Intramolecular cobalt-catalyzed [2+2+2] cycloaddition of o-protected diyne-cyanohydrins

Article abstract of DOI:10.1055/s-0029-1219572

O-Protected cyanohydrins were found to serve as a source of the nitrile within the intramolecular cobalt-mediated [2+2+2] cycloaddition to pyridines. Several 6-substituted 1,2,3,4,7,8,9,10-octahydrophenanthridines were synthesized using this cycloaddition of diyne-cyanohydrins. By introduction a TMS group a divergent way to such phenanthridine derivatives was elaborated. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1219572

LETTER
1051
Intramolecular Cobalt-Catalyzed [2+2+2] Cycloaddition of O-Protected
Diyne-Cyanohydrins
From
D
iyne-Cyano
n
hydrins to
O
j
ctahyd
a
rophenanthridine
M
s
eißner, Ulrich Groth*
Department of Chemistry and Konstanz Research School Chemical Biology, University of Konstanz,
Universitätsstr. 10, 78457 Konstanz, Germany
Fax +49(7531)884155; E-mail: Ulrich.Groth@uni-konstanz.de
Received 19 January 2010
Abstract: O-Protected cyanohydrins were found to serve as a
source of the nitrile within the intramolecular cobalt-mediated
[2+2+2] cycloaddition to pyridines. Several 6-substituted
1,2,3,4,7,8,9,10-octahydrophenanthridines were synthesized using
this cycloaddition of diyne-cyanohydrins. By introduction a TMS
group a divergent way to such phenanthridine derivatives was elab-
orated.
CpCo(CO)2
hν, Δ
N
N
OTBS
OTBS
1
2
Scheme 1 Model system for the cycloaddition of diyne-cyano-
hydrins
Key words: cyanohydrin, cycloaddition, pyridines, alkynes, het-
erocycles
with an O-protected cyanohydrin taking the risk of sterical
hindrance disturbing the cycloaddition in account.
The cobalt-mediated [2+2+2] cycloaddition has already
been proven to be a powerful tool in organic synthesis.1
Especially intermolecular cycloadditions to polycyclic
benzene derivatives as well as to pyridines have widely
been explored.1,2 Nevertheless, the regioselectivity of this
intermolecular approach has always been problematic, al-
though several electronic and steric effects take certain in-
fluence on this issue.1f,p To solve this problem, several
intramolecular alternatives have been developed.1i,l,3
However, to build up pyridine rings intramolecularly, a
nitrile group has to be introduced into a diyne, which often
causes problems.
The synthesis of compound 1 could be started in analogy
to a sequence elaborated by Slowinski et al.7 Hence, we
started from 1,7-octadiyne 4 which was coupled with 4-
bromobutanol protected as a THP ether (compound 3).8
Within this coupling HMPA could successfully be substi-
tuted by 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidin-
one (DMPU).9 Further deprotection of the alcohol group
with p-toluene sulfonic acid monohydrate and oxidation
to the according aldehyde 7 under Swern conditions pro-
ceeded smoothly as described by Slowinski. The follow-
ing transformation of the aldehyde to a cyanohydrin could
be done in analogy to a procedure of Rawal and co-
workers10 by in situ generation of TBSCN from TBSCl
and KCN using a one-pot procedure. This reaction already
resulted in compound 1, the desired cyclization precursor
(Scheme 2).
To facilitate this challenge, based on previous work of
Chelucci and co-workers,4 Heller et al.,5 and the Kotora
group,6 we tried to introduce the nitrile group via an O-
protected cyanohydrin, which is usually built up much
more easily.
Herein we wish to present the [2+2+2] cycloaddition of
O-protected diyne-cyanohydrins to diverse substituted
octahydrophenanthridines catalyzed by a cobalt catalyst.
Br
a
+
OTHP
OTHP
3
4
5
A nitrile group embedded in a cyanohydrin has an elec-
tronical environment which is quite different from that of
an alkyl nitrile group. Hence, we wondered if a cyano-
hydrin would be able to provide the nitrile group for the
cycloaddition. Therefore, we designed a model system
containing no other functional groups than two triple
bonds and the cyanohydrin connected by alkyl bridges
(Scheme 1). In order to avoid problems caused by an un-
protected alcohol group of the cyanohydrin, which could
coordinate to the metal of the catalyst, we decided to work
b
c
O
OH
6
7
d
N
OTBS
1
Scheme 2 Model system for the cycloaddition of diyne-cyanohy-
drins. Reagents and conditions: (a) n-BuLi, DMPU, THF, –78 °C to
r.t. (66%); (b) PTSA, acetone–H2O (100:1), reflux; (c) (COCl)2,
DMSO, Et3N, CH2Cl2, –78 °C to r.t.; (d) KCN, TBSCl, ZnBr2, MeCN
(24% over 3 steps).
SYNLETT 2010, No. 7, pp 1051–1054
Advanced online publication: 05.03.2010
DOI: 10.1055/s-0029-1219572; Art ID: G00910ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
1
0

1052
A. Meißner, U. Groth
LETTER
As we did not carry out this synthesis stereoselectively, Using 1-TMS-octa-1,7-diyne instead of unprotected octa-
we got a racemic mixture of compound 1, which was also 1,7-diyne in the synthesis shown in Scheme 1 we could
used within the cyclization experiments. Since we were successfully build up a TMS-containing precursor 10 for
interested in the synthesis of aza-naphthochinones start- the cycloaddition. The cycloaddition was carried out as
ing from 2, the use of a racemate is unimportant.
described before in refluxing degassed toluene using 10
mol% CpCo(CO)2 as catalyst under irradiation with a
tungsten lamp. When no starting material could be detect-
ed by TLC the product was chromatographically purified
over silica gel resulting 98% of the unsubstituted cycliza-
tion product 2. Obviously, the desired product was pro-
todesilylated because of the acidic silica gel.14 The yield
of 2 could be improved from 40% up to 98% using the
TMS-diyne derivative. The use of neutral aluminium ox-
ide for purification instead of silica gel yielded the desired
TMS-substituted octahydrophenanthridine 11 in a 77%
yield and only little amounts of the protodesilylated side
product (Scheme 4).
Because of its convenient handling CpCo(CO)2 was used
as catalyst (10 mol%) for the intramolecular [2+2+2] cy-
cloaddition of the diyne-cyanohydrin 1. Heating to reflux
in degassed toluene under irradiation of a 250 W tungsten
lamp yielded the desired product 2 in 40% yield.11 The
successful cycloaddition could easily be confirmed in a
1
recorded H NMR spectrum showing the only pyridine
proton at d = 8.15 ppm.12 It is important to note, that no
elimination of the a-hydroxy group could be observed un-
der these harsh reaction conditions.
Having this first octahydrophenanthridine 2 in hand, we
tried to explore the influence of further sterical hindrance
within the cycloaddition by the construction of 6-substi-
tuted octahydrophenanthridines. Therefore, different
groups were introduced at the terminal acetylene of the
cyclization precursors (Scheme 3).
purification
with silica gel
98%
CpCo(CO)2,
hν, toluene,
reflux
N
To synthesize the precursors for the cycloaddition, a sim-
ilar route to the one shown in Scheme 2 could be used.
The substituents were introduced by alkylation of the bro-
mide with an already substituted diyne. The rest of the
synthesis could be done in analogy to the first route de-
scribed above.
OTBS
2
N
TMS
purification
with neutral
alumina
OTBS
10
77%
N
TMS
The cyclization of the substituted diyne-cyanohydrins 8
proceeded in good yields up to 78% (Scheme 3). This
means, even further sterical bulkyness did not disturb the
cycloaddition.
OTBS
11
Scheme 4 Cycloaddition of the TMS-substituted diyne-cyanohy-
drin and purification of the cyclization product
This TMS group could now further be substituted or func-
tionalized using various methods, for example, oxidation
according to Tamao15 or Hiyama16 coupling reaction,
which is under current investigation. Thus, a divergent
way to 6-substituted octahydrophenanthridines was
opened.
CpCo(CO)2 (10 mol%)
hν, toluene, reflux, 5 h
N
N
R
R
OTBS
OTBS
1
R = H
8a R = Me
8b R = Ph
2
R = H
40%
9a R = Me 70%
9b R = Ph
78%
In summary, we could demonstrate O-protected cyanohy-
drins to provide their nitrile group for an intramolecular
cobalt catalyzed [2+2+2] cycloaddition. By application of
this method several differently 6-substituted octahydro-
phenanthridines could be built up. The introduction of a
TMS group in position 6 of the cyclization product offers
the access to a divergent synthetic strategy for the prepa-
ration of further 6-substituted octahydrophenanthridines.
Scheme 3 Cycloaddition of diyne-cyanohydrins to 6-substituted
octahydrophenanthridines
As in these cases of 6-substituted octahydrophenan-
thridines there was no proton at the pyridine ring. Thus,
the identification was not as easy as before. 2D NMR
spectra and IR spectra, showing no acetylene or nitrile any
more, had to be recorded to identify the structures unam-
biguously. In addition, correct mass spectra and CHN
analyses were obtained for this compound as well as for
all other ones.13
Acknowledgment
A.M. thanks the Landesgraduiertenförderung Baden-Württemberg
for a doctoral fellowship and the Konstanz Research School Chemi-
cal Biology (KoRS-CB) for financial support and scientific encou-
ragement. We are grateful to the Bayer AG, the BASF AG, the
Merck KGaA and the Wacker AG for generous gifts of reagents.
In order to avoid the necessity of a very early introduction
of the substituents, we tried to introduce a functionality
that could be further derivatized after the cycloaddition.
Synlett 2010, No. 7, 1051–1054 © Thieme Stuttgart · New York

LETTER
From Diyne-Cyanohydrins to Octahydrophenanthridines
1053
0.06 [s, 3 H, Si(CH3)2t-Bu], 0.21 [s, 3 H, Si(CH3)2t-Bu], 0.89
[s, 9 H, SiMe2C(CH3)3], 1.76 (m, 6 H, 3 × CH2), 1.94–2.13
(m, 2 H, CH2), 2.37–2.64 (m, 4 H, 2 × CH2), 2.71 (m, 2 H,
CH2), 4.78 (m, 1 H, H4), 8.15 (s, 1 H, H6) ppm. 13C NMR
(100.5 MHz, CDCl3): d = –4.9, –4.0 [Si(CH3)2t-Bu], 16.9
(C2), 18.3, 22.2, 22.7, 25.0, 25.5 (C7, C8, C9, C10, and
SiMe2CMe3), 25.9 [SiMe2C(C)H3)3], 26.8 (C1), 31.9 (C3),
70.2 (C4), 130.0, 131.3 (C6a and C10a), 144.2 (C10b), 147.4
(C5), 153.8 (C4a) ppm. GC-MS: m/z (%) = 317 (1) [M]+,
260 (100) [ M – t-Bu]+, 186 (16) [M – OTBS]+, 75 (10).
IR (neat): 2927.1 (m), 2854.4 (m), 1580.7 (w), 1567.2 (w),
1461.9 (w), 1243.0 (m), 1077.7 (s), 1030.5 (s), 831.2 (s),
777.1 (s) cm–1. Anal. Calcd for C19H31NOSi: C, 71.87; H,
9.84; N, 4.41. Found: C, 71.89; H, 9.79; N, 3.50.
References and Notes
(1) For [2+2+2] cycloadditions in general, see: (a) Vollhardt,
K. P. C.; Bergman, R. G. J. Am. Chem. Soc. 1974, 96, 4996.
(b) Hillard, R. L.; Vollhardt, K. P. C. J. Am. Chem. Soc.
1977, 99, 4058. (c) Wakatsuki, Y.; Yamazaki, H.
J. Organomet. Chem. 1977, 139, 169. (d) Vollhardt, K. P.
C. Angew. Chem., Int. Ed. Engl. 1984, 23, 539. (e) Lecker,
S. H.; Nguyen, N. H.; Vollhardt, K. P. C. J. Am. Chem. Soc.
1986, 108, 856. (f) Saá, C.; Crotts, D. D.; Hsu, G.;
Vollhardt, K. P. C. Synlett 1994, 487. (g) Malacria, M.
Chem. Rev. 1996, 96, 289. (h) Groth, U.; Richter, N.;
Kalogerakis, A. Eur. J. Org. Chem. 2003, 4634.
(i) Kalogerakis, A.; Groth, U. Synlett 2003, 1886.
(j) Varela, J. A.; Saá, C. Chem. Rev. 2003, 103, 3787.
(k) Chouraqui, G.; Petit, M.; Aubert, C.; Malacria, M. Org.
Lett. 2004, 6, 1519. (l) Kesenheimer, C.; Groth, U. Org.
Lett. 2006, 8, 2507. (m) Gandon, V.; Aubert, C.; Malacria,
M. Chem. Commun. 2006, 21, 2209. (n) Chopade, P.;
Louie, J. Adv. Synth. Catal. 2006, 348, 2307. (o) Heller, B.;
Hapke, M. Chem. Soc. Rev. 2007, 36, 1085. (p) Koegl, M.;
Brecker, L.; Warrass, R.; Mulzer, J. Angew. Chem. Int. Ed.
2007, 46, 9320. (q) Heller, B.; Gutnov, A.; Fischer, C.;
Drexler, H.-J.; Spannenberg, A.; Redkin, D.; Sundermann,
C.; Sundermann, B. Chem. Eur. J. 2007, 13, 1117.
(r) Varela, J. A.; Saá, C. Synlett 2008, 2571. (s) Omae, I.
Appl. Organomet. Chem. 2008, 22, 149. (t) Shibata, T.;
Tsuchikama, K. Org. Biomol. Chem. 2008, 6, 1317.
(u) Nicolaus, N.; Strauss, S.; Neudörfl, J.-M.; Prokop, A.;
Schmalz, H.-G. Org. Lett. 2009, 11, 341. (v) Shibata, T.;
Uchiyama, T.; Endo, K. Org. Lett. 2009, 11, 3906.
(2) (a) Bönnemann, H.; Brinkmann, R.; Schlenkluhn, H.
Synthesis 1974, 575. (b) Bönnemann, H. Angew. Chem.
1978, 90, 517. (c) Bönnemann, H. Angew. Chem. 1985, 97,
264.
(13) 4-(tert-Butyldimethylsilyloxy)-6-methyl-1,2,3,4,7,8,9,10-
octahydrophenanthridine (9a)
Yellow wax; Rf = 0.67 (petroleum benzene–EtOAc = 5:1).
1H NMR (400 MHz, CDCl3): d = 0.06 [s, 3H, Si(CH3)2t-Bu],
0.23 [s, 3 H, Si(CH3)2t-Bu], 0.90 [s, 9 H, SiMe2C(CH3)3],
1.77 (m, 6 H, 3 × CH2), 1.95, 2.06 (2 × m, 2 × 1 H, CH2), 2.34
(s, 3 H, CH3), 2.40, 2.52 (2 × m, 2 × 1 H, CH2), 2.59 (m, 6 H,
3 × CH2), 4.75 (t, 1 H, 3J = 3.6 Hz, H4) ppm. 13C NMR
(100.5 MHz, CDCl3): d = –4.8, –4.0 [Si(CH3)2t-Bu], 17.5,
18.4 (2 × CH2), 22.0 (CH3), 22.3 (CH2), 22.4 (SiCMe3), 25.0
(CH2), 26.0 [SiC(CH3)3], 26.1, 26.4 (2 × CH2), 32.1 (C3),
70.3 (C4), 127.6, 129.1 (C6a and 10b), 143.9 (C10b), 152.5,
153.5 (C4a and C6) ppm. GC-MS: m/z (%) = 331 (1) [M]+,
274 (100), 200(14), 75 (12). IR (neat): 2928.6 (m), 2854.4
(m), 1575.9 (w), 1427.0 (m), 1247.3 (m), 1080.9 (s), 1028.8
(s), 1003.8 (m), 956.8 (m), 877.0 (m), 832.1 (s), 774.2 (s)
cm–1. Anal. Calcd for C20H33NOSi: C, 72.45; H, 10.03; N,
4.22. Found: C, 71.12; H, 9.76; N, 4.21.
4-(tert-Butyldimethylsilyloxy)-6-phenyl-1,2,3,4,7,8,9,10-
octahydrophenanthridine (9b)
Colorless solid; mp 116 °C. Rf = 0.70 (petroleum benzene–
EtOAc = 5:1). 1H NMR (400 MHz, CDCl3): d = 0.05 [s, 3 H,
Si(CH3)2t-Bu], 0.19 [s, 3 H, Si(CH3)2t-Bu], 0.90 [s, 9 H,
SiMe2C(CH3)3], 1.55 (m, 2 H, H9), 1.77, 1.93 (2 × m, 2 × 1
H, H10), 1.82, 2.16 (2 × m, 2 × 1H, H2), 1.84, 2.02 (2 × m,
2 × 1 H, H3), 2.49, 2.70 (2 × m, 2 × 1 H, H1), 2.60, 2.77 (2
× m, 2 × 1 H, H7), 2.62 (m, 2 H, H8) ppm. 13C NMR (100.5
MHz, CDCl3): d = –4.9, –4.0 [Si(CH3)2t-Bu], 17.1 (C2), 18.4
(SiMe2CMe3), 22.4 (C10), 22.5 (C9), 25.2 (C1), 25.9
[SiMe2C(CH3)3], 26.4 (C8), 28.4 (C7), 31.9 (C3), 70.2 (C4),
127.3 (C4¢), 127.7 (C2¢), 129.0 (C10a), 129.1 (C1¢), 129.3
(C3¢), 141.1 (C6a), 144.9 (C10b), 153.1 (C4a), 155.6 (C6)
ppm. GC-MS: m/z (%) = 393 (1) [M]+, 336 (100), 262 (11),
75 (15). IR (neat): 3050.3 (w), 2925.8 (s), 2853.4 (m),
1571.9 (m), 1558.2 (m), 1471.4 (m), 1460.5 (m), 1451.9 (m),
1416.5 (m), 1358.8 (m), 1252.4 (m), 1068.0 (s), 1021.2 (s),
957.7 (s), 878.2 (s), 830.3 (s), 769.8 (s), 742.1 (s), 695.5 (s)
cm–1. Anal. Calcd for C25H35NOSi: C, 76.28; H, 8.96; N,
3.56. Found: C, 75.45; H, 8.89; N, 3.31.
(3) (a) Groth, U.; Huhn, T.; Kesenheimer, C.; Kalogerakis, A.
Synlett 2005, 1758. (b) Groth, U.; Richter, N.; Kalogerakis,
A. Synlett 2006, 905. (c) Garcia, P.; Moulin, S.; Miclo, Y.;
Leboeuf, D.; Gandon, V.; Aubert, C.; Malacria, M. Chem.
Eur. J. 2009, 15, 2129.
(4) Chelucci, G.; Cabras, M. A.; Saba, A. Tetrahedron:
Asymmetry 1994, 5, 1973.
(5) (a) Heller, B.; Sundermann, B.; Fischer, C.; You, J.; Chen,
W.; Drexler, H.-J.; Knochel, P.; Bonrath, W.; Gutnov, A.
J. Org. Chem. 2003, 68, 9221. (b) Heller, B.; Redkin, D.;
Gutnov, A.; Fischer, C.; Bonrath, W.; Karge, R.; Hapke, M.
Synthesis 2008, 69.
(6) Hrdina, R.; Dračínský, M.; Valterová, I.; Hodačová, J.;
Císařová, I.; Kotora, M. Adv. Synth. Catal. 2008, 350, 1449.
(7) Slowinski, F.; Aubert, C.; Malacria, M. Eur. J. Org. Chem.
2001, 3491.
(8) Dickschat, J. S.; Bode, H. B.; Kroppenstedt, R. M.; Müller,
R.; Schulz, S. Org. Biomol. Chem. 2005, 3, 2824.
(9) Bengtsson, M.; Liljefors, T. Synthesis 1988, 250.
(10) Rawal, V. H.; Rao, J. A.; Cava, M. P. Tetrahedron Lett.
1985, 26, 4275.
(11) A Typical Procedure for the Cycloaddition Reaction
To the diyne-cyanohydrin (0.5 mmol) a solution of
CpCo(CO)2 (0.05 mmol) in toluene (15 mL) was added. The
reaction mixture was refluxed with contemporaneous
irradiation by a 250 W tungsten lamp until no starting
material could be detected by TLC. After addition of silica
gel and evaporation of the solvent the product was subjected
to column chromatography yielding the desired product.
(12) 4-(tert-Butyldimethylsilyloxy)-1,2,3,4,7,8,9,10-
octahydrophenanthridine (2)
4-(tert-Butyldimethylsilyloxy)-6-(trimethylsilyl)-
1,2,3,4,7,8,9,10-octahydrophenanthridine (11)
Yellowish solid; mp 58 °C. Rf = 0.60 (PE–Et2O = 5:1). 1H
NMR (400 MHz, CDCl3): d = 0.06 [s, 3 H, OSi(CH3)2], 0.24
[s, 3 H, OSi(CH3)2], 0.34 [s, 9 H, Si(CH3)3], 0.90 [s, 9 H,
OSiMe2C(CH3)3], 1.68–1.88 (m, 6 H, 3 × CH2), 1.97–2.14
(m, 2 H, CH2), 2.38–2.68 (m, 4 H, 2 × CH2), 2.82 (m, 2 H,
H3), 4.82 (s, 1 H, H4) ppm. 13C NMR (100.5MHz, CDCl3):
d = –4.9, –4.0 [OSi(CH3)2], 0.03 [Si(CH3)3], 16.9, 18.3, 22.5,
22.6, 25.3 (5 × CH2), 25.9 (OSiMe2CCH3)3), 26.0
[OSiMe2CCH3)3], 28.4 (CH2), 32.0 (C3), 70.3 (C4), 129.7,
137.4, 141.9 (C7, C10a, C10b), 153.5, 162.6 (C4a, C6) ppm.
GC-MS: m/z (%) = 389 (1) [M]+, 374 (4) [M – Me]+, 332
(100) [M – t-Bu]+, 316 (5) [M – TMS]+, 258 (9) [M –
Yellowish solid; mp 60–62 °C. Rf = 0.43 (petroleum
benzene–EtOAc = 5:1). 1H NMR (400 MHz, CDCl3): d =
Synlett 2010, No. 7, 1051–1054 © Thieme Stuttgart · New York

1054
A. Meißner, U. Groth
LETTER
OTBS]+, 242 (12), 73 (26), 57 (13). IR (neat): 2943.7 (m),
2928.1 (m), 2854.9 (m), 1558.5 (w), 1542.6 (w), 1470.9 (m),
1243.9 (s), 1076.3 (s), 1033.2 (s), 826.8 (s), 775.8 (s) cm–1.
Anal. Calcd for C22H39NOSi2: C, 67.80; H, 10.09; N, 3.59.
Found: C, 67.33; H, 10.15; N, 3.25.
Matsumoto, H.; Kurita, A.; Kumada, M. J. Am. Chem. Soc.
1978, 100, 290. (b) Tamao, K.; Kakui, T.; Kumada, M.
J. Am. Chem. Soc. 1978, 100, 2268. (c) Tamao, K.; Ishida,
N.; Tanaka, T.; Kumada, M. Organometallics 1983, 2,
1694. (d) Tamao, K.; Maeda, K.; Yamaguchi, T.; Ito, Y.
J. Am. Chem. Soc. 1989, 111, 4984. (e) Tamao, K.;
Hayashi, T.; Ito, Y. In Frontiers of Organosilicon
Chemistry; Bassindale, A. R.; Gaspar, P. P., Eds.; RSC:
Cambridge, 1991, 197.
(14) For acidic protodesilylation, see: (a) Geiger, R. E.; Lalonde,
M.; Stoller, H.; Schleich, K. Helv. Chim. Acta 1984, 67,
1274. (b) Parnell, C. A.; Vollhardt, K. P. C. Tetrahedron
1985, 41, 5791.
(15) For the Tamao oxidation in general, see: (a) Tamao, K.;
Yoshida, J.-L.; Takahashi, M.; Yamamoto, H.; Kakui, T.;
(16) For reviews of the Hiyama reaction, see, for example:
(a) Hiyama, T.; Shirakawa, E. Top. Curr. Chem. 2002, 219,
61. (b) Denmark, S. E.; Sweis, R. F. In Metal-Catalyzed
Cross-Coupling Reactions; De Meijere, A.; Diederich, F.,
Eds.; Wiley-VCH: Weinheim, 2004, Chap. 4.
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