Dehydrogenative heck reaction (Fujiwara-Moritani Reaction) of unactivated olefins with simple dihydropyrans under aprotic conditions

Article abstract of DOI:10.1002/adsc.201300370

The dehydrogenative Heck coupling (Fujiwara-Moritani reaction) of unactivated olefins with 3,4-dihydro-2H-pyrans is described. The two main highlights of the work are the use of unconventional unactivated olefins as coupling partners in the palladium-catalyzed reaction and the use of aprotic conditions for the coupling reaction of the acid-labile dihydropyrans.

Full text of DOI:10.1002/adsc.201300370

COMMUNICATIONS
DOI: 10.1002/adsc.201300370
Dehydrogenative Heck Reaction (Fujiwara–Moritani Reaction)
of Unactivated Olefins with Simple Dihydropyrans under Aprotic
Conditions
Govind Goroba Pawar,a Gaurav Singh,a Virendra Kumar Tiwari,a
and Manmohan Kapura,*
a
Department of Chemistry, Indian Institute of Science Education and Research Bhopal, ITI (Gas Rahat) Building, Raisen
Road, Bhopal – 462023, India
Fax : (+91)-755-4092-392; phone: (+91)-755-4092-324; e-mail: mk@iiserb.ac.in
Received: April 30, 2013; Revised: July 2, 2013; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300370.
Abstract: The dehydrogenative Heck coupling (Fu-
jiwara–Moritani reaction) of unactivated olefins
with 3,4-dihydro-2H-pyrans is described. The two
main highlights of the work are the use of uncon-
ventional unactivated olefins as coupling partners in
the palladium-catalyzed reaction and the use of
aprotic conditions for the coupling reaction of the
acid-labile dihydropyrans.
the recent times, there have been reports of hetero-
AHCTUNGTREGaNNUN tom-guided C-palladation either on non-aromatic
heterocycles or heteroatom-substituted alkenes.[5–7]
This process is followed by the standard carbopallada-
tion with an olefin substrate and b-hydride elimina-
tion, resulting in overall alkenylation (Scheme 1).
Unactivated olefins are often quite unwilling cou-
pling partners under the usual dehydrogenative Heck
reaction conditions. Barring a few reports, most of the
olefin substrates used for such reactions are activated
ones (a,b-unsaturated or styrene analogues)[6] and are
often used in conjunction with standard protic condi-
À
Keywords: alkenylation; C H activation; dehydro-
genative Heck reaction; dihydropyrans; Fujiwara–
Moritani reaction
À
tions for C H functionalization or with Lewis acidic
salts. The reason is obvious, if the electronic nature of
both coupling partners is the same, then the dehydro-
genative coupling often results in reduced reactivity
The palladium-catalyzed Fujiwara–Moritani reaction[1] and more of homo-coupled products than cross-cou-
or the dehydrogenative Heck reaction (DHR) has pled ones. However, using activated olefins not only
become one of the most popular transformations fall- limits the scope of the reaction but also often ham-
À
ing under the class of modern C H functionalization pers the synthetic utility by having an unwanted func-
reactions.[2,3] Several excellent reviews have covered tionality in the reactant. It is therefore necessary to
À
the recent advances in this C C bond forming reac- come up with efficient catalyst systems capable of ef-
tion.[4] Not limited to just arenes or heteroarenes, in fecting cross-couplings of olefins of similar electronic
natures.
Functionalized pyrans and, in particular, dihydro-
pyrans are ubiquitous building blocks in several natu-
ral products, including polyether compounds possess-
ing important biological activities (Figure 1).[8] They
are also important intermediates in several natural
product syntheses.[9] Although several methods for
the synthesis of 2-substituted pyrans are available, not
many methods are available for the functionalization
of the 3-position of pyrans.
Recently, Liu and co-workers reported a palladium-
catalyzed method for the alkenylation of glycals with
activated alkenes.[5i] This method works very well with
Scheme 1. The Fujiwara–Moritani reaction.
glycals, which are fairly stable molecules and activat-
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
ÞÞ
These are not the final page numbers!

Govind Goroba Pawar et al.
COMMUNICATIONS
ed olefins as coupling partners. To the best of our
knowledge, there seems to be no literature report on
the dehydrogenative Heck coupling of simple dihy-
dropyrans and unactivated alkenes. We report herein
a general method for the alkenylation of labile dihy-
dropyrans with unactivated olefins under aprotic de-
hydrogenative Heck conditions. The reaction is fairly
general and results in moderate yields with both unac-
tivated as well as activated alkenes. Our efforts began
with using simple 3,4-dihydro-2H-pyran, scanning sev-
eral of the catalyst systems reported in the literature,
which resulted in a mixed bag of results (Table 1).[10,11]
Figure 1. Natural occurrence of the dihydropyran moiety.
Table 1. Efforts in screening various catalyst systems.
[a]
All yields are isolated yields.
NR=no reaction.
[b]
2
asc.wiley-vch.de
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

Dehydrogenative Heck Reaction (Fujiwara–Moritani Reaction) of Unactivated Olefins
Table 2. Substrate scope with unactivated olefins.
[a]
All yields are isolated yields.
NR=no reaction.
[b]
Many of the catalyst systems indeed did result in al- combinations of copper and silver salts as oxidants
kenylation products with activated olefins but fared were tried, either individually or together, to check
very poorly in the case of unactivated ones. Notable any effect on regioselectivity.[13] In the cases where
À
was the catalyst system using protic media (entries 14, the reaction worked, we obtained only the C-3 C H
15 and 16, Table 1) which resulted in a very good iso- functionalization product, the C-2 regioisomers were
lated yield for benzyl acrylate but failed with O-allyl- not obtained.
phenol and styrene. To our delight, the best yields
and cleanest reactions were obtained with Pd(OAc)2, ed olefins is depicted in Table 2. In all cases, only the
using Cu(OAc)2/AgOAc as the oxidant combination E-isomer was selectively obtained and the C H func-
The substrate scope of the reaction with unactivat-
AHCTUNGTRENNUNG
À
ACHTUNGTRENNUNG
in THF. Various combinations of the relative stoichio- tionalization was also highly regioselective. As expect-
metries were attempted to improve the yield and min- ed, small amounts of self-coupling of the dihydropyr-
imize side-reactions. Copper and silver salts as termi- an were observed in all reactions and the amount
nal oxidants have been used by several research varied based upon the reactivity of the coupling part-
groups in the past, either individually or together. ner (unactivated olefin) used. In some cases, upto
DeBoef and others have also suggested that, in some 20% of homo-coupled olefin was also observed. In
cases, the regioselectivity is oxidant controlled and is cases where there were multiple options for b-hydride
a consequence of the formation of polymetallic cata- elimination, the reaction expectedly afforded isomeric
lytically active clusters.[12] For this reason, several mixtures (Table 2).[14] In some cases coupling products
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3
ÞÞ
These are not the final page numbers!

Govind Goroba Pawar et al.
COMMUNICATIONS
Table 3. Substrate scope with activated olefins.
[a]
[b]
All yields are isolated yields.
By GC-MS, product not isolated.
arising out of regioisomeric carbopalladation (migra- in moderate yields with unactivated olefins and good
tory insertion) were also observed (3a, 3gb, Table 2). yields with activated olefins. This system works well
À
These could also arise via C H activation of the where other catalyst combinations utilizing protic
olefin instead of the dihydropyran. The overall con- methods fail to afford the desired results. The reac-
versions in most cases were good (as indicated by tion has a good substrate scope with a few exceptions.
GC-MS) but some products had low isolated yields The additional advantage of using unactivated olefins
due to problems in purification (3h, 3j, Table 2).
is that various synthetically useful transformations
The reaction worked decently well with terminal like carbonyl insertions are also feasible, which en-
olefins but fared poorly with internal and 1,1’-disub- hances the scope and utility of the methodology. The
stituted olefins (3m, Table 2). The reasons for this are resulting electron-rich dienes are potential partners in
not quite understood but in these cases it could be Diels–Alder cycloadditions,[15] which can give rise to
due to reduced reactivity more on account of both interesting molecular frameworks and thereby are
electronic and steric reasons. With electron-rich ole- proposed as potential building blocks in many poly-
fins, the reactions resulted in several side-products ether-type natural products containing the pyran skel-
(3l, Table 2). In order to test the generality of the cat- eton.
alyst system, the reaction was attempted on activated
olefins and gratifyingly found to be compatible to
these systems too. Depicted in Table 3 is the scope of
the reaction with electron-deficient olefins. Here too,
1,1’-disubstituted olefins did not result in the desired
products (3q, Table 3), most probably due to steric
Experimental Section
reasons in this instance.
The reaction follows the plausible pathway for het-
eroatom-guided regioselective C H functionalization
General Procedure for Dehydrogenative Heck
Coupling of Dihydropyrans with Alkenes
À
(Scheme 2), starting with electrophilic palladation at In a pressure tube equipped with a stir bar, the 3, 4-dihydro-
2H-pyran (1.19 mmol) and olefin (2.38 mmol) in 3.5 mL dry
THF were charged. Then Pd(OAc)2 (0.059 mmol), AgOAc
(2.38 mmol), and Cu(OAc)2 (1.19 mmol) were added under
an argon flow. The tube was fitted with Teflon screw cap
and the reaction mixture was heated at 658C for 24 h. Upon
cooling to room temperature, the reaction mixture was dilut-
ed with about 10 mL of diethyl ether or dichloromethane
and the slurry was filtered through a pad of Celite; the fil-
trate was concentrated under reduced pressure. The crude
product was purified by a basic alumina column chromatog-
the most nucleophilic position (C-3), followed by
olefin coordination and carbopalladation.[4d] Subse-
quent b-hydride elimination leads to the coupled
product. The oxidant system acts as a base as well as
an oxidant to regenerate the Pd(II) species. Since the
C-3 palladated species is not very stable, moderate
yields are obtained with unactivated olefins.[5d]
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
In summary, we have developed a new catalyst
system for the dehydrogenative alkenylation of labile
dihydropyrans under aprotic conditions which results raphy (eluent: Petroleum ether:EtOAc).
4
asc.wiley-vch.de
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

Dehydrogenative Heck Reaction (Fujiwara–Moritani Reaction) of Unactivated Olefins
Scheme 2. Plausible reaction mechanism.
8960–9009; l) J. Wencel-Delord, T. Drçge, F. Liu, F.
Glorius, Chem. Soc. Rev. 2011, 40, 4740–4761.
Acknowledgements
[4] For extensive reviews related to this topic see a) J. L.
Bras, J. Muzart, Chem. Rev. 2011, 111, 1170–1214;
b) C. S. Yeung, V. M. Dong, Chem. Rev. 2011, 111,
1215–1292; see also: c) S. Kozhushkov, L. Ackermann,
Chem. Sci. 2013, 4, 886–896; d) X. Shang, Z-Q. Liu,
Chem. Soc. Rev. 2013, 42, 3253–3260.
We wish to thank DST-INDIA for a research grant (SR/S1/
OC-60/2010). We are indebted to CSIR for the grant of re-
search fellowships to GGP and VKT respectively. GS thanks
IISER Bhopal for a BS-MS fellowship. We also thank the Di-
rector, IISER Bhopal, for research facilities.
[5] For selected references, see: a) A. Stadler, H. von
Schenck, K. S. A. Vallin, M. Larhed, A. Hallberg, Adv.
Synth. Catal. 2004, 346, 1773–1781; b) Y. Hatamoto, S.
Sakaguchi, Y. Ishii, Org. Lett. 2004, 6, 4623–4625; c) H.
Yu, W. Jin, C. Sun, J. Chen, W. Du, S. He, Z. Yu,
Angew. Chem. 2010, 122, 5928–5933; Angew. Chem.
Int. Ed. 2010, 49, 5792–5797; d) D. Kim, S. Hong, Org.
Lett. 2011, 13, 4466–4469; e) Y. Bai, M. Leow, J. Zeng,
X-W. Liu, Org. Lett. 2011, 13, 5648–5651; f) L. Bi, G.
Georg, Org. Lett. 2011, 13, 5413–5415; g) Y-Y. Yu, M. J.
Niphakis, G. Georg, Org. Lett. 2011, 13, 5932–5935;
h) S. Xiang, S. Cai, J. Zeng, X-W. Liu, Org. Lett. 2011,
13, 4608–4611; i) Y. Bai, J. Zeng, S. Cai, X-W. Liu, Org.
Lett. 2011, 13, 4394–4397; j) M. Min, S. Hong, Chem.
Commun. 2012, 48, 9613–9615; k) Y. Li, Z. Qi, H.
Wang, X. Fu, C. Duan, J. Org. Chem. 2012, 77, 2053–
2057; l) M. Khoobi, M. Alipour, S. Zarei, F. Jafarpour,
A. Shafiee, Chem. Commun. 2012, 48, 2985–2987; m) Y.
Moon, S. Hong, Chem. Commun. 2012, 48, 7191–7193;
n) Y. Moon, D. Kwon, S. Hong, Angew. Chem. 2012,
124, 11495–11498; Angew. Chem. Int. Ed. 2012, 51,
11333–11336; o) H. Wang, L.-N. Guo, X-H. Duan, Org.
Lett. 2012, 14, 4358–4361; p) S. Pankajakshan, Y-H. Xu,
J. K. Cheng, M. T. Low, T.-P. Loh, Angew. Chem. 2012,
124, 5799–5803; Angew. Chem. Int. Ed. 2012, 51, 5701–
5705; q) N. Gigant, I. Gillaizeau, Org. Lett. 2012, 14,
3304–3307; r) A. Petit, J. Flygare, A. T. Miller, G.
Winkel, D. H. Ess, Org. Lett. 2012, 14, 3680–3683; s) W-
L. Chen, Y-R. Gao, S. Mao, Y-L. Zhang, Y-F. Wang, Y-
Q. Wang, Org. Lett. 2012, 14, 5920–5923; t) M. Min, Y.
Kim, S. Hong, Chem. Commun. 2013, 49, 196–198;
References
[1] a) I. Moritani, Y. Fujiwara, Tetrahedron Lett. 1967,
1119–1122; b) Y. Fujiwara, I. Moritani, S. Danno, R.
Asano, S. Teranishi, J. Am. Chem. Soc. 1969, 91, 7166–
7169; c) C. Jia, T. Kitamura, Y. Fujiwara, Acc. Chem.
Res. 2001, 34, 633–639; d) E. M. Ferreira, H. Zhang,
B. M. Stoltz, in: The Mizoroki–Heck Reaction, (Ed.: M.
Oestreich), John Wiley & Sons, Ltd., Chichester, 2009,
pp 345–382.
À
[2] C H Activation, (Eds.: J.-Q. Yu, Z. Shi), Topics in Cur-
rent Chemistry, Vol. 292, Springer, Berlin, 2010.
[3] a) J. A. Labinger, J. E. Bercaw, Nature 2002, 417, 507–
À
514; for special issues dedicated to C H activation and
functionalization, see: b) R. H. Crabtree, Chem. Rev.
2010, 110, 575–575; c) J. A. Gladysz, Chem. Rev. 2011,
111, 1167–1169; d) M. Beller, Chem. Soc. Rev. 2011, 40,
4891–4892; e) M. P. Doyle, K. I. Goldberg, Acc. Chem.
Res. 2012, 45, 777–777; see also: f) A. E. Shilov, G. B.
Shul’pin, Chem. Rev. 1997, 97, 2879–2932; g) V. Ritleng,
C. Sirlin, M. Pfeffer, Chem. Rev. 2002, 102, 1731–1769;
h) F. Kakiuchi, T. Kochi, Synthesis 2008, 3013–3039;
i) X. Chen, K. M. Engle, D.-H. Wang, J-Q. Yu, Angew.
Chem. 2009, 121, 5196–5217; Angew. Chem. Int. Ed.
2009, 48, 5094–5115; j) L. Ackermann, R. Vicente,
A. R. Kapdi, Angew. Chem. 2009, 121, 9976–10011;
Angew. Chem. Int. Ed. 2009, 48, 9792–9826; k) Y. Ya-
maguchi, A. D. Yamaguchi, K. Itami, Angew. Chem.
2012, 124, 9092–9142; Angew. Chem. Int. Ed. 2012, 51,
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
5
ÞÞ
These are not the final page numbers!

Govind Goroba Pawar et al.
COMMUNICATIONS
u) V. K. Tiwari, G. G. Pawar, R. Das, A. Adhikary, M.
Kapur, Org. Lett. 2013, 15, 3310–3313.
[6] a) C. Aouf, E. Thiery, J. Le Bras, J. Muzart, Org. Lett.
2009, 11, 4096–4099; b) Y. Zhang, Z. Li, Z-Q. Liu, Org.
Lett. 2012, 14, 226–229.
2949–2951; c) A. Armstrong, F. W. Goldberg, D. A.
Sandham, Tetrahedron Lett. 2001, 42, 4585–4587;
d) N. J. Kim, J. M. Kim, K. Y. Lee, S. Gowrisankar,
Bull. Korean Chem. Soc. 2004, 25, 1733–1736.
[10] Although styrene is often classified as an activated
olefin, our attempts at standardization with other unac-
tivated olefins yielded similar trends. Styrene was used
only because the reaction is easier to follow by UV de-
tection and decreases volatility of the products.
[11] 3,4-Dihydro-2H-pyran was freshly distilled over sodium
before use, which greatly improved the yield. Exclusion
of traces of water is the key to a clean reaction. The al-
[7] For some selected references related to indole and
furan systems see: a) T. Itahara, I. Ikeda, T. Sakaki-
bara, J. Chem. Soc. Perkin Trans. 1 1983, 1361–1363;
b) N. P. Grimster, C. Gauntlett, C. R. A. Godfrey, M. J.
Gaunt, Angew. Chem. 2005, 117, 3185–3189; Angew.
Chem. Int. Ed. 2005, 44, 3125–3129; c) D. R. Stuart, K.
Fagnou, Science 2007, 316, 1172–1175; d) D. R. Stuart,
E. Villemure, K. Fagnou, J. Am. Chem. Soc. 2007, 129,
12072–12073; e) E. M. Ferreira, H. Zhang, B. M. Stolz,
Tetrahedron 2008, 64, 5987–6001; see also: f) S. R. Neu-
feldt, M. S. Sanford, Acc. Chem. Res. 2012, 45, 936–946.
[8] a) B. Sato, H. Muramatsu, M. Miyauchi, Y. Hori, S.
Takase, M. Hino, S. Hashimoto, H. Terano, J. Antibiot.
2000, 53, 123–130; b) M. A. Adio, W. A. Konig, Phyto-
chemistry, 2005, 66, 599–609; c) P. J. Stephens, J. J. Pan,
F. J. Devlin, K. Krohn, T. Kurtꢁn, J. Org. Chem. 2007,
72, 3521–3536, and references cited therein; d) P. J. Ste-
phens, J.-J. Pan, K. Krohn, J. Org. Chem. 2007, 72,
7641–7649.
kenylation products were analyzed after
a quick
column chromatography over basic alumina. See the
Supporting Information for further details.
[12] S. Potavathri, A. S. Dumas, T. A. Dwight, G. R. Nau-
miec, J. M. Hammann, B. DeBoef, Tetrahedron Lett.
2008, 49, 4050–4053, and references cited therein.
[13] See the Supporting Information for details.
[14] The diene products are best stored at À208C and were
analyzed immediately upon isolation. Stability is found
to be greatly increased upon selective hydrogenation of
one olefin (exocylic). See the Supporting Information
for a selected example.
[9] a) L. F. Tietze, G. Kettschau, J. A. Gewert, A. Schuffen-
hauer, Curr. Org. Chem. 1998, 2, 19–62; b) S. R. Chem-
ler, U. Iserloh, S. J. Danishefsky, Org. Lett. 2001, 3,
[15] B. Potthoff, E. Breitmaier, Chem. Ber. 1986, 119, 3204–
3207.
6
asc.wiley-vch.de
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

COMMUNICATIONS
Dehydrogenative Heck Reaction (Fujiwara–Moritani
Reaction) of Unactivated Olefins with Simple
Dihydropyrans under Aprotic Conditions
7
Adv. Synth. Catal. 2013, 355, 1 – 7
Govind Goroba Pawar, Gaurav Singh,
Virendra Kumar Tiwari, Manmohan Kapur*
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
7
ÞÞ
These are not the final page numbers!