Enantioconvergent Alkylations of Amines by Alkyl Electrophiles: Copper-Catalyzed Nucleophilic Substitutions of Racemic α-Halolactams by Indoles

Article abstract of DOI:10.1021/jacs.9b07875

Transition-metal catalysis has the potential to address shortcomings in the classic S_N2 reaction of an amine with an alkyl electrophile, both with respect to reactivity and to enantioselectivity. In this study, we describe the development of a user-friendly method (reaction at room temperature, with commercially available catalyst components) for the enantioconvergent nucleophilic substitution of racemic secondary alkyl halides (α-iodolactams) by indoles. Mechanistic studies are consistent with the formation of a copper(I)-indolyl complex that reacts at different rates with the two enantiomers of the electrophile, which interconvert under the reaction conditions (dynamic kinetic resolution). This investigation complements earlier work on photoinduced enantioconvergent N-alkylation, supporting the premise that this important challenge can be addressed by a range of strategies.

Full text of DOI:10.1021/jacs.9b07875

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Enantioconvergent Alkylations of Amines by Alkyl Electrophiles:
Copper-Catalyzed Nucleophilic Substitutions of Racemic
α‑Halolactams by Indoles
Agnieszka Bartoszewicz, Carson D. Matier, and Gregory C. Fu*
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United States
S
* Supporting Information
ABSTRACT: Transition-metal catalysis has the potential to
address shortcomings in the classic SN2 reaction of an amine with
an alkyl electrophile, both with respect to reactivity and to
enantioselectivity. In this study, we describe the development of a
user-friendly method (reaction at room temperature, with
commercially available catalyst components) for the enantiocon-
vergent nucleophilic substitution of racemic secondary alkyl
halides (α-iodolactams) by indoles. Mechanistic studies are
consistent with the formation of a copper(I)−indolyl complex
that reacts at different rates with the two enantiomers of the
electrophile, which interconvert under the reaction conditions
(dynamic kinetic resolution). This investigation complements earlier work on photoinduced enantioconvergent N-alkylation,
supporting the premise that this important challenge can be addressed by a range of strategies.
construction; for example, in one analysis of reactions used by
the pharmaceutical industry, the coupling of an alkyl
electrophile with a nitrogen nucleophile was the most
frequently employed method for achieving N-substitution,
exceeding approaches such as reductive amination and
Ullmann/Buchwald−Hartwig reactions.5 Nevertheless, uncata-
lyzed SN2 reactions of alkyl electrophiles with amines have
substantial limitations: with less reactive electrophiles,
elimination to form an olefin can occur in preference to
substitution, whereas with more reactive electrophiles, over-
alkylation can be a significant side reaction. Transition-metal
catalysis has the potential to address this challenge of
controlling reactivity and to thereby expand the scope of
substitution reactions of alkyl electrophiles by amines;
however, progress to date has been rather limited (right side
of Figure 1).6,7
INTRODUCTION
■
Because a wide array of organic molecules (including
pharmaceuticals, agrochemicals, and polymers) contain car-
bon−nitrogen bonds, the development of methods for the
construction of C−N bonds is of great interest.1 The
nucleophilic substitution of an electrophile by an amine is a
particularly straightforward strategy for the generation of C−N
bonds; unfortunately, however, thermal/uncatalyzed ap-
proaches do not satisfactorily address a variety of challenges
with regard to scope and/or stereoselectivity (Figure 1).
In the case of substitution reactions of alkyl electrophiles,
there can be a challenge not only of achieving the desired C−N
bond construction but also of controlling stereochemistry in
the event that a chiral electrophile is used (Figure 2a). Because
an array of bioactive molecules include chiral amines wherein
nitrogen is attached to a stereogenic carbon (Figure 2b),8,9 the
development of catalysts that can simultaneously address the
dual challenges of reactivity and stereoselectivity is a
worthwhile goal.6,10,11
Figure 1. Nucleophilic substitution of electrophiles by amines:
Qualitative overview.
Consequently, efforts have turned to catalysis of this
transformation by transition metals. In the case of substitution
reactions of aryl electrophiles by amines, the Ullmann reaction
(copper catalysis)2 and the Buchwald−Hartwig reaction
(palladium catalysis)3 can achieve this important objective
with a much broader spectrum of electrophiles than is possible
using uncatalyzed approaches, such as nucleophilic aromatic
substitution (left side of Figure 1).4
We have recently demonstrated the feasibility of this
objective, specifically, that enantioconvergent N-alkylations
by racemic tertiary alkyl chlorides can be achieved in the
The uncatalyzed substitution reaction of alkyl electrophiles
by amines is a widely applied approach to C−N bond
Received: July 23, 2019
© XXXX American Chemical Society
A
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Table 1. Enantioconvergent N-Alkylation: Effect of
a
Reaction Parameters
b
entry
change from the “standard conditions”
ee (%)
yield (%)
1
2
3
4
5
6
7
8
none
no Cu-Mes, no L*
no L*
87
−
−
32
82
68
83
85
84
8
55
39
64
76
67
74
L1, instead of L*
5 mol % Cu-Mes, 10 mol % L*
14, instead of 20, mol % L*
under air in a capped vial
0.1 equiv of water added
Figure 2. Chiral amines wherein nitrogen is attached to a stereogenic
carbon: (a) synthesis via metal-catalyzed enantioconvergent alkyla-
tion; (b) examples of bioactive compounds.
a
b
All data represent the average of two experiments. Determined
through H NMR spectroscopy, with the aid an internal standard.
1
presence of light and a chiral copper catalyst (Figure 3).11 In
this report, we describe complementary reactivity, wherein, in
the reaction mixture, only a small amount of a background
reaction is observed (entry 2:8% yield), whereas, if only L* is
omitted, considerable N-alkylation occurs (entry 3:55% yield).
The use of a different chiral monodentate phosphine,
phosphepine L1, results in modest ee and yield (entry 4).
With half of the standard catalyst loading, the ee and the yield
decrease somewhat (entry 6), and with less phosphine L*, a
significant loss in ee is observed (87 → 68% ee; entry 7). This
method for the catalytic enantioconvergent synthesis of 3-
indolyl lactams is not highly air- or moisture-sensitive (entries
7 and 8).
With suitable reaction conditions in hand, we explored the
scope of this new enantioconvergent N-alkylation with respect
to the electrophile (Table 2). The substituent on the nitrogen
of the lactam can be an electron-rich or an electron-poor
aromatic ring (entries 2 and 3), or it can be an alkyl group
(entries 4 and 5).14 Furthermore, six-membered α-iodolactams
can serve as electrophiles (entries 6 and 7). Finally, in the case
Figure 3. Complementary metal-catalyzed enantioconvergent sub-
stitution reactions of alkyl electrophiles by amines.
Table 2. Enantioconvergent N-Alkylation: Scope with
Respect to the Electrophile
a
the absence of light, a chiral copper catalyst effects
enantioconvergent N-alkylations by racemic secondary alkyl
iodides (Figure 3).
RESULTS AND DISCUSSION
■
3-Indolyl lactams exhibit a wide range of interesting bioactivity
(Figure 2b).8,12 When the photoinduced, copper-catalyzed
method that we had developed for enantioconvergent
alkylations by racemic tertiary alkyl chlorides (top of Figure
3)11 was applied to the alkylation of 3-methylindole by
secondary alkyl iodide A (Table 1), the results were
unsatisfactory (<1% ee, 24% yield). Upon exploring a variety
of conditions, we have determined that the desired
enantioconvergent coupling can be achieved in the absence of
light at room temperature (entry 1:87% ee, 84% yield; both Cu-
Mes and L* are commercially available).13 Control reactions
have established that, if Cu-Mes and L* are both omitted from
b
entry
R
n
ee (%)
yield (%)
1
2
3
4
5
6
7
Ph
1
1
1
1
1
2
2
88
91
90
90
82
80
88
73
78
73
72
80
88
74
4-(OMe)C6H4
4-(CF3)C6H4
Bn
Ph(CH2)3
Ph
4-(OMe)C6H4
a
b
All data represent the average of two experiments. Yield of purified
product.
B
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of an electrophile that bears a second stereogenic center, the
catalyst can predominantly control the stereochemistry of the
N-alkylation product (Figure 4).
Table 3. Enantioconvergent N-Alkylation: Scope with
Respect to the Nucleophile
a
Figure 4. Stereochemistry of the catalyst, rather than of the substrate,
predominantly controls the stereochemistry of an N-alkylation.
The standard conditions that we developed for copper-
catalyzed N-alkylations by a racemic alkyl iodide can also be
applied to an alkyl bromide (eq 1).15 A significantly higher
yield is observed in the presence of a larger excess of the
electrophile.
Next, we examined the scope of this copper-catalyzed
stereoconvergent N-alkylation with respect to the nucleophile
(Table 3).16 When indoles are used as the nucleophile (entries
1−11), substituents can be present in a range of positions,
including the 2 position. Furthermore, a variety of functional
groups are compatible with the coupling, such as an alkene, a
cyano group, an ether, an aryl bromide, and a secondary amide.
The method can be applied without further optimization to the
enantioconvergent alkylation of carbazoles (entries 12 and 13)
and an indoline (entry 14), with good enantioselectivity. On a
gram scale, the stereoconvergent N-alkylation depicted in entry
12 proceeds in 92% ee and 85% yield (1.06 g of product).17
Taken together, the ee and the yield establish that the
copper-catalyzed substitution of alkyl iodide A by 3-
methylindole (Table 1: 87% ee, 84% yield) is an
enantioconvergent process (not a simple kinetic resolution),
wherein both enantiomers of the electrophile are being
transformed by the chiral catalyst into a particular enantiomer
of the product. To gain insight into the mechanism, we
monitored the ee of the unreacted electrophile as a function of
time (Figure 5). We hypothesize that the initial increase in ee
is due to the chiral copper catalyst reacting more rapidly with
one enantiomer of the electrophile than the other. With each
N-alkylation, iodide anion is generated, which serves as a
nucleophile that racemizes the unreacted electrophile via an
SN2 reaction,18 thereby enabling a dynamic kinetic resolution
as well as leading to a decrease in the ee of the electrophile
during the later stages of the reaction.
a
b
All data represent the average of two experiments. Yield of purified
product.
phosphine L* provided a 65% yield of L*2Cu(3-methyl-
indolyl) (B; eq 2), which we have crystallographically
characterized (see the Supporting Information). When
complex B (10%) is used in place of Cu−Mes/L* for the N-
alkylation illustrated in Table 1, the enantioconvergent
coupling proceeds in similar ee and yield (78% ee and 96%
yield). Furthermore, in a stoichiometric reaction, copper
complex B couples with electrophile A within 15 min at
room temperature to afford the N-alkylation product with high
ee and high yield, thereby establishing its competence as a
possible intermediate (eq 3; 87% ee and 94% yield).19 An
investigation of the impact of the ee of L* on the ee of the
We have synthesized a possible intermediate in this copper-
catalyzed enantioconvergent N-alkylation. Treatment of Cu-
Mes with 3-methylindole in the presence of 2 equiv of chiral
C
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in contrast to our data for the iodide (Figure 5). Given that
racemization of the alkyl iodide is not extremely rapid under
the reaction conditions (Figure 5), the lack of significant
racemization of the alkyl bromide is understandable on the
basis of its lower propensity to undergo an SN2 reaction, as
well as being consistent with our observation that the use of
2.0, rather than 1.5, equiv of the alkyl bromide is necessary to
obtain a high yield in the asymmetric substitution reaction (eq
1).
We have examined the reaction of enantiopure copper
complex B with each enantiomer of 3-bromo-1-phenyl-
pyrrolidin-2-one (Table 4). In each case, the product is
Table 4. Stoichiometric Substitution Reactions of an
Enantiopure Electrophile by Enantiopure Copper Complex
B: Inversion of Stereochemistry
Figure 5. Copper-catalyzed enantioconvergent N-alkylation of an
indole by a racemic alkyl iodide via a dynamic kinetic resolution: ee of
the electrophile as a function of time.
product revealed a small positive nonlinear effect, consistent
with the presence of a copper complex that contains more than
one L*.
We have also examined the mechanism of the copper-
catalyzed enantioselective N-alkylation of a racemic alkyl
bromide (eq 1), and we have observed a noteworthy difference
versus the corresponding iodide. In the case of the bromide, a
time-course experiment revealed that kinetic resolution of the
electrophile occurs without significant racemization (Figure 6),
a
Determined through 1H NMR spectroscopy, with the aid of an
internal standard.
generated with complete inversion at the carbon undergoing
substitution.20 Chiral copper complex B reacts with the S
enantiomer of the electrophile more than 10 times faster than
with the R enantiomer.
Two catalytic cycles that are consistent with the above
mechanistic observations are provided in Figure 7.21 In one
pathway (Figure 7a), copper(I)−nucleophile complex C
(complex B, above) undergoes oxidative addition of the
electrophile via a two-step SN2 mechanism to afford
organocopper(III) intermediate D. Reductive elimination of
D then furnishes N-alkylation product E and copper(I)−halide
complex F, which engages in ligand exchange to regenerate
complex C.
Alternatively, copper complex C may simply serve as a chiral
nitrogen-based nucleophile, reacting directly with the electro-
phile via an SN2 reaction to generate N-alkylation product E
and copper−halide complex F (Figure 7b). Complex F then
undergoes ligand exchange with the nucleophile to regenerate
copper−nucleophile complex C.
The time-course experiments for these enantioselective N-
alkylations indicate that the electrophile undergoes racemiza-
tion under the reaction conditions in the case of the alkyl
iodide, but not of the bromide (Figures 5, 6, and 8). Thus, in
the case of the iodide, a dynamic kinetic resolution is
occurring, whereas, in the case of the bromide, a simple (not
a dynamic) kinetic resolution is operative. For the mechanism
outlined in Figure 7a, our observation that, for both
Figure 6. Copper-catalyzed asymmetric N-alkylation of an indole by a
racemic alkyl bromide via a simple kinetic resolution: ee of the
electrophile as a function of time.
D
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with an α-iodolactam. Furthermore, we have established that
the starting alkyl iodide racemizes under the reaction
conditions, which enables a dynamic kinetic resolution.
Further investigations of copper-catalyzed enantioconvergent
N-alkylations, both photoinduced and nonphotoinduced, are
underway.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.9b07875.
■
S
Procedures and characterization data (PDF)
AUTHOR INFORMATION
Corresponding Author
*gcfu@caltech.edu
■
ORCID
Agnieszka Bartoszewicz: 0000-0002-1534-2690
Carson D. Matier: 0000-0002-1618-7944
Gregory C. Fu: 0000-0002-0927-680X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support has been provided by the National Institutes of Health
(National Institute of General Medical Sciences; Grant No.
R01-GM109194), the Bengt Lundqvist Memorial Foundation
of the Swedish Chemical Society (fellowship for A.B.),
Boehringer−Ingelheim Pharmaceuticals (Scientific Advance-
ment Grant to G.C.F.), and the Dow Next Generation
Educator Fund (grant to Caltech). We thank Prof. Jonas C.
Peters, Dr. Quirin M. Kainz, Dr. J. M. Ahn, Lawrence M.
Henling, Dr. Nathan D. Schley, Dr. Mona Shahgholi, Dr.
Michael K. Takase, Dr. Scott C. Virgil, and Dr. Susan L.
Zultanski for assistance and helpful discussions.
Figure 7. Outline of two possible mechanisms for copper-catalyzed
enantioselective N-alkylations of indoles by racemic secondary alkyl
electrophiles. (a) Copper as the nucleophile: oxidative addition via an
SN2 reaction to form a copper(III) intermediate. (b) Nitrogen as the
nucleophile: direct SN2 reaction.
REFERENCES
■
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CONCLUSIONS
■
We have developed a straightforward method for the
enantioconvergent alkylation of amines by racemic alkyl
electrophiles (primarily, couplings of indoles with secondary
α-iodolactams) that proceeds in the absence of light; this
complements our earlier investigation, which focused on
photoinduced, enantioconvergent reactions of carbazoles
(and some indoles) with racemic tertiary alkyl chlorides. We
have isolated and structurally characterized a proposed
intermediate (a copper(I)−indolyl complex) and demonstra-
ted that it is competent in C−N bond formation when treated
E
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1
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F
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