by migratory insertion of the alkyne takes place,
giving D via C. While C-C bond-forming reductive elimination
from D gives the hydrocarbamoylation product 4,9 the sterically
demanding 1-arylalkyl group retards this pathway and induces
C(sp3)-H activation through a concerted cyclometalation, pre-
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membered nickelacycle E.11 A second migratory insertion of a
coordinating alkyne takes place at the sp-carbon bearing the
bulkier substituent R2 to give seven-membered nickelacycle F,
which reductively eliminates the cycloadduct 3. Decomplexation
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formation of η2-nickel complex A, which reenters the proposed
catalytic cycle. The observed difference in the 3af/4af-d and
3af-d5/4af-d6 ratios (Scheme 2) possibly suggests that the
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