Facile 1,3-diaza-Claisen rearrangements of tertiary allylic amines bearing an electron-deficient alkene

Article abstract of DOI:10.1021/ol802577z

(Chemical Equation Presented) Tertiary allylic amines with an electron-deficient alkene react with isocyanates and isothiocyanates to give highly substituted ureas and thioureas arising from formal 1,3-diaza-Claisen rearrangements. Isocyanates and isothiocyanates with strong electron-withdrawing groups are more reactive. Similarly, the data suggest that a stronger electron-withdrawing substituent on the alkene favors a faster reaction, but this may be offset by sterlcs in the cyclic transition state.

Full text of DOI:10.1021/ol802577z

ORGANIC
LETTERS
2009
Vol. 11, No. 3
575-578
Facile 1,3-diaza-Claisen Rearrangements
of Tertiary Allylic Amines Bearing an
Electron-Deficient Alkene
Rachel M. Aranha, Amy M. Bowser, and Jose S. Madalengoitia*
Department of Chemistry, UniVersity of Vermont, Burlington, Vermont 05405
jmadalen@uVm.edu
Received November 7, 2008
ABSTRACT
Tertiary allylic amines with an electron-deficient alkene react with isocyanates and isothiocyanates to give highly substituted ureas and thioureas
arising from formal 1,3-diaza-Claisen rearrangements. Isocyanates and isothiocyanates with strong electron-withdrawing groups are more reactive.
Similarly, the data suggest that a stronger electron-withdrawing substituent on the alkene favors a faster reaction, but this may be offset by sterics
in the cyclic transition state.
We have previously reported that isocyanates, isothiocyan-
ates, and N-sulfonyl-N′-alkyl carbodiimides (generated in situ
Scheme 1
from N-sulfonyl-N′-alkyl-thioureas) react with azanor-
bornenes 1 to transiently form zwitterionic intermediates 5
that in turn undergo a 1,3-diaza-Claisen rearrangement to
give ureas, thioureas, and guanidines 6, respectively (Scheme
1).1-3 Interestingly, attempts to effect this transformation
with simpler tertiary allylic amines did not afford the
rearrangement product. For example, the attempted reaction
of N,N-dimethylallylamine 7 with TsNCO at rt did not afford
the rearrangement product. The evaluation of more forcing
conditions (e.g., triallylamine, BzNCO, in xylenes at reflux)
resulted only in isocyanate decomposition. These results
indicate that 1,3-diaza-Claisen rearrangements with simple
tertiary allylic amines are not as facile.
(1) Bowser, A. M.; Madalengoitia, J. S. Org. Lett. 2004, 6, 3409
.
(2) Bowser, A. M.; Madalengoitia, J. S. Tetrahedron Lett. 2005, 46,
Since we have previously provided evidence that the rate-
determining step appears to be the rearrangement step,2 our
focus became devising a strategy that would lower the energy
of activation of the rearrangement step. A review of the Claisen
rearrangement literature indicated that an electron-withdrawing
group at the 5-position accelerates the rate of the Claisen
rearrangement (Figure 1).4 We therefore hypothesized that
2869
.
(3) For examples of zwitterionic 3-aza-Claisen rearrangements see: (a)
Maruya, A.; 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. (e) Vedejs, E.; Gingras, M. J. Am. Chem. Soc. 1994,
116, 579
.
10.1021/ol802577z CCC: $40.75
Published on Web 01/06/2009
2009 American Chemical Society

the Baylis-Hillman reaction of the respective Michael
acceptors with formaldehyde.5 The alcohol 10c was synthe-
sized by the procedure described by Carpino.6 Acylation of
the alcohol functionality with p-NO2-benzoyl chloride and
Et3N gave the corresponding esters 11a-c. Benzoate dis-
placement in an SN2′-type fashion with pyrrolidine afforded
the rearrangement precursors 12a-c.5
The synthesis of rearrangement precursors 17a-c begins
with the Stille reaction of the corresponding benzoyl
chlorides 13a-c with tri-n-butylvinyl stannane to give the
arylvinylketones 14a-c.7 DABCO-catalyzed Baylis-Hillman
reaction of the unsaturated ketones 14a-c with formaldehyde
afforded the alcohols 15a-c. As before, acylation of the
alcohols 15a-c with p-NO2-benzoyl chloride gave the esters
16a-c. Finally, SN2′ displacement of the benzoate with
pyrrolidine afforded the rearrangement precursors 17a-c.
We have found that the p-NO2-benzoyl derived compound
17c is highly unstable and must be used immediately.
We are pleased to report that indeed tertiary allylic amines
bearing an electron-deficient alkene undergo facile 1,3-diaza-
Claisen rearrangements. The rearrangement reactions are
summarized in Tables 1 and 2. Tertiary allylic amine 12a
smoothly undergoes reaction with p-TsNCO in benzene at
reflux affording the urea 18 in 93% yield. Substrate 12b also
reacts with p-TsNCS in CHCl3 at room temperature giving
the thiourea 19 in 67% yield.8 We have reported that in the
case of azanorbornenes, isocyanates and isothiocyanates with
stronger electron-withdrawing groups are more reactive, and
the same trend is apparent with tertiary allylic amines bearing
an electron-deficient alkene. As an example, p-nitrophenyl
isothiocyanate reacts with substrate 12a affording the thiourea
20 in 78% yield, while phenyl isothiocyanate failed to yield
product under analogous conditions. The fact that none of
the alkyl-isocyanates or isothiocyanates we investigated
yielded the rearrangement product (data not shown) also
supported this trend. These rearrangements thus require an
electron-withdrawing substituent on the isocyanate or isothio-
cyanate.
Figure 1. Do electron-deficient alkenes accelerate zwitterionic
diaza-Claisen rearrangements in analogy to Claisen rearrangements?
tertiary allylic amines bearing an electron-withdrawing sub-
stituent at the analogous position would be better substrates for
zwitterionic 1,3-diaza-Claisen rearrangements.
The synthesis of the rearrangement precursors is shown
on Schemes 2 and 3. The alcohols 10a,b can be obtained by
Scheme 2
Scheme 3
In evaluating the scope of the reaction, we have found
that substrate 25 yielded only decomposition products when
subjected to rearrangement conditions with a number of
isocyanates. We suspect that amine 25 does indeed rearrange,
but the product eliminates and then undergoes decomposition.
The failed rearrangement of substrate 26 highlights that the
position of the electron-withdrawing substituent on the alkene
significantly affects the rate of the rearrangement.9 The
ketones 17a-c also undergo rearrangement affording the
rearrangement products 21-24. Similarly, the vinyl sulfone-
based rearrangement precursor 12c also underwent rear-
(4) Burrows, C. J.; Carpenter, B. K. J. Am. Chem. Soc. 1981, 103, 6983.
(5) Huang, H.; Liu, X.; Deng, J.; Qiu, M.; Zheng, Z. Org. Lett. 2006, 8,
3359.
(6) Philbin, M.; Carpino, L. A. J. Org. Chem. 1999, 64, 4315.
(7) Labadie, J. W.; Tueting, D.; Stille, J. K. J. Org. Chem. 1983, 48,
4634.
(8) For the synthesis of TsNCS, see: Barton, D.H. R.; Fontana, G.; Yang,
Y. Tetrahedron 1996, 52, 2705.
(9) Tsou, H.-R.; Overbeek-Klumpers, E. G.; Hallett, W. A.; Reich, M. F.;
M. Floyd, M. B.; Johnson, B. D.; Michalak, R. S.; Nilakantan, R.; Discafani,
C.; Golas, J.; Rabindran, S. K.; Shen, R.; Shi, X.; Wang, Y.-F.; Upeslacis,
J.; Wissner, A. J. Med. Chem. 2005, 48, 1107.
576
Org. Lett., Vol. 11, No. 3, 2009

Table 1. Reaction of Isocyanates and Isothiocyanates with
Table 2. Reaction of Substrate 12c with Iso(thio)cyanates
Various Tertiary Allylic Amines
Figure 2. Room-temperature reaction of 12a with TsNCO putatively
affords isourea 31 that on mild heating rearranges to the urea 18.
rangement with electron-deficient iso(thio)cyanates in modest
to excellent yields (Table 2).
In the course of these studies, we noted that when TsNCO
was allowed to react with tertiary allylic amine 12a at room
temperature, a product other than urea 18 quickly formed
within 15 min. We could not isolate this product but noted
that at room temperature it slowly converted to the urea 18,
and if heated to 50 °C, it would convert to the urea 18 within
1 h (Figure 2). We propose that the initial product is the
isourea 31 that in turn isomerizes to the urea 18.10 Thus, the
urea 18 arises from two [3,3]-sigmatropic rearrangements,
and it is possible that additional examples noted in Tables 1
and 2 also arise from two [3,3]-rearrangements.
rate of zwitterionic rearrangements, we sought to establish
if a stronger electron-withdrawing group favored a faster rate
of rearrangement.
To establish reactivity trends, we performed competition
experiments (Figure 3). When substrates 12a and 12c were
allowed to compete for limiting TsNCO, a 1.8:1 mixture of
products 18 and 27 was formed. If product 27 had formed
in excess, this would suggest that a stronger electron-
withdrawing group (SO2Ph > CO2Et) favored a faster
rearrangement rate. These results do not necessarily suggest
that a weaker EWG favors a faster rearrangement because
the steric differences between the substrates complicate the
picture. For example, comparison of chair transition states
33 and 34 (Figure 4) predicts that transition state 33 would
We have additionally investigated the influence of the
alkene electron-withdrawing substituent on the rate of the
rearrangement. Although the studies above demonstrate that
an electron-withdrawing group can significantly increase the
Org. Lett., Vol. 11, No. 3, 2009
577

favoring faster formation of product 18. These competition
studies are inconclusive because electronic effects (due to
the electron-withdrawing groups) may be offset by the steric
effects noted above. When the substrates 17a and 17b (that
are size matched) were allowed to compete for limiting
TsNCO, a 1:3.7 mixture of products 23 to 21 was obtained.12
These results thus suggest that a stronger electron-withdraw-
ing group (benzoyl vs p-methoxybenzoyl) favors a faster
rearrangement rate, but the results obtained with substrates
12b and 12c suggest that these electronic effects may be
offset by sterics.
In conclusion, these studies demonstrate the tertiary allylic
amines bearing electron-withdrawing substituents exhibit
dramatic rate acceleration toward formal zwitterionic 1,3-
diaza-Claisen rearrangements. The reasons for this accelera-
tion are not clear at this juncture but will be the focus of
future studies.
Figure 3. Competition experiments. Ratios were determined by
integration of 1H NMR spectra of product mixtures. All resonances
in the crude spectra could be assigned to either product or starting
material indicating minimal decomposition of products or starting
materials under reaction conditions.
Acknowledgment. Support for this work was provided
by CHE-041283 from the NSF.
Supporting Information Available: Experimental pro-
cedures for 14a, 15a-c, 16a-c, 17a-c, 18-21, 23-25, and
1
27-30 and H and 13C NMR spectra for representative
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL802577Z
Figure 4. Proposed mechanism for the reaction of heterocumulenes
with tertiary allylic amines 12b and 12c.
(10) A referee suggested that the rearrangement could proceed through
an ionic mechanism in which the zwitterionic intermediate fragments to a
urea anion/2-(ethoxycarbonyl)allyl cation pair that then recombines to give
the isourea 31. Although an ionic mechanism can not be ruled out for some
of the rearrangements/conditions, an ionic mechanism for the rearrangement
of 12b with TsNCO at rt is unlikely since dimethylallylamine and TsNCO
did not rearrange at rt and it could have proceeded through an allyl cation
that would be more electron-rich than the 2-(ethoxycarbonyl)allyl cation.
(11) According to Figure 4, the rate of formation of rearrangement
product ) k2[zwitterionic intermediate]. Thus, reaction conditions that
increase the concentration of the zwitterionic intermediate (i.e., neat
conditions, Table 1) should increase the overall rate of reaction.
(12) Although we initially synthesized the substrate 17c for comparison
with 17a and 17b in competition studies, its high lability made it unsuitable
for these studies.
be higher in energy than TS 34 due to the 1,3-diaxial
interaction of the larger SO2Ph group with the pyrrolidine
methylene. It is also worth noting that although the rear-
rangement is the rate-determining step the equilibrium for
the formation of the zwitterionic intermediate can not be
disregarded since the rate of formation of product )
k2[zwitterionic intermediate].11 Due to the steric differences
between 12b and 12c, it is expected that the concentration
of zwitterionic intermediate 31 would be lower than 32 thus
578
Org. Lett., Vol. 11, No. 3, 2009