Highly efficient Cu(I)-catalyzed synthesis of N-heterocycles through a cyclization-triggered addition of alkynes

Article abstract of DOI:10.1021/ja908883n

(Chemical Equation Presented) An aminoalkyne (terminal or internal) and a terminal alkyne furnish functionalized five-, six-, and seven-membered N-heterocycles in excellent yields via a Cu(I)-catalyzed, one-pot, tandem hydroamination/alkynylation process.

Full text of DOI:10.1021/ja908883n

Published on Web 12/30/2009
Highly Efficient Cu(I)-Catalyzed Synthesis of N-Heterocycles through a
Cyclization-Triggered Addition of Alkynes
Junbin Han, Bo Xu,* and Gerald B. Hammond*
Department of Chemistry, UniVersity of LouisVille, LouisVille, Kentucky 40292
Received October 23, 2009; E-mail: bo.xu@louisville.edu; gb.hammond@louisville.edu
Table 1. Screening of Conditionsa
N-Heterocycles containing five-, six-, or seven-membered rings
and various substitution patterns are indisputably important as
building blocks and targets.1,2 In this regard, the transition metal
catalyzed hydroamination of alkynes has played a preponderant role
in their synthesis.2,3 Depending on the substitution pattern of the
entry
catalyst
1b/equiv
solvent
temp/time
yield%
starting material and of the catalyst used, the hydroamination of
alkynes can yield an enamine or imine (in the case of primary
amines). The reported methodologies have focused mostly on
hydroamination using primary amines. The addition of a terminal
alkyne to an activated enamine is the methodology of choice for
the synthesis of racemic or chiral propargyl amines.4 We conceived
an alternative approach: if a secondary amine attacks an electro-
philically activated alkyne, the resulting activated enamine inter-
mediate then becomes a new electrophilic precursor capable of
reacting with a second nucleophile, such as a terminal alkyne, to
give a new addition product. This essentially corresponds to a
double addition to a triple bond. If the first step is an intramolecular
cyclization using an aminoalkyne (Scheme 1), then the second step
adds a second alkynyl group (Ct CsR3), which can then interact
with R1 or R2 and spur further transformations (e.g., cycloisomer-
ization). We call this strategy a cyclization-triggered addition and
are now pleased to report its proof of concept, namely, a highly
efficient and atom-economical synthesis of functionalized five-, six-,
and seven-membered N-heterocycles, via a Cu(I)-catalyzed, one-
pot, tandem hydroamination/alkynylation.
1
2
3
4
5
6
7
8
AuCl
4
4
4
4
4
4
4
4
4
4
1.5
1.5
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
toluene
CH3CN
dioxane
dioxane
MWb/100 °C/0.5 h
MW/100 °C/0.5 h
MW/100 °C/0.5 h
MW/100 °C/0.5 h
MW/100 °C/0.5 h
MW/100 °C/0.5 h
MW/60 °C/0.5 h
heat/100 °C/12 h
MW/100 °C/0.5 h
MW/100 °C/0.5 h
MW/100 °C/0.5 h
MW/100 °C/0.5 h
15
50
15
42
95
99
65
99
98
98
99
99
Cu(OTf)2
PdCl2
AgNO3
CuI
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
9
10
11
12c
a The reactions were conducted on a 0.25 mmol scale. b MW )
microwave. c The reaction was conducted on a 3 mmol scale.
alkynylation (Sonogashira-type reactions). Under microwave condi-
tions, this reaction is very fast and gives excellent yields, but
conventional heating also works very well if longer reaction times
are employed (Table 1, entry 8). This reaction was initially
conducted in dioxane; however, toluene and acetonitrile also give
excellent results (Table 1, entries 9 and 10). At first, we used a
large excess of terminal alkyne 2a to avert a potential competition
between the two terminal alkynes, but to our surprise, even when
the number of equivalents of 2a was reduced from 4.0 to 1.5, the
reaction still furnished 3a in excellent yields (Table 1, entry 11).
Operating on a larger scale did not reduce the yield of product
(Table 1, entry 12).
Scheme 1. Cyclization-Triggered Alkynylation
The scope of this tandem amination/alkynylation reaction is
outlined in Table 2. The reaction worked extremely well in all cases
giving near quantitative chemical yields of five-, six-, and seven-
membered rings. Complete regioselectivity was observed. When
N-methyliminodiacetic acid (MIDA) boronate7 alkyne 2f was used,
the terminal alkyne product 3k was obtained (Table 2, entry 11);
this may be due to cleavage of MIDA boronate during the reaction.
When a chiral aminoalkyne was used (1g), a small chiral induction
was observed (dr ) 1:1.3, Table 2, entry 12), probably because
the existing chiral center is relatively far away from the newly
generated chiral center. The sterically encumbered TMS-substituted
aminoalkyne 1h did not give the desired product (Table 2, entry
13). And the reaction of proline derivative 1i gave a fused ring
product (Table 2, entry 14). The regioselectivity obeyed Baldwin’s
rules.8 The cyclization of 3-yn-amine 1b and 1a gave five-
membered ring products through 5-endodig and 5-exodig processes.
And the reactions of 5-yn-amine (e.g., 1c) and 6-yn-amine (e.g.,
1e) give six-membered and seven-membered rings, through 6-exodig
and 7-exodig processes, respectively.
Che and co-workers have reported a gold(I) catalyzed tandem
synthesis of pyrrolo[1,2-a]quinolines;5a their reaction requires
aromatic amines and terminal alkynes. On the other hand, Li and
co-workers reported the tandem addition of an amine and alkyne
to R,ꢀ-unsaturated esters through an iminium intermediate.6 We
envisioned a broader scope for a tandem hydroamination/alkyny-
lation process, namely, the amination of inactive alkynes (terminal
or internal) in the presence of a single metal catalyst operating on
the hydroamination and alkynylation steps. The reaction of ami-
noalkyne 1a, readily prepared from alkynyl alcohol by a tosylation/
amination sequence, with phenylacetylene 2a was used as a model
(Table 1).
Among the various coinage metal catalysts screened, copper was
the best, and Cu(I) was better than Cu(II) (Table 1, entries 1-5).
Copper’s excellent performance may be due to its higher tolerance
toward basic amines and the fact that it is a superior catalyst for
9
916 J. AM. CHEM. SOC. 2010, 132, 916–917
10.1021/ja908883n  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Scope of Tandem Amination/Alkynylation Reactiona
ring (eq 2). Taking this as a cue for a possible intermolecular variant,
we then reacted an unfunctionalized alkyne 1l with a simple
secondary amine, using similar conditions (eq 3). This reaction gave
the desired product 4b, albeit in lower chemical yield. We have
not yet conducted optimization studies for this intermolecular
version.
The cycloisomerization of 1,n-enynes and 1,n-diynes is currently
a highly competitive field in organic synthetic chemistry.9 Our
newly found method provides direct entry to functionalized 1,n-
enynes, as showcased by the synthesis of 1,6-enyne (3e) in high
yield in a single step (Table 2, entry 5). Our reaction is also capable
of furnishing fused ring systems, if a cyclic secondary amine is
present (Table 2, entry 14).
In conclusion, we have developed a powerful strategy to access
N-heterocycles of the most common ring sizes (5, 6, and 7) through
a tandem hydroamination/alkynylation sequence catalyzed by a
cheap and environmentally friendly copper catalyst. The broader
implications of this reaction, including an asymmetrical version,
and its application to natural product synthesis, are currently under
investigation.
Acknowledgment. We are grateful to the National Science
Foundation for financial support (CHE-0809683).
Supporting Information Available: Experimental procedures,
characterization, spectroscopic spectra for 3 and 4. This material is
available free of charge via the Internet at http://pubs.acs.org.
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a 1 (0.5 mmol), 2 (2.0 mmol), 1 mL dioxane.
Attempts to form three- or four-membered rings under similar
conditions, using 1j, were unsuccessful (eq 1). Surprisingly, the
reaction of 7-yn-amine 1k led to the intermolecular hydroamination/
alkynylation product 4a in good yield, through a double addition
to phenyl acetylene, rather than the corresponding eight-membered
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