Optimization of methods for the generation of carbodiimides for zwitterionic 1,3-diaza-Claisen rearrangements

Article abstract of DOI:10.1016/j.tetlet.2015.04.064

Strained, tertiary, allylic, amine 2-benzyl-2-azabicyclo[2.2.1]hept-5-ene reacts with in situ generated carbodiimides in a 1,3-diaza-Claisen rearrangement to afford structurally interesting bicyclic guanidines. Use of more electron deficient carbodiimides makes these rearrangements more facile; however, there are not sufficient methods for the synthesis of highly electron deficient carbodiimides. Herein reported is the exploration of the synthesis of such carbodiimides from parent ureas and isothioureas and their use in 1,3-diaza-Claisen rearrangements.

Full text of DOI:10.1016/j.tetlet.2015.04.064

Tetrahedron Letters 56 (2015) 3786–3789
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Optimization of methods for the generation of carbodiimides
for zwitterionic 1,3-diaza-Claisen rearrangements
⇑
Joel D. Walker, José S. Madalengoitia
Department of Chemistry, University of Vermont, Burlington, VT 05403, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Strained, tertiary, allylic, amine 2-benzyl-2-azabicyclo[2.2.1]hept-5-ene reacts with in situ generated car-
bodiimides in a 1,3-diaza-Claisen rearrangement to afford structurally interesting bicyclic guanidines.
Use of more electron deficient carbodiimides makes these rearrangements more facile; however, there
are not sufficient methods for the synthesis of highly electron deficient carbodiimides. Herein reported
is the exploration of the synthesis of such carbodiimides from parent ureas and isothioureas and their
use in 1,3-diaza-Claisen rearrangements.
Received 31 March 2015
Revised 15 April 2015
Accepted 17 April 2015
Available online 28 April 2015
Keywords:
Ó 2015 Elsevier Ltd. All rights reserved.
Carbodiimides
[3,3]-Sigmatropic rearrangements
Guanidines
Thioureas
Isothioureas
Ureas
Introduction
The reaction of in situ generated carbodiimides 4 (Fig. 1) with
aza-norbornenes affords zwitterionic intermediates that
undergo 1,3-diaza-Claisen rearrangement to afford bicyclic
5
6
a
guanidines 7. We have previously reported the in situ generation
of carbodiimides through the desulfurization of thioureas 1 with
either EDCI or the Mukaiyama salt.1,2 In this work, we explore
and compare alternate methods for the generation of carbodi-
imides through the dehydration of ureas 2 or desulfurization of
isothioureas 3. The motivation for undertaking this work is to
expand the scope of the reaction that is somewhat limited cur-
rently by the availability of thioureas. For example, while diacyl
thiourea is known,3 thioureas with more powerful electron with-
drawing groups on both nitrogens are unknown.
Results and discussion
Figure 1. Potential methods for the generation of carbodiimides and subsequent
reaction to afford bicyclic guanidines.
The ureas for this study were easily synthesized as shown in
Table 1. Urea 7a was synthesized through the reaction of Ns-NH2
with BnNCO under CuCl catalysis in 96% yield in order to avoid
potential Smiles rearrangement chemistry.4 Urea 7b was synthe-
sized through the reaction of Ts-NH2 with i-PrNCO using NaH as
a base in 95% yield. Ureas 7c and 7d were synthesized through
reaction of the corresponding n-hexyl and benzyl amines with
TsNCO in 91% and 84% yields, respectively. The synthesis of urea
7e required heating benzamide and TsNCO in toluene with pyri-
dine.5 Finally, urea 7f was synthesized through the reaction of
TfNH2 and BnNCO with NaH in 88% yield.
⇑
Corresponding author. Tel.: +1 802 656 8247.
E-mail address: jmadalen@uvm.edu (J.S. Madalengoitia).
http://dx.doi.org/10.1016/j.tetlet.2015.04.064
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

J. D. Walker, J. S. Madalengoitia / Tetrahedron Letters 56 (2015) 3786–3789
3787
Table 1
Synthesis of ureas
O
O
R2
R1
R2
R1
N
C
+
H2N
N
H
N
H
7a-f
Urea
Conditions
Yield (%)
7a: R1 = Bn, R2 = Ns
7b: R1 = i-Pr, R2 = Ts
10 mol % CuCl, DMF, rt, 20 h
NaH, THF, 0 °C
CH2Cl2, 0 °C
CH2Cl2, 0 °C
Toluene, reflux 4 h, pyridine
96
95
91
84
79
88
7c: R1 = Ts, R2 = n-hexyl
7d: R1 = Ts, R2 = Bn
7e: R1 = Bz, R2 = Ts
7f: R1 = Bn, R2 = Tf
NaH, THF, 0 °C to rt
The isothioureas were synthesized from known N-sulphonyl
S,S-dimethylcarbodithioimidates 8a and 8b.6,7 Reaction of 8a with
benzyl amine in methanol under reflux for 3 h afforded the isoth-
iourea 9a in 97% yield (Table 2). Isothioureas 9b and 9c were sim-
ilarly synthesized in 70% and 89% yields, respectively. In contrast,
N-Ts, N0-Bz isothiourea 9d was synthesized through deprotonation
of benzamide with NaH in THF, followed by reaction of the subse-
quent anion with 8a. We found the N-Tf S,S-dimethylcarbod-
ithioimidate 8b to be highly reactive such that the addition of
benzyl amine could take place at 0 °C in 30 min to afford the isoth-
iourea 9e in 75% yield.
Figure 2. Optimization of urea dehydration conditions.
With the synthesis of the urea and isothiourea carbodiimide
precursors in hand, we next turned our attention to exploring
methods for the dehydration of ureas. Several methods for the
dehydration of ureas have been reported in the literature.8–10 For
example, ureas have been dehydrated with the Burgess reagent,
CBr4/Ph3P, and TsCl, R3N.8–10 To the best of our knowledge, these
reagents have not been utilized to dehydrate ureas that possess
an electron withdrawing-group, let alone a powerful electron-
withdrawing group such as tosyl. To evaluate the dehydration
chemistry, rather than attempting to isolate a highly reactive N-
Ts, N0-alkyl carbodiimide, the dehydrations were carried out in
the presence of aza-norbornene 10 as a ‘trap’ for carbodiimide gen-
erated in the dehydration reaction.
phosgene. After addition of aza-norbornene 10, the reaction mix-
ture was allowed to warm to 0 °C. While the crude reaction mix-
ture looked clean by 1H NMR spectroscopy, the yield of
guanidine 11a after flash chromatography was only 45% and we
could not account for the mass balance despite various attempts
to modify the procedure. Finally, we attempted the dehydration
of urea 7d with phosgene and Et3N as the base in THF at 0 °C fol-
lowed by addition of aza-norbornene 10. This method at last
afforded the rearrangement product 11a in 71% yield after purifica-
tion. These conditions were subsequently applied to the dehydra-
tion of all ureas synthesized for this study (shown below).
The results that allow a comparison of the three different meth-
ods for carbodiimide generation (from thioureas, ureas and isoth-
ioureas) are summarized in Table 3. The data for carbodiimide
generation from thioureas with EDCI or the Mukaiyama reagent
have been previously reported,1,2 but is shown for comparison.
Overall, yields of bicyclic guanidine 11a were quite comparable
irregardless of whether the carbodiimide was generated from the
thiourea with EDCI, the urea with phosgene, or the isothiourea
with HgCl2. As for guanidines 11b and 11c, the yields are also com-
parable for all three methods, but the yields are slightly better
when the carbodiimide was generated from the thiourea with
EDCI.
The attempted dehydration of N-Ts, N0-Bn-urea 7d followed by
subsequent reaction of the generated carbodiimide with aza-nor-
bornene 10 is detailed in Figure 2. Neither the Burgess reagent,
nor CBr4/Ph3P afforded any rearrangement product when urea 7d
was subjected to these reagents in the presence of aza-norbornene
10. TsCl/Et3N did dehydrate urea 7d to some extent as the rear-
rangement product 11a was isolated in 30% yield. However, these
results signified that an alternative dehydrating method was
needed. We next attempted a one pot di-deprotonation of urea
7d with 2 equiv n-Buli at ꢀ78 °C followed by reaction with
Table 2
Synthesis of isothioureas
In stark contrast to the reactions noted above in which all meth-
ods for carbodiimide generation afforded rearrangement product,
the next set of reactions exhibited varied results. For example,
while the reaction of N-Tf, N0-Bn thiourea 12d afforded the guani-
dine 11d in 62% yield, the dehydration of urea 7f with phosgene
and the desulfurization of the isothiourea 9e with HgCl2 afforded
complex mixtures. We have found that the choice of solvent can
have a profound effect on the outcome of these reactions, but a
range of different solvents did not improve the reactions originat-
ing from urea 7f and isothiourea 9e. The next series incorporating
the Ns-group features only the dehydration of N-Ns, N0-Bn urea 7a.
The reactions originating from the corresponding thiourea and
isothiourea were not investigated since a search of the literature
did not reveal any N-Ns, N0-alkyl thioureas or isothioureas. We sus-
pect this is due to Smiles chemistry that is possible when using the
MeS
O
O
R1
R2
S
MeS
O
N
O
R1
N
H
N
R2
S
MeS
8a
NH2
: R = Ts
9a-e
8b: R = Tf
Isothiourea
Conditions
Yield (%)
9a: R1 = Ts, R2 = Bn
9b: R1 = Ts, R2 = i-Pr
9c: R1 = Ts, R2 = n-hexyl
9d: R1 = Ts, R2 = Bz
9e: R1 = Tf, R2 = Bn
MeOH, reflux, 3 h
97
70
89
51
75
MeOH, Et3N, reflux, 3 ha
MeOH, reflux, 3 h
NaH, THF, rt
MeOH, 0 °C, 30 min
a
Isopropyl amine hydrochloride was used instead of the free base.

3788
J. D. Walker, J. S. Madalengoitia / Tetrahedron Letters 56 (2015) 3786–3789
Table 3
Comparison of methods for carbodiimide generation for subsequent 1,3-diaza-Claisen generation
R2 R1
H
H
MeS
S
O
N
N
Bn
R2
R1
R2
R1
R2
R1
or
N
or
N
H
N
N
H
N
H
N
H
N
H
N
conditions
Bn
11a: R1 = Ts, R2 = Bn
11b: R1 = Ts, R2 = i-Pr
11c: R1 = Ts, R2 = n-hexyl
: R = Tf, R2 = Bn
1
11d
11e
11f
: R = Ns, R2 = Bn
1
: R1 = Ts, R2 = Bz
11g: R1 = Bz, R2 = Ts
Thiourea
Conditions
Yield
Urea
7d: R1 = Ts,
2 = Bn
7b: R1 = Ts,
2 = i-Pr
7c: R1 = Ts,
2 = n-hex
7f: R1 = Tf,
R2 Bn
7a: R1 = Ns,
2 = Bn
7e: R1 = Ts,
2 = Bz
Conditions
Yield
Isothio-Urea
Conditions
Yield
12a: R1 = Ts,
R2 = Bn
EDCI, EtNi-Pr2,
CHCl3, rt
EDCI, EtNi-Pr2,
CHCl3, rt
EDCI, EtNi-Pr2,
CHCl3, rt
Mukaiyama salt,
67%
(11a)
72%
(11b)
77%
(11c)
62%
COCl2, THF, 0 °C to rt, 71% (11a)
6 h
COCl2, THF, 0 °C to rt, 61% (11b)
6 h
COCl2, THF, 0 °C to rt, 67% (11c)
6 h
COCl2, THF, 0 °C to rt, Complex
9a: R1 = Ts,
2 = Bn
9b: R1 = Ts,
2 = i-Pr
9c: R1 = Ts,
2 = n-hex
9e: R1 = Tf,
2 = Bn
HgCl2, Et3N, THF, 69% (11a)
rt
HgCl2, Et3N, THF, 56% (11b)
rt
HgCl2, Et3N,
DMF, rt
HgCl2, Et3N,
DMF, rt
—
R
R
12b: R1 = Ts, R2
i-Pr
=
R
R
12c: R1 = Ts,
R2 = n-hexyl
12d: R1 = Tf,
R2 = Bn
67% (11c)
R
R
Complex
Mixture
—
EtNi-Pr2, CHCl3, rt (11d)
=
6 h
mixture
R
—
—
—
—
—
—
COCl2, Ch2Cl2, 0 °C to 78% (11e)
rt, 6 h
COCl2, THF, 0 °C to rt, Complex
R
—
R1 = Ts, R2 = Bz
HgCl2, Et3N,
CH2Cl2, rt
54% (11f)
36% (11g)
R
6 h
mixture
usual methods for the synthesis of thioureas and isothioureas.6,11
Dehydration of the N-Ns, N0-Bn urea 7a followed by reaction of
the subsequent carbodiimide with aza-norbornene 10 afforded
the guanidine 11e in 78% yield. The reaction of nosyl-urea 7a, thus
exemplifies how alternate methods for the generation of carbodi-
imides can expand the scope of the reaction if the corresponding
thiourea or isothiourea is not easily accessible.
The final entries in Table 3 correspond to the Ts-Bz-thiourea/
urea/isothioureas. It should be noted that the corresponding
N-Ts, N0-Bz thiourea is unknown, most likely due to its instabil-
ity,12 however, the corresponding N-Ts, N0-Bz urea 7e is known.
Unfortunately, the attempted dehydration of this urea with phos-
gene in the presence of aza-norbornene 10 afforded a complex
mixture. Out of this complex mixture we were able to isolate the
bicyclic ureas 16 and 17 (Fig. 3). In addition, a mass spectrum of
the crude reaction mixture revealed products of mass to charge
ratio = 422 (corresponding to guanidine 14, Fig. 3) and mass to
charge ratio = 472 (corresponding to guanidine 15). From these
data, we propose a plausible mechanism for the formation of these
products (Fig. 3). Dehydration of urea 7e affords the highly reactive
N-Ts, N0-Bz carbodiimide as expected. However, deprotonation of
either nitrogen of urea 7e by Et3N followed by addition of the
subsequent anions to N-Ts, N0-Bz carbodiimide would afford
the isomeric urea-guanidines 12 and 13. We propose that
urea-guanidine 12 eliminates TsNCO to afford guanidine 14
(detected by MS). TsNCO, in turn, reacts with aza-norbornene 10
through a 1,3-diaza-Claisen rearrangement to afford the isolated
urea 16. We additionally propose that urea-guanidine 13 also elim-
inates to afford BzNCO and guanidine 15 (detected by MS). BzNCO
then reacts with aza-norbornene 10 through a 1,3-diaza-Claisen
rearrangement to afford the urea 17. It is worth noting that the
reaction of BzNCO and TsNCO with aza-norbornene 10 affords
urea/isourea mixtures and that while we did not isolate the corre-
sponding isoureas they should have contributed to the complexity
of the reaction mixture. Overall, the factors that contribute to this
alternate undesired reaction pathway are the highly electrophilic
nature of the N-Ts, N0-Bz carbodiimide as well as the acidity of
the nitrogen protons of urea 7e.
The final entry, features the reaction of isothiourea 9d with
HgCl2 in the presence of aza-norbornene 10 which afforded the iso-
meric guanidines 11f and 11g in 54% and 36% yields, respectively,
(90% combined yield). This was another case in which the choice of
solvent was critical, with CH2Cl2 being the optimal solvent. The
regiochemical assignment was accomplished through NOE experi-
ments (Fig. 4). The hydrogens ortho to the sulfonyl group in isomer
11f exhibited an NOE enhancement with the ring junction and
alkene hydrogens, while in 11g, they exhibited an NOE enhance-
ment with the benzylic hydrogens. It is worth noting that it is
Figure 3. Proposed mechanism for the formation of compounds 14, 15, 16, and 17.

J. D. Walker, J. S. Madalengoitia / Tetrahedron Letters 56 (2015) 3786–3789
3789
and isothioureas, and subsequent reaction with aza-norbornene
10 afforded the corresponding bicyclic guanidines in comparable
yields. However, in the N-Tf, N0-Bn series, carbodiimide generation
from the urea and isothiourea only resulted in a complex mixture.
Only carbodiimide generation from the thiourea afforded bicyclic
guanidine 11d. In addition, dehydration of N-Ns, N0-Bn followed
by reaction with aza-norbornene 10 afforded the bicyclic guani-
dine 11e in 78% yield. The corresponding urea and thiourea in
the nosyl series are unknown. Lastly, in the N-Ts, N0-Bz series, only
desulfurization of the isothiourea 9d followed by reaction with
aza-norbornene 10 was the only method that afforded the corre-
sponding regioisomeric guanidines 11f and 11g in 90% combined
yield. The conclusion that can be drawn from these results is that
no one method for carbodiimide generation works effectively for
all carbodiimides.
Figure 4. Observed NOE enhancements for guanidines 11f and 11g.
Acknowledgments
Funding for this work was provided by grant CHE-1111694
from the NSF. Exact mass measurements were performed at the
UCI Mass Spec Facility and the Vermont Genetics Network through
grant 8P20GM103449.
Figure 5. Addition of the anion 18 to the highly electrophilic N-Ts, N0-Bz
carbodiimide would afford 19. This addition is most likely reversible allowing for
reaction of N-Ts, N0-Bz carbodiimide with aza-norbornene 10.
Supplementary data
somewhat unusual that the major product has the sulfonyl group
on the endocyclic nitrogen in contrast to the imine nitrogen. For
example, for guanidines 11a–11c, the only product we can detect
has the sulfonyl group on the imine nitrogen. In light of the com-
plex mixture obtained from the dehydration of urea 7e, it is inter-
esting that while this transformation proceeds through the same
highly electrophilic N-Ts, N0-Bz carbodiimide the products are
obtained in high overall yield. We hypothesize that this reaction
is so much cleaner because addition of the anion 18 (Fig. 5) to give
the intermediate 19 is reversible (while 19 cannot undergo an
elimination like urea-guanidines 12 and 13). Thus, N-Ts, N0-Bz car-
bodiimide can be regenerated from intermediate 19 for reaction
with aza-norbornene 10.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.04.
064.
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In this work, we have examined the generation of carbodiimides
for 1,3-diaza-Claisen rearrangements through desulfurization of
thioureas with EDCI, dehydration of ureas, and desulfurization of
isothioureas with HgCl2. Through the course of this work, we found
that ureas could be dehydrated with phosgene with Et3N as a base.
Generation of carbodiimides from N-Ts, N0-alkyl thioureas, ureas
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12. We have observed that highly electron-deficient thioureas are unstable. For
example, when we attempted the addition of p-nitro aniline to Pmc-NCS, we
always noted the presence of p-nitro aniline even after purification suggesting
that the resulting thiourea eliminates to reform Pmc-NCS and p-nitro aniline.
Flemer, S.; Madalengoitia, J. S. Synthesis 2007, 12, 1848.