Grubbs catalysts in intramolecular carbene C(sp3)-H insertion reactions from α-diazoesters

Article abstract of DOI:10.1039/c8cc09089k

Grubbs catalysts are described as a useful alternative to promote intramolecular carbene C-H insertion from α-diazoesters. Moreover, no competition arises from the possible metathesis reactions on substrates bearing alkene and alkyne moieties. DFT calculations were also carried out to gain insight into the reaction mechanism involved in these transformations.

Full text of DOI:10.1039/c8cc09089k

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Grubbs catalysts in intramolecular carbene
C(sp3)–H insertion reactions from a-diazoesters†
Cite this: Chem. Commun., 2019,
55, 1160
Daniel Sole, *a Arianna Amenta,a M-Lluısa Bennasara and Israel Fernandez
*
b
´
´
¨
Received 15th November 2018,
Accepted 2nd January 2019
DOI: 10.1039/c8cc09089k
rsc.li/chemcomm
Grubbs catalysts are described as a useful alternative to promote strategies7 and intramolecular transition metal-catalyzed carbene
intramolecular carbene C–H insertion from a-diazoesters. Moreover, C–H insertion reactions as annulation methodologies.8 Ruthenium
no competition arises from the possible metathesis reactions on alkylidene complexes, which are the key intermediates in olefin
substrates bearing alkene and alkyne moieties. DFT calculations were metathesis, clearly resemble the ruthenium-carbene species
also carried out to gain insight into the reaction mechanism involved generated from diazo compounds. We therefore wondered
in these transformations.
if typical olefin metathesis catalysts (Fig. 1) could also be used
to promote carbene C(sp3)–H insertion reactions from diazo
The rich coordination chemistry of ruthenium and hence the derivatives and whether competition would arise between
diversity of ruthenium complexes have led to the development alkene metathesis and C–H insertion. Herein we report a joint
of a number of catalytic transformations that can be used for experimental-computational study of the Grubbs catalyst-promoted
the rapid assembly of complex molecules with high atom C–H insertion from amino-tethered a-diazoesters to prepare
economy.1 In particular, the ruthenium carbenes collectively pyrrolidines, providing insight into the scope and mechanism
known as Grubbs catalysts have been extensively applied in of this novel, synthetically useful nonmetathetic reaction.
metathesis reactions.2 The outstanding performance of these
We began our investigation by focusing on the reaction of
reactions derives from the remarkable selectivity of Grubbs N-benzyl-N-tbutyl-a-diazoesters 1a–e (Table 1), comparing the
complexes for unsaturated reactants, which allows chemo- efficiency of Ru-1, Ru-2, and Ru-3 with that of [Ru( p-cymene)Cl2]2,
selective targeting of alkenes and alkynes in intricate frameworks which has been successfully used to promote similar insertion
of organic functional groups. Moreover, a growing number of processes.5a,8b To our delight, treatment of 1a with first generation
nonmetathetic catalytic transformations promoted by Grubbs Grubbs catalyst Ru-1 in refluxing CH2Cl2 resulted in the stereo-
carbene complexes have also been described and after optimiza- selective formation of the cis-pyrrolidine 2a in excellent yield
tion some of them are showing synthetic utility.3
(entry 1). Similar reactions were observed with second generation
In parallel, it has also been reported that the reaction of Grubbs catalyst Ru-2 (entry 2) and Hoveyda–Grubbs catalyst Ru-3
diazo compounds with different ruthenium complexes affords (entry 3). Strikingly, all three catalysts were considerably more
ruthenium-carbene species, which can participate, inter alia, efficient than [Ru(p-cymene)Cl2]2 in promoting this C(sp3)–H
in cyclopropanation4 and C–H insertion reactions.5 However, insertion reaction (entry 4). The same behavior was observed
in comparison with the well-established rhodium catalysts,6 when starting from a-diazoesters 1b and 1c (entries 5–12).
ruthenium complexes are relative newcomers in these fields,
despite being considerably more cost-effective.
In contrast, each ruthenium catalyst was differently affected
by the presence of rather bulky ortho-substituents. Thus, Ru-1
As part of our ongoing research on the synthesis of nitrogen gave the highest yield when the substrate had an ortho-bromo
heterocycles, we have been exploring both ring-closing metathesis group (entries 13–16), but was less efficient in promoting the
a
´
`
`
`
´
Laboratori de Quımica Organica, Facultat de Farmacia i Ciencies de l’Alimentacio,
Universitat de Barcelona, Av. Joan XXIII 27-31, 08028 Barcelona, Spain.
E-mail: dsole@ub.edu
b
´
´
´
´
Departamento de Quımica Organica I and Centro de Innovacion en Quımica
´
Avanzada (ORFEO–CINQA), Facultad de Ciencias Quımicas, Universidad
Complutense de Madrid, 28040 Madrid, Spain. E-mail: israel@quim.ucm.es
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
Fig. 1 Commonly used Grubbs catalysts.
c8cc09089k
1160 | Chem. Commun., 2019, 55, 1160--1163
This journal is ©The Royal Society of Chemistry 2019

View Article Online
Communication
ChemComm
Table 1 C–H insertion reactions of a-diazoesters 1a–ea
Table 2 C–H insertion reactions of a-diazoesters 3, 5, 7 and 9a–ba
Entry
Diazoester
[Ru cat.]
Product yieldb (%)
Entry 1 (X)
[Ru cat.]
dr
Productsb (%)
1
2
3
3
3
3
Ru-1
Ru-2
Ru-3
4 (98, cis/trans 1.5 : 1)
4 (92, cis/trans 1 : 1)
4 (87, cis/trans 1 : 1)
1
2
3
4
5
6
7
8
1a (H)
1a (H)
1a (H)
1a (H)
Ru-1
Ru-2
Ru-3
498 : 2 2a (90)
498 : 2 2a (92)
498 : 2 2a (82)
498 : 2 2a (69)
498 : 2 2b (89)
498 : 2 2b (80)
498 : 2 2b (74)
498 : 2 2b (57)
498 : 2 2c (98)
498 : 2 2c (80)
498 : 2 2c (85)
498 : 2 2c (70)
498 : 2 2d (80)
498 : 2 2d (62)
498 : 2 2d (73)
c
[Ru( p-cymene)Cl2]2
Ru-1
Ru-2
Ru-3
[Ru( p-cymene)Cl2]2
Ru-1
Ru-2
Ru-3
[Ru( p-cymene)Cl2]2
Ru-1
Ru-2
Ru-3
1b (4-Cl)
1b (4-Cl)
1b (4-Cl)
1b (4-Cl)
1c (2-F)
1c (2-F)
1c (2-F)
1c (2-F)
1d (2-Br)
1d (2-Br)
1d (2-Br)
1d (2-Br)
d
d
d
d
4
5
6
5
5
5
Ru-1
Ru-2
Ru-3
6 (91, cis/trans 1 : 1.4)
6 (80, cis/trans 1 : 1.7)
6 (82, cis/trans 1 : 1.3)
9
10
11
12
13
14
15
16
17
18
19
20
e
[Ru( p-cymene)Cl2]2
—
7
8
7
7
Ru-1
Ru-3
8 (70)
1e (2-MeO) Ru-1
1e (2-MeO) Ru-2
1e (2-MeO) Ru-3
1e (2-MeO) [Ru( p-cymene)Cl2]2
498 : 2 2e (60)
498 : 2 2e (81)
c
—
f
—
—
g
a
Reaction conditions: catalyst (3 mol%) in CH2Cl2 at reflux for 24 h.
b
e
c
d
Yields refer to products isolated by chromatography. 31 h. 48 h.
f
A 1 : 1 mixture of 1d and 2d was obtained. A 1 : 1.4 mixture of 1e and
g
2e was obtained. A 6 : 1 mixture of 1e and 2e was obtained.
9
9a, X = I
9a, X = I
9a, X = I
9b, X = F
9b, X = F
9b, X = F
Ru-1
Ru-2
Ru-3
Ru-1
Ru-2
Ru-3
10a (87, cis/trans 6 : 1)
10a (79, cis/trans 12 : 1)
10a (95, cis/trans 3 : 1)
10b (86, cis/trans 4.4 : 1)d
10b (73, cis/trans 7 : 1)e
10b (60, cis/trans 2.3 : 1) f
10
11
12
13
14
insertion from a-diazoester 1e, which bears an ortho-methoxy
substituent (entries 17–20). On the other hand, when using
Ru-3 the reaction of 1e (entry 19) progressed more slowly than
that of 1d (entry 15). Once again, [Ru(p-cymene)Cl2]2 afforded
poor results.
To ascertain whether the efficiency of the C–H insertion
depends on the activation inherent to the benzylic position, the obtained. A 2.5 : 1 mixture of 10b and 10b0 was obtained.
reaction of a-diazoesters 3, 5, and 7 was explored (Table 2). The
a
Reaction conditions: catalyst (3 mol%) in CH2Cl2 at reflux for 24 h.
b
c
Yields refer to products isolated by chromatography. A 5 : 1 mixture
d
of 7 and 8 was obtained. A 8 : 1 mixture of 10b and the regioisomeric
e
pyrrolidine 10b0 was obtained. A 2.8 : 1 mixture of 10b and 10b0 was
f
three Grubbs catalysts regioselectively promoted the insertion
Seeking more information about the Grubbs catalyst-mediated
reaction of 3 (entries 1–3) to give pyrrolidine 4 (cis/trans
carbene C–H insertion, we then explored the reaction of a-diazoester
mixtures). Similar results were observed when these catalysts
11 (Table 3).
were used with N-(benzyloxyethyl) a-diazoester 5 (entries 4–6).
The use of the three catalysts to promote the decomposition of 11
In contrast, treatment of 7 with Ru-1 resulted in both regio- and
led to mixtures of pyrrolidines 12, arising from the insertion into the
stereoselective insertion to give cis-pyrrolidine 8 in 70% yield
benzylic C–H bond, and 13, which results from the insertion into the
(entry 7), while in the presence of Ru-3 a slow reaction was
observed (entry 8). These results therefore indicate that the
Grubbs catalysts can promote carbene C–H insertion into less
Table 3 C–H insertion reactions of a-diazoester 11a
activated C(sp3)–H bonds, and that remote electronic effects
may accelerate the reaction.
Interestingly, the Grubbs catalysts were able to discriminate
between the two secondary benzylic C(sp3)–H bonds of
a-diazoesters 9a and 9b, probably due to a combination of
steric and electronic effects. Thus, the reaction of 9a regio-
selectively afforded pyrrolidine 10a (cis/trans mixtures) in good
yields (entries 9–11). In contrast, the reactions of 9b provided
10b as the major product along with minor amounts of the
pyrrolidine arising from the insertion into a C–H bond at the
2-fluorobenzyl position (entries 12–14).
Entry
[Ru cat.]
Products yieldb (%)
1
2
3
Ru-1
Ru-2
Ru-3
12 (61, cis/trans 5.8 : 1), 13 (32)
12 (56, cis/trans 7.8 : 1), 13 (41)
12 (36, cis/trans 3.6 : 1), 13 (58)
a
Reaction conditions: catalyst (3 mol%) in CH2Cl2 at reflux for 24 h.
Yields refer to products isolated by chromatography.
b
This journal is ©The Royal Society of Chemistry 2019
Chem. Commun., 2019, 55, 1160--1163 | 1161

View Article Online
ChemComm
Communication
Table 4 C–H insertion reactions of a-diazoesters 14, 16a–c and 18a–ca
Entry
Diazoester
[Ru cat.]
Product yieldb (%)
Scheme 1 Reactions of a-diazoester 20.
Finally, N-allyl-a-diazoester 20 was prepared (Scheme 1).
This diazo derivative proved to be thermally unstable and in
CH2Cl2 solution at room temperature evolved to pyrazolo[4,3-c]-
pyridine 21 through an intramolecular dipolar cycloaddition
reaction.11 However, treatment of 20 with Ru-1 in CH2Cl2 at reflux
afforded a 1 : 2 : 1 mixture of 21, 22 (arising from a 1,3-hydrogen
shift from 21),11 and the C–H insertion product 23. The use
of Ru-2 and Ru-3 led to only trace amounts of 23 along with 21
and 22. Once again, no product from the ring-closing meta-
thesis was detected in any of the reaction mixtures.
To shed light on the reaction mechanism and selectivity of
the C–H insertion catalyzed by Grubbs complexes, Density
Functional Theory (DFT) calculations at the dispersion
corrected PCM(CH2Cl2)-B3LYP-D3/def2-TZVPP//PCM(CH2Cl2)-
B3LYP-D3/def2-SVP level were carried out.12 To this end, the
process involving 1a and the Ru-1 catalyst was explored (Fig. 2).
The process begins with the formation of the corresponding
ruthena-carbene intermediate with the concomitant release
of N2. Our calculations indicate that the formation of INT0,
where the new carbene ligand replaces a phosphine in Ru-1, is
strongly favoured (DDG = 29.2 kcal molꢀ1) over the formation of
INT00, where the carbene ligands are interchanged. From INT0,
the zwitterionic intermediate INT1-cis is produced in a highly
exergonic process (DGR = ꢀ8.3 kcal molꢀ1) via the transition
state TS1-cis (DGa = 11.1 kcal molꢀ1). This step can be viewed
as a 1,5-hydrogen migration that is not directly assisted by the
metal, therefore resembling the mechanism involved in related
Ru(II)8b and Pd(II)–C–H activation processes previously reported
1
2
14
14
Ru-1
Ru-3
15 (70, cis/trans 6 : 1)
15 (52, cis/trans 5 : 1)
3
4
5
6
7
8
9
10
11
16a, X = Me
16a, X = Me
16a, X = Me
16b, X = Br
16b, X = Br
16b, X = Br
16c, X = I
Ru-1
Ru-2
Ru-3
Ru-1
Ru-2
Ru-3
Ru-1
Ru-2
Ru-3
17a (93, cis/trans 4 : 1)
17a (98, cis/trans 2 : 1)
17a (89, cis/trans 5.6 : 1)
17b (98, cis/trans 10 : 1)
17b (40, cis/trans 11 : 1)c
17b (70, cis/trans 10 : 1)d
17c (52, cis/trans 7 : 1)
e
16c, X = I
16c, X = I
—
e
—
12
13
14
15
16
17
18
19
20
18a, R = H
18a, R = H
18a, R = H
18b, R = Me
18b, R = Me
18b, R = Me
18c, R = TMS
18c, R = TMS
18c, R = TMS
Ru-1
Ru-2
Ru-3
Ru-1
Ru-2
Ru-3
Ru-1
Ru-2
Ru-3
19a (70, cis/trans 6 : 1)
18a
19a (88, cis/trans 7 : 1)
19b (89, cis/trans 3 : 1)
f
—
19b (75, cis/trans 4 : 1)
19c (87, cis/trans 4 : 1)
19c (62, cis/trans 4.5 : 1)
19c (80, cis/trans 7 : 1)
a
Reaction conditions: catalyst (3 mol%) in CH2Cl2 at reflux for 24 h.
Yields refer to products isolated by chromatography. The cyclo-
b
c
propanation product (50%) was also obtained (see the ESI). d The cyclopro-
panation product (20%) was also obtained. e Complex mixture. A 1.3:1
f
mixture of 18b and 19b was obtained.
tertiary C(sp3)–H bond (entries 1–3). While Ru-1 and Ru-2 gave 12 as by us.8d Interestingly, the analogous transformation leading to the
the major product, Ru-3 led predominantly to 13.
isomer INT1-trans is both kinetically (DDGa = 7.4 kcal molꢀ1) and
The C–H insertion catalyzed by Grubbs complexes was also thermodynamically (DDGR = 4.4 kcal molꢀ1) disfavoured over
suitable for allylic and propargylic C(sp3)–H bonds (Table 4).
the process involving INT1-cis, which is fully consistent with
Thus, a-diazoester 14 chemoselectively afforded pyrrolidine 15 the complete stereoselectivity observed experimentally. Finally,
(cis/trans mixture) in yields of 70% in the presence of Ru-1 (entry 1) the transformation ends up with the highly exergonic (DGR
=
and 52% with Ru-3 (entry 2). Notably, no product resulting from the ꢀ26.2 kcal molꢀ1) formation of the observed pyrrolidine 2a.
possible ring-closing metathesis was observed in either reaction.9
This final step proceeds via TS2-cis, a saddle point associated
Gem-disubstituted alkenes 16a–c also underwent C–H inser- with the formation of the new C–C bond and the concomitant
tion to give pyrrolidines under the action of Grubbs catalysts. regeneration of the active Ru(II)-catalyst, with a rather low
Starting from a-diazoester 16a, the three catalysts chemoselec- activation barrier of 10.5 kcal molꢀ1
.
tively promoted C–H insertion to give 17a in good yields
In addition, we wished to understand why the alternative
(entries 3–5). In contrast, while the insertion reaction from metathesis reaction is not competitive in substrates that also
bromo alkene 16b was selectively promoted by Ru-1 (entry 6), have a reactive unsaturated C–C bond. Our calculations suggest
the use of either Ru-2 or Ru-3 led to the formation of significant that the formation of the key metallacyclobutane intermediate
amounts of the corresponding cyclopropanation product from the substrate bearing an allyl substituent is strongly
(entries 7 and 8).10 On the other hand, for iodo alkene 16c, disfavored (DDG = 32.4 kcal molꢀ1) over the formation of the
only Ru-1 was able to promote the C–H insertion (entry 9).
zwitterionic intermediate involved in the C–H insertion reaction
The Grubbs catalysts were also used to promote insertion (see Fig. S1 in the ESI†).
into propargylic C(sp3)–H bonds of a-diazoesters bearing either
Finally, it should be noted that although a wide range of
terminal or internal alkynes (entries 12–20), Ru-1 and Ru-3 functional groups are well tolerated under metathesis condi-
being far more active than Ru-2.
tions, the use of substrates with a strong Lewis base such as an
1162 | Chem. Commun., 2019, 55, 1160--1163
This journal is ©The Royal Society of Chemistry 2019

View Article Online
Communication
ChemComm
Fig. 2 Computed reaction profile for the formation of 2a from 1a. Relative free energies (DG, at 298 K) and bond lengths are given in kcal molꢀ1 and
angstroms, respectively. All data have been computed at the PCM(CH2Cl2)-B3LYP-D3/def2-TZVPP//PCM(CH2Cl2)-B3LYP-D3/def2-SVP level.
amine usually deactivates the catalyst.13 In contrast, not only
does the amine moiety not hinder the carbene C–H insertion
catalyzed by Grubbs complexes, but it seems crucial for the
success of the reaction, which nicely agrees with the computed
reaction profile depicted in Fig. 2.14
In summary, we have described the first examples of Grubbs
complexes used to catalyze carbene C–H insertion from diazo
derivatives. On the whole, the first generation Grubbs catalyst
was the most versatile, although it did not always give the
highest yield. Our studies clearly demonstrate not only that
Grubbs complexes constitute a useful alternative to promote
intramolecular carbene C–H insertion, but also that no compe-
tition from the possible metathesis reactions arises when
starting from substrates with alkene or alkyne moieties.
We gratefully acknowledge financial support for this work
from MINECO-FEDER (Projects CTQ2015-64937-R, CTQ2016-
78205-P and CTQ2016-81797-REDC).
3 (a) B. Alcaide, P. Almendros and A. Luna, Chem. Rev., 2009, 109,
3817–3858; (b) S. Kotha, S. Misra, G. Sreevani and B. V. Babu, Curr.
Org. Chem., 2013, 17, 2776–2795.
4 G. Maas, Chem. Soc. Rev., 2004, 33, 183–190.
5 (a) M. K.-W. Choi, W.-Y. Yu and C.-M. Che, Org. Lett., 2005, 7,
1081–1084; (b) M. Grohmann and G. Maas, Tetrahedron, 2007, 53,
12172–12178; (c) M. K.-W. Choi, W.-Y. Yu, M.-H. So, C.-Y. Zhou,
Q.-H. Deng and C.-M. Che, Chem. – Asian J., 2008, 3, 1256–1265;
(d) C. Y. Zhou, J. S. Huang and C. M. Che, Synlett, 2010, 2681–2700;
(e) W.-W. Chan, T.-L. Kwong and W.-Y. Yu, Org. Biomol. Chem., 2012,
10, 3749–3755; ( f ) A. R. Reddy, C.-Y. Zhou, Z. Guo, J. Wei and
C.-M. Che, Angew. Chem., Int. Ed., 2014, 53, 14175–14180.
6 H. M. L. Davies and B. T. Parr, Rhodium Carbenes, in Contemporary
Carbene Chemistry, ed. R. A. Moss and M. P. Doyle, John Wiley &
Sons, Hoboken, NJ, 2014, pp. 363–403.
´
7 (a) M.-L. Bennasar, E. Zulaica, D. Sole and S. Alonso, Tetrahedron,
´
2007, 63, 861–866; (b) M.-L. Bennasar, E. Zulaica, D. Sole and
S. Alonso, Chem. Commun., 2009, 3372–3374; (c) M.-L. Bennasar,
´
D. Sole, E. Zulaica and S. Alonso, Org. Lett., 2011, 13, 2042–2045;
´
(d) M.-L. Bennasar, D. Sole, T. Roca and M. Valldosera, Tetrahedron,
´
2015, 71, 2246–2254; (e) D. Sole, M.-L. Bennasar, T. Roca and
M. Valldosera, Eur. J. Org. Chem., 2016, 1355–1366.
´
´
8 (a) D. Sole, F. Mariani, M.-L. Bennasar and I. Fernandez, Angew.
´
Chem., Int. Ed., 2016, 55, 6467–6470; (b) D. Sole, A. Amenta,
´
F. Mariani, M.-L. Bennasar and I. Fernandez, Adv. Synth. Catal.,
´
´
´
2017, 359, 3654–3664; (c) D. Sole, F. Perez-Janer and I. Fernandez,
Conflicts of interest
´
´
Chem. Commun., 2017, 53, 3110–3113; (d) D. Sole, F. Perez-Janer,
´
M.-L. Bennasar and I. Fernandez, Eur. J. Org. Chem., 2018, 4446–4455.
There are no conflicts to declare.
9 For RCM involving electron-deficient alkylidene species, see: T. R. Hoye,
C. S. Jeffrey, M. A. Tennakoon, J. Wang and H. Zhao, J. Am. Chem. Soc.,
2004, 126, 10210–10211.
10 X.-H. Pan, P. Jiang, Z.-H. Jia, K. Xu, J. Cao, C. Chen, M.-H. Shen and
H.-D. Xu, Tetrahedron, 2015, 71, 5124–5129.
Notes and references
1 (a) Ruthenium Catalysts and Fine Chemistry, in Topics in Organometallic
Chemistry, ed. C. Bruneau and P. H. Dixneuf, Springer-Verlag, Berlin, 11 D. S. Brown, M. C. Elliot, C. J. Moody, T. J. Mowlem, J. P. Marino Jr.
2004; (b) Ruthenium in Organic Synthesis, ed. S.-I. Murahashi, Wiley-VCH, and A. P. Padwa, J. Org. Chem., 1994, 59, 2447–2455.
Weinheim, 2005; (c) B. M. Trost, M. U. Frederiksen and M. T. Rudd, 12 See computational details in the ESI†.
Angew. Chem., Int. Ed., 2005, 44, 6630–6666.
2 (a) Handbook of Metathesis, ed. R. H. Grubbs, Wiley-VCH, Weinheim,
2003, vol. 1–3; (b) L. Yet, Org. React., John Wiley & Sons, Hoboken,
13 See, for example: (a) S. J. P’Poo and H.-J. Schanz, J. Am. Chem. Soc.,
´
2007, 129, 14200–14212; (b) K. Lafaye, L. Nicolas, A. Guerinot,
S. Reymond and J. Cossy, Org. Lett., 2014, 16, 4972–4975.
NJ, 2016, vol. 89, pp. 1–1303; (c) G. C. Vougioukalakis and 14 For instance, the reaction of the p-toluene sulfonamide analogue of
R. H. Grubbs, Chem. Rev., 2010, 110, 1746–1787; (d) O. M. Ogba,
N. C. Warner, D. J. O’Leary and R. H. Grubbs, Chem. Soc. Rev., 2018,
47, 4510–4544.
20 with Ru-1 resulted in the exclusive formation of the corres-
ponding pyrazolo[4,3-c]pyridine, arising from the cycloaddition
reaction.
This journal is ©The Royal Society of Chemistry 2019
Chem. Commun., 2019, 55, 1160--1163 | 1163