A dramatic effect of double bond configuration in N-oxy-3-aza Cope rearrangements-a simple synthesis of functionalised allenes

Article abstract of DOI:10.1016/j.tetlet.2009.02.228

The first examples of low temperature N-oxy-3-aza Cope rearrangements, leading to functionalised allenes are described, where the Z-configuration of the enaminic double bond in the rearranging system proves critical.

Full text of DOI:10.1016/j.tetlet.2009.02.228

Tetrahedron Letters 50 (2009) 3446–3449
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A dramatic effect of double bond configuration in N-oxy-3-aza Cope
rearrangements—a simple synthesis of functionalised allenes
Luis F. V. Pinto a, Paulo M. C. Glória a, Mário J. S. Gomes a, Henry S. Rzepa b,
a,
Sundaresan Prabhakar a, , Ana M. Lobo
*
*
a Chemistry Department, REQUIMTE/CQFB, Faculty of Sciences and Technology, New University of Lisbon, and SINTOR-UNINOVA, 2829-516 Monte de Caparica, Portugal
b Chemistry Department, Imperial College London, South Kensington Campus, SW7 2AY London, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The first examples of low temperature N-oxy-3-aza Cope rearrangements, leading to functionalised
allenes are described, where the Z-configuration of the enaminic double bond in the rearranging system
proves critical.
Received 24 February 2009
Accepted 25 February 2009
Available online 14 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
3-Aza Cope rearrangements
Hydroxylamines
Enamines
Allenes
Configuration
Intermediates
Transition states
With the decrease in the availability of fossil fuels and the
necessity to guarantee the sustainability of life in the planet, chem-
ists’ attention has been increasingly focused in low and room tem-
perature reactions that can provide access to functionalised
molecules with a minimum of energy expenditure, and a maxi-
mum of atom economy.1,2 Among [3,3]-sigmatropic rearrange-
ments the 3-aza Cope (also known as the 3-aza Claisen)
rearrangement is especially flexible for the different types of mol-
ecules that it can lead to.3,4 The caveat for its wider use resides in
its need for high temperatures and prolonged reaction times, asso-
ciated with sometimes modest yields. We report in this Letter an
N-oxy-3-aza Cope rearrangement occurring at or below room
temperature, which is gated by the configuration of the rearrang-
ing N-oxy-enaminic double bond, and which leads to functional-
ised oxime-allenes.5
tert-propargyl acetate. Next they were added to an activated acety-
lenic sulfone and the products were analysed. For example addi-
tion of 4a to the acetylenic p-toluylsulfone8 in DCM at rt gave
rise after 60 h to allene 6a in 95%, the only other product detected
being enamine E-5a in 5%. The allene showed the characteristic IR
absorption at 1954 cmꢀ1 and a 13C NMR high chemical shift at d
211.5 for the allene carbon.9 The results obtained with other
hydroxylamine derivatives are summarised in Table 1. Good to
excellent yields of functionalised allenes are found in reactions
where the hydroxylamine oxygen substituent is tertiary and bulky
[e.g., adamantyl, tert-butyl, 1,1-dimethyl-3-phenylpropyl and
1-methyl-cyclohexyl], or is attached to a tertiary silyl group as in
Table 1, entries (Z) 1, 8, 11–13. Similar results are obtained when
the hydroxylamine derivatives are disubstituted in the
a-carbon
of the propargyl [entries (Z) 2, 7, 9, 10], a marked decrease being,
however, observed when the disubstitution is achieved through a
spiro carbon, by incorporation of a six- or specially a five-mem-
bered ring [entries (Z) 5, 6]. When the triple bond of 2 bears a ter-
minal substituent (entries 3, 4) no allene product is obtained at rt,
the only product isolated being the unrearranged E-enamine Mi-
chael adduct E-5. The obtention of allenes 6 can be rationalised
by invoking a sigmatropic 3-aza Cope rearrangement, as shown
in Scheme 2, through either a zwitterionic intermediate10 such as
Z-5A or a neutral enaminic Z-5.
The required hydroxylamine derivatives 4 (R1,R2 = H) could be
routinely obtained from the O-substituted hydroxylamines 1 by
propargylation of the corresponding N-Boc derivatives6 2 followed
by deprotection of 3 with TFA (Scheme 1, method a), whereas by
adapting Imada procedure7 (Scheme 1, method b) compounds 4
(R1,R2 – H) were easily made available from the corresponding
* Corresponding authors. Fax: +351 212948550 (A.M.L.).
E-mail address: aml@fct.unl.pt (A. M. Lobo).
URL: http://www.dq.fct.unl.pt/qoa/lpg.html (A. M. Lobo).
In order to detect possible intermediates the reactions were fol-
lowed by 1H NMR in CD2Cl2. Immediately after addition of 4a to the
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.228

L. F. V. Pinto et al. / Tetrahedron Letters 50 (2009) 3446–3449
3447
R2
When the rearrangement of Z-5 is slower, competition from isom-
erisation to E-5 occurs and such enamine accumulates. For the
rearrangement of E-5 to take place heating at above 70 °C (typi-
cally at 180 °C) is now needed [Table 1, entries (E) 2–4, 8, 12,
14]. At that temperature allene 6 is no longer stable and a cascade
of reactions may lead to different compounds through triene 7. For
R3
OAc
method b
CuCl (0.1.eq), TEA
OR1
NH2
THF
R2,R3
OR1
NH
R4
R2
H
R3
1
example if there are no substituents on the
a-carbon of the
propargylic unit, a substituted pyridine 8 is formed as shown in
Scheme 3, resulting from elimination of R1OH in the dihydropyri-
dine after N–O bond cleavage [entries (E) 1, 3, 4, 8, 12, 14]. If, how-
ever, R2 and R3 are not hydrogens, then triene 9 is isolated [entry
(E) 2] (cf. Scheme 4).
The oxime allenes 6 are themselves liable to acid-catalysed
isomerisation, when, for example, in prolonged contact with silica
gel at room temperature (as while being subjected to purification),
in which case triene-type 7 is obtained by prototropy. Upon heat-
ing 6 at 180 °C the same isomeric triene 9 as above is obtained as in
Scheme 4, which can be due to the facile formation of an ion-pair
60, followed by attack of the leaving sulfone moiety to the allene
central carbon.
To gain insight into the stereoelectronic influences for the reac-
tion path outlined in Scheme 5, the potential energy surface was
modelled at the B3LYP/6-31G(d) level (Web Table), reaction barriers
being computed from thermal and entropy corrected free energies.
The initial transition state (TS1) involves a zwitterionic product,
and this was modelled with a continuum solvation field applied
(CPCM, specifying water or dichloromethane).11 The subsequent
non-ionic intermediates and transition states were modelled for
the gas phase. We first note that nucleophilic addition by the amine
to the arylsulfonylalkyne is predicted to exhibit a more stable tran-
method a
Boc2O, I2
R4
OR1
R2
4
R3
N
1) Na H
OR1
HN
Br CH2
R4
Boc
2)
TFA
R2,R3 = H
DCM
Boc
R4
2
3
a: R1 = adamantyl ; R2,R3,R4 = H
b: R1 = adamantyl ; R2,R3 = Me; R4 = H
c: R1 = adamantyl ; R2,R3 = H; R4 = Me
d: R1 = adamantyl ; R2,R3 = H; R4 = Et
e: R1 = adamantyl ; R2,R3 = CH2(CH2)3CH2; R4 = H
f: R1 = adamantyl ; R2,R3 = CH2(CH2)2CH2; R4 = H
g: R1 = adamantyl ; R2 = Me; R3 = Et; R4 = H
h: R1 = tert-butyl; R2,R3,R4 = H
i: R1 = CMe2(CH2)2Ph; R2,R3 = Me; R4 = H
j: R1 = 1-methylcyclohexyl ; R2,R3 = Me; R4 = H
k: R1 = Si(i -Pr)3; R2,R3,R4 = H
l: R1 = SiMe2CMe3; R2,R3,R4 = H
m: R1 = SiPh2CMe3; R2,R3,R4 = H
sition state TS1 (by ꢁ1.6 kcal molꢀ1/water and 0.9 kcal molꢀ1
/
n: R1 = benzyl; R2,R3,R4 = H
dichloromethane in thesolvation free energy)if thedeveloping vinyl
carbanioninthetransitionstateisorientedantiratherthansyntothe
nucleophile. The effect arises predominantly from the greater solva-
tion stabilisation in the anti configuration (dipole moment 14.1 D)
compared to syn (dipole moment 11.2 D). This result agrees with
an earlier suggestion by Evans and Kirby12 that such nucleophilic
Scheme 1.
acetylenic sulfone enamine Z-5 is formed in a fast reaction, and this
intermediate then suffers the rt rearrangement to yield allene 6.
Table 1
3-Aza-Cope rearrangements of enamines 5 produced via Scheme 2.
#
O-Substituted hydroxylamines 4
Configuration of enamines 5
Conditions
Temp/Time
Product
Yielda (%)
Allene 6
Others
1
2
a: R1 = adamantyl; R2 = R3 = R4 = H
Z
E
Z
Z
Z
E
E
E
E
Z
Z
Z
Z
E
Z
Z
Z
Z
E
Z
Z
E
rt/60 h
95b
—
E-5a (5c)
8a (80)
—
—
—
180 °C/15 min
ꢀ20 °C/90 d
ꢀ4 °C/25 d
rt/48 h
70 °C/200 h
180 °C/15 min
180 °C/1 h
180 °C/1 h
rt/96 h
rt/96 h
rt/96 h
rt/72 h
180 °C/15 min
rt/72 h
rt / 72 h
rt/24 h
rt/24 h
180 °C/15 min
rt/96 h
rt/72 h
180 °C/15 min
b: R1 = adamantyl; R2 = R3 = Me; R4 = H
91, 99b
98, 99b
90, 99b
50, 54b
—
E-5b (15c)
9b (70)
8c (80)
8d (71)
E-5e (28c)
E-5f (70c)
—
3
4
5
6
7
8
c: R1 = adamantyl; R2 = R3 = H; R4 = Me
d: R1 = adamantyl; R2 = R3 = H; R4 = Et
e: R1 = adamantyl; R2 = R3 = CH2(CH2)3CH2; R4 = H
f: R1 = adamantyl; R2 = R3 = CH2(CH2)2CH2; R4 = H
g: R1 = adamantyl; R2 = Me; R3 = Et; R4 = H
h: R1 = tert-Bu; R2 = R3 = R4 = H
—
—
61, 64b
27, 28b
70, 93b
64b
E-5h (30c)
8h (71)
—
—
9
i: R1 = 1,1-dimethyl-3-propyl; R2 = R3 = Me; R4 = H
j: R1 = 1-methylcyclohexyl; R2 = R3 = Me; R4 = H
k: R1 = (i-Pr)3Si; R2 = R3 = R4 = H
80, 99b
78, 96b
64, 98b
65, 68b
—
10
11
12
-
—
l: R1 = (Me)2(tert-Bu)Si; R2 = R3 = R4 = H
E-5l (32c)
8l (88)
—
13
14
m: R1 = Ph2(tert-Bu)Si; R2 = R3 = R4 = H
n: R1 = benzyl; R2 = R3 = R4 = H
75, 92b
60b
E-5n (30c)
8n (77)
—
a
Isolated yields after flash-chromatography.
b
c
Yields calculated from 1H NMR of crude reaction mixtures.
Recovered E-enamine after chromatography.

3448
L. F. V. Pinto et al. / Tetrahedron Letters 50 (2009) 3446–3449
addition does indeed proceed via a vinylcarbanion intermediate in
4
antiperiplanar fashion. The transition state for Z-5A/E-5A isomerisa-
tionby inversion at the vinylcarbanioncentre(TS3) has a free energy
8.1 kcal molꢀ1 higher than that for TS1/Z-5A. The stereospecific anti-
carbanion is thus presumed to be rapidly and irreversibly quenched
with a proton to produce the Z enamine before any isomerisation to
the syn-carbanion E-5A can occur. This stereochemistry represents a
classical example of kinetic rather than thermodynamic control,
since the alternative enamine E-5 is in fact 9.1 kcal molꢀ1 more sta-
ble in free energy.
DCM
-20°C–RT
X = SO2Ar
OR1
X
OR1
H
R2
R3
R2
H
N
N
R3
X
X
R4
R4
Either enamine now undergoes a [3,3] sigmatropic rearrange-
ment (via TS2) to give 6, the more facile reaction being that
commencing from the less stable Z-5 enamine with a free energy
barrier of 20.2 kcal molꢀ1 and the less facile from the (more stable)
E enamine, the barrier for which is 27.8 kcal molꢀ1. The free energy
barrier for double-bond isomerisation of the neutral Z-5/E-5 inter-
mediates (TS4) is too high to compete (free energy barrier
34.6 kcal molꢀ1, 14.4 kcal molꢀ1 higher than that for [3,3]-rear-
rangement (TS2) of E-5). A viable mechanism for Z-5/E-5 isomeri-
sation, a process which is in fact observed to slowly take place,
may in fact occur by prior protonation of the enamine on the sulfo-
nyl oxygen, enhancing the electronic push/pull, and reducing the
free energy barrier for double-bond rotation (TS5) down to a more
feasible 20.0 kcal molꢀ1 (from protonated Z-5). This would allow
Z-5 to isomerise at a similar rate to the competing [3,3] rearrange-
ment. This overall free energy analysis rationalises the experimen-
tal observations that initial product Z-enamine reacts at low
temperatures, whereas the more stable E-enamine has an observa-
ble lifetime, and only undergoes Cope rearrangement at >70 °C.
In conclusion, it has been shown that for low to room tempera-
ture N-oxy-3-aza Cope rearrangements, leading to oxime allenes,
the Z-configuration of the rearranging enaminic double bond
proves to be a critical factor.
Z- 5A
E- 5A
OR1
N
OR1
N
R2
R3
R2
R3
X
X
R4
R4
E- 5
Z- 5
R4 = H
-20°C – RT
OR1
R2
N
R3
X
6
Scheme 2.
OR1
R2
OR1
N
OR1
N
R3
R2,R3 = H
- HOR1
N
R2
70°C – 180°C
3-aza Cope
R3
X
X
180°C
X
R4
R4
R4
E- 5
6
7
SiO2
RT
OR1
N
N
R2,R3
R4= H
H
X
X
R4
R2
R3
8
7
Scheme 3.
OR1
N
OR1
OR1
N
R2
N
R2
R3
180°C
R3
X
R2
X
X
R3
6
6'
9
R1 = adamantyl
X = SO2Ar
R2,R3 = Me
Scheme 4.

L. F. V. Pinto et al. / Tetrahedron Letters 50 (2009) 3446–3449
3449
Z- 5A
Z- 5
OR1
OR1
H
20.2 kcal/mol
[3,3]
N
N
OR1
NH
X
X
OR1
TS2
N
TS1
TS3
OR1
TS4
OR1
N
X
X
H
N
6
[3,3]
TS2
X = SO2Ar
R1= tert-butyl
X
X
27.8 kcal/mol
E- 5A
E- 5
Scheme 5.
2000, 65, 4938–4943; Suh, Y.-G.; Kim, S.-A.; Jung, J.-K.; Shin, D.-Y.; Min, K.-H.;
Koo, B.-A.; Kim, H.-S. Angew. Chem., Int. Ed. 1999, 38, 3545–3547.
Acknowledgements
5. Modern Allene Chemistry; Krauser, A., Stephen, A., Hashmi, K., Eds.; Wiley-VCH:
Weinheim, 2004.
6. Varala, R.; Nuvula, S.; Adapa, S. R. J. Org. Chem. 2006, 71, 8283–8286.
7. Imada, Y.; Yuasa, M.; Nakamura, I.; Murahashi, S. J. Org. Chem. 1994, 59, 2282–
2284.
8. For acetylenic sulfones, see: Back, T. G. Tetrahedron 2001, 57, 5263–5301;
Chen, Z.; Trudell, M. L. Synth. Commun. 1994, 24, 3149–3155; Bhattacharya,
S. N.; Josiah, B. M.; Walton, D. R. M. Organomet. Chem. Synth. 1971, 1,
145–149.
We thank Fundação para a Ciência e a Tecnologia (FC&T, Lisbon,
Portugal) for partial financial support (Project POCTI/QUI/36456).
Three of us (L.F.V.P., P.M.C.G., M.J.S.G.) are grateful for the award
of doctoral fellowships from FC&T. A.J.G. Bento is thanked for the
preparation of some starting materials.
Supplementary data
9. Typical experimental procedure: To
a 0.5 M solution of tert-butyl N-(O-
adamantyl)carbamate 2a (mp 99–100 °C), under N2 atmosphere in dry DMF,
were added NaH (1 equiv, 60% dispersion in oil) and after 5 min propargyl
bromide (1 equiv). The reaction was left at rt for 2 h. After work-up the
product was purified by flash chromatography to yield the hydroxylamine
derivative 3a as a yellowish oil (95%). Next this oil (1 equiv) was dissolved
in DCM, TFA (4 equiv) was added and the mixture was left to react at rt for
24 h, after which the reaction was stopped and compound 4a was obtained
as a white solid (77%), mp 50–51 °C (Et2O). Addition to sulfone: A DCM 0.4 M
solution of 4a (Table 1, entry 1) (20 mg) and ethynyl p-toluylsulfone
(1 equiv) were left to react at rt for 60 h, when only allene 6a (95%) and
enamine E-5a (5%) could be identified. After ca. 30 h of reaction enamine Z-
5a was clearly visible in the 1H NMR of the mixture, but no trace was
observed at the end. After completion of the reaction the solvent was
evaporated and the products were purified by flash chromatography (silica,
Et2O/n-hex, 1:4).Selected data: Z-5a, 1H NMR (400 MHz, CD2Cl2) d: 7.81 (2H,
d, J = 8.2 Hz), 7.35 (2H, d, J = 8.2 Hz), 6.59 (1H, d, J = 10.1 Hz), 5.43 (1H, d,
J = 10.1 Hz); E-5a, mp 138–9 °C; 1H NMR (CD2Cl2) d: 7.71 (2H, d, J = 8.2 Hz),
7.36 (1H, d, J = 12.7 Hz), 7.30 (2H, d, J = 8.2 Hz), 5.77 (1H, d, J = 12.7 Hz);
HRMS m/z: 386.17882 (M++1) (C22H28NO3S requires 386.17899); 6a, IR
Supplementary data associated with this article can be at
http://www.ch.imperial.ac.uk/rzepa/j.tetlet. 2009.02.228.
References and notes
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10. For zwitterionic intermediates, reported earlier in low-temperature 3-aza Cope
rearrangements, see Refs.
3 (Nubbemeyer) and 4 (Weston et al.). In our
reactions the Z-5/E-5 isomerisation occurs after an irreversible protonation. It is
unlikely that the reaction conditions could result in the deprotonation of the
vinyl proton of the enamines, which would require a very strong base to be
present.
11. Barone, V.; Cossi, M. J. Phys. Chem. A 1998, 102, 1995–2001.
12. Evans, C. M.; Kirby, A. J. J. Chem. Soc., Perkin Trans. 2 1984, 1269–1275.