Expanded Chemistry of Formamidine Ureas

Article abstract of DOI:10.1021/ol035995f

(Equation presented) Formamidine ureas display a rich manifold of reactivity. Thiols induce substitution at the carbonyl carbon to give thiolcarbamates; base-mediated alkylation and acylation occurs at the terminal urea nitrogen, and a new fragmentation/acylation pathway has been uncovered with isocyanates.

Full text of DOI:10.1021/ol035995f

ORGANIC
LETTERS
2004
Vol. 6, No. 1
43-46
Expanded Chemistry of Formamidine
Ureas
David D. D´ıaz and M. G. Finn*
Department of Chemistry and The Skaggs Institute for Chemical Biology,
The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, California 92037
mgfinn@scripps.edu
Received October 13, 2003
ABSTRACT
Formamidine ureas display a rich manifold of reactivity. Thiols induce substitution at the carbonyl carbon to give thiolcarbamates; base-
mediated alkylation and acylation occurs at the terminal urea nitrogen, and a new fragmentation/acylation pathway has been uncovered with
isocyanates.
We have recently described a facile entry to the formamidine
urea skeleton 1 and the tunable electrophilicity of the
formamidine center in such compounds.1,2 Thus, primary
amine nucleophiles undergo exchange (Scheme 1), and rates
In contrast to the exchange reaction observed with amines,
which requires nucleophilic attack on the formamidine
carbon, thiols cleave the central N-acyl bond to generate
thiolcarbamates in good yields (Scheme 2); the putative
Scheme 1
Scheme 2
of hydrolysis vary over 3 orders of magnitude depending
on the steric and electronic properties of the R1 substituent.2
We report here several additional modes of reactivity of these
multifunctional structures. In addition to standard alkylation
of the distal urea nitrogen, thiols have been found to react
much differently than nitrogen nucleophiles and a new
formamide fragment exchange process has been uncovered.
amidine byproduct 3 was not characterized. Neither 1,3-
disubstituted ureas nor several N-acylureas underwent any
trace of the corresponding reaction, demonstrating that the
amidine group is activating. Note also that treatment of N,N′-
diphenylformamidine with thiols did not give nitrogen
substitution, in contrast to the facile reactivity of this group
with amines.3 When made electron-rich by a heteroatom
donor in R1, as in the oxime ether 1a, the formamidine urea
(1) Ripka, A. S.; D´ıaz, D. D.; Sharpless, K. B.; Finn, M. G. Org. Lett.
2003, 5, 1531-1533.
(2) D´ıaz, D. D.; Finn, M. G. Chem. Eur. J. In press.
10.1021/ol035995f CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/11/2003

was rendered inert to thiols, similar to its stability toward
attack at the formamidine carbon in hydrolysis.2
The reaction of formamidine ureas and thiols is catalyzed
by base and gave the best yields in THF or CH3CN. Table
1 outlines the scope of the reaction with 1-(tert-butylimino-
ment,7 and various procedures involving phosgene8 or other
highly energetic reagents.9 More recently, a variety of
methods have been reported, including aminolysis of cyclic
thioxocarbonates,10 carbonate-mediated addition of alkyl
halide to carbon disulfide,11 elaboration of activated car-
bamoyl derivatives5a,12 and thiocarbonates,13 O-to-S allylic
rearrangement,14
re-
arrangement of N-alkyl carbonimidodithionates,15 various
carbonylation and thiocarbonylation reactions,16 and thiola-
tion of isocyanates,4k the last being the most general. The
process described here is notable for its convenience and
lack of hazardous reagents.
Table 1. Reactions of 1b with Thiolsa
Given the differing apparent sites of attack of amines and
thiols on thiolcarbamate electrophiles, the internal competi-
tion offered by a nucleophile containing both groups was of
interest. As shown in Scheme 3, L-cysteine ethyl ester
hydrochloride and formamidine 1b gave enantiomerically
pure thiazoline17 (+)-4 and 1,3-dimethylurea as the only
observed products, the former in 78% isolated yield. The
absence of racemization was confirmed by reduction to the
known18 hydroxymethyl derivative. The nature of the product
allows us to propose that amine substitution at the forma-
midine carbon (path a) is initially favored, followed by
intramolecular cyclization of thiol (or thiolate) in the
formamidine urea intermediate 5. It is difficult to propose a
reasonable mechanism for the formation of 4 from initial
thiol addition to 1b (path b) to give intermediate 6. A similar
reaction is observed in the interaction of acyclic 1,2-diamines
with formamidine ureas. Thus, enantiomerically pure (R,R)-
1,2-diphenylethylenediamine 7 smoothly afforded the cor-
responding chiral imidazoline 8 (Scheme 3),19 presumably
entry
1
R
% yielda
product
p-X-C6H4 (X ) H, Me, OMe,
Br, Cl, OH)
66-70
2a -f
2
3
4
5
6
7
8
9
10
2-naphthyl
CH2CH2Ph
CH2Ph
n-C6H13
68
69
67
71
62
70
61
63
67
2g
2h
2i
2j
2k
2l
2m
2n
2o
CH2CH2CH2Cl
CH2CH2CO2Et
(CH2)4OH
CH2CH2NH(n-C4H9)
(CH2)8SH
a Yields are reported for pure products after column chromatography
and are based on 1b.
methyl)-1,3-dimethyl urea hydrochloride 1b, which is con-
veniently available in large quantities.1 Triethylamine (1
equiv) was used to neutralize the starting hydrochloride salt.
The process allows the introduction of side chains bearing
other reactive functionalities, including halide, ester, alcohol,
amine, and thiol groups (entries 6-10).
The biological properties of thiolcarbamates have received
much attention,4 including their use in herbicides,4b-f
pesticides,4g-i antifertility agents,4j and antivirals.4k The
cleavage of the acyl-S bond of thiolcarbamates by protic
solvents and nucleophiles is well-known5,7a and may be
related to the biological activity of these compounds.4k Early
routes to thiolcarbamates included acid-mediated addition
of alcohols to thiocyanates,6 the Newman-Kwart rearrange-
(6) (a) Riemschneider, R.; Wojahn, F. Pharmazie 1949, 4, 460-462.
(b) Riemschneider, R. J. Am. Chem. Soc. 1956, 78, 844-847. (c) Kochansky,
J. P.; Wright, F. C. J. Economic Entomol. 1985, 78, 599-606. (d) Isobe,
T.; Ishikawa, T. J. Org. Chem. 1999, 64, 5832-5835.
(7) (a) Newman, M. S.; Karnes, H. A. J. Org. Chem. 1966, 31, 3980-
3984. (b) Kwart, H.; Evans, E. R. J. Org. Chem. 1966, 31, 410-413. (c)
Beaulieu, F.; Snieckus, V. Synthesis 1992, 112-118.
(8) (a) Eilingsfield, H.; Mo¨bius, L. Chem. Ber. 1965, 98, 1293-1307.
(b) Walter, W.; Bode, K.-D. Angew. Chem., Int. Ed. Engl. 1967, 6, 281-
293.
(9) (a) Akiba, K.; Inamoto, N. J. Chem. Soc., Chem. Commun. 1973,
13-14. (b) Adamski, R. J.; Numajiri, S.; Poe, R.; Spears, L. J. J. Med.
Chem. 1971, 14, 1244-1244.
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Okubo, I.; Kuwatsuka, S. Agr. Biol. Chem. 1973, 37, 165-173. (d)
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Andersson, M. J. Enzyme Inhib. 1985, 1, 1-11. (h) Kochansky, J.;
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44
Org. Lett., Vol. 6, No. 1, 2004

formamidine ureas incorporating the elements of isocyanate
in place of the original urea were the major isolable products
(10a-d, Scheme 4). Similarly, the reaction of 1c with
Scheme 3
Scheme 4
by an analogous mechanism. The X-ray crystal structure of
8 is shown in Scheme 3.
Formamidine ureas of the type 1 were deprotonated by a
strong base and trapped with alkyl or acyl halides at the distal
urea nitrogen to give the N-alkylated/acylated products 9
(Table 2), thus extending the range of formamidine urea
bromoacetyl bromide in the presence of a 2,6-lutidine (or
n-BuLi, but in lower yield) gave the exchanged formamidine
urea 11 along with a small amount of the expected acylated
product 12 (Scheme 4). Compound 12, obtained in very low
yield in the absence of base, is stable to 2,6-lutidine and so
is not an intermediate on the way to 11.
Table 2. Alkylation of Formamidine Ureasa
entry
R1
t-Bu
t-Bu
t-Bu
R2-X
% yieldb
product
1
2
3
4
5
6
7
8
9
MeI
68
69
71
67
66
70
72
69
67
9a
9b
9c
9d
9e
9f
9g
9h
9i
n-C8H17Br
HCtCCH2Br
PhCOCl
MeI
t-Bu
PhCH2
PhCH2O
PhCH2O
MeO
MeI
n-C5H11COCl
MeI
PhCOCl
MeO
a Representative selection of these reactions was also found to work
equally well with LiN(SiMe3)2, NaN(SiMe3)2, and NaH in place of n-BuLi;
2,6-lutidine was not effective b Yields are reported for pure products after
column chromatography.
structures available beyond that provided by the original
synthetic method. While such reactivity is unsurprising, being
shared by simple ureas, the process took a different and
unexpected course with isocyanate electrophiles. In these
cases, the reaction mixtures were much less clean, but new
Figure 1. (Top) Proposed mechanism of formamidine urea
fragmentation and trapping with isocyanate reagents. (Bottom)
Crossover experiment.
Org. Lett., Vol. 6, No. 1, 2004
45

Figure 1 shows a possible mechanism for the formation
of products such as 10 and 11. We suggest that structures
13 are unstable under the reaction conditions, allowing base-
induced fragmentation of the formamidine urea to give
amidine and isocyanate pieces. Capture of the former with
added isocyanates or bromoketene (generated from bro-
moacetyl bromide and base20) would give 10 and 11,
respectively (Scheme 4). In the case of the tert-butyl and
oxime formamidines used as starting materials, the expected
product isomers (10 and iso-10) could differ markedly in
their energies or rates of formation; in the event, only one
isomer of each compound was characterized. The proposed
pathway was supported by the observation of crossover
products 1a and 1e from treatment of a mixture of 1b and
1d with base (Figure 1) and by the observation of isocyanate
from 1b + n-BuLi by IR spectroscopy (Supporting Informa-
tion).
In summary, along with the amine exchange chemistry
previously reported,2 the carbonyl electrophilicity toward
thiols, deprotonation/alkylation at nitrogen, access to thi-
azoline and imidazoline rings, and amide fragment exchange
described here comprise a unique landscape of chemical
reactivity of the formamidine urea unit. Current studies are
directed toward the synthesis of new molecules with
pharmacological and metal-binding properties.
Acknowledgment. We thank The Skaggs Institute for
Chemical Biology for support of this work. D.D. thanks the
Spanish MECD (Ministerio de Educacio´n, Cultura y De-
portes de Espan˜a; Secretar´ıa de Estado de Educacio´n y
Universidades) for a postdoctoral fellowship cofinanced by
Fondo Social Europeo. We are grateful to Dr. Michal Sabat
(University of Virginia) for the X-ray crystal structure of 8.
Supporting Information Available: Experimental pro-
(19) For preparation of enantiopure imidazolines, see: (a) Boland, N.
A.; Casey, M.; Hynes, S. J.; Matthews, J. W.; Smyth, M. P. J. Org. Chem.
2002, 67, 3919-3922 and references therein. (b) Gust, R.; Keilitz, R.;
Schimidt, K. J. Med. Chem. 2001, 44, 1963-1970.
(20) (a) Dey, P. D.; Sharma, A. K.; Rai, S. N.; Mahajan, M. P.
Tetrahedron 1995, 51, 7459-7468. (b) de Faria, A. R.; Matos, C. R. R.;
Correia, C. R. D. Tetrahedron Lett. 2003, 34, 27-30.
cedures and full characterization of new compounds and
1
selection of H NMR and 13C NMR spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL035995F
46
Org. Lett., Vol. 6, No. 1, 2004