Photoredox-Catalyzed Cα-H Cyanation of Unactivated Secondary and Tertiary Aliphatic Amines: Late-Stage Functionalization and Mechanistic Studies

Article abstract of DOI:10.1021/acs.joc.8b01700

This paper describes the development and mechanistic studies of a general, high-yielding amine C_α-H cyanation protocol via photoredox catalysis. Inexpensive NaCN is employed as the cyanide source and air is the external oxidant, resulting in mild and highly functional group tolerant conditions. Notably, efficient C_α-H cyanations of secondary and tertiary aliphatic amines and of complex, biologically active compounds (drugs) can be performed using the established methodology. Mechanistic studies suggest that the carboxylic acid additive has three effects: formation of a stabilizing hemiaminal intermediate, prevention of catalyst decomposition by protonating the substrate, and modulation of fluorescence quenching of the photoexcited catalyst species.

Full text of DOI:10.1021/acs.joc.8b01700

Article
pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
Photoredox-Catalyzed Cα−H Cyanation of Unactivated Secondary
and Tertiary Aliphatic Amines: Late-Stage Functionalization and
Mechanistic Studies
Ozgur Yilmaz,† Martins S. Oderinde,*,‡ and Marion H. Emmert*,†
†Department of Chemistry and Biochemistry, Worcester Polytechnic Institute, 100 Institute Road, Worcester, Massachusetts 01609,
United States
‡Medicine Design & Oncology, Medicinal Chemistry, Pfizer, Inc., Groton, Connecticut 06340, United States
S
* Supporting Information
ABSTRACT: This paper describes the development and mechanistic studies of a general, high-yielding amine Cα−H cyanation
protocol via photoredox catalysis. Inexpensive NaCN is employed as the cyanide source and air is the external oxidant, resulting
in mild and highly functional group tolerant conditions. Notably, efficient Cα−H cyanations of secondary and tertiary aliphatic
amines and of complex, biologically active compounds (drugs) can be performed using the established methodology.
Mechanistic studies suggest that the carboxylic acid additive has three effects: formation of a stabilizing hemiaminal
intermediate, prevention of catalyst decomposition by protonating the substrate, and modulation of fluorescence quenching of
the photoexcited catalyst species.
(aryl, benzyl, and cyclic) amine substrates with easily cleavable
Cα−H bonds, often under strongly oxidizing conditions.20−25
Few known reports substitute oxidants for O2 or air to create
milder protocols.26,27
INTRODUCTION
■
α-Aminonitriles are versatile intermediates for the synthesis of
difunctionalized molecules such as amino acids, heterocycles,
and pharmaceuticals.1−4 Approaches toward their synthesis
include the classical Strecker reaction,5 the addition of cyanide
nucleophiles to imines,6−12 and reductive Strecker reactions via
the cyanation of amides and lactams.13 In contrast to such
functional group interconversion strategies, Cα−H cyanations
of amines promise to introduce cyano groups directly into
complex molecules, thus enabling highly desirable late-stage
diversifications of biologically active compounds.14−19 Recent
advances to this end (Scheme 1A) have focused on activated
In contrast to common functionalizations of amines with
activated Cα−H bonds (e.g., benzylic, aryl amines),28 fewer
examples are known that employ tertiary alkyl amines as
substrates for Cα−H functionalization.29,30 Among these, only
a handful of Cα−H cyanations affording high yields are
known,26,28,29,31 but it is often unclear how known methods
would tolerate more complex molecules as substrates.
Finally, a general challenge in cyanation is the source of
cyanide as a nucleophile, as more desirable cyanide sources
such as NaCN are often insoluble in organic solvents. More
soluble cyanide sources such as TMS-CN22 are hazardous and
thus less desirable to use on larger scales.
Scheme 1. Previously Reported Cα−H Cyanations and
Herein Described General Protocol
Herein, we report a general, high-yielding Cα−H cyanation
protocol driven by photoredox catalysis. Inexpensive NaCN is
employed as the cyanide source, and air is the external oxidant,
resulting in mild and highly functional group tolerant
conditions. Notably, the established protocol allows the
efficient Cα−H cyanation of unactivated and unprotected, secon-
dary and tertiary aliphatic, complex amine substrates (Scheme
1B).
Received: July 5, 2018
© XXXX American Chemical Society
A
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RESULTS AND DISCUSSION
Table 1. Selected Optimization and Background Studies
■
Reaction Optimization. Our initial investigations to
establish a general, photoredox-catalyzed amine Cα−H
cyanation focused on tributylamine as substrate. We reasoned
that NBu3 would be a suitable model compound due to the
lack of proximal activating groups (i.e., arenes, double bonds,
cyclic structures). Furthermore, we reasoned that the use of
similarly simple tertiary amines as sacrificial reductants in
photoredox catalysis32 should readily provide access to reactive
iminium ions, which could then react with a cyanide
nucleophile present in solution.
a
b
entry
changes to conditions
yield (%)
1
2
3
4
5
6
7
8
none
Ru(bpy)3(PF6)2 (4 mol %)
[Ir(dF(CF3)ppy)2(dtbpy)]PF6 (2 mol %)
MeOH instead of MeCN
KCN instead of NaCN
AcOH (1.5 equiv)
45
10
26
41
38
67
93
47
49
82
54
46
95
<5
<5
12
17
As such, we first evaluated the reactivity of different
photoredox catalysts (Figure 1) in combination with NaCN
AcOH (3.0 equiv)
AcOH (3.0 equiv), 2 mol % [Ir]
AcOH (3.0 equiv), 2 mol % [Ir], air balloon
AcOH (3.0 equiv), DMA instead of MeCN
AcOH (3.0 equiv), DMSO instead of MeCN
KCN, 18-crown-6 (1.5 equiv)
PhCO2H (3 equiv)
9
10
11
12
13
14
15
16
17
AcOH (3.0 equiv), no light
AcOH (3.0 equiv), no photocatalyst
c
N2 atmosphere
AcOH (5.0 equiv), KCN (1.2 equiv), 1 mol % [Ir]
a
Standard conditions: NBu3 (50 mg, 0.27 mmol), MeCN (3 mL),
blue LED reactor (72 W), NaCN (3 equiv), [Ir(dF(CF3)-
b
Figure 1. Structures of photoredox catalysts employed in the
optimization studies.
ppy)2(dtbpy)]PF6 (4 mol %), 24 h. Yields were determined by
quantitative, crude 1H NMR using 1,3-dinitrobenzene or
c
ClH2CCHCl2 as internal standard. All liquid reagents were purged
for 20 min and introduced into a N2-filled glovebox. The reaction
mixture was prepared in a N2-filled glovebox, and the reaction vial was
sealed before removing it from the glovebox and placing it into the
LED reactor.
as nucleophile and blue LEDs as light source. Gratifyingly,
these conditions afforded 45% of the desired product with 4
mol % of [Ir(dF(CF3)ppy)2(dtbpy)]PF6 as photoredox
catalyst (Table 1, entry 1); however, only 10% of α-
aminonitrile 1a was obtained with Ru(bpy)3(PF6)2 (entry 2).
Lower amounts of Ir catalyst (2 mol %; Table 1, entry 3)
resulted in a significant decrease in yield to 26%. These
data suggest a significant dependence of the reaction yield on
the amount and identity of the used photoredox catalyst.
Changing the solvent to MeOH did not result in a dramatic
decrease in yield (41%; Table 1, entry 4), suggesting that
protic solvents are not detrimental to catalytic activity in this
system. KCN provided very similar activity to NaCN (38%,
entry 5).
In an effort to improve the yields of the reaction, we
speculated that AcOH as additive may aid the reaction, in
analogy to observations made in the Cα−H cyanation of
activated amines by Rueping and co-workers.27 The result of a
reaction with 1.5 equiv of AcOH as additive (entry 6) was
encouraging (67% yield); increasing the AcOH loading to 3.0
equiv afforded 93% of 1a (entry 7). When the Ir photoredox
catalyst loading was lowered under these conditions, the yield
still suffered (both in the absence or presence of an excess of
air; see entries 8/9), suggesting that catalyst decomposition
may be an issue. Interestingly, high reactivity was observed in
DMA as solvent (entry 10; 82%), while DMSO led to a
decrease in yield (entry 11; 54%).
implying that the beneficial effect of AcOH is not only due to
increasing the solubility of NaCN. Alternatively, the structure
or pKa of the carboxylic acid additive may also have an
influence on the Cα−H cyanation reactivity. Interestingly, the
use of benzoic acid (entry 13; pKa (PhCO2H) = 4.1935)
afforded an equally high yield of the α-aminonitrile 1a (95%)
as observed in the presence of AcOH.
Subsequently, a series of background reactions were
performed to ensure the importance of each reaction
parameter for reactivity. In the absence of light or photo-
catalyst, only traces (<5%, entries 14 and 15) of the desired
compound were obtained, suggesting that the transformation is
indeed driven by the energy of the blue LED light. Reactions
prepared in a N2-filled glovebox showed significantly decreased
yield (entry 16; 12%), supporting the importance of O2 as
oxidant in the reaction.
Finally, the use of excess AcOH in combination with KCN
(conditions reported for the oxidative cyanation of anilines)27
was tested (entry 17). The low yield obtained (17%) suggests
that the conditions optimized for NBu3 (entry 7) may be more
effective with regard to broad substrate scopes than the
protocol devised in the previous report.
Substrate Scope: Simple Substrates. We then turned
our attention to demonstrating the synthetic utility of the
catalytic system. Excitingly, both unactivated secondary
(Scheme 2) and tertiary amines (Scheme 3) are readily
functionalized by the developed methodology.
Intrigued by the reaction-enhancing effect of AcOH, several
control experiments were performed to gain insights into the
role of AcOH in the reaction. To test the hypothesis that
AcOH may simply be enhancing the solubility of NaCN
[pKa(AcOH) = 4.76;33 pKa(HCN) = 9.40],34 we performed a
cyanation reaction with a more soluble source of cyanide:
KCN in the presence of 18-crown-6 (1.5 equiv; entry 12).
However, this reaction afforded only a moderate yield (46%),
Due to the volatility of the products, the substrate scope for
simple secondary amines was performed in MeCN-d3, and
1
yields were measured by quantitative H NMR. Secondary
amines with little steric hindrance around the amine
B
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a
H cyanation of HNBn2 was also successful (albeit low
yielding), providing 14% of 10a (30% rsm).
Scheme 2. Substrate Scope of Simple Secondary Amines
In all cases with moderate yields, significant amounts of
starting materials (34−54% rsm) were detected in the reaction
mixtures, signifying excellent mass balances (>90%). This
excludes substrate overoxidation or decomposition as the
reason for low yields. To test if the observed low yields are due
to catalyst and/or reagent decomposition, a second batch of Ir
photoredox catalyst or both photocatalyst and NaCN (Scheme
2, bottom) were added to a reaction mixture with morpholine
as substrate. Then the mixture was irradiated for another 24 h.
Excitingly, significantly higher yields of 9a (83% and 91%,
respectively) were thus obtained, suggesting that catalyst
decomposition is the reason for low yields with secondary
amine substrates.
A wide range of tertiary aliphatic amines was successfully
subjected to the optimized conditions (84 to 94% isolated
yields for 1a, 11a, 12a, and 13a; Scheme 3). Additionally,
activated (benzylic and aniline-type) amines provided good
yields (14a; 74% isolated yield; 18a; 71% isolated yield).
Furthermore, the cyanation of tertiary, cyclic amines affords
excellent yields, with a distinct preference for ring Cα−H
cyanation (15a/b, 16a/b,17/b) vs Cα−H cyanation at the
acyclic substituent. Substrates without discernible Cα−H
cyanation reactivity include DABCO and Boc-protected pyrro-
lidine (19). Such amines are often easily modified with LDA
under highly basic conditions,36 which makes the developed
method complementary to existing approaches. Amine 21
bearing a ketone group forms the corresponding cyanohydrin
by cyanide addition, thereby preventing formation of Cα−H
cyanation to afford product 21a. Overall, this substrate scope
study of simple tertiary amines suggests that ketone functional
groups, amines containing electron-withdrawing protecting
groups, and conformationally strongly constrained amine
substrates (e.g., DABCO) are incompatible with the
established conditions.
a
1
Yields were determined by quantitative H NMR in the presence of
an internal standard. [Ir] = [Ir(dF(CF3)ppy)2(dtbpy)]PF6.
Scheme 3. Substrate Scope of Simple Tertiary Amines
Exploring Functional Group Tolerance via Intermo-
lecular Reaction Screening. To gain further information on
the functional group tolerance of the reaction, an intermo-
lecular reaction screening protocol37 was employed (Table 2).
Interestingly, the reaction tolerates tertiary alcohols and cyano,
ester, and pyridine functionalities well, with product yields not
below 72% and >82% remaining additive in all cases (entries
2−5). Surprisingly, a drop in reactivity (62% 1a) is observed in
the case of anisole as additive, with only 77% of PhOMe
remaining after the reaction. This indicates potential reactivity
of aryl ethers or electron-rich aromatics under these
conditions. Moreover, alkenes such as in 1-octene also slow
reactivity (71% yield of 1a), and only 69% of 1-octene remains
after the reaction. Finally, ketones and aldehydes are not
compatible with the protocol (entries 8 and 9) due to direct
attack of the cyanide nucleophile at their carbonyl moiety.
Substrate Scope: Complex Substrates and Drugs. We
then shifted our focus toward the late-stage functionalization of
biologically active molecules. We chose two alkaloids (nicotine,
gramine) and several known drugs (lidocaine, imipramine,
gefitinib, (R)-(−)-phenylephrine, and Chantix; see Scheme 4)
as model compounds to further explore the reactivity and
functional group tolerance of the established protocol.
Excitingly, many different functional groups (heterocycles,
amides, ethers, unprotected alcohols, and phenols) were well
tolerated. The Cα−H cyanation of nicotine resulted in the
highest achieved yield in this series, affording 92% of ring
functionality (HNEt2, HNPr2, HNnBu2) provided a mixture of
mono- and dicyanated products (e.g., 2a/b, 3a/b, 4a/b). In
contrast, HNPent2, HNiPr2, and HNiBu2 afforded the
monocyanation products in 92%, 50%, and 44% yield,
respectively (5a, 6a, 7a). Furthermore, Cα−H cyanation of
cyclic, secondary amines was also successful: both pyrrolidine
and morpholine reacted to afford moderate yields of the
respective products 8a (49%) and 9a (54%). Finally, the Cα−
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a
Table 2. Results of Intermolecular Reaction Screening
Scheme 4. Substrate Scope of Complex Amines and Drug
Substrates*
a
Conditions: NBu3 (50 mg, 0.27 mmol), additive (0.27 mmol),
MeCN (3 mL), blue LED reactor (72W), NaCN (3 equiv),
b
[Ir(dF(CF3)ppy)2(dtbpy)]PF6 (4 mol %), 24 h. Yields were
1
determined by quantitative, crude H NMR.
cyanation (22a) and 8% of methyl cyanation (22b). Likewise,
Cα−H cyanation of lidocaine resulted in high yields (86% 23a
crude, 82% isolated).
Similar to a previous report,26 the reaction of gramine
resulted in low yields of Cα−H cyanated product 24a (17%).
An interesting deamination reaction is responsible for this low
yield (24b is the major product). In the case of imipramine,
two expected Cα−H cyanation products were obtained in
relatively low yields under our standard conditions (23% 25a,
4% 25b). Further studies with isolated Cα−H cyanation
product 25b (see SI) showed that hydrolysis of 25b occurs at
room temperature, which can be minimized by adding
NaHCO3 to the reaction mixture; this affords cyanation
product 25b in higher yield (29%).
*
a
Conditions as described in Schemes 2 and 3. Reaction in the
b
presence of 2 equiv of NaHCO3. Yield after addition of a second
batch of Ir catalyst (4 mol %) and NaCN (3 equiv) after 24 h and
additional reaction time of 24 h.
Mechanistic Studies. As mentioned above, studies by
Rueping and co-workers27 had previously shown that AcOH
improves photoredox-catalyzed Cα−H cyanations of activated
amines (anilines). However, no detailed studies of the
enhancing effect of AcOH were performed, resulting in the
absence of a mechanistic explanation for the phenomenon
(Scheme 5).27 To enable further development by rationally
guided reaction design, we thus focused on elucidating the role
of AcOH in the reported methodology.
In contrast to the mixture of products obtained with the
relatively simple substrate imipramine, the Cα−H cyanation of
the complex drug gefitinib cleanly formed 26a (49% crude,
46% isolated) as the only product. Excitingly, this yield can be
significantly improved to 83% when a second batch of Ir
catalyst (4 mol %) and NaCN (3 equiv) is added after 24 h,
followed by another 24 h of irradiation. This suggests that low
conversions and yields can generally be addressed by
recharging catalyst and nucleophile. (R)-(−)-Phenylephrine,
a drug with an unprotected phenol functionality, an
unprotected secondary alcohol group, and a secondary amine
moiety also underwent Cα−H cyanation under the standard
reaction conditions, providing 34% (26% isolated) of product
27a. Excitingly, Chantix, a drug with a bicyclic secondary
amine substructure, provided the resulting Cα−H cyanation
product 28a quantitatively (90% isolated) as a single cis-
diastereomer.
Scheme 5. Previously Proposed Mechanistic Possibilities of
Iminium Ion Formation in C−H Cyanation of Tertiary
Anilines
a
a
Adapted from ref 27.
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To this end, fluorescence-quenching experiments were
performed. The ability of NBu3 to quench the fluorescence
of the photoexcited state *[Ir(dF(CF3)ppy)2(dtbpy)]PF6 in
the absence of additional reagents was first established (blue
trace, Scheme 6). The quenching constant kq obtained by
If amine oxidation is rate determining in Cα−H cyanation,
slower fluorescence quenching in the presence of acids as
shown by Stern−Volmer analysis would typically be expected
to also result in lower yields in the presence of acid. However,
higher yields of Cα−H cyanation products were observed in
the presence of AcOH and PhCO2H than in their absence. As
such, we hypothesized that these carboxylic acid additives have
additional, beneficial effects.
Scheme 6. Stern−Volmer Analysis of [Ir] Fluorescence
a
Quenching by NBu3
For further mechanistic studies, we therefore considered
three mechanistic hypotheses for the involvement of the
carboxylic acid additive: (a) The formation of carboxyl
radicals; (b) the stabilization of a reaction intermediate by
AcOH (or PhCO2H), i.e. carboxylic acids functioning as co-
catalysts; and (c) a role for carboxylic acid in preventing
catalyst decomposition.
Formation of carboxyl radicals via photoredox catalysis using
[Ir(dF(CF3)ppy)2(dtbbpy)]PF6 (E1/2 (IrIII*/IrII) = +1.21 V
red
versus SCE in MeCN)38,39 have previously been described,40,41
particularly as precursors for stabilized, tertiary, and secondary
alkyl radicals. To investigate the possibility of carboxyl radical
formation in the protocol under investigation, we tested if the
acid additive is being consumed under the conditions of Cα−H
cyanation, indicating decomposition pathways of carboxyl
radicals. Thus, we analyzed the mass balance of a reaction in
the presence of PhCO2H (Scheme 8), as byproducts formed
a
kq = quenching constant.
Scheme 8. Mass Balance of Amine Cα−H Cyanation
Stern−Volmer analysis of the data (see SI) was determined to
be 1.16 × 1010 M−1 s−1, which is in a similar range as the
previously measured kq for NEt3 (1.20 × 109 M−1 s−1).38,35
Interestingly, in the presence of acid (PhCO2H; orange trace,
Scheme 6) and NaCN (gray trace, Scheme 6), the obtained kq
values for fluorescence quenching by NBu3 are much lower
(1.54 × 108 M−1 s−1 and 3.87 × 107 M−1 s−1, respectively).
This suggests that photoredox-catalyzed oxidation of NBu3 is
slower in the presence of acid, which may be rationalized by
equilibrium protonation of NBu3 under catalytic conditions.
Mechanistically, two different scenarios may cause the low
rates of *Ir fluorescence quenching in the presence of acid/
NaCN: (a) Inherently slow oxidation of the protonated
ammonium salt [HNBu3][O2CR] or (b) slow oxidation that is
due to the small amount of free amine in solution. To
distinguish these two possibilities, we reasoned that the first
scenario may be modeled by the use of a “permanent”
ammonium salt, mimicking the charge and electronic proper-
ties of the protonated amine. Therefore, we attempted to
perform Cα−H cyanation of NBu4OAc (Scheme 7).
by decarboxylation of PhCO2H (e.g., PhH or PhPh) are more
easily detectable than volatile byproducts formed from AcOH
1
(e.g., CH4 and CH3CH3). Interestingly, quantitative H NMR
analysis showed that 99% of PhCO2H remained after the
reaction, and no other aromatic products were detected in the
reaction mixture. These data imply that the additive PhCO2H
•
does not decompose via decarboxylation of PhCO2 radicals.
Therefore, carboxyl radicals formed from AcOH and PhCO2H
under the reaction conditions are either stable against
decarboxylation or are not involved in the catalytic pathway.
To compare the rate of carboxyl radical formation by
photoredox-catalyzed oxidation of carboxylic acid additives to
the rate of photoredox-catalyzed amine oxidation, a series of
*Ir fluorescence quenching studies were performed with
AcOH as quencher (Scheme 9; for details, see the SI).
Scheme 7. Reaction To Probe Direct Oxidation of
Ammonium Salt
Scheme 9. Stern−Volmer Analysis of [Ir] Fluorescence
Quenching by AcOH
Interestingly, no trace of cyanation product was observed;
1
instead, quantitative H NMR analysis of the crude reaction
mixture showed >99% of NBu4+ after 24 h. We conclude from
this experiment that catalytic amine Cα−H cyanation proceeds
via oxidation of the equilibrium concentration of non-
protonated amine.
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Interestingly, very small rates of *[Ir(dF(CF3)ppy)2(dtbbpy)]-
PF6 fluorescence quenching were observed with only AcOH as
quencher (kq = 0.93 × 106 M−1 s−1) or with a mixture of
AcOH and NaCN (kq = 0.27 × 106 M−1 s−1). Both values are
much lower than the quenching rate constants associated with
NBu3 (1.16 × 1010 M−1 s−1 in the absence of acid; 1.54 × 108
M−1 s−1 in the presence of acid; Scheme 6 above), implying
that amine oxidation outperforms carboxyl radical formation
by several orders of magnitude. Put together, these studies
show that carboxyl radical formation is significantly slower
than amine oxidation under catalytic conditions. Therefore, the
concentration of carboxyl radicals in the reaction is too low to
play an important role in the observed catalytic reactivity.
One alternative mechanistic possibility for the role of
carboxylic acids (as mentioned above) is that these additives
act as co-catalysts by stabilizing transient intermediates. To
pinpoint relevant intermediates, we attempted to separate the
steps of the reaction pathway leading to Cα−H cyanation;
these reactions were performed in MeCN-d3 to allow direct
formation of 14% of Cα−H cyanation product 1a. Noteworthy,
the yield of 1a was significantly higher (23%) in the second
experiment, suggesting that the addition of AcOH is beneficial
for cyanation of the iminium intermediate. Interestingly, a new
compound 31 (41%) was detected in the reaction mixture
right after AcOH addition. The 41% yield of 31 is comparable
to the yield of 29 in the first step; however, the Cα−H signal
undergoes a downfield shift of ∼0.3 ppm in comparison to 29.
This suggests that compound 31 is either the hemiaminal
Bu2NCH(OAc)Pr, a tight ion pair of [Bu2N = CHPr]OAc, or
an equilibrium mixture of both compounds, as shown in
Scheme 10B.
We conclude from these experiments that the steps shown in
Scheme 10B are analogous to the reaction pathway of Cα−H
cyanation in the presence of AcOH. Furthermore, the obtained
data imply a mechanistic role for AcOH: The stabilization of
the iminium intermediate by the formation of a hemiaminal or
iminium ion pair 31. The resulting mechanistic pathway for the
photoredox-mediated amine Cα−H cyanation in the presence
of AcOH is shown in Scheme 11. This pathway begins with the
1
analysis by H NMR.
First, the reaction mixture was irradiated for 24 h in the
absence of any acid additive or NaCN (Scheme 10A/B).
Scheme 11. Proposed Reaction Mechanism for Amine Cα−
H Cyanation
Scheme 10. Stepwise Cα−H Cyanation Experiments
free amine oxidation by the long-lived photoexcited state *IrIII
(2.25 μs),38b producing an aminyl radical cation and an IrII
species. The IrII species is reoxidized to its IrIII ground state by
•−
red
O2, forming O2 (E1/2 (IrIII/IrII) = −1.37 V versus SCE in
red
MeCN; E1/2
(O2/O2•−) = −0.87 V versus SCE in
MeCN).35,39 Hydrogen atom transfer from the aminyl radical
cation to O2 produces an iminium intermediate, which is in
•−
equilibrium with the corresponding hemiaminal intermediate.
Analogous hemiaminals and their substitution reactivity in the
presence of cyanide have previously been described in the
literature.42,43 Reaction of the iminium compound with
cyanide produces the α-functionalized amine. As an alternative
mechanistic pathway, a direct SN2-type substitution could
occur at the hemiaminal, if required by the substrate geometry.
We then set out to gain further insight into the role of O2 in
the reaction mixture. Our mechanistic hypothesis (Scheme 11
above) suggests that O2 is responsible for reoxidation of the IrII
species formed by amine oxidation. However, production of
singlet O2, which may directly react with the substrate, has
been considered as a mechanistic possibility in previous
work;44 thus, the effect of O2 on *Ir fluorescence quenching
needs to be investigated. To this end, we performed Stern−
Volmer quenching studies under an air atmosphere. The
quenching constants kq in air and under N2 were then
compared (Table 3). Expectedly, *Ir fluorescence quenching
by NBu3 in the absence of any other reagents is significantly
less effective in air, as characterized by a kq value that is smaller
by one order of magnitude (1.10 × 109 M−1 s−1 in air vs 1.16 ×
Under these conditions, ∼45% of NBu3 was converted to form
two new compounds 29 and 30. The lower yielding compound
30 (4%) was identified as the enamine Bu2NCHCHEt by
independent synthesis (see the SI). Based on this knowledge
and the similarity of the 1H NMR shifts of 29 to the spectrum
of NBu3, we propose that compound 29 (41−42% yield) is the
iminium compound [Bu2NCHPr]+. This mixture of
enamine, NBu3, and 29 was then treated with 3 equiv of
NaCN and allowed to react for 24 h (Scheme 10A) or treated
with 1 equiv of AcOH before NaCN addition (Scheme 10B).
In the first experiment, NaCN addition resulted in the
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that the solubility of acetate salts plays a role in the reaction. As
NaOAc precipitation is typically observed in the catalytic
reaction mixture, precipitation may be an important contrib-
utor to the reaction driving force.
Table 3. Comparison of Quenching Constants kq Obtained
via *Ir Fluorescence Quenching Studies under N2 and Air
Atmospheres
conditions
kq under N2
kq under air
These data also imply that acetate salts are inferior to AcOH
as an additive. Based on the Stern−Volmer analysis of *Ir
fluorescence quenching by NBu3 (Table 3), it is clear that the
rate of amine oxidation is higher in the absence of acid.
However, one critical factor, the stability of the photoredox
catalyst, is yet to be considered; as our data on the Cα−H
cyanation of morpholine and gefitinib shows, catalyst
decomposition is an important limitation in this chemistry. Ir
catalyst decomposition can occur by ligand exchange. Such
reactivity would be expected to be highly pronounced in the
presence of nucleophilic additives (e.g., a mixture of NaOAc,
NaCN, and amines, especially less sterically hindered
secondary amines). In contrast, exchange of ligands at the Ir
center would be less pronounced in a buffer system (e.g.,
AcOH/NaCN/amine), in which the potential nucleophiles
cyanide and amine are partially protonated; this likely results in
slowing down catalyst decomposition. In conclusion, the
detailed mechanistic studies discussed in the previous
paragraphs provide three distinct explanations for the
beneficial role of carboxylic acid additives: formation of a
stabilizing hemiaminal intermediate, modulating fluorescence
quenching of the photoexcited catalyst species, and preventing
catalyst decomposition by protonating amine and cyanide
catalyst poisons.
a
no acid, no NaCN
1.16 × 1010 M−1 s−1
1.54 × 108 M−1 s−1
3.87 × 107 M−1 s−1
1.10 × 109 M−1 s−1
0.85 × 108 M−1 s−1
1.33 × 108 M−1 s−1
b
with PhCO2H, no NaCN
with PhCO2H, with NaCN
c
a
Conditions: 4.0 mg (3.47 μmol) of [Ir(dF(CF3)ppy)2(dtbpy)]PF6,
MeCN (2.00 mL), standard solution of NBu3 in MeCN added.
Conditions as in fnt with PhCO2H (20 mg, 0.16 mmol); standard
solution of NBu3 in MeCN added. Conditions as in fnt with
PhCO2H (20 mg, 0.16 mmol) and NaCN (8 mg, 0.16 mmol);
standard solution of NBu3 in MeCN added.
b
a
c
a
1010 M−1 s−1 under N2). This suggests that the majority of
excited-state *Ir reacts with O2 under these conditions,
possibly via a process that produces singlet O2. Interestingly,
this is not observed in the presence of PhCO2H and NaCN:
Those conditions show kq values in similar ranges (0.85 × 108
M−1 s−1 in air vs 1.54 × 108 M−1 s−1 under N2 for PhCO2H
added; 1.33 × 108 M−1 s−1 in air vs 3.87 × 107 M−1 s−1 under
N2 for PhCO2H/NaCN added). These data imply that *Ir
fluorescence quenching by O2 does not play a major role under
the reaction conditions of Cα−H cyanation. These findings
further suggest that formation of singlet O2 is not a major
pathway for product formation in the established protocol;
analogous conclusions have been drawn in prior investigations
due to vastly different concentrations of substrate and O2 in
solution, which affect the relevant *Ir quenching rates during
catalysis.44b
Synthetic Utility of α-Aminonitriles Obtained from
Drugs. To demonstrate the application of α-aminonitriles as
versatile intermediates for the synthesis of new compounds and
pharmaceutical molecules, cyanated lidocaine 23a was selected
for further derivatization.
To further support the role of carboxylate in the proposed
mechanism, we performed a series of reactions with different
carboxylic acids and acetate salts (Scheme 12). We reasoned
(Z)-N-(3-Ethyl-2-methyloxazolidin-5-ylidene)-2,6-dimethy-
laniline (32) is a major metabolite of lidocaine in
monkeys.45,46 Studies into the identification of enzyme(s)
responsible for this metabolism in monkeys is of interest.46
While 32 can be accessed from lidocaine through enzymatic
synthesis,45 its nonenzymatic chemical synthesis remains
elusive. Delightfully, after exploration of various reaction
conditions, a unique reductive condition (NaBH4, catalytic
amount of CoCl2 in MeOH at room temperature) was
discovered for the chemical synthesis of compound 32 as the
only product from 23a (Scheme 13).
Scheme 12. Reactions To Probe the Role of Different
Carboxylic Acid Additives
SUMMARY AND CONCLUSIONS
■
In summary, this paper describes the development and
mechanistic elucidation of a general Cα−H cyanation method-
ology, which introduces a cyanide group in secondary and
that acids with low nucleophilicity (e.g., with very low pKa or
bulky substitutents) would lead to significantly decreased
yields. Indeed, very low yields (17% and 15%) of product 1a
were obtained with BuCO2H and F3CCO2H as acid additives
(Scheme 12A), supporting the importance of carboxylic acid as
a nucleophilic co-catalyst.
Scheme 13. Chemical Synthesis of Lidocaine Metabolite 32
via Cα−H Cyanation
t
If the role of acid is to provide access to a hemiaminal
intermediate, addition of acetate salts should also prove
beneficial for reactivity. Thus, we substituted AcOH for
NaOAc, KOAc, and NBu4OAc as additives (Scheme 12B).
Excitingly, all these reactions provided Cα−H cyanation
product 1a in higher yields than in the absence of any
additive. The highest yield was obtained with the least soluble
acetate salt NaOAc (88%), while the most soluble salt
NBu4OAc (57%) afforded the lowest yield. This suggests
G
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The Journal of Organic Chemistry
Article
NBu3 concentrations detailed in the legend of each corresponding
figure (see the SI). After each NBu3 addition, a fluorescence spectrum
was recorded. Stern−Volmer analysis of the obtained signals was
performed by averaging the observed absorption intensity I for the
wavelengths between 498 and 502 nm (λmax = 500 nm) and correcting
for the respective change in volume of the solution.
tertiary amines via aerobic photoredox catalysis under mild
conditions. The broad functional group tolerance allows
functionalizations of complex molecules such as known drugs
and alkaloids. Detailed mechanistic studies elucidate the role of
carboxylate additives and suggest iminium ions and hemi-
aminals as key intermediates. We further conclude that
hemiaminal intermediates act as a “stable” reservoir of iminium
intermediates that are less prone to other side reactions such as
hydrolysis or dealkylation, thus promoting Cα−H cyanation.
Overall, the presented studies provide a convenient method-
ology for the direct Cα−H diversification of basic amines with
applications in late-stage functionalization, as well as insights
into the mechanism of this process.
General Procedure for Amine Cα−H Cyanation. A tertiary or
secondary amine (0.27 mmol, 1.0 equiv) was dissolved in 3 mL of
MeCN, and then NaCN (0.81 mmol, 0.040 g, 3.0 equiv),
[Ir(dF(CF3)ppy)2(dtbbpy)]PF6 (0.011 mmol, 0.012 g, 4.0 mol %),
and AcOH (0.81 mmol, 0. 49 g, 46 μL, 3.0 equiv) were added to the
stirred solution under an air atmosphere. The vial was then sealed
tightly with a Teflon-lined vial cap, and the mixture was stirred at
room temperature under irradiation with blue LEDs for 24 h.
Reactions were monitored by TLC. After the reaction time was
completed, the solvent was removed under reduced pressure. To
determine crude yields, 1,3-dinitrobenzene (0.5 mL of a standard
solution of 300 mg of 1,3-dinitrobenzene in 10 mL of CDCl3 or
MeCN-d3) or 1,1,2-trichloroethane (0.5 mL of a standard solution of
300 mg of 1,3-dinitrobenzene in 10 mL of CDCl3 or MeCN-d3) was
added the mixture as internal standard and the crude yield was
determined by quantitative 1H NMR (15 s relaxation time to improve
accuracy of measurement). Alternatively, the crude residue was
directly purified on silica gel using EtOAc or EtOAc−hexanes
mixtures as eluent to provide the corresponding α-cyanated amines.
Characterization and Spectral Data. 2-(Dibutylamino)-
pentanenitrile (1a). Eluent: EtOAc. Yield: 52.8 mg (93%). 1H
NMR (500 MHz, CDCl3): δ 3.51 (t, J = 7.8 Hz, 1H), 2.50 (ddd, J =
13.0, 8.4, 7.3 Hz, 2H), 2.27 (ddd, J = 13.0, 8.1, 4.9 Hz, 2H), 1.64−
1.62 (m, 2H), 1.45−1.18 (m, 10H), 0.88 (t, J = 7.4 Hz, 3H), 0.85 (t, J
= 7.3 Hz, 6H) ppm. The spectral data were in agreement with
literature data.26
EXPERIMENTAL SECTION
■
General Information. All chemicals were obtained from
commercial suppliers (e.g., Alfa Aesar, TCI America, Sigma-Aldrich)
and used as obtained unless otherwise specified in the procedure.
Deuterated solvents used as reaction media or for NMR measure-
ments were obtained from Cambrige Isotopes or Sigma-Aldrich.
All NMR experiments were carried out on a Bruker BioSpin 500
MHz Avance III Digital NMR spectrometer. All quantitative 1H NMR
measurements were performed using an adjusted method (15 s
relaxation time, NS = 32) with 1,3-dinitrobenzene or 1,1,2-
trichloroethane as internal standard. All NMR spectra were recorded
at room temperature unless otherwise noted. Alternatively, NMR
spectra were recorded on a Bruker 400 Avance III with a 5 mm BBFO
1
probe (400 MHz for H; 101 MHz for 13C). The proton signal for
nondeuterated solvent (δ = 2.50 ppm for DMSO) was used as an
internal reference for 1H NMR spectra. For 13C NMR spectra,
chemical shifts are reported relative to δ = 39.51 ppm resonance of
DMSO-d6.
2-(Ethylamino)propanenitrile (2a) and 2,2′-Azanediyldipropa-
1
nenitrile (2b). The H NMR spectra of compounds 2a and 2b were
extracted from 1H NMR and COSY spectra of the crude mixture. The
13C NMR spectra of compounds 2a and 2b were extracted from 13C
NMR, HSQC, and HMBC spectra of the crude mixture.
2a. Crude yield: 50%. 1H NMR (500 MHz, CD3CN): δ 3.66 (q, J =
7.0 Hz, 1H), 2.71 (dq, J = 13.1, 7.3 Hz, 1H), 2.36 (dq, J = 13.1, 7.0
Hz, 1H), 1.39 (d, J = 7.0 Hz, 3H), 1.08 (t, J = 7.1 Hz, 3H) ppm. 13C
NMR (126 MHz, CD3CN): δ 110.4, 44.7, 43.2, 18.6, 13.8 ppm.
HRMS (ESI) m/z: [M + H]+ calcd for C5H10N2 99.0917 , found
99.0911.
High-resolution mass spectrometry was performed at the
University of Massachusetts Medical School mass spectroscopy
facility. Alternatively, HRMS spectra were recorded by Intertek.
Analyses were conducted on an Agilent 6220 TOF mass spectrometer
(Agilent Technologies, Wilmington, DE) in positive or negative
electrospray mode. The system was calibrated to greater than 1 ppm
accuracy across the mass range prior to analyses according to
manufacturer’s specifications. The mass accuracy was calculated for all
observed isotopes against the theoretical mass ions derived from the
chemical formula using MassHunter software (Agilent Technologies,
Wilmington, DE).
Reactions were observed by in situ FTIR, using a Mettler Toledo
ReactIR 10 instrument with MCT Detector using HappGenzel
apodization. As probe, a SiComp (Silicon) probe connected via AgX
(Silver Halide; 6 mm × 1.5 m fiber) was employed. Measurement was
performed between 3000 and 650 cm−1 at a resolution of 4 cm−1
(scan option: AutoSelect; gain: 1×). Data collection and analysis were
performed using Mettler Toledo iCIR v4.3.35 SP1 software and
Microsoft Excel 2010.
Representative Procedure for Stern−Volmer Studies: [Ir-
(dF(CF3)ppy)2(dtbbpy)]PF6 Fluorescence Quenching by NBu3
under N2. A 4.0 mg (3.47 × 10−3 mmol) portion of [Ir(dF(CF3)-
ppy)2(dtbbpy)]PF6 was dissolved in dry, degassed MeCN (2.00 mL)
in a glovebox filled with N2 atmosphere. The solution was transferred
to a fluorimeter cuvette (Starna Cells 3-Q-10-GL14-S, window
material Spectrosil Quartz or equivalent, usable range: 170−2700
nm), equipped with a septum. A standard solution of NBu3 was
degassed and transferred to a microliter syringe under N2. The syringe
was capped with a septum. Both the filled fluorimeter cuvette and the
syringe containing the standard solution of the quencher were
removed from the glovebox. The filled fluorimeter cuvette was placed
in the fluorimeter (Hitachi F-4500 FL spectrophotometer), and Ir
fluorescence was recorded (excitation wavelength: 380 nM; measure-
ment between 440 and 560 nM; scan speed 60 nm/s; delay: 0 s;
excitation and emission slit 5.0 nm; response: 0.5 s). Then aliquots of
the standard solution of NBu3 were added to obtain the respective
2b. Crude yield: 10%. 1H NMR (500 MHz, CD3CN): δ 3.89 (q, J
= 7.2 Hz, 2H), 1.38 (d, J = 7.2 Hz, 6H) ppm. 13C NMR (126 MHz,
CD3CN): δ 121.0, 44.5, 17.1 ppm. HRMS (ESI) m/z: [M + H]+
calcd for C6H9N3 124.0869, found 124.0864. The 13C NMR data of
2b were in agreement with literature data.47
2 - ( P r o p y l a m i n o ) b u t a n e n i t r i l e ( 3 a ) a n d 2 , 2 ′ -
1
Azanediyldibutanenitrile(3b). The H NMR spectra of compounds
3a and 3b were determined using 1H NMR and COSY spectra of the
crude mixture. The 13C NMR spectra of compound 3b were
determined using 13C NMR, HSQC, and HMBC spectra of the crude
mixture.
3a. Crude yield: 47%. 1H NMR (500 MHz, CD3CN): δ 3.41 (dd, J
= 7.6, 6.3 Hz, 1H), 2.78 (ddd, J = 11.1, 8.0, 6.5 Hz, 1H), 2.53 (ddd, J
= 11.1, 8.1, 6.1 Hz, 1H), 1.80−1.65 (m, 2H), 1.55−1.37 (m, 2H),
1.04 (dd, J = 7.5, 7.5 Hz, 3H), 0.89 (dd, J = 7.4, 7.4 Hz, 3H) ppm.
HRMS (ESI) m/z: [M + H]+ calcd for C7H15N2 127.1230, found
127.1227. The spectral data of 3a were in agreement with literature
data.31a
3b. Crude yield: 9%. 1H NMR (500 MHz, CD3CN): δ 3.62 (t, J =
7.9 Hz, 2H), 2.32 (ddd, J = 12.8, 7.9, 4.7 Hz, 4H), 0.91 (t, J = 7.4 Hz,
1H). 13C NMR (126 MHz, CD3CN): δ 120.4, 55.7, 24.6, 10.6 ppm.
HRMS (ESI) m/z: [M + H]+ calcd for C8H13N3 152.1182, found
152.1176.
2-(Butylamino)pentanenitrile (4a) and 2,2′-Azanediyldipenta-
1
nenitrile (4b). The H NMR spectra of compounds 4a and 4b were
1
determined using H NMR and COSY spectra of the crude mixture.
H
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The Journal of Organic Chemistry
Article
1
Also, the 13C NMR spectra of compounds 4a and 4b were determined
using 13C NMR, HSQC, and HMBC spectra of the crude mixture.
4a. Crude yield: 39%. 1H NMR (500 MHz, CD3CN): δ 3.56 (t, J =
7.2 Hz, 1H), 2.75 (ddd, J = 12.8, 7.5, 5.0 Hz, 1H), 2.27 (ddd, J = 12.8,
7.5, 5.0 Hz, 1H), 1.71−1.62 (m, 2H), 1.51−1.22 (m, 6H), 0.93 (t, J =
7.3 Hz, 6H). 13C NMR (126 MHz, CD3CN): δ 110.5, 50.8, 49.9,
46.6, 34.8, 19.9, 19.7, 12.9, 12.8 ppm. HRMS (ESI) m/z: [M + H]+
calcd for C9H18N2 155.1543, found 155.1536.
2-(Dipentylamino)hexanenitrile (13a). Yield: 57.2 mg (84%). H
NMR (500 MHz, CDCl3): δ 3.60 (t, J = 7.8 Hz, 1H), 2.62−2.55 (m,
2H), 2.37 (ddd, J = 13.1, 8.4, 4.8 Hz, 2H), 1.80−1.67 (m, 2H), 1.52−
1.25 (m, 16H), 0.98−0.89 (m, 9H) ppm. The spectral data were in
agreement with literature data.52
2-(Dibenzylamino)-2-phenylacetonitrile (14a). Eluent: 1:9
EtOAc/hexane. Yield: 62.7 mg (74%). 1H NMR (500 MHz,
CDCl3): δ 7.53−7.49 (m, 2H), 7.35−7.24 (m, 11H), 7.22−7.19
(m, 2H), 4.84 (s, 1H), 3.81 (d, J = 13.4 Hz, 2H), 3.34 (d, J = 13.4 Hz,
2H) ppm. The spectral data were in agreement with literature data.53
2-Morpholinopropanenitrile (15a). Eluent: EtOAc. Yield: 11.4 mg
(30%). Compound 15a was isolated from a reaction mixture that also
contained 15b. 1H NMR (500 MHz, CDCl3): δ 3.73−3.63 (m, 4H),
3.55 (q, J = 7.3 Hz, 1H), 2.66−2.60 (m, 2H), 2.45−2.39 (m, 2H),
1.40 (d, J = 7.3 Hz, 3H) ppm. 13C NMR (126 MHz, CDCl3): δ 117.3,
66.6, 52.6, 16.8 ppm. HRMS (ESI) m/z: [M + H]+ calcd for
C7H12N2O 141.1022, found 141.1016. FT-IR (KBr) ν = 2957, 2921,
2851, 2164, 1454, 1115 cm−1.
4b. Crude yield: 8%. 1H NMR (500 MHz, CD3CN): δ 3.68 (t, J =
7.8 Hz, 2H), 1.71−1.62 (m, 4H), 1.51−1.22 (m, 4H), 0.93 (t, J = 7.3
Hz, 6H). 13C NMR (126 MHz, CD3CN): δ 120.6, 53.7, 33.2, 18.6,
12.5 ppm. HRMS (ESI) m/z: [M + H]+ calcd for C10H17N3 180.1495,
found 180.1488.
2-(Pentylamino)hexanenitrile (5a). The 1H NMR spectrum of
1
compound 5a was determined using H NMR and COSY spectra of
the crude reaction mixture in MeCN-d3. Also, the 13C NMR spectrum
of compound 5a was determined using 13C NMR, HSQC, and
1
HMBC spectra of the crude mixture. Crude yield: 92%. H NMR
(500 MHz, CDCl3): δ 3.53 (t, J = 7.2 Hz, 1H), 3.10 (s, 1H), 2.88
(ddd, J = 11.1, 8.2, 6.4 Hz, 1H), 2.62 (ddd, J = 11.1, 8.3, 6.0 Hz, 1H),
1.81−1.72 (m, 2H), 1.58−1.44 (m, 4H), 1.43−1.32 (m, 6H), 0.97−
0.90 (m, 6H). 13C NMR (126 MHz, CDCl3) δ 120.38, 50.65, 47.68,
33.16, 29.25, 29.20, 27.66, 22.37, 22.06, 13.86, 13.68. HRMS (ESI)
m/z: [M + H]+ calcd for C11H22N2 183.1856, found 183.1849.
4-Ethylmorpholine-3-carbonitrile (15b). Eluent: EtOAc. Yield:
20.4 mg (54%). Compound 15b was isolated from a reaction mixture
that also contained 15a. 1H NMR (500 MHz, CDCl3): δ 3.95 (dd, J =
11.4, 0.9 Hz, 1H), 3.82 (dt, J = 11.4, 2.1 Hz, 1H), 3.67 (dd, J = 11.4,
2.7 Hz, 1H), 3.63 (d, J = 2.0 Hz, 1H), 3.55 (ddd, J = 11.36, 10.70,
3.33 Hz, 1H), 2.58−2.42 (m, 4H), 1.04 (t, J = 7.2 Hz, 3H) ppm. 13C
NMR (126 MHz, CDCl3): δ 115.4, 67.9, 67.0, 52.2, 50.1, 48.6, 11.7
ppm. HRMS (ESI) m/z: [M + H]+ calcd for C7H12N2O 141.1022,
found 141.1017. FT-IR (KBr) ν = 2959, 2922, 2855, 2165, 1455,
1116 cm−1.
1
2-(Isopropylamino)-2-methylpropanenitrile (6a). The H NMR
spectrum of compound 6a was determined using 1H NMR and COSY
1
spectra. Crude yield: 50%. H NMR (500 MHz, CD3CN): δ 3.00
(hept, J = 6.2 Hz, 1H), 1.39 (s, J = 1.8 Hz, 6H), 1.08 (d, J = 6.4 Hz,
6H) ppm. The spectral data were in agreement with literature data.48
(Isobutylamino)-3-methylbutanenitrile (7a). The 1H NMR
spectrum of compound 7a was determined using 1H NMR and
COSY spectra. Also, the 13C NMR spectrum of compound 7a was
determined using 13C NMR, HSQC and HMBC spectra. Crude yield:
43%. 1H NMR (500 MHz, CD3CN): δ 3.37 (d, J = 6.6 Hz, 1H), 2.60
(dd, J = 11.3, 7.0 Hz, 1H), 2.40 (dd, J = 11.0, 4.4 Hz, 1H), 1.99−1.91
(m, 1H), 1.75−1.64 (m, 1H), 0.94 (d, J = 5.4 Hz, 3H), 0.94 (d, J =
5.4 Hz, 6H), 0.93 (d, J = 5.4 Hz, 3H) ppm. 13C NMR (126 MHz,
CD3CN): δ 119.7, 57.0, 55.2, 30.9, 25.6, 19.7, 19.6 ppm. HRMS
(ESI) m/z: [M + H]+ calcd for C9H18N2 155.1543, found 155.1536.
Pyrrolidine-2-carbonitrile (8a). The 1H NMR spectrum of
2-(Piperidin-1-yl)propanenitrile (16a). Yield 6.3 mg (17%).
Compound 16a was isolated from a reaction mixture that also
1
contained 16b. H NMR (500 MHz, CDCl3): δ 3.65 (q, J = 7.3 Hz,
1H), 1.47 (d, J = 7.3 Hz, 3H) ppm. The spectral data were in
agreement with literature data.54
1-Ethylpiperidine-2-carbonitrile (16b). Eluent: EtOAc. Yield: 24.3
mg (65%). Compound 16b was isolated from a reaction mixture that
1
also contained 16a. H NMR (500 MHz, CDCl3): δ 3.84 (t, J = 3.6
Hz, 1H), 2.76−2.70 (m, 1H), 2.52−2.36 (m, 2H), 2.23 (td, J = 11.7,
3.0 Hz, 1H), 1.89−1.82 (m, 1H), 1.79−1.70 (m, 1H), 1.67−1.57 (m,
2H), 1.57−1.44 (m, 2H), 1.03 (t, J = 7.2 Hz, 3H) ppm. The spectral
data were in agreement with literature data.54
2-(Piperidin-1-yl)acetonitrile (17a). Eluent: 1:3 EtOAc/hexane.
Yield: 5.4 mg (16%). Compound 17a was isolated from a reaction
mixture that also contained 17b. 1H NMR (500 MHz, CDCl3): δ 3.43
(s, 2H), 2.46 (t, J = 5.4 Hz, 4H), 1.57 (p, J = 5.6 Hz, 4H), 1.38 (p, J =
5.9 Hz, 2H) ppm. The spectral data were in agreement with literature
data.54
1-Methylpiperidine-2-carbonitrile (17b). Eluent: 1:3 EtOAc/
hexane. Yield: 23.1 mg (69%). Compound 17b was isolated from a
reaction mixture that also contained 17a. 1H NMR (500 MHz,
CDCl3): δ 3.67 (t, J = 3.6 Hz, 1H), 2.58 (dt, J = 11.2, 2.9 Hz, 1H),
2.30 (s, 4H), 1.88−1.73 (m, 2H), 1.63−1.57 (m, 2H), 1.54−1.43 (m,
3H) ppm. The spectral data were in agreement with literature data.54
1-Phenylpyrrolidine-2-carbonitrile (18a). Eluent: 1:3 EtOAc/
hexane. Yield: 34.1 mg (73%). 1H NMR (500 MHz, CDCl3): δ
7.23 (dd, J = 8.73, 7.37 Hz, 2H), 6.76 (tt, J = 7.40, 0.97 Hz, 1H), 6.63
(dd, J = 8.72, 0.93 Hz, 2H), 4.38 (dd, J = 7.30, 1.70 Hz, 1H), 3.40 (td,
J = 8.51, 8.31, 2.81 Hz, 1H), 3.31 (dt, J = 10.78, 7.89 Hz, 1H), 2.39−
2.32 (m, 1H), 2.28−2.11 (m, 3H) ppm. The spectral data were in
agreement with literature data.55
Regioisomers 22a and 22b and 5′-Cyanonicotine (22c). The
mixture of cyanation products was identified by 1H NMR in a crude
mixture, as a similar product mixture had been previously described.
The spectral data were in agreement with literature data.26
22a. Crude yield: 33%. 1H NMR (500 MHz, CDCl3): δ 8.54 (dd, J
= 8.6, 2.0 Hz, 1H), 8.52 (d, J = 1.8 Hz, 1H), 7.73 (dt, J = 7.8, 2.0, Hz,
1H), 7.32−7.25 (m, 1H), 3.37 (t, J = 7.9 Hz, 1H), 3.36 (d, J = 7.7 Hz,
1H), 2.52−2.08 (m, 3H), 2.31 (s, 3H), 1.93−1.69 (m, 1H) ppm.
22b. Crude yield: 59%. 1H NMR (500 MHz, CDCl3): δ 8.54 (dd, J
= 8.6, 2.0 Hz, 1H), 8.52 (d, J = 1.8 Hz, 1H), 7.64 (dt, J = 7.8, 2.0, Hz,
1
compound 8a was determined using H NMR and COSY spectra.
Crude yield: 42%. 1H NMR (500 MHz, CD3CN): δ 4.06 (dd, J = 8.0,
4.5 Hz, 1H), 3.01−2.89 (m, 2H), 2.15−2.06 (m, 1H), 1.90−1.85 (m,
2H), 1.80−1.72 (m, 1H). The spectral data were in agreement with
literature data.31a
Morpholine-3-carbonitrile (9a). The 1H NMR spectrum of
1
compound 9a was determined using H NMR and COSY spectra.
1H NMR (500 MHz, CD3CN): δ 3.92 (td, J = 2.8, 0.5 Hz, 1H), 3.82
(dd, J = 11.5, 2.6 Hz, 1H), 3.77 (dt, J = 11.2, 2.9 Hz, 1H), 3.70 (dt, J
= 11.5, 3.3 Hz, 1H), 3.56 (ddd, J = 11.2, 10.2, 2.8 Hz, 1H), 3.07
(dddd, J = 12.5, 10.2, 3.2, 0.6 Hz, 2.75 (dt, J = 12.5, 2.7 Hz, 1H). The
spectral data were in agreement with literature data.49
2-(Benzylamino)-2-phenylacetonitrile (10a). The 1H NMR
spectrum of compound 9a was determined using 1H NMR and
1
COSY spectra. Crude yield: 15%. H NMR (500 MHz, CD3OD): δ
7.55 (dd, J = 7.3, 1.8 Hz, 2H), 7.45−7.40 (m, 4H), 7.40 (m, 3H),
7.33−7.29 (m, 1H), 4.76 (s, 1H), 4.07 (d, J = 13.0 Hz, 1H), 3.97 (d, J
= 13.0 Hz, 1H), 1.89 (bs, 1H). The spectral data were in agreement
with literature data.50
2-(Diethylamino)propanenitrile (11a). Eluent: EtOAc. Yield: 31.3
mg (99%). 1H NMR (500 MHz, CDCl3): δ 3.83 (q, J = 7.2 Hz, 1H),
2.77 (dq, J = 13.1, 7.3 Hz, 2H), 2.46 (dq, J = 13.0, 7.0 Hz, 1H), 1.48
(d, J = 7.2 Hz, 3H), 1.12 (t, J = 7.2 Hz, 6H) ppm. The spectral data
were in agreement with literature data.51
2-(Dipropylamino)butanenitrile (12a). Eluent: EtOAc. Yield: 42.7
mg (99%). 1H NMR (500 MHz, CDCl3): δ 3.50 (t, J = 7.8 Hz, 1H),
2.54 (ddd, J = 13.0, 8.4, 7.7 Hz, 1H), 2.39 (ddd, J = 13.0, 8.2, 4.7 Hz,
1H), 1.86−1.72 (m, 2H), 1.57−1.41 (m, 4H), 1.07 (t, J = 7.4 Hz,
3H), 0.92 (t, J = 7.4 Hz, 6H) ppm. The spectral data were in
agreement with literature data.26
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The Journal of Organic Chemistry
Article
1H), 7.32−7.25 (m, 1H), 4.14 (d, J = 7.8 Hz, 1H), 3.57 (d, J = 8.0
Hz, 1H), 2.52−2.08 (m, 3H), 2.29 (s, 3H), 1.93−1.69 (m, 1H) ppm.
(s, 1H), 7.70 (ddd, J = 8.9, 4.1, 2.7 Hz, 1H), 7.29 (t, J = 9.0 Hz, 1H),
7.20 (s, 1H), 4.29 (t, J = 6.1 Hz, 2H), 4.06−4.02 (m, 4H), 4.00 (d, J =
11.7 Hz, 1H), 3.91−3.86 (m, 1H), 3.74 (dd, J = 11.6, 2.6 Hz, 1H),
3.62 (td, J = 11.4, 2.7 Hz, 1H), 2.82−2.75 (m, 3H), 2.61 (td, J = 11.7,
3.2 Hz, 1H), 2.13 (p, J = 6.5 Hz, 2H) ppm. 13C NMR (126 MHz,
CD3OD): δ 157.1, 155.6, 152.5, 149.2, 146.4, 124.5, 122.6, 122.5,
116.1, 115.9, 115.4, 109.1, 105.9, 102.0, 67.7, 66.8, 66.7, 55.2, 52.5,
48.5, 25.8 ppm. HRMS (ESI) m/z: [M + H]+ calcd for
C23H23ClFN5O3 472.1546, found 472.1530. FT-IR (KBr) ν = 3380,
3075, 2926, 2856, 2164, 1625, 1578, 1499, 1426, 1213, 1144, 1117,
856 cm−1.
1
22c. Crude yield: 8%. H NMR (500 MHz, CDCl3): δ 8.60−8.44
(m, 2H), 7.76−7.58 (m, 1H), 7.32−7.25 (m, 1H), 3.62−3.60 (m,
1H), 3.59 (d, J = 17.3 Hz, 1H), 3.31 (d, J = 17.3 Hz, 1H), 3.21 (td, J
= 8.4, 3.0 Hz), 2.75 (q, J = 8.8 Hz), 2.05−2.08 (m, 2H), 2.08−1.91
(m, 2H) ppm.
2-((1-Cyanoethyl)(ethyl)amino)-N-(2,6-dimethylphenyl)-
acetamide (23a). Purification solvent: 1:1 EtOAc/hexane. Yield: 57.4
1
mg (82%). H NMR (500 MHz, CDCl3): δ 8.26 (bs, 1H), 7.04 (m,
3H), 3.84 (q, J = 7.2 Hz, 1H), 3.43 (d, J = 17.6 Hz, 1H), 3.21 (d, J =
17.6 Hz, 1H), 2.82 (dq, J = 12.8, 7.3 Hz, 1H), 2.77−2.68 (m, 1H),
2.15 (s, 6H), 1.51 (d, J = 7.2 Hz, 3H), 1.19 (t, J = 7.2 Hz, 3H) ppm.
13C NMR (126 MHz, CDCl3): δ 168.3, 135.0, 133.4, 128.4, 127.5,
117.9, 54.7, 49.9, 48.8, 18.6, 18.0, 13.4 ppm. HRMS (ESI) m/z: [M +
H]+ calcd for C15H21N3O 260.1657, found 260.1647. FT-IR (KBr) ν
= 3232, 2978, 2943, 2921, 2164, 1663, 1595, 1507, 1458, 1428, 1204,
1118, 1096, 782 cm−1.
(R)-2-((2-Hydroxy-2-(3-hydroxyphenyl)ethyl)amino)acetonitrile
1
(27a). Purification solvent: EtOAc. Yield: 13 mg (26%). H NMR
(500 MHz, CD3OD): δ 7.17 (t, J = 8.0 Hz, 1H), 6.87−6.84 (m, 2H),
6.71 (ddd, J = 8.1, 2.4, 1.0 Hz, 1H), 4.73 (dd, J = 8.9, 3.8 Hz, 1H),
3.76 (s, 2H), 2.70 (dd, J = 13.1, 8.9 Hz, 1H), 2.60 (dd, J = 13.1, 3.9
Hz, 1H) ppm. 13C NMR (126 MHz, CD3OD) δ 157.20, 144.51,
128.99, 116.86, 114.88, 114.06, 112.52, 70.94, 63.23, 44.63 ppm.
HRMS (ESI) m/z: [M + H]+ calcd for C10H12N2O2 193.0972, found
193.0967. FT-IR (KBr) ν = 3270, 3080, 2920, 2165, 1592, 1456,
1280, 1156, 1073, 842 cm−1.
2-(((1H-Indol-3-yl)methyl)(methyl)amino)acetonitrile (24a).
Compound 24a was obtained in a mixture with 24b; 24b was
1
purified by flash chromatography. Crude yield: 17%. H NMR (500
(6R,7S,10S)-7,8,9,10-Tetrahydro-6H-6,10-methano-azepino[4,5-
g]quinoxaline-7-carbonitrile (28a). The reaction was carried out on
a 200 mg scale (0.95 mmol), following the general procedure above.
Purification: Silica gel column chromatography, 5:95 MeOH/CHCl3.
MHz, CDCl3): δ 8.17 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.38 (dt, J =
8.0, 1.1 Hz, 1H), 7.23 (ddd, J = 8.0, 7.0, 0.9 Hz, 1H), 7.18 (d, J = 2.5
Hz, 1H), 7.15 (ddd, J = 8.0, 7.0, 1.1 Hz, 1H), 3.81 (s, 2H), 3.46 (s,
2H), 2.50 (s, 3H) ppm. The spectral data were in agreement with
literature data.26
1
Yield: 201 mg (90% isolated yield, single cis-diastereomer). H NMR
(400 MHz, DMSO-d6): δ 9.33 (s, 2H), 8.41 (s, 1H), 8.40 (s, 1H),
4.64 (d, 4.0 Hz, 1H), 4.09 (d, 4.0 Hz, 1H), 3.91 (s, 1H), 3.83 (d, 12
Hz, 1H), 3.43 (d, 12 Hz, 1H), 2.97 (s, 2H) ppm. 13C NMR (100
MHz, DMSO-d6): δ188.6, 186.1, 183.7, 183.5, 182.8, 161.5, 161.1,
159.6, 156.5, 88.3, 86.2, 82.4, 80.3, 78.7 ppm. HRMS (ESI) m/z: [M
+ H]+ calcd for C14H13N4 237.1100; Found 237.1080. FT-IR (KBr) ν
= 529, 536, 553, 563, 576, 603, 610, 636, 699, 725, 748, 773, 808, 856,
880, 902, 936, 965, 1007, 1028, 1054, 1069, 1103, 1134, 1164, 1186,
1205, 1253, 1288, 1327, 1359, 1455, 1470, 1477, 1559, 1669, 1987,
2110, 2217, 2822, 2963, 3348, 3648, 3903.
2-(1H-Indol-3-yl)acetonitrile (24b). Purification solvent: 1:3
EtOAc/hexane. Yield: 29.5 mg (56%). 1H NMR (500 MHz,
CD3OD): δ 7.48 (dt, J = 8.0, 0.9 Hz, 1H), 7.28 (dt, J = 8.2, 0.9
Hz, 1H), 7.14 (s, 1H), 7.06 (ddd, J = 8.2, 7.1, 1.1 Hz, 1H), 6.98 (ddd,
J = 8.0, 7.1, 1.0 Hz, 1H), 3.84 (d, J = 0.9 Hz, 2H) ppm. The spectral
data were in agreement with literature data.56
2-((3-(10,11-Dihydro-5H-dibenzo[b,f ]azepin-5-yl)propyl)-
(methyl)amino)acetonitrile (25a). Compound 25a was obtained in a
mixture with 25b and 25c; each of these compounds was purified by
flash chromatography. Purification solvent: 1:3 EtOAc/hexane. Yield:
18.3 mg (22%). 1H NMR (500 MHz, CDCl3): δ 7.08−6.98 (m, 6H),
6.85 (td, J = 7.40, 1.30 Hz, 2H), 3.71 (t, J = 6.80 Hz, 2H), 3.37 (s,
2H), 3.09 (s, 4H), 2.42 (dd, J = 9.44, 4.63 Hz, 2H), 2.21 (s, 3H), 1.65
(p, J = 7.00 Hz, 2H) ppm. 13C NMR (126 MHz, CDCl3): δ 148.2,
134.3, 129.9, 126.4, 122.6, 119.9, 114.6, 53.6, 48.2, 45.3, 42.0, 32.2,
25.9 ppm. HRMS (ESI) m/z: [M + H]+ calcd for C20H23N3 306.1965,
found 306.1951. FT-IR (KBr) ν = 3057, 3002, 2924, 2949, 2164,
1585, 1573, 1499, 1452, 1330, 1180, 851 cm−1.
2-(10, 11-Dihydro-5H-dibenzo[b, f ]azepin-5-yl)-4-
(dimethylamino)butanenitrile (25b). Compound 25b was obtained
in a mixture with 25a and 25c; each of these compounds was purified
by flash chromatography. Compound 25b is stable in CDCl3 solution
at 8 °C and below but decomposes in solution at room temperature
and higher temperature to 10,11-dihydro-5H-dibenzo[b,f ]azepine
(25c). Purification solvent: 1:3 EtOAc/hexane. Yield: 18.5 mg (23%).
1H NMR (500 MHz, CDCl3): δ 7.19−7.08 (m, 6H), 6.97 (td, J = 7.4,
Synthesis of 3-(2,6-Dimethylphenyl)-1-ethyl-2-methylimidazoli-
din-4-one (32) from Cyanated Lidocaine 23a. The procedure was
adapted from a literature procedure.58 Nitrile 23a (1 mmol) was
added to a reaction flask; then MeOH (3 mL), NaBH4 (2 mmol), and
cobalt chloride (5 mol %) were added. The reaction was stirred for 24
h. The solvent was removed under reduced pressure, and the crude
reaction was purified over a short pad of silica (elution with EtOAc).
The expected reduction product was not obtained; instead, the
1
decyanation product 32 was obtained, as characterized by H NMR
and comparison with the relevant literature; the spectral data were in
agreement with literature data.45 Purification solvent: EtOAc. Yield:
1
28 mg (62%). H NMR (500 MHz, CDCl3): δ 7.15−7.04 (m, 3H),
4.39 (qt, J = 5.7, 1.5 Hz, 1H), 3.71 (dd, J = 14.7, 1.2 Hz, 1H), 3.12
(dd, J = 14.6, 1.8 Hz 1H), 2.86 (dq, J = 11.7, 7.4 Hz, 1H), 2.40 (dq, J
= 11.7, 7.0 Hz, 1H), 2.20 (s, 3H), 2.15 (s, 3H), 1.12 (t, J = 7.2 Hz,
3H), 1.07 (d, J = 5.7 Hz, 3H) ppm.
1.3 Hz, 2H), 3.96−3.86 (m, 2H), 3.67 (t, J = 7.8 Hz, 1H), 3.19 (s,
4H), 2.29 (s, 6H), 2.07−1.98 (m, 2H) ppm. 13C NMR (126 MHz,
CDCl3): δ 147.87, 134.30, 130.05, 126.59, 123.03, 119.69, 116.56,
56.39, 46.50, 41.82, 32.10, 30.02. HRMS (ESI) m/z: [M + H]+ calcd
for C20H23N3 306.1965, found 306.1955.FT-IR (KBr) ν = 3055, 3004,
2923, 2949, 2165, 1583, 1500, 1450, 1330, 1181, 851 cm−1.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.8b01700.
10,11-Dihydro-5H-dibenzo[b,f ]azepine (25c). Compound 25c
was obtained in a mixture with 25a and 25b; each of these
compounds was purified by flash chromatography. Purification
Reaction optimization details, synthetic procedures, and
characterization for new and known compounds (PDF)
1
solvent: 1:3 EtOAc/hexane. Yield: 26.5 mg (50%). H NMR (500
MHz, CDCl3): δ 7.00 (td, J = 6.82, 1.57 Hz, 2H), 6.97 (dd, J = 7.45,
1.24 Hz, 2H), 6.70 (td, J = 7.39, 1.14 Hz, 2H), 6.66 (dd, J = 7.94, 1.01
Hz, 2H), 5.91 (bs, 1H), 3.01 (s, 4H) ppm. The spectral data were in
agreement with literature data.57
4-(3-((4-((3-Chloro-4-fluorophenyl)amino)-7-methoxyquinazo-
lin-6-yl)oxy)propyl)morpholine-3-carbonitrile (26a). Purification
solvent: 1:7 MeOH/CHCl3. Yield: 62 mg (49%). 1H NMR (500
MHz, CD3OD): δ 8.47 (s, 1H), 8.02 (dd, J = 6.7, 2.6 Hz, 1H), 7.75
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: martin.oderinde@bms.com.
*E-mail: mhemmert@wpi.edu.
ORCID
Marion H. Emmert: 0000-0003-4375-8295
J
DOI: 10.1021/acs.joc.8b01700
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The Journal of Organic Chemistry
Article
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
O.Y. thanks Tubitak Bideb 2219 and Mersin University
(Turkey) for a visiting scholar fellowship. We thank Howard
W. Ward II and Courtney Talicska (Analytical Research &
Development, Pharmaceutical Sciences, Pfizer, Inc.), for
assistance with setting up the ReactIR instrumentation.
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