Synthesis of allene ferrocenes through CuI-mediated Crabbe homologation reaction

Article abstract of DOI:10.1039/c2ra22806h

A concise and efficient method for the synthesis of bifunctional allene ferrocenes based on the modified Crabbe homologation reaction of ferrocenylacetylenes with paraformaldehyde promoted by CuI was developed. The presented synthesis proceeded readily with high compatibility of sensitive functional groups on the cyclopentadiene ring providing good to excellent yields of the desired products.

Full text of DOI:10.1039/c2ra22806h

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Synthesis of allene ferrocenes through CuI-mediated
´
Crabbe homologation reaction3
Cite this: RSC Advances, 2013, 3, 1758
Shufeng Chen, Binglong Wang, Qing Yan, Jinxiang Shi, Haiying Zhao
and Baoguo Li*
Received 7th November 2012,
Accepted 3rd December 2012
DOI: 10.1039/c2ra22806h
www.rsc.org/advances
A concise and efficient method for the synthesis of bifunctional
´
allene ferrocenes based on the modified Crabbe homologation
reaction of ferrocenylacetylenes with paraformaldehyde pro-
moted by CuI was developed. The presented synthesis proceeded
readily with high compatibility of sensitive functional groups on
the cyclopentadiene ring providing good to excellent yields of the
desired products.
Scheme 1 Synthesis of allene ferrocenes.
´
and co-workers have reported a modified Crabbe reaction of
terminal 1-alkyne that generates terminal allene products with
moderate to high yields by using CuI and Cy2NH.9g
Introduction
Recently, there has been a resurgence of interest in the chemistry
of ferrocene and its derivatives1 due to their increasing applica-
tions in many areas such as material science,2 asymmetric
catalysis,3 and bioorganometallic chemistry.4 Undoubtedly, the
design motif and synthesis strategy for ferrocene-based architec-
tures play the most important roles in delivering the required
properties. Although ferrocene derivatives are classical aromatic
compounds, traditional methods for the derivatization of aromatic
compounds may not work for ferrocene due to its specific
geometric and electronic properties.5 In view of the importance of
ferrocene derivatives, there has been a continuing interest in
developing efficient methods for their synthesis under mild
reaction conditions.
On the other hand, the chemistry of allenes is currently a field
of interest because of the diverse reactivities that these
compounds exhibit in organic synthesis.6 Furthermore, allene
moieties have also been found in many natural products and
pharmacologically active compounds.7 Thus, the development of
efficient methods to synthesise novel structured allene derivatives
from commonly used starting materials is highly desirable. Over
the past decades, enormous efforts have been devoted to the
development of highly efficient allene synthesis.8 Among which,
Table 1 Optimization of reaction conditionsa
Entry Cat. (mol%)
Base
Solvent Time (h) Yield (%)b
1
2
3
4
5
6
7
8
CuBr (200)
CuCl (200)
CuI (200)
CuCl2 (200)
Cu(OAc)2 (200) i-Pr2NH
i-Pr2NH
i-Pr2NH
i-Pr2NH
i-Pr2NH
Dioxane 5.5
Dioxane 5.5
Dioxane 5.5
Dioxane
Dioxane
Dioxane
Dioxane 5.5
Dioxane 5.5
Dioxane 5.5
Dioxane 5.5
THF
DMSO
Toluene 5.5
Toluene 5.5
56
58
78
Trace
Trace
Trace
82
81
84
6
6
4
ZnI2 (200)
CuI (150)
CuI (100)
CuI (80)
CuI (50)
CuI (80)
CuI (80)
CuI (80)
CuI (80)
CuI (80)
CuI (80)
CuI (80)
CuI (80)
CuBr (80)
CuCl (80)
i-Pr2NH
i-Pr2NH
i-Pr2NH
i-Pr2NH
i-Pr2NH
i-Pr2NH
i-Pr2NH
i-Pr2NH
Cy2NH
Morpholine Toluene 5.5
Pyrrolidine Toluene 5.5
Cy2NH
i-Pr2NH
i-Pr2NH
i-Pr2NH
9
10
11
12
13
14
15
16
17
18d
19d
20d
45
5.5
5.5
ndc
ndc
85
57
Trace
Trace
80
90
69
Dioxane 6
Toluene 5.5
Toluene 5.5
Toluene 5.5
´
the Crabbe homologation reaction and its modifications are
widely used in the synthesis of simple allenes.9,10 For example, Ma
61
a
All the reactions were carried out with 1a (0.24 mmol),
paraformaldehyde (0.60 mmol) and base (0.48 mmol) in 3.0 mL of
b
College of Chemistry and Chemical Engineering, Inner Mongolia University, Hohhot
010021, China. E-mail: baoguol@sohu.com
solvent if not otherwise indicated. Yield of isolated product after
c
d
chromatography. 2a was not detected. Ratio of 1a/(CH2O)n/
i-Pr2NH was 1.0 : 1.8 : 1.7; in 3.0 mL of toluene.
Electronic supplementary information (ESI) available. See DOI: 10.1039/c2ra22806h
3
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Moreover, the incorporation of ferrocenyl groups to the
frameworks of allenes would offer effective modification of their
original properties. However, to the best of our knowledge, there
are very few examples in the literature that report this type of
ferrocene-containing allene.11 In continuation of our work on the
synthesis of ferrocene derivatives,12 we herein report an efficient
method for the synthesis of bifunctional allenyl ferrocene
Results and discussion
Our initial study was performed with commercially available
ferrocenylacetylene 1a as a model substrate in the presence of
paraformaldehyde. The results are summarized in Table 1. Under
the reported conditions,9 the reaction of ferrocenylacetylene with
paraformaldehyde and i-Pr2NH mediated by CuBr in dioxane
afforded the desired ferrocenyl allene 2a in 56% yield (entry 1,
Table 1). Further experiments led to the observation that CuCl may
play the same role affording 2a in a slightly higher yield (entry 2).
Moreover, we were delighted to find that the isolated yield of 2a
´
derivatives based on the modified Crabbe homologation reaction
of ferrocenylacetylenes with paraformaldehyde promoted by CuI
(Scheme 1).
Table 2 Preparation of 19-ethynyl-1-acylferrocenes
Entry
1
Product 3
Yield (%)a
68
Product 1
Yield (%)a
73
3b
3c
1b
1c
2
45
77
3
4
3d
3e
76
72
1d
1e
79
71
5
6
3f
65
70
1f
63
57
3g
1g
a
Yield of isolated product after chromatography.
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Scheme 2 Synthesis of 19-ethynylferrocene-1-carboxylic esters.
was increased to 78% when CuI was used as the catalyst (entry
3).9g Other catalysts, such as CuCl2, Cu(OAc)2 and ZnI2, were
confirmed to be ineffective for this transformation (entries 4–6).
Encouraged by these results, we next carefully examined the effect
of the catalyst loading on this homologation reaction (entries 7–
10). The results indicated that 80 mol% of CuI could give the best
yield of the product under the same conditions (entry 9). After CuI
(80 mol%) was identified as the most efficient catalyst, the effect of
the solvent on this reaction was next examined (entries 11–13).10a
No product was formed in THF and DMSO; toluene turned out to
be the best. Next, we went on to screen the effect of different
was found that a 1a/(CH2O)n/i-Pr2NH ratio of 1.0 : 1.8 : 1.7 led to
the highest yield of 2a (entry 18). Once again, the reactivities of
other Cu(I) salts were checked carefully under optimal conditions
and the results indicated that CuI was still the most effective for
this transformation (entries 19 and 20).
To define the generality of the present method, we firstly
synthesized a series of 19-ethynyl-1-acylferrocenes from the
corresponding 19-acetyl-1-acylferrocenes by a two-step procedure.13
The overall yields for the two-step procedure ranged from 35–51%
(Table 2). Moreover, three 19-ethynylferrocene-1-carboxylic esters
were easily prepared by the reaction of 19-ethynylferrocene-1-
amines, because previous investigations showed that the amine
carboxylic
acid
with
methanol
or
phenol
using
(DCC/
9g
´
may be crucial for the Crabbe homologation reaction. It was
N,N9-dicyclohexylcarbodiimide/4-dimethylaminopyridine
DMAP) as dehydrating agents (Scheme 2).14 The 19-ethynyl-1-
carbonylferrocenes were sufficiently stable to withstand purifica-
tion by column chromatography and could also be stored at room
temperature.
found that Cy2NH also led to the formation of ferrocenyl allene 2a
in moderate yield (entry 14). However, only a trace of 2a was
detected when morpholine or pyrrolidine was used in this reaction
(entries 15 and 16). It was noted that when the reaction was
carried out in dioxane using Cy2NH as base and CuI as catalyst,
80% yield of product 2a was obtained (entry 17). Therefore, by
comparing to Ma’s report,9g we observed that the most appropriate
amine for this ferrocene-containing allene forming reaction is
i-Pr2NH. Furthermore, the ratio of substrates was examined, and it
Having prepared a variety of 19-ethynyl-1-carbonylferrocenes,
we next turned our attentions to the homologation reaction for the
synthesis of allene ferrocenes using these compounds as the
substrates and the results are summarized in Table 3. Various
substitutions on the cyclopentadiene ring could be tolerated, and
the reaction gave moderate to high yields of the ferrocenyl allene
products 2a–i. For aroyl-substituted ferrocenylacetylenes, the
reaction afforded the corresponding allenes 2b–g in 70–86%
isolated yields (entries 2–7). We were curious to know if a
ferrocenylacetylene containing ester group such as 1h (entry 8)
would behave similarly to aroyl-substituted ferrocenylacetylenes
under our reaction conditions. We were pleased to discover that
the reaction proceeded readily to give the corresponding allene
product 2h in 83% yield. However, when methyl 19-ethynyl-1-
ferrocenecarboxylate 1i was used as the substrate in this reaction,
Table 3 CuI promoted Crabbe´ homologation reaction of various ferrocenyla-
cetylenes 1a–i with paraformaldehydea
Entry
1, R
Reaction time (h)
2, yield (%)b
1
2
3
4
5
6
7
8
9
1a, H
1b, PhCO
4
3.5
2
5.5
1.5
2.5
5
2a, 90
2b, 74
2c, 74
2d, 86
2e, 82
2f, 70
2g, 73
2h, 83
2i, 61
1c, o-ClC6H4CO
1d, p-ClC6H4CO
1e, 3,5-Cl,ClC6H3CO
1f, o-BrC6H4CO
1g, o-IC6H4CO
1h, CO2Ph
6
5
1i, CO2CH3
a
Reactions were carried out with 1a–i (0.24 mmol),
paraformaldehyde (0.43 mmol) and i-Pr2NH (0.41 mmol) in 3.0 mL
b
of toluene. Yield of isolated product after chromatography.
Scheme 3 Reaction of 1j.
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On the basis of the results presented above and the previous
understanding of this type of reaction,9,10,15 we propose the
following possible mechanism for this homologation reaction, as
shown in Scheme 5. In the presence of base and copper(I) salt,
copper acetylide 4 is formed from ferrocenylacetylene 1a. The
reaction of copper acetylide 4 with the iminium ion 5, which is
generated in situ from paraformaldehyde and i-Pr2NH, leads to the
formation of the corresponding propargylic amine intermediate 6
and regenerated CuI. CuI coordinates to the carbon–carbon triple
bonds in 6 to give intermediate 7, which undergoes an
intramolecular hydride transfer and b-elimination to afford the
ferrocenyl allene product 2a. It is noted that the formation of 2a
could also be attributed to the SN29 reaction of intermediate 7
instead of intermediate 8.
Scheme 4 Reaction of propargylic amine intermediate 6.
only a moderate yield of product 2i was obtained after workup
(entry 9).
More interestingly, when N,N9-dicyclohexylcarbamimidoyl
19-ethynylferrocene-1-carboxylate 1j was employed in this modified
Conclusions
´
Crabbe homologation reaction, we surprisingly found that the
ferrocenyl allene product 2j was formed in moderate yield under
identical reaction conditions (Scheme 3). The formation of 2j
suggested that the reaction proceeded accompanied by the
rearrangement of the ester group under these conditions. To
examine whether CuI catalyses the displacement of CyNH2 in this
transformation, we carried out control experiments by treating 1j
with i-Pr2NH in the absence of formaldehyde, and in the absence
of both formaldehyde and copper. However, no new product could
be identified in these reactions and the starting material was
recovered after refluxing in toluene for 10 h. Therefore, the
mechanism for the formation of the corresponding product 2j
remains not completely clear.
Besides, it is noted that we have isolated the propargylic amine
6 which was formed in the reaction of ferrocenylacetylene,
paraformaldehyde and i-Pr2NH at 130 uC in toluene for 15 min.
Treatment of compound 6 with CuI, CuBr or CuCl in toluene
resulted in the formation of the allene product 2a in 63%, 42%
and 46% isolated yields, respectively (Scheme 4). Moreover, no
reaction was observed in the absence of a copper catalyst.
In conclusion, we have developed a concise and efficient method
for the synthesis of bifunctional allene ferrocenes based on the
´
modified Crabbe homologation reaction of ferrocenylacetylenes
with paraformaldehyde in the presence of i-Pr2NH using CuI as
the catalyst. Due to the increasing importance of allenes and
ferrocenes in organic chemistry, this method will be a valuable
choice for organic synthesis and it may open up new possibilities
to incorporate ferrocene chemistry with allenes. Further studies on
the applications as well as the transformations of these novel
allene ferrocenes are being actively pursued in our laboratory.
Acknowledgements
This project is generously supported by the National Natural
Science Foundation of China (Nos. 20902044 and 21262023)
and the Program for Young Talents of Science and Technology
in the Universities of Inner Mongolia Autonomous Region
(NJYT-12-B03).
Scheme 5 Possible reaction pathway.
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