General one-pot reductive gem-bis-alkylation of tertiary lactams/amides: Rapid construction of 1-azaspirocycles and formal total synthesis of (±)-cephalotaxine

Article abstract of DOI:10.1002/chem.201302096

Amides are a class of highly stable and readily available compounds. The amide functional group constitutes a class of powerful directing/activating and protecting group for C-C bond formation. Tertiary tert-alkylamine, including 1-azaspirocycle is a key structural feature found in many bioactive natural products and pharmaceuticals. The transformation of amides into tert-alkylamines generally requires several steps. In this paper, we report the full details of the first general method for the direct transformation of tertiary lactams/amides into tert-alkylamines. The method is based on in situ activation of amide with triflic anhydride/2,6-di-tert-butyl-4-methylpyridine (DTBMP), followed by successive addition of two organometallic reagents of the same or different kinds to form two C-C bonds. Both alkyl and functionalized organometallic reagents and enolates can be used as the nucleophiles. The method displayed excellent 1,2- and good 1,3-asymmetric induction. Construction of 1-azaspirocycles from lactams required only two steps or even one-step by direct spiroannelation of lactams. The power of the method was demonstrated by a concise formal total synthesis of racemic cephalotaxine. Four bonds in one pot! Cleavage of two bonds of an amide carbonyl group and replacement by two new C-C bonds can be achieved in one pot under mild conditions by using amide activation with triflic anhydride (Tf₂O). A concise formal total synthesis of racemic cephalotaxine has been accomplished by means of this methodology (see scheme; DTBMP=2,6-di-tert-butyl-4-methylpyridine). Copyright

Full text of DOI:10.1002/chem.201302096

FULL PAPER
DOI: 10.1002/chem.201302096
General One-Pot Reductive gem-Bis-Alkylation of Tertiary Lactams/Amides:
Rapid Construction of 1-Azaspirocycles and Formal Total Synthesis of
(Æ)-Cephalotaxine
Kai-Jiong Xiao, Jie-Min Luo, Xiao-Er Xia, Yu Wang, and Pei-Qiang Huang*[a]
À
Abstract: Amides are a class of highly
stable and readily available com-
pounds. The amide functional group
constitutes a class of powerful direct-
ing/activating and protecting group for
method for the direct transformation
of tertiary lactams/amides into tert-al-
kylamines. The method is based on in
situ activation of amide with triflic an-
hydride/2,6-di-tert-butyl-4-methylpyri-
dine (DTBMP), followed by successive
addition of two organometallic re-
agents of the same or different kinds to
form two C C bonds. Both alkyl and
functionalized organometallic reagents
and enolates can be used as the nucleo-
philes. The method displayed excellent
1,2- and good 1,3-asymmetric induc-
tion. Construction of 1-azaspirocycles
from lactams required only two steps
or even one-step by direct spiroannela-
tion of lactams. The power of the
method was demonstrated by a concise
formal total synthesis of racemic ceph-
alotaxine.
À
C C bond formation. Tertiary tert-al-
kylamine, including 1-azaspirocycle is a
key structural feature found in many
bioactive natural products and pharma-
ceuticals. The transformation of amides
into tert-alkylamines generally requires
several steps. In this paper, we report
the full details of the first general
À
Keywords: alkylation · C C bond
formation · lactams · reduction ·
synthetic methods
Introduction
Simplicity is one of the major pursuits of organic synthe-
sis.[1]The development of general synthetic methods using
simple and stable starting materials[2] and multicomponent
À
reactions leading to the formation of two or more carbon
carbon bonds in a one-pot process[3] are two powerful strat-
egies directed at this goal. Tertiary tert-alkylamine, particu-
larly 1-azaspirocyclic motif A (Figure 1), is a salient structur-
al feature of many bioactive natural products and medicinal
agents. Representative bioactive alkaloids containing 1-aza-
ACHTUNGTRENNUNG
spirocycles are shown in Figure 1.[4] Although much effort
has been made to construct such structural motif,[5,6] the
transformation of lactams and amides into the correspond-
ing tert-alkylamines by one-pot reductive bis-alkylation with
different organometallic reagents (Scheme 1) is both a
highly desirable and a challenging objective.[6] The merit of
this transformation is also linked to the high stability of lac-
Figure 1. Selected alkaloids containing the 1-azaspirocyclic motif A.
tams/amides, the powerful directing ability of lactams/
[8]
amides for metallation[7] and C H activation, as well as
À
Scheme 1. One-pot transformation of lactams/amides to tert-alkylamines
À
with cleavage of the C=O bond and the formation of two C C bonds.
[a] Dr. K.-J. Xiao, Dr. J.-M. Luo,+ X.-E. Xia,+ Y. Wang,
Prof. Dr. P.-Q. Huang
the ready availability of both lactams/amides[9] and
Grignard/organolithium reagents.[10]
The challenges for the one-pot reductive bis-alkylation of
an amide to give an a-tert-alkylamine are threefold: first,
the low reactivity of an amide requires the use of highly re-
active organometallic reagents as the nucleophiles and harsh
reaction conditions; second, the chemoselective formation
Department of Chemistry and
Fujian Provincial Key Laboratory of Chemical Biology
College of Chemistry and Chemical Engineering
Xiamen University, Xiamen, Fujian 361005 (P.R. China)
E-mail: pqhuang@xmu.edu.cn
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201302096.
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
1
&
ÞÞ
These are not the final page numbers!

Table 1. Screen of base additives for the direct reductive diethylation of
of an iminium ion intermediate instead of a more probable
ketone; third, chemoselective and stereoselective addition
of two different nucleophiles to form a new chiral centre at
the a-carbon to the nitrogen atom. Due to these formidable
challenges, only direct reductive dimethylation,[11] diallyla-
tion[12] of lactams and cyclopropanation (intramolecular Ku-
linkovich–de Meijere reactions)[13] of amides have been re-
ported. To achieve the desired transformation, three indirect
tactics have been developed.
The first one involves the conversion of lactams to lactim
ethers, however, the method is limited to the introduction of
two same alkyl groups to lactams.[14] The second tactic is
based on activation of amide by conversion to N-carbamoyl
lactam derivatives, followed by stepwise transformations
such as organometallic reagents addition and a-amidoalkyla-
tion of the resulting N-acyliminium ion precursors.[4,6] The
third one, developed by Murai[15] and Renaud,[16] consists of
transforming amides/lactams into thioamide or selenoamide
derivatives, followed by in situ activation by using S-methyl-
ation and the addition of organometallic reagents. On the
basis of the latter work, Renaud and co-workers have thus
established a flexible approach to 1-azaspirocycles.[16]
lactam 6a.[a]
Entry
Base
Product yield[%][b]
1
2
3
4
5
6
7
8
Et3N
iPr2NEt
pyridine
2-chloropyridine
2-fluoropyridine
2,6-lutidine
DTBMP
9
5
20
38
15
57
87
63
none
[a] Reaction conditions (procedure A): 1) lactam 6a (1.0 equiv), base
(1.2 equiv), Tf2O (1.2 equiv), CH2Cl2, À788C, 45 min; 2) EtMgBr
(3.0 equiv), À788C, then RT, 3 h; [b] Yield of the isolated product. Bn=
benzyl; Tf2O=trifluoromethanesulfonic anhydride; DTBMP=2,6-di-tert-
butyl-4-methylpyridine.
Hꢁnig base, pyridine, 2,6-lutidine, 2-chloropyridine, 2-fluro-
pyridine,
and
2,6-di-tert-butyl-4-methylpyridine
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
(DTBMP),[22d,24] DTBMP afforded the best result, providing
the desired 2,2-diethylpyrrolidine 10a in 87% yield (Table 1,
entry 7). The success with DTBMP may be attributed to the
appropriate basicity and low nucleophilicity of DTBMP as
well as the low electrophilicity of the plausible pyridinium
ion intermediate.
It is worth noting that a reasonable yield (63%) was also
obtained in the absence of base additive (Table 1, entry 8).
The result made us have a reconsideration of the mechanism
of the reaction. In our preliminary communication,[20] the
pyridinium intermediate G (Scheme 2) was suggested as a
Meijere and co-workers recently reported a TiACTHNURGTNEUNG(O-iPr)4/tri-
methylsilyl chloride (TMSCl)-mediated addition to forma-
mides, but their method is restricted to N,N-dialkylforma-
mides.[17]
In connection with our longstanding interest in the syn-
thesis of bioactive alkaloids[18] and the development of relat-
ed synthetic methodologies,[19] we have embarked on a pro-
gram to develop a general one-pot method for the direct
conversion of lactams and amides into tertiary tert-alkyl-
ACHTUNGTRENNUNG
amines.[20,21] We now report the full account of this investiga-
tion, which includes the application of this method to the
synthesis of 1-azaspirocycles and a formal racemic synthesis
of alkaloid cephalotaxine (2).
Results and Discussion
Reductive bis-alkylation of tertiary lactams/amides: We first
investigated the reductive bis-alkylation of lactams by intro-
duction of two same alkyl groups. To achieve the required
one-pot reaction under mild conditions, triflic anhydride
(Tf2O)[22] was selected as an amide activator.[23] As demon-
strated by many Tf2O-mediated transformations,[22] the addi-
tion of a base additive is usually necessary. Thus, a screening
of base additives was undertaken with lactam 6a as the sub-
strate, Tf2O as the activating reagent, and EtMgBr as the
nucleophile. In the event, Tf2O (1.2 equiv) was added to a
dichloromethane solution of lactam 6a (1.0 equiv) and base
additive (1.2 equiv) at À788C. After stirring for 45 min,
EtMgBr (3.0 equiv) was added, and the mixture was stirred
at RT for 3 h. The results are summarized in Table 1. As can
be seen from Table 1, among the bases tested (triethylamine,
Scheme 2. Proposed reaction mechanism.
plausible intermediate. The fact here, however, seemed to
preclude the role of DTBMP as a nucleophile to first react
with triflic anhydride. Indeed, it has been reported that due
to its steric hindrance, DTBMP does not react with triflic
anhydride to generate the reactive pyridinium intermediate
G.[22a] Thus, although the exact role of DTBMP is not yet
clear at this stage, a new plausible mechanism for the Tf2O-
activated addition of organometallic reagents to lactams and
&
2
&
www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Reductive gem-Bis-Alkylation of Tertiary Lactams/Amides
FULL PAPER
amides is proposed as shown in Scheme 2. The amide car-
bonyl reacts with triflic anhydride to form highly electro-
philic triflyloxyiminium intermediate D, which reacts with
one molecule of R1M1 to give O-triflyl aminal E. The subse-
quent elimination of ÀOTf, assisted by the nitrogen lone pair
and metal cation, leads to the formation of iminium ion F,
which is trapped by a second molecule of nucleophile
(R2M2) to give amine C.
We next investigated the scope of the reaction. Successive
treatment of lactam 6a with Tf2O/DTBMP (À788C, 45 min)
and n-BuMgBr (3.0 equiv) gave the desired amine 10b in
83% yield (Table 2, entry 1). Use of BnMgBr as the
Grignard reagent produced amine 10c in 71% (Table 2,
entry 2). Similarly, reductive alkylation of lactam 7 and 8
with EtMgBr, n-BuMgBr and BnMgBr produced the corre-
sponding dialkylated cyclic amines 11a–12c in 60–81%
(Table 2, entries 3–8). Mention should be made that to
ensure complete lactam activation, the activation time may
be prolonged to 2 h, or the reaction temperature may rise
from À78 to 08C before cooling back to À788C for
Grignard reagent addition.
The method was successfully extended to the reductive
bis-alkylation of amides. Reductive dialkylation of amide 9a
with EtMgBr and BnMgBr yielded smoothly the desired
amines 13a and 13b in 86 and 90% yield, respectively
(Table 2, entries 9 and 10). Reductive diphenylation of N,N-
dimethylformamide gave the desired amine in 93% yield
(Table 2, entry 11). The dialkylation reaction of sterically
hindered amide 9c with BnMgBr afforded the dibenzylated
amine 13d in 81% yield (Table 2, entry 12).
It is worth mentioning that higher yields were obtained
with amides than lactams. This may be ascribed to the easier
formation of activation intermediates from amides than lac-
tams.
Table 2. Scope of the Tf2O-activated direct reductive dialkylation of lactams and amides.[a]
Entry
Substrate
R1MgX
Product
Entry
Substrate
R1MgX
Product
yield [%][b]
yield [%][b]
1
2
6a
6a
n-BuMgBr
10b (83)
10c (71)
11
12
9b
9c
PhMgBr
BnMgBr
13c (93)
13d (81)
BnMgBr
3
4
5
6
7
7
7
8
EtMgBr
nBuMgBr
BnMgBr
EtMgBr
11a (74)
11b (70)
11c (60)
12a (81)
13
14
15
16
6a
6a
6a
6a
10d (85)
10e (64)
10 f (76)
14
15
10g (trace)
7
8
nBuMgBr
12b (80)
17
6a
10h (trace)
8
8
BnMgBr
EtMgBr
BnMgBr
12c (68)
13a (86)
13b (90)
18
19
20
7
7
7
11d (75)
11e (60)
11 f (78)
9
9a
9a
14
15
10
[a] Reaction conditions (Procedure A): 1) amide (1.0 equiv), DTBMP (1.2 equiv), Tf2O (1.2 equiv), CH2Cl2, À788C, 45 min; 2) R1MgBr (3.0 equiv),
À788C, then RT, 3 h; [b] Yield of the isolated product. TBS=tert-butyldimethylsilyl.
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
3
&
ÞÞ
These are not the final page numbers!

P.-Q. Huang et al.
The methodology was further extended to the addition of
functionalized Grignard reagents. As can be seen from
Table 2, not only allylmagnesium bromide (entries 13 and
18) and TBSO-containing Grignard reagent 14 (entries 14
and 19) can be used, but also acetal-containing Grignard re-
agent 15 can be tolerated (entries 15 and 20). However, the
reaction failed with less reactive vinylmagnesium bromide
and ethynylmagnesium bromide (Table 2, entries 16 and 17).
bromide as the second nucleophile provided the desired bis-
alkylation products 16b and 16c in 71 and 74% yield, re-
spectively (Table 3, entries 2 and 3). Organolithium reagents
such as n-butyllithium can also be used as the second addi-
tion nucleophiles (Table 3, entry 4). The sequential one-pot
reductive bis-alkylation with two different organometallic
reagents can be extended to other lactams as well as amides
(Table 3, entries 5–9).
Employment of functionalized nucleophiles as the second
addition nucleophiles was also investigated. To our delight,
sp2- and sp-hybridized carbon nucleophiles, such as vinyl-
magnesium bromide, ethynylmagnesium bromide, and phe-
nylethynyllithium, could serve as effective second addition
nucleophiles (Table 3, entries 10–12), although they had pre-
viously failed to give the reductive dialkylation products
(Table 2, entries 16 and 17). In these cases, products arising
from the addition of two molecules of the first Grignard re-
agent were not detected. In view of enolates as versatile nu-
cleophiles, we also carried out the one-pot sequential reduc-
tive bis-alkylation of 2-pyrrolidinone 6a with ethylmagnesi-
um bromide and lithium enolate 20. The desired pyrrolidine
16 f was produced in 73% yield (Table 3, entry 13). Kno-
chelꢂs functional arylmagnesium reagents,[25] a new class of
versatile nucleophiles, were also tested. Thus, successive
treatment of 2-pyrrolidinone 6a with triflic anhydride, iso-
propylmagnsium bromide, and Knochelꢂs functional aryl-
Reductive bis-alkylation with two different organometallic
reagents: We next turned our attention to the more de-
manding and also more challenging task, namely, the intro-
duction of two different substituents by sequential reaction
with two different organometallic reagents. For this purpose,
a CH2Cl2 solution of lactam 6a and DTBMP (1.2 equiv) was
successively treated with 1.2 molar equivalents of Tf2O
(À788C, 45 min), 1.0 molar equivalent of ethylmagnesium
bromide (À788C, then warmed-up to RT, 1 h), and 2.0
molar equivalents of n-butylmagnesium bromide (À788C,
3 h). Pyrrolidine 16a bearing two different alkyl groups (Et,
n-Bu) was obtained in 75% yield, along with 9% of pyrroli-
dine 10b arising from the addition of two molecules of n-bu-
tylmagnesium bromide (Table 3, entry 1). To avoid the dia-
lkylation with the first Grignard reagent, it is beneficial to
add the first Grignard reagent as a ꢀ0.5m solution. Similar-
ly, use of benzylmagnesium bromide and allylmagnesium
Table 3. Tf2O-Activated sequential addition of two organometallic reagents to lactams/amides.[a]
Entry
Substrate
R1MgBr
R2M2
Product
Entry
Substrate
R1MgBr
R2M2
Product
yield [%][b]
yield [%][b]
16a (75)
10b (9)
19a (78)
13a (8)
1
2
6a
6a
EtMgBr
EtMgBr
n-BuMgBr
8
9
9a
9a
nBuMgBr
nBuMgBr
EtMgBr
BnMgBr
16b (71)
10c (8)
19b (74)
13b (7)
BnMgBr
16c (74)
10d (8)
3
4
6a
6a
EtMgBr
EtMgBr
allylMgBr
10
11
7
nBuMgBr
17d (65)
16d (72)
16a (76)
10b (9)
nBuLi
6b
EtMgBr
17a (66)
11a (6)
5
6
7
7
7
7
nBuMgBr
EtMgBr
EtMgBr
EtMgBr
12
13
14
6a
6a
6a
EtMgBr
EtMgBr
iPrMgBr
16e (70)
16 f (73)
16g (70)
17b (63)
11c (4)
BnMgBr
AllylMgBr
17c (68)
11d (7)
[a] Reaction conditions (Procedure B): 1) amide (1.0 equiv), DTBMP (1.2 equiv), Tf2O (1.2 equiv), CH2Cl2, À788C, 45 min; 2) R1 MgBr (1.0 equiv),
À788C, then RT, 1 h; 3) R2M2, RT, 3 h; [b] Yield of the isolated product.
&
4
&
www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Reductive gem-Bis-Alkylation of Tertiary Lactams/Amides
FULL PAPER
magnesium reagent 21, prepared in situ from methyl p-iodo-
benzoate,[25] furnished the expected pyrrolidine 16g in 70%
yield (Table 3, entry 14).
azaspirocyclic ring system A as a salient structural feature in
many bioactive natural products[4] (Figure 1), we next
turned our attention to the construction of such ring sys-
tems. Although the introduction of two functionalized side
chains such as those shown in entries 14, 15, 19, and 20 in
Table 2 would serve well for this purpose, we envisioned
that the introduction of two olefinic side chains would
afford a more concise approach by means of RCM.[29] Thus
the hydrochloride salt of the reductive di-allylation product
10d (Table 2, entry 13) was treated[12,16,30] with the Grubbs
second-generation catalyst,[30] and the N-a-spiro-pyrrolidine
28a was obtained in excellent yield (90%, Table 4, entry 1).
Encouraged by this result, the protocol was extended to
other lactams/amides and alkenyl Grignard reagents. As
outlined in Table 4, the desired N-a-spiro-pyrrolidines were
provided in good overall yields (Table 4, entries 2–8).
By varying two different alkenyl groups, the spiro-cyclic
alkenes could be built with C=C double bonds located at
different positions (Table 5).
1,3-Asymmetric induction in the reductive bis-alkylation: To
explore the use of this method for asymmetric synthesis, the
reductive bis-alkylation of the chiral ring systems 22, 24, and
26 have been investigated. Following the procedure for the
sequential reductive bis-alkylation of lactams/amides, (S)-3-
benzyloxy-2-pyrrolidinone 22[26] was treated successively
with triflic anhydride, ethylmagnsium bromide, and benzyl-
magnesium chloride to produce pyrrolidine 23 as the only
diastereomer in 70% yield (Scheme 3). The Tf2O-activated
Direct one-step spiroannelation of lactams: For the con-
struction of the N-a-spiro ring systems, an even more direct
access would be the one-pot reductive bis-alkylation of lac-
tams by a,w-bis-Grignard reagent.[31] Thus lactams 6a and 7
were treated with Grignard reagent 30, which produced the
N-a-spiro ring systems 31a and 31b in 62 and 63% yield, re-
spectively (Scheme 4). Similarly, bis-alkylation of lactams 6a
and 7 with a,w-bis-Grignard reagent 32 afforded compounds
33a and 33b in 65 and 60% yield, respectively.
Scheme 3. 1,2 and 1,3-asymmetric induction in the sequential reductive
bis-alkylation of lactams.
sequential ethylation and benzylation of (S)-glutamic acid
derived 2-pyrrolidinone 24[27] also proceeded with good 1,3-
asymmetric induction, yielding pyrrolidine 25 and its diaste-
ACHTUNGTRENNUNGreomer in a ratio of 7.7:1 (HPLC) with 75% combined
yield. Similarly, the Tf2O-activated sequential ethylation and
benzylation of (S)-malimide derived 2-pyrrolidinone 26[28]
exhibited good 1,3-asymmetric induction, giving pyrrolidine
27 and its diastereomer in 7.7: 1 ratio (HPLC) with 72%
combined yield.
Scheme 4. One-pot approach to 1-azaspirocycles starting from lactams.
The configurations of the newly formed quaternary ster-
eocenters in pyrrolidines 23, 25, and 27 were determined by
using nuclear Overhauser effect spectroscopy (NOESY) ex-
periments. In all cases, the second alkyl groups (benzyl
group) are trans to the substituents originally existing in the
starting materials. The results are in agreement with the pro-
posed mechanism shown in Scheme 2. Namely, to avoid the
steric hindrance, the second Grignard reagent (benzylmag-
nesium chloride) approaches the cyclic iminium ion inter-
mediate F from the direction opposite to the existing sub-
stituent at the ring.
Formal synthesis of racemic cephalotaxine (2): The synthesis
of racemic cephalotaxine (2),[32] a member of the cephalo-
taxus family of cytotoxic alkaloids,[33] was then undertaken.
The requisite lactam 36 was prepared from 2-arylethanol 34
in a total yield of 65%, through succinimide formation
under the Mitsunobu conditions (PPh3, diisopropyl azodicar-
boxylate (DIAD), RT, 4 h),[34] followed by partial reduction
of the crude succinimide 35 with sodium borohydride in
CHCl3/MeOH, and reductive dehydroxylation of the result-
ing hemiaminal (Scheme 5).
Two-step construction of 1-azaspirocycles by reductive bis-
alkylation and ring-closing metathesis (RCM): In view of 1-
Successive treatment of lactam 36 with DTBMP
(1.2 equiv), Tf2O (1.1 equiv, CH2Cl2, À788C, 45 min), buten-
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
5
&
ÞÞ
These are not the final page numbers!

P.-Q. Huang et al.
Table 4. Two-step synthesis of 1-azaspirocycles 28a–f and aminocyclopentenes 28g and h from amides/lactams.[a,b]
Entry
1
Substrate
R1MgX
Product yield [%][c]
N-a-spiro-amines 28 yield [%][c]
6a
6a
7
10d (85)
28a (90)
28b (85)
28c (91)
2
3
10i (72)
11d (75)
4
5
7
8
11g (75)
12d (77)
28d (88)
28e (91)
6
7
8
12e (70)
13e (76)
28 f (87)
28g (83)
9d
8
9e
13 f (65)
28h (87)
[a] Reaction conditions (Procedures A and D): 1) amide (1.0 equiv), DTBMP (1.2 equiv), Tf2O (1.2 equiv), CH2Cl2, À788C, 45 min; 2) R1MgBr
(3.0 equiv), À788C, then RT, 3 h; [b] 1) amine (1.0 equiv), AcCl (2.0 equiv), MeOH; 2) Grubbs G II cat. (5 mol%), CH2Cl2, reflux, 2 h; [c] Yield of the
isolated product.
Table 5. Two step synthesis of 1-azaspirocycles 29 from lactams 6a.[a,b]
duced the desired pyrrolidine
37 in 65% yield (Scheme 6).
Subjection of the hydrochloride
salt of the dienic pyrrolidine 37
to the RCM conditions (Grubbs
generation II catalyst, CH2Cl2,
reflux, 2 h) produced the
known spiro-pyrrolidine 38 in a
high yield (94%). The spectral
data (1H and 13C NMR spectro-
scopic analysis) of compound
38 are in agreement with those
reported.[5f] The palladium-cata-
lyzed Heck-type cyclization of
38 (and also the bromo ana-
logue of 38) to give compound
39 has been achieved by the
groups of Yoshida[5f] and Tiet-
ze,[32e,f] and the conversion of 39
into cephalotaxine (2) has been
reported by Isono and Mori.[32d]
Entry
R1MgX
R2MgBr
Product 16
N-a-spiropyrrolidines
29 [%][c]
Yield [%][c]
1
2
16h (75)
16i (71)
29a (85)
29b (89)
3
16j (75)
29c (90)
[a] Reaction conditions (Procedures B and D): 1) lactam 6a (1.0 equiv), DTBMP (1.2 equiv), Tf2O (1.2 equiv),
CH2Cl2, À788C, 45 min; 2) R1MgBr (1.0 equiv), À788C, then RT, 1 h; 3) R2MgBr, RT, 3 h; [b] 1) amine 16
(1.0 equiv), AcCl (2.0 equiv), MeOH; 2) Grubbs G II cat. (5 mol%), CH2Cl2, reflux, 2 h; [c] Yield of the isolat-
ed product.
1-ylmagnesium bromide (1.0 equiv, À788C, then warmed up
Our synthesis of compound 38 thus constitutes a formal syn-
thesis of racemic cephalotaxine (2).
to RT, 1 h), and vinylmagnesium bromide (3.0 equiv) pro-
&
6
&
www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Reductive gem-Bis-Alkylation of Tertiary Lactams/Amides
FULL PAPER
has found applications in the synthesis of azacycles[35] and al-
kaloid FR901483 (1).[18b]
Experimental Section
General methods: Unless otherwise stated, reactions were performed in
oven-dried glassware under a nitrogen atmosphere. Dichloromethane
was distilled over calcium hydride under a nitrogen atmosphere. Ether
and THF were distilled over sodium benzophenone ketyl under a nitro-
gen atmosphere. Silica gel (300–400 mesh) was used for flash column
chromatography, eluting (unless otherwise stated) with ethyl acetate
(EtOAc)/hexane. Melting points were uncorrected. Infrared spectra were
measured using film KBr pellet techniques. 1H NMR spectra were re-
corded in CDCl3 with tetramethylsilane as an internal standard. Chemical
shifts are expressed in d (ppm) units downfield from TMS. Mass spectra
were obtained using electrospray ionization and an FT-ICR analyzer
(ESI-MS) for high resolution mass spectra (HRMS). Tf2O was distilled
over phosphorous pentoxide and was stored for use within a week. All
the Grignard reagents were titrated before use.[36] All other commercially
available compounds were used as received.
Scheme 5. Preparation of lactam 36.
General procedure for the Tf2O-activated one-pot reductive di-alkylation
of lactams/amides: General procedure A: use of only one kind of organo-
metallic reagent: Tf2O (1.2 mmol) was added dropwise to
a cooled
(À788C) CH2Cl2 (10 mL) solution of a lactam/amide (1.0 mmol) and
DTBMP (1.2 mmol). After the resulting mixture was stirred at À788C
for 45 min, a solution of an organometallic reagent (3.0 mmol) was added
dropwise. The mixture was allowed warming slowly to RT and stirred for
3 h. The reaction was quenched with a saturated ammonium chloride sol-
ution and extracted with CH2Cl2 (5ꢃ4 mL). The combined organic layers
were washed with brine, dried over anhydrous Na2SO4, filtered, and con-
centrated under reduced pressure. The residue was purified by flash chro-
matography (EtOAc/hexane) on silica gel to give the desired amine.
Scheme 6. Concise synthesis of racemic cephalotaxine (2).
General procedure for the Tf2O-activated one-pot reductive bis-alkyla-
tion of lactams/amides: General procedure B: use of two different organo-
metallic reagents: Tf2O (1.2 mmol) was added dropwise to a cooled
(À788C) CH2Cl2 (10 mL) solution of a lactam/amide (1.0 mmol) and
DTBMP (1.2 mmol). After the resulting mixture was stirred at À788C
for 45 min, a solution of an organometallic reagent (1.0 mmol) was added
dropwise. The mixture was allowed warming slowly to RT and stirred for
1 h. A solution of another organometallic reagent (2.0 mmol) was added
dropwise to this mixture and then stirred for 3 h. The reaction was
quenched with a saturated ammonium chloride solution and extracted
with CH2Cl2 (5ꢃ4 mL). The combined organic layers were washed with
brine, dried over anhydrous Na2SO4, filtered, and concentrated under re-
duced pressure. The residue was purified by flash chromatography
(EtOAc/hexane) on silica gel to give the desired amine.
Conclusion
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: 1) this is a multicomponent
À
reaction with two C C bond formations in one pot; 2) both
lactams and amides can be used as substrates; 3) two differ-
ent Grignard reagents can be used in the one-pot process;
4) both Grignard reagents and organolithium reagents can
be used in the one-pot process; 5) for the second addition,
either sp3, sp2-, or sp-hybridized carbon nucleophiles, func-
tionalized carbon nucleophiles such as enolates, and Kno-
chelꢂs functional arylmagnesium reagent can be used; 6) the
sequential addition afforded excellent 1,2- and 1,3-asymmet-
ric induction in substituted g-lactams; 7) the method pro-
vides a versatile entry to 1-azaspirocycles, a key structural
feature of many bioactive alkaloids. The high stability of lac-
tams/amides combined with the ready availability of both
lactams/amides and Grignard/organolithium reagents make
this a general method for the synthesis of various tert-alkyl-
General procedure for the direct synthesis of 1-azaspirocycles from lac-
tams/amides: General procedure C: use of a,w-dinucleophilic organome-
tallic reagent: Tf2O (1.2 mmol) was added dropwise to a cooled (À788C)
CH2Cl2 (10 mL) solution of
a lactam (1.0 mmol) and DTBMP
(1.2 mmol). After being stirred at À788C for 45 min, a solution of a,w-di-
nucleophilic organometallic reagent (1.0 mmol) was added dropwise. The
mixture was allowed to warm slowly to RT and stirred for 3 h. The reac-
tion was quenched with saturated ammonium chloride solution and ex-
tracted with CH2Cl2 (5ꢃ4 mL). The combined organic layers were
washed with brine, dried over anhydrous Na2SO4, filtered, and concen-
trated under reduced pressure. The residue was purified by flash chroma-
tography (EtOAc/hexane) on silica gel to give the desired 1-azaspirocy-
cle.
General procedure for the ring closing metathesis of dienic amines: Gen-
eral procedure D: Acetyl chloride (71 mL, 1 mmol) was added at 08C to
MeOH (4 mL). The mixture was stirred for 5 min and a dienic amine
(0.5 mmol) was added. After being stirred at RT for 30 min, the resulting
mixture was concentrated under reduced pressure. The residue was used
in the next step without further purification.
ACHTUNGTRENNUNGamines from amides and lactams. The power of this method
is demonstrated by a concise formal total synthesis of race-
mic cephalotaxine. It is worth mentioning that this method
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
7
&
ÞÞ
These are not the final page numbers!

P.-Q. Huang et al.
To a solution of the foregoing residue (0.5 mmol estimated based on a
100% yield) in CH2Cl2 (50 mL) at RT was added Grubbs II catalyst
(21 mg, 0.025 mmol), and the mixture was heated at reflux for 2 h. The
reaction was quenched with a saturated aqueous solution of NaHCO3
and extracted with CH2Cl2 (5ꢃ10 mL). The combined organic layers
were washed with brine, dried over anhydrous Na2SO4, filtered, and con-
centrated under reduced pressure. The residue was purified by flash chro-
matography (EtOAc/hexane) on silica gel to give the corresponding 1-
azaspirocycle.
910, 732, 697 cmÀ1
242.1903; found: 242.1915.
;
HRMS (ESI): m/z calcd for C17H24N [M+H]+:
1-Benzyl-2,2-di(but-3-en-1-yl)pyrrolidine (10i): Following the general
procedure A, addition of 3-butenylmagnesium bromide to 1-benzylpyrro-
lidin-2-one (120 mg, 0.68 mmol) gave, after flash column chromatography
on silica gel (eluent: EtOAc/hexane=1:20), pyrrolidine 10i (132 mg,
yield: 72%) as a colorless oil. 1H NMR (400 MHz, CDCl3): d=1.46–1.61
(m, 4H), 1.62–1.76 (m, 4H), 2.01–2.14 (m, 2H), 2.20–2.32 (m, 2H), 2.62
(t, J=6.5 Hz, 2H), 3.62 (s, 2H), 4.92–5.06 (m, 2H), 5.03 (dd, J=17.1,
1.7 Hz, 2H), 5.80–5.92 (m, 2H), 7.18–7.36 ppm (m, 5H); 13C NMR
(100 MHz, CDCl3): d=21.9, 28.9, 32.8, 34.6, 50.6, 52.0, 64.2, 113.9 (2C),
126.4, 128.1 (2C), 128.2 (2C), 139.6 (2C), 141.1 ppm; IR (film): n˜ =3058,
2931, 1601, 1450, 735, 696 cmÀ1; HRMS (ESI): m/z calcd for C19H28N:
270.2216 [M+H]+; found: 270.2224.
1-Benzyl-2,2-bis(4-(tert-butyldimethylsilyloxy)butyl)pyrrolidine
(10e):
Following the general procedure A, addition of Grignard Reagent 14 to
1-benzylpyrrolidin-2-one (120 mg, 0.69 mmol) gave, after flash column
chromatography on silica gel (eluent: EtOAc/hexane=1:20), pyrrolidine
1
10e (235 mg, yield: 64%) as a colorless oil. H NMR (400 MHz, CDCl3):
2,2-Diallyl-1-benzylpiperidine (11d): Following the general procedure A,
addition of allylmagnesium bromide to 1-benzylpiperidin-2-one (129 mg,
0.68 mmol) gave, after flash chromatography on silica gel (eluent:
EtOAc/hexane=1:40), piperidine 11d (139 mg, yield: 75%) as a colorless
oil. 1H NMR (400 MHz, CDCl3): d=1.42–1.57 (m, 6H), 2.11 (ddt, J=
14.2, 7.6, 1.2 Hz, 2H), 2.41 (t, J=5.5 Hz, 2H), 2.60 (ddt, J=14.2, 7.0,
1.2 Hz, 2H), 3.61 (s, 2H), 5.01–5.09 (m, 4H), 5.88–6.02 (m, 2H), 7.17–
7.39 ppm (m, 5H); 13C NMR (100 MHz, CDCl3): d=20.5, 26.2, 32.3, 38.0,
46.0, 52.9, 58.2, 116.8 (2C), 126.3, 128.1 (2C), 128.2 (2C), 135.3 (2C),
d=0.06 (s, 12H), 0.90 (s, 18H), 1.32–1.54 (m, 12H), 1.58–1.70 (m, 4H),
2.60 (t, J=6.4 Hz, 2H), 3.60 (s, 2H), 3.63 (t, J=6.4 Hz, 4H), 7.15–
7.33 ppm (m, 5H); 13C NMR (100 MHz, CDCl3): d=À5.2 (4C), 18.4, 20.8
(2C), 21.9, 26.0 (6C), 33.0, 33.9 (2C), 35.4, 50.8, 52.2, 63.3, 64.5, 126.3,
128.1 (2C), 128.2 (2C), 141.4 ppm; IR (film): n˜ =3064, 3027, 2953, 2928,
2857, 2791, 1471, 1462, 1255, 1102, 836, 774 cmÀ1; HRMS (ESI) m/z calcd
for C31H60NO2Si2: 534.4157 [M+H]+; found: 534.4165.
1-Benzyl-2,2-bis(4-(tert-butyldimethylsilyloxy)butyl)piperidine (11e): Fol-
lowing the general procedure A, addition of Grignard reagent 14 to 1-
benzylpiperidin-2-one (130 mg, 0.69 mmol) gave, after flash column chro-
matography on silica gel (eluent: EtOAc/hexane=1:40), piperidine 11e
(226 mg, yield: 60%) as a colorless oil. 1H NMR (400 MHz, CDCl3): d=
0.04 (s, 12H), 0.90 (s, 18H), 1.30–1.54 (m, 16H), 1.68–1.78 (m, 2H), 2.38
(t, J=5.2 Hz, 2H), 3.52 (s, 2H), 3.61 (t, J=6.4 Hz, 4H), 7.15–7.33 ppm
(m, 5H); 13C NMR (100 MHz, CDCl3): d=À5.2 (4C), 18.3, 19.8 (2C),
20.8, 26.0 (6C), 26.3, 31.5, 33.4, 33.9 (2C), 45.8, 52.8, 57.6, 63.2 (2C),
126.2, 128.0 (2C), 128.1 (2C), 141.5 ppm; IR (film): n˜ =3062, 3025, 2948,
2929, 2857, 2974, 1470, 1255, 1101, 836, 775 cmÀ1; HRMS (ESI): m/z
calcd for C32H62NO2Si2: 548.4314 [M+H]+; found: 548.4317.
140.9 ppm; IR (film): n˜ =3073, 2930, 2794, 1450, 1382, 909, 725, 696 cmÀ1
;
HRMS (ESI): m/z calcd for C18H26N: 256.2060 [M+H]+; found:
256.2067.
1-Benzyl-2,2-di(but-3-enyl)piperidine (11g): Following the general proce-
dure A, addition of 3-butenylmagnesium bromide to 1-benzylpiperidin-2-
one (129 mg, 0.68 mmol) gave, after flash chromatography on silica gel
(eluent: EtOAc/hexane=1:40), piperidine 11g (144 mg, yield: 75%) as a
colorless oil. 1H NMR (400 MHz, CDCl3): d=1.36–1.51 (m, 6H), 1.52–
1.57 (m, 2H), 1.78–1.92 (m, 2H), 2.01–2.21 (m, 4H), 2.41 (t, J=5.2 Hz,
2H), 3.55 (s, 2H), 4.89–4.95 (m, 2H), 4.96–5.04 (ddd, J=17.1, 3.5, 1.5 Hz,
2H), 5.77–5.91 (m, 2H), 7.16–7.36 ppm (m, 5H); 13C NMR (100 MHz,
CDCl3): d=20.7, 26.2, 27.9, 31.3, 32.8, 45.8, 52.6, 57.4, 113.9 (2C), 126.3,
127.9 (2C), 128.2 (2C), 139.7 (2C), 141.1 ppm; IR (film): n˜ =3075, 2936,
2795, 1639, 1451, 1067, 907, 696 cmÀ1; HRMS (ESI): m/z calcd for
C20H30N [M+H]+: 284.2373; found: 284.2379.
2,2-Bis(2-(1,3-dioxolan-2-yl)ethyl)-1-benzylpyrrolidine (10 f): Following
the general procedure A, addition of Grignard Reagent 15 to 1-benzyl-
pyrrolidin-2-one (140 mg, 0.80 mmol) gave, after flash column chroma-
tography on silica gel (eluent: EtOAc/hexane=1:5), pyrrolidine 10 f
(220 mg, yield: 76%) as a colorless oil. 1H NMR (400 MHz, CDCl3): d=
1.54–1.75 (m, 10H), 1.78–1.89 (m, 2H), 2.61 (t, J=6.4 Hz, 2H), 3.62 (s,
2H), 3.82–3.90 (m, 4H), 3.92–4.00 (m, 4H), 4.86 (t, J=4.7 Hz, 2H), 7.16–
7.34 ppm (m, 5H); 13C NMR (100 MHz, CDCl3): d=21.8, 29.0 (4C), 32.6,
50.4, 51.8, 63.6, 64.8 (2C), 64.9 (2C), 105.1 (2C), 126.4, 128.1 (2C), 128.2
(2C), 141.0 ppm; IR (film): n˜ =2953, 2882, 1454, 1408, 1363, 1141, 1033,
943, 731, 702 cmÀ1; HRMS (ESI): m/z calcd for C21H32NO4: 362.2326
[M+H]+; found: 362.2324.
2,2-Diallyl-1-benzylazepane (12d): Following the general procedure A,
addition of allylmagnesium bromide to 1-benzylazepan-2-one (112 mg,
0.55 mmol) gave, after flash column chromatography on silica gel
(eluent: EtOAc/hexane=1:80), azepane 12d (114 mg, yield: 77%) as a
colorless oil. 1H NMR (400 MHz, CDCl3): d=1.27–1.33 (m, 2H), 1.37–
1.45 (m, 2H), 1.62–1.73 (m, 4H), 2.29 (dd, J=14.0, 7.8 Hz, 2H), 2.44
(ddt, J=14.0, 7.2, 1.2 Hz, 2H), 2.61–2.68 (m, 2H), 3.82 (s, 2H), 5.01–5.10
(m, 4H), 5.91–6.04 (m, 2H), 7.16–7.45 ppm (m, 5H); 13C NMR
(100 MHz, CDCl3): d=22.7, 30.0, 31.9, 37.2, 42.8, 48.7, 54.8, 61.2, 116.9
(2C), 126.4, 127.9 (2C), 128.4 (2C), 136.1 (2C), 142.3 ppm; IR (film): n˜ =
2975, 2926, 1493, 1450, 909, 697 cmÀ1; HRMS (ESI): m/z calcd for
C19H28N: 270.2216 [M+H]+; found: 270.2220.
2,2-Bis(2-(1,3-dioxolan-2-yl)ethyl)-1-benzylpiperidine (11 f): Following
the general procedure A, addition of Grignard Reagent 15 to 1-benzylpi-
peridin-2-one (151 mg, 0.80 mmol) gave, after flash column chromatogra-
phy on silica gel (eluent: EtOAc/hexane=1:5), piperidine 11 f (234 mg,
yield: 78%) as a colorless oil. 1H NMR (400 MHz, CDCl3): d=1.40–1.54
(m, 8H), 1.64–1.80 (m, 4H), 1.86–1.96 (m, 2H), 2.41 (t, J=5.7 Hz, 2H),
3.56 (s, 2H), 3.79–3.88 (m, 4H), 3.92–3.98 (m, 4H), 4.84 (t, J=4.8 Hz,
2H), 7.15–7.36 ppm (m, 5H); 13C NMR (100 MHz, CDCl3): d=20.5, 26.1,
27.2 (2C), 28.0 (2C), 31.3, 45.6, 52.5, 56.8, 64.8 (2C), 64.8 (2C), 105.1
(2C), 126.2, 127.9 (2C), 128.1 (2C), 141.0 ppm; IR (film): n˜ =3025, 2940,
2878, 2795, 1452, 1406, 1139, 1037, 972, 943, 732, 700 cmÀ1; HRMS (ESI):
m/z calcd for C22H34NO4: 376.2482 [M+H]+; found: 376.2486.
1-Benzyl-2,2-di(but-3-en-1-yl)azepane (12e): Following the general pro-
cedure A, addition of 3-butenylmagnesium bromide to 1-benzylazepan-2-
one (140 mg, 0.69 mmol) gave, after flash chromatography on silica gel
(eluent: EtOAc/hexane=1:80), azepane 12e (143 mg, yield: 70%) as a
colorless oil. 1H NMR (400 MHz, CDCl3): d=1.30–1.37 (m, 2H), 1.39–
1.47 (m, 2H), 1.55–1.75 (m, 8H), 2.05–2.25 (m, 4H), 2.61–2.68 (m, 2H),
3.74 (s, 2H), 4.90–5.06 (m, 4H), 5.76–5.89 (m, 2H), 7.17–7.44 ppm (m,
5H); 13C NMR (100 MHz, CDCl3): d=23.1, 29.2, 30.0, 31.4, 37.2, 37.5,
48.2, 54.2, 60.1, 113.9 (2C), 126.3, 128.0 (2C), 128.4 (2C), 139.6 (2C),
142.4 ppm; IR (film): n˜ =2928, 2852, 1493, 1451, 908, 697 cmÀ1; HRMS
(ESI): m/z calcd for C21H32N: 298.2529 [M+H]+; found: 298.2528.
2,2-Diallyl-1-benzylpyrrolidine (10d): Following the general procedure
A, addition of allylmagnesium bromide to 1-benzylpyrrolidin-2-one
(140 mg, 0.8 mmol) gave, after flash column chromatography on silica gel
(eluent: EtOAc/hexane=1:20), pyrrolidine 10d (141 mg, yield: 85%) as
a colorless oil. 1H NMR (400 MHz, CDCl3): d=1.61–1.78 (m, 4H), 2.22
(dd, J=13.9, 7.8 Hz, 2H), 2.30 (dd, J=13.9, 6.8 Hz, 2H), 2.62 (t, J=
7.0 Hz, 2H), 3.67 (s, 2H), 5.03–5.12 (m, 4H), 5.87–6.01 (m, 2H), 7.16–
7.35 ppm (m, 5H); 13C NMR (100 MHz, CDCl3): d=21.2, 32.6, 39.9 (2C),
50.8, 52.1, 64.6, 116.9 (2C), 126.5, 128.1 (2C), 128.3 (2C), 135.8 (2C),
140.9 ppm; IR (film): n˜ =3073, 2965, 2792, 1637, 1494, 1453, 1154, 1027,
N,N-Diethyl-4-isobutylhepta-1,6-dien-4-amine (13e): Following the gen-
eral procedure A, addition of allylmagnesium bromide to N,N-diethyl-3-
methylbutanamide (116 mg, 0.74 mmol) gave, after flash column chroma-
tography on silica gel (eluent: EtOAc/hexane=1:10), diene 13e (125 mg,
yield: 76%) as a colorless oil. 1H NMR (400 MHz, CDCl3): d=0.94 (d,
J=6.7 Hz, 6H), 1.01 (t, J=7.1 Hz, 6H), 1.33 (d, J=5.3 Hz, 2H), 1.75–
1.88 (m, 1H), 2.22 (dd, J=14.4, 7.2 Hz, 2H), 2.32 (dd, J=14.4, 7.2 Hz,
&
8
&
www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Reductive gem-Bis-Alkylation of Tertiary Lactams/Amides
FULL PAPER
2H), 2.67 (q, J=7.1 Hz, 4H), 4.98–5.07 (m, 4H), 5.82–5.94 ppm (m, 2H);
13C NMR (100 MHz, CDCl3): d=17.9 (2C), 23.7, 25.1 (2C), 40.5 (2C),
43.7 (2C), 44.4, 62.4, 116.5 (2C), 136.3 ppm (2C); IR (film): n˜ =2959,
1-Benzyl-1-azaspiroACTHNGUTERN[UNG 4.6]undec-8-ene (28b): Following the general proce-
dure D, the Grubbs generation II (17 mg, 0.02 mmol) -catalyzed RCM of
azepine hydrochloride salt 10i (122 mg, 0.4 mmol) gave, after flash
column chromatography on silica gel (eluent: EtOAc/ hexane=1:5),
spiro-pyrrolidine 28b (82 mg, yield: 85%) as a pale-yellow oil. 1H NMR
(400 MHz, CDCl3): d=1.56–1.84 (m, 8H), 2.01–2.13 (m, 2H), 2.14–2.28
(m, 2H), 2.62 (t, J=6.8 Hz, 2H), 3.60 (s, 2H), 5.79 (s, 2H), 7.15–
7.36 ppm (m, 5H); 13C NMR (100 MHz, CDCl3): d=20.7, 24.6, 29.7, 34.0,
34.5, 50.6, 52.7, 66.3, 126.4, 128.1 (2C), 128.4 (2C), 131.9 (2C), 141.3 ppm;
IR (film): n˜ =3021, 2923, 2848, 2789, 1598, 1493, 1452, 1363, 1113, 737,
2925, 1611, 1258, 910 cmÀ1
; HRMS (ESI): m/z calcd for C15H30N:
224.2373 [M+H]+; found: 224.2374.
N,N-Diethyl-4-phenylhepta-1,6-dien-4-amine (13 f): Following the general
procedure A, addition of allylmagnesium bromide to N,N-diethylbenza-
mide (110 mg, 0.62 mmol) gave, after flash chromatography on silica gel
(eluent: EtOAc/ hexane=1:30), diene 13 f (98 mg, yield: 65%) as a col-
orless oil. 1H NMR (400 MHz, CDCl3): d=1.01 (t, J=7.1 Hz, 6H), 2.60
(dd, J=13.6, 6.9 Hz, 2H), 2.65 (q, J=7.1 Hz, 4H), 2.71 (dd, J=13.6,
7.4 Hz, 2H), 4.94–5.05 (m, 4H), 5.56–5.66 (m, 2H), 7.14–7.50 ppm (m,
5H); 13C NMR (100 MHz, CDCl3): d=18.1 (2C), 40.9 (2C), 45.3 (2C),
65.8, 117.1 (2C), 125.9, 127.4 (2C), 127.5 (2C), 135.7 (2C), 147.3 ppm; IR
(film): n˜ =3074, 2966, 2924, 1637, 1470, 1444, 911, 699 cmÀ1; HRMS
(ESI): m/z calcd for C17H26N: 244.2060 [M+H]+; found: 244.2057.
698 cmÀ1 HRMS (ESI): m/z calcd for C17H24N: 242.1903 [M+H]+;
;
found: 242.1909.
6-Benzyl-6-azaspiroACTHNUTRGNEU[GN 4.5]dec-2-ene (28c): Following the general procedure
D, the Grubbs generation II (21 mg, 0.025 mmol) -catalyzed RCM of aze-
pine hydrochloride salt 11d (146 mg, 0.5 mmol) gave, after flash column
chromatography on silica gel (eluent: EtOAc/hexane=1:5), spiro-piperi-
dine 28c (103 mg, yield: 91%) as a pale-yellow oil. 1H NMR (400 MHz,
CDCl3): d=1.43–1.54 (m, 4H), 1.67–1.73 (m, 2H), 2.15–2.24 (m, 2H),
2.32–2.40 (m, 2H), 2.56–2.65 (m, 2H), 3.31 (s, 2H), 5.67 (s, 2H), 7.15–
7.38 ppm (m, 5H); 13C NMR (100 MHz, CDCl3): d=22.0, 26.3, 40.5, 48.2,
54.5, 65.1, 126.3, 128.0 (2C), 128.3 (2C), 129.3 (2C), 141.2 ppm; IR (film):
n˜ =3041, 2925, 2848, 1451, 730, 696 cmÀ1; HRMS (ESI) m/z calcd for
C16H22N: 228.1747 [M+H]+; found: 228.1751.
1-Benzyl-2-(but-3-en-1-yl)-2-vinylpyrrolidine (16h): Following the general
procedure B, sequential addition of 3-butenylmagnesium bromide and vi-
nylmagnesium bromide to 1-benzylpyrrolidin-2-one (123 mg, 0.7 mmol)
gave, after flash column chromatography on silica gel (eluent: EtOAc/
hexane=1:20), pyrrolidine 16h (127 mg, yield: 75%) as a colorless oil.
1H NMR (400 MHz, CDCl3): d=1.61–1.90 (m, 6H), 2.06–2.25 (m, 2H),
2.39–2.48 (m, 1H), 2.79–2.87 (m, 1H), 3.31 (d, J=13.3 Hz, 1H), 3.82 (d,
J=13.3 Hz, 1H), 4.95–5.01 (m, 1H), 5.03–5.15 (m, 2H), 5.23 (dd, J=10.9,
1.2 Hz, 1H), 5.80–5.97 (m, 2H), 7.20–7.38 ppm (m, 5H); 13C NMR
(100 MHz, CDCl3): d=21.1, 29.1, 33.9, 35.0, 50.7, 52.8, 66.3, 113.9 (2C),
126.5, 128.1 (2C), 128.4 (2C), 139.4, 140.2, 140.9 ppm; IR (film): n˜ =3077,
3026, 2961, 2922, 2797, 1640, 1602, 1450, 912, 697 cmÀ1; HRMS (ESI):
m/z calcd for C17H24N: 242.1903 [M+H]+; found: 242.1909.
1-Benzyl-1-azaspiroACTHNUTRGNEU[GN 5.6]dodec-9-ene (28d): Following the general proce-
dure D, the Grubbs generation II (17 mg, 0.02 mmol) -catalyzed RCM of
azepine hydrochloride salt 11g (128 mg, 0.4 mmol) gave, after flash
column chromatography on silica gel (eluent: EtOAc/hexane=1:5),
spiro-piperidine 28d (90 mg, yield: 88%) as a pale-yellow oil. 1H NMR
(400 MHz, CDCl3): d=1.41–1.52 (m, 4H), 1.58–1.64 (m, 2H), 1.76–1.93
(m, 4H), 2.05–2.16 (m, 2H), 2.17–2.29 (m, 2H), 2.44 (t, J=5.4 Hz, 2H),
3.63 (s, 2H), 5.62–5.71 (m, 2H), 7.15–7.40 ppm (m, 5H); 13C NMR
(100 MHz, CDCl3): d=20.3, 24.4 (2C), 25.5, 33.4, 46.5, 52.7, 57.7, 126.3,
128.0 (2C), 128.2 (2C), 130.8 (2C), 142.1 ppm; IR (film): n˜ =2926, 2851,
2792, 1492, 1451, 1130, 732, 697 cmÀ1; HRMS (ESI): m/z calcd for
C18H26N: 256.2060 [M+H]+; found: 256.2067.
2-Allyl-1-benzyl-2-(but-3-enyl)pyrrolidine (16i): Following the general
procedure B, sequential addition of 3-butenylmagnesium bromide and al-
lylmagnesium bromide to 1-benzylpyrrolidin-2-one (123 mg, 0.7 mmol)
gave, after flash column chromatography on silica gel (eluent: EtOAc/
hexane=1:20), pyrrolidine 16i (127 mg, yield: 71%) as a colorless oil.
1H NMR (400 MHz, CDCl3): d=1.48–1.80 (m, 6H), 2.02–2.31 (m, 4H),
2.48–2.60 (m, 1H), 2.64–2.74 (m, 1H), 3.56 (d, J=13.3 Hz, 1H), 3.71 (d,
J=13.3 Hz, 1H), 4.91–5.11 (m, 4H), 5.80–6.01 (m, 2H), 7.17–7.35 ppm
(m, 5H); 13C NMR (100 MHz, CDCl3): d=21.5, 28.7, 32.6, 34.8, 39.8,
50.7, 52.0, 64.4, 113.9, 116.9, 126.5, 128.1 (2C), 128.2 (2C), 136.0, 139.6,
6-Benzyl-6-azaspiroACTHNUTRGNEU[GN 4.6]undec-2-ene (28e): Following the general proce-
dure D, the Grubbs generation II (13 mg, 0.015 mmol) -catalyzed RCM
of azepine hydrochloride salt 12d (92 mg, 0.3 mmol) gave, after flash
column chromatography on silica gel (eluent: EtOAc/hexane=1:10),
spiro-azepane 28e (66 mg, yield: 91%) as
a
colorless oil. 1H NMR
141.0 ppm; IR (film): n˜ =3022, 2922, 1602, 1452, 1362, 1028, 696 cmÀ1
;
(400 MHz, CDCl3): d=1.37–1.45 (m, 2H), 1.48–1.55 (m, 2H), 1.66–1.74
(m, 2H), 1.76–1.82 (m, 2H), 2.16–2.29 (m, 2H), 2.47–2.64 (m, 4H), 3.49
(s, 2H), 5.65 (s, 2H), 7.15–7.44 ppm (m, 5H); 13C NMR (100 MHz,
CDCl3): d=22.9, 29.7, 31.2, 43.8, 44.0, 48.3, 55.4, 68.2, 126.3, 127.9 (2C),
128.4 (2C), 129.4 (2C), 142.1 ppm; IR (film): n˜ =3048, 2926, 1451, 1261,
HRMS (ESI) m/z calcd for C18H26N:256.2060 [M+H]+; found: 256.2068.
1-Benzyl-2-(pent-4-en-1-yl)-2-vinylpyrrolidine (16j): Following the gener-
al procedure B, sequential addition of pent-4-en-1-ylmagnesium bromide
and vinylmagnesium bromide to 1-benzylpyrrolidin-2-one (436 mg,
2.49 mmol) gave, after flash column chromatography on silica gel
(eluent: EtOAc/hexane=1:100), pyrrolidine 16j (475 mg, yield: 75%) as
a pale yellow oil.; 1H NMR (400 MHz, CDCl3): d=1.36–1.56 (m, 3H),
1.65–1.89 (m, 5H), 2.08 (dd, J=14.0, 7.2 Hz, 2H), 2.34–2.44 (m, 1H),
2.74–2.82 (m, 1H), 3.26 (d, J=13.2 Hz, 1H), 3.78 (d, J=13.2 Hz, 1H),
4.93–5.22 (m, 4H), 5.74–5.88 (m, 2H), 7.17–7.33 ppm (m, 5H); 13C NMR
(100 MHz, CDCl3): d=21.0, 24.1, 33.9, 34.5, 35.3, 50.7, 52.9, 66.4, 113.8,
114.5, 126.5, 128.1 (2C), 128.4 (2C), 139.0, 140.3, 141.0 ppm; IR (film):
n˜ =3066, 3023, 2971, 2902, 2794, 1637, 1493, 1451, 1126, 910, 725,
697 cmÀ1 HRMS (ESI): m/z calcd for C17H24N: 242.1903 [M+H]+;
;
found: 242.1903.
1-Benzyl-1-azaspiroACTHNUTRGNEU[GN 6.6]tridec-10-ene (28 f): Following the general proce-
dure D, the Grubbs generation II (6 mg, 0.0075 mmol) -catalyzed RCM
of azepine hydrochloride salt 12e (50 mg, 0.15 mmol) gave, after flash
column chromatography on silica gel (eluent: EtOAc/hexane=1:10),
spiro-azepane 28 f (35 mg, yield: 87%) as
a
colorless oil. 1H NMR
(400 MHz, CDCl3): d=1.29–1.35 (m, 2H), 1.43–1.50 (m, 2H), 1.60–1.72
(m, 6H), 1.86–1.94 (m, 2H), 2.04–2.24 (m, 4H), 2.58 (t, J=5.3 Hz, 2H),
3.76 (s, 2H), 5.61–5.71 (m, 2H), 7.15–7.45 ppm (m, 5H); 13C NMR
(100 MHz, CDCl3): d=21.9, 24.7, 29.6, 30.7, 35.0, 37.2, 46.8, 53.8, 60.9,
126.2, 127.9 (2C), 128.4 (2C), 130.9 (2C), 142.8 ppm; IR (film): n˜ =3017,
2925, 1450, 1260, 734, 697 cmÀ1; HRMS (ESI): m/z calcd for C19H28N:
270.2216 [M+H]+; found: 270.2218.
697 cmÀ1 HRMS (ESI): m/z calcd for C18H26N: 256.2060 [M+H]+;
;
found: 256.2060.
1-Benzyl-1-azaspiroACHTUNGTRENNUNG[4.4]non-7-ene (28a): Following the general proce-
dure D, the Grubbs generation II (21 mg, 0.025 mmol) -catalyzed RCM
of azepine hydrochloride salt 10d (139 mg, 0.5 mmol) gave, after flash
column chromatography on silica gel (eluent: EtOAc/hexane=1:5),
spiro-pyrrolidine 28a (96 mg, yield: 90%) as a pale-yellow oil.; 1H NMR
(400 MHz, CDCl3): d=1.73–1.85 (m, 2H), 1.90–1.99 (m, 2H), 2.21–2.34
(m, 2H), 2.58–2.68 (m, 4H), 3.48 (s, 2H), 5.75 (s, 2H), 7.21–7.41 ppm (m,
5H); 13C NMR (100 MHz, CDCl3): d=20.5, 39.3, 40.3, 50.4, 53.3, 70.8,
126.5, 128.1 (2C), 128.6 (2C), 129.3 (2C), 140.6 ppm; IR (film): n˜ =3052,
N,N-Diethyl-1-isobutylcyclopent-3-enamine (28g): Following the general
procedure D, the Grubbs generation II (7 mg, 0.008 mmol) -catalyzed
RCM of azepine hydrochloride salt 13e (41 mg, 0.16 mmol) gave, after
flash column chromatography on silica gel (eluent: EtOAc/hexane=1:2),
aminocyclopentene 28g (26 mg, yield: 83%) as
a pale-yellow oil.
1H NMR (400 MHz, CDCl3): d=0.91 (d, J=6.7 Hz, 6H), 1.06 (t, J=
7.2 Hz, 6H), 1.38 (d, J=5.4 Hz, 2H), 1.59–1.70 (m, 1H), 2.20–2.30 (m,
2H), 2.41–2.65 (m, 6H), 5.63 ppm (s, 2H); 13C NMR (100 MHz, CDCl3):
d=16.7, 24.4, 25.3, 43.5, 45.0, 46.6, 69.9, 129.7 ppm; IR (film): n˜ =2956,
2950, 2841, 2790, 1619, 1611, 1432, 1363, 1260, 1027, 947, 698 cmÀ1
;
HRMS (ESI): m/z calcd for C15H20N: 214.1590 [M+H]+; found:
214.1600.
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
9
&
ÞÞ
These are not the final page numbers!

P.-Q. Huang et al.
2923, 1615, 1260, 798 cmÀ1; HRMS (ESI): m/z calcd for C13H26N [M+H]+
: 196.2060; found: 196.2062.
33.6 (2C), 39.0, 48.9, 54.4, 66.6, 126.3, 128.0 (2C), 128.3 (2C), 141.5 ppm;
IR (film): n˜ =3062, 3025, 2936, 2877, 2794, 1493, 1451, 1127, 1067 cmÀ1
;
HRMS (ESI): m/z calcd for C16H24N: 230.1903 [M+H]+; found:
230.1906.
N,N-Diethyl-1-phenylcyclopent-3-enamine (28h): Following the general
procedure D, the Grubbs generation II (11 mg, 0.0135 mmol) -catalyzed
RCM of azepine hydrochloride salt 13 f (75 mg, 0.27 mmol) gave, after
flash column chromatography on silica gel (eluent: EtOAc/hexane=
1:10), aminocyclopentene 28h (50 mg, yield: 87%) as a pale-yellow oil.
1H NMR (400 MHz, CDCl3): d=1.02 (t, J=7.1 Hz, 6H), 2.46 (q, J=
7.1 Hz, 4H), 2.59 (d, J=15.6 Hz, 2H), 2.80 (d, J=15.6 Hz, 2H), 5.69 (s,
2H), 7.15–7.51 ppm (m, 5H); 13C NMR (100 MHz, CDCl3): d=16.9 (2C),
42.8 (2C), 45.6 (2C), 73.5, 125.8, 126.4 (2C), 127.8 (2C), 129.2 (2C),
1-Benzyl-1-azaspiroACTHNUTRGNE[NUG 4.5]decane (33a): Following the general procedure
C, addition of Grignard reagent 32 to 1-benzylpyrrolidin-2-one (218 mg,
1.24 mmol) gave, after flash column chromatography on silica gel
(eluent: EtOAc/hexane=1:30), spiro-pyrrolidine 33a (185 mg, yield:
65%) as a colorless oil. 1H NMR (400 MHz, CDCl3): d=1.28–1.50 (m,
7H), 1.61–1.78 (m, 7H), 2.64 (t, J=6.8 Hz, 2H), 3.59 (s, 2H), 7.17–
7.36 ppm (m, 5H); 13C NMR (100 MHz, CDCl3) d=21.0, 24.4 (2C), 26.4,
32.6 (2C), 34.3, 50.6, 52.5, 63.1, 126.4, 128.1 (2C), 128.5 (2C), 141.4 ppm;
IR (film): n˜ =3063, 3026, 2964, 2933, 2861, 2791, 1494, 1454, 1165,
1067 cmÀ1; HRMS (ESI): m/z calcd for C16H24N: 230.1903 [M+H]+;
found: 230.1905.
150.1 ppm; IR (film): n˜ =2965, 2925, 2856, 1467, 1295, 700, 671 cmÀ1
HRMS (ESI): m/z calcd for C15H22N [M+H]+: 216.1747; found: 216.1750.
1-Benzyl-1-azaspiro[4.4]non-6-ene (29a): Following the general proce-
;
ACHTUNGTRENNUNG
dure D, the Grubbs generation II catalyst (14 mg, 0.0165 mmol) -cata-
lyzed RCM of azepine hydrochloride salt 16h (91 mg, 0.33 mmol) gave,
after flash column chromatography on silica gel (eluent: EtOAc/
hexane=1:5), spiro-pyrrolidine 29a (60 mg, yield: 85%) as a pale-yellow
oil. 1H NMR (400 MHz, CDCl3): d=1.64–1.72 (m, 1H), 1.74–1.84 (m,
3H), 1.85–1.94 (m, 1H), 1.99–2.08 (m, 1H), 2.30–2.42 (m, 2H), 2.50–2.58
(m, 1H), 2.64–2.73 (m, 1H), 3.36 (d, J=13.1 Hz, 1H), 3.51 (d, J=
13.1 Hz, 1H), 5.63–5.68 (m, 1H), 5.85–5.90 (m, 1H), 7.16–7.36 ppm (m,
5H); 13C NMR (100 MHz, CDCl3): d=21.4, 29.8, 31.6, 38.3, 51.1, 53.5,
77.5, 126.4, 128.1 (2C), 128.5 (2C), 132.1, 135.3, 140.9 ppm; IR (film): n˜ =
3047.8, 2849, 2790, 1611, 1493, 1452, 732, 697 cmÀ1; HRMS (ESI): m/z
calcd for C15H20N: 214.1590 [M+H]+; found: 214.1595.
1-Benzyl-1-azaspiroACTHNUTRGNE[NUG 5.5]undecane (33b): Following the general proce-
dure C, addition of Grignard reagent 32 to 1-benzylpiperidin-2-one
(200 mg, 1.06 mmol) gave, after flash column chromatography on silica
gel (eluent: EtOAc/hexane=1:30), spiro-piperidine 33b (154 mg, yield:
60%) as a colorless oil. 1H NMR (400 MHz, CDCl3): d=1.30–1.68 (m,
16H), 2.50 (t, J=5.4 Hz, 2H), 3.63 (s, 2H), 7.16–7.38 ppm (m, 5H);
13C NMR (100 MHz, CDCl3): d=20.3, 22.3 (2C), 24.9, 26.6, 31.4 (2C),
32.1, 46.1, 52.0, 55.2, 126.2, 128.0 (2C), 128.2 (2C), 142.3 ppm; IR (film):
n˜ =3063, 3025, 2930, 2876, 2862, 2792, 1494, 1454, 1126, 1067 cmÀ1
;
HRMS (ESI): m/z calcd for C17H26N: 244.2060 [M+H]+; found:
224.2066.
1-Benzyl-1-azaspiroACHTUNGTRENNUNG[4.5]dec-7-ene (29b): Following the general proce-
1-(2-(6-Iodobenzo[d]
G
(35):
dure D, the Grubbs generation II (15 mg, 0.018 mmol) -catalyzed RCM
of azepine hydrochloride salt 16i (105 mg, 0.36 mmol) gave, after flash
column chromatography on silica gel (eluent: EtOAc/hexane=1:5),
spiro-pyrrolidine 29b (73 mg, yield: 89%) as a pale-yellow oil. 1H NMR
(400 MHz, CDCl3): d=1.45–1.55 (m, 1H), 1.66–1.77 (m, 5H), 1.80–1.88
(m, 1H), 2.10–2.30 (m, 3H), 2.57–2.67 (m, 1H), 2.68–2.79 (m, 1H), 3.54
(d, J=13.1 Hz, 1H), 3.66 (d, J=13.1 Hz, 1H), 5.55–5.75 (m, 2H), 7.18–
7.35 ppm (m, 5H); 13C NMR (100 MHz, CDCl3): d=20.8, 24.9, 29.6, 31.5,
35.1, 50.9, 52.8, 61.4, 126.3, 126.5, 126.6, 128.1 (2C), 128.5 (2C),
DIAD (0.34 mL, 1.69 mmol) was added to a solution of alcohol 34
(446 mg, 1.53 mmol), PPh3 (442 mg, 1.69 mmol), and succinimide (152,
1.53 mmol) in THF (6.0 mL) under N2 at RT. After being stirred at RT
for 4 h, the solid was filtered off and washed with Et2O to give compound
35 (526 mg, yield: 92%) as a white solid without further purification.
M.p. 212–2148C (Et2O); 1H NMR (400 MHz, CDCl3): d=2.67 (s, 4H),
2.94 (t, J=7.30 Hz, 2H), 3.72 (t, J=7.30 Hz, 2H), 5.94 (s, 2H), 6.74 (s,
1H), 7.20 ppm (s, 1H); 13C NMR (100 MHz, CDCl3): d=28.1 (2C), 38.1,
38.8, 87.7, 101.6, 109.6, 118.7, 134.3, 147.4, 148.7, 176.8 ppm (2C); IR
(film): n˜ =2978, 2917, 1698, 1499, 1142, 919, 757, 663 cmÀ1 HRMS (ESI):
m/z calcd for C13H12INO4Na: 395.9703 [M+Na]+; found: 395.9708.
141.1 ppm; IR (film): n˜ =3022, 2922, 2790, 1602, 1452, 1260, 696 cmÀ1
;
HRMS (ESI): m/z calcd for C16H22N: 228.1747 [M+H]+; found:
228.1750.
1-(2-(6-Iodobenzo[d]ACTHNUTRGENUGN[1,3]dioxol-5-yl)ethyl)pyrrolidin-2-one (36): NaBH4
1-Benzyl-1-azaspiroACHTUNGTRENNUNG[4.5]dec-6-ene (29c): Following the general procedure
(291 mg, 7.67 mmol) was added portion-wise to a solution of cyclic imide
35 (286 mg, 0.767 mmol) in CHCl3 and MeOH (40 mL) at 08C. The re-
sulting suspension was stirred at 08C for 2 h before quenching with a sa-
turated aqueous solution of NaHCO3. After completion of the addition,
the mixture was stirred for 30 min and then filtered through Celite. The
filter was concentrated under reduced pressure. The residue was extract-
ed with CHCl3 (3ꢃ10 mL). The combined organic layers were washed
with brine, dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure. The residue was dissolved in anhydrous CH2Cl2
(80 mL) under nitrogen. Triethylsilane (1.21 mL, 7.67 mmol) and boron
trifluoride etherate (0.28 mL, 2.30 mmol) were added dropwise at À788C
to the resulting solution. After being stirred at À788C for 2 h, the reac-
tion mixture was allowed to warm to RT and stirred overnight. The reac-
tion was quenched with a saturated aqueous solution of NaHCO3 and ex-
tracted with CH2Cl2 (4ꢃ10 mL). The combined organic layers were dried
over anhydrous Na2SO4, filtered, and concentrated under reduced pres-
sure. The residue was purified by flash chromatography on silica gel
(eluent: EtOAc/hexane=2:1) to give compound 36 (195 mg, yield: 71%)
as a white solid. M.p. 136–1388C (EtOAc/hexane). 1H NMR (400 MHz,
CDCl3): d=1.92–2.04 (m, 2H), 2.36 (t, J=8.0 Hz, 2H), 2.84–2.91 (m,
2H), 3.33 (t, J=7.0 Hz, 2H), 3.40–3.46 (m, 2H), 5.94 (s, 2H), 6.78 (s,
1H), 7.21 ppm (s, 1H); 13C NMR (100 MHz, CDCl3): d=18.0, 31.0, 38.3,
42.9, 47.8, 87.6, 101.6, 109.7, 118.6, 134.7, 147.2, 148.6, 174.9 ppm; IR
(film): n˜ =2917, 1679, 1501, 1475, 1260, 1227, 1035, 928 cmÀ1; HRMS
(ESI): m/z calcd for C13H14INO3Na: 381.9911 [M+Na]+; found: 381.9917.
D, the Grubbs generation II (9 mg, 0.0105 mmol) -catalyzed RCM of aze-
pine hydrochloride salt 16j (61 mg, 0.21 mmol) gave, after flash column
chromatography on silica gel (eluent: EtOAc/hexane=1:5), spiro-pyrroli-
dine 29c (43 mg, yield: 90%) as a pale-yellow oil. 1H NMR (400 MHz,
CDCl3): d=1.57–1.81 (m, 8H), 1.94–2.03 (m, 2H), 2.55–2.66 (m, 1H),
2.69–2.78 (m, 1H), 3.49 (d, J=13.3 Hz, 1H), 3.63 (d, J=13.3 Hz, 1H),
5.54–5.62 (m, 1H), 5.75–5.85 (m, 1H), 7.16–7.35 ppm (m, 5H); 13C NMR
(100 MHz, CDCl3): d=21.2, 21.4, 25.3, 28.9, 38.4, 50.3, 53.5, 63.4, 126.4,
128.1 (2C), 128.4 (2C), 128.9, 133.9, 141.2 ppm; IR (film): n˜ =2917, 2848,
2792, 1578, 1493, 1124, 734, 697 cmÀ1; HRMS (ESI): m/z calcd for
C16H22N: 228.1747 [M+H]+; found: 228.1752.
1-Benzyl-1-azaspiroACHTUNGTRENNUNG[4.4]nonane (31a): Following the general procedure
C, addition of Grignard reagent 30 to 1-benzylpyrrolidin-2-one (174 mg,
1.0 mmol) gave, after flash column chromatography on silica gel (eluent:
EtOAc/hexane=1:50), spiro-pyrrolidine 31a (133 mg, yield: 62%) as a
colorless oil. 1H NMR (400 MHz, CDCl3): d=1.40–1.46 (m, 2H), 1.57–
1.79 (m, 10H), 2.57 (t, J=6.8 Hz, 2H), 3.54 (s, 2H), 7.18–7.34 ppm (m,
5H); 13C NMR (100 MHz, CDCl3): d=20.8, 24.3 (2C), 32.0 (2C), 39.7,
51.7, 53.3, 72.2, 126.5, 128.1 (2C), 128.6 (2C), 140.8 ppm; IR (film): n˜ =
3062, 3026, 2956, 2930, 2791, 1493, 1454, 1162, 1067 cmÀ1; HRMS (ESI):
m/z calcd for C15H22N: 216.1747 [M+H]+; found: 216.1747.
6-Benzyl-6-azaspiroACHTUNGTRENNUNG[4.5]decane (31b): Following the general procedure
C, addition of Grignard reagent 30 to 1-benzylpiperidin-2-one (214 mg,
1.13 mmol) gave, after flash column chromatography on silica gel
(eluent: EtOAc/hexane=1:40), spiro-piperidine 31b (162 mg, yield:
63%) as a colorless oil. 1H NMR (400 MHz, CDCl3): d=1.39–1.69 (m,
12H), 1.74–1.86 (m, 2H), 2.35 (t, J=6.7 Hz, 2H), 3.47 (s, 2H), 7.16–
7.38 ppm (m, 5H); 13C NMR (100 MHz, CDCl3): d=22.3, 25.5, 25.9 (2C),
2-(But-3-en-1-yl)-1-(2-(6-iodobenzo[d]ACTHNUGRTNEUNG[1,3]dioxol-5-yl)ethyl)-2-vinylpyr-
rolidine (37): Following the general procedure B, sequential addition of
3-butenylmagnesium bromide and vinylmagnesium bromide to lactam 36
(83 mg, 0.23 mmol) gave, after flash column chromatography on silica gel
&
10
&
www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Reductive gem-Bis-Alkylation of Tertiary Lactams/Amides
FULL PAPER
(eluent: EtOAc/hexane=1:5), pyrrolidine 37 (63 mg, yield: 65%) as a
colorless oil. 1H NMR (400 MHz, CDCl3): d=1.42–1.52 (m, 1H), 1.65–
1.84 (m, 5H), 1.91–2.06 (m, 2H), 2.29–2.39 (m, 1H), 2.54–2.64 (m, 1H),
2.65–2.86 (m, 3H), 3.14–3.22 (m, 1H), 4.85–5.05 (m, 3H), 5.12 (dd, J=
11.0, 1.4 Hz, 1H), 5.69 (dd, J=17.6, 11.0 Hz, 1H), 5.75–5.88 (m, 1H),
5.93 (s, 2H), 6.74 (s, 1H), 7.21 ppm (s, 1H); 13C NMR (100 MHz, CDCl3):
d=21.1, 29.0, 33.7, 34.7, 40.9, 49.4, 50.9, 66.6, 87.8, 101.4, 109.7, 113.8,
113.9, 118.5, 136.8, 139.4, 139.8, 146.7, 148.3 ppm; IR (film): n˜ =2920,
1501, 1474, 1245, 1040, 935, 912 cmÀ1; HRMS (ESI): m/z calcd for
C19H25INO2: 426.0924 [M+H]+; found: 426.0924.
Stockman, P. L. Fuchs, J. Am. Chem. Soc. 2006, 128, 12656–12657;
f) S. Suga, M. Watanabe, J. Yoshida, J. Am. Chem. Soc. 2002, 124,
14824–14825; g) H. Abe, S. Aoyagi, C. Kibayashi, J. Am. Chem.
Soc. 2000, 122, 4583–4592; h) K. M. Werner, J. M. de Los Santos,
S. M. Weinreb, M. Shang, J. Org. Chem. 1999, 64, 4865–4873; i) A.
Luzzio, R. W. Fitch, J. Org. Chem. 1999, 64, 5485–5493; j) N. Yama-
zaki, T. Ito, C. Kibayashi, Tetrahedron Lett. 1999, 40, 739–742.
[6] For some examples illustrating the key role and challenge of such
transformations in alkaloid syntheses, see: a) S. T. M. Simila, S. F.
Martin, J. Org. Chem. 2007, 72, 5342–5349; b) H. Abe, S. Aoyagi, C.
Kibayashi, J. Am. Chem. Soc. 2005, 127, 1473–1480; c) T. Arai, H.
Abe, S. Aoyagi, C. Kibayashi, Tetrahedron Lett. 2004, 45, 5921–
5924; d) J. Liu, R. P. Hsung, S. D. Peters, Org. Lett. 2004, 6, 3989–
3992; e) M. D. B. Fenster, G. R. Dake, Org. Lett. 2003, 5, 4313–
4316; f) P. Sun, C. Sun, S. M. Weinreb, J. Org. Chem. 2002, 67, 4337–
4345.
[7] For a review on the directed ortho-metalation of tertiary amide, see:
a) V. Snieckus, Chem. Rev. 1990, 90, 879–933; for selected examples,
see: b) P. Beak, R. A. Brown, J. Org. Chem. 1982, 47, 34–46; c) R.
Casas, C. Cavꢄ, J. d’Angelo, Tetrahedron Lett. 1995, 36, 1039–1042.
For directed lithiation in non-aromatic systems, see: d) P. Beak, D. J.
Kempf, K. D. Wilson, J. Am. Chem. Soc. 1985, 107, 4745–4756; f) P.
Beak, J. E. Hunter, Y. M. Jun, A. P. Wallin, J. Am. Chem. Soc. 1987,
109, 5403–5412.
1-(2-(6-Iodobenzo[d]ACHTUNGTRENNUNG[1,3]dioxol-5-yl)ethyl)-1-azaspiroACHUTNGTREN[NUNG 4.4]non-6-ene
(38): Following the general procedure D, the Grubbs generation II (2 mg,
0.0025 mmol) -catalyzed RCM of azepine hydrochloride salt 37 (23 mg,
0.05 mmol) gave, after flash column chromatography on silica gel
(eluent: EtOAc/ hexane=1:2), spiro-pyrrolidine 38 (17.5 mg, yield: 94%)
as a pale-yellow oil. 1H NMR (400 MHz, CDCl3): d=1.58–1.67 (m, 1H),
1.75–1.98 (m, 5H), 2.30 (tt, J=7.0, 2.2 Hz, 2H), 2.38–2.50 (m, 2H), 2.73–
2.89 (m, 3H), 2.92–3.02 (m, 1H), 5.56 (dt, J=5.6, 2.2 Hz, 1H), 5.80 (dt,
J=5.6, 2.3 Hz, 1H), 5.92 (s, 2H), 6.74 (s, 1H), 7.20 ppm (s, 1H);
13C NMR (100 MHz, CDCl3): d=21.4, 29.7, 31.5, 38.2, 40.8, 50.0, 51.3,
77.7, 87.8, 101.4, 109.6, 118.5, 132.2, 134.7, 136.8, 146.7, 148.4 ppm; IR
(film): n˜ =2921, 2850, 1501, 1402, 1225, 1041, 935 cmÀ1; HRMS (ESI):
m/z calcd for C17H21INO2: 398.0611 [M+H]+; found: 398.0606.
[8] For selected examples, see: a) J. Wencel-Delord, C. Nimphius, F. W.
Patureau, F. Glorius, Angew. Chem. 2012, 124, 2290–2294; Angew.
Chem. Int. Ed. 2012, 51, 2247–2251; b) J. Wencel-Delord, C. Nim-
phius, F. W. Patureau, F. Glorius, Chem. Asian J. 2012, 7, 1208–
1212; for a related review, see: c) N. Kuhl, M. N. Hopkinson, J.
Wencel-Delord, F. Glorius, Angew. Chem. 2012, 124, 10382–10401;
Angew. Chem. Int. Ed. 2012, 51, 10236–10254.
[9] For recent reviews on amide bond formation, see: a) S.-Y. Han, Y.-
A. Kim, Tetrahedron 2004, 60, 2447–2467; b) C. A. G. N. Montalbet-
ti, V. Falque, Tetrahedron 2005, 61, 10827–10852; c) E. Valeur, M.
Bradley, Chem. Soc. Rev. 2009, 38, 606–631. For selected recent
methods, see: d) S. C. Ghosh, J. S. Y. Ngiam, A. M. Seayad, D. T.
Tuan, C. L. L. Chai, A. Chen, J. Org. Chem. 2012, 77, 8007–8015.
[10] For selected reviews, see: a) B. J. Wakefield, Organomagnesium:
Methods in Organic Synthesis, Academic Press, San Diego, CA,
1995; b) Grignard Reagents: New Development (Ed.: H. G. Richey);
Wiley, Chichester, UK, 2000; c) Handbook of Grignard Reagents
(Eds.: P. E. Silverman, G. S. Rakita), Marcel Dekker, New York,
1996; d) J. Clayden, Organolithiums: Selectivity for Synthesis, Perga-
mon, Oxford, 2002; e) A. Boudier, L. O. Bromm, M. Lotz, P. Kno-
chel, Angew. Chem. 2000, 112, 4584–4606; Angew. Chem. Int. Ed.
2000, 39, 4414–4435; f) R. Chinchilla, C. Nꢅjera, M. Yus, Tetrahe-
dron 2005, 61, 3139–3176.
Acknowledgements
The authors are grateful for financial support from the National Basic
Research Program (973 Program) of China (Grant No. 2010CB833200),
the NSF of China (21072160; 20832005), and the Program for Changjiang
Scholars and Innovative Research Team in University (PCSIRT) of Min-
istry of Education, China.
[1] For a related review involving the concept of step-economy, see:
P. A. Wender, V. A. Verma, T. J. Paxton, T. H. Pillow, Acc. Chem.
Res. 2008, 41, 40–49.
[2] For selected reviews, see: a) J.-Q. Yu, R. Giri, X. Chen, Org.
Biomol. Chem. 2006, 4, 4041–4047; b) C.-J. Li, Acc. Chem. Res.
2009, 42, 335–344. For selected examples, see: c) Z.-P. Li, C.-J. Li, J.
Am. Chem. Soc. 2004, 126, 11810–11811; d) B.-G. Zhao, H.-F. Du,
Y. Shi, J. Am. Chem. Soc. 2008, 130, 7220–7221; e) M. Wasa, J.-Q.
Yu, J. Am. Chem. Soc. 2008, 130, 14058–14059.
[3] For selected reviews, see: a) Multicomponent Reactions (Eds.: J.-P.
Zhu, H. Bienaymꢄ), Wiley-VCH, Weinheim, 2005; b) H. Bienaymꢄ,
C. Hulme, G. Oddon, P. Schmitt, Chem. Eur. J. 2000, 6, 3321–3329;
c) C. Wei, Z. Li, C.-J. Li, Synlett 2004, 1472–1483; d) K. C. Nicolaou,
D. J. Edmonds, P. G. Bulger, Angew. Chem. 2006, 118, 7292–7344;
Angew. Chem. Int. Ed. 2006, 45, 7134–7186; e) A. Dçmling, Chem.
Rev. 2006, 106, 17–89; f) B. Ganem, Acc. Chem. Res. 2009, 42, 463–
472.
[4] For reviews on synthetic studies towards bioactive alkaloids contain-
ing 1-azaspirocycles, see: a) S. M. Weinreb, Acc. Chem. Res. 2003,
36, 59–65; b) D. L. J. Clive, M. Yu, J. Wang, V. S. C. Yeh, S. Kang,
Chem. Rev. 2005, 105, 4483–4514; c) C. Kibayashi, Chem. Pharm.
Bull. 2005, 53, 1375–1386; d) G. Dake, Tetrahedron 2006, 62, 3467–
3492; e) S. M. Weinreb, Chem. Rev. 2006, 106, 2531–2549; f) M. A.
Ciufolini, N. A. Braun, S. Canesi, M. Ousmer, J. Chang, D. Chai,
Synthesis 2007, 3759–3772.
[11] S. M. Denton, A. Wood, Synlett 1999, 55–56.
[12] For reductive bis-allylation of secondary lactams, see: a) Y. N.
Bubnov, F. V. Pastukhov, I. V. Yampolsky, A. V. Ignatenko, Eur. J.
Org. Chem. 2000, 1503–1505; b) Z. F. Li, Y. M. Zhang, Tetrahedron
2002, 58, 5301–5306; c) P. Nieczypor, J. C. Mol, N. B. Bespalova,
Y. N. Bubnov, Eur. J. Org. Chem. 2004, 812–819; d) N. Y. Kuznetsov,
G. D. Kolomnikova, V. N. Khrustalev, D. G. Golovanov, Y. N.
Bubnov, Eur. J. Org. Chem. 2008, 5647–5655.
[13] For reviews on Kulinkovich-type reactions, see: a) O. G. Kulinko-
vich, A. de Meijere, Chem. Rev. 2000, 100, 2789–2834; b) A. de
Meijere, S. I. Kozhushkov, A. I. Savchenko, in Titanium and Zirconi-
um in Organic Synthesis (Ed.: I. Marek), Wiley-VCH, Weinheim,
2002, pp. 390–434; c) A. Wolan, Y. Six, Tetrahedron 2010, 66, 15–
61. For selected examples, see: d) V. Chaplinski, A. de Meijere,
Angew. Chem. 1996, 108, 491–492; Angew. Chem. Int. Ed. Engl.
1996, 35, 413–414; e) V. Chaplinski, H. Winsel, M. Kordes, A. de
Meijere, Synlett 1997, 111–114; f) A. de Meijere, C. M. Williams, A.
Kourdioukov, S. V. Sviridov, V. Chaplinski, M. Kordes, A. I. Savtch-
enko, C. Stratmann, M. Noltemeyer, Chem. Eur. J. 2002, 8, 3789–
3801; g) S. Wiedemann, I. Marek, A. de Meijere, Synlett 2002, 879–
882; h) A. Wolan, M. Soueidan, A. Chiaroni, P. Retailleau, S. Py, Y.
Six, Tetrahedron Lett. 2011, 52, 2501–2504.
[5] For a recent feature article, see: a) J. Clayden, M. Donnard, J. Le-
franc, D. J. Tetlow, Chem. Commun. 2011, 47, 4624–4639; for select-
ed recent methods, see: b) M. G. Kamau, L. S. Harikrishnan, H. J.
Finlay, J. X. Qiao, J. Jiang, M. A. Poss, M. E. Salvati, R. R. Wexler,
R. M. Lawrence, Tetrahedron 2012, 68, 2696–2703; c) J. Han, B. Xu,
G. B. Hammond, J. Am. Chem. Soc. 2010, 132, 916–917; d) L. Zhou,
Q. Shuai, H.-f. Jiang, C.-J. Li, Chem. Eur. J. 2009, 15, 11668–11674;
e) M. S. Karatholuvhu, A. Sinclair, A. F. Newton, M. Alcaraz, R. A.
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
11
&
ÞÞ
These are not the final page numbers!

P.-Q. Huang et al.
[14] a) O. Cervinka, Collect. Czech. Chem. Commun. 1959, 24, 1146–
1150; b) R. Lukes, M. Cerny, Collect. Czech. Chem. Commun. 1961,
26, 2886–2890; c) M. F. Semmelhack, B. P. Chong, R. D. Stauffer,
T. D. Rogerson, A. Chong, L. D. Jones, J. Am. Chem. Soc. 1975, 97,
2507–2516; d) C. A. Zena, M. B. Smith, B. A. Ross, A. Archin,
P. L. E. Cronin, J. Org. Chem. 1984, 49, 4397–4399.
[15] For a review, see: a) T. Murai, Y. Mutoh, Chem. Lett. 2012, 41, 2–8.
For bis-alkylation of thioamides, see: b) T. Murai, Y. Mutoh, Y.
Ohta, M. Murakami, J. Am. Chem. Soc. 2004, 126, 5968–5969; c) T.
Murai, R. Toshio, Y. Mutoh, Tetrahedron 2006, 62, 6312–6320; thio-
formamides: d) T. Murai, F. Asai, J. Am. Chem. Soc. 2007, 129, 780–
781; e) T. Murai, F. Asai, J. Org. Chem. 2008, 73, 9518–9521; f) T.
Murai, K. Ui, Narengerile, J. Org. Chem. 2009, 74, 5703–5706; sele-
noamides: g) T. Murai, S. Nogawa, Y. Mutoh, Bull. Soc. Chem. Jpn.
2007, 80, 2220–2225.
[16] A. Agosti, S. Britto, P. Renaud, Org. Lett. 2008, 10, 1417–1420.
[17] O. Tomashenko, V. Sokolov, A. Tomashevskiy, H. A. Buchholz, U.
Welz-Biermann, V. Chaplinski, A. de Meijere, Eur. J. Org. Chem.
2008, 5107–5111.
[18] S.-P. Luo, L.-D. Guo, L.-H. Gao, S. Li, P.-Q. Huang, Chem. Eur. J.
2013, 19, 87–91; b) H.-H. Huo, H.-K. Zhang, X.-E. Xia, P.-Q.
Huang, Org. Lett. 2012, 14, 4834–4837.
[19] a) C.-P. Xu, Z.-H. Xiao, B.-Q. Zhuo, Y.-H. Wang, P.-Q. Huang,
Chem. Commun. 2010, 46, 7834–7836; b) K.-J. Xiao, Y. Wang, K.-Y.
Ye, P.-Q. Huang, Chem. Eur. J. 2010, 16, 12792–12796; c) K.-J. Xiao,
A.-E. Wang, P.-Q. Huang, Angew. Chem. 2012, 124, 8439–8442;
Angew. Chem. Int. Ed. 2012, 51, 8314–8317; d) K.-J. Xiao, A.-E.
Wang, Y.-H. Huang, P.-Q. Huang, Asian J. Org. Chem. 2012, 1, 130–
132; e) K.-J. Xiao, A.-E. Wang, Y.-H. Huang, P.-Q. Huang, Acta
Chim. Sinica 2012, 70, 1917–1922.
[20] K.-J. Xiao, J.-M. Luo, K.-Y. Ye, Y. Wang, P.-Q. Huang, Angew.
Chem. 2010, 122, 3101–3104; Angew. Chem. Int. Ed. 2010, 49, 3037–
3040. After the publication of this Communication, two reviews and
several methods regarding the reductive alkylation and reductive
bis-alkylation of amides appeared, see ref. [21].
[21] Review on gem-dialkylation of carbonyl compounds: a) D. Seebach,
Angew. Chem. 2011, 123, 99–105; Angew. Chem. Int. Ed. 2011, 50,
96–101; direct reductive allylation/cynation of N-methoxyamides:
b) K. Shirokane, Y. Kurosaki, T. Sato, N. Chida, Angew. Chem. 2010,
122, 6513–6516; Angew. Chem. Int. Ed. 2010, 49, 6369–6372; direct
reductive alkylation/allylation/arylation, and direct reductive bis-al-
1998, 39, 711–714; g) G. E. Keck, M. D. McLaws, T. T. Wager, Tetra-
hedron 2000, 56, 9875–9883; h) C. E. McDonald, A. M. Galka, A. I.
Green, J. M. Keane, J. E. Kowalchick, C. M. Micklitsch, D. D. Wis-
noski, Tetrahedron Lett. 2001, 42, 163–166; i) A. B. Charette, M.
Grenon, Can. J. Chem. 2001, 79, 1694–1703; j) A. B. Charette, M.
Grenon, A. Lemire, M. Pourashraf, J. Martel, J. Am. Chem. Soc.
2001, 123, 11829–11830; k) M. Movassaghi, M. D. Hill, J. Am.
Chem. Soc. 2006, 128, 4592–4593; l) F. Lꢄvesque, G. Bꢄlanger, Org.
Lett. 2008, 10, 4939–4942; m) S.-L. Cui, J. Wang, Y.-G. Wang, J. Am.
Chem. Soc. 2008, 130, 13526–13527; n) V. Valerio, D. Petkova, C.
Madelaine, N. Maulide, Chem. Eur. J. 2013, 19, 2606–2610, and ref-
erences therein.
[23] For the use of POCl3 and other amide activators, see: a) D. C.
Smith, S. W. Lee, P. L. Fuchs, J. Org. Chem. 1994, 59, 348–354. For
the use of COCl2 as an amide activator, see: b) J. Marchand-Bry-
naert, L. Ghosez, J. Am. Chem. Soc. 1972, 94, 2869–2870.
[24] a) P. J. Stang, T. Warren, Synthesis 1980, 283–284; b) I. Harder, M.
Hanack, Chem. Ber. 1984, 117, 3004–3020.
[25] a) W. Dohle, D. M. Lindsay, P. Knochel, Org. Lett. 2001, 3, 2871–
2873; b) A. Krasovskiy, P. Knochel, Angew. Chem. 2004, 116, 3396–
3399; Angew. Chem. Int. Ed. 2004, 43, 3333–3336; c) I. Sapountzis,
H. Dube, R. Lewis, N. Gommermann, P. Knochel, J. Org. Chem.
2005, 70, 2445–2454; d) F. Kopp, G. Sklute, K. Polborn, J. Marek, P.
Knochel, Org. Lett. 2005, 7, 3789–3791; e) C.-Y. Liu, H. Ren, P.
Knochel, Org. Lett. 2006, 8, 617–619.
[26] P. Pires, K. Burger, Tetrahedron 1997, 53, 9213–9218.
[27] D. J. Oliveira, F. Coelho, Synth. Commun. 2000, 30, 2143–2159.
[28] J.-M. Luo, C.-F. Dai, S.-Y. Lin, P.-Q. Huang, Chem. Asian J. 2009, 4,
328–335.
[29] For recent reviews on olefin metathesis, see: a) I. Dragutan, V. Dra-
gutan, C. Mitan, H. C. M. Vosloo, L. Delaude, A. Demonceau, Beil-
stein J. Org. Chem. 2011, 7, 699–716; b) J. Prunet, Eur. J. Org.
Chem. 2011, 3634–3647; c) S. Kotha, M. K. Dipak, Tetrahedron
2012, 68, 397–421.
[30] G. C. Fu, S. T. Nguyen, R. H. Grubbs, J. Am. Chem. Soc. 1993, 115,
9856–9857.
[31] P. A. Wender, A. W. White, J. Am. Chem. Soc. 1988, 110, 2218–
2223.
[32] For selected synthesis of cephalotaxine, see: a) M. E. Kuehne, W. G.
Bornmann, W. H. Parsons, T. D. Spitzer, J. F. Blount, J. Zubieta, J.
Org. Chem. 1988, 53, 3439–3450; b) T. P. Burkholder, P. L. Fuchs, J.
Am. Chem. Soc. 1990, 112, 9601–9613; c) X. Lin, R. W. Kavash, P. S.
Mariano, J. Am. Chem. Soc. 1994, 116, 9791–9792; d) N. Isono, M.
Mori, J. Org. Chem. 1995, 60, 115–119; e) L. F. Tietze, H. Schirok,
Angew. Chem. 1997, 109, 1159–1160; Angew. Chem. Int. Ed. Engl.
1997, 36, 1124–1125; f) L. F. Tietze, H. Schirok, J. Am. Chem. Soc.
1999, 121, 10264–10269; g) J. D. Eckelbarger, J. T. Wilmot, D. Y.
Gin, J. Am. Chem. Soc. 2006, 128, 10370–10371; h) Q. Liu, E. M.
Ferreira, B. M. Stoltz, J. Org. Chem. 2007, 72, 7352–7358; i) W. R.
Esmieu, S. W. Worden, D. Catterick, C. Wilson, C. J. Hayes, Org.
Lett. 2008, 10, 3045–3048; j) Q.-W. Zhang, K. Xiang, Y.-Q. Tu, S.-Y.
Zhang, X.-M. Zhang, Y.-M. Zhao, T.-C. Zhang, Chem. Asian J.
2012, 7, 894–898.
[33] For isolation of new members of cephalotaxus family of alkaloids,
see: a) H. Morita, Y. Nagakura, T. Hosoya, W. Ekasari, A. Widya-
waruyanti, K. Mori-Yasumoto, S. Sekita, Y. Hirasawa, Heterocycles
2010, 81, 441–450; b) H. Morita, M. Yoshinaga, J. Kobayashi, Tetra-
hedron 2002, 58, 5489–5495; c) H. Morita, M. Arisaka, N. Yoshida,
J. Kobayashi, Tetrahedron 2000, 56, 2929–2934.
[34] A. R. Chamberlin, H. D. Nguyen, J. Y. L. Chung, J. Org. Chem.
1984, 49, 1682–1688.
[35] C. Guꢄrot, B. H. Tchitchanov, H. Knust, E. M. Carreira, Org. Lett.
2011, 13, 780–783.
kylation/allylation/phenylation–allylation/cyanation
of
alkoxy
amides: c) G. Vincent, R. Guillot, C. Kouklovsky, Angew. Chem.
2011, 123, 1386–1389; Angew. Chem. Int. Ed. 2011, 50, 1350–1353;
direct reductive bis-alkylation/alkynylation/arylation–allylation/cyn-
ation of N-methoxyamides: d) Y. Yanagita, H. Nakamura, K. Shiro-
kane, Y. Kurosaki, T. Sato, N. Chida, Chem. Eur. J. 2013, 19, 678–
684; highly chemoselective direct conversion of secondary amides
into ketones: e) W. S. Bechara, G. Pelletier, A. B. Charette, Nat.
Chem. 2012, 4, 228–234; synthesis of chiral a-tertiary a-silylamines
through sequential organometallic reagents addition to aryl sulfony-
limidate derivatives: f) X.-J. Han, M. Yao, C.-D. Lu, Org. Lett. 2012,
14, 2906–2909; review highlighting the important advancements
made in recent years in the development of chemoselective addi-
tions of nucleophiles to amide carbonyls: g) V. Pace, W. Holzer,
Aust. J. Chem. 2013, 66, 507–510.
[22] For reviews on the chemistry of triflic acid and its derivatives, see:
a) P. J. Stang, M. Hanack, M. L. R. Subramanian, Synthesis 1982,
85–126; b) I. L. Baraznenok, V. G. Nenajdenko, E. S. Balenkova,
Tetrahedron 2000, 56, 3077–3119. For selected examples on the use
of Tf2O as a powerful amide activator for a variety of transforma-
tions, see: c) J.-B. Falmagne, J. Escudero, T.-S. Saa, L. Ghosez,
Angew. Chem. 1981, 93, 926–931; Angew. Chem. Int. Ed. Engl.
1981, 20, 879–880; d) L.-Y. Chen, L. Ghosez, Tetrahedron Lett.
1990, 31, 4467–4470; e) G. Barbaro, A. Battaglia, C. Bruno, P. Gior-
gianni, A. Guerrini, J. Org. Chem. 1996, 61, 8480–8488; f) S. Sforza,
A. Dossena, R. Corradini, E. Virgili, R. Marchelli, Tetrahedron Lett.
[36] B. E. Love, E. G. Jones, J. Org. Chem. 1999, 64, 3755–3756.
Received: June 1, 2013
Published online: && &&, 2013
&
12
&
www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Reductive gem-Bis-Alkylation of Tertiary Lactams/Amides
FULL PAPER
Synthetic Methods
K.-J. Xiao, J.-M. Luo, X.-E. Xia,
Y. Wang, P.-Q. Huang* . . . . . &&&& — &&&&
General One-Pot Reductive gem-Bis-
Alkylation of Tertiary Lactams/
Amides: Rapid Construction of
1-Azaspirocycles and Formal Total
Synthesis of (Æ)-Cephalotaxine
Four bonds in one pot! Cleavage of
two bonds of an amide carbonyl group
total synthesis of racemic cephalotax-
ine has been accomplished by means
of this methodology (see scheme;
DTBMP=2,6-di-tert-butyl-4-methyl-
pyridine).
À
and replacement by two new C C
bonds can be achieved in one pot
under mild conditions by using amide
activation with Tf2O. A concise formal
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
13
&
ÞÞ
These are not the final page numbers!