Intramolecular Alkene Aminocarbonylation Using Concerted Cycloadditions of Amino-Isocyanates

Article abstract of DOI:10.1002/chem.201600574

The ubiquity of nitrogen heterocycles in biologically active molecules challenges synthetic chemists to develop a variety of tools for their construction. While developing metal-free hydroamination reactions of hydrazine derivatives, it was discovered that carbazates and semicarbazides can also lead to alkene aminocarbonylation products if nitrogen-substituted isocyanates (N-isocyanates) are formed in situ as reactive intermediates. At first this reaction required high temperatures (150-200 °C), and issues included competing hydroamination and N-isocyanate dimerization pathways. Herein, improved conditions for concerted intramolecular alkene aminocarbonylation with N-isocyanates are reported. The use of βN-benzyl carbazate precursors allows the effective minimization of N-isocyanate dimerization. Diminished dimerization leads to higher yields of alkene aminocarbonylation products, to reactivity at lower temperatures, and to an improved scope for a reaction sequence involving alkene aminocarbonylation followed by 1,2-migration of the benzyl group. Furthermore, fine-tuning of the blocking (masking) group on the N-isocyanate precursor, and reaction conditions relying on base catalysis for N-isocyanate formation from simpler precursors resulted in room temperature reactivity, consequently minimizing the competing hydroamination pathway. Collectively, this work highlights that controlled reactivity of aminoisocyanates is possible, and provides a broadly applicable alkene aminocarbonylation approach to heterocycles possessing the β-aminocarbonyl motif. Unusual cycloadditions: Rare N-substituted isocyanates are shown to provide efficient access to cyclic heterocycles containing β-aminocarbonyl motifs through an alkene aminocarbonylation reaction. This study includes an investigation using DFT and the development of several reaction variants. These provide controlled reactions of reactive N-isocyanate intermediates, resulting in milder conditions, improved yields, and a better substrate scope (see scheme).

Full text of DOI:10.1002/chem.201600574

DOI: 10.1002/chem.201600574
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Synthetic Methods |Hot Paper|
Intramolecular Alkene Aminocarbonylation Using Concerted
Cycloadditions of Amino-Isocyanates
Ryan A. Ivanovich, Christian Clavette, Jean-FranÅois Vincent-Rocan, Jean-GrØgoire Roveda,
Serge I. Gorelsky, and AndrØ M. Beauchemin*[a]
Dedicated to the memory of Professor Walter Lwowski
Abstract: The ubiquity of nitrogen heterocycles in biologi-
cally active molecules challenges synthetic chemists to de-
velop a variety of tools for their construction. While develop-
ing metal-free hydroamination reactions of hydrazine deriva-
tives, it was discovered that carbazates and semicarbazides
can also lead to alkene aminocarbonylation products if nitro-
gen-substituted isocyanates (N-isocyanates) are formed in
situ as reactive intermediates. At first this reaction required
high temperatures (150–2008C), and issues included com-
peting hydroamination and N-isocyanate dimerization path-
ways. Herein, improved conditions for concerted intramolec-
ular alkene aminocarbonylation with N-isocyanates are re-
ported. The use of bN-benzyl carbazate precursors allows
the effective minimization of N-isocyanate dimerization. Di-
minished dimerization leads to higher yields of alkene ami-
nocarbonylation products, to reactivity at lower tempera-
tures, and to an improved scope for a reaction sequence in-
volving alkene aminocarbonylation followed by 1,2-migra-
tion of the benzyl group. Furthermore, fine-tuning of the
blocking (masking) group on the N-isocyanate precursor,
and reaction conditions relying on base catalysis for N-isocy-
anate formation from simpler precursors resulted in room
temperature reactivity, consequently minimizing the com-
peting hydroamination pathway. Collectively, this work high-
lights that controlled reactivity of aminoisocyanates is possi-
ble, and provides a broadly applicable alkene aminocarbony-
lation approach to heterocycles possessing the b-aminocar-
bonyl motif.
Introduction
Conversely, metal-free reactions allowing effective CÀN bond
formation from simple and readily accessible reagents have
also attracted significant interest in recent years.[5]
The abundance and importance of nitrogen-containing func-
tional groups in biologically active molecules such as natural
products,[1] agrochemicals[2] and pharmaceuticals[3] cannot be
overstated. It is therefore no surprise that numerous CÀN
bond-forming reactions of alkenes, such as aminohydroxyla-
tion, hydroamination, aziridination, aminocyanation, and ami-
noboration, have been developed to meet the synthetic de-
mands of these increasingly complex nitrogen-rich products.
Many of these synthetic transformations remain of high aca-
demic and industrial interest,[4] to improve the reaction scope
for both intra- and intermolecular variants, increase reaction ef-
ficiency or develop enantioselective processes. While these
processes have relied on a variety of activation modes, cataly-
sis is generally required to overcome the high activation
energy typically associated with amination reactions of alkenes.
In our efforts to develop metal-free alkene amination reac-
tions, we have demonstrated the utility of bifunctional re-
agents for the formation of CÀN bonds from alkenes, alkynes
and allenes under metal-free, thermal conditions.[6,7] In particu-
lar, hydroxylamines proved to be effective reagents for intra-
and intermolecular Cope-type (concerted) alkene hydroamina-
tions.[6] However, the instability of hydroxylamines upon heat-
ing at approximately 1008C led to the development of related
reactivity with other bifunctional reagents possessing in-
creased thermal stability. This led to the discovery that hydra-
zine derivatives also engage in concerted, Cope-type hydroa-
mination reactions of alkenes and alkynes.[7] However, the
need to heat at higher temperatures (up to 2008C) in some
systems resulted in divergent reactivity:[7b] both alkene hydroa-
mination and aminocarbonylation[8] reactions were observed
with some hydrazine derivatives (Scheme 1).
[a] R. A. Ivanovich, C. Clavette, J.-F. Vincent-Rocan, J.-G. Roveda,
Dr. S. I. Gorelsky, Prof. Dr. A. M. Beauchemin
Unexpectedly, at elevated temperatures, carbazate (X=OR4,
Scheme 1) and semicarbazide (X=NR3 ) reagents generated
Centre for Catalysis Research and Innovation
2
Department of Chemistry and Biomolecular Sciences
University of Ottawa, 10 Marie-Curie, Ottawa, ON, K1N 6N5 (Canada)
E-mail: andre.beauchemin@uottawa.ca
a rare and highly reactive intermediate in situ. This nitrogen-
substituted isocyanate (N-isocyanate) could then engage in
a [3+2] cycloaddition reaction with the terminal alkene. From
the perspective of the alkene, this reactivity is an intramolecu-
lar alkene aminocarbonylation[8] process, and synthetically this
Supporting information and ORCID from the author for this article are
available on the WWW under
http://dx.doi.org/10.1002/chem.201600574.
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Figure 1. Pharmaceuticals and natural products possessing cyclic b-amino-
carbonyl motifs.
Scheme 1. Divergent reactivity of hydrazine derivatives: hydroamination
(above) and aminocarbonylation (below) reactivity. P.T. =proton transfer.
carbonylation. To the best of our knowledge, the intramolecu-
lar aminocarbonylation reaction of N-isocyanates shown in
Scheme 1 is unique as it relies on a concerted [3+2] cycloaddi-
tion to afford the aminocarbonylation products, and does not
rely on external reagents or catalysts.
provides access to cyclic b-aminocarbonyl products. Such
products are present in a variety of natural products and
small-molecule drugs (Figure 1). b-Amino acids are also used
as building blocks to assemble synthetic peptides.[9] In general,
the usefulness of b-aminocarbonyl motifs, the scarcity of reac-
tions allowing the transformation of alkenes into b-aminocar-
bonyls and the fact that reactions involving N-isocyanates are
rare prompted further study of this alkene aminocarbonylation
reactivity.
This concerted reactivity of amino-isocyanates is also a rare
example of a reaction occurring through an N-isocyanate.
There are only few reports in the literature of the reactivity of
these amphoteric (ambident) isocyanates, probably due to
their tendency to dimerize at temperatures as low as À408C if
Despite the importance of the b-aminocarbonyl
motif, intramolecular alkene aminocarbonylation re-
actions are quite rare: only few examples exist in the
literature (Scheme 2). Hegedus reported the first ex-
amples, initially under conditions that required stoi-
chiometric quantities of palladium.[10a,b] However,
a subsequent report disclosed that a palladium-cata-
lyzed variant was possible using olefinic tosylami-
des.[10c] Tamaru and Yoshida further improved this re-
activity with the use of Wacker-type conditions, in
which an external oxidant allowed the process to
proceed with catalytic palladium and with a broader
range of substrates.[11a] Continued work by this group
led to the discovery of conditions for the synthesis of
6-membered rings, an important advance since all
previous examples were limited to 5-membered pro-
ducts.[11b] Unfortunately, the reactions were difficult
to control and a mixture of cyclic (A) and acyclic (B)
aminocarbonylation products were often obtained.
Recently, Sasai reported the first enantioselective in-
tramolecular aminocarbonylation reaction using alke-
nylureas.[12] Alternatively, Livinghouse developed an
approach by a metalloamination/cyclization reaction,
which relies on an anionic mechanism for the cycliza-
tion step and on a subsequent Fukuyama coupling
to provide the desired aminocarbonylation prod-
ucts.[13] A few other routes have also been studied,[14]
and intramolecular aminocarbonylation reactions
have even been the key step in syntheses of natural
products[15] but as for the examples highlighted
above, these reports typically necessitate the use of
metal catalysis and an external source of CO for the Scheme 2. Review of intramolecular aminocarbonylation reactions.
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the nitrogen atom is sp3-hybridized.[16j] There are also impor-
tant limitations on the methods to generate N-isocyanates. In
a remarkable report however, Lwowski used an amino-isocya-
nate (Me2N-NCO) in intermolecular alkyne aminocarbonyla-
tions.[13b] Since our initial report on alkene aminocarbonylation
using amino-isocyanates,[7b] our group has expanded the use
of blocked (masked) isocyanate precursors to form N-isocya-
nates in situ. This approach has led to increased control of N-
isocyanate reactivity, and allowed their generation at lower
temperatures. Synthetically, this enabled the development of
intermolecular aminocarbonylation reactions of imino-isocya-
nates,[17] as well as many cascade reactions for the synthesis of
NNCO-containing molecules.[18]
Table 1. Thermolysis of hydrazine derivatives: hydroamination versus
aminocarbonylation.[a]
Entry
X
T [8C]
t [h]
Product (yield [%])[b]
1
2
3
4
5
6
7
8
Ph (1a)
120
150
170
140
200 (mW)
200 (mW)
150 (mW)
200 (mW)
18
16
42
16
0.5
0.5
0.5
0.25
2a (93)
2b (66)
2c (64)
2d (25)+3a (6)
2d (13)+3a (46)
2e (0)+3a (71)
2 f (50)+3a (20)[c]
2 f (10)+3a (85)[c]
tBu (1b)
2-pyridyl (1c)
OEt (1d)
OEt (1d)
OtBu (1e)
NH2 (1 f)
NH2 (1 f)
From a reaction development perspective, amino-isocya-
nates are probably the most difficult N-isocyanate reagents to
work with due to the relatively high nucleophilicity of the b-ni-
trogen atom. Using hydrazine-derived amino-isocyanate pre-
cursors, efforts to expand the intramolecular aminocarbonyla-
tion reactivity shown in Scheme 1 were met with tremendous
difficulty, due to competing homodimerization of the N-isocya-
nate or intramolecular hydroamination side-reactions. Howev-
er, a thorough survey of blocked (masked) isocyanate precur-
sors and milder conditions were expected to provide increased
control of N-isocyanate formation, and consequently minimize
dimerization. Herein, a detailed account of efforts to improve
their intramolecular aminocarbonylation reactivity is provided.
Specifically, improved reactivity proved possible through:
1) The use of bN-benzylated carbazates in an aminocarbonyla-
tion/1,2 benzyl shift cascade; 2) The use of N-isocyanate pre-
cursors with more labile leaving groups; and 3) The use of
base catalysis to perform alkene aminocarbonylation at lower
temperatures.
[a] Conditions: heating performed in PhCF3 (0.05m, sealed tube) using
conventional heating or microwave irradiation (mW). [b] Isolated yield.
[c] NMR yield using 1,4-dimethoxybenzene as internal standard.
Table 2. Preliminary substrate scope of aminocarbonylation reaction.[a,b]
LG=OtBu, 70% (3a)
LG=NH2, 86% (3a)
LG=OtBu, 74% (3b)[c]
LG=NH2, 84% (3b)[c]
Results and Discussion
During the initial optimization of hydroamination reactivity
with hydrazine derivatives, interesting results were obtained
with carbazates 1d and 1e (Table 1). An unexpected com-
pound formed in addition to the hydroamination products
(2d, e), and was later identified as aminocarbonylation product
3a. The formation of this product was hypothesized to occur
from a reactive intermediate: a nitrogen-substituted isocyanate
(N-isocyanate). Initial reaction optimization revealed that in-
creased temperatures resulted in a higher yield of the amino-
carbonylation product. Naturally, this provoked interest in the
ability of semicarbazides to undergo a similar transformation,
which led to the synthesis of semicarbazide 1 f. Preliminary re-
sults suggested that semicarbazides were more stable amino-
carbonylation precursors: hydroamination was more prevalent
at 1508C (entry 7), while aminocarbonylation was favored at
2008C (entry 8).
LG=OtBu, 66% (3c)
LG=NH2, 52% (3c)[d]
LG=OtBu, 71% (3d)
[a] Conditions: heating performed in MeCN (2008C, 0.5 h, 0.05m, micro-
wave reactor). [b] Isolated yield. [c] 2:1 d.r.; [d] NMR yield using 1,4-dime-
thoxybenzene as internal standard; 13% of epimer 3d was also present.
It was noted that products 3a, b formed in higher yield
from the corresponding semicarbazide precursors. Both precur-
sors for 3b (LG=OtBu and NH2) provided the aminocarbonyla-
tion product 3b with very similar diastereoselectivity (ca. 2:1
d.r.), an observation that is again consistent with a common
amino-isocyanate intermediate. The reaction also tolerated
substitution at the alkene distal position (products 3c, d), with
slight epimerization (4:1 d.r.) of product 3c when it was gener-
ated from the corresponding semicarbazide (1j). The structure
of 3c was unambiguously assigned through derivatization (see
the Supporting Information). Interestingly, the reaction was
stereospecific: the stereochemical information present in the
cis- and trans-substituted alkene was transferred to the result-
ing aminocarbonylation product. This observation is important
as it provides insight towards the mechanism of the transforma-
Knowing that both carbazates and semicarbazides engaged
in this aminocarbonylation reaction, the synthetic scope was
explored with the hope of gaining insights into this unknown
reactivity (Table 2). As such, a comparative study using several
related substrates was first conducted with distinct carbonyl
substituents (LG=OtBu, and NH2).
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tion. Indeed, the stereospecificity of this reaction strongly sug-
gested a concerted (syn) aminocarbonylation reaction.
In summary, two conclusions could be drawn from this initial
survey. First, the convergent reactivity observed with both car-
bazate and semicarbazide reagents supported the involvement
of a common intermediate. Second, the cycloaddition (amino-
carbonylation) of this intermediate is likely concerted. A nitro-
gen-substituted isocyanate (amino-isocyanate) was suggested
as the intermediate involved in the aminocarbonylation reac-
tion [Eq. (1)].
step from the resulting aminocarbonylation dipole intermedi-
ate (DG° =33.3 kcalmolÀ1), which is reminiscent of studies per-
formed on Cope-type hydroaminations.[7] However, only this
difficult (intramolecular) proton-transfer pathway was investi-
gated, and it is likely that more facile pathways are accessible.
Overall, the DFT calculations suggested that despite the neces-
sity for harsh thermal conditions to form the N-isocyanate (up
to 2008C), the subsequent alkene cycloaddition (aminocarbony-
lation) should be quite favorable and could occur at room tem-
perature. Therefore, calculations also suggested that the gener-
ation of N-isocyanate was rate-determining for the transforma-
tion.
Combining the insights gained from DFT calculations
(Figure 2) with conclusions from pioneering work on the gen-
eration of N-isocyanates from the literature,[16] efforts were ini-
tiated towards an improved aminocarbonylation process.
These targeted new aminocarbonylation precursors, and the
study of their reactivity under thermolytic conditions, to identi-
fy milder aminocarbonylation conditions.
To account for the observed stereospecificity, addition of the
amino-isocyanate to the alkene was suggested to undergo
a [3+2] cycloaddition. The possibility that a N-isocyanate
would be formed upon thermolysis of carbazate or semicarba-
zide precursors was consistent with the literature on N-isocya-
nates,[16a,d,e] and Lwowski’s prior report of intermolecular cyclo-
additions with electron-poor alkynes also supported this hy-
pothesis.[16b] However, since N-isocyanates are reactive inter-
mediates that are difficult to isolate,[16k,l] DFT calculations
emerged as an ideal approach to probe this possibility. The re-
sults of exploratory calculations are shown in Figure 2.
Due to the known propensity of N-isocyanates to undergo
a competing dimerization at temperatures as low as À408C,[16j]
minimizing this side reaction was considered to be crucial to
achieve a milder, and a more broadly applicable aminocarbo-
nylation reaction. Although N-isocyanate dimers can undergo
cycloreversion and regenerate the reactive intermediate, this
typically only occurs upon heating.[16i] With this in mind, the
desired precursor would either need to be unlikely to undergo
N-isocyanate dimerization; or readily undergo cycloreversion.
Therefore, we turned our attention to the nature of N-alkyl
substitution on N-isocyanate derivatives. The added steric hin-
drance of dialkyl N-isocyanates over their monoalkyl counter-
parts was expected to slow the rate of dimerization, thereby
increasing the yields of aminocarbonylation products. Addi-
tionally, assessment of Lwowski’s work[16b] suggested that hin-
dered ammonium ylides undergo cycloreversion more readily
to regenerate the reactive N-isocyanate [Eq. (2)].[19] Further-
more, the added N-alkyl substituent could increase the HOMO
energy of the nitrogen atom participating in the cycloaddition,
resulting in a more reactive aminocarbonylation reagent. Final-
ly, substituting a hydrogen atom for an alkyl group would re-
quire the zwitterionic ammonium ylide generated from the in-
tramolecular [3+2] to undergo a 1,2-alkyl-shift. bN-Benzyl car-
bazates emerged as an ideal candidate, fulfilling the steric and
electronic demands above in conjunction with the fact that
benzyl groups can undergo a 1,2-rearrangement under thermal
conditions comparable to that of our initial aminocarbonyla-
tion process.[20]
Support for a concerted cycloaddition was obtained, indeed
an asynchronous cycloaddition transition state was found to
possess an activation energy of 19.1 kcalmolÀ1 from the N-iso-
cyanate. In comparison to the N-isocyanate intermediate, the
transient ammonium ylide intermediate is slightly less stable
(DG=2.4 kcalmolÀ1), but the overall reaction after proton
transfer was found to be thermodynamically favorable by
DGr =À17.6 kcalmolÀ1. However, calculations also revealed the
difficulty associated with an intramolecular proton-transfer
Figure 2. Proposed reaction pathway of intramolecular aminocarbonylation
via a N-isocyanate intermediate investigated by DFT calculations (at the
B3LYP/TZVP level of theory) including calculated gas-phase energies (above),
and transition state structure for the intramolecular alkene aminocarbonyla-
tion with N-isocyanate (below). Internuclear distances [Š] are shown for rele-
vant chemical bonds. P.T. =proton transfer.
Presented in Table 3 is a comparison of the reactivity of
monoalkenyl carbazates (R1 =H) to that of bN-benzylated car-
bazates (R1 =Bn). Under standard aminocarbonylation condi-
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tions (2008C), monoalkenyl carbazate 1e provided the amino-
carbonylation product 3a in good yield (Table 3, entry 1). In
turn, preliminary results from N-benzyl alkenyl carbazate 1l
provided excellent yield for the [3+2]/1,2-rearrangement se-
quence (3e) at 2008C (entry 2).
To gain insight on the 1,2-rearrangement step, the tempera-
ture was decreased to 1508C with several substrates (Table 3,
entries 3, 7 and 9). Using carbazate 1l at 1508C (entry 3), pro-
vided a mixture of the desired [3+2]/1,2-rearrangement cas-
cade (3e) and the corresponding ammonium ylide precursor
(4e). This provided the proof that this sequence could be used
as a tool to improve aminocarbonylation reactivity. We ques-
tioned whether bN-benzyl substrates could enable more chal-
lenging reactions. In a prior survey, efforts were devoted to
cyclizations forming 6,5-bicyclic ring systems. Unfortunately,
monoalkenyl carbazates and semicarbazides (1m and 1n)
could not provide the desired 6,5-bicyclic product (entries 4
and 5), since aminations to form 6-membered ring systems are
in general significantly more challenging than related 5-mem-
bered forming cyclizations. Comparatively, N-benzyl precursor
1o cyclized in nearly quantitative yield to the desired 6,5-bicy-
clic product at 2008C (entry 6). The temperature of the reac-
tion was then lowered to 1508C (entry 7), upon which only the
desired product was obtained, albeit in lower yield, with no
traces of the ammonium ylide. Encouragingly, bN-benzylation
could expand the synthesis of 6,5-bicyclic substrates to include
morpholine-based bicyclic derivative 3h (entry 8 and 9) in ex-
cellent yield. In this case, generation of 3h proved optimal at
lower temperature (1508C) and could be obtained in nearly
quantitative yield (entry 9).
Table 3. Aminocarbonylation with mono- and bisalkyl carbazate precur-
sors.[a]
Entry
LG
R1
T [8C] Yield [%] (product)[b]
1
2
3
OtBu
R1 =H (1e)
R1 =Bn (1l)
R1 =Bn (1l)
200
200
150
0 (4a)
0 (4e)
49 (4e)
74 (3a)
90 (3e)
24 (3e)
4
5
6
7
OtBu
NH2
OtBu
OtBu
R1 =H (1m)
R1 =H (1n)
R1 =Bn (1o)
R1 =Bn (1o)
200
200
200
150
0 (4 f)
0 (4 f)
0 (4g)
0 (4g)
0 (3 f)
0 (3 f)
99 (3g)
66 (3g)
To elucidate the effects of bN-benzylation on aminocarbony-
lation, the reactivity was expanded to other benzylic substrates
(entries 10–12). Investigations began with monoalkenyl carba-
zate 1q. Arguably this carbazate allows to probe the electronic
and steric influence of the benzyl group also present in benzyl-
ic precursors such as 1l. Encouragingly, the 2-phenyl substitut-
ed product 3i could be obtained in good yield (76%,
entry 10), a result similar to that of unsubstituted product 3a
(74%, entry 1). Carbazate 1r also provided its aminocarbonyla-
tion product 3j (entry 11), albeit in modest yield after heating
for 30 min and improved yield after 2 h (entry 12). It should be
noted that solubility issues could have contributed to the di-
minished reactivity of 1r, and this limits the conclusions that
could be drawn from entries 11 and 12. The investigation was
then expanded to substrates possessing internal alkenes. In
our initial survey, yields were fairly consistent with these sub-
strates (3c, d, Table 2). In contrast, bN-benzylated cis and trans
methyl-alkenyl carbazates 1s and 1t cyclized in modest yields
(3k, l, entries 13 and 14), despite several optimization at-
tempts. However, again the aminocarbonylation event in this
reaction sequence proved stereospecific.
8
9
OtBu
OtBu
(1p)
(1p)
200
82 (3h)
98 (3h)
150[c]
10
(1q)
200
76 (3i)[d]
11
12
OtBu
(1r)
(1r)
200
200[e]
40 (3j)
55 (3j)
Overall, the data shown in Table 3 show that the [3+2]/1,2-
rearrangement sequence developed with N-benzyl substrates
is more efficient for challenging reactions. Possible explana-
tions for this improved reactivity include that substitution is in-
creasing the HOMO of the b-nitrogen, minimizing N-isocyanate
dimerization, and/or favoring cycloreversion of an isocyanate
dimer similar to Equation (2) above. A more facile cyclorever-
sion is an attractive explanation, as it would allow the dimer to
reform the reactive N-isocyanate and undergo aminocarbonyla-
13
14
OtBu
R3 =Me, R4 =H (1s) 200
R3 =H, R4 =Me (1t)
44[f] (3k)
43[f] (3l)
[a] Conditions: heating performed in PhCF3 (0.5 h, 0.05m, microwave re-
actor) unless indicated otherwise. [b] Isolated yields unless noted other-
wise. [c] Heated for 6 h. [d] Obtained as a mixture of diastereomers (3:2
d.r.). [e] Heated for 2 h. [f] NMR yield using 1,3,5-trimethoxybenzene as in-
ternal standard P.T. =proton transfer.
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tion. Wentrup has shown that dimerization of sp3-hydridized
N-isocyanates occurs at low temperatures (À408C).[13j] Lwowski
also reported that cycloreversion of hindered N,N-dialkyl amini-
mides [Eq. (2)] occurs at appreciable rates between 60 and
110 8C.[16b] The observation of the ammonium ylide (4e,
entry 3) at 1508C suggests that the 1,2-benzyl migration is rel-
atively slow, and this could allow for cycloreversion to the N-
isocyanate to occur. Finally, the lower efficiency of the reaction
with internal alkenes could also be rationalized by invoking
the stability of the parent ammonium ylide intermediate.
Indeed, DFT calculations indicated that forming this intermedi-
ate was already thermodynamically uphill with a terminal
alkene (by 2.4 kcalmolÀ1, see Figure 2) and would therefore be
more difficult with more stable, internal alkenes. This implies
more reversibility for the alkene aminocarbonylation step rela-
tive to the 1,2-rearrangement, and could allow for other side-
reactions to compete with the desired reaction sequence.
Although bN-benzylated substrates provided access to more
complex aminocarbonylation products, additional complica-
tions arose as more complex substrates were synthesized. Pre-
sented in Table 4 are substrates that failed to perform a selec-
tive aminocarbonylation reaction. Indeed, Cope-type hydroami-
nation (hydro-hydrazination[8]) proved to be a competing side-
reaction with select substrates.
proved over their monoalkenyl equivalents (1w and 1x, re-
spectively). More specifically, 30% aminocarbonylation was ob-
served with 1u and 21% with 1v, while Thorpe–Ingold influ-
enced monoalkenyl carbazates 1w and 1x only showed 22
and 0% aminocarbonylation, respectively. Since a modest in-
crease of aminocarbonylation was observed with bN-benzyla-
tion and no evidence of hydroamination was detected by NMR
spectroscopy, we were initially excited to have apparently sup-
pressed the competing hydroamination reaction. This excite-
ment dissipated proceeding exhaustive attempts to further in-
crease the yield of the aminocarbonylation reaction. This indi-
cated that, although bN-benzylation could increase aminocar-
bonylation, indiscriminately favoring cyclization ultimately
could not provide a broadly applicable aminocarbonylation re-
action (see Supporting Information, Table S6 for a full list of
failed attempts). Collectively, these examples of failed reactions
demonstrate the need for new aminocarbonylation reagents
that could react below the threshold temperatures required
for hydro-hydrazination (roughly 808C),[7c,18a] or decomposition
pathways that are consistent with uncontrolled benzyl-group-
transfer reactions.
The search for milder aminocarbonylation conditions led to
the consideration of other methods of isocyanate formation.
Phosgenation of hydrazine was attractive given that the subse-
quent acylation products are known to release isocyanates at
room temperature.[21] Unfortunately, hydrazine synthesis can
be challenging due to chemoselectivity issues inherent to pos-
sessing two nucleophilic nitrogen atoms.[22] Gratifyingly, TFA-in-
duced Boc-deprotection of the bN-benzyl carbazate precursors
provided the required unsymmetrical hydrazines, which in turn
could be treated with phosgene equivalents. These substrates
allowed N-isocyanate formation under mild conditions, due to
the lability of the resultant blocking group following acylation.
Results from this survey are presented in Table 5.
Table 4. Selected reactions showcasing hydroamination as a significant
side-reaction.[a]
As predicted by DFT, mild N-isocyanate formation enabled
room temperature aminocarbonylation. The products were ob-
tained in the form of zwitterionic dipole 5a since 1,2-benzyl
migration could not occur at room temperature (Table 5).
Oxalyl chloride provided a modest yield of the desired amino-
carbonylation product (entry 1) whereas no product could be
observed upon treatment of bisalkyl hydrazine with p-nitro-
phenyl chloroformate (entry 2). Other phosgene equivalents re-
acted more effectively. Carbonyldiimidazole (CDI) resulted in
an excellent yield of product 5a at room temperature (entry 3).
Compared to other acylating agents, CDI was slower to form
the N-isocyanate. To overcome the long reaction time, temper-
ature was increased, but this resulted in lower yields (entry 4
and 5). This negative effect could be explained either by a re-
versible aminocarbonylation reaction or by a higher N-isocya-
nate concentration, making the reaction more prone to isocya-
nate dimerization. Triphosgene provided excellent yield of the
desired product (entry 6). Excess DMAP was used both as
a base (given the formation of two equivalents of HCl upon re-
action with phosgene) and as a potential catalyst.[21a] Unfortu-
nately, this method used to achieve room temperature reactivi-
ty is not practical. For one, Boc-deprotection with TFA is diffi-
cult to control given the resulting product’s ability to undergo
[a] Conditions: heating performed in PhCF3 (2008C, 0.5 h, 0.05m, micro-
wave reactor), NMR yields using 1,3,5-trimethoxybenzene as internal stan-
dard.
In general, hydroamination was a competing side-reaction
for substrates possessing exhibiting a strong conformational
bias (Table 4). For the case of bN-benzyl Thorpe–Ingold biased
substrates 1u and 1v, the yield of aminocarbonylation was im-
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Table 5. Intramolecular aminocarbonylation by acylation of a N,N-dialkyl
hydrazine.[a]
Table 6. Scope of intramolecular alkene aminocarbonylation with O-Ph
carbazates.[a]
Entry
1
Substrate
T
[8C]
Products
Yield
[%][b]
Entry
Reagent
T
[8C]
t
[h]
Yield
[%][c]
1y
120
120
120
(3a) 28
(3b) 70
(3i) 60
1
2
RT
RT
1
32
2
3
1z
1
0
3
4
5
RT
12
12
3
81
62
16
40[b]
60[b]
1aa
6[d]
RT
1
93
[a] Conditions: performed in PhCF3 in a sealed tube (0.05m). [b] Conven-
tional heating was used. [c] NMR yield using 1,3,5-trimethoxybenzene as
an internal standard. [d] 5.0 equivalents of DMAP was added to the reac-
tion.
4
1bb
1cc
120
(3n) 35
5
6
7
120
150
200[d]
(3j) 20[c]
(3j) 50[c]
(3j) 75
side-reactions (such as acid-catalyzed hydroamination). Ulti-
mately, TFA deprotection followed by basic quench of the re-
action could only provide moderate yield of the corresponding
free hydrazine. Additionally, the resulting dipole product from
this aminocarbonylation sequence could not be isolated by
chromatography.
8
1dd
200[d]
(3q) 95
The study of intramolecular alkene aminocarbonylation led
to the realization that although the objectives initially estab-
lished were achieved, the reactivity developed still had impor-
tant synthetic limitations. However, several conclusions regard-
ing the use of bN-benzyl carbazates could be made: 1) They
are more reactive than their monoalkyl counterparts under
thermolysis; 2) They are capable of achieving room tempera-
ture reactivity with suitable N-isocyanate precursors; and
3) They have enabled the synthesis of 6,5-bicyclic systems by
alkene aminocarbonylation. However, the reaction still suffered
from a relatively limited scope, and difficult synthesis of the re-
quired starting materials. With these issues in mind, carbazate
precursors with more labile leaving groups (e.g., LG=O-Ph)
were targeted. Such carbazates would be less susceptible to
hydroamination side-reactions, since milder formation of the
N-isocyanate would allow exploration of the aminocarbonyla-
tion reactivity of monoalkyl N-isocyanates at lower tempera-
tures (Table 6).
[a] Conditions: heating performed in PhCF3 (2 h, 0.05m, microwave reac-
tor) unless indicated otherwise. [b] Isolated yields. [c] NMR yield using
1,3,5-trimethoxybenzene as an internal standard. [d] Heating for 0.5 h.
P.T. =proton transfer.
dom (entries 7 and 8). The remaining mass balance for most
entries in Table 6 was found to be N-isocyanate dimers. The
use of more labile blocking groups (i.e., O-Ph vs. OtBu) would
facilitate N-isocyanate formation and potentially increase their
concentration, thus promoting isocyanate dimerization. Under
these milder conditions, a large dependence on steric hin-
drance of the N-isocyanate intermediate was noted (3a vs. 3b
and 3i). A high-yielding, selective aminocarbonylation reaction
with Thorpe–Ingold biased substrate (entry 4) was still impossi-
ble, since hydroamination reactivity was operating at lower
temperatures than N-isocyanate formation in this system. How-
ever, the yield of styrene-derived carbazate was increased to
afford the fused tricyclic core in 20% higher yield than using
OtBu carbazate (Table 3, entries 11 and 12). Furthermore, the
use of O-Ph carbazate also enabled the efficient synthesis of
tricyclic product 3q through a challenging cyclization forming
the 6,5-ring system, a cyclization that was impossible from the
corresponding OtBu carbazates.
Using O-Ph as the N-isocyanate blocking group, efficient in-
tramolecular aminocarbonylation reactions were achieved with
several substrates (Table 6). The reactions of a-substituted sub-
strates were more efficient at a lower temperature (1208C, en-
tries 2 and 3), and increased yields at higher temperature were
observed for substrates possessing less conformational free-
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With more control over N-isocyanate generation and reactiv-
ity, efforts were devoted to explore recently developed base-
catalyzed N-isocyanate formation procedures of O-Ph substitut-
ed carbazates (Table 7).[18e] The optimization of room tempera-
ture reactivity began with methyl-substituted carbazate 1z,
and a variety of organic and inorganic bases were screened
(see Supporting Information Table S2). Although several bases
were able to form the N-isocyanate under catalytic or stoichio-
metric conditions, only dimerization was observed. Under con-
ditions where the dimerization reaction would be operating
(i.e., lower temperatures) it was hypothesized that more steri-
cally hindered N-isocyanates would be less prone to dimerize.
Encouragingly, using a substrate with a larger substituent at
the R1 position (R1 =Ph, carbazate 1aa) led to a 10% amino-
carbonylation yield at room temperature with 1.0 equiv K3PO4
(Table 7). This result supported that steric hindrance near the
b-nitrogen of the N-isocyanate could help minimize dimeriza-
tion and promote aminocarbonylation.
ture using 1.0 equiv K3PO4 with substrate 1bb displaying
a Thorpe–Ingold bias and, importantly, no competing hydroami-
nation was observed (Table 7, entry 4). From this point, bases
were further screened and 20 mol% DBU emerged as an addi-
tive that provided a similar yield to the reaction with K3PO4
(see Supporting Information Table S3). The following trends
were noted: when loadings of base increased or when stron-
ger bases were used, the amount of the N-isocyanate dimeriza-
tion byproduct increased; however, when the loadings of base
were decreased starting material remained. This was expected,
since increased base loadings or the use of stronger bases
would increase the concentration of N-isocyanates in situ, re-
sulting in increased isocyanate dimerization. Gratifyingly, dime-
rization was minimal at lower base loadings (e.g., 5 mol%
DBU) resulting in only the aminocarbonylation product and
the starting material present in the reaction media. This rein-
forced the need for controlling the concentration of these am-
photeric intermediates. Mild heating was needed to promote
the cyclization, since base-induced formation of the intermedi-
ate at room temperature proved too slow. At 508C and with
5 mol% DBU, a selective aminocarbonylation reaction proceed-
ed with the gem-dimethyl carbazate 1bb to yield product 3n
in 82% yield. It should be noted that this transformation re-
quired a long reaction time (60 h), which further highlights the
need for a carefully controlled concentration of N-isocyanate.
These mildly basic conditions in THF facilitate the slow release
of the N-isocyanate, while the thermal energy provided from
heating in conjunction with a Thorpe–Ingold effect provide
a basis for the intramolecular cycloaddition to occur rather
than the intermolecular dimerization. From this point, the
scope of the reaction was expanded to a subset of Thorpe–
Ingold biased aminocarbonylation substrates (Table 8).
Table 7. Base-catalyzed aminocarbonylation of O-Ph derived monoalkenyl
carbazates.[a]
Pleasingly, the yields remained consistent for these reactions
and control experiments confirmed the need for base catalysis.
This included the synthesis of substrates possessing 5- and 6-
membered thioketals (entries 4 and 6, respectively). By per-
forming the reaction at low temperature the competing hydro-
amination reaction could be avoided; however, if the sub-
strates did not possess a Thorpe–Ingold bias, dimerization was
the major pathway (see Supporting Information Table S1).
To avoid the necessity of lengthy reaction times, additives
could be used. Experimentation revealed that p-nitroaniline
was an excellent additive (see Supporting Information, Ta-
bles S4 and S5 for other additives tested), presumably by con-
trolling the concentration of N-isocyanate in situ. Excess p-ni-
troaniline used in tandem with 10 mol% MTBD at 508C could
provide, overnight, reactivity in comparable yield (Scheme 3)
to a 60 h reaction with 5 mol% DBU for the gem-dimethyl car-
bazate 1bb. This increased yield can be attributed to the abili-
ty of p-nitroaniline to reversibly add to the N-isocyanate under
the reaction conditions, thereby effectively minimizing the
concentration of reactive intermediate in situ. The exploration
of this effect in other reactions, as well as extrapolations of the
strategies discussed above that enable new reactivity of
amino-isocyanates are currently ongoing and will be reported
in due course.
[a] Conditions: performed in THF (RT, 16 h, 0.05m); NMR yields using
1,3,5-trimethoxybenzene as internal standard. [b] Isolated yield.
Despite providing a low yield, this preliminary result proved
that it was possible to achieve aminocarbonylation at tempera-
tures far below typical hydroamination conditions with bNÀH
carbazate precursors. However, the substrate needed to be ca-
pable of outcompeting the intermolecular dimerization reac-
tion. It was expected that a Thorpe–Ingold biased substrate
could selectively perform the aminocarbonylation reaction.
This would be significant, because under thermolytic condi-
tions the hydroamination reaction outcompetes the aminocar-
bonylation reaction with all other carbazate substrates (see
Table 4 and Table 6). Pleasingly, a modest yield of 23% of the
corresponding cycloaddition was observed at room tempera-
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Conclusions
Table 8. Base-catalyzed aminocarbonylation of Thorpe–Ingold biased car-
bazates.[a]
A variety of cyclic b-aminocarbonyl motifs can be accessed
using novel intramolecular alkene aminocarbonylation reactivi-
ty of amino-isocyanate intermediates. Support for the involve-
ment of transient N-isocyanates in a 5-membered concerted
aminocarbonylation transition state was obtained by DFT cal-
culations, and experimentally by the stereospecificity observed
with internal alkenes. Several reactions were developed using
hydrazine derivatives such as carbazates and semicarbazides as
blocked (masked) N-isocyanate precursors, allowing the forma-
tion of the reactive N-isocyanate in situ upon heating or using
a base as catalyst. Complementary methodologies were devel-
oped to overcome side reactions, such as hydroamination and
N-isocyanate dimerization, which were observed depending on
the substrate. Initially, the reaction of bNÀH carbazates (LG=
OtBu) and semicarbazides (LG=NH2) required heating at
2008C to form the N-isocyanate and subsequent pyrazolidi-
nones after aminocarbonylation and proton-transfer steps. An
alternative, related approach was developed: the thermolysis
of bN-benzyl carbazates. Using these substrates in an alkene
aminocarbonylation/N-benzyl 1,2-rearrangement sequence typ-
ically afforded the desired products in higher yields, and ena-
bled the synthesis of 6,5-bicyclic ring systems. These increased
yields were attributed to the minimization of N-isocyanate di-
merization, and/or to a more facile cycloreversion of these iso-
cyanate dimers. Alternatively, a transacylation sequence of bN-
benzyl carbazates (Boc cleavage followed by reaction with
phosgene equivalents such as CDI) provided a method to form
the N-isocyanate at lower temperatures, and led to room tem-
perature aminocarbonylation reactivity. However, since the 1,2-
rearrangement could not occur at room temperature, the re-
sultant dipole could not be isolated. The combined insights
from these two strategies led to the use of hemilabile N-isocy-
anate precursors. O-Ph substituted carbazates enabled amino-
carbonylation by thermolysis of monoalkenyl carbazates at
lower temperatures (ca. 1208C). Encouragingly, base-catalyzed
N-isocyanate formation occurred at even lower temperatures
(RT to 508C), which resulted in high yielding aminocarbonyla-
Entry
Additive
Carbazate
Product
Yield [%][b]
1
2
none
DBU
n.r.
82
1bb
3n
3
4
none
DBU
n.r.
81
1ee
3r
5
6
none
DBU
n.r.
83
1 ff
3s
[a] Conditions: heating performed in the presence of 5 mol% DBU in THF
(60 h, 0.05m) in a sealed tube. [b] Isolated yields are shown. n.r.=no reac-
tion. DBU=1,8-diazabicycloundec-7-ene.
tion reactions for substrates containing
a Thorpe–Ingold
(which were problematic under previously established thermo-
lytic conditions). Lastly, p-nitroaniline as an additive was shown
to provide control of N-isocyanate concentration, allowing for
faster reactions with higher base loadings and the prevention
of N-isocyanate dimerization. Collectively, these results demon-
strate the unique reactivity of N-isocyanates as reactive inter-
mediates in intramolecular alkene aminocarbonylations. This
work also presents several strategies and tools to achieve con-
trolled reactivity using these amphoteric (ambident) intermedi-
ates, and prevent the N-isocyanate dimerization pathway
which has been a major hindrance to the development of new
reactions involving these rare isocyanates.
Scheme 3. The use of additives as a method to control for N-isocyanate con-
centration. A representative scheme using p-nitroaniline as additive in base-
catalyzed intramolecular aminocarbonlyation sequence is shown. MTBD=7-
methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene.
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chemin, J. Am. Chem. Soc. 2009, 131, 8740–8741; c) F. Loiseau, C. Clav-
ette, M. Raymond, J.-G. Roveda, A. Burrell, A. M. Beauchemin, Chem.
Commun. 2011, 47, 562–564; d) A. D. Hunt, I. Dion, N. Das Neves, S.
Taing, A. M. Beauchemin, J. Org. Chem. 2013, 78, 8847–8852; e) J. M.
Baxter Vu, J. L. Leighton, Org. Lett. 2011, 13, 4056–4059.
Experimental Section
General procedure: intramolecular aminocarbonylation by
thermolysis
[8] Aminocarbonylation has been used to refer to different reactions, such
as metal-catalyzed aminocarbonylation of aromatic halides using CO
and amines, which is also a carbamoylation reaction. Herein, alkene
aminocarbonylation illustrates the addition of a nitrogen atom and
a carbonyl group across an olefin.
[9] D. J. Craik, D. P. Fairlie, S. Liras, D. Price, Chem. Biol. Drug Des. 2013, 81,
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[10] a) L. S. Hegedus, G. F. Allen, D. J. Olsen, J. Am. Chem. Soc. 1980, 102,
3583–3587; b) L. S. Hegedus, P. M. Winton, S. Varaprath, J. Org. Chem.
1981, 46, 2215–2221; c) L. S. Hegedus, J. M. McKearin, J. Am. Chem. Soc.
1982, 104, 2444–2451.
To an oven-dried 5–20 mL mW tube, a stir bar was added and the
vial was capped with a septum and purged with argon for 5 min.
The carbazate (1.00 equiv) dissolved in solvent (acetonitrile or
a,a,a-trifluorotoluene, 0.05m) was added to the sealed tube. The
tube was then sealed with a microwave cap and heated for the
time specified at the temperature indicated. The reaction solution
was cooled to ambient temperature, concentrated under reduced
pressure and then purified by silica gel chromatography to give
the corresponding pure aminocarbonylation products.
[11] a) Y. Tamaru, T. Kobayashi, S.-I. Kawamura, H. Ochiai, Z.-I. Yoshida, Tetra-
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[12] a) T. Shinohara, M. A. Arai, K. Wakita, T. Arai, H. Sasai, Tetrahedron Lett.
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14352–14356; Angew. Chem. 2014, 126, 14580–14584.
General procedure: intramolecular aminocarbonlyation by
base catalysis
To an oven-dried 5–20 mL mW tube, a stir bar was added and the
vial was capped with a septum and purged with argon for 5 min.
The corresponding carbazate (1.00 equiv) dissolved in THF (0.05m)
was added to the sealed vial. To this solution was added DBU
(0.05 equiv). The reaction vessel was sealed with a microwave cap
and heated in an oil bath at 508C for 60 h. The reaction solution
was cooled to ambient temperature, concentrated under reduced
pressure and then purified by silica gel chromatography to give
the corresponding pure aminocarbonylation products.
[14] a) T. A. Cernak, T. H. Lambert, J. Am. Chem. Soc. 2009, 131, 3124–3125;
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Acknowledgements
We thank the University of Ottawa, NSERC (DAS, CREATE, and
CRD grants to A.M.B.), CFI, and the Ontario MRI for generous fi-
nancial support. Support of related work by AstraZeneca
Canada, OmegaChem and GreenCentre Canada is also grateful-
ly acknowledged. R.A.I, C.C. and J.F.V.R. thank NSERC (CREATE
on medicinal chemistry and biopharmaceutical development,
PGS-D for J.F.V.R.) and OGS for scholarships. Amy B. Toderian is
thanked for early experimental assistance (Table 3, entry 6).
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Keywords: amination · amphoteric molecules · intramolecular
aminocarbonylation
synthetic methods
·
nitrogen-substituted isocyanates
·
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[19] Considering the ease with which proton transfer occurs in comparison
to a 1,2-alkyl shift, this observation seems valid.
[20] a) S. Wawzonek, E. Yeakey, J. Am. Chem. Soc. 1960, 82, 5711–5718. For
a review on aminimides, see: b) W. J. McKillip, E. A. Sedor, B. M. Culbert-
son, S. Wawzonek, Chem. Rev. 1973, 73, 255–281.
using silated hydrazides see reference [16d]; c) A. D. Kirilin, A. A. Doku-
chayev, N. B. Sokova, E. A. Chernyshev, Russ. Chem. Bull. 1999, 48, 169–
172.
[22] E. Licandro, D. Perdicchia, Eur. J. Org. Chem. 2004, 665–675.
[21] For isocyanate synthesis using phosgene at low temperature see: a) Iso-
cyanates, Organic, Kirk-Othmer Encyclopedia of Chemical Technology, 3rd
ed., Wiley, New York, 1982, Vol. 19, pp. 28–62. b) For a similar approach
Received: February 6, 2016
Published online on April 26, 2016
Chem. Eur. J. 2016, 22, 7906 – 7916
www.chemeurj.org
7916
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim