Direct, one-pot sequential reductive alkylation of lactams/amides with grignard and Organolithium reagents through lactam/amide activation

Article abstract of DOI:10.1002/anie.201000652

(Figure Presented) Be dazzled by the sequence: The first efficient and general one-pot method for the reductive bisalkylation of lactams/ amides with Grignard and organolithium reagents has been developed (see scheme; DTBMP = 2,6-di-tert-butyl-4methylpyridine, Tf=trifluoromethanesulfonyl).

Full text of DOI:10.1002/anie.201000652

Angewandte
Chemie
DOI: 10.1002/anie.201000652
Synthetic Methods
Direct, One-pot Sequential Reductive Alkylation of Lactams/Amides
with Grignard and Organolithium Reagents through Lactam/Amide
Activation**
Kai-Jiong Xiao, Jie-Min Luo, Ke-Yin Ye, Yu Wang, and Pei-Qiang Huang*
Simplicity is one of the major goals in current organic
synthesis.[1] The development of versatile methods using
simple starting materials[2] and multicomponent reactions
leading to the formation of two or more carbon–carbon bonds
in a one-pot process[3] are two powerful strategies directed at
this goal. The transformation of lactams and amides into the
corresponding tert-alkylamines by a one-pot reductive bisal-
kylation with different organometallic reagents is both a
highly desirable and a challenging objective (Scheme 1). The
sequential addition of two organometallic reagents, which
may be the same or different from one another.
To achieve the required one-pot reaction under milder
conditions, triflic anhydride[8,9] was selected as an amide
activator and 2,6-di-tert-butyl-4-methylpyridine (DTBMP)[9d]
as a base. When a CH2Cl2 solution of lactam 1 and DTBMP
(1.2 equiv) was successively treated with 1.2 molar equiva-
lents of Tf2O (À788C, 45 min), and 3.0 molar equivalents of
ethylmagnesium bromide in Et2O (RT, 3 h; general proce-
dure A), the desired 2,2-diethylpyrrolidine 3a was obtained in
87% yield (Table 1, entry 1). By using the same procedure,
Table 1: Double addition of Grignard reagents to lactams activated by
Tf2O.
Scheme 1. One-pot transformation of lactams/amides into the corre-
=
sponding tert-alkylamines with cleavage of a C O bond and formation
À
of two C C bonds.
Entry
Substrate
RMgX
Product (yield[%])[a]
merit of such a process is linked to the high stability of
lactams/amides and the ready availability of both lactams/
amides and Grignard/organolithium reagents. Moreover, tert-
alkylamines are important target compounds in synthetic
chemistry.[4] The research groups of Murai[5] and Renaud[6]
have recently reported their synthesis of tert-alkylamines
from thioamide derivatives. To develop a more convenient
and less noxious general method, the direct use of readily
available lactams and amides is highly desirable (Scheme 1).
In this regard, de Meijere and co-workers recently reported
an addition to formamides mediated by Ti(OiPr)4/TMSCl, but
their method is restricted to N,N-dialkylformamides.[7] Herein
we report the first general and direct one-pot method for the
conversion of lactams and amides into tert-alkylamines by the
1
2
3
4
5
6
7
8
1
1
1
1
2
2
2
2
EtMgBr
3a (87)
3b (83)
3c (85)
3d (71)
4a (74)
4b (70)
4c (75)
4d (60)
nBuMgBr
allylMgBr
BnMgBr
EtMgBr
nBuMgBr
allylMgBr
BnMgBr
[a] Yield of isolated product. Bn=benzyl, Tf=trifluoromethanesulfonyl.
the reactions of lactam 1 with n-butyl, allyl, and benzyl
Grignard reagents gave the corresponding pyrrolidines 3b–d
in 71–85% yield (Table 1, entries 2–4). Similar results were
obtained with lactam 2, which provided the corresponding
piperidines 4a–d in good yield (Table 1, entries 5–8).
Encouraged by these results, the introduction of two
different substituents was investigated. After successive
treatment of a CH2Cl2 solution of lactam 1 and DTBMP
(1.2 equiv) with 1.2 molar equivalents of Tf2O at À788C for
45 minutes, 1.0 molar equivalent of ethylmagnesium bromide
and 2.0 molar equivalents of n-butylmagnesium bromide,
pyrrolidine 5a bearing two different alkyl groups (Et, nBu)
was obtained in 75% yield. A 9% yield of pyrrolidine 3b
arising from the addition of two molecules of n-butylmagne-
sium bromide was also obtained (Table 2, entry 1). The one-
pot reaction was then extended to other Grignard reagents
and lactam 2, and similar results were obtained (Table 2,
[*] K.-J. Xiao,[+] J.-M. Luo,[+] K.-Y. Ye, Y. Wang, Prof. P.-Q. Huang
Department of Chemistry and The Key Laboratory for Chemical
Biology of Fujian Province
College of Chemistry and Chemical Engineering, Xiamen University
Xiamen, Fujian 361005 (China)
Fax: (+86)592-218-6400
E-mail: pqhuang@xmu.edu.cn
[+] These authors contributed equally to this work.
[**] We are grateful to the NSF of China (20832005) and the National
Basic Research Program (973 Program) of China (grant
no. 2010CB833200) for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201000652.
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Table 2: Sequential addition of two organometallic reagents to lactams
activated by Tf2O.
Entry
Substrate
R1MgBr, R2M2
Product (yield[%])[a]
1
2
3
4
5
6
7
8
1
1
1
2
2
2
1
2
EtMgBr, nBuMgBr
EtMgBr, allylMgBr
EtMgBr, BnMgBr
nBuMgBr, EtMgBr
EtMgBr, allylMgBr
EtMgBr, BnMgBr
EtMgBr, nBuLi
5a (75), 3b (9)
5b (74), 3c (8)
5c (71), 3d (8)
6a (66), 4a (6)
6b (68), 4c (7)
6c (63), 4d(4)
5a (76), 3b (9)
6d (65)
nBuMgBr, vinylMgBr
EtMgBr,
Scheme 2. Proposed reaction mechanism.
9
mediate[10] C, which reacts with amide A to form highly
electrophilic iminium triflate intermediate D. The latter
reacts with one molecule of R1M1 to give N,O-acetal E.
Then, elimination of ÀOTf assisted by the lone pair of
electrons on the nitrogen atom and metal cation leads to the
formation of iminium ion F, which is trapped by a second
molecule of nucleophile (R2M2) to give amine B.
EtMgBr,
10
[a] Yield of isolated product.
entries 2–6). Other varieties of organometallic reagent such as
n-butyllithium and phenylethynyllithium were also effective
(Table 2, entries 7 and 10). Notably, the reaction of sp2- and
sp-hybridized carbon nucleophiles led solely to the desired
amines. Products arising from the addition of two molecules
of the first Grignard reagent were not detected (Table 2,
entries 8–10).
Similarly, the sequential addition of two of the same or
different Grignard reagents to amides proceeded smoothly
and gave the desired products in high yield (Table 3,
entries 1–6).
To further reveal the scope of this approach, employment
of functionalized nucleophiles other than allyl (Table 1,
entries 3 and 7; Table 2, entries 2 and 5), vinyl (Table 2,
entry 8), and alkynyl magnesium/lithium reagents (Table 2,
entries 9 and 10) were investigated. We were aware that
enolates are versatile nucleophiles, therefore we first tested
the one-pot sequential introduction of ethyl and ethoxycar-
bonylmethyl groups. By using the general procedure B (see
the Supporting Information for details), successive treatment
of 2-pyrrolidinone 1 with triflic anhydride, ethylmagnesium
bromide, and lithium enolate of ethyl acetate provided the
desired pyrrolidine 14 in 73% yield (Scheme 3). Next, we
Table 3: Sequential addition of two Grignard reagents to amides
activated by Tf2O.
Scheme 3. Sequential reductive alkylation with an enolate.
Entry Substrate
R1MgBr, R2MgBr
Product (yield[%])[a]
1
2
3
4
5
6
11a, R=Me, R’=H PhMgBr, PhMgBr
11b, R=Bn, R’=Ph BnMgBr, BnMgBr
11c, R=Bn, R’=Me EtMgBr, EtMgBr
12a (93)
12b (81)
12c (86)
12d (90)
tried to use the functional aryl magnesium reagents devel-
oped by Knochel and co-workers.[10] These reagents are a
novel class of versatile nucleophiles. Thus successive treat-
ment of 2-pyrrolidinone 1 with triflic anhydride, isopropyl-
magnesium bromide, and Knochelꢀs functional aryl magne-
sium reagent 15 (prepared in situ from methyl p-iodoben-
zoate)[10] furnished the expected pyrrolidine 16 in 70% yield
(Scheme 4).
11c
11c
11c
BnMgBr, BnMgBr
nBuMgBr, EtMgBr 13a (78), 12c (8)
nBuMgBr, BnMgBr 13b (74), 12d (7)
[a] Yield of isolated product.
A plausible mechanism for the sequential addition of
organometallic reagents to lactams and amides activated by
Tf2O is shown in Scheme 2. The DTBMP first reacts with
triflic anhydride to generate the reactive pyridinium inter-
To explore the use of this method for asymmetric syn-
thesis, three-ring systems have been investigated. By using the
general procedure B, successive treatment of (S)-3-benzyl-
oxy-2-pyrrolidinone 17[11] with triflic anhydride, ethylmagne-
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Scheme 4. Sequential reductive alkylation with a Knochel’s reagent.
sium bromide, and benzylmagnesium chloride produced
pyrrolidine 18 as the only diastereomer in 70% yield
(Scheme 5). Compound 20 was easily available from the
Scheme 7. 1,3-Asymmetric induction in the sequential reductive alkyla-
tion of lactam 23. Diastereomeric ratio was determined by HPLC
analysis (Shim-pack VP-ODS) with a mobile phase of acetonitrile/
water.
C3 (for 17), the silyloxymethyl group at C5 (for 20), or the
benzyloxy group at C3 (for 23).
Scheme 5. 1,2-Asymmetric induction in the sequential reductive alkyla-
tion of lactam 17. Diastereomeric ratio was determined by HPLC
analysis (Shim-pack VP-ODS) with a mobile phase of acetonitrile/
water.
In summary, by taking advantage of both the high
electrophilicity of Tf2O and excellent leaving group ability
of ÀOTf, we have developed a highly efficient and general
one-pot method for the synthesis of tert-alkylamines from
lactams/amides. The advantages of this method are that:
1) this is a multicomponent reaction involving the one-pot
known 19 (derived from (S)-glutamic acid)[12] and its sequen-
tial ethylation and benzylation activated by Tf2O proceeded
with good 1,3-asymmetric induction, and yielded pyrrolidine
21 and its diastereomer with d.r. = 7.7:1 in a combined yield of
75% (Scheme 6). Similarly 2-pyrrolidinone 23 was available
formation of two C C bonds, 2) both lactams and amides can
À
be used as substrates, 3) two different Grignard reagents can
be used in this one-pot process, 4) both Grignard and
organolithium reagents can be used in this one-pot process,
5) for the second addition, either sp3-, sp2-, or sp-hybridized
carbon nucleophiles, functionalized carbon nucleophiles such
as enolates, and Knochelꢀs functional aryl magnesium reagent
can be used, 6) the sequential addition afforded excellent 1,2-
and 1,3-asymmetric induction in substituted g-lactams. The
high stability of lactams/amides combined with the ready
availability of both lactams/amides and Grignard/organo-
lithium reagents make this a versatile method for the
synthesis of various tert-alkylamines. Further work on the
application of other kinds of nucleophile in this method is
currently in progress and will be reported in due course.
Scheme 6. 1,3-Asymmetric induction in the sequential reductive alkyla-
tion of lactam 20. Diastereomeric ratio was determined by HPLC
analysis (Shim-pack VP-ODS) with a mobile phase of acetonitrile/
water. imid=imidazole, TBDPS=tert-butyldiphenylsilyl.
Experimental Section
General procedure A for the double addition of Grignard Reagents
to lactams/amides activated by Tf2O: To a cooled (À788C) solution of
lactam/amide (1.0 equiv) and 2,6-di-tert-butyl-4-methylpyridine
(1.2 equiv) in CH2Cl2 (5 mL) was added Tf2O (1.2 equiv) in a
dropwise manner and stirred at À788C for 45 min. A solution of
RMgBr (3.0 equiv) in Et2O was added dropwise to the resultant
mixture. Then the reaction mixture was warmed slowly to RT and
from (S)-malimide 22,[13] and underwent sequential ethylation
and benzylation activated by Tf2O with good 1,3-asymmetric
induction, and gave pyrrolidine 24 and its diastereomer with
d.r. = 7.7:1 in a combined yield of 72% (Scheme 7).
The newly formed quaternary stereocenters in pyrroli-
dines 18, 21, and 24 were confirmed by NOESY experiments.
It was shown in all three cases that the second alkyl groups
(benzyl group) are trans with respect to the substituents in the
starting materials. These results are in agreement with the
proposed mechanism shown in Scheme 2. Namely, to avoid
steric hindrance the second Grignard reagent (benzylmagne-
sium chloride) approaches the intermediate cyclic iminium
ion F from the direction opposite to the benzyloxy group at
stirred for 3 h. The reaction was quenched with
a saturated
ammonium chloride solution and extracted with CH2Cl2. The
combined organic layers were washed with brine, dried over
anhydrous Na2SO4, filtered, and concentrated under reduced pres-
sure. The residue was purified by flash column chromatography on
silica gel to afford the desired amine.
Received: February 3, 2010
Published online: March 18, 2010
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3039

Communications
Org. Chem. 2008, 5107 – 5111; for a related work, see: b) S. M.
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Keywords: amides · multicomponent reactions ·
sequential reductive alkylation · synthetic methods ·
tert-alkylamines
.
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