Halocyclization of Unsaturated Guanidines Mediated by Koser's Reagent and Lithium Halides

Article abstract of DOI:10.1021/acs.joc.5b01750

The synthesis of halogenated cyclic guanidines through iodine(III)-mediated umpolung of halide salts is described. Cyclic guanidines of various sizes can be obtained with generally excellent regioselectivities through either a chloro- or a bromocyclization, using Koser's reagent and the corresponding lithium salt.

Full text of DOI:10.1021/acs.joc.5b01750

Article
pubs.acs.org/joc
Halocyclization of Unsaturated Guanidines Mediated by Koser’s
Reagent and Lithium Halides
Marion Daniel, Florent Blanchard, Sophie Nocquet-Thibault, Kevin Cariou,* and Robert H. Dodd*
Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Univ. Paris-Sud, Universite
Gif-sur-Yvette, France
́
Paris-Saclay, 1, av. de la Terrasse, 91198
S
* Supporting Information
ABSTRACT: The synthesis of halogenated cyclic guanidines through iodine(III)-mediated umpolung of halide salts is described.
Cyclic guanidines of various sizes can be obtained with generally excellent regioselectivities through either a chloro- or a
bromocyclization, using Koser’s reagent and the corresponding lithium salt.
ered as rigid analogues of arginine, and most of these have been
found to be constituents of antibiotic cyclopeptides such as
enduracidin,9 capreomycin, or the very recently discovered
teixobactin 3, highly promising for treating resistant bacteria.10
While construction of cyclic guanidines is often tedious, as
we previously experienced,5,6 the synthesis of acyclic guanidines
can be readily achieved from the corresponding amines using a
variety of guanidylating reagents.11 Thus, devising a modular
cyclization strategy from these available starting materials
seemed rather appealing. Following this strategy, several
methods have been described relying on the Rh-,12 Pd-,13 or
Ag-catalyzed14 amination of propargylic derivatives and on the
iodine-15 or NBS-triggered16 aminohalogenation of allylic
compounds (Scheme 1, eq 1). In particular, the halocyclization
of guanidines has been performed as the key step for the total
synthesis of saxitoxin17 and axinellamines.18 In order to
broaden the scope of this strategy, we anticipated that the
hypervalent iodine(III)-mediated umpolung of halide salts that
INTRODUCTION
■
Among nitrogen-containing heterocycles, cyclic guanidines
hold a special place because of their particular properties
such as strong basicity and rigidity. Guanidines in general
possess interesting features from the organic chemist’s point of
view,1 which has thus led to the development of many strategies
for their synthesis.2 Additionally, the guanidine motif can be
found in a myriad of natural products.3 Specifically, many of
them incorporate the synthetically challenging cyclic guanidine
moiety, toward which a considerable number of studies have
been devoted in the field of total synthesis.4
Our own interest has been directed toward the synthesis of
cyclic guanidine-containing amino acids such as enduracididine
15 and tetrahydrolathyrine 2 (Figure 1).6 These nonproteino-
genic amino acids, as well as related congeners such as β-
hydroxy-enduracididine7 and capreomycidine,8 can be consid-
Scheme 1. Previous Studies and Envisioned Strategy
Figure 1. Structures of enduracididine 1, tetrahydrolathyrine 2, and
teixobactin 3.
Received: July 28, 2015
© XXXX American Chemical Society
A
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we recently employed for the ethoxyhalogenation of various
enamides (eq 2)19 should be amenable to initiating such a
halocyclization (eq 3).
regardless of the pathway that is effectively operational, similar
adducts would be obtained.
Hypervalent iodine derivatives have drawn much attention in
the past few years because of their versatile reactivity, their
accessibility, and their low toxicity.20 Several cyclizations of
guanidines21 or amidines22 have previously been reported
relying on the oxidative properties of (diacetoxyiodo)benzene
(PIDA). For our part, we wished to use the I(III) reagent to
trigger the umpolung of a halide salt through a series of ligand
exchanges around the central iodine atom,19b thereby
generating an electrophilic species X+ (Scheme 2, A → B)
RESULTS AND DISCUSSION
■
We chose bis-Cbz-protected allyl guanidine 4a as a model
substrate and began our study by probing the feasibility of the
bromocyclization. Remarkably, the combination of 1.2 equiv of
PIDA and 2.5 equiv of LiBr in acetonitrile at room temperature
provided cyclic guanidine 5a in 78% yield (Table 1, entry 1).
The reaction was equally efficient in more (EtOH) or less
(DCM) polar solvents, and an excellent 82% yield was obtained
in both cases (entries 2−3). While a 2-fold amount of Br vs
OAc is optimal for the ligand exchange process, only one halide
is transferred to the substrate. The amount of LiBr was thus
decreased to 1.2 equiv, and the desired product was isolated
with an improved 85% yield (Table 1, entry 4). However, under
the same reaction conditions using 2.5 equiv of LiCl (instead of
LiBr) in ethanol, only a 20% yield of the chlorinated product 6a
was obtained (Table 1, entry 5). A slightly higher yield of 6a
was obtained in acetonitrile (Table 1, entry 6), but changing
the chloride sources to FeCl3,19b ZnCl2, or TBACl did not lead
Scheme 2. Plausible Mechanistic Pathways
24
to further improvement. PhICl2 also provided 6a but with
only a moderately improved yield (entry 7). Finally, [hydroxy-
(tosyloxy)iodo]benzene (Koser’s reagent)25,26 was examined,
and although the reaction time was extended, it allowed the
formation of the desired adduct 6a in a much better 75% yield
(entry 8). The latter could be further increased to 88% by
running the reaction in dichloromethane at 0 °C (entry 9).
Interestingly, when a lower amount of LiCl (1.2 equiv) was
used, a competitive tosyloxycyclization took place (entries 10,
11).
In the absence of lithium halide, this tosyloxycyclization
remained the only effective process, providing cyclic guanidine
7a and the corresponding mono-deprotected adduct 7a′ in a
40% overall yield (entry 12). Finally, the optimal chlorocycliza-
tion conditions were applied to the bromocyclization reaction
that could activate the double bond of an olefinic guanidine and
enable the cyclization. While only the exo mode is represented,
both exo and endo modes can be operative depending on the
substitution pattern. An alternative scenario, whereby the
starting material would be oxidized first to give an aziridinium,
can also be envisaged (A → C).23 Subsequent trapping by the
halide should lead to the same adduct D. In this latter case, the
regiochemistry governing the opening of the aziridinium C
would also depend on the substitution pattern. Overall,
Table 1. Optimization of Reaction Conditions for the Bromo- and Chlorocyclization of 4a
a
entry
I(III)
LiX (x equiv)
solvent
temp.
t (h)
yield (%)
1
2
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
LiBr (2.5)
LiBr (2.5)
LiBr (2.5)
LiBr (1.2)
LiCl (2.5)
LiCl (2.5)
MeCN
EtOH
DCM
EtOH
EtOH
MeCN
MeCN
MeCN
DCM
MeCN
DCM
DCM
DCM
RT
RT
RT
RT
RT
RT
RT
RT
1
1
5a, 78
5a, 82
5a, 82
5a, 85
6a, 20
6a, 31
6a, 38
6a, 75
6a, 88
3
2
4
1
5
2
6
1
7
PhICl2
1
8
Koser’s reagent
Koser’s reagent
Koser’s reagent
Koser’s reagent
Koser’s reagent
Koser’s reagent
LiCl (2.4)
LiCl (2.4)
LiCl (1.2)
LiCl (1.2)
24
18
24
24
24
1
9
0 °C
RT
b
10
11
12
13
6a, 33
c
RT
6a, 73
d
0 °C to RT
0 °C
7a, 20
LiBr (1.2)
5a, 89
a
b
c
Isolated yields. The desired product was obtained in a mixture with 7a (31%). The desired product was obtained in a mixture with 7a (15%).
Along with 20% of mono-Cbz adduct 7a′.
d
B
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Table 2. Substrate Scope for the Bromo- and Chlorocyclization of Allylic Guanidines
a
b
c
Isolated yields; quant.: quantitative yield. X-ray analysis confirmed the structure of both diastereomers. X-ray analysis confirmed the relative
d
e
configuration and the position of the remaining Cbz group. X-ray analysis of the mono-deprotected 9d′ confirmed the relative configuration. X-ray
analysis of the mono-deprotected 5g′ confirmed the relative configuration.
which proceeded smoothly to give 89% yield of the desired
product 5a (entry 13).
some strong discrepancies between the bromo- and chlorocyc-
lization processes were observed (entry 3). On the one hand,
the bromocyclization proceeded in an exo fashion to give a
mixture of bis- and mono-protected diastereoisomers 5c and
5c′, respectively. On the other hand, the chlorocyclization of 4c
exclusively led to mono-protected guanidines, though as a
mixture of exo and endo adducts, 6c′ and 9c′, respectively. In
the cases of cinnamyl, prenyl, and methallyl derivatives 4d−f,
the endo mode became exclusive for both halides, leading to six-
We then went on to explore the scope of both processes
starting with diversely substituted allylic guanidines (Table 2).
First, the Cbz protecting groups of 4a (entry 1) were replaced
by Boc groups (4b). The reaction still proceeded but with a
decreased efficiency (entry 2) aggravated by the moderate
stability of the t-butylcarbamate group on silica gel. The N-Cbz-
protected E-crotyl derivative 4c is the only substrate for which
C
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membered halo-guanidines (entries 4−6). Interestingly, starting
from 4d, the process yielded only single diastereoisomers of
adducts 8d′ (mono-protected) and 9d; for both compounds,
the relative configuration was confirmed by X-ray analysis.27 In
this case, as well as that of the prenyl derivative 4e, the
divergence in cyclization mode (from 5-exo to 6-endo) may be
due to the stabilization of a positive charge (whether a
carbocation or a partial transient charge) at the 6-position.
However, in the case of methallyl derivative 4f, steric hindrance
at the 5-position may rather be the determining factor. For
cyclohexenyl compound 4g, the 5-exo cyclization mode was
fully re-established to yield the corresponding halo spiro
compounds 5g and 6g (entry 7). Easily accessing this
chlorinated spiro-guanidine framework is particularly interest-
ing when considering the tremendous synthetic efforts that
have recently been devoted to generate this type of scaffold.18
Finally, bis-allylic substrate 4h was subjected to the reaction
conditions and cleanly afforded monoallylated guanidines 5h
and 6h, which were obtained in excellent yields (entry 8).
While the substrate scope was quite general for allylic
derivatives, some limitations were evidenced (Figure 2). First,
only led to complex mixtures due to a lack of selectivity of both
brominating and chlorinating processes.
Regardless, the halo-cyclization reaction was still operative
when longer unsaturated chains were appended to the
guanidine moiety (Table 3). Homoallylic guanidine 4l yielded
the corresponding six-membered bromo- and chloro-adducts
with good yields, concomitant with the partial (chloro) or total
(bromo) loss of one Cbz group in the final product (entry 1).
In both cases, the cyclization mode was exclusively exo as it
was for the substrate having an additional methyl on the double
bond 4m (entry 2). Contrary to what was observed for the
methallyl substrate 4f, no product of endocyclization could be
detected for substrate 4m, presumably because the formation of
a seven-membered ring is highly disfavored. Nevertheless, the
seven-membered ring can be obtained, albeit in moderate yield,
through the exo cyclization of pentenyl derivative 4n (entry 3).
In order to appreciate the synthetic potential of the
compounds prepared by our methodology, the five-membered
bromo guanidine 5a was subjected to several transformations.
First, the bromide could be converted to nitrile 10 in a modest
(unoptimized) 33% yield (Scheme 3). This homologation
could serve as the basis for the synthesis of tiruchanduramine,
an α-glucosidase inhibitor that has been isolated from Synoicum
macroglossum.28 Substitution by an azide to give 11, which can
thereafter be reduced to the corresponding primary amine 12,
was also possible. This simple synthon can be viewed as an
easily accessible precursor for synthesizing analogues of
anatoxin-a(s), a highly potent anticholinesterase isolated from
the green alga Anabaena flos-aquae.29
Figure 2. Substrate limitations.
mono-protected guanidine 4i failed to react under the optimal
reaction conditions (using either LiBr or LiCl). This was also
true for the di-protected propargylic derivative 4j that remained
virtually untouched, which noticeably differs from metal-
catalyzed strategies.12−14 Finally, geranyl-derived substrate 4k
In summary, either the bromo- or the chlorocyclization of
unsaturated guanidines can be achieved through Koser’s
reagent-mediated umpolung of the corresponding lithium
halide. This versatile and tunable transformation tolerates a
wide substrate scope, and depending on the substitution
Table 3. Substrate Scope for the Bromo- and Chlorocyclization of Unsaturated Guanidines
a
b
Isolated yields. X-ray analysis confirmed the structure and the position of the remaining Cbz group.
D
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Scheme 3. Substrate Diversification
N-Allyl-N′,N″-bis-Cbz-guanidine (4a). Following GP1 using 0.8
pattern of the starting olefin, various functionalized rings were
obtained in moderate to high yields with overall good regio-
and stereoselectivity. These compounds can serve as linchpins
toward biologically relevant compounds, a line of research that
is currently pursued in our group. Additionally, implementation
of an asymmetric version of these transformations, using chiral
hypervalent iodine reagents,30 can be envisioned and will be
investigated.
mL (0.57 g, 10 mmol, 2 equiv) of allylamine. 1.671 g, 91% yield,
1
colorless oil; H NMR (500 MHz, CDCl3) δ 11.80 (brs, 1H), 8.44
(brs, 1H), 7.44−7.31 (m, 10H), 5.91 (ddt, J = 17.4, 10.4, 5.5 Hz, 1H),
5.27 (d, J = 17.4 Hz, 1H), 5.21 (d, J = 10.4 Hz, 1H), 5.21 (s, 2H), 5.17
(s, 2H), 4.12−4.09 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 163.9,
156.0, 154.0, 136.9, 134.8, 133.1, 128.9, 128.8, 128.6, 128.5, 128.3,
128.1, 117.0, 68.3, 67.3, 43.5; IR (neat) 3336, 1728, 1634, 1572, 1418,
1382, 1318, 1239, 1207, 1134, 1055, 742, 697 cm−1; HRMS calcd for
C20H21N3O4, (M + H)+ 368.1610 found, 368.1604. Data in accordance
with those described in the literature.15g
N-Allyl-N′,N″-bis-Boc-guanidine (4b). To a solution of S-methyl-
N,N′-bis(tert-butoxycarbonyl)isothiourea (2.06 mmol, 595 mg, 1
equiv) in acetonitrile (60 mL) was added allylamine (0.30 mL, 228
mg, 4.0 mmol, 2 equiv). The solution was stirred under argon for 24 h
at room temperature. The solvent was removed under reduced
pressure to afford 597 mg, 97% yield, of the product as a light yellow
solid; 1H NMR (500 MHz, CDCl3) δ 11.45 (brs, 1H), 8.32 (brs, 1H),
5.83−5.78 (m, 1H), 5.17−5.07 (m, 2H), 4.00−3.97 (m, 2H), 1.41 (s,
18H); 13C NMR (75 MHz, CDCl3) δ 163.3, 155.8, 153.0, 133.1,
116.4, 82.8, 79.0, 43.0, 28.0, 27.8. Data in accordance with those
described in the literature.15g
EXPERIMENTAL SECTION
■
General Methods. Melting points were measured in capillary
tubes and are uncorrected. 1H and 13C NMR spectra were recorded on
a 300 or 500 MHz NMR spectrometer. 13C NMR spectra were
recorded at 125 or 75 MHz using a broadband decoupled mode with
the multiplicities obtained using a DEPT sequence. NMR experiments
were carried out in CDCl3, for which chemical shifts (δ) are reported
in parts per million (ppm) with reference to CDCl3 (1H: 7.26; 13C:
77.36) and MeOD, for which chemical shifts (δ) are reported in parts
per million (ppm) with reference to MeOD (1H: 3.34; 13C: 49.86).
Coupling constants (J) are reported in hertz (Hz). Mass spectra were
obtained either with a LCT instrument using electrospray ionization
(ES) or from a time-of-flight analyzer (ESI-MS) for the high-
resolution mass spectra (HRMS). Flash chromatography was
conducted on silica gel 60 (40-63 μm) at medium pressure (300
mbar). All reagents were obtained from commercial suppliers unless
otherwise stated. Allylamine, geranylamine, and propargylamine were
commercially available. 3-Methylbut-2-en-1-amine hydrochloride, 2-
methylprop-2-en-1-amine hydrochloride, but-2-en-1-amine hydro-
chloride, but-3-en-1-amine hydrochloride, (E)-3-phenylprop-2-en-1-
amine hydrochloride, and pent-4-en-1-amine hydrochloride were
synthesized from the corresponding bromides by a previously reported
two-step sequence (potassium phthalimide addition, followed by
hydrazine-mediated deprotection).15g 3-Methylbut-3-en-1-amine was
synthesized from the corresponding alcohol by a previously reported
two-step sequence (phthalimide addition under Mitsunobu conditions,
followed by hydrazine-mediated deprotection).15g Cyclohex-1-en-1-
ylmethanamine hydrochloride was synthesized from the corresponding
ester by a four-step sequence (reduction and bromination,31 then
potassium phthalimide addition, followed by hydrazine-mediated
deprotection15g).
N-But-2-enyl-N′,N″-bis-Cbz-guanidine (4c). Following GP1′ using
108 mg (1 mmol, 2 equiv) of but-2-en-1-amine hydrochloride. 91 mg,
1
48% yield, white solid; H NMR (300 MHz, CDCl3) δ 11.64 (brs,
1H), 8.17 (brs, 1H), 7.31−7.15 (m, 10H), 5.60−5.53 (m, 1H), 5.44−
5.36 (m, 1H), 5.06 (s, 2H), 5.02 (s, 2H), 3.90−3.85 (m, 2H), 1.60−
1.55 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 164.0, 155.9, 154.1,
137.1, 134.9, 134.1, 129.0, 128.9, 128.7, 128.6, 128.4, 128.2, 125.8,
68.4, 67.4, 43.3, 18.0; IR (neat) 3340, 3034, 2939, 1727, 1600, 1568,
1425, 1381, 1318, 1205, 1133, 1052 cm−1; HRMS calcd for
C21H23N3O4, (M + H)+ 382.1767 found, 382.1758.
N-(E)-3-Phenylprop-2-enyl-N′,N″-bis-Cbz-guanidine (4d). Follow-
ing GP1′ using 170 mg (1 mmol, 2 equiv) of (E)-3-phenylprop-2-en-
1-amine hydrochloride. 122 mg, 55% yield, white solid.(The product
was contaminated with ca. 30% of N-3-phenylpropanyl-N′,N″-bis-Cbz-
1
guanidine that was unreactive under the cyclization conditions); H
NMR (300 MHz, CDCl3) δ 11.67 (brs, 1H), 8.34 (brs, 1H), 7.30−
7.08 (m, 15H), 6.44 (d, J = 15.8 Hz, 1H), 6.10 (dt, J = 15.8, 6.3 Hz,
1H), 5.07 (s, 2H), 5.03 (s, 2H), 4.12 (dd, J = 6.0, 6.2 Hz, 2H); 13C
NMR (75 MHz, CDCl3) δ 163.9, 156.1, 154.1, 137.0, 136.6, 134.9,
133.0, 129.0, 128.9, 128.8, 128.7, 128.6, 128.4, 128.2, 128.1, 126.7,
124.4, 68.5, 67.5, 43.3; IR (neat) 3337, 3031, 2949, 1726, 1633, 1618,
1566, 1422, 1380, 1353, 1315, 1201, 1131, 1048 cm−1; HRMS calcd
for C26H25N3O4, (M+H)+ 444.1923 found, 444.1918.
General Procedure 1: Guanidine Synthesis. To a solution of
1,3-bis(benzoxycarbonyl)-2-methyl-2-isothiourea (0.5 mmol, 179 mg,
1 equiv) in MeCN (15 mL) was added the amine (1 mmol, 2 equiv).
The solution was stirred under argon for 20−48 h at room
temperature. The solvent was removed under reduced pressure to
give the crude product, which was purified by flash column
chromatography on silica gel (17:3 nHept/EtOAc).
N-3-Methylbut-2-enyl-N′,N″-bis-Cbz-guanidine (4e). Following
GP1′ using 122 mg (1 mmol, 2 equiv) of 3-methylbut-2-en-1-amine
1
hydrochloride. 83 mg, 42% yield, white solid; H NMR (300 MHz,
CDCl3) δ 11.62 (brs, 1H), 8.02 (brs, 1H), 7.31−7.15 (m, 10H), 5.15−
5.11 (m, 1H), 5.06 (s, 2H), 5.03 (s, 2H), 3.90−3.86 (m, 2H), 1.62 (s,
3H), 1.56 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 163.6, 155.5, 153.8,
137.6, 136.8, 134.6, 128.7, 128.6, 128.3, 128.1, 127.8, 118.7, 68.0, 67.1,
General Procedure 1′: Guanidine Synthesis. The procedure
was identical to GP1 except that triethylamine (1 mmol, 0.14 mL, 101
mg, 2 equiv) was added to the reaction mixture before addition of the
amine hydrochloride (1 mmol, 2 equiv).
E
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39.3, 25.6, 17.9; IR (neat) 3341, 3065, 2994, 1727, 1622, 1567, 1425,
1381, 1331, 1304, 1240, 1203, 1134, 1053 cm−1; HRMS calcd for
C22H25N3O4, (M + H)+ 396.1923 found, 396.1916. Data in accordance
with those described in the literature.15g
yield, yellow oil; 1H NMR (300 MHz, CDCl3) δ 11.64 (brs, 1H), 8.05
(brs, 1H), 7.31−7.15 (m, 10H), 5.13 (t, J = 6.6 Hz, 1H), 5.06 (s, 2H),
5.03 (s, 2H), 4.97 (t, J = 7.0 Hz, 1H), 3.93−3.89 (m, 2H), 2.02−1.88
(m, 4H), 1.58 (s, 3H), 1.56 (s, 3H), 1.49 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 163.9, 155.9, 154.1, 141.2, 136.9, 135.0, 131.9, 129.0, 128.9,
128.7, 128.6, 128.4, 128.1, 124.0, 118.9, 68.3, 67.4, 39.7, 39.5, 26.6,
25.9, 18.0, 16.7; IR (neat) 3340, 2924, 1727, 1635, 1619, 1565, 1423,
1380, 1301, 1236, 1201, 1129, 1050 cm−1; HRMS calcd for
C27H33N3O4, (M + H)+ 464.2549 found, 464.2540.
N-2-Methylprop-2-enyl-N′,N″-bis-Cbz-guanidine (4f). Following
GP1′ using 108 mg (1 mmol, 2 equiv) of 2-methylprop-2-en-1-amine
1
hydrochloride. 117 mg, 61% yield, colorless oil; H NMR (500 MHz,
CDCl3) δ 11.67 (brs, 1H), 8.34 (brs, 1H), 7.14−7.29 (m, 10H), 5.07
(s, 2H), 5.01 (s, 2H), 4.78−4.77 (m, 2H), 3.90 (d, J = 5.5 Hz, 2H),
1.65 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 164.0, 156.3, 154.1,
140.9, 137.0, 134.9, 129.0, 128.9, 128.7, 128.6, 128.4, 128.2, 111.5,
68.5, 67.5, 46.7, 20.8; IR (neat) 3338, 3034, 2924, 1717, 1633, 1619,
1571, 1422, 1381, 1314, 1232, 1135, 1093, 1043 cm−1; HRMS calcd
for C21H23N3O4, (M + H)+ 382.1767 found, 382.1769.
N-Methylcyclohex-1-enyl-N′,N″-bis-Cbz-guanidine (4g). Follow-
ing GP1′ using 148 mg (1 mmol, 2 equiv) of cyclohex-1-en-1-
ylmethanamine hydrochloride. 136 mg, 64% yield, yellow oil; 1H
NMR (300 MHz, CDCl3) δ 11.67 (brs, 1H), 8.22 (brs, 1H), 7.30−
7.16 (m, 10H), 5.51−5.50 (m, 1H), 5.07 (s, 2H), 5.01 (s, 2H), 3.83 (d,
J = 4.7 Hz, 2H), 1.91−1.84 (m, 4H), 1.54−1.43 (m, 4H); 13C NMR
(75 MHz, CDCl3) δ 163.8, 155.9, 153.8, 136.7, 134.6, 133.0, 128.8,
128.7, 128.4, 128.4, 128.1, 127.9, 123.8, 68.1, 67.1, 47.0, 26.6, 25.0,
22.4, 22.2; IR (neat) 3341, 2931, 2606, 2499, 1727, 1640, 1571, 1437,
1383, 1319, 1230, 1206, 1127, 1052 cm−1; HRMS calcd for
C24H27N3O4, (M + H)+ 422.2080 found, 422.2065.
N-Diallyl-N′,N″-bis-Cbz-guanidine (4h). To a solution of diallyl-
amine (70 μL, 58 mg, 0.6 mmol, 1.2 equiv) in DCM (3 mL) was
added 1,3-bis(benzoxycarbonyl)-2-methyl-2-thiopseudourea (179 mg,
0.5 mmol, 1 equiv) in DCM (2 mL). Then, silver triflate (180 mg, 0.7
mmol, 1.4 equiv) was added. The solution was stirred under argon for
62 h at room temperature. Water was added, and the solution was
extracted with DCM (2 × 10 mL). The combined organic phases were
dried with MgSO4, filtered, and evaporated under reduced pressure to
give the crude product. Flash column chromatography (17:3 nHept/
EtOAc) afforded 85 mg, 42% yield, of the product as a colorless oil. 1H
NMR (300 MHz, CDCl3) δ 10.27 (brs, 1H), 7.36−7.28 (m, 10H),
5.88−5.75 (m, 2H), 5.23 (s, 2H), 5.19 (d, J = 6.7 Hz, 1H), 5.187 (d, J
= 6.7 Hz, 1H), 5.15 (d, J = 6.9 Hz, 4H), 4.06−4.03 (m, 4H); 13C
NMR (75 MHz, CDCl3) δ 163.3, 156.0, 136.9, 135.5, 132.6, 128.9,
128.8, 128.7, 128.5, 128.2, 119.1, 68.4, 67.7, 51.2, 1CO not visible; IR
(neat) 3150, 3033, 2949, 1752, 1641, 1600, 1483, 1442, 1411, 1378,
1276, 1251, 1212, 1173, 1108 cm−1; HRMS calcd for C23H25N3O4, (M
+ H)+ 408.1923 found, 408.1916.
N-But-3-enyl-N′,N″-bis-Cbz-guanidine (4l). Following GP1′ using
108 mg (1 mmol, 2 equiv) of but-3-en-1-amine hydrochloride. 121 mg,
1
63% yield, white solid; H NMR (300 MHz, CDCl3) δ 11.64 (brs,
1H), 8.23 (brs, 1H), 7.15−7.31 (m, 10H), 5.68 (ddt, J = 16.8, 10.2, 6.9
Hz, 1H), 5.07−5.01 (m, 2H), 5.07 (s, 2H), 5.03 (s, 2H), 3.42 (td, J =
6.8, 5.4 Hz, 2H), 2.23 (tdt, J = 6.8, 6.6, 1.1 Hz, 2H); 13C NMR (75
MHz, CDCl3) δ 163.8, 156.2, 154.0, 137.0, 134.9, 129.0, 128.9, 128.6,
128.6, 128.4, 128.1, 118.0, 66.3, 67.4, 40.5, 33.3; IR (neat) 3338, 3128,
2952, 1729, 1640, 1572, 1426, 1382, 1322, 1263, 1213, 1138, 1054
cm−1; HRMS calcd for C21H23N3O4, (M + H)+ 382.1767 found,
382.1786.
N-3-Methylbut-3-enyl-N′,N″-bis-Cbz-guanidine (4m). Following
GP1 using 85 mg (1 mmol, 2 equiv) of 3-methylbut-3-en-1-amine. 151
mg, 76% yield, white solid; 1H NMR (500 MHz, CDCl3) δ 11.62 (brs,
1H), 8.19 (brs, 1H), 7.30−7.15 (m,10H), 5.08 (s, 2H), 5.02 (s, 2H),
4.77 (s, 1H), 4.69 (s, 1H), 3.47 (td, J = 6.8, 5.2 Hz, 2H), 2.19 (t, J =
6.8 Hz, 2H), 1.64 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 164.0,
156.2, 154.1, 142.2, 136.9, 135.0, 129.0, 129.0, 128.7, 128.7, 128.4,
128.2, 113.2, 68.4, 67.4, 39.3, 37.0, 22.3; IR (neat) 3336, 3034, 2893,
1728, 1625, 1621, 1565, 1423, 1314, 1235, 1199, 1133, 1042 cm−1;
HRMS calcd for C22H25N3O4, (M + H)+ 396.1923 found, 396.1911.
Data in accordance with those described in the literature.15g
N-Pent-4-enyl-N′,N″-bis-Cbz-guanidine (4n). Following GP1′
using 122 mg (1 mmol, 2 equiv) of pent-4-en-1-amine hydrochloride.
191 mg, 96% yield, white solid; 1H NMR (300 MHz, CDCl3) δ 11.78
(brs, 1H), 8.35 (brs, 1H), 7.43−7.30 (m, 10H), 5.82 (ddt, J = 16.9,
9.9, 6.8 Hz, 1H), 5.20 (s, 2H), 5.15 (s, 2H), 5.05−5.00 (m, 2H), 3.47
(td, J = 7.0, 6.0 Hz, 2H), 2.14 (td, J = 7.2, 6.8 Hz, 2H), 1.71 (tt, J = 7.0,
7.0 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 164.0, 156.2, 154.2, 137.6,
137.1, 134.9, 129.0, 128.9, 128.7, 128.6, 128.4, 128.1, 115.8, 68.4, 67.4,
40.8, 31.2, 28.4; IR (neat) 3319, 2928, 1720, 1637, 1621, 1578, 1431,
1256, 1209, 1137, 1050 cm−1; HRMS calcd for C22H25N3O4, (M +
H)+ 396.1923 found, 396.1920. Data in accordance with those
described in the literature.21c
N-Allyl-N′-Cbz-guanidine (4i). To a solution of (N)-benzyloxy-
carbonyl-1H-pyrazole-1-carboxamidine32 (4.2 mmol, 1.026 g, 1 equiv)
was added allylamine (40 mmol, 2.289 g, 3.0 mL, 9.5 equiv). The
solution was stirred under argon for 2 h 30 min at 35 °C. The solution
was cooled to room temperature, and the solvent was removed under
reduced pressure to give the crude product. Flash column
chromatography on silica gel (gradient from 15:5 to 0/20 nHept/
EtOAc) afforded 0.806 g, 82% yield, of the product as a yellow solid.
1H NMR (300 MHz, CDCl3) δ 7.94 (brs, 1H), 7.57−7.58 (m, 1H),
7.35−7.27 (m, 4H), 5.74−5.64 (m, 1H), 5.23 (d, J = 17.1 Hz, 1H),
5.16 (d, J = 10.3 Hz, 1H), 5.07 (s, 2H), 3.69 (d, J = 5.3 Hz, 2H); 13C
NMR (75 MHz, CDCl3) δ 163.7, 162.6, 137.5, 133.7, 128.6, 128.2,
128.0, 117.1, 66.4, 43.8. Data in accordance with those described in the
literature.15g
Benzyl 2-(((Benzyloxy)carbonyl)imino)-5-((tosyloxy)methyl)-
imidazolidine-1-carboxylate (7a) and (2-(((Benzyloxy)carbonyl)-
imino)imidazolidin-4-yl)methyl 4-Methylbenzenesulfonate (7a′). A
solution of guanidine 4a (37 mg, 0.1 mmol, 1 equiv) in DCM (2.5
mL) was cooled to 0 °C. Koser’s reagent (0.12 mmol, 47 mg, 1.2
equiv) was added, and the solution was stirred for 24 h at 0 °C and
then for 48 h at room temperature. The solvent was removed under
reduced pressure to give the crude product. Flash column
chromatography (DCM + 1.5% MeOH) afforded 11 mg (0.02
mmol, 20% yield) of the product 7a as a white solid and 8 mg (0.02
1
mmol, 20% yield) of the product 7a′ as a white solid. H NMR (300
MHz, CDCl3) δ 7.70 (d, J = 8.0 Hz, 2H), 7.41−7.27 (m, 12H), 5.19
(s, 2H), 5.14 (s, 2H), 4.46−4.43 (m, 1H), 4.18−4.09 (m, 2H), 3.77−
3.75 (m, 1H), 3.67−3.57 (m, 1H), 3.48−3.44 (m, 1H), 2.40 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 164.4, 145.6, 135.5, 132.5, 130.3, 129.0,
128.8, 128.7, 128.6, 128.5, 128.4, 128.3, 128.2, 69.0, 68.6, 67.8, 54.3,
44.2, 21.9, 3C not visible; IR (neat) 3345, 2893, 1760, 1712, 1653,
1598, 1306, 1237, 1163, 1025 cm−1; HRMS calcd for C27H27N3O7S,
(M + Na)+ 560.1467 found, 560.1485.
N-Propargyl-N′,N″-bis-Cbz-guanidine (4j). Following GP1 using
0.13 mL (110 mg, 2 mmol, 2 equiv) of propargylamine. Evaporation of
the reaction mixture afforded 365 mg, quantitative yield, of the
1
product as a yellow oil. H NMR (300 MHz, CDCl3) δ 11.60 (brs,
1H), 8.35 (brs, 1H), 7.31−7.17 (m, 10H), 5.07 (s, 2H), 5.03 (s, 2H),
4.12 (dd, J = 5.1, 2.7 Hz, 2H), 2.18 (t, J = 2.7 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ 163.6, 155.6, 153.8, 136.7, 134.6, 129.0, 128.8, 128.6,
128.6, 128.3, 128.1, 78.6, 72.6, 68.5, 67.5, 31.0; IR (neat) 3336, 3289,
3034, 1728, 1617, 1563, 1424, 1380, 1346, 1310, 1288, 1237, 1201,
1133, 1085, 1050 cm−1; HRMS calcd for C20H19N3O4, (M + H)+
366.1454 found, 366.1440.
1H NMR (300 MHz, CDCl3) δ 7.72 (d, J = 8.1 Hz, 2H), 7.31−7.29
(m, 7H), 4.97 (s, 2H), 4.03−3.96 (m, 1H), 3.89−3.82 (m, 2H), 3.62
(dd, J = 9.5, 9.5 Hz, 1H), 3.34 (dd, J = 9.5, 5.8 Hz, 1H), 2.43 (s, 3H), 2
NH not visible; IR (neat) 3376, 3066, 2921, 2850, 1647, 1610, 1364,
1305, 1292, 1244, 1174, 1127, 1086, 956 cm−1; HRMS calcd for
C19H21N3O5S, (M + H)+ 404.1280 found, 404.1286.
N-Geranyl-N′,N″-bis-Cbz-guanidine (4k). Following GP1 using
0.18 mL (153 mg, 1 mmol, 2 equiv) of geranylamine. 218 mg, 94%
General Procedure for Bromocyclization. A solution of
guanidine 4 (0.1 mmol, 1 equiv) and LiBr (0.12 mmol, 10 mg, 1.2
F
DOI: 10.1021/acs.joc.5b01750
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
equiv) in DCM (2.5 mL) was cooled to 0 °C. Koser’s reagent (0.12
mmol, 47 mg, 1.2 equiv) was added, and the solution was stirred for
1−4 h at 0 °C. The solvent was removed under reduced pressure to
give the crude product, which was purified by flash column
chromatography on silica gel (DCM + 1−1.5% MeOH).
129.9, 129.8, 129.6, 70.5, 62.2, 61.3, 53.9, 41.8, 24.5, 3C not visible; IR
(neat) 3389, 2974, 1745, 1655, 1620, 1498, 1455, 1382, 1290, 1083
cm−1; HRMS calcd for C21H2279BrN3O4, (M + H)+ 460.0872, found
460.0871.
(5R*,6S*)-Benzyl 2-(((Benzyloxy)carbonyl)imino)-6-bromo-1,3-
diazaspiro[4.5]decane-1-carboxylate (5g). 33 mg, 66% yield, yellow
oil; the product is not stable in CDCl3. Attempts to recrystallize 5g in
CH2Cl2 led to the formation of crystals of mono-deprotected 5g′ that
were suitable for X-ray analysis; 1H NMR (300 MHz, MeOD) δ 7.51−
7.49 (m, 2H), 7.41−7.29 (m, 8H), 5.32 (s, 2H), 5.19−5.10 (m, 2H),
3.90 (d, J = 11.8 Hz, 1H), 3.66 (d, J = 11.8 Hz, 1H), 2.42−2.33 (m,
1H), 2.24 (d, J = 13.3 Hz, 1H), 1.98 (d, J = 13.3 Hz, 1H), 1.81−1.64
(m, 4H), 1.47−1.27 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 163.8,
157.7, 137.4, 128.8, 128.7, 128.6, 128.4, 128.2, 128.1, 68.8, 67.6, 55.4,
34.7, 34.2, 26.5, 22.3, 3C and 1CH not visible; IR (neat) 3335, 2941,
2865, 1713, 1649, 1620, 1436, 1382, 1326, 1294, 1264, 1162, 1138,
1118 cm−1; HRMS calcd for C24H2679BrN3O4, (M + H)+ 500.1184,
found 500.1183.
Benzyl 2-(((Benzyloxy)carbonyl)imino)-5-(bromomethyl)-
imidazolidine-1-carboxylate (5a). 40 mg, 89% yield, white solid;
1H NMR (500 MHz, MeOD) δ 7.49−7.47 (m, 2H), 7.42−7.40 (m,
2H), 7.38−7.31 (m, 6H), 5.36 (d, J = 12.4 Hz, 1H), 5.27 (d, J = 12.4
Hz, 1H), 5.18−5.12 (m, 2H), 4.66−4.62 (m, 1H), 3.86−3.84 (m, 1H),
3.78−3.75 (m, 1H), 3.63−3.57 (m, 2H); 13C NMR (75 MHz, CDCl3)
δ 150.8, 136.4, 134.9, 128.6, 128.4, 128.3, 128.0, 127.9, 68.5, 67.3, 55.6,
44.9, 32.9, 2C not visible; IR (neat) 3350, 1763, 1713, 1654, 1616,
1439, 1395, 1313, 1152, 740, 698 cm−1; HRMS calcd for
C20H2079BrN3O4, (M + H)+ 446.0715, found 446.0721.
tert-butyl 5-(Bromomethyl)-2-((tert-butoxycarbonyl)imino)-
imidazolidine-1-carboxylate (5b). 18 mg, 47% yield, colorless oil;
1H NMR (300 MHz, MeOD) δ 4.48−4.53 (m, 1H), 3.91 (dd, J = 13.0,
Benzyl 3-Allyl-2-(((benzyloxy)carbonyl)imino)-5-(bromomethyl)-
imidazolidine-1-carboxylate (5h). 46 mg, 95% yield, colorless oil;
1H NMR (500 MHz, CDCl3) δ 7.38−7.26 (m, 10H), 5.77 (ddt, J =
9.8 Hz, 1H), 3.80 (dd, J = 10.2, 5.9 Hz, 1H), 3.59−3.65 (m, 2H), 1.58
(s, 9H), 1.52 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 86.1, 82.8, 58.1,
36.6, 29.2, 29.1, 4C not visible; IR (neat) 3314, 2978, 2931, 1760,
1706, 1650, 1606, 1530, 1368, 1248, 1140 cm−1; HRMS calcd for
C14H2479BrN3O4, (M + H)+ 378.1028 found, 378.1022.
17.3, 9.6, 6.4 Hz, 1H), 5.29−5.28 (m, 1H), 5.25−5.23 (m, 1H), 5.18
(d, J = 12.3 Hz, 1H), 5.06 (d, J = 8.2 Hz, 1H), 5.02 (d, J = 8.2 Hz,
1H), 4.98 (d, J = 12.3 Hz, 1H), 4.53 (dddd, J = 8.7, 8.5, 2.8, 2.6 Hz,
1H), 4.0 (d, J = 6.4 Hz, 2H), 3.65−3.58 (m, 2H), 3.47 (dd, J = 10.3,
8.7 Hz, 1H), 3.36 (dd, J = 10.7, 2.6 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 159.8, 151.4, 150.9, 137.1, 135.0, 131.3, 128.9, 128.8, 128.6,
128.5, 127.9, 120.0, 69.0, 67.5, 55.9, 47.8, 47.2, 32.9; IR (neat) 3033,
2952, 1753, 1712, 1615, 1487, 1455, 1389, 1260, 1190, 1109, 1026
cm−1; HRMS calcd for C23H2479BrN3O4, (M + H)+ 486.1028, found
486.1052.
Benzyl (4-(Bromomethyl)tetrahydropyrimidin-2(1H)-ylidene)-
carbamate (5l′). 17 mg, 52% yield, white solid; mp: 151−155 °C
(CH2Cl2);1H NMR (300 MHz, MeOD) δ 7.40−7.29 (m, 5H), 5.07
(s, 2H), 3.78−3.75 (m, 1H), 3.64−3.59 (m, 1H), 3.55−3.49 (m, 1H),
3.40−3.37 (m, 2H), 2.10−2.04 (m, 1H), 1.94−1.88 (m, 1H); 13C
NMR (75 MHz, CDCl3) δ 163.5, 158.9, 137.7, 128.7, 128.4, 128.1,
66.5, 49.8, 36.2, 34.6, 30.0; IR (neat) 3250, 2922, 1630, 1561, 1455,
1387, 1341, 1245, 1158, 1052 cm−1; HRMS calcd for C13H1679BrN3O2,
(M + H)+ 326.0504, found 326.0510.
Benzyl 2-(((Benzyloxy)carbonyl)imino)-6-(bromomethyl)-6-
methyltetrahydropyrimidine-1(2H)-carboxylate (5m). 23 mg, 49%
yield, colorless oil; the product is not stable in CDCl3; 1H NMR (300
MHz, MeOD) δ 7.44−7.27 (m, 10H), 5.23 (s, 2H), 5.12 (d, J = 12.2
Hz, 1H), 5.06 (d, J = 12.2 Hz, 1H), 4.05 (d, J = 10.6 Hz, 1H), 3.77 (d,
J = 10.6 Hz, 1H), 3.41−3.37 (m, 2H), 2.41−2.32 (m, 1H), 1.96−1.87
(m, 1H), 1.52 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 137.4, 134.9,
129.0, 128.9, 128.8, 128.6, 128.6, 128.4, 128.3, 128.1, 128.0, 70.3, 67.2,
51.8, 40.7, 36.1, 30.1, 23.6, 3C not visible; IR (neat) 3256, 2927, 1742,
1631, 1608, 1497, 1455, 1384, 1348, 1262, 1228, 1160, 1083 cm−1;
HRMS calcd for C22H2479BrN3O4, (M + H)+ 474.1028, found
474.1034.
Benzyl 2-(((Benzyloxy)carbonyl)imino)-5-(1-bromoethyl)-
imidazolidine-1-carboxylate (5c). 12 mg, 47% yield, mixture of two
1
diastereoisomers (2:1), white solid, mp: 144−146 °C (CH2Cl2); H
NMR (500 MHz, MeOD) δ 7.48−7.47 (m, 2H), 7.41−7.32 (m, 8H),
5.39−5.34 (m, 1H), 5.28−5.25 (m, 1H), 5.19−5.09 (m, 2H), 4.77−
4.70 (m, 1H), 4.61−4.42 (m, 1H), 4.26−4.27 (m, 1H), 3.95−3.60 (m,
2H), 1.62 (d, J = 7.2 Hz, 3H), 1.55 (d, J = 7.2 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 134.6, 129.0, 128.9, 128.8, 128.7, 128.6, 128.5, 128.3,
128.2, 128.2, 123.9, 69.0, 67.8, 67.7, 66.9, 66.6, 60.2, 58.1, 52.5, 50.1,
50.0, 49.5, 45.0, 44.3, 40.7, 30.0, 21.7, 21.5, 20.5, 17.6, 6C not visible;
IR (neat) 3347, 2955, 1762, 1712, 1651, 1615, 1436, 1396, 1380, 1310,
1265, 1235, 1144, 1026 cm−1; HRMS calcd for C21H2279BrN3O4, (M +
H)+ 460.0872, found 460.0870.
Benzyl (4-(1-Bromoethyl)imidazolidin-2-ylidene)carbamate (5c′).
1
3 mg, 15% yield, one diastereoisomer, white solid; H NMR (300
MHz, MeOD) δ 7.30−7.42 (m, 5H), 5.02 (s, 2H), 4.26−4.31 (m,
1H), 3.86 (dd, J = 14.1, 3.8 Hz, 1H), 3.75−3.80 (m, 1H), 3.56 (dd, J =
14.1, 5.5 Hz, 1H), 1.37 (d, J = 7.1 Hz, 3H).
Benzyl ((4S*,5R*)-5-Bromo-4-phenyltetrahydropyrimidin-2(1H)-
ylidene)carbamate (8d′). 20 mg, 51% yield, white solid; mp: 185−
1
188 °C (CH2Cl2); H NMR (300 MHz, CDCl3) δ 9.82 (brs, 1H),
7.36−7.29 (m, 8H), 7.17−7.15 (m, 2H), 4.97 (d, J = 12.3 Hz, 1H),
4.93 (d, J = 12.3 Hz, 1H), 4.73 (m, 1H), 4.12 (ddd, J = 4.2, 4.2, 3.9 Hz,
1H), 3.43 (dd, J = 14.1, 3.9 Hz, 1H), 3.31 (dd, J = 14.1, 4.2 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ 163.3, 158.3, 140.3, 137.4, 129.2, 128.8,
128.7, 128.5, 128.1, 126.7, 66.5, 60.4, 44.1, 43.1; IR (neat) 3242, 2989,
2855, 1628, 1558, 1454, 1387, 1336, 1245, 1204, 1160, 1052 cm−1;
HRMS calcd for C18H1879BrN3O2, (M + H)+ 388.0655, found
388.0638.
Benzyl 2-(((Benzyloxy)carbonyl)imino)-7-(bromomethyl)-1,3-dia-
zepane-1-carboxylate (5n). 11 mg, 23% yield, colorless oil; the
product is not stable in CDCl3; 1H NMR (300 MHz, MeOD) δ 7.41−
7.29 (m, 10H), 5.19 (s, 2H), 5.18 (d, J = 12.5 Hz, 1H), 5.12 (d, J =
12.5 Hz, 1H), 4.43−4.35 (m, 1H), 3.76−3.71 (m, 1H), 3.51−3.40 (m,
2H), 3.31−3.29 (m, 1H), 2.07−2.02 (m, 1H), 1.97−1.92 (m, 1H),
1.77−1.69 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 135.9, 130.2,
128.8, 128.7, 128.4, 128.3, 128.1, 68.6, 67.8, 56.1, 42.4, 31.4, 27.3, 22.9,
3C not visible; IR (neat) 3266, 2942, 1721, 1615, 1455, 1428, 1384,
1280, 1256, 1213, 1137 cm−1; HRMS calcd for C22H2479BrN3O4, (M +
H)+ 474.1023, found 474.1024.
Benzyl 2-(((Benzyloxy)carbonyl)imino)-5-bromo-6,6-dimethyl-
tetrahydropyrimidine-1(2H)-carboxylate (8e). 27 mg, 57% yield,
1
colorless oil; H NMR (300 MHz, MeOD) δ 7.45−7.48 (m, 2H),
7.35−7.40 (m, 4H), 7.30−7.33 (m, 4H), 5.28 (s, 2H), 5.07 (s, 2H),
4.50 (t, J = 4.5 Hz, 1H), 4.04 (dd, J = 14.6, 4.5 Hz, 1H), 3.73 (dd, J =
14.6, 4.5 Hz, 1H), 1.53 (s, 3H), 1.48 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 159.5, 137.2, 131.0, 128.9, 128.7, 128.6, 128.6, 128.4, 128.3,
128.0, 69.7, 66.4, 49.9, 44.3, 28.6, 25.7, 2C not visible; IR (neat) 3234,
2977, 2875, 1727, 1640, 1553, 1455, 1387, 1345, 1281, 1263, 1144,
1037 cm−1; HRMS calcd for C22H2479BrN3O4, (M + H)+ 474.1028,
found 474.1032.
General Procedure for Chlorocyclization. A solution of
guanidine 4 (0.1 mmol, 1 equiv) and LiCl (0.24 mmol, 10 mg, 2.4
equiv) in DCM (2.5 mL) was cooled to 0 °C. Koser’s reagent (0.12
mmol, 47 mg, 1.2 equiv) was added, and the solution was stirred for
15−24 h at 0 °C. The solvent was removed under reduced pressure to
give the crude product, which was purified by flash column
chromatography on silica gel (DCM + 1−1.5% MeOH).
Benzyl 2-(((Benzyloxy)carbonyl)imino)-5-bromo-5-methyltetra-
hydropyrimidine-1(2H)-carboxylate (8f). 35 mg, 76% yield, light
1
yellow oil; the product is not stable in CDCl3; H NMR (300 MHz,
MeOD) δ 7.48−7.51 (m, 2H), 7.32−7.43 (m, 8H), 5.32 (s, 2H), 5.16
(s, 2H), 4.06 (d, J = 10.7 Hz, 1H), 3.84 (d, J = 11.7 Hz, 1H), 3.64 (d, J
= 10.7 Hz, 1H), 3.52 (d, J = 11.7 Hz, 1H), 1.63 (s, 3H); 13C NMR (75
MHz, MeOD) δ 139.5, 136.0, 130.4, 130.4, 130.3, 130.2, 130.2, 130.0,
G
DOI: 10.1021/acs.joc.5b01750
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The Journal of Organic Chemistry
Article
Benzyl 2-(((Benzyloxy)carbonyl)imino)-5-(chloromethyl)-
imidazolidine-1-carboxylate (6a). 35 mg, 88% yield, white solid;
1H NMR (500 MHz, MeOD) δ 7.48−7.32 (m, 10H), 5.36 (d, J = 12.4
3.90 (d, J = 11.6 Hz, 1H), 3.62 (d, J = 11.6 Hz, 1H), 2.39−2.31 (m,
1H), 2.20−2.11 (m, 1H), 2.07−1.90 (m, 1H), 1.73−1.28 (m, 5H), CH
not visible; 13C NMR (75 MHz, CDCl3) δ 163.5, 157.7, 137.4, 135.2,
128.8, 128.7, 128.6, 128.5, 128.2, 127.9, 68.8, 67.6, 56.0, 48.7, 34.3,
33.8, 25.4, 22.3, 2C not visible; IR (neat) 3331, 2941, 2865, 1713,
1616, 1454, 1457, 1382, 1327, 1291, 1260, 1165, 1120, 1039 cm−1;
HRMS calcd for C24H2635ClN3O4, (M + H)+ 456.1690, found
456.1685.
Hz, 1H), 5.26 (d, J = 12.4 Hz, 1H), 5.18−5.12 (m, 2H), 4.66−4.65
(m, 1H), 3.91−3.83 (m, 2H), 3.74 (dd, J = 11.5, 2.3 Hz, 1H), 3.63
(dd, J = 11.5, 2.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 165.0,
137.0, 135.0, 128.9, 128.8, 128.8, 128.6, 128.4, 128.3, 69.9, 69.0, 67.8,
56.4, 44.2, 2C not visible; IR (neat) 3346, 3033, 1762, 1713, 1653,
1614, 1497, 1438, 1395, 1380, 1238, 1157, 1015, 740, 697 cm−1;
HRMS calcd for C20H2035ClN3O4, (M + H)+ 402.1221, found
402.1223.
Benzyl 3-Allyl-2-(((benzyloxy)carbonyl)imino)-5-(chloromethyl)-
imidazolidine-1-carboxylate (6h). 32 mg, 73% yield, colorless oil;
1H NMR (300 MHz, CDCl3) δ 7.38−7.26 (m, 10 H), 5.76 (ddt, J =
17.2, 9.8, 6.4 Hz, 1H), 5.30−5.28 (m, 1H), 5.25−5.23 (m, 1H), 5.17
(d, J = 12.4 Hz, 1H), 5.06 (d, J = 8.8 Hz, 1H), 5.01 (d, J = 8.8 Hz,
1H), 4.98 (d, J = 12.4 Hz, 1H), 4.51 (dddd, J = 8.5, 8.5, 3.3, 2.4 Hz,
1H), 4.02−3.97 (m, 2H), 3.76 (dd, J = 11.1, 3.3 Hz, 1H), 3.65−3.58
(m, 2H), 3.38 (dd, J = 10.6, 2.4 Hz, 1H); 13C NMR (75 MHz, CDCl3)
δ 159.8, 151.4, 151.0, 137.1, 135.0, 131.4, 128.9, 128.8, 128.5, 128.0,
120.0, 69.0, 67.5, 56.1, 47.8, 46.3, 44.0; IR (neat) 3033, 2923, 1751,
1712, 1613, 1487, 1455, 1388, 1251, 1191, 1107, 1009 cm−1; HRMS
calcd for C23H2435ClN3O4, (M + H)+ 442.1528, found 442.1526.
Benzyl 2-(((Benzyloxy)carbonyl)imino)-6-(chloromethyl)tetra-
hydropyrimidine-1(2H)-carboxylate (6l). 8 mg, 19% yield, white
tert-Butyl 2-((tert-Butoxycarbonyl)imino)-5-(chloromethyl)-
imidazolidine-1-carboxylate (6b). 19 mg, 58% yield, white solid;
1H NMR (300 MHz, MeOD) δ 4.55−4.50 (m, 1H), 3.94−3.87 (m,
2H), 3.74 (dd, J = 11.5, 2.6 Hz, 1H), 3.67 (dd, J = 13.0, 3.9 Hz, 1H),
1.58 (s, 9H), 1.52 (s, 9H); 13C NMR (75 MHz, MeOD) δ 86.1, 82.7,
58.5, 52.2, 47.4, 29.2, 29.1, 3C not visible; IR (neat) 3321, 2978, 2933,
1760, 1706, 1650, 1607, 1531, 1368, 1319, 1248, 1140 cm−1; HRMS
calcd for C14H2435ClN3O4, (M + H)+ 334.1534, found 334.1537.
Benzyl (4-(1-Chloroethyl)imidazolidin-2-ylidene)carbamate (6c′)
and Benzyl (5-Chloro-4-methyltetrahydropyrimidin-2(1H)-ylidene)-
carbamate (9c′). 28 mg, quantitative yield, white solid; 1H NMR (300
MHz, CDCl3) δ 9.70 (brs, 1H), 9.16 (brs, 1H), 7.42−7.27 (m, 10H),
5.30−5.28 (m, 2H), 5.17−5.15 (m, 2H), 5.01 (s, 2H), 4.60−4.38 (m,
3H), 3.79−3.77 (m, 1H), 3.68−3.63 (m, 1H), 3.48−3.42 (m, 2H),
3.19−3.12 (m, 1H), 1.43 (d, J = 6.9 Hz, 3H), 1.38 (d, J = 6.5 Hz, 3H),
1.21 (d, J = 6.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 163.5, 158.1,
137.4, 134.6, 128.7, 128.6, 128.2, 68.9, 67.7, 66.6, 57.3, 54.8, 53.6, 52.1,
44.2, 20.9, 17.1; IR (neat) 3252, 2978, 2876, 1761, 1715, 1630, 1563,
1438, 1387, 1315, 1242, 1165, 1155, 1098, 1053, 1027 cm−1; HRMS
calcd for C13H1635ClN3O2, (M + H)+ 282.1009, found 282.1010.
(5R*,6S*)-Benzyl 2-(((Benzyloxy)carbonyl)imino)-5-chloro-6-
phenyltetrahydropyrimidine-1(2H)-carboxylate (9d). 31 mg, 65%
yield, one diastereoisomer, white solid; attempts to recrystallize 9d in
CH2Cl2 led to the formation of crystals of mono-deprotected 9d′ that
1
solid; H NMR (300 MHz, CDCl3) δ 8.93 (brs, 1H), 7.39−7.26 (m,
10H), 5.17 (d, J = 2.3 Hz, 2H), 5.06 (d, J = 1.3 Hz, 2H), 3.65 (tt, J =
6.2, 6.0 Hz, 1H), 3.50−3.46 (m, 2H), 3.24 (t, J = 6.0 Hz, 2H), 1.89−
1.85 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 137.7, 135.6, 128.9,
128.8, 128.7, 128.6, 128.4, 128.1, 69.9, 66.5, 50.2, 46.3, 36.4, 23.5; IR
(neat) 3265, 2923, 1744, 1630, 1565, 1455, 1388, 1340, 1313, 1263,
1161, 1053 cm−1; HRMS calcd for C21H2235ClN3O4, (M + H)+
416.1377, found 416.1363.
Benzyl (4-(Chloromethyl)tetrahydropyrimidin-2(1H)-ylidene)-
carbamate (6l′). 14 mg, 50% yield, white solid; mp: 141−145 °C
1
(CH2Cl2); H NMR (300 MHz, CDCl3) δ 9.21 (brs, 1H), 7.29−7.18
(m, 5H), 4.98 (d, J = 1.4 Hz, 2H), 3.58−3.53 (m, 1H), 3.46−3.31 (m,
2H), 3.11 (t, J = 6.0 Hz, 2H), 1.77 (dt, J = 6.1, 6.0 Hz, 2H); 13C NMR
(75 MHz, CDCl3) δ 163.5, 158.9, 137.7, 128.7, 128.4, 128.1, 66.4,
50.0, 46.1, 36.1, 23.1; IR (neat) 3242, 2921, 1620, 1562, 1455, 1441,
1386, 1339, 1312, 1243, 1158, 1052 cm−1; HRMS calcd for
C13H1635ClN3O2, (M + H)+ 282.1009, found 282.1002.
1
were suitable for X-ray analysis; H NMR (300 MHz, CDCl3) δ 9.86
(brs, 1H), 7.41−7.25 (m, 13H), 7.17−7.15 (m, 2H), 5.19−5.18 (m,
2H), 4.97 (d, J = 12.1 Hz, 1H), 4.92 (d, J = 12.1 Hz, 1H), 4.65 (d, J =
4.0 Hz, 1H), 4.05 (dt, J = 4.0, 4.0 Hz, 1H), 3.34 (dd, J = 13.9, 3.3 Hz,
1H), 3.24 (dd, J = 13.9, 3.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
163.5, 158.4, 139.9, 137.5, 135.5, 129.2, 128.9, 128.8, 128.8, 128.7,
128.6, 128.5, 128.1, 126.7, 69.9, 66.5, 60.1, 53.5, 42.6, 1C not visible;
IR (neat) 3253, 2864, 1744, 1630, 1561, 1455, 1387, 1338, 1281, 1246,
1152, 1081, 1053, 1027 cm−1; HRMS calcd for C26H2435ClN3O4, (M +
H)+ 478.1533, found 478.1541.
Benzyl 2-(((Benzyloxy)carbonyl)imino)-6-(chloromethyl)-6-
methyltetrahydropyrimidine-1(2H)-carboxylate (6m). 26 mg, 60%
yield, colorless oil; the product is not stable in CDCl3; 1H NMR (300
MHz, MeOD) δ 7.44−7.25 (m, 10H), 5.22 (s, 2H), 5.12 (d, J = 12.5
Hz, 1H), 5.06 (d, J = 12.5 Hz, 1H), 4.15 (d, J = 11.4 Hz, 1H), 3.81 (d,
J = 11.4 Hz, 1H), 3.46−3.37 (m, 2H), 2.33 (ddd, J = 14.0, 8.1, 5.2 Hz,
1H), 1.88 (ddd, J = 14.0, 6.7, 4.7 Hz, 1H), 1.47 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 163.7, 158.6, 137.6, 135.5, 129.0, 128.9, 128.8, 128.6,
128.4, 128.2, 69.9, 66.4, 58.4, 51.3, 35.6, 29.4, 25.5, 1C not visible; IR
(neat) 3242, 2947, 1743, 1630, 1552, 1455, 1385, 1349, 1280, 1268,
1242, 1153, 1082 cm−1; HRMS calcd for C22H2435ClN3O4, (M + H)+
430.1534, found 430.1547.
Benzyl 2-(((Benzyloxy)carbonyl)imino)-7-(chloromethyl)-1,3-dia-
zepane-1-carboxylate (6n). 9 mg, 21% yield, colorless oil; the product
is not stable in CDCl3; 1H NMR (300 MHz, MeOD) δ 7.43−7.31 (m,
10H), 5.26 (s, 2H), 5.14 (s, 2H), 3.65−3.60 (m, 1H), 3.56−3.54 (m,
1H), 3.46−3.41 (m, 3H), 1.70−1.63 (m, 4H); 13C NMR (75 MHz,
CDCl3) δ 164.0, 156.3, 154.2, 137.1, 134.9, 129.1, 129.0, 128.7, 128.7,
128.4, 128.2, 68.5, 67.4, 60.0, 45.4, 41.1, 29.5, 25.0; IR (neat) 3339,
2953, 1727, 1623, 1573, 1426, 1382, 1322, 1259, 1206, 1137, 1049
cm−1; HRMS calcd for C22H2435ClN3O4, (M + H)+ 430.1534, found
430.1546.
Benzyl 2-(((Benzyloxy)carbonyl)imino)-5-(cyanomethyl)-
imidazolidine-1-carboxylate (10). A round-bottom flask under
argon was charged with guanidine 5a (0.1 mmol, 45 mg, 1 equiv)
and DMF (1.0 mL). KCN (0.3 mmol, 20 mg, 3 equiv) was added, and
the solution was stirred for 48 h at room temperature. 1 M NaOH (10
mL) was added, and the solution was extracted with MTBE (3 × 10
mL). The combined organic phases were washed with water, dried
with MgSO4, filtered, and evaporated under reduced pressure. Flash
column chromatography (DCM + 1.5% MeOH) afforded 13 mg
Benzyl 2-(((Benzyloxy)carbonyl)imino)-5-chloro-6,6-dimethyl-
tetrahydropyrimidine-1(2H)-carboxylate (9e). 35 mg, 81% yield,
1
colorless oil; H NMR (300 MHz, MeOD) δ 7.48−7.45 (m, 2H),
7.37−7.29 (m, 8H), 5.27 (s, 2H), 5.07 (s, 2H), 4.34 (t, J = 4.0 Hz,
1H), 3.91 (dd, J = 14.6, 4.0 Hz, 1H), 3.59 (dd, J = 14.6, 4.0 Hz, 1H),
1.49 (s, 3H), 1.44 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 164.0,
156.8, 154.1, 137.5, 134.9, 129.0, 128.8, 128.6, 128.2, 128.0, 70.4, 67.3,
58.8, 58.2, 44.3, 25.4, 22.2; IR (neat) 3259, 2928, 1746, 1633, 1600,
1497, 1455, 1387, 1348, 1270, 1257, 1220, 1150, 1094, 1026 cm−1;
HRMS calcd for C22H2435ClN3O4, (M + H)+ 430.1534, found
430.1514.
Benzyl 2-(((Benzyloxy)carbonyl)imino)-5-chloro-5-methyltetra-
hydropyrimidine-1(2H)-carboxylate (9f). 22 mg, 76% yield, colorless
1
oil; H NMR (500 MHz, MeOD) δ 7.50−7.48 (m, 2H), 7.42−7.31
(m, 8H), 5.32 (s, 2H), 5.15 (s, 2H), 4.15 (d, J = 11.7 Hz, 1H), 3.86 (d,
J = 11.7 Hz, 1H), 3.71 (d, J = 11.7 Hz, 1H), 3.51 (d, J = 11.7 Hz, 1H),
1.57 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 136.9, 134.6, 129.0,
128.7, 128.7, 128.6, 128.5, 128.3, 69.0, 67.7, 52.0, 50.4, 48.7, 24.1, 3C
not visible; IR (neat) 3341, 2957, 1755, 1715, 1651, 1610, 1437, 1380,
1295, 1255, 1218, 1151, 1118, 1077 cm−1; HRMS calcd for
C21H2235ClN3O4, (M + H)+ 416.1377, found 416.1358.
(5R*,6S*)-Benzyl 2-(((Benzyloxy)carbonyl)imino)-6-chloro-1,3-
diazaspiro[4.5]decane-1-carboxylate (6g). 28 mg, 61% yield, yellow
oil; the product is not stable in CDCl3; 1H NMR (300 MHz, MeOD)
δ 7.51−7.49 (m, 2H), 7.42−7.27 (m, 8H), 5.33 (s, 2H), 5.15 (s, 2H),
H
DOI: 10.1021/acs.joc.5b01750
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
(0.033 mmol, 33% yield) of the product as a colorless oil: H NMR
(300 MHz, CDCl3) δ 9.81 (brs, 1H), 7.37−7.33 (m, 10 H), 5.22 (d, J
= 3.2 Hz, 2H), 5.19 (d, J = 3.7 Hz, 2H), 4.35 (m, 1H), 4.02 (dd, J =
10.1, 9.7 Hz, 1H), 3.70 (dd, J = 10.1, 6.2 Hz, 1H), 2.79 (dd, J = 16.9,
5.3 Hz, 1H), 2.63 (dd, J = 16.9, 7.1 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 165.5, 139.1, 129.2, 129.1, 129.0, 128.8, 128.7, 128.6, 117.2,
69.1, 68.2, 58.8, 49.4, 24.9, 3C not visible; IR (neat) 3333, 2960, 1759,
1715, 1655, 1601, 1442, 1381, 1308, 1254, 1170, 1022 cm−1; HRMS
calcd for C21H21N4O4, (M + H)+ 393.1563, found 393.1558.
ACKNOWLEDGMENTS
■
We thank the ANR (ANR-12-BSV1-0031-01) and the Institut
de Chimie des Substances Naturelles for financial support and
for fellowships (M.D. and S.N.-T., respectively).
REFERENCES
■
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Benzyl 5-(Azidomethyl)-2-(((benzyloxy)carbonyl)imino)-
imidazolidine-1-carboxylate (11). A round-bottom flask under
argon was charged with guanidine 5a (0.11 mmol, 50 mg, 1 equiv)
and DMF (1.0 mL). NaN3 (0.2 mmol, 13 mg, 1.8 equiv) was added,
and the solution was stirred for 96 h at room temperature. Water (10
mL) was added, and the solution was extracted with MTBE (1 × 10
mL). The organic phase was washed with 5% Na2CO3 (1 × 10 mL)
and then brine (1 × 10 mL), dried with MgSO4, filtered, and
evaporated under reduced pressure, affording 40 mg (0.098 mmol,
1
̃
89% yield) of the product as a colorless oil: H NMR (300 MHz,
CDCl3) δ 8.66 (brs, 1H), 7.45−7.29 (m, 10 H), 5.33 (d, J = 12.0 Hz,
1H), 5.26 (d, J = 12.0 Hz, 1H), 5.15 (m, 2H), 4.37−4.36 (m, 1H),
3.87−3.70 (m, 1H), 3.61−3.50 (m, 3H); 13C NMR (75 MHz, CDCl3)
δ 176.2, 165.4, 163.6, 136.7, 135.0, 128.9, 128.8, 128.7, 128.6, 128.3,
128.2, 68.9, 67.7, 54.9, 53.1, 52.4; IR (neat) 3345, 3033, 2920, 2104,
1759, 1712, 1651, 1606, 1439, 1395, 1379, 1304, 1240, 1141, 1022
cm−1; HRMS calcd for C20H20N6O4, (M + H)+ 409.1624, found
409.1611.
Benzyl 5-(Aminomethyl)-2-(((benzyloxy)carbonyl)imino)-
imidazolidine-1-carboxylate (12). A round-bottom flask under
argon was charged with guanidine 11 (0.29 mmol, 117 mg, 1 equiv)
and dry THF (2.6 mL). PPh3 (0.57 mmol, 150 mg, 2.0 equiv) and
water (10 μL) were added, and the solution was stirred for 36 h at 50
°C.33 The solution was warmed to room temperature, and the solvent
was evaporated under reduced pressure. MTBE was added, and the pH
of the solution was lowered to 1 with 2 M HCl with vigorous stirring.
The aqueous layer was washed with MTBE (2 × 20 mL). Then, the
pH was adjusted to 13 with 1 M NaOH. The solution was extracted
with DCM (6 × 20 mL). The combined organic phases were dried
with MgSO4, filtered, and evaporated under reduced pressure,
affording 51 mg (0.13 mmol, 46% yield) of the product as a colorless
oil: 1H NMR (300 MHz, CDCl3) δ 7.90 (brs, 1H), 7.36−7.27 (m, 10
H), 5.18 (brs, 2H), 5.06 (s, 2H), 5.01 (s, 2H), 3.87−3.83 (m, 1H),
3.59 (dd, J = 9.6, 9.6 Hz, 1H), 3.30 (dd, J = 9.6, 7.0 Hz, 1H), 3.16−
3.13 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 165.5, 163.5, 156.9,
137.3, 136.6, 128.8, 128.7, 128.5, 128.4, 128.3, 67.2, 66.9, 53.8, 45.5,
44.2; IR (neat) 3316, 2947, 2471, 2225, 1686, 1630, 1598, 1502, 1452,
1372, 1297, 1276, 1217, 1160, 1056 cm−1; HRMS calcd for
C20H22N4O4, (M + H)+ 383.1719, found 383.1716.
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ASSOCIATED CONTENT
* Supporting Information
(11) Katritzky, A. R.; Rogovoy, B. V. ARKIVOC 2005, iv, 49.
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■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b01750.
1
Copies of H NMR and 13C NMR spectra (PDF)
Crystallographic data for compound 5c (CIF)
Crystallographic data for compound 5g′ (CIF)
Crystallographic data for compound 5l′ (CIF)
Crystallographic data for compound 6l′ (CIF)
Crystallographic data for compound 8d′ (CIF)
Crystallographic data for compound 9d′ (CIF)
(c) Albrecht, C.; Barnes, S.; Bockemeier, H.; Davies, D.; Dennis, M.;
̈
Evans, D. M.; Fletcher, M. D.; Jones, I.; Leitmann, V.; Murphy, P. J.;
Rowles, R.; Nash, R.; Stephenson, R. A.; Horton, P. N.; Hursthouse,
M. B. Tetrahedron Lett. 2008, 49, 185. (d) Davies, D.; Fletcher, M. D.;
AUTHOR INFORMATION
Corresponding Authors
*E-mail: kevin.cariou@cnrs.fr (K.C.).
*E-mail: robert.dodd@cnrs.fr (R.H.D.).
Notes
Franken, H.; Hollinshead, J.; Kahm, K.; Murphy, P. J.; Nash, R.;
̈
■
Potter, D. M. Tetrahedron Lett. 2010, 51, 6825. (e) Bentya, A. V.;
Vas'kevich, R. I.; Turov, A. V.; Rusanov, E. B.; Vovk, M. V.; Staninets,
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