Intramolecular C-H insertion in ring-expanded N-heterocyclic carbenes

Article abstract of DOI:10.1016/j.tetlet.2009.11.090

Mild heating of the ring-expanded N-heterocyclic carbenes 7-Mes and 6-Mes results in intramolecular insertion of the carbene into an ortho-methyl C-H bond. In the presence of traces of acid, the resulting products ring-open to afford N-alkyl indoles.

Full text of DOI:10.1016/j.tetlet.2009.11.090

Tetrahedron Letters 51 (2010) 557–559
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Intramolecular C–H insertion in ring-expanded N-heterocyclic carbenes
*
Robert S. Holdroyd, Michael J. Page, Mark R. Warren, Michael K. Whittlesey
Department of Chemistry, 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:
Mild heating of the ring-expanded N-heterocyclic carbenes 7-Mes and 6-Mes results in intramolecular
insertion of the carbene into an ortho-methyl C–H bond. In the presence of traces of acid, the resulting
products ring-open to afford N-alkyl indoles.
Received 2 October 2009
Accepted 20 November 2009
Available online 26 November 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
N-Heterocyclic carbenes
C–H insertion
Indoles
N-Heterocyclic carbenes (NHCs) are a well-established class of
compounds of considerable importance due to their roles as li-
gands in metal-mediated catalysis and as organocatalysts in their
own right.1 While the majority of studies have focused on the
unsaturated and saturated five-membered ring species A and B
(Scheme 1), the so-called ring-expanded carbenes that is, those
containing seven- and six-membered rings, such as C and D have
recently started to receive some attention.2 These species display
a significantly wider N–C–N angle than their five-membered coun-
terparts, which in turn considerably increases their basicity.3 We
now report another remarkable difference with the observation
that mild heating of the seven- and six-membered carbenes with
N-mesityl substituents (7-Mes, 1; 6-Mes, 2: Scheme 2) leads to
insertion of the carbene into one of its own ortho-methyl C–H
bonds. Although such intramolecular C–H activation has been ob-
served with unstable acyclic monoaminocarbenes, we believe it
to be unknown for diaminocarbenes.4 Indeed there is only one
example of this class of carbenes reacting with non-acidic C–H
bonds,5 that being the low yielding insertion of a mixed N-Et/
N-iPr six-membered carbene into a methyl C–H bond of toluene.6
Substitution of the five-membered carbenes IMes and SIMes
(Scheme 1: A and B, R = mesityl) into a range of ruthenium com-
plexes, including Ru(PPh3)3(CO)H2, Ru(PPh3)3(CO)HX (X = F, Cl)
and Ru(PPh3)3HCl has been previously described.7 Efforts to react
these same precursors with 7-Mes 1 at elevated temperatures
failed to generate any Ru–NHC containing products but instead,
in all cases, gave the C–H insertion product 3 (Scheme 2).8 Further
examination revealed that 3 could be formed by simply heating an
in situ-generated solution of 1 by itself in benzene at 70 °C for
24 h.9 Similarly, heating the six-membered ring carbene 2 at
70 °C gave the insertion product 4, although the reaction pro-
ceeded a lot more slowly, requiring 72 h to go to completion.10
Proton NMR spectroscopy provided unequivocal evidence for
the structures of 3 and 4 with the appearance of a doublet of dou-
blets resonance for the unique aminal proton at the C2 position (3:
d 4.97; 4: d 4.87) and two doublets of doublets arising from the dia-
stereotopic protons of the activated arm (3: d 2.77, 2.62; 4: d 2.55,
2.46). In contrast to the 1H NMR spectra of 1 and 2, which display
only two methyl signals, four and five methyl resonances were
seen for 3 and 4, respectively, consistent with the activation of
one of the mesityl rings. The high frequency quaternary C2
resonances of 1 (d 257.3) and 2 (d 244.9) in the 13C{1H} PENDANT
RN
NR
R
RN
NR
N R
N
R
N
N R
B
C
A
D
Scheme 1.
Mes
HN
n
n
n
N
N
H+
N
N
Δ
N
Mes
Mes
H
5
1
3
(n = 2)
(n = 2)
(n = 2)
6 (n = 1)
2 (n = 1)
4 (n = 1)
Mes = 2,4,6-Me
3C6H2
* Corresponding author. Tel.: +44 (0)1225 383768; fax: +44 (0)1225 382631.
E-mail address: m.k.whittlesey@bath.ac.uk (M.K. Whittlesey).
Scheme 2.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.090

558
R. S. Holdroyd et al. / Tetrahedron Letters 51 (2010) 557–559
Nolan, S. P., Ed.; Wiley-VCH: Weinheim, 2006; (d) Glorius, F. Top. Organomet.
Chem. 2007, 21; (e) Enders, D.; Niemeier, O.; Henseler, A. Chem. Rev. 2007, 107,
5606; (f) Hahn, F. E.; Jahnke, M. C. Angew. Chem., Int. Ed. 2008, 47, 3122;.
2. (a) Mayr, M.; Wurst, K.; Ongania, K.-H.; Buchmeiser, M. R. Chem. Eur. J. 2004, 10,
1256; (b) Yang, L. R.; Mayr, M.; Wurst, K.; Buchmeiser, M. R. Chem. Eur. J. 2004,
10, 5761; (c) Scarborough, C. C.; Grady, M. J. W.; Guzei, I. A.; Gandhi, B. A.;
Bunel, E. E.; Stahl, S. S. Angew. Chem., Int. Ed. 2005, 44, 5269; (d) Bantu, B.;
Wang, D. R.; Wurst, K.; Buchmeiser, M. R. Tetrahedron 2005, 61, 12145; (e)
Rogers, M. M.; Wendlandt, J. E.; Guzei, I. A.; Stahl, S. S. Org. Lett. 2006, 8, 2257;
(f) Iglesias, M.; Beetstra, D. J.; Stasch, A.; Horton, P. N.; Hursthouse, M. B.; Coles,
S. J.; Cavell, K. J.; Dervisi, A.; Fallis, I. A. Organometallics 2007, 26, 4800; (g)
Scarborough, C. C.; Bergant, A.; Sazama, G. T.; Guzei, I. A.; Spencer, L. C.; Stahl, S.
S. Tetrahedron 2009, 65, 5084; (h) Binobaid, A.; Iglesias, M.; Beetstra, D. J.;
Kariuki, B.; Dervisi, A.; Fallis, I. A.; Cavell, K. J. Dalton Trans. 2009, 7099.
3. Iglesias, M.; Beetstra, D. J.; Knight, J. C.; Ooi, L. L.; Stasch, A.; Coles, S. J.; Male, L.;
Hursthouse, M. B.; Cavell, K. J.; Dervisi, A.; Fallis, I. A. Organometallics 2008, 27,
3279.
Figure 1. ORTEP diagram of 6. Ellipsoids are shown at 50% probability while all
hydrogen atoms have been removed for clarity.
4. (a) Goumri, S.; Leriche, Y.; Gornitzka, H.; Baceiredo, A.; Bertrand, G. Eur. J. Inorg.
Chem. 1998, 1539; (b) Solé, S.; Gornitzka, H.; Schoeller, W. W.; Bourissou, D.;
Bertrand, G. Science 2001, 292, 1901; (c) Canac, Y.; Conejero, S.; Soleilhavoup,
M.; Donnadieu, B.; Bertrand, G. J. Am. Chem. Soc. 2006, 128, 459; (d) Vignolle, J.;
Asay, M.; Miqueu, K.; Bourissou, D.; Bertrand, G. Org. Lett. 2008, 10, 4299; (e)
Vignolle, J.; Cattoën, X.; Bourissou, D. Chem. Rev. 2009, 109, 3333. While this
manuscript was being refereed, there have been reports of intramolecular C-H
insertion in a free diamidocarbene (Hudnall, T. W.; Bielawski, C. W. J. Am. Chem.
Soc. 2009, 131, 16039) and a free abnormal N-heterocyclic carbene (Aldeco-
Perez, E.; Rosenthal, A. J.; Donnadieu, B.; Parameswaran, P.; Frenking, G.;
Bertrand, G. Science 2009, 326, 556).
5. For examples of NHC insertion into acidic (pKa ꢁ 25) C–H bonds see: (a)
Arduengo, A. J., III; Calabrese, J. C.; Davidson, F.; Dias, H. V. R.; Goerlich, J. R.;
Krafczyk, R.; Marshall, W. J.; Tamm, M.; Schmutzler, R. Helv. Chim. Acta 1999,
82, 2348; (b) Korotkikh, N. I.; Ytayenko, G. F.; Shvaika, O. P.; Pekhtereva, T. M.;
Cowley, A. H.; Jones, J. N.; Macdonald, C. L. B. J. Org. Chem. 2003, 68, 5762; (c)
Nyce, G. W.; Csihony, S.; Waymouth, R. M.; Hedrick, J. L. Chem. Eur. J. 2004, 10,
4073.
spectra were replaced by signals at d 82.6 (3) and d 81.8 (4) for the
newly formed methine C2 carbon centres.11 Despite a number of
attempts, 3 and 4 could only be isolated as viscous oils, excluding
any possibility of crystallographic characterisation.
Dissolution of either 3 or 4 in CDCl3 resulted in opening of the
saturated seven- and six-membered rings to afford the N-alkyl in-
dole products 5 and 6.12 Proton NMR spectra revealed the presence
of two new high frequency doublets for both 5 (d 6.86, 6.26) and 6
(d 6.70, 6.51), characteristic of the indolyl protons. The structure of
6 was confirmed unequivocally by X-ray crystallography (Fig. 1)
following the successful crystallisation of the compound from a
concentrated MeOH solution at ꢀ78 °C.13 Exposure of 3 and 4 to
a silica gel column led to their conversion into 5 and 6, which along
with the chloroform result, suggests that traces of acid are likely to
be responsible for the ring-opening reaction.14
Further work is necessary to elucidate fully the factors that gov-
ern the insertion chemistry seen for 1 and 2. The order of basicity
(7-NHC > 6-NHC > 5-NHC)15 makes it very likely that this is an
important contributor. In line with this, thermolysis of SIMes
(Scheme 1: B, R = mesityl) at 70 °C for 72 h resulted in no insertion
chemistry. The proximity of the carbene lone pair of electrons to a
C–H bond does not appear to be paramount given that the distance
from the carbenic carbon to the nearest methyl substituent is in
fact longer in the more reactive species 1 (3.348 Å) than it is in 2
(3.281 Å).3 The same two structures show quite different CMes–
N–N–CMes torsion angles, and it may be that these are altered
upon generating the bicyclic ring systems present in 3 and 4. It is
also worth noting that upon changing the N-substituent on the se-
ven-membered carbene from mesityl to 2,6-diisopropylphenyl, no
activation of an isopropyl methyl C–H bond was observed even
after heating at 70 °C for 48 h, implying that it is unfavourable to
form a second six- rather than five-membered ring.
6. Lloyd-Jones, G. C.; Alder, R. W.; Owen-Smith, G. J. J. Chem. Eur. J. 2006, 12, 5361.
7. (a) Jazzar, R. F. R.; Macgregor, S. A.; Mahon, M. F.; Richards, S. P.; Whittlesey, M.
K. J. Am. Chem. Soc. 2002, 124, 4944; (b) Abdur-Rashid, K.; Fedorkiw, T.; Lough,
A. J.; Morris, R. H. Organometallics 2004, 23, 86; (c) Dharmasena, U. L.; Foucault,
H. M.; dos Santos, E. N.; Fogg, D. E.; Nolan, S. P. Organometallics 2005, 24, 1056;
(d) Reade, S. P.; Mahon, M. F.; Whittlesey, M. K. J. Am. Chem. Soc. 2009, 131,
1847.
8.
A
suspension of 1ꢂHBF4 (528 mg, 1.25 mmol) and KN(SiMe3)2 (250 mg,
1.25 mmol) in benzene (10 mL) was heated at 70 °C for 24 h. The solution
was cooled, filtered to remove KBF4 and the volatiles were removed in vacuo to
yield a pale yellow oil corresponding to 3 (418 mg, 99% yield). 1H NMR (see
Supplementary data for assignments; 500 MHz, C6D6, 298 K): d 6.79 (s, 1H,
CHm), 6.76 (s, 1H, CHm), 6.69 (s, 1H, CH7), 6.59 (s, 1H, CH5), 4.97 (dd, 1H,
0
0
3JHH = 8.2 Hz, JHH = 5.6 Hz, CH2), 3.92 (m, 1H, CH21 ), 3.21 (m, 1H, CH21 ), 3.00
3
0
2
3
(m, 2H, CH24 ), 2.77 (dd, 1H, JHH = 16.2 Hz, JHH = 5.6 Hz, CH23), 2.62 (dd, 1H,
2JHH = 16.2 Hz, 3JHH = 8.2 Hz, CH23), 2.29 (s, 3H, C8CH3), 2.21 (s, 6H, CoCH3), 2.18
0
0
(s, 3H, C6CH3), 2.15 (s, 3H, CpCH3), 1.73 (m, 1H, CH22 ), 1.60 (m, 1H, CH22 ), 1.53
0
0
(m, 1H, CH23 ), 1.46 (m, 1H, CH23 ). 13C{1H}: d 147.7 (s, C9), 145.0 (s, Ci), 138.6 (s,
Co), 137.7 (s, Co), 135.0 (s, Cp), 132.0 (s, C7), 130.6 (s, Cm), 130.3 (s, Cm), 130.0 (s,
0
0
C4), 127.8 (s, C6), 123.4 0(s, C5), 118.7 0(s, C8), 82.6 (s, C2), 53.7 (s, C4 ), 48.8 (s, C1 ),
35.2 (s, C3), 31.4 (s, C3 ), 29.2 (s, C2 ), 21.2 (s, C6CH3), 21.1 (s, CpCH3), 20.5 (s,
CoCH3), 20.4 (s, CoCH3), 20.0 (s, C8CH3). ESI-TOF MS: [M+H]+ m/z = 335.2495
(theoretical 335.2487).
9. The in situ route was adopted simply for convenience, as isolation of 1 and 2
(see Ref. 3 for their reported preparation and isolation) in our hands proved
possible only in low yields. Nevertheless, thermolysis of an isolated
In conclusion, we have demonstrated that increasing the ring
size (5 ? 6 ? 7) in N-heterocyclic carbenes results in the unprece-
dented observation of intramolecular C–H insertion in a diamino-
carbene. We believe that these results have ramifications not
only in organocarbene chemistry, but also in the application of
these ligands in transition metal catalysis.
crystalline sample of
was slower.
1 in benzene generated 3, although the conversion
10.
A
suspension of 2ꢂHBF4 (510 mg, 1.25 mmol) and KN(SiMe3)2 (250 mg,
1.25 mmol) in benzene (10 mL) was heated at 70 °C for 72 h. The solution
was cooled, filtered to remove KBF4 and the volatiles were removed in vacuo to
yield an oil, which was purified by distillation under vacuum (100 °C,
6 ꢃ 10ꢀ2 mmHg) to afford 4 as a pale yellow oil (304 mg, 76% yield). 1H NMR
(see Supplementary data for assignments; 500 MHz, C6D6, 298 K): d 6.78 (s, 1H,
CHm), 6.68 (s, 1H, CHm), 6.64 (s, 1H, CH7), 6.59 (s, 1H, CH5), 4.87 (dd, 1H,
Acknowledgement
0
0
3JHH = 6.1 Hz,0 JHH = 4.5 Hz, CH2), 4.12 (m, 1H, CH212 ), 3.13 (m, 1H, CH24 ), 3.00
3
0
3
(m, 1H, CH21 ), 2.79 (m, 1H, CH24 ), 2.55 (dd, 1H, JHH = 15.0 Hz, JHH = 6.1 Hz,
CH23), 2.46 (dd, 1H, 2JHH = 15.0 Hz, 3JHH = 4.5 Hz, CH23), 2.26 (s, 3H, C8CH3), 2.18
(s, 3H, C6CH3), 2.15 (s, 3H, CoCH3), 2.13 (s, 3H, CpCH3), 2.10 (s, 3H, CoCH3), 1.92
The EPSRC is acknowledged for funding (M.J.P.).
0
0
(m, 1H, CH22 ), 1.12 (m, 1H, CH22 ). 13C{1H}: d 146.5 (s, C9), 144.2 (s, Ci), 140.3 (s,
Supplementary data
Co), 137.1 (s, Co), 135.5 (s, Cp), 132.1 (s, C7), 130.9 (s, C4), 130.6 (s, Cm), 130.0 (s,
0
0
C
m), 127.6 (s, C6), 124.3 (s, C5), 117.9 (s, C8), 81.8 (s, C2), 50.6 (s, C3 ), 47.4 (s, C1 ),
0
34.3 (s, C3), 26.3 (s, C2 ), 21.2 (s, CpCH3), 21.1 (s, C6CH3), 20.4 (s, CoCH3), 20.3 (s,
C8CH3), 19.6 (s, CoCH3). ESI-TOF MS: [M+H]+ m/z = 321.2325 (theoretical
321.2331). Analysis found: C, 81.01; H, 8.63; N, 8.63. C22H28N2ꢂ0.33 MeOH
requires: C, 81.02; H, 8.93; N, 8.46.
Supplementary data (NMR numbering schemes for compounds
3–6) associated with this article can be found, in the online version,
at doi:10.1016/j.tetlet.2009.11.090.
11. (a) Chen, Y.-T.; Jordan, F. J. Org. Chem. 1991, 56, 5029; (b) Alder, R. W.; Blake, M.
E.; Chaker, L.; Harvey, J. N.; Paolini, F.; Schutz, J. Angew. Chem., Int. Ed. 2004, 43,
5896.
References and notes
12. Solutions of 3 or 4 (1.10 mmol) were stirred in CHCl3 (10 mL) for 24 h. These
solutions were reduced to dryness, redissolved in MeOH (2 mL) and cooled at
1. (a) Bourissou, D.; Guerret, O.; Gabba, F. P.; Bertrand, G. Chem. Rev. 2000, 100, 39;
(b) Enders, D.; Balensiefer, T. Acc. Chem. Res. 2004, 37, 534; (c) N-Heterocyclic

R. S. Holdroyd et al. / Tetrahedron Letters 51 (2010) 557–559
559
ꢀ
ꢀ78 °C overnight to afford white crystals of the products (5, 86%; 6, 90%). Data
for 5: 1H NMR (see Supplementary data for assignments; 500 MHz, CDCl3,
13. Crystal data for 6: C22H28N2, M = 320.46, k = 0.71073 Å, triclinic, space group P1
(No. 2), a = 8.6573(16), b = 14.410(3), c = 15.828(4) Å,
105.834(18),
= 98.632(16)°, U = 1823.1(7) Å3, Z = 4, Dc = 1.168 g cmꢀ3
= 0.068 mmꢀ1
F(0 0 0) = 696, crystal size 0.30 ꢃ 0.09 ꢃ 0.07 mm, unique
reflections = 6102 [Rint = 0.0246], observed I > 2 3199, data/restraints/
a = 100.81(2), b =
3
298 K): d 7.14 (s, 1H, CH5), 6.86 (d, 1H, JHH = 3.0 Hz, CH2), 6.70 (s, 2H, CHm),
c
,
,
3
3
6.65 0 (s, 1H, CH7), 6.26 (d, 1H, JHH = 3.0 Hz, CH3), 4.20 (t, 2H, JHH = 7.3 Hz,
l
0
CH21 ), 2.80 (t, 2H, 3JHH = 7.3 Hz, CH24 ), 2.56 (s, 3H, C8CH3), 2.28 (s, 3H, C6CH3),
rI =
0
0
2.11 (s, 3H, CpCH3), 2.10 (s, 6H, CoCH3), 1.76 (m, 2H, CH22 ), 1.49 (m, 2H, CH23 ).
13C{1H}: d 143.6 (s, Ci), 133.0 (C9), 131.6 (s, Cp), 130.4 (s, Co), 129.9 (s, C4), 129.7
(s, C2), 129.6 (s, Cm), 128.9 (s, C6), 126.5 (s, C7), 120.5 (s, C8), 118.9 (s, C5), 101.1
parameters = 6102/2/452, R1 = 0.0433, wR2 = 0.0879 (obs. data), R1 = 0.0862,
wR2 = 0.0942 (all data), max peak/hole 0.251 and ꢀ0.197 e Åꢀ3, software used,
SHELXS, SHELXL and ORTEX. Sheldrick, G. M. Acta. Crystallogr. 1990, 467–473, A46.
0
0
0
0
(s, C3), 48.9 (s, C1 ), 48.7 (s, C4 ), 30.6 (s, C2 ), 28.7 (s, C3 ), 21.2 (s, C6CH3), 20.8 (s,
CpCH3), 20.0 (s, C8CH3), 18.5 (s, CoCH3). ESI-TOF MS: [M+H]+ m/z = 335.2473
(theoretical 335.2487). Data for 6: 1H NMR (see Supplementary data for
assignments; 500 MHz, C6D6, 298 K): d 7.39 (s, 1H, CH5), 6.80 (s, 1H, CH7), 6.77
Sheldrick, G. M. SHELXL-97, a computer program for crystal structure refinement,
University of Göttingen, 1997. Crystallographic data for 6 has been deposited
with the Cambridge Crystallographic Data Centre as supplementary
publication CCDC 741905. Copies of the data can be obtained free of charge
on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax(+44) 1223
336033, e-mail: deposit@ccdc.cam.ac.uk].
(s, 2H, CHm), 6.70 (d, 1H, JHH = 2.9 Hz, CH2), 6.51 (d, 1H, JHH = 2.9 Hz, CH3),
3
3
0
0
3
3
3.88 (t, 2H, JHH = 7.2 Hz, CH21 ), 2.62 (t, 2H, JHH = 7.2 Hz, CH23 ), 2.48 (s, 3H,
C8CH3), 2.42 (s, 3H, C6CH3), 2.17 (s, 3H, CpCH3), 2.07 (s, 6H, CoCH3), 1.58 (m, 2H,
14. For examples of acid-induced ring-opening of aminals, see: (a) Shinohara, T.;
Deng, H.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2005, 127, 7334; (b)
López-Alvarado, P.; Caballero, E.; Avendaño, C.; Menéndez, J. C. Org. Lett. 2006,
8, 4303.
15. (a) Magill, A. M.; Cavell, K. J.; Yates, B. F. J. Am. Chem. Soc. 2004, 126, 8717; (b)
See Ref. 3.; (c) Iglesias, M.; Beetstra, D. J.; Kariuki, B.; Cavell, K. J.; Dervisi, A.;
Fallis, I. A. Eur. J. Inorg. Chem. 2009, 1913.
0
CH22 ). 13C{1H}: d 144.2 (s, Co), 134.1 (s, C9), 131.8 (s, Ci), 131.5 (s, C4), 130.4 (s,
Cp), 130.2 (s, Cm), 129.6 (s, C2), 129.1 (s, C6), 127.2 (s, C7), 120.6 (s, C8), 119.9 (s,
0
0
0
C5), 102.0 (s, C3), 47.4 (s, C1 ), 46.4 (s, C3 ), 34.3 (s, C2 ), 21.7 (s, C6CH3), 21.1 (s,
CpCH3), 20.3 (s, C8CH3), 18.8 (s, CoCH3). ESI-TOF MS: [M+H]+ m/z = 321.2303
(theoretical 321.2331). Analysis found: C, 82.50; H, 8.78; N, 8.63. C22H28N2
requires: C, 82.45; H, 8.81; N, 8.74.