Iodocyclisations reactions of Boc- and Cbz-protected N-allylguanidines

Article abstract of DOI:10.1016/j.tet.2014.03.087

The cyclisation of mono-protected and bis-protected guanidines 8a-j under standard iodocyclisation conditions (I₂/K₂CO₃) gave the guanidine heterocycles 9-25 via either a direct cyclisation or by a cyclisation/ring-contrac

Full text of DOI:10.1016/j.tet.2014.03.087

Tetrahedron xxx (2014) 1e8
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Iodocyclisations reactions of Boc- and Cbz-protected
N-allylguanidines
,
Zainab Al Shuhaib a b, Deiniol H. Davies a, Mark Dennis a, Daniel M. Evans a,
Matthew D. Fletcher a, Herjan Franken a, Paul Hancock a, Jackie Hollinshead c,
a
a
a,
c
d
*
€
Iestyn Jones , Kristina Kahm , Patrick J. Murphy , Robert Nash , David Potter ,
Richard Rowles a
a School of Chemistry, Bangor University, Gwynedd LL57 2UW, UK
b Department of Chemistry, University of Basra, College of Education, Basra, Iraq
c Phytoquest Limited, Plas Gogerddan, Aberystwyth, Ceredigion SY23 3EB, UK
d Menai Organics Ltd, MENTEC, Deiniol Road, Bangor, Gwynedd LL57 2UP, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The cyclisation of mono-protected and bis-protected guanidines 8aej under standard iodocyclisation
conditions (I2/K2CO3) gave the guanidine heterocycles 9e25 via either a direct cyclisation or by a cycli-
sation/ring-contraction process, which could be controlled by careful selection of conditions.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 14 January 2014
Received in revised form 12 March 2014
Accepted 24 March 2014
Available online xxx
Keywords:
Guanidine
Iodocyclisation
Rearrangement
1. Introduction
OH
CO2H
NH2
H
N
H
H
-O3SO
Me
O
Me
NH
NH
We have previously reported1e3 on the iodocyclisation4e11 of
allyl substituted guanidines as part of a synthetic approach to
a variety of natural products including the hepatotoxin cylin-
drospermopsin 112,13 the unusual amino acid enduracididine 2,14
NH HN
NH
HN
NH
NH
Me
N
Me
H
H
2
NH
O
1
3
enduracididine
Nitensidine E
Cylindrospermopsin
H
N
the cytotoxin nitensidine E 3,15 the
rivative tiruchanduramine 416 a potent
b
a
-carboline guanidine de-
-glucosidase inhibitor and
NH2
N
H
N
H
O
N
N
the cytotoxic guanidine trachycladindole G17 (Fig. 1).
As part of this work we have studied the cyclisation of a range of
mono- and bis-protected allylic and homoallylic substituted gua-
nidines, which have led to the formation of a range of five- and six-
membered guanidine heterocycles with a predictable protecting
group substitution pattern. We take this opportunity to report our
findings in full.
N
H
Me
CO2H
N
5
N
4
H
N
H
Tiruchanduramine
Trachycladindole G
Fig. 1. Target natural products 1e5.
carboxamidines18e20 6aed and the amines 7 resulting in the syn-
thesis of the corresponding guanidine in high yields (Scheme 1,
Table 1).
Our initial investigations focused on the formation of five- and
six-membered guanidine heterocycles from the bis-protected
guanidines and the outcome of this work was much as expected.
For example, cyclisation of the guanidine 8a with iodine in the
presence of potassium carbonate gave the corresponding five-
membered heterocycle 9a in 86% yield and similarly the bis-Cbz-
protected allyl guanidine 8b gave 9b in a 79% yield (Scheme 2).
2. Results and discussion
We initially prepared a series of N-allyl and N-homoallyl gua-
nidines 8aej via the reaction between the protected pyrazole-
* Corresponding author. E-mail address: chs027@bangor.ac.uk (P.J. Murphy).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.03.087
Please cite this article in press as: Al Shuhaib, Z.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.03.087

2
Z. Al Shuhaib et al. / Tetrahedron xxx (2014) 1e8
R3
R4
is possible that compound 11 has arisen via a base-mediated ring
R3
H2N
contraction via the anion 12 and the aziridine 13. In order to test
this hypothesis we took a purified sample of compound 11 and
treated it with 5 equiv of finely powdered potassium carbonate in
acetonitrile for 16 h at rt. It was found that a mixture of compounds
10b and 11 was formed, which supports this mechanistic
supposition.
n
6a R1 = R2 = Boc
6b R1 = R2 = Cbz
6c R1 = H R2 = Boc
6d R1 = H R2 = Cbz
N
N
R5
HN
R4
N
7
n
R5
(a)
HN
R1 R2
N
HN
R1 R2
6a-d
8a-j
Scheme 1. (a) (Method A) Amine 7, MeCN/MeOH, 16 h, rt. (Method B) 7. HCl,
NEt3, MgSO4, CH3Cl/MeCN, 16 h, rt. (Method C) Amine 7, reflux, 2.5 h, n¼1,2, R1, R2,
R3¼H, Me.
We next investigated the cyclisation of the homoallylic guani-
dine 8e under these standard conditions to give the six-membered
guanidine 14 in 68% yield after chromatography, with the expected
signals for the CH2I group being observed at dH 3.09 (1H, dd, J 10.6,
9.8 Hz) and dH 3.52 (1H, dd, J 9.8, 3.8 Hz) and dC 6.4 ppm. Similarly
the bis-Boc-protected guanidine 8f was cyclised under the standard
conditions to give the six-membered product 15a in 99% yield,
which proved unstable to column chromatography. Diagnostic
signals for the CH2I group were observed at dH 3.47 (d, 1H, J 10.6 Hz)
and 3.74 (d, 1H, J 10.6 Hz) and dC 12.8 ppm. The bis-Cbz-protected
guanidine 8g was again cyclised under the standard conditions and
compound 15b was obtained in 68% yield by precipitation from
dichloromethane/petrol. Similar diagnostic signals for the CH2I
group were observed at dH 3.53 (d, 1H, J 10.6 Hz) and 3.73 (d, 1H, J
10.6 Hz) and dC 12.4 ppm (Scheme 4).
Table 1
Preparation of the N-allyl and N-homoallyl guanidines 8aej
8
n
R1
R2
R3
R4
R5
6
Method
Yield (%) mp/(ꢀC)
8a
8b
8c
8d
8e
8f
8g
8h
8i
1
1
1
1
2
2
2
1
1
1
Boc Boc
Cbz Cbz
H
H
H
H
H
H
H
H
H
6a A (MeCN) 78
6b A (MeCN) 92
6a B (MeCN) 97
6b B (CH3Cl)
6a B (MeCN) 88
87e89
46e48
129e132
73e76
82e83
70e72
Wax
75e78
119e121
81e83
Boc Boc Me Me
Cbz Cbz Me Me
90
Boc Boc
Boc Boc
Cbz Cbz
H
H
H
H
H
H
H
H
H
H
Me 6a A (MeOH) 55
Me 6b A (MeOH) 86
H
H
H
Boc
Cbz
H
H
H
6c
6d
C
C
80
61
8j
Cbz Me Me
6d B (MeCN) 62
HN
R1
HN
I
HN
HN
HN
(a)
1 = R2 = Boc, 86%
R1 = R2 = Cbz, 79%
(a)
N
N
R2
Boc
I
HN
R1 R2
N
N
N
N
R
68%
9a,b
8a,b
Boc Boc 8e
Boc
14
Scheme 2. (a) CH3CN, 4 equiv K2CO3, 4 equiv I2, ꢁ15 ꢀCdrt, 16 h.
Me
HN
Me
(a)
HN
HN
R1 R2
R1
I
N
N
R1 = R2 = Boc, 99%
R1 = R2 = Z, 68%
Cyclisation of the dimethylallyl guanidine 8c was found to be
more problematic, the six-membered product 10a was initially
obtained in high yield (ca. 85%) as evidenced by the CH at dH 4.27
(1H, dd, J 9.1, 5.5 Hz) and dC 30.1 ppm, however purification was
difficult as the material decomposed on silica gel chromatography.
This decomposition was presumably due to the loss of the more
sterically hindered Boc-protecting group as similar migration/loss
of protecting groups has been observed in the corresponding ep-
oxidation studies.2 Attempts to recrystallize 10a were also un-
successful. Cyclisation of the corresponding Cbz-protected
guanidine 8d was also successful and gave as the major compound
a solid product 10b in 91% yield. This was easily purified by
recrystallisation from dichloromethane/petroleum ether and had
diagnostic signals at dH 4.27 (1H, dd, J 8.8 and 5.5 Hz) and dC
29.2 ppm corresponding to the CH position. Interestingly, another
product compound 11 was also obtained in varying amounts, which
gave signals at dH 3.17e3.25 (1H, m, CH) and 3.29 (1H, dd, J 4.7, 10.1,
CH) and dC 3.2 ppm indicating that it is a CH2I containing structure.
We repeated the cyclisation with varying amounts of potassium
carbonate and found that in the absence of potassium carbonate
only the six-membered product 10b was observed in the crude
reaction mixture, however, when more than 4 equiv of base were
utilized the side product compound 11 was observed (Scheme 3). It
N
R2
8f,g
15a,b
Scheme 4. (a) CH3CN, 4 equiv K2CO3, 4 equiv I2, ꢁ15 ꢀCdrt, 16 h.
We next investigated the cyclisation of the mono-protected
guanidines 8hej, which proved to be more problematic. Cyclisa-
tion reaction of the mono-Boc-allylguanidine 8h predominantly led
to the formation of the product 16 in high yield, however great care
was needed as poor stirring led to the formation of rearranged or
deprotected products possibly due to the build-up of HI as the re-
action proceeds. Cyclisation occurred at the Boc-substituted nitro-
gen of the guanidine as was apparent from HMBC studies
(Scheme 5).
HN
HN
H2N
I
(a)
HN
N
N
98%
8h
16
Boc
Boc
Scheme 5. (a) CH3CN, 4 equiv K2CO3, 4 equiv I2, ꢁ15 ꢀCdrt, 16 h.
Attempts at purifying compound 16 by column chromatography
were problematic as several new products were formed. Previous
work2 on the epoxidation of bis-protected guanidines had dem-
onstrated that cyclic guanidines protected at this position with Boc-
and Cbz-protecting groups were prone to migration to hydroxyl
groups and it was possible to mediate this by stirring with moist
silica gel. An attempt to mimic this with compound 16 was found to
give a complex mixture of products and on purification, four
compounds were isolated including compound 19 (3% yield), in
which the Boc group had migrated, the initially formed compound
16 (4% yield) and a deprotected guanidine 20 (13% yield). In-
terestingly the urea 17 was also isolated in a low 2% yield, which
may have arisen via a sequence of Boc-transfer reactions (possibly
via the hydrolysis of a C]N-Boc containing intermediate, such as
compound 18, by water3,21 (Scheme 6)).
Me
Me
I
I
HN
HN
(a)
HN
HN
R1 R2
R1
N
N
N
N
R2
R1 = R2 = Boc, 86%
R1 = R2 = Cbz, see text
N
Cbz
11
8c,d
Cbz
10a,b
I-
R1 = R2 = Cbz
K2CO3
I
Eq. K2CO3 Ratio 10b:11
0.0
1.0
2.0
3.0
4.5
6.0
100:0
100:0
100:0
100:0
78:22
46:54
N
N
N
N
N
Cbz
N
Cbz Cbz
Cbz
13
12
Scheme 3. (a) CH3CN, 0e6 equiv K2CO3, 4 equiv I2, ꢁ15 ꢀCdrt, 16 h.
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Z. Al Shuhaib et al. / Tetrahedron xxx (2014) 1e8
3
Boc
HN
HN
H2N
I
(c)
N
HN
(a)
22
I
I
HN
(b)
N
N
HN
HN
N
N
Cbz 21
Cbz 8i
H
H
19
HN
20
I
(a)
HN
N
Boc
N
Boc
O
Cbz
HN
16
Boc
N
N
N
HN
Boc
I
I
I
I
HN
N
N
N
N
H
22
H
18
17
Boc
20
Boc
Scheme 8. (a) CH3CN, 4 equiv K2CO3, 4 equiv I2, ꢁ15 ꢀCdrt, 16 h. (b) SiO2, DCM, stir, 5
Scheme 6. (a) SiO2, CH2Cl2, stir, 5 d.
days (c) TFA, MeOH, 16 h, 28%.
On further analysis it was apparent that on standing, chloroform
solutions of the crude product 16 underwent considerable de-
composition/rearrangement, with NMR analysis indicating the
presence of at least four different compounds. It was thought that
trace moisture or acid might be mediating this and we thus took
a solution of crude 16 and treated it with an excess of trifluoroacetic
acid (TFA) in methanol for 16 h (Scheme 7). On NMR analysis it was
We next investigated the cyclisation of the Cbz-dimethylallyl
guanidine 8j, which was treated under the previously employed
conditions and cyclised to give a mixture of two compounds 23 and
24 in a 60:40 ratio. Compound 23 displayed an ABX pattern at dH
3.43 (1H, dd, J 9.2, 13.6 Hz), 3.55 (1H, dd, J 4.6,13.6 Hz) and 3.97 (1H,
dd, J 4.6, 9.2 Hz, CH) ppm and a carbon signal at dC 27.5 ppm for the
CHI group. The other compound 24 displayed a similar ABX pattern
at dH 3.12 (1H, dd, J 8.4,10.0 Hz), 3.23 (1H, dd, J 5.0,10.0 Hz) and 3.78
(1H, dd, J 5.0, 8.4 Hz) ppm whilst giving a signal at dC 5.8 ppm for
a CH2 group (Scheme 9). As with previous examples both 23 and 24
Boc
HN
HN
.CF3CO2H
I
I
N
(b)
(a)
HN
N
H2N
8h
N
HN
N
Boc
Boc
H
16
19
I
I
(c)
I
HN
H2N
HN
HN
HN
(a)
(b)
HN
I
N
N
N
N
HN
.CF3CO2H
N
N
HN
H
H
N
Cbz
8j
Cbz
Cbz
25
24
23
Cbz
H
20
Eq. K2CO3 Ratio 23:24
K2CO3
I
K2CO3
Scheme 7. (a) CH3CN, 4 equiv K2CO3, 4 equiv I2, ꢁ15 ꢀCdrt. (b) TFA, MeOH, 16 h, 51%.
0.0
1.0
3.0
4.0
4.5
>02:98
>02:98
40:60
60:40
40:60
43:57
77:23
(c) TFA/CH2Cl2 (1:1), 16 h, 63%.
HN
I2
HN
apparent that the initial compound 16 had been converted into
a single major compound, which had a 1H NMR spectrum similar to
that observed for structure 19. Final determination of the structure
of compound 19 was obtained by HMBC with a correlation between
the ring CH2N signal and the Boc-carbonyl quaternary carbon being
observed. Pure compound 19 could be obtained as its tri-
fluoroacetate salt in 51% overall yield by crystallisation from
dichloromethane/petroleum ether (5:1). Further to this process
treatment of the crude mixture from the iodocyclisation of com-
pound 8h with a 1:1 mixture of TFA and dichloromethane led to the
formation of the fully deprotected guanidine 20 as its TFA salt in
63% overall yield from 8h (Scheme 7).
We further investigated this process by utilising a Cbz-protected
guanidine in the hope that this protecting group might be less likely
to undergo rearrangement. Thus cyclisation of mono-Cbz protected
allylguanidine 8i was attempted. Again the expected 5-exo-product
21 was observed, which had similar NMR data to compound 16
N
HN
HN
NK
26
27
6.0
10.0
Cbz
Cbz
Scheme 9. (a) CH3CN, K2CO3, 0e6 equiv I2, ꢁ15 ꢀCdrt, 16 h, (b) TFA, MeOH, 16 h.
decomposed extensively when in contact with silica gel and they
were thus treated with methanolic TFA to give a rearranged mix-
ture containing two products. NMR analysis of the crude mixture
indicated that the signals for the major product 23 remained un-
changed whilst the minor compound had rearranged to give gua-
nidine 25, in which the Cbz-group had migrated to the exocyclic
nitrogen. This compound displayed an ABX pattern at dH 3.36 (1H,
dd, J 7.6, 11.0 Hz), 3.54 (1H, dd, J 4.4, 11.0 Hz) and 3.91 (1H, dd, J 4.4,
7.6 Hz) ppm whilst giving a signal at dC 2.4 ppm for a CH2 group.
Interestingly, it was observed that in the reaction of 8j in the
absence of potassium carbonate the rearranged product 24 was
formed almost exclusively and only a trace amount of 23 was ob-
served. As the amount of base was increased a general increase in
the amount of 23 formed was observed. This would seem to suggest
that under acidic conditions (no carbonate) the cyclisation proceeds
via the CbzNH function, leading to intermediate 27 and that 27
undergoes rearrangement under the reaction conditions to give 24.
In comparing the rearrangement of 10b and 27 the reason for
the different conditions required to effect these two ring contrac-
tion reactions might lie in the nature of the guanidine substituents.
In compound 12 the delocalization of electron density by the two
Cbz-protecting groups reduces the nucleophilicity of the remaining
ring nitrogen, but leads to increased NH acidity enabling the re-
action to proceed under basic conditions. In the case of compound
26 it is possible that the single Cbz-protecting group does not have
such a profound effect and it is postulated that sufficient nucleo-
philicity is present to enable a similar rearrangement under neutral
or mildly acidic conditions (Scheme 10).
[
dH 3.28 (1H, dd, J 6.5, 9.8 Hz), 3.38 (1H, dd, J 4.7, 9.8 Hz), 3.70 (1H,
dd, J 5.7, 10.7 Hz), 4.05 (1H, dd, J 9.1, 10.5 Hz) 4.16 (1H, dddd, J 6.5,
4.7, 5.7, 9.1 Hz), 5.35 (2H, d, J 12.3 Hz) and 7.5 (5H, m) and dC 9.5,
51.7, 57.3, 68.0, 128.0, 128.5, 134.6, 138.3, 153.5, 154.6]. However this
was accompanied by a large number of side-products as was evi-
denced by a complex NMR spectrum of the crude reaction. Again,
attempted purification of this mixture led to further decomposition
resulting in the isolation of two compounds, the previously iden-
tified de-protected product 20 in 28% yield and the rearranged
compound 22 in 8% yield. In order to ascertain if the Cbz-protecting
group was migrating in a similar manner to that observed in the
Boc-protected series, the reaction was repeated and the resulting
crude compound 19 treated with TFA in methanol overnight. This
resulted in the formation of a compound 22, with similar data to 19
at dH 3.45 (1H, dd, J 11.7, 4.1 Hz, CH), 3.48 (1H, dd, J 11.0, 2.2 Hz, CH),
3.63 (1H, dd, J 11.0, 5.5 Hz, CH), 3.89 (1H, dd, J 10.7, 9.8 Hz, CH), 4.54
(1H, dddd, J 11.0, 5.5, 4.1, 2.2 Hz, CH) and dC 9.0, 48.3, 58.3, 71.0,
129.9, 129.9, 130.2, 135.7, 152.6, 157.6, but in a much lower yield of
28% (Scheme 8).
In conclusion, we have demonstrated that the cyclisation of
mono-protected guanidines is
a considerably more complex
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4
Z. Al Shuhaib et al. / Tetrahedron xxx (2014) 1e8
I
4.06 (2H, apparent tt, J 5.6, 1.5 Hz, CH2), 5.15 (1H, dq, J 10.4, 1.5 Hz,
I
CH), 5.22 (1H, dq, J 17.2, 1.5 Hz, CH), 5.87 (1H, ddt, J 17.2, 10.4, 5.6 Hz,
CH), 8.39 (1H, br t, J 5.6 Hz, NH), 11.51 (1H, br s, NH); dC (100.6 MHz,
CHCl3) 28.0, 28.2, 43.2, 79.2, 83.1, 116.7, 133.3, 153.2, 156.0, 163.5;
MS (CI) m/z 300 (100% [MþHþ]); HRMS (CI) found 300.1920.
H
N
HN
HN
-I-
HN
HN
N
N
N
HN
Cbz
Cbz
Cbz 24
27
30
C
14H25N3O4 ([MþH]þ) requires 300.1918.
Scheme 10. Rearrangement of intermediate 27.
3.2.5. N-Allyl-N0,N00-bis-Cbz-guanidine 8b. Method A: allylamine
(0.58 g, 10.2 mmol) and 6b (1.90 g, 5.02 mmol) in acetonitrile gave
8b (1.70 g, 92%) as a white solid after chromatography (PE to 10:90
EtOAc/PE). Mp 46e48 ꢀC; Rf 0.45 (25:75 EtOAc/PE); dH (400 MHz,
CHCl3) 3.98e4.02 (2H, m, CH2), 5.05e5.18 (6H, m, 2ꢂ CH2, 2ꢂ CH),
5.76e5.85 (1H, m, CH), 7.15e7.35 (10H, m, 2ꢂ Ph), 8.32 (1H, br, NH),
11.67 (1H, br, NH); dC (100.6 MHz, CHCl3) 43.4, 67.2, 68.2, 116.9,
127.9, 128.1, 128.4, 128.5, 128.7, 128.8, 132.9, 134.6, 136.7, 153.8,
155.9, 163.7; nmax 3339, 3094, 3066, 3034, 2953, 1730, 1637, 1620,
1571; MS (CI) m/z 368.1 (2%, ([MþH]þ); HRMS (CI) m/z found
368.1608. C20H22N3O4 [MþH]þ) requires 368.1605.
process than for the bis-protected analogues and the products of
these reactions proved to be very sensitive to silica gel chroma-
tography and acid. However, the reactions of simple allyl-
substituted guanidines do proceed in high yield and in a predict-
able manner. Both the bis-Cbz-protected and mono-Cbz-protected
guanidines 8d and 8j undergo ring contraction rearrangements,
which can be controlled to some extent by selecting the conditions
and these processes should be of synthetic interest in preparing
highly substituted cyclic guanidines.
3. Experimental
3.2.6. N-(3,3-Dimethylallyl)-N0,N00-bis-Boc-guanidine 8c. Method B:
3.1. General conditions
1-amino-3-methyl-2-butene
hydrochloride
salt
(0.93
g,
7.68 mmol), 6a (1.65 g, 5.32 mmol), triethylamine (1.56 g, 1.14 mL,
15.4 mmol) and MgSO4 (ca. 1.00 g) in MeCN (15 mL) gave 8c (1.68 g,
97%) as a white solid after chromatography (5:95 diethyl ether/PE).
Mp 129e132 ꢀC; Rf 0.08 (5:95 diethyl ether/PE); dH (400 MHz,
CHCl3) 1.49, (9H, s, tBu), 1.51, (9H, s, tBu), 1.67 (3H, s, CH3), 1.73 (3H,
d, J 0.8 Hz, CH3), 3.99 (2H, br t, J 6.0 Hz, CH2), 5.20e5.26 (1H, m, CH),
8.13 (1H, br s, NH), 11.49 (1H, br s, NH); dC (100.6 MHz, CHCl3) 18.0,
25.7, 28.0, 28.3, 39.1, 79.2, 82.9, 119.1, 137.2, 153.2, 156.8, 163.5; nmax
3344, 1715, 1636; MS (ES) 328 (100%, [MþHþ]); HRMS (ESI) found
328.2235. C16H30N3O4 ([MþHþ]) requires 328.2231.
Column chromatography was carried out on silica gel (particle
size 40e63 mm) and TLCs were conducted on precoated Kieselgel
60 F254 (Art. 5554; Merck) with the eluent specified in each
case. All non-aqueous reactions were conducted in oven-dried ap-
paratus under a static atmosphere of argon. Ether, THF and
dichloromethane were dried on a Pure Solv MD-3 solvent purifica-
tion system. Dry methanol and DMF was purchased from Aldrich.
Chemical shifts are reported in d values relative to chloroform (7.27/
77.0 ppm) as an internal standard. Proton and carbon were recorded
in CDCl3 on a Bruker AC400 spectrometer unless otherwise stated.
Mass spectra data were obtained at the EPSRC Mass Spectrometry
Service Centre at the University of Wales, Swansea. Infrared spectra
were recorded as thin films (oils) on a Bruker Tensor 27 series in-
strument. Protected pyrazole carboxamidines 6 and amines 7 or
their salts were obtained from commercial sources or prepared as
described in the Supplementary data.
3.2.7. N-(3,3-Dimethylallyl)-N0-N00-bis-Cbz-guanidine 8d. Method B:
a solution of 1-amino-3-methyl-2-butene hydrochloride salt (5.79 g,
47.6 mmol) in chloroform (50 mL) and 6b (3.0 g, 7.93 mmol) and
triethylamine (8.4 mL, 6.06 g, 60 mmol) in acetonitrile (40 mL) dried
with MgSO4 (ca. 2.0 g) gave 8d (2.81 g, 90%) afterchromatography (PE
to 10:90 EtOAc/PE) as a white solid. Mp 73e76 ꢀC; Rf 0.16 (10:90
EtOAc/PE); dH (400 MHz, CHCl3) 1.69 (3H, s, CH3), 1.75 (3H, s, CH3),
4.00e4.05 (2H, m, CH2), 5.15 (2H, s, CH2), 5.18 (2H, s, CH2), 5.22e5.27
(1H, m, CH), 7.28e7.44 (10H, m, 2ꢂ Ph), 8.17 (1H, s, NH), 11.75 (1H, s,
NH); dC (100.6 MHz, CHCl3) 18.0, 25.6, 39.3, 67.1, 68.0, 118.8, 127.8,
128.1, 128.3, 128.6, 128.7, 134.6, 136.8, 137.6, 153.8, 155.5, 163.6; nmax
3342, 3066, 3044, 2933, 1729, 1640; MS (CI) 396 (100%, [MþHþ]);
HRMS(ESI)found396.1920.C22H26N3O4 ([MþHþ])requires396.1918.
3.2. Preparation of guanidines 8aej
3.2.1. Method A. The required amine 7 (1.5e2.0 equiv) and pyr-
azole-1-carboxamide 6 (1.0 equiv) were dissolved in acetonitrile or
methanol (ca. 1 mL per mmol of 6) and stirred at rt. After the re-
action was complete (ca.16 h, TLC), the mixture was evaporated and
purified by column chromatography on silica.
3.2.8. N-Homoallyl-N0,N00-bis-(Boc)guanidine 8e. Method B: but-3-
en-1-amine hydrochloride (3.55 g, 33.2 mmol), 6a (2.0 g,
6.44 mmol), triethylamine (6.2 mL, 44.3 mmol) and MgSO4 in ace-
tonitrile (50 mL) gave 8e (1.78 g, 5.68 mmol, 88%) after chromatog-
raphy (10:90 EtOAc/PE) as a white solid. Mp 82e83 ꢀC; Rf 0.51 (30:70
EtOAc/PE); dH (400 MHz, CHCl3) 1.49 (9H, s, tBu),1.51 (9H, s, tBu), 2.32
(2H, app qt, J 6.8,1.2Hz), 3.51 (2H, dt, J 6.8, 5.5, CH2), 5.09e5.17, (2H, m,
2ꢂ CH), 5.74e5.84 (1H, m, CH), 8.35 (1H, brs, NH) 11.49 (1H, br s, NH);
dC (100.6 MHz, CHCl3) 28.0, 28.3, 33.2, 40.0, 79.2, 83.0, 117.5, 134.8,
153.2, 156.1, 163.6; vmax 3333, 3293, 3134, 3082, 2980, 2934, 1722,
3.2.2. Method B. The required amine hydrochloride salt
7
(1.5e6.0 equiv) and pyrazole-1-carboxamide 6a (1.0 equiv) were
dissolved in acetonitrile or chloroform (ca. 1 mL per mmol) and
triethylamine (twofold excess based on 7) was added drop-wise
with stirring, together with anhydrous MgSO4 to dryness. After
16 h the mixture was filtered, evaporated and purified by column
chromatography on silica.
3.2.3. Method C. The pyrazole-1-carboxamide 6c or 6d was dis-
solved in allylamine (10 mL, excess) and the solution heated
at reflux for 2.5 h. The excess amine was removed under
vacuum and the residue purified by recrystallization or column
chromatography.
1640,1622,1575; MS (EI) 313 (2%, [Mþ]), 201 (100%); HRMS (EI) (MD
)
found 313.2002. C15H27N3O4 ([Mþ]) requires 313.2002.
3.2.9. N,N0-bis-Boc-N00-1-(3-methylbut-3-en-1-yl)guanidine
8f. Method A: 3-methylbut-3-en-1-amine (24.16 mmol), 6a (5.00 g,
16.11 mmol) and MgSO4 (ca. 2 g) in methanol (120 mL) gave 8f
(2.89 g, 8.83 mmol, 55% yield) as a white solid after chromatogra-
phy (10:90 EtOAc/PE). Mp 70e72 ꢀC; Rf 0.20 (10% EtOAc/PE); dH
(400 MHz, CHCl3) 1.50 (9H, s, tBu), 1.52 (9H, s, tBu), 1.76 (3H, s, CH3),
3.2.4. N-Allyl-N0,N00-bis-Boc-guanidine 8a.19 Method A: allylamine
(1.60 g, 28.0 mmol) and 6a (4.5 g, 14.50 mmol) in acetonitrile gave
8a (3.40 g, 78%) as a white solid after chromatography (5:95 diethyl
ether/PE). Mp 87e89 ꢀC (lit.19 83e85 ꢀC); Rf 0.17 (5:95 diethyl
t
t
ether/PE); dH (400 MHz, CHCl3) 1.48 (9H, s, Bu), 1.49 (9H, s, Bu),
Please cite this article in press as: Al Shuhaib, Z.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.03.087

Z. Al Shuhaib et al. / Tetrahedron xxx (2014) 1e8
5
2.28 (2H, t, J 6.8 Hz, CH2), 3.57 (2H, td, J 6.8, 3.4 Hz, CH2), 4.80 (1H, s,
CH), 4.86 (1H, s, CH), 8.34 (1H, br t, J 3.4 Hz, NH), 11.49 (1H, br s,
NH); dC (100.6 MHz, CHCl3) 22.1, 28.0, 28.3, 36.9, 38.8, 79.2, 82.9,
112.6, 142.0, 153.1, 156.1, 163.6; vmax 3335, 3291, 3148, 3085, 2981,
2936, 1725, 1638, 1617, 1577; MS (ES) 328 (100%, ([MþH]þ)); HRMS
(ES) found 328.2234. C16H30N3O4 ([MþH]þ) requires 328.2231.
by column chromatography on silica gel (EtOAc/PE) or re-
crystallization gave the desired products.
3.3.2. tert-Butyl-1-(Boc)-5-(iodomethyl)imidazolidin-2-
ylidenecarbamate 9a. Using the general method, iodine (0.95 g,
3.74 mmol), 8a (0.28 g, 0.935 mmol) and potassium carbonate
(0.52 g, 0.77 mmol) gave 9a (0.34 g, 0.80 mmol, 86%) after re-
crystallization (50:50 Et2O/PE). Mp 60e62 ꢀC; Rf 0.22 (10:90 Et2O/
PE); dH (400 MHz, CHCl3) 1.46 (9H, s, tBu), 1.52 (9H, s, tBu), 3.25 (1H,
dd, J 9.3, 8.9 Hz, CH), 3.35 (1H, br d, J 9.3 Hz, CH), 3.58 (1H, dd, J 2.4,
13.5 Hz, CH), 3.85e3.95 (1H, m, CH), 4.15e4.25 (1H, br m, CH), 9.30
(1H, br s, NH) dC (100.6 MHz, CHCl3) 8.0, 27.9, 28.0, 56.7, 81.0, 83.9,
150.7 (2ꢂ C not detected); vmax 3316, 2976, 2933, 1760, 1708, 1530;
MS (CI) 426 (30%, [MþH]þ); HRMS (CI) found 426.0886.
3.2.10. N,N0-bis-Cbz-N00-1-(3-methylbut-3-en-1-yl)guanidine
8g. Method B: 3-methylbut-3-en-1-amine (23.25 mmol), 6b
(5.80 g, 15.32 mmol) and MgSO4 (ca. 1e2 g) in methanol (120 mL)
gave 8g (5.18 g, 13.10 mmol, 86% yield) as a wax after chromatog-
raphy (10:90 EtOAc/PE). Rf 0.20 (10:90 EtOAc/PE); dH (400 MHz,
CHCl3) 1.77 (3H, s, CH3), 2.31 (2H, t, J 6.7 Hz, CH2), 3.59 (2H, td, J 6.7,
5.2 Hz, CH2), 4.83 (1H, br s, CH), 4.91 (1H, br s, CH), 5.16 (2H, s, CH2),
5.18 (2H, s, CH2), 7.27e7.43 (10H, m, 2ꢂ Ph), 7.56 (1H, br t, J 5.2 Hz,
NH), 11.78 (1H, s, NH); dC (100.6 MHz, CHCl3) 22.0, 36.7, 39.0, 67.2,
68.1, 112.9, 126.9, 127.9, 128.1, 128.4, 128.5, 128.7, 128.8, 134.7, 136.8,
141.9, 153.8, 155.9, 163.7; vmax (cmꢁ1) 3313, 3282, 3067, 3036, 2940,
2926, 1724, 1622; MS (ES) 395 (100%, ([MþH]þ)); HRMS (ES) found
396.1917. C22H26N3O4 ([MþH]þ) requires 396.1918.
C
14H25IN3O4 ([MþH]þ) requires 426.0884.
3.3.3. Benzyl-1-((benzyloxy)-carbonyl)-5-(iodomethyl)-imidazoli-
din-2-ylidene carbamate 9b. Using the general method, iodine
(1.38 g, 5.44 mmol), 8b (0.5 g, 1.36 mmol) and potassium carbonate
(0.75 g, 5.44 mmol) gave 9b (0.53 g, 1.07 mmol, 79%) after chro-
matography (EtOAc/PE 20/80e50/50) as a pale yellow solid. Mp
103e105 ꢀC; Rf 0.23 (50:50 EtOAc/PE); dH (400 MHz, CHCl3) 3.31
(1H, dd, J 9.0, 9.8 Hz, CH), 3.43 (1H, dd, J 9.8, 2.2 Hz, CH), 3.60 (1H,
dd, J 11.6, 3.2 Hz, CH), 3.86 (1H, dd, J 11.6, 9.1 Hz, CH), 4.39e4.46 (1H,
m, CH), 5.17 (2H, s, CH2), 5.28 (1H, d, J 12.3 Hz, CH), 5.34 (1H, d, J
12.3 Hz, CH), 7.29e7.47 (10H, m, 2ꢂ Ph), 8.5 (1H, br s, NH) dC
(100.6 MHz, CHCl3) 7.1, 46.2, 57.5, 68.7, 128.1 (CH), 128.0, 128.1,
128.2, 128.4, 128.6, 128.7, 134.8, 136.2, 151.1, 161.0, 167.7; vmax 3350,
3050, 3025, 1761, 1713, 1652, 1605; MS (EI) 493 (8%), 218 (100%);
HRMS (EI) found 493.0498. C20H20IN3O4 ([Mþ]) requires 493.0499.
3.2.11. N-Boc-N0-allylguanidine 8h. Method C: allylamine (10 mL)
and 6c (2.0 g, 9.51 mmol) give 8h (1.51 g, 7.58 mmol, 80%) after
recrystallization from dichloromethane/petrol (ca. 1:1) as a white
solid. Mp 75e78 ꢀC; dH (400 MHz, CHCl3) 1.46 (9H, s, tBu), 3.83 (2H,
d, J 4.9 Hz, CH2), 5.24 (1H, br d, J 10.4 Hz, CH) 5.33 (1H, br d, J 17.1 Hz,
CH), 5.83 (1H, ddt, J 17.1, 10.4, 4.9 Hz, CH), 6.34 (1H, br s, NH), 7.60
(2H, br s, 2ꢂ NH); dC (100.6 MHz, CHCl3) 28.4, 43.9, 78.1,117.3,133.5,
162.1, 163.6; vmax 3468, 3238, 3134, 3010, 1649, 1635, 1591; HRMS
(ESD) found 200.1391. C9H18N3O2 ([MþH]þ) requires 200.1394.
3.2.12. N-Cbz-N0-allylguanidine 8i. Method C: allylamine (10 mL)
and 6d (4.00 g, 16.37 mmol) gave 8i (2.32 g, 9.94 mmol, 61%) as
a white solid after chromatography (0:100 to 60:40 EtOAc/PE). Mp
119e121 ꢀC; Rf 0.24 (75:25 EtOAc/PE); dH (400 MHz, CHCl3) 3.73
(2H, d, J 4.9 Hz, CH2), 5.07 (2H, s, CH2), 5.23 (1H, d, J 11.3 Hz, CH),
5.25 (1H, d, J 16.8 Hz, CH), 5.73 (1H, ddd, J 16.8, 11.3, 4.9 Hz, CH),
7.19e7.32 (5H, m, Ph), 7.40 (3H, br s, 3ꢂ NH) dC (100.6 MHz, CHCl3)
41.9, 66.2, 116.4, 127.8, 128.0, 128.4, 133.6, 137.3, 162.5, 163.6; vmax
3401, 3314, 3254, 3089, 3068, 3032, 2991, 2924, 1629, 1592, 1387;
HRMS (ESD) found 234.1245. C12H16N3O2 ([MþH]þ) requires
234.1237.
3.3.4. 2-tert-Butoxycarbonylimino-5-iodo-6,6-dimethyl-tetrahy-
dropyrimidine-1-carbozylic acid tert-butylester 10a. Using the gen-
eral method, iodine (1.16 g, 4.57 mmol), 8c (0.50 g, 1.53 mmol) and
potassium carbonate (0.86 g, 6.22 mmol) gave 10a (588 mg,
1.30 mmol, 85%) as an unstable oil. dH (400 MHz, CHCl3) 1.41 (9H, s,
tBu), 1.50 (3H, s, Me), 1.51 (9H, s, tBu), 1.52 (3H, s, Me), 3.72 (1H, dd, J
13.4, 9.2 Hz, CH), 3.83 (1H, dd, J 13.4, 5.4 Hz, CH), 4.23 (1H, dd, J 9.2,
5.4 Hz, CH), 9.40 (1H, bd s, NH); dC (100.6 MHz, CHCl3) 24.1, 26.6,
27.4, 28.2, 30.1, 46.8, 57.1, 77.7, 84.0, 152.0, 156.2, 163.5 vmax 3268,
1750, 1603; HRMS (CI) compound underwent decomposition.
3.3.5. Benzyl-2-(benzyloxycarbonyl)-5-iodo-6,6-dimethyl-tetrahy-
dropyrimidine-1(2H)-carboxylate 10b. Using the general method,
iodine (0.52 g, 2.04 mmol, 4.0 equiv), 8d (0.202 g, 0.51 mmol) and
potassium carbonate (0.07 g, 0.51 mmol, 1.0 equiv) gave 10b
(0.242 g, 91%) on recrystallization from dichloromethane/PE (1:4).
Mp 123e125 ꢀC dH (400 MHz, CHCl3) 1.51 (3H, CH3), 1.53 (3H, CH3),
3.78 (1H, dd, J 13.6, 8.8 Hz, CH), 3.90 (1H, dd, J 13.6, 5.5 Hz CH) 4.26
(1H, dd, J 8.8, 5.5 Hz CH) 5.09 (2H, AB pattern, J 12.6, CH2), 5.30 (2H,
AB pattern, J 12.0, CH2), 7.25e7.48 (10H, m, 2ꢂ Ph), 9.71 (1H, br s,
NH); dC (100.6 MHz, CHCl3) 24.6, 26.4, 29.2, 46.9, 57.8, 66.9, 70.0,
127.6, 127.9, 128.3, 128.5,128.6, 134.5, 137.2, 153.6, 156.6, 163.6; vmax
3253, 3066, 3017, 2952 (CeH), 1752, 1631, 1605; MS (CI) 522 (100%,
[MþHþ]); HRMS (CI) found 522.0886. C22H25IN3O4 [MþHþ] re-
quires 522.0884.
3.2.13. N-Cbz-N0-(dimethylallyl)guanidine 8j. Method B: 1-amino-
3-methyl-2-butene hydrochloride salt (1.5 g, 12.33 mmol), 6d
(1.00 g, 4.094 mmol), triethylamine (2.5 g, 3.5 mL, 22.7 mmol) and
MgSO4 (ca. 1.0 g) in acetonitrile (10 mL) at rt for 16 h followed by
reflux for 8 h gave 8j (0.667 g, 2.55 mmol, 62%) as an off-white solid
after chromatography (0:100 to 80:40 EtOAc/PE). Mp 81e83 ꢀC; Rf
0.21 (70:30 EtOAc/PE); dH (400 MHz, CHCl3) 1.52 (3H, s, CH3), 1.61
(3H, s, CH3), 3.56 (2H, d, J 6.3 Hz, CH2), 4.97 (2H, s, CH2), 5.00e5.06
(1H, m, CH), 6.60 (2H, br s, NH2) 7.16e7.28 (5H, m, Ph), 9.0 (1H, br s,
NH); dC (100.6 MHz, CHCl3) 17.7, 25.5, 39.2, 66.0, 120.0, 127.5, 127.7,
128.2, 136.4, 137.4, 162.2, 163.6; vmax 3306, 3018, 1627, 1589; HRMS
(ESD) found 262.1551. C14H20N3O2 ([MþHD]) requires 262.1550.
3.3. Iodocyclisation reactions
3.3.6. Benzyl-2-(((benzyloxy)carbonyl)imino)-4-(iodomethyl)-5,5-
dimethylimidazolidine-1-carboxylate 11. Evaporation of the com-
bined mother liquors from several preparations of 10b followed by
chromatography in diethyl ether/PE (50:50) gave 11 as a waxy solid.
Rf 0.21 (25:75 EtOAc/PE); dH (100.6 MHz, CHCl3) 1.44 (3H, CH3), 1.57
(3H, CH3), 3.17e3.25 (1H, m, CH), 3.29 (1H, dd, J 10.1, 4.7 Hz, CH)
3.82e3.85 (1H, m, CH), 5.18 (2H, AB pattern, J 12.4 Hz, CH2), 5.29
(2H, s, CH2) 7.30e7.50 (10H, m, 2ꢂ Ph), 9.19 (1H, br s, NH); dC
(100.6 MHz, CHCl3) 3.2, 19.3, 26.1, 46.7, 64.0, 67.3, 68.5, 127.9, 128.1,
3.3.1. General method. Iodine (3e4 equiv) is added to a cooled
(ꢁ15 ꢀC), stirred mixture of the guanidines 8aej (1 equiv) and finely
powdered anhydrous potassium carbonate (0e6 equiv) in dry
MeCN (ca. 20 mL per mmol 8aej). The resulting mixture was stirred
to rt over 16 h, then sodium thiosulfate solution (aq, satd) was
added until decolourisation occurred. The resulting mixture was
then extracted with dichloromethane (3ꢂ20 mL) and the combined
organic phases dried (MgSO4), filtered and evaporated. Purification
Please cite this article in press as: Al Shuhaib, Z.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.03.087

6
Z. Al Shuhaib et al. / Tetrahedron xxx (2014) 1e8
128.2, 128.3, 128.4, 128.5, 134.8, 136.4, 151.5, 153.6, 156.5; vmax 3331,
3034, 3006, 2960, 2932, 1758, 1726, 1652, 1613; MS (CI) 522 (85%,
[MþHþ]), 544 (85%, [MþNaþ]), 1065 (65%, [2MþNaþ]); HRMS (CI)
found 522.0874. C22H25IN3O4 [MþHþ] requires 522.0884.
10.4, 2.0 Hz, CH), 3.47e3.55 (2H, m, 2ꢂ CH), 3.96 (1H, dd, J 10.4,
9.6 Hz, CH), 4.34e4.44 (1H, m, CH), 8.03 (2H, br s 2ꢂ NH); dC
(100.6 MHz, CD3OD) 10.5, 28.3, 54.7, 58.5 79.5, 152.0, 157.1; dC
(100.6 MHz, (CD3)2SO) 11.7, 27.5, 48.4, 56.3, 84.9, 150.0, 154.6; dC
(100.6 MHz, CHCl3) 7.7, 28.0, 49.9, 57.2, 86.6, 2ꢂ C not detected.
3.3.7. Benzyl-3-((benzyloxy)carbonyl)-tetrahydro-4-(iodomethyl)
pyrimidin-2-(1H)-ylidene carbamate 14. Using the general method,
iodine (1.19 g, 4.69 mmol), 8e (0.37 g, 1.18 mmol) and potassium
carbonate (0.65 g, 4.70 mmol) gave 14 (0.35 g, 68%) after chroma-
tography (EtOAc/PE 15/85e30/70) as a white solid. Mp 107e108 ꢀC;
Rf 0.34 (30:70 EtOAc/PE); dH (400 MHz, CHCl3) 1.47 (9H, s, tBu) 1.52
(9H, s, tBu), 2.07e2.15 (1H, m, CH), 2.23e2.32 (1H, m, CH), 3.09 (1H,
dd, J 10.6, 9.8 Hz, CH), 3.35 (2H, t, J 6.2 Hz, CH2), 3.52 (1H, dd, J 9.8,
3.8 Hz, CH), 4.36e4.43 (1H, m, CH), 9.0 (1H, br s, NH); dC
(100.6 MHz, CHCl3) 6.1, 27.6, 28.0, 28.2, 36.7, 54.1, 79.4, 83.5, 151.9,
157.9, 162.2; vmax 3153, 2920, 2725, 1735, 1714, 1650; MS (EI) 439
(3%, [Mþ]); HRMS (EI) found 439.0967. C15H26IN3O4 [Mþ] requires
439.0968.
3.3.11. Rearrangement of 16 on silica gel. Crude 16 (0.74 g) was
dissolved in dichloromethane (5 mL) and silica gel (5 g) was added
and the resultant slurry (ensuring sufficient dichloromethane was
added to maintain a slurry) stirred for 5 days. The slurry was then
washed onto a sintered filter using dichloromethane, which was
washed with excess dichloromethane to give after evaporation
a crude extract (0.15 g). The silica pad was further washed with
excess methanol to give after evaporation a further crude extract
(0.43 g). Column chromatography of the dichloromethane extract
(EtOAc/petrol, 0:100 to 20:80 in 10% steps) gave the urea 17
(15.0 mg,1.5%) as a solid. Chromatography of the methanolic extract
(0:100 to 30:70 MeOH/CHCl3) gave 19 (19.0 mg, 3%) and 20
(95.0 mg, 13%) as solids.
3.3.8. tert-Butyl 2-(tert-butoxycarbonylimino)-6-(iodomethyl)-6-
methyl tetrahydropyrimidine-1(2H)-carboxylate 15a. Using the
general method, iodine (1.55 g, 6.11 mmol), 8f (0.50 g, 1.53 mmol)
and potassium carbonate (1.26 g, 9.12 mmol) gave 15a (0.69 g, 99%)
as a yellow gum, which was unstable to chromatography. dH
(400 MHz, CHCl3) 1.44 (9H, s, tBu),1.53 (9H, s, CH3),1.56 (3H, s, CH3),
1.90 (1H, ddd, J 13.6, 98, 6.1 Hz, CH), 2.33 (1H, dt, J 13.6, 5.9 Hz, CH),
3.25e3.37 (2H, m, CH2), 3.47 (1H, d, J 10.6 Hz, CH), 3.74 (1H, d, J
10.6 Hz, CH), 9.54 (1H, br s, NH); dC (100.6 MHz, CHCl3) 12.8, 24.0,
27.6, 28.3, 33.2, 35.7, 55.7, 77.9, 84.1, 152.6, 157.2, 163.6; vmax 3263,
2977, 2932, 1738, 1614; MS (ESI) 454 (100%, [MþHþ]); HRMS (ES)
found 454.1195. C16H29IN3O4 ([MþHþ]) requires 454.1197.
3.3.11.1. 4-Iodomethyl-2-oxo-imidazolidine-1,3-dicarboxylic acid
di-tert-butyl ester 17. Mp 123e125 ꢀC; Rf 0.21 (5:95 EtOAc/PE
petrol); dH (400 MHz, CHCl3) 1.49 (9H, s, tBu), 1.50 (9H, s, tBu), 3.31
(1H, dd, J 10.1, 8.5 Hz, CH), 3.45 (1H, dd, J 10.1, 2.5 Hz, CH), 3.56 (1H,
dd, J 11.0, 3.2 Hz, CH), 3.76 (1H, dd, J 11.0, 9.2 Hz, CH), 4.16e4.22 (1H,
m, CH); dC (100.6 MHz, CHCl3) 7.7, 28.0, 29.7, 45.9, 51.2, 83.7,
84.1 (3ꢂ C not observed); vmax 1789, 1738; HRMS (ESD) found
427.0726. C14H23IN2O5 [(MþH)D] requires 427.0724.
3.3.11.2. tert-Butyl 2-imino-4-(iodomethyl)imidazolidine-1-
carboxylate 19. Rf 0.29 (10:90 MeOH/CHCl3); dH (400 MHz,
t
CD3OD) 1.57 (9H, s, Bu), 3.41 (2H, d, J 4.1 Hz, CH2), 3.70 (1H, dd, J
3.3.9. Benzyl 2-(((benzyloxy)carbonyl)imino)-6-(iodomethyl)-6-
methyltetrahydropyrimidine-1(2H)-carboxylate 15b. Using the gen-
eral method, iodine (1.27 g, 5.04 mmol), 8g (0.50 g, 1.264 mmol)
and potassium carbonate (1.05 g, 7.58 mmol) gave crude 15b
(0.69 g), which was dissolved in dichloromethane (ca. 5 mL) and
diluted with petrol to the cloud point. After cooling (ꢁ20 ꢀC)
overnight a small amount of dark oil precipitated. The supernatant
liquid was decanted, warmed to rt and diluted with further PE
(50 mL). After cooling (ꢁ20 ꢀC) overnight, the supernatant was
removed again and the precipitated gum was washed with a small
portion of PE, which was again decanted to give on drying under
vacuum the product 15b (0.45 g, 0.86 mmol, 68% yield) as a yellow
gum. dH (400 MHz, CHCl3) 1.52 (3H, s, CH3),1.90 (1H, ddd, J 13.8, 9.0,
6.0 Hz, CH), 2.37 (1H, dt, J 13.8, 4.9 Hz, CH), 3.27e3.40 (2H, m, CH2),
3.53 (1H, d, J 10.6 Hz, CH), 3.73 (1H, d, J 10.6 Hz, CH), 5.07 (1H, d, J
12.5 Hz, CH), 5.13 (1H, d, J 12.5 Hz, CH), 5.23 (1H, d, J 12.1 Hz, CH),
5.32 (1H, d, J 12.1 Hz, CH), 7.28e7.48 (10H, m, 2ꢂ Ph), 9.81 (1H, br s,
NH); dC (100.6 MHz, CHCl3) 12.4, 24.0, 33.1, 35.7, 56.5, 66.9, 70.0,
127.7, 127.9, 128.3, 128.5, 128.7, 134.6, 137.2, 154.1, 157.6, 163.7; vmax
(cmꢁ1) 3263, 3173, 3063, 3032, 2943, 2886, 1743, 1700, 1610; MS
(ES) 521 (100%, ([MþH]þ)); HRMS (ES) found 522.0878.
10.5, 4.6 Hz, CH), 4.03e4.08 (1H, m, CH), 4.09 (1H, dd, J 10.5,
9.6 Hz, CH) dC (100.6 MHz, CD3OD) 11.4, 28.8, 57.8, 55.5, 83.6,
154.6, 165.4.
3.3.11.3. 4-Iodomethyl-imidazolidin-2-ylideneamine-H2CO3
20. Rf 0.29 (20:80 MeOH/CHCl3); dH (400 MHz, CD3OD) 3.39e3.49
(3H, m, CH, CH2), 3.87 (1H, app t, J 10.0 Hz, CH), 4.13e4.18 (1H, m,
CH); dC (100.6 MHz, CD3OD) 11.2, 50.7, 57.0, 151.2, 161.2; vmax 3419,
1731, 1687; HRMS (ESD) found 225.9836. C4H8IN3 [(MþH)D] re-
quires 225.9836.
3.3.12. Rearrangement of 16 using trifluoroacetic acid: tert-butyl 2-
imino-4-(iodomethyl)imidazolidine-1-carboxylate
trifluoroacetate
salt 19. Crude 16 (0.498 g, from 8h (0.30 g, 1.51 mmol)) was dis-
solved in methanol (5 mL) and trifluoroacetic acid (0.38 mL,
4.9 mmol) was added and the reaction stirred for 16 h. On evap-
oration a solid (0.65 g) was obtained, which was dissolved in
minimum volume of DCM (ca. 5e10 mL), which was diluted with
a small volume of PE (1e2 mL) and placed in a freezer overnight to
give 19 (0.34 g, 51%) as a pale yellow solid. Mp 90e92 ꢀC; Rf 0.29
t
(10:90 MeOH/CHCl3); dH (400 MHz, CD3OD) 1.60 (9H, s, Bu), 3.42
C
22H25IN3O4 ([MþH]þ) requires 522.0884.
(1H, dd, J 10.6, 4.5 Hz, CH), 3.54 (1H, dd, J 11.0, 2.0 Hz, CH), 3.74 (1H,
dd, J 11.0, 5.5 Hz, CH), 3.90 (1H, dd, J 10.6, 9.9 Hz, CH), 4.51 (1H, J 9.9,
5.5, 4.5, 2.0 Hz, CH) dH (400 MHz, CHCl3) 1.56 (9H, s, tBu), 3.36 (1H,
dd, J 10.8, 2.2 Hz, CH), 3.46 (1H, dd, J 10.8, 4.3 Hz, CH), 3.52 (1H, dd, J
10.8, 6.6 Hz, CH), 3.87 (1H, dd, J 10.8, 9.4 Hz, CH), 4.39 (1H, dddd, J
9.4, 6.6, 4.3, 2.2 Hz, CH) 7.75 (1H, br s, NH), 11.07 (1H, br s, NH),
11.88 (1H, br s, NH); dH (400 MHz, DMSO) 1.52 (9H, s, tBu), 3.24 (1H,
dd, J 10.5, 4.2 Hz, CH), 3.52 (1H, dd, J 10.6, 2.0 Hz, CH), 3.64 (1H, dd, J
10.6, 5.2 Hz, CH), 3.77 (1H, dd, J 10.5, 9.9 Hz, CH), 4.42 (1H, dddd, J
9.9, 5.2, 4.2, 2.0 Hz, CH) 7.75 (1H, br s, NH), 11.07 (1H, br s, NH),
11.88 (1H, br s, NH); dC (100.6 MHz, CHCl3) 7.0, 27.8, 46.9, 56.8, 87.4,
3.3.10. tert-Butyl 2-imino-5-(iodomethyl)imidazolidine-1-
carboxylate 16. Using the general method, iodine (2.55 g,
10.1 mmol), 8h (0.50 g, 2.51 mmol) and potassium carbonate
(1.40 g, 10.1 mmol) gave crude 16 (0.80 g, 98%) as an oil. dH
(400 MHz, CD3OD) 1.60 (9H, s, tBu), 3.45 (1H, dd, J 11.5, 4.2 Hz, CH),
3.52 (1H, dd, J 10.7, 2.1 Hz, CH), 3.72 (1H, dd, J 10.7, 5.8 Hz, CH), 3.89
(1H, dd, J 11.5, 9.7 Hz, CH), 4.47 (1H, dddd, J 9.7, 5.8, 4.2, 2.1 Hz, CH)
dH (DMSO) 1.50 (9H, s, tBu), 3.17 (1H, dd, J 11.7, 4.2, CH) 3.46 (1H, dd,
J 10.5,1.9 Hz, CH), 3.57 (1H, dd, J 10.5, 5.6 Hz, CH), 3.71 (1H, dd, J 11.7,
9.6 Hz, CH), 3.88 (1H, dd, J 11.5, 9.7 Hz, CH), 4.47 (1H, dddd, J 9.6, 5.6,
4.2, 1.9 Hz, CH); dH (400.MHz, CHCl3) 1.58 (9H, s, tBu), 3.38 (1H, dd, J
1
2
116.5 (q, JCeF 292.0 Hz), 149.9, 156.9, 163.2 (q, JCeCeF 35.0 Hz);
vmax 3306, 1752, 1679; MS (ESD) 326 (45%, [MþH]þ), 270 (100%);
Please cite this article in press as: Al Shuhaib, Z.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.03.087

Z. Al Shuhaib et al. / Tetrahedron xxx (2014) 1e8
7
HRMS (ESD) found 326.0363. C9H17IN3O2 [(MþH)D] requires
dimethylimidazolidine-1-carboxylate
24. Using
the
general
326.0360.
method, iodine (1.31 g, 5.17 mmol, 4.5 equiv), potassium carbonate
(0.48 g, 3.44 mmol, 3 equiv) and 8j (0.30 g, 1.148 mmol) gave
a solid (0.417 g), which was composed of 23 and 24 in a 40:60
ratio. This mixture was dissolved in methanol (ca. 5 mL), cooled
(ꢁ20 ꢀC) and on standing overnight 23 (0.115 g, 0.297 mmol, 26%)
was obtained as off white solid. The remaining mother liquor on
evaporation gave 24 (0.302 g, 68%, ca. 90% pure) as an oil. Com-
pound 23 mp 160e162 ꢀC; Rf 0.29 (5:95 MeOH/CHCl3); dH
(400 MHz, CHCl3) 1.35 (3H, s, CH3), 1.37 (3H, s, CH3), 3.43 (1H, dd, J
9.2, 13.6 Hz, CH), 3.55 (1H, dd, J 4.6, 13.6 Hz, CH), 3.97 (1H, dd, J 4.6,
9.2 Hz, CH), 5.02 (2H, s, CH2), 7.30e7.36 (5H, m, Ph), 8.70 (1H, br s,
NH), 9.70 (1H, br s, NH); dH (400 MHz, CD3OD) 1.46 (3H, s, CH3),
1.47 (3H, s, CH3), 3.73 (1H, dd, J 7.0, 14.2 Hz, CH), 3.94 (1H, dd, J 4.4,
14.2 Hz, CH), 4.45 (1H, dd, J 4.4, 7.0 Hz), 5.09 (2H, s, CH2),
7.28e7.40 (5H, m, Ph); dC (100.6 MHz, CHCl3) 27.5, 29.2, 29.3, 46.3,
52.5, 66.3, 128.0, 128.3, 128.6, 137.0, 157.6, 163.1; dC (100.6 MHz,
CD3OD) 28.8, 30.4, 31.3, 48.9, 54.9, 68.3, 129.6, 129.7, 130.2, 139.6,
159.2, 165.0; vmax 3340, 1706, 1634, 1553; HRMS (ESD) found
388.0522. C14H19IN3O2 [(MþH)D] requires 388.0517. Compound 24
(partial data) dH (400 MHz, CHCl3) 1.35 (3H, s, CH3), 1.51 (3H, s,
CH3), 3.17 (1H, dd, J 8.3, 10.0 Hz, CH), 3.22 (1H, dd, J 5.0, 10.0 Hz,
CH), 3.78 (1H, dd, J 8.3, 5.0 Hz, CH), 5.24 (2H, s, CH2), 7.31e7.45
(5H, m, Ph); dC (100.6 MHz, CHCl3) 5.7, 19.1, 27.5, 46.1, 67.8, 71.9,
128.1, 128.4, 128.5, 134.5, 152.9, 162.9.
3.3.13. 4-(Iodomethyl)imidazolidin-2-imine 2,2,2-trifluoroacetate
20. Using the general method, iodine (1.05 g, 4.13 mmol), 8h
(0.203 g, 1.02 mmol) and potassium carbonate (1.15 g, 8.33 mmol)
gave crude 16 (0.297 g, 90%) as an oil. This was dissolved in CH2Cl2
(3 mL), cooled (0 ꢀC) and trifluoroacetic acid (3 mL) added and the
mixture stirred for 1 h. Evaporation and chromatography (0e20%
MeOH in CHCl3 containing 0.1% TFA) gave 20.HCO2CF3 (0.219 g,
0.65 mmol, 63%) as a clear gum. dH (400 MHz, CD3OD) 3.35e3.44
(3H, m, 3ꢂ CH), 3.83 (1H, t, J 9.9 Hz, CH), 4.07e4.14 (1H, m, CH); dC
(100.6 MHz, CD3OD) 10.1, 50.2, 56.6, 118.0 (q, JCeF 291.0 Hz) 160.9,
2
162.8 (q, JCeCeF 36.0 Hz); vmax 3425, 1730, 1685; HRMS (ESD)
found 225.9838. C4H8IN3 [(MþH)D] requires 225.9836.
3.3.14. Benzyl-2-imino-4-(iodomethyl)imidazolidine-1-carboxylate
22. Using the general method, iodine (2.44 g, 9.61 mmol), 8i
(0.50 g, 2.14 mmol) and potassium carbonate (1.33 g, 9.62 mmol)
gave crude benzyl 2-imino-4-(iodomethyl)imidazolidine-1-
carboxylate 21 (0.722 g) as a solid. Partial data: dH (400 MHz,
CDCl3) 3.28 (1H, dd, J 9.8, 6.5 Hz, CH), 3.38 (1H, dd, J 9.8, 4.7 Hz, CH),
3.70 (1H, dd, J 10.7, 5.7 Hz, CH), 4.05 (1H, dd, J 10.7, 9.1 Hz, CH) 4.20
(1H, dddd, J 9.1, 6.5, 5.7, 4.7 Hz, CH), 5.35 (2H, AB pattern, J 12.3 Hz,
CH2), 7.37e7.49 (5H, m, Ph) dC (100.6 MHz, CHCl3) 9.5, 51.7, 57.3,
68.0, 128.0, 128.5, 134.6, 138.3, 153.5, 154.6. Rearrangement of 21
using silica gel: Crude 21 (0.722 g, 2.14 mmol) was dissolved in
dichloromethane (5 mL) and silica gel (5 g) was added and the
resultant slurry (sufficient dichloromethane was added to maintain
a slurry) was stirred for 5 days. The slurry was then washed onto
a sintered filter and washed with excess dichloromethane to give
after evaporation a crude extract (0.366 g). The silica pad was fur-
ther washed with excess methanol to give after evaporation a sec-
ond crude extract (0.262 g). The dichloromethane was subject to
chromatography (EtOAc/PE, 0:100 to 70:30 in 10% steps) to give 22
(61 mg, 8%) as a solid, Rf 0.10 (50:50 EtOAc/PE). Chromatography of
the methanolic extract (0:100 to 30:70 MeOH/CHCl3) gave the
previously isolated 20 (0.135 g, 28%) as a solid. Rearrangement of 21
using trifluoroacetic acid: Crude 21 (0.529 g, from 8i (0.30 g,
1.286 mmol)) was dissolved in methanol (5 mL) and trifluoroacetic
acid (0.32 mL, 4.2 mmol) was added and the reaction was stirred for
16 h. On evaporation a solid (0.69 g) was obtained, which was
dissolved in dichloromethane (ca. 5 mL) and diluted with ether (ca.
1e2 mL) and placed in a freezer. An off white solid (81 mg) initially
precipitated, which was removed by decanting the mother liquor
and proved to be very hygroscopic and gave a complex NMR
spectrum. Further dilution of the decanted mother liquor with
hexane (ca. 1e2 mL) and standing overnight in the freezer gave
a pale yellow precipitate of 22 (0.222 g, 48%), which was of ca. 90%
purity. A higher purity sample (0.129 g, 28%) was obtained on re-
peating this procedure. Mp 114e116 ꢀC; Rf 0.16 (10% MeOH/CHCl3);
dH (400 MHz, CHCl3) 3.32 (1H, br d, J 10.4 Hz, CH), 3.41e3.45 (1H, m,
CH), 3.54 (1H, dd, J 10.8, 4.1 Hz, CH), 3.88 (1H, dd, J 10.8, 9.8 Hz, CH),
4.43e4.47 (1H, m, CH), 5.31 (1H, d, J 11.7 Hz, CH), 5.40 (1H, d, J
11.7 Hz, CH), 7.38e7.45 (5H, m, Ph), 7.71 (1H, br s, NH), 11.55 (1H, br
s, NH), 12.48 (1H, br s, NH); dH (400 MHz, CD3OD) 3.45 (1H, dd,
J 11.7, 4.1 Hz, CH), 3.48 (1H, dd, J 11.0, 2.2 Hz, CH), 3.63 (1H, dd, J 11.0,
5.5 Hz, CH), 3.89 (1H, dd, J 10.7, 9.8 Hz, CH), 4.54 (1H, dddd, J 11.0,
5.5, 4.1, 2.2 Hz, CH), 5.34 (1H, d, J 12.0 Hz, CH), 5.45 (1H, d, J 12.0 Hz,
CH), 7.37e7.47 (5H, m, Ph); dC (100.6 MHz, CD3OD) 9.0, 48.3, 58.3,
71.0, 129.9, 129.9, 130.2, 135.7, 152.6, 157.6; vmax (Nujol) 3324, 1714,
3.3.16. Rearrangement of 22 using trifluoroacetic acid: preparation of
benzyl (5-(iodomethyl)-4,4-dimethylimidazolidin-2-ylidene)carba-
mate 25. A mixture of 23 and 24 (33:67, 0.421 g, from 8j
(1.027 mmol)) was dissolved in methanol (5 mL) and trifluoroacetic
acid (0.13 mL, 194 mg, 1.7 mmol) was added and the mixture stirred
for 16 h. On evaporation a solid (0.607 g) was obtained, which was
dissolved in dichloromethane (3 mL), diluted with ether (ca. 10 mL)
and cooled (ꢁ20 ꢀC) overnight to give 25 (66.0 mg, 17%) as a pale
yellow solid. The remaining supernatant liquid was evaporated
(0.484 g) and on chromatography (0:100 to 80:20 EtOAc/PE in 10%
steps) gave the previously isolated 23 (58.2 mg, 15%), as a white
solid. Mp 86e88 ꢀC; Rf 0.17 (10:90 MeOH/CHCl3); dH (400 MHz,
CD3OD) 1.56 (3H, s, CH3), 1.58 (3H, s, CH3), 3.36 (1H, dd, J 11.0,
7.6 Hz, CH), 3.54 (1H, dd, J 11.0, 4.4 Hz, CH), 3.91 (1H, dd, J 7.6, 4.4 Hz,
CH), 5.42 (2H, s, CH2), 7.40e7.51 (5H, m, Ph) dC (100.6 MHz, CD3OD)
2.4, 19.8, 27.4, 65.4, 69.1, 71.0, 139.9, 130.1, 130.2, 135.6, 153.2, 157.4;
vmax 3335, 1716, 1611, 1515; HRMS (ESD) found 388.0510.
C
14H19IN3O2 [(MþH)D] requires 388.0516.
Acknowledgements
Thanks are given to the EPSRC (D.M.E., EP/J01821X/1), the Eu-
ropean Social Fund (D.H.D., P.H., I.J.), Menai Organics (D.H.D.),
Phytoquest Limited (I.J.) and to the Leonardo Da Vinci programme
(K.K. and H.F.) for funding and to the EPSRC Mass Spectrometry
Centre at Swansea for invaluable assistance.
Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.03.087.
References and notes
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