Enantioselective synthesis of isochromans and tetrahydroisoquinolines by C-H insertion of donor/donor carbenes

Article abstract of DOI:10.1039/c9sc05111b

Reports of C-H insertions forming six-membered rings containing heteroatoms are rare due to Stevens rearrangements occurring after nucleophilic attack on the carbene by a heteroatom. Using donor/donor carbenes and Rh₂(R-PTAD)₄ as a catalyst, we have synthesized a collection of isochroman substrates in good yield, with excellent diastereo- and enantioselectivity, and no rearrangement products were observed. Furthermore, we report the first synthesis of six-membered rings containing nitrogen by C-H insertion to form tetrahydroisoquinolines. In one case, a Stevens rearrangement product was isolated at elevated temperature from a carbamate-protected amine substrate and computational evidence suggests formation through a free ylide not bound to rhodium.

Full text of DOI:10.1039/c9sc05111b

Chemical
Science
View Article Online
View Journal | View Issue
EDGE ARTICLE
Enantioselective synthesis of isochromans and
tetrahydroisoquinolines by C–H insertion of donor/
donor carbenes†
Cite this: Chem. Sci., 2020, 11, 494
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
Leslie A. Nickerson,
Yuan-Shin Shiue,
Walker A. Knauss,
Benjamin D. Bergstrom,
Croix J. Laconsay,
James C. Fettinger,
Mingchun Gao,
Matthew R. Culberson,
Dean J. Tantillo and Jared T. Shaw
*
Reports of C–H insertions forming six-membered rings containing heteroatoms are rare due to Stevens
rearrangements occurring after nucleophilic attack on the carbene by a heteroatom. Using donor/donor
carbenes and Rh2(R-PTAD)4 as a catalyst, we have synthesized a collection of isochroman substrates in
good yield, with excellent diastereo- and enantioselectivity, and no rearrangement products were
observed. Furthermore, we report the first synthesis of six-membered rings containing nitrogen by C–H
insertion to form tetrahydroisoquinolines. In one case, a Stevens rearrangement product was isolated at
Received 9th October 2019
Accepted 11th November 2019
DOI: 10.1039/c9sc05111b
elevated temperature from
a carbamate-protected amine substrate and computational evidence
rsc.li/chemical-science
suggests formation through a free ylide not bound to rhodium.
Insertion reactions of metal carbenes into C–H bonds are useful rearrangement products when heteroatoms are present (Fig. 1).
methods for making C–C bonds.1–6 In most cases, C–H insertion Previous work to synthesize 1,6-C–H insertion products without
reactions are catalyzed with dirhodium tetracarboxylate heteroatoms consistently observed mixtures of ve- and six-
complexes, oen using chiral ligands to provide enantiose- membered ring products when a 1,5-C–H insertion site was
lectivity.1,6–8 Asymmetric C–H insertion has been well-docu- available.25–29 Installing heteroatoms can eliminate 1,5-C–H
mented for carbenes with two electron withdrawing insertion however this introduces the possibility of nucleophilic
substituents (CO2R, COR, CN, SO2R, acceptor/acceptor)7 or with attack on the carbene by the heteroatom.17,19,24 This reaction
one electron donating (aryl, alkenyl) and one electron with- forms an ylide that undergoes the Stevens rearrangement (or
drawing group (donor/acceptor).9 Acceptor and acceptor/ a Stevens-type rearrangement when the heteroatom is oxygen),
acceptor carbenes are very reactive and can react indiscrimin- forming a ve-membered ring (5).24,30 Despite these challenges,
ately with other functionalities on the molecule.7,10,11 Donor/ there are scattered reports of forming tetrahydropyran, chro-
acceptor carbenes are less electrophilic due to the donating man, and chromanone cores through 1,6-C–H insertion using
substituent, which increases selectivity for C–H insertion donor/acceptor or acceptor carbenes.18,20,22–24,31–33 In 2012, Cossy
(Fig. 1).3,5,9 Recently, we have been interested in donor/donor and coworkers demonstrated the use of donor carbenes gener-
carbenes,12–14 which have two electron-donating groups and, as ated from cyclopropenes in the synthesis of tetrahydropyrans by
a result, are highly selective for C–H insertion while also toler- C–H insertion,22,31 further expanding the diazo-free insertion
ating many functional groups present in complex substrates.15,16 work demonstrated by Zhu.34,35 In the cases where chiral cata-
Although C–H insertion reactions have been used in the lysts were used, enantioselectivity was oen moderate;19,20 it
synthesis of a wide variety of ve-membered ring (1,5-C–H wasn't until 2015 when Hashimoto achieved higher levels of
insertion) heterocycles,1,7,10 there are few examples of six- enantioselectivity using Rh2(S-PTTL)4 (up to 97 : 3 er).24 We
membered ring (1,6-C–H insertion) formation and the hypothesized that using donor/donor carbenes would reduce
substrates are limited to oxygen-containing rings.17–24
the electrophilicity of the rhodium carbene enough to allow C–
Accessing 1,6-C–H insertion is difficult due to the kinetic H insertion to proceed selectively without interference by the
favorability of 1,5-C–H insertion and the potential for heteroatom.
Due to the propensity of C–H insertions to form ve-
membered rings, we designed substrates that would eliminate
the possibility for 1,5-insertion by installing the requisite
heteroatom at the 5-position. We started by developing
substrates with benzylic insertion sites, as we had found those
to be favored with benzodihydrofuran systems.15 We were
Chemistry Department, University of California, Davis, One Shields Ave, Davis, CA
95616, USA. E-mail: jtshaw@ucdavis.edu
† Electronic supplementary information (ESI) available: Synthetic details,
spectroscopic characterization and crystallographic data. CCDC 1921673,
1921674, 1916890 and 1920825. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c9sc05111b
494 | Chem. Sci., 2020, 11, 494–498
This journal is © The Royal Society of Chemistry 2020

View Article Online
Edge Article
Chemical Science
With this result we were encouraged to expand the scope of
benzylic insertions to form isochromans. We saw a modest
increase in yield and enantioselectivity when a methoxy group
was installed para to the insertion site (Table 1, entry 2). We
then wanted to explore electronic effects at the carbene center
and interestingly found no discernible effect when there was
a nitrile group versus a methoxy group para to the carbene
(Table entries 3, 4). Furthermore, heterocycles with a Lewis
basic moiety were also well-tolerated as substituents off of the
carbene (Table 1, entry 5). Encouraged by these results we
wanted to explore the effect of alkyl substituents on the carbene
in combination with an aryl substituent (Table 1, entry 6). The
yield was slightly lower, and we saw a signicant decrease in
enantioselectivity, suggesting that the other aryl ring plays
a role in tting the substrate into the chiral catalyst pocket.
Allylic and propargylic ethers were excellent substrates for C–
H insertion (Fig. 2). Although the analogous substrates for the
synthesis of benzodihydrofurans can suffer from competing
dipolar cycloaddition reactions,36,37 this side reaction was not
observed in the reactions leading to isochromans. Stevens-type
rearrangement products were also not observed for unsaturated
substrates. Notably, 12a did not undergo any Stevens-type
rearrangement under reaction conditions, in contrast to
a similar substrate derived from a donor/acceptor carbene in
work by Hashimoto and co-workers.24 These results appear to
support our hypothesis that the reduced electrophilicity of the
donor/donor carbene prevents the competing rearrangement
reaction. Additionally, while an unsubstituted allyl group
underwent insertion with modest yield, the addition of a single
substituent resulted in yields of 90% or greater. The crystal
structure of 13b demonstrated that the absolute conguration
produced with Rh2(R-PTAD)4 is the same for isochromans as
was observed with benzodihydrofurans and related heterocy-
cles.15,16,38 Cis and trans alkene hydrazones 13d and 13e led to
their respective insertion products with no detectable isomeri-
zation. A propargyl substituted insertion site proved to be the
Fig. 1 Six-membered ring formation has proven difficult in the past
due to the kinetic favorability of five-membered ring insertions and the
possibility of Stevens rearrangement products. By utilizing donor/
donor carbenes, which are less electrophilic than donor/acceptor or
acceptor/acceptor carbenes, the Stevens rearrangement product is
not observed.
pleased to nd that hydrazone 10a was successfully oxidized
to the diazo with eight equivalents of MnO2 and inserted into
the benzylic C–H bond with 1 mol percent catalyst loading
affording a single diastereomer, with excellent enantiose-
lectivity, and with no observed rearrangement product
(Table 1, entry 1).
Table 1 Insertion into benzylic C–H Bonds
Entry Product R1
R2
H
Solvent Yield (%) er
CH2Cl2 60 97 : 3
1
11a
11ba
11c
11d
11e
11f
Ph
2
Ph
OCH3 CH2Cl2 69
OCH3 CH3CN 97
>99.5 : 0.5
99 : 1
99 : 1
94 : 6
60 : 40
3
4-CNC6H4
4-H3COC6H4 OCH3 CH2Cl2 98
3-Pyridyl
CH3
4b
5
OCH3 CH3CN 82
OCH3 CH2Cl2 56
6
a
With Rh2(S-PTAD)4 as catalyst. b Catalyst added at rt.
Fig. 2 Unsaturated isochroman substrates.
Chem. Sci., 2020, 11, 494–498 | 495
This journal is © The Royal Society of Chemistry 2020

View Article Online
Chemical Science
Edge Article
lowest yielding isochroman (13f). Although the yield was
comparatively lower than the other unsaturated substrates, no
evidence of dipolar cycloaddition was observed. We hypothesize
that a larger ring size helps to limit the dipolar cycloaddition
pathway.36,37
Aliphatic substrates also react with high diastereo- and
enantioselectivity. There is a clear trend of decreasing yield
from substrates that have two alkyl substituents versus one alkyl
substituent at the insertion site. Isochromans 15a–c were
synthesized in excellent yield with insertion into a carbon with
two alkyl substituents (Fig. 3). When inserting into a carbon
with one alkyl substituent the yields decreased signicantly
(15d–e, 54–62%) indicating some substrate preference for
inserting into more highly substituted carbons. Importantly,
throughout the isochroman examples, all products were formed
as a single diastereomer and no Stevens-type rearrangement
products were observed.
With the formation of six-membered rings comes the
opportunity to explore the inuence of 1,3-diaxial interactions
in the diastereoselective formation of the stereogenic centers
that form during insertion (Fig. 4). A single diastereomer (17a)
was observed from hydrazone 16a using Rh2(Mes)4 as the
catalyst, the conguration of which was determined by a NOE
NMR experiment. This indicates that the C–H insertion step
occurs in a diastereoselective manner despite having a bulky
group close to the rhodium carbene. Furthermore, compounds
17b and 17c were also isolated in good yields with excellent
diastereoselectivity when Rh2(R-TCPTTL)4 was used as the
catalyst to accelerate the rate of C–H insertion. The chiral
phthalimido catalysts generally exhibit higher activity than any
of the achiral catalysts used with donor/donor carbenes. The
structure of compound 17c was also determined by X-ray
diffraction.38
Fig.
4
Diastereoselective insertions to form tri-substituted iso-
chromans.a With Rh2(Mes)4.b With Rh2(R-TCPTTL)4.
coworkers demonstrated related work involving a C(sp2)–H
insertion on pyrrole using an acceptor carbene.39–41 Using our
prior work to synthesize indolines as inspiration,16 we rst
developed amine- and aniline-based substrates. These
substrates proved unsuccessful as the crude reactions were
oen complex mixtures with no discernible traces of product.
In order to reduce the possibility of side reactions, N-sulfonyl
groups were installed to reduce the nucleophilicity of the
nitrogen lone pair. No identiable products were isolated with
these substrates.
Computational evidence suggests that donor/donor C–H
insertions forming benzodihydrofurans proceed through
a stepwise mechanism that has a zwitterionic intermediate in
which a carbocation is formed on the insertion carbon.36 Based
on this observation we reasoned that a sulfonyl protecting
group on nitrogen might be too electron withdrawing, to the
detriment of stabilizing a possible carbocation intermediate.
We hypothesized that an amide would reduce the nucleophi-
licity of the nitrogen but to a lesser extent than a sulfonyl pro-
tecting group.
Our success in synthesizing isochromans motivated our
attempts to synthesize the more challenging nitrogen
analogues. To the best of the authors' knowledge, 1,6-C–H
insertion on aliphatic systems has never been done to
synthesize nitrogen-containing heterocycles. Jefford and
We next attempted substrates using lactams and were
pleased to synthesize tetrahydroisoquinoline 23a as a single
diastereomer in 54% yield and with 99 : 1 er (Fig. 5). We went on
to synthesize tetrahydroisoquinoline 23b in good yield and with
slightly reduced er. Carbamate derived tetrahydroisoquinoline
23c was also synthesized in moderate yield and with excellent
stereoselectivity. X-ray crystallography of 23c showed the same
absolute stereochemistry as is observed with isochromans.38 As
these insertions occur rapidly, we found that reducing the
temperature before the addition of catalyst allowed the reaction
to complete within 30 minutes to 3 hours while producing
a cleaner reaction mixture.
Fig. 3 Aliphatic isochroman substrates.a Run with Rh2(S-PTAD)4.
496 | Chem. Sci., 2020, 11, 494–498
This journal is © The Royal Society of Chemistry 2020

View Article Online
Edge Article
Chemical Science
was isoindoline 26, resulting from an apparent Stevens [1,2]-
rearrangement (Fig. 6A).42,43 A similar product involving attack
by an amide nitrogen leading to Stevens rearrangement was
observed by Padwa.42
Aer identifying the isoindoline as the primary product of
the reaction using Rh2(R-PTAD)4, a second run using Rh2(TFA)4
proceeded in 50% yield. The isolation of Stevens product 26
indicates that the properties of the insertion site are as impor-
tant as the electron withdrawing effect on the nitrogen, given
that tetrahydroisoquinoline 23c was isolated from insertion of
hydrazone 22c. Although previous studies propose a stepwise
diradical mechanism for the Stevens rearrangement,43 density
functional theory (DFT) studies support N-attack to the metal
carbene, but then a concerted free ylide Stevens rearrangement
(Fig. 6B).44 This model suggests that the metal catalyst is not
essential in the Stevens rearrangement step.45
Fig. 5 Scope of tetrahydroisoquinoline substrates.
In analogy to our work with indolines, in which insertion
into methyl C–H bonds was possible,16 we attempted to
synthesize a mono-substituted tetrahydroisoquinoline. We
synthesized hydrazone 24 with a carbamate protecting group,
which we reasoned would provide roughly an equivalent level of
electron withdrawing potential as an amide and is easily
removed for further functionalization. This substrate reacted
much more slowly and eventually required heating to reux for
the diazo to be fully consumed. Upon consumption of diazo no
insertion product was observed. The sole identiable product
Conclusions
In conclusion, we have used donor/donor rhodium carbenes to
synthesize isochromans in good to excellent yields and with
overall excellent stereoselectivity. For isochroman substrates,
no Stevens-type rearrangement products were observed.
Furthermore, we also explored the synthesis of isochromans in
a diastereoselective fashion by installing a substituent on the
benzylic carbon alpha to oxygen and were gratied to see
a single diastereomer formed. Additionally, we synthesized the
rst six-membered rings containing nitrogen through 1,6-
C(sp3)–H insertion in moderate yields and with excellent ster-
eoselectivity. A Stevens rearrangement product was isolated
from one substrate using increased temperature and compu-
tational evidence suggests that isoindoline formation occurs via
a free ylide not bound to rhodium.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
This work was supported by grants from the National Institutes
of Health (R01/GM124234). Research reported in this publica-
tion was supported by the National Institute of General Medical
Sciences of the National Institutes of Health under Award
Number R01GM124234. The content is solely the responsibility
of the authors and does not necessarily represent the official
views of the National Institutes of Health. LAN and BDB
acknowledge UC Davis for nancial support in the form of
Borge and Corson/DOW fellowships. MRC thanks the California
Alliance for Minority Participation (CAMP) for nancial support
(NSF grant 1826900). We thank the Franz group for providing
access to a chiral HPLC and particularly Austin Kelly and Jake
Jagannathan (Franz group, UC Davis) for providing assistance
with HPLC traces. We also thank the Kurth group, (UC Davis)
for use of their IR with assistance from Winston Chow (Olson
group, UC Davis). We thank the National Science Foundation
(Grant CHE-1531193) for the Dual Source X-ray diffractometer.
Fig. 6 (A) Stevens rearrangement product synthesis. (B) The DFT
(uB3LYP/LANL2DZ[6-31G(d)]) computed mechanism suggests that N-
attack to the rhodium carbene and the subsequent Stevens rear-
rangement is energetically feasible at experimental conditions; relative
free energies (electronic energies in parentheses) for metal-bound
(normal text) and ylide (italics) reactions are reported in kcal molÀ1
.
This journal is © The Royal Society of Chemistry 2020
Chem. Sci., 2020, 11, 494–498 | 497

View Article Online
Chemical Science
Edge Article
We gratefully acknowledge support from the XSEDE program 23 D. F. Taber, C. M. Paquette, P. Gu and W. Tian, J. Org. Chem.,
via TG-CHE050017N for computational resources.
2013, 78, 9772–9780.
24 M. Ito, Y. Kondo, H. Nambu, M. Anada, K. Takeda and
S. Hashimoto, Tetrahedron Lett., 2015, 56, 1397–1400.
Notes and references
´
25 F. Estevan, K. Herbst, P. Lahuerta, M. Barberis and J. Perez-
1 M. P. Doyle, M. Ratnikov and Y. Liu, Org. Biomol. Chem.,
2011, 9, 4007–4016.
2 M. P. Doyle, R. Duffy, M. Ratnikov and L. Zhou, Chem. Rev.,
2010, 110, 704–724.
3 H. M. L. Davies and J. R. Denton, Chem. Soc. Rev., 2009, 38,
3061–3071.
4 H. M. L. Davies and J. R. Manning, Nature, 2008, 451, 417–
424.
5 H. M. L. Davies and D. Morton, Chem. Soc. Rev., 2011, 40,
1857–1869.
6 H. M. L. Davies and P. M. Pelphrey, in Organic Reactions,
John Wiley & Sons, Inc., Hoboken, NJ, USA, 2011, pp. 75–212.
7 H. M. L. Davies and R. E. J. Beckwith, Chem. Rev., 2003, 103,
2861–2904.
Prieto, Organometallics, 2001, 20, 950–957.
26 C. Slattery, L.-A. Clarke, S. O'Neill, A. Ring, A. Ford and
A. Maguire, Synlett, 2012, 23, 765–767.
27 M. Franck-Neumann, P. Geoffroy, D. Gassmann and
A. Winling, Tetrahedron Lett., 2004, 45, 5407–5410.
28 P. S. Aburel, C. Rømming and K. Undheim, J. Chem. Soc.,
Perkin Trans. 1, 2001, 1024–1029.
29 F. G. West, T. H. Eberlein and R. W. Tester, J. Chem. Soc.,
Perkin Trans. 1, 1993, 2857.
30 M. P. Doyle, D. G. Ene, D. C. Forbes and J. S. Tedrow,
Tetrahedron Lett., 1997, 38, 4367–4370.
31 A. Archambeau, F. Miege, C. Meyer and J. Cossy, Angew.
Chem., Int. Ed., 2012, 51, 11540–11544.
´
32 T. Ye, C. F. Garcıa and M. A. McKervey, J. Chem. Soc., Perkin
8 H. M. L. Davies and T. Hansen, J. Am. Chem. Soc., 1997, 119,
9075–9076.
Trans. 1, 1995, 1373–1379.
33 N. McCarthy, M. A. McKervey, T. Ye, M. McCann, E. Murphy
and M. P. Doyle, Tetrahedron Lett., 1992, 33, 5983–5986.
34 D. Zhu, J. Ma, K. Luo, H. Fu, L. Zhang and S. Zhu, Angew.
Chem., Int. Ed., 2016, 55, 8452–8456.
35 D. Zhu, L. Chen, H. Zhang, Z. Ma, H. Jiang and S. Zhu,
Angew. Chem., Int. Ed., 2018, 57, 12405–12409.
9 H. M. Davies and Ø. Loe, Synthesis, 2004, 16, 2595–2608.
10 G. A. Sulikowski, K. L. Cha and M. M. Sulikowski,
Tetrahedron: Asymmetry, 1998, 9, 3145–3169.
11 M. P. Doyle, M. A. McKervey and T. Ye, in Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds: From
Cyclopropanes to Ylides, Wiley, 1998, pp. 112–162.
36 K. N. Lamb, R. A. Squitieri, S. R. Chintala, A. J. Kwong,
¨
12 G. Seidel and A. Furstner, Angew. Chem., Int. Ed., 2014, 53,
˜
E. I. Balmond, C. Soldi, O. Dmitrenko, M. Castineira Reis,
4807–4811.
R. Chung, J. B. Addison, J. C. Fettinger, J. E. Hein,
D. J. Tantillo, J. M. Fox and J. T. Shaw, Chem.–Eur. J., 2017,
23, 11843–11855.
´
`
¨
13 C. Werle, R. Goddard, P. Philipps, C. Fares and A. Furstner, J.
Am. Chem. Soc., 2016, 138, 3797–3805.
´
`
¨
14 C. Werle, R. Goddard, P. Philipps, C. Fares and A. Furstner,
˜
37 C. A. Dimirjian, M. Castineira Reis, E. I. Balmond,
Angew. Chem., Int. Ed., 2016, 55, 10760–10765.
N. C. Turman, E. P. Rodriguez, M. J. Di Maso,
J. C. Fettinger, D. J. Tantillo and J. T. Shaw, Org. Lett.,
2019, 21, 7209–7212.
´
´
15 C. Soldi, K. N. Lamb, R. A. Squitieri, M. Gonzalez-Lopez,
M. J. Di Maso and J. T. Shaw, J. Am. Chem. Soc., 2014, 136,
15142–15145.
16 L. W. Souza, R. A. Squitieri, C. A. Dimirjian, B. M. Hodur,
L. A. Nickerson, C. N. Penrod, J. Cordova, J. C. Fettinger
and J. T. Shaw, Angew. Chem., Int. Ed., 2018, 57, 15213–15216.
17 N. McCarthy, M. A. McKervey, T. Ye, M. McCann, E. Murphy
and M. P. Doyle, Tetrahedron Lett., 1992, 33, 5983–5986.
18 E. Lee, I. Choi and S. Y. Song, J. Chem. Soc., Chem. Commun.,
1995, 321–322.
38 CCDC 1921674 (11c), 1921673 (13b), 1916890 (17c), and
1920825 (23c) contain the supplementary crystallographic
data for this paper.†
39 C. W. Jefford and W. Johncock, Helv. Chim. Acta, 1983, 66,
2666–2671.
40 C. W. Jefford and A. Zaslona, Tetrahedron Lett., 1985, 26,
6035–6038.
41 C. W. Jefford, Q. Tang and A. Zaslona, J. Am. Chem. Soc.,
1991, 113, 3513–3518.
´
19 T. Ye, C. F. Garcıa and M. A. McKervey, J. Chem. Soc., Perkin
Trans. 1, 1995, 1373–1379.
42 A. Padwa, L. S. Beall, C. K. Eidell and K. J. Worsencro, J. Org.
Chem., 2001, 66, 2414–2421.
43 G. Ghigo, S. Cagnina, A. Maranzana and G. Tonachini, J. Org.
Chem., 2010, 75, 3608–3617.
´
´
˜
´
´
20 A. Rosales, I. Rodrıguez-Garcıa, C. Lopez-Sanchez,
´
M. Alvarez-Corral and M. Munoz-Dorado, Tetrahedron,
2011, 67, 3071–3075.
21 A. Archambeau, F. Miege, C. Meyer and J. Cossy, Angew.
Chem., Int. Ed., 2012, 51, 11540–11544.
22 A. Archambeau, F. Miege, C. Meyer and J. Cossy, Angew.
Chem., 2012, 124, 11540–11544.
44 See ESI† for complete computational work.
45 J. G. Harrison, O. Gutierrez, N. Jana, T. G. Driver and
D. J. Tantillo, J. Am. Chem. Soc., 2016, 138, 487–490.
498 | Chem. Sci., 2020, 11, 494–498
This journal is © The Royal Society of Chemistry 2020