Synthesis of polycyclic guanidines by cyclocondensation reactions of N-amidinyliminium ions

Article abstract of DOI:10.1021/jo0100998

A new method for the synthesis of polycyclic guanidines is described. The N-amidinyliminium ion generated from α-(phenylthio)amidine precursor 16 by reaction with Cu(OTf)₂ undergoes cyclocondensation with 1,3-dienes, styrenes, and Β-dicarbonyl compounds to give 1-iminohexahydropyrrolo[1,2-c]pyrimidines having side chains at C3 and C7. In all cases, major products have a cis relationship of the C7 side chain and angular C4a hydrogen, whereas C3 side chains are incorporated with lower stereoselectivity (dr = 2-5:1) in cyclocondensations with dienes and styrenes to give stereoisomer 39 as the major product. In contrast to most cycloadditions of alkenes with N-acyliminium ions, cyclocondensations of alkenes with N-amidinyliminium ions proceed by a stepwise pathway. Cyclocondensation of the cognate ureido aminal 31 with styrene provides the rare 2-imino-5,6-dihydro-4H-1,3-oxazine derivative 32, rather than a pyrimidine as the major product. The high stereoselectivity observed in condensations of 16 with benzyl acetoacetate to afford Biginelli adduct 29 supports the intermediacy of N-amidinyliminium ions in related tethered Biginelli condensations of guanidines reported earlier from our laboratories.

Full text of DOI:10.1021/jo0100998

J . Org. Chem. 2001, 66, 3167-3175
3167
Syn th esis of P olycyclic Gu a n id in es by Cyclocon d en sa tion
Rea ction s of N-Am id in ylim in iu m Ion s
Larry E. Overman* and J ohn P. Wolfe
Department of Chemistry, 516 Rowland Hall, University of California, Irvine, California 92697-2025
leoverma@uci.edu
Received J anuary 24, 2001
A new method for the synthesis of polycyclic guanidines is described. The N-amidinyliminium ion
generated from R-(phenylthio)amidine precursor 16 by reaction with Cu(OTf)2 undergoes cyclo-
condensation with 1,3-dienes, styrenes, and â-dicarbonyl compounds to give 1-iminohexahydro-
pyrrolo[1,2-c]pyrimidines having side chains at C3 and C7. In all cases, major products have a cis
relationship of the C7 side chain and angular C4a hydrogen, whereas C3 side chains are incorporated
with lower stereoselectivity (dr ) 2-5:1) in cyclocondensations with dienes and styrenes to give
stereoisomer 39 as the major product. In contrast to most cycloadditions of alkenes with
N-acyliminium ions, cyclocondensations of alkenes with N-amidinyliminium ions proceed by a
stepwise pathway. Cyclocondensation of the cognate ureido aminal 31 with styrene provides the
rare 2-imino-5,6-dihydro-4H-1,3-oxazine derivative 32, rather than a pyrimidine as the major
product. The high stereoselectivity observed in condensations of 16 with benzyl acetoacetate to
afford Biginelli adduct 29 supports the intermediacy of N-amidinyliminium ions in related tethered
Biginelli condensations of guanidines reported earlier from our laboratories.
In tr od u ction
Guanidine functionality is found in a strikingly high
percentage of pharmacologically active natural products,
as well as being an important feature of several clinical
agents and numerous exploratory drug candidates.1 The
wide occurrence of bioactive guanidines likely reflects the
multiple ways that guanidinium cations can participate
in noncovalent associations, for example, by electrostatic,
hydrogen-bonding, and π-stacking interactions. Among
the most structurally complex guanidine natural products
are those containing a 1-iminohexahydropyrrolo[1,2-c]-
pyrimidine fragment (1). This ring system is found in
alkaloids such as saxitoxin (2)2 and in crambescidin and
batzelladine alkaloids exemplified by crambescidin 800
(3)3 and batzelladine A (4).4,5 These latter marine natural
products display a variety of potentially important phar-
macological activities including powerful anticancer ac-
tivity3,6 and inhibition of protein-protein interactions.4,7
(1) (a) Greenhill, J . V.; Lue, P. Prog. Med. Chem. 1993, 30, 203-
326. (b) Berlinck, R. G. S. Nat. Prod. Rep. 1999, 16, 339-365. (c)
Berlinck, R. G. S. Nat. Prod. Rep. 1996, 13, 377-409. (d) Berlinck, R.
G. S. Prog. Chem. Org. Nat. Prod. 1995, 66, 119-295.
(2) Structure: (a) Schantz, E. J .; Ghazarossian, V. E.; Schnoes, H.
K.; Strong, F. M.; Springer, J . P.; Pezzanite, J . O.; Clardy, J . J . Am.
We have previously developed a general synthesis of
guanidines 1 and documented procedures whereby a C7
substituent can be incorporated with either a cis or trans
relationship to an angular C4a hydrogen.8 The pivotal
step in this synthesis is an intramolecular variant of the
Biginelli reaction9 that we first reported in 1993 (eq 1).10
Chem. Soc. 1975, 97, 1238-1239. (b) Bordner, J .; Thiessen, W. E.;
Bates, H. A.; Rapoport, H. Ibid. 1975, 97, 6008-6012. Total synthe-
sis: (c) Tanino, H.; Nakata, T.; Kaneko, T. Kishi, Y. J . Am. Chem. Soc.
1977, 99, 2818-2819. (d) Hannick, S. M.; Kishi, Y. J . Org. Chem. 1983,
48, 3833-3835. (e) J acobi, P. A.; Martinelli, M. J .; Polanc, S. J . Am.
Chem. Soc. 1984, 106, 5594-5598.
(3) Structure: (a) J ares-Erijman, E. A.; Sakai, R.; Rinehart, K. L.
J . Org. Chem. 1991, 56, 5712-5715. Total synthesis: (b) Coffey, D.
S.; McDonald, A. I.; Overman, L. E.; Rabinowitz, M. H.; Renhowe, P.
A. J . Am. Chem. Soc. 2000, 122, 4893-4903.
(4) For recent reviews of guanidine alkaloids, see: Faulkner, D. J .
Natl. Prod. Rep. 1999, 16, 155-198, and earlier reviews in this series;
see also refs 1b-d.
(6) For a recent summary, see ref 3b.
(7) Patil, A. D.; Freyer, A. J .; Taylor, P. B.; Carte, B.; Zuber, G.;
J ohnson, R. K.; Faulkner, D. J . J . Org. Chem. 1997, 62, 1814-1819.
(8) McDonald, A. I.; Overman, L. E. J . Org. Chem. 1999, 64, 1520-
1528.
(5) (a) Patil, A. D.; Kumar, N. V.; Kokke, W. C.; Bean, M. F.; Freyer,
A. J .; De Brosse, C.; Mai, S.; Truneh, A.; Faulkner, D. J .; Carte, B.;
Breen, A. L.; Hertzberg, R. P.; J ohnson, R. K.; Westley, J . W.; Potts,
B. C. M. J . Org. Chem. 1995, 60, 1182-1188. (b) Snider, B. B.; Chen,
J .; Patil, A. D.; Freyer, A. J . Tetrahedron Lett. 1996, 37, 6977-6980.
(9) For
a review of the Biginelli reaction, see: Kappe, C. O.
Tetrahedron 1993, 49, 6937-6963.
(10) Overman, L. E.; Rabinowitz, M. H. J . Org. Chem. 1993, 58,
3235-3237.
10.1021/jo0100998 CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/12/2001

3168 J . Org. Chem., Vol. 66, No. 9, 2001
Overman and Wolfe
F igu r e 1. Two mechanistic possibilities for tethered Biginelli condensations under Knoevenagel conditions.
This tethered Biginelli reaction has played a central role
in stereocontrolled total syntheses of crambescidin3b,11
and batzelladine12 alkaloids accomplished recently in our
laboratories.
these mechanistic objectives, we were interested to see
if N-amidinyliminium ions could be trapped with other
nucleophiles such as alkenes to provide a new method
for constructing complex guanidines containing substruc-
ture 1.14 The results of these studies are described herein.
Resu lts
Gen er a tion of N-Am id in ylim in iu m Ion s. Iminium
ions having an amidine substituent on nitrogen have
previously been implicated as reactive intermediates in
Pictet-Spengler and other electrophilic aromatic substi-
tution reactions.15 In these cases, the N-amidinyliminium
cation was generated by dehydrative condensation of
guanidines with aldehydes or ketones, by dehydration of
N-(1-hydroxyalkyl)guanidines, or by protonation of N-
alkenylguanidines with strong acids.15
To test the viability of utilizing N-amidinyliminium
ions in cyclocondensation processes, we first examined
the reaction of guanidine hemiaminal 148 with styrene
in the presence of a stoichiometric amount of sulfuric acid
(eq 2). One major product, 3-phenylhexahydropyrrolo[1,2-
c]pyrimidine 15, was isolated in ∼35% yield as a 4:1
mixture of C3 epimers when this reaction was carried
out in acetic acid at room temperature.
The stereochemical outcome of tethered Biginelli
reactions is dependent upon both the nature of Y and
the reaction conditions.8 Substrates containing a urea
(Y ) O) or a N-arylsulfonylguanidine (Y ) NSO2Ar) unit
yield products having cis stereochemistry around the
pyrrolidine ring when the cyclocondensation is promoted
with morpholinium acetate. In contrast, substrates con-
taining an unprotected guanidine (Y ) NH2+) provide the
trans stereoisomer under identical conditions. To explain
these results, we postulated that cis stereoisomer 10
arises from stereochemistry-determining cyclization of
Knoevenagel adduct 8, whereas trans stereoisomer 13
results from stereochemistry-determining addition of the
â-ketoester-derived nucleophile 7 to N-amidinyliminium
ion 11 from the face opposite the alkyl chain (Figure 1).8
This latter mechanistic scenario was consistent with the
observation that tethered Biginelli reactions promoted
by the strong dehydrating reagent polyphosphate ester
give trans products regardless of the nature of Y.13
To probe mechanism and stereochemical control ele-
ments in tethered Biginelli reactions further, we set out
to unambiguously generate N-amidinyliminium ions 11
under conditions that would eliminate the possibility of
a precursor reacting with a â-ketoester, or its enamine
derivative, by a Knoevenagel pathway. In addition to
Although this initial result was promising, we felt that
these strongly acidic conditions would be too harsh for
(14) For reviews of the chemistry of N-acyliminium ions, see: (a)
Speckamp, W. N.; Moolenaar, M. J . Tetrahedron 2000, 56, 3817-3856.
(b) Hiemstra, H.; Speckamp, W. N. In Comprehensive Organic Syn-
thesis; Trost, B. M.; Fleming, I., Eds.; Pergamon: New York, 1991;
Vol. 2, pp 1047-1082. (c) Zaugg, H. E. Synthesis 1984, 181-212. (c)
Weinreb, S. M.; Scola, P. M. Chem. Rev. 1989, 89, 1525-1534. (d)
Speckamp, W. N.; Hiemstra, H. Tetrahedron 1985, 41, 4367-4416.
(15) For representative reactions where N-amidinyliminium ions are
believed to be intermediates, see: (a) Esser, F.; Pook, K.-H.; Carpy, A.
Synthesis 1990, 72-78. (b) Esser, F.; Pook, K.-H.; Carpy, A.; Leger,
J .-M. Synthesis 1994, 77-82. (c) Lyssikatos, J . P.; Chang, S.-P.; Clancy,
J .; Dirlam, J . P.; Finegan, S. M.; Girard, A. E.; Hayashi, S. F.; Larson,
D. P.; Lee, A. S.; Linde, R. G., II; MacLelland, C. P.; Petitpas, J . W.;
Seibel, S. B.; Vu, C. B. Bioorg. Med. Chem. Lett. 1997, 7, 1145-1148.
(11) (a) Overman, L. E.; Rabinowitz, M. H.; Renhowe, P. A. J . Am.
Chem. Soc. 1995, 117, 2657-2658. (b) Coffey, D. S.; McDonald, A. I.;
Overman, L. E.; Stappenbeck, F. J . Am. Chem. Soc. 1999, 121, 6944-
6945. (c) Coffey, D. S.; McDonald, A. I.; Overman, L. E. J . Org. Chem.
1999, 64, 8741-8742. (d) Coffey, D. S.; Overman, L. E.; Stappenbeck,
F. J . Am. Chem. Soc. 2000, 122, 4904-4914.
(12) (a) Franklin, A. S.; Ly, S. K.; Mackin, G. H.; Overman, L. E.;
Shaka, A. J . J . Org. Chem. 1999, 64, 1512-1519. (b) Cohen, F.;
Overman, L. E.; Sakata, S. K. L. Org. Lett. 1999, 1, 2169-2172.
(13) Studies by Kappe indicate the intermediacy of N-amidinyl-
iminium ions in classical Biginelli condensations carried out in the
presence of mineral acids; see: Kappe, C. O. J . Org. Chem. 1997, 62,
7201-7204.

Synthesis of Polycyclic Guanidines
J . Org. Chem., Vol. 66, No. 9, 2001 3169
20
Sch em e 1
Use of stoichiometric Cu(OTf)2 in 3:1 CH2Cl2-CHCl3
at 0 °C was found to promote the desired cycloconden-
sation in highest yield and diastereoselectivity.21 Utilizing
these conditions, 16 reacted with 2 equiv of styrene to
give cycloadduct 15 in 83% yield as a 5:1 mixture of C3
epimers. No products having a trans relationship of the
phenethyl side chain and the angular C4a hydrogen were
observed. The epimers of 15 could be separated by flash
1
chromatography, and detailed H NMR NOE studies on
the pure isomers showed that the phenyl substituent was
equatorial (trans to the angular C4a hydrogen) in the
major epimer.
Cyclocon d en sa tion s of N-Am id in ylim in iu m Ion s
w ith Alk en es, 1,3-Dien es, a n d â-Ketoester s. To as-
certain the scope of N-amidinyliminium ion cycloconden-
sations, a number of π-nucleophiles were allowed to react
with 16 under the conditions optimized with styrene.
Results of these studies are summarized in Table 1.
Styrenes and 1,3-dienes reacted in useful yields to
provide cycloadducts as mixtures of C3 epimers. With but
one exception, the product of endo addition having the
C3 side chain equatorial predominated. Only products
having a cis relationship of the phenethyl side chain and
angular C4a hydrogen were observed. Reaction of 16 with
styrenes afforded a 4-5:1 mixture of endo and exo
cycloadducts as judged by 1H NMR analysis of the crude
reaction mixtures. Lower endo/exo selectivities (∼2-3:
1) were observed with 1,3-dienes, whereas a 1:1 mixture
of C3 epimers was formed in the reaction of 16 with
allyltrimethylsilane. Stereochemical assignments for the
products summarized in Table 1 were based on extensive
1H NMR NOE experiments. Particularly diagnostic were
NOE enhancements of 2-3% observed between the
methine hydrogens at C3 and C4a in the major epimer
and the corresponding lack of these enhancements in the
minor epimer. The trans relationship between H7 and
H4a was established by evaluation of NOE enhancements
resulting from sequential irradiation of all hydrogens on
the five-membered ring. Full details of these 1H NMR
NOE studies are provided in the Supporting Information.
Cyclocondensations of 16 with styrenes, or 1,3-dienes
containing a terminal vinyl group, generally proceeded
smoothly; however, reactions of other alkenes and dienes
were problematic. For example, styrenes or 1,3-dienes
having 1,1-disubstitution gave complex product mixtures
containing adducts that incorporated more than one
diene or styrene unit. Simple terminal alkenes did not
undergo cyclocondensation with 16. Reaction of allyltri-
methylsilane and 16 gave a ∼2.6:1 mixture of cycload-
ducts 26 (isolated in 37% yield) and the corresponding
2-allyl N-guanylpyrrolidine.22 Electron-rich alkenes such
as vinyl ethers and enamines decomposed prior to cyclo-
condensation; the major products observed in these
reactions were ethoxy aminals or N,N-acetals resulting
from replacement of the phenylthio group by the alkoxy
or amino group of the nucleophile. Similarly, attempted
reaction of 16 with (E)-4-methoxy-3-buten-2-one or (E)-
4-(dimethylamino)-3-buten-2-one23 resulted in decomposi-
more complex molecules. Moreover, guanidine aminal 14
and related species previously employed by us in tethered
Biginelli condensations are complex mixtures that resist
purification and are prone to oligomerization.8,10,11 We
sought an alternative iminium ion precursor that would
be synthesized and purified easily. To this end, the
corresponding R-phenylthioguanidine was prepared by
reaction of guanidine hemiaminal 14 with thiophenol in
the presence of anhydrous HCl. These conditions pro-
vided a mixture of the desired thioaminal 16 and the
corresponding acyclic guanidine dithioacetal. In contrast
to 14,8 thioaminal 16 is easily purified by flash chroma-
tography and is a stable solid at room temperature.
An improved synthesis of 16 was subsequently devel-
oped (Scheme 1). Treatment of hydrocinnamaldehyde
with Grignard reagent 1716 followed by Mitsunobu reac-
tion of the resulting alcohol with HN3 provided azide 18.17
This intermediate was reduced with LiAlH4 to give amine
19. Guanylation of 19 with bis(BOC)thiourea18 followed
by reaction of the resulting BOC-protected guanidine
with 1 equiv of thiophenol in 1:1 TFA-CH2Cl2 yielded
the trifluoroacetate salt of 16. Under these conditions,
formation of the undesired dithioacetal was minimized.
Because preliminary scouting experiments had shown
that cyclocondensations with this trifluoroacetate salt led
to the generation of a substantial amount of the enamide
resulting from deprotonation of the N-amidinyliminium
ion, the trifluoroacetate salt was converted to the hydro-
chloride salt by treatment with aqueous HCl.19 Thiophen-
ylguanidine hydrochloride 16 prepared in this way was
a 9:1 mixture of epimers.
A variety of Lewis acids and thiophilic reagents such
as methylthiodimethylsulfonium tetrafluoroborate were
examined for effecting the reaction of 16 with styrene.
(20) Chloroform was added to improve the solubility of the substrate.
(21) At -15 °C, no reaction was observed.
(22) Similar mixtures were observed in reactions of allyltrimethyl-
silane with iminium ions derived from BOC-protected R-methoxy
pyrrolidine or piperidine. Brocherieux-Lanoy, S.; Dhimane, H.; Poupon,
J .-C.; Vanucci, C.; Lhommet, G. J . Chem. Soc., Perkin Trans. 1 1997,
2163-2165.
(23) Burgi, D.; Sterchi, A.; Neuenschwander, M. Helv. Chim. Acta
1977, 60, 2195-2207.
(16) Bu¨chi, G.; Wuest, H. J . Org. Chem. 1969, 34, 1122-1123.
(17) Loibner, H.; Zbiral, E. Helv. Chim. Acta 1976, 59, 2100-2113.
(18) Yong, Y. F.; Kowalski, J . A.; Lipton, M. A. J . Org. Chem. 1997,
62, 1540-1542.
(19) Greater than 95% exchange of the counterion was obtained as
judged by 19F NMR analysis.

3170 J . Org. Chem., Vol. 66, No. 9, 2001
Overman and Wolfe
Ta ble 1. Cyclocon d en sa tion of Alk en es a n d Dien es
w ith 16a
addition of the alkene and Cu(OTf)2 also failed to provide
cycloadducts.
Only cyclocondensations of E alkenes proved to be
stereospecific. For example, reaction of 16 with trans-â-
methylstyrene provided 1-iminohexahydropyrrolo[1,2-c]-
pyrimidine 20 and stereoisomer 27, both of which have
a trans relationship of phenyl and methyl substituents,
in a 2:1 ratio (Table 1, entry 2). These stereoisomeric
products were formed in equal amounts from an identical
reaction of 16 and cis-â-methylstyrene (eq 3). Similarly,
reaction of trans-piperylene and 16 gave exclusively
epimeric products 23 having (E)-propenyl side chains
(Table 1, entry 5). However, identical reaction of cis-
piperylene provided a 1.4:1 mixture of 23 and (Z)-pro-
penyl isomers 28 (eq 4). Control experiments conducted
in the absence of 16 showed that cis-piperylene and cis-
â-methylstyrene were not isomerized by Cu(OTf)2 in the
amount of time required for the cyclocondensation reac-
tions to proceed to completion.
To pursue the possible intermediacy of N-amidinyl-
iminium ions in tethered Biginelli condensations, guani-
dine thioaminal 16 was allowed to react with benzyl
acetoacetate in the presence of Cu(OTf)2. Under these
conditions, the Biginelli products 29 were obtained in
69% yield, with the stereoisomer having a cis relationship
of the phenethyl side chain and angular C4a hydrogen
predominating to the extent of 9:1 (eq 5).25
a
Reaction conditions: 16 (1.0 equiv, 0.25 M), alkene/diene (2.0
b
equiv), Cu(OTf)2 (1.0 equiv), 3:1 CH2Cl2-CHCl3, 0 ° C. Isolated
yields and diastereomer ratios of the mixture of stereoisomeric
products after purification on silica gel. Diastereomer ratios in the
crude reaction product were typically 2:1-5:1; chromatographic
purification often led to enrichment in the major stereoisomer. See
the Supporting Information for full details. c The minor product
Cyclocon d en sa t ion s of N-(Acyla m in o)im in iu m
Ion s w ith Rep r esen ta tive π-Nu cleop h iles. Previous
studies in our laboratories suggested that tethered Bigi-
nelli condensations of N-(acylamino)aminals also proceed
through iminium ion intermediates when strong dehy-
drating reagents were employed as promoters.8 To probe
the validity of this hypothesis, we prepared 31, the urea
analogue of 16, and examined its reactivity with styrene
(Scheme 2). The synthesis of 31 began with amine 19,
which upon reaction with trimethylsilyl isocyanate gave
urea 30. Formation of thioaminal 31 from ureido acetal
30 required more forcing conditions than the correspond-
d
is epimeric at both C3 and C4. The 2-allyl-N-guanylpyrrolidine
was isolated in 14% yield.
tion of the heterosubstituted alkene prior to cyclocon-
densation.24 Due to the acid-sensitive nature of vinyl
ethers and enamines, attempts were made to buffer their
cyclocondensations with 16. However, reactions con-
ducted in the presence of amine bases also failed to
provide the desired products; typically, either no reaction
or slow hydrolysis of the substrate was observed. At-
tempts to employ the guanidine free base in these
cyclocondensations by treating 16 with NaH prior to the
(25) Stereochemical assignments were made by 1H NMR NOE
experiments and by comparison of the chemical shifts of the angular
methine hydrogens H4a and H7 with those of related compounds
previously reported.8
(24) Side products observed by electrospray MS included hemi-
aminals and methoxy aminals.

Synthesis of Polycyclic Guanidines
J . Org. Chem., Vol. 66, No. 9, 2001 3171
Sch em e 2
urea series, a 1:1 mixture of 16 and 31 was allowed to
react with 1 equiv each of styrene and Cu(OTf)2 (eq 8).
The major product obtained from this competition was
iminodihydro-1,3-oxazine derivative 32, which was iso-
lated in 10% yield. No products resulting from ionization
of 16 and subsequent cyclocondensation of the N-ami-
1
dinyliminium ion were detected as judged by H and 13C
NMR analysis of the crude reaction mixture; 16 was
recovered in 73% yield.
Discu ssion
Syn th esis of Gu a n id in es fr om N-Am id in ylim in i-
u m Ion s a n d Alk en es. Reaction of N-amidinyl-2-(phen-
ylthio)pyrrolidine 16 with Cu(OTf)2 was found to be a
mild method for chemoselectively generating N-amidin-
yliminium ion 37 (Figure 2). Cyclocondensation of this
intermediate with alkenes provides a new route for
preparing polycyclic guanidines. This method is useful
for the synthesis of 1-iminohexahydropyrrolo[1,2-c]pyrim-
idines 39 containing aryl or alkenyl substituents at the
C3 position. Cyclocondensation occurs exclusively from
the face opposite the preexisting C7 side chain to give
products having a trans relationship of the methine
hydrogens flanking nitrogen. Mixtures of C3 epimers,
typically 2:1-5:1 favoring the endo product 39, are
observed. The scope of this reaction as currently practiced
is limited to conjugated alkenes that are not disubstituted
at their termini. Cyclocondensations of N-amidinylimin-
ium ions with 1,3-dienes could potentially be applied to
the synthesis of batzelladine A and related alkaloids;
however, further optimization of stereoselectivity would
be needed for this to represent a practical entry into these
compounds.
Cyclocondensation of ureido aminal 31 with styrene
provides 2-imino-5,6-dihydro-4H-1,3-oxazine derivative
32 rather than a pyrimidine as the major product
(Scheme 2). Although vinylogous esters or amides de-
compose prior to cyclocondensation with the guanidine
substrate, they form 4-acyl-1-oxohexahydropyrrolo[1,2-
c]pyrimidines under identical conditions in reactions with
ureido aminal 31 (eq 6).
The observed loss of stereochemistry of the disubsti-
tuted double bond in the reaction of cis-piperylene with
16 strongly suggests that cyclocondensations with N-
amidinyliminium ion 37 proceed by a stepwise mecha-
nism involving an intermediate allylic or benzylic cation
38. In the case of cis-piperylene, stereomutation of the
initially formed allylic cation 38, R ) (Z)-1-propenyl, is
competitive with trapping by the neighboring guanidine.
The formation of the same products from trans- and cis-
â-methylstyrene is also consistent with a stepwise path-
way. The stepwise nature of cyclocondensations of N-
amidinyliminium ion 37 with styrenes and 1,3-dienes
contrasts to what has previously been observed in related
hetero Diels-Alder reactions of N-acyliminium ions.26
ing conversion in the guanidine series. This transforma-
tion could be realized in low yield by reaction of 30 at
room temperature with excess PhSH and 4 M HCl.
Subsequent reaction of 31 with Cu(OTf)2 and styrene
under the conditions developed in the guanidine series
provided as the major product (53% yield) iminodihydro-
1,3-oxazine derivative 32. The corresponding cyclic urea
33 was obtained in 9% yield. Both products were isolated
as ∼4:1 mixtures of endo and exo cycloadducts. As
observed for reactions of 16, all products formed from 31
have the cis relationship of the phenethyl side chain and
C4a hydrogen. The structure of 32 was apparent from
the diagnostic signal for the C3 methine hydrogen at
1
δ5.16 in its H NMR spectrum, whereas the stereochem-
istry of 32 and 33 was secured by 1H NMR NOE
experiments.
In contrast to guanidine thioaminal 16, 31 reacted with
(E)-4-methoxy-3-buten-2-one and (E)-4-(dimethylamino)-
3-buten-2-one to give 4-acyl-1-oxohexahydropyrrolo[1,2-
c]pyrimidine 34 in 58-70% yield (eq 6). This product
undoubtedly arises by cyclocondensation followed by
elimination of the â methoxy or dimethylamino groups.
Interestingly, reaction of 31 with (E)-4-(dimethylamino)-
3-buten-2-one was highly stereoselective (dr ) 20:1),
whereas face selectivity was much lower (dr ) 2:1) in the
reaction with (E)-4-methoxy-3-buten-2-one. Reaction of
31 with benzyl acetoacetate in the presence of Cu(OTf)2
afforded Biginelli adduct 35 in 64% yield as a 2:1 mixture
of epimers, with the major isomer having the trans
stereochemistry (eq 7).
(26) (a) Schmidt, R. R. Angew. Chem., Int. Ed. Engl. 1969, 8, 602.
(b) Schmidt, R. R. Chem. Ber. 1970, 103, 3242-3251. (c) Schmidt, R.
R.; Hoffmann, A. R. Chem. Ber. 1974, 107, 78-92. (d) Bradsher, C. K.
Adv. Heterocycl. Chem. 1974, 16, 289-324.
To pursue whether cycloadducts would be formed more
readily from thioaminal precursors in the guanidine or

3172 J . Org. Chem., Vol. 66, No. 9, 2001
Overman and Wolfe
F igu r e 2. Proposed mechanism of the cyclocondensation.
F igu r e 3. Cyclocondensation of 16 with cis-â-methyl styrene.
These latter reactions are believed to proceed by con-
certed [4 + 2]-cycloaddition mechanisms.
would lead to two limiting reactive conformers of the
intermediate benzylic cation, 40 and 42, in which the
empty p-orbital was oriented toward the nucleophilic
guanidine. Conformer 40 suffers from an unfavorable
steric interaction between the C3 phenyl group and the
C4 methyl group, as well as a 1,3-diaxial interaction
between the phenyl group and the angular C4a hydrogen.
These steric effects presumably lead to the preferential
formation of 20 rather than 44. Similarly, endo addition
of cis-â-methyl styrene to 16 would lead to reactive
intermediate cation conformers 41 and 43; the severe
steric interaction between the methyl and phenyl groups
disfavors reaction via 41, and the observed product 27
arises from trapping of cation 43. Although isomer 43
places the phenyl group in an axial orientation, examina-
tion of molecular models27 suggests that the steric
interaction of the phenyl and methyl groups is more
On the basis of these observations, the mechanism we
postulate for the cyclocondensation of alkenes with 16
involves initial activation of the thiophenyl group by Cu-
(OTf)2 to form the protonated amidinyl iminium ion 36
(Figure 2). This species most likely transfers a proton to
the copper thiophenylate to form iminium ion 37 prior
to trapping by a styrene or 1,3-diene, although no
experimental evidence precludes direct reaction of these
π-nucleophiles with 36. Preferential formation of cycload-
ducts containing an R C3 side chain from cycloconden-
sations of styrenes and 1,3-dienes having a terminal vinyl
group presumably arises from preferred pseudoequatorial
orientation of the side chain in 38 during intramolecular
trapping of the benzylic cation. In a similar vein, only
two of the four possible stereoisomers are formed in the
cyclocondensation of 16 with trans- or cis-â-methylsty-
rene, one of which, 27, contains the C3 phenyl group in
an axial orientation. As shown in Figure 3, initial
addition of cis-â-methyl styrene to 16 in an exo fashion
(27) Bond angles and bond lengths used in models depicted in Figure
3 were obtained from previously described theoretical studies of
benzylic cations; see: Nakata, K.; Fujio, M.; Saeki, Y.; Mishima, M.;
Tsuno, Y.; Nishimoto, K. J . Phys. Org. Chem. 1996, 9, 561-572.

Synthesis of Polycyclic Guanidines
J . Org. Chem., Vol. 66, No. 9, 2001 3173
severe than the developing 1,3-diaxial interaction be-
tween the phenyl group and the angular C4a hydrogen.
An identical analysis predicts formation of 20 and 27 in
the reaction of 16 with trans-â-methyl styrene, which is
consistent with our experimental observations.
in good yields with complete control of relative stereo-
chemistry at C4a and C7, whereas C3 side chains are
incorporated with lower stereoselectivity (dr ) 2-5:1).
Stereochemical evidence demonstrates that cycloconden-
sations of the N-amidinyliminium ion derived from 16
proceed by a stepwise mechanism rather than by a
concerted [4 + 2]-cycloaddition pathway.
The Biginelli product 29 was formed in 9:1 stereo-
selectivity from Cu(OTf)2-promoted condensation of 16
with benzyl acetoacetate. This result supports the imin-
ium ion pathway outlined in Figure 1 for tethered
Biginelli condensations of guanidines we described earlier
from our laboratories.8
Mech a n ism of Teth er ed Bigin elli Con d en sa tion
of Gu a n id in e P r ecu r sor s. In addition to providing a
new method for the synthesis of 1-iminohexahydropyr-
rolo[1,2-c]pyrimidines, these studies provide further sup-
port for our earlier speculation on the origin of stereo-
selection in tethered Biginelli condensations of guanidines
(Figure 1).8 We originally posited the intermediacy of an
N-amidinyliminium ion to explain preferential formation
of trans iminopyrrolopyrimidine stereoisomer 13 in con-
densations promoted by morpholinium acetate.8 The
current study demonstrates that N-amidinyliminium ion
37 does indeed add nucleophiles preferentially from the
face opposite the phenethyl side chain. In the reaction
of direct relevance to tethered Biginelli condensations,
the putative N-amidinyliminium ion generated from 16
and Cu(OTf)2 reacts at room temperature with benzyl
acetoacetate with 9:1 facial selectivity from the face
opposite the phenylethyl group. Under the conditions
employed for this cyclocondensation, a sequence analo-
gous to the Knoevenagel pathway outlined in Figure 1
is highly unlikely.28
At first glance, the relative reactivity of 16 and 31 in
cyclocondensations with styrene appears to be inconsis-
tent with our earlier analysis of stereoselection in
tethered Biginelli reaction.8 In that discussion, we sug-
gested that an iminium ion bearing a less electron-
withdrawing N-amidinyl substituent should form more
readily by loss of HY from precursor 5 than the corre-
sponding intermediate having N-aminocarbonyl func-
tionality (Figure 1). However, the first species generated
from 16 upon reaction with Cu(OTf)2 is undoubtedly the
protonated N-amidinyliminium ion 36 (Figure 2), a
species that would be considerably higher in energy than
an N-amidinyliminium ion or an N-(acylamino)iminium
ion. In contrast, tethered Biginelli reactions employing
morpholinium acetate as the promoter would avoid the
formation of 36 by transferring a proton from the
guanidinium functionality to morpholine as the C-Y
bond undergoes heterolytic cleavage.29 Unfortunately,
attempts to directly probe this hypothesis by examining
the relative rates of reactions of the free base of 16 were
unsuccessful. Presumably, the free guanidine is basic
enough to coordinate to the Cu(II) and prevent activation
of the phenylthio leaving group.
Exp er im en ta l Section 30
2-(3-Azid o-5-p h en ylp en tyl)-1,3-d ioxola n e (18). An oven-
dried flask was cooled under a stream of nitrogen and charged
with magnesium turnings (2.33 g, 96 mmol). To the flask was
added THF (80 mL), followed by one small crystal of iodine.
The mixture was cooled to 0 °C, and 2-(2-bromoethyl)-1,3-
dioxolane (9.4 mL, 80 mmol) was added in one portion. The
mixture was stirred at 0 °C for 3 h, and then 3-phenylpro-
pionaldehyde (5.3 mL, 40 mmol) was added dropwise. The
mixture was stirred at 0 °C for 20 min, and then aqueous
ammonium chloride (80 mL) was added and the mixture was
allowed to warm to room temperature. The mixture was
diluted with ether (100 mL), and the layers were separated.
The aqueous layer was extracted with ether (3 × 50 mL), and
the combined organic extracts were washed with brine (50
mL), dried over anhydrous sodium sulfate, filtered, and
concentrated in vacuo. The crude product was purified by flash
chromatography on silica gel using 30% ethyl acetate/hexanes
as the eluant to afford 7.37 g (78%) of 1-[1,3]-dioxolan-2-yl-5-
phenylpentan-3-ol as a colorless oil. This material was judged
1
to be ∼80% pure by H NMR analysis and was used without
further purification: 1H NMR (500 MHz, CDCl3) δ 7.31-7.26
(m, 2 H), 7.22-7.17 (m, 3 H), 4.89 (t, J ) 4.5 Hz, 1 H), 3.97-
3.82 (m, 4 H), 3.67-3.62 (m, 1 H), 2.83-2.78 (m, 1 H), 2.70-
2.65 (m, 2 H), 1.85-1.75 (m, 4 H), 1.70-1.64 (m, 1 H), 1.59-
1.52 (m, 1 H); 13C NMR (125 MHz, CDCl3) δ 142.1, 128.3, 128.2,
125.6, 104.3, 70.6, 64.8, 64.7, 39.0, 32.0, 31.3, 29.8; IR (film)
3425, 1040 cm-1
.
An oven-dried flask was cooled under a stream of nitrogen
and charged with triphenylphosphine (9.65 g, 36.8 mmol),
1-[1,3]-dioxolan-2-yl-5-phenylpentan-3-ol (7.25 g, 30.7 mmol),
and THF (307 mL). The mixture was cooled to 0 °C, and HN3
(17.7 mL, 2.08 M in toluene) was added. Diethyl azodicar-
boxylate (5.8 mL) was added dropwise over 30 min, and the
mixture was stirred at 0 °C for 15 min, warmed to room
temperature, and stirred for 2 h. The mixture was concen-
trated in vacuo to 100 mL and then diluted with hexanes (400
mL), filtered, and concentrated. The crude product was puri-
fied by flash chromatography on silica gel using 10% ethyl
acetate/hexanes as the eluant to afford 6.48 g (80%) of 18 as
a colorless oil: 1H NMR (500 MHz, CDCl3) δ 7.3-7.29 (m,
2 H), 7.22-7.19 (m, 3 H), 4.89 (t, J ) 4.2 Hz, 1 H), 3.98-3.85
(m, 4 H), 3.33 (p, J ) 7.4 Hz, 1 H), 2.82-2.79 (m, 1 H), 2.71-
2.67 (m, 1 H), 1.87-1.84 (m, 3 H), 1.73-1.53 (m, 3 H); 13C NMR
(125 MHz, CDCl3) δ 141.1, 128.44, 128.35, 126.0, 103.9, 64.90,
Con clu sion
Our efforts to further explore the mechanism of teth-
ered Biginelli condensations have led to a new method
for the synthesis of 1-iminohexahydropyrrolo[1,2-c]pyrim-
idines by formal [4 + 2]-cycloaddition of N-amidinylimin-
ium ions with alkenes. This cyclocondensation allows
1-iminohexahydropyrrolo[1,2-c]pyrimidines containing side
chains at C3 and C7 to be readily prepared. Although
the scope of these reactions is currently limited to 1,3-
dienes and styrene derivatives, cycloadducts are obtained
64.86, 61.9, 36.1, 32.2, 30.2, 28.5; IR (film) 2096, 1031 cm-1
;
MS (CI) m/z 262.1553 (262.1555 calcd for
C14H20N3O2,
M + H+).
1-(2-[1,3]-Dioxolan -2-yleth yl-3-ph en ylpr opylam in e (19).
An oven-dried flask was cooled under a stream of nitrogen and
charged with a solution of LAH in ether (28 mL, 28 mmol, 1.0
M) and additional ether (170 mL). The solution was cooled to
0 °C, and a solution of 2-(3-azido-5-phenylpentyl)-1,3-dioxolane
(6.14 g, 23.2 mmol) in ether (34 mL) was added dropwise. The
mixture was stirred at 0 °C for 15 min, warmed to room
(28) Such a sequence would require Cu(OTf)2-promoted ring opening
of 16 to give an R-thiocarbenium ion, which then adds the acetoacetate.
(29) The high acidity of 36 may be responsible for the apparent
decomposition of 4-methoxy or 4-(dimethylamino)-3-buten-2-one during
attempted cyclocondensations with 16.
(30) General experimental details have been described: Ando, S.;
Minor, K. P.; Overman, L. E. J . Org. Chem. 1997, 62, 6379-6387.

3174 J . Org. Chem., Vol. 66, No. 9, 2001
Overman and Wolfe
temperature, and stirred for 1.5 h. The mixture was then
cooled to 0 °C, and water (4 mL), sodium hydroxide (5 mL, 10
M), and additional water (8 mL) were added dropwise sequen-
tially. The mixture was warmed to room temperature and
stirred for 10 min, and then the solution was decanted, dried
over anhydrous sodium sulfate, filtered, and concentrated in
for the major diastereomer: 1H NMR (500 MHz, CDCl3) δ
7.60-7.40 (m, 4 H), 7.32-7.30 (m, 3 H), 7.24-7.20 (m, 3 H)
7.16-7.13 (m, 4 H), 5.10 (dd, J ) 3.4, 6.9 Hz, 1 H), 4.34-4.32
(m, 1 H), 2.79 (td, J ) 5.4, 13.6 Hz, 1 H), 2.47 (td, J ) 5.1,
12.0 Hz, 1 H), 2.38-2.33 (m, 1 H), 2.16-2.13 (m, 2 H), 2.04-
2.00 (m, 1 H), 1.88-1.84 (m, 1 H), 1.30-1.26 (m, 1 H); 13C NMR
(125 MHz, CDCl3) δ 155.8, 141.1, 135.0, 129.6, 129.5, 128.3,
125.9, 68.2, 59.8, 35.1, 32.4, 31.6, 28.9; IR (film) 3300, 1648,
1586 cm-1; MS (FAB) m/z 326.1692 (326.1691 calcd for
1
vacuo to afford 5.44 g (99%) of 19 as a colorless oil. H NMR
(500 MHz, CDCl3) δ 7.35-7.25 (m, 2 H), 7.20-7.16 (m, 3 H),
4.87 (t, J ) 4.6 Hz, 1 H), 3.95-3.84 (m, 4 H), 2.77-2.70 (m, 2
H), 2.63-2.55 (m, 1 H), 1.77-1.58 (m, 5 H), 1.41-1.33 (m, 1
H), 1.24 (s, br, 2 H); 13C NMR (125 MHz, CDCl3) δ 142.2, 128.3,
125.7, 104.5, 64.84, 64.78, 50.6, 39.8, 32.5, 32.2, 30.4; IR (film)
3365, 1031 cm-1; MS (EI) m/z 235.1578 (235.1572 calcd for
C
19H24N3S).
[1-(2-[1,3]-Dioxolan -2-yleth yl)-3-ph en ylpr opylu r ea (30).
An oven-dried flask was cooled under a stream of nitrogen and
charged with 1-(2-[1,3]-dioxolan-2-yl-ethyl-3-phenylpropyl-
amine (19) 1.2 g (5.0 mmol) and 2-propanol (7 mL). Trimeth-
ylsilyl isocyanate (0.95 mL, 7.0 mmol) was added, and the
mixture was stirred at room temperature for 5 h. The mixture
was concentrated in vacuo and purified by flash chromatog-
raphy on silica gel using 3% methanol/chloroform as the eluant
to afford 850 mg (61%) of 30 as a colorless solid: mp 128-130
C
14H21NO2).
2-P h en eth yl-5-p h en ylsu lfa n ylp yr r olid in e-1-ca r boxa m -
id in e HCl (16). An oven-dried flask was cooled under a stream
of nitrogen and charged with 1-(2-[1,3]dioxolan-2-ylethyl-3-
phenylpropylamine (4.0 g, 17 mmol), bis-BOC-thiourea31 (5.63
g, 20.4 mmol), triethylamine (5.21 mL, 37.4 mmol), and DMF
(4 mL). A suspension of 2-chloro-N-methylpyridinium iodide
(5.21 g, 20.4 mmol) in DMF (13 mL) was added dropwise, and
the resulting mixture was stirred at room temperature for 14
h. The mixture was then diluted with water (20 mL) and
extracted with ether (3 × 40 mL). The combined organic
extracts were washed with brine (50 mL), dried over anhy-
drous sodium sulfate, filtered, and concentrated in vacuo. The
crude product was then purified by flash chromatography on
silica gel using ethyl acetate/hexanes as the eluant (10% to
20%) to afford 4.75 g (60%) of N,N′-bis(tert-butoxycarbonyl)-
N′′-[1-(2-[1,3]-dioxolan-2-ylethyl)-3-phenylpropyl]guanidine as
a viscous oil. This material was judged to be ∼90% pure by
1H NMR analysis and was used without further purification:
1H NMR (400 MHz, CDCl3) δ 8.25 (d, J ) 9.2 Hz, 1 H), 7.26-
7.24 (m, 2 H), 7.20-7.14 (m, 3 H), 4.87 (t, J ) 4.4 Hz, 1 H),
4.27 (s, br, 1 H), 3.96-3.82 (M, 4 H), 2.66 (t, J ) 8.0 Hz, 2 H),
1.90-1.59 (m, 7 H), 1.50 (s, 9 H), 1.49 (s, 9 H); 13C NMR (100
MHz, CDCl3) δ 163.8, 156.0, 153.2, 141.8, 128.3, 128.2, 125.7,
104.1, 82.9, 78.9, 64.8, 49.6, 36.5, 31.9, 29.7, 28.8, 28.3, 28.0;
IR (film) 3323, 3281, 1718, 1637, 1613, 1054 cm-1; MS (CI)
500.2724 (500.2736 calcd for C25H39N3O6Na). An oven-dried
flask was cooled under a stream of nitrogen and charged with
N,N′-bis(tert-butoxycarbonyl)-N′′-[1-(2-[1,3]-dioxolan-2-ylethyl)-
3-phenylpropyl]guanidine (4.75 g, 10.0 mmol), thiophenol (1.03
mL, 10.0 mmol), trifluoroacetic acid (20 mL), and methylene
chloride (20 mL). The mixture was stirred at room temperature
for 17 h and then was concentrated in vacuo. The crude
product was purified by flash chromatography on silica gel to
afford 3.2 g (73%) of a viscous oil which solidified upon
standing to give 2-phenethyl-5-phenylsulfanylpyrrolidine-1-
carboxamidine hydrotrifluoroacetate as a colorless solid, mp
133-135 °C. This material was determined to be a 10/1
mixture of diastereomers by 1H NMR analysis. Data are for
the major diastereomer. 1H NMR (400 MHz, CDCl3) δ 7.90 (s,
br, 2 H), 7.48-7.46 (m, 2 H), 7.38-7.35 (m, 3 H), 7.26-7.24
(m, 3 H), 7.20-7.18 (m, 1 H), 7.12-7.10 (m, 2 H), 5.03 (dd,
J ) 3.2, 6.8 Hz, 1 H), 4.09-4.06 (m, 1 H), 2.60-2.55 (m, 2 H),
2.33-2.16 (m, 3 H), 2.03-1.55 (m, 2 H), 1.42-1.36 (m, 1 H);
13C NMR (125 MHz, CDCl3) δ 161.9 (q, J ) 36.5 Hz), 156.0,
140.7, 135.0, 130.7, 129.9, 129.7, 128.4, 128.1, 126.4, 116.2 (q,
J ) 292 Hz), 68.5, 59.3, 35.1, 32.6, 31.5, 28.9; 19F NMR (375
MHz, CDCl3) δ -76.7; IR (film) 3443, 3343, 1779, 1656, 1590,
1135 cm-1; MS (FAB) m/z 326.1696 (326.1691 calcd for
1
°C; H NMR (500 MHz, CDCl3) δ 7.25-7.22 (m, 2 H), 7.15-
7.13 (m, 3 H), 5.23 (s, br, 1 H), 4.85 (s, br, 2 H), 4.83 (t, J )
4.3 Hz, 1 H), 3.91-3.75 (m, 4 H), 3.66 (s, br, 1 H), 2.71-2.59
(m, 2 H), 1.80-1.63 (m, 5 H), 1.51-1.46 (m, 1 H); 13C NMR
(125 MHz, CDCl3) δ 159.2, 141.8, 128.3, 125.7, 104.2, 64.8,
64.7, 49.8, 37.6, 32.2, 29.8, 29.5; IR (film) 3312, 3212, 1648,
1565, 1139, 1034 cm-1; MS (CI)m/z 278.1631 (278.1630 calcd
for C15H22N2O3).
2-P h en et h yl-5-p h en ylsu lfa n ylp yr r olid in eca r b oxylic
Acid Am id e (31). An oven-dried flask was cooled under a
stream of nitrogen and charged with [1-(2-[1,3]dioxolan-2-
ylethyl)-3-phenylpropylurea (1.10 g, 3.96 mmol), thiophenol
(1.63 mL, 15.84 mmol), dichloromethane (1 mL), and a solution
of anhydrous HCl in dioxane (1 mL, 4.0 mmol, 4 M). The
mixture was stirred at room temperature for 16 h, triethyl-
amine (1 mL) was added, and the mixture was concentrated
in vacuo. The crude material was purified by flash chroma-
tography on silica gel using 30% ethyl acetate/hexanes as the
eluant to afford 470 mg (36%) of 31 as a colorless solid: mp
124-127 °C; 1H NMR (500 MHz, CDCl3) δ 7.51-7.47 (m, 2
H), 7.33-7.29 (m, 3 H), 7.28-7.25 (m, 2 H), 7.19-7.15 (m, 3
H), 5.10 (dd, J ) 3.0, 6.4 Hz, 1 H), 4.96 (s, br, 2 H), 4.02-3.98
(m, 1 H), 2.59 (t, J ) 8.15 Hz, 2 H), 2.24-2.15 (m, 3 H), 1.83-
1.79 (m, 1 H), 1.45-1.41 (m, 1 H); 13C NMR (125 MHz, CDCl3)
δ 157.6, 141.8, 134.4, 132.1, 129.2, 128.6, 128.3, 128.2, 125.7,
68.5, 58.5, 36.4, 33.3, 32.2, 28.9; IR (film) 3408, 1668 cm-1
;
MS (CI) m/z 327.1521 (327.1531 calcd for
C19H23N2OS,
M + H+).
Gen er a l P r oced u r e for N-Am id in ylim in iu m Ion Cyclo-
con d en sa tion Rea ction s. An oven-dried flask was cooled
under a stream of nitrogen and charged with Cu(OTf)2 (145
mg, 0.4 mmol), the alkene (0.8 mmol), and methylene chloride
(400 µL). The mixture was cooled to 0 °C, and a solution of
2-phenethyl-5-phenylsulfanylpyrrolidine-1-carboxamidine HCl
(16) (144 mg, 0.40 mmol) in methylene chloride/chloroform (1.2
mL, 2/1 v/v) was added dropwise. The mixture was stirred at
0 °C until the starting material had been completely consumed
as judged by electrospray MS analysis. Reactions were gener-
ally complete in 2 h at 0 °C. The mixture was then diluted
with methylene chloride (5 mL), filtered, and concentrated in
vacuo. The crude material was purified by flash chromatog-
raphy on silica gel using methanol/chloroform as the eluant
(0% to 3%). The products were isolated as mixtures of diaster-
eomers; ratios of the diastereomers were determined by 1H
NMR analysis. The diastereomers were separated by flash
chromatography or preparative HPLC for characterization
purposes. Stereochemistry of the products was assigned by
NOE experiments.
C
19H24N3S).
2-Phenethyl-5-phenylsulfanylpyrrolidine-1-carboxamidine hy-
drotrifluoroacetate (3.1 g, 7.1 mmol) was dissolved in chloro-
form (75 mL). The solution was washed with 0.1 M HCl
saturated with sodium chloride (5 × 80 mL) and then
concentrated in vacuo. The crude material was dried in vacuo
on a rotary evaporator by azeotropic removal of water with
toluene (2 × 150 mL) to afford 2.32 g (91%) of 16 as a colorless
solid, mp 174-177 °C. This material was determined to be a
9/1 mixture of diastereomers by 1H NMR analysis. Data are
Rea ction of 16 w ith Styr en e. The general procedure
afforded 156 mg (83%) of 7-phenethyl-3-phenylhexahydropyr-
rolo[1,2-c]pyrimidine-1-ylideneamine (15) as a 5/1 mixture of
diastereomers (the crude reaction mixture was judged to be a
1
5/1 mixture of diastereomers by H NMR analysis).
(3R,4a R,7R)-7-P h en eth yl-3-p h en ylh exa h yd r op yr r olo-
[1,2-c]p yr im id in e-1-ylid en ea m in e Hyd r otr iflu or om eth -
a n esu lfon a te (15). This material was obtained as a colorless
(31) Iwanowicz, E. J .; Poss, M. A.; Lin, J . Synth. Commun. 1993,
23, 1443-1445.

Synthesis of Polycyclic Guanidines
J . Org. Chem., Vol. 66, No. 9, 2001 3175
solid: mp 66-68 °C; 1H NMR (500 MHz, CDCl3) δ 7.39-7.15
(m, 11 H), 6.52 (s, 2 H), 4.37 (dd, J ) 2.9, 8.6 Hz, 1 H), 4.17-
4.12 (m, 1 H), 3.73-3.67 (m, 1 H), 2.89-2.84 (m, 1 H), 2.63-
2.55 (m, 1 H), 2.35-2.30 (m, 2 H), 2.26-2.10 (m, 2 H), 1.87-
1.70 (m, 2 H), 1.56-1.50 (m, 2 H); 13C NMR (125 MHz, CDCl3)
δ 151.9, 141.0, 138.3, 128.9, 128.5, 128.4, 128.3, 126.0, 120.0
(q, J ) 318 Hz), 58.1, 56.5, 54.0, 36.3, 35.5, 31.2, 31.1, 29.6;
19F NMR (375 MHz, CDCl3) δ -79.5; IR (film) 3350, 1652, 1027
cm-1; MS (CI) m/z 320.2120 (320.2127 calcd for C21H26N3).
(3S,4a R,7R)-7-P h en eth yl-3-p h en ylh exa h yd r op yr r olo-
[1,2-c]p yr im id in e-1-ylid en ea m in e Hyd r otr iflu or om eth -
a n esu lfon a te. This material was obtained as a viscous oil and
judged to be a 4/1 mixture of diastereomers by 1H NMR
analysis after purification: 1H NMR (500 MHz, CDCl3) δ 7.82
(d, J ) 4.9 Hz, 1 H), 7.36-7.34 (m, 2 H), 7.33-7.28 (m, 3 H),
7.23-7.20 (m, 3 H), 7.12 (d, J ) 7.5 Hz, 2 H), 6.52 (s, 2 H),
4.82-4.79 (m, 1 H), 4.17-4.10 (m, 1 H), 3.27-3.21 (m, 1 H),
2.73-2.68 (m, 1 H), 2.61-2.55 (m, 1 H), 2.35-2.30 (m, 2 H),
2.22-2.18 (m, 1 H), 2.13-2.07 (m, 1 H), 1.85 (td, J ) 5.0, 13.1
Hz, 1 H), 1.72-1.63 (m, 2 H), 1.61-1.50 (m, 1 H); 13C NMR
(125 MHz, CDCl3) δ 152.1, 140.8, 140.3, 128.9, 128.6, 128.3,
127.8, 126.3, 125.3, 58.3, 52.1, 51.3, 36.1, 33.5, 31.20, 31.17,
29.63; 19F NMR (375 MHz, CDCl3) δ -79.5; IR (film) 3346,
3223, 1652, 1027 cm-1; MS (CI) m/z 320.2116 (320.2127 calcd
for C21H26N3).
with CDCl3 (500 µL) and filtered. Analysis of the crude mixture
by 1H NMR showed no isomerization of the olefin had occurred.
Com p etition Exp er im en t. An oven-dried vial was cooled
under a stream of nitrogen and charged with Cu(OTf)2 (25 mg,
0.07 mmol), styrene (9 µL, 0.07 mmol), and methylene chloride
(70 µL). The mixture was cooled to 0 °C, and a solution of 16
(25 mg, 0.07 mmol) and 31 (23 mg, 0.07 mmol) in methylene
chloride/chloroform (210 µL, 2/1 v/v) was added dropwise. The
mixture was stirred at 0 °C for 2 h. The mixture was then
diluted with methylene chloride (5 mL), filtered, and concen-
1
trated in vacuo. Analysis of the crude reaction mixture by H
and 13C NMR showed that 22 had been completely consumed
and 16 remained unreacted. A small amount of 32 was also
detected. The crude material was purified by flash chroma-
tography on silica gel using ethyl acetate/hexanes as the eluant
(60% to 80%) to afford 2 mg (10%) of 32 and 24 mg (73%) of
the hydrotrifluoromethanesulfonate salt of 16.
Ack n ow led gm en t. We thank the NIH NHLBIS
(HL-25854) for financial support of this research. J .P.W.
was supported by an NIH postdoctoral fellowship (GM
20140), for which he is grateful. NMR and mass spectra
were determined at UCI using instruments acquired
with the assistance of NSF and NIH shared instrumen-
tation grants.
Con tr ol Exp er im en ts. cis-â-Methyl styrene (26 µL, 0.1
mmol) was treated with Cu(OTf)2 (37 mg, 0.1 mmol) in
methylene chloride/chloroform (400 µL, 3/1 v/v) for 2 h at 0
°C. The mixture was then diluted with 2 mL of methylene
chloride, filtered, and concentrated in vacuo. Analysis of the
crude product by 1H NMR showed no isomerization of the
olefin had occurred. In a separate experiment, cis-piperylene
(20 µL, 0.2 mmol) was treated with Cu(OTf)2 (37 mg, 0.1 mmol)
in CDCl3 (400 µL) at 0 °C for 2 h. The mixture was then diluted
Su p p or tin g In for m a tion Ava ila ble: Characterization
data for compounds 20-29 and 32-35, tables of NOE data,
and copies of 1H and 13C NMR spectra of all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
J O0100998