Cyclisation reactions of bis-protected guanidines

Article abstract of DOI:10.1016/j.tetlet.2007.10.143

The cyclisation of N-allyl- and N-homoallylguanidines using DMDO or I₂/K₂CO₂ leading to novel heterocycles is reported.

Full text of DOI:10.1016/j.tetlet.2007.10.143

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 185–188
Cyclisation reactions of bis-protected guanidines
Christiane Albrecht,a Sarah Barnes,a Henning Bockemeier,a Deiniol Davies,a
¨
Mark Dennis,a Daniel M. Evans,a Matthew D. Fletcher,a Iestyn Jones,a
Vera Leitmann,a Patrick J. Murphy,a,* Richard Rowles,a Robert Nash,b
Richard A. Stephenson,c Peter N. Hortonc and Michael B. Hursthousec
aSchool of Chemistry, University of Wales, Bangor, Gwynedd LL57 2UW, United Kingdom
bVASTox Wales, Plas Gogerddan, Aberystwyth, Ceredigion SY23 3EB, United Kingdom
cEPSRC National Crystallography Service, Department of Chemistry, University of Southampton,
Highfield, Southampton SO17 1BJ, United Kingdom
Received 9 August 2007; revised 12 October 2007; accepted 25 October 2007
Available online 30 October 2007
Abstract—The cyclisation of N-allyl- and N-homoallylguanidines using DMDO or I2/K2CO2 leading to novel heterocycles is
reported.
ꢀ 2007 Published by Elsevier Ltd.
OH
As part of a project directed towards the synthesis of the
marine hepatotoxin cylindrospermopsin 11 we wished to
investigate further2 the electrocyclic reactions of N-allyl
and N-homoallyl guanidines 4. The substrates were pre-
pared in high yields by reaction of the corresponding
N,N0-bis-Z- or -bis-Boc-1H-pyrazole carboxamidine 23
with amines 3 (Table 1, Scheme 1).
H
N
H
-O3SO
Me
O
NH HN
NH
H
NH
O
1
R1
R1
We have previously reported2 that the Boc-protected
guanidine 4a underwent cyclisation on treatment with
DMDO under neutral conditions to give the 5-mem-
bered guanidine 5 in good yield after 16 h. On reinvesti-
gation of this reaction we found that the formation of 5
was observed, but on column chromatography, a second
product was always isolated in variable yield which cor-
responded to the rearranged product 6 as shown by
X-ray crystallography (Fig. 1).4 The complete conver-
sion of 5 into 6 could be effected if a solution of the
crude reaction mixture in dichloromethane was stirred
with silica gel overnight giving 6 in 63% yield after puri-
fication. A similar result was observed with the Z-pro-
tected guanidine 4b which was again treated with an
excess of DMDO in acetone at ꢀ20 ꢁC and the reaction
monitored by proton NMR. Epoxidation of 4b was
3
N
H
R1
N
R1
H2N
N
n
n
H
N
P
N
P
(a)
N
P
N
P
4
2
Table 1
R1
Method
4
P
n
Yield
79%
92%
93%
95%
85%
Mpt
4a
4b
4c
4d
4e
Boc
Z
Boc
Z
1
1
1
1
2
H
H
A
A
B
B
B
87-89 °C
46-48 °C
129-132 °C
73-76 °C
82-83 °C
Me
Me
H
Boc
Scheme 1. Reagents and conditions: (Method A) amine 3, CH3CN,
16–24 h; (Method B) 3ÆHCl, NEt3, CH3CN, 16–24 h.
found to occur rapidly as evidenced by signals at d
2.62 (1H), 2.80 (1H) and 3.20 (1H) ppm, but on contin-
ued stirring, signals at d 3.45 (1H), 3.50 (1H), 3.85 (1H),
3.92 (1H) and 4.09 (1H) appeared which are evidence for
Keywords: Guanidines; DMDO epoxidation; Iodocyclisation.
*
Corresponding author. Tel.: +44 1248 382392; fax: +44 1248
370528; e-mail: paddy@bangor.ac.uk
0040-4039/$ - see front matter ꢀ 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.10.143

186
C. Albrecht et al. / Tetrahedron Letters 49 (2008) 185–188
Figure 2.
Figure 1.
(1H) and 4.07 (3H) ppm and the two guanidine protons
at d 7.87 (1H) and d 8.03 (1H) ppm assigned the struc-
ture as 8. Again it was possible to effect this rearrange-
ment by stirring the crude reaction product with silica
gel in dichloromethane.
structure 7. However, on purification on silica gel a new
product was formed in 64% yield, which had a consider-
ably simpler spectrum with signals at d 3.34 (1H), 3.67
H
H
H
N
N
N
N
(a)
(a)
(b)
Boc
OH
Boc
OBoc
H
N
N
N
63%
N
N
H
Boc Boc
4a
Boc
6
5
H
H
H
N
N
N
(b)
Z
OH
Z
OZ
H
N
N
64%
N
Z
N
Z
N
N
4b
Z
H
7
8
H
OH
H
OBoc
H
N
N
N
N
(a)
Boc
Boc
H
N
N
N
N
N
10
Boc
H
Boc Boc
4c
9
H
H
H
N
OZ
N
N
N
(b)
(a)
(a)
O
H
H
Z
87%
N
Z
N
Z
N
Z
N
Z
N
H
4d
12
11
H
N
H
N
H
N
N
N
N
H
Boc
OH
Boc
OBoc
14
N
N
N
H
82%
Boc Boc
Boc
4e
13
Scheme 2. Reagents and conditions: (a) DMDO, acetone, ꢀ20 ꢁC–rt, 1–7 days; (b) silica gel, CH2Cl2, 16–24 h.5

C. Albrecht et al. / Tetrahedron Letters 49 (2008) 185–188
187
H
H
H
N
H
N
N
N
N
(a)
(a)
Boc
I
Z
I
H
H
N
N
N
85%
N
Z
N
Z
79%
N
N
Z
Boc Boc
Boc
4b
16
4a
15
H
N
I
H
I
H
H
N
N
N
N
(a)
(a)
Boc
Z
H
H
64%
85%
N
N
N
N
N
N
Z
N
Z
Boc
Z
4d
Boc Boc
4c
18
17
H
N
H
N
N
(a)
H
Boc
I
68%
N
N
N
Boc Boc
Boc
4e
19
Scheme 3. Reagents and conditions: (a) I2, CH3CN, K2CO3, 0 ꢁC–rt, 16–24 h.5
We next investigated the epoxidation of the dimethyl-
allyl guanidine 4c and found that on treatment with
DMDO an epoxide (CH at d 2.97, dd, J 4.4, 7.6 Hz)
was formed which slowly underwent ring opening to
give initially the 6-membered guanidine 9 after 2–3 days
but ultimately (7 days) gave the rearranged 6-membered
product 10, as evidenced by the methine signal at d 4.15
(1H, dd, J 2.5, 8.5 Hz) giving an axial coupling constant
of 8.5 Hz. Attempted purification of this material was
difficult as the product obtained was a gum which could
not be recrystallised and was also prone to decomposi-
tion on silica gel which was presumably occurring via
the loss of a Boc protecting group. A similar reaction
of bis-Z protected 4d gave epoxide 11 as a stable prod-
uct, which on attempted recrystallisation from dichloro-
methane/petrol (10:1) deposited a precipitate of the
cyclised and rearranged guanidine 12. Again the methine
signal at d 4.10 ppm (1H, dd, J 10.5, 6.1 Hz) and the
guanidine protons at d 8.17 ppm (1H, br s, NH) and d
8.93 ppm (1H, br s, NH) were indicative of the 6-mem-
bered product. The slow rearrangement could be accel-
erated if a solution of the crude reaction mixture in
dichloromethane was stirred with silica gel overnight,
to give an 87% yield of 12. Finally, we investigated the
DMDO cyclisation of the homoallyl guanidine 4e and
found that it smoothly cyclised and rearranged to give
the 6-membered guanidine 14 in 82% yield; the structure
being determined by X-ray crystallography (Fig. 2)4
(Scheme 2).
chromatography, presumably due to the loss of the
Boc group adjacent to the two methyl groups. Guani-
dine 17 was also freely soluble in petroleum ether and
gave only an amorphous solid on slow evaporation.
The reaction of Z-protected 4d was more successful in
that the cyclised product was easily purified by recrystal-
lisation from dichloromethane/petroleum ether and was
obtained in 64% yield with signals at dH 4.27 (1H, dd, J
8.8 and 5.5 Hz) and dC 29.2 ppm corresponding to the
methine proton. Finally, the homoallyl guanidine 4e
was cyclised under standard conditions and gave the
6-membered guanidine 19 in 68% yield after chromato-
graphy with signals for the CH2I group being observed
at dH 3.08 (1H, dd, J 10.4, 9.9 Hz) and dH 3.50 (1H,
dd, J 3.8, 9.9 Hz) and dC 6.1 ppm (Scheme 3).
In conclusion, we have demonstrated that guanidines
4a–e undergo cyclisation to give 5- and 6-membered
cyclic guanidines and in the epoxide cyclisation both
the N-Boc and N-Z protecting group are prone to
migration to the alcohol function in a predictable
manner. We are currently investigating this process in
more detail and applying this methodology to a synthe-
sis of cylindrospermopsin.
Acknowledgements
Thanks are given to VASTox Wales and the ESF for a
PhD studentship (I.J.) and the EFS for two MSc stu-
dentships (D.D., D.E.), the ERASMUS and SOCRA-
TES schemes (C.A., H.B., V.L.) and to Pfizer for a
summer studentship (S.B.). Thanks are also given to
the EPSRC Mass Spectrometry centre at Swansea.
We next investigated the iodocyclisation2,6 of the allylat-
ed guanidines and found that both the Boc- and Z-pro-
tected allyl guanidines 4a and 4b gave the corresponding
5-membered heterocycles 15 and 16 in high yields on
treatment with I2 in acetonitrile. Reaction of the Boc-
protected dimethylallyl guanidine 4c was more problem-
atic in that a high yield (ca. 85%) of the 6-membered
product 17 was obtained as evidenced by the CH at
dH 4.27 (1H, dd, J 9.1, 5.5 Hz) and dC 30.1 ppm, how-
ever, the material decomposed on attempted silica gel
References and notes
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188
C. Albrecht et al. / Tetrahedron Letters 49 (2008) 185–188
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(500 MHz, DMSO-d6) 3.31 (2H, m) 3.61 (1H, t, J
10 Hz), 4.1–4.2 (2H, m), 5.0 (2H, s), 5.15 (2H, s), 7.2–7.4
(10H, m), 7.87 (1H, br s), 8.03 (1H, br s); dC (125 MHz,
CDCl3) 44.5 (CH2), 52.3 (CH), 66.4 (CH2), 68.1 (CH2),
69.9 (CH2), 127.7 (CH), 127.9 (CH), 128.3 (CH), 128.6
(CH), 134.9 (C), 137.2 (C), 154.6 (C), 163.1 (C), 165.1 (C);
mmax cmꢀ1 3398, 3100–2900 (br), 3065, 3035, 2956, 1748,
1654, 1623, 1264; MS (CI, NH3) m/z 384 (M+H, 33%);
HRMS (ES+) C20H22N3O5 [M+H+] requires 384.1554,
found 384.1558. 2-tert-Butoxycarbonylimino-6-iodo-
methyl-tetrahydro-pyrimidine-1-carboxylic acid tert-butyl
ester 19: N-homoallyl-N0N0-bis-(tert-butoxycarbonyl)-
guanidine 4e (0.37 g, 1.18 mmol), iodine (1.19 g,
4.72 mmol, 4 equiv) and potassium carbonate (0.65 g,
4.72 mmol, 4 equiv) were dissolved in dry acetonitrile
(10 mL) and left to stir overnight under an argon
atmosphere. The solution was then treated dropwise with
sodium thiosulfate solution (saturated) until the excess
iodine was consumed, then diluted with chloroform
(20 mL) and water (50 mL). After separation, the organic
phase was washed with water (3 · 20 mL), dried (MgSO4)
and evaporated in vacuo. Silica gel column chromato-
graphy (gradient elution 15–60% EtOAc) gave 19 (0.35 g,
0.68 mmol, 68%) as a white crystalline solid. Rf 0.34 (30%
EtOAc in petrol). Mp 107–108 ꢁC; dH (500 MHz, CD3OD,
NH exchanged) 1.47 (9H, s, 3 · Me) 1.51 (9H, s, 3 · Me),
1.82 (1H, m, CH), 2.04 (1H, m, CH), 3.37 (1H, m, CH),
3.44 (1H, m, CH), 3.77 (1H, m, CH), 4.08 (1H, dd, J 11.0,
6.6 Hz, CH), 4.23 (1H, dd, J 11.0, 4.9 Hz, CH); dC
(125 MHz, CDCl3) 6.4(CH2), 25.6 (CH2), 27.8 (CH3), 28.0
(CH3), 36.0 (CH2), 54.0 (CH), 79.2 (C), 83.2 (C), 151.6 (C),
158.0 (C), 162.7 (C); vmax cmꢀ1(Nujol Mull) 3153, 2920,
2725, 1735, 1714, 1650, 1549, 1457, 1376, 1296, 1154. MS
(EI) m/z 439.0 (M+, 3%); HRMS (EI) C15H26N3O4I [M+]
requires 439.0968, found 439.0967.
the biological activity and synthetic approaches to cylin-
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Chem. Soc. Rev. 2001, 30, 300–310.
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Nash, R.; Winters, A. L.; Hursthouse, M. B.; Light, M. E.;
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3389–3392.
4. X-ray data crystal structure analyses: Suitable crystals
were selected and data collected on a Bruker Nonius
KappaCCD Area Detector equipped with a Bruker
˚
Nonius FR591 rotating anode (kMo-Ka = 0.71073 A) at
120 K driven by COLLECT,7 and processed by DENZO
8
software and corrected for absorption by using SADABS.9
The structures were determined in SHELXS-97 and refined
using SHELXL-97.10 All non-hydrogen atoms were refined
anisotropically with hydrogen atoms included in idealised
positions with thermal parameters riding on those of the
parent atom. Crystal Data for 6: C14H25N3O5, M =
˚
˚
329.40, triclinic, a = 9.0231(6) A, b = 9.1863(6) A,
˚
c = 12.5757(9) A, a = 106.174(4)ꢁ, b = 97.221(4)ꢁ, c =
3
˚
110.245(4)ꢁ, U = 910.30(11) A , T = 120(2) K, space
group P1, Z = 2, l(Mo-Ka) = 1.239 mmꢀ1, 17,747 reflec-
ꢀ
tions measured, 4139 unique (Rint = 0.0682) which were
used in all calculations. Final R1 = 0.0883, wR2 = 0.1374
[F2 > 2r(F2)], R1 = 0.1405, wR2 = 0.1583 (all data). Full
crystallographic details in the form of a CIF have been
deposited with the Cambridge Crystallographic Data
Centre with deposition number 654570. Crystal Data for
14:
C15H27N3O5,
M = 329.40,
monoclinic,
a =
˚
˚
˚
15.2537(9) A, b = 10.4010(5) A, c = 11.1871(6) A, b =
95.981(2)ꢁ, U = 1765.21(16) A , T = 120(2) K, space
3
˚
6. For related iodocyclisations see: (a) Bruni, E.; Cardillo,
G.; Orena, M.; Sandri, S.; Tomasini, C. Tetrahedron Lett.
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group P21/c, Z = 4, l(Mo Ka) = 1.239 mmꢀ1, 26,343
reflections measured, 4036 unique (Rint = 0.0855) which
were used in all calculations. Final R1 = 0.1158,
wR2 = 0.2434 [F2 > 2r(F2)], R1 = 0.1597, wR2 = 0.2649
(all data). Full crystallographic details in the form of a
CIF have been deposited with the Cambridge Crystallo-
graphic Data Centre with deposition number 654569.
5. Typical experimental procedures: Benzyl-((2Z)-2-{[(benzyl-
oxy)carbonyl]imino}imidazolidin-4-yl)-methyl carbonate
8: Finely powdered N-allyl-N0,N00-bis-Z-guanidine 4b
(0.309 g, 0.84 mmol) was cooled in an ice/salt bath for
20 min prior to the addition of pre-cooled (ꢀ78 ꢁC), dried
DMDO (excess) solution in acetone. The solution was
stirred to rt slowly (overnight) and then for a further 5
days. After evaporation of the acetone the crude product
was dissolved in dichloromethane (5 mL) and silica gel
(1 g) was added and the slurry stirred overnight. Evapo-
ration of the dichloromethane and column chromatogra-
phy of the residue (0–100% EtOAc in petrol) gave 8
(0.208 g, 0.54 mmol, 64%) as a white solid. Mp 155–
157 ꢁC; Rf 0.46 (EtOAc); dH (500 MHz, CDCl3) 3.34 (1H,
dd, J 10, 4 Hz) 3.67 (1H, m), 4.07 (3H, m), 5.06 (2H, s),
5.16 (2H, s), 7.4 (10H, m), 8.1–9.4 (2H, br s); dH
8. Otwinowski, Z.; Minor, W. Methods in Enzymology. In
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