Utilization of Cyclic Amides as Masked Aldehyde Equivalents in Reductive Amination Reactions

Article abstract of DOI:10.1021/acs.joc.9b00816

An operationally simple protocol has been discovered that couples primary or secondary amines with N-aryl-substituted lactams to deliver differentiated diamines in moderate to high yields. The process allows for the partial reduction of a lactam in the presence of Cp₂ZrHCl (Schwartz's reagent), followed by a reductive amination between the resulting hemiaminal and primary or secondary amine. These reactions can be telescoped in a one-pot fashion to significantly simplify the operation. The scope of amines and substituted lactams of various ring sizes was demonstrated through the formation of a range of differentiated diamine products. Furthermore, this methodology was expanded to include N-aryl pyrrolidinone substrates with an enantiopure ester group at the 5-position, and α-amino piperidinones were prepared with complete retention of stereochemical information. The development of this chemistry has enabled the consideration of lactams as useful synthons.

Full text of DOI:10.1021/acs.joc.9b00816

Article
pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
Utilization of Cyclic Amides as Masked Aldehyde Equivalents in
Reductive Amination Reactions
Robin J. Prince,*,† Fang Gao,*,† Jessica E. Pazienza, Isaac E. Marx, Jurgen Schulz,
and Brian T. Hopkins*
Biotherapeutics and Medicinal Sciences, Biogen Inc., 225 Binney Street, Cambridge, Massachusetts 02142, United States
S
* Supporting Information
ABSTRACT: An operationally simple protocol has been
discovered that couples primary or secondary amines with N-
aryl-substituted lactams to deliver differentiated diamines in
moderate to high yields. The process allows for the partial
reduction of a lactam in the presence of Cp2ZrHCl
(Schwartz’s reagent), followed by a reductive amination
between the resulting hemiaminal and primary or secondary
amine. These reactions can be telescoped in a one-pot fashion
to significantly simplify the operation. The scope of amines
and substituted lactams of various ring sizes was demonstrated
through the formation of a range of differentiated diamine products. Furthermore, this methodology was expanded to include
N-aryl pyrrolidinone substrates with an enantiopure ester group at the 5-position, and α-amino piperidinones were prepared
with complete retention of stereochemical information. The development of this chemistry has enabled the consideration of
lactams as useful synthons.
However, if a partial reduction product of an amide, for
instance, an aminol or other masked aldehyde equivalent,
could be readily further functionalized in a coupling reaction,
such a protocol would be synthetically attractive, effectively
rendering the amide group a useful synthon for further
manipulations. Indeed, lactams have been reported to be
utilized as starting materials to build molecular complexity.9
Substituted N-Boc pyrrolidinones (functionally imides) have
been treated with a variety of reducing agents (generally
DIBAL-H, LAH, or LiEt3BH) to afford isolable aminol
intermediates, which have been used effectively in a variety
of subsequent transformations (Scheme 1, top).10,11
Due to the lack of generality of reaction conditions and the
sensitive or incompatible reducing agents employed in prior
works, the utilization of an in situ-prepared reactive
intermediate of a lactam reduction for further functionalization
has not been a widely adopted synthetic strategy, specifically to
access differentiated diamines. Herein, we report an inves-
tigation of lactams as masked aldehyde equivalents, generated
by the treatment of an N-aryl lactam with a chemoselective
reducing agent (Cp2ZrHCl, Schwartz’s reagent12) under mild
conditions (0 °C) and its subsequent in situ functionalization
through a reductive amination sequence. We have telescoped
the reaction conditions to enable an operationally simple, one-
pot procedure to produce a set of differentiated diamines
(Scheme 1, bottom). The rationale behind the choice of N-
arylated lactams as substrates in this study is 2-fold. First, these
INTRODUCTION
■
The propensity of amide groups to participate in resonance
stabilization is the fundamental attribute which affords them
uncharacteristic durability, as compared to other members of
the carboxylic acid family.1 As such, amide bonds are
incredibly robust and require forcing conditions to facilitate
their hydrolysis.2 The implementation and commercialization
within the pharmaceutical industry3 of this resilient chemotype
and their applications in the synthesis of high strength
materials4 serve as testaments to the strength and utility of
these bonds.
Due to their sturdiness, utilization of amides as enabling
precursors for functional group manipulation in synthetic
organic chemistry has been limited in scope, focusing primarily
on complete reductions to afford amines.5 Recent advances in
the use of increasingly mild reducing conditions, and even
chemoselective reducing conditions, have expanded the
application of reductions of amides.6 Additionally, imines,
enamines, alcohols, and aldehydes compose a significant
minority of amide reduction products.7 Even though the
aforementioned array of functionalities could be accessed via
amide reduction reactions, these transformations require
specialized reagents that lack compatibility with a wide range
of other functional groups.8 Due to this limitation, alternative
synthetic strategies are often more desirable for the synthesis of
these functional groups over direct amide reductions.
Furthermore, syntheses of diamines directly from amides are
under-represented in the literature and in all examples,
multistep sequences are necessary (vide infra).
Received: March 22, 2019
Published: May 22, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.9b00816
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 1. Original Scope of Research Project
a
Table 1. Screen of Conditions in Optimizing the One-Pot Coupling Reaction
b
c
entry
reducing agent (X)
amine (Y)
T1 (°C)
T2 (°C)
Conv. (%)
Yield: 3a; 4a
1
2
3
4
5
6
7
8
DIBAL-H; 1.0 equiv
Cp2ZrHCl; 1.0 equiv
Cp2ZrHCl; 2.0 equiv
Cp2ZrHCl; 2.0 equiv
Cp2ZrHCl; 2.0 equiv
Cp2ZrHCl; 2.0 equiv
Cp2ZrHCl; 2.0 equiv
1.0 equiv
1.0 equiv
1.0 equiv
2.0 equiv
3.0 equiv
4.0 equiv
4.0 equiv
4.0 equiv
23
23
23
23
23
23
23
0
23
23
23
23
23
23
60
23
73
67
<5%; 30%
15%; 30%
15%; 30%
45%; 30%
43%; 24%
55%; 15%
60%; 18%
>98
>98
>98
>98
>98
>98
d
Cp2ZrHCl; 1.5 equiv
63% ; <5%
a
b
c
Average of two runs for each entry. Conversion refers to the disappearance of lactam starting material. Determined by liquid chromatography
d
mass spectroscopy (LCMS). Yield by silica gel chromatography.
lactams can be readily accessed via copper-catalyzed Ullmann
couplings between commercially available cyclic carboxamides
and various aryl iodides. Second, reactions with these N-aryl
lactams afford differentiated diamines featuring a versatile aryl
amine functionality. Other synthetic strategies for nonvicinal
diamines (specifically 1,3-,13 1,4-,14 and 1,5-diamines) involved
multiple steps to selectively functionalize one amine at a time.
Additionally, these diamine products could not be selectively
formed from the previously disclosed Boc-protected amines
through palladium-catalyzed C−N coupling chemistry because
of the competing secondary amine present in those
molecules.15
Combinations of DIBAL-H or Schwartz’s reagent with
aluminum or zirconium Lewis acid additives17 to activate the
lactam carbonyl for a more facile reduction afforded no
improvement in reactivity or product distribution. When the
reducing reagent was omitted in either step of the sequence,
the corresponding reactions did not lead to any desired
diamine product. Our initial solvent screen showed that
tetrahydrofuran (THF) was the most effective solvent18 for
both the partial reduction of 1a and the following utilization of
the resulting aldehyde equivalent in a reductive amination
reaction with 2a. Therefore, N-aryl-substituted lactam 1a was
treated with DIBAL-H in THF and a minimal amount of
desired diamine 3a was formed, with mostly over-reduced
pyrrolidine 4a identified in the crude mixture (entry 1, Table
1). Switching from DIBAL-H to Schwartz’s reagent
(Cp2ZrHCl) in this reductive coupling reaction delivered
15% yield of 3a and 30% 4a with 33% of the remaining lactam
1a (entry 2, Table 1). Subsequently, we observed full
consumption of 1a when 2.0 equiv of Cp2ZrHCl was used
but did not note an improvement in yield of desired product
3a (entry 3, Table 1). We surmised that the amine might be
RESULTS AND DISCUSSION
■
We began our investigation by identifying conditions which
would allow both the reduction of the lactam and the
reduction of the imine to be carried out in one pot. Our
optimization results are summarized in Table 1. We initially
evaluated a variety of reducing agents but only saw productive
reactions when using DIBAL-H or Schwartz’s reagent.16
B
DOI: 10.1021/acs.joc.9b00816
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
coordinating to the metal center which would render it
unavailable to participate in the reductive amination reaction
to produce 3a. Hence, we increased the equivalents of amine to
2.0 equiv and obtained 45% yield of diamine 3a with 30% of
pyrrolidine 4a (entry 4, Table 1). A comparable yield of
diamine 3a and a slight reduction in yield of pyrrolidine 4a
were observed when the 3.0 equiv. of amine was investigated
(entry 5, Table 1). Further increase to 4.0 equiv. of 2a led to
55% yield of 3a in the reaction mixture and a decreased
amount of pyrrolidine 4a (15%, entry 6, Table 1). However, no
boost in yield of 3a was noted when more than four
equivalents of amine were utilized. Later optimization of
reaction temperatures for both sequential steps identified that
performing the partial reduction of lactam 1a at 0 °C followed
by the standard reductive amination at ambient temperature
completely consumed lactam 1a, affording diamine 3a in 63%
yield and <5% byproduct 4a (entry 8, Table 1).
Table 2. Scope of Aryl-substituted Lactams in One-Pot
Reductive Coupling
a
With the optimized conditions in hand, we set out to explore
the scope of N-aryl-substituted lactam substrates (Table 2). As
shown from entries 1−4, para-substituted electron-deficient
aromatic substituents on the lactams were capable substrates
for this chemistry, giving desired diamines in 35−82% yield
with a minimal amount of pyrrolidine byproducts. Electron-
withdrawing functional groups on the aryl ring, such as cyano,
nitro, and carboxylic ester, were tolerated in this reaction;
diamines 3e, 3f, and 3g were obtained in 34−49% yield.
However, pyrrolidines 4f and 4g were afforded in 40 and 35%,
respectively (entries 6 and 7, Table 2). Moreover, as
demonstrated in entry 8 of Table 2, the reductive coupling
reaction of disubstituted arene containing lactam 1h resulted in
the formation of diamine 3h in 42% yield and 37% pyrrolidine
4h. An electron neutral phenyl substituent was also tolerated
on the pyrrolidinone substrate. Diamine 3i was obtained in
36% yield along with 32% fully reduced pyrrolidine 4i, as
shown in entry 9 of Table 2. On the contrary, electron-
donating para-methoxy substituent containing substrate 1j
decomposed to complex reaction mixtures with <5% desired
diamines detected by LCMS (entry 10, Table 2). ortho-
Methoxyphenyl-substituted lactam 1k, which was presumably
less electron donating due to the inductive effect, was
examined in hopes of restoring a certain extent of reaction
efficiency; however, 1k was proven to be an ineffective
coupling partner as well, the reaction with which only led to
the formation of pyrrolidine 4k in 35% yield (entry 11).
Next, we investigated steric effects surrounding the lactam
functionality. As illustrated in entries 1 and 2 in Table 3, when
a methyl group was placed at the 3- or 5-position on the lactam
ring, reductive coupling reactions of lactams 1l and 1m
delivered methyl-substituted diamines 3l and 3m in 43 and
34% yields, respectively. Unlike the result observed in entry 1
(Table 2), pyrrolidines 4l and 4m were also afforded in high
yield (35−45%). In addition to pyrrolidinones, six- and four-
membered N-arylated lactams were examined as well. Upon
treatment with the standard reaction conditions, piperidinone
1n was transformed into diamine 3n with a five-carbon linker
in between the two nitrogen centers in 72% yield (entry 3,
Table 3). Strained azetidinones were more capable coupling
partners than either the pyrrolidinones or piperidinones in this
sequence of reactions. As shown in entry 4, diamine 3o was
obtained in 92% yield. Interestingly, azetidinones with
electron-rich aromatic substituents, entries 5 and 6 (Table
3), were effectively converted into diamines 3p and 3q in 30
and 48% yield, respectively. Although some azetidines 4p and
a
Average of at least two runs for each entry. >98% conversion in all
b
c
cases unless noted otherwise. 95% conversion. 90% conversion.
d
e
f
85% conversion. Complicated reaction mixtures observed. Yield by
g
silica gel chromatography. Determined by liquid chromatography
mass spectroscopy (LCMS).
4q accompanied the desired products in these reactions, the
results were still very encouraging given that electron-rich
arene containing pyrrolidinones were ineffective substrates.
Having examined the scope of the N-aryl-substituted
lactams, we set forth to investigate the range of amines that
were able to participate in this class of reductive coupling
reactions. As illustrated in Table 4, a variety of primary amines
were tested in combination with the substrate 1a. Cyclo-
hexylmethylamine reacted with 1a to furnish diamine 5a in
69% yield with <5% of pyrrolidine 4a present in the crude
mixture. Similarly, reductive coupling reactions with cyclo-
hexylamine and nonylamine afforded 5b and 5c in 58 and 63%
yield, respectively. Amines with an α-stereogenic center were
also tolerated in these reactions, as represented by the
formation of diamines 5d and 5e (61 and 50% yield, Table
4). Reductive coupling of 1a with p-CF3 benzylamine 2f
resulted in a lower yield of diamine 5f; pyrrolidine 4a, in this
C
DOI: 10.1021/acs.joc.9b00816
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
process increased. Similarly, the reductive coupling reaction
with less nucleophilic aniline 2g furnished only 22% yield of
diamine 5g. Furthermore, when a primary alkylamine with a
carboxylic ester substituent one carbon away was utilized, only
5% yield of product 5h was obtained along with 80%
pyrrolidine 4a, presumably due to the reduced nucleophilicity
of the amine group caused by the electron-withdrawing
inductive effect from the ester carbonyl.
Table 3. Additional Scope of Aryl-substituted Lactams in
One-Pot Reductive Coupling
a
In addition to reactions with primary amines, we have also
investigated the reductive coupling of lactams with secondary
amines, which would give a distinct set of diamine products.
The results are summarized in Table 5. Treatment of 1a with
Table 5. Scope of Secondary Amines in One-Pot Reductive
a
Coupling Reactions
a
Average of at least two runs for each entry; Ar = p-OMePh; >98%
b
c
conversion in all cases unless otherwise noted. 70% conversion. 87%
conversion. Yield by silica gel chromatography. Determined by
liquid chromatography mass spectroscopy (LCMS).
d
e
Table 4. Scope of Primary Amines in One-Pot Reductive
a
Coupling Reactions
a
Average of at least two runs for each entry; >98% conversion and
<5% 4 observed in all cases unless Indicated otherwise; yields for 6
b
c
are of isolated diamine products. 72% conversion of 1r. The second
portion of this reaction was carried out at 22 °C; >98% conversion of
1o.
N-Boc-piperazine under the standard coupling conditions
resulted in diamine 6a in 42% yield. Further optimization of
this reaction sequence led to the production of 6a in 75% yield,
when the temperature of the reductive amination step was
raised to 80 °C. With the new conditions in hand, we
examined several other substrates with N-Boc-piperazine.
Product 6b, derived from the reductive coupling of an N-
arylated piperidinone, was afforded in 48% yield, and desired
diamine 6c, which was generated from an N-arylated
azetidinone, was furnished in comparable yield. Similarly,
reductive coupling reactions using pyrrolidine as the amine
nucleophile resulted in diamines 6e, 6f, and 6g in 56%, 32%,
and 59% yield, respectively. Notably, pyrrolidinone 1r, which
contains an OCF3 substituent, was also proven to be a capable
coupling partner (i.e., 6f). Additionally, the secondary amine
does not need to be cyclic; as exemplified by diamine 6d, such
a reaction between N-methyl-p-methoxybenzylamine and
lactam 1a delivered the desired product in 30% yield. To
further showcase the practicality of this chemistry, we have
performed the reductive coupling reaction on gram scale. As
illustrated in eq 1, upon treatment of 1.83 g (8.0 mmol) of 1a
under standard conditions, the coupling with 2a furnished
a
Average of at least two runs for each entry; >98% conversion in all
cases unless indicated otherwise; yields for 5 are of isolated diamine
products, Ar = p-CF3C6H4. 90% conversion of 1a.
b
case, was afforded in 50% yield. The data from reactions with
benzyl amines 2a and 2f identified the trend of decreased
diamine formation as the nucleophilicity of underlying amines
decreased; meanwhile, the competing lactam over-reduction
D
DOI: 10.1021/acs.joc.9b00816
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
piperidinones could become readily accessible. In Table 6, we
summarized the results of reductive coupling reactions with
pyrrolidinones that contain a 5-ester substituent, which were
prepared in enantiopure form via Ullmann couplings between
commercially available ethyl (R)-5-oxopyrrolidine-2-carboxy-
late and a range of aryl iodides.
As shown in entry 1, Table 6, upon treatment of 7a with
benzylamine 2a under slightly varied conditions, N-arylated
piperidinone 8a was identified to be the major product from
the reaction mixture, which was isolated in 75% yield and more
importantly was obtained with full retention of the stereo-
chemical information. An elevated temperature (80 °C) was
needed to induce the cyclization of the benzylic amine center
onto the ester after the diamine formation. As established in
Tables 2 and 3, a similar trend was observed: electron-
withdrawing substrates were generally more capable coupling
partners. Piperidinones 8b−g were afforded in good yields,
with minimal formation of over-reduced pyrrolidine by-
products (65−77% yield, <5−13% pyrrolidines). Interestingly,
electron-rich substrates, which were previously incapable of
participation in the coupling reactions (Table 2), were now
effective in the formation of piperidinones. For examples, 8h
and 8i were furnished in 51 and 55% yield, respectively, albeit a
higher production of pyrrolidines was observed (7−20%).
Reductive coupling of more hindered and electron-rich 7j did
not proceed to completion within 18 h, resulting in 35% yield
of 8j. Additionally, 88−100% ee was obtained for N-arylated
piperidinones. The complete retention of stereochemistry in
this transformation was purported to be derived from two
complementary factors: (1) the lack of a basic reducing agent
interacting directly with the α-stereocenter and (2) a proposed
zirconacycle masked aldehyde equivalent V, as depicted in
Scheme 4, which would reinforce the retention of the α-
stereocenter. Additionally, intermediate V disfavors the
collapsed iminium ion VI, which would lead to the pyrrolidine
byproduct. This explains our observation of relatively
insignificant yields of pyrrolidines in various examples in
Table 6 as compared to the amounts of pyrrolidines formed as
side products from the diamine formation reactions described
in previous sections (see Tables 2−5).
diamine 3a in 63% yield (1.77 g; 5.0 mmol) with minimal
formation of pyrrolidine 4a. The result demonstrated the
amiability to scale up of the current semireduction/reductive
amination sequence.
Extensive mechanistic discussions of Schwartz’s reagent
reductions of amides have suggested that secondary amide
reductions proceed through imine intermediates,19,20 whereas
tertiary amide reductions proceed through metal-stabilized
complexes.8a Based on the precedent, the mechanism for this
transformation, as proposed in Scheme 2, invokes a zirconium
complex I to serve as the masked aldehyde equivalent, as
opposed to an iminium intermediate II. Nucleophilic primary
amines attack the tetrahedral intermediate, which subsequently
collapses to form the imine III or aminal IV. Upon treatment
with sodium triacetoxyborohydride (STAB), this imine/aminal
is reduced to the corresponding amine, thereby generating an
overall diamine product. This mechanism is also invoked when
utilizing secondary nucleophilic amines as coupling partners
(i.e., the substrates of Table 5).
One benefit of using Schwartz’s reagent to reduce the lactam
into a masked aldehyde equivalent is the compatibility of these
conditions with esters. To take advantage of this tolerability,
we investigated the installation of a pendant ester in close
proximity to the amide, as indicated in Scheme 3. When
treated with Schwartz’s reagent, we expected the formation of
the masked aldehyde equivalent and upon addition of the
amine nucleophile, an ester bearing intermediate diamine was
anticipated.21 We surmised that this intermediate, when
treated with heat, would lead to intramolecular lactam
formation between the pendant ester and the newly formed
amine, a transformation which would not have been feasible
with traditional amide reducing reagents. Standard reagents,
such as LAH, LiEt3BH, lithium borohydride, DIBAL-H, and
lithium aminoborohydrides, directly reduced the pendant ester
or over-reduced the starting lactam. Moreover, if such a
transformation were to retain the stereochemical configuration
of the starting material, a class of enantioenriched α-amino
Scheme 2. Proposed Mechanism
E
DOI: 10.1021/acs.joc.9b00816
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 3. Expanded Scope of Research to Synthesize Enantioenriched Piperidinones
Table 6. Examples of Reductive Coupling/Cyclization
Sequence of α-Ester Containing N-Arylated Pyrrolidinones
CONCLUSIONS
■
a
In summary, we have established an operationally simple
protocol that couples a primary or secondary amine with an N-
aryl-substituted lactam, delivering a differentiated diamine in
22−91% yield. We have successfully optimized conditions to
allow semireduction/reductive amination sequence to be
telescoped in a one-pot fashion. Nucleophilic amines and
electron-deficient arylated lactams were generally more capable
coupling partners in these reactions. Azetidinones, pyrrolidi-
nones, and piperidinones were shown to participate in
reductive coupling reactions effectively. This was significant
as it allowed for a singular synthetic strategy to access 1,3-, 1,4-,
and 1,5-diamines (which, if targeted individually, would
require differing synthetic approaches based on the length of
the carbon chain). A range of primary and secondary amines
were included in the study to diversify the scope of diamine
products. This work was further strengthened with a class of α-
carboxylic ester containing pyrrolidinones and their efficient
conversion to enantiomerically pure α-amino piperidinones in
35−77% yield and complete retention of stereochemical
information. Through an operationally simple, one-pot
procedure to convert N-aryl lactams into masked aldehyde
equivalents for use in reductive amination reactions, we have
shown that lactams can be considered viable functional group
handles potentially for a wider array of further transformations.
Additional exploration in the use of lactams in this fashion is
currently underway and will be disclosed in due course.
EXPERIMENTAL SECTION
■
Unless otherwise noted, all reactions were carried out with anhydrous
solvents (dichloromethane, toluene, tetrahydrofuran, 1,4-dioxane,
acetonitrile) purchased from Fisher Scientific and in standard glass
vials and round-bottom flasks. All reagents were purchased from
Sigma-Aldrich or Combi-Blocks and used as received, unless noted
otherwise. A nitrogen atmosphere was maintained using standard
vacuum line technique. The final compounds were analyzed or
purified according to one of the analytical or purification methods
referred to below unless otherwise described and characterized by 1H,
13C NMR, and high-resolution mass spectrometry. For LC/MS
analysis, a sample is dissolved in a suitable solvent such as MeCN,
dimethyl sulfoxide (DMSO), or MeOH and is injected directly into
the column using an automated sample handler. The analysis used
one of the following methods: (1) acidic method (1.5, 2, 3.5, 4, or 7
min runs, see Supporting Information (SI) for additional details):
conducted on a Shimadzu 2010 Series, Shimadzu 2020 Series, or
Waters Acquity UPLC BEH. (MS ionization: ESI) instrument
equipped with a C18 column (2.1 mm × 30 mm, 3.0 mm or 2.1
mm × 50 mm, C18, 1.7 μm), eluting with 1.5 mL/4 L of
trifluoroacetic acid (TFA) in water (solvent A) and 0.75 mL/4 L of
TFA in acetonitrile (solvent B) or (2) basic method (3, 3.5, 7 min
runs, see SI for additional details): conducted on a Shimadzu 2020
Series or Waters Acquity UPLC BEH (MS ionization: ESI)
instrument equipped with XBridge Shield RP18, 5um column (2.1
mm × 30 mm, 3.0 mm i.d.) or 2.1 mm × 50 mm, C18, 1.7 μm
column, eluting with 2 mL/4 L NH3·H2O in water (solvent A) and
acetonitrile (solvent B). Silica gel column chromatography was
performed using 20−40 μM (particle size), 250−400 mesh, or 400−
a
Average of at least two runs for each entry; >98% conversion in all
cases unless indicated otherwise; ee = enantiomer excess as
determined by chiral supercritical fluid chromatography (SFC)
analysis in comparison with an authentic racemic sample; yield by
silica gel chromatography; Ar = p-OMePh; pyrrolidine refers to ester
b
containing over-reduction byproducts similar to 4. 90% conversion
of 7i. 60% conversion of 7j.
c
F
DOI: 10.1021/acs.joc.9b00816
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 4. Proposed Mechanism for the Synthesis of Enantioenriched α-amino Piperidinones
632 mesh silica gel using either a Teledyne ISCO Combiflash RF or a
Grace Reveleris X2 with ELSD purification systems. SFC chiral
separation was performed using a Waters UPC2 analytical SFC (SFC-
H). Column: ChiralCel OJ, 150 mm × 4.6 mm i.d., 3 μm. Mobile
phase: A for CO2 and B for ethanol (0.05% DEA). Gradient: B 40%.
Flow rate: 2.5 mL/min. Back pressure: 100 bar. Column temperature:
35° C. Wavelength: 220 nm. Preparative HPLC purifications were
performed on a Gilson UV/VIS-156 with UV detection at 220/254
nm, Gilson 281 automatic collection, utilizing acidic, basic and neutral
The filtrate was concentrated, and the crude material was purified by
silica gel column chromatography (EtOAc/heptanes, 1:1) to give the
desired N-aryl azetidinones, N-aryl pyrrolidinones, or N-aryl
piperidinones.
1-(4-(Trifluoromethyl)phenyl)pyrrolidin-2-one (1a, White Solid,
2.6 g, Yield: 96%).22 1H NMR (DMSO-d6, 500 MHz): δ 7.89 (2H, br
d, J = 9.2 Hz), 7.73 (2H, d, J = 8.5 Hz), 3.88 (2H, t, J = 7.0 Hz),
2.57−2.52 (2H, m), 2.08 (2H, br t, J = 7.6 Hz). LRMS (ESI)+: 192.2.
1-(Pyridin-4-yl)pyrrolidin-2-one (1b, White Solid, 2.7 g, Yield:
72%). 1H NMR (DMSO-d6, 500 MHz): δ 8.52−8.45 (2H, m), 7.71−
7.63 (2H, m), 3.88−3.80 (2H, m), 2.58−2.52 (2H, m), 2.12−2.03
(2H, m). LRMS (ESI)+: 163.1.
1-(4-Bromophenyl)pyrrolidin-2-one (1c, White Solid, 2.2 g, yield:
78%).23 1H NMR (DMSO-d6, 500 MHz): δ 7.68−7.61 (2H, m),
7.58−7.52 (2H, m), 3.84−3.78 (2H, m), 2.49−2.44 (2H, m), 2.10−
2.01 (2H, m). LRMS (ESI)+: 240.1.
1-(4-Chlorophenyl)pyrrolidin-2-one (1d, White Solid, 2.4 g, Yield:
53%).24 1H NMR (DMSO-d6, 500 MHz): δ 7.74−7.64 (2H, m),
7.47−7.39 (2H, m), 3.85−3.78 (2H, m), 2.48 (2H, s), 2.11−2.00
(2H, m). LRMS (ESI)+: 196.1.
4-(2-Oxopyrrolidin-1-yl)benzonitrile (1e, White Solid, 2.3 g,
Yield: 71%).25 1H NMR (DMSO-d6, 500 MHz): δ 7.92−7.80 (4H,
m), 3.91−3.84 (2H, m), 2.58−2.53 (2H, m), 2.13−2.04 (2H, m).
LRMS (ESI)+: 187.1.
1-(4-Nitrophenyl)pyrrolidin-2-one (1f, Yellow Solid, 3.2 g, Yield:
67%).26 1H NMR (DMSO-d6, 500 MHz): δ 8.29−8.24 (2H, m),
7.97−7.91 (2H, m), 3.91 (2H, t, J = 7.3 Hz), 2.58 (2H, t, J = 8.2 Hz),
2.13−2.05 (2H, m). LRMS (ESI)+: 207.1.
Ethyl 4-(2-Oxopyrrolidin-1-yl)benzoate (1g, White Solid, 3.6 g,
Yield: 67%).27 1H NMR (DMSO-d6, 500 MHz): δ 8.00−7.93 (2H,
m), 7.85−7.80 (2H, m), 4.29 (2H, q, J = 7.1 Hz), 3.87 (2H, t, J = 7.3
Hz), 2.54 (2H, t, J = 8.2 Hz), 2.12−2.03 (2H, m), 1.31 (3H, t, J = 7.0
Hz). LRMS (ESI)+: 234.2.
1
methods (see SI for additional details). The H NMR spectra were
recorded on a Bruker Avance III HD 500 MHz, Bruker Avance III
500 MHz, Bruker Avance III 400 MHz, Varian-400 VNMRS, or
Varian-400 MR. Chemical shifts are expressed in parts per million
(ppm) units and referenced to the residual solvent resonance as noted
in the spectra (i.e., CDCl3; 7.27 ppm). Coupling constants (J) are in
units of Hertz (Hz). Splitting patterns describe apparent multiplicities
and are designated as: s (singlet), d (doublet), t (triplet), q (quartet),
quin (quintet), dd (doubled doublet), dt (doubled triplet), dq
(doubled quartet), m (multiplet), or br (broad). The 13C{1H} NMR
spectra were recorded on a Bruker Avance III HD 500 MHz, Bruker
Avance III 500 MHz, Bruker Avance III 400 MHz, Varian-400
VNMRS, or Varian-400 MR. Chemical shifts are expressed in parts
per million (ppm) units and referenced to the residual solvent
resonance as noted in the spectra (i.e., CDCl3; 77.0 ppm). Coupling
constants (J) are in units of Hertz (Hz). Splitting patterns describe
apparent multiplicities and are designated as: s (singlet), d (doublet),
t (triplet), dd (doubled doublet), dt (doubled triplet), dq (doubled
quartet), m (multiplet), or br (broad). High-resolution mass
spectrometry data were recorded using Sciex Triple TOF 6600
mass spectrometer (column: Waters UPLC Acquity HSS T3 C18 1.8
μm, 2.1 mm × 50 mm; mobile phase: A = 0.1% formic acid in H2O; B
= 0.1% formic acid in acetonitrile; method: 7 min, A to B gradient 5−
65%, positive ionization mode). All masses were reported as the exact
masses in the format of [M + H]+, unless noted otherwise.
Representative Experimental Procedure for Ullmann Cou-
plings. Compounds 1a−r were Prepared by ChemPartner, Except
Where Noted Otherwise. Nonetheless, Many are Commercially
Available. A round-bottom flask was charged with aryl iodide or aryl
bromide (1 equiv), 2-pyrrolidinone OR 2-piperidinone OR 2-
azetidinone (1.4 equiv), copper iodide (0.25 equiv), cesium carbonate
(2 equiv), and p-dioxane (0.5 M reaction concentration) under an
atmosphere of nitrogen. Then, tetramethylethylenediamine
(TMEDA) or 1,2-dimethylethylenediamine (DMEDA) (0.5 equiv)
was added, and the resulting mixture was heated to 40 °C and stirred
at that temperature for 5 h. Additional portions of copper iodide (0.12
equiv) and TMEDA or DMEDA (0.25 equiv) were added (as
needed). The reaction mixture continued to stir at 40 °C overnight.
The reaction mixture was cooled to ambient temperature and filtered.
1-(3-Chloro-5-fluorophenyl)pyrrolidin-2-one (1h, Yellow Solid,
1
3.5 g, Yield: 70%). H NMR (DMSO-d6, 500 MHz): δ 7.71−7.63
(1H, m), 7.58 (1H, td, J = 11.6 Hz, 2.1 Hz), 7.18 (1H, td, J = 8.5 Hz,
2.2 Hz), 3.83 (2H, t, J = 7.3 Hz), 2.55−2.52 (2H, m), 2.10−2.01 (2H,
m). LRMS (ESI)+: 214.1.
1-Phenylpyrrolidin-2-one (1i, White Solid). This material was
purchased from Sigma-Aldrich and used as received. 1H NMR
(CDCl3, 400 MHz): δ 7.65−7.59 (2H, m), 7.42−7.34 (2H, m),
7.19−7.12 (1H, m), 3.88 (2H, t, J = 7.0 Hz), 2.63 (2H, t, J = 8.0 Hz),
2.23−2.12 (2H, m). LRMS (ESI)+: 162.1.
1-(4-Methoxyphenyl)pyrrolidin-2-one (1j, White Solid, 3.2 g,
Yield: 72%).28 1H NMR (DMSO-d6, 500 MHz): δ 7.59−7.49 (2H,
m), 6.99−6.90 (2H, m), 3.78 (2H, t, J = 7.0 Hz), 3.74 (3H, s), 2.45
(2H, t, J = 8.2 Hz), 2.04 (2H, quin, J = 7.5 Hz). LRMS (ESI)+: 192.2.
1-(2-Methoxyphenyl)pyrrolidin-2-one (1k, Clear Oil, 2.1 g, Yield:
64%).29 1H NMR (CDCl3, 500 MHz): δ 7.31−7.24 (2H, m), 7.02−
G
DOI: 10.1021/acs.joc.9b00816
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
6.94 (2H, m), 3.84 (3H, s), 3.79−3.74 (2H, m), 2.60−2.53 (2H, m),
2.24−2.15 (2H, m). LRMS (ESI)+: 192.0.
d, J = 6.8 Hz), 7.40 (2H, d, J = 8.8 Hz), 6.98 (2H, d, J = 8.6 Hz), 6.87
(2H, br t, J = 5.7 Hz), 4.07 (2H, br s), 3.76 (3H, s), 3.28 (2H, q, J =
6.3 Hz), 2.92 (2H, br s), 1.74-1.54 (4H, m). 13C{1H} NMR (DMSO-
d6, 100 MHz): δ 159.7, 157.9, 140.8, 138.5, 131.5, 123.7, 114.0, 109.8,
104.7, 55.2, 49.5, 45.8, 41.5, 25.0, 22.8. HRMS (ESI+): calcd for
C17H24N3O [M + H]+: 286.1914; found: 286.1908.
3-Methyl-1-(4-(trifluoromethyl)phenyl)pyrrolidin-2-one (1l,
1
White Solid, 900 mg, Yield: 78%). H NMR (CDCl3, 400 MHz):
δ 7.80 (2H, d, J = 8.5 Hz), 7.62 (2H, d, J = 8.5 Hz), 3.85−3.78 (2H,
m), 2.78−2.64 (1H, m), 2.42 (1H, tdd, J = 13.0 Hz, 8.1 Hz, 5.0 Hz),
1.90−1.75 (1H, m), 1.33 (3H, d, J = 7.0 Hz). LRMS (ESI)+: 244.1.
5-Methyl-1-(4-(trifluoromethyl)phenyl)pyrrolidin-2-one (1m,
White Solid, 854 mg, Yield: 87%).30 1H NMR (CDCl3, 500 MHz):
δ 7.67−7.63 (2H, m), 7.61−7.57 (2H, m), 4.45−4.36 (1H, m), 2.75−
2.65 (1H, m), 2.63−2.53 (1H, m), 2.46−2.36 (1H, m), 1.86−1.75
(1H, m), 1.27 (3H, d, J = 6.1 Hz). LRMS (ESI)+: 244.0.
1-(4-(Trifluoromethyl)phenyl)piperidin-2-one (1n, White Solid,
2.1 g, Yield: 78%).31 1H NMR (DMSO-d6, 500 MHz): δ 7.74 (2H, d,
J = 8.5 Hz), 7.53 (2H, d, J = 8.5 Hz), 3.66 (2H, t, J = 5.5 Hz), 2.43
(2H, t, J = 6.4 Hz), 1.93−1.80 (4H, m). LRMS (ESI)+: 244.1.
1-(4-(Trifluoromethyl)phenyl)azetidin-2-one (1o, White Solid).
This material was purchased from Sigma-Aldrich and used as received.
1H NMR (DMSO-d6, 500 MHz): δ 7.74 (2H, d, J = 8.5 Hz), 7.51
N1-(4-Bromophenyl)-N4-(4-methoxybenzyl)butane-1,4-diamine
1
(3c; 118.7 mg, 82% Yield). H NMR (DMSO-d6, 400 MHz): δ 8.81
(2H, br s), 7.40 (2H, d, J = 8.6 Hz), 7.21 (2H, d, J = 8.6 Hz), 6.98
(2H, d, J = 8.6 Hz), 6.57−6.50 (2H, m), 4.07 (2H, br t, J = 5.4 Hz),
3.76 (3H, s), 2.99 (2H, t, J = 6.7 Hz), 2.94−2.85 (2H, m), 1.68 (2H,
quin, J = 7.5 Hz), 1.61−1.49 (2H, m). 13C{1H} NMR (DMSO-d6,
100 MHz): δ 159.7, 147.7, 131.5, 131.4, 123.7, 117.5, 114.2, 114.0,
55.2, 49.5, 46.0, 42.3, 25.4, 23.1. HRMS (ESI+): calcd for
C18H23BrN2O [M + H]+: 363.1067; found: 363.1066.
N1-(4-Chlorophenyl)-N4-(4-methoxybenzyl)butane-1,4-diamine
(3d; 44.5 mg, 35% Yield). 1H NMR (CDCl3, 400 MHz): δ 8.51 (1H,
br s), 7.30 (2H, br d, J = 8.1 Hz), 7.07 (2H, d, J = 8.6 Hz), 6.84 (2H,
br d, J = 7.8 Hz), 6.46 (2H, d, J = 8.6 Hz), 5.42 (1H, br s), 3.83 (2H,
br s), 3.72 (3H, s), 2.98 (2H, br t, J = 6.0 Hz), 2.77 (2H, t, J = 5.9
Hz), 1.77 (2H, br s), 1.64−1.52 (2H, m). 13C{1H} NMR (CDCl3,
100 MHz): δ 160.0, 146.8, 131.3, 128.9, 123.4, 121.5, 114.2, 113.6,
55.2, 50.3, 45.8, 43.0, 26.1, 23.8. HRMS (ESI+): calcd for
C18H23ClN2O [M + H]+: 319.1572; found: 319.1569.
(2H, d, J = 8.5 Hz), 3.70 (2H, t, J = 4.9 Hz), 3.14 (2H, t, J = 4.9 Hz).
LRMS (ESI)+: 216.1.
1-(p-Tolyl)azetidin-2-one (1p, White Solid, 1.0 g, Yield: 44%).32
1H NMR (CD3OD, 500 MHz): δ 7.30−7.24 (2H, m), 7.16 (2H, d, J
= 7.9 Hz), 3.65 (2H, t, J = 4.3 Hz), 3.08 (2H, t, J = 4.6 Hz), 2.30 (3H,
s). LRMS (ESI)+: 162.1.
4-((4-((4-Methoxybenzyl)amino)butyl)amino)benzonitrile (3e;
1
1-(4-Methoxyphenyl)azetidin-2-one (1q, White Solid, 830 mg,
Yield: 34%).32 1H NMR (CD3OD, 500 MHz): δ 7.35−7.30 (2H, m),
6.94−6.89 (2H, m), 3.77 (3H, s), 3.64 (2H, t, J = 4.3 Hz), 3.07 (2H,
t, J = 4.6 Hz). LRMS (ESI)+: 178.1.
60.5 mg, 49% Yield). H NMR (CDCl3, 400 MHz): δ 9.30 (1H,
br s), 7.35 (2H, br d, J = 8.6 Hz), 7.25 (2H, br d, J = 8.1 Hz), 6.83
(2H, br d, J = 8.1 Hz), 6.48 (2H, br d, J = 8.3 Hz), 4.59 (1H, br s),
3.85 (2H, br s), 3.69 (3H, s), 3.05 (2H, br t, J = 6.2 Hz), 2.85 (2H, br
s), 1.71 (2H, m), 1.64−1.52 (2H, m). 13C{1H} NMR (CDCl3, 100
MHz): δ 160.4, 151.2, 133.6, 131.3, 121.9, 120.4, 114.4, 112.0, 98.3,
55.2, 50.7, 46.0, 42.0, 25.5, 23.3. HRMS (ESI+): calcd for C19H23N3O
[M + H]+: 310.1914; found: 310.1908.
1-(4-(Trifluoromethoxy)phenyl)pyrrolidin-2-one (1r, White Solid,
1
2.2 g, Yield: 78%). H NMR (DMSO-d6, 500 MHz): δ 7.83−7.73
(2H, m), 7.38 (2H, d, J = 9.2 Hz), 3.84 (2H, t, J = 7.0 Hz), 2.54−2.51
(2H, m), 2.13−2.00 (2H, m). LRMS (ESI)+: 246.1.
Representative Experimental Procedure for Reductive Coupling
of Nonester Containing Aryl Lactams with Primary and Secondary
Amines (for Tables 1−5). To a 2-dram vial equipped with a magnetic
stir bar was added Schwartz’s reagent (155 mg, 0.6 mmol, 1.5 equiv;
preferably less than 1 month old) as a solid in the air. The vial was
then sealed with a red open top cap (with a solvent-resistant Teflon
cover), and a N2 flow ran through the sealed vial for 5 min. The N2
line was then removed, and THF (2 mL) was added through a syringe
under positive pressure. The reaction mixture was cooled to 0 °C in
an ice-water cooling bath and subjected to vigorous stirring, followed
by the injection of a solution of the substrate (0.4 mmol in 1 mL of
THF). After 1 h at 0 °C, to the milky white suspension was added
neat amine coupling partner (1.6 mmol, 4 equiv). The vial was then
removed from the ice-water bath, and STAB (170 mg, 0.8 mmol, 2
equiv) was added in one portion as a solid to the reaction mixture.
The vial was capped and stirred at 23 °C for 18 h. A sample was taken
from the vial to be analyzed by LCMS. Upon reaction completion,
water (1 mL) was added to the vial. The mixture was stirred for 10
min before the addition of EtOAc (2 mL). The mixture was filtered
through a plug of Celite into a 30 mL vial. The filtrate was dried by a
V10 rotovap. The residue was purified by silica gel column
chromatography (4g of silica gel column) with an automatic
purification system (grading from 0% MeOH/EtOAc to 50%
MeOH/EtOAc over 13 min). The fractions were collected and
dried to give the desired diamine products as clear films.
N1-(4-Methoxybenzyl)-N4-(4-nitrophenyl)butane-1,4-diamine
(3f; 51.3 mg, 39% Yield). 1H NMR (CD3OD, 400 MHz): δ 8.02 (2H,
d, J = 8.0 Hz), 7.27 (2H, d, J = 8.0 Hz), 6.90 (2H, d, J = 8.0 Hz), 6.59
(2H, d, J = 8.0 Hz), 3.80 (2H, s), 3.78 (3H, s), 3.24−3.19 (2H, m),
2.75−2.70 (2H, m), 1.71−1.65 (4H, m). 13C{1H} NMR (CD3OD,
125 MHz): δ 161.0, 156.2, 138.0, 131.4, 130.7, 127.5, 115.1, 111.8,
55.9, 53.5, 43.8, 27.7, 27.2. One carbon signal under solvent multiplet.
HRMS (ESI+): calcd for C18H23N3O3 [M + H]+: 330.1812; found:
330.1806.
Ethyl 4-((4-((4-Methoxybenzyl)amino)butyl)amino)benzoate
1
(3g; 48.4 mg, 34% Yield). H NMR (DMSO-d6, 400 MHz): δ 7.67
(2H, d, J = 8.8 Hz), 7.42 (2H, d, J = 8.6 Hz), 6.93 (2H, d, J = 8.6 Hz),
6.64−6.60 (1H, m), 6.57 (2H, d, J = 8.6 Hz), 4.19 (2H, q, J = 7.1
Hz), 3.92 (2H, s), 3.75 (3H, s), 3.11−3.02 (2H, m), 2.75 (2H, br t, J
= 7.3 Hz), 1.76−1.63 (2H, m), 1.62−1.51 (2H, m), 1.26 (4H, t, J =
7.1 Hz). 13C{1H} NMR (DMSO-d6, 100 MHz): δ 165.9, 159.2, 152.8,
131.0, 130.9, 126.2, 115.8, 113.8, 110.8, 59.5, 55.1, 50.1, 46.4, 41.8,
25.7, 24.0, 14.4. HRMS (ESI+): calcd for C21H28N2O3 [M + H]+:
357.2173; found: 357.2168.
N1-(3-Chloro-5-fluorophenyl)-N4-(4-methoxybenzyl)butane-1,4-
diamine (3h; 56.4 mg, 42% Yield). 1H NMR (DMSO-d6, 400 MHz):
δ 8.93 (2H, br s), 7.42 (2H, br d, J = 8.1 Hz), 6.99 (2H, br d, J = 7.8
Hz), 6.43 (1H, s), 6.42−6.37 (1H, m), 6.35−6.28 (1H, m), 4.08 (2H,
br t, J = 5.4 Hz), 3.77 (3H, s), 3.02 (2H, t, J = 6.8 Hz), 2.92 (2H, br
s), 1.69 (2H, br s), 1.60−1.50 (2H, m). 13C{1H} NMR (DMSO-d6,
100 MHz): δ 163.4 (d, J = 242 Hz), 159.7, 151.4 (d, J = 13 Hz),
134.2 (d, J = 14 Hz), 131.5, 123.8, 114.0, 107.7, 101.9 (d, J = 26 Hz),
96.8 (d, J = 25 Hz), 55.2, 49.5, 46.0, 41.9, 25.4, 23.1. HRMS (ESI+):
calcd for C18H22ClFN2O [M + H]+: 337.1477; found: 337.1474.
N1-(4-Methoxybenzyl)-N4-phenylbutane-1,4-diamine (3i; 40.9
N1-(4-Methoxybenzyl)-N4-(4-(trifluoromethyl)phenyl)butane-1,4-
1
diamine (3a; 88.7 mg, 63% Yield). H NMR (CDCl3, 400 MHz): δ
9.33 (1H, br s), 7.38 (2H, br d, J = 8.1 Hz), 7.25 (2H, d, J = 8.0 Hz),
6.83 (2H, br d, J = 7.8 Hz), 6.61 (2H, br d, J = 8.3 Hz), 4.56 (1H, br
s), 3.86 (2H, br s), 3.70 (3H, s), 3.06 (2H, br t, J = 5.6 Hz), 2.85 (2H,
br s), 1.73 (2H, br s), 1.61 (2H, br s). 13C{1H} NMR (CDCl3, 100
MHz): δ 160.4, 150.0, 131.4, 126.6 (q, J = 4 Hz), 124.9 (q, J = 271
Hz), 122.0, 119.3 (q, J = 32 Hz), 114.4, 112.2, 55.2, 50.7, 46.0, 42.8,
25.6, 23.4. HRMS (ESI+): calcd for C19H23F3N2O [M + H]+:
353.1835; found: 353.1828.
1
mg, 36% Yield). H NMR (CD3OD, 500 MHz): δ 7.60−7.52 (2H,
m), 7.52−7.46 (3H, m), 7.43−7.38 (2H, m), 7.01−6.95 (2H, m),
4.12 (2H, s), 3.80 (3H, s), 3.49−3.39 (2H, m), 3.10−3.02 (2H, m),
1.88−1.74 (4H, m). 13C{1H} NMR (CD3OD, 125 MHz): δ 162.3,
137.5, 132.7, 131.6, 130.5, 124.4, 123.5, 115.7, 56.0, 52.0, 47.6, 24.4,
24.3. One carbon signal under solvent multiplet. HRMS (ESI+): calcd
for C18H24N2O [M + H]+: 285.1961; found: 285.1967.
N1-(4-Methoxybenzyl)-N4-(pyridin-4-yl)butane-1,4-diamine (3b;
67.3 mg, 59% Yield). 1H NMR (DMSO-d6, 400 MHz): δ 8.97
(1H, br s), 8.70 (1H, br s), 8.24 (1H, br d, J = 6.8 Hz), 8.08 (1H, br
H
DOI: 10.1021/acs.joc.9b00816
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
N1-(4-Methoxybenzyl)-2-methyl-N4-(4-(trifluoromethyl)phenyl)-
8.65 (1H, br s), 7.36 (2H, br d, J = 8.3 Hz), 6.66 (2H, br d, J = 8.6
Hz), 6.46 (1H, br t, J = 5.4 Hz), 3.08 (2H, q, J = 6.4 Hz), 2.99−2.82
(3H, m), 2.02 (2H, br d, J = 10.3 Hz), 1.79−1.64 (4H, m), 1.62−1.53
(3H, m), 1.34−1.15 (4H, m), 1.15−1.02 (1H, m). 13C{1H} NMR
(DMSO-d6, 100 MHz): δ 151.8, 126.2 (q, J = 4 Hz), 125.4 (q, J = 270
Hz), 114.8 (q, J = 32 Hz), 111.1, 55.8, 43.2, 41.7, 28.4, 25.5, 24.8,
23.9, 23.3. HRMS (ESI+): calcd for C17H25F3N2 [M + H]+: 315.2043;
found: 315.2037.
1
butane-1,4-diamine (3l; 62.9 mg, 43% Yield). H NMR (CDCl3,
500 MHz): δ 7.38 (2H, d, J = 8.5 Hz), 7.25 (2H, d, J = 8.5 Hz), 6.88
(2H, d, J = 8.5 Hz), 6.54 (2H, d, J = 8.5 Hz), 4.53 (1H, br s), 3.83−
3.79 (3H, m), 3.74 (2H, s), 3.24−3.16 (1H, m), 3.15−3.07 (1H, m),
2.55 (2H, d, J = 6.1 Hz), 1.84−1.70 (2H, m), 1.61−1.49 (2H, m),
0.99 (3H, d, J = 6.7 Hz). 13C{1H} NMR (CDCl3, 125 MHz): δ 158.7,
150.9, 132.3, 129.3, 126.5 (q, J = 4 Hz), 125.1 (d, J = 270 Hz), 118.2
(q, J = 33 Hz), 113.8, 111.5, 55.3, 55.3, 53.5, 41.3, 34.2, 31.6, 18.6.
HRMS (ESI+): calcd for C20H25F3N2O [M + H]+: 367.1992; found:
367.1985.
N1-Nonyl-N4-(4-(trifluoromethyl)phenyl)butane-1,4-diamine (5c;
1
90.2 mg, 63% Yield). H NMR (DMSO-d6, 400 MHz): δ 8.71 (1H,
br s), 7.35 (2H, d, J = 8.6 Hz), 6.66 (2H, d, J = 8.6 Hz), 6.47 (1H, br
s), 3.07 (2H, br d, J = 5.4 Hz), 2.90−2.71 (4H, m), 1.69 (2H, quin, J
= 7.4 Hz), 1.64−1.52 (4H, m), 1.25 (12H, br s), 0.85 (3H, br t, J =
6.6 Hz). 13C{1H} NMR (DMSO-d6, 100 MHz): δ 151.7, 126.1 (d, J =
4 Hz), 125.4 (q, J = 269 Hz), 114.8 (q, J = 32 Hz), 111.1, 46.6, 46.3,
41.6, 31.2, 28.8, 28.6, 28.5, 26.0, 25.4, 25.3, 23.1, 22.1, 13.9. HRMS
(ESI+): calcd for C20H33F3N2 [M + H]+: 359.2669; found: 359.2661.
(S)-N1-(1-Methoxypropan-2-yl)-N4-(4-(trifluoromethyl)phenyl)-
butane-1,4-diamine (5d; 74.1 mg, 61% Yield). 1H NMR (DMSO-d6,
400 MHz): δ 8.78 (1H, br s), 8.65 (1H, br s), 7.36 (2H, d, J = 8.6
Hz), 6.66 (2H, m, J = 8.6 Hz), 6.45 (1H, br t, J = 5.4 Hz), 3.58−3.43
(2H, m), 3.31 (3H, s), 3.08 (2H, q, J = 6.3 Hz), 2.99−2.82 (2H, m),
1.77−1.66 (2H, m), 1.66−1.51 (2H, m), 1.21 (3H, d, J = 6.6 Hz).
13C{1H} NMR (DMSO-d6, 100 MHz): δ 151.8, 126.2 (q, J = 4 Hz),
N1-(4-Methoxybenzyl)-N4-(4-(trifluoromethyl)phenyl)pentane-
1,4-diamine (3m; 49.2 mg, 34% Yield). 1H NMR (CDCl3, 400
MHz): δ 8.82 (2H, br s), 7.39 (2H, d, J = 8.8 Hz), 7.34 (2H, d, J = 8.8
Hz), 6.97 (2H, d, J = 8.6 Hz), 6.65 (2H, d, J = 8.6 Hz), 4.06 (2H, br t,
J = 5.6 Hz), 3.76 (3H, s), 3.54−3.40 (1H, m), 2.94−2.81 (2H, m),
1.77−1.60 (2H, m), 1.57−1.41 (2H, m), 1.11 (3H, d, J = 6.4 Hz).
13C{1H} NMR (DMSO-d6, 100 MHz): δ 159.0, 151.2, 130.8, 126.7,
126.2 (q, J = 3 Hz), 125.4 (q, J = 270 Hz), 114.5 (q, J = 32 Hz),
113.7, 111.4, 55.1, 50.2, 46.8, 46.7, 33.1, 23.4, 20.1. HRMS (ESI+):
calcd for C20H25F3N2O [M + H]+: 367.1992; found: 367.1985.
N1-(4-Methoxybenzyl)-N5-(4-(trifluoromethyl)phenyl)pentane-
1
1,5-diamine (3n; 105.4 mg, 72% Yield). H NMR (DMSO-d6, 400
MHz): δ 8.81 (2H, br s), 7.41 (2H, d, J = 7.5 Hz), 7.35 (2H, d, J = 8.5
Hz), 6.99 (2H, d, J = 7.7 Hz), 6.64 (2H, d, J = 8.6 Hz), 4.08 (2H, t, J
= 5.6 Hz), 3.76 (3H, s), 3.04 (2H, t, J = 6.8 Hz), 2.93−2.83 (2H, m),
1.64 (2H, br quin, J = 7.7 Hz), 1.55 (2H, br quin, J = 7.1 Hz), 1.38
(2H, br quin, J = 7.6 Hz). 13C{1H} NMR (DMSO-d6, 100 MHz): δ
159.7, 151.8, 131.5, 126.2 (q, J = 4 Hz), 125.4 (q, J = 270 Hz), 123.8,
114.9 (q, J = 32 Hz), 114.0, 111.1, 55.2, 49.5, 46.1, 42.0, 27.8, 25.1,
23.5. HRMS (ESI+): calcd for C20H25F3N2O [M + H]+: 367.1992;
found: 367.1985.
125.5 (q, J = 269 Hz), 114.9 (q, J = 32 Hz), 111.2, 71.8, 58.4, 52.4,
44.0, 41.7, 25.5, 23.3, 13.6. HRMS (ESI+): calcd for C15H23F3N2O [M
+ H]+: 305.1835; found: 305.1829.
(S)-N1-(1-Phenylethyl)-N4-(4-(trifluoromethyl)phenyl)butane-1,4-
diamine (5e; 67.2 mg, 50% Yield). 1H NMR (DMSO-d6, 400 MHz):
δ 8.92 (1H, br s), 8.78 (1H, br s), 7.55-7.39 (5H, m), 7.36 (2H, d, J =
8.6 Hz), 6.63 (2H, d, J = 8.6 Hz), 4.42−4.29 (1H, m), 3.04 (2H, t, J =
6.7 Hz), 2.88 (1H, br s), 2.74−2.59 (1H, m), 1.71−1.59 (2H, m),
1.58−1.46 (5H, m). 13C{1H} NMR (DMSO-d6, 100 MHz): δ 151.7,
137.5, 128.8, 128.7, 127.9, 126.2, 125.4 (q, J = 269 Hz), 114.9 (q, J =
32 Hz), 111.1, 57.2, 44.7, 41.7, 25.5, 23.2, 19.8. HRMS (ESI+): calcd
for C19H23F3N2 [M + H]+: 337.1886; found: 337.1878.
N1-(4-Methoxybenzyl)-N3-(4-(trifluoromethyl)phenyl)propane-
1
1,3-diamine (3o; 123.0 mg, 91% Yield). H NMR (DMSO-d6, 400
MHz): δ 8.87 (2H, br s), 7.40 (2H, d, J = 8.6 Hz), 7.38 (2H, d, J = 8.6
Hz), 6.98 (2H, d, J = 7.7 Hz), 6.66 (2H, d, J = 8.6 Hz), 4.09 (2H, t, J
= 5.5 Hz), 3.76 (3H, s), 3.15 (2H, t, J = 6.8 Hz), 3.05−2.94 (2H, m),
1.88 (2H, quint, J = 7.1 Hz). 13C{1H} NMR (CD3OD, 125 MHz): δ
160.8, 151.2, 131.1, 126.0 (q, J = 4 Hz), 125.2 (q, J = 268 Hz), 122.8,
117.7 (q, J = 32 Hz), 114.2, 111.4, 54.4, 50.5, 44.9, 39.7, 26.2. HRMS
(ESI+): calcd for C18H22F3N2O [M + H]+: 339.1679; found:
339.1673.
N1-(4-(Trifluoromethyl)benzyl)-N4-(4-(trifluoromethyl)phenyl)-
butane-1,4-diamine (5f; 49.9 mg, 32% Yield). 1H NMR (DMSO-d6,
400 MHz): δ 9.13 (2H, br s), 7.82 (2H, d, J = 8.1 Hz), 7.72 (2H, d, J
= 8.3 Hz), 7.36 (2H, d, J = 8.6 Hz), 6.65 (2H, d, J = 8.6 Hz), 4.26
(2H, br t, J = 5.5 Hz), 3.08 (2H, t, J = 6.7 Hz), 2.98 (2H, br s), 1.78−
1.65 (2H, m), 1.65−1.53 (2H, m). 13C{1H} NMR (DMSO-d6, 100
MHz): δ 151.8, 136.7, 130.9, 129.6 (q, J = 32 Hz), 126.4 (q, J = 4
Hz), 125.7 (q, J = 4 Hz), 125.5 (q, J = 269 Hz), 124.2 (q, J = 272
Hz), 115.0 (q, J = 32 Hz), 111.4, 49.6, 46.8, 41.8, 25.5, 23.3. HRMS
(ESI+): calcd for C19H20F6N2 [M + H]+: 391.1603; found: 391.1595.
N1-(4-Methoxyphenyl)-N4-(4-(trifluoromethyl)phenyl)butane-
N1-(4-Methoxybenzyl)-N3-(p-tolyl)propane-1,3-diamine (3p; 34.1
mg, 30% Yield). 1H NMR (CDCl3, 400 MHz): δ 7.31−7.23 (2H, m),
7.05−6.98 (2H, m), 6.94−6.86 (2H, m), 6.60−6.52 (2H, m), 3.82
(3H, s), 3.76 (2H, s), 3.21 (2H, t, J = 6.6 Hz), 2.79 (2H, t, J = 6.6
Hz), 2.27 (3H, s), 1.83 (2H, quin, J = 6.6 Hz). 13C{1H} NMR
(CDCl3, 125 MHz): δ 158.7, 146.4, 132.5, 129.8, 129.3, 126.3, 113.9,
113.0, 55.3, 53.5, 47.7, 43.3, 29.6, 20.4. HRMS (ESI+): calcd for
C18H24N2O [M + H]+: 285.1961; found: 285.1967.
1
1,4-diamine (5g; 29.7 mg, 22% Yield). H NMR (DMSO-d6, 400
MHz): δ 7.35 (2H, d, J = 8.6 Hz), 6.70 (2H, d, J = 8.8 Hz), 6.65 (2H,
d, J = 8.6 Hz), 6.52 (2H, d, J = 8.8 Hz), 6.36 (1H, br t, J = 5.1 Hz),
5.09 (1H, br s), 3.63 (3H, s), 3.13−3.04 (2H, m), 2.97 (2H, br s),
1.72−1.56 (4H, m). 13C{1H} NMR (DMSO-d6, 100 MHz): δ 151.9,
150.5, 143.4, 126.2 (q, J = 4 Hz), 125.4 (q, J = 270 Hz), 114.8 (q, J =
32 Hz), 114.6, 112.9, 111.1, 55.3, 43.5, 42.2, 26.5, 26.2. HRMS
(ESI+): calcd for C18H21F3N2O [M + H]+: 339.1679; found:
339.1670.
tert-Butyl 4-(4-((4-(Trifluoromethyl)phenyl)amino)butyl)-
piperazine-1-carboxylate (6a; 120.3 mg, 75% Yield). 1H NMR
(CD3OD, 500 MHz): δ 7.32 (2H, d, J = 9.2 Hz), 6.64 (2H, d, J = 8.5
Hz), 3.42 (4H, br, s), 3.15 (2H, br t, J = 6.4 Hz), 2.47−2.35 (6H, m),
1.71−1.56 (4H, m), 1.45 (9H, s). 13C{1H} NMR (CD3OD, 125
MHz): δ 156.5, 153.4, 127.4 (q, J = 4 Hz), 126.9 (q, J = 269 Hz),
118.4 (q, J = 32 Hz), 112.6, 81.4, 59.5, 54.1, 44.5 (br d, rotameric
quaternary carbon), 44.0, 28.8, 28.1, 25.2. HRMS (ESI+): calcd for
C20H30F3N3O2 [M + H]+: 402.2363; found: 402.2370.
N1-(4-Methoxybenzyl)-N3-(4-methoxyphenyl)propane-1,3-dia-
1
mine (3q; 57.6 mg, 48% Yield). H NMR (CDCl3, 500 MHz): δ
7.20−7.13 (2H, m), 6.79 (2H, br d, J = 7.9 Hz), 6.70 (2H, br d, J =
9.2 Hz), 6.49 (2H, br d, J = 9.2 Hz), 3.73 (3H, s), 3.68−3.64 (5H,
m), 3.08 (2H, t, J = 6.4 Hz), 2.68 (2H, t, J = 6.4 Hz), 1.73 (2H, quin,
J = 6.6 Hz). 13C{1H} NMR (CDCl3, 125 MHz): δ 158.6, 151.9,
142.9, 132.5, 129.2, 114.9, 114.0, 113.8, 55.8, 55.3, 53.5, 47.7, 43.8,
29.6. HRMS (ESI+): calcd for C18H24N2O2 [M + H]+: 301.1911;
found: 301.1924.
N1-(Cyclohexylmethyl)-N4-(4-(trifluoromethyl)phenyl)butane-
1
1,4-diamine (5a; 90.5 mg, 69% Yield). H NMR (DMSO-d6, 400
MHz): δ 8.35 (2H, br s), 7.36 (2H, d, J = 8.6 Hz), 6.65 (2H, d, J = 8.6
Hz), 3.08 (2H, t, J = 6.6 Hz), 2.99−2.86 (2H, m), 2.81−2.69 (2H,
m), 1.81−1.49 (10H, m), 1.34−1.08 (3H, m), 1.03−0.82 (2H, m).
13C{1H} NMR (DMSO-d6, 100 MHz): δ 151.7, 126.2 (q, J = 4 Hz),
125.4 (q, J = 270 Hz), 115.0 (q, J = 32 Hz), 111.2, 52.6, 47.2, 41.7,
34.4, 29.9, 25.5, 25.4, 25.0, 23.0. HRMS (ESI+): calcd for C18H27F3N2
[M + H]+: 329.2199; found: 329.2191.
tert-Butyl 4-(5-((4-(Trifluoromethyl)phenyl)amino)pentyl)-
piperazine-1-carboxylate (6b; 79.7 mg, 48% Yield). 1H NMR
(CDCl3, 500 MHz): δ 7.39 (2H, d, J = 8.5 Hz), 6.58 (2H, d, J = 8.5
Hz), 3.97 (1H, br s), 3.49−3.38 (4H, m), 3.19−3.11 (2H, m) 2.42−
2.31 (6H, m), 1.73−1.61 (2H, m), 1.59−1.51 (2H, m), 1.48−1.41
N1-Cyclohexyl-N4-(4-(trifluoromethyl)phenyl)butane-1,4-dia-
1
mine (5b; 72.8 mg, 58% Yield). H NMR (DMSO-d6, 400 MHz): δ
I
DOI: 10.1021/acs.joc.9b00816
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(11H, m). 13C{1H} NMR (CDCl3, 125 MHz): δ 154.7, 150.7, 126.6
(q, J = 4 Hz), 125.0 (q, J = 271 Hz), 118.5 (q, J = 33 Hz), 111.6, 79.6,
58.5, 53.1, 43.7 (br d, rotameric quaternary carbon), 43.4, 29.2, 28.4,
26.6, 24.9. HRMS (ESI+): calcd for C21H32F3N3O2 [M + H]+:
416.2519; found: 416.2522.
(q, J = 270 Hz), 120.7, 61.8, 60.6, 31.1, 22.7, 14.4. HRMS (ESI+):
calcd for C14H14F3NO3 [M + H]+: 302.0999; found: 302.1003.
Ethyl (R)-5-Oxo-1-(3-(trifluoromethyl)phenyl)pyrrolidine-2-car-
1
boxylate (7b, Yellow Oil, 10.0 g, Yield: 80%, 97.5% ee). H NMR
(DMSO-d6, 500 MHz) δ: 7.98 (1H, s), 7.71−7.65 (1H, m), 7.65−
7.60 (1H, m), 7.52 (1H, d, J = 7.9 Hz), 5.15−5.10 (1H, m), 4.17−
4.09 (2H, m), 2.66−2.53 (2H, m), 2.49−2.44 (1H, m), 2.17−2.07
(1H, m), 1.13 (3H, t, J = 7.3 Hz). 13C{1H} NMR (DMSO-d6, 125
MHz) δ: 174.4, 171.5, 139.2, 130.1, 129.4 (q, J = 32 Hz), 124.3, 124.0
(q, J = 272 Hz), 121.1 (q, J = 4 Hz), 117.1 (q, J = 4 Hz), 61.3, 60.3,
30.5, 22.2, 13.8. HRMS (ESI+): calcd for C14H14F3NO3 [M + H]+:
302.0999; found: 302.1005.
tert-Butyl 4-(3-((4-(Trifluoromethyl)phenyl)amino)propyl)-
piperazine-1-carboxylate (6c; 69.7 mg, 45% Yield). 1H NMR
(CDCl3, 400 MHz): δ 7.39 (2H, d, J = 8.3 Hz), 6.58 (2H, d, J = 8.3
Hz), 5.13 (1H, br s), 3.52−3.42 (4H, m), 3.24 (2H, q, J = 6.0 Hz),
2.51 (2H, t, J = 6.4 Hz), 2.42 (4H, t, J = 5.0 Hz), 1.82 (2H, quin, J =
6.4 Hz), 1.48 (9H, s). 13C{1H} NMR (CDCl3, 125 MHz): δ 154.7,
151.0, 126.6 (q, J = 4 Hz), 125.0 (q, J = 270 Hz), 118.4 (q, J = 32
Hz), 111.6, 79.8, 57.2, 53.1, 43.7 (br d, rotameric quaternary carbon),
43.0, 28.4, 25.3. HRMS (ESI+): calcd for C19H28F3N3O2 [M + H]+:
388.2206; found: 388.2208.
Ethyl (R)-1-(3-Fluoro-5-(trifluoromethyl)phenyl)-5-oxopyrroli-
dine-2-carboxylate (7c, Yellow Oil, 3.2 g, Yield: 58%, 97.0% ee).
1H NMR (DMSO-d6, 500 MHz) δ: 7.77 (1H, s), 7.73 (1H, dd, J =
N1-(4-Methoxybenzyl)-N1-methyl-N4-(4-(trifluoromethyl)phenyl)-
11.3 Hz, 2.1 Hz), 7.49 (1H, br d, J = 8.5 Hz), 5.21 (1H, dd, J = 8.9
Hz, 2.7 Hz), 4.14 (2H, q, J = 7.1 Hz), 2.68−2.53 (2H, m), 2.50−2.44
(1H, m), 2.18−2.10 (1H, m), 1.14 (3H, t, J = 7.0 Hz). 13C{1H} NMR
(DMSO-d6, 125 MHz) δ: 174.7, 171.2, 162.0 (d, J = 245 Hz), 141.1
(d, J = 11 Hz), 131.1 (dq, J = 33 Hz, 10 Hz), 123.2 (dq, J = 272 Hz, 4
Hz), 112.8 (q, J = 4 Hz), 111.1 (d, J = 26 Hz), 108.5 (dq, J = 25 Hz, 4
Hz), 61.4, 60.2, 30.6, 22.1, 13.8. HRMS (ESI+): calcd for
C14H13F4NO3 [M + H]+: 320.0904; found: 320.0910.
1
butane-1,4-diamine (6d; 43.9 mg, 30% Yield). H NMR (CD3OD,
400 MHz): δ 7.35−7.31 (2H, m), 7.31−7.26 (2H, m), 6.90 (2H, d, J
= 7.8 Hz), 6.64 (2H, d, J = 8.5 Hz), 3.78 (3H, s), 3.75 (2H, s), 3.14
(2H, t, J = 6.7 Hz), 2.72−2.62 (2H, m), 2.40 (3H, s), 1.78−1.68 (2H,
m) 1.68−1.59 (2H, m). 13C{1H} NMR (CDCl3, 125 MHz): δ 159.0,
150.8, 130.7, 128.9, 126.5 (q, J = 4 Hz), 125.0 (q, J = 270 Hz), 118.1
(q, J = 32 Hz), 113.7, 111.5, 60.9, 56.0, 55.2, 43.1, 41.2, 26.7, 24.3.
HRMS (ESI+): calcd for C20H25F3N2O [M + H]+: 367.1992; found:
367.2008.
Ethyl (R)-1-(3-Chloro-5-fluorophenyl)-5-oxopyrrolidine-2-car-
1
boxylate (7d, Yellow Oil, 3.1 g, Yield: 55%, 95.5% ee). H NMR
(DMSO-d6, 500 MHz) δ: 7.48 (1H, s), 7.43 (1H, td, J = 11.1 Hz, 2.1
Hz), 7.24 (1H, td, J = 8.5 Hz, 2.1 Hz), 5.12 (1H, dd, J = 9.2 Hz, 3.1
Hz), 4.15 (2H, q, J = 7.3 Hz), 2.66−2.52 (2H, m), 2.48−2.40 (1H,
m), 2.14−2.07 (1H, m), 1.15 (3H, t, J = 7.0 Hz). 13C{1H} NMR
(DMSO-d6, 125 MHz) δ: 174.5, 171.2, 162.1 (d, J = 245 Hz), 141.0
(d, J = 13 Hz), 134.1 (d, J = 13 Hz), 116.1 (d, J = 4 Hz), 111.8 (d, J =
25 Hz), 106.2 (d, J = 26 Hz), 61.2, 60.2, 30.6, 22.1, 13.9. HRMS
(ESI+): calcd for C13H13ClF3NO3 [M + H]+: 286.0641; found:
286.0643.
N-(4-(Pyrrolidin-1-yl)butyl)-4-(trifluoromethyl)aniline (6e; 64.0
1
mg, 56% Yield). H NMR (CD3OD, 400 MHz): δ 7.34 (2H, d, J
= 8.5 Hz), 6.68 (2H, d, J = 8.5 Hz), 3.68−3.59 (2H, m), 3.24−3.17
(4H, m), 3.11−3.00 (2H, m), 2.19−2.07 (2H, m), 2.07−1.95 (2H,
m), 1.88−1.79 (2H, m), 1.75−1.66 (2H, m). 13C{1H} NMR (CDCl3,
125 MHz): δ 150.2, 126.5 (q, J = 4 Hz), 124.9 (q, J = 268 Hz), 118.7
(q, J = 33 Hz), 112.0, 55.0, 53.8, 42.4, 25.6, 23.2, 23.1. HRMS (ESI+):
calcd for C15H21F3N2 [M + H]+: 287.1730; found: 287.1732.
N-(4-(Pyrrolidin-1-yl)butyl)-4-(trifluoromethoxy)aniline (6f; 38.7
1
Ethyl (R)-5-Oxo-1-(pyridin-4-yl)pyrrolidine-2-carboxylate (7e,
mg, 32% Yield). H NMR (CD3OD, 400 MHz): δ 7.12 (2H, d, J =
1
White Solid, 12.5 g, Yield: 76%, 97.4% ee). H NMR (DMSO-d6,
8.6 Hz), 6.87 (2H, d, J = 7.8 Hz), 3.64 (2H, br s), 3.26−3.18 (4H,
m), 3.14−2.99 (2H, m), 2.20−2.08 (2H, m), 2.08−1.95 (2H, m),
1.88−1.78 (2H, m), 1.78−1.68 (2H, m). 13C{1H} NMR (CDCl3, 125
MHz): δ 144.8, 140.8, 122.4, 120.4 (q, J = 257 Hz), 118.7, 54.8, 53.8,
47.2, 24.3, 23.0, 22.9. HRMS (ESI+): calcd for C15H21F3N2O [M +
H]+: 303.1679; found: 303.1683.
N-(3-(Pyrrolidin-1-yl)propyl)-4-(trifluoromethyl)aniline (6g; 64.2
mg, 59% Yield). 1H NMR (CDCl3, 400 MHz): δ 7.39 (2H, d, J = 8.3
Hz), 6.57 (2H, d, J = 8.5 Hz), 5.14 (1H, br s), 3.26−3.21 (2H, m),
2.61 (2H, t, J = 6.7 Hz), 2.56−2.49 (4H, m), 1.87−1.78 (6H, m).
13C{1H} NMR (CDCl3, 125 MHz): δ 151.2, 126.5 (q, J = 4 Hz),
500 MHz) δ: 8.54−8.44 (2H, m), 7.57−7.49 (2H, m), 5.07 (1H, dd, J
= 9.2 Hz, 2.4 Hz), 4.21−4.08 (2H, m), 2.70−2.54 (2H, m), 2.49−
2.42 (1H, m), 2.17−2.08 (1H, m), 1.18 (3H, t, J = 7.3 Hz). 13C{1H}
NMR (DMSO-d6, 125 MHz) δ: 175.1, 171.2, 150.4, 145.1, 113.1,
61.5, 59.3, 30.8, 22.2, 13.9. HRMS (ESI+): calcd for C12H14N2O3 [M
+ H]+: 235.1077; found: 235.1080.
Ethyl (R)-5-Oxo-1-(pyridin-3-yl)pyrrolidine-2-carboxylate (7f,
1
Yellow Oil, 10.6 g, Yield: 91%, 99.3% ee). H NMR (DMSO-d6,
500 MHz) δ: 8.69 (1H, d, J = 2.4 Hz), 8.36 (1H, dd, J = 4.6 Hz, 1.5
Hz), 7.96−7.89 (1H, m), 7.45−7.39 (1H, m), 5.12−5.05 (1H, m),
4.18−4.07 (2H, m), 2.63−2.52 (3H, m), 2.19−2.08 (1H, m), 1.14
(3H, t, J = 7.0 Hz). 13C{1H} NMR (DMSO-d6, 125 MHz) δ: 174.4,
171.4, 145.6, 142.3, 135.1, 128.2, 123.6, 61.3, 59.9, 30.1, 22.5, 13.9.
HRMS (ESI+): calcd for C12H14N2O3 [M + H]+: 235.1077; found:
235.1081.
122.9 (q, J = 271 Hz), 118.1 (q, J = 32 Hz), 111.6, 54.9, 54.2, 43.1,
27.6, 23.5. HRMS (ESI+): calcd for C14H19F3N2 [M + H]+: 273.1573;
found: 273.1581.
Representative Experimental Procedure for Ullmann Cou-
plings. Compounds 7a−j were Prepared by ChemDiscover LLC. A
round-bottom flask was charged with aryl iodide or aryl bromide (1
equiv), ethyl (R)-5-oxopyrrolidine-2-carboxylate (1.4 equiv), copper
iodide (0.25 equiv), cesium carbonate (2 equiv), and p-dioxane (0.5
M reaction concentration) under an atmosphere of nitrogen. Then,
TMEDA or DMEDA (0.5 equiv) was added, and the resulting
mixture was heated to 40 °C and stirred at that temperature for 5 h.
Additional portions of copper iodide (0.12 equiv) and TMEDA or
DMEDA (0.25 equiv) were added (as needed). The reaction mixture
continued to stir at 40 °C overnight. The reaction mixture was cooled
to ambient temperature and filtered. The filtrate was concentrated,
and the crude material was purified by silica gel column
chromatography (EtOAc/petroleum ether, 1:2) to give the desired
N-aryl pyrrolidinones.
Ethyl (R)-5-Oxo-1-(pyridin-2-yl)pyrrolidine-2-carboxylate (7g,
1
Yellow Oil, 11.1 g, Yield: 95%, 98.6% ee). H NMR (DMSO-d6,
500 MHz) δ: 8.34−8.22 (2H, m), 7.89−7.77 (1H, m), 7.13 (1H, ddd,
J = 7.3 Hz, 4.9 Hz, 1.2 Hz), 4.99 (1H, dd, J = 9.8 Hz, 3.1 Hz), 4.18−
4.08 (2H, m), 2.71−2.54 (2H, m), 2.43 (1H, qd, J = 13.0 Hz, 9.5 Hz),
2.06−1.97 (1H, m), 1.16 (3H, t, J = 7.0 Hz). 13C{1H} NMR (DMSO-
d6, 125 MHz) δ: 174.4, 172.0, 150.7, 147.4, 138.0, 119.7, 113.5, 60.7,
59.1, 31.5, 21.2, 13.9. HRMS (ESI+): calcd for C12H14N2O3 [M +
H]+: 235.1077; found: 235.1079.
Ethyl (R)-5-Oxo-1-phenylpyrrolidine-2-carboxylate (7h, 15.0 g,
Yield: 87%, 95.7% ee). 1H NMR (DMSO-d6, 500 MHz) δ: 7.47 (2H,
br d, J = 7.3 Hz), 7.36 (2H, t, J = 7.9 Hz), 7.20-7.11 (1H, m), 4.99−
4.93 (1H, m), 4.19−4.06 (2H, m), 2.63−2.52 (2H, m), 2.48−2.42
(1H, m), 2.12−2.01 (1H, m), 1.13 (3H, t, J = 7.3 Hz). 13C{1H} NMR
(DMSO-d6, 125 MHz) δ: 173.9, 171.8, 138.5, 128.8, 124.8, 120.9,
61.1, 60.6, 30.5, 22.4, 13.9. HRMS (ESI+): calcd for C13H15NO3 [M +
H]+: 234.1125; found: 234.1132.
Ethyl (R)-5-Oxo-1-(4-(trifluoromethyl)phenyl)pyrrolidine-2-car-
1
boxylate (7a, Yellow Oil, 18.2 g, Yield: 86%, 99.5% ee). H NMR
(DMSO-d6, 500 MHz) δ: 7.82−7.67 (4H, m), 5.10 (1H, dd, J = 8.9
Hz, 2.7 Hz), 4.21−4.07 (2H, m), 2.66−2.53 (3H, m), 2.17−2.07 (1H,
m), 1.15 (3H, t, J = 7.0 Hz). 13C{1H} NMR (DMSO-d6, 125 MHz) δ:
175.0, 171.9, 142.5, 126.5 (q, J = 4 Hz), 124.9 (q, J = 32 Hz), 124.7
Ethyl (R)-1-(3-Methoxyphenyl)-5-oxopyrrolidine-2-carboxylate
1
(7i, Yellow Oil, 14.6 g, Yield: 93%, 99.8% ee). H NMR (DMSO-
d6, 500 MHz) δ: 7.27 (1H, t, J = 8.2 Hz), 7.20−7.13 (1H, m), 6.98
J
DOI: 10.1021/acs.joc.9b00816
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(1H, dd, J = 8.2 Hz, 1.5 Hz), 6.75 (1H, dd, J = 8.2 Hz, 2.1 Hz), 4.95
(1H, dd, J = 8.9 Hz, 2.7 Hz), 4.12 (2H, q, J = 6.9 Hz), 3.73 (3H, s),
2.62−2.52 (1H, m), 2.49−2.40 (2H, m), 2.10−2.02 (1H, m), 1.21−
1.11 (3H, m). 13C{1H} NMR (DMSO-d6, 125 MHz) δ: 174.0, 171.8,
159.4, 139.6, 129.6, 112.8, 110.0, 107.0, 61.2, 60.7, 55.1, 30.7, 22.3,
13.9. HRMS (ESI+): calcd for C14H17NO4 [M + H]+: 264.1230;
found: 264.1232.
3.81 (3H, s), 3.36−3.24 (2H, m), 2.51−2.39 (1H, m), 1.99−1.88
(2H, m), 1.70−1.55 (1H, m). 13C{1H} NMR (CDCl3, 100 MHz): δ
169.5, 164.6 (d, J = 244 Hz), 159.1, 149.6 (d, J = 11 Hz), 132.7 (dq, J
= 33 Hz, 11 Hz), 129.4, 128.6, 123.5 (dq, J = 272 Hz, 4 Hz), 114.0,
105.9 (t, J =3 Hz), 102.6 (d, J = 26 Hz), 101.1 (dd, J = 26 Hz, 4 Hz),
55.2, 54.1, 50.1, 46.1, 27.2, 20.4. HRMS (ESI+): calcd for
C20H21N2F4O2 [M + H]+: 397.1534; found: 397.1528. Product
enantiomer excess: 100% ee.
Ethyl (R)-1-(2-Methoxyphenyl)-5-oxopyrrolidine-2-carboxylate
1
(7j, Yellow Oil, 14.8 g, Yield: 80%, 99.7% ee). H NMR (DMSO-
(R)-3-((3-Chloro-5-fluorophenyl)amino)-1-(4-methoxybenzyl)-
1
d6, 500 MHz) δ: 7.33−7.26 (1H, m), 7.21 (1H, dd, J = 7.6 Hz, 1.5
Hz), 7.09 (1H, d, J = 7.9 Hz), 6.95 (1H, dt, J = 7.6 Hz, 1.2 Hz), 4.68−
4.60 (1H, m), 4.04 (2H, qq, J = 10.9 Hz, 7.0 Hz), 3.78 (3H, s), 2.50−
2.34 (3H, m), 2.15−2.05 (1H, m), 1.09 (3H, t, J = 7.0 Hz). 13C{1H}
NMR (DMSO-d6, 125 MHz) δ: 174.3, 171.6, 154.3, 129.5, 128.7,
125.6, 120.2, 112.2, 60.9, 55.6, 29.1, 22.9, 13.9. One carbon signal
under solvent multiplet. HRMS (ESI+): calcd for C14H17NO4 [M +
H]+: 264.1230; found: 264.1234.
piperidin-2-one (8d; 105.7 mg, 73% Yield). H NMR (DMSO-d6,
400 MHz): δ 7.19 (2H, d, J = 8.3 Hz), 6.89 (2H, d, J = 8.6 Hz), 6.56
(1H, s), 6.46−6.40 (3H, m), 4.49−4.38 (2H, m), 4.15−4.09 (1H, m),
3.73 (3H, s), 3.27−3.15 (2H, m), 2.12−2.06 (1H, m), 1.84−1.77
(2H, m), 1.63−1.57 (1H, m). 13C{1H} NMR (CD3OD, 125 MHz): δ
172.2, 166.3, 164.4, 160.7, 152.3 (d, J = 13 Hz), 136.4 (d, J = 14 Hz),
130.5 (d, J = 45 Hz), 115.2, 110.1 (d, J = 2 Hz), 104.6 (d, J = 25 Hz),
99.2 (d, J = 25 Hz), 55.8, 54.8, 51.0, 48.0, 28.8, 21.7. HRMS (ESI+):
calcd for C19H21ClFN2O2 [M + H]+: 363.1270; found: 363.1265.
Product enantiomer excess: 94% ee.
Representative Experimental Procedure for Reductive Coupling/
Cyclization of Ester Containing Aryl Lactams with Primary Amines
(for Table 6). To a 2-dram vial equipped with a magnetic stir bar was
added Schwartz’s reagent (155 mg, 0.6 mmol, 1.5 equiv; preferably
less than 1 month old) as a solid in the air. The vial was then sealed
with a red open top cap (with a solvent-resistant Teflon cover), and a
N2 flow ran through the sealed vial for 5 min. The N2 line was then
removed, and THF (2 mL) was added through a syringe under
positive pressure. The reaction mixture was cooled to 0 °C in an ice-
water cooling bath and subjected to vigorous stirring, followed by the
injection of a solution of the substrate (0.4 mmol in 1 mL of THF).
After 1 h at 0 °C, to the milky white suspension was added neat amine
coupling partner (1.6 mmol, 4 equiv). The vial was then removed
from the ice-water bath, and STAB (254 mg, 1.2 mmol, 3 equiv) was
added in one portion as a solid to the reaction mixture. The vial was
capped and stirred at 80 °C for 18 h. A sample was taken from the vial
to be analyzed by LCMS. Upon reaction completion, water (1 mL)
was added to the vial. The mixture was stirred for 10 min before the
addition of EtOAc (2 mL). The layers were separated, and the
aqueous phase was extracted with additional portions of EtOAc (3 mL
× 3 mL). The combined organic extracts were dried (MgSO4) and
filtered. The filtrate was concentrated. The residue was purified by
silica gel column chromatography (12g silica gel column) with an
automatic purification system (grading from 0% EtOAc/heptanes to
30% EtOAc/heptanes over 18 min). The fractions were collected and
dried to give the desired lactam products as white solids.
(R)-1-(4-Methoxybenzyl)-3-(pyridin-4-ylamino)piperidin-2-one
1
(8e; 90.8 mg, 73% Yield). H NMR (DMSO-d6, 400 MHz): δ 8.71
(1H, d, J = 8.3 Hz), 8.24 (1H, br d, J = 6.8 Hz), 8.12 (1H, br d, J =
6.8 Hz), 7.20 (2H, d, J = 7.2 Hz), 7.08−6.99 (1H, m), 6.97−6.93
(1H, m), 6.92−6.87 (2H, m), 4.57 (1H, ddd, J = 10.6 Hz, 8.3 Hz, 6.0
Hz), 4.51−4.40 (2H, m, 2H), 3.74 (3H, s), 3.31−3.19 (2H, m), 2.13
(1H, br dd, J = 12.5 Hz, 5.6 Hz), 1.92−1.83 (2H, m), 1.82−1.70 (1H,
m). 13C{1H} NMR (DMSO-d6, 100 MHz): δ 167.5, 158.6, 158.5,
140.3, 138.7, 129.2, 129.0, 113.9, 109.9, 106.2, 55.1, 52.2, 48.9, 46.4,
26.9, 20.4. HRMS (ESI+): calcd for C18H21N3O2 [M + H]+:
312.1707; found: 312.1700. Product enantiomer excess: 100% ee.
(R)-1-(4-Methoxybenzyl)-3-(pyridin-3-ylamino)piperidin-2-one
1
(8f, 95.8 mg, 77% Yield). H NMR (DMSO-d6, 400 MHz): δ 8.04
(1H, d, J = 2.4 Hz), 7.75 (1H, d, J = 4.4 Hz), 7.20 (2H, d, J = 8.3 Hz),
7.08−6.97 (2H, m), 6.90 (2H, d, J = 8.3 Hz), 6.02 (1H, d, J = 7.1
Hz), 4.50−4.39 (2H, m), 4.08 (1H, dt, J = 10.4 Hz, 6.4 Hz), 3.74
(3H, s), 3.30−3.16 (2H, m), 2.11 (1H, br d, J = 12.7 Hz, 5.1 Hz),
1.89−1.80 (2H, m), 1.69−1.58 (1H, m). 13C{1H} NMR (DMSO-d6,
100 MHz): δ 169.6, 158.4, 144.5, 136.8, 135.8, 129.3, 129.1, 123.3,
118.1, 113.8, 55.0, 52.3, 48.8, 46.3, 27.4, 20.3. HRMS (ESI+): calcd
for C18H21N3O2 [M + H]+: 312.1707; found: 312.1700. Product
enantiomer excess: 98% ee.
(R)-1-(4-Methoxybenzyl)-3-(pyridin-2-ylamino)piperidin-2-one
1
(8g; 81.0 mg, 65% Yield). H NMR (CD3OD, 500 MHz): δ 7.95−
7.92 (1H, m), 7.44 (1H, ddd, J = 8.5 Hz, 6.7 Hz, 1.8 Hz), 7.24 (2H, d,
J = 8.6 Hz), 6.91−6.87 (2H, m), 6.61 (1H, d, J = 8.5 Hz), 6.59−6.56
(1H, m), 4.60−4.49 (m, 2H), 4.48 (1H, dd, J = 10.4 Hz, 6.1 Hz), 3.78
(3H, s), 3.35−3.32 (2H, m), 2.29−2.21 (1H, m), 1.96−1.89 (2H, m),
1.86−1.76 (1H, m). 13C{1H} NMR (DMSO-d6, 125 MHz): δ 169.8,
158.4, 158.3, 147.1, 136.5, 129.4, 129.0, 113.8, 111.8, 109.0, 55.0,
51.1, 48.9, 46.5, 27.8, 20.8. HRMS (ESI+): calcd for C18H21N3O2 [M
+ H]+: 312.1707; found: 312.1701. Product enantiomer excess: 88%
ee.
(R)-1-(4-Methoxybenzyl)-3-((4-(trifluoromethyl)phenyl)amino)-
piperidin-2-one (8a; 113.9 mg, 75% Yield). 1H NMR (CD3OD, 400
MHz): δ 7.36 (2H, br d, J = 8.3 Hz), 7.29−7.17 (2H, m), 6.92−6.86
(2H, m), 6.77 (2H, br d, J = 8.5 Hz), 4.53 (2H, s), 4.16 (1H, br dd, J
= 10.2 Hz, 5.9 Hz), 3.79−3.76 (3H, m), 3.36−3.33 (2H, m), 2.23
(1H, br dd, J = 12.7 Hz, 5.1 Hz), 1.96−1.85 (2H, m), 1.84−1.68 (1H,
m). 13C{1H} NMR (CD3OD, 125 MHz): δ 172.3, 160.8, 152.3,
130.7, 130.3, 127.4 (q, J = 4 Hz), 126.8 (q, J = 269 Hz), 119.5 (q, J =
32 Hz), 115.2, 113.8, 55.8, 54.8, 51.1, 48.1, 28.7, 21.8. HRMS (ESI+):
calcd for C20H22N2F3O2 [M + H]+: 379.1628; found: 379.1623.
Product enantiomer excess: 100% ee.
(R)-1-(4-Methoxybenzyl)-3-(phenylamino)piperidin-2-one (8h;
1
63.2 mg, 51% Yield). H NMR (CD3OD, 400 MHz): δ 7.20 (2H,
d, J = 8.6 Hz), 7.07 (2H, t, J = 7.7 Hz), 6.90 (2H, d, J = 8.3 Hz), 6.66
(2H, d, J = 8.1 Hz), 6.55 (1H, t, J = 7.2 Hz), 5.70 (1H, d, J = 6.6 Hz),
4.53−4.40 (2H, m), 4.04−3.94 (1H, m), 3.74 (3H, s), 3.27−3.16
(2H, m), 2.17−2.10 (1H, m), 1.86−1.79 (2H, m), 1.65−1.57 (1H,
m). 13C{1H} NMR (DMSO-d6, 100 MHz): δ 169.8, 158.4, 148.2,
129.4, 129.1, 128.7, 115.9, 113.8, 112.6, 55.0, 52.9, 48.9, 46.2, 27.5,
20.2. HRMS (ESI+): calcd for C19H22N2O2 [M + H]+: 311.1754;
found: 311.1747. Product enantiomer excess: 100% ee.
(R)-1-(4-Methoxybenzyl)-3-((3-methoxyphenyl)amino)piperidin-
2-one (8i; 74.8 mg, 55% Yield). 1H NMR (CDCl3, 400 MHz): δ 7.21
(2H, d, J = 8.6 Hz), 7.11 (1H, t, J = 8.2 Hz), 6.87 (2H, d, J = 8.3 Hz),
6.33−6.31 (2H, m), 6.24 (1H, s), 4.60−4.52 (2H, m), 3.85 (1H, dd, J
= 11.3 Hz, 5.6 Hz), 3.81 (3H, s), 3.78 (3H, s), 3.33−3.22 (2H, m),
2.53−2.46 (1H, m), 1.95−1.88 (2H, m), 1.65−1.59 (1H, m).
13C{1H} NMR (CDCl3, 100 MHz): δ 170.4, 160.7, 159.1, 148.9,
(R)-1-(4-Methoxybenzyl)-3-((3-(trifluoromethyl)phenyl)amino)-
1
piperidin-2-one (8b; 105.9 mg, 70% Yield). H NMR (CDCl3, 400
MHz): δ 7.27 (1H, t, J = 8.0 Hz), 7.21 (2H, d, J = 8.3 Hz), 6.97 (1H,
d, J = 7.6 Hz), 6.90−6.80 (4H, m), 4.64-4.50 (2H, m), 3.89 (1H, dd, J
= 11.3 Hz, 5.4 Hz), 3.81 (3H, s), 3.38-3.23 (2H, m), 2.52−2.42 (1H,
m), 1.99−1.90 (2H, m), 1.70−1.58 (1H, m). 13C{1H} NMR (CDCl3,
100 MHz): δ 170.0, 159.1, 147.7, 131.5 (q, J = 32 Hz), 129.6, 129.5,
128.8, 124.3 (q, J = 273 Hz), 116.7, 114.3 (q, J = 4 Hz), 114.0, 109.3
(q, J = 4 Hz), 55.2, 54.3, 50.2, 46.3, 27.5, 20.5. HRMS (ESI+): calcd
for C20H22N2F3O2 [M + H]+: 379.1628; found: 379.1623. Product
enantiomer excess: 100% ee.
(R)-3-((3-Fluoro-5-(trifluoromethyl)phenyl)amino)-1-(4-
methoxybenzyl)piperidin-2-one (8c; 104.5 mg, 66% Yield). 1H
NMR (CDCl3, 400 MHz): δ 7.21 (2H, d, J = 8.3 Hz), 6.88 (2H, d, J =
8.6 Hz), 6.68-6.62 (2H, m), 6.48 (1H, d, J = 11.0 Hz), 5.39 (1H, br
s), 4.56 (2H, d, J = 14.4 Hz), 3.86 (1H, br dd, J = 11.2 Hz, 5.1 Hz),
129.9, 129.5, 128.9, 114.0, 106.8, 102.9, 99.7, 55.3, 55.1, 54.7, 50.2,
K
DOI: 10.1021/acs.joc.9b00816
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
46.3, 27.8, 20.5. HRMS (ESI+): calcd for C20H25N2O3 [M + H]+:
341.1860; found: 341.1853. Product enantiomer excess: 100% ee.
(R)-1-(4-Methoxybenzyl)-3-((2-methoxyphenyl)amino)piperidin-
2-one (8j; 47.6 mg, 35% Yield). 1H NMR (CDCl3, 400 MHz): δ 7.23
(2H, d, J = 8.6 Hz), 6.90−6.86 (3H, m), 6.80 (1H, d, J = 7.6 Hz),
6.73 (1H, t, J = 7.6 Hz), 6.62 (1H, d, J = 7.8 Hz), 4.61−4.53 (2H, m),
3.88 (3H, s), 3.87−3.83 (1H, m), 3.81 (3H, s), 3.34−3.23 (2H, m),
2.52−2.43 (1H, m), 1.98−1.89 (2H, m), 1.78−1.66 (1H, m).
13C{1H} NMR (CDCl3, 100 MHz): δ 170.3, 159.0, 147.6, 137.4,
materials. We also thank Jiansheng Huang at Biogen for his
assistance in obtaining HRMS data.
REFERENCES
■
(1) Greenberg, A.; Breneman, C.; Liebman, J. The Amide Linkage:
Structural Significance in Chemistry. In Biochemistry, and Materials
Science; Wiley-Interscience: NY, 2000.
(2) (a) Kemnitz, C.; Loewen, M. “Amide resonance” correlates with
a breadth of C-N rotation barriers. J. Am. Chem. Soc. 2007, 129,
2521−2528. (b) Gooßen, L.; Ohlmann, D.; Lange, P. The thermal
amidation of carboxylic acids revisited. Synthesis 2009, 1, 160−164.
(c) Arnott, G. Reduction of carboxylic acids and their derivatives to
alcohols, ethers, and amines. In Comprehensive Organic Synthesis II;
Knochel, P., Molander, G., Eds.; Elsevier, Ltd.: Waltham, 2014; pp
390−399.
(3) (a) Blagbrough, I.; Carrington, S.; Geall, A. Polyamines and
polyamine amides as potent selective receptor probes, novel
therapeutic lead compounds, and synthetic vectors in gene therapy.
Pharm. Sci. 1997, 3, 223−233. (b) Ghose, A.; Viswanadhan, N.;
Wendoloski, J. A knowledge-based approach in designing combina-
torial or medicinal chemistry libraries for drug discovery. 1. A
qualitative and quantitative characterization of known drug databases.
J. Comb. Chem. 1999, 1, 55−68. (c) Lundberg, H.; Tinnis, F.;
Selander, N.; Adolfsson, H. Catalytic amide formation from non-
activated carboxylic acids and amines. Chem. Soc. Rev. 2014, 43,
2714−2742. (d) Chaudhari, P.; Salim, S.; Sawant, R.; Akamanchi, K.
Sulfated tungstate: a new solid heterogeneous catalyst for amide
synthesis. Green Chem. 2010, 12, 1707−1710.
(4) (a) Deopura, B.; Gupta, B.; Joshi, M.; Alagirusami, R. Polyesters
and Polyamides; CRC Press: Boca Raton, 2008. (b) Deming, T.
Synthetic polypeptides for biomedical applications. Prog. Polym. Sci.
2007, 32, 858−875. (c) Pramanik, P.; Chakraborty, R. The unique
story of a high-tech polymer. Resonance 2004, 9, 39−50. (d) Sharma,
R.; Goel, A.; Mehtab, S. High Performance Fibre Aramids; Elsevier,
2012; Vol. 11, pp 373−377.
(5) (a) Das, S. Chemoselective reduction of amides and imides. In
New Strategies in Chemical Synthesis and Catalysis; Pignataro, B., Ed.;
Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, 2012; pp 59−78.
(b) Dodds, D.; Cole-Hamilton, D. Catalytic reduction of amides
avoiding LiAlH4 or B2H6. In Sustainable Catalysis: Challenges and
Practices for the Pharmaceutical and Fine Chemical Industries; Dunn, P.,
Hii, K., Krische, M., Willams, M., Eds.; John Wiley & Sons, Inc:
Hoboken, 2013; pp 1−36. (c) Flaniken, J.; Collins, C.; Lanz, M.;
Singaram, B. Aminoborohydrides. 11. Facile reduction of N-alkyl
lactams to the corresponding amines using lithium aminoborohy-
drides. Org. Lett. 1999, 1, 799−801. (d) Das, S.; Zhou, S.; Addis, D.;
Enthaler, S.; Junge, K.; Beller, M. Selective catalytic reductions of
amides and nitriles to amines. Top Catal. 2010, 53, 979−984.
(6) Volkov, A.; Tinnis, F.; Slagbrand, T.; Trillo, P.; Adolfsson, H.
Chemoselective reduction of carboxamides. Chem. Soc. Rev. 2016, 45,
6685−6697.
(7) (a) Brown, H.; Tsukamoto, A. Selective reductions. V. The
partial reduction of tertiary amides by lithium di- and triethox-
yaluminohydridesa new aldehyde synthesis via the dimethylamides.
J. Am. Chem. Soc. 1964, 86, 1089−1095. (b) Hutchins, R.; Learn, K.;
El-Telbany, F.; Stercho, Y. Aminoborohydrides as Reducing Agents. 1.
Sodium (dimethylamino)- and (tert-butylamino)borohydrides as
selective reducing agents. J. Org. Chem. 1984, 49, 2438−2443.
(c) Schedler, D.; Godfrey, A.; Ganem, B. Reductive deoxygenation by
Cp2ZrHCl: Selective formation of imines via zirconation/hydro-
zirconation of amides. Tetrahedron Lett. 1993, 34, 5035−5038.
(d) Dieter, R.; Sharma, R. A facile preparation of enecarbamates. J.
Org. Chem. 1996, 61, 4180−4184. (e) Bower, S.; Kreutzer, K.;
Buchwald, S. A mild general procedure for the one-pot conversion of
amides to aldehydes. Angew. Chem., Int. Ed. 1996, 35, 1515−1516.
(f) Myers, A.; Yang, B.; Kopecky, D. Lithium amidotrihydroborate, a
powerful new reductant. Transformation of tertiary amides to primary
alcohols. Tetrahedron Lett. 1996, 37, 3623−3626. (g) Godjoian, G.;
Singaram, B. Controlled reduction of tertiary amides to the
129.6, 129.0, 120.9, 117.4, 114.0, 110.2, 109.5, 55.4, 55.3, 54.7, 50.1,
46.5, 28.0, 20.6. HRMS (ESI+): calcd for C20H25N2O3 [M + H]+:
341.1860; found: 341.1853. Product enantiomer excess: 100% ee.
Preparation and Isolation of Compound 9. The compound was
prepared following the same general procedure that was used for the
preparation of compound 8a except that the reaction mixture was
stirred at 22 °C instead of 80 °C after the addition of STAB. After
keeping the reaction mixture at 22 °C overnight, 9 was present in the
reaction mixture as a major component. The reaction was worked-up
following the same protocol, and the crude was purified by mass-
directed prep-HPLC (SunFire C18 column, 60 mL/min flow rate,
10% acetonitrile in water to 70% acetonitrile in water, with 0.1% TFA
modifier) to give ethyl (R)-5-((4-methoxybenzyl)amino)-2-((4-
(trifluoromethyl)phenyl)-amino)pentanoate as a colorless oil. Yield
was not determined since it was isolated just for characterization.
Ethyl (R)-5-((4-Methoxybenzyl)amino)-2-((4-(trifluoromethyl)-
1
phenyl)amino)pentanoate (9). H NMR (CD3OD, 400 MHz): δ
7.41−7.36 (4H, m), 6.98−6.94 (2H, m), 6.71 (2H, br d, J = 12.0 Hz),
4.20−4.08 (5H, m), 3.79 (3H, s), 3.07−3.03 (2H, m), 2.02−1.82
(4H, m), 1.22 (3H, t, J = 8.0 Hz). 13C{1H} NMR (CD3OD, 100
MHz): δ 174.9, 162.3, 152.1, 132.6, 127.6 (q, J = 3 Hz), 126.6 (q, J =
267 Hz), 124.3, 120.2 (q, J = 36 Hz), 115.7, 113.6, 62.6, 56.9, 55.9,
52.0, 47.8, 30.4, 24.0, 14.6. HRMS (ESI+): calcd for C22H27N2F3O3
[M + H]+: 425.2047; found: 425.2051.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.9b00816.
Descriptions of LCMS and HPLC methods; chiral SFC
traces of the chiral piperidinone products in Table 6;
1
and H and 13C NMR spectra of the products (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: robin.prince@biogen.com (R.J.P.).
*E-mail: fang.gao@biogen.com (F.G.).
*E-mail: brian.hopkins@biogen.com (B.T.H.).
ORCID
Robin J. Prince: 0000-0002-1177-1981
Author Contributions
†R.J.P. and F.G. contributed equally to this work.
Funding
The team is grateful for Biogen Inc. for providing financial
support to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank our collaborators at BioDuro for scope expansion in
selected examples in Tables 2−4 and for collecting analytical
data for these final products. We thank ChemPartner and
ChemDiscover LLC for the preparation of the Ullmann
products and for collecting analytical data for these starting
L
DOI: 10.1021/acs.joc.9b00816
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
corresponding aldehydes or amines using dialkylboranes. Tetrahedron
Lett. 1997, 38, 1717−1720. (h) Cossy, J.; Cases, M.; Pardo, D. A
convenient procedure for the conversion of N-Boc protected
pyrrolidinone derivatives into their corresponding enecarbamates.
Synth. Commun. 1997, 27, 2769−2776. (i) Myers, A.; Yang, B.; Chen,
H.; McKinstry, L.; Kopecky, D.; Gleason, J. Pseudoephedrine as a
practical chiral auxiliary for the synthesis of highly enantiomerically
enriched carboxylic acids, alcohols, aldehydes, and ketones. J. Am.
Chem. Soc. 1997, 119, 6496−6511. (j) Choi, Y.; Kim, M.; A, D. Partial
reduction of tertiary amides to aldehydes using a new reducing agent,
lithium diisobutyl-iso-propoxyaluminum hydride (LDBIPA). Bull.
Korean Chem. Soc. 2009, 30, 2825−2826.
(8) (a) Spletstoser, J.; White, J.; Tunoori, A.; Georg, G. Mild and
selective hydrozirconation of amides to aldehydes using Cp2Zr(H)Cl:
scope and mechanistic insight. J. Am. Chem. Soc. 2007, 127, 3408−
3419. (b) Bailey, C.; Joh, A.; Hurley, Z.; Anderson, C. Controlled
reduction of tertiary amides to the corresponding alcohols, aldehydes,
or amines using dialkylboranes and aminoborohydride reagents. J.
Org. Chem. 2016, 81, 3619−3628.
(9) (a) Delcros, J.-G.; Tomasi, S.; Carrington, S.; Martin, B.;
Renault, J.; Blagbrough, I.; Uriac, P. Effect of spermine conjugation on
the cytotoxicity and cellular transport of acridine. J. Med. Chem. 2002,
for probing the secondary binding pocket. Bioorg. Med. Chem. Lett.
2018, 28, 1897−1902.
(11) Examples of Wittig reactions: (a) Hara, O.; Sugimoto, K.;
Makino, K.; Hamada, Y. New synthesis of a pyrroloquinoline skeleton,
the martinelline core, using a tandem Michael-aldol strategy. Synlett
2004, 9, 1625−1627. (b) Davies, S.; Garrido, N.; Kruchinin, D.;
Ichihara, O.; Kotchie, L.; Price, P.; Mortimer, A.; Russell, A.; Smith,
A. Homochiral lithium amides for the asymmetric synthesis of β-
amino acids. Tetrahedron: Asymmetry 2006, 17, 1793−1811.
(c) Yoshitomi, Y.; Arai, H.; Makino, K.; Hamada, Y. Enantioselective
synthesis of martinelline chiral core and its diastereomer using
asymmetric tandem Michael-aldol reaction. Tetrahedron 2008, 64,
11568−11579. (d) Peixoto, S.; Nguyen, T.; Crich, D.; Delpech, B.;
Marazano, C. One-pot formation of piperidine- and pyrrolidine-
substituted pyridinium salts via addition of 5-alkylaminopenta-2,4-
dienals to N-acyliminium ions: application to the synthesis of
( )-nicotine and analogs. Org. Lett. 2010, 12, 4760−4763.
(e) Benedetti, F.; Berti, F.; Budal, S.; Campaner, P.; Dinon, F.;
Tossi, A.; Argirova, R.; Genova, P.; Atanassov, V.; Hinkov, A.
Synthesis and biological activity of potent HIV-1 protease inhibitors
based on Phe-Pro dihydroxyethylene isosteres. J. Med. Chem. 2012,
55, 3900−3910. (f) Azuma, T.; Murata, A.; Kobayashi, Y.; Inokuma,
T.; Takemoto, Y. A dual arylboronic acid-aminothiourea catalytic
system for the asymmetric intramolecular hetero-Michael reaction of
α,β-unsaturated carboxylic acids. Org. Lett. 2014, 16, 4256−4259.
(12) (a) Kautzner, B.; Wailes, P.; Weigold, H. Hydrides of
bis(cyclopentadienyl)zirconium. J. Chem. Soc. D 1969, No. 1105.
(b) White, J.; Tunoori, A.; Georg, G. A Novel and expeditious
reduction of tertiary amides to aldehydes using Cp2Zr(H)Cl. J. Am.
Chem. Soc. 2000, 122, 11995−11996. (c) White, J.; Tunoori, A.;
Georg, G. Selective reduction with Cp2ZrHCl. Chem. Innov. 2000, 30,
17−21, https://pubsapp.acs.org/subscribe/archive/ci/30/i12/html/
12georg.html. (d) Zhao, Y.; Snieckus, V. A practical in situ generation
of the Schwartz reagent. Reduction of tertiary amides to aldehydes
and hydrozirconation. Org. Lett. 2014, 16, 390−393.
̀
45, 5098−5111. (b) Piperno, A.; Carnovale, C.; Giofre, S.; Iannazzo,
D. Hydrozirconation of four-, five-, six-, and seven-membered N-
alkoxycarbonyl lactams to lactamols. Tetrahedron Lett. 2011, 52,
6880−6882. (c) Shi, S.-L.; Wei, X.-F.; Shimizu, Y.; Kanai, M.
Copper(I)-catalyzed enantioselective incorporation of ketones to
cyclic hemiaminals for the synthesis of versatile alkaloid precursors. J.
Am. Chem. Soc. 2012, 134, 17019−17022. (d) Yazici, A.; Pyne, S.
Intermolecular addition reactions of N-acyliminium ions (Part 1).
Synthesis 2009, 3, 339−368. (e) Bach, J.; Bull, S.; Davies, S.;
Nicholson, R.; Sanganee, H.; Smith, A. N-Acyl-5,5-dimethyl-
oxazolidin-2-ones as latent aldehyde equivalents. Tetrahedron Lett.
̀
1999, 40, 6677−6680. (f) Bach, J.; Blachere, C.; Bull, S.; Davies, S.;
Nicholson, R.; Price, P.; Sanganee, H.; Smith, A. N-Acyl-5,5-dimethyl-
oxazolidin-2-ones as latent aldehyde equivalents. Org. Biomol. Chem.
2003, 1, 2001−2010.
(13) Ji, X.; Huang, H. Synthetic methods for 1,3-diamines. Org.
Biomol. Chem. 2016, 14, 10557−10566.
(10) Examples of reductive aminations: (a) Quibell, M.; Turnell, W.;
Johnson, T. Synthesis of azapeptides by the fmoc/tert-butyl/
polyamide technique. J. Chem. Soc. Perkin Trans. 1. 1993, 2843−
2849. (b) Boeglin, D.; Lubell, W. Aza-amino acid scanning of
secondary structure suited for solid-phase peptide synthesis with fmoc
chemistry and aza-amino acids with hereroatomic side chains. J.
Comb. Chem. 2005, 7, 864−878. (c) Busnel, O.; Bi, L.; Baudy-Floc’h,
M. Synthesis of fmoc-protected aza-β3-amino acids via reductive
amination of glyoxylic acid. Tetrahedron Lett. 2005, 46, 7073−7075.
(d) Narumi, T.; Ochiai, C.; Yoshimura, K.; Harada, S.; Tanaka, T.;
Nomura, W.; Arai, H.; Ozaki, T.; Ohashi, N.; Matsushita, S.;
Tamamura, H. CD4 mimics targeting HIV entry mechanism and their
hybrid molecules with a CXCR4 antagonist. Bioorg. Med. Chem. Lett.
2010, 20, 5853−5858. (e) Truax, V.; Zhao, H.; Katzman, B.; Prosser,
A.; Alcaraz, A.; Saindane, M.; Howard, R.; Culver, D.; Arrendale, R.;
Gruddanti, P.; Evers, T.; Natchus, M.; Snyder, J.; Liotta, D.; Wilson,
L. Discovery of tetrahydroisoquinoline-based CXCR4 antagonists.
ACS Med. Chem. Lett. 2013, 4, 1025−1030. (f) Kabeshov, M.; Musio,
B.; Murray, P.; Browne, D.; Ley, S. Expedient preparation of nazlinine
and a small library of indole alkaloids using flow electrochemistry as
an enabling technology. Org. Lett. 2014, 16, 4618−4621. (g) Song, A.;
Tom, J.; Yu, Z.; Pham, V.; Tan, D.; Zhang, D.; Fang, G.; Yu, T.;
Deshayes, K. Development of orthogonally protected hypusine for
solid-phase peptide synthesis. J. Org. Chem. 2015, 80, 3677−3681.
(h) Kimishima, A.; Wenthur, C.; Zhou, B.; Janda, K. An advance in
prescription opioid vaccines: overdose mortality reduction and
extraordinary alteration of drug half-life. ACS Chem. Biol. 2017, 12,
36−40. (i) Bremer, P.; Schlosburg, J.; Banks, M.; Steele, F.; Zhou, B.;
Poklis, J.; Janda, K. Development of a clinically viable heroin vaccine.
J. Am. Chem. Soc. 2017, 139, 8601−8611. (j) Omran, A.; Eslamimehr,
S.; Crider, A.; Neumann, W. Synthesis of 3-(3-hydroxyphenyl)-
pyrrolidine dopamine D3 receptor ligands with extended functionality
(14) (a) Chowdari, N.; Ahmad, M.; Albertshofer, K.; Tanaka, F.;
Barbas, C., III Expedient synthesis of chiral 1,2- and 1,4-diamines:
Protecting group dependent regioselectivity in direct organocatalytic
asymmetric Mannich reactions. Org. Lett. 2006, 8, 2839−2842.
(b) Tsiakopoulos, N.; Vassis, S.; Militsopoulou, M.; Damianakos, C.;
Gatos, P.; Voyiatzi, K.; Pantazaka, E.; Papaioannou, D. Recent
applications of the amide approach to the synthesis of medicinally
interesting polyamine analogues. In Drug Discovery and Design:
Medical Aspects; Matsoukas, J., Mavromoustakos, T., Eds.; IOS Press:
Amsterdam, 2002; pp 53−63. (c) Grasa, G.; Zanotti-Gerosa, A.;
Medlock, J.; Hems, W. Asymmetric hydrogenation of isobutyrophe-
none using a [(diphosphine) RuCl2 (1,4-diamine)] catalyst. Org. Lett.
2005, 7, 1449−1451.
(15) For a review on application of Buchwald-Hartwig coupling
chemistry, see: Ruiz-Castillo, P.; Buchwald, S. Applications of
palladium-catalyzed C−N cross-coupling reactions. Chem. Rev.
2016, 116, 12564−12649.
(16) We did not evaluate LAH as a reducing agent in this initial
screen as we needed a reducing agent compatible with esters.
(17) (a) Hara, R.; Takahashi, T. Zirconium Lewis Acids. In Lewis
Acids in Organic Synthesis; Yamamoto, H., Ed.; Wiley-VCH Verlag
GmbH: Weinheim, 2000; pp 865−881. (b) The Lewis acids screened
included: zircocene dichloride, zirconium chloride, and methylalumi-
num bis(2,6-di-tert-butyl-4-methylphenoxide) (MAD).
(18) Different solvents were tested to identity the best reaction
medium. While dichloromethane and acetonitrile were largely
ineffective to promote the reductive coupling reaction, tetrahydrofur-
an and toluene were capable solvents. However, in toluene, diamine
3a was formed in 43% yield, presumably due to the lower solubility of
reactants in comparison to reactions with THF. Therefore, THF was
chosen to be the optimal solvent going forward.
M
DOI: 10.1021/acs.joc.9b00816
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(19) Schedler, D.; Li, J.; Ganem, B. Reduction of secondary
carboxamides to imines. J. Org. Chem. 1996, 61, 4115−4119.
́
(20) Szczesniak, P.; Maziarz, E.; Stecko, S.; Furman, B. Synthesis of
polyhydroxylated piperidine and pyrrolidine peptidomimetics via one-
́
pot sequential lactam reductions/Joullie-Ugi reaction. J. Org. Chem.
2015, 80, 3621−3633.
(21) See the Experimental Section for a detailed characterization of
one such intermediate diamine (compound 9) bearing a pendant ester
functionality and the Supporting Information file for the correspond-
1
ing H and 13C{1H} NMR spectra.
(22) Haldon, E.; Alvarez, E.; Nicasio, M. C.; Perez, P. Dinuclear
copper(I) complexes as precatalysts in Ullmann and Goldberg
coupling reactions. Organometallics 2009, 28, 3815−3821.
(23) Lucas-Lopez, C.; Patterson, S.; Blum, T.; Straight, A.; Toth, J.;
Slawin, A.; Mitchison, T.; Sellers, J.; Westwood, N. Absolute
stereochemical assignment and fluorescence tuning of the small
molecule tool, (-)-blebbistatin. Eur. J. Org. Chem. 2005, 9, 1736−
1740.
(24) Heine, H.; Love, P.; Bove, J. On cyclic intermediates in
substitution reactions. VII. The alkaline solvolysis of some N-aryl-4-
bromobutanamides. J. Am. Chem. Soc. 1955, 77, 5420−5422.
(25) Phillips, D.; Zhu, X.-F.; Lau, T.; He, X.; Yang, K.; Liu, H.
Copper-catalyzed C−N coupling of amides and nitrogen-containing
heterocycles in the presence of cesium fluoride. Tetrahedron Lett.
2009, 50, 7293−7296.
(26) Yang, Y.-H.; Shi, M. Ring-expanding reaction of cyclopropyl
amides with triphenylphosphine and carbon tetrahalide. J. Org. Chem.
2005, 70, 8645−8648.
(27) Bigham, E.; Hodson, S.; Mallory, W.; Wilson, D.; Duch, D.;
Smith, G.; Ferone, R. Synthesis and biological activity of open-chain
analogs of 5,6,7,8-tetrahydrofolic acid-potential antitumor agents. J.
Med. Chem. 1992, 35, 1399−1410.
(28) Easton, C.; Pitt, M.; Ward, C. Functionalization of pyrrolidin-2-
ones at C4 and C5. Tetrahedron 1995, 51, 12781−12790.
(29) Duplantier, A.; Andresen, C.; Cheng, J.; Cohan, V.; Decker, C.;
DiCapua, F.; Krauss, K.; Johnson, K.; Turner, C.; Umland, J.; Watson,
J.; Wester, R.; Williams, A.; Williams, J. 7-Oxo-4,5,6,7-tetrahydro-1H-
pyrazolo[3,4-c]pyridines as novel inhibitors of human eosinophil
phosphodiesterase. J. Med. Chem. 1998, 41, 2268−2277.
(30) Guyonnet, M.; Baudoin, O. Synthesis of tricyclic nitrogen
heterocycles by a sequence of palladium-catalyzed N−H and C(sp3)
H arylations. Org. Lett. 2012, 14, 398−401.
(31) Guazzelli, G.; Duffy, L.; Procter, D. A Samarium(II)mediated,
stereoselective cyclization for the synthesis of azaspirocycles. Org. Lett.
2008, 10, 4291−4294.
(32) Lange, J.; Bissember, A.; Banwell, M.; Cade, I. Synthesis of 2,3-
dihydro-4(1H)quinolones and the corresponding 4(1H)quinolones
via low-temperature Fries rearrangement of N-arylazetidin-2-ones.
Aust. J. Chem. 2011, 64, 454−470.
N
DOI: 10.1021/acs.joc.9b00816
J. Org. Chem. XXXX, XXX, XXX−XXX