Alkyl transfer from C-C cleavage

Article abstract of DOI:10.1002/anie.201303696

Hydrogenation was only the beginning: Hantzsch esters have now been used to transfer alkyl groups to imines under mild catalytic conditions to provide a variety of amines (see scheme). Benzyl, secondary alkyl, and tertiary alkyl groups containing ether, ester, and hydroxy functionalities were transferred successfully. The use of Hantzsch esters as alkylation reagents offers a practical and complementary alternative to organometallic processes. Copyright

Full text of DOI:10.1002/anie.201303696

Angewandte
Chemie
Communications
Alkylation
G.-X. Li, R. Chen, L. Wu, Q. Fu,
X.-M. Zhang, Z. Tang*
&&&& — &&&&
ꢀ
Alkyl Transfer from C C Cleavage
Hydrogenation was only the beginning:
Hantzsch esters have now been used to
transfer alkyl groups to imines under mild
catalytic conditions to provide a variety of
amines (see scheme). Benzyl, secondary
alkyl, and tertiary alkyl groups containing
ether, ester, and hydroxy functionalities
were transferred successfully. The use of
Hantzsch esters as alkylation reagents
offers a practical and complementary
alternative to organometallic processes.
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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DOI: 10.1002/anie.201303696
Alkylation
ꢀ
Alkyl Transfer from C C Cleavage**
Guangxun Li, Rong Chen, Lei Wu, Qingquan Fu, Xiaomei Zhang, and Zhuo Tang*
Modern organic synthesis requires the development of
efficient methods for the construction of complex molecules,
challenge. The development of such a transfer alkylation
could be hindered by 1) competitive hydrogen transfer and
2) the lack of knowledge about the mechanism of hydrogen
transfer, which could involve hydride (Hꢀ) transfer, the
transfer of a hydrogen radical (HC), or a concerted process.[7]
However, there are a great deal of examples of dealkylation
at the 4-position of the pyridine ring during the oxidation of
dihydropyridine derivatives (DHPs) with numerous oxidizing
reagents.[8] Furthermore, the use of Hantzsch esters as
a potential method for alkyl transfer would benefit from the
advantages of these reagents over organometallic reagents in
ꢀ
and C C bond formation continues to be key to methodo-
logical advancement. In spite of the myriad methods avail-
able,[1] advantageous methodologies in terms of the avail-
ability of starting materials, operational simplicity, functional-
group tolerance, and the absence of metals are in constant
demand.[2] The beauty and diversity of the biochemical
pathways developed by nature to produce complex molecules
is a good source of inspiration for chemists.[3] Examination of
the chemical building blocks, modes of substrate activation,
and biosynthetic pathways in nature provides insight into
possibilities for similar transformations by chemical synthesis.
terms of their stability, availability, and low toxicity.[9]
A
ꢀ
transfer hydrogenative C C coupling enables addition to
carbonyl groups without the need for preformed organome-
tallic reagents; however, the reaction is restricted to limited
substrates.[10]
In this way, chemists have designed many biomimetic organo-
[4]
ꢀ
catalytic C C bond-forming reactions. Herein we report
a mild, metal-free, operationally simple strategy for the
ꢀ
ꢀ
formation of C C bonds by alkyl transfer through C C bond
cleavage. We demonstrate the broad utility of this strategy
based on the use of Hantzsch ester (HEH) analogues as alkyl
donors and imines as acceptors. The transfer of alkyl groups
bearing hydroxy, ether, and ester substituents occurred with
high efficiency.
cat:
Hydrogen transfer DH þ A
D þ AH
H
ð1Þ
ð2Þ
G
2
2
cat:
Alkyl transfer RꢀDH þ A
D ¼ donor; A ¼ acceptor
D þ RꢀAH
H
G
Intrigued by these challenges and advantages, we pursued
HEHs are biologically inspired hydride donors that are
commonly known as synthetic analogues of reduced nicotin-
amide adenine dinucleotide (NADH). Their potential as
a hydrogen source was acknowledged for the first time in 1955
by Mauzerall and Westheimer, who showed that HEHs can
reduce carbonyl compounds by direct hydrogen transfer to
the substrate.[5] Since then, a broad range of transfer-hydro-
genation reactions conducted with HEHs in combination with
different catalysts and additives have been reported
[Eq. (1)].[6] Considerable effort has been directed towards
the design of effective HEH reagents that operate in
conjunction with different catalysts for asymmetric transfer
hydrogenation;[7] however, alkyl transfer in this way has never
been investigated and poses a distinct and formidable
ꢀ
a significant and unprecedented C C bond-forming reaction
by alkyl transfer. This synthetic method offers not only the
advantage of convenience, but also a strategic divergence
from traditional approaches. Herein, we define this significant
reaction as an “alkyl transfer” or “transfer alkylation” owing
to the innate character of the reaction: the transfer of an alkyl
group from an organic donor molecule to an organic acceptor
through carbon–carbon bond cleavage [Eq. (2)]. Although
Sai et al. reported a similar alkyl transfer promoted by an N-
heterocyclic carbene/copper complex, the reaction was lim-
ited to the transfer of allyl, allenyl, and propargyl groups.[11]
To our knowledge, there is only one example of such a process
in nature: The weakly basic histidine motif of polyketide
synthase (PKS) activates the malonic acid half-thioester
(MAHT) toward decarboxylation, and the resulting thioester
enolate undergoes electrophilic trapping with an acyl unit to
furnish the Claisen condensation product.[12] However, the
essence of this reaction is transfer acylation, which in fact
finally gives an adol,[13] Mannich,[14] or Michael[15] product.
[*] G.-X. Li, R. Chen, L. Wu, Q. Fu, Prof. Dr. Z. Tang
Natural Products Research Center, Chengdu Institute of Biology
Chinese Academy of Sciences
Chendu Sichuan 610041 (China)
E-mail: tangzhuo@cib.ac.cn
G.-X. Li, Prof. Dr. X.-M. Zhang
Chengdu Institute of Organic Chemistry
Chinese Academy of Sciences
Our study of the alkyl-transfer reaction started with the
hypothesis that DHPs with two alkyl substituents at the C4
position should only transfer the alkyl group without the
competition of transfer hydrogenation. DHP 1a bearing
cyano groups was the only C4-disubstituted DHP that we
could obtain. However, the designed reaction did not take
place (Table 1, entry 1). In contrast, the transfer of hydrogen
proceeded effectively when DHP 1b with one alkyl substitu-
ent was used in the same reaction (Table 1, entry 2). We
speculated that the benzyl group was too big to compete with
Chendu Sichuan 610041 (China)
[**] We are grateful for the financial support of the Chinese Academy of
Sciences (Hundred Talents Program), the National Sciences
Foundation of China (Grant No. 21102139), and the Innovation
Program of the Chinese Academy of Sciences (Grant No. KSCX2-
EW-J-22).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201303696.
2
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ꢀ
Table 1: Development of a method for C C bond formation on the basis
Table 2: Influence of the catalyst and reaction conditions on the alkyl-
transfer reaction.[a]
of alkyl transfer.[a]
Entry
T [8C]
Catalyst
Yield [%][b]
3a
8
1
2
RT
50
90
RT
90
RT
RT
RT
RT
40
50
TsOH
TsOH
TsOH
TsOH
TsOH
AlCl3
GaCl3
InCl3
BF3·Et2O
BF3·Et2O
BF3·Et2O
8
20
50
–
42
20
Entry
DHP
R1
R2
R3
R4
Yield [%][b]
3[c]
4[d]
5[c,d]
6
<5
60
65
20
10
9
3
2
<1
6
3
–
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1 f
1g
1h
1i
Me
H
H
H
H
H
H
H
H
Bn
Bn
Me
Me
Me
Bn
Bn
Bn
Bn
CN
CN
H
H
H
H
H
H
H
H
Me
–
30
30
40
57
67
80
80
82
80
40
20
10
10
10
7
8
9
CO2Me
CO2Et
CO2tBu
CO2Me
CO2Et
CO2tBu
CO2Et
10
30
50
20
45
11[e]
[a] Reaction conditions: imine 2a (0.2m in chloroform, 1 equiv), alkyl-
transfer donor 1 (1.2 equiv), catalyst (30 mol)%. [b] Yield of the isolated
product. [c] Toluene was used as the solvent. [d] Compound 5a was used
instead of 1g as the DHP substrate. [e] The reaction was carried out with
1.2 equivalents of BF3·Et2O.
[a] Reaction conditions: imine 2a (0.2m in toluene, 1 equiv), alkyl-
transfer donor 1 (1.2 equiv), TsOH (0.3 equiv). [b] Yield of the isolated
product. Bn=benzyl, PMP=p-methoxyphenyl, Ts=p-toluenesulfonyl.
BF3·Et2O (1.2 equiv) in chloroform at 508C for 2 days.
Under the optimized conditions, alkylation product 3a was
obtained as the sole product in 80% yield.
the hydrogen atom. Therefore, we screened C4-methyl-
substituted DHPs 1c–1e with different ester groups from
the point of view of steric hindrance and found that the
reaction proceeded with hydrogen transfer only (Table 1,
entries 3–5). Encouragingly, when we exchanged the methyl
substituent for a benzyl group, the desired reaction occurred,
despite a little concomitant transfer hydrogenation (Table 1,
entry 6). We investigated the reaction of DHPs with different
ester substituents and found that the corresponding DHP with
an ethyl ester group was most effective (Table 1, entries 7 and
8). Further study revealed that DHP 1i with an N-methyl
substituent was also suitable for the alkyl transfer, despite
a slightly lower alkyl-transfer efficiency (Table 1, entry 9).
To ascertain the initial scope of the reaction, we optimized
the reaction conditions by using 1g as the alkyl-transfer donor
and imine 2a as the acceptor (Table 2). When we decreased
the reaction temperature, we found that the expected alkyl
transfer became inefficient, and an unexpected product 8
appeared (Table 2, entries 1–3). We assumed that a side
reaction may proceed between imine 2a and side product 5a
according to the previously reported mechanism,[16] and this
hypothesis was supported by reactions of the dealkylation
product 5a as a substrate with imine 2a (Table 2, entries 4 and
5). To further improve the alkyl-transfer efficiency, we
screened a range of Lewis acid catalysts (Table 2, entries 6–
9). Of all the Lewis acids tested, BF3·Et2O turned out to be the
most efficient catalyst and most capable of minimizing the
side reaction. By optimizing the reaction conditions, we
developed a standard experimental protocol for the novel
alkyl-transfer reaction: The alkyl-transfer donor 1 (1.2 equiv)
was stirred with the imine acceptor 2 (1.0 equiv) and
We then evaluated the scope of the alkyl-transfer process
in terms of the imine acceptor by using the benzyl-substituted
DHP 1g as a representative donor (Scheme 1). Imine accept-
ors bearing an electron-withdrawing group or an electron-
donating group on the aniline ring readily underwent the
alkyl-transfer reaction with high efficiency (products 3a–c).
We were also delighted to observe that imines formed from
aldehydes bearing electron-withdrawing groups or electron-
donating groups were transformed into the desired products
3e–h and 3i–l, respectively, with high alkyl-transfer efficiency.
The DHP component was similarly examined with differ-
ent benzyl substituents in the reaction with imine 2a
(Scheme 1, products 3m–r). We found that the transformation
proceeded well regardless of whether the benzyl ring was
substituted with electron-withdrawing or electron-donating
groups and isolated the desired amines in good yield (mostly
> 80%). Particular attention was paid to common functional
groups that might cause difficulties in amine preparation with
the relevant Grignard reagent (Scheme 1, products 3m,n).
However, the alkyl-transfer efficiency was unaffected. Fur-
thermore, an unprotected DHP bearing a hydroxy-substituted
benzyl group was converted into the corresponding amine 3r
in 80% yield (Scheme 1).
The unexpected high efficiency of alkyl transfer with
benzyl-substituted DHPs prompted us to investigate whether
DHPs with simple alkyl substituents could also efficiently
transfer the alkyl group. At the beginning of our research, we
found that a methyl group could not be transferred in the
reaction (Table 1, entries 3–5). Further studies revealed that
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Scheme 1. Bioinspired benzyl transfer with DHPs.
ethyl and propyl groups could also not be transferred (data
not shown). However, when DHPs substituted with secondary
alkyl groups were used as substrates, high efficiency of alkyl
transfer was observed (Scheme 2, mostly > 80%). We exam-
ined substituents attached at the benzylic position and found
that alkyl-substituted and even alkoxy-substituted DHPs
performed well, although the products were formed with
a low diastereomeric ratio (Scheme 2, products 4a,b). To our
knowledge, this alkylation is impossible with the correspond-
ing organometallic reagents. Secondary alkyl groups, whether
open-chain (Scheme 2, products 4c–f) or cyclic (Scheme 2,
products 4g–i), short-chain (Scheme 2, products 4c,d) or long-
chain (Scheme 2, products 4e,f), small-ring (Scheme 2, prod-
uct 4i) or large-ring substituents (Scheme 2, product 4g),
could be transferred with high efficiency. Furthermore, an
ester-substituted DHP efficiently provided the Mannich-type
product 4j, which could not be formed easily in a traditional
Mannich reaction owing to the low acidity of the a hydrogen
atom (Scheme 2).[17] To ascertain if other primary alkyl groups
can be transferred, we screened several DHPs with typical
alkyl substituents, such as a DHP substituted with a long alkyl
chain and the corresponding phenethyl-substituted DHP.
However, none of these DHPs transferred the alkyl group in
the model reaction; instead, hydrogen was transferred
(Scheme 2, products 4k,l). We inferred from the above
experimental results that the alkyl-transfer reaction may
proceed through a free-radical mechanism.
Scheme 2. Bioinspired alkyl transfer with DHPs.
reaction still proceeded well without loss of yield. In another
experiment, the addition of azobisisobutyronitrile (AIBN) to
the reaction mixture without the catalyst did not afford any
product even after 3 days. Furthermore, we found that the
alkyl-transfer reaction was insusceptible to light. On the other
hand, when DHP 1j with a 1-phenylpropan-2-yl substituent
was used as the substrate in our reaction, only one alkyl-
transfer product was obtained (Scheme 3, product 4m). If the
alkyl-transfer reaction proceeded through a radical process,
the reaction of 1u could also afford the rearrangement
product 4n, which was not observed. On the basis of these
experiments, we excluded the possibility of a radical mech-
anism. Moreover, we could also rule out the possibility that
the alkyl group was transferred to imine 2a as a free
carbanion, since the alkyl-transfer reaction was immune to
an excess amount of a Brønsted acid catalyst (see the
Supporting Information). Therefore, we propose that the
alkyl-transfer reaction may proceed through a concerted
process in analogy with the similar transfer-hydrogenation
process;[9] thus, the DHP may transfer the alkyl functional
group directly to the imine in a concerted way (see the
Supporting Information).
To verify this mechanism, we designed a chiral DHP
substituted with a chiral alkyl group as an alkyl-transfer
substrate (see Figure S2 in the Supporting Information). We
thought that the transfer group would be able to transfer its
chirality to the product if the reaction proceeded by
a concerted mechanism. However, the products turned out
We next turned our attention to the elucidation of the
reaction mechanism and carried out a series of experiments
(see the Supporting Information). In one experiment, we
added 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) as a rad-
ical scavenger to the reaction mixture and found that the
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Scheme 4. Bioinspired alkyl transfer with benzothiazoles.
the transfer capacity of DHP substrates thoroughly and found
that benzyl groups and secondary alkyl substituents can be
transferred efficiently, whereas primary alkyl and olefinic
groups can not be transferred. At the levels of strategy and
mechanism, this alkyl transfer reaction appears to proceed
through an indirect concerted process. Factors that affect the
transfer process include electronic effects and aromatization
tendency. In all, this strategic shift may ultimately become
a practical and complementary alternative to organometallic
processes. It also overturns more than half a century of
received wisdom regarding the reactivity of HEHs in hydro-
gen transfer. We hope that our preliminary investigation will
attract great attention to the field of carbon-substituent
transfer and broaden the scope of bioinspired synthesis.
Scheme 3. Alkyl-transfer reaction with a 4-(1-phenylpropan-2-yl)-substi-
tuted DHP substrate.
to be racemic. Moreover, the diastereomeric ratio of the
product was identical to that of the alkylation product formed
with the corresponding racemic DHP (see Figure S3).
Another chiral DHP characterized by the presence of bulky
chiral ester groups was also used as an alkyl-transfer substrate
(see Figure S2), as we hypothesized that the steric bulk of the
chiral ester groups might induce chirality in the alkyl-transfer
product. However, this product was also racemic (see Fig-
ure S3). Furthermore, a chiral Lewis acid and Brønsted acid Experimental Section
The DHP (0.13 mmol, 1.3 equiv), the imine (0.1 mmol, 1.0 equiv),
were used as catalysts for asymmetric alkyl transfer (see the
Supporting Information). However, the alkyl-transfer prod-
uct was racemic, although a chiral sulfonic acid could catalyze
the reaction in moderate yield. Therefore, in our alkyl-
BF3·Et2O (1.2 equiv), and chloroform (1 mL) were placed in a reac-
tion tube, and the mixture was heated at 508C with stirring under
a nitrogen atmosphere. When the reaction was complete (as shown by
TLC), the crude reaction mixture was allowed to reach room
temperature, the solvent was evaporated, and a 3n solution of
aqueous hydrochloride acid and dichloromethane were added. The
aqueous and organic layers were separated, and the aqueous phase
was extracted three times with dichloromethane. The combined
organic layers were washed twice with water, then with brine, and
were dried over MgSO4. The solvent was removed under reduced
pressure, and the product was purified by chromatography on silica
gel.
ꢀ
transfer reaction, a process involving simultaneous C C
ꢀ
cleavage and C C formation is unreasonable. We thus
inferred that the alkyl transfer may proceed through a practi-
ꢀ
cally concerted mechanism in which C C bond cleavage
occurs to provide a carbanion that undergoes nearly instanta-
neous addition to the imine.
Benzothiazole was another type of biologically inspired
hydrogen-transfer donor that had been used successfully for
the hydrogenation of imines.[18] Therefore, we hoped that our
alkyl-transfer reaction would also take place with benzothia-
zole substrates. As we had imagined, the designed alkyl
transfer proceeded smoothly in the synthesis of amines with
high yield (Scheme 4, products 3a and 4c). Furthermore,
a tertiary carbon substituent was transferred with high
efficiency, which was not possible with the corresponding
DHP (Scheme 4, product 4o).
Received: April 30, 2013
Published online: && &&, &&&&
Keywords: alkylation · biomimetic synthesis · Hantzsch esters ·
.
imines · organocatalysis
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ꢀ
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ꢀ
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