Rhodium(I)-Catalyzed Sequential C(sp)-C(sp3) and C(sp3)-C(sp3) Bond Formation through Migratory Carbene Insertion

Article abstract of DOI:10.1002/anie.201503140

A Rh^I-catalyzed three-component reaction of tert-propargyl alcohol, diazoester, and alkyl halide has been developed. This reaction can be considered as a carbene-involving sequential alkyl and alkynyl coupling, in which C(sp)-C(sp³) and C(sp³)-C(sp³) bonds are built successively on the carbenic carbon atom. The Rh^I-carbene migratory insertion of an alkynyl moiety and subsequent alkylation are proposed to account for the two separate C-C bond formations. This reaction provides an efficient and tunable method for the construction of all-carbon quaternary center.

Full text of DOI:10.1002/anie.201503140

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201503140
Carbenes
Hot Paper
German Edition:
DOI: 10.1002/ange.201503140
3
3
3
À
À
Rhodium(I)-Catalyzed Sequential C(sp) C(sp ) and C(sp ) C(sp )
Bond Formation through Migratory Carbene Insertion**
Ying Xia, Sheng Feng, Zhen Liu, Yan Zhang, and Jianbo Wang*
Abstract: A RhI-catalyzed three-component reaction of tert-
propargyl alcohol, diazoester, and alkyl halide has been
developed. This reaction can be considered as a carbene-
involving sequential alkyl and alkynyl coupling, in which
3
3
3
À
À
C(sp) C(sp ) and C(sp ) C(sp ) bonds are built successively
on the carbenic carbon atom. The RhI-carbene migratory
insertion of an alkynyl moiety and subsequent alkylation are
À
proposed to account for the two separate C C bond forma-
tions. This reaction provides an efficient and tunable method
for the construction of all-carbon quaternary center.
Scheme 1. Transition-metal-catalyzed a) normal and b) carbene-involv-
T
ransition-metal-catalyzed cross-coupling reactions have
ing coupling of alkynyl nucleophiles with alkyl halides.
À
been established as indispensable tools for carbon carbon
bond formation in modern organic synthesis. In this context,
the Sonogashira coupling, the coupling of aryl or alkenyl
shira-type coupling, in which the direct coupling of terminal
alkynes and aryl halides is impeded, instead, both the alkynyl
and aryl moiety are connected to the carbenic carbon atom.
Similarly, Yu and co-workers later reported a RhI-catalyzed
carbene-involving Suzuki–Miyaura-type coupling, in which
a large excess of coupling partners was needed to obtain the
products in good yields, and the reaction was restricted to
activated alkyl halides.[10] Herein, we report a RhI-catalyzed
carbene-involving sequential alkyl and alkynyl coupling of
alkynyl nucleophiles with general alkyl halides by using
donor–acceptor diazo compounds as the carbene precur-
sors.[11] This reaction represents a highly efficient and tunable
method for the construction of all-carbon quaternary centers
(Scheme 1b).[12]
halides with terminal alkynes, is a straightforward method-
2
À
ology for the construction of C(sp) C(sp ) bonds, which has
been widely practiced in various areas.[1] Compared to the
À
traditional Sonogashira coupling, the construction of C(sp)
C(sp3) bonds is much more challenging.[2–7] The direct strategy
is the transition-metal-catalyzed coupling of alkyl halides with
alkynyl nucleophiles.[2–5] However, the difficulty in oxidative
addition of unactivated alkyl halides and the competitive b-
hydride elimination of the alkyl metal intermediates are the
two major challenges in those coupling reactions.[6] Never-
theless, several catalytic systems have been successfully
developed during the past decade to achieve such couplings,
which has largely expanded the scope of the classic Sonoga-
shira coupling (Scheme 1a).
At the beginning of our study, terminal alkyne 3a, donor–
acceptor diazo compound 2a, and benzyl bromide 1a were
chosen as the substrates to test the carbene-inserted sequen-
tial alkyl and alkynyl coupling. With [Rh(cod)(OH)]2
(2.0 mol%) and BINAP (5.0 mol%) as the catalyst and
NaOMe (1.5 equiv) as the base, the three substrates were
reacted in toluene (0.2m) at 908C for 1 h and the expected
product 4a was isolated in 25% yield. However, the terminal
alkyne 3a easily underwent dimerization under the RhI-
catalysis conditions,[13] which made improving the yield by
optimizing the reaction conditions difficult. On the other
hand, we have noticed that tert-propargyl alcohol is a good
alkynyl nucleophile in RhI-catalyzed reactions, in which the
alkynyl RhI species is generated in situ through selective b-
carbon elimination.[13,14] It is assumed that the dimerization of
terminal alkynes might be suppressed under such conditions.
Gratifyingly, when tert-propargyl alcohol 3b was employed in
place of terminal alkyne 3a under otherwise identical reaction
conditions, the carbene-inserted sequential alkyl and alkynyl
On the other hand, transition-metal-catalyzed carbene-
involving cross-coupling reactions have attracted consider-
able attention in recent years.[8] We have previously devel-
oped a Pd0-catalyzed three-component reaction of N-tosylhy-
drazones, terminal alkynes, and aryl halides.[9] This reaction
can be considered a carbene-involving traditional Sonoga-
[*] Y. Xia, S. Feng, Z. Liu, Dr. Y. Zhang, Prof. Dr. J. Wang
Beijing National Laboratory of Molecular Sciences (BNLMS) and
Key Laboratory of Bioorganic Chemistry and Molecular Engineering
of Ministry of Education, College of Chemistry, Peking University
Beijing 100871 (China)
E-mail: wangjb@pku.edu.cn
Prof. Dr. J. Wang
The State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences
354 Fenglin Lu, Shanghai 200032 (China)
[**] The project is supported by National Basic Research Program of
China (973 Program, No. 2012CB821600), NSFC (Grant 21472004
and 21332002).
coupling product 4a was obtained in 79% yield [Eq. (1)].[15]
A
series of tert-propargyl alcohols were studied in this RhI-
catalyzed coupling, and (iPr)3Si-protected tert-propargyl
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201503140.
Angew. Chem. Int. Ed. 2015, 54, 7891 –7894
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7891

.
Angewandte
Communications
Next, the scope of benzyl halides was investigated. A
series of benzyl halides 1 were subjected to the optimized
reaction conditions, affording the corresponding products in
good to excellent yields (Scheme 3). The benzyl bromides
alcohol generally afforded the desired products in moderate
to good yields.[15]
With the optimized reaction conditions established, we
proceeded to investigate the scope of this RhI-catalyzed
carbene-involving sequential alkyl and alkynyl coupling. A
number of aryl diazoesters 2 were first examined under the
optimized reaction conditions, and the corresponding prod-
ucts were obtained in 55–87% yield (Scheme 2). We were
Scheme 3. Scope of benzyl halides 1 in RhI-catalyzed coupling of tert-
propargyl alcohol 3b and diazoester 2a. The reaction conditions were
the same as those described in Scheme 2. All the yields refer to the
isolated products.
bearing p-CN, p-CO2Me, p-Cl, m-OMe, o-Br substituents
(1b–f) and 2-naphthyl methyl bromide 1g are all suitable
substrates for this reaction, giving the corresponding products
in good yields, except in the case of the p-CN-substituted
benzyl bromide (1b). Apart from benzyl bromides, benzyl
chlorides were also suitable substrates for this transformation,
although the yields of the products were a little lower than the
ones obtained with benzyl bromides. For example, the yield of
p-CO2Me-substituted product 5c was 80% when obtained
from benzyl bromide 1c and 69% when obtained from benzyl
chloride 1cꢀ. Other benzyl chlorides gave the corresponding
products (5h–j) in moderate to good yields.
After the exploration of the reaction scope of benzyl
halides, we next turned our attention to the scope of
unactivated alkyl halides (Scheme 4). Gratifyingly, the reac-
tion of n-butyl iodide 6a under slightly modified conditions
was successful, affording the corresponding product 7a in
80% yield. Other primary alkyl iodides (6b–e) gave similar
results, but a diminished yield was observed in the reaction of
w-chlorine-substituted alkyl iodide 6 f. Furthermore, secon-
dary alkyl iodide 6g could also be employed as the substrate
to give the corresponding product 7g in excellent yield.
Subsequently, the reaction of alkyl bromides was examined.
When n-butyl bromide 6a’ was subjected to the same
conditions as the reaction with alkyl iodides, the expected
product 7a could only be isolated in 55% yield. The yield
could be improved to 89% when 20 mol% TBAI (tetrabu-
tylammonium iodide) was added to the reaction mixture.
Scheme 2. Scope of diazoesters 2 in RhI-catalyzed coupling of tert-
propargyl alcohol 3b and benzyl bromide 1a. Unless otherwise noted,
the reaction was carried out on a 0.1 mmol (3b) scale with 1.2 equiv
of 2 and 1.3 equiv of 1a. All the yields refer to the isolated products.
[a] The reaction was carried out on a 5 mmol (3b) scale. [b] The
reaction time was 2 h.
delighted to find that the reaction of diazoester 2a (bearing
a methyl ester moiety) was feasible on a gram scale under the
same reaction conditions, affording the product in high yield
(4a, 85% yield, 1.79 g). Diazo compound 2b bearing a tert-
butyl ester moiety gave the corresponding product 4b in
a comparable yield, thus indicating that the steric hindrance
of the ester moiety had a negligible effect on this reaction.
Aryl diazoesters bearing para (4c–g), meta (4h–j), and ortho
(4l,m) substituents were all compatible with this transforma-
tion, thus indicating that the reaction is little influenced by the
electronic properties and the steric hindrance of the sub-
stituents. Diazo compounds bearing strongly electron-with-
drawing groups needed longer reaction time (2 h) for
a complete conversion (4k,l). Notably, the halogen substitu-
ents on the aromatic ring of the diazo substrates all tolerated
the reaction, thus providing the opportunity for further
transformations through coupling reactions (4e,f,j,k).
7892 www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 7891 –7894

Angewandte
Chemie
Scheme 5. Scope of diazoesters 2 in RhI-catalyzed coupling of tert-
propargyl alcohol 3b and n-butyl bromide 6a’. The reactions were
carried out on 0.1 mmol scale, with 1.3 equiv of diazoester 2, 2.0 equiv
of alkyl halide 6a’, and 20 mol% TBAI. All the yields refer to the
isolated products. [a] The reaction time was 2 h.
Scheme 4. Scope of alkyl halides 6 in RhI-catalyzed coupling of tert-
propargyl alcohol 3b and diazoester 2a. Unless otherwise noted, the
reactions were carried out on 0.1 mmol (3b) scale, with 1.3 equiv of
diazoester 2a and 2.0 equiv of alkyl halides 6. All the yields refer to the
isolated products. [a] 20 mol% TBAI was added. [b] Reaction in the
absence of TBAI. [c] The reaction was carried out on a 5 mmol (3b)
scale.
Moreover, the reaction was also successful on a gram scale,
affording 1.77 g of 7a (92% yield). Again, secondary and
long-chain alkyl bromides were good substrates for the
reaction (7g, 7h). Alkyl bromides bearing phenyl, cyclo-
propyl, terminal alkene, and acetal moieties were all reacted
smoothly to give the corresponding products in moderate to
good yields (7i–l).
Finally, the scope of the reaction was further examined by
reacting a series of aryl diazoesters 2 with tert-propargyl
alcohol 3b and n-butyl bromide 6a’ (Scheme 5). The diazo
compound 2b with its bulky tBu moiety needed a longer
reaction time for the reaction to reach completion (product
8b). The reactions of other diazo esters 2 with n-butyl
bromide 6a’ gave similar results to those obtained in the
reactions of 2 with benzyl bromide 1a (compare with
Scheme 2), affording the corresponding products (8c–h,j,m)
in moderate to excellent yields.
Scheme 6. Proposed reaction mechanism.
merizes to generate the active catalyst, which deprotonates
3b to form alkoxy RhI species A. Then A undergoes a b-
alkynyl elimination to generate alkynyl rhodium complex
B,[13,14] with the extrusion of a ketone. Alkynyl rhodium
complex B reacts with diazoester 2a to afford RhI-carbene
complex C,[10,16,17] followed by migratory insertion of the
alkynyl RhI-carbene species to generate oxa-p-allyl RhI
intermediate D.[10,12d] At this point, two pathways toward
the product are possible.
Path (a) is the direct alkylation of the enolate-like RhI
species D with the aid of base NaOMe. The final product is
then produced with generation of a methoxy RhI complex E,
which reacts with 3b to regenerate complex A and completes
the catalytic cycle. Path (b) depends on an exchange of the
enolate-like RhI species D with NaOMe to give the corre-
sponding Na enolate species F, followed by alkylation to
afford the final product. The generated methoxy RhI complex
E then undergoes the same process as the one described for
path (a) to complete the catalytic cycle.
As this RhI-catalyzed carbene-involving sequential alkyl
and alkynyl coupling is a straightforward methodology to
construct all-carbon quaternary centers starting from readily
available materials, we subsequently turned our attention to
the asymmetric version of the transformation. However, high
stereoselectivity could not be achieved with either the chiral
ligand (R)-BINAP or by employing a diazo compound
bearing a chiral auxiliary.[15]
A plausible mechanism is shown in Scheme 6. First, in the
presence of the BINAP ligand, the [Rh(cod)(OH)]2 dedi-
As mentioned above, the enantioselectivity of this reac-
tion could not be achieved by using a chiral ligand on rhodium
Angew. Chem. Int. Ed. 2015, 54, 7891 –7894
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7893

.
Angewandte
Communications
13510 – 13511; b) G. Cahiez, O. Gager, J. Buendia, Angew. Chem.
Int. Ed. 2010, 49, 1278 – 1281; Angew. Chem. 2010, 122, 1300 –
1303; c) M. Chen, X. Zheng, W. Li, J. He, A. Lei, J. Am. Chem.
Soc. 2010, 132, 4101 – 4103; d) T. Thaler, L.-N. Guo, P. Mayer, P.
Knochel, Angew. Chem. Int. Ed. 2011, 50, 2174 – 2177; Angew.
Chem. 2011, 123, 2222 – 2225; e) Y. Ano, M. Tobisu, N. Chatani,
J. Am. Chem. Soc. 2011, 133, 12984 – 12986; f) F. Ye, X. Ma, Q.
Xiao, H. Li, Y. Zhang, J. Wang, J. Am. Chem. Soc. 2012, 134,
5742 – 5745; g) X. Liu, Z. Wang, X. Cheng, C. Li, J. Am. Chem.
Soc. 2012, 134, 14330 – 14333; h) J. He, M. Wasa, K. S. L. Chan,
J.-Q. Yu, J. Am. Chem. Soc. 2013, 135, 3387 – 3390.
center, thus indicating that path (b) is more likely than path
(a). This is similar to that reported by Yu and co-workers.[10]
However, further investigation is needed to unambiguously
distinguish these two reaction routes.
In conclusion, we have developed a highly efficient RhI-
catalyzed carbene-inserted sequential alkyl and alkynyl
coupling. The alkynyl and alkyl moieties of the coupling
partners are both linked with a carbene moiety, resulting in
3
3
À
À
the formation of one C(sp) C(sp ) bond and one C(sp )
C(sp3) bond on a carbenic center. The reaction tolerates
a wide range of functional groups and can be applied in gram-
scale syntheses with high efficiency. The transformation thus
represents a tunable and practicable methodology for the
construction of all-carbon quaternary center, starting from
readily available substrates. Further investigation will be
focused on the asymmetric catalysis and other types of
carbene-involving coupling reactions. The results will be
reported in due course.
[8] For reviews, see: a) Y. Zhang, J. Wang, Eur. J. Org. Chem. 2011,
1015 – 1026; b) J. Barluenga, C. ValdØs, Angew. Chem. Int. Ed.
2011, 50, 7486 – 7500; Angew. Chem. 2011, 123, 7626 – 7640; c) Z.
Shao, H. Zhang, Chem. Soc. Rev. 2012, 41, 560 – 572; d) Q. Xiao,
Y. Zhang, J. Wang, Acc. Chem. Res. 2013, 46, 236 – 247; e) Z. Liu,
J. Wang, J. Org. Chem. 2013, 78, 10024 – 10030; f) Y. Xia, Y.
Zhang, J. Wang, ACS Catal. 2013, 3, 2586 – 2598.
[9] L. Zhou, F. Ye, Y. Zhang, J. Wang, J. Am. Chem. Soc. 2010, 132,
13590 – 13591.
[10] Y.-T. Tsoi, Z. Zhou, W.-Y. Yu, Org. Lett. 2011, 13, 5370 – 5373.
[11] For selected reviews on diazo compounds as carbene precursors,
see: a) T. Ye, M. A. McKervey, Chem. Rev. 1994, 94, 1091 – 1160;
b) M. P. Doyle, M. A. McKervey, T. Ye, Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds, Wiley-
Interscience, New York, 1998; c) H. M. L. Davies, J. R. Manning,
Nature 2008, 451, 417 – 424; d) Z. Zhang, J. Wang, Tetrahedron
2008, 64, 6577 – 6605.
Keywords: carbenes · cross-couplings · diazo compounds ·
migratory insertion · quaternary carbon center
How to cite: Angew. Chem. Int. Ed. 2015, 54, 7891–7894
Angew. Chem. 2015, 127, 8002–8005
[12] For examples of all-carbon quaternary center formation based
on metal carbene intermediatea, see: a) Z.-S. Chen, X.-H. Duan,
P. -X. Zhou, S. Ali, J.-Y. Luo, Y.-M. Liang, Angew. Chem. Int. Ed.
2012, 51, 1370 – 1374; Angew. Chem. 2012, 124, 1399 – 1403;
b) H. Qiu, M. Li, L.-Q. Jiang, F.-P. Lv, L. Zan, C.-W. Zhai, M. P.
Doyle, W.-H. Hu, Nat. Chem. 2012, 4, 733 – 738; c) D. Xing, C.
Jing, X. Li, H. Qiu, W. Hu, Org. Lett. 2013, 15, 3578 – 3581; d) Y.
Xia, Z. Liu, Z. Liu, R. Ge, F. Ye, M. Hossain, Y. Zhang, J. Wang,
J. Am. Chem. Soc. 2014, 136, 3013 – 3015.
[13] T. Nishimura, T. Katoh, K. Takatsu, R. Shintani, T. Hayashi, J.
Am. Chem. Soc. 2007, 129, 14158 – 14159.
[14] A. Funayama, T. Satoh, M. Miura, J. Am. Chem. Soc. 2005, 127,
15354 – 15355.
[1] a) K. Sonogashira, Handbook of Organopalladium Chemistry
for Organic Synthesis (Ed.: E. Negishi), Wiley-Interscience, New
York, 1997, pp. 493 – 529; b) R. Chinchilla, C. Nµjera, Chem.
Rev. 2007, 107, 874 – 922.
[2] For Pd catalysis, see: a) M. Eckhardt, G. C. Fu, J. Am. Chem.
Soc. 2003, 125, 13642 – 13643; b) L.-M. Yang, L.-F. Huang, T.-Y.
Luh, Org. Lett. 2004, 6, 1461 – 1463; c) G. Altenhoff, S. Würtz, F.
Glorius, Tetrahedron Lett. 2006, 47, 2925 – 2928.
[3] For Ni catalysis, see: a) O. Vechorkin, D. Barmaz, V. Proust, X.
Hu, J. Am. Chem. Soc. 2009, 131, 12078 – 12079; b) O. Vechorkin,
A. Godinat, R. Scopelliti, X. Hu, Angew. Chem. Int. Ed. 2011, 50,
11777 – 11781; Angew. Chem. 2011, 123, 11981 – 11985; c) J. Yi,
X. Lu, Y.-Y. Sun, B. Xiao, L. Liu, Angew. Chem. Int. Ed. 2013, 52,
12409 – 12413; Angew. Chem. 2013, 125, 12635 – 12639.
[4] For Fe catalysis, see: a) T. Hatakeyama, Y. Okada, Y. Yoshimoto,
M. Nakamura, Angew. Chem. Int. Ed. 2011, 50, 10973 – 10976;
Angew. Chem. 2011, 123, 11165 – 11168; b) C. W. Cheung, P.
Ren, X. Hu, Org. Lett. 2014, 16, 2566 – 2569.
[15] For the details, see Supporting Information.
À
[16] C C bond activation merged with carbene migratory insertion
has been reported recently, see: Ref. [12d], and also: A. Yada, S.
Fujita, M. Murakami, J. Am. Chem. Soc. 2014, 136, 7217 – 7220.
[17] For an experimental and computational study on RhI-carbene,
see: R. Cohen, B. Rybtchinski, M. Gandelman, H. Rozenberg,
J. M. L. Martin, D. Milstein, J. Am. Chem. Soc. 2003, 125, 6532 –
6546.
[5] For Co catalysis, see: H. Ohmiya, H. Yorimitsu, K. Oshima, Org.
Lett. 2006, 8, 3093 – 3096.
[6] A. Rudolph, M. Lautens, Angew. Chem. Int. Ed. 2009, 48, 2656 –
2670; Angew. Chem. 2009, 121, 2694 – 2708.
3
À
[7] For other selected examples of C(sp) C(sp ) bond formation,
Received: April 6, 2015
Published online: May 15, 2015
see: a) D. Rayabarapu, J. A. Tunge, J. Am. Chem. Soc. 2005, 127,
7894 www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 7891 –7894