Nucleophilic carbenes in synthesis. [1 + 4] cycloaddition of bis(alkylthio)carbenes with vinyl isocyanates

Full text of DOI:10.1021/jo9823801

1766
J . Org. Chem. 1999, 64, 1766-1767
Communications
reported some interesting and synthetically useful chemistry
Nu cleop h ilic Ca r ben es in Syn th esis. [1 + 4]
Cycloa d d ition of Bis(a lk ylth io)ca r ben es w ith
Vin yl Isocya n a tes
for a mixed S,O-carbene.5
It was reasoned that dithiocarbenes should behave in a
manner quite similar to that of the corresponding dioxy
species in their reactions with isocyanates; however, it was
also expected that the resultant dithioacetal function would
offer a complementary range of post-cycloaddition functional
group interchanges that would be of particular synthetic
value.
J ames H. Rigby* and Ste´phane Laurent
Department of Chemistry, Wayne State University,
Detroit, Michigan 48202-3489
Heating the readily available dithiooxadiazoline 16 (2.5
equiv) in the presence of vinyl isocyanate 2 afforded the 2:1
adduct 37 in excellent yield (eq 1). This result closely
Received December 4, 1998
Carbene centers possessing donor substituents such as
oxygen, nitrogen and sulfur frequently exhibit nucleophilic
properties, in contrast to the well-established electrophilic
character of dihalocarbenes.1 This reactivity profile is be-
lieved to result from conjugative donation of electron density
from the heteroatoms into the vacant p-orbital of the singlet
state of the carbene. The nucleophilic character of these
carbenes offers numerous opportunities for developing novel,
synthetically useful transformations for the construction of
functionally rich targets.
parallels observations made in the addition of dimethoxy-
carbene to isocyanate 2 except that considerably higher
temperatures were required for efficient reaction with the
oxygen-based carbene (80 vs 145 °C). The generality of this
[1 + 4] cycloaddition process is illustrated by other examples
depicted in eqs 2-4. Several salient features of the cycliza-
Recently, dimethoxycarbene was demonstrated to be a
particularly useful carbonyl 1,1-dipole equivalent in [1 + 4]
cycloaddition reactions with various vinyl isocyanate part-
ners.2 Subsequently, this process was exploited as the key
strategy-level transformation in a total synthesis of the
amaryllidaceae alkaloid tazettine.3 We now wish to report
that the corresponding dithiocarbene species can also par-
ticipate in an efficient [1 + 4] cycloaddition with vinyl
isocyanates; however, several intriguing differences have
been noted between the chemistries of the two carbene
series, both during and after the ring-forming event. While
several dithiocarbenes have been reported previously, the
chemistry observed for these reactive intermediates has
been, for the most part, restricted to a very facile dimeriza-
tion that is a characteristic reaction pathway available to
most related species.4 Recently, Warkentin and co-workers
(1) For some leading references to nucleophilic carbenes, see: (a) Pole,
D. L.; Sharma, P. K.; Warkentin, J . Can. J . Chem. 1996, 74, 1335. (b) Pole,
D. L.; Warkentin, J . J ustus Liebigs Ann. Chem. 1995, 1907. (c) Arduengo,
A. J ., III; Dias, H. V. R.; Dixon, D. A.; Harlow, R. L.; Klooster, W. T.; Koetzle,
T. F. J . Am. Chem. Soc. 1994, 116, 6812. (d) Ge, C.-J .; J efferson, E. A.;
Moss, R. A. Tetrahedron Lett. 1993, 34, 7549. (e) Arduengo, A. J ., III; Dias,
H. V. R.; Harlow, R. L.; Kline, M. J . Am. Chem. Soc. 1992, 114, 5530. (f)
Homberger, G.; Kirmse, W.; Lelgemann, R. Chem. Ber. 1991, 124, 1867. (g)
Moss, R. A. Acc. Chem. Res. 1989, 22, 15. (h) Moss, R. A.; Wlostowski, M.;
Shen, S.; Krogh-J espersen, K.; Matro, A. J . Am. Chem. Soc. 1988, 110, 4443.
(2) Rigby, J . H.; Cavezza, A.; Ahmed, G. J . Am. Chem. Soc. 1996, 118,
12848.
(3) Rigby, J . H.; Cavezza, A.; Heeg, M. J . J . Am. Chem. Soc. 1998, 120,
3664.
(4) (a) Benati, L.; Calestani, G.; Nanni, D.; Spagnolo, P.; Volta, M.
Tetrahedron 1997, 53, 9269. (b) Benati, L.; Calestani, G.; Montevecchi, P.
C.; Spagnolo, P. J . Chem. Soc., Chem. Commun. 1995, 1999. (c) Bittner, S.;
Moradpour, A.; Krief, P. Synthesis 1989, 132. (d) Nakayama, J . Sulfur Rep.
1985, 4, 159. (e) Nakayama, J .; Seki, E.; Hoshino, M. J . Chem. Soc., Perkin
tion process emerge from these entries. For instance, a
mixture of epimers resulted at the newly created bridgehead
position in hydroindolone 57 when remote stereogenic cen-
ters were present in the substrate. The capability, as shown
in eq 4, of producing a quaternary carbon center during the
ring-forming event to yield compound 77 is also particularly
noteworthy.
Chem. Soc. 1973, 95, 4379. (l) Carlson, R. M.; Helquist, P. M. Tetrahedron
Lett. 1969, 173. (m) Seebach, D. Angew. Chem., Intl. Ed. Engl. 1967, 6,
443. (n) Scho¨llkopf, U.; Wiskott, E. J ustus Liebigs Ann. Chem. 1966, 694,
44. (o) Lemal, D. M.; Banitt, E. H. Tetrahedron Lett. 1964, 245.
(5) (a) Er, H.-T.; Pole, D. L.; Warkentin, J . Can. J . Chem. 1996, 74, 1480.
(b) For the apparent preparation of another bis(alkylthio)oxadiazoline,
see: Warkentin, J . In Advances in Carbene Chemistry; Brinker, U., Ed.;
J AI Press: 1998; Vol. 2, p 263.
Trans.
1
1978, 468. (f) Cohen, T. Ouellette, D.; Daniewski, W. M.
(6) Prepared by a variation of the Warkentin procedure: Couture, P.;
Terlouw, J . K.; Warkentin, J . J . Am. Chem. Soc. 1996, 118, 4214.
(7) This compound exhibited spectral (1H NMR, 13C NMR, IR, MS) and
analytical (combustion analysis and/or HRMS) data in complete accord with
the assigned structure.
Tetrahedron Lett. 1978, 5063. (g) Nitsche, M.; Seebach, D.; Beck, A. K. Chem.
Ber. 1978, 111, 3644. (h) Obata, N. Bull. Chem. Soc. J pn. 1977, 50, 2187.
(i) Nakayama, J .; Fujiwara, K.; Hoshino, M. Bull. Chem. Soc. J pn. 1976,
49, 3567. (j) Nakayama, J . Synthesis 1975, 168. (k) Hartzler, H. D. J . Am.
10.1021/jo9823801 CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/25/1999

Communications
J . Org. Chem., Vol. 64, No. 6, 1999 1767
One of the more appealing features of this chemistry is
the range of synthetically useful post-cycloaddition manipu-
lations that are available with the dithiocarbene adducts,
many of which are not easily achieved in the corresponding
dialkoxy series. An obvious potential advantage of the
current methodology is the expectation that reductive des-
ulfurization would afford functionalized hydroindolones at
oxidation levels found in many alkaloid targets such as in
the lycorine, crinine, and erythrina families. Equations 5 and
6 illustrate this point. Of particular significance is the ability
to control the desulfurization process to produce either the
enamide 87 or the fully reduced system 97 depending on the
conditions employed.8
vinyl isocyanates have been achieved previously, but pyri-
done products (via heteroatom elimination) have normally
resulted.9 The absence of N-H insertion in the final product
is also consistent with this pathway since the initial dimer-
ization event would exhaust most of the supply of carbene
needed for subsequent insertion. In the event, heating
preformed dimer 15 with isocyanate 2 in refluxing benzene
did not afford any of the anticipated adduct 12 (eqs 10 and
11). Furthermore, in a companion experiment, adduct 12
was exposed to excess oxadiazoline in refluxing benzene to
afford N-H insertion product 167 in good yield. In concert,
these two observations clearly suggest the possible involve-
ment of a rapid set of multiple carbene additions that
precede the key ring-forming step.
In light of these latter developments, it is believed that
the abnormal 2:1 adducts arise from the very rapid produc-
tion of a large amount of carbene that is present in sufficient
quantities to competitively add a second equivalent of
reactive intermediate to the initial dipolar 1:1 adduct
prior to ring closure (eq 12). In addition, the absence of
In an effort to improve the efficiency of the cycloaddition
process, an experiment was performed in which a large
excess of oxadiazoline 1 (10 equiv) was added rapidly to a
solution of vinyl isocyanate 2 in refluxing benzene. Remark-
ably, under these conditions the reaction followed an unan-
ticipated pathway to deliver an alternative 2:1 adduct 12,7
in good yield.
Several features of this product are quite unusual when
compared to adducts from the “normal” reaction channel.
Most notable is the apparent addition of 2 equiv of carbene
to the isocyanate prior to ring formation, a process that leads
to a six-membered lactam product. Furthermore, unlike the
examples in equations 1-4, no carbene addition occurred
at the amide N-H bond. This is apparently not an isolated
event, since the observations depicted in eq 7 seem to apply
whenever a large excess of oxadiazoline is rapidly decom-
posed in the presence of an isocyanate reaction partner (i.e.,
eqs 8 and 9).
N-H insertion in these products could be due to a slow
N-acylimine-enamide tautomerization in the six-membered
ring series. In contrast, this isomerization process appears
to be quite fast in the related hydroindolone system, thus
facilitating N-H insertion. The initially formed imine spe-
cies in the six-membered ring series cannot undergo N-H
insertion and serves to “protect” the amide from reaction
during the relatively short lifetime of the carbene. Further
investigation of this intriguing double addition pathway is
currently underway.10
In conclusion, dithiocarbenes have been found to react
smoothly with vinyl isocyanates to afford a variety of
interesting adducts that are amenable to useful functional
group interchange to afford building blocks for alkaloid
synthesis.
Ack n ow led gm en t. The authors wish to thank the
National Science Foundation for their generous support of
this research.
Su p p or tin g In for m a tion Ava ila ble: Typical experimental
A possible rationale for these observations that would
satisfy each of the novel features of the reaction is that the
carbene generated under these conditions rapidly dimerizes
to 15, which then undergoes a thermal [4 + 2] cycloaddition
with the isocyanate to deliver the observed product. Some-
what related cyclizations between electron-rich alkenes and
conditions for cycloadditions and 1H NMR data for 4, 5, 7, and
13.
J O9823801
(9) (a) Fuks, R. Tetrahedron 1970, 26, 2161. (b) Rigby, J . H. Balasubra-
manian, N. J . Org. Chem. 1989, 54, 224.
(10) It should be noted that no 2:1 adducts of the type shown in eqs 7-9
could be identified under similar conditions using the corresponding
dimethoxycarbene precursor.
(8) Spero, G. B.; McIntosh, A. V., J r.; Levin, R. J . Am. Chem. Soc. 1948,
70, 1907.