Amine-directed intramolecular hydroacylation of alkenes and alkynes

Article abstract of DOI:10.1016/j.tetlet.2011.12.125

Medium-ring heterocycles are prepared via an amine-directed, rhodium(I)-catalyzed intramolecular hydroacylation. The presence of an allyl substituent on the amine accelerates the reaction and increases product yields.

Full text of DOI:10.1016/j.tetlet.2011.12.125

Tetrahedron Letters 53 (2012) 1275–1277
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Tetrahedron Letters
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Amine-directed intramolecular hydroacylation of alkenes and alkynes
⇑
Holly D. Bendorf , Kyle E. Ruhl, Andrew J. Shurer, Jennie B. Shaffer, Tess O. Duffin, Theresa L. LaBarte,
Michelle L. Maddock, Oscar W. Wheeler
Department of Chemistry, Lycoming College, Williamsport, PA 17701, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Medium-ring heterocycles are prepared via an amine-directed, rhodium(I)-catalyzed intramolecular
hydroacylation. The presence of an allyl substituent on the amine accelerates the reaction and increases
product yields.
Received 22 November 2011
Accepted 30 December 2011
Available online 9 January 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Intramolecular hydroacylation
Rhodium(I) catalyst
Heteroatom-directed
Medium-ring heterocycles
Heteroatom-directed C–H activation is of substantial synthetic
interest and has seen extensive use in organometallic chemistry.1
Most synthetically useful examples of rhodium-catalyzed intermo-
lecular hydroacylation invoke a chelation-assisted strategy where
b-heteroatom-substituted aldehydes or imines, formed in situ from
2-aminopyridines, are used as substrates.2,3 Coordination of the
heteroatom to rhodium stabilizes the acylrhodium intermediate
and suppresses the competing decarbonylation pathway. Pyri-
dines,4 sulfides,5 thioacetals,5 phenols,6 and phosphines7 have been
exploited as directing groups.
In contrast, only a few examples of heteroatom-directed intra-
molecular hydroacylation exist. In 2002, Tanaka and Fu reported
an enantioselective synthesis of 4-methoxycyclopent-2-enones
via the kinetic resolution of 3-methoxy-4-alkynals.8 In the absence
of the methoxy group, substantially lower yields of racemic hydro-
acylation products were obtained. In the same year, we reported a
sulfur-directed intramolecular hydroacylation, the first example of
a medium-ring heterocycle synthesis via hydroacylation (Scheme
1).9 While this reaction fails in the absence of the sulfide, we also
found the position of the sulfur moiety relative to the aldehyde
directed intramolecular hydroacylation, benzoxazepines, and
benzoxazecines are prepared by hydroacylation of ketones.12
Recent efforts in our laboratory have focused on the develop-
ment of a nitrogen-directed hydroacylation of alkenes and alkynes,
catalyzed by Rh(PPh3)3Cl. We report herein the synthesis of med-
ium-ring nitrogen heterocycles from allyl-substituted amines.
O
CHO
X
0.10 eq Rh(PPh3)3Cl
CH2Cl2, 24 h
X
X = S, 92%
X = CH2, 0%
Scheme 1. S-directed intramolecular hydroacylation.
Table 1
Effect of amine substituent, Ra
O
CHO
0.10 eq Rh(PPh3)3Cl
to be critical, as c-thioaldehyde substrates do not undergo hydro-
acylation with Wilkinson’s catalyst.10
N
R
CH2Cl2
24 h
N
R
More recently, the Dong group has described elegant asymmet-
ric heteroatom-directed hydroacylations facilitated by chiral
[Rh(diphosphine)]+ catalysts. Medium ring sulfides and ethers are
obtained via sulfur- and oxygen-directed intramolecular hydroacy-
lation of alkenes and ketones.11 In the first example of a nitrogen-
1
2
Substrate
Yield of 2 (%)
1a, R = CH3
1b, R = CH2Ph
1c, R = CH2CH2CH@CH2
1d, R = CH2CH@CH2
11
10
35
72
a
⇑
Corresponding author. Tel.: +1 570 321 4365; fax: +1 570 321 4073.
E-mail address: bendorf@lycoming.edu (H.D. Bendorf).
Conditions: amine (1.00 equiv), Rh(PPh3)3Cl (0.10 equiv), CH2Cl2
(0.10 M in amine), room temperature, 24 h, isolated yields reported.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.125

1276
H. D. Bendorf et al. / Tetrahedron Letters 53 (2012) 1275–1277
Initial experiments subjected compounds 1a–d (prepared in
trast, a 72% yield of 2d is obtained from the reaction of allylamine
1d with Wilkinson’s catalyst. These results are suggestive of a syn-
ergistic effect where both the allyl alkene and the amine coordinate
to the rhodium, stabilizing the metal–substrate complex. Willis
observes a similar effect in the intermolecular hydroacylation of
aldehydes substituted with methylthiomethyl ethers, where effec-
tive hydroacylation requires coordination of both the oxygen and
sulfur atoms to the metal center.15 Notably, the reaction of 1d is
selective for hydroacylation of the alkene within the homoallyl
fragment; products due to hydroacylation of the allyl alkene are
not observed.
three steps from the commercially available 2-aminobenzyl alco-
hol) to the hydroacylation conditions used for the analogous sulfide
substrates (Table 1).9,13 In contrast to Dong’s observations with cat-
ionic rhodium catalysts, hydroacylation with Wilkinson’s catalyst is
significantly slower for amine substrates than for the analogous
sulfides.12,14 The reactions are clean, yielding only hydroacylation
products, 2, and recovered starting material. Interestingly, the iden-
tity of the R-group has a significant effect on the yield of cyclized
product. The methyl-, benzyl-, and homoallyl-substituted amines,
1a–c, give only modest yields of hydroacylation products. In con-
Optimization experiments (Table 2) reveal that coordinating
solvents and elevated temperatures provide the highest yields
and considerably shorter reaction times (entries 5 and 7). We ques-
tioned whether the allyl substituent was still necessary under the
optimized conditions; therefore substrates 1a, 1b, and 1c were
screened under these conditions (entries 8–10). Although the
yields of hydroacylation products 2a–c are significantly higher
when the reaction is run in refluxing acetonitrile rather than in
room temperature CH2Cl2, the effect of the allyl group is still evi-
dent. A noticeably higher yield and shorter reaction time is
observed for 1d (entry 7) as compared to compounds 1a–c (entries
8–10). Compounds 1a and 1d were also screened with the cationic
rhodium(I) catalyst, [Rh(dppe)]BF4 (entries 11 and 12). Reduced
yields of 2 are obtained under these conditions, due to decreased
selectivity. A significant yield (21%) of 3a was obtained for 1a. Even
under mild reaction conditions, compound 1d gives a complex
mixture of by-products including compounds tentatively identified
as 3d and products due to hydroacylation and isomerization of the
allyl alkene.
Table 2
Optimization experimentsa
O
O
CHO
catalyst
solvent
N
R
N
R
N
R
2
3
1
Entry Substrate Catalyst
Solvent Time Temperature Yield of
(h)
2 (%)
1
2
3
4
5
6
7
8
9
1d
1d
1d
1d
1d
1d
1d
1a
1b
1c
1a
Rh(PPh3)3Cl
Rh(PPh3)3Cl
Rh(PPh3)3Cl
Rh(PPh3)3Cl
Rh(PPh3)3Cl
Rh(PPh3)3Cl
Rh(PPh3)3Cl
Rh(PPh3)3Cl
Rh(PPh3)3Cl
Rh(PPh3)3Cl
DCM
DCM
DCE
24
8
8
rt
72
75
68
82
83
74
84
61
66
74
64
(21 of 3a)
56
Reflux
Reflux
rt
Reflux
rt
Reflux
Reflux
Reflux
Reflux
Reflux
Acetone 24
Acetone
MeCN
MeCN
MeCN
MeCN
MeCN
2
24
2
6
18
20
1
While not a requirement for successful hydroacylation of the
amine substrates, optimal results are obtained when an allyl substi-
tuent is present on the amine. Furthermore, the allyl group is a well-
documented protecting group for amines and a variety of methods
for its removal are known; thus, the synthetic utility of the reaction
was probed using a series of allylamine substrates (Table 3).16 Sub-
10
11
[Rh(dppe)]BF4 DCE
12
1d
[Rh(dppe)]BF4 DCE
4
rt
a
Conditions: amine (1.00 equiv), catalyst (0.10 equiv), solvent (0.10 M in amine),
reaction progress monitored by GC or TLC, isolated yields reported.
Table 3
Hydroacylation of allylamine substratesa
Entry
Substrate
CHO
Product
Yield (%)
84
Entry
6
Substrate
CHO
Product
Yield (%)
75b
O
O
N
N
1
N
N
O
CHO
N
CHO
N
O
N
2
83
7
0
N
O
CHO
N
O
Ph
CHO
N
Ph
N
3
4
5
77
0
8
9
78
77
0
N
O
N
N
N
N
CHO
N
CHO
O
N
N
N
O
N
CHO
N
CHO
N
O
84b
10
N
a
Conditions: amine (1.00 equiv), Rh(PPh3)3Cl (0.10 equiv), CH3CN (0.10 M in amine), reflux, isolated yields reported.
Reaction run at room temperature in CH2Cl2.
b

H. D. Bendorf et al. / Tetrahedron Letters 53 (2012) 1275–1277
1277
2. For reviews of rhodium-catalyzed hydroacylation, see: (a) Willis, M. C. Chem.
Rev. 2010, 110, 725–748; (b) Fu, G. C. In Modern Rhodium-Catalyzed Organic
Reactions; Evans, P. A., Ed.; Wiley-VCH: Weinheim, Germany, 2005; pp 79–91.
3. For examples of intermolecular hydroacylation with unfunctionalized
aldehydes, see: (a) Tanaka, K.; Shibata, Y.; Suda, T.; Hagiwara, Y.; Hirano, M.
Org. Lett. 2007, 9, 1215–1218; (b) Shibata, Y.; Tanaka, K. J. Am. Chem. Soc. 2009,
131, 12552–12553.
4. For examples of hydroacylation with picolyl and quinolyl imines, see: (a) Park,
Y. J.; Park, J.-W.; Jun, C.-H. Acc. Chem. Res. 2008, 41, 222–234; (b) Suggs, J. W. J.
Am. Chem. Soc. 1979, 101, 489; (c) Suggs, J. W.; Wovkulich, M. J.; Cox, S. D.
Organometallics 1985, 4, 1101–1107; (d) Willis, M. C.; Sapmaz, S. Chem.
Commun. 2001, 2258–2259; (e) Marcé, P.; Godard, C.; Feliz, M.; Yáñez, X.; Bo,
C.; Castillón, S. Organometallics 2009, 28, 2976–2985; (f) Vautravers, N. R.;
Regent, D. D.; Breit, B. Chem. Commun. 2011, 47, 6635–6637.
5. For examples of hydroacylation with b-S-substituted aldehydes, see: (a) Willis,
M. C.; McNally, S. J.; Beswick, P. J. Angew. Chem., Int. Ed. 2004, 43, 340–343; (b)
Willis, M. C.; Randell-Sly, H. E.; Woodward, R. L.; Currie, G. S. Org. Lett. 2005, 7,
2249–2251; (c) Willis, M. C.; Randall-Sly, H. E.; Woodward, R. L.; McNally, S. J.;
Currie, G. S. J. Org. Chem. 2006, 71, 5291–5297; (d) Osborne, J. D.; Randell-Sly, H.
E.; Currie, G. S.; Cowley, A. R.; Willis, M. C. J. Am. Chem. Soc. 2008, 130, 17232–
17233; (e) González-Rodriguez, C.; Pawley, R. J.; Chaplin, A. B.; Thompson, A. L.;
Weller, A. S.; Willis, M. C. Angew. Chem., Int. Ed. 2011, 50, 5134–5138; (f)
Lenden, P.; Entwistle, D. A.; Willis, M. C. Angew. Chem., Int. Ed. 2011, 50, 10657–
10660.
6. For examples of hydroacylation with salicylaldehydes, see: (a) Imai, M.;
Tanaka, M.; Tanaka, K.; Yamamoto, Y.; Imai-Ogata, N.; Shimowatari, M.;
Nagumo, S.; Kawahara, N.; Suemune, H. J. Org. Chem. 2004, 69, 1144–1150; (b)
Imai, M.; Tanaka, M.; Nagumo, S.; Kawahara, N.; Suemune, H. J. Org. Chem.
2007, 72, 2543–2546; (c) Inui, Y.; Masakazu, T.; Imai, M.; Tanaka, K.; Suemune,
H. Chem. Pharm. Bull. 2009, 57, 1158–1160; (d) Stemmler, R. T.; Bolm, C. Adv.
Synth. Catal. 2007, 349, 1185–1198; (e) Zhang, H.-J.; Bolm, C. Org. Lett. 2011, 13,
3900–3903; (f) Coulter, M. M.; Kou, K. G. M.; Galligan, B.; Dong, V. M. J. Am.
Chem. Soc. 2010, 132, 16330–16333; (g) Phan, D. H. T.; Kou, K. G. M.; Dong, V.
M. J. Am. Chem. Soc. 2010, 132, 16354–16355.
7. (a) Jun, C.-H.; Lee, H. Bull. Korean Chem. Soc. 1995, 16, 66–68; (b) Jun, C.-H.; Lee,
H. Bull. Korean Chem. Soc. 1995, 16, 1135–1138.
8. (a) Tanaka, K.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 10296–10297; (b) Tanaka,
K.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 8078–8079; (c) Takeishi, K.; Sugishima,
K.; Sasaki, K.; Tanaka, K. Chem.-Eur. J. 2004, 10, 5681–5688.
9. Bendorf, H. D.; Colella, C. M.; Dixon, E. C.; Marchetti, M.; Matukonis, A. N.;
Musselman, J. D.; Tiley, T. A. Tetrahedron Lett. 2002, 43, 7031–7034.
10. Willis has reported a similar requirement for b-S-substituted aldehydes in the
[Rh(dppe)]ClO4-catalyzed intermolecular hydroacylation of alkenes and
alkynes. See Ref. 5c.
11. (a) Coulter, M. M.; Dornan, P. K.; Dong, V. M. J. Am. Chem. Soc. 2009, 131, 6932–
6933; (b) Shen, Z.; Dornan, P. K.; Khan, H. A.; Woo, T. K.; Dong, V. M. J. Am.
Chem. Soc. 2009, 131, 1077–1091; (c) Shen, Z.; Khan, H. A.; Dong, V. M. J. Am.
Chem. Soc. 2008, 130, 2916–2917.
strates are prepared from commercially available materials in one
to three steps.13 The reaction proves to be successful with mono-
substituted alkenes as well as cis- and trans-disubstituted alkenes
(entries 1–3). However, the reaction fails for the vinylidine sub-
strate (entry 4), presumably due to steric inhibition. Larock and
Bosnich have noted a similar effect in their studies of the intramo-
lecular hydroacylation of substituted 4-pentenals.17,18 Alkyne sub-
strates react rapidly with Wilkinson’s catalyst, even under mild
reaction conditions. Internal alkynes (entries 5 and 6) yield densely
functionalized 7- and 8-membered rings. Terminal alkynes undergo
hydroacylation in similar yields (by GC), but the enone products
prove difficult to isolate and purify.19 While the 4-alkynyl substrate
(entry 6) produces the benzazocine product in 75% yield, the anal-
ogous 4-alkenyl substrate (entry 7) fails to react. Aromatic hetero-
cycles are compatible with the reaction as the pyridyl and quinolyl
aldehydes (entries 8–9) give hydroacylation products in 78% and
77% yields, respectively. The bis-allyl substrate (entry 10) does
not undergo hydroacylation with Wilkinson’s catalyst, although
modest yields of the hydroacylation product are obtained with
[Rh(dppe)]BF4. Current work in our laboratory focuses on the
hydroacylation of allylamines using cationic rhodium(I) catalysts.
In conclusion, we report that the amine directed-hydroacylation
of alkenes and alkynes permits rapid synthesis of benzazepines
and related medium-ring nitrogen heterocycles. On-going work
in our laboratory is directed at expanding the scope and synthetic
utility of this reaction.
Acknowledgments
Acknowledgement is made to the donors of the American Chem-
ical Society Petroleum Research Fund (ACS PRF #49342-UR1) for
support of this research. We thank the alumni-supported Lycoming
College Chemistry Research fund for providing housing for summer
research students. K.E.R. is grateful for support from a Joanne
and Arthur Haberberger Fellowship. We thank Professor Chriss
McDonald for helpful suggestions.
12. Khan, H. A.; Kou, K. G. M.; Dong, V. M. Chem. Sci. 2011, 2, 407–410.
13. Syntheses of the substrates are reported in the Supplementary data for this
article.
Supplementary data
14. Consistent with Dong’s observations (Ref. 12), our amine substrates react
significantly faster with [Rh(dppe)]BF4 than do the analogous sulfide
substrates.
15. Parsons, S. R.; Hooper, J. F.; Willis, M. C. Org. Lett. 2011, 13, 998–1000.
16. Wuts, P. G. M.; Greene, T. W. Greene’s Protective Groups in Organic Synthesis, 4th
ed.; Wiley-Interscience: Hoboken, NJ, 2007. pp 806–808.
Supplementary data (experimental details and analytical data)
associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2011.12.125.
References and notes
17. Larock, R. C.; Oertle, K.; Potter, G. F. J. Am. Chem. Soc. 1980, 102, 190–197.
18. Fairlie, D. P.; Bosnich, B. Organometallics 1988, 7, 936–945.
19. We observed similar results in our earlier work with sulfur substrates.
Unsubstituted enones dimerized via a hetero-Diels–Alder pathway. See Ref. 9
and Traynelis, V. J.; Sih, J. C.; Borgnaes, D. M. J. Org. Chem. 1973, 38, 2629–2637.
1. For reviews on heteroatom-directed C–H activation, see: (a) Colby, D. A.;
Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624–655; (b) Kakiuchi, F. Top.
Organomet. Chem. 2007, 24, 1–33.