One-Pot Reductive Allylation of Amides by Using a Combination of Titanium Hydride and an Allylzinc Reagent: Application to a Total Synthesis of (-)-Castoramine

Article abstract of DOI:10.1055/s-0037-1610435

A one-pot direct reductive allylation protocol has been developed for the synthesis of secondary amines by using titanium hydride and an allylzinc reagent. This protocol is applicable to a broad range of substrates, including acyclic amides, benzamides, α,β-unsaturated amides, and lactams. The stereochemical outcome obtained from the reaction with crotylzinc reagent suggested that the allylation reaction proceeds through a six-membered cyclic transition state. A total synthesis of (-)-castoramine was accomplished by following this protocol for the highly stereoselective construction of contiguous stereocenters.

Full text of DOI:10.1055/s-0037-1610435

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–E
letter
A
en
S. Itabashi et al.
Letter
Synlett
One-Pot Reductive Allylation of Amides by Using a Combination
of Titanium Hydride and an Allylzinc Reagent: Application to a
Total Synthesis of (–)-Castoramine
Suguru Itabashi
OH
Masashi Shimomura
MgCl
H
Manabu Sato
(3.0 equiv)
ZnCl2
(1.5 equiv)
H
N
Ti(Oi-Pr)4
Ph2SiH2
Hiroki Azuma
Kentaro Okano
Juri Sakata
O
H
R2
R1
N
R2
0
0
0
0
0-
0
0
3
2-
0
2
9
8-
5
0
5
R2
R1
N
R1
N
H
THF, r.t.
–78 to 0 °C
H
O
one-pot
20 examples
Hidetoshi Tokuyama*
(–)-castoramine
Graduate School of Pharmaceutical Sciences, Tohoku
University, Aoba 6-3, Aramaki, Aoba-ku, Sendai,
980-8578, Japan
tokuyama@m.tohoku.ac.jp
Received: 26.04.2018
Accepted after revision: 29.05.2018
Published online: 26.06.2018
ry and secondary amides into α-allylated amines by using
Schwartz’s reagent and allylzinc halides; this method ex-
hibited superior chemoselectivity to previously reported
methods (Scheme 1b).5–7 Currently, there is no useful meth-
od, in terms of functional-group compatibility and practical
utility, for the large-scale conversion of amides into amines,
and the development of an efficient protocol is still re-
quired.
DOI: 10.1055/s-0037-1610435; Art ID: st-2018-u0260-l
Abstract A one-pot direct reductive allylation protocol has been de-
veloped for the synthesis of secondary amines by using titanium
hydride and an allylzinc reagent. This protocol is applicable to a broad
range of substrates, including acyclic amides, benzamides, α,β-unsatu-
rated amides, and lactams. The stereochemical outcome obtained from
the reaction with crotylzinc reagent suggested that the allylation reac-
tion proceeds through a six-membered cyclic transition state. A total
synthesis of (–)-castoramine was accomplished by following this proto-
col for the highly stereoselective construction of contiguous stereo-
centers.
a) Nucleophilic addition to amide via preactivation step
O
SMe
R3
OTf
R3
O
R1
O
R1
R1
preactivation
N
R3
N
R2
N
R2
R1
or
or
N
R3
R2
OR
Key words amides, reduction, allylation, amines, total synthesis, alka-
loids
1
2
3
R4 R5
LiAlH4
DIBAL
R1
The amide group is a ubiquitous functional group that
can be found in natural products, pharmaceutical agents,
functional materials, and agrochemicals. In contrast to de-
velopments in protocols available for the formation of am-
ides,1 the conversion of the amide group into other func-
tional groups, particularly amines, has not been thoroughly
investigated. The most frequently used transformation of
amides into amines is through reduction to the correspond-
ing primary amines with LiAlH4. The conversion into α- or
α,α-branched amines by a one-pot sequential nucleophilic
addition of a hydride anion and a carbon nucleophile is not
straightforward due to the low nucleophilicity of the start-
ing amides and the imine intermediates, together with the
challenging control of each step of the reaction. To facilitate
the nucleophilic addition to amides, preactivation of the
starting amides as an imide 1, thioamide 2, or iminium tri-
flate 3, and the use of highly reactive nucleophiles such as
DIBAL, LiAlH4, Grignard reagents, or organolithium reagents
are generally required (Scheme 1a).2–4 Recently, Chida, Sato,
and their co-workers reported a direct conversion of tertia-
N
R3
Grignard reagent
organolithium
R2
b) Direct reductive allylation developed by Chida (2012, 2014)
H
O
H
ZnBr
R1
Cp2ZrHCl
R1
R1
R3
N
R2
R3
N
N
R2
R3
CH2Cl2
one-pot
R2
Scheme 1 Conversion of amides into α-branched amines
During the course of our recent total synthesis of (–)-
histrionicotoxin (HTX; 7), we obtained preliminary results
on a one-pot reductive allylation of a nonactivated second-
ary amide (Scheme 2).8 In following Buchwald’s protocol,
the spirocyclic lactam 4 was exposed to titanium hydride,
generated from Ti(O-i-Pr)4(10 equiv) and diethylsilane (40
equiv), to give the partially reduced imine intermediate
5;9,10 subsequent allylation under Ishihara’s conditions af-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

B
S. Itabashi et al.
Letter
Synlett
forded the homoallylic amine 6 in a one-pot process
(71%).11,12 In the present study, this preliminary one-pot se-
quence was reinvestigated in detail for the optimization of
both the selective partial reduction to the imine and the al-
lylation, and its scope and limitations were explored. Here,
we report the practical and chemoselective one-pot reduc-
tive allylation of nonactivated amides by using a combina-
tion of titanium hydride and an allylzinc reagent, and its
application to a total synthesis of (–)-castoramine.
Table 1 Optimization of the Reduction Conditions
silane (X equiv)
Ti(Oi-Pr)4 (Y equiv)
O
N
H
Ph
N
Ph
THF
temp, time
8
9
MgCl
(3.0 equiv)
ZnCl2 (23 mol%)
+
N
H
Ph
N
Ph
H
THF
–78 to 0 °C, 2 h
11
10
Et2SiH2 (40 equiv)
Ti(Oi-Pr)4 (10 equiv)
Entry Silane
Xa
40
Yb
10
1.5
Temp
Time (h) Product [Yieldc,d (%)]
H
N
O
N
H
THF, reflux
1
2
Et2SiH2
reflux
reflux
1
5
10 (35)
11 (28)
OTBS
OTBS
4
5
Et2SiH2
5
10 (40)
11 (28)
MgCl
(3.0 equiv)
3
4
Et2SiH2
Ph2SiH2
5
5
1.5
1.5
r.t.
r.t.
8
5
no reaction
N
ZnCl2 (23 mol%)
N
H
H
H
H
10 (71)
11 (6)
OTBS
THF
–78 to 0 °C, 2 h
OH
5
Ph2SiH2
3
1.5
r.t.
40
10 (50)
11 (10)
6 (71%)
(–)-HTX (7)
Scheme 2 Results of our previous studies
6
7
8
Ph2SiH2
Et3SiH
1
5
5
1.5
1.5
1.5
r.t.
r.t.
r.t.
96
22
22
no reaction
no reaction
no reaction
Ph3SiH
Initially, we investigated the optimization of the reduc-
tion conditions,13 and the resultant imine was subsequently
allylated under the conditions that were used for the syn-
thesis of HTX (Table 1).9 The reaction of the model substrate
8 with diethylsilane (40 equiv) and Ti(O-i-Pr)4(10 equiv)
gave the desired product 10 in 35% yield as a single diaste-
reomer,14 together with the over-reduction product 11 in
28% yield (Table 1, entry 1).
A series of experiments were then performed in an at-
tempt to prevent the overreduction of 8. Decreasing the
amount of reducing agent proved ineffective (Table 1, entry
2), whereas lowering the reaction temperature suppressed
the initial reduction (entry 3). By further screening, we
found that the use of diphenylsilane was key to the sup-
pression of the overreduction. When substrate 8 was treat-
ed with Ti(O-i-Pr)4(1.5 equiv) and diphenylsilane (5 equiv),
the reduction of lactam 8 reached completion even at room
temperature, and the yield of 10 dramatically increased to
71%, along with a trace amount of the fully reduced amine
11 (entry 4). A further decrease in the amount of Ph2SiH2
was ineffective (entries 5 and 6), whereas the silanes Et3SiH
(entry 7) and Ph3SiH (entry 8) did not promote the initial
reduction at all.
a Equivalents of the silane.
b Equivalents of Ti(O-i-Pr)4.
c In all cases, amine 10 was obtained as a single diastereomer.
d Isolated yield.
with allylmagnesium chloride gave product 10 in a slightly
lower yield (entry 3), whereas allylzinc bromide did not
give 10 at all (entry 4). Finally, allylpinacol boronate gave
Table 2 Optimization of the Allyl Nucleophile
Ph2SiH2 (5 equiv)
Ti(Oi-Pr)4 (1.5 equiv)
nucleophiles
O
N
H
Ph
THF
–78 to 0 °C, 2 h
N
H
Ph
THF
r.t., 5 h
8
10
Entry
Nucleophiles
Yielda,b (%) of 10
1
AllMgCl (3.0 equiv), ZnCl2 (23 mol%)
AllMgCl (3.0 equiv), ZnCl2 (1.5 equiv)
AllMgCl (1.5 equiv)
71
74c
56
0
2
3
4
AllZnBr (1.5 equiv)
5d
6d
7d
AllB(pin) (1.5 equiv)
66
0
With the optimal reduction conditions in hand, we next
searched for a suitable allylating reagent (Table 2). The reac-
tion with a zinc reagent freshly prepared from allylmagne-
sium chloride and ZnCl2 (2:1) afforded the desired product
10 in a higher yield (Table 2, entry 2) than that obtained un-
der the original conditions using a lower amount of ZnCl2
(23 mol%) (entry 1). In the absence of ZnCl2, the reaction
AllTMS (1.5 equiv), TiCl4 (1.5 equiv)
AllSnBu3 (1.5 equiv), Sc(OTf)3 (1.5 equiv)
0
a In all cases, amine 10 was obtained as a single diastereomer.
b Isolated yield.
c Amine 11 was obtained in 3% yield.
d Reaction temperature 25 °C.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

C
S. Itabashi et al.
Letter
Synlett
product 10 in a comparable yield (66%; entry 5), whereas
allylsilane or allylstannane with Lewis acids proved unsuc-
cessful (entries 6 and 7).
a)
Ph2SiH2 (5.0 equiv)
Ti(Oi-Pr)4 (1.5 equiv)
Having established the optimal conditions, we then in-
vestigated the generality, scope, and limitations of the
method (Scheme 3).15 A variety of benzylic amides derived
from aliphatic or aromatic carboxylic acids 12a–d were al-
lylated in good to almost quantitative yield. The protocol
was also practical and applicable to a gram-scale reaction.
Thus, amide 12d (1.0 g) was converted into the desired al-
lylated compound in 91% yield without such precautions as
the use of a glovebox to completely exclude oxygen or mois-
ture.16 In the case of the cinnamyl amide 12e, no byproduct
stemming from 1,4-reduction was observed. The reductive
allylation proceeded smoothly for the six- to eight-mem-
bered lactam compounds 8, 12f, and 12g.17,18 We found that
the present method was also applicable to the tertiary am-
ide 12h (84%). Furthermore, a number of functional groups
were compatible with the one-pot allylation protocol. In
addition, the electron-rich N-benzyl-4-methoxybenzamide
(12ia) and the electron-deficient N-benzyl-4-bromoben-
zamide (12ib) and N-benzyl-4-(chloromethyl)benzamide
(12ic) gave the corresponding products in excellent yields
(96, 94, and 91%, respectively). Interestingly, despite bear-
ing a sensitive nitro group, benzamide 12id tolerated the
reaction conditions, giving a 90% yield of the allylated prod-
uct. Moreover, the aromatic methyl ester group in 12ie re-
mained intact during the chemoselective reduction and al-
lylation (product yield: 60%). Various protecting groups for
alcohols, including THP (12ja, 58%), TBS (12jb, 72%), and
MOM (12jc, 88%) were also tolerated, as were two protect-
ing groups for nitrogen, Boc carbamate 12ka and Ts amide
12kc, which gave the corresponding allylated compounds in
low to good yields.
H
N
Ph
O
N
H
Ph
THF (0.1 M)
r.t., 5 h
MgBr
8
9
(3.0 equiv)
ZnCl2 (1.5 equiv)
–78 to 0 °C
H
H
Me
Ph
N
N
Ph
H
H
15 (not obtained) 14 (58%, single diastereomer)
b)
H
MgBr
axial attack
Me
ZnCl2
N
H
Ph
14
N
H
Ph
ZnR
16
pseudoequatorial
MgCl
17
Scheme 4 Rationale for the observed stereoselectivity
To obtain some mechanistic insights into the allylation
step, the reaction with a crotylzinc reagent was examined.
Thus, crotylation of the imine intermediate 9 proceeded in
a highly diastereoselective manner to give the branched
product 14 exclusively in 58% yield Scheme 4a,19 which
strongly suggests the formation of a six-membered chair-
like transition state on the half-chair conformation of the
initially formed imine intermediate 16. The axial attack by
the crotylzinc reagent must occur via the six-membered
transition state 17 to form the branched product 14 ste-
reospecifically Scheme 4b.
MgCl
Ph2SiH2 (5.0 equiv)
Ti(Oi-Pr)4 (1.5 equiv)
O
(3.0 equiv)
ZnCl2 (1.5 equiv)
H
R2
R2
R1
N
H
R1
N
THF, r.t.
–78 to 0 °C
H
12
13
O
O
O
O
O
n-C7H15
N
N
H
N
N
N
H
H
H
H
12a: 88%
12b: 86%
12c: 98%
12d: 91%a
12e: 94%
O
Me
N
N
N
O
O
H
O
O
N
H
H
Me
8: 74%
12f: 66%b
12g: 68%b
12h: 84%
O
O
12ia: R1 = OMe; R2 = H, 96%
12ib: R1 = Br; R2 = H, 94%
H
12ja: R = THP, 58%
12jb: R = TBS, 72%
12jc: R = MOM, 88%
12ka: R = Boc, 43%
12kb: R = Ns, 0%
12kc: R = Ts, 66%
N
12ic: R1 = CH2Cl; R2 = H, 91%
12id: R1 = NO2; R2 = H, 90%
R2
12ie: R1 = H; R2 = CO2Me, 60%
N
H
N
OR
R
N
5
H
H
R1
Scheme 3 Generality, scope, and limitations of the reductive allylation a Gram-scale reaction. b Obtained as single diastereomer.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

D
S. Itabashi et al.
Letter
Synlett
To demonstrate the utility of this highly diastereo-
selective reductive allylation protocol, we chose (–)-castor-
amine (23) as a target compound and we examined its
synthesis (Scheme 5).20 The reaction of lactam (+)-1821 with
Ti(O-i-Pr)4 (5.0 equiv) and diphenylsilane (0.5 equiv), fol-
lowed by addition of the crotylzinc reagent, resulted in the
expected partial reduction to yield product 19 with perfect
stereoselectivity.22 The facial selectivity of the crotylation
was completely controlled by the siloxymethyl group on the
piperidine ring. Crotylation of 19 followed by ring-closing
metathesis then gave the cyclic product 21. After reduction
of the double bond, a 3-furyl moiety was introduced by fol-
lowing Shenvi’s procedure to give 22 in 59% yield as a single
diastereomer.23 Finally, removal of the TBDPS group afford-
ed (–)-castoramine (23), whose physical properties were in
agreement with the reported data.20c
Science Research (BINDS)) from AMED under Grant Number
JP18am0101100.
)(
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610435.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
References and Notes
(1) For selected recent reviews on amide formation, see:
(a) Humphrey, J. M.; Chamberlin, A. R. Chem. Rev. 1997, 97,
2243. (b) Han, S.-Y.; Kim, Y.-A. Tetrahedron 2004, 60, 2447.
(c) Montalbetti, C. A. G. N.; Falque, V. Tetrahedron 2005, 61,
10827. (d) Valeur, E.; Bradley, M. Chem. Soc. Rev. 2009, 38, 606.
(e) El-Faham, A.; Albericio, F. Chem. Rev. 2011, 111, 6557.
(f) Pattabiraman, V. R.; Bode, J. W. Nature 2011, 480, 471.
(g) Lanigan, R. M.; Sheppard, T. D. Eur. J. Org. Chem. 2013, 7453.
(h) Lundberg, H.; Tinnis, F.; Selander, N.; Adolfsson, H. Chem.
Soc. Rev. 2014, 43, 2714.
(2) For a review on nucleophilic addition to amides, see: Pace, V.;
Holzer, W.; Olofsson, B. Adv. Synth. Catal. 2014, 356, 3697.
(3) For a review and a recent example through a thioamide, see:
(a) Murai, T.; Mutoh, Y. Chem. Lett. 2012, 41, 2. (b) Murai, T.;
Mutoh, N. J. Org. Chem. 2016, 81, 8131.
OTBDPS
Ph2SiH2
(0.5 equiv)
Ti(Oi-Pr)4
(5 equiv)
MgCl
(6.0 equiv)
OTBDPS
H
ZnCl2 (3.0 equiv)
N
H
O
N
H
–78 to 0 °C
THF, r.t.;
19 (single diastereomer)
(+)-18
35% (52%, brsm)
(4) For recent examples through iminium triflates, see: (a) Huang,
P.-Q.; Huang, Y.-H.; Xiao, K.-J.; Wang, Y.; Xia, X.-E. J. Org. Chem.
2015, 80, 2861. (b) Wang, A.-E.; Yu, C.-C.; Chen, T.-T.; Liu, Y.-P.;
Huang, P.-Q. Org. Lett. 2018, 20, 999. (c) Chen, H.; Ye, J.-L.;
Huang, P.-Q. Org. Chem. Front. 2018, 5, 943.
(5) (a) Oda, Y.; Sato, T.; Chida, N. Org. Lett. 2012, 14, 950.
(b) Nakajima, M.; Oda, Y.; Wada, T.; Minamikawa, R.; Shirokane,
K.; Sato, T.; Chida, N. Chem. Eur. J. 2014, 20, 17565.
(6) For examples of direct reductive nucleophilic additions to
amides by using Vaska’s complex, see: (a) Xie, L.-G.; Dixon, D. J.
Chem. Sci. 2017, 8, 7492. (b) Fuentes de Arriba, Á. L.; Lenci, E.;
Sonawane, M.; Formery, O.; Dixon, D. J. Angew. Chem. Int. Ed.
2017, 56, 3655.
(7) For direct reductive nucleophilic additions to N-alkoxy amides,
see: (a) Shirokane, K.; Kurosaki, Y.; Sato, T.; Chida, N. Angew.
Chem. Int. Ed. 2010, 49, 6369. (b) Yanagita, Y.; Nakamura, H.;
Shirokane, K.; Kurosaki, Y.; Sato, T.; Chida, N. Chem. Eur. J. 2013,
19, 678. (c) Shirokane, K.; Wada, T.; Yoritate, M.; Minamikawa,
R.; Takayama, N.; Sato, T.; Chida, N. Angew. Chem. Int. Ed. 2014,
53, 512. (d) Sato, T.; Chida, N. Org. Biomol. Chem. 2014, 12, 3147.
(e) Nakajima, M.; Sato, T.; Chida, N. Org. Lett. 2015, 17, 1696.
(f) Fukami, Y.; Wada, T.; Meguro, T.; Chida, N.; Sato, T. Org.
Biomol. Chem. 2016, 14, 5486.
OTBDPS
OTBDPS
O
Cl
H
Grubbs’ 2nd cat.
(20 mol%)
H
N
EtN(i-Pr)2
N
CH2Cl2
reflux
CH2Cl2, r.t.
O
O
21
60% (2 steps)
OTBDPS
20
OH
1) H2, Pd/C
EtOH
r.t., 97%
H
H
TBAF
N
N
THF, r.t.
2)
Li
75%
O
O
22
O
Et2O
(–)-castoramine (23)
–78 to r.t.
NaBH(OAc)3
59%
single diastereomer
Scheme 5 Application to the total synthesis of (–)-castoramine
In summary, we have established a highly chemoselec-
tive, one-pot, direct reductive allylation of a variety of sec-
ondary amides by using titanium hydride and a diallylic
zinc reagent. The utility of this protocol was demonstrated
by performing a stereocontrolled total synthesis of (–)-cas-
toramine.
(8) When spirocyclic lactam 4 was treated with the Schwartz
reagent, a fully reduced amine was detected as the major prod-
uct.
(9) Sato, M.; Azuma, H.; Daigaku, A.; Sato, S.; Takasu, K.; Okano, K.;
Tokuyama, H. Angew. Chem. Int. Ed. 2017, 56, 1087.
(10) Bower, S.; Kreutzer, K. A.; Buchwald, S. L. Angew. Chem. Int. Ed.
Engl. 1996, 35, 1515.
(11) Hatano, M.; Suzuki, S.; Ishihara, K. J. Am. Chem. Soc. 2006, 128,
9998.
Funding Information
(12) For an example of a titanium hydride-mediated one-pot partial
reduction/intramolecular Henry reaction of a tertiary amide,
see: Jakubec, P.; Hawkins, A.; Felzmann, W.; Dixon, D. J. J. Am.
Chem. Soc. 2012, 134, 17482.
This work was financially supported by KAKENHI (16H01127,
16H00999, 26253001, 18H02549, 18H04231, 18H04379, 18K18462)
and Platform Project for Supporting Drug Discovery and Life Science
Research (Basis for Supporting Innovative Drug Discovery and Life
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

E
S. Itabashi et al.
Letter
Synlett
(13) For details of the preparation of lactam 8, see the Supporting
Information.
(14) The relative stereochemistry (trans) of compound 10 was deter-
mined after conversion to the known compound; see the Sup-
porting Information.
(15) The conditions of Table 2, entry 2 gave the allylated compounds
in higher yields than those of Table 2, entry 1. For instance, the
latter conditions gave 13a (62%), 13b (54%), 13ie (0%), 13ka
(31%), and 13kc (53%).
3068, 3028, 2916, 2835, 1455, 1119, 916, 749, 703 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.39–7.21 (m, 10 H), 5.76–5.65
(m, 1 H), 5.07 (d, J = 17.2 Hz, 1 H), 5.03 (d, J = 10.0 Hz, 1 H), 3.71-
3.66 (m, 2 H), 3.52 (d, J = 13.2 Hz, 1 H), 2.45-2.35 (m, 2 H). 13C
NMR (100 MHz, CDCl3): δ = 143.7, 140.6, 135.4, 128.34, 128.28,
128.1, 127.3, 127.0, 126.8, 117.5, 61.6, 51.4, 43.0. HRMS (ESI):
m/z [M + H]+ calcd. for C17H20N: 238.1590; found: 238.1580.
Spectroscopic data were identical with those reported for this
compound (see Ref. 5a).
(16) N-Benzyl-1-phenylbut-3-en-1-amine (13d): Gram-Scale Syn-
thesis
(17) Four- and five-membered lactams were not suitable substrates
for this protocol. Initial reduction of a four-membered lactam
did not proceed at all, and in the case of a five-membered
lactam, the reduction step was sluggish.
(18) The relative stereochemistry (trans) of compound 13f was
determined after conversion into the known compound; see the
Supporting Information.
(19) The structure of compound 14 was determined by NOE experi-
ments after several transformations; see the Supporting Infor-
mation.
(20) For the isolation, see: (a) Valenta, Z.; Khaleque, A. Tetrahedron
Lett. 1959, 1, 1(12): 1. For total syntheses, see: (b) Bohlmann, F.;
Winterfeldt, E.; Laurent, H.; Ude, W. Tetrahedron 1963, 19, 195.
(c) Goodenough, K. M.; Moran, W. J.; Raubo, P.; Harrity, J. P. A.
J. Org. Chem. 2005, 70, 207.
A 1.0 M solution of allylmagnesium chloride in THF (14.2 mL,
14.2 mmol) was added to a suspension of ZnCl2 (1.00 g, 7.35
mmol) in THF (7.7 mL) at r.t., and the mixture was stirred for 1 h
at r.t., before being used in the next reaction.
Ti(O-i-Pr)4 (2.1 mL, 7.1 mmol) was added to a solution of amide
12d (1.00 g, 4.74 mmol) and Ph2SiH2(4.4 mL, 24 mmol) in THF
(47 mL) at r.t., and the mixture was stirred at r.t. for 7.5 h. The
mixture was then cooled to –78 °C, and the freshly prepared
allylzinc reagent was added at –78 °C. The resulting mixture
was warmed to 0 ℃ and stirred at 0 ℃ for 1 h before the reaction
was quenched with sat. aq NH4Cl (100 mL). The mixture was
then filtered through a pad of Celite, which was washed with
EtOAc (100 mL). The resulting mixture was extracted with
EtOAc (3 × 100 mL), and the combined organic extracts were
washed with brine, dried (Na2SO4), and filtered. The organic sol-
vents were removed under reduced pressure to give a crude
material that was purified by column chromatography [silica
gel, hexanes–EtOAc (1:1)] to give a colorless oil; yield: 1.02 g
(4.31 mmol, 91%); Rf = 0.75 (hexanes–EtOAc, 1:1). IR (neat):
(21) For the preparation of amide 18, see the Supporting Informa-
tion.
(22) Under the optimal conditions, we obtained compound 19 (19%)
together with a considerable amount of the over-reduced
amine (18%).
(23) Jansen, D. J.; Shenvi, R. A. J. Am. Chem. Soc. 2013, 135, 1209.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E