One-Pot Synthesis of Less Accessible N-Boc-Propargylic Amines through BF3-Catalyzed Alkynylation and Allylation Using Boronic Esters

Article abstract of DOI:10.1021/acs.orglett.9b00931

An efficient synthesis of α-alkynyl- or α-allyl-substituted N-Boc-propargylic amines is described via an alkynylation or allylation of alkynyl-substituted N-Boc-imines. Our strategy relies on the BF₃-mediated in situ generation of alkynyl imine

Full text of DOI:10.1021/acs.orglett.9b00931

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
One-Pot Synthesis of Less Accessible N‑Boc-Propargylic Amines
through BF3‑Catalyzed Alkynylation and Allylation Using Boronic
Esters
Kento Yasumoto,† Taichi Kano,*,† and Keiji Maruoka*,†,‡
†Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan
‡School of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou 510006, China
S
* Supporting Information
ABSTRACT: An efficient synthesis of α-alkynyl- or α-allyl-substituted N-
Boc-propargylic amines is described via an alkynylation or allylation of
alkynyl-substituted N-Boc-imines. Our strategy relies on the BF3-mediated in
situ generation of alkynyl imines followed by alkynylation or allylation with
the corresponding boronic esters. A range of less accessible N-Boc-
propargylic amines were obtained in moderate to good yields under mild
and acidic conditions with higher atom economy compared to the previous
methods.
ropargylic amines represent an important class of versatile
building blocks for the synthesis of nitrogen-containing
instead of organometallic reagents such as Grignard
reagents.5−7 Addition reactions using 3 to imines or enones
are known to be promoted by ligand exchange with an
equimolar amount of BF3 or a catalytic amount of BINOL on
the boron atom.6 Herein we describe the efficient synthesis of
α-alkynyl or alkenyl-substituted N-Boc-propargylic amines 2
under mild conditions through the reaction between the
activated 3 and the alkynyl-substituted N-Boc-imines, which
are generated in situ from aldehydes and BocNH2 with the aid
of an acid catalyst (Scheme 1c). Allyl-substituted N-Boc-imines
as well as alkynyl-substituted ones are inaccessible due to rapid
isomerization to α,β-unsaturated imines or enecarbamates.
Accordingly α-allyl-substituted N-Boc-propargylic amines 6
cannot be synthesized by alkynylation. Synthesis of 6 via
allylation of in situ generated alkynyl imines from N-Boc-
aminals 4 with allylboronic ester 5 is also presented.
We began our investigation with the expectation that
alkynylboronic ester 36 could be activated with an equimolar
amount of BF3·OEt2 through ligand exchange. When N-Boc-
aminal 4a8,9 was treated with 3 equiv of 3a and BF3·OEt2,
respectively, in CH2Cl2 at room temperature, a small amount
of the desired N-Boc-propargylic amine 2a was observed
(Scheme 2). With 1 equiv of BF3·OEt2, the yield was
significantly increase to 57%. Interestingly, use of a catalytic
amount of BF3·OEt2 led to a similar yield (63%).
P
organic compounds.1 The alkynyl moiety can be subject to a
variety of reactions, and the easily deprotectable tert-
butoxycarbonyl (Boc) is one of the most commonly used
protecting groups for propargylic amines. Synthetically useful
N-Boc-protected propargylic amines are readily prepared by
the nucleophilic addition of alkynyl metal reagents to N-Boc-
imines. Since reactive N-Boc-imines are prone to be hydro-
lyzed or isomerized to the corresponding enecarbamates, they
are often generated in situ by treatment of its precursors with
bases including basic nucleophiles and used without iso-
lation.2,3 However, this method is limited to N-Boc-imines
with a C-aryl, C-alkyl, or a handful of C-alkenyl groups, as most
N-Boc-imine precursors with C-alkynyl group still remain
unobtainable probably due to their instability. Accordingly, in
the synthesis of N-Boc-propargylic amines, alkynyl groups
should be introduced as nucleophiles and not as part of
electrophiles (Scheme 1a), and hence some N-Boc-propargylic
amines have been inaccessible directly.
Recently we have developed N-Boc-aminals 1,4a which
generate unprecedented alkynyl-substituted N-Boc-imines
under basic conditions, and the synthesis of previously
inaccessible α-alkynyl- or α-alkenyl-substituted N-Boc-prop-
argylic amines 2 has been achieved via the reaction between 1
and Grignard reagents (Scheme 1b).4b This reaction requires
an excess amount of Grignard reagents as both nucleophile and
base. Additionally, formation of the metal salt of (Boc)2NH as
a byproduct makes this method less atom-efficient. Moreover,
preparation of 1 requires a time-consuming protocol to
introduce the third Boc group.4a Use of strong base at low
temperature limits providing a practical and general procedure,
thus leaving plenty of room for improvement.
Encouraged by the successful BF3-mediated alkynylation of
4a, we then investigated the possibility of using other acid
catalysts as shown in Table 1. In the case of Brønsted acids
such as diphenyl phosphate and trifluoroacetic acid, 2a was
obtained, albeit in low yields (entries 1 and 2), while use of
sulfonic acids completely shut down the reaction (entries 3 and
We then became interested in employing boronic ester 3,
which can be used as a nucleophile under acidic conditions,
Received: March 15, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00931
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
4). Among Lewis acids tested, Sc(OTf)3, In(OTf)3, TiCl4, and
GaCl3 gave 2a in low to moderate yields (entries 6, 8, 9, and
11); however, they were found to be less effective catalysts
compared to BF3·OEt2 (entry 12). Based on these result, BF3·
OEt2 was selected as the catalyst of choice for further studies.
A higher reaction temperature did not increase the yield (entry
13). An increase in the catalyst loading (20 mol %) resulted in
a higher yield (entry 14).
Scheme 1. One-Pot Synthesis of N-Boc-Propargylic Amines
To improve the yield, the in situ generation of the alkynyl
imine from phenylpropiolaldehyde and BocNH2 (1 equiv), in
which the total amount of Lewis basic BocNH2 is reduced
compared to the previous method using N-Boc-aminal 4a, was
then examined (Scheme 3).10 Under identical conditions, the
Scheme 3. Alkynylation of the in Situ Generated N-Boc-
Imine from 3-Phenylpropiolaldehyde and BocNH2
yield was improved to 82%. The amount of boronic ester 3a
could be reduced to 1.5 equiv without deleterious effects. This
method was found to be superior in terms of atom economy to
the previous one.
With the optimized conditions in hand, the scope of the
reaction was studied (Table 2). Both electron-deficient and
Scheme 2. Alkynylation of the in Situ Generated N-Boc-
Imine from N-Boc-Aminal
Table 2. Alkynylation of the in Situ Generated N-Boc-
Protected Alkynyl Imines
a
b
entry
R
yield (%)
1
2
3
4
5
6
7
Ph
2a
2b
2c
2d
2e
2f
83
63
75
75
81
86
70
4-MeO-C6H4
4-Br-C6H4
4-MeO2C-C6H4
Bu
Cy
Me3Si
Table 1. Catalyst Screening for the Alkynylation of N-Boc-
Aminal 4a with Alkynylboronic Ester 3a
a
2g
a
Reactions were performed on a 0.1 mmol scale in 1.0 mL of CH2Cl2.
Isolated yield.
b
b
b
entry
catalyst
yield (%)
entry
catalyst
yield (%)
electron-rich arylpropiolaldehydes gave the corresponding α-
alkynyl-substituted N-Boc-propargylic amines 2 in moderate to
good yields (entries 2−4), and this method was applicable to
the synthesis of 2d, which cannot be synthesized by the
previous method using Grignard reagents due to the base-labile
ester group.4b Alkyl- and trimethylsilyl-substituted propiolalde-
hydes also provided the respective addition products in good
yields (entries 5−7). In addition, the reaction of aldehydes
bearing an alkyl, aryl, or alkenyl group with 3a gave N-Boc-
propargylic amines 7 in satisfactory yields (Scheme 4).2,4b
We next examined the scope of the reaction by varying the
alkynylboronic ester used (Table 3). Use of electron-rich
alkynylboronic ester led to a moderate yield due to the
1
2
3
4
5
6
7
(PhO)2PO2H
CF3CO2H
PTSA
25
24
0
0
0
8
9
10
11
12
In(OTf)3
TiCl4
ZnCl2
14
7
0
33
63
60
78
TfOH
GaCl3
Me3SiOTf
Sc(OTf)3
Cu(OTf)2
BF3·OEt2
BF3·OEt2
BF3·OEt2
c
41
0
13
14
d
a
Reactions were performed on a 0.1 mmol scale in 1.0 mL of CH2Cl2.
b
c
1H NMR yield utilizing DMF as internal standard. Performed in
d
1,2-dichloroethane at 70 °C. Use of 20 mol % of BF3·OEt2.
B
DOI: 10.1021/acs.orglett.9b00931
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
smoothly to give propargyl alcohol 9 in quantitative yield, and
the desired N-Boc-propargylic amine 6a was not observed
(Scheme 5a).14 In order to prevent the undesired allylation of
aldehyde, N-Boc-aminal 4a (R = Ph) instead of phenyl-
propiolaldehyde was then employed as the imine precursor
under identical conditions, and α-allyl-substituted N-Boc-
propargylic amines 6a was obtained in 39% yield without
forming propargyl alcohol 9. With increased amounts of BF3·
OEt2 (30 mol %) and 5 (3 equiv), the reaction of 4 afforded 6
in good yields (Scheme 5b).15 These results clearly
demonstrated the advantage of using N-Boc-aminals, which
are more suitable imine precursors, when the imine formation
from aldehydes is slower than the addition reaction of
nucleophiles to aldehydes.
Scheme 4. Alkynylation of the in Situ Generated N-Boc-
Imines
Table 3. One-Pot Synthesis of N-Boc-Propargylic Amines
a
2
A catalytic cycle and plausible transition state models for the
present reaction are proposed in Figures 1 and 2. We believe
b
entry
R
yield (%)
c
1
4-MeO-C6H4-CC
4-Br-C6H4-CC
Bu-CC
2b
2c
2e
2f
41
72
70
65
64
8
15
2
d
3
d
4
d
Cy-CC
5
(E)-Ph-CHCH
2h
a
Reactions were performed on a 0.1 mmol scale in 1.0 mL of CH2Cl2.
Isolated yield. Performed at 0 °C. Use of 20 mol % of BF3·OEt2.
b
c
d
concomitant formation of cyclic carbamate 8 (entry 1),11 while
electron-deficient alkynylboronic ester afforded a good yield of
product (entry 2). Since alkyl-substituted alkynylboronic esters
were less reactive compared to aryl-substituted ones, higher
catalyst loadings (20 mol %) were used (entries 3 and 4).
When styrylboronic ester was employed, a 64% yield of the
desired alkenylation product was obtained (entry 5).
Figure 1. Proposed catalytic cycle.
We then examined the allylation of the in situ generated N-
Boc-imine using allylboronic ester 5 (Scheme 5).12,13
However, the allylation of phenylpropiolaldehyde proceeded
Scheme 5. Allylation of the in Situ Generated N-Boc-Imines
Figure 2. Plausible transition state models.
that BF3·OEt2 plays two different roles: one is the Lewis acid
catalyst for the in situ imine generation, and the other is the
activation of boronic ester. Boronic ester 3 is known to form
the more Lewis acidic fluoroborane intermediate 10 by the
ligand exchange with BF3·OEt2.6b,16 The alkynyl group adds to
the imine, which is activated by coordination to the boron
center, through either a four-membered transition state TS16d
or a six-membered transition state TS2 (Figure 2).6b
A
catalytic amount of fluoride source is employed in the present
reaction, and triisopropyl borate was observed in the 1H NMR
spectrum of the reaction mixture. These facts indicate the
recycling of fluoride as shown in Figure 1.
C
DOI: 10.1021/acs.orglett.9b00931
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Asakawa, D.; Maruoka, K. Chem. Commun. 2015, 51, 16472.
(d) Yurino, T.; Aota, Y.; Asakawa, D.; Kano, T.; Maruoka, K.
Tetrahedron 2016, 72, 3687. (e) Bai, J.-F.; Sasagawa, H.; Yurino, T.;
Kano, T.; Maruoka, K. Chem. Commun. 2017, 53, 8203.
(9) Boc-protected imines having an alkynyl group can also be
genarated from Boc-protected hemiaminal ethers; see: (a) Wang, Y.;
Mo, M.; Zhu, K.; Zheng, C.; Zhang, H.; Wang, W.; Shao, Z. Nat.
Commun. 2015, 6, 8544. (b) Wang, Y.; Jiang, L.; Li, L.; Dai, J.; Xiong,
D.; Shao, Z. Angew. Chem., Int. Ed. 2016, 55, 15142.
In summary, we have synthesized N-Boc-protected prop-
argylic amines via the BF3-catalyzed addition reaction of
alkynyl and allylboronic esters to the in situ generated N-Boc-
imines. This method is performed under mild reaction
conditions and allows direct synthesis of less accessible α-
alkynyl, α-alkenyl, and α-allyl-substituted N-Boc-propargylic
amines in a more operationally simple and atom economic
process compared to the previous reactions using strongly
basic organometallic reagents.
(10) Kano, T.; Homma, C.; Maruoka, K. Org. Biomol. Chem. 2017,
15, 4527.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00931.
(11) Kano, T.; Yasumoto, K.; Maruoka, K. Asian J. Org. Chem. 2018,
7, 1575.
(12) For allylation of alkynylimines with allylboronic esters, see:
(a) Silverio, D. L.; Torker, S.; Pilyugina, T.; Vieira, E. M.; Snapper, M.
L.; Haeffner, F.; Hoveyda, A. H. Nature 2013, 494, 216. (b) Jiang, Y.;
Schaus, S. E. Angew. Chem., Int. Ed. 2017, 56, 1544.
■
S
(13) For allylation of imines with allylboronic esters, see:
(a) Hoffmann, R. W.; Eichler, G.; Endesfelder, A. Liebigs Ann.
Chem. 1983, 1983, 2000. (b) Yamamoto, Y.; Komatsu, T.; Maruyama,
K. J. Chem. Soc., Chem. Commun. 1985, 814. (c) Watanabe, K.; Ito, K.;
Itsuno, S. Tetrahedron: Asymmetry 1995, 6, 1531. (d) Lou, S.;
Moquist, P. N.; Schaus, S. E. J. Am. Chem. Soc. 2007, 129, 15398.
(e) Barker, T. J.; Jarvo, E. R. Org. Lett. 2009, 11, 1047. (f) Vieira, E.
M.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2011, 133,
3332. (g) Kojima, M.; Mikami, K. Chem. - Eur. J. 2011, 17, 13950.
(h) Cui, Y.; Yamashita, Y.; Kobayashi, S. Chem. Commun. 2012, 48,
10319. (i) Ghosh, D.; Bera, P. K.; Kumar, M.; Abdi, S. H. R.; Khan,
N. H.; Kureshy, R. I.; Bajaj, H. C. RSC Adv. 2014, 4, 56424. (j) Zhao,
Y.-S.; Liu, Q.; Tian, P.; Tao, J.-C.; Lin, G.-Q. Org. Biomol. Chem.
2015, 13, 4174.
Experimental procedures and spectral data for all new
compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: maruoka@kuchem.kyoto-u.ac.jp.
*E-mail: kano@kuchem.kyoto-u.ac.jp.
ORCID
Taichi Kano: 0000-0001-5730-3801
Keiji Maruoka: 0000-0002-0044-6411
Notes
(14) Lachance, H.; Hall, D. G. Org. React. 2009, 73, 1.
The authors declare no competing financial interest.
(15) Use of 10 mol % of diphenyl phosphate gave 6a in 69% yield. A
chiral phosphoric acid catalyst derived from BINOL also promoted
the reaction, but afforded the racemic product.
(16) Allylation of 4a with allylboronic acid pinacol ester did not
proceed, and this result suggests that boronic esters may be activated
through ligand exchange on the boron atom.
ACKNOWLEDGMENTS
This work was supported by JSPS KAKENHI Grant Numbers
JP17H06450, JP26220803, and JP18H01975.
■
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DOI: 10.1021/acs.orglett.9b00931
Org. Lett. XXXX, XXX, XXX−XXX