Telescoped synthesis of C3-functionalized (E)-arylamidines using Ugi-Mumm and regiospecific quinazolinone rearrangements

Article abstract of DOI:10.1039/c9ob00073a

An efficient four-step, six-transformation protocol was developed to afford bioactive N-alkyl- or N-arylamide (E)-arylamidines featuring strategic amidine C3 modifications which were inaccessible or low yielding by previous methods. This synthetic approac

Full text of DOI:10.1039/c9ob00073a

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Telescoped synthesis of C3-functionalized
(E)-arylamidines using Ugi–Mumm and
Cite this: DOI: 10.1039/c9ob00073a
regiospecific quinazolinone rearrangements†
Victor A. Jaffett,‡a Alok Nerurkar,‡b Xufeng Cao,b Ilia A. Guzei c and
a,b
Jennifer E. Golden
*
An efficient four-step, six-transformation protocol was developed to afford bioactive N-alkyl- or
N-arylamide (E)-arylamidines featuring strategic amidine C3 modifications which were inaccessible or low
yielding by previous methods. This synthetic approach, exemplified with 24 amidines and requiring only a
single purification, highlights a multicomponent Ugi–Mumm rearrangement to afford highly diversified
quinazolinones which undergo regiospecific rearrangement to afford new amidines. The method exten-
sively broadens the structural scope of this new class of trisubstituted amidines and demonstrates the tol-
erance of regional C3 amidine steric bulk, visualized with X-ray crystallographic analysis.
Received 10th January 2019,
Accepted 29th January 2019
DOI: 10.1039/c9ob00073a
rsc.li/obc
In the context of our anti-infective programs and ongoing
synthetic method development, we attempted substitution of
Introduction
Trisubstituted amidines are known for a diverse therapeutic the C3 position of benzamidine 3; however, poor yields of C3-
range that includes antiarrhythmic,1a–c anthelmintic,2a–c anti- modified products were obtained. It was unclear if this was
parasitic,3a,b antidepressant,4a–e and antipsychotic5a–f appli- due to steric congestion of substitution at this site or fault of
cations (Fig. 1). Derivatives of the antipsychotic tricyclic the method. It was also difficult to generate amidobenzami-
amidine, olanzapine, are also reported to be helpful in treating dines bearing N-alkyl substituents on the amide group. While
relapsing–remitting forms of multiple sclerosis.6
a few N-alkyl substituted amides were made in low yield, it was
This N′,N,N-trisubstituted amidine motif was revealed to be desirable to construct an array to survey bioactivity. Given the
critical in our discovery and development of novel (E)-amido- importance of the scaffold to our program and the inadequate
benzamidines as potent antiviral agents7a,b (3, Scheme 1). This synthetic means to regionally diversify it, we sought a method
unique scaffold originated from a regiospecific rearrangement that would comprehensively address these needs. In 2011,
of chloroalkylquinazolinone 1a treated with 1,2-bis(methyl- Mossetti reported10
amino)ethane to exclusively yield (E)-amidobenzamidine 3a
(Scheme 1). We subsequently reported a one-pot method8 by
which extended N-Boc-protected amino acids were converted to
quinazolinones 1b that could be efficiently transformed into
more diverse amidines 3b. Both methods relied on generation
of quinazolinone intermediates 1a–b from standard acylation of
anthranilic acids, followed by amidation/cyclization.7a,8,9
a
Ugi–Mumm rearrangement,11a–h
aDepartment of Chemistry, University of Wisconsin, 1101 University Ave., Madison,
WI 53706, USA. E-mail: jennifer.golden@wisc.edu
bPharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin,
777 Highland Ave., Madison, WI 53705-2222, USA
cMolecular Structure Laboratory, Department of Chemistry, University of Wisconsin-
Madison, 1101 University Ave., Madison, WI 53706, USA
†Electronic supplementary information (ESI) available. CCDC 1880156. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c9ob00073a
‡Co-first authors; Authors contributed equally to syntheses and manuscript
Fig. 1 Drugs of diverse application containing a trisubstituted amidine
writing.
motif, highlighted in blue.
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thrust of this effort was to determine if unique quinazolinones
could be efficiently prepared and successfully transformed
into novel, C3-substituted amidines to probe unexplored bio-
logical space.
Results and discussion
Scheme 1 Previous approaches to N-aryl benzamidines.7a,8
A brief feasibility study employing published reaction con-
ditions10 was done using 2-azidobenzoic acid, cyclohexyl- or
4-methoxyphenyl isocyanide, one of three aldehydes of vari-
followed by Staudinger/aza-Wittig ring closure12a,b to generate able steric demand and a requisite mono-N-Boc-protected 1,2-
quinazolinones 6 (Scheme 2). Importantly, these products bore bis(methylamino)ethane 9a used in our rearrangement chem-
R1 and R2 substituents that would be expected to afford the istry (Scheme 3). Key intermediates were isolated to assess the
desired C3-substituted, N-alkyl amide derivatives 8 if a core efficiency of each reaction in the sequence. The desired imides
containing a suitably tethered diamine, as shown in 7, was 10a–b, resulting from the Ugi–Mumm assembly with cyclo-
subjected to our rearrangement conditions.
hexyl isocyanide and bearing a C3-isopropyl or isobutyl group,
The approach potentially offered convenient access to R1 were isolated in 83% and 55% yield, respectively (Scheme 3).
and R2 quinazolinone 7 substitutions and ultimately, potential While some starting material remained, by-products 11a–b
corresponding substitutions in amidines 8 that were challen- were not observed. Formaldehyde was not productive, only
ging to otherwise incorporate. Furthermore, the Ugi–Mumm- affording Passerini α-acyloxy carboximide 11c. Use of 4-meth-
aza-Wittig protocol was furnished as a one-pot method.10 oxyphenyl isocyanide with non-formaldehyde components also
Nonetheless, limitations of the method as published were also generated imides 10d–e in 58–61% yield. Imides 10a–b or 10d–
noted. The two-step overall yields for the 13 examples cited e were individually subjected to Staudinger/aza-Wittig con-
were evenly distributed between 40–81%, and use of aryl alde- ditions, and afforded corresponding quinazolinones in
hydes required significantly longer reaction times (3 days). In 60–88% yield. Subsequent TFA treatment to remove the N-Boc
some cases, Passerini product formation10,13a–c predominated protecting group, followed by base-promoted rearrangement
over desired imide formation in the first step. Additionally, gave the amidines in 30–51% yield over two steps. The best
direct use of formaldehyde was not permitted in the Ugi– outcome for this 4-step, 6-transformation sequence was
Mumm reaction, a feature that would limit access to C3-unsub- observed for amidine 13a, isolated in 32% overall yield, corre-
stituted, N-alkyl amides that are important to ongoing projects
in our lab. With these pros and cons in mind, we set out to see
if this approach could advance our rearrangement strategies
and medicinal chemistry goals. Specifically, we aimed to
survey a broad range of Ugi substrates and explore the use of
problematic Ugi–Mumm partners such as formaldehyde, aryl
aldehydes, and heterocyclic azido acids. Importantly, the
Scheme 3 Pilot chemistry to N-alkyl/C3 modified amidines. Reaction
conditions: (a) 2-Azidobenzoic acid, R1NC, R2CHO (1 eq. each), 4 Å MS,
CH2Cl2, rt, 12 h; (b) PPh3, toluene, reflux, 12 h; (c) TFA, CH2Cl2, 0 °C–rt,
Scheme 2 Known Ugi–Mumm quinazolinones and adaptation to
N-alkyl amide/C3-substituted amidine construction.
12 h; (d) aq. K2CO3, CH3CN, μW, 150 °C, 1 h. Yields are based on isolated
and purified products.
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sponded to a 75% average yield per step, and confirmed that a cyanide B would irreversibly afford nitrilium ion I and push
C3-isopropyl group was well tolerated in the quinazolinone the process towards the desired outcome. Interception of I
rearrangement. We then set out to (a) maximize imide for- with acid D would afford a different O-acylimidate intermedi-
mation, (b) minimize Passerini side reactions, (c) improve qui- ate J; however, in this case, O-to-N-acyl transfer via Mumm
nazolinone and amidine yields, (d) streamline the overall rearrangement would provide imide K. Staudinger/aza-Wittig
process, and (e) generate diversely functionalized N-alkyl/ ring closure would form quinazolinone M featuring an N-alkyl
C3-modified amidines.
amide (R1), R2 substitution from the incorporated aldehyde,
To start, the mechanism of each step was considered and an appended Boc-protected amine of suitable length that,
(Scheme 4). Fortunately, the historic Ugi, Mumm, Staudinger once liberated and rendered basic (O), will undergo rearrange-
and aza-Wittig reactions have been substantially reviewed, and ment to amidine Q. Previous work has shown that tethered
mechanisms for each are well documented.11a–g,12c For our amines capable of forming a 5- or 6-membered spirocyclic
own quinazolinone rearrangement, control experiments were intermediate such as P (latter case shown only), productively
previously executed and published7a,8 that support the follow- affords an amidine. Amine tethers of longer length require for-
ing discussion. Contrary to our previous work in which chlor- mation of unfavored ring sizes and do not rearrange.7a,8
oalkylquinazolinones were prepared by a standard three-step Attention was first directed to promoting complete imide for-
process, this effort required an alternate assembly of the requi- mation and preventing side reactions (see ESI†). Imide 10d for-
site N-alkylamide/C3-substituted amidines (Scheme 4). mation was used initially to scout reaction parameters.
Specifically, the formation of an iminium ion H between alde- According to the published protocol, equimolar quantities of
hyde A and amine G was a critical part of this effort. Any Ugi–Mumm components were combined concomitantly with
unreacted aldehyde could participate in a competing three- molecular sieves in CH2Cl2 at ambient temperature.10,14 We
component Passerini reaction. In that circumstance, isocya- observed that 2-azidobenzoic acid was poorly soluble in
nide B adds to the activated aldehyde, forming nitrilium ion C CH2Cl2, likely contributing to suboptimal conversion. Adding
that is intercepted by acid D, forming an O-acylimidate E. the acid as a 1.0 M solution in 3 : 1 CH2Cl2/CH3OH resulted in
Pericyclic acyl transfer then affords undesired α-acyloxy carbox- a 10% increase in the isolated imide 10d (68%). This change,
amide F.
in combination with stoichiometric increase of the other
In the desired pathway, favoring complete formation of reagents to 1.5 equiv. relative to the 2-azidobenzoic acid,
iminium ion H was a priority, as subsequent addition of iso- improved imide 10d yield (85%), though Passerini product 11d
formation was also noted. By implementing these changes and
premixing the aldehyde and amine for 6–12 min prior to the
addition of acid and isocyanide, Passerini product 11d for-
mation was avoided, and 10d was obtained in 92% yield.
Further optimization of stoichiometry revealed that a 2 : 4 : 1 : 4
ratio of diamine : aldehyde : carboxylic acid : isocyanide was
ideal, resulting in significantly improved yields across all pilot
examples 10a–e, which notably included the first successful
direct implementation of formaldehyde (10c, 45%, Scheme 5).
The intramolecular Staudinger/aza-Wittig pilot reactions
afforded quinazolinones in reasonable yields (Scheme 3). As
such, focus shifted to optimization of the quinazolinone
rearrangement. Historically, quinazolinone N-Boc deprotection
was effected with TFA (12 h), followed by neutralization with
aqueous Na2CO3 to promote amidine formation.7a,8 While pro-
ductive for substrates not bearing C3 amidine substitution
and/or N-alkyl amides, in the present cases, impurities formed
in addition to the desired amidines. Resultantly, purification
Scheme 4 Mechanistic considerations for a Ugi–Mumm–Staudinger-
aza-Wittig- and rearrangement of functionalized quinazolinones leading
to N-alkylamide/C3 functionalized arylamidines and avoiding Passerini
by-products.
Scheme 5 Optimized Ugi–Mumm imide formation. Conditions: (a) 9a,
R2CHO, 6–12 min, then 2-azidobenzoic acid in 3 : 1 CH2Cl2/CH3OH,
R1NC, (2 : 4 : 1 : 4), 4 Å MS, CH2Cl2, rt, 12 h. Yields are based on isolated
and purified products.
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was more complicated and yields were diminished. To address purification and yields of the reactions following the aza-
this, we explored other deprotection/base catalyzed conditions. Wittig reaction. As such, polymer-bound triphenylphosphine
Ultimately, treating 12a with 4 M HCl in dioxane for 12 h, fol- was used in the Staudinger/aza-Wittig reaction to simplify end-
lowed by microwave irradiation in Et3N/CH3OH yielded stage, triphenylphosphine oxide removal.16 With this change,
amidine 13a in 66% yield (45% overall), as compared to 53% the undesired by-product was filtered off after the reaction,
(32% overall). With optimized conditions in hand, we sampled greatly facilitating work-up and clean isolation of quinazoli-
a variety of Ugi–Mumm coupling partners to assess efficiency none. As such, a telescoped version of the sequence using
of the stepwise protocol (Table 1). Five aldehydes, ranging in 2-azidobenzoic acid, isobutyraldehyde, cyclohexylisocyanide
size from formaldehyde to benzaldehyde, were successfully and 9a was attempted, affording amidine 13a in an improved
transformed into C3-modified amidines in acceptable yield. 61% overall yield (versus 45% stepwise) and in 64% yield when
This effort revealed that (a) benzaldehyde could be efficiently executed at 1.0 mmol scale. Amidines 13a–k, first prepared by
incorporated in 12 h instead of 3 days, (b) direct use of formal- our stepwise approach at the start of this project, were then
dehyde was feasible and (c) that C3-amidine carbon substi- generated by the streamlined protocol, revealing an 11–40%
tution was reasonably accommodated despite the increased improvement in yield (Scheme 6). Encouraged by these results,
steric demand introduced at this position.
a more extensive survey of the telescoped protocol was exam-
We anticipated that yields may be enhanced if the six-trans- ined. With the exception of 2-azido-6-fluorobenzoic acid and
formation sequence could be executed without purification of 2-azido-6-methylbenzoic acid, substituted azido benzoic
intermediates.15 In our estimation, this approach had a good acids17 were generally well-tolerated throughout the sequence
chance of success given that the Mossetti team had demon- (Scheme 6, 13l–n). Use of these 6-substituted benzoic acids
strated that their version of the Ugi–Mumm–Staudinger/aza- exclusively led to Passerini α-acyloxy carboxamide formation.
Wittig sequence could be done without isolation of the imide Presumably, 6-substitution may present significant steric
resulting from the Ugi–Mumm rearrangement.10 Further, we repulsion in the Mumm-rearrangement, thus favoring
had reported previously a differentiated telescoped method by Passerini by-product formation. Compared to most substituted
which simplified quinazolinones were converted to benzami- acids, 2-azido 4-fluorobenzoic acid led to lower yield of
dines.8 Nonetheless, it was uncertain if the new process was amidine 13l (21%, or 68% average yield over 4 steps); however,
amenable to being streamlined in this way, as excess reagents this starting material was limited by poor solubility.
in the Ugi reaction and the new process as a whole introduced
by-products that would be carried throughout and may inter- part to evaluate the tolerance of regional steric bulk. The
fere with the efficiency of progressive reactions. absence of (Z)-amidines was attributed to the planar
As we assessed this option, it was determined that the pres- N-amidine substituent that would otherwise clash with the
ence of triphenylphosphine oxide by-product complicated phenyl ring core if
(Z)-configuration was adopted.7a,8
Introduction of C3 amidine substituents was motivated in
a
Table 1 Feasibility assessment and yields for optimized stepwise sequence leading to novel quinazolinones and benzamidinesa,b
Quinazolinone
12a–k
Imide 10a–k
Benzamidine 13a–k
Isocyanide
R1
Aldehyde
R2
Acid
R3
Overall yield
13a–k (%)
Entry
Cmpd
Yield (%)
Cmpd
Yield (%)
Cmpd
Yield (%)
1
2
3
4
5
6
7
8
Cyclohexyl
Cyclohexyl
Cyclohexyl
4-CH3O-phenyl
4-CH3O-phenyl
Cyclohexyl
Cyclohexyl
Isopropyl
Isopropyl
Isobutyl
H
Isopropyl
Isobutyl
Cyclopropyl
Phenyl
Isopropyl
Isopropyl
Isopropyl
Isopropyl
H
H
H
H
H
H
H
H
10a
10b
10c
10d
10e
10f
10g
10h
10i
89
98
45
85
78
89
97
88
78
ND
67
12a
12b
12c
12d
12e
12f
12g
12h
12i
76
60
89
88
88
70
82
71
69
84
70
13a
13b
13c
13d
13e
13f
13g
13h
13i
66
34
58
23c
39c
65
68
52
64
40
61
45
20
23
17
27
40
54
32
34
34
29
9
10
11
Cyclohexyl
Cyclohexyl
Cyclohexyl
5-CH3
5-F
4-CH3
10j
10k
12j
12k
13j
13k
a Conditions: (a) 9a, R2CHO, 6–12 min, then 2-azidobenzoic acid in 3 : 1 CH2Cl2/CH3OH, R1NC, (2 : 4 : 1 : 4), 4 Å MS, CH2Cl2, rt, 12 h; (b) PPh3,
toluene, rt, 30 min, then 110 °C, 12 h; (c) 4 N HCl, dioxane, 0 °C–rt, 12 h; (d) Et3N, CH3OH, MWI 100 °C, 30 min. b Isolated yields: avg of n ≥ 2
expts. c 1 h reaction time; ND = not determined, crude material advanced.
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Fig. 2 Molecular drawing of 13t shown with 50% probability ellipsoids.
The conformation of the amidine ring is a distorted envelope the puck-
ering amplitude Q = 0.5488(11) Ang.
stand how C3 substitutions were accommodated, we pursued
crystallization of multiple compounds in the set. Fortunately,
an X-ray crystal structure of amidine 13t, featuring a C3-posi-
tioned phenyl ring, revealed a puckered and twisted amidine
ring (Fig. 2). As a result, the amidine N–C double bond is out
of the plane of the core phenyl ring, thus allowing the
α-amidine substituent to adopt an energetically favorable
arrangement relative to the core. Nonetheless, limitations were
found. Benzofuran- and benzothiophene-derived azido acids,
in combination with cyclopropanecarboxaldehyde, led to iso-
lation of the free-based aminoalkylquinazolinones that would
not rearrange to the corresponding amidines even under
forcing conditions, likely due to increased steric intolerance.
Despite this, smaller heterocyclic azido acids (ref. 18) com-
petently rearranged to amidines, 13v–x. Amidines 13u and 13x
were generated with unsymmetrical diamines, thereby demon-
strating the potential for extensive library generation and
incorporation of chiral components.
Conclusions
The N′,N,N-trisubstituted amidine framework features promi-
nently in a variety of approved drugs with diverse pharmaco-
logical value. Having discovered a series of structurally unique,
antiviral (E)-amidobenzamidines bearing this motif, we
explored a new strategy by which the scaffold could be bi-direc-
tionally functionalized. Ultimately, a multicomponent, dual
rearrangement strategy was developed that efficiently afforded
a diverse assortment of C3-functionalized (E)-arylamidines
bearing either N-alkyl or N-aryl amides. As part of this effort, a
stepwise approach was first scouted and optimized before
Scheme 6 Amidines resulting from
Staudinger/aza-Wittig-quinazolinone
a
telescoped Ugi–Mumm–
rearrangement sequence.
Conditions: (a) Amine, R2CHO, 6–12 min, then 2-azidobenzoic acid in
3 : 1 CH2Cl2/CH3OH, R1NC, (2 : 4 : 1 : 4), 4 Å MS, CH2Cl2, rt, 12 h; (b)
PS-PPh3, tol, rt, 30 min, then 110 °C, 12 h; (c) 4 N HCl, dioxane, 0 °C–rt,
12 h; (d) Et3N, CH3OH, MWI 100 °C, 30 min. Yields: avg of n ≥ 2 expts.
Parenthetical yields: stepwise protocol. PMP = p-methoxyphenyl, Cy =
cyclohexyl.
Introduction of C3 substituents would force the amidine ring refining this process such that only a single, final purification
to potentially adopt a more extreme puckered and/or twist to was necessary. By implementing the Ugi–Mumm rearrange-
accommodate the increased steric bulk. To further test the tol- ment, a broad array of aldehydes, including formaldehyde, was
erance of substitution in this region, two analogs were also used to deliver novel quinazolinones that transformed into
prepared that featured a methyl group (13m) or a fluorine both α-substituted and unsubstituted (E)-arylamidines in mod-
atom (13n) positioned off of the core phenyl ring which would erate to excellent yield over the 4-step, 6-transformation
be oriented towards the amidine C3-substituted isopropyl sequence. Further, we demonstrated that the α-amidine posi-
group. Surprisingly, 3-substituted azido acids, which were tion was quite permissive of bulky substituents, a feature visu-
expected to yield poorly due to increased regional congestion alized with the aid of an X-ray structure of a C3-phenyl deriva-
with C3-substituted isopropyl group, still generated amidines tive. Moreover, heterocycles were successfully incorporated
13m and 13n in 35% and 42% yield, respectively. To under- into the amidine scaffold, enriching our understanding of bio-
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logical targets with which these compounds interact. The com- solution of the crude reaction mixture in dry toluene (2.0 mL)
pounds are currently being screened across a spectrum of bio- was added dropwise and the reaction mixture was stirred at rt
logical assays to evaluate known and orthogonal activity. for 1 h. After 1 h at rt, the reaction mixture was heated to
Results from those studies will detailed separately.
110 °C and stirred for 12 h at reflux after which the reaction
was complete as judged by complete consumption of the inter-
mediate by TLC (30% EtOAc/hexanes). The crude reaction
mixture was filtered through a pad of Celite, rinsed with
CH2Cl2 (10 mL × 5), and the filtrate was concentrated in vacuo.
To a flame-dried, 10 mL round bottom flask under nitrogen
was dissolved the crude reaction mixture in dry CH2Cl2
(3.0 mL, 0.1 M) and the solution cooled to 0 °C in an ice-bath
while stirring for 20 min. HCl in dioxane (4.0 M, 0.8 mL, 10.0
equiv.) was added dropwise. The reaction mixture was allowed
to slowly warm to rt. The reaction mixture was stirred at rt for
12 h after which the reaction was complete as judged by com-
plete consumption of intermediate on TLC (30% EtOAc/
hexanes). The reaction mixture was dried in vacuo.
Triethylamine (0.4 mL, 3.1 mmol, 10.0 equiv.) was added to a
solution of the crude reaction mixture in MeOH (3.1 mL, 0.1
M) in a 10 mL microwave vial and the reaction mixture was
heated in a microwave reactor at 100 °C for 1 h. The reaction
mixture was allowed to cool to rt and the solvent was removed
in vacuo. The crude mixture was dissolved in CH2Cl2 (10 mL)
and washed with water (10 mL), then saturated brine solution
(10 mL), the organic layer was dried over MgSO4, filtered and
concentrated in vacuo. The crude residue was purified by
normal-phase chromatography (0–60% EtOAc/Hex) to yield the
Experimental
General information
Compounds not described in ESI† were purchased from com-
mercial vendors. All synthesized compounds were character-
ized with the following instrumentation: Varian Unity-Inova
400 MHz NMR spectrometer (operating at 400 and 101 MHz,
respectively) or a Varian Unity-Inova 500 MHz NMR spectro-
meter (operating at 500 and 126 MHz, respectively) in CDCl3
1
(CDCl3: H = δ 7.26 ppm, 13C = δ 77.16 ppm). Microwave irra-
diated (MWI) reactions were carried out using an Anton Paar
Monowave 300 Microwave Synthesis Reactor. Flash chromato-
graphy separations were carried out using a Teledyne Isco
CombiFlash Rf 200 purification system with silica gel columns
(normal-phase). High resolution mass spectra (HRMS) were
performed by Analytical Instrument Center at the School of
Pharmacy on an Electron Spray Injection (ESI) mass spectro-
meter. Melting points were measured on OptiMelt MPA100
Automated Melting Point System.
General procedure for the telescoped synthesis of
C3-functionalized (E)-arylamidines
1
benzamidine, 13a (69 mg, 61%) as a pale-yellow oil. H NMR
(E)-N-Cyclohexyl-2-((3-isopropyl-1,4-dimethylpiperazin-2-ylidene) (500 MHz, CDCl3) δ 8.93 (d, J = 8.0 Hz, 1H), 8.17 (dd, J = 7.9,
amino)benzamide 13a. An oven-dried, 10 mL round bottom 1.7 Hz, 1H), 7.28–7.24 (m, 1H), 7.05–7.01 (m, 1H), 6.59 (dd, J =
flask under nitrogen was charged with activated, powdered, 7.8, 1.2 Hz, 1H), 3.95 (tdt, J = 11.5, 7.9, 3.9 Hz, 1H), 3.47–3.39
4 Å molecular sieves (50 mg). The flask was placed under (m, 2H), 3.36 (ddd, J = 12.3, 7.1, 4.6 Hz, 1H), 3.23 (ddd, J =
vacuum and flame-dried, then backfilled with nitrogen. N,N′- 11.9, 7.0, 4.4 Hz, 1H), 3.11 (s, 3H), 2.63 (ddd, J = 12.0, 6.6, 4.7
Dimethylethylenediamine (115 mg, 0.61 mmol, 2.0 equiv.) was Hz, 1H), 2.49 (s, 3H), 2.07–1.97 (m, 2H), 1.76–1.69 (m, 3H),
dissolved in dry CH2Cl2 (0.5 mL, 1.3 M) and added to the reac- 1.68–1.61 (m, 1H), 1.38 (ddt, J = 17.9, 12.8, 6.4 Hz, 2H),
tion vessel. Isobutyraldehyde (112 µL, 1.2 mmol, 4.0 equiv.) 1.21–1.10 (m, 3H), 0.79 (d, J = 6.7 Hz, 3H), 0.63 (d, J = 6.9 Hz,
was dissolved in dry CH2Cl2 (0.46 mL, 2.6 M) in a 1-dram glass 3H); 13C NMR (126 MHz, CDCl3) δ 165.9, 160.5, 148.5, 131.2,
vial and added dropwise over 1 min via syringe to the reaction 131.1, 125.8, 122.4, 122.0, 63.9, 48.7, 48.4, 47.8, 45.0, 37.4,
vessel while stirring at rt. Upon completion of the addition, 33.8, 33.7, 32.4, 25.9, 25.3, 20.1, 19.2; HRMS (ESI): Calculated
2-azidobenzoic acid (50 mg, 0.31 mmol, 1.0 equiv.) was dis- for C22H34N4O (M+ + H): 371.28054; Found: 371.28091.
solved in a 3 : 1 mixture of dry CH2Cl2/MeOH (0.4 mL, 0.8 M),
(E)-N-Cyclohexyl-2-((3-isobutyl-1,4-dimethylpiperazin-2-ylidene)
taken up into a syringe and the needle was placed into the amino)benzamide 13b. Obtained using isovaleraldehyde follow-
septum of the reaction vessel. Cyclohexyl isocyanide (153 µL, ing general procedure. Purified by normal-phase chromato-
1.2 mmol, 4.0 equiv.) was dissolved in dry CH2Cl2 (0.3 mL, 3.6 graphy (0–10% MeOH/CH2Cl2) to yield the benzamidine, 13b
M) in a 1-dram glass vial, taken up into a syringe and the (71 mg, 60%) as a pale-yellow gum. 1H NMR (400 MHz, CDCl3)
needle was placed into the septum of the reaction vessel. δ 8.56 (d, J = 8.1 Hz, 1H), 8.18 (dd, J = 7.9, 1.6 Hz, 1H),
2-Azidobenzoic acid was added dropwise to the reaction vessel 7.30–7.25 (m, 2H), 7.05 (td, J = 7.6, 1.1 Hz, 1H), 6.61 (dd, J =
while stirring over 1 min followed immediately by cyclohexyl 7.8, 1.1 Hz, 1H), 3.97 (dddd, J = 14.6, 10.6, 7.9, 3.9 Hz, 1H),
isocyanide. The reaction mixture was stirred at rt for 12 h after 3.61 (td, J = 11.8, 5.3 Hz, 1H), 3.49 (dd, J = 10.6, 3.7 Hz, 1H),
which the reaction was complete as judged by complete con- 3.41 (ddd, J = 14.0, 11.7, 5.2 Hz, 1H), 3.12 (ddd, J = 12.1, 5.3,
sumption of carboxylic acid 1 on TLC (10% MeOH/CH2Cl2). 1.7 Hz, 1H), 3.08 (s, 3H), 2.73–2.66 (m, 1H), 2.50 (s, 3H),
The crude reaction mixture was filtered through a 0.45 μM 2.02–1.94 (m, 2H), 1.71 (dq, J = 11.7, 4.0 Hz, 2H), 1.63 (dt, J =
syringe filter and the filtrate was concentrated in vacuo. To a 12.6, 3.8 Hz, 1H), 1.54 (ddd, J = 14.1, 10.6, 3.9 Hz, 1H),
flame-dried, 10 mL round bottom flask under nitrogen was 1.49–1.34 (m, 3H), 1.16 (dddd, J = 26.0, 15.5, 12.6, 5.6 Hz, 3H),
added triphenylphosphine on resin (438 mg, 0.61 mmol, 0.91 (ddd, J = 13.6, 9.7, 3.6 Hz, 1H), 0.66 (d, J = 6.6 Hz, 3H),
1.4 meq g−1, 2.0 equiv.) followed by dry toluene (1.0 mL). A 0.27 (d, J = 6.5 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 165.7,
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161.8, 148.6, 131.4, 131.3, 125.6, 122.9, 122.4, 56.8, 48.2, 44.9,
(E)-N-Cyclohexyl-2-((1,4-dimethyl-3-phenylpiperazin-2-ylidene)
43.8, 42.2, 40.1, 37.3, 33.8, 33.6, 25.9, 25.1, 25.1, 24.4, 23.4, amino)benzamide 13g. Obtained using benzaldehyde following
20.3. HRMS (ESI): Calculated for C23H36N4O (M+ + H): general procedure. Purified by normal-phase chromatography
385.29619; Found: 385.29719.
(0–10% MeOH/CH2Cl2) to yield benzamidine, 13g (85 mg,
1
(E)-2-((3-Isopropyl-1,4-dimethylpiperazin-2-ylidene)amino)- 68%) as a pale-yellow gum. H NMR (500 MHz, CDCl3) δ 8.36
N-(4-methoxyphenyl)benzamide 13d. Obtained using 4-meth- (d, J = 7.7 Hz, 1H), 7.88 (dd, J = 7.9, 1.5 Hz, 1H), 7.18 (t, J = 7.4
oxyphenyl isocyanide following general procedure. Purified by Hz, 1H), 7.11 (t, J = 7.5 Hz, 2H), 7.08–7.03 (m, 1H), 6.93–6.89
normal-phase chromatography (0–10% MeOH/CH2Cl2) to yield (m, 1H), 6.85 (d, J = 7.2 Hz, 2H), 6.37 (d, J = 7.7 Hz, 1H), 4.41
the benzamidine, 13d (120 mg, 40%) as a pale-yellow waxy (s, 1H), 3.86–3.83 (m, 1H), 3.57–3.51 (m, 2H), 3.24 (s, 3H),
1
solid. H NMR (400 MHz, CDCl3) δ 10.97 (s, 1H), 8.24 (dd, J = 3.03–2.95 (m, 1H), 2.62–2.58 (m, 1H), 2.16 (s, 3H), 2.05–1.94
8.0, 1.7 Hz, 1H), 7.53 (d, J = 8.5 Hz, 2H), 7.36–7.29 (m, 1H), (m, 2H), 1.80–1.69 (m, 2H), 1.68–1.584 (m, 1H), 1.46–1.34 (m,
7.09 (t, J = 7.6 Hz, 1H), 6.88 (d, J = 8.7 Hz, 2H), 6.67 (d, J = 7.9 2H), 1.23–1.11 (m, 3H). 13C NMR (126 MHz, CDCl3) δ 165.3,
Hz, 1H), 3.79 (d, J = 1.3 Hz, 3H), 3.46–3.35 (m, 3H), 3.27–3.21 165.2, 157.6, 148.1, 135.7, 130.8, 130.6, 129.3, 128.0, 127.9,
(m, 1H), 3.19 (s, 3H), 2.63 (dt, J = 11.9, 5.7 Hz, 1H), 2.52 (s, 125.5, 123.2, 122.1, 65.3, 49.1, 48.3, 46.6, 42.1, 37.4, 33.7,
3H), 1.75 (h, J = 6.8 Hz, 1H), 0.77 (d, J = 6.7 Hz, 3H), 0.65 (d, J = 33.7, 25.9, 25.2, 25.2. HRMS (ESI): Calculated for C25H32N4O
6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 165.0, 161.0, 156.1, (M+ + H): 405.26489; Found: 405.26680.
148.6, 132.0, 131.7, 131.3, 125.9, 122.6, 122.3, 122.0, 114.3,
(E)-N-Isopropyl-2-((3-isopropyl-1,4-dimethylpiperazin-2-ylidene)
64.0, 55.6, 48.3, 47.7, 44.9, 37.6, 32.5, 20.0, 19.3. HRMS (ESI): amino)benzamide 13h. Obtained using isopropyl isocyanide
Calculated for C23H30N4O2 (M+ + H): 395.24415; Found: following general procedure. Purified by normal-phase chrom-
395.24443.
atography (0–5% MeOH/CH2Cl2) to yield the benzamidine, 13h
1
(E)-2-((3-Isobutyl-1,4-dimethylpiperazin-2-ylidene)amino)-N- (51 mg, 50%) as a pale-yellow oil. H NMR (500 MHz, CDCl3)
(4-methoxyphenyl)benzamide 13e. Obtained using isovaleral- δ 8.94 (d, J = 7.6 Hz, 1H), 8.18 (dd, J = 7.9, 1.6 Hz, 1H), 7.28
dehyde and 4-methoxyphenyl isocyanide following general pro- (dd, J = 7.5, 1.7 Hz, 1H), 7.06–7.02 (m, 1H), 6.60 (dd, J = 7.9,
cedure. Purified by normal-phase chromatography (0–20% 1.2 Hz, 1H), 4.31–4.22 (m, 1H), 3.48–3.41 (m, 2H), 3.36 (ddd,
EtOAc/CH2Cl2) to yield the benzamidine, 13e (56 mg, 45%) as J = 12.2, 7.0, 4.6 Hz, 1H), 3.24 (ddd, J = 11.8, 7.0, 4.4 Hz, 1H),
a light-brown solid. M.p.: 109–111 °C. 1H NMR (400 MHz, 3.13 (s, 3H), 2.64 (ddd, J = 12.0, 6.7, 4.7 Hz, 1H), 2.50 (s, 3H),
CDCl3) δ 10.68 (s, 1H), 8.25 (dd, J = 8.0, 1.7 Hz, 1H), 7.62–7.50 1.72 (h, J = 6.7 Hz, 1H), 1.22 (d, J = 6.5 Hz, 6H), 0.80 (d, J =
(m, 2H), 7.34 (td, J = 7.6, 1.7 Hz, 1H), 7.19–7.06 (m, 1H), 6.7 Hz, 3H), 0.64 (d, J = 6.8 Hz, 3H). 13C NMR (126 MHz,
6.94–6.85 (m, 2H), 6.76–6.64 (m, 1H), 3.80 (s, 3H), 3.61 (ddd, CDCl3) δ 166.0, 160.5, 148.6, 131.3, 131.2, 125.8, 122.4, 122.1,
J = 12.4, 8.8, 4.4 Hz, 2H), 3.38 (ddd, J = 14.0, 11.6, 5.3 Hz, 1H), 64.0, 48.8, 47.9, 45.1, 41.3, 37.3, 32.5, 23.3, 23.2, 20.2, 19.3.
3.18 (s, 3H), 3.11 (ddd, J = 12.1, 5.4, 1.7 Hz, 1H), 2.69 (dd, J = HRMS (ESI): Calculated for C19H30N4O (M+ + H): 331.24924;
14.3, 5.1 Hz, 1H), 2.50 (s, 3H), 1.56 (ddd, J = 14.0, 10.6, 3.7 Hz, Found: 331.24986.
1H), 1.47 (dqd, J = 10.4, 6.6, 3.9 Hz, 0H), 0.92 (ddd, J = 13.5,
(E)-N-Cyclohexyl-2-((3-isopropyl-1,4-dimethylpiperazin-2-ylidene)
9.7, 3.5 Hz, 1H), 0.65 (d, J = 6.7 Hz, 3H), 0.28 (d, J = 6.5 Hz, amino)-5-methylbenzamide 13i. Obtained using 2-azido-5-
3H). 13C NMR (101 MHz, CDCl3) δ 164.6, 162.2, 155.9, 148.5, methylbenzoic acid following general procedure. Purified by
132.1, 131.7, 131.3, 125.6, 123.0, 122.5, 121.6, 114.2, 77.4, 77.0, normal-phase chromatography (0–5% MeOH/CH2Cl2) to yield
76.7, 56.8, 55.5, 44.7, 43.4, 42.1, 39.9, 37.3, 24.4, 23.3, 20.2. the benzamidine, 13i (53 mg, 45%) as a pale-yellow oil. 1H
HRMS (ESI): Calculated for C24H32N4O2 (M+ + H): 409.25980; NMR (400 MHz, CDCl3) δ 8.90 (d, J = 8.1 Hz, 1H), 7.96 (d, J =
Found: 409.25931.
2.2 Hz, 1H), 7.06 (dd, J = 8.0, 2.2 Hz, 1H), 6.49 (d, J = 8.0 Hz,
(E)-N-Cyclohexyl-2-((3-cyclopropyl-1,4-dimethylpiperazin-2- 1H), 3.93 (tdt, J = 11.4, 7.8, 3.9 Hz, 1H), 3.48–3.36 (m, 2H), 3.34
ylidene)amino)benzamide 13f. Obtained using cyclopropane- (ddd, J = 12.0, 7.0, 4.6 Hz, 1H), 3.22 (ddd, J = 11.8, 7.0, 4.5 Hz,
carboxaldehyde following general procedure. Purified by 1H), 3.09 (s, 3H), 2.62 (ddd, J = 11.9, 6.6, 4.7 Hz, 1H), 2.48
normal-phase chromatography (0–5% MeOH/CH2Cl2) to yield (s, 3H), 2.30 (s, 3H), 2.07–1.94 (m, 3H), 1.73 (ddt, J = 11.9, 8.0,
amidine 13f (80 mg, 70%) as a pale-yellow gum. 1H NMR 4.5 Hz, 2H), 1.71–1.58 (m, 1H), 1.38 (tdt, J = 16.5, 12.1, 3.8 Hz,
(400 MHz, CDCl3) δ 8.62 (d, J = 8.1 Hz, 1H), 8.18 (dt, J = 7.9, 1.5 2H), 1.13 (qdt, J = 10.6, 6.7, 3.2 Hz, 3H), 0.79 (d, J = 6.7 Hz,
Hz, 1H), 7.28–7.21 (m, 1H), 7.09–7.01 (m, 1H), 6.56 (d, J = 7.8 3H), 0.63 (d, J = 6.9 Hz, 3H). 13C NMR (101 MHz, CDCl3)
Hz, 1H), 3.96 (dtt, J = 11.2, 7.8, 4.1 Hz, 1H), 3.58–3.44 (m, 2H), δ 166.1, 160.6, 146.0, 131.9, 131.5, 125.5, 122.3, 64.0, 48.7,
3.30 (dd, J = 10.3, 4.2 Hz, 1H), 3.09 (s, 3H), 2.92 (d, J = 8.6 Hz, 48.5, 47.9, 45.0, 37.4, 33.8, 33.8, 32.5, 25.9, 25.3, 20.8, 20.1,
1H), 2.76 (dd, J = 11.8, 4.6 Hz, 1H), 2.46 (s, 3H), 1.98 (d, J = 19.3. HRMS (ESI): Calculated for C23H36N4O (M+ + H):
12.9 Hz, 2H), 1.78–1.62 (m, 4H), 1.41 (qd, J = 12.5, 6.0 Hz, 3H), 385.29619; Found: 385.29605.
1.23–1.06 (m, 3H), 0.90 (ddt, J = 13.8, 8.8, 4.3 Hz, 1H), 0.40 (td,
(E)-N-Cyclohexyl-5-fluoro-2-((3-isopropyl-1,4-dimethylpiperazin-
J = 8.7, 4.5 Hz, 1H), 0.28 (tt, J = 8.6, 5.4 Hz, 1H). 13C NMR 2-ylidene)amino)benzamide 13j. Obtained using 2-azido-5-
(101 MHz, CDCl3) δ 165.8, 160.4, 148.9, 131.3, 131.1, 126.4, fluorobenzoic acid following general procedure. Purified by
122.6, 122.3, 62.1, 48.3, 47.4, 45.5, 42.3, 37.3, 33.8, 33.7, 25.9, normal-phase chromatography (0–5% MeOH/CH2Cl2) to yield
25.2, 25.2, 11.6, 4.1, 3.7, 1.2. HRMS (ESI): Calculated for the benzamidine, 13j (67 mg, 56%) as a pale-yellow gum.
C22H32N4O (M+ + H): 369.26489; Found: 369.26570.
1H NMR (400 MHz, CDCl3) δ 8.99 (d, J = 7.4 Hz, 1H), 7.90 (dd,
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J = 10.1, 2.9 Hz, 1H), 6.99 (td, J = 8.4, 3.1 Hz, 1H), 6.56 (dd, J = 11.4, 9.6, 3.6 Hz, 1H), 2.38 (s, 3H), 2.11 (d, J = 3.8 Hz, 4H),
8.6, 4.9 Hz, 1H), 4.03–3.87 (m, 1H), 3.48–3.46 (m, 1H), 2.07–1.94 (m, 1H), 1.72 (tdd, J = 12.8, 8.1, 5.1 Hz, 1H), 1.63
3.41–3.31 (m, 2H), 3.28–3.22 (m, 1H), 3.13 (s, 3H), 2.70–2.60 (qd, J = 7.0, 3.0 Hz, 1H), 1.49–1.30 (m, 2H), 1.14 (tddd, J = 11.6,
(m, 1H), 2.50 (s, 3H), 2.10–1.95 (m, 2H), 1.80–1.59 (m, 4H), 8.7, 6.3, 3.8 Hz, 3H), 0.83 (d, J = 6.9 Hz, 3H), 0.67 (d, J = 6.9 Hz,
1.51–1.35 (m, 2H), 1.24–1.18 (m, 3H), 0.81 (d, J = 6.7 Hz, 3H), 4H). 13C NMR (101 MHz, CDCl3) δ 166.1, 160.5, 147.5, 133.2,
0.65 (d, J = 6.8 Hz, 3H). 19F NMR (376 MHz, CDCl3) δ −122.09. 129.1, 127.8, 126.0, 121.6, 65.8, 51.5, 49.0, 48.4, 47.4, 37.2,
13C NMR (101 MHz, CDCl3) δ 164.6, 164.6, 160.9, 159.6, 157.2, 33.8, 33.7, 32.8, 25.8, 25.3, 25.2, 21.2, 19.2, 17.6. HRMS (ESI):
149.9, 127.1, 127.1, 123.5, 123.4, 118.1, 117.8, 117.3, 117.1, Calculated for C22H33FN4O (M+ + H): 389.27112; Found:
63.9, 48.7, 48.6, 47.8, 45.1, 37.3, 33.7, 33.6, 32.5, 25.8, 25.2, 389.27196.
20.0, 19.1. HRMS (ESI): Calculated for C22H33FN4O (M+ + H):
389.27112; Found: 389.27059.
(E)-N-Cyclohexyl-3-fluoro-2-((3-isopropyl-1,4-dimethylpiperazin-
2-ylidene)amino)benzamide 13n. Obtained using 2-azido-3-
(E)-N-Cyclohexyl-2-((3-isopropyl-1,4-dimethylpiperazin-2-ylidene) fluorobenzoic acid following general procedure. Purified by
amino)-4-methylbenzamide 13k. Obtained using 2-azido-4- normal-phase chromatography (0–15% EtOAc/CH2Cl2) to yield
1
methylbenzoic acid following general procedure. Purified by the benzamidine, 13n (65 mg, 42%) as a pale-yellow gum. H
normal-phase chromatography (0–5% MeOH/CH2Cl2) to yield NMR (400 MHz, CDCl3) δ 9.00 (s, 1H), 7.99 (d, J = 7.9 Hz, 1H),
the benzamidine, 13k (53 mg, 45%) as a pale-yellow gum. 7.10 (ddd, J = 10.1, 8.0, 1.6 Hz, 1H), 6.94 (td, J = 8.0, 5.1 Hz,
1H NMR (400 MHz, CDCl3) δ 8.84 (d, J = 8.0 Hz, 1H), 8.06 (d, 1H), 3.94 (tdt, J = 11.4, 7.8, 3.8 Hz, 1H), 3.51 (ddd, J = 12.1, 8.0,
J = 8.0 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 6.39 (s, 1H), 3.94 (dtd, 3.8 Hz, 1H), 3.33 (ddd, J = 12.6, 5.9, 4.1 Hz, 1H), 3.19 (s, 3H),
J = 11.3, 7.6, 4.1 Hz, 1H), 3.49–3.30 (m, 3H), 3.23 (ddd, J = 11.8, 3.12 (t, J = 3.2 Hz, 2H), 2.66 (ddd, J = 12.1, 8.0, 4.1 Hz, 1H),
6.9, 4.5 Hz, 1H), 3.10 (s, 3H), 2.63 (ddd, J = 12.0, 6.7, 4.7 Hz, 2.45 (s, 3H), 2.07–1.97 (m, 2H), 1.77–1.61 (m, 4H), 1.46–1.34
1H), 2.50 (s, 3H), 2.29 (s, 3H), 2.01 (tt, J = 8.4, 3.8 Hz, 2H), (m, 2H), 1.16 (dddd, J = 12.4, 8.6, 6.8, 2.7 Hz, 3H), 0.82 (d, J =
1.78–1.59 (m, 4H), 1.46–1.31 (m, 2H), 1.21–1.06 (m, 3H), 0.80 6.8 Hz, 3H), 0.70 (d, J = 6.9 Hz, 3H). 19F NMR (376 MHz,
(d, J = 6.7 Hz, 3H), 0.64 (d, J = 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ −127.01. 13C NMR (101 MHz, CDCl3) δ 165.1, 162.9,
CDCl3) δ 166.0, 160.5, 148.4, 141.3, 131.3, 123.3, 123.1, 123.0, 153.8, 151.4, 137.2, 137.1, 127.9, 126.7, 121.4, 121.4, 118.0,
64.1, 48.8, 48.4, 47.9, 45.01, 37.4, 33.9, 33.8, 32.6, 25.9, 117.8, 66.0, 49.9, 48.6, 48.3, 46.0, 37.5, 33.8, 33.7, 33.6, 29.8,
25.3, 21.4, 20.1, 19.4. HRMS (ESI): Calculated for C23H36N4O 25.9, 25.3, 20.6, 18.7. HRMS (ESI): Calculated for C22H33FN4O
(M+ + H): 385.29619; Found: 385.29585.
(M+ + H): 389.27112; Found: 389.27196.
(E)-N-Cyclohexyl-4-fluoro-2-((3-isopropyl-1,4-dimethylpiperazin-
(E)-5-Cyano-2-((3-cyclopropyl-1,4-dimethylpiperazin-2-ylidene)
2-ylidene)amino)benzamide 13l. Obtained using 2-azido-4- amino)-N-isopropylbenzamide 13o. Obtained using cyclopropa-
fluorobenzoic acid following general procedure. Purified by necarboxaldehyde, 2-azido-5-cyanobenzoic acid and isopropyl
normal-phase chromatography (0–40% EtOAc/hexane) to yield isocyanide following general procedure. Purified by normal-
the benzamidine, 13l (25 mg, 21%) as a pale-yellow gum. phase chromatography (0–15% MeOH/EtOAc) to yield the ben-
1H NMR (400 MHz, CDCl3) δ 8.81 (d, J = 8.0 Hz, 1H), 8.19 (dd, zamidine, 13o (48 mg, 44%) as a light-brown solid. M.p.:
1
J = 8.8, 7.1 Hz, 1H), 6.73 (td, J = 8.4, 2.5 Hz, 1H), 6.30 (dd, J = 147–148 °C. H NMR (400 MHz, CDCl3) δ 8.61 (d, J = 7.7 Hz,
10.3, 2.5 Hz, 1H), 3.94 (tdt, J = 11.5, 7.9, 3.9 Hz, 1H), 3.52–3.42 1H), 8.52 (d, J = 2.1 Hz, 1H), 7.50 (dd, J = 8.2, 2.1 Hz, 1H), 6.62
(m, 2H), 3.37 (ddd, J = 12.3, 6.8, 4.7 Hz, 1H), 3.24 (ddd, J = (d, J = 8.2 Hz, 1H), 4.32–4.18 (m, 1H), 3.58 (td, J = 11.0, 5.5 Hz,
11.7, 6.8, 4.5 Hz, 1H), 3.13 (s, 3H), 2.65 (ddd, J = 12.0, 6.8, 1H), 3.45 (ddd, J = 12.8, 10.4, 5.1 Hz, 1H), 3.35 (ddd, J = 11.7,
4.7 Hz, 1H), 2.52 (s, 3H), 2.02 (dt, J = 11.8, 4.1 Hz, 2H), 1.70 5.1, 2.4 Hz, 1H), 3.13 (s, 3H), 2.93 (d, J = 8.4 Hz, 1H), 2.79
(ddt, J = 29.4, 14.9, 5.2 Hz, 5H), 1.40 (qd, J = 12.5, 3.3 Hz, 2H), (ddd, J = 13.2, 5.7, 2.3 Hz, 1H), 2.46 (s, 3H), 1.23 (d, J = 6.6 Hz,
1.22–1.06 (m, 3H), 0.82 (d, J = 6.7 Hz, 3H), 0.68 (d, J = 6.9 Hz, 3H), 1.20 (d, J = 6.5 Hz, 3H), 0.89 (dtd, J = 13.3, 8.3, 5.0 Hz,
3H). 19F NMR (376 MHz, CDCl3) δ −109.97. 13C NMR 1H), 0.51–0.40 (m, 1H), 0.36–0.25 (m, 1H), 0.14 (dq, J = 10.5,
(101 MHz, CDCl3) δ 165.2, 165.0, 162.7, 160.8, 150.5, 150.4, 5.2 Hz, 1H), −0.48 (dq, J = 10.3, 5.2 Hz, 1H). 13C NMR
133.5, 133.4, 122.2, 122.2, 108.9, 108.7, 108.6, 108.4, 63.8, 48.6, (101 MHz, CDCl3) δ 163.8, 160.6, 153.0, 135.7, 134.2, 126.8,
48.4, 47.7, 45.1, 37.3, 33.8, 33.7, 32.5, 29.7, 25.8, 25.2, 20.1, 123.3, 119.2, 105.0, 61.9, 47.2, 45.3, 42.3, 41.4, 37.2, 23.1, 23.0,
19.1. HRMS (ESI): Calculated for C22H33FN4O (M+ + H): 11.5, 3.9, 3.6. HRMS (ESI): Calculated for C20H27N5O (M+ + H):
389.27116; Found: 389.27155.
354.22884; Found: 354.22999.
(E)-N-Cyclohexyl-2-((3-isopropyl-1,4-dimethylpiperazin-2-ylidene)
(E)-2-((3-Isopropyl-1,4-dimethylpiperazin-2-ylidene)amino)-
amino)-3-methylbenzamide 13m. Obtained using 2-azido-3- N-(4-methoxyphenyl)-5-nitrobenzamide 13p. Obtained using
methylbenzoic acid following general procedure. Purified by 2-azido-5-nitrobenzoic acid 4-methoxyphenyl isocyanide fol-
normal phase chromatography (0–30% EtOAc/CH2Cl2) to yield lowing general procedure. Purified by normal-phase chromato-
the benzamidine, 13m (41 mg, 35%) as a pale-yellow oil. 1H graphy (0–3% EtOAc/CH2Cl2) to yield the benzamidine, 13p
NMR (400 MHz, CDCl3) δ 8.66 (d, J = 7.9 Hz, 1H), 8.04 (dd, J = (49 mg, 36%) as yellow solid. M.p.: 167–168 °C. 1H NMR
7.9, 1.6 Hz, 1H), 7.23 (dd, J = 7.4, 1.5 Hz, 1H), 6.97 (t, J = (400 MHz, CDCl3) δ 10.93 (s, 1H), 9.17 (d, J = 2.8 Hz, 1H), 8.16
7.6 Hz, 1H), 3.92 (dtt, J = 11.6, 8.0, 4.0 Hz, 1H), 3.60 (ddd, J = (dd, J = 8.8, 2.9 Hz, 1H), 7.59–7.46 (m, 2H), 6.97–6.84 (m, 2H),
12.6, 9.6, 3.2 Hz, 1H), 3.20 (s, 4H), 3.13 (s, 1H), 3.05 (ddd, J = 6.71 (d, J = 8.8 Hz, 1H), 3.81 (s, 3H), 3.57–3.46 (m, 2H), 3.45 (d,
15.4, 8.6, 3.7 Hz, 1H), 2.94 (d, J = 3.0 Hz, 1H), 2.62 (ddd, J = J = 6.4 Hz, 1H), 3.27 (s, 4H), 2.76–2.65 (m, 1H), 2.55 (s, 3H),
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1.76 (h, J = 6.7 Hz, 1H), 0.80 (d, J = 6.7 Hz, 3H), 0.70 (d, J = 6.8 25.2, 25.1. Calculated for HRMS (ESI): C29H34N4O (M+ + H):
Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 162.5, 162.0, 156.3, 455.28054; Found: 455.28019.
154.3, 142.3, 131.3, 127.8, 126.4, 125.7, 122.6, 121.8, 114.3,
(E)-N-Cyclohexyl-2-((1,4-dimethyl-3-phenylpiperazin-2-ylidene)
64.3, 55.5, 48.0, 47.5, 44.9, 37.8, 32.8, 20.0, 19.1. Calculated for amino)-5-iodobenzamide 13t. Obtained using benzaldehyde
HRMS (ESI): C23H29N5O4 (M+
440.22903.
+
H): 440.22923; Found: and 2-azido-5-iodobenzoic acid following general procedure.
Purified by normal-phase chromatography (0–15% EtOAc/
(E)-N-Isopropyl-2-((3-isopropyl-1,4-dimethylpiperazin-2-ylidene) CH2Cl2) to yield benzamidine 13t (144 mg, 88%) as pale yellow
amino)-5-nitrobenzamide 13q. Obtained using 2-azido-5-nitro- oil. Recrystallized from acetonitrile to form clear colorless
benzoic acid and isopropyl isocyanide following general pro- crystal (see ESI† for crystallographic Experimental section). M.
1
cedure. Purified by normal-phase chromatography (0–7% p.: 85–87 °C. H NMR (400 MHz, CDCl3) δ 8.27 (d, J = 7.9 Hz,
EtOAc/CH2Cl2) to yield the benzamidine, 13q (36 mg, 31%) as 1H), 8.15 (d, J = 2.2 Hz, 1H), 7.32 (dd, J = 8.3, 2.3 Hz, 1H),
a yellow-orange solid. M.p.: 140–141 °C. 1H NMR (400 MHz, 7.24–7.18 (m, 1H), 7.14 (d, J = 7.6 Hz, 2H), 7.13 (d, J = 8.6 Hz,
CDCl3) δ 9.10 (d, J = 2.8 Hz, 1H), 8.93 (d, J = 7.6 Hz, 1H), 8.12 0H), 6.85 (d, J = 6.9 Hz, 1H), 6.12 (d, J = 8.3 Hz, 1H), 4.33 (s,
(dd, J = 8.8, 2.9 Hz, 1H), 6.65 (d, J = 8.8 Hz, 1H), 4.27 (dq, J = 1H), 3.80 (dtd, J = 10.9, 7.3, 3.9 Hz, 1H), 3.64–3.42 (m, 2H),
13.2, 6.5 Hz, 1H), 3.53 (ddd, J = 11.9, 6.9, 4.5 Hz, 1H), 3.46 (dd, 3.22 (s, 3H), 2.98 (ddd, J = 12.7, 7.6, 5.2 Hz, 1H), 2.59 (dt, J =
J = 6.7, 4.9 Hz, 1H), 3.42 (d, J = 6.0 Hz, 1H), 3.25 (ddd, J = 12.6, 12.5, 5.0 Hz, 1H), 2.15 (s, 3H), 2.04–1.88 (m, 2H), 1.80–1.61 (m,
6.6, 4.5 Hz, 1H), 3.19 (s, 3H), 2.71 (ddd, J = 12.1, 6.9, 4.8 Hz, 2H), 1.48–1.32 (m, 2H), 1.15 (dtdd, J = 23.1, 11.8, 7.9, 3.5 Hz,
1H), 2.53 (s, 3H), 1.71 (h, J = 6.7 Hz, 1H), 1.23 (dd, J = 6.6, 1.4 2H). 13C NMR (101 MHz, CDCl3) δ 163.7, 157.7, 147.9, 139.3,
Hz, 6H), 0.83 (d, J = 6.7 Hz, 3H), 0.69 (d, J = 6.8 Hz, 3H). 139.0, 135.4, 129.2, 128.0, 128.0, 127.4, 125.2, 84.9, 65.5, 49.2,
13C NMR (101 MHz, CDCl3) δ 163.7, 161.3, 154.4, 142.0, 127.68, 48.3, 46.8, 42.1, 37.3, 33.5, 33.5, 25.8, 25.1, 25.1. Calculated for
126.0, 125.6, 122.5, 77.4, 77.0, 76.7, 64.2, 48.5, 47.7, 45.1, 41.6, HRMS (ESI): C21H35IN4O (M+
37.4, 32.9, 23.02, 23.0, 20.1, 19.0. Calculated for HRMS (ESI): 531.16069.
+ H): 531.16154; Found:
C19H29N5O3 (M+ + H): 376.23432; Found: 376.23487.
(E)-3-((1-Benzyl-3,4-dicyclopropylpiperazin-2-ylidene)amino)-
(E)-N-Cyclohexyl-2-((1,4-dimethyl-3-(thiazol-5-yl)piperazin-2- N-(2-morpholinoethyl) thiophene-2-carboxamide 13x. Obtained
ylidene)amino)benzamide 13r. Obtained using 5-thiazolecar- using tert-butyl benzyl((2-cyclopropylamino)ethyl) carbamate,
boxaldehyde following general procedure. Purified by normal- cyclopropanecarboxaldehyde,
3-azidothiophene-2-carboxylic
phase chromatography (0.5–3.5% MeOH/CH2Cl2) to yield the acid, and 2-morphalinoethyl isocyanide following general pro-
benzamidine, 13r (76 mg, 60%) as an amber gum. 1H NMR cedure. Purified by normal-phase chromatography (0–3%
(400 MHz, CDCl3) δ 8.70 (s, 1H), 8.05 (d, J = 7.9 Hz, 1H), 7.99 MeOH/CH2Cl2) to yield the thiophene carboxamidine, 13x
(dd, J = 7.9, 1.7 Hz, 1H), 7.30 (s, 1H), 7.15 (td, J = 7.6, 1.7 Hz, (54 mg, 40%) as a pale-yellow gum. (54 mg, 40%). 1H NMR
1H), 7.06–6.99 (m, 1H), 6.38 (d, J = 7.8 Hz, 1H), 4.86 (s, 1H), (400 MHz, CDCl3) δ 7.70 (t, J = 5.9 Hz, 1H), 7.43–7.24 (m, 7H),
3.87 (dtd, J = 10.9, 7.4, 4.0 Hz, 1H), 3.55 (td, J = 11.0, 5.1 Hz, 6.49 (d, J = 5.2 Hz, 1H), 5.29 (d, J = 15.3 Hz, 1H), 4.40 (d, J =
1H), 3.38 (ddd, J = 11.5, 4.6, 2.7 Hz, 1H), 3.18 (s, 3H), 2.97 15.3 Hz, 1H), 3.64–3.47 (m, 6H), 3.32 (ddd, J = 24.2, 11.5,
(ddd, J = 12.6, 10.6, 4.6 Hz, 1H), 2.64 (ddd, J = 12.9, 5.3, 2.4 Hz, 7.1 Hz, 3H), 3.19 (dq, J = 13.0, 6.4 Hz, 1H), 2.97 (q, J = 6.2, 5.1
1H), 2.17 (s, 3H), 2.03–1.94 (m, 2H), 1.79–1.61 (m, 5H), Hz, 1H), 2.39–2.16 (m, 7H), 1.11 (dp, J = 12.5, 4.3, 3.7 Hz, 1H),
1.46–1.32 (m, 1H), 1.16 (dq, J = 14.3, 11.5, 11.0 Hz, 3H). 13C 0.62–0.26 (m, 5H), 0.16 (dq, J = 10.0, 5.1 Hz, 1H), −0.30 (dq, J =
NMR (101 MHz, CDCl3) δ 165.1, 156.3, 153.5, 147.3, 143.9, 10.2, 5.1 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 163.3, 162.3,
131.1, 131.0, 130.9, 125.8, 122.8, 122.6, 56.5, 49.2, 48.4, 45.8, 149.1, 137.5, 129.0, 127.8, 127.5, 127.1, 124.0, 122.9, 66.9, 62.2,
41.6, 37.3, 33.6, 25.8, 25.1. HRMS (ESI): Calculated for 58.0, 53.5, 51.6, 45.2, 43.6, 36.1, 34.2, 12.3, 7.9, 6.7, 3.9, 3.8.
C22H29N5OS (M+ + H): 412.21656; Found: 412.21798.
HRMS (ESI): Calculated for C28H37N5O2 (M+ + H): 508.274073;
(E)-N-Cyclohexyl-3-((1,4-dimethyl-3-phenylpiperazin-2-ylidene) Found: 508.27490.
amino)-2-naphthamide 13s. Obtained using benzaldehyde and
Modified procedure for the telescoped synthesis of C3-
unsubstituted (E)-arylamidines
3-azido-2-naphthanoic acid following general procedure.
Purified by normal-phase chromatography (0–20% EtOAc/
CH2Cl2) to yield the naphthamidine, 13s (69 mg, 50%) as a An oven-dried, 10 mL round bottom flask under nitrogen was
pale-yellow gum. 1H NMR (400 MHz, CDCl3) δ 8.68 (d, J = charged with activated, powdered
molecular sieves
4
Å
8.0 Hz, 1H), 8.47 (s, 1H), 7.79 (dd, J = 8.3, 1.2 Hz, 1H), 7.36 (d, (150 mg). The flask was placed under vacuum and flame-dried,
J = 3.8 Hz, 2H), 7.29 (dd, J = 8.2, 3.9 Hz, 1H), 7.23–7.17 (m, then backfilled with nitrogen, N,N′-Dimethylethylenediamine
1H), 7.09 (t, J = 7.6 Hz, 2H), 6.81 (dd, J = 7.9, 1.4 Hz, 2H), 6.66 (115 mg, 0.61 mmol, 2.0 equiv.) was dissolved in dry CH2Cl2
(s, 1H), 4.51 (s, 1H), 3.90 (tdt, J = 11.3, 7.8, 3.9 Hz, 1H), (0.9 mL, 0.7 M) and added to the reaction vessel. Formalin,
3.63–3.51 (m, 2H), 3.29 (s, 3H), 3.02 (ddd, J = 12.5, 8.7, 5.0 Hz, 37 wt% in H2O (0.1 mL, 1.2 mmol, 4.0 equiv.) was measured
1H), 2.62 (dt, J = 12.5, 4.7 Hz, 1H), 2.14 (s, 3H), 2.10–1.98 (m, with syringe added dropwise over a minute to the reaction
2H), 1.84–1.57 (m, 2H), 1.53–1.35 (m, 2H), 1.28–1.13 (m, 4H). vessel while stirring at rt. Remainder of the procedure follows
13C NMR (101 MHz, CDCl3) δ 164.9, 157.8, 145.04, 135.7, general procedure.
134.7, 131.7, 129.3, 129.3, 128.9, 127.9, 127.8, 127.0, 126.1,
(E)-N-Cyclohexyl-2-((1,4-dimethylpiperazin-2-ylidene)amino)
126.0, 124.0, 119.1, 64.9, 49.2, 48.4, 46.3, 42.0, 37.4, 33.6, 25.8, benzamide 13c. Obtained using 2-azidobenzoic acid and cyclo-
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hexyl isocyanide following modified procedure. Purified by 5.6 Hz, 2H), 3.31 (s, 2H), 3.20 (s, 3H), 2.69 (t, J = 5.6 Hz, 2H),
normal-phase chromatography (0–10% MeOH/CH2Cl2) to yield 2.35 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 157.7, 157.5, 155.7,
the benzamidine, 13c (48 mg, 48%) as an amber gum. 1H 143.8, 137.5, 136.7, 132.0, 121.2, 114.2, 108.9, 55.5, 55.4, 51.9,
NMR (500 MHz, CDCl3) δ 8.42 (d, J = 8.0 Hz, 1H), 8.12 (dd, J = 49.7, 45.5, 36.9. HRMS (ESI): Calculated for C18H22N4O3
7.9, 1.7 Hz, 1H), 7.29–7.25 (m, 1H), 7.09–7.04 (m, 1H), 6.65 (d, (M+ + H): 343.17647; Found: 343.17700.
J = 7.8 Hz, 1H), 3.94 (tdt, J = 11.0, 7.8, 3.8 Hz, 1H), 3.37 (t, J =
5.5 Hz, 2H), 3.12 (s, 3H), 2.95 (s, 2H), 2.61 (t, J = 5.6 Hz, 2H),
2.19 (s, 3H), 1.99 (dq, J = 12.4, 4.0 Hz, 2H), 1.71 (dp, J = 11.9, Conflicts of interest
3.9 Hz, 2H), 1.63 (dt, J = 12.2, 3.9 Hz, 1H), 1.40 (tdd, J = 15.5,
There are no conflicts to declare.
12.0, 3.6 Hz, 2H), 1.15 (td, J = 12.4, 9.1 Hz, 3H). 13C NMR
(126 MHz, CDCl3) δ 166.0, 155.5, 148.3, 131.3, 131.2, 126.0,
123.2, 122.7, 55.1, 52.4, 49.7, 48.4, 45.5, 36.5, 33.6, 25.9, 25.1.
Acknowledgements
HRMS (ESI): Calculated for C19H28N4O (M+ + H): 329.23359;
Found: 329.23434.
JEG acknowledges funding from the National Institutes of
Health (1R01AI118814-01) and institutional support from the
Office of the Vice Chancellor for Research and Graduate
Education and WARF: UW2020 infrastructure grant (JEG, PI).
VAJ acknowledges support from the U.S. Army Advanced Civil
Schooling Program.
(E)-5-Fluoro-N-isopropyl-2-((2-methylhexahydropyrrolo[1,2-a]
pyrazin-4(1H)-ylidene)amino) benzamide 13u. Obtained using
tert-butyl
2-((methylamino)methyl)pyrrolidine-1-carboxylate,
2-azido-5-fluorobenzoic acid, and isopropyl isocyanide follow-
ing modified procedure. Purified by normal-phase chromato-
graphy (0–3% EtOAc/CH2Cl2) to yield the benzamidine, 13u
(51 mg, 50%) as a pale-yellow gum. 1H NMR (400 MHz, CDCl3)
δ 8.62 (d, J = 7.7 Hz, 1H), 7.85 (dd, J = 10.0, 3.1 Hz, 1H),
7.07–6.94 (m, 1H), 6.69 (dd, J = 8.7, 5.0 Hz, 1H), 4.31–4.15 (m,
1H), 3.78–3.51 (m, 3H), 3.30 (d, J = 16.3 Hz, 1H), 3.08 (dd, J =
10.8, 3.8 Hz, 1H), 2.56 (d, J = 16.2 Hz, 1H), 2.24 (s, 3H), 2.09
(dq, J = 11.8, 6.2, 5.7 Hz, 2H), 1.95 (dd, J = 12.7, 8.7 Hz, 2H),
1.48 (qd, J = 11.7, 7.9 Hz, 1H), 1.19 (dd, J = 6.5, 1.6 Hz, 6H).
19F NMR (376 MHz, CDCl3) δ −121.28. 13C NMR (101 MHz,
CDCl3) δ 170.2, 164.7, 164.7, 159.9, 157.5, 154.5, 144.7, 144.7,
144.6, 127.2, 127.1, 124.7, 124.6, 118.3, 118.1, 117.2, 116.9,
57.9, 57.8, 54.2, 45.8, 45.2, 41.3, 30.4, 23.1, 23.0, 22.5. HRMS
(ESI): Calculated for C18H25FN4O (M+ + H): 333.20852; Found:
333.20814.
Notes and references
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(E)-3-((1,4-Dimethylpiperazin-2-ylidene)amino)-N-(4-methoxy-
phenyl)thiophene-2-carboxamide 13v. Obtained using 3-azi-
dothiophene-2-carboxylic acid and 4-methoxyphenyl isocya-
nide following modified procedure. Purified by normal-phase
chromatography (0–3% MeOH/EtOAc) to yield the thiophene
carboxamidine, 13v (32 mg, 29%) as a light-brown solid.
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M.p.: 125–127 °C. H NMR (400 MHz, CDCl3) δ 10.21 (s, 1H),
7.55–7.46 (m, 2H), 7.35 (d, J = 5.2 Hz, 1H), 6.89–6.83 (m, 2H),
6.60 (d, J = 5.2 Hz, 1H), 3.80 (s, 3H), 3.43 (t, J = 5.6 Hz, 2H),
3.22 (s, 4H), 2.67 (t, J = 5.6 Hz, 2H), 2.30 (s, 3H). 13C NMR
(101 MHz, CDCl3) δ 160.9, 157.1, 155.7, 147.9, 132.1, 128.1,
124.5, 123.8, 121.2, 114.2, 55.5, 55.4, 52.0, 49.7, 45.5, 36.7.
HRMS (ESI): Calculated for C18H22N4O2S (M+ + H): 359.15362;
Found: 359.15459.
(E)-3-((1,4-Dimethylpiperazin-2-ylidene)amino)-N-(4-methoxy-
phenyl)furan-2-carboxamide 13w. Obtained using 3-azido-
furan-2-carboxylic acid and 4-methoxyphenyl isocyanide
following modified procedure. Purified by normal-phase
chromatography (5–30% EtOAc/CH2Cl2) to yield furan carbox-
amidine, 13w (21 mg, 20%) as
a light-brown solid.
M.p.: 150–151 °C. 1H NMR (400 MHz, CDCl3) δ 9.82 (s, 1H),
7.51 (d, J = 9.0 Hz, 2H), 7.44 (d, J = 1.9 Hz, 1H), 6.87 (d, J =
9.1 Hz, 2H), 6.17 (d, J = 1.9 Hz, 1H), 3.79 (s, 3H), 3.43 (t, J =
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