A 1,3-Diaza-Claisen rearrangement that affords guanidines

Article abstract of DOI:10.1021/ol048575e

(Chemical Equation Presented) N-Alkyl-N′-tosylthioureas activated by EDCI react with azanorbonenes at room temperature through a 1,3-diaza-Claisen rearrangement, affording highly substituted, bicyclic guanidines in moderate to good yields.

Full text of DOI:10.1021/ol048575e

ORGANIC
LETTERS
2004
Vol. 6, No. 19
3409-3412
A 1,3-Diaza-Claisen Rearrangement that
Affords Guanidines
Amy M. Bowser and Jose´ S. Madalengoitia*
Department of Chemistry, UniVersity of Vermont, Burlington, Vermont 05405
jmadalen@uVm.edu
Received July 22, 2004
ABSTRACT
N-Alkyl-N′-tosylthioureas activated by EDCI react with azanorbonenes at room temperature through a 1,3-diaza-Claisen rearrangement, affording
highly substituted, bicyclic guanidines in moderate to good yields.
The synthesis of guanidines from thioureas is one of the most
commons strategies used for the construction of the guanidine
functionality.1-3 In this transformation, a thiourea is activated
through reaction with DIC, EDCI, Hg(II), 2-chloro-1-
methylpyridinium iodide, 2,4-dinitrofluorobenzene, etc. While
we were attempting the synthesis of guanidines 2 and 5a-c
from thioureas 1 and 4a-c, respectively, in a reaction
mediated by EDCI, we noticed a remarkable reactivity
(Scheme 1). In all instances, an intramolecular cyclization
pathway was preferred, affording the cyclic guanidines 3 and
6a-c. In particular, the cyclization of 4b and 4c in which
the nitrogens are highly deactivated through protection with
methyltrityl (Mtt) and trifluoromethylacyl groups, respec-
tively, indicates that the activation of the thioureas affords a
highly electrophilic intermediate.
2) would also afford a highly electrophilic N-alkyl-N′-tosyl
carbodiimide 9 on activation with EDCI. We expected that
the carbodiimide 9 might be reactive enough to undergo a
reaction with azanorbornene 7, affording the zwitterionic
intermediate 10. In turn, the intermediate 10 would then be
Scheme 1
The most commonly accepted mechanism for the activa-
tion of thioureas involves the transformation of thioureas into
carbodiimides. We thus hypothesized that the highly elec-
trophilic intermediate involved in the reactions of Scheme 1
was an N-alkyl-N′-sulfonyl carbodiimide.4,5 We further
hypothesized that an N-alkyl-N′-tosyl thiourea (8, Scheme
(1) For examples, see: (a) Atwal, K. S.; Ahmed, S. Z.; O’Reilly, B. C.;
Tetrahedron Lett. 1989, 30, 7313. (b) Poss, M. A.; Iwanowicz, E.; Reid, J.
A.; Lin, J.; Gu, Z. Tetrahedron Lett. 1992, 33, 5933. (c) Yong, Y. F.;
Kowalski, J. A.; Lipton, M. A. J. Org. Chem. 1997, 62, 1540. (d) Kim, K.
S.; Qian, L. Tetrahedron Lett. 1993, 34, 7677. (e) Linton, B. R.; Carr, A.
J.; Orner, B. P.; Hamilton, A. D. J. Org. Chem. 2000, 65, 1566.
(2) For a review, see: Manimala, J. C.; Anslyn, E. V. Eur. J. Org. Chem.
2002, 3909.
(3) For an alternative synthesis of guanidines from thioureas, see:
Ostresh, J. M.; Schoner, C. C.; Hamashin, V. T.; Nefzi, A.; Meyer, J.-P.
Houghten, R. A. J. Org. Chem. 1998, 63, 8622.
10.1021/ol048575e CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/19/2004

The N-alkyl-N′-tosyl thioureas 16a-e were synthesized
through reaction of either N-tosylisothiocyanate or N-Pmc-
isothiocyanate with primary amines as shown in Scheme 4.9,10
Scheme 2
Scheme 4
After the completion of the synthesis of a representative
set of azanorbornenes and thioureas, the scope and limitations
of the rearrangement were investigated (Table 1). The
poised for a 1,3-diaza-Claisen rearrangement, affording the
bicyclic guanidine 13 in analogy to the reaction of aza-
norbornenes with ketenes.6 Due to the novelty of the
transformation and the ease with which it would increase
chemical complexity, the feasibility of using highly electro-
philic carbodiimides to mediate 1,3-diaza-Claisen rearrange-
ments was investigated.
Table 1. EDCI-Mediated Reaction of Azanorbornenes with
Thioureas
The synthesis of the azanorbornenes was accomplished
as described by Grieco.7 A solution of cyclopentadiene, form-
aldehyde, and an amine hydrochloride in water was main-
tained at room temperature, affording the azanorbornenes
14a-d in uniformly excellent yields (Scheme 3). In addition,
Scheme 3
a bis-azanorbornene was synthesized from m-xylylenedi-
amine hydrochloride, affording the bis-azanorbornenes 14e
as a mixture of diastereomers.8 In all, the azanorbornenes
are chosen to reflect a range of functionality, sterics, and
complexity.
(4) Anslyn has reported that thioureas similar to 4a, but bearing a benzoyl
protecting group instead of a Pmc protecting group, do not undergo
intramolecular cyclization on activation with EDCI. This provides further
evidence that the unusal reactivity observed is due to the powerful electron-
withdrawing nature of the sulfonyl group. Schneider, S. E.; Bishop, P. A.;
Salazar, M. A.; Bishop, O. A. Anslyn, E. V. Tetrahedron, 1998, 54, 15063.
(5) For examples of N-sulfonylguanidines from N-sulfonylthioureas,
see: (a) Zhang, J.; Shi, Y. Tetrahedron Lett. 2000, 41, 8075. (b) Li, J.;
Zhang, G.; Zhang, Z.; Fan, E. J. Org. Chem. 2002, 68, 1611.
3410
Org. Lett., Vol. 6, No. 19, 2004

N-benzyl azanorbornene 14a smoothly underwent reaction
with thioureas 16a-e, affording the rearrangement products
17a-e in good to moderate yields. To the best of our
knowledge, this work represents the first example of a
zwiterionic 1,3-diaza-Claisen rearrangement. It is noteworthy
that a set of diverse groups could be tolerated on the thiourea
ranging from a fairly hindered isopropyl group (16b) to an
ester functionality (16c). Furthermore, the reaction of the
thiourea 16d bearing a Pmc protecting group indicates that
additional sulfonyl groups are also tolerated. We next
investigated the reaction of azanorbornenes 14a-e with
N-benzyl-N′-tosylthiourea 16a. In this instance, the reaction
of the azanorbornenes 14b-c with 16a afforded the re-
arrangement products 17f and 17g in good yields. However,
the reaction of the N-isopropyl azanorbornene 14d with 16a
failed to afford any rearrangement product. The unreactivity
of 14d is most likely due to sterics since the nucleophilic
tertiary nitrogen is now bonded to two secondary carbons
and one primary carbon. Thus, a limitation of this reaction
is that it cannot tolerate an azanorbornene substituent that
has R-branching. The reaction of the bis-azanorbornenes 14e
with the thiourea 16a smoothly afforded the diastereomeric
guanidines 17h in 75% yield (Scheme 5). This reaction may
thus be useful in the synthesis of multivalent ligands.
Scheme 6
is required for the addition step, the rearrangement step, or
both steps.
An alternative mechanistic pathway was also explored.
Grieco has reported that the azanorbornenes are highly prone
to a retro-Diels-Alder reaction when the nitrogen bears a
positive charge.12 Therefore, an alternative mechanistic
pathway could be envisioned as arising from a retro-Diels-
Alder reaction of the zwitterionic intermediate 10 (Scheme
7), affording cyclopentadiene and the 1,4-dipole 19. The 1,4-
Scheme 7
Scheme 5
To further explore the scope of the reaction, we attempted
the rearrangement of azanorbornene 14a with the known
carbamoyl-protected thiourea 18 (Scheme 6).11 However, this
reaction did not afford any rearrangement product. This
suggests that the in situ-generated carbodiimides must bear
a strongly electron-withdrawing substituent (such as sulfonyl)
for the transformation to proceed. However, it is not known
at this juncture if the strongly electron-withdrawing group
dipole 19 and cyclopentadiene could in turn react by a 4 +
2 cycloaddition, furnishing the cyclic guanidine. To rule out
this potential pathway, we designed a crossover experiment
in which the rearrangement of 14a was run in the presence
of cyclohexadiene. If the retro-Diels-Alder pathway were
viable, one would expect that 17a would be formed along
with its homolgue 20. However, when the experiment was
conducted, only 17a could be detected. This result rules out
the possibility that the “rearrangement” product arises from
the retro-Diels-Alder pathway.
The regiochemistry of the rearrangement was also inves-
tigated, as two potential regioisomeric products are possible.
It may be envisioned, for example, that a zwitterionic
intermediate 21 may rearrange to afford the guanidine 24 or
its thermodynamically more stable regioisomer 17d (Scheme
(6) For examples of aza-Claisen rearrangements, see: (a) Maurya, R.;
Pittol, C. A.; Pryce, R. J.; Roberts, S. M.; Thomas, R. J.; Williams, J. O.
J. Chem. Soc., Perkin Trans. 1 1992, 1617. (b) Yoon, T. P.; Dong, V. M.;
MacMillan, D. W. C. J. Am. Chem. Soc. 1999, 121, 9726. (c) Cid, M. M.;
Pombo-Villar, E. HelV. Chim. Acta 1993, 76, 1591. (d) Cid, M. M.;
Eggnauer, U.; Weber, H. P.; Pombo-Villar, E. Tetrahedron Lett. 1991, 32,
7233.
(7) (a) Larsen, S. D.; Grieco, P. A. J. Am. Chem. Soc. 1985, 107, 1768.
(b) Grieco, P. A.; Bahsas, A. J. Org. Chem. 1987, 52, 5746.
(8) It is assumed that a ∼1:1 mixture of diastereomers is formed. Neither
1
the H NMR and 13C NMR spectra nor TLC indicate the presence of two
diastereomers, but this is not surprising, as the diastereomers are expected
to have very similar physical properties.
(9) (a) Compper, R.; Haegle, W. Chem. Ber. 1966, 99, 2885. (b) Barton,
D. H. R.; Fontana, G.; Yang, Y. Tetrahedron 1996, 52, 2705.
(10) Synthesis of N-Pmc-isothiocyanate will be reported separately.
(11) Mamai, A.; Madalengoitia, J. S. Org. Lett. 2001, 3, 561.
(12) Grieco, P. A.; Parker, D. T.; Fobare, W. F.; Ruckle, R. J. Am. Chem.
Soc. 1987, 109, 5859.
Org. Lett., Vol. 6, No. 19, 2004
3411

protons did not exhibit a cross-peak with any other protons,
indicating that the deprotected product is 23 and the
rearrangement product is 17d. It is expected by analogy that
the reaction of the N-tosyl thioureas with azanorbornenes
also proceeds with the same regiochemistry.
Scheme 8
In conclusion, this paper describes a novel EDCI-mediated
reaction between N-sulfonyl thioureas and azanorbornenes
that we propose proceeds through a 1,3-diaza-Claisen re-
arrangement and affords guanidines. The reaction proceeds
in modest to good yields and is fairly functional group
tolerant.
Acknowledgment. Funding for this project was provided
in part by DE-FG02-00ER45828 from the DOE EPSCoR
Initiative in Structural Biology and Computational Biology/
Bioinformatics and NSF CHE 0412831.
8). In the reaction of ketenes, with azanorbornenes, the
product is an amide, thus suggesting that the propensity in
these rearrangements is for the most electronegative atom
to end up double bonded and exocyclic in the product. This
suggests that 17d (in which NPmc is double bonded and
exocyclic) should be the major product. To unambiguously
establish this, the product of the reaction of 14a with 16d
was subjected to Pmc deprotection with TFA. TOCSY
spectroscopy of this sample revealed that the exchangeable
Supporting Information Available: Representative ex-
perimental conditions, characterization data, and copies of
1H NMR and 13C spectra for new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL048575E
3412
Org. Lett., Vol. 6, No. 19, 2004