A mild, copper-catalysed amide deprotection strategy: Use of tert-butyl as a protecting group

Article abstract of DOI:10.1016/j.tet.2014.07.080

Mild methods for the deprotection of organic substrates are of fundamental importance in synthetic chemistry. A new room temperature method using a catalytic amount of Cu(OTf)₂is reported. This allows use of the tert-butyl group as an amide protecting group. The methodology is also extended to Boc-deprotection.

Full text of DOI:10.1016/j.tet.2014.07.080

Tetrahedron 70 (2014) 7593e7597
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A mild, copper-catalysed amide deprotection strategy:
use of tert-butyl as a protecting group
*
Vikki Evans, Mary F. Mahon, Ruth L. Webster
University of Bath, Claverton Down, Bath BA2 7AY, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 June 2014
Received in revised form 14 July 2014
Accepted 21 July 2014
Available online 1 August 2014
Mild methods for the deprotection of organic substrates are of fundamental importance in synthetic
chemistry. A new room temperature method using a catalytic amount of Cu(OTf)2 is reported. This allows
use of the tert-butyl group as an amide protecting group. The methodology is also extended to Boc-
deprotection.
Ó 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
Keywords:
Amides
Deprotection
Catalysis
Copper
1. Introduction
Boc group, which also shows a propensity for mild cleavage.
Compared to strong acids, the use of a simple copper salt offers
The functional group protection of amines is a fundamental
prerequisite in the manipulation and synthesis of a range of key
organic moieties, for example, amino acids and peptides.1 Whilst
protection strategies are often mild, facile and high yielding, the
corresponding deprotection should, ideally, also fulfil these re-
quirements. Despite this, removal of common nitrogen protection
groups such as Boc, tend to rely on strong acids. Although other
stoichiometric2 and catalytic methods are known,3 in general the
reagents used are often difficult to handle and may be incompatible
with other sensitive moieties that are present elsewhere in the
substrate. Meanwhile, very simple functionality, for example, alkyl
groups, are rarely used in protection-deprotection strategies prin-
cipally because removal requires the use of strong acid and/or high
temperatures,4 which can be detrimental to sensitive functionality
elsewhere in the molecule. Reports of the use of Lewis acids to
deprotect tert-butyl substituted tertiary amides exist.4g,h However,
many of the reagents are difficult to handle (SnCl4, TiCl4,
ZnCl2$OEt2, BF3$OEt2, TMSOTf) and no comprehensive account of
reaction conditions and substrate scope exists.
a very favourable set of handling conditions.
Secondary amides are important substrates, where accessing
them from the tertiary precursor is an important step. For example,
Shi and co-workers have used Pd-catalysed diamination to access
a range of enantiopure tert-butyl substituted imidazolidinones,4e,f
where the tert-butyl group is removed using TFA to allow for fur-
ther N-functionalisation. Secondary amides are also commonly
used in directing group mediated catalytic CeH functionalisation.5
It could be envisaged that amide N-protection as the tertiary
moiety would allow functionalisation elsewhere in the molecule,
prior to mild deprotection of the tert-butyl group and then sub-
sequent CeH functionalisation. This would allow the build-up
molecular complexity under mild, catalytic conditions.
2. Results and discussion
During recent studies into the novel reactivity of sterically
congested amides,6 an unusual facet of reactivity was observed.7,8
Upon exposure to a quantitative amount of Cu(OTf)2 at room
temperature, bulky malonamide 1 reacts to form a new all-trans
chelate, 2-Cu (Scheme 1). X-ray diffraction shows this to be the
desymmetrised malonamide, which has undergone loss of one tert-
butyl group (Fig. 1). Further investigation shows that the tert-butyl
is lost as isobutylene, which begins to form within minutes at room
temperature: the signals corresponding to isobutylene can be
clearly seen by 13C{1H} NMR.9 Heating the chelate in MeOH releases
the pure unsymmetrical malonamide, 2. This is a highly selective
Reported herein is the use of the tert-butyl group as an amide N-
protecting species, which undergoes mild, catalytic cleavage with
Cu(OTf)2. To the best of our knowledge this is the first catalytic
report of de-tert-butylation. The reaction has been extended to the
* Corresponding author. Tel.: þ44 (0) 1225 386103; fax: þ44 (0) 1225 386231;
e-mail address: r.l.webster@bath.ac.uk (R.L. Webster).
http://dx.doi.org/10.1016/j.tet.2014.07.080
0040-4020/Ó 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

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V. Evans et al. / Tetrahedron 70 (2014) 7593e7597
Table 1
Optimisation of catalytic de-tert-butylation
Entry
Conditions
Spectroscopic yield (%)a
1
2
3
4
5
6
7
8
Cu(OTf)2, CH2Cl2
Cu(OAc)2, CH2Cl2
CuCl2, CH2Cl2
Zn(OAc)2, CH2Cl2
ZnCl2, CH2Cl2
100 [82]
N.r.
N.r.
N.r.
N.r.
N.r.
100
94
45
10
92
6
YbCl3, CH2Cl2
Bi(OTf)3, CH2Cl2
Sc(OTf)3, CH2Cl2
Cu(OTf)2, toluene
Cu(OTf)2, THF
Cu(OTf)2, 1,4-dioxane
Cu(OTf)2, EtOH
Cu(OTf)2, MeCN
9
10
11
12
13
Scheme 1. Stoichiometric Cu(OTf)2 can be used to desymmetrise sterically congested
malonamides within minutes at room temperature.
55
Conditions: amide (0.5 mmol), metal salt (0.025 mmol, 5 mol %), solvent (5 mL), rt,
18 h.
a
Spectroscopic yield, [isolated yield]. N.r.¼no reaction.
Table 2
Extent of de-tert-butylation reactivity
Starting material
Product
R/n
Yielda
87b
1
2
3a
3b
4a
4b
H
96
3
4
5
3c
3d
3e
4c
4d
4e
4-Me
4-OMe
3,5-CF3
82
92, 94c
91
6
3f
4f
57
95d
Fig. 1. Crystal structure of 2-Cu. Selected bond lengths: CueO1 1.945(2), CueO2
ꢀ
1.925(1), CueO3 2.517(2) A. Selected bond angles: O1eCueO2 91.82(6), O1eCueO3
92.93(6), O2eCueO3 89.13 (6)ꢀ.
7
8
3g
3h
4g
4h
1
4
75, 95d
74d
method for the desymmetrisation of malonamides and to the best
of our knowledge, a selective transformation of this type has never
been reported.
Conditions: amide (0.5 mmol), Cu(OTf)2 (5 mol %), CH2Cl2 (5 mL).
a
Isolated yield (%).
Wishing to explore this chemistry further, we questioned the
potential of developing a Cu(OTf)2-catalysed de-tert-butylation
protocol. To our delight, this is indeed possible using a sterically
congested amide under mild conditions with only 5 mol % copper
salt (Table 1, Entry 1). The reaction proceeds at room temperature to
give the de-alkylated product cleanly, in high yield and no stirring is
necessary. Reactivity is only observed in the presence of triflate
salts (Table 1, Entries 1 and 7e13) and is most efficient in CH2Cl2
and 1,4-dioxane. This is the first report of a completely air stable,
room temperature, metal-catalysed method of de-tert-butylation.
We then investigated the substrate scope and noted that re-
ducing the steric bulk around the nitrogen to an N-tert-butyl-N-
ethyl amide (3a, Table 2, Entry 1) necessitates more forcing reaction
conditions to remove the tert-butyl group (no reaction is observed
after 18 h at rt but complete conversion to 3a is observed after 15 h
at 50 ꢀC). No reaction is observed with secondary N-tert-butyl-
b
15 h, 50 ꢀC.
c
Scale-up: 1.0 g 3d, 24 h, rt.
d
18 h, 50 ꢀC.
hindered naphthalenecarboxamide, 3f, requires gentle heating to
enable the reaction to go to completion (Entry 6). Aliphatic amides
also undergo de-tert-butylation by employing heating (Entries 7
and 8). Deprotection of tertiary amines (e.g., tert-butylpiperidine)
does not take place and only starting material is obtained. Likewise,
lactam deprotection (1-(tert-butyl)azetidin-2-one, 1-(tert-butyl)
pyrrolidin-2-one and 1-(tert-butyl)piperidin-2-one) does not take
place, even after heating to 80 ꢀC.
Our next goal was to investigate the applicability to Boc-
deprotection (Table 3). Again, mild cleavage is observed across
a range of benzamide substrates (Entries 1e3), whilst deprotection
of an aliphatic substrate (Entry 5) and common lactam motifs
(Entries 6e9) under gentle heating (50 ꢀC) is possible. Intrigued by
the possibility of selectively removing a tert-butyl group in the
presence of a Boc group, we synthesised a sterically congested N-
benzamides.
A
range
of
aromatic
N-tert-butyl-N-iso-
propylbenzamides undergo this transformation (Entries 2e6) with
many proceeding with excellent yields after 18 h at rt. Sterically

V. Evans et al. / Tetrahedron 70 (2014) 7593e7597
7595
Table 3
NEt3, no reaction is observed. Exposure of 3c to 10 mol % TfOH in
CH2Cl2 produces 100% spectroscopic yield of 4c after 18 h at rt.
However, Boc-deprotection of 5b using 10 mol % TfOH is less
favourable, only producing a 45% spectroscopic yield of 4c. In terms
of handling, the use of an air stable solid such as Cu(OTf)2 is clearly
more attractive than use of TfOH. To reiterate the benefits of
Cu(OTf)2, a comparison of trifluoroacetic acid (TFA) in the depro-
tection of these substrates does not result in the de-tert-butylation
of 3c, with only 10% of 4c observed after 18 h at rt, similarly no
reaction is observed on exposure of 3e to TFA.
Extent of Boc-deprotection reactivity
Starting material
Product
R/n
H
Yielda
73
1
5a
4b
2
3
5b
5c
4c
4d
4-Me
4-OMe
77
80
Monitoring the transformation of 3c, over time appears to show
little difference between 5 mol % and 10 mol % loadings (Fig. 2),
however the rate of the reaction in the initial stages shows the
reaction rate doubles when the loading of Cu(OTf)2 is doubled
(Fig. 4). There is a very rapid initiation period of de-tert-butylation,
until the first data point is captured after 5 min. De-tert-butylation
of 3c is also rapid, with the reaction giving complete conversion to
4c in 7 h. In comparison the Boc-deprotection of 5b proceeds more
slowly (Fig. 3). However, a first order relationship is also observed
between the 5 mol % and 10 mol % catalyst loadings, there is no fast
4
5d
4f
73
5
6
5e
5f
4h
6a
4
1
64, 94b
94b
initiation period and initial rates are 0.540
m
mol sꢁ1 and
7
8
5g
5h
4k
6b
2
3
95b
54b
1.046
m
mol sꢁ1, respectively.
Further studies are underway, particularly focussing on the
unexpected reduced level of reactivity observed with 5j (Table 3,
Entry 10). We are also investigating the extension of the substrate
scope beyond simple amides and amino acids to look at the use of
the de-tert-butylation methodology for synthesis/deprotection
strategies of more biologically and pharmaceutically relevant
substrates.
9
5i
5j
6c
83
10
6d
39c
11
5k
6e
82
12
13
5l
6f
90
96
5m
6g
Conditions: amide (0.5 mmol), Cu(OTf)2 (5 mol %), CH2Cl2 (5 mL).
a
Isolated yield (%).
b
18 h, 50 ꢀC.
c
18 h, 80 ꢀC.
tert-butyl-N-Boc-p-toluamide (5j, Entry 10). To our surprise, nei-
ther group was removed at RT and only starting material was ob-
served even after 18 h at 50 ꢀC. Further heating to 80 ꢀC resulted in
39% de-tert-butylation to give Boc protected amide 6d. N,N-di-Boc
protection is commonly used in organic synthesis10 and we dem-
onstrate that mono-deprotection of non-amido derivatives is pos-
sible (Entry 11), with mild deprotection of the aniline substrate
taking place in high yield. Entries 12 and 13 demonstrate an ex-
tension to amino acids, with mono-deprotection taking place even
in the presence of a tert-butyl ester. 6f and 6g are obtained in near
quantitative yield at rt whilst heating to 50 ꢀC gives no evidence for
cleavage of the remaining protecting groups.
Fig. 2. Consumption of 3c with time, varying Cu(OTf)2 loading (5 mol % -; 10 mol%
:). Conditions: 3c 0.1 M in CH2Cl2, RT.
We hypothesise the deprotection proceeds via slow release of
small quantities of TfOH over the course of the reaction: indeed
during the de-tert-butylation of 3c, the pH slowly decreases from
pH 7 to pH 5 after 18 h. Repeating the reaction using inert, anhy-
drous reaction conditions and recrystallised Cu(OTf)2 gives 45%
product after 24 h at rt. This would intimate that limiting the ex-
posure to TfOH acts to reduce the de-tert-butylation capacity, re-
iterating the importance of the triflate observed in Table 1. When
the deprotection of 3c is undertaken in the presence of 10 mol %
Fig. 3. Consumption of 5b with time, varying Cu(OTf)2 loading (5 mol % -; 10 mol %
:). Conditions: 5b 0.1 M in CH2Cl2, rt.

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V. Evans et al. / Tetrahedron 70 (2014) 7593e7597
4.3. General method for de-tert-butylation and Boc-
deprotection
Substrate (0.5 mmol) was added to a reaction vial with CH2Cl2
(5 mL) and Cu(OTf)2 (9 mg, 0.025 mmol, 5 mol %). The reaction was
allowed to stand at room temperature for 18 h before being
quenched with H2O and extracted into CH2Cl2 (3ꢂ20 mL). The or-
ganic extracts were dried over MgSO4 and concentrated in vacuo.
This yielded the pure product without need for further purification
procedures: if pure product was not obtained the reaction was
undertaken at 50 ꢀC or 80 ꢀC in a sealed J-Young tube.
4.4. Analysis data for products
Compound 4a, Table 2, Entry 1. Colourless oil, 71 mg (87%). 1H
NMR (250 MHz; 298 K; CDCl3)
d 7.67 (d, 2H, J 8.2 Hz, ArH), 7.22 (d,
Fig. 4. Comparison of the initial rate of deprotection of 3c and 5b with time, varying
Cu(OTf)2 loading. 3c: 5 mol % Cu(OTf)2 ,, y¼ꢁ5.00 Eꢁ6þ9.63 Eꢁ2, R2¼98.1; 10 mol %
2H, J 8.2 Hz, ArH), 6.24 (br s, 1H, NH), 3.48 (q, 2H, J 7.3 Hz, CH2CH3),
2.38 (s, 2H, ArCH3), 1.24 (t, 3H, J 7.3 Hz, CH2CH3); 13C NMR (63 MHz;
Cu(OTf)2
D
,
y¼ꢁ1.01 Eꢁ5þ9.94 Eꢁ2
,
R2¼98.9. 5b:
5 mol % Cu(OTf)2 -,
y¼ꢁ5.40 Eꢁ7þ1.00 Eꢁ1
,
R2¼97.3; 10 mol
%
Cu(OTf)2 :, y¼ꢁ1.05 Eꢁ6þ1.00 Eꢁ1
,
298 K; CDCl3)
d 167.4 (C]O), 141.6 (Arq), 131.9 (Arq), 129.1 (Ar),
R2¼95.8). Conditions: 0.1 M in CH2Cl2, rt.
126.8 (Ar), 34.8 (CH2CH3), 21.4 (ArCH3), 14.9 (CH2CH3); IR (neat)
n
3254, 2974, 1626, 1546, 1509 cmꢁ1. Data matches that of commer-
cial sample (CAS: 26819-08-9).
3. Conclusions
Compound 4b, Table 2, Entry 2. White solid, 78 mg (96%). 1H
NMR (250 MHz; 298 K; CDCl3) d 7.76 (d, 2H, J 7.9 Hz, ArH), 7.49e7.36
We have shown that a catalytic amount of Cu(OTf)2 can be used
to affect a mild de-tert-butylation of N,N-disubstituted amides.
Cu(OTf)2 proves to be an easily handled and mild reagent for the
slow release of TfOH. Alternative sources of strong acid (TFA) fail to
de-tert-butylate under these reaction conditions and we have
shown that the procedure is first order in catalyst and is driven by
the release of isobutylene. De-tert-butylation is fast and occurs
within hours at rt. This protocol can also be used to Boc-deprotect
N,N-disubstituted amides, di-Boc protected anilines and di-Boc
protected amino acids, albeit more slowly. However, Cu(OTf)2 ap-
pears to be a far more favourable reagent for Boc-deprotection both
in terms of handling and yield of secondary amide product.
(m, 3H, ArH), 6.16 (br s, 1H, NH), 4.26 (septet, 1H, J 6.6 Hz,
CH(CH3)2), 1.25 (d, 6H, J 6.6 Hz, CH(CH3)2); 13C NMR (75 MHz;
298 K; CDCl3) d 166.7 (C]O),134.8 (Arq),131.2 (Ar),128.4 (Ar),126.8
(Ar), 41.8 (CH(CH3)2), 22.7 (CH(CH3)2); IR (solid)
n 3297, 2971, 2929,
1631, 1531 cmꢁ1; mp 98e99 ꢀC.10
Compound 4c, Table 2, Entry 3. White solid, 72 mg (82%). 1H
NMR (300 MHz; 298 K; CDCl3)
d 7.65 (d, 2H, J 8.1 Hz, ArH), 7.21 (d,
2H, J 8.1 Hz, ArH), 6.01 (br s, 1H, NH), 4.28 (septet, 1H, J 6.6 Hz,
CH(CH3)2), 2.39 (s, ArCH3), 1.25 (d, 6H, J 6.6 Hz, CH(CH3)2); 13C NMR
(63 MHz; 298 K; CDCl3)
(Ar), 126.8 (Ar), 41.7 (CH(CH3)2), 22.8 (CH(CH3)2), 21.4 (ArCH3); IR
(solid)
3303, 2973, 1627, 1531 cmꢁ1; mp 99e101 ꢀC. Data matches
d 166.6 (C]O), 141.6 (Arq), 132.0 (Arq), 129.1
n
that of commercial sample (CAS: 2144-17-4).
Compound 4d, Table 2, Entry 4. White solid, 89 mg (92%). 1H
4. Experimental
NMR (250 MHz; 298 K; CDCl3)
d 7.72 (d, 2H, J 8.9 Hz, ArH), 6.90 (d,
4.1. General considerations
2H, J 8.9 Hz, ArH), 5.95 (br s, 1H, NH), 4.26 (septet, 1H, J 6.6 Hz,
CH(CH3)2), 3.83 (s, OCH3), 1.25 (d, 6H, J 6.6 Hz, CH(CH3)2); 13C NMR
Reagents were purchased from Sigma Aldrich and used without
further purification. Laboratory grade dichloromethane was pur-
chased from Fisher Scientific and used without further purification.
The anhydrous test reaction was undertaken using CH2Cl2, which
had been dried over CaH2 (reflux), distilled and then degassed us-
ing three freezeepumpethaw cycles. NMR data was collected at
250, 300, 400 or 500 MHz on Bruker instruments in CDCl3 at 293 K
and referenced to residual protic solvent. Room temperature re-
actions were carried out in 7 mL reaction vials under air in the
absence of stirring. Heated and anhydrous reactions were un-
dertaken in Teflon-sealed J-Young reaction tubes. High resolution
mass spectrometry (HRMS) analyses were carried out using
a Bruker liquid chromatography instrument coupled to an elec-
trospray time-of-flight (ESI-TOF) mass spectrometer.
(63 MHz; 298 K; CDCl3)
(Arq), 113.6 (Ar), 55.33 (OCH3), 41.7 (CH(CH3)2), 22.8 (CH(CH3)2); IR
(solid)
3316, 2973, 1606, 1506 cmꢁ1; mp 113 ꢀC. Data matches that
d 166.2 (C]O), 161.9 (Arq), 128.5 (Ar), 127.2
n
of commercial sample (CAS: 7464-44-0).
Compound 4e, Table 2, Entry 5. White solid, 136 mg (91%). 1H
NMR (250 MHz; 298 K; CDCl3)
d 8.19 (s, 2H, ArH), 7.92 (s, 1H, ArH),
6.89 (d, 1H, J 7.4 Hz, NH), 4.28 (septet, 1H, J 6.6 Hz, CH(CH3)2), 1.28
(d, 6H, J 6.6 Hz, CH(CH3)2); 13C NMR (63 MHz; 298 K; CDCl3)
d
163.9 (C]O), 136.9 (Arq), 131.6 (q, J 34.4 Hz, Arq), 127.3 (d, J
3.0 Hz, Ar), 124.3 (app. quintet, J 3.7 Hz, CF3) 121.6 (Ar), 42.6
(CH(CH3)2), 22.6 (CH(CH3)2); IR (solid)
n 3292, 3094, 2973,
1640 cmꢁ1; mp 127 ꢀC.11
Compound 4f, Table 2, Entry 6. White solid, 101 mg (95%). 1H
NMR (250 MHz; 298 K; CDCl3)
d 8.26 (dd, 1H, J 6.5, 2.7 Hz, ArH),
7.89e7.83 (m, 2H, ArH), 7.57e7.37 (m, 4H, ArH), 6.00 (br s, 1H, NH),
4.35 (septet, 1H, J 6.6 Hz, CH(CH3)2), 1.28 (d, 6H, J 6.6 Hz, CH(CH3)2);
4.2. Crystal data for C28H52CuF6N4O10S2 (2-Cu)
13C NMR (75 MHz; 298 K; CDCl3)
d
168.7 (C]O), 134.8 (Arq), 133.5
ꢀ
M¼846.40,
l
¼0.71073 A, monoclinic, space group P21/n,
(Arq), 130.2 (Ar), 130.0 (Arq), 128.2 (Ar), 126.9 (Ar), 126.3 (Ar), 125.3
a¼8.2630(1), b¼20.6860(4), c¼11.7690(2) A,
b
¼106.119(1)ꢀ,
(Ar), 124.6 (2Ar), 41.9 (CH(CH3)2), 22.7 (CH(CH3)2); IR (solid) n 3286,
ꢀ
3
ꢀ
ꢁ3
m
U¼1932.57(5) A , Z¼2, Dc¼1.455 g cm
,
¼0.757 mmꢁ1, F(000)¼
2973, 1633, 1529 cmꢁ1; mp 124e125 ꢀC; HRMS (LCMS) 236.1051
(calcd for C14H15NNaO), 236.1068 (obs.).
886. Crystal size¼0.25ꢂ0.20ꢂ0.20 mm, unique reflections¼4409
[R(int)¼0.0612], observed reflections [I>2
s(I)]¼3455, data/re-
Compound 4g, Table 2, Entry 7. Volatile liquid, 55 mg (95%). 1H
straints/parameters¼4409/1/243. Observed data; R1¼0.0418,
wR2¼0.0974. All data; R1¼0.0597, wR2¼0.1072. Max peak/
NMR (250 MHz; 298 K; CDCl3) d 5.58 (br s, 1H, NH), 4.08 (septet,
1H, J 6.5 Hz, CH(CH3)2), 2.16 (q, 2H, J 7.4 Hz, CH2CH3), 1.17 (t, 3H, J
ꢀꢁ3
hole¼0.470 and ꢁ0.590 e A , respectively. CCDC 990427.
7.4 Hz, CH2CH3), 1.14 (d, 6H, J 6.5 Hz, CH(CH3)2); 13C NMR

V. Evans et al. / Tetrahedron 70 (2014) 7593e7597
7597
(125 MHz; 298 K; CDCl3)
(CH2CH3), 22.7 (CH(CH3)2), 9.8 (CH2CH3); IR (neat)
1544 cmꢁ112
Compound 4h, Table 2, Entry 8. Colourless oil, 58 mg (74%). 1H
NMR (250 MHz; 298 K; CDCl3) 5.63 (br s,1H, NH) 3.91 (septet,1H, J
d
173.6 (C]O), 41.2 (CH(CH3)2), 29.8
Boc); 13C NMR (63 MHz; 298 K; CDCl3)
d
170.9 (C¼Oester), 155.0
n
2972, 1642,
(C¼OBoc), 136.3 (Arq), 129.4 (Ar), 128.2 (Ar), 126.7 (Ar), 81.8
.
(C(CH3)3 ester), 79.5 (C(CH3)3 Boc), 54.8 (CH2CH), 38.9 (CH2CH), 28.2
(C(CH3)3), 27.8 (C(CH3)3); IR (neat)
1366 cmꢁ116
n 2977, 2929, 1712, 1496, 1455,
d
.
6.6 Hz, CH(CH3)2), 2.10 (t, 2H, J 7.3 Hz, C(O)CH2), 1.65e1.53 (m, 2H,
C(O)CH2CH2), 1.29e1.25 (m, 4H, CH2CH2CH3), 1.11 (d, 6H, J 6.6 Hz,
CH(CH3)2), 0.86 (t, 3H, J 6.8 Hz, CH2CH3); 13C NMR (75 MHz; 298 K;
Acknowledgements
CDCl3)
(CH2CH2CH3), 25.5 (C(O)CH2CH2), 22.7 (CH(CH3)2), 22.3 (CH2CH3),
13.9 (CH2CH3); IR (neat)
3075, 2873, 1637 cmꢁ113
Compound 6a, Table 3, Entry 6. White solid, 46 mg (94%). 1H
NMR (250 MHz; 298 K; CDCl3) 6.78 (br s, 1H, NH), 3.25 (m, 2H,
NHCH2), 2.29 (m, 2H, C(O)CH2), 1.73 (m, 4H, C(O)CH2CH2CH2); 13C
NMR (63 MHz; 298 K; CDCl3) 172.9 (C]O), 42.0 (HNCH2), 31.5
(C(O)CH2), 22.3, 20.9 (CH2 alkyl); IR (solid)
3190, 2936, 1668 cmꢁ1
Data matches that of commercial sample (CAS: 675-20-7).
Compound 4k, Table 3, Entry 7. White solid, 54 mg (95%). 1H
NMR (400 MHz; 298 K; CDCl3) 6.56 (br s, 1H, NH), 3.21 (m, 2H,
NHCH2), 2.47 (m, 2H, C(O)CH2), 1.77e1.43 (m, 6H, C(O)
CH2CH2CH2CH2); 13C NMR (63 MHz; 298 K; CDCl3)
175.2 (C]O),
45.7 (HNCH2), 39.0 (C(O)CH2), 28.7, 28.2, 23.1 (CH2 alkyl); IR (solid)
3195, 2928, 1652 cmꢁ1. Data matches that of commercial sample
d 172.3 (C]O), 41.1 (CH(CH3)2), 36.8 (C(O)CH2), 31.4
R.L.W. would like to thank the University of Bath for a Prize
Fellowship.
n
.
d
Supplementary data
d
Supplementary data contains experimental details, full spec-
troscopic analysis data and crystallographic data. Supplementary
data related to this article can be found at http://dx.doi.org/10.1016/
j.tet.2014.07.080.
n
.
d
References and notes
d
1. (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis; Wiley-
Interscience, 1999; (b) Kocienski, P. J. Protecting Groups; Georg Thieme, 1994.
n
(CAS: 105-60-2).
ꢁ
2. (a) Singh, O. V.; Han, H. Tetrahedron Lett. 2007, 48, 7094e7098; (b) Hernandez, J.
Compound 6b, Table 3, Entry 8. White solid, 34 mg (54%). 1H
ꢁ
N.; Crisostomo, F. R. P.; Martín, T.; Martín, V. S. Eur. J. Org. Chem. 2007, 5050e5058;
ꢁ
(c) Hernandez, J. N.; Ramírez, M. A.; Martín, V. S. J. Org. Chem. 2002, 68, 743e746;
NMR (400 MHz; 298 K; CDCl3)
2H, NHCH2), 2.37 (m, 2H, C(O)CH2), 1.76e1.53 (m, 2H, C(O)
CH2CH2CH2CH2CH2); 13C NMR (63 MHz; 298 K; CDCl3)
177.9 (C]
d 6.72 (br s, 1H, NH), 3.31e3.23 (m,
(d) Yadav, J. S.; Reddy, B. V. S.; Reddy, K. S.; Reddy, K. B. Tetrahedron Lett. 2002, 43,
1549e1551; (e) Yadav, J. S.; Subba Reddy, B. V.; Reddy, K. S. Synlett 2002, 468e470;
(f) Oba, M.; Nakajima, S.; Nishiyama, K. Chem. Commun.1996,1875e1876; (h) Wei,
Z.-Y.; Knaus, E. E. Tetrahedron Lett. 1994, 35, 847e848.
3. (a) Zheng, J.; Yin, B.; Huang, W.; Li, X.; Yao, H.; Liu, Z.; Zhang, J.; Jiang, S. Tet-
rahedron Lett. 2009, 50, 5094e5097; (b) Gheorghe, A.; Schulte, M.; Reiser, O. J.
Org. Chem. 2006, 71, 2173e2176; (c) Kotsuki, H.; Ohishi, T.; Araki, T.; Arimura, K.
Tetrahedron Lett. 1998, 39, 4869e4870.
4. (a) Olimpieri, F.; Bellucci, M. C.; Volonterio, A.; Zanda, M. Eur. J. Org. Chem. 2009,
6179e6188; (b) Lee, C.-C.; Wang, P.-S.; Viswanath, M. B.; Leung, M.-k. Synthesis
2008, 1359e1366; (c) France, S.; Boonsombat, J.; Leverett, C. A.; Padwa, A. J. Org.
Chem. 2008, 73, 8120e8123; (d) Albrecht, D.; Basler, B.; Bach, T. J. Org. Chem. 2008,
73, 2345e2356; (e) Du, H.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2007,129, 762e763; (f)
Du, H.; Yuan, W.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2007, 129, 11688e11689; (g)
Padwa, A.; Crawford, K. R.; Straub, C. S.; Pieniazek, S. N.; Houk, K. N. J. Org. Chem.
2006, 71, 5432e5439; (h) Crawford, K. R.; Bur, S. K.; Straub, C. S.; Padwa, A. Org.
Lett. 2003, 5, 3337e3340; (i) Iley, J.; Tolando, R. J. Chem. Soc., Perkin Trans. 2 2000,
2328e2336; (j) Metallinos, C.; Nerdinger, S.; Snieckus, V. Org. Lett. 1999, 1,
1183e1186; (k) Rosenberg, S. H.; Rapoport, H. J. Org. Chem. 1985, 50, 3979e3982;
(l) Knapp, S.; Patel, D. V. J. Am. Chem. Soc. 1983, 105, 6985e6986.
5. Selected examples of the CeH functionalisation of NH-benzamides: (a) Ka-
nyiva, K. S.; Kuninobu, Y.; Kanai, M. Org. Lett. 2014, 16, 1968e1971; (b) Aihara,
Y.; Chatani, N. J. Am. Chem. Soc. 2013, 135, 5308e5311; (c) Hyster, T. K.; Rovis, T.
J. Am. Chem. Soc. 2010, 132, 10565e10569; (d) Bedford, R. B.; Engelhart, J. U.;
Haddow, M. F.; Mitchell, C. J.; Webster, R. L. Dalton Trans. 2010, 39,
10464e10472; (e) Kametani, Y.; Satoh, T.; Miura, M.; Nomura, M. Tetrahedron
Lett. 2000, 41, 2655e2658.
d
O), 41.81 (NHCH2), 32.18, 27.98, 25.67, 24.38 (CH2 alkyl); IR (solid)
n
3226, 2923, 1647 cmꢁ1. Data matches that of commercial sample
(CAS: 673-66-5).
Compound 6c, Table 3, Entry 9. White solid, 61 mg (83%). 1H
NMR (250 MHz; 298 K; CDCl3)
4H, ArH), 2.98 (dd, 2H, J 7.9, 7.1 Hz, C(O)CH2CH2), 2.65 (dd, 2H, J 7.9,
7.1 Hz, C(O)CH2CH2); 13C NMR (75 MHz; 298 K; CDCl3)
172.5 (C]
d 9.50 (br s, 1H, NH), 7.17e6.86 (m,
d
O), 137.2 (Arq), 127.8 (Ar), 127.4 (Ar), 123.5 (Arq), 122.9 (Ar), 115.6
(Ar), 30.6 (C(O)CH2), 27.6 (C(O)CH2CH2). Data matches that of
commercial sample (CAS: 553-03-7).
Compound 6d, Table 3, Entry 10. White solid, 45 mg (39%). 1H
NMR (300 MHz; 298 K; CDCl3)
2H, J 8.3 Hz, ArH), 5.97 (br s, 1H, NH), 2.37 (s, 3H, ArCH3), 1.46 (s, 9H,
C(CH3)3); 13C NMR (63 MHz; 298 K; CDCl3)
165.5 (C¼Oamide),150.6
d 7.61 (d, 2H, J 8.3 Hz, ArH), 7.19 (d,
d
(C¼OBoc), 141.2 (Arq), 129.5 (Ar), 128.0 (Arq), 127.6 (Ar), 82.6
(C(CH3)3), 27.9 (C(CH3)3), 21.6 (ArCH3); IR (solid) n 3150, 2990, 1752,
1659 cmꢁ1; mp 130 ꢀC.14
Compound 6e, Table 3, Entry 11. Colourless oil, 85 mg (82%).
1H NMR (250 MHz; 298 K; CDCl3)
7.16 (d, 2H, J 9.2 Hz, ArH),
7.00 (d, 2H, J 9.2 Hz, ArH), 6.41 (br s, 1H, NH), 2.21 (s, 3H, ArCH3),
1.43 (s, 9H, C(CH3)3); 13C NMR (63 MHz; 298 K; CDCl3)
152.9
(C]O), 135.7 (Arq), 132.4 (Arq), 129.4 (Ar), 118.7 (Ar), 80.2
(C(CH3)3), 28.3 (C(CH3)3), 20.6 (ArCH3); IR (neat) 3287, 3131,
2966, 1685 cmꢁ1 15
Compound 6f, Table 3, Entry 12. Colourless oil, 129 mg (90%).
1H NMR (250 MHz; 298 K; CDCl3)
4.91 (d, 1H, J 8.2 Hz, NH), 4.15
6. Tyler, S. N. G.; Webster, R. L. Chem. Commun. 2014, 50, 10665e10668.
7. Sterically hindered amides have been shown to display unusual reactivity: (a)
Hutchby, M.; Houlden, C. E.; Haddow, M. F.; Tyler, S. N. G.; Lloyd-Jones, G. C.;
Booker-Milburn, K. I. Angew. Chem., Int. Ed. 2012, 51, 548e551; (b) Clayden, J.;
Foricher, Y. J. Y.; Lam, H. K. Eur. J. Org. Chem. 2002, 3558e3565.
8. Bulky amines, for example, 2,2,6,6-tetramethylpiperidine, have been shown to
undergo ring-opening reactions: Kennedy, A. R.; Klett, J.; McGrath, G.; Mulvey, R.
E.; Robertson, G. M.; Robertson, S. D.; O’Hara, C. T. Inorg. Chim. Acta 2014, 411,1e4.
9. See Supplementary data.
d
d
n
.
10. Selected recent examples of N,N-di-Boc protected aromatics and amino acids:
d
ꢁ
(a) Artigas, G.; Marchan, V. J. Org. Chem. 2013, 78, 10666e10677; (b) Yoshimura,
(app. q, 1H, J 8.2 Hz, CH2CH), 1.68 (septet, 1H, J 6.5 Hz, CH(CH3)2),
1.43 (s, 11H, CH2CH & C(CH3)3), 1.41 (s, 9H, C(CH3)3), 0.92 (d, 6H, J
T.; Kinoshita, T.; Yoshioka, H.; Kawabata, T. Org. Lett. 2013, 15, 864e867; (c)
€
Schmidt, G.; Timm, C.; Grube, A.; Volk, C. A.; Kock, M. Chem.dEur. J. 2012, 18,
6.5 Hz, CH(CH3)2); 13C NMR (63 MHz; 298 K; CDCl3)
d 172.6
8180e8189; (d) Ilies, M.; Di Costanzo, L.; North, M. L.; Scott, J. A.; Christianson,
ꢁ
D. W. J. Med. Chem. 2010, 53, 4266e4276; (e) Arda, A.; Soengas, G.; Nieto, R.;
(C¼Oester), 155.3 (C¼OBoc), 81.3 (C(CH3)3 ester), 79.4 (C(CH3)3 Boc),
ꢁ
Jimenez, M. I.; Rodríguez, C. J. Org. Lett. 2008, 10, 2175e2178; (f) Durow, A. C.;
52.6 (CH2CH), 42.0 (CH2CH), 28.2 (C(CH3)3), 27.9 (C(CH3)3), 24.7
Long, G. C.; O’Connel, S. J.; Willis, C. L. Org. Lett. 2006, 8, 5401e5404.
11. Rolfe, A.; Probst, D. A.; Volp, K. A.; Omar, I.; Flynn, D. L.; Hanson, P. R. J. Org.
Chem. 2008, 73, 8785e8790.
12. LaPlanche, L. A.; Rogers, M. T. J. Am. Chem. Soc. 1964, 86, 337e341.
13. Krawczyk, W.; Piotrowski, G. T. J. Chromatogr. 1989, 463, 297e304.
14. Tanaka, K.; Yoshifuji, S.; Nitta, Y. Chem. Pharm. Bull. 1988, 36, 3125e3129.
15. Reddy, N. V.; Prasad, K. R.; Reddy, P. S.; Kantam, L. M.; Reddy, K. R. Org. Biomol.
Chem. 2014, 12, 2172e2175.
(CH(CH3)2), 22.0 (CH(CH3)2); IR (neat)
n 2960, 1713, 1501, 1455,
1366 cmꢁ1; HRMS (LCMS) 310.1994 (calcd for C15H29NNaO4),
310.1985 (obs.).
Compound 6g, Table 3, Entry 13. Colourless oil, 155 mg (96%).
1H NMR (250 MHz; 298 K; CDCl3)
d 7.37e7.21 (m, 5H, ArH), 5.09
(d, 1H, J 7.9 Hz, NH), 4.50 (app. q, 1H, J 7.90 Hz, CH2CH), 3.10 (d, 2H,
J 7.90 Hz, CH2CH), 1.47 (s, 9H, C(CH3)3 ester), 1.44 (s, 9H, C(CH3)3
16. Konda, Y.; Takahashi, Y.; Arima, S.; Sato, N.; Takeda, K.; Dobashi, K.; Baba, M.;
Harigaya, Y. Tetrahedron 2001, 57, 4311e4321.