Enantioselective Alkylation of 2-Alkylpyridines Controlled by Organolithium Aggregation

Article abstract of DOI:10.1021/jacs.9b08659

Direct enantioselective α-alkylation of 2-alkylpyridines provides access to chiral pyridines via an operationally simple protocol that obviates the need for prefunctionalization or preactivation of the substrate. The alkylation is accomplished using chiral lithium amides as noncovalent stereodirecting auxiliaries. Crystallographic and solution NMR studies provide insight into the structure of well-defined chiral aggregates in which a lithium amide reagent directs asymmetric alkylation.

Full text of DOI:10.1021/jacs.9b08659

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Communication
Enantioselective Alkylation of 2-Alkyl Pyridines
Controlled by Organolithium Aggregation
Joshua Gladfelder, Santanu Ghosh, Maša Podunavac, Andrew W Cook, Yun Ma, Ryan
A Woltornist, Ivan Keresztes, Trevor W. Hayton, David B. Collum, and Armen Zakarian
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b08659 • Publication Date (Web): 28 Aug 2019
Downloaded from pubs.acs.org on August 28, 2019
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Table 2. Scope of alkyl halide
gates between the chiral lithium amide and !-lithio-2-alkyl
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
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4
4
4
5
5
5
5
5
5
5
5
5
5
6
pyridines, supporting a hypothesis for the origin of enantio-
control.
1
R!# $" &$)ꢀ;AD=E!"ꢀn#2D5="ꢀ4671ꢀ %$,*ꢀ;AD=E!
7<6;"ꢀꢀ%ꢀ@30ꢀC<;?ꢀ8#9"ꢀ#,-ꢀ@3
$
$
2
To identify the optimal reagent for the enantioselective al-
kylation, several chiral amines were screened first (Table 1).
#
&
1(
1
3
C
2
-Symmetrical amines (R)- TA- TA that gave excellent
enantioselectivity in enediolate alkylation provided only
$
$
$
$
moderate level of enantiocontrol (entries 1-3). In contrast,
#
#
"#
#
#
1
4
diamines such as (R)- DA- DA showed an improved enanti-
omeric ratio (er), with N-tert-butyl-substituted amine (R)-
!)
ꢀ)b
*-ꢁꢀF=;>:
(/,ꢀ;B
ꢀ*
ꢀ+
ꢀ,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
*,ꢁꢀF=;>:
.)/+ꢀ;B
+*ꢁꢀF=;>:
-,/&(ꢀ;B
*+ꢁꢀF=;>:
.-/'ꢀ;B
DA being the best (entries 5-8). Given the importance of
additives for aggregation states of organolithium com-
.
1ꢀ
pounds, we screened the effect of common lithium ligands.
HMPA displayed an enhancement in both conversion (from
$
$
$
$
#
#
#
#
2
2% to 55%) and er (from 87:13 to 97:3, entries 5,10).
#%!
While LiBr also produced an increased er, the conversion was
suppressed due to incomplete lithiation of the substrate. We
found that in general, lithiation of 1a was inhibited by lithi-
um compounds, including n-BuLi itself. Toluene proved to
%
%
'
&
('ꢀ
ꢀ/b
ꢀ-
ꢀ.
ꢀ0
*
,ꢁꢀF=;>:
*-ꢁꢀF=;>:
.)/+ꢀ;B
*+ꢁꢀF=;>:
,+ꢁꢀF=;>:
.*/*ꢀ;B
.,/(ꢀ;B
.)/+ꢀ;B
be the optimal solvent; ethereal solvents (THF, Et O, 1,4-
2
dioxane, 1,2-dimethoxyethane) resulted in no enantioselec-
tivity, while the use of hydrocarbon solvents (hexane, cyclo-
hexane) encountered solubility problem.
$
$
$
$
#
#
#
#
$
$
'
'
Table 1. Identification of the optimal reaction conditions for
a
benzylation of 2-butylpyridine.
%
%
ꢀ
ꢁb
ꢀ2
ꢀ3
ꢀ4
"
$%)!&ꢀ!'%(#:
+&ꢁꢀF=;>:
.,/(ꢀ;B
**ꢁꢀF=;>:
.(/,ꢀ;B
+)ꢁꢀF=;>:
../&ꢀ;B
,)ꢁꢀF=;>:
-%/'%ꢀ;B
1
(
(
(
ꢀ" '!ꢁ = * #
#$
= $#
2
1(
ꢀ" '!ꢁ = * $
$
$
%
) %)
ꢀ" '!ꢁ = * %
a
6
9:?4; 4<:=8
Reaction conditions: All reactions were carried out on a 0.44
mmol scale unless otherwise noted. Isolated yields are shown.
Results are normalized to bases with the R configuration, enan-
tiomeric ratios (er) measured by HPLC analysis. 0.5 equiv of
A8A?44<:=8@ ('!ꢀ
(
"+B/:! 477:A:C8! 2908! # >,)
5
8=ED; 5?><:78! "&' >
,
&
(
(
(
(
ꢀ"1"!ꢁ 3 * *"+B
#$
2
ꢀ" "!ꢁ 3 * -A
b
$
2(
%)
ꢀ" "!ꢁ 3 * 474<4=AD;
1
HMPA and 1.0 equiv of (R)- DA were used.
H B!
7:4<:=8@ ("!ꢀ
ꢀ" "!ꢁ 3 * 081,.%,.%
entry
amine
additive
yield(%)
31
er, 2a
74:26
78:22
53:47
65:35
87:13
64:36
73:27
79:21
91:9
High enantioselectivity was obtained upon reaction of 1a
with a range of activated electrophiles (Table 2). Methylation
proceeded with enantiomer ratio of 93:7 (2a). Allyl bromide
and methallyl bromide afforded alkylation products in 94:6
er and 87:13 er, respectively (2b, 2c). High enantioselectivi-
ty was observed for a variety of benzylic bromides (2d-2i).
Highly reactive heteroaromatic benzylic bromides proved to
be effective alkylating agents. 2-Thienyl bromide and 2-
1
b
b
b
b
1
2
3
4
5
6
7
8
9
(R)- TA
-
2
(R)- TA
-
45
3
(R)- TA
-
20
2
(R)- TA
HMPA
65
1
(R)- DA
-
22
2
(R)- DA
-
-
25
(
bromomethyl)pyridine reacted rapidly to form 2j in 93:7 er
3
(R)- DA
21
and 2k in 99:1 er. Despite attempted additional refinement
of reaction conditions, alkylation with 2-(bromomethyl)-1,3-
benzothiazole afforded 2l in 80:20 er.
4
(R)- DA
-
32
1
(R)- DA
LiBr
HMPA
DMPU
TMEDA
11
The scope of 2-alkylpyridines was investigated by enanti-
oselective benzylation employing the conditions developed
for 1a; however, for several substrates improved results were
achieved by modifying the stoichiometry of HMPA and the
chiral lithium amide (Table 3). Increasing the length of the
alkyl chain (3b) produced results similar to those observed
during benzylation of 1a. Benzylation of 2-ethylpyridine
1
1
0
(R)- DA
55
97:3
1
11
(R)- DA
25
80:20
50:50
1
1
2
(R)- DA
70
aReaction conditions: 0.44 mmol butyl pyridine, 0.90 mmol
n-BuLi, 0.45 mmol amine, 0.22 mmol additive, 0.53 mmol
BnBr, toluene (5.0 mL), see the Supporting Information for
details. Isolated yields are shown. Enantiomeric ratios (er) were
(
1c) occurred in similar yield (76%) but diminished er
85:15) compared to 1a. When the stoichiometry of the chi-
(
b
determined by HPLC analysis. 3.03 equiv of n-BuLi were used.
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ral amine and HMPA was reduced, the reaction proceeded
with greater er (92:8) and somewhat reduced yield (58%).
Substrates containing "-branching (3g, 3h) were initially
alkylated in poor er (<3:1) under the original procedure, but
good results were observed by adjusting the quantity of
1
2
3
4
5
6
7
8
9
Table 3. Scope of 2-alkyl pyridines.
1
HMPA to 1.25 equiv while lowering the amount of (R)- DA
1
ꢁ
R!# $"ꢁꢁ&$) =CF?G!" #3F7?" 68:2 ꢁꢀ$,* =CF?G!
>8=" ꢀ B40 E>=A 3A3D" #,- B
to 1.0 equiv. Substrates with ", -unsaturation were alkylated
with poor er (<2:1), but ,!- and !,ꢀ-unsaturation was toler-
ated furnishing 3i and 3j with good enantioselectivity. Pyri-
dine 3k gave results identical to those observed for benzyla-
tion of 2-ethylpyridine, 3c. Quinolines are useful compounds
:
4
)
)
)1
%
)1
&
!
&
1
#9
!
-" ;& 1 46'ꢁ46'!)46(
ꢁ+,% H?=@<
,26
#
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
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3
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3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
)1
%
in medicinal chemistry. Quinoline 3l was accessed with
very good enantioselectivity by this protocol. Halogen sub-
stitution at the 6-position resulted in moderate erosion of
enantioselectivity (3m, 3n). In contrast, C6-substitution
with a methoxy group enhanced enantioselectivity, furnish-
ing 3o in 98:2 er. The presence of a morpholine group was
detrimental, resulting in racemic product under the original
conditions. Remarkably, in the absence of HMPA, a strong
boost in er to 89:11 was observed (3p), potentially due to
internal chelation.
&
&
&
.*/* =D
%
#9
#9
%
#9
," ;& 1 46'46'46(
!
!." ;& 1 46(
!/
!0b
,
*% H?=@<
ꢁ*-% H?=@<
.'/- =Db
-*% H?=@<
.ꢀ/&ꢀ =D
+&% H?=@<
.-/' =D
.*/* =D
&
&
&
&
%
#9
%
#9
%
#9
%
#9
!4
!ꢀb
!2c
!3cꢁ
,)% H?=@<
-./&& =D
,-% H?=@<
.ꢀ/&ꢀ =D
,,% H?=@<
*
*% H?=@<
,/( =D
.'/- =D
.
When an ether or ketal are present at the -position, an
exceptional increase in enantioselectivity is observed (3q, 3r,
3s). Benzylation of 1q also proceeded in very good yield
(80%) and excellent er (97:3) in the absence of HMPA when
(
3
)!
&
&
&
&
1
3
%
#9
% #9
%
#9
5b
%
#9
(R)- DA was replaced with the chiral amide (R)- TA. Nota-
bly, no enhancement was observed upon alkylation of the
!8 " ;(
-)% H?=@<
(/&, =D
1 4@
!6b
!
!7
+(% H?=@<
*-% H?=@<
.'/- =D
)&% H?=@<
.'/- =D
1
,3-dioxane 3t, in which no internal chelation by the !-alkoxy
group is feasible.
-
-,/&( =D
!9 " ;( 1 5
ꢀ% H?=@<
+/&) =D
Table 4. Enantioselective alkylation of 2-(3-methoxy-1-
propyl)pyridine (1r).
-
'
-
+
#*'
&
&
&
%
#9
!:" ;( 1 98=
-% H?=@<
-/' =D
%
#9
1
ꢁ
R!# #"ꢀꢁ&$( :@C<D!" n#1C4<" 3560 ꢁꢀ$+) :@C<D!
6;5:" ꢀ ?2/ B;:> 7#8" #+, ?
)
!;!
!<
,ꢀ% H?=@<
-/' =D
2
.
ꢁ
"
"
+
+% H?=@<
!
!
.
-
./&& =D
!
1$
4
'
O
'
&
"
&
!
&
'
%
#9
!?
%
#9
!>
%
#9
'
"
"
!
!
!=
)% H?=@<
./& =D
$!ꢀ,*% E<:=9" --.& :A
-
-'% H?=@<
.-/' =D
+,% H?=@<
.ꢀ/&ꢀ =D
!
#
.
"
!
"
! #
"
"
a
Reaction conditions: All reactions were performed on a 0.44
%
&
'
mmol scale unless otherwise noted. Isolated yields are shown.
*
'% E<:=9
+ꢀ% E<:=9
--.& :A
,*% E<:=9
--.& :A
Results are normalized to bases with the R configuration, enan-
--.& :A
b
tiomeric ratios (er) measured by HPLC analysis. 0.5 equiv of
1
c
a
HMPA and 1.0 equiv of (R)- DA were used. 1.0 equiv of (R)-
Reaction conditions: Reactions were performed on a 0.44
1
d
1
DA and 1.25 equiv of HMPA. 1.4 equiv of (R)- DA and 1.0
equiv of HMPA. LDA used instead of n-BuLi. 1.0 equiv of (R)-
mmol scale unless otherwise noted. Isolated yields are shown.
Results are normalized to bases with the R configuration, enan-
tiomeric ratios, determined by HPLC analysis.
e
1
DA and no HMPA.
Alkylation of tetrahydroquinoline 3d proceeded smoothly
We explored this intriguing enhancement of enantioselec-
tivity by the !-alkoxy substituents in greater detail, testing
additional electrophiles with 1r (Table 4). Methylation oc-
curred in very good yield and excellent enantioselectivity
(4a, er 99:1). Alkylation was also successful with less reactive
electrophiles. Ethylation of 1a resulted in only 14% conver-
sion, however, under identical conditions 1r reacted with
in very good yield and enantioselectivity. Branching at the !-
position of the C-2 alkyl chain (3e, 3f) had a detrimental
impact on enantioselectivity under the standard conditions;
however, when the amount of HMPA and chiral lithium am-
ide was reduced, excellent enantioselectivity was observed
with only slightly diminished conversion.
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aggregates involved in the alkylation reactions and allow for a
1
2
3
4
5
6
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structure-based design of new lithium amide reagents for
expanded applications in the future.
(
10) Lu, P.; Jackson, J. J.; Eickhoff, J. A.; Zakarian, A. Direct enantiose-
ASSOCIATED CONTENT
lective conjugate addition of carboxylic acids with chiral lithium amides as
traceless auxiliaries. J. Am. Chem. Soc. 2015, 137, 656-659.
The Supporting Information is available free of charge on the
ACS Publications website.
1 13
Full experimental procedures and copies of H, C NMR
spectra and HPLC traces.
(11) Yu, K.; Lu, P.; Jackson, J. J.; Nguyen, T.; Alvarado, J.; Stivala, C. E.;
Ma, Y.; Mack, K. A.; Hayton, T. W.; Collum, D. B.; Zakarian, A. Lithium
enolates in the enantioselective construction of tetrasubstituted carbon
centers with chiral lithium amides as noncovalent auxiliaries. J. Am. Chem.
Soc. 2017, 139, 527-533.
1
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Crystallographic data for 1c-Li and 1r-Li.
(
12) Reich, H. J. Role of organolithium aggregates and mixed aggregates
in organolithium mechanisms. Chem. Rev. 2013, 113, 7130-7178.
13) Ma, Y.; Stivala, C. E.; Wright, A. M.; Hayton, T.; Liang, J.;
AUTHOR INFORMATION
Corresponding Author
(
Keresztes, I.; Lobkovsky, E.; Collum, D. B.; Zakarian, A. “Enediolate-
Dilithium amide mixed aggregates in the enantioselective alkylation of
arylacetic acids: structural studies and a stereochemical model” J. Am.
Chem. Soc. 2013, 135, 16853-16864
(14) Ma, Y.; Mack, K. A.; Liang, J.; Keresztes, I.; Collum, D. B.; Zakari-
an, A. Mixed aggregates of dilithiated Koga tetraamine: NMR spectroscop-
ic and computational studies. Angew. Chem. Int. Ed. 2016, 55, 10093-
10097.
(15) Asymmetric alkylation of typical enolates mediated by CLAs: Imai,
M.; Hagihara, A.; Kawasaki, H.; Manabe, K.; Koga, K. Catalytic asymmetric
benzylation of achiral lithium enolates using a chiral ligand for lithium in
the presence of achiral ligand. J. Am. Chem. Soc. 1994, 116, 8829-8830.
*
zakarian@chem.ucsb.edu
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
T.W.H. and A.W.C. thank the National Science Foundation
(CHE 1361654) for financial support. A.W.C. thanks the Mel-
lichamp Academic Initiative in Sustainability at UCSB for a
(16) Frizzle, M. J.; Nani, R. R.; Martinelli, M. J.; Moniz, G. A. Asymmet-
summer fellowship. This work was supported by the NIH
ric alkylation of 5-alkyl-2-aminothiazolones using a C
tetraamine base. Tetrahedron Lett. 2011, 52, 5613-5616.
(17) Vitaku, E.; Smith, D. T.; Njardarson, J. T. Analysis of the structural
diversity, substitution patterns, and frequency of nitrogen heterocycles
among U.S. FDA approved pharmaceuticals. J. Med. Chem. 2014, 57,
2
-symmetric chiral
(NIGMS, R01-077379 to A.Z.; R01-131713 to D.B.C.). Dr.
Hongjun Zhou is acknowledged for assistance with NMR spec-
troscopy. Dr. Dmithry Uchenik is and the UCSB mass spectros-
copy facility are thanked for assistance with mass spectral analy-
sis. Dr. Guang Wu and the UCSB X-ray analytical facility are
acknowledged for the assistance with the X-ray diffractometry.
1
0257-10274.
18) Trost, B. M.; Thaisrivongs, D. A. Palladium-catalyzed region-, dia-
(
stereo-, and enantioselective benzylic allylation of 2-substituted pyridines. J.
Am. Chem. Soc. 2009, 131, 12056-12057.
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