Copper-Catalyzed Alkylation of Aliphatic Amines Induced by Visible Light

Article abstract of DOI:10.1021/jacs.7b09582

Although the alkylation of an amine by an alkyl halide serves as a textbook example of a nucleophilic substitution reaction, the selective mono-alkylation of aliphatic amines by unactivated, hindered halides persists as a largely unsolved challenge in organic synthesis. We report herein that primary aliphatic amines can be cleanly mono-alkylated by unactivated secondary alkyl iodides in the presence of visible light and a copper catalyst. The method operates under mild conditions (-10 °C), displays good functional-group compatibility, and employs commercially available catalyst components. A trapping experiment with TEMPO is consistent with C-N bond formation via an alkyl radical in an out-of-cage process.

Full text of DOI:10.1021/jacs.7b09582

Communication
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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Copper-Catalyzed Alkylation of Aliphatic Amines Induced by Visible
Light
Carson D. Matier, Jonas Schwaben, Jonas C. Peters,* and Gregory C. Fu*
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United States
S
* Supporting Information
alkylation of an array of aliphatic amines with unactivated sec-
ondary alkyl halides under mild conditions (−10 °C; eq 1).
ABSTRACT: Although the alkylation of an amine by an
alkyl halide serves as a “textbook example” of a
nucleophilic substitution reaction, the selective mono-
alkylation of aliphatic amines by unactivated, hindered
halides persists as a largely unsolved challenge in organic
synthesis. We report herein that primary aliphatic amines
can be cleanly mono-alkylated by unactivated secondary
alkyl iodides in the presence of visible light and a copper
catalyst. The method operates under mild conditions (−10
°C), displays good functional-group compatibility, and
employs commercially available catalyst components. A
trapping experiment with TEMPO is consistent with C−N
In earlier work, we have described a variety of coupling
reactions of nucleophiles with organic (aryl, alkenyl, alkynyl, and
alkyl) electrophiles that are induced by light and catalyzed by
copper;6,9 an outline of one of the possible pathways for such
bond formation via an alkyl radical in an out-of-cage
processes is provided in Figure 1.10,11 To date, all of our reported
process.
ecause amines are a privileged functional group in bioactive
1
Bmolecules, the development of more versatile methods for
their synthesis is an important objective.2 Whereas the alkylation
of an amine by an alkyl halide via an SN2 pathway is a classic
transformation, at the same time the process represents an
ongoing challenge in synthesis.3 Thus, rather than the desired
C−N bond formation, undesired pathways such as E2 reactions
and over-alkylation often intervene. Furthermore, because SN2
reactions are sensitive to steric effects, unactivated secondary and
tertiary alkyl halides oftentimes do not serve as useful
electrophilic partners. Due in part to these limitations, an array
of methods other than the substitution reaction of an amine with
an alkyl halide have been developed in order to selectively and
efficiently introduce an alkyl group to an amine.2
Figure 1. Outline of one of the possible pathways for photoinduced,
copper-catalyzed coupling reactions.
couplings have employed nucleophiles wherein the nucleophilic
site is part of a π system (N: carbazole, indole, and imidazole; S:
aryl thiol; O: phenol; C: cyanide). On the other hand, our initial
efforts to utilize nucleophiles that lack this feature were
unsuccessful. For example, under conditions in which
carbazole6a and cyclohexanecarboxamide6b undergo alkylation
by an unactivated secondary halide in good yield, the
corresponding alkylation of a primary aliphatic amine does not
proceed (eq 2 and eq 3). Having the nucleophilic site
incorporated within a π system might be important for any of
a variety of reasons, including determining the viability of the
initial photoexcitation (A → B in Figure 1)12 and/or of electron
transfer from that excited state to the electrophile to generate a
copper(II) complex (B → C).13
Whereas transition-metal catalysis has been pursued very
extensively to address the challenge of effecting substitution
reactions of aryl halides by nitrogen nucleophiles,4 until recently
there were essentially no systematic investigations of corre-
sponding metal-catalyzed substitution reactions of alkyl halides.5
During the past few years, this deficiency has begun to be
addressed, including through our work on photoinduced,
copper-catalyzed processes (carbazoles, carboxamides, and
indoles as nucleophiles)6,7 and a study by Hartwig on
palladium-catalyzed reactions (benzophenone imines as nucle-
ophiles).8
Nevertheless, to date, a general method for transition-metal-
catalyzed substitution of an alkyl halide by an aliphatic amine,
which can be regarded as the prototypical nitrogen nucleophile,
has not been described. In this study, we report a photoinduced,
copper-catalyzed process that achieves the selective mono-
Received: September 7, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.7b09582
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
mono-alkylation of a primary aliphatic amine by an unactivated
secondary alkyl halide under mild conditions (−10 °C) in good
yield (92%; Table 1, entry 1).
Table 1. Effect of Reaction Parameters
a
entry
variation from the “standard” conditions
none
yield (%)
1
92
<1
<1
84
86
81
82
<1
70
48
14
<1
50
14
56
62
62
54
<1
39
78
2
no CuI or no rac-BINOL or no hv or no BTPP
no CuI, no rac-BINOL, no hv
CuBr, instead of CuI
3
While examining the functional-group compatibility of a
method that we developed for photoinduced, copper-catalyzed
arylations of phenols,9d we discovered that the presence of 1.0
equiv of an aliphatic amine additive unexpectedly leads to
predominant N-arylation of the aliphatic amine, rather than O-
arylation of the phenol (eq 4; in the absence of n-BuNH2: 80%
yield of PhO−Ar).
4
5
CuCl, instead of CuI
6
CuBr2, instead of CuI
7
Cu(OTf)2, instead of CuI
copper nanopowder, instead of CuI
6% rac-BINOL
8
9
10
11
12
13
14
15
16
17
18
19
20
21
4% rac-BINOL
2-naphthol, instead of rac-BINOL
rac-BINOL dimethyl ether, instead of rac-BINOL
1,1,3,3-tetramethylguanidine, instead of BTPP
LiOt-Bu, instead of BTPP
room temperature
1.2 equiv CyI
1.0 equiv BTPP
One of the possible pathways by which phenol might enable
the photoinduced, copper-catalyzed cross-coupling of an
aliphatic amine is depicted in Figure 2. Thus, photoexcitation
2.5% CuI, 5% rac-BINOL
CyBr or CyCl or CyOTs, instead of CyI
under air (capped vial)
0.1 equiv H2O added
a
Yields were determined via 1H NMR analysis versus an internal
standard (average of two experiments).
Control reactions establish that essentially none of the
coupling product is generated in the absence of CuI, rac-
BINOL, light, or BTPP (Table 1, entries 2 and 3). A variety of
copper(I) and copper(II) sources furnish a good yield of the
desired secondary amine, whereas copper nanopowder does not
(entries 4−8). N-Alkylation proceeds less efficiently with less
BINOL (entries 9 and 10), when BINOL is replaced with related
ligands (entries 11 and 12), with other Brønsted bases (entries
13 and 14), at room temperature (entry 15), with less
electrophile or BTPP (entries 16 and 17), and with less catalyst
(entry 18; no further reaction after 24 h). Under our standard
conditions, other cyclohexyl electrophiles (bromide, chloride,
and tosylate) do not serve as suitable coupling partners (entry
19). Cross-coupling does occur in the presence of a small
amount of air or water, although less effectively (entries 20 and
21).
An array of unactivated secondary alkyl iodides, both cyclic
and acyclic, serve as suitable electrophiles in this photoinduced,
copper-catalyzed mono-alkylation of aliphatic amines (Table
2).16 The efficiency of the coupling is sensitive to steric effects,
with more hindered electrophiles furnishing more modest yields
(entries 6 and 7). Saturated oxygen and sulfur heterocycles are
compatible with the reaction conditions (entries 8 and 9), and
C−N bond formation can be achieved with excellent
diastereoselectivity (entries 10 and 11; >20:1). In a gram-scale
Figure 2. Simplified outline of one of the possible pathways for the
photoinduced, copper-catalyzed coupling of an aliphatic amine in the
presence of a phenol.
of a copper(I)−phenoxide complex (E → F) and then electron
transfer to an electrophile (R−X) affords a copper(II)−
phenoxide (G) and an organic radical (R•). Ligand exchange
of the copper(II)−phenoxide with an amine (NH2R) leads to a
copper(II)−amido (H)14 that engages in C−N bond formation
with the organic radical to furnish the cross-coupling product
(R−NHR) and a copper(I) complex (I).15 Ligand substitution
then regenerates a copper(I)−phenoxide complex (E).
Given the paucity of systematic studies of metal-catalyzed
substitution reactions of unactivated alkyl halides by aliphatic
amines, we attempted to exploit our initial observation (eq 4) to
devise a photoinduced, copper-catalyzed process that would
address this deficiency. Indeed, building on this lead result, we
have been able to develop a method that achieves the selective
B
DOI: 10.1021/jacs.7b09582
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Table 2. Scope with Respect to the Electrophile
Table 3. Scope with Respect to the Nucleophile
a
b
Yields of purified product (average of two experiments). Isolated as
the trifluoroacetamide derivative.
a
b
Yields of purified product (average of two experiments). Catalyst
c
(nitrocyclopentane) or an aldehyde (cyclohexanecarboxalde-
hyde) impedes coupling (<5% and 51% yield, respectively).
If desired, N-protection of the secondary amine can be
affected in situ in good yield. For example, upon completion of
the alkylation illustrated in entry 1 of Table 2, direct
trifluoroacetylation followed by purification provides the TFA-
protected amine in 86% yield. Similarly, a 73% yield of the
purified carbamate can be obtained after in situ protection with
Boc2O.
Although reaction development is the primary focus of this
investigation, we have also carried out preliminary mechanistic
studies; as mentioned earlier, one of the possible pathways for
this process is outlined in Figure 2. With regard to the identity of
the primary photoreductant, ESI-MS of a reaction mixture after
partial conversion reveals the presence of a copper(I)−
binaphtholate complex; alternatively, deprotonated BINOL
itself could also fill this role.18,19 The illustrated mechanism
includes d9 copper(II) complexes as intermediates, and we have
indeed detected such species via EPR spectroscopy by sampling
a catalyzed coupling at partial conversion; at least two copper(II)
species are evident (hyperfine coupling to copper), which
together account for ∼60% of the copper present in the reaction
mixture.
loading: 10% CuI, 20% rac-BINOL. Starting material: cis/trans = 5/1;
product: trans/cis > 20/1. Starting material: β/α > 20/1; product: α/
d
β > 20/1.
reaction, the alkylation illustrated in entry 1 proceeds in good
yield with 10% CuI/20% BINOL (1.32 g, 81%).
Although many unactivated primary alkyl halides can serve as
useful electrophiles in SN2 reactions, neopentyl halides typically
are poor substrates.17 Nevertheless, the combination of a CuI/
BINOL catalyst and blue-LED irradiation enables the alkylation
of an aliphatic amine by neopentyl iodide in good yield at −10
°C (eq 5). In contrast, a simple SN2 reaction proceeds very
slowly even at 100 °C, and the addition of CuI/BINOL is not
beneficial (eq 5).
According to the pathway depicted in Figure 2, C−N bond
formation occurs through out-of-cage coupling of an organic
radical (R•) with a copper(II)−amido complex.15 Consistent
with this hypothesis, the addition of TEMPO (1.5 equiv) to a
reaction mixture leads to formation of a TEMPO adduct (eq 6).
We have also examined the scope of this photoinduced,
copper-catalyzed N-alkylation with respect to the nucleophile
(Table 3). Thus, the efficiency of C−N bond formation does not
appear to be highly sensitive to the steric demand of the aliphatic
amine (entries 1 and 2). The method is compatible with a variety
of functional groups, including an ether, an acetal, an aryl
chloride, an aryl bromide, a furan, and a thiophene (entries 3−
11).
Through an additive study, we have further assessed the
functional-group compatibility of this method. For the coupling
illustrated in entry 1 of Table 2, the addition of 1.0 equiv of an
alcohol (5-nonanol), an alkyne (5-decyne), an ester (methyl
octanoate), a ketone (2-nonanone), a cis olefin (cis-5-decene),
and a trans olefin (trans-5-decene) has little impact on N-
alkylation (>75% yield), and the additive is virtually unaffected
(>90% recovery). On the other hand, addition of a nitroalkane
In summary, we have determined that the combination of
visible light and a copper catalyst provides the first general
method for the transition-metal-catalyzed alkylation of aliphatic
amines by unactivated secondary alkyl halides. This process
addresses some of the deficiencies of the classic SN2 approach,
C
DOI: 10.1021/jacs.7b09582
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
(5) For early examples of reactions of unactivated alkyl electrophiles
(all are primary alkyl bromides) that proceed in the presence of a
substoichiometric quantity of a transition metal, see: (a) Aydin, A.;
Kaya, I. Electrochim. Acta 2012, 65, 104−114 (165 °C). (b) Tu, X.; Fu,
X.; Jiang, Q.; Liu, Z.; Chen, G. Dyes Pigm. 2011, 88, 39−43 (80 °C).
(c) Kozuka, M.; Tsuchida, T.; Mitani, M. Tetrahedron Lett. 2005, 46,
4527−4530 (83 °C).
(6) (a) Bissember, A. C.; Lundgren, R. J.; Creutz, S. E.; Peters, J. C.;
Fu, G. C. Angew. Chem., Int. Ed. 2013, 52, 5129−5133. (b) Do, H.-Q.;
Bachman, S.; Bissember, A. C.; Peters, J. C.; Fu, G. C. J. Am. Chem. Soc.
2014, 136, 2162−2167. (c) For activated tertiary alkyl halides, see:
Kainz, Q. M.; Matier, C. M.; Bartoszewicz, A.; Zultanski, S. L.; Peters, J.
C.; Fu, G. C. Science 2016, 351, 681−684.
(7) For examples of work by others on photoinduced, copper-
catalyzed couplings (not with alkyl electrophiles), see: (a) Paria, S.;
Reiser, O. ChemCatChem 2014, 6, 2477−2483. (b) Ye, Y.; Sanford, M.
S. J. Am. Chem. Soc. 2012, 134, 9034−9037. (c) Sagadevan, A.; Hwang,
K. C. Adv. Synth. Catal. 2012, 354, 3421−3427.
(8) Peacock, D. M.; Roos, C. B.; Hartwig, J. F. ACS Cent. Sci. 2016, 2,
647−652.
including its need for reactive electrophiles and its propensity for
over-alkylation. With respect to our efforts to expand photo-
induced, copper-catalyzed coupling reactions, this represents our
first success with nucleophiles wherein the nucleophilic site is
not part of a π system. With our optimized method, C−N bond
formation proceeds without significant over-alkylation (<1%)
under mild conditions (−10 °C) in the presence of a variety of
functional groups, upon irradiation by blue-LED lamps of a
catalyst derived from commercially available components. A
preliminary mechanistic study is consistent with the formation of
an alkyl radical that engages in out-of-cage C−N bond
formation.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.7b09582.
■
S
Procedures and characterization data (PDF)
(9) (a) Creutz, S. E.; Lotito, K. J.; Fu, G. C.; Peters, J. C. Science 2012,
338, 647−651. (b) Uyeda, C.; Tan, Y.; Fu, G. C.; Peters, J. C. J. Am.
Chem. Soc. 2013, 135, 9548−9552. (c) Ziegler, D. T.; Choi, J.; Munoz-
Molina, J. M.; Bissember, A. C.; Peters, J. C.; Fu, G. C. J. Am. Chem. Soc.
2013, 135, 13107−13112. (d) Tan, Y.; Munoz-Molina, J. M.; Fu, G. C.;
Peters, J. C. Chem. Sci. 2014, 5, 2831−2835. (e) Ratani, T. S.; Bachman,
S.; Fu, G. C.; Peters, J. C. J. Am. Chem. Soc. 2015, 137, 13902−13907.
(10) For mechanistic studies, see: (a) Johnson, M. W.; Hannoun, K. I.;
Tan, Y.; Fu, G. C.; Peters, J. C. Chem. Sci. 2016, 7, 4091−4100. (b) Ahn,
J. M.; Ratani, T. S.; Hannoun, K. I.; Fu, G. C.; Peters, J. C. J. Am. Chem.
Soc. 2017, 139, 12716−12723.
(11) For leading references on photoredox catalysis, see: (a) Prier, C.
K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev. 2013, 113, 5322−
5363. (b) Skubi, K. L.; Blum, T. R.; Yoon, T. P. Chem. Rev. 2016, 116,
10035−10074.
(12) For example, see: (a) Lotito, K. J.; Peters, J. C. Chem. Commun.
2010, 46, 3690−3692. (b) Miller, A. J. M.; Dempsey, J. L.; Peters, J. C.
Inorg. Chem. 2007, 46, 7244−7246.
(13) For examples of a role for the π system of the nucleophile in the
electronic structure of copper(I) and copper(II) intermediates in
photoinduced cross-couplings, see ref 10.
AUTHOR INFORMATION
■
Corresponding Authors
*jpeters@caltech.edu
*gcfu@caltech.edu
ORCID
Jonas C. Peters: 0000-0002-6610-4414
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 R01-
GM109194) and the Alexander von Humboldt Foundation
(fellowship for J.S.). We thank Jun Myun Ahn, Bradley J.
Gorsline, Dr. Paul H. Oyala (Caltech EPR Facility, supported by
National Science Foundation grant NSF-1531940), Dr. Mona
Shahgholi (Caltech Mass Spectrometry Facility), Dr. Yichen
Tan, Dr. David G. VanderVelde (Caltech NMR Facility), and
Dr. Scott C. Virgil (Caltech Center for Catalysis and Chemical
Synthesis) for assistance and helpful discussions.
(14) For ease of discussion, the transformation of G → H in Figure 2 is
drawn as a simple ligand exchange, whereas our data (e.g., out-of-cage
C−N bond formation (vide infra)) point to a more complex pathway.
(15) In the case of a photoinduced, copper-catalyzed decarboxylative
coupling, we have described evidence for out-of-cage C−N coupling
after ligand exchange: Zhao, W.; Wurz, R. P.; Peters, J. C.; Fu, G. C. J.
Am. Chem. Soc. 2017, 139, 12153−12156. See also ref 10b.
(16) Notes: (a) For all N-alkylations illustrated in Tables 2 and 3, no
over-alkylation is observed (<1%). (b) Preliminary observations: this
process can be conducted under flow conditions; an unactivated tertiary
alkyl halide is not a suitable electrophile; in a light-on/light-off
experiment, alkylation stops when irradiation stops, and alkylation
resumes when irradiation resumes.
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D
DOI: 10.1021/jacs.7b09582
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX