Selective Phthalimido-N-oxyl (PINO)-Catalyzed C-H Cyanation of Adamantane Derivatives

Article abstract of DOI:10.1055/s-0037-1610403

We present a new method for the selective C(sp ³)-H cyanation of adamantane derivatives with PINO as the hydrogen abstracting reagent. A cyano radical is thereby transferred from p - toluenesulfonyl cyanide, allowing the cyanation of adamantane derivatives in up to 71% yield. The protocol presents a novel way to orthogonally functionalized adamantanes that are otherwise difficult to prepare. Mechanistic studies support the hypothesis of a radical pathway.

Full text of DOI:10.1055/s-0037-1610403

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Georg Thieme Verlag Stuttgart · New York
2018, 29, A–F
letter
A
en
J.-P. Berndt et al.
Letter
Synlett
Selective Phthalimido-N-oxyl (PINO)-Catalyzed C–H Cyanation of
Adamantane Derivatives
Jan-Philipp Berndt
H
CN
Frederik R. Erb
metal-free, catalytic
direct C–CN
Lukas Ochmann
Jaqueline Beppler
Peter R. Schreiner*
R
R
R
hydrogen atom abstraction
bond coupling
0
0
0
0-0
0
0
2-
3
6
0
8-5
5
1
5
R = CH3, Ph, CO2Me, N3, C=C, CN, OR, NHR, Br
=
Institute of Organic Chemistry, Justus Liebig University,
Heinrich-Buff-Ring 17, 35392 Giessen, Germany
prs@uni-giessen.de
17 examples • up to 71% yield • high selectivity • cheap • substrate (1 equiv)
Published as part of the 30 Years SYNLETT – Pearl Anniversary Issue
Received: 05.10.2018
Accepted after revision: 09.11.2018
Published online: 14.12.2018
adamantanes would greatly streamline the synthesis of
these diamondoids and facilitate their use even more. The
incorporation of nitriles is particularly desirable, as they are
widely present as key functional groups in a variety of nat-
ural products and pharmaceuticals.7 They can readily be
converted into carboxylic acids, esters, amines, or amides.
Furthermore, they can be used in [3+2] cycloadditions af-
fording heterocycles such as tetrazoles and oxadiazolines
(Scheme 1).8
DOI: 10.1055/s-0037-1610403; Art ID: st-2018-b0640-l
License terms:
Abstract We present a new method for the selective C(sp3)–H cyana-
tion of adamantane derivatives with PINO as the hydrogen abstracting
reagent. A cyano radical is thereby transferred from p-toluenesulfonyl
cyanide, allowing the cyanation of adamantane derivatives in up to 71%
yield. The protocol presents a novel way to orthogonally functionalized
adamantanes that are otherwise difficult to prepare. Mechanistic stud-
ies support the hypothesis of a radical pathway.
N
N
N
N
O
X
R
CN
Key words adamantane, C–H activation, cyanation, N-hydroxyph-
thalimide, NHPI, PINO
OR
R
R
R
X = NH2, OH
NHR
N3
N
Adamantane exhibits fascinating properties, such as ri-
gidity, lipophilicity, steric bulkiness, electron richness, and
chemical inertness.1 By virtue of these desirable features di-
amondoids, i.e., diamond-like, nanometer-sized aliphatic
cage hydrocarbons, for which adamantane is the parent, are
used as catalyst backbones,2 dispersion energy donors,3 or
molecular rectifiers.4 Adamantane is an attractive moiety in
the design of drugs, e.g., memantine and saxagliptin (both
belonging to the top 200 drugs by worldwide sales 2016),5
favorably affecting administration, distribution, metabo-
lism, and excretion (ADME) properties.6 The selective func-
tionalization of diamondoids is essential for their applica-
tion, and this presents a formidable challenge in selective
sp3-C–H bond functionalization. Usually hydroxylation,
bromination, or amination (via Ritter reaction) are used as
the first step.1 The resulting compounds can then readily be
functionalized further. However, due to the chemical inert-
ness of unactivated aliphatic C–H-bonds, functionalization
requires harsh conditions, making the synthesis of orthogo-
nally disubstituted adamantanes challenging (Scheme 1). A
mild direct C(sp3)–H functionalization of monosubstituted
NH2
O
N
CN
Br
CO2Me
Ph
Scheme 1 Orthogonally bifunctionalized adamantane derivatives
Due to the versatility of nitriles, a variety of cyanation
methods were developed. While C(sp2)–H cyanations are
well established,9 C(sp3)–H cyanations remain challenging.
They are often limited to the synthesis of pre-functional-
ized precursors such as alkyl iodides,10 allylic compounds,11
or enolates.12 Recently, two photocatalytic systems for
C(sp3) cyanation were reported utilizing alkyltrifluorobo-
rates13 and carboxylates14 as precursors. Additionally,
Sun and coworkers reported an oxidative or free radical
C(sp3)–H cyanation for alkanes, ethers, and tertiary
amines.15 Moreover, cyanations of activated C(sp3)–H
bonds, such as α-heteroatoms16 and an enantioselective
benzylic C–H cyanation17 have been established. Although
some of these methods tolerate a broad range of functional
groups, their use is restricted due to elaborate precursor
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

B
J.-P. Berndt et al.
Letter
Synlett
synthesis. Direct cyanations of unactivated C(sp3)–H bonds
are rare. Only a few direct cyanations exist, including the
pioneering studies by Müller and Huber in 1963, who intro-
duced an unselective cyanation with cyanogen chloride18
and a photoexcited benzophenone mediated C(sp3)–H cya-
nation.19 While the latter approach is applicable to benzylic
and aliphatic C–H bonds, the differentiation of these bonds
is only modest, due to the use of benzophenone as the hy-
drogen atom transfer (HAT) reagent. Furthermore, aliphatic
substrates often require the use of excess of substrate.
In continuation of our work with phthalimido-N-oxyl
(PINO),20 we envisioned a selective C(sp3)–H cyanation of
adamantanes using N-hydroxyphthalimide (NHPI).21 To the
best of our knowledge, PINO has never been used in aliphat-
ic C–H bond cyanations.22 We envisioned a three-step pro-
cess, consisting of the formation of PINO from its precursor
NHPI, followed by HAT from adamantane 1 to PINO, gener-
ating an adamantyl radical 1•, which is trapped by p-tolue-
nesulfonyl cyanide (TsCN), thereby affording the desired cy-
anated product 2 (Scheme 2).
Table 1 Screening of Systems for the PINO-Catalyzed Cyanationa
NHPI, TsCN
CN
DCE, 75 °C, 16 h
1
2
SET reagent
AIBNc
2 (%)b
5
7
d
Co(acac)3
d
Co(OAc)2
8
CANe
CASe
42
9
e
HNO3
47
a Reaction conditions: 0.5 mmol scale, ratio of1/NHPI/TsCN (1:0.1:2), 5 mL
1,2-dichloroethane, 16 h, 75 °C.
b Yields determined by GC with hexadecane as internal standard.
c 3 mol% AIBN.
d 1 mol% of the corresponding metal salt, 1 atm air.
e 1 equiv.
yield increased with decreasing cation radius; 1 equiv
Li2CO3 worked best. Furthermore, we tested Co(acac)3, a
known cocatalyst28 for PINO, but it was ineffective under
the chosen conditions. Importantly, the cyanation selective-
ly proceeds at the tertiary C–H position, thus indicating that
PINO performs a chemoselective hydrogen abstraction due
to its polarity.21b
O
HAT
NHPI
PINO
N
OH
O
H
CN
PINO
NHPI
TsCN
O
O
HAT
Ts
N
1
1
2
O
Scheme 2 PINO-catalyzed C(sp3)–H cyanation concept
Table 2 Influence of Inorganic Basesa
NHPI, CAN, TsCN, base
+
DCE, 75 °C, 16 h
We commenced our studies with 1 as a model substrate
and p-toluenesulfonyl cyanide (TsCN) as the electrophilic
cyanide source23 (Table 1). At first we performed an initial
screening to elaborate suitable reaction conditions for the
generation of PINO. Systems such as α,α′-azobisisobutyro-
nitrile (AIBN), cobalt (II/III) salts/O2, and cerium(IV) ammo-
nium sulfate (CAS) afforded only low yields of 1-cyano ada-
mantane 224 and significant amounts of starting material 1
remained. However, cerium(IV) nitrate (CAN)25 was shown
to be superior, resulting in 42% yield of 2. On the other
hand, the use of CAN also led to the formation of significant
amounts of 1-nitro adamantane 326 (13%). This side product
forms by reduction of Ce(IV) → Ce(III), thus generating
HNO3.22 HNO3 itself is capable to generate PINO, thereby re-
leasing •NO2 that recombines with the intermittently
formed 1-adamantyl radical.27 This pathway was confirmed
with the use of 1 equiv HNO3, affording 15% of 1-nitro ada-
mantane 3.
NO2
CN
1
2
3
Base (1 equiv)
2 (%)b
3 (%)b
Cs2CO3
0
56
73
77
47
51
71
60
0
<5
7
Ag2CO3
Na2CO3
Li2CO3
5
Li2CO3 (1.5 equiv)
Li2CO3 (0.5 equiv)
<5
11
8
c
Na2CO3
c,d
Na2CO3
14
a Reaction conditions: 0.5 mmol scale, ratio of 1/NHPI/CAN/TsCN/base
(1:0.2:1:2:1), 5 mL 1,2-dichloroethane, 16 h, 75 °C.
b Yields determined by GC with hexadecane as internal standard.
c 0.1 equiv NHPI.
d 1 mol% Co(acac)3.
We envisioned to suppress the formation of 3 by captur-
ing the released HNO3 (Table 2). Initial screening of bases
including MgO, acetates, and carbonates, showed that car-
bonates performed best. The use of Cs2CO3 afforded no
product, while Ag2CO3, Na2CO3, and Li2CO3 led to an in-
crease of the yield with up to 77% for Li2CO3. In general, the
With the optimized conditions in hand, we focused on
the cyanation of various substrates (Scheme 3). Common
C–H activation procedures require excess of the starting
material, in order to suppress a second C–H activation of
the product. Under our conditions, the cyanation requires
only 1 equiv starting material, thereby affording, e.g., 1-cya-
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

C
J.-P. Berndt et al.
Letter
Synlett
H
no adamantane 2 in 69% yield without formation of the di-
cyanated product. The strong electron-withdrawing cyano
group deactivates the cage, thus suppressing subsequent
cyanation. This was illustrated by utilizing 2, affording 1,3-
dicyano adamantane 429 in only 20% yield. Hence, only 1
equiv substrate is necessary in the cyanation. Methyl ada-
mantane (5)30 was isolated in 71% yield, while dimethyl 631
and trimethyl 732 substituted adamantanes were isolated in
33% and 28% yield, respectively. The same reactivity trend
for the corresponding halogenated derivatives was ob-
served by Olah and coworkers in a Lewis acid catalyzed cya-
nation.33 The di- and trisubstituted adamantanes were cya-
nated in comparable yields to the corresponding methyl de-
rivatives, affording cyanated products 834 and 9.35 The
cyanation of 1-bromo adamantane afforded product 1036 in
25% yield, with traces of N-tosyloxyphthalimide S1,37 for-
mally a product of the radical recombination of tosylsulfo-
nyl and a PINO radical. Upon addition of 20 mol% NHPI after
6 h the yield of 10 increased to 34%. 1-Cyano-3-phenyl ada-
mantane 1138 was obtained in 47% and the alkynyl deriva-
tive 1239 in 41% yield. Notably, 12 represents an orthogonal
building block, containing a triple bond, which is otherwise
not easily accessible. Adamantane carboxylic acid methyl
ester was cyanated in 50% yield (13).40 Silyl-protected alco-
hols can be also used under the chosen conditions, afford-
ing 39% (14a).41 Use of phthalimides, acetamides, and
azides in the cyanation results in the formation of γ-amino
acid derivatives 15–17.42 Note that the use of 17 results in
another orthogonally difunctionalized building block readi-
ly available for ‘click-reactions’. Furthermore, diamantane
can be cyanated in 60% yield, affording 1843 in a ratio of
4.3:1 in favor of the medial position. The cyanation of 4-dia-
mantane carboxylic acid methyl ester afforded 35% yield in
a ratio of 1:1.1 (19m1:19m2).44 Particular the syntheses of
these cyanated products 19 would require considerably
more steps in comparison to established methods.
CN
NHPI, CAN, TsCN, Li2CO3
DCE, 75 °C, 16 h
CN
CN
CN
CN
CN
2
69%
4
20%
5
6
71%
33%
CN
CN
CN
CN
CO2Me
CO2Me
Br
CO2Me
8
9
10
34%a
7
28%
35%a
30%a
CN
CN
CN
CN
Ph
CO2Me
OR
11
47%a
12
41%a
13
50%
14a R = Tbdps 39%a
14b R = H, traces
CN
CN
CN
NHAc
N3
NPht
17
27%
15
22%a
16
22%a
R1
CO2Me
18
60%
1:4.3 (18a/18m
19
35%a
b
R1
R2
R2
b
)
1:1.1 (19m1/19m2)
18a (R1 = CN, R2 = H)
18m (R1 = H, R2 = CN)
19m1 (R1 = CN, R2 = H)
18m2 (R1 = H, R2 = CN)
Scheme 3 Substrate scope of the PINO-catalyzed C(sp3)–H cyanations.
Yields of isolated, pure products are given. Reaction conditions: 0.5
mmol starting material, ratio of SM/NHPI/CAN/TsCN/base (1:0.2:1:2:1),
5 mL 1,2-dichloroethane, 16 h, 75 °C. a 20 mol% NHPI added after 6 h. b
Ratio determined by GC-MS.
In order to support our initial mechanistic hypothesis of
a radical pathway, several tests were performed (Table 3). In
the presence of a radical scavenger such as I2, no product
formed. The isolation of traces of N-tosyloxyphthalimide
S1, a result of a radical recombination, supports this hy-
pothesis. By performing a control experiment with the op-
timized conditions (1 equiv TsCN, 1 equiv Li2CO3, 0.2 equiv
NHPI, 75 °C, 16 h) the formation of S1 by a nucleophilic
substitution could be excluded. In addition, the absence of
NHPI afforded only 10% of the cyanated product. This un-
derscores that PINO indeed is the catalytically active spe-
cies. The exclusion of light decreased the yield to 40% yield.
CAN is known to produce nitroxyl radicals upon UV irradia-
tion, while CeIV is reduced to CeIII.45 However, irradiation of
the reaction mixture at 365 nm afforded only 37% yield of 2.
This result may indicate that low concentrations of nitroxyl
radicals facilitate the cyanation, while a higher concentra-
Table 3 Mechanistic Investigationsa
NHPI, CAN, TsCN, base
CN
DCE, 75 °C, 16 h
1
2
Conditions
2 (%)b
NaCN (2 equiv), TBACN (0.15 equiv)
traces (< 1%)
I2 (1 equiv)
0 mol% NHPI
dark
0
10
40
37
•
tion of NO3 leads to a higher probability of termination
365 nm
events, consequently lowering the yield. Furthermore, CAN
is reduced upon UV irradiation, thus it is not available for
the generation of PINO and finally affording a lower yield.
a Reaction conditions: 0.5 mmol scale, ratio of 1/NHPI/CAN/TsCN/base
(1:0.2:1:2:1), 5 mL 1,2-dichloroethane, 16 h, 75 °C.
b Yields determined by GC with hexadecane as internal standard.
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Moreover, the oxidation of the adamantyl radical 1• to the
cation25,46 could be excluded by the use of a CN− source
(NaCN) in combination with a phase-transfer catalyst
(TBACN), affording less than 1% yield.
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In summary, we report a novel direct C(sp3)–H cyana-
tion of adamantane and two diamantane derivatives, utiliz-
ing only 1 equiv of substrate.47 The method allows the effi-
cient synthesis of substituted cyano adamantanes. A variety
of these valuable compounds was synthesized for the first
time. Mechanistic experiments support a radical mecha-
nism.
Funding Information
This work was supported by the Justus Liebig University.()
Acknowledgment
(17) Zhang, W.; Wang, F.; McCann, S. D.; Wang, D.; Chen, P.; Stahl, S.
S.; Liu, G. Science 2016, 353, 1014.
J.-P. Berndt and F. R. Erb contributed equally to this work. We thank
Prof. A. A. Fokin for fruitful discussions.
(18) (a) Müller, E.; Huber, H. Chem. Ber. 1963, 96, 670. (b) Müller, E.;
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Supporting Information
(19) Hoshikawa, T.; Yoshioka, S.; Kamijo, S.; Inoue, M. Synthesis
2013, 45, 874.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610403.
(20) (a) Combe, S. H.; Hosseini, A.; Song, L.; Hausmann, H.; Schreiner,
P. R. Org. Lett. 2017, 19, 6156. (b) Combe, S. H.; Hosseini, A.;
Parra, A.; Schreiner, P. R. J. Org. Chem. 2017, 82, 2407. (c) Zhuk,
T. S.; Gunchenko, P. A.; Korovai, Y. Y.; Schreiner, P. R.; Fokin, A.
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(30) 1-Cyano-3-methyladamantane (5)
Yield 0.062 g (0.359 mmol, 71%). Rf = 0.40 (n-hexane/EtOAc,
15:1). HRMS (ESI): m/z calcd for C12H17NNa+: 198.1253; found:
198.1254 [M + Na+]+. IR (ATR): 2906, 2850, 2232, 1532, 1456,
1
1360, 1343, 1162, 1112, 974, 923, 756, 692 cm–1. H NMR (400
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

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J.-P. Berndt et al.
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Synlett
MHz, CDCl3): δ = 2.09–2.02 (m, 2 H), 2.00–1.87 (m, 4 H), 1.73 (s,
2 H), 1.64–1.57 (m, 2 H), 1.49–1.41 (m, 4 H), 0.84 (s, 3 H) ppm.
13C NMR (101 MHz, CDCl3): δ = 125.2 (C), 46.4 (C), 42.9 (CH2),
39.4 (2 CH2), 35.1 (2 CH2), 31.0 (CH2), 30.5 (C), 29.8 (CH3), 27.9
(2 CH) ppm.
1H NMR (400 MHz, CDCl3): δ = 7.39–7.31 (m, 4 H), 7.25–7.20
(m, 1 H), 2.27–2.23 (m, 2 H), 2.20 (s, 2 H), 2.12–2.04 (m, 4 H),
1.95–1.89 (m, 4 H), 1.80–1.73 (m, 2 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 148.6 (C), 128.6 (2 CH), 126.5 (CH), 125.0 (CN), 124.7
(2 CH), 45.1 (CH2), 41.6 (2 CH2), 39.3 (2 CH2), 36.0 (C), 35.1
(CH2), 31.5 (C), 28.1 (2 CH) ppm.
(31) 1-Cyano-3,5-dimethylcyanoadamantane (6)
Yield 0.031 g (0.164 mmol, 33%). Rf = 0.43 (n-hexane/EtOAc,
15:1). HRMS (ESI): m/z calcd for C13H19NNa+: 212.1410; found:
212.1412 [M + Na+]+. IR (ATR): 2902, 2848, 2235, 1455, 1378,
(39) 1-Cyano-3-ethynyladamantane (12)
Yield 0.038 g (0.204 mmol, 41%). Rf = 0.56 (n-hexane/EtOAc,
1:1). HRMS (ESI): m/z calcd for C13H15NNa+: 208.1097; 208.1095
[M + Na+]+. IR (ATR): 3261, 2917, 2857, 2236, 2110, 1726, 1579,
1
1359, 1342, 1232, 1144, 965, 934, 912, 772, 733 cm–1. H NMR
1
(400 MHz, CDCl3): δ = 2.11 (hept, J = 3.1 Hz, 1 H), 1.86–1.83 (m,
2 H), 1.70–1.59 (m, 4 H), 1.41–1.31 (m, 4 H), 1.17 (s, 2 H), 0.85
(s, 6 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 125.1 (C), 50.1
(CH2), 45.9 (2 CH2), 42.2 (2 CH2), 38.7 (CH2), 31.8 (C), 30.6 (C),
30.1 (2 CH3), 28.5 (2 CH) ppm.
1451, 1345, 1260, 1088, 1014, 869, 795, 688, 50 cm–1. H NMR
(400 MHz, CDCl3): δ = 2.15 (s, 1 H), 2.14 (s, 2 H), 2.13–2.09 (m, 2
H), 1.99 (d, J = 3.0 Hz, 4 H), 1.89–1.84 (m, 4 H), 1.70–1.66 (m, 2
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 124.3 (C), 90.2 (C), 68.5
(CH), 44.4 (CH2), 41.3 (2 CH2), 39.0 (2 CH2), 34.6 (CH2), 30.5 (C),
29.2(C), 27.2 (2 CH).
(32) 1-Cyano-3,5,7-trimethyladamantane (7)
Yield 0.028 g (0.138 mmol, 28%). Rf = 0.71 (n-hexane/EtOAc,
5:1). HRMS (ESI): m/z calcd for C14H21NNa+ m/z = 226.1566;
found: 226.1563 [M + Na+]+. IR (ATR): 2948, 2918, 2865, 2843,
(40) 3-Cyanoadamantane-1-carboxylic Acid Methyl Ester (13)
Yield 0.055 g (0.250 mmol, 50%). Rf = 0.47 (n-hexane/EtOAc,
+
3:1). HRMS (ESI): m/z calcd for
C13H17NNaO2
:
242.1152;
2230, 1455, 1377, 1358, 1257, 1233, 912, 788 cm–1
.
1H NMR
242.1149 [M + Na+]+. IR (ATR): 2952, 2915, 2859, 2229, 1720,
1480, 1446, 1346, 1323, 1265, 1240, 1192, 1151, 1125, 1106,
1029, 952, 866, 777, 747, 728, 570, 481, 445 cm–1. 1H NMR (400
MHz, CDCl3): δ = 3.67 (s, 3 H), 2.19–2.13 (m, 4 H), 2.04–1.96 (m,
4 H), 1.93–1.80 (m, 4 H), 1.70 (s, 2 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 176.2 (C), 124.4 (C), 52.1 (CH3), 40.7 (CH2), 40.3 (C),
39.1 (2 CH2), 37.5 (2 CH2), 34.8 (CH2), 30.6 (C), 27.2 (2 CH).
(41) 1-O-(tert-Butyldiphenylsilyl)-3-cyanoadamantanol (14a)
Yield 0.080 g (0.193 mmol, 39%). Rf = 0.39 (n-hexane/EtOAc,
15:1). HRMS (ESI): m/z calcd for C27H33NNaOSi+: 438.2224;
found: 438.2226 [M + Na+]+. IR (ATR): 3071, 2931, 2858, 2235,
1590, 1472, 1455, 1428 1357, 1337, 1316, 1155, 1143, 1110,
1068, 975, 903, 821, 740, 702, 610, 503 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 7.74–7.70 (m, 4 H), 7.45–7.36 (m, 6 H), 2.09 (s, 2 H),
1.99 (s, 2 H), 1.84–1.73 (m, 4 H), 1.70–1.64 (m, 4 H), 1.50–1.37
(m, 2 H), 1.02 (s, 9 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 136.1
(4 CH), 135.7 (2 C), 129.7 (2 CH), 127.6 (4 CH), 124.2 (C), 71.0
(C), 47.5 (CH2), 44.3 (2 CH2), 38.8 (2 CH2), 34.4 (CH2), 33.0 (C),
29.9 (3 CH3), 27.1 (2 CH), 19.3 (C) ppm.
(400 MHz, CDCl3): δ = 1.58 (s, 6 H), 1.16–1.02 (m, 6 H), 0.86 (s, 9
H) ppm.13C NMR (101 MHz, CDCl3): δ = 125.0 (C), 49.5 (3 CH2),
45.3 (3 CH2), 32.5 (C), 31.5 (3 C), 29.7 (3 CH3) ppm.
(33) Olah, G. A.; Farooq, O.; Surya Prakash, G. K. Synthesis 1985, 1140.
(34) 1-Cyanoadamantane-3,5-acetic Acid Methyl Ester (8)
Yield 0.054 g (0.177 mmol, 35%). Rf = 0.23 (n-hexane/EtOAc,
3:1). HRMS (ESI): m/z calcd for C17H23NNaO4+: 328.1519; found:
328.1516 [M + Na+]+. IR (ATR): = 2910, 2857, 2235, 1731, 1438,
1330, 1242, 1162, 1128, 1057, 1022, 851 cm–1 1H NMR (400
.
MHz, CDCl3): δ = 3.65 (s, 6 H), 2.21–2.17 (m, 1 H), 2.16 (s, 4 H),
1.93–1.87 (m, 4 H), 1.87–1.80 (m, 2 H), 1.62–1.55 (m, 2 H),
1.55–1.46 (m, 4 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 171.2
(2 C), 124.2 (C), 51.5 (2 CH3), 47.1 (2 CH2), 45.6 (CH2), 43.4 (2
CH2), 39.8 (2 CH2), 38.5 (CH2), 33.1 (2 C), 31.6 (C), 28.0 (CH)
ppm.
(35) 1-Cyanoadamantane-3-acetic Acid Methyl Ester (9)
Yield 0.039 g (0.149 mmol, 30%). Rf = 0.08 (n-pentane/Et2O,
10:1). HRMS (ESI): m/z calcd for C16H23NNaO2+: 284.1621;
found: 284.1623 [M + Na+]+. IR (ATR): 2950, 2924, 2900, 2866,
2849, 2232, 1735, 1456, 1356, 1312, 1231, 1192, 1147, 1087,
1012 cm–1. 1H NMR (400 MHz, CDCl3): δ = 3.66 (s, 3 H), 2.16 (s, 2
H), 1.76 (s, 2 H), 1.62 (s, 4 H), 1.33–1.20 (m, 4 H), 1.20–1.10 (m,
2 H), 0.88 (s, 6 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 171.5 (C),
124.5 (C), 51.5 (CH3), 49.4 (CH2), 47.2 (2 CH2), 47.0 (CH2), 45.2 (2
CH2), 43.0 (CH2), 34.06 (C), 32.37 (C), 31.4 (2 C), 29.7 (2 CH3)
ppm.
(42) 1-Cyano-3-acetamidoadamantane (15)
Yield 0.024 g (0.110 mmol, 22%). Rf = 0.46 (CH2Cl2/MeOH, 20:1).
HRMS (ESI): m/z calcd for C13H18N2NaO+: 241.1311; found:
241.1317 [M + Na+]+. IR (ATR): 3295, 3078, 2918, 2856, 2232,
1731, 1651, 1548, 1456, 1366, 1307, 1144, 1061, 1007, 702, 602,
541, 452 cm–1. 1H NMR (400 MHz, CDCl3): δ = 5.32 (s, 1 H), 2.35
(s, 2 H), 2.21 (s, 2 H), 2.11–2.06 (m, 2 H), 2.03–1.93 (m, 4 H),
1.92 (s, 3 H), 1.88–1.80 (m, 2 H), 1.67 (s, 2 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 169.8 (C), 124.1 (C), 51.0 (C), 42.9(CH2),
40.3 (2 CH2), 39.0 (2 CH2), 34.8 (CH2), 31.8 (C), 28.5 (2 CH), 24.6
(CH3) ppm.
(36) 1-Cyano-3-bromoadamantane (10)
Yield 0.040 g (0.167 mmol, 34%). Rf = 0.16 (n-pentane/Et2O,
20:1). HRMS (ESI): m/z calcd for C11H14BrNNa+: 262.0202;
262.0204 [M + Na+]+. IR (ATR): 2948, 2925, 2862, 2228, 1455,
1344, 1330, 1311, 1245, 1121, 1097, 966, 990, 822, 726, 677,
457 cm–1. 1H NMR (400 MHz, CDCl3): δ = 2.58 (s, 2 H), 2.35–2.26
(m, 4 H), 2.25–2.17 (m, 2 H), 2.04 (d, J = 2.9 Hz, 4 H), 1.75–1.69
(m, 2 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 123.2 (C), 59.6 (C),
50.1 (CH2), 47.4 (2 CH2), 38.4 (2 CH2), 33.9 (CH2), 33.5 (C), 31.0
(2 CH) ppm.
1-N-Adamantylphthalimide-3-cyano (16)
Yield 0.033 g (0.108 mmol, 22%). Rf = 0.28 (n-hexane/EtOAc,
3:1). HRMS (ESI): m/z calcd for C19H18N2NaO2+: 329.1261;
found: 329.1262 [M + Na+]+. IR (ATR): 2926, 2863, 2226, 1768,
1703, 1611, 1468, 1361, 1341, 1313, 1155, 1111, 1070, 999,
980, 969, 870, 790, 715, 643, 532, 407 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 7.79–7.74 (m, 2 H), 7.72–7.66 (m, 2 H), 2.80 (s, 2 H),
2.58–2.46 (m, 4 H), 2.30 (s, 2 H), 2.14–1.98 (m, 4 H), 1.82–1.66
(m, 2 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 169.5 (2 C), 134.1
(2 CH), 131.8 (2 C), 124.01 (C), 123.0 (2 CH), 58.6 (C), 41.8 (CH2),
38.9 (2 CH2), 38.9 (2 CH2), 34.6 (CH2), 32.3 (C), 28.8 (2 CH) ppm.
1-Azido-3-cyano-adamantane (17)
(37) Chanmiya Sheikh, M.; Takagi, S.; Ogasawara, A.; Ohira, M.;
Miyatake, R.; Abe, H.; Yoshimura, T.; Morita, H. Tetrahedron
2010, 66, 2132.
(38) 1-Cyano-3-phenyladamantane (11)
Yield 0.056 g (0.236 mmol, 47%). Rf = 0.23 (n-pentane/Et2O,
20:1). HRMS (ESI): m/z calcd for
260.1411 [M + Na+]+. IR (ATR): = 2926, 2853, 2234, 1599, 1498,
1447, 1343, 1261, 1106, 1080, 1031, 978, 758, 700, 532 cm–1
C
17H19NNa+: 260.1410;
Yield 0.027 g (0.133 mmol, 27%). Rf = 0.13 (n-pentane/Et2O,
20:1). HRMS (ESI): m/z calcd for C11H14N4Na+: 225.1114; found:
225.1111 [M + Na+]+. IR (ATR): 2919, 2861, 2230, 2087, 1456,
.
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

F
J.-P. Berndt et al.
Letter
Synlett
1360, 1339, 1318, 1244, 1130, 1108, 997, 925, 872, 836, 714,
678, 561, 489 cm–1 1H NMR (400 MHz, CDCl3): δ = 2.33–2.27
(m, 2 H), 2.04 (s, 2 H), 2.02–1.93 (m, 4 H), 1.84–1.76 (m, 4 H),
1.69–1.63 (m, 2 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 123.6
(C), 57.3 (C), 43.7 (CH2), 40.1 (2 CH2), 38.8 (2 CH2), 34.3 (CH2),
32.2 (C), 28.9 (2 CH) ppm.
H), 2.22 (s, 1 H), 2.20–2.16 (m, 3 H), 2.01–1.98 (m, 2 H), 1.97–
1.94 (m, 2 H), 1.92–1.83 (m, 6 H), 1.77–1.73 (m, 4 H) ppm. 13C
NMR (101 MHz, CDCl3): δ = 176.5 (C), 123.6 (C), 52.1 (CH3), 42.1
(CH2), 39.1 (C), 38.8 (2 CH2), 38.5 (C), 38.2 (2 CH), 37.1 (CH2),
36.5 (2 CH), 35.3 (CH), 34.3 (2 CH2), 24.7 (CH) ppm.
.
1-Cyano-4-diamantane Carboxylic Acid Methyl Ester (19m2
Rf = 0.13 (n-hexane/EtOAc, 10:1). HRMS (ESI): m/z calcd for
C
17H21NnaO2+: 294.1465; found: 294.1462 [M + Na+]+. IR (ATR):
)
(43) 4-Cyanodiamantane (18a)
Rf = 0.23 (n-pentane/Et2O, 10:1). HRMS (ESI): m/z calcd for
C
15H19NNa+: 236.1410; found: 236.1411 [M + Na+]+. IR (ATR):
2906, 2881, 2853, 2224, 1714, 1466, 1444, 1427, 1341, 1321,
1283, 1247, 1221, 1142, 1123, 1091, 1072, 1060, 1045, 1012,
980, 949, 883, 860, 814, 787, 758, 744, 698, 628, 566, 543, 519,
490, 427 cm–1. 1H NMR (400 MHz, CDCl3): δ = 3.67 (s, 3 H), 2.34
(s, 1 H), 2.31 (s, 1 H), 2.10–2.03 (m, 4 H), 1.96 (q, J = 3.1 Hz, 1 H),
1.92–1.90 (m, 1 H), 1.89–1.82 (m, 6 H), 1.77–1.72 (m, 4 H) ppm.
13C NMR (101 MHz, CDCl3): δ = 177.1 (C), 123.9 (C), 52.0 (CH3),
40.8 (CH2), 39.4 (CH2), 38.9 (2 CH), 38.4 (C), 37.3 (C), 36.5 (2
CH2), 36.5 (2 CH2), 36.1 (CH), 35.6 (2 CH), 25.3 (CH) ppm.
(45) (a) Glass, R. W.; Martin, T. W. J. Am. Chem. Soc. 1970, 92, 5084.
(b) Fokin, A. A.; Peleshanko, S. A.; Gunchenko, P. A.; Gusev, D. V.;
Schreiner, P. R. Eur. J. Org. Chem. 2000, 3357.
2908, 2884, 2847, 2228, 1440, 1377, 1358, 1314, 1258, 1126,
1090, 1047, 984, 902, 799, 572, 545, 462 cm–1 1H NMR (400
.
MHz, CDCl3): δ = 2.03–1.97 (m, 6 H), 1.85 (s, 3 H), 1.83–1.79 (m,
1 H), 1.77–1.74 (m, 3 H), 1.73–1.69 (m, 6 H) ppm. 13C NMR (101
MHz, CDCl3): δ = 125.5 (C), 40.9 (3 CH2), 37.6 (3 CH2), 36.4 (3
CH), 36.1 (3 CH), 28.8 (C), 25.4 (CH) ppm.
1-Cyanodiamantane (18m)
Rf = 0.27 (n-pentane/Et2O, 10:1). HRMS (ESI): m/z calcd for
C
15H19NNa+: 236.1410; found: 236.1408 [M + Na+]+. IR (KBR):
2918, 2889, 2850, 2227, 1636, 1460, 1443, 1340, 1314, 1260,
1057, 1048, 984, 800, 615 cm–1. 1H NMR (400 MHz, CDCl3): δ =
2.23–2.15 (m, 2 H), 2.05–2.00 (m, 2 H), 2.00–1.92 (m, 3 H), 1.87
(s, 3 H), 1.71 (s, 9 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 124.6
(C), 41.4 (CH2), 39.0 (2 CH), 38.1 (C), 37.7 (CH2), 37.1 (2 CH2),
36.6 (2 CH), 36.3 (CH), 35.1 (2 CH2), 25.6 (CH), 25.0 (CH) ppm.
(46) Mella, M.; Freccero, M.; Soldi, T.; Fasani, E.; Albini, A. J. Org.
Chem. 1996, 61, 1413.
(47) PINO-Catalyzed Cyanations of Adamantane Derivatives –
General Procedure
(44) 1-Cyano-3-diamantane Carboxylic Acid Methyl Ester (19m1
Rf = 0.13 (n-hexane/EtOAc, 10:1). HRMS (ESI): m/z calcd for
17H21NnaO2+: 294.1465; found: 294.1467 [M + Na+]+. IR (ATR):
)
1 equiv substrate, 2 equiv TsCN, 1 equiv CAN, 1 equiv Li2CO3, 0.2
equiv NHPI and 5 mL DCE were stirred for 16 h at 75 °C. The
reactions mixture was allowed to cool down to room tempera-
ture and filtered over silica gel (50 mL EtOAc, 50 mL MeCN, 50
mL EtOAc).
C
2909, 2890, 2858, 2227, 1726, 1463, 1433, 1280, 1254, 1228,
1215, 1133, 1115, 1068, 1033, 985, 889, 846, 790, 767, 739, 709,
632, 507 433, 422 cm–1. 1H NMR (400 MHz, CDCl3): δ = 3.68 (s, 3
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F