Highly Stereoselective Synthesis of Terminal Chloro-Substituted Propargylamines and Further Functionalization

Article abstract of DOI:10.1021/acs.orglett.5b02408

The highly stereoselective addition of lithiated chloroacetylene, derived in situ from cis-1,2-dichloroethene and methyl lithium, to Ellman chiral N-tert-butanesulfinyl imines is reported. The reaction proceeds in high yield (up to 98%) and with excellent

Full text of DOI:10.1021/acs.orglett.5b02408

Letter
pubs.acs.org/OrgLett
Highly Stereoselective Synthesis of Terminal Chloro-Substituted
Propargylamines and Further Functionalization
Savannah Jordan,† Samuel A. Starks,† Michael F. Whatley, and Mark Turlington*
Department of Chemistry, Berry College, Mount Berry, Georgia 30149, United States
S
* Supporting Information
ABSTRACT: The highly stereoselective addition of lithiated
chloroacetylene, derived in situ from cis-1,2-dichloroethene and
methyl lithium, to Ellman chiral N-tert-butanesulfinyl imines is
reported. The reaction proceeds in high yield (up to 98%) and
with excellent diastereoselectivity (up to >20:1) for a variety of
aryl, heteroaromatic, alkyl, and α,β-unsaturated imine sub-
strates. Transformations of the terminal chloro-substituted
propargylamine products are described in which lithium−
halogen exchange yields nucleophilic acetylides that can be quenched to yield terminal alkynes or intercepted by carbon
electrophiles.
he asymmetric addition of chemically diverse alkynes to
imines is an important goal in synthetic organic chemistry
T
due to the utility of optically active propargylamines in the
synthesis of a variety of natural products, heterocycles, and
bioactive compounds.1 In light of their synthetic potential,
many strategies for the stereoselective synthesis of propargyl-
amines have been developed. Featuring predominately in this
methodology are several classes of catalytic systems including
copper-catalyzed alkyne additions to imines in the presence of
chiral tridentate ligands (e.g., Pybox)2 or chiral Bronsted acids;3
copper-catalyzed three-component couplings of aldehydes,
amines, and alkynes in the presence of chiral ligands;4 and
the addition of zinc acetylides to imines in the presence of
chiral amino alcohol and BINOL-based ligands.5 In addition to
asymmetric catalysis, diastereoselective addition of metal
acetylides to chiral imines is also a robust method for the
synthesis of chiral propargylic amines.6 In particular the
addition of lithium acetylide,7 alkynyl Grignard,8 and aluminum
acetylide9 reagents to Ellman N-tert-butanesulfinyl (N-t-BS)
imines has been studied extensively and the utility of this
approach has been demonstrated in the synthesis of complex
molecules.8 Alternate strategies to access optically active
propargylamines including kinetic resolution,10 biocatalytic
syntheses,11 and radical alkynylation12 have also been recently
developed.
Figure 1. Directly accessible classes of chiral propargylamines and
current method to access terminal halo-substituted propargylamines.
stereoselective synthesis of terminal halo-substituted propargyl-
amines would constitute a significant advance in making these
molecules more readily accessible. In light of the absence of
such a method for the preparation of terminal halo-substituted
propargylamines (racemic or asymmetric), and the synthetic
potential of this class of propargylamines, we have developed a
highly stereoselective method for the synthesis of these
molecules and have initiated investigations into their synthetic
utility.
The addition of halogenated acetylenes to imine electrophiles
is hampered by the limited commercial availability and volatility
of the haloacetylenes, as only chloroacetylene is commercially
available and is a gas at room temperature. However, reaction
of commercially available 1,2-dihaloethenes with organolithium
reagents efficiently generates lithiated haloacetylides in situ14a
via E2 elimination and deprotonation as shown in Scheme 1. As
lithiated haloacetylides generated in this manner have been
To date, optically active propargylamines prepared using
these methods bear aryl, alkyl, or silyl alkyne substituents
(Figure 1). We envisioned that propargylic amines 1 bearing an
acetylenic halogen constitute a useful class of propargylamines
as the halogen provides access to additional modes of acetylene
reactivity. Indeed, terminal halo-substituted propargylamines
have been used in route to more complex molecular
structures;13 however, preparation of these substrates requires
halogenation of propargylamines bearing a terminal alkyne
which in turn must be prepared from a terminal acetylene
precursor13 (Figure 1). Thus, a direct method for the
Received: August 20, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02408
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
compound.16 Screening reaction solvents revealed that THF
decreased the diastereoselectivity of the reaction (entry 3)
while hexanes severely diminished reactivity (entry 4). CH2Cl2
was found to be an unsuitable solvent (entry 5). Excellent yield
(95%) and diastereoselectivity (>20:1) were achieved with 1,4-
dioxane (entry 6).
Scheme 1. In Situ Generation of Lithiated Chloroacetylide
shown to be effective nucleophiles with carbonyl electro-
philes,14 we envisioned that this approach could be applied in
the diastereoselective addition to chiral imines. Due to the good
diastereoselectivities observed in the addition of lithium
acetylides to Ellman N-t-BS imines (up to >99:1 dr)7 and the
success of a similar strategy by Poisson and co-workers in the
addition of lithiated ynol ethers (derived from dichloroenol
ethers) to N-t-BS imines,7b we chose to explore the use of these
chiral imines to access optically active terminal halo-substituted
propargylamines.
We began our studies by testing the addition of lithiated
chloroacetylene generated in Et2O from cis-1,2-dichloroe-
thene15 and MeLi (1.6 M in Et2O) at 0 °C14a to phenyl N-t-
BS imine 2a as shown in Table 1. We were pleased to find that
Having identified 1,4-dioxane as the optimal solvent several
bases were tested. Use of n-BuLi (2.5 M in hexanes, entry 7)
afforded similar results to MeLi, while use of LDA significantly
diminished the isolated yield (entry 8). LiHMDS, shown to be
an effective base in the addition of lithium acetylides to N-t-BS
imines,7a was also tested. LiHMDS (1.0 M in THF) negatively
affected diastereoselectivity (entry 9); however, LiHMDS (1.0
M in hexanes) displayed high stereoselectivity and good yield
(entry 10). Dilution of the reaction mixture by 2-fold (entry
11) did not significantly impact reactivity or diastereoselectivity.
The use of BF3·OEt2 as a Lewis acid additive was also tested,
as this has been shown to reverse the diastereoselectivity of the
reaction in related additions with the reaction presumably
proceeding through an open transition state.7b,c However, use
of BF3·OEt2 with our optimized conditions resulted in the
formation of only a trace amount of product (entry 12). Finally,
we also explored whether the optimal reaction conditions in
entry 6 could be utilized with 1,2-dibromoethene in order to
access terminal bromo-substituted propargylamines. Unfortu-
nately, no desired product was obtained when 1,2-dibromoe-
thene (commercially available as a mixture of cis and trans
isomers) was used.
Table 1. Optimization of Reaction Conditions for Addition
a
of Lithium Chloroacetylide to Ellman Imine 2a
Having identified the use of cis-1,2-dichloroethene and MeLi
in 1,4-dioxane (entry 6) as the optimal reaction conditions we
then explored the substrate scope of the transformation as
shown in Table 2. Good to excellent yields (64−98%) and
diastereoselectivities (10:1−>20:1) were obtained for a range of
aromatic, heteroaromatic, alkyl, and α,β-unsaturated N-t-BS
imines (Table 2). For aryl derivatives the reaction tolerated
electron-donating and -withdrawing substituents and substitu-
tion at the ortho-, meta-, and para-positions. Interestingly, lower
diastereoselectivities were observed for ortho-substituted phenyl
derivatives bearing a chlorine or methoxy group (entries 1 and
7), but this effect was not observed with the ortho-methyl group
(entry 5). Heterocycles were also tolerated in the reaction
(entries 9 and 10), although furyl derivative 3k was obtained
with the lowest observed diastereoselectivity (10:1, entry 10). It
is possible that imines 2b, 2h, and 2k exhibit lower
diastereoselectivity due to competing coordination of lithium
chloroacetylide by the proximal 2-position heteroatom, which
may partially disrupt the chair transition state responsible for
the high stereoselectivity in the other products.17
Reaction of alkyl N-t-BS imines proceeded in uniformly high
yield and dr for straight-chain, branched, and cyclic substrates
(entries 11 to 18) with the exception of isobutyl compound 3n
(entry 13). For this substrate, diminished diastereoselectivity
(14:1) and significant side product formation were observed in
analysis of the crude 1H NMR. Finally, reactions of α,β-
unsaturated N-t-BS imines were also found to proceed with
good selectivity and yield (entries 19 and 20). Pleasingly, the
reaction was scalable and could be performed on gram scale (5
mmol imine) for 3a and 3l with no erosion of diastereose-
lectivity and comparable yields to those reported in Tables 1
and 2 (93% and 88% respectively).
b
c
entry
base
solvent
Et2O
yield (%)
dr
d
1
MeLi
81
71
66
>20:1
>20:1
15:1
d
d
d
d
d
2
MeLi
MeLi
MeLi
MeLi
toluene
3
THF
e
4
hexanes
37
>20:1
5
CH2Cl2
−
−
6
MeLi
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
95
89
58
57
92
92
trace
>20:1
>20:1
>20:1
15:1
f
7
n-BuLi
g
8
LDA
h
i
9
LiHMDS
LiHMDS
10
11
12
>20:1
>20:1
N.D.
d
,
j
MeLi
MeLi
d,
k
a
Reaction conditions: cis-1,2-dichloroethene (1.5 mmol) dissolved in
solvent (1.0 mL) and cooled to 0 °C. A solution of base (1.5 mmol)
was added, and reaction was stirred at 0 °C for 30 min to generate
lithiated chloroacetylide. A solution of imine 2a (0.5 mmol) in solvent
(1.0 mL) was added, and the reaction was stirred for 1.5 h allowing it
b
c
1
to warm to rt. Isolated yield. Determined by analysis of crude H
d
e
f
NMR spectra. 1.6 M soln in Et2O. 3 h, 45% yield. 2.5 M soln in
g
hexanes. Prepared from diisopropylamine (1.5 mmol) and n-BuLi
(1.5 mmol, 2.5 M soln in hexanes) in 1,4-dioxane (1 mL). 1.0 M soln
in THF. 1.0 M soln in hexanes. 2-fold dilution: lithiated
chloroacetylide formed in 2.0 mL of 1,4-dioxane, and imine 2a was
h
i
j
k
added in 2.0 mL of 1,4-dioxane. Solution of imine (0.5 mmol)
precomplexed with BF3·Et2O (0.55 mmol).
the reaction proceeded in good yield (81%) and excellent
stereoselectivity (dr >20:1) with complete consumption of the
imine within 1.5 h. The stereochemistry of the amine
stereocenter was assigned in analogy to the accepted model
for lithium acetylide additions to N-t-BS imines7 and was later
confirmed through comparison of an analog derived from a
terminal chloro-substituted propargylamine to a known
Having determined the scope of the reaction, we next turned
our attention to exploring the utility of the terminal chloro-
substituted propargylamines. Treatment with n-BuLi (2.5
B
DOI: 10.1021/acs.orglett.5b02408
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 2. Substrate Scope for Addition of Lithium
Chloroacetylide to Ellman Imines 2
Scheme 2. Transformations of Terminal Chloro-Substituted
Propargylamines
a
b
c
entry
R
product
yield (%)
dr
1
2-ClC6H4
3-ClC6H4
4-ClC6H4
4-FC6H4
2-MeC6H4
4-MeC6H4
2-MeOC6H4
4-MeOC6H4
3-thienyl
2-furyl
3b
3c
3d
3e
3f
86
71
64
80
90
82
84
74
75
77
82
98
73
83
91
93
90
95
77
14:1
19:1
2
3
>20:1
>20:1
>20:1
>20:1
13:1
4
5
6
3g
3h
3i
7
8
>20:1
>20:1
10:1
9
3j
10
11
12
13
14
15
16
17
18
19
20
3k
3l
n-C5H11
n-C7H15
iBu
iPr
tBu
>20:1
>20:1
14:1
3m
3n
3o
3p
3q
3r
3s
3t
>20:1
19:1
c-C6H11
>20:1
>20:1
>20:1
19:1
c-C5H9
PhCH2CH2
PhCHCH
MeCHCH
3u
96
>20:1
a
b
Reaction conditions from Table 1, entry 6. Isolated yield.
Determined by analysis of crude H NMR spectra.
c
1
equiv) at −78 °C effected lithium−halogen exchange to afford
an intermediate dianion. Quenching with saturated aqueous
NH4Cl led to the corresponding terminal acetylenes in good
yield (84−99%, Scheme 2). Compound 4b matched the
reported compound16 in all aspects (1H NMR, 13C NMR,
optical rotation), allowing verification of the stereochemistry at
the propargylic carbon. Notably this approach to optically
active terminal propargylamines serves as an alternative among
a handful of methods providing access to these substrates.18
More interestingly, the intermediate lithium acetylide could
be intercepted with carbonyl electrophiles such as CO2 or
aldehydes to furnish the corresponding carboxylic acid (5) or
propargylic alcohol derivatives (6a/6b) in moderate to good
yield (Scheme 2). This strategy is a significant improvement
over previous methods to access these classes of compounds
which typically rely on silyl acetylenes as the terminal acetylene
surrogate and require separate deprotection and deprotonation
steps to generate the acetylene nucleophile.19 Considering that
the yields reported for deprotonation of terminal propargyl-
amines and addition to aldehydes are moderate (typically
∼50%),19 the use of chloro-substituted propargylamines
represents an attractive improvement over current methods
used in the synthesis of molecules such as 6a and 6b. Finally,
we have demonstrated that the acetylenic chlorine can be left
intact while selectively alkylating the nitrogen atom as
demonstrated in derivatives 7a and 7b. Substrates similar to
7b represent an important scaffold for cyclization reactions,20
and the acetylenic halogen is often desired for these
substrates13a and in related cyclizations.21
In summary we have developed a method for the direct
stereoselective synthesis of terminal chloro-substituted prop-
argylamines. Notably the method uses commercially available
materials, operates at easily accessible temperatures (0 °C), is
scalable (5 mmol scale), and is applicable for a range of
aromatic, heteroaromatic, alkyl, and α,β-unsaturated N-t-BS
imines. We have also demonstrated the useful reactivity of this
class of propargylamines, showing efficient access from these
substrates to terminal acetylenes, carboxylic acid and
propargylic alcohol derivatives, and N-alkylated compounds
maintaining the acetylenic chlorine. Studies toward developing
methods for the stereoselective synthesis of terminal bromo-
substituted propargylamines and further applications of this
intriguing class of molecules are ongoing and will be reported in
due course.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02408.
Proposed transition state explaining stereoselectivity,
experimental procedures and characterization data,
1
1
crude H NMR spectra for dr determination, and H
NMR and 13C NMR spectra (PDF)
C
DOI: 10.1021/acs.orglett.5b02408
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Botta, L. J. Am. Chem. Soc. 2010, 132, 11350. (c) Schevenels, F.;
Tinant, B.; Declercq, J.-P.; Marko, I. E. Chem. - Eur. J. 2013, 19, 4335.
́
AUTHOR INFORMATION
Corresponding Author
■
(15) We have not tested the use of trans-1,2-dichloroethene.
(16) Ye, L.; He, W.; Zhang, L. Angew. Chem., Int. Ed. 2011, 50, 3236.
(17) Disruption of the chair transition state for organometallic
additions to 2-pyridyl N-t-BS imines has been reported: Kuduk, S. D.;
Dipardo, R. M.; Chang, R. K.; Ng, C.; Bock, M. G. Tetrahedron Lett.
2004, 45, 6641. While Kuduk et al. observed a reversal of
stereoinduction, we observed only erosion of dr. The major
diastereomers of 3b, 3h, and 3k all exhibit an upfield chemical shift
for the propargylic proton indicating an anti relationship between the
propargylic proton and sulfinamide tert-butyl. This upfield shift for the
diastereomer bearing an anti relationship is consistent with all other
compounds 3 reported herein and with related propargylamines.7b,c
(18) Methods to access optically active terminal propargylamines:
(a) Gommermann, N.; Knochel, P. Chem. Commun. 2004, 2324.
(b) Patterson, A. W.; Ellman, J. A. J. Org. Chem. 2006, 71, 7110.
(c) Fan, W.; Ma, S. Chem. Commun. 2013, 49, 10175.
*E-mail: mturlington@berry.edu.
Author Contributions
†S.J. and S.A.S. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank Berry College and S.J. thanks the Richards
Scholar Program for financial support. The authors gratefully
thank Craig Lindsley and Matt Mulder of Vanderbilt University
for providing HRMS analysis and Frank McDonald of Emory
University for access to their departmental polarimeter.
(19) (a) Wipf, P.; Aoyama, Y.; Benedum, T. E. Org. Lett. 2004, 6,
3593. (b) Ko, E.; Burgess, K. Org. Lett. 2011, 13, 980.
(20) Bauer, R. A.; DiBlasi, C. M.; Tan, D. S. Org. Lett. 2010, 12, 2084.
(21) Baik, M.-H.; Mazumder, S.; Ricci, P.; Sawyer, J. R.; Song, Y.-G.;
Wang, H.; Evans, P. A. J. Am. Chem. Soc. 2011, 133, 7621.
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DOI: 10.1021/acs.orglett.5b02408
Org. Lett. XXXX, XXX, XXX−XXX