An efficient and general iron-catalyzed C-C bond activation with 1,3-dicarbonyl units as a leaving groups

Article abstract of DOI:10.1002/anie.201006779

(Chemical Equation Presented) With our compliments: The 1,3-dicarbonyl unit has been shown to be a new and useful leaving group for iron-catalyzed bond cleavage (see scheme). This new strategy can complement the traditional Friedel-Crafts reaction and was applied in the synthesis of indene derivatives.

Full text of DOI:10.1002/anie.201006779

DOI: 10.1002/anie.201006779
Synthetic Methods
À
An Efficient and General Iron-Catalyzed C C Bond Activation with
1,3-Dicarbonyl Units as a Leaving Groups**
Huanrong Li, Wenjuan Li, Weiping Liu, Zhiheng He, and Zhiping Li*
The substitution reaction is one of the fundamental reactions
in chemistry and is widely applied in synthesis. Usually, a
polarized and labile leaving group (LG), such as halides,
tosylate, or psedohalides, is required for the success of a
substitution reaction (Scheme 1). Recently, the use of carbon-
À
Scheme 2. Iron-catalyzed C C bond cleavage. DCE=1,2,-dichloroethane.
We realized that this reaction can be regarded as a
substitution reaction and the 1,3-dicarbonyl functionality as a
leaving group. The intermediate generated in this reaction
could be the free cation A (SN1-type mechanism) or an ion
pair. We envisioned that if a different nucleophile is
introduced, a new substitution reaction can be achieved. To
this end, we had to firstly test for the best dicarbonyl leaving
group (Table 1). The desired product 4a was obtained in 93%
yield when 1a was used (Table 1, entry 1).[13] Meanwhil, b-
keto ester substrate 1b gave much lower yields of 4a (Table 1,
entries 2 and 3). Both 1c and 1d were less effective substrates,
even at higher temperature (Table 1, entries 4 and 5).
Scheme 1. The 1,3-dicarbonyl units as a leaving group. Ts=4-toluene-
sulfonyl, Y=nucleophile or electrophile.
À
based leaving groups through C C bond cleavage has
emerged as an attractive alternative in organic synthesis.[1]
Three general strategies have been extensively studied: 1) the
releasing of strain energy,[2] 2) cleavage of a C C bond
À
adjacent to carbonyl,[3] cyano,[4] carboxylic acid,[5] or hydroxy
groups,[6] and 3) chelation assistance.[7] The discovery of new
À
processes used to cleave unstrained C C bonds still remain a
major challenge.[8] Herein, we disclose the first method that
uses a 1,3-dicarbonyl unit as a leaving group in a substitution
reaction catalyzed by FeCl3 (Scheme 1). We also demonstrate
that this new strategy complements the traditional Friedel–
Crafts reaction and can find application in the synthesis of
indene derivatives.
Table 1: The reaction of diones 1 with 5-bromoindole 3a.[a]
In the course of developing iron-catalyzed reactions,[9,10]
we unexpectedly observed that in the presence of catalytic
amount of FeCl3, 2-benzhydryl-1,3-diphenylpropane-1,3-
dione 1a and ethyl 2-benzhydryl-3-oxo-3-phenylpropanoate
2a underwent a clean exchange reaction[11] to give 1b and 2b
(Scheme 2). We hypothesize that this reaction proceeds
through a FeCl3-assisted dissociation of the dicarbonyl–iron
complex to give a carbocation intermediate A or its equiv-
alents,[12] which can then be trapped by 2a to give 1b or by 2b
to give 1a.
Entry
1
Dione 1
T [8C]
t [h]
Yield [%][b]
93
1a
1b
1c
1d
1e
1 f
25
1
2
3
25
50
3
3
trace
10
[*] Dr. H. Li, W. Li, W. Liu, Z. He, Prof. Dr. Z. Li
Department of Chemistry
4
5
6
7
50
50
50
50
3
3
15
Renmin University of China
Beijing 100872 (P.R. China)
Fax: (+86)10-6251-6444
trace
90
E-mail: zhipingli@ruc.edu.cn
[**] Financial support by the National Science Foundation of China
(20832002 and 21072223), the Fundamental Research Funds for the
Central Universities, and the Research Funds of the Renmin
University of China (10XNB018 and 10XNL017) is acknowledged.
We thank Profs. Zhenfeng Xi and Zhi-Xiang Yu (Peking University)
for helpful discussion.
24
24
33
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201006779.
[a] Reaction conditions:
(0.01 mmol), DCE (5.0 mL). [b] Yield of isolated product.
1
(0.2 mmol), 3a (0.2 mmol), FeCl3
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Although tert-butyl substrate 1e afforded 4a in a 90% yield,
afforded the desired products 5d–5 f smoothly (Table 2,
entries 4–6). Importantly, allyl 1,3-dicarbonyl substrates also
gave the corresponding products (Table 2, entries 7 and 8).
Product 5h was selectively obtained under the present
reaction conditions (Table 2, entry 8).[15] Moreover, alkynyl
substrate 1o was efficiently transformed into the desired
product 5i (Table 2, entry 9). To demonstrate that our
substitution reaction is complementary to the classical
Friedel–Crafts reaction, we examined the reaction of 6 and
3a using 5 mol% of FeCl3. In this case, the Friedel–Crafts
reaction gave a mixture of 5 f, 7, and 8[16] [Eq. (1)]. This
outcome is dramatically different from our reaction shown in
Table 2, entry 6.
high temperature had to be applied (Table 1, entry 6).
Tertiary 1,3-dicarbonyl substrate 1 f was also treated with 3a
to give the desired product 4a, albeit in a 33% yield (Table 1,
entry 7). These results indicate that a large dipole moment
and bulky substituents on the 1,3-dicarbonyl group assist the
À
present C C bond cleavage. In other words, the efficiency of
the substitution reaction depends on the thermodynamic
stability of 1.
Subsequently, the scope of aromatic compounds was
À
investigated for the present iron-catalyzed C C bond cleav-
age. A variety of aromatic compounds 3 were effectively
transformed into the corresponding products 4 when 1a was
used as the model substrate (Scheme 3).[14] The desired indole
products 4b–4d were obtained with good yields. A slightly
low yield of 4e was obtained as a result of the formation of a
dialkylation phenol product. b-Naphthenol led to a-alkyla-
tion product 4 f in good yield. Other electron-rich aromatic
compounds were also effective substrates in the present
transformation. Even though dialkylation thiophene 4i
instead of the monoalkylation product was selectively gen-
erated. Friedel–Crafts reactions of aromatic compounds with
alkyl halides or alcohols in the presence of Lewis acid are
widely used. However, these reactions generally suffer from a
lack of regioselectivity and low efficiency.[14b,c] In light of this,
the reactions using diphenylmethanol as the alkylation
reagent were also investigated (Table 2). Based on compar-
ison, our present method shows higher efficiency (such as with
4b and 4c) and excellent selectivity (such as with 4e and 4g).
The variation of diones 1 was also examined using 5-
bromoindole 3a as a model substrate (Table 2). An electron-
donating group on the phenyl ring facilitated the reaction
(Table 2, entry 1). Although an electron-withdrawing group
lowered the efficiency of the transformation at room temper-
ature, 5b and 5c were obtained with 98% and 76% yields at
508C, respectively (Table 2, entries 2 and 3). Cyclic substrates
Table 2: The reaction of diones 1 with 5-bromoindole 3a.[a]
Entry
1
Dione 1
Product 5
Yield [%][b]
95
1g
5a
2[c]
1h
1i
5b
5c
98
76
3[d]
4[c]
1j
5d
83
5[c]
1k
1l
5e
5 f
92
80
6
7
8
9
1m
1n
1o
5g
5h
5i
73
90
96
Scheme 3. The reaction of 1a with aromatic compounds 3. Reaction
conditions: 1a (0.2 mmol), 3 (0.2 mmol), FeCl3 (5 mol%), DCE
(5.0 mL), RT, 1 h. Yield for when diphenylmethanol was used instead
of 1a. The yield in parentheses for when 4 was used. [a] FeCl3
(10 mol%), 508C , 24 h. [b] 2,4-Dialkylation product 4e’ was obtained
in 5% yield. [c] 4e’ was obtained in 38% yield. [d] 2,4-Dialkylation
product 4g’ was obtained in 46% yield.
[a] Reaction conditions:
(0.01 mmol), DCE (5.0 mL), 258C, 1 h. [b] Yield of isolated product.
[c] 508C, 1 h. [d] 508C, 24 h.
1
(0.2 mmol), 3a (0.2 mmol), FeCl3
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Angew. Chem. Int. Ed. 2011, 50, 2975 –2978

the SnCl4-promoted reaction of diphenylmethanol with 9a,
for which two epimers were obtained with a 1:1.3 ratio.[17a]
trans-Stilbene 9c and cis-stilbene 9d also gave only one
epimer 10b, however, cis-stilbene 9d showed lower reactivity
(Table 3, entries 3 and 4). These results indicate that the
cyclization proceeds in a stepwise manner via the cationic
intermediate B and affords the thermodynamically most
stable product. Trisubstituted alkenes also worked well under
the present conditions (Table 3, entry 5). Meanwhile, 2,3-
dimethylbut-2-ene did not react with 1a because of steric
effects. Diene 9 f led to the corresponding product 10d in
93% yield (Table 3, entry 6). Furthermore, indene derivatives
10e–10g were formed in moderate yields when alkyne
substrates were used (Table 3, entries 7–9). The desired
product 10g was obtained by the treatment of 3-hexyne
with 1a, albeit with a low yield (Table 3, entry 9). Interesting,
a 24% yield of the dibenzylmethylation product 10g’ was also
formed in this case. We hypothesized that the electron-rich
properties of 10g further reacted with the dibenzylmethyl
cation that was generated in situ.
We further demonstrated the generality of our synthesis
by applying this strategy in the synthesis of indene derivatives
(Table 3). Although several methods have been developed for
the preparation of dihydroindenes,[17] an efficient and selec-
tive method is still valuable to overcome the limitations of
known methods; such as the lack of stereoselectivity and low
efficiency. Both trans- and cis-b-methylstyrene (9a and 9b)
afforded exclusively one single dihydroindene isomer 10a
with quantitative yields (Table 3, entries 1 and 2). The
stereoselectivity of this reaction is in sharply contrast with
It should be noted that b-alkylation product 12 was
obtained as a major product in 41% yield when a-methyl-
styrene 11 was used [Eq. (2)]. This result indicates that, in this
case, b-proton elimination from the proposed intermediate B
is faster than intramolecular electrophilic aromatic cycliza-
tion. Interestingly, styrene 13 reacted with 1a to give a formal
Table 3: The reaction of 1a with alkenes and alkynes 9.[a]
À
=
C C bond insertion, C C bond product 14 [Eq. (3)]. Gen-
eration of 14 results from the further intercepted of proposed
intermediate B by the dicarbonyl group.
Entry Alkene/alkyne 9
T/t [8C/
Product 10
Yield [%][b]
h]
1
9a
9b
9c
9d
50/3
50/3
50/3
50/24
10a
10a
10b
10b
99
99
85
61
2
3[c]
4[c]
5
6
9e
9 f
50/8
50/1
10c
10d
89
93
Based on the above results, a possible reaction pathway is
proposed (Scheme 4). The reagent FeCl3 acts as a Lewis acid
À
catalyst to cleave a C C bond through the coordination of
iron with the 1,3-dicarbonyl unit. By taking advantage of the
reversibility of the alkylation reaction of 1,3-dicarbonyl
compounds, the carbocation intermediates that are generated
in situ, such as A and B, are trapped by the other nucleophiles
to give thermodynamically most stable alkylation products.
Other possible reaction mechanisms can not be excluded at
this stage and further studies on this reaction are undergoing.
In summary, we have reported a novel and efficient iron-
7[c]
8[c]
9[c]
9g
9h
9i
80/1
80/24
80/1
10e
10 f
10g
80
60
32[d]
À
catalyzed C C bond cleavage under mild reaction conditions.
The 1,3-dicarbonyl unit was shown to be a new and useful
leaving group. The advantages of the present method include
its efficiency, selectivity, and generality for organic synthesis.
[a] Recation conditions: 1a (0.2 mmol),
(0.01 mmol), DCE (5.0 mL). [b] Yield of isolated product. [c] FeCl3
(10 mol%). [d] Dibenzylmethyl product 10g’ was obtained in 24% yield.
9
(0.4 mmol), FeCl3
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2977

Communications
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Scheme 4. A tentative reaction pathway.
Furthermore, the 1,3-dicarbonyl compound could be recov-
ered and reused. The scope, mechanism, and synthetic
applications of the present reaction are under investigation.
Experimental Section
1,2-Dichloroethane (5.0 mL) was added to a mixture of 1 (0.2 mmol),
3 (0.2 mmol), and FeCl3 (0.01 mmol) under nitrogen at RT. The
reaction mixture was stirred at RT for 1 h. The resulting solution was
quenched with saturated NaHCO3 (2 mL) and extracted with
dichloromethane (3 ꢀ 3 mL). The extract was washed with saturated
NaHCO3 (2 ꢀ 10 mL) and deionized water (10 mL) and the organic
extract was dried over MgSO4. The solvent was evaporated and the
residue was purified by flash column chromatography on silica gel
with dichloromethane/petroleum ether (1:20) as the eluent. The
fraction with a Rf = 0.6 (dichloromethane/petroleum ether= 1:2) was
collected to give the desired product 4a. 1H NMR (400 MHz, CDCl3):
d = 7.86 (bs, 1H), 7.35 (d, J = 1.6 Hz, 1H), 7.28–7.24 (m, 4H), 7.21–
7.14 (m, 8H), 6.52 (d, J = 1.6 Hz, 1H), 5.58 ppm (s, 1H); 13C NMR
(100 MHz, CDCl3): d = 143.5, 135.3, 128.9, 128.7, 128.4, 126.4, 125.2,
125.0, 122.3, 119.6, 112.7, 112.5, 48.5 ppm; ATR-FTIR: nmax = 3425,
3024, 2862, 1589, 1485, 1454, 1446, 1415, 1323, 1215, 1097, 1078, 1029,
918, 883, 794, 750, 729, 700, 677, 630, 582 cmÀ1; MS (EI): m/z (%):
363(100), 361, 286, 284, 242, 204, 176, 165, 151, 141, 126, 102, 59, 43;
HRMS calcd for C21H16BrNa(M+Na): 384.0358; found: 384.0360.
À
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ˇ
´
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when the combination of FeCl3 (5 mol%) and AgOTf
(15 mol%) was used as the catalyst.
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Received: October 28, 2010
Revised: January 7, 2011
Published online: February 23, 2011
À
Keywords: C C activation · 1,3-dicarbonyls · dihydroindenes ·
indenes · iron
.
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