Synthesis of N-Boc-Propargylic and Allylic Amines by Reaction of Organomagnesium Reagents with N-Boc-Aminals and Their Oxidation to N-Boc-Ketimines

Article abstract of DOI:10.1021/acs.orglett.5b03446

Previously inaccessible N-Boc-protected propargylic and allylic amines were synthesized by the reaction between N-Boc-aminals and organomagnesium reagents through the in situ generated N-Boc-imine intermediates. The obtained N-Boc-propargylic amines could be readily converted into unprecedented N-Boc-ketimines by oxidation with manganese dioxide.

Full text of DOI:10.1021/acs.orglett.5b03446

Letter
pubs.acs.org/OrgLett
Synthesis of N‑Boc-Propargylic and Allylic Amines by Reaction of
Organomagnesium Reagents with N‑Boc-Aminals and Their
Oxidation to N‑Boc-Ketimines
Taichi Kano, Ryohei Kobayashi, and Keiji Maruoka*
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan
S
* Supporting Information
ABSTRACT: Previously inaccessible N-Boc-protected propargylic and allylic
amines were synthesized by the reaction between N-Boc-aminals and organo-
magnesium reagents through the in situ generated N-Boc-imine intermediates. The
obtained N-Boc-propargylic amines could be readily converted into unprecedented
N-Boc-ketimines by oxidation with manganese dioxide.
ropargylic and allylic amines represent an important class
of versatile building blocks for the synthesis of nitrogen-
imines with various substituents on the imine carbon atom.6
P
Based on these results, we initially examined the synthesis of N-
Boc-propargylic amines via the in situ generated N-Boc-imine 7
from the reaction of N-Boc-aminal 5a with organometallic
bases and nucleophiles (Scheme 2). When butyllithium was
containing organic compounds.1 Among these, synthetically
useful N-Boc-protected propargylic and allylic amines 1 are
readily prepared from the nucleophilic addition of alkynyl and
alkenyl metal reagents to N-Boc-imines, which can be
generated from their precursors 2 upon treatment with bases
including basic nucleophiles (Scheme 1).2,3 However, this
Scheme 2. Reactions of N-Boc-Aminal 5a with
Organometallic Reagents
Scheme 1. Synthesis of N-Boc-Protected Propargylic and
Allylic Amines
employed at −78 °C, N-Boc-aminal 5a was consumed
immediately. However, the desired addition product 8a (R =
Bu) was obtained in low yield, probably due to the presence of
multiple reaction sites in 5a and 7. Indeed, cleavage of the Boc
group was observed for 5a. Conversely, treatment of 5a with
methylmagnesium bromide at −20 °C afforded the desired
adduct 8b (R = Me) cleanly.7 Furthermore, diethylzinc could
also be used for the synthesis of propargylic amine 8c (R = Et).
Consequently, we chose the readily available organomagnesium
reagents as nucleophiles for further investigations into the
scope of this reaction.
Initially, N-Boc-aminals 5 with C-alkynyl and C-alkenyl
groups were treated with alkynyl and alkenylmagnesium halides
in THF at −20 °C (Table 1). The desired 1,2-addition to the
resulting N-Boc-imines proceeded exclusively and furnished
unprecedented N-Boc-propargylic and allylic amines 4 in good
yields, while possible 1,4-adducts were not observed. The
method is applicable to N-Boc-imines with C-aryl or C-alkyl
groups, as most N-Boc-imine precursors 3 with a C-alkynyl or
C-alkenyl group still remain unobtainable.4 Accordingly, in the
synthesis of N-Boc-protected propargylic and allylic amines 1,
alkynyl and alkenyl groups should be introduced as
nucleophiles and not as part of electrophiles. Therefore, α-
alkynyl and α-alkenyl-substituted N-Boc-propargylic and allylic
amines 4 have not been synthesized to date.5 Herein, we report
the synthesis of previously inaccessible N-Boc-propargylic and
allylic amines 4 via the reaction of N-Boc-aminals 5 with
organomagnesium reagents and the subsequent oxidation to
furnish unprecedented N-Boc-ketimines 6 that can be used for
the generation of tetrasubstituted carbon centers.
We have previously reported that the treatment of N-Boc-
protected aminals with an inorganic base can generate N-Boc-
Received: December 2, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03446
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Organic Letters
Letter
a
Table 1. Synthesis of α-Alkynyl and α-Alkenyl-Substituted N-
Boc-Propargylic and Allylic Amines 4
Table 2. Synthesis of Various N-Boc-Propargylic Amines 8
a
b
entry
R-MgX
(equiv) ZnCl2 (equiv) yield (%)
1
2
3
4
5
6
7c
8
9
Bu-MgCl
2.2
2.2
3.3
3.3
4.4
3.3
3.3
2.2
3.3
0
8a
8b
8d
8d
8e
8f
70
93
19
93
69
19
78
93
89
Me-MgBr
i-Pr-MgCl
i-Pr-MgCl
t-Bu-MgCl
Allyl-MgCl
Allyl-MgCl
Ph-MgBr
0
0
1.1
1.5
0
1.1
0
8f
8g
8h
2-Furyl-MgBr
0
a
The reaction between 5a (0.05 mmol) and the corresponding
organomagnesium reagent (0.11−0.22 mmol) was carried out in the
presence of ZnCl2 (0−0.08 mmol) in THF (0.5 mL) at −20 °C.
b
c
Isolated yield. t = 40 min.
The present method was found to be applicable to a wide
variety of N-Boc-aminals (Table 3). The in situ generated N-
Table 3. Synthesis of N-Boc-Amines 9 Having Various α-
a
Substituents
a
a
The reaction between 5 (0.05 mmol) and the corresponding
The reaction between 5 (0.05 mmol) and the corrsponding
organomagnesium reagent (0.11−0.33 mmol) was carried out in
organomagnesium reagent (0.11 mmol) was carried out in THF
b
c
b
c
d
THF (0.5 mL) at −20 °C. Isolated yield. Performed on a 2.2 mmol
(0.5 mL) at −20 °C. Isolated yield. Cis/trans = >20/1. Cis/trans =
d
e
f
scale. Performed on a 1.0 mmol scale. Cis/trans = 15/1. Cis/trans =
1/>20.
g
>20/1. Cis/trans = 1/>20.
Boc-imine intermediate from an N-Boc-aminal with a 1-
heptynyl group contains an acidic proton at the γ-position, and
its deprotonation under basic conditions seems to be a possible
side reaction. However, even with highly basic methylmagne-
sium bromide, the desired adduct 9a (R = 1-heptynyl) was
obtained in good yield (entry 1). The addition of
methylmagnesium bromide to an N-Boc-aminal carrying a 2-
phenylethyl group proceeded in preference to the deprotona-
tion of the α-proton of the in situ generated N-Boc-imine
intermediate (entry 4). The use of a phenyl-substituted N-Boc-
aminal afforded adduct 9e (R = Ph) in high yield (entry 5), and
the reaction of Cbz-protected aminal 10 with methylmagne-
sium bromide furnished Cbz-protected propargylic amine 11 in
good yield (Scheme 3).
The obtained α-vinyl-substituted N-Boc-propargylic amine 4f
could be converted into N-Boc-protected 1,2-aminoalcohol 12
in good yield by an ozonolysis and a subsequent reduction with
NaBH4 (Scheme 4). In this transformation, the vinyl group
reacted with ozone selectively, despite the presence of the
phenylethynyl group.9
reactions of N-Boc-imine intermediates containing a C-alkenyl
group afforded the corresponding cis/trans isomerized product
in only trace amounts (entries 10−15).
We then investigated the scope of this method by examining
a variety of alkyl and arylmagnesium reagents (Table 2). While
the reaction of 5a with linear alkylmagnesium reagents afforded
the desired adducts 8a (R = Bu) and 8b (R = Me) in good
yields (entries 1 and 2), the use of isopropylmagnesium
chloride resulted in the generation of 8d (R = i-Pr) in low yield
on account of the undesired reduction of the N-Boc-imine
intermediate (entry 3). Interestingly, the addition of zinc
chloride proved to be effective in suppressing this side reaction,
leading to a significantly increased yield (entry 4).8 Positive
effects of zinc chloride were also observed in the reaction of
allylmagnesium chloride (entry 6 vs 7). Aromatic and
heteroaromatic magnesium reagents also furnished N-Boc-
propargylic amines 8g (R = Ph) and 8h (R = 2-furyl) in good
yields (entries 8 and 9).
B
DOI: 10.1021/acs.orglett.5b03446
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Organic Letters
Letter
presence of an alkynyl, alkenyl, or aryl substituent is necessary
Scheme 3. Reaction of N-Cbz-Aminal 10 with
Methylmagnesium Bromide
at the α-position for the oxidation to proceed.
Scheme 5. Effects of the α-Substituent in N-Boc-Propargylic
Amines on the Oxidation To Give N-Boc-Imines
Scheme 4. Synthesis of N-Boc-1,2-Aminoalcohol 12
N-Boc-protected ketimines are valuable prochiral electro-
philes to produce N-Boc-protected chiral α-tertiary amines.10
To the best of our knowledge, however, available N-Boc-
ketimines have been limited to those substituted with aryl or
electron-withdrawing groups.11 In the course of the present
study on N-Boc-protected imines, we became interested in
developing an efficient method for the synthesis of novel N-
Boc-ketimines. We found that the oxidation of α-alkynyl and
alkenyl-substituted N-Boc-propargylic amines 4 with manga-
nese dioxide afforded unprecedented N-Boc-protected dia-
lkynyl ketimines and alkenyl alkynyl ketimines 6 in good yields
(Table 4).12,13 While N-Boc-dialkynyl ketimines were obtained
Treatment of the obtained dialkynyl imine 6a with lithium
trimethylsilylacetylide resulted in the formation of the N-Boc-
protected tris(alkynyl)methylamine 16 with three different
terminal substituents (Scheme 6).15 The Boc group was cleanly
deprotected by treatment with trimethylsilyl iodide in
acetonitrile (see Supporting Information).
Scheme 6. Synthesis of N-Boc-Tris(alkynyl)methylamine 16
Table 4. Oxidation of N-Boc-Propargylic Amines 4 To
a
Furnish N-Boc-ketimines 6
In summary, we have synthesized N-Boc-protected prop-
argylic and allylic amines via the reaction between N-Boc-
aminals and organomagnesium reagents, in which N-Boc-
imines are generated as reactive intermediates under basic
conditions and are subsequently subjected to an addition
reaction. This process allows direct synthetic access to
unprecedented α-alkynyl and α-alkenyl-substituted N-Boc-
propargylic and allylic amines in an operationally simple
process. The obtained N-Boc-propargylic and allylic amines are
readily oxidized by manganese dioxide to afford previously
unobtainable ketimines. Accordingly, this method represents a
rare example for the oxidation of N-Boc-amines to N-Boc-
ketimines. We are currently exploring applications of the newly
obtained N-Boc-ketimines in other transformations including
catalytic asymmetric reactions.
a
The reaction between 4 (0.05 mmol) and manganese dioxide (1.0
mmol) was carried out in dichloromethane (0.5 mL) at room
temperature. Isolated yield. Performed in 1,2-dichloroethane at 50
°C. Performed on a 1.0 mmol scale. E/Z = 1/>20. Cis/trans = 1/
>20. Performed in 1,2-dichloroethane at 80 °C.
b
c
d
e
f
ASSOCIATED CONTENT
■
g
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03446.
as a 1:1 mixture of E- and Z-isomers (entries 1−3 and 5), Z-
ketimine 6d was formed exclusively in the case of an N-Boc-
alkenyl alkynyl ketimine (entry 4), and a cis/trans isomerization
of the styryl group was not observed (entry 4).14
Experimental procedures and spectral data for all new
compounds (PDF)
While oxidation of N-Boc-protected α-phenylpropargylic
amine 8g with manganese dioxide afforded the corresponding
N-Boc-ketimine 13 exclusively as the Z-isomer in good yield,11q
the reaction of the non-α-substituted N-Boc-propargylic amine
14 did not yield the desired N-Boc-aldimine 15, even at higher
temperature (Scheme 5). These results suggested that the
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: maruoka@kuchem.kyoto-u.ac.jp.
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.5b03446
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
17, 1433. (r) Wang, D.-L.; Liang, Z.-Q.; Chen, K.-Q.; Sun, D.-Q.; Ye,
S. J. Org. Chem. 2015, 80, 5900.
ACKNOWLEDGMENTS
■
This work was supported by a grant-in-aid for Scientific
Research from MEXT, Japan. R.K. thanks the Japan Society for
the Promotion of Science for a Young Scientists for Research
fellowship.
(12) For reviews on the oxidation of N-carbamate-protected amines
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give trans-isomer 6d as a major stereoisomer at room temperature.
(15) Convertino, V.; Manini, P.; Schweizer, W. B.; Diederich, F. Org.
Biomol. Chem. 2006, 4, 1206.
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DOI: 10.1021/acs.orglett.5b03446
Org. Lett. XXXX, XXX, XXX−XXX