Comprehensive and facile entry into substituted amidines via the condensation of N-Pmc-substituted thioamides with amines using mukaiyama reagent as a thiophile

Article abstract of DOI:10.1055/s-0030-1260011

A convenient approach is presented for the preparation of substituted amidines through the fusion of N-Pmc-substituted thioamides with amines, facilitated by a variety of thiophilic reagents. Assorted thiophiles were evaluated for their effectiveness as c

Full text of DOI:10.1055/s-0030-1260011

1638
PAPER
Comprehensive and Facile Entry into Substituted Amidines via the
Condensation of N-Pmc-Substituted Thioamides with Amines Using
Mukaiyama Reagent as a Thiophile
Substituted A
m
t
idine
s
evenson Flemer, José S. Madalengoitia*
Department of Chemistry, 232 Cook Physical Sciences Building, University of Vermont, Burlington, VT 05405, USA
Fax +1(802)6568705; E-mail: jose.madalengoitia@uvm.edu
Received 18 February 2011; revised 21 March 2011
primary amines, respectively. The one-pot, multicompo-
nent reactions developed by Chang11 and Jin12 represent
some of the more novel entries into (N-sulfonyl) amidines
described in the literature.
Abstract: A convenient approach is presented for the preparation
of substituted amidines through the fusion of N-Pmc-substituted
thioamides with amines, facilitated by a variety of thiophilic re-
agents. Assorted thiophiles were evaluated for their effectiveness as
condensation reagents between the two partners, with the Mukaiya-
ma reagent emerging as the optimal candidate for this process. The
scope and limitations of this method were explored, revealing inter-
esting synthetic challenges and constraints. Many of these limita-
tions were overcome through the application of alternative reaction
pathways in the construction of troublesome products. Treatment of
the resultant Pmc-amidines with trifluoroacetic acid and trimethyl-
silyl trifluoromethanesulfonate cleanly afforded the deprotected
substituted amidines.
The present approach makes use of a masked electrophile
in the form of an electron-deficient thioamide that is acti-
vated toward an incoming amine through treatment with
an appropriate thiophile (Scheme 1). Although amidine
formation by reaction of N-alkoxycarbonyl thioamides
with amines has been reported,13 the transformation is car-
ried out in ethanol at reflux and does not have the benefit
of a gentle desulfurization reagent to allow the introduc-
tion of a high degree of architectural diversity. An analo-
gous transformation has been thoroughly explored by our
research group in previously published accounts14 in
which substituted guanidines are generated through the N-
ethyl-N¢-(3-dimethylaminopropyl)carbodiimide (EDCI)
mediated desulfurization of N-Pmc-N¢-alkyl thioureas in
the presence of amines (Scheme 1). While it was envi-
sioned that an analogous entry into substituted amidines
could be achieved by EDCI activation of an N-Pmc-thio-
amide followed by reaction of an amine, initial efforts to-
ward this end were unsuccessful.
Key words: amidine, thioamide, Mukaiyama reagent, thiophile, N-
sulfonyl
The amidine functionality, whether as a discrete unit or a
substructure within a larger molecular framework, repre-
sents a noteworthy template of connectivity in a variety of
important compounds. Many bioactive molecules,1 natu-
ral products,2 and drug leads3 contain the amidine func-
tionality as a central or peripheral moiety within their
architecture. As a discrete structure, the amidine connec-
tivity can be thought of as either a nitrogenous analogue
of a carboxylic acid or a carbon-substituted isoform of
guanidine. This latter structural relationship is significant
because the amidine functionality may be used as an isos-
teric replacement of the guanidine group in arginine-
containing peptides.4
amidine formation:
R2
S
HN
R2-NH2
R1-MgBr
S
Pmc
Pmc
Pmc
C
R1
N
R1
N
N
thiophile
H
O
O
N-Pmc-N'-alkyl
amidine
N-Pmc thioamide
S
Pmc =
Because of the relevance of the amidine architecture in
naturally occurring organic compounds, new and more
globally applicable methods toward the synthesis of the
amidine core are desired. The vast majority of approaches
described in the literature toward the synthesis of
amidines involves the functionalization of nitriles through
either variations on the Pinner reaction,5 the organometal-
lic insertion strategy,6 or the reaction of thioalkylated in-
termediates with amines.7 Activation of amides with
Et3OBF4, Tf2O, PyBrop, etc., followed by reaction with
amines has also provided a practical approach toward
more substituted amidines,8 as has nucleophilic addition
to carbodiimides9 and ketenimines10 by alkyl lithiates and
O
R2
guanidine formation:
R1-NH2
S
HN
R2-NH2
EDCI
R1
Pmc
R1
Pmc
S
N
N
N
N
Pmc
C
H
H
H
N
N-Pmc-N',N''-alkyl
guanidine
N-Pmc-N'-alkyl
thiourea
Scheme 1
The basis of the present research effort was to first survey
potential thiophiles and reaction conditions that would re-
sult in the development of a viable route into N-Pmc-sub-
stituted amidines from the corresponding thioamides, a
transformation that has, until now, remained elusive.
Once optimized, the scope and limitations of the general
SYNTHESIS 2011, No. 10, pp 1638–1648
x
x.
x
x
.
2
0
1
1
Advanced online publication: 20.04.2011
DOI: 10.1055/s-0030-1260011; Art ID: M20911SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Substituted Amidines
1639
reaction were carefully mapped with regard to steric and was used as the thiophile, although complete reaction was
electronic constraints.
apparent from the reactions mediated by HATU, PyBOP,
and the Mukaiyama reagent, with PyBOP yielding the
least by-products following reaction workup. Further-
more, the reactions carried out in dichloromethane ap-
peared to be much cleaner than those using N,N-
dimethylformamide as a solvent. Thus, three candidates
were initially identified as optimal thiophiles for
amidinylation on the test system using dichloromethane
as solvent.
Given the unsuccessful results of our initial attempts at
amidine formation through reaction of an N-Pmc-substi-
tuted thioamide and an amine under EDCI-mediated de-
sulfurization conditions, we wanted to identify conditions
that might effect this transformation. We hypothesized
that the transformation might be achievable through the
use of alternative thiophiles. As such, the primary variable
in this assay became the identity of the most effective
thiophile for amidinylation.
Table 1 Synthesis of Thioamides 2a–i
S
R MgBr
Pmc
N
C
S
Pmc
N
R
H
THF, 0 °C
1–3 h
1
2a–i
Entry
2
R
Yield (%)
Me
1
2
2a
2b
74
89
3
4
2c
90
48
2d
5
6
2e
2f
62
80
OMe
7
8
9
2g
2h
2i
58
52
77
Figure 1 Crude TLC reaction profile of the thiophile assay,
showing condensation efficiency between N-Pmc thioamide 2a with
benzylamine in DMF and CH2Cl2 solvent systems; the amidine 3a
product Rf value is highlighted for clarity
CF3
S
Four common thiophiles were assayed for their ability to
mediate the amidinylation between N-Pmc-thioacetamide
(2a) and benzylamine to yield N-Pmc-N¢-benzylacetami-
dine (3a; Figure 1). A variation on the method developed
by Walter was used to construct the N-Pmc-thioacetamide
(2a) test system, through addition of methylmagnesium
bromide to N-Pmc-isothiocyanate 1.15 In addition to the
EDCI thiophile, diisopropylcarbodiimide (DIC), 2-(1H-7-
azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexa-
fluorophosphate (HATU), benzotriazol-1-yl-oxytripyrro-
lidinophosphonium hexafluorophosphate (PyBOP), and
2-chloro-1-methylpyridinium iodide (Mukaiyama reagent)
were each evaluated under identical conditions for their
ability to promote the desired reaction in both N,N-di-
methylformamide and dichloromethane. DIC was imme-
diately excluded because it failed to yield any desired
product. A comparative analysis of the remaining four
thiophiles was undertaken, and the results can be com-
pared in the TLC image shown in Figure 1. As expected,
there was very little amidine product evident when EDCI
To fully investigate the scope and limitations of the now-
viable amidinylation process, a series of N-Pmc-thioam-
ides was synthesized that allowed a full exploration of
steric and electronic effects on the reactivity of thioamide
and amine partners. The methodology developed by
Walter and Röhr15 was again used to synthesize a series of
N-Pmc-thioamides 2, which were obtained from addition
of a series of Grignard reagents to N-Pmc-isothiocyanate
1. Table 1 illustrates the range of aryl and alkyl architec-
ture achievable from this process, comprising a spectrum
of steric, functional, and electronic properties. Although
the above conditions were satisfactory for the addition of
methylmagnesium bromide to N-Pmc-isothiocyanate 1 to
form N-Pmc-thioacetamide 2a, a significant number of N-
Pmc-thioamides 2 failed to form in acceptable yields. This
was especially apparent when classic Grignard conditions
were used in the attempted synthesis of thioamide 2h,
Synthesis 2011, No. 10, 1638–1648 © Thieme Stuttgart · New York

1640
S. Flemer, J. S. Madalengoitia
PAPER
bearing an electron-deficient aryl group. To gain access to an alkenyl architecture, and homoallylic thioamide 2d
reasonable amounts of these intermediates, augmented re- was chosen for this representation due to the ready
action conditions were applied. A LiCl-mediated ‘turbo- commercial availability of
a
suitable halide
Grignard’ approach (Mg/RBr, LiCl, THF, 0 °C) was (CH2=CHCH2CH2Br) from which to derive the corre-
initiated16 for the synthesis of the remaining N-Pmc-thio- sponding Grignard reagent. However, all attempts to syn-
amides, which allowed access to the remaining alkyl- and thesize thioamide 2d through Grignard addition to N-
aryl-substituted thioamides in moderate to good yields Pmc-isothiocyanate 1 were unsuccessful (Scheme 2). In
(Table 1).
contrast, when the synthesis of N-Pmc-thioacrylamide
was attempted through addition of vinylmagnesium bro-
mide to N-Pmc-isothiocyanate 1, to our surprise we recov-
ered thioamide 2d as the sole isolable product. A review
of the literature revealed a similar reaction as noted by
Lubell and co-workers,19 and was likely the result of addi-
tion of the vinyl nucleophile to isothiocyanate 1, followed
by addition of a second equivalent of vinyl nucleophile in
a conjugate fashion.
Mg,
Br
S
C
S
S
Pmc
Pmc
Pmc
C
C
N
H
N
1
2j
S
C
NaBH4
Pmc
Pmc
N
H
H
N
Having a series of N-Pmc-thioamides to work with, we
next focused on optimizing the three thiophiles initially
identified as having the ability to mediate an amidinyla-
tion reaction. Further investigations revealed that PyBOP
was not able to mediate the reaction of aryl-substituted
thioamides with amines and was thus not chosen for fur-
ther studies. In contrast, HATU performed well on all
solution-based reactions investigated, but was not as effi-
cient in solid-phase amidinylations (data not shown),
while the Mukaiyama reagent was easily able to carry out
both solution-based and resin-bound amidinylations. As a
result of these findings, the Mukaiyama reagent emerged
as the optimal overall thiophile to advance in this study.
1
2k
S
C
Mg,
Br
S
S
Pmc
Pmc
C
C
N
H
N
1
2d
BrMg
S
Pmc
C
N
N
1,2-addition
1
BrMg
1,4-addition
S
C
With the synthesis of N-Pmc-thioamides 2a–i accom-
plished and an optimal thiophile identified, we explored
the scope and limitations of the amidinylation reaction.
Table 2 illustrates the wide functional and electronic tol-
erance this mild methodology allows. Through judicious
selection of alkyl and aryl amine partners in the syntheses
of these amidines, we are able to show the broad scope of
this methodology, which allowed access to amidines with
high steric bulk (3b), secondary and cyclic amidines (3b
and 3c), functionalized amidines (3f), and bis-amidines
(3j). The reaction sequence for all amidines represented in
Table 2 was facile, rapid, and straightforward. It could be
carried out without the requirement for an inert atmo-
sphere and was forgiving of excess thiophile and/or
amine, with any excess reagents and by-products being
easily removed during aqueous workup. Yields of
amidines 3 were somewhat variable, depending upon the
starting substrates, but generally ranged between 70–
85%. Purification of the crude isolates was similarly
straightforward, requiring only standard silica gel chro-
matography to afford the pure N-Pmc-amidine products.
Pmc
N
H
2d
Scheme 2
Although most of the desired thioamides were accessible
by the Grignard approach, some thioamides resisted all ef-
forts toward their synthesis (Scheme 2). Desiring a thio-
amide that bore functionality of high steric bulk, we
attempted to gain access to the tert-butyl-substituted vari-
ant 2j. Using the previously mentioned standard and ‘tur-
bo-Grignard’ methodology both resulted in the formation
1
of a complex mixture of products, as evidenced by H
NMR analysis of the crude reaction mixtures. This unex-
pected result could be due to the known propensity of tert-
butyl anions to undergo unusual reaction pathways, pri-
marily as potential hydride donors.17 Attempted hydride
addition to Pmc-isothiocyanate to afford the thioform-
amide 2k, through the use of sodium borohydride as the
hydride source, resulted in a colorless precipitate that was
only sparingly soluble and could not be identified. A re- In our efforts to demonstrate the utility of this methodolo-
view of the literature revealed that hydride reductions of gy, we explored the scope and limitations of the amidiny-
isothiocyanates18 do not afford thioformamides.
lation reaction. Accordingly, some amidinylation
reactions failed to afford the desired product. For exam-
ple, the electron-deficient p-nitroaniline failed to react
with N-Pmc-thioamide 2c to afford amidine 3k
(Scheme 3, a).
One unexpected result was the synthetic route by which
thioamide 2d was achieved. One of the functionalities we
wanted to be represented in the collection of thioamides
was an alkene. Toward this end, we wanted to synthesize
Synthesis 2011, No. 10, 1638–1648 © Thieme Stuttgart · New York

PAPER
Substituted Amidines
1641
The majority of the p-nitroaniline was recovered unreact- identical intractable mixture of products. Furthermore, al-
ed, implying that it was not a strong enough nucleophile. though in other cases the reaction solution remained col-
Fortunately, the lack of reactivity of this type of substitut- orless throughout the course of the reaction, in this
ed aniline nucleophile seemed to be constrained only to instance, the solution took on a deep purple color over a
the electron-deficient variety, since amidine 3d was readi- period of ten minutes. We noted that this color change oc-
ly prepared using ordinary aniline as the nucleophile. An- curred regardless of whether an amine was added to the
other limitation arose when we attempted to condense reaction mixture or not. The components of this reaction
benzyl-substituted thioamide 2e with a variety of amines mixture were not readily separable over silica gel to ob-
under the standard amidinylation conditions. Regardless tain a product profile, so the reasons for this coloring phe-
of which amine was used in these condensation attempts, nomenon can only be theorized (see below).
analysis of the reaction mixtures gave evidence of an
Table 2 Scope of the Amidinylation Reaction
R2
N
R3
R1
R2
R3
R1
S
N
N
R2
R3
Mukaiyama reagent
CH2Cl2, r.t., 0.5 h
TFA; TMSOTf
r.t., 4 h
Pmc
Pmc
R1
N
N
H
X
H2N
H
2a–i
3a–j
4a–j
R1
Amine
3
Protected amidine product
Yld 4 Amidine product
(%)
Yld
(%)
HN
H
HN
N
Me
3a
73 4a
91
80
H
Pmc
N
H2N
HCO2
N
N
3b
3c
87 4b
N
H2N
H
N
HCO2
Pmc
N
N
82 4c
45
N
H2N
H
N
HCO2
Pmc
NH
3d
3e
72 4d
66
53
H
NH
N
Pmc
N
H2N
TFA
H
HN
80 4e
H
H
H
HN
N
H
H2N
Pmc
N
HCO2
HN
CONH2
HN
CONH2
Pmc
Pmc
3f
52 4f
78 4g
48
41
N
H
CONH2
N
N
H2N
TFA
HN
HN
OMe
3g
N
H
H2N
HCO2
OMe
OMe
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1642
S. Flemer, J. S. Madalengoitia
PAPER
Table 2 Scope of the Amidinylation Reaction (continued)
R2
N
R3
R1
R2
R3
R1
S
N
N
R2
R3
Mukaiyama reagent
TFA; TMSOTf
r.t., 4 h
Pmc
Pmc
R1
N
N
H
H
X
H2N
CH2Cl2, r.t., 0.5 h
2a–i
3a–j
4a–j
R1
Amine
3
Protected amidine product
Yld 4 Amidine product
(%)
Yld
(%)
CF3
HN
HN
3h
74 4h
54
71
H
Pmc
N
N
H
H2N
HCO2
CF3
CF3
S
3i
3j
85 4i
HN
HN
H
Pmc
S
S
N
H
H2N
TFA
N
H2N
NH2
Pmc
Pmc
70 4j
66
N
N
N
N
H2N
TFA
N
N
NH2
H
H
H
H
TFA
NO2
traditionally removed by standard acidolysis using tri-
fluoroacetic acid (TFA) and suitable scavengers.20 It was
used very successfully as a protecting/activating group in
our methodology for the synthesis of substituted
guanidines.15 However, when the Pmc-deprotection of the
amidines 3 was attempted, NMR analysis of the crude
product mixtures showed only partial Pmc-deprotection
took place, even in the presence of scavengers such as
HSCH2CH2SH, thioanisole, phenol, etc., and after long
reaction times (data not shown). After some optimization,
we found that a 95:5 (v/v) mixture of trifluoroacetic acid
and trimethylsilyl trifluoromethanesulfonate allowed
complete Pmc-deprotection in all cases. Standard workup
involved trituration with cold diethyl ether to yield the
crude amidines 4a–j as either colorless crystalline solids
or brown gums. The majority of the deprotected amidines
were pure enough to undergo NMR characterization in
their crude form, further illustrating the utility of this
method for producing substituted amidines without re-
quiring arduous purification procedures.
H2N
NO2
S
C
HN
C
Pmc
Pmc
N
H
N
2c
3k
Mukaiyama reagent
H2N
S
C
NH
C
Pmc
Pmc
N
H
N
2e
3l
Mukaiyama reagent
Scheme 3
To effectively generate the deprotected amidine core, the
Pmc-protecting group that facilitated thioamide/amine
condensation had to be removed as the final step in the se-
quence. This sulfonyl-based blocking group for the guani-
dine head-group in arginine-containing peptides is
R2 NH
S
X
C
R1
Pmc
N
-
R2NH2
HS
X
H
6
– H+
R2
X
S
C
HN
C
S
C
thiophile
(X)
R1 R2NH2
– H+
-
HS
X
X
R1
R1
Pmc
R1
Pmc
Pmc
Pmc
N C
N
N
N
H
7
– H+
-
5
HS
R2NH2
amidine product
N-Pmc thioamide
– H+
R1
Pmc
N
C
8
Scheme 4
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PAPER
Substituted Amidines
1643
The mechanism of the amidine-forming step warrants sets of peaks were approximately equal in integration.
some discussion. With all thiophiles, we envision activa- That there are two sets of signals particular to aryl-substi-
tion of the thioamide with the thiophile to form an inter- tuted thioamides has some literature precedent,22 and can
mediate 5 (Scheme 4). This intermediate may eliminate be explained by the presence of s-cis/s-trans isomers re-
the sulfur–thiophile adduct to afford either the nitrilium sulting from slow rotation about the C–N thioamide bond
ion 7 or the keteneimine 8; addition of amine to either of on the NMR timescale.
these intermediates would afford the amidine product,
As illustrated in Figure 2 (b), it was believed that the
however, evidence that the reaction does not proceed
cause of the NMR peak doubling of the amidines was due
through the keteneimine intermediate 8 comes from the
to the presence of cis/trans isomers about the imino C=N
bond. Evidence that supports this observation comes from
the NMR spectra of amidines 3b and 3c, which do not
show doubling of resonances because it is expected that
the A(1,3)-strain in 3b and 3c would favor the trans iso-
mer (Pmc-group is trans to NR2) as shown in Table 2.
Further evidence of cis/trans isomerism about the imino
failure of thioamide 2e to afford the product. While thio-
amide 2e is the most likely candidate to form ketenimine
8, due to conjugation with the phenyl ring, the aforemen-
tioned deep-blue color of the solution it produces upon
treatment with Mukaiyama reagent and its resistance to
reaction with added amine, suggests that if the ketenimine
forms, it leads to products other than the desired amidine.
bond also comes from the Pmc-deprotected samples, be-
Although the reaction of N-sulfonyl keteneimines with
cause loss of the Pmc group would be expected to elimi-
amines has been proposed in the literature,21 these find-
nate cis/trans isomerism. Indeed, Figure 3 shows a
ings would support a reaction intermediate other than 8.
1
comparison of representative H NMR peak regions be-
Furthermore, although the arene-substituted thioamides
fore and after Pmc-deprotection. As expected, in these
2f–i cannot possibly proceed through a keteneimine inter-
(and all) cases, conversion of Pmc-amidines 3 into the
mediate 8, they nevertheless do afford the corresponding
deprotected amidines 4 results in NMR spectra that do not
amidine products; these results suggest that, at least in
exhibit resonance doubling.
these cases, amidine formation proceeds through either in-
In conclusion, a new and versatile methodology has been
presented for the facile synthesis of substituted amidines.
The Mukaiyama-mediated condensation between an
termediate 6 or 7.
Interestingly, the 1H and 13C NMR spectra of the aryl-sub-
stituted N-Pmc-thioamides 2f–h, as well as the majority of
amine and an N-Pmc-thioamide cleanly affords N-Pmc-
N-Pmc-amidines 3, exhibited a doubling of some reso-
amidines in good yield, which can then be deprotected to
nances. After careful chromatographic purification of
afford the native substituted amidine system. The scope
these compounds, certain regions of each of their corre-
and limitations of this synthetic process have been care-
1
sponding H and 13C NMR spectra exhibited fully re-
fully explored and optimized, resulting in a methodology
solved peaks corresponding to at least two apparent
that allows installment of the greatest diversity of substi-
tution of the native amidine core. This procedure is well
positioned for use in the synthesis of compounds contain-
ing an amidine functional group. Current efforts focus on
the use of this chemistry on solid support in the synthesis
of peptidomimetic systems.
species. In the case of aryl-substituted N-Pmc-thioamides
2f–h, this phenomenon was most evident in the aromatic
region of the 1H NMR spectra (Figure 2, a). In the case of
thioamides 2f and 2g, there were clear major and minor
components; however, in the case of thioamide 2h, the
X
S
O
O
S
N
a)
H
O
S
O
X
O
N
S
H
O
R2
R1
R1
HN
O
O
R2
O
S
N
N
b)
O
S
N
H
O
O
Figure 2 (a) Putative dual conformations of aryl-substituted N-Pmc thioamides 2, showing the aromatic 1H NMR region of N-Pmc thioamide
2h as a representative example. (b) Theorized dual conformations of N-Pmc amidines 3, showing the upfield 1H NMR region of N-Pmc amidine
3h as a representative example.
Synthesis 2011, No. 10, 1638–1648 © Thieme Stuttgart · New York

1644
S. Flemer, J. S. Madalengoitia
PAPER
Figure 3 (a) Benzylic 1H NMR peak coalescence of amidine 3j and 4j following removal of the Pmc group. (b) Upfield 1H NMR peak coale-
scence of amidine 3h and 4h following removal of the Pmc group.
All solvents were purchased from Fisher Scientific (Pittsburgh,
PA). Unless otherwise specified, all reagents were purchased from
Sigma–Aldrich (St. Louis, MO) and were used without further pu-
rification. Flash chromatography was carried out on Sorbent Tech-
nologies silica gel (230–400 mesh). Melting points were recorded
with an Electrothermal MelTemp capillary melting point apparatus
and are uncorrected. Infrared spectra were obtained with a Shimad-
zu IR Affinity-1 FT-IR spectrophotometer. 1D NMR spectra (500
and 125 MHz) were collected using standard pulse sequences pro-
vided by Bruker. High-resolution mass spectra (HRMS) were ac-
quired by John Greaves at the Mass Spectrometry Resource of UC-
Irvine.
1H NMR (500 MHz, CDCl3): d = 2.67 (t, J = 6.8 Hz, 2 H), 2.58 (s,
3 H), 2.57 (s, 3 H), 2.14 (s, 3 H), 1.84 (t, J = 6.9 Hz, 2 H), 1.33 (s,
6 H).
13C NMR (125 MHz, CDCl3): d = 155.9, 137.4, 137.3, 126.3, 125.1,
118.7, 74.37, 32.27, 26.56, 21.29, 17.95, 17.06, 12.16, 12.1.
HRMS: m/z [M + Na] calcd for C16H23NNaO3S2: 364.1017; found:
364.1010.
N-Pmc-Butanethioamide (2b)
Yield: 0.76 g (89%); light-yellow friable foam; mp 153–155 °C.
IR (film): 3207, 1450 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.67 (t, J = 6.8 Hz, 2 H), 2.56–
2.65 (m, 8 H), 2.13 (s, 3 H), 1.83 (t, J = 6.8 Hz, 2 H), 1.64–1.72 (m,
2 H), 1.33 (s, 6 H), 0.86 (t, J = 7.0 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 156.6, 138.7, 138.2, 126.8, 125.8,
119.3, 75.1, 33.2, 27.4, 23.2, 22.2, 18.8, 17.9, 13.9, 12.9.
Preparation of N-Pmc-Substituted Thioamides 2a–i from Thio-
cyanate 1; General Procedure
A variation on the method developed by Walter and Röhr15 was
used to prepare all thioamides in this series. Magnesium turnings
(140 mg, 5.75 mmol) and LiCl (214 mg, 5.06 mmol) were suspend-
ed in anhydrous THF (4 mL) under an N2 atmosphere. Alkyl or aryl
halide (4.60 mmol, 2 equiv) was added in one portion and the mix-
ture was stirred until heat began to evolve. Additional THF (8 mL)
was then added and the reaction was allowed to progress until no
more heat evolution was evident (0.5–2 h, depending on the halide
used). The Grignard solution was then cooled to 0 °C in an ice–wa-
ter bath, and thiocyanate 1 (0.75 g, 2.30 mmol) dissolved in THF
(10 mL) was then added dropwise over 20 min. The mixture was al-
lowed to stir at 0 °C for an additional 30 min. The reaction was
quenched by careful, slow addition of 1% aq HCl (25 mL). The mix-
ture was partitioned between 1% HCl (50 mL) and EtOAc (50 mL)
and the aqueous layer was further extracted with additional EtOAc
(2 × 25 mL). The organic portions were combined, dried over
MgSO4, and concentrated in vacuo to yield the crude N-Pmc thio-
amide, which was then purified over silica gel by flash chromato-
graphy (EtOAc–hexane, 10–20%).
HRMS: m/z [M + Na] calcd for C18H27NNaO3S2: 392.1330; found:
392.1334.
N-Pmc-(3-Methyl)butanethioamide (2c)
Yield: 0.80 g (90%); light-yellow friable foam; mp 107–110 °C.
IR (film): 2928, 1549 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.66 (t, J = 6.8 Hz, 2 H), 2.58 (s,
6 H), 2.49 (d, J = 7.2 Hz, 2 H), 2.15–2.23 (m, 1 H), 2.13 (s, 3 H),
1.84 (t, J = 6.9 Hz, 2 H), 1.33 (s, 6 H), 0.85 (d, J = 7.0 Hz, 6 H).
13C NMR (125 MHz, CDCl3): d = 156.0, 138.0, 137.5, 126.6, 125.1,
118.6, 74.4, 32.5, 29.1, 26.7, 21.9, 21.5, 18.2, 17.2, 12.2.
HRMS: m/z [M + Na] calcd for C19H29NNaO3S2: 406.1487; found:
406.1489.
N-Pmc-Pent-4-enethioamide (2d)
Yield: 0.42 g (48%); yellow amorphous solid; mp 134–136 °C.
N-Pmc-Ethanethioamide (2a)
IR (film): 3204, 1549 cm–1.
1H NMR (500 MHz, CDCl3): d = 9.98 (br s, 1 H), 5.64–5.73 (m,
1 H), 4.91–5.00 (m, 2 H), 2.71 (t, J = 7.4 Hz, 2 H), 2.67 (t,
Yield: 0.58 g (74%); light-yellow friable foam; mp 135–137 °C.
IR (film): 1448, 3214 cm–1.
Synthesis 2011, No. 10, 1638–1648 © Thieme Stuttgart · New York

PAPER
Substituted Amidines
1645
J = 6.8 Hz, 2 H), 2.59 (s, 3 H), 2.58 (s, 3 H), 2.35–2.43 (m, 2 H),
2.13 (s, 3 H), 1.83 (t, J = 6.8 Hz, 2 H), 1.33 (s, 6 H).
13C NMR (125 MHz, CDCl3): d = 156.0, 138.1, 137.5, 136.0, 126.4,
125.1, 118.6, 115.9, 74.4, 32.7, 32.5, 26.7, 21.4, 18.1, 17.2, 12.2.
13C NMR (125 MHz, CDCl3): d = 156.2, 142.9, 138.6, 137.8, 133.4,
133.1, 132.8, 127.3, 125.6, 125.4, 125.1, 124.5, 122.5, 118.6, 115.5,
74.5, 32.5, 26.7, 21.5, 18.2, 17.2, 12.2.
HRMS: m/z [M + Na] calcd for C22H24F3NNaO3S2: 494.1047;
found: 494.1046.
HRMS: m/z [M + Na] calcd for C18H25NNaO3S2: 404.1330; found:
404.1338.
N-Pmc-2-Thiophenecarbothioamide (2i)
Yield: 0.58 g (58%); dark-yellow friable foam; mp 126–128 °C.
IR (film): 3184, 1551 cm–1.
N-Pmc-(2-Phenyl)ethanethioamide (2e)
Yield: 0.79 g (62%); light-yellow friable foam; mp 142–143 °C.
IR (film): 3208, 1667 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.61 (dd, J = 3.9, 1.5 Hz, 1 H),
7.55 (dd, J = 5.1, 1.0 Hz, 1 H), 7.07 (dd, J = 5.1, 4.0 Hz, 1 H), 2.67
(t, J = 6.8 Hz, 2 H), 2.64 (s, 3 H), 2.63 (s, 3 H), 2.12 (s, 3 H), 1.82
(t, J = 6.8 Hz, 2 H), 1.32 (s, 6 H).
13C NMR (125 MHz, CDCl3): d = 186.3, 156.0, 146.7, 138.5, 137.8,
135.4, 128.6, 126.1, 125.5, 124.9, 118.5, 74.4, 32.5, 26.7, 21.5,
18.2, 17.3, 12.3.
1H NMR (500 MHz, CDCl3): d = 9.24 (br s, 1 H), 7.29–7.35 (m,
3 H), 7.18–7.23 (m, 2 H), 4.01 (s, 2 H), 2.60 (t, J = 6.8 Hz, 2 H),
2.39 (s, 3 H), 2.35 (s, 3 H), 2.08 (s, 3 H), 1.82 (t, J = 6.8 Hz, 2 H),
1.32 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 155.9, 138.7, 137.7, 134.6, 129.1,
128.0, 124.9, 118.4, 74.4, 32.5, 26.7, 21.4, 17.8, 17.0, 12.2.
HRMS: m/z [M + Na] calcd for C19H23NNaO3S3: 432.0738; found:
432.0750.
HRMS: m/z [M + Na] calcd for C22H27NNaO3S2: 440.1330; found:
440.1337.
Preparation of N-Pmc-Substituted Amidines 3a–j; General
Procedure
N-Pmc-Thiobenzamide (2f)
Yield: 0.74 g (80%); dark-yellow amorphous solid; mp 131–
In a 50 mL round-bottom flask, N-Pmc thioamide (2a–i; 1.30
mmol) was dissolved in CH2Cl2 (10 mL). To this stirred solution
was sequentially added DIPEA (450 mL, 2.60 mmol, 2 equiv) and
2-chloro-N-methylpyridinium iodide (Mukaiyama reagent; 400 mg,
1.56 mmol, 1.2 equiv). This solution was incubated with stirring for
5 min, then the required amine nucleophile (1.95 mmol, 1.5 equiv)
was added. The reaction was stirred for an additional 30 min. At the
end of this time, the contents of the reaction vessel were poured into
a 125 mL separating funnel containing EtOAc (150 mL) and 2%
HCl (150 mL). The phases were separated and the organic layer was
washed with 2% HCl (100 mL). The organic layer was then separat-
ed, dried over MgSO4, and evaporated in vacuo to afford the crude
N-Pmc amidine product. Purification over silica gel (EtOAc–
hexane, 20–40%) afforded the amidine products.
132 °C.
IR (film): 3214, 1448 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.06 (d, J = 7.4 Hz, 0.4 H), 7.73
(d, J = 7.4 Hz, 1.6 H), 7.51 (t, J = 7.5 Hz, 1 H), 7.47 (t, J = 7.9 Hz,
2 H), 7.38 (t, J = 7.9 Hz, 2 H), 2.67 (t, J = 6.9 Hz, 2 H), 2.61 (s,
2.5 H), 2.60 (s, 2.5 H), 2.34 (s, 0.5 H), 2.31 (s, 0.5 H), 2.18 (s,
0.5 H), 2.12 (s, 2.5 H), 1.83 (t, J = 6.8 Hz, 2 H), 1.33 (s, 6 H).
13C NMR (125 MHz, CDCl3): d = 198.3, 156.6, 154.9, 141.8, 141.3,
140.8, 139.1, 138.4, 132.8, 132.0, 129.2, 127.6, 127.5, 126.7, 125.5,
125.2, 119.4, 119.1, 75.0, 74.5, 33.2, 27.4, 22.2, 18.9, 18.0, 13.0,
12.9.
N-Pmc-(4-Methoxy)thiobenzamide (2g)
Yield: 0.58 g (58%); dark-yellow amorphous solid; mp 101–
103 °C.
IR (film): 2974, 1601 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.17 (d, J = 8.9 Hz, 0.3 H), 7.83
(d, J = 8.9 Hz, 1.7 H), 7.01 (d, J = 8.9 Hz, 0.3 H), 6.84 (d,
J = 8.9 Hz, 1.7 H), 3.88 (s, 0.4 H), 3.82 (s, 2.6 H), 2.65 (t,
J = 6.8 Hz, 2 H), 2.62 (s, 5.2 H), 2.34 (s, 0.4 H), 2.32 (s, 0.4 H),
2.15 (s, 0.4 H), 2.11 (s, 2.6 H), 1.81 (t, J = 6.8 Hz, 2 H), 1.31 (s,
6 H).
13C NMR (125 MHz, CDCl3): d = 163.2, 155.7, 138.3, 137.7, 134.0,
132.5, 131.8, 130.3, 129.0, 128.2, 126.4, 124.7, 118.3, 114.5, 113.7,
74.2, 60.0, 55.5, 32.5, 26.7, 21.5, 21.1, 18.2, 17.4, 17.3, 14.2, 12.6,
12.2.
N-Pmc-N¢-Benzylacetamidine (3a)
Yield: 0.39 g (73%); light-yellow semisolid.
IR (film): 3294, 1585 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.12–7.23 (m, 5 H), 6.85 (br s,
1 H), 4.41 (d, J = 5.8 Hz, 0.3 H), 4.37 (d, J = 5.2 Hz, 1.7 H), 2.57 (t,
J = 6.3 Hz, 2 H), 2.52 (s, 0.4 H), 2.51 (s, 0.4 H), 2.45 (s, 2.6 H),
2.43 (s, 2.6 H), 2.19 (s, 3 H), 2.10 (s, 0.4 H), 2.07 (s, 2.6 H), 1.79 (t,
J = 6.1 Hz, 2 H), 1.30 (s, 6 H).
13C NMR (125 MHz, CDCl3): d = 167.8, 165.2, 154.2, 153.6, 137.0,
136.1, 136.0, 135.5, 135.4, 134.9, 132.7, 132.3, 131.4, 130.8, 129.0,
128.7, 128.3, 127.9, 127.3, 126.6, 124.3, 123.9, 118.1, 117.8, 73.7,
73.6, 68.1, 47.8, 45.4, 38.6, 32.7, 30.8, 30.2, 28.8, 26.6, 25.3, 23.6,
22.9, 21.2, 20.3, 18.3, 17.3, 17.2, 14.0, 12.0, 10.9.
HRMS: m/z [M + Na] calcd for C22H27NNaO4S2: 456.1279; found:
456.1279.
HRMS: m/z [M + Na] calcd for C23H30N2NaO3S: 437.1875; found:
437.1874.
N-Pmc-(4-Trifluoromethyl)thiobenzamide (2h)
Yield: 0.56 g (52%); dark-yellow amorphous solid; mp 158–
160 °C.
IR (film): 3196, 1323 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.79 (d, J = 8.1 Hz, 1.7 H), 7.58
(d, J = 8.1 Hz, 1.7 H), 7.47 (d, J = 8.1 Hz, 0.3 H), 6.87 (d,
J = 8.1 Hz, 0.3 H), 2.65 (t, J = 6.8 Hz, 2 H), 2.58 (s, 2.9 H), 2.56 (s,
2.9 H), 2.34 (s, 0.1 H), 2.31 (s, 0.1 H), 2.17 (s, 0.1 H), 2.12 (s,
2.9 H), 1.83 (t, J = 6.8 Hz, 2 H), 1.32 (s, 6 H).
N-Pmc-N¢,N¢-Diisopropylbutanamidine (3b)
Yield: 0.49 g (87%); colorless amorphous solid; mp 165–167 °C.
IR (film): 2930, 1533 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.97–4.03 (m, 1 H), 3.43–3.55 (m,
1 H), 2.76–2.82 (m, 2 H), 2.63 (t, J = 6.8 Hz, 2 H), 2.57 (s, 3 H),
2.55 (s, 3 H), 2.11 (s, 3 H), 1.81 (t, J = 6.8 Hz, 2 H), 1.44–1.58 (m,
2 H), 1.34 (d, J = 6.7 Hz, 6 H), 1.31 (s, 6 H), 1.22 (d, J = 6.6 Hz,
6 H), 0.93 (t, J = 7.2 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 168.1, 166.9, 153.8, 136.2, 135.2,
135.1, 133.3, 124.3, 117.5, 74.7, 50.5, 48.6, 39.6, 35.3, 33.7, 30.9,
Synthesis 2011, No. 10, 1638–1648 © Thieme Stuttgart · New York

1646
S. Flemer, J. S. Madalengoitia
PAPER
30.3, 29.5, 27.4, 24.4, 23.7, 22.0, 21.3, 21.2, 20.9, 19.2, 17.6, 14.9,
14.7, 13.6, 11.9.
IR (film): 3296, 667 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.14 (br s, 1 H), 7.46 (d,
J = 8.0 Hz, 1.3 H), 7.23 (d, J = 7.9 Hz, 0.7 H), 6.88 (d, J = 8.2 Hz,
1.3 H), 6.73 (d, J = 7.4 Hz, 0.7 H), 5.86–5.96 (m, 0.4 H), 5.74–5.84
(m, 0.6 H), 5.27–5.36 (m, 0.4 H), 5.18–5.27 (m, 0.6 H), 4.07–4.12
(m, 0.8 H), 3.88–3.93 (m, 1.2 H), 3.81 (s, 1.8 H), 3.78 (s, 1.2 H),
2.55–2.68 (m, 4.9 H), 2.48–2.54 (m, 0.9 H), 2.43 (s, 1.2 H), 2.37 (s,
1.2 H), 2.11 (s, 1.8 H), 2.03 (s, 1.2 H), 1.74–1.82 (m, 2 H), 1.58 (s,
1.3 H), 1.30 (s, 4.7 H).
13C NMR (125 MHz, CDCl3): d = 165.0, 161.7, 161.0, 154.2, 136.1,
135.6, 135.0, 133.5, 132.9, 131.9, 130.1, 129.0, 126.4, 125.3, 124.3,
123.7, 118.0, 117.9, 117.2, 113.8, 113.2, 73.7, 73.5, 55.4, 55.3,
48.2, 44.7, 32.8, 26.7, 21.4, 18.5, 17.4, 17.2, 12.0, 11.9.
HRMS: m/z [M + Na] calcd for C24H40N2NaO3S: 459.2657; found:
459.2657.
N-Pmc-3-Methyl-1-(piperidin-1-yl)butan-1-imine (3c)
Yield: 0.46 g (82%); colorless gum.
IR (film): 2936, 1520 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.61–3.70 (m, 2 H), 3.40–3.50 (m,
2 H), 2.87 (d, J = 7.7 Hz, 2 H), 2.63 (t, J = 6.8 Hz, 2 H), 2.58 (s,
3 H), 2.57 (s, 3 H), 2.11 (s, 3 H), 1.80 (t, J = 6.7 Hz, 2 H), 1.43–1.69
(m, 7 H), 1.30 (s, 6 H), 0.98 (d, J = 6.7 Hz, 6 H).
13C NMR (125 MHz, CDCl3): d = 165.8, 153.1, 135.3, 134.5, 134.3,
123.6, 117.6, 73.4, 48.1, 45.8, 38.1, 32.8, 27.6, 26.6, 25.5, 24.1,
22.2, 21.3, 18.3, 17.2, 11.9.
HRMS: m/z [M + Na] calcd for C25H32N2NaO4S: 479.1980; found:
479.1971.
HRMS: m/z [M + Na] calcd for C24H38N2NaO3S: 457.2501; found:
457.2500.
N-Pmc-N¢-(1-Methylpropyl)-4-trifluoromethylbenzamide (3h)
Yield: 0.49 g (74%); light-yellow gum.
IR (film): 3264, 1530 cm–1.
N-Pmc-N¢-Phenyl-3-methylbutanamidine (3d)
Yield: 0.41 g (72%); colorless friable foam; mp 148–150 °C.
1H NMR (500 MHz, CDCl3): d = 7.92 (br s, 1 H), 7.66 (d,
J = 8.1 Hz, 1 H), 7.53 (d, J = 8.0 Hz, 1 H), 7.36 (d, J = 8.1 Hz, 1 H),
7.17 (d, J = 8.0 Hz, 1 H), 5.45 (d, J = 8.2 Hz, 0.5 H), 4.18–4.29 (m,
0.5 H), 3.94 (s, 0.5 H), 3.26–3.36 (m, 0.5 H), 2.63 (t, J = 6.8 Hz,
1 H), 2.59 (s, 1.5 H), 2.59 (s, 1.5 H), 2.45 (t, J = 6.8 Hz, 1 H), 2.35
(s, 1.5 H), 2.22 (s, 1.5 H), 2.11 (s, 1.5 H), 2.00 (s, 1.5 H), 1.80 (t,
J = 6.8 Hz, 1 H), 1.76 (t, J = 6.8 Hz, 1 H), 1.53–1.62 (m, 1 H),
1.43–1.52 (m, 1 H), 1.29 (s, 6 H), 1.23 (d, J = 6.6 Hz, 1.5 H), 1.18
(d, J = 6.5 Hz, 1.5 H), 0.96 (t, J = 7.4 Hz, 1.5 H), 0.86 (t,
J = 7.4 Hz, 1.5 H).
IR (film): 3308, 1537 cm–1.
1H NMR (500 MHz, CDCl3): d = 9.82 (br s, 1 H), 7.43–7.60 (m,
1 H), 7.27–7.41 (m, 2 H), 6.90–7.24 (m, 2 H), 2.45–2.68 (m, 8 H),
1.99–2.20 (m, 5 H), 1.82 (t, J = 6.5 Hz, 2 H), 1.32 (s, 6 H), 0.90–
0.96 (m, 1 H), 0.71–0.89 (m, 6 H).
13C NMR (125 MHz, CDCl3): d = 166.0, 154.1, 136.9, 136.0, 135.6,
130.9, 129.4, 127.7, 126.9, 124.2, 120.5, 118.0, 73.7, 41.8, 32.7,
26.7, 22.1, 21.3, 18.5, 17.4, 12.0.
13C NMR (125 MHz, CDCl3): d = 163.2, 163.0, 154.3, 153.6, 140.8,
137.6, 137.4, 136.0, 135.9, 135.6, 135.5, 135.0, 133.9, 132.6, 132.2,
131.9, 131.5, 131.4, 131.3, 128.0, 127.6, 125.6, 124.6, 124.4, 123.9,
122.4, 118.1, 117.6, 113.3, 73.8, 73.5, 53.5, 49.4, 45.8, 32.7, 30.6,
28.9, 26.7, 26.6, 26.5, 21.7, 21.3, 21.1, 19.8, 18.4, 18.3, 17.3, 16.8,
12.0, 11.7, 10.3, 10.2.
HRMS: m/z [M + Na] calcd for C25H34N2NaO3S: 465.2188; found:
465.2192.
N-Pmc-N¢-Cyclobutyl-4-pentenamidine (3e)
Yield: 0.44 g (80%); light-yellow gum.
IR (film): 2976, 2531 cm–1.
HRMS: m/z [M + Na] calcd for C26H33F3N2NaO3S: 533.2062;
found: 533.2039.
1H NMR (500 MHz, CDCl3): d = 8.11 (br s), 5.67–5.82 (m, 1 H),
4.94–5.06 (m, 2 H), 4.32–4.40 (m, 0.4 H), 3.97–4.08 (m, 0.6 H),
2.76 (t, J = 7.8 Hz, 1 H), 2.64 (t, J = 6.8 Hz, 2 H), 2.57 (s, 3 H), 2.56
(s, 3 H), 2.25–2.41 (m, 5 H), 2.11 (s, 3 H), 1.97–2.06 (m, 1 H),
1.77–1.87 (m, 4 H), 1.62–1.77 (m, 2 H), 1.31 (s, 6 H).
13C NMR (125 MHz, CDCl3): d = 180.5, 165.3, 154.0, 153.2, 136.5,
136.4, 136.0, 135.7, 135.4, 134.9, 133.3, 132.1, 124.1, 124.0, 118.0,
117.9, 116.4, 115.7, 73.7, 73.6, 48.3, 46.5, 32.8, 32.7, 32.6, 32.4,
31.4, 30.7, 30.0, 26.7, 21.3, 18.4, 17.4, 17.3, 15.2, 14.8, 12.0.
N-Pmc-N¢-(2-Adamantyl)-2-thiopheneamidine (3i)
Yield: 0.58 g (85%); colorless friable foam; mp 177–179 °C.
IR (film): 2911, 1578 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.87 (br d, J = 9.6 Hz, 1 H), 7.49
(d, J = 4.8 Hz, 1 H), 7.44 (d, J = 3.1 Hz, 1 H), 7.06 (t, J = 4.0 Hz,
1 H), 4.08 (d, J = 8.7 Hz, 1 H), 2.58–2.69 (m, 7.6 H), 2.36 (s,
0.2 H), 2.31 (s, 0.2 H), 2.16 (s, 0.2 H), 2.10 (s, 2.8 H), 11.93–2.01
(m, 2 H), 1.82–1.92 (m, 3 H), 1.79 (t, J = 6.7 Hz, 2 H), 1.63–1.77
(m, 7 H), 1.29 (s, 6 H).
HRMS: m/z [M + Na] calcd for C23H34N2NaO3S: 441.2188; found:
441.2182.
13C NMR (125 MHz, CDCl3): d = 156.5, 153.9, 136.1, 135.5, 132.3,
130.9, 130.8, 127.4, 124.1, 118.0, 73.7, 59.1, 37.2, 36.9, 33.3, 32.7,
31.2, 26.9, 26.7, 21.3, 18.6, 17.5, 12.0.
N-Pmc-N¢-(2-Acetamidyl)benzamide (3f)
Yield: 0.30 g (52%); colorless dense solid; mp 193–195 °C.
IR (film): 3053, 1620 cm–1.
HRMS: m/z [M + Na] calcd for C29H38N2NaO3S2: 549.2222; found:
549.2210.
1H NMR (500 MHz, CDCl3): d = 7.22 (t, J = 7.2 Hz, 1 H), 7.02–
7.11 (m, 4 H), 6.76 (br s, 1 H), 6.13 (br s, 1 H), 4.24 (d, J = 4.4 Hz,
2 H), 2.44 (t, J = 6.4 Hz, 2 H), 2.30 (s, 3 H), 2.23 (s, 3 H), 1.96 (s,
3 H), 1.74 (t, J = 6.7 Hz, 2 H), 1.28 (s, 6 H).
13C NMR (125 MHz, CDCl3): d = 170.2, 164.9, 153.6, 135.5, 135.0,
132.9, 132.1, 129.7, 127.3, 127.1, 123.8, 117.6, 73.5, 71.8, 70.5,
70.4, 58.9, 44.6, 32.7, 26.6, 21.1, 18.2, 16.9, 11.7.
N,N¢-[1,3-Phenylenebis(methylene)]bis(N¢-Pmc-butanamidine)
(3j)
Yield: 0.74 g (70%); colorless friable foam; mp 118–120 °C.
IR (film): 3304, 1121 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.24–8.26 (m, 0.1 H), 8.16–8.22
(m, 0.3 H), 7.12–7.20 (m, 2.4 H), 7.08–7.11 (m, 0.4 H), 7.03–7.09
(m, 1.2 H), 6.46 (br s, 1.2 H), 6.11 (br s, 0.4 H), 4.48 (d, J = 6.1 Hz,
0.3 H), 4.43 (d, J = 5.4 Hz, 0.7 H), 4.39 (d, J = 6.0 Hz, 0.8 H), 4.35
(d, J = 5.4 Hz, 2.2 H), 2.69–2.74 (m, 0.8 H), 2.57–2.66 (m, 6.3 H),
HRMS: m/z [M + Na] calcd for C23H29N3NaO4S: 466.1776; found:
466.1758.
N-Pmc-N¢-Allyl-4-methoxybenzamide (3g)
Yield: 0.46 g (78%); colorless gum.
Synthesis 2011, No. 10, 1638–1648 © Thieme Stuttgart · New York

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Substituted Amidines
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2.56 (d, J = 4.6 Hz, 1 H), 2.53 (d, J = 4.4 Hz, 2.2 H), 2.51 (s, 2.1 H),
2.45–2.50 (m, 6.6 H), 2.23–2.31 (m, 0.9 H), 2.06–2.13 (m, 6 H),
1.75–1.84 (m, 4 H), 1.55–1.69 (m, 2 H), 1.47–1.57 (m, 2 H), 1.26–
1.37 (m, 10.3 H), 1.26 (s, 1.7 H), 0.84–0.93 (m, 3 H), 0.81 (t,
J = 7.3 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 168.2, 168.1, 167.6, 153.6, 138.5,
137.4, 135.6, 134.9, 133.3, 131.9, 129.4, 128.8, 127.8, 127.7, 127.1,
126.5, 125.9, 124.0, 118.0, 117.9, 73.8, 73.6, 47.2, 45.4, 35.5, 35.4,
35.3, 32.8, 29.7, 26.7, 21.4, 20.8, 20.7, 19.6, 18.4, 17.3, 13.8, 12.0.
N-(2-Acetamidyl)benzamide (4f)
Yield: 21 mg (48%); isolated as its TFA salt.
1H NMR (500 MHz, CD3OD): d = 7.76–7.81 (m, 2 H), 7.70–7.75
(m, 1 H), 7.58–7.65 (m, 2 H), 4.26 (s, 2 H).
MS (APCI): m/z = 178 [M + H].
N-Allyl-4-methoxybenzamide (4g)
Yield: 19 mg (41%); isolated as its formate salt.
1H NMR (500 MHz, CD3OD): d = 7.72 (d, J = 8.9 Hz, 2 H), 7.13 (d,
J = 8.9 Hz, 2 H), 5.92–6.02 (m, 1 H), 5.29–5.38 (m, 2 H), 4.06–
4.12 (m, 2 H), 3.90 (s, 3 H).
HRMS: m/z [M + Na] calcd for C44H62N4NaO6S2: 829.4009; found:
829.4000.
MS (APCI): m/z = 191 [M + H].
Pmc-Deprotection of Substituted Amidines 4a–j
In a 25 mL round-bottom flask, N-Pmc-substituted amidine 3 (0.25
mmol) was dissolved in TFA (4 mL), and TMSOTf (50 mL) was
added. The solution was stirred for 4 h at r.t., then reduced to ap-
proximately 1/4 of its volume under a stream of nitrogen, and the
residue was then taken up in ice-cold anhydrous Et2O (20 mL). In
approximately half of the instances, the desired deprotected
amidines precipitated directly from the ethereal solution and were
isolated by centrifugation as their representative TFA salts. In the
other instances, the amidine did not directly precipitate, necessitat-
ing the reduction of the ethereal solution in vacuo and purification
of the resultant black gum over silica (EtOAc–MeOH–HCO2H,
1:2:7) to yield the desired amidine products as their representative
formate salts.
N-(1-Methylpropyl)-4-trifluoromethylbenzamide (4h)
Yield: 33 mg (54%); isolated as its formate salt.
1H NMR (500 MHz, CD3OD): d = 7.79–7.84 (m, 4 H), 3.18–3.24
(m, 1 H), 1.57–1.69 (m, 2 H), 1.27 (d, J = 6.5 Hz, 3 H), 0.95 (t,
J = 7.4 Hz, 3 H).
MS (APCI): m/z = 244 [M + H].
N-(2-Adamantyl)-2-thiopheneamidine (4i)
Yield: 46 mg (71%); isolated as its TFA salt.
1H NMR (500 MHz, CD3OD): d = 8.53 (br s, 1 H), 7.93–7.97 (m,
1 H), 7.82–7.85 (m, 1 H), 7.27–7.31 (m, 1 H), 3.99 (br s, 1 H),
2.05–3.02 (m, 2 H), 1.90–2.00 (m, 7 H), 1.83–1.87 (m, 2 H), 1.72–
1.78 (m, 2 H).
N-Benzylacetamidine (4a)
Yield: 34 mg (91%); isolated as its formate salt.
1H NMR (500 MHz, CD3OD): d = 7.31–7.44 (m, 5 H), 4.44 (d,
J = 5.4 Hz, 1 H), 2.26 (s, 3 H).
MS (APCI): m/z = 261 [M + H].
N,N¢-[1,3-Phenylenebis(methylene)]bisbutanamidine (4j)
Yield: 45 mg (66%); isolated as its TFA salt.
1H NMR (500 MHz, CD3OD): d = 7.44–7.50 (m, 1 H), 7.34–7.41
(m, 3 H), 4.50 (d, J = 3.2 Hz, 4 H), 4.49 (t, J = 7.7 Hz, 4 H), 1.69–
1.80 (m, 4 H), 1.02 (t, J = 7.4 Hz, 6 H).
MS (APCI): m/z = 149 [M + H].
N,N-Diisopropylbutanamidine (4b)
Yield: 34 mg (80%); isolated as its formate salt.
1H NMR (500 MHz, CD3OD): d = 8.80 (br s, 1 H), 7.52 (br s, 1 H),
4.21–4.30 (m, 1 H), 4.05–4.13 (m, 1 H), 2.58 (t, J = 7.8 Hz, 2 H),
1.64–1.76 (m, 2 H), 1.42 (d, J = 7.2 Hz, 6 H), 1.33 (d, J = 6.6 Hz,
6 H), 1.06 (t, J = 7.4 Hz, 3 H).
MS (APCI): m/z = 275 [M + H].
Acknowledgment
MS (APCI): m/z = 171 [M + H].
Funds for this work were provided by grant CHE-041283 and in-
strumentation grant CHE-0821501 from the NSF.
3-Methyl-1-(piperidin-1-yl)butan-1-imine (4c)
Yield: 19 mg (45%); isolated as its formate salt.
References
1H NMR (500 MHz, CD3OD): d = 8.79 (br s, 1 H), 8.29 (br s, 1 H),
3.64 (t, J = 4.5 Hz, 2 H), 3.57 (t, J = 4.5 Hz, 2 H), 2.49 (d,
J = 7.7 Hz, 2 H), 1.95–2.04 (m, 1 H), 1.66–1.80 (m, 8 H), 1.03 (d,
J = 6.7 Hz, 6 H).
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S. Flemer, J. S. Madalengoitia
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Synthesis 2011, No. 10, 1638–1648 © Thieme Stuttgart · New York