Hetero Diels-Alder reactions of nitrosoamidines: An efficient method for the synthesis of functionalized guanidines

Article abstract of DOI:10.1021/ol0363117

Hetero Diels-Alder reactions of transient nitrosoamidines are reported. Transient nitrosoamidines are formed by oxidation of protected N-hydroxylguanidines and are trapped in situ by 1,3-dienes to give [4 + 2] cycloadducts in good yields and regioselectivity. The resultant cycloadducts are versatile intermediates for the formation of functionalized guanidines.

Full text of DOI:10.1021/ol0363117

ORGANIC
LETTERS
2004
Vol. 6, No. 5
699-702
Hetero Diels−Alder Reactions of
Nitrosoamidines: An Efficient Method
for the Synthesis of Functionalized
Guanidines
Craig A. Miller and Robert A. Batey*
DaVenport Research Laboratories, Department of Chemistry, UniVersity of Toronto,
80 St. George Street, Toronto, Ontario M5S 3H6, Canada
rbatey@chem.utoronto.ca
Received November 26, 2003
ABSTRACT
Hetero Diels−Alder reactions of transient nitrosoamidines are reported. Transient nitrosoamidines are formed by oxidation of protected
N-hydroxylguanidines and are trapped in situ by 1,3-dienes to give [4 + 2] cycloadducts in good yields and regioselectivity. The resultant
cycloadducts are versatile intermediates for the formation of functionalized guanidines.
Nitroso heterodienophiles (i.e., R-NdO) have been widely
used since the initial discovery by Wichterle over 50 years
ago.1 Kirby2 later significantly advanced this methodology
from a synthetic standpoint, through the development of
transient acylnitroso dienophiles (i.e., RCO-NdO).3 Very
reactive acylnitroso species could thus be generated by the
oxidation of hydroxamic acids and trapped in situ with a
variety of 1,3-dienes. The increased reactivity of acylnitroso
intermediates in normal electron-demand Diels-Alder reac-
tions occurs because the electron-withdrawing acyl group
lowers the LUMO energy of the dienophile. This methodol-
ogy has since been used as the key step in a wide range of
natural product syntheses4 and has expanded to include a
number of structurally diverse derivatives including imino-
nitroso,5 R-chloronitroso,6 cyanonitroso,7 vinylnitroso,8 and
most recently P-nitroso phosphine oxide9 heterodienophiles,
each with varying degrees of utility in [4 + 2] cycloaddition
reactions. We now report the reactivity and synthetic utility
of transient nitrosoamidines as heterodienophiles.
The increasing number of structurally diverse guanidine
compounds with biological relevancy10 highlights a need for
new strategies to address the significant synthetic challenges
associated with the introduction and manipulation of sub-
stituted guanidines. Our interest in the synthesis of func-
(4) For representative examples, see: (a) Abe, H.; Aoyagi, S.; Kibayashi,
C. J. Am. Chem. Soc. 2000, 122, 4583-4592. (b) Carbanal-Duvillard, I.;
Berrien, J. F.; Royer, J. Tetrahedron: Asymmetry 2000, 12, 2525-2532.
(c) Zhang, D.; Miller, M. J. J. Org. Chem. 1998, 63, 755-759. (c) Ritter,
A. R.; Miller, M. J. J. Org. Chem. 1994, 59, 4602-4611. (d) Ledford, B.
E.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, 11811-11812. (e)
Kibayashi, C.; Aoyagi, S.; Synlett 1995, 873-879. (f) Trost, B. M.; Van
Vranken, D. L. J. Am. Chem. Soc. 1993, 115, 444-458. (g) King, S. B.;
Ganem, B. J. Am. Chem. Soc. 1991, 113, 5089-5090.
(5) Gilchrist, T. L.; Harris, C. J.; Hawkins, D. G.; Moody, C. J.; Rees,
C. W. J. Chem. Soc., Perkin Trans. 1 1976, 2166-2715.
(6) Zuman, P.; Shah, B. Chem. ReV. 1994, 94, 1621-1641.
(7) Horsewood, P. K.; Kirby, G. W. J. Chem. Soc., Perkin Trans. 1980,
1587-1591.
(8) Gilchrist, T. L.; Gonsalves, A. M.; Pinhoe Melo, T. M. V. D. Pure
Appl. Chem. 1996, 68, 853-861.
(1) Wichterle, O. Collect. Czech. Chem. Commun. 1947, 12, 292-299.
(2) Kirby, G. W. Chem. Soc. ReV. 1977, 6, 1-24.
(3) For reviews of nitroso Diels-Alder reactions, see: (a) Vogt, P. F.;
Miller, M.J. Tetrahedron 1998, 54, 1317-1348. (b). Streith, J.; Defoin, A.
Synthesis 1994, 1107-1117. (c) Weinreb, S. M.; Staib, R. R. Tetrahedron
1982, 38, 3087-3128.
(9) (a) Ware, R. W.; King, S. B. J. Am. Chem. Soc. 1999, 121, 6769-
6770. (b) Ware, R. W.; King, S. B. J. Org. Chem. 2000, 65, 8725-8729.
(c) Ware, R. W.; King, S. B. J. Org. Chem. 2002, 67, 6174-6180.
(10) For reviews of guanidine natural products, see: Berlink, R. G. S
Nat. Prod. Rep. 2002, 19, 617-649 and references therein.
10.1021/ol0363117 CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/10/2004

tionalized guanidines11 has prompted us to consider alter-
native methods for guanidine synthesis. We envisaged that
a nitrosoamidine 1 could serve as a precursor for the
formation of highly functionalized guanidines and provide
a new entry point for the synthesis of complex guanidine
targets. Although nitrosoamidines 1 are likely to be less
reactive than acylnitroso compounds, the amidinyl group of
1 should be sufficiently electron-withdrawing to facilitate a
hetero Diels-Alder reaction with 1,3-dienes in a synthetically
useful manner. Thus, reaction of 1 with a diene would lead
to the formation of cycloadduct 2 (Scheme 1). Moreover,
CH2Cl2 at room temperature. Complete disappearance of the
starting material occurred after 8 h, yielding cycloadduct 6
in 61% isolated yield, presumably via the transient nitroso-
amidine 5. Although nitrosoamidine 5 was not directly
observed,15 cycloadduct 6 is formally the product of a [4 +
2] cycloadddition reaction between 5 and 1,3-cyclohexadiene.
An extensive optimization study was subsequently performed
and revealed that slow addition of 4 in small portions over
2 h to a stirred solution of a stoichiometric amount of oxidant
and 1,3-cyclohexadiene was found to produce cycloadduct
16
6 in as high as 85% yield using Pr4NIO4 in MeOH and
produced satisfactory results under a variety of conditions.
Interestingly, the use of Pr4NIO4 led to consistently higher
product yields than were obtained using Bu4NIO4. Investiga-
tion into increasing the concentration of both the diene and
oxidant from 1.1 to 5 equiv, respectively, had no apparent
effect on the reaction. The use of Dess-Martin reagent in
CH2Cl2 or CHCl3 was found to be a suitable replacement
for Pr4NIO4 providing similar, though slightly diminished,
yields.
Scheme 1
The scope of the reaction was investigated using a series
of symmetrical 1,3-dienes employing the optimized condi-
tions17 (Table 1). Cyclic dienes locked in the required and
reactive s-cis conformation were found to react rapidly with
5 to produce the cycloadducts at room temperature (Table
1, entries 1 and 2). On the other hand, for reactions with
acyclic dienes in which free rotation about the C-C σ bond
of the diene can occur, maximal yields were obtained when
the reactions were conducted at 0 °C (Table 1, entries 3 and
4). The origin of this difference is not clear at this point.
The issue of regioselectivity of the cycloaddition is a
complicating feature in the reactions of 5 with unsymmetric
dienes. Following the same general procedure as for the
reaction with symmetric dienes, a number of cycloadducts
were produced in good yield and excellent regioselectivity
(Table 2). In the case of acylnitroso compounds, it is
postulated that electronic dissymmetry in the LUMO of the
dienophile accounts for the high levels of regioselectivity
by comparison with the results of acylnitroso reactions,
regioselective additions should also be possible with sub-
stituted 1,3-dienes. The functionality of oxazinyl amidines
2 provides multiple opportunities for synthetic elaboration,
including reductive cleavage of the N2-O1 bond, C6-O1
bond cleavage, and alkene functionalization.
N,N′-Bis-Boc-N′′-hydroxylguanidine 4 was chosen as a
suitable nitrosoamidine precursor, since Boc substituents are
one of the most widely used guanidine-protecting groups,12
and their presence should further enhance the electron-
withdrawing capacity of the amidinyl group, leading to
greater reactivity in the Diels-Alder cycloaddition. Com-
pound 4 can be synthesized in moderate yield from N,N′-
bis-Boc-S-methylisothiourea13 3 via guanylation14 of hy-
droxylamine hydrochloride with stoichiometric HgCl2 and
Amberlyst A21 exchange resin in acetonitrile (Scheme 2).
(11) (a) Batey, R. A.; Powell, D. A. Chem. Commun. 2001, 2362-2363.
(b) Powell, D. A.; Batey, R. A. Org. Lett. 2002, 4, 2913-2916. (c) Evindar,
G.; Batey, R. A. Org. Lett. 2003, 5, 133-136. (d) Powell, D. A.; Ramsden,
P. D.; Batey, R. A. J. Org. Chem. 2003, 68, 2300-2309.
Scheme 2 a
(12) (a) Yong, Y. Y.; Kowalshi. J. A.; Lipton, M. A. J. Org. Chem.
1997, 62, 1540-1542. (b) Levallet, C.; Lerpiniere, J.; Ko, S. Y. Tetrahedron
1997, 53, 5291-5304. (c) Gou, Z.; Cammidge, A.; Horwell, D. C. Synth.
Commun. 2000, 30, 2933-2943.
(13) Bergeron, R. J.; McManis, J. S. J. Org. Chem. 1987, 52, 1700-
1711.
(14) For discussion of the term guanylation see ref 11d and references
therein.
(15) Until recently no methods existed for the direct observation of
acylnitroso species in solution. Time-resolved infrared spectroscopy has
recently been employed in the direct detection of acylnitroso compounds
in solution. See: Cohen, A. D.; Zeng, B.; King, S. B.; Toscano, J. P. J.
Am. Chem. Soc. 2003, 125, 1444-1445.
(16) Crystalline Pr4NIO4 is conveniently prepared by treatment of
equimolar amounts of Pr4NOH and HIO4 in water; see: Keck, G. E.;
Fleming, S. A. Tetrahedron Lett. 1978, 19, 4763-4766.
a Reagents and conditions: (a) NH2OH‚HCl, HgCl2, Amberlyst
A21, 12 h, 61%; (b) Bu4NIO4, 1,3-cyclohexadiene, CH2Cl2, 61%.
(17) General Procedure for Cycloaddition of 2. A stirred solution of
diene (1.1 equiv) and Pr4NIO4 (1.1 equiv) in MeOH was cooled to 0 °C in
an ice-water bath, and to this was added 4 in small portions over 2 h. The
solution was allowed to warm to room temperature over 12 h. The reaction
mixture was diluted with water and extracted with CH2Cl2. The combined
organic extracts were washed with saturated sodium thiosulfate and brine
and dried with MgSO4. The solvent was removed under vacuum, and the
resulting product was purified by silica gel chromatography.
A variety of conditions have been developed for acylnitroso
chemistry, but the most commonly used procedures involve
mild periodate-based oxidants or the Swern protocol. Analo-
gous conditions were used in the test reaction of 4 with 1,3-
cyclohexadiene and Bu4NIO4 as the oxidant in anhydrous
700
Org. Lett., Vol. 6, No. 5, 2004

Table 1. Reaction of 4 with Symmetric 1,3-Dienes in the
Table 2. Reaction of 4 with Unsymmetric 1,3-Dienes in the
Presence of Pr4NIO4
Presence of Pr4NIO4
a Isolated yields
observed in most reactions. The observed regioselectivity
was found to be consistent with that of other nitroso
dienophiles18 with 1-subsituted dienes reacting to form the
cycloadduct where the proximal regioisomer dominates
(Table 2, entries 1-3 and 6), whereas 2-substituted dienes
preferentially form the distal isomers (Table 2, entry 5). The
nomenclature employed to describe the regiochemistry of
these cycloadducts is the same as that employed by Boger.19
The proximal regioisomer is the one in which the diene
substituent is closest to oxygen and the distal isomer is that
with the substituent furthest from oxygen. Increased steric
hindrance at the 1-position of the 1,3-dienes did not
appreciably alter the regioselectivity, as shown by the
comparison of ethyl- and tert-butyl-substituted dienes (Table
2, entries 1 and 2). The presence of a strongly electron-
donating substituent at the 1-position of the diene gave
excellent results, with only one regioisomer detected by 1H
NMR (Table 2, entry 3). Dienes with electron-withdrawing
substituents failed in their reaction with 4, indicating that
this reaction falls into the class of normal electron-demand
Diels-Alder reactions. Thus, ethyl sorbate, sorbic acid, and
sorbic aldehyde produced none of the desired cycloadduct
with only decomposition of 4 observed even when a large
excess of diene was used and under numerous temperature
profiles.
a Isolated yield. b Regioisomeric ratio was determined by 1H NMR of
the crude reaction mixtures.
procedures were attempted to cleave the N-O bond of 6,
including Mo(CO)6,20 LiAlH4,21 Zn in acetic acid,22 and
hydrogenation over Raney nickel,23 without success. How-
ever, reduction of 6 to 7 could be accomplished in high yield
with the use of Na(Hg) amalgam24 (Scheme 3).
Scheme 3 a
Having produced a variety of cycloadducts in good overall
yield and regioselectivity, our attention turned toward
generating useful guanidine-containing compounds by simple
transformations of the initial cycloadducts. Perhaps the most
important such transformation is N-O bond reduction, which
for cycloadducts 6 would result in the formation of hydroxy-
cyclohexenyl guanidine 7. A number of standard reductive
a Reagents and conditions: (a) Na(Hg) amalgam, Na2HPO4,
EtOH, 95%.
Alternatively, N-O bond cleavage can be achieved
following alkene reduction. Hydrogenation of 6 over Pearl-
(20) Cicchi, S.; Goti, A.; Brandi, A.; Guarna, A.; De Sarlo, F.
Tetrahedron Lett. 1990, 31, 3351-3358.
(21) Oppolzer, W.; Petrzilka, M. J. Am. Chem. Soc. 1978, 98, 6722-
6723.
(18) Leach, A. G.; Houk, K. N. J. Org. Chem. 2001, 66, 5192-5200.
(19) Boger, D. L.; Patel, M.; Takusagawa, F. J. Org. Chem. 1985, 50,
1911-1916.
(22) Shishido, Y.; Kibayashi, C. J. Org. Chem. 1992, 57, 2876-2882.
Org. Lett., Vol. 6, No. 5, 2004
701

man’s catalyst gave 8, which then underwent facile reduction
to 9 via hydrogenation over Raney nickel. Subsequent Boc
deprotection under acidic conditions generated guanidine 10
as an HCl salt (Scheme 4)
generate transient nitrosoamidines that undergo rapid [4 +
2] cycloaddition. Optimal conditions for the oxidation utilize
Pr4NIO4 in MeOH at 0 °C. The cycloadducts are formed in
good yields, and in reactions with unsymmetrical dienes, a
strong preference for the proximal isomer is observed with
1-substituted dienes and for the distal isomer with 2-substi-
tuted dienes. These regioselectivity patterns are similar to
those observed with acylnitroso Diels-Alder adducts. The
cycloadducts are versatile intermediates for further elabora-
tion, and applications of their utility in complex guanidine
target synthesis, such as the batzelladine alkaloids, will be
reported in due course.
Scheme 4 a
Acknowledgment. This work was supported by the
Natural Sciences and Engineering Research Council of
Canada (NSERC). We are indebted to Ms. Leonie Soltay
for performing some preliminary experiments. C.A.M.
acknowledges the Ontario Government for receipt of an
Ontario Graduate Scholarship. R.A.B gratefully acknowl-
edges receipt of a Premier’s Research Excellence Award.
We thank Dr. A. B. Young for mass spectrometric analysis.
a Reagents and conditions: (a) H2, Pd(OH)2 MeOH, 73%; (b)
H2, Raney Ni, MeOH, 91%; (c) 2 M HCl, MeOH, 89%.
In conclusion, nitrosoamidines constitute a new class of
substituted NdO heterodienophiles. N-Protected hydroxyl-
guanidines can be oxidized in the presence of 1,3-dienes to
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(23) Koizumi, T.; Hirai, H.; Yoshii, E. J. Org. Chem. 1982, 47, 4004-
4005.
(24) Keck, G. E.; Nickell, D. G. J. Am. Chem. Soc. 1980, 102, 3632-
3634.
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