Rhodium-catalyzed [2+2+2] cycloaddition of oximes and diynes to give pyridines

Article abstract of DOI:10.1002/chem.201203909

Oximes and diynes undergo efficient cycloaddition in the presence of a catalytic amount of a cationic rhodium(I)/dppf complex (see scheme). Spontaneous dehydration of the initially formed cycloadducts leads to the formation of a variety of substituted pyridines in moderate to good yields. The transformation could also be achieved in a one-pot procedure using aldehydes. Copyright

Full text of DOI:10.1002/chem.201203909

DOI: 10.1002/chem.201203909
Rhodium-Catalyzed [2+2+2] Cycloaddition of Oximes
and Diynes To Give Pyridines
Fen Xu, Chunxiang Wang, Dongping Wang, Xincheng Li, and Boshun Wan*[a]
Transition-metal-catalyzed [2+2+2] cycloaddition reac-
tions are valuable for the synthesis of pyridine derivatives
with high atom efficiency.[1,2] Despite numerous studies in
this field,[3,4] the nitrogen source is restricted to nitriles
(Scheme 1a). Therefore the development of a straightfor-
directing groups can undergo [2+2+2] cycloaddition to
afford 1,2-dihydropyridines under conditions of high temper-
ature (1008C),[6] the low reactivity of the C=N bond remains
a challenging problem for simple oximes to participate in
metal-catalyzed [2+2+2] cycloaddition (Scheme 1c). In ad-
dition, avoiding metal-catalyzed rearrangements[7] and the
Beckmann rearrangement[8] of oximes to give the corre-
sponding amides are challenges that need to be overcome.
Furthermore, water, which would be generated in situ from
the dehydration of the initial cycloadduct (for example, N-
hydroxy-1,2-dihydropyridine) may greatly affect the efficien-
cy of metal catalyzed cycloaddition reaction. Despite these
challenges, we surmised that precious metals that could tol-
erate stoichiometric amounts of water could be used as cata-
lysts for the effective activation of the oxime substrates.
Herein, we report the first example of a rhodium-catalyzed
cycloaddition of oximes and diynes that gives substituted
pyridines (Scheme 1c). Moreover, the formation of pyri-
dines from a one-pot reaction of an aldehyde, a hydroxyla-
mine, and a diyne, as well as a possible reaction pathway are
also discussed.
Based on our previous work on [2+2+2] cycloaddition re-
actions,[4] we used a combination of [Rh
ACHTUNTRGENUNG(cod)2]BF4 and
binap as a catalyst system. Initially, the reaction of diyne 1a
with (E)-benzaldehyde oxime 2a was conducted in the pres-
À
Scheme 1. Synthesis of pyridines through either cycloaddition or C H
bond functionalization.
ence of a catalytic amount of [RhACHTNUTRGNEUNG(cod)2]BF4 and binap. The
ward and efficient strategy for the generation of pyridines is
a formidable challenge in this field. An alternative nitrogen
source, oximes, can be easily accessed from hydroxylamine
and carbonyl compounds (for example, aldehydes and ke-
tones). The reactivity of the C=N bond makes oximes an al-
ternative coupling partner for cycloaddition reactions; how-
ever, only the reaction of a,b-unsaturated oximes and al-
kynes has been reported to generate substituted pyridines
solvent is critical for this reaction. The use of MeOH and
CF3CH2OH afforded 3aa in 26% and 31% yield, respec-
tively (Table 1, entries 3 and 4). However, only a trace
amount of 3aa was obtained when the reaction was conduct-
ed in either toluene, EtOH, dioxane, or DMF (Table 1, en-
tries 1, 2, 5, and 6). Other bidentate phosphine ligands in
combination with [RhACHTUNRGTNEUNG(cod)2]BF4 were screened for catalytic
activity (Table 1). We were pleased to find that the use of
dppf as a ligand led to the highest catalytic activity, and pyr-
idine 3aa was obtained in moderate yield (Table 1, entry 8).
Subsequently, we found that increasing the loading of [Rh-
(Scheme 1b).[5] In these cases, either intramolecular [4+2]
cycloaddition[5a] or C H bond functionalization
was in-
[5b–d]
À
volved, both of which occurred using a rhodium catalyst. Al-
though there are a few reports that show that imines bearing
AHCTUNTGRENN(GUN cod)2]BF4 and dppf to 10 mol% and then to 20 mol% led
to a decrease in yield (Table 1, entries 13 and 14). Increasing
the catalyst-to-ligand ratio from 1:1 to 1:1.2 resulted in a
slight improvement in the yield (Table 1, entry 15). Impor-
tantly, the efficiency of the reaction could be drastically en-
hanced by increasing the amount of 2a from 2 to 4 equiva-
lents (69% yield as determined using HPLC, Table 1, entries
15 and 16). Therefore, the optimized reaction conditions
[a] F. Xu, C. Wang, Dr. D. Wang, Dr. X. Li, Prof. Dr. B. Wan
Dalian Institute of Chemical Physics, Chinese Academy of Sciences
457 Zhongshan Road, Dalian 116023 (P. R. China)
Fax : (+86)411-8437-9223
E-mail: bswan@dicp.ac.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203909.
were as follows: [RhACHTNUTRGNEUNG(cod)2]BF4 (5 mol%), dppf (6 mol%),
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COMMUNICATION
Table 1. Optimization of reaction conditions for pyridine formation.[a]
Table 2. Synthesis of pyridines from diynes (1a–1e) and oxime (2a–
2n).[a]
Entry
Diyne
R2
Yield [%][c]
1
2
3
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
C6H5 (2a)
69 (3aa)
67 (3ab)
69 (3ac)
75 (3ad)
88 (3ae)
76 (3af)
78 (3ag)
81 (3ah)
61 (3ai)
78 (3aj)
67 (3ak)
69 (3al)
60 (3am)
4-MeOC6H4 (2b)
4-MeC6H4 (2c)
4-ClC6H4 (2d)
4-FC6H4 (2e)
4-CF3C6H4 (2 f)
3-BrC6H4 (2g)
3-MeC6H4 (2h)
3-CF3C6H4 (2i)
3-FC6H4 (2j)
4[b]
5[b]
6
Entry
Solvent
x/y
Ligand
Yield [%][b]
1
2
toluene
EtOH
MeOH
CF3CH2OH
dioxane
5/5
5/5
5/5
5/5
5/5
5/5
5/5
5/5
5/5
5/5
5/5
5/5
10/10
20/20
5/6
binap
binap
binap
binap
binap
binap
segphos
dppf
dppe
xantphos
MeO-biphep
(R)-Tol-binap
dppf
dppf
dppf
trace
trace
26
7
8[b]
9[b]
10
11[b]
12
13
3[c]
4
31
5
6
7
8
trace
trace
25
2-MeC6H4 (2k)
2-napthyl (2l)
4-pyridyl (2m)
DMF
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
44
9
trace
trace
27
24
41
27
53
69
14
15
16
1a
41 (3an)
74 (3be)
40 (3ce)
10
11
12
13
14
15
16[d]
4-FC6H4 (2e)
4-FC6H4 (2e)
5/6
dppf
[a] Reaction conditions: diyne 1a (0.125 mmol), oxime 2a (2 equiv,
0.25 mmol), [Rh(cod)2]BF4 (x mol%), ligand (y mol%), 4 ꢁ molecular
ACHTUNGTRENNUNG
sieves (200 mg), solvent (3 mL) at 808C for 48 h. [b] Determined by
HPLC with 1-methylnaphthalene as internal standard. [c] 608C. [d] 2a
(4 equiv). binap=2,2’-bis(diphenylphosphino)-1,1’-binaphthyl, cod=1,5-
cyclooctadiene, dppe=1,2-bis(diphenylphosphino)ethane, Ts=p-toluene-
sulfonyl.
17
18
4-FC6H4 (2e)
C6H5 (2a)
26 ACHTUNGTRENNUNG(3de)
46 (4ea)
CF3CH2OH as solvent, and conducting the reaction at 808C
in the presence of 4 ꢁ molecular sieves (200 mg/0.125 mmol
diyne).
[a] 1a–1e (0.25 mmol), 2a–2nACTHNUTRGENN(UG 1 mmol), [RhAHCUTNGTREN(NUNG cod)2]BF4 (5 mol%), dppf
(6 mol%), and CF3CH2OH (6 mL) in the presence of 4 ꢁ molecular
sieves (0.4 g); then stirred for 48 h. [b] 1a was added slowly by syringe.
[c] Yield of isolated product.
With optimized reaction conditions established, we ex-
plored the substrate scope using various diynes and oximes
(Table 2). In general, a range of electron-rich, electron-neu-
tral, and electron-deficient aryl oximes were tolerated to
afford the corresponding products in good yields (Table 2,
entries 1–12, 61–88%). Oximes bearing electron-withdraw-
ing groups at the para position gave better results than
those with electron-donating groups (Table 2, entries 2–6).
Notably, the reaction of sterically demanding substrate 2k
(R=2-MeC6H4, Table 2, entry 11) and diyne 1a led to the
corresponding product in a yield that was lower than the re-
action of substrate 2h (R=3-MeC6H4, Table 2, entry 8). Im-
portantly, 2-naphthaldehyde oxime 2l and heteroaryl oxime
2m can also be used for this reaction, thus furnishing the
pyridine product 3al and 3am in 69% and 60% yield, re-
spectively (Table 2, entries 12 and 13). The reaction of diyne
1b with oxime 2e gave the cycloadduct 3be in 74% yield
(Table 2, entry 15). When we applied this method to the cy-
cloaddition of C-tethered diynes and an O-tethered diyne,
we fortunately found that 3ce, 3de, and 4ea were formed in
moderate yield (Table 2, entries 16–18). Notably, the use of
a one-pot procedure (Scheme 2) was successful for the syn-
thesis of pyridine 3aa from aldehyde 4a, hydroxylamine,
and diyne 1a, albeit with a yield that was lower than that of
the two-step protocol (60% versus 69% yield; Table 2,
Scheme 2. One-pot formation of pyridines from aldehyde 4a, hydroxyl-
AHCTUNGTREGaNNNU mine, and diyne 1a.
Chem. Eur. J. 2013, 19, 2252 – 2255
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B. Wan et al.
Scheme 3. Possible pathways to form pyridines.
entry 1); this lower yield might be due to the influence of
residual aldehyde[9] and the relatively low amount of oxime.
Two possible pathways for the formation of pyridines are
shown in Scheme 3: 1) pathway A: dehydration of the
oxime to generate the corresponding nitrile followed by the
cycloaddition of the nitrile and the alkynes to afford the pyr-
idine; 2) pathway B: cycloaddition of the oxime and the al-
kynes to form intermediate 5, which then undergoes dehy-
dration (Scheme 3). To determine which one of these hy-
potheses was more likely, two experiments were first carried
out (Scheme 4). The reaction of oxime 2a under standard
Scheme 5. Proposed mechanism for the [2+2+2] cycloaddition of alkynes
and oximes.
followed by its incorporation into the metallacycle either by
a [4+2] cycloaddition or an insertion process. Finally the
product, J, could be obtained by regeneration of the catalyst
and dehydration.
In conclusion, we have developed a new method for the
preparation of pyridine derivatives; the method involves a
rhodium-catalyzed [2+2+2] cycloaddition of diynes and
oximes, can be conducted under mild conditions, and gives
the pyridine products in moderate to high yields. This trans-
formation complements traditional metal-catalyzed cycload-
dition reactions used for the synthesis of pyridines. More-
over, the ability to form these pyridines by using a one-pot
reaction of an aldehyde, a hydroxylamine, and a diyne
makes this method a more practical alternative because
simple aldehydes can be used as starting materials. Investi-
gations of other cycloaddition reactions involving oximes
are currently underway.
Scheme 4. Control experiments for determining the feasibility of path-
way A.
reaction conditions (Table 2) only gave a trace amount of
benzonitrile (<5%, Scheme 4a). In addition, when benzoni-
trile was subjected to the reaction with diyne 1a instead of
oxime 2a (Scheme 4b), the corresponding pyridine product
3aa was detected in less than 20% yield (compare with
69% yield, Table 2, entry 1) together with a side product de-
rived from dimerization of the diyne. Therefore, pathway A
in Scheme 3 is not feasible for the formation of pyridines.
Although attempts to isolate the key intermediate, N-hy-
droxy-1,2-dihydropyridine, did not succeed, on the basis of
the cycloaddition of an imine reported by both Ogoshi et
al.[6b] and Yoshikai and co-workers,[6c] we suspected that this
reaction would begin with the oxidative coupling between
the alkyne and the oxime, thus affording five-membered
azametallacycle E (Scheme 5). Subsequent alkyne insertion
could afford seven-membered aza-metallacycle G, which
could then undergo reductive elimination and dehydration
to provide the final pyridine product, J. Alternatively, the
reaction could start with intramolecular oxidative cyclization
of two alkyne moieties to obtain metallacyclopentadiene in-
termediate K. The coordination of oxime A could then be
Experimental Section
Representative procedure: [RhACHTNUGTRNEUNG(cod)2]BF4 (5.1 mg, 0.0125 mmol) and
dppf (8.3 mg, 0.015 mmol) were dissolved in CF3CH2OH (6 mL) in the
presence of 4 ꢁ molecular sieves, and the mixture was stirred at room
temperature for 5 min. Oxime was added and the resulting mixture was
stirred at 808C for 30 min. To this solution was added diyne (0.25 mmol).
Then the mixture was stirred at 808C for 48 h. The 4 ꢁ molecular sieves
were filtered off and the filtrate was evaporated. The oily residue was pu-
rified by column chromatography on silica gel with petroleum ether/ethyl
acetate (4:1 to 1:2) as eluent to afford products.
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Cycloaddition of Oximes and Diynes
COMMUNICATION
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Acknowledgements
Financial support from the National Basic Research Program of China
(2010CB833300) and the National Natural Science Foundation of China
(21172218) is gratefully acknowledged.
Keywords: cycloaddition · heterocycles · oximes · pyridines ·
rhodium
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Received: November 1, 2012
Published online: December 27, 2012
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